NZ620426B2 - 4-piperidinyl compounds for use as tankyrase inhibitors - Google Patents

Abstract

Disclosed are compounds of formula (I), wherein the substituents are as defined in the specification. Also disclosed are pharmaceutical compositions and combinations comprising a compound of formula (I) as well as the use of such compounds as tankyrase inhibitors and in the treatment of Wnt signaling and tankyrase 1 and 2 signaling related disorders which include, but are not limited to, cancer. Examples of a compound of formula (I) are: 2-Chloro-6-{3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}benzonitrile 2-{3-[4-(4-Methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one g and tankyrase 1 and 2 signaling related disorders which include, but are not limited to, cancer. Examples of a compound of formula (I) are: 2-Chloro-6-{3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}benzonitrile 2-{3-[4-(4-Methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one

Description

-PIPERIDINYL COMPOUNDS FOR USE AS TANKYRASE INHIBITORS FIELD OF THE INVENTION The present invention relates to novel ridinyl compounds, pharmaceutical compositions containing them, and the use of such nds as tankyrase inhibitors and in the treatment of Wnt signaling and tankyrase 1 and 2 signaling related ers which e, but are not limited to, cancer.

BACKGROUND OF THE INVENTION The evolutionarily conserved canonical Wnt/B-catenin signal transduction e controls many aspects of metazoan pment. Context-dependent activation of the pathway is involved in embryonic cell fate decisions, stem cell regulation and tissue homeostasis (Clevers, H. Cell 2006, 127, 469-80).

A key feature of the Wnt/B-catenin pathway is the regulated proteolysis of the downstream effector B—catenin by the B-catenin destruction complex. The principal constituents of the B-catenin destruction complex are adenomatous polyposis coli (APC), Axin, and GSK3d/B. In the absence of Wnt pathway activation, cytosolic B-catenin is constitutively phosphorylated and targeted for degradation. Upon Wnt stimulation, the B- catenin destruction complex disassociates, which leads to the accumulation of nuclear B- catenin and transcription of Wnt pathway responsive genes.

Inappropriate activation of the pathway, mediated by over expression of Wnt proteins or mutations ing components of the B-catenin destruction complex, thus leading to stabilization of B-catenin, has been observed in many cancers. Notably, truncating ons of the tumour suppressor APC are the most prevalent genetic tions In colorectal carcinomas (Miyaki, M. et al. Cancer Res 1994, 54, 3011-20; Miyoshi, Y. etal. Hum Mol Genet 1992, 1, 229-33; and Powell, 8. M. etal. Nature 1992, 359, 235-7). In addition, Axin1 and Axin2 mutations have been identified in patients with hepatocarcinomas and colorectal cancer tively (Taniguchi, K. et al. Oncogene 2002, 21, 4863—71; Liu, W. et al. Nat Genet 2000, 26, 146-7; Lammi, L. et al. Am J Hum Genet 2004, 74, 1043-50). These somatic ons result in dependent ization of B-catenin and constitutive activation of B-catenin-mediated transcription.

Deregulated Wnt pathway ty has also been implicated in many other cancers (Polakis, P. Curr Opin Genet Dev 2007,1 7, 45-51; and Barker, N. et al. Nat Rev Drug Discov 2006, 5, 997-1014), including colorectal, melanoma, , liver, lung and gastric cancers. Other disorders associated with aberrant Wnt ing include osteoporosis, osteoarthritis, polycystic kidney disease, pulmonary fibrosis, diabetes, schizophrenia, ar disease, cardiac disease, non-oncogenic proliferative diseases, and neurodegenerative diseases such as Alzheimer's disease.

The efficient ly of the multi-protein B-catenin destruction x is dependent on the steady state levels of its principal constituents. Axin has been reported to be the concentration-limiting factor in regulating the efficiency of the B-catenin destruction complex (Salic, A., et al. Mol Cell 2000, 5, 523-32; and Lee, E. et al. PLoS Biol 2003, 1, E10) and increased expression of Axin can enhance B-catenin degradation in cell lines sing truncated APC (Behrens, J. et al. Science 1998, 280, 596—9; Kishida, M. et al. Oncogene 1999, 18, 979-85; and Hart, M. J., et al. Curr Biol 1998, 8, 573-81). Thus, it is likely that Axin protein levels need to be tightly regulated to ensure proper Wnt y signaling.

It has recently been found that B-catenin degradation can be promoted by stablising Axin through the inhibition of the DP—ribose polymerase (PARP) enzymes tankyrase 1 and tankyrase 2, as explained in and Huang et al., (Huang, 8. M., et al. Nature 2009, 461, 614-620). Both tankyrase isoforms interact with a highly conserved domain of Axin and stimulate its degradation through the tin-proteasome y. This previously unknown mechanism for stabilising Axin protein, thereby enhancing B-catenin degradation, can be exploited for treating Wnt signaling-related disorders. Axin proteins are essential regulators of a spectrum of physiological processes, including brain oligodendrocyte progenitor cell differentiation for ination (Fancy, 8., et al. Nature ci2011, 14, 1009-1017), and epithelial-to- mesenchymal transition during pulmonary fibrosis er, A., et al. J Bio Chem 2012, 287, 5164-5172). Thus, by way of stabilizing Axin proteins, Tankyrase inhibitors could be used as a therapy for remyelination post brain injury and pulmonary fibrosis.

Tankyrase has several binding protein partners, ing TRF1, a double- stranded telomeric repeat binding protein (Smith, 8., et al. Science 1998, 282, 1484- 1487); NuMA, an ial protein in mitotic spindle assembly (Chang, W., et al.

Biochem J, 2005, 391, 177-184); lRAP, an integral membrane n involved in e uptake in response to insulin (Chi, N.W., et al. J Biol Chem 2000, 275, 38437- 3O 38444); and MCI-1, a pro-apoptotic protein (Bae, J., et al. J Biol Chem 2003, 278, 5195- 5204).

By way of its various interacting proteins, tankyrase proteins have been implicated in different biological functions. Tankyrase poly (ADP-ribosyl)ates TRF1, releasing it from telomeres and enhancing telomere access to telomerase. Thus, tankyrase functions as a positive regulator for re elongation by telomerase, supported by the findings that long-term overexpression of ase leads to telomere elongation (Cook, B.D., et al Mol Cell Bio/2002, 22, 332-242). Telomere maintenance by telomerase has been uted to the uncontrolled eration of cancer cells (Hahn, W.C., et al, Nat Med 1999, 5, 1164-1169). Tankyrase could be a target for cancer therapy by inhibiting the telomere accessibility for telomerase. Tankyrase inhibition could be used as an effective cancer therapy to treat patients with a wide spectrum of cancers, including leukemia, lymphoma, multiple myeloma, lung, and breast cancer.

Tankyrase also plays a role in cell mitosis by :1) poly(ADP-ribosyl)ating NuMA during mitosis and regulating its functions at spindle poles (Chang, W., et al. Biochem J 2005, 391, 177-184); 2) by regulating spindle assembly and structure , P., et al.

Nature 2004, 432, 645-649); and 3) by maintaining sister chromatid resolution at telomeres , J., et al. Science 2004, 304, 97-100). Inhibition of tankyrase leads to cell c arrest or senescence, and thus could be exploited for treating diseases that have al mitotic division, such as cancer. Examples include breast, lung, ovarian, leukemia, lymphoma, and melanoma. In addition, tankyrase 1 was fied as a gene required for centrosome clustering, a mechanism that cancer cells with supernumerary centrosomes employs to suppress multipolar mitosis and enable bipolar s (Kwon, M., et al. Genes Dev 2008, 22, 2189-2203). Thus inhibition of tankyrase could be exploited for treating cancers with centrosome amplification, ing both solid and haematological cancers, examples include , bladder, lung, colon, and leukemia.

Moreover, One of the cellular localizations of tankyrase is at the Golgi apparatus co-localizing with the glucose transporter GLUT4 vesicles where tankyrase is ated with IRAP, and tankyrase is implicated in the regulation of GLUT4 trafficking in adipocytes (Chi, N.W., et al. J Biol Chem 2000, 275, 38437-38444). Tankyrase-deficient mice exhibit reduced adiposity and sed energy expenditure by increases in both fatty acid oxidation and n-stimulated glucose utilization (Yeh, T., et al. Diabetes 2009). This supports tankyrase involvement in energy homeostasis in mammals and inhibiting tankyrase can be exploited for treating metabolic diseases, such as obesity.

Tankyrase has been repoted to be a host n targeted by Herpes Simplex Virus (HSV), modulated by HSV through hyperphosphorylation, nuclear ort and proteasomal degradation (Li 2., et al. J of Wei 2012, 86, 492-503). More antly, efficient HSV viral replication requires the enzymatic activity of ase proteins.

Inhibition of tankyrase activity by inhibitor XAV939 (, Huang, 8. M., et al. Nature 2009, 461, 614-620) suppressed HSV viral protein expression and decreased viral growth. Thus, inhibition of tankyrase can be exploited as anti-viral therapeutics, including but not limited to treatment of HSV infection.

Consequently, compounds that inhibit tankyrase (TNKS) and/or Wnt Signaling may be useful for treatment of diseases mediated by such inhibitions.

Y OF THE ION The present invention provides for compounds of formula (I): RVNQN)n R3 O R4 wherein R1— R4 and n are defined herein. The present invention also provides for pharmaceutical compositions and combinations comprising a nd of formula (l) as well as for the use of such compounds as tankyrase inhibitors and in the treatment of Wnt signaling and tankyrase 1 and 2 signaling related ers which include, but are not limited to, cancer.

DETAILED DESCRIPTION OF THE INVENTION The present ion es for compounds of formula (I) wherein: R1 is R2 or R2-NHC(O)-; R2 is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: halo, OH, CN, N02, C145 alkyl, 01-6 alkoxy, 01-5 haloalkyl, C(O)Ra, COORa, NRaRb, NHC(O)Ra, and C(0)NRaRb; R2 is a 5 membered heteroaryl having one to four heteroatoms selected from the group consisting of N, O, and S, or R2 is a 6 membered heteroaryl having one or two N, said 5 and 6 membered heteroaryl rings being optionally substituted with one to three substituents each independently selected from the group consisting of: halo, oxo, OH, CN, N02, 01-6 alkyl, C1-6 alkoxy, C1_6 haloalkyl, C(O)Ra, COORa, NRaRb, NHC(O)Ra, and C(O)NRaRb; R2 is an 8-10 membered bicyclic heteroaryl having 1 to 4 heteroatoms selected from the group consisting of N, O, and 8, said 8-10 membered aryl being optionally tuted with one to three substituents each independently selected from the group consisting of: (a) halo, (b) oxo, (O) OH, (d) CN, (e) N02, (f) C1 -6 alkyl optionally substituted with one hydroxy or one 01-6 alkoxy, (9) (31—6 alkoxy, (h) 01-6 haloalkyl, (i) C(OlRa, (j) COORa, (k) NRaRb, (l) NHC(O)Ra, and (m) C(O)NRaRb; R3 is H and R4 is phenyl optionally tuted with one to three substituents each independently selected from the group consisting of: halo, OH, CN, N02, C1_6alkyl, 01-6 alkoxy, 01-6 haloalkyl, C(O)Ra, COORa, NRaRb, NHC(O) Ra, and C(O)NRaRb; R3 and R4 together with the atoms to which they are attached form optionally substituted indan-1 -one, said indan-t-one is ed to the piperidine ring of formula (I) through spiro carbon 4 and is optionally substituted with one to three substituents each independently selected from the group consisting of: halo and 01-6 alkoxy; Ra is H or 01-6 alkyl; Rb is H or 01-6 alkyl; and nis1or2.

As used herein, the term “alkyl” refers to a fully saturated branched or unbranched arbon moiety having up to 6 carbon atoms. Unless othenNise WO 08217 provided, alkyl refers to hydrocarbon moieties having 1 to 6 carbon atoms. Alkyl groups may be optionally substituted with one or more substituents as d. Representative examples of alkyl include, but are not d to, methyl, ethyl, n-propyl, iso-propyl, n- butyl, tyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

As used herein, the term “alkoxy" refers to an alkyl moiety attached through a oxygen bridge (Le. a —O-C1_6 alkyl wherein alkyl is d herein). Typically, alkoxy groups have 1 to 6 carbon atoms. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy.

As used herein, the term “cycloalkyl” refers to a 4 to 7 membered monocyclic saturated arbon ring system. lkyl groups may be optionally substituted with one or more substituents as defined herein. lkyl includes cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

As used herein, the term “cycloalkenyl” refers to a 5 to 7 membered monocyclic unsaturated, but not aromatic, hydrocarbon ring system. Cycloalkenyl groups may be ally substituted with one or more substituents as defined here. Cycloalkenyl includes cyclopentenyl, cyclohexenyl, and cycloheptenyl.

As used herein, the term “halo" refers to fluorine, bromine, chlorine or iodine, in particular fluorine or chlorine. Halogen-substituted groups and moieties, such as alkyl substituted by halogen lkyl) can be mono-, poly- or per—halogenated.

As used herein, the term lkyl” refers to an alkyl as defined herein, which is substituted by one or more halo groups as defined herein. The haloalkyl can be monohaloalkyl, alkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically the polyhaloalkyl contains up to 12, or ,1 O, or 8, or 6, or 4, or 3, or 2 halo groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A o-alkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms.

As used herein, the term “heteroatoms” refers to nitrogen (N), oxygen (0) or sulfur (S) atoms, in particular en or oxygen.

As used herein, the term "heteroaryl" refers to a 5 or 6 membered monocyclic aromatic ring system, having 1 to 4 heteroatoms unless specified ise. Typical 5 or 6 membered aryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2— or 3-pyrrolyl, 2—, 4-, or 5-imidazolyl, 3-, 4—, or 5- pyrazolyl, 2-, 4—, or 5-thiazolyl, 3-, 4—, or 5-isothiazolyl, 2-, PCT/lBZOlZ/053613 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5—1,2, zolyl, furazanyl, thiadiazolyl, tetrazolyl, 2-, 3-, or dyl, 3- or 4-pyridazinyl, 3-, 4-, or 5- pyrazinyl, 2—pyrazinyl, and 2-, 4-, or 5-pyrimidinyl.

Heteroaryl also refers to an 8 to 10 membered ic aromatic ring system having 1 to 4 heteroaroms unless otherwise specificed. Heteroaryl also refers to an 8 to membered ring system in which a heteroaromatic ring is fused to one phenyl, cycloalkyl, cycloalkenyl, or heterocyclyl ring, where the radical or point of ment is on the heteroaromatic ring. Nonlimiting examples include 1-, 2-, 3-, 5-, 6—, 7-, or 8- indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2~, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, 1O or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8- purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl, 1-, 3-, 4-, 5-, 6—, 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or 8- phthalazinyl, 2-, 3-, 4—, 5-, or 6—naphthyridinyl, 2-, 3- , 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, -, 6-, 7-, or olinyl, 2-, 4—, 6—, or 7-pteridinyl, 1-, 2—, 3-, 4-, 5-, 6—, 7-, or 8-4aH carbazolyl, 1-, 2—, 3-, 4-, 5—, 6—, 7-, or 8—carbzaolyl, 1-, 3-, 4-, 5-, 6—, 7-, 8—, or 9-carbolinyl, 1-, 2—, 3-, 4—, 6-, 7-, 8—, 9-, or nanthridinyl, 1- , 2-, 3-, 4-, 5-, 6—, 7-, 8—, or 9-acridinyl, 1-, 2—, 4-, 5-, 6-, 7-, 8—, or 9-perimidinyl, 2-, 3-, 4-, 5-, 6—, 8—, 9-, or 10-phenathrolinyl, 1-, 2- , 3-, 4—, 6-, 7-, 8—, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8—, 9-, or 10-phenoxazinyl, 2-, 3-, 4—, 5-, 6-, or |—, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or - benzisoqinolinyl, 2-, 3-, 4-, or [2,3-b]furanyl, 2-, 3-, 5-, 6—, 7-, 8—, 9-, 10 -, or 11- 7H-pyrazino[2,3-c]carbazolyl,2-, 3—, 5—, 6-, or 7-2H- furo[3,2—b]—pyranyl, 2—, 3-, 4-, 5—, 7-, or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazo|o[4,3-d]-oxazolyl, 2-, 4-, or 54H- imidazo[4,5-d] thiazolyl, 3-, 5-, or 8-pyrazino[2,3-d]pyridaziny|, 2-, 3-, 5-, or 6- imidazo[2,1-b] thiazolyl, 1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinno|inyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6—, or 7-imidazo[1,2-b][1,2,4]triazinyl, 7- benzo[b]thienyl, 2-, 4-, 5- , 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9- apinyl, 2-, 4-, 5-, 6-, 7-, or 8—benzoxazinyl, 1-, 2-, 3-, 5—, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo[1,2-b][2]benzazapinyl.

Typical fused heteroaryl groups include, but are not limited to 2—, 3-, 4—, 5—, 6-, 7—, or 8- quinolinyl, 1-, 3-, 4-, 5-, 6-, 7—, or 8-isoquinolinyl, 2-, 3-, 4-, 5—,>6-, or 7—indolyl, 2-, 3-, 4—, 5— 3O , 6-, or 7-benzo[b]thienyl, 2-, 4-, 5- , 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7- benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl, cyclohepta[d]imidazolyl, 7,8-dihydro- 5H-pyrano[4,3-d]pyrimidinyl,1H-pyrazolo[3,4-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, 6,7- dihydro-5H-cyclopentapyrimidinyl, ' hydro-thiazo|o[2,3-c][1 ,2,4]triazo|yl, [1 ,2,4]triazolo[4,3-a]pyridinyl, hydro-5H-pyrano[3,4-d]pyridazinyl, and isoxazolo[5,4— b]pyridiny|.

Heteroaryl groups ning more than one heteroatom may contain different heteroatoms unless specified othenNise. Heteroaryl groups may be optionally substituted with one or more substituents as defined herein.

As used herein the term “heterocyclyl” refers to a 4 to 7 ed monocyclic saturated or rated ring containing from 1 to 4 heteroatoms. Heterocyclyl rings are not aromatic. cyclyl containing more than one heteroatom may contain different heteroatoms. Heterocyclyl groups may be optionally substituted with one or more substituents as defined . Examples of heterocyclyl include tetrahydrofuran (THF), dihydrofuran, 1, 4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3— dioxolane, imidazolidine, imidazoline, pyrroline, idine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, and the like.

When any group or moiety, such as alkyl, heteroaryl, or phenyl, is defined herein as being “optionally substituted with one, one or two, or one to three substituents each independently selected from the group consisting of” it is understood that the group or moiety is unsubstituted or substituted with one, one or two, or one to three substituents, wherein each substituent is independently selected from the d group of tuents.

The d artisan will appreciate that salts, including pharmaceutically acceptable salts, of the compounds according to formula (I) may be prepared. These salts may be prepared in situ during the final isolation and cation of the compound, or by separately reacting the purified compound in its free acid or free base form with a le base or acid, respectively. ceutically acceptable acid addition salts can be formed with inorganic acids and c acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed with nic and organic bases.

Inorganic bases from which salts can be derived include, for e, ammonium salts and metals from columns | to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, , zinc, and copper; particularly suitable salts include ammonium, ium, sodium, calcium and ium salts.

Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic , basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods. lly, such salts can be ed by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these nds with a stoichiometric amount of the appropriate acid. Such reactions are lly carried out in water or in an organic solvent, or in a mixture of the two.

Generally, use of ueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., ; and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Solvates, including pharmaceutically acceptable solvates, of the compounds of formula (I) may also be prepared. “Solvate” refers to a complex of variable iometry formed by a solute and t. Such solvents for the purpose of the invention may not interfere with the biological ty of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent le are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

WO 08217 As used herein, the term “pharmaceutically acceptable” means a compound which is suitable for pharmaceutical use. Salts and solvates (e.g. hydrates and hydrates of salts) of compounds of the invention which are suitable for use in medicine are those where in the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having armaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates.

The compounds of formula (I), including salts and solvates thereof, may exist in crystalline forms, non-crystalline forms, or mixtures thereof. The compound or salt or solvate thereof may also exhibit polymorphism, i.e. the capacity of occurring in different crystalline forms. These different crystalline forms are typically known as “polymorphs”. rphs have the same chemical composition but differ in g, geometrical arrangement, and other descriptive properties of lline solid state. Polymorphs, ore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. rphs typically exhibit different melting points, IR a, and X-ray powder ction patterns, all of which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or ing the conditions used in crystallizing/recrystallizing a compound of formula (I).

The invention also includes various isomers of the compounds of formula (I).

“Isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereosiomers). With regard to stereoisomers, the compounds of formula (I) may have one or more tric carbon atom and may occur as racemates, racemic mixtures and as dual enantiomers or reomers. All such isomeric forms are included within the present invention, ing mixtures thereof. If the compound contains a double bond, the tuent may be in the E or 2 configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans- uration. A“ tautomeric forms are also intended to be included.

Any asymmetric atom (e.g., carbon or the like) of a compound of formula (I) can be present in racemic or enantiomerically enriched, for example the (H)-, (S)- or (RS)- configuration. In certain embodiments, each asymmetric atom has at least 50 °/o enantiomeric excess, at least 60 % enantiomeric excess, at least 70 °/o omeric excess, at least 80 % enantiomeric excess, at least 90 °/o enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- 012/053613 configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.

Accordingly, as used herein a compound of formula (I) can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures f.

Any resulting mixtures of isomers can be separated on the basis of the ochemical differences of the constituents, into the pure or ntially pure ric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

Any resulting tes of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. in particular, a basic moiety may thus be employed to resolve the compounds of the present ion into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., ic acid, oyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor—10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.

The invention includes unlabeled forms as well as ically labeled forms of compounds of a (l). lsotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include es of en, , nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18F 31P, 32F, 358, 36Cl, 125| respectively. The invention includes various isotopically labeled compounds as defined herein, for e those into which radioactive isotopes, such as 3H and 14C, or those into which non-radioactive isotopes, such as 2H and ‘30 are present. Such isotopically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In ular, an 18F or labeled compound may be particularly desirable for PET or SPECT studies. lsotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and PCT/IBZOIZ/053613 ations using an appropriate isotopically-labeled reagents in place of the non- labeled reagent previously employed.

Furthermore, substitution with r isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages ing from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor.

The term "isotopic enrichment factor" as used herein means the ratio between the isotopic nce and the l abundance of a specified isotope. if a substituent in a compound of this ion is denoted deuterium, such compound has an isotopic ment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% ium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

Representative Embodiments Various embodiments of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide for further embodiments.

One ment of the present invention is a compound ing to formula (ll): RVN?N)n R3 O ' (II).

In another embodiment of the present invention R3 is H and R4 is optionally substituted . Suitably R4 is phenyl substituted by one or two substituents each independently selected from the group consisting of halo, 01-6 alkyl, and C1-6 alkoxy.

More suitably R4 is phenyl optionally substituted by one or two tuents each independently selected from the group ting of fluoro, chloro, methyl, and methoxy.

PCT/lBZOlZ/053613 In partocular R4 is 4-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, or 4-methoxyl methylphenyl.

In another embodiment R3 and R4 together with the atoms to which they are attached form optionally substituted indan-t-one. Suitably the indan-t-one is optionally tuted with one C1_6 alkoxy, for example methoxy.

In another embodiment n is 1. In another embodiment n is 2. Suitably n is 1.

In another embodiment R1 is R2. Suitably R2 is optionally substituted .

More suitably R2 is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: halo, for example chloro, and cyano. In particular R2 is 2-chlorobenzonitrile.

In another embodiment R2 is an optionally substituted 5 or 6 ed heteroaryl. ly R2 is an optionally substituted pyrimidinyl or tetrazolyl.

In another embodiment R2 is an optionally substituted 8-10 membered bicyclic heteroaryl.

In another embodiment R2 is O O o o O NH foL/ NH dLNHS NH l I A N/& N N/& \ N * * H * N/J\ k (a), (b) , (C), (d), (e), , *(g>, *(h), /N~i\l : 'N l/NJ\* T1 ,,N‘N o t 5“: * NNJ\* (i), (1), Mar H wherein each of ) is optionally tuted with one or two substituents each independently selected from the group consisting of halo, OH, CN, N02, 01-6 alkyl, C1_6 alkoxy, 01-6 haloalkyl, a, cooaa, NRaRb, NHC(O)Ra, and C(O)NRaRb.

Suitably R2 is (a)-(|) optionally tuted with one or two substituents each independently ed from the group consisting of halo, CN, and C1_6 alkyl. More suitably R2 is (a)-(I) optionally substituted with one or two substituents each independently selected from the group consisting of chloro, bromo, CN, methyl, and ethyl. Suitably R2 is optionally substituted (b), (g), or (h). More suitably R2 is (b), (g), or (h).

Specific compounds of the present ion e: 2-Chloro-6—{3-[4-(4-methoxy-benzoyl)-piperidinyl]oxo-pyrrolidiny|methyl}- benzonitrile; 2—{3-[4-(4—Methoxy-benzoyl)-piperidin—1—y|]oxo-pyrrolidin—1-ylmethy|}-3,5,7,8— tetrahydro-pyrano[4,3-d]pyrimidinone; 2—{(S)—3-[4-(4-Methoxy-benzoyI)-piperidinyI]oxo-pyrro|idinylmethy|}-3,5,7,8— tetrahydro—pyrano[4,3-d]pyrimidinone; 1O 2-{(R)[4—(4-Methoxy-benzoyl)pipe-ridinyl]oxo-pyrro|idiny|methy|}-3,5,7,8- tetrahydro-pyrano[4,3-d]pyrimidinone; 2—ChIoro((3—(4—(4-methoxybenzoyl)piperidiny|)oxopyrrolidin-1 - yl)methyl)benzonitrile; 6-{3-[4-(4-Methoxy-benzoyl)—piperidinyl]oxo-pyrro|idiny|methy|}methyl- 1 ,3a,5,7a-tetrahydro-pyrazolo[3,4-d]pyrimidinone; 2-{3-[4-(4-Methoxy-benzoyl)—piperidinyl]oxo-pyrro|idiny|methyI}-4a,7a-dihydro- 3H-thieno[3,2-d]pyrimidin-4—one; 2-{3-[4-(4-Methoxy-benzoyI)-piperidiny|]oxo-pyrrolidinylmethy|}-6—methyI-4a,7a- dihydro-3H-thieno[2,3-d]pyrimidinone; 2-{3-[4-(4—ChIoro-benzoyl)—piperidinyl]oxo—pyrrolidiny|methyl}-3,5,7,8-tetrahydro- [4,3—d]pyrimidin—4—one; 2—{3-[4-(4-Fiuoro-benzoyI)-piperidiny|]—2-oxo-pyrrolidiny|methy|}-3,5,7,8—tetrahydro- pyrano[4,3-d]pyrimidinone; 2-{(S)[4-(4-Fluoro-benzoy|)-piperidinyl]oxo—pyrrolidinylmethy|}-3,5,7,8— tetrahydro-pyrano[4,3-d]pyrimidinone; 2-{(R)[4-(4-Fluoro-benzoyl)-piperidinyI]oxo-pyrrolidin-1~y|methy|}-3,5,7,8— tetrahydro-pyrano[4,3—d]pyrimidinone; 2-{(S)[4-(4-Methoxymethyl—benzoyl)-piperidiny|]oxo-pyrro|idin-1 -ylmethyl}- 3,5,7,8—tetrahydro-pyrano[4,3-d]pyrimidinone; 3O 2-{(R)—3-[4—(4-Methoxy—3-methyI-benzoyl)-piperidiny|]oxo-pyrro|idiny|methy|}- 3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4—one; 2—((3-(5-methoxyoxo-1 ydrospiro[indene-2,4'-piperidine]-1'-y|)oxopyrro|idin yl)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one; (S)((3-(5-methoxyoxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)oxopyrrolidin- 1-y|)methyl)—7,8—dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one; (R)—2-((3—(5—methoxy-1—oxo-1 ,3-dihydrospiro[indene-2,4'-piperidine]—1'-y|)-2—oxopyrro|idin- 1-y|)methyl)—7,8—dihydro—3H-pyrano[4,3-d]pyrimidin—4(5H)-one; 2—[4-(4-Methoxy-benzoyl)-2’-oxo-[1,3']bipiperidinyl-1'-ylmethy|]-3,5,7,8—tetrahydro- [4,3-d]pyrimidinone; 2-[(S)(4-Methoxy-benzoyI)-2'-oxo-[1 ,3']bipiperidinyl-1'-y|methy|]-3,5,7,8-tetrahydro- pyrano[4,3-d]pyrimidinone; 2-[(R)(4—Methoxy—benzoy|)-2'-oxo-[1,3']bipiperidinyl-1'-ylmethy|]-3,5,7,8—tetrahydro- pyrano[4,3-d]pyrimidinone; 2-((3-(4—(4-methoxybenzoyl)piperidinyl)oxopyrro|idin-1—yI)methyI)-6,7-dihydro-3H- cyclopenta[d]pyrimidin-4(5H)-one; 4-(4-Methoxy-benzoyl)-piperidin-1—yl]oxo-pyrrolidinylmethy|}-3H-pyrimidin one; 2-{3-[4-(4—Methoxy-benzoyI)-piperidin-1—yl]oxo-pyrro|idiny|methy|}methyI-3H- pyrimidinone; 6-EthyI—2-{3-[4—(4-methoxy—benzoyl)—piperidiny|]—2—oxo—pyrrolidin—1—ylmethyI}-3H— pyrimidin—4-one; 2—{3-[4—(4—Methoxy-benzoyI)-piperidin—1—yl]oxo—pyrro|idinylmethyl}methyI-3H- din-4—one; 2—{3-[4-(4-Methoxy—benzoyI)-piperidiny|]oxo-pyrrolidiny|methyl}-5,6-dimethyI-3H- pyrimidin-4—one; 2-((3-(4-(4-methoxybenzoyl)piperidinyl)oxopyrrolidin yl)methyl)cyclohepta[d]imidazol-4(3H)-one; 2—{(S)[4-(4-Methoxymethyl-benzoyl)-piperidin—1-yl]oxo-pyrrolidiny|methyl}-3H- cycloheptaimidazolone; 2-{(R)[4-(4—Methoxy-S-methyl-benzoyl)-piperidiny|]oxo-pyrrolidiny|methy|}-3H- cycloheptaimidazolone; 2-{(S)[4-(4-Methoxy-benzoyl)-piperidiny|]oxo-pyrro|idinylmethyl}-3H- eptaimidazolone; 2—{(R)[4—(4-Methoxy-benzoyl)—piperidiny|]oxo-pyrro|idiny|methy|}-3H- cycloheptaimidazol-4—one; N-(5,6-dihydrothiazo|o[2,3—c][1 ,2,4]triazoly|)(3—(4-(4— methoxybenzoyl)piperidin- 1 -y|)oxopyrrolidiny|)acetamide; N-(5,6-Dihydro-thiazolo[2,3-c][1,2,4]triazoly|)-2—{(S)[4-(4—methoxy-benzoyl)- piperidiny|]oxo-pyrrolidiny|}-acetamide; N-(5,6-Dihydro-thiazo|o[2,3-c][1,2,4]triazoly|){(R)[4-(4—methoxy—benzoyl)- piperidinyl]-2—oxo-pyrro|idiny|}-acetamide; N-([1,2,4]triazolo[4,3-a]pyridinyl)(3-(4-(4-methoxybenzoyl)piperidinyI) oxopyrrolidinyl)acetamide; PCT/IBZOIZ/053613 2—(3-(4-(4-methoxybenzoyl)piperidiny|)oxopyrro|idinyl)-N-(1-methyl-1 azol yl)acetamide; N-(3,4-dihydro-2H-pyrano[2,3-d]pyridazinyl)-2—(3-(4-(4-methoxybenzoyl)piperidinyl)- 2—oxopyrrolidinyl)acetamide; and N-|soxazo|o[5,4-b]pyridinyl-2—{3-[4-(4—methoxy-benzoyl)-piperidiny|]oxo- pyrrolidin-i -y|}-acetamide.

Enumerated ments Embodiment 1. A compound according to formula (I) )n ' \/N N R3 O R4 0 (I) wherein: R1 is R2 or R2-NHC(O)-; R2 is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: halo, OH, CN, N02, 01-6 alkyl, C1-6 alkoxy, 01-5 haloalkyl, C(O)Ra, coona, NRaRb, NHC(O)Ra, and C(O)NRaRb; R2 is a 5 membered heteroaryl having one to four atoms selected from the group consisting of N, O, and S, or R2 is a 6 membered ryl having one or two N, said 5 and 6 membered heteroaryl rings being optionally substituted with one to three tuents each independently selected from the group consisting of: halo, oxo, OH, CN, N02, C1_6 alkyl, 01-6 alkoxy, 01-6 haloalkyl, C(O)Ra, COORa, NRaRb, NHC(O)Ra, and laRb; R2 is an 8-10 membered bicyclic heteroaryl having 3 or 4 heteroatoms selected from the group consisting of N, O, and 8, said 8-10 membered heteroaryl being optionally substituted with one to three substituents each independently selected from the group consisting of: (a) halo, (b) oxo, PCT/IBZOIZ/053613 (C) OH, (d) CN, (6) N02, (f) C1_6alkyl optionally substituted with one hydroxy or one C1-6 , (g) C1-s alkoxy, (h) 01-6 haloalkyl, (i) C<O)Ra, (j) COORa, (k) NRaRb, (I) NHC(O)Ra, and (m) C(0)NRaRb; R3 is H and R4 is phenyl ally substituted with one to three substituents each independently selected from the group consisting of: halo, OH, CN, N02, C1_6alkyl, 01-6 alkoxy, C1_6haloalkyl,C(O)Ra, coona, NRaRb, NHC(O) Ra, and C(0)NRaRb; R3 and R4 together with the atoms to which they are attached form optionally substituted indanone, said indanone is ed to the piperidine ring of formula (I) through spiro carbon 4 and is optionally substituted with one to three substituents each independently selected from the group consisting of: halo and C1_5 alkoxy; Ra is H or C1.5 alkyl; Rb is H or c1_5 alkyl; and n is 1 or 2; or a ceutically acceptable salt thereof.

Embodiment 2. The compound according to embodiment 1 having the following formula (II); or a ceutically acceptable salt thereof.

Embodiment 3. The compound according to embodiment 1 or 2 wherein R3 is H; or a pharmaceutically acceptable salt thereof.

Embodiment 4. The compound according to any one of embodiments 1-3 wherein R4 is optionally substituted phenyl; or a pharmaceutically acceptable salt f.

Embodiment 5. The compound according to embodiment 4 wherein R4 is substituted phenyl; or a pharmaceutically acceptable salt thereof.

Embodiment 6. The compound according to embodiment 5 wherein R4 is phenyl substituted by one or two substituents each independently selected from the group consisting of halo, C1 -6 alkyl, and 01-6 alkoxy; or a pharmaceutically acceptable salt thereof.

Embodiment 7. The compound according to embodiment 1 or 2 n R3 and R4 together with the atoms to which they are attached form optionally substituted indan- 1-one; or a pharmaceutically acceptable salt thereof.

Embodiment 8. The compound according to any one of ments 1-7 wherein n is 1 ; or a pharmaceutically acceptable salt thereof.

Embodiment 9. The nd according to any one of embodiments 1-7 wherein n is 2; or a pharmaceutically acceptable salt thereof.

Embodiment 10. The nd according to any one of ments 1-9 wherein Ft1 is R2; or a pharmaceutically acceptable salt thereof.

Embodiment 11. The compound according to any one of embodiments 1-10 wherein R2 is optionally substituted phenyl; or a pharmaceutically acceptable salt thereof.

Embodiment 12. The nd according to any one of embodiments 1-10 n R2 is an ally substituted 5 or 6 membered heteroaryl; or a pharmaceutically acceptable salt thereof.

Embodiment 13. The compound according to any one of embodiments 1-10 wherein R2 is an optionally substituted 8-10 membered bicyclic heteroaryl; or a pharmaceutically acceptable salt thereof. ment 14. The compound according to any one of ments 1-10 wherein R2 is O O o o O NH NH S NH I / N/& N‘ N” A N Nx/K \ /J\ N ‘A- * H 1: N * a), (b) . I (d) / NH NJ\*(e) GH N~N / / N stk,‘/ S NJ\ N,J\ * U () (g), (h), / \ “x (k), or (l) wherein each of(aa()-l) is optionally tuted with one or two substituents each independently selected from the group consisting of halo, OH, CN, N02, 01-6 alkyl, 01-6 alkoxy, 01-6 haloalkyl, C(O)Ra, cooaa, NRaRb, Ra, and C(O)NRaRb; or a pharmaceutically acceptable salt thereof.

General Synthetic ures The compounds of the present invention may be made by a variety of methods, including standard chemistry. Illustrative general synthetic methods are set out below and specific compounds of the invention as prepared are given in the Examples.

The compounds of formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated ing to rd methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third n, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using s that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of formula (I).

Those skilled in the art will ize if a stereocenter exists in the compounds of formula (I). Accordingly, the present invention includes both le stereoisomers and includes not only c compounds but the individual enantiomers as well. When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting al may be effected by any suitable method known in the art. See, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-interscience, 1994).

The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.

Scheme1 0 o 2/\ + R3 N a R R x N HN LN X=C|,Br,| ] n l n 2 3 a) NaH or KHMDS, MeCN, THF or DMF, -30 to 70°C As shown in Scheme 1, 1 can be prepared by alkylation of the lactam moiety of 3 can be accomplished by a variety of methods, ing the treatment of the lactam with an alkylating agent, such as an alkyl halide 2 or alkyl sulfonic ester in the ce of a suitable base, such as sodium hydride or KHMDS, in a suitable t, such as acetonitrile, THF or DMF over a range of suitable temperatures.

Scheme 2 O O O RM0 R 3 NH I I R N/J\/Cl 4 5 a) TEA, 2-chloroacetamidine, MeOH W0 2013/008217 2012/053613 Alkyl halides 2 are commercially available or can be made a shown in Scheme 2.

There are several methods for making chloromethyl pyrimidinones 5 including the treatment of B-keto esters 4 with 2-chloromethyl acetamide in the presence of a suitable base, such as triethylamine, in a le solvent, such as methanol.

Scheme 3 O O O in x Hm 0 0A HN R4 N R4 ] HN$. R3 6 7 3 X = Cl, Br, OMS, OTs n = 1,2 or 3 a) DIEA, MeCN or DMF or eCn (1:1), 15-85C The synthesis of 3 can be accomplished by a variety of methods, including the elaboration of appropriately substituted 5 and 6 member lactams 6 as shown in Scheme 3. The substitution of a leaving group at the 3-position, such as a chloro, bromo, or mesylate, by an appropriate nucleophile, such as a tuted piperidine 7 in a suitable t, such as acetonitrile or DMF or a t mixture such as acetonitrile and toluene, can be accomplished over a range of temperatures and reaction durations.

Scheme 4 o O ,O 4 >mrON ———» >mrON —-—> O O 8 9 7 a) R4—Br, n—BuLi, THF, 78°C or Ar—MgBr, THF, 0°C; b) TFA, DCM The synthesis of 7 can be achieved by way of the Weinreb ketone synthesis as shown in Scheme 4. In this scheme, Weinreb amide 8 is treated with a Grignard reagent or an organometallic reagent such as n-butyllithium in the presence of R4-Br to form ketone 9. The utyl protecting group of 9 is removed through the addition of trifluoroacetic acid in dichloromethane to yield the secondary amine 7.

Scheme 5 O O O OH 4 a b R c R4 XOTN —> ——> —.

O >I/O\n/N O >r0\n/N 1o 11 9 7 (a) Ar-SH (Ar = Ph or 4—MePh), HATU, DIEA, DMF; b) R-B(OH)2), Pd2(dba)3, ligand TFP, copper (I) enecarboxylate, DME, 50°C; c) TFA, DCM or 4 N HCI, dioxane The synthesis of 7 can also be achieved through a thioester boronic acid cross coupling reaction as shown in Scheme 5. Thioester 11 is achieved through the treatment of 10 with the appropriate aryl thiol in the presence of HATU, DIEA and DMF. 11 is converted into ketone 12 through the addtion of the approprate boronic acid in the presense of a palladium metal catalyst such as Pd2(dba)3 in the presence of tris(2— phosphine and copper (I) thiophene-Z-carboxylate in dimethoxyethane (DME). The tert-butyl protecting group of 9 is removed through the addition of oroacetic acid in dichloromethane to yield the secondary amine 7.

Schemes H O a 0 OK Br/\/N\/\Br + Cl/lLO/\ R ——> Y + 14 BFN \ABrN 13 X=CH2 or CHZCHZ 16 o o b c _. \— )—N R __. HNmR O X X 17 a) NaOH, H20; b) NaH, DMF, 50°C; 0) 6 N HCI, reflux The formation of substituted spiro[indene-2,4'-piperidin]-1(3H)—ones can be accomplished by a variety of methods, including those described below. A suitable bis- (2-bromo-ethyl)-carbamic acid alkyl ester, such as -bromo-ethyl)-carbamic acid ethyl ester can by synthesized by protection of bis-(2—bromo-ethyl)-amine with a suitable protecting group, such as a carbamate, such as ethyl carbamate, via reaction with carbamoylating agents, such as alkyl formates, such as ethyl chloroformate, in a le solvent, such as water, in the presence of a base, such as NaOH at temperatures from -40°C to 40°C. Formation of the protected spiro[indene-2,4'- piperidin]-1(3H)-ones can be accomplished by reacting a suitable ketone, such as a substituted indanone, with a strong base, such as sodium hydride, in a polar t, such as Dmolecular formula at temperatures from 0°C to 100°C. Deprotection of the dinyl nitrogren can be accomplished via a variety of methods, such as such as treatment with a strong acid or base, such as 6 N HCl at temperatures between 0°C and 100°C.

Scheme 7 Br O CIWBF N N + \\\/NH2 a,b N/ Z + R4- C o 0 Br HN 24 25 26 7 O O 0 R4 O R4 R3 d R3 R N + o/ e [N b/N R o N NH 27 28 4 7C O | N’k 0 R4 R6 R3 29 a) TEA, DCM; b) NaH, PhMe; c) TEA, MeCN; d) i. NaOMe, MeOH; ii. NH4Cl; e) NaOEt, EtOH The synthesis of (2-[3-(4-piperidinyl)oxo-pyrrolidiny|methyl]-3H-pyrimidin- 4-one analogs 29 can be accomplished by a variety of methods, including routes that rely on the use of amidine intermediates to form the dinone ring. The sis of lactam acetonitrile intermediates, such as 2-(3-bromo—2-oxopyrrolidiny|)acetonitrile 26 can be accomplished by a variety of methods, including reacting aminoacetonitrile 25 with a suitable electrophile, such as 2,4—dibromobutanoyl de 24, in the presence of a suitable base, such as an amine base, such as triethylamine, in a suitable solvent such as dichloromethane. Installation of the piperidine moiety, such as aryl-piperidinyl- methanone analogs 7, can be accomplished by a variety of methods, such as displacement of a suitable g group, such as a e, in the presence of a suitable base, such as an amine base, such as triethylamine, in a suitable solvent such as acetonitrile. Conversion of the resulting nitrile 27 to the amidine 28 can be PCT/lBZOlZ/0536l3 accomplished via a variety of methods, including treatment with an alkoxide base, such as sodium methoxide, and an ammonium source, such as ammonium chloride, in a le solvent, such as methanol. Formation of the pyrimidinone moiety 29 can be accomplished by a variety of methods, including reacting the amidine 28 with an appropriately substituted [S-ketoester 4, such as methyl yclopentanecarboxylate, in the ce of a suitable base, such as an alkoxide base, such as sodium de, in a suitable solvent, such as ethanol.

Scheme8 O 0 BrNo. +V Y‘NH. —> MEN V —»0 a Br 0 b Br 0 Br 0 24 30 31 / 34 32 33 ONg o\ e R N N gN 0\ 35 36 a) DCM,water,O°C; b) NaH, PhH; c) TEA, MeCN, 70°C; d) NaOH, water, EtOH; e) R- NH2, HATU, DIEA, DCM The synthesis of N-heterocyc/ic-Z-(3—(4-(4-methoxybenzoyl)piperidiny/) oxopyrrolidinyl)acez‘amide analogs 36 can be accomplished by a variety of methods, including routes that rely on the use of carboxylic acid intermediates to form the heterocyclic acetamide. The synthesis of ethyl 2-(2,4-dibromobutanamido)acetate intermediate 31 can be accomplished by reacting ethyl 2-aminoacetate hydrochloride 30 with a suitable electrophile, such as 2,4-dibromobutanoyl chloride 24, in a suitable solvent e, such as dichloromethane and water. Cyclization to ethyl 2-(3-bromo oxopyrrolidinyl)acetate 32 can be accomplished by reaction with a suitable base, such as sodium e, in a suitable solvent, such as benzene. Installation of the piperidine moiety, such as (4-methoxyphenyl)(piperidin-4—yl)methanone, can be accomplished by a y of methods, such as displacement of a suitable g group, such as a bromide, in the ce of a suitable base, such as an amine base, such as triethylamine, in a suitable solvent such as acetonitrile. sion of the resulting carboxylic ester 34 to the carboxylic acid 35 can be accomplished via a variety of methods, including treatment with an inorganic base, such as sodium hydroxide, in a suitable solvent combination, such as ethanol and water. ion of cyclic acetamides 36 can be accomplished by a y of methods, including reacting 2-(3-(4—(4- ybenzoyl)piperidinyl)oxopyrrolidinyl)acetic acid 35 with suitable heterocyclic amines in the presence of a suitable coupling reagent, such as HATU, and a le amine base, such as diisopropylethylamine, in a suitable solvent, such as dichloromethane.

Compositions In another , the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for ular routes of administration such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical compositions of the present ion can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain tional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsiters and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or nylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated ing to methods known in the art.

Suitable compositions for oral administration include an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt f, in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or es, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening , flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ient in admixture with nontoxic pharmaceutically acceptable ents which are suitable for the manufacture of tablets.

These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or c acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the intestinal tract and thereby e a sustained action over a longer period. For example, a time delay al such as glyceryl earate or glyceryl distearate can be employed. Formulations for oral use 3O can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for eXample, calcium carbonate, calcium ate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous ic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.

Said compositions may be sterilized and/or contain nts, such as preserving, stabilizing, wetting or emulsifying agents, solution ers, salts for regulating the WO 08217 osmotic re and/or buffers. In addition, they may also contain other therapeutically le substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.

The present invention further provides anhydrous ceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the ation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or 1O low humidity conditions. An anhydrous ceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, ically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.

The invention further es pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose. Such agents, which are ed to herein as "stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.

The pharmaceutical composition or ation of the present invention can be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 05-100 mg, or about 1-50 mg of active ingredients. The eutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the t, the body weight, age and dual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.

Methods of Use The compounds of formula (I) are tankyrase inhibitors and therefore may be useful in the treatment of diseases mediated by tanykyrase, ing Wnt signaling related disorders and tankyrase 1 and 2 (TNKS/TNKSZ) signaling related ers.

Wnt signaling d disorders include diseases and conditions associated with aberrant Wnt signaling including but not limited to Wnt signaling-related cancers (e.g., colorectal cancer, malignant medulloblastoma and other primary CNS malignant neuroectodermal tumors, rhabdomyosarcoma, lung cancer, in particular small cell lung cancer, gut-derived tumors, including but not limited to cancer of the esophagus, stomach, pancreas, and biliary duct , prostate and bladder cancers, and liver cancer); other, non-oncogenic proliferative diseases, such as erative skin disorders (e.g., psoriasis, dermatitis); orosis; osteoarthritis; fibrosis; schizophrenia; vascular disease; c disease; neurodegenerative diseases such as Alzheimer's disease; remyelination, including remyelination after brain and/or spinal code injury; and pulmonary fibrosis. Aberrant upregulation of Wnt signaling is associated with cancer, rthritis, and polycystic kidney disease, while aberrant down regulation of Wnt signaling has been linked to osteoporosis, obesity, diabetes, and neuronal degenerative diseases. ase ing related disorders include diseases and conditions associated with nt tankyrase 1 and 2 signaling, including but not limited to cancer (e.g., leukemia, lymphoma, melanoma, multiple myeloma, lung, ovarian, and breast cancer) metabolic diseases and viral infection (e.g. Herpes Simplex Virus infection).

The term "a therapeutically effective amount" of a compound of the present invention refers to an amount of a nd of formula (I) that will elicit the biological or l response of a t, for example, ion or inhibition of an enzyme or a protein ty, or ameliorate symptoms, alleviate conditions, slow or delay e progression, or prevent a disease, etc. In one non-limiting embodiment, the term “a therapeutically ive amount" refers to the amount of a compound of formula (I) when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by tankyrase, or (ii) associated with tankyrase activity, or (iii) characterized by activity (normal or abnormal) of tankyrase; or (2) reducing or ting the activity of tankyrase or (3) reducing or inhibiting the expression of tankyrase. In another non-limiting embodiment, the term “a therapeutically effective amount" refers to the amount of a compound of formula (I) when administered to a cell, or a tissue, or a non-cellular biological material, or a , is effective to at least lly reducing or inhibiting the activity of tankyrase; or at least partially reducing or inhibiting the expression of tankyrase.

As used herein, the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

W0 2013/008217 As used herein, the term “inhibit”, "inhibition" or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

As used herein, the term “treat”, ing" or "treatment" of any disease or disorder refers in one ment, to ameliorating the disease or disorder (i.e., slowing or ing or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat”, "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat”, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a nible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treat”, "treating" or "treatment" refers to preventing or delaying the onset or pment or progression of the disease or disorder.

As used herein, a subject is ‘v‘in need of" a treatment if such subject would benefit biologically, lly or in y of life from such treatment.

Thus, as a further embodiment, the present ion provides the use of a compound of a (I) or a pharmaceutically acceptable salt thereof, in therapy. In a further embodiment, the therapy is selected from a disease which may be treated by tankyrase tion. In one embodiment the disease is a Wnt signaling related disorder.

In another embodiment the e is a tankyrase signaling related disorder. In another embodiment, the disease is cancer, in particular a cancer selected from the group consisting of ia, melanoma, multiple myeloma, lymphoma, lung , esophageal cancer, stomach cancer, pancreas cancer, biliary duct system cancer, ovarian cancer, breast cancer, prostate cancer, bladder cancer, colon cancer and liver cancer. In another embodiment, the disease is cancer, in particular, a cancer selected from the group consisting of leukemia, lung cancer, pancreas cancer, breast cancer and colon cancer. In another embodiment the e is a cancer selected from the group consisting of colon, pancreas, and breast.

In another embodiment, the invention provides a use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in that cture of a medicament for the treatment of a disease mediated by tankyrase inhibition. In one embodiment the disease is a Wnt signaling related disorder. In another ment the e is a tankyrase signaling related disorder. In another embodiment, the disease is cancer, in particular a cancer selected from the group ting of ia, melanoma, multiple myeloma, lymphoma, lung cancer, esophageal cancer, stomach cancer, pancreas cancer, biliary duct system , ovarian cancer, breast cancer, prostate , bladder cancer, colon cancer and liver cancer. In another embodiment, the disease is PCT/132012/053613 cancer, in particular a cancer selected from the group consisting of leukemia, lung cancer, pancreas cancer, breast cancer and colon cancer. In another embodiment the disease is a cancer selected from the group consisting of colon, pancreas, and breast.

In another embodiment, the invention provides a method for the ent of a disease mediated by tankyrase inhibition comprising administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof. In one embodiment the disease is a Wnt signaling related disorder. In another ment the disease is a tankyrase signaling related disorder. In a further embodiment, the disease is cancer, in particular a cancer selected from the group consisting of leukemia, melanoma, le myeloma, lymphoma, lung cancer, esophageal cancer, stomach cancer, pancreas cancer, biliary duct system cancer, ovarian cancer, breast , prostate cancer, bladder cancer, colon cancer and liver cancer. In another embodiment, the disease is , in particular a cancer selected from the group ting of leukemia, lung cancer, pancreas cancer, breast .15 cancer and colon cancer. In another embodiment the disease is a cancer selected from the group ting of colon, pancreas, and .

Combinations The compounds of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic s). The compounds of the t invention may be stered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.

In one embodiment, the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition mediated by TNKS inhibition. Products provided as a combined preparation e a composition comprising the compound of formula (I) and the other eutic agent(s) together in the same pharmaceutical composition, or 3O the compound of formula (I) and the other therapeutic agent(s) in separate form, 9.9. in the form of a kit.

In one embodiment, the invention es a pharmaceutical ition comprising a compound of formula (I) and another therapeutic agent(s). ally, the pharmaceutical ition may comprise a pharmaceutically acceptable excipient, as described above.

In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I).

In one embodiment, the kit comprises means for separately retaining said itions, such as a container, divided , or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of s, capsules and the like.

The kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for ing the separate compositions against one another. To assist compliance, the kit of the invention lly comprises directions for administration.

In the combination therapies of the invention, the nd of the ion and the other therapeutic agent may be manufactured and/or ated by the same or different cturers. Moreover, the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the ation product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, 9.9. during sequential administration of the compound of the invention and the other therapeutic agent.

Accordingly, the invention provides the use of a compound of formula (I) for treating a e or condition mediated by tankyrase inhibition wherein the medicament is prepared for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or condition ed by tankyrase inhibition, wherein the ment is administered with a compound of formula (I).

The invention also provides a compound of formula (I) for use in a method of treating a disease or ion mediated by tankyrase inhibition, wherein the compound of formula (I) is prepared for administration with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by tankyrase inhibition, wherein the other therapeutic agent is prepared for administration with a compound of formula (I). The invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by tankyrase inhibition, wherein the compound of formula (I) is stered with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by tankyrase tion, wherein the other therapeutic agent is administered with a compound of formula (I).

The invention also provides the use of a nd of formula (I) for treating a disease or condition mediated by tankyrase inhibition, wherein the patient has previously (e.g. within 24 hours) been d with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or condition WO 08217 mediated by tankyrase inhibition, wherein the patient has previously (e.g. within 24 hours) been treated with a nd of formula (I).

In one embodiment, the other therapeutic agent is selected from selected from the group of, but not limited to Hedgehog antagonists, PI3K inhibitors, MEK inhibitors, tyrosine kinase inhibitors, alkylating agents, etabolites, microtubule inhibitors, telomerase inhibitors, PARP inhibitors, and RAF inhibitors.

An example of a Hedgehog antagonist is 2-chloro-N-[4-chloro—3-(2— pyridinyl)phenyl]-4—(methylsulfonyl)- benzamide (also known as GDC-0449, and described in PCT Publication No. WO 06/028958).

Some examples of P|3K inhibitors include: 4-[2-(1H-Indazoly|)[[4- (methylsulfonyl)piperazinyl]methyl]thieno[3,2-d]pyrimidinyl]morpholine (also known as GDC 0941 and described in PCT Publication Nos. WO 09/036082 and WO 730) and 2—Methyl-2—[4—[3-methyl-2—oxo(quinolinyl)-2,3-dihydroimidazo[4,5— c]quinolinyl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in PCT Publication No. WO 06/122806).

An example of a Mitogen-activated protein kinase kinase (MEK) inhibitor is XL- 518 (Gas No. 10298724, available from ACC Corp.).

Some examples of tyrosine kinase inhibitors include: Erlotinib hydrochloride (sold under the trademark Tarceva® by Genentech/Roche), Linifanib (N-[4-(3-amino-1H- indazolyl)phenyl]-N'-(2-fluoromethylphenyl)urea, also known as ABT 869, available from Genentech), sunitinib malate (sold under the tradename ® by Pfizer), bosutinib (4-[(2,4-dichloromethoxyphenyl)amino]methoxy[3-(4—methylpiperazin- 1-yl)propoxy]quinolinecarbonitrile, also known as SKI-606, and bed in US Patent No. 6,780,996), dasatinib (sold under the tradename l® by Bristol-Myers ), nib (also known as ArmalaTM sold under the tradename Votrient® by GIaxoSmithKIine), and imatinib and imatinib mesylate (sold under the ames Gilvec® and Gleevec® by Novartis).

Some examples of ting agents include: temozolomide (sold under the tradenames Temodar® and Temodal® by Schering-Plough/Merck), dactinomycin (also known as actinomycin-D and sold under the tradename en®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexalen®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Myleran®), carboplatin (sold under the ame Paraplatin®), lomustine (also known as CCNU, sold under the tradename CeeNU®), cisplatin (also known as CDDP, sold under the ames Platino|® and Platinol®-AQ), chlorambucil (sold under the tradename Leukeran®), cyclophosphamide (sold under the tradenames n® and Neosar®), dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the tradename DTlC-Dome®), altretamine (also known as hexamethylmelamine (HMM) sold under the ame Hexalen®), ifosfamide (sold under the ame lfex®), procarbazine (sold under the tradename ne®), mechlorethamine (also known as nitrogen mustard, e and mechloroethamine hydrochloride, sold under the tradename Mustargen®), streptozocin (sold under the tradename Zanosar®), thiotepa (also known as thiophosphoamide, and TESPA and TSPA, sold under the tradename Thioplex®.

Some examples of Anti-metabolites e: claribine (2-chlorodeoxyadenosine, sold under the tradename leustatin®), 5-fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (sold under the tradename Purinetho|®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar—U®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCytTM), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, DroxiaTM and lTM), abine (sold under the tradename Fludara®), floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradename LeustatinTM), methotrexate (also known as amethopterin, methotrexate sodim (MTX), sold under the tradenames Rheumatrex® and TrexallTM), and pentostatin (sold under the tradename Nipent®).

Some examples of microtubule inhibitors are vinorelbine (sold under the trade name Naveibine®), vindesine (sold under the trade name ne®), estramustine (sold under the trade name Emcyt®), vincristine (Oncovin®), triclabendazole (Egaten®), secnidazole, quinfamide, podophyllotoxin, mebendazole, griseofulvin, flubendazole, in, colchicine, ciclobendazole, cabazitaxel, albendazoie, and vinorelbine.

An example of a telomerase inhibitor is imetelstat.

Some examples of PARP tors include: olaparib (from Astrazeneca), iniparib (also known as BSl—201) , AG014699 (Pfizer), veiiparib (also known as ABT-888 from Enzo), and MK4827 (Merck).

Some examples of RAF inhibitors include: 2-ChIoro[2-PhenyI(4-pyridinyl)- 1H-imidazolyl]phenol (also known as L-779450), 3-(dimethylamino)-N-[3-[(4— hydroxybenzoyl)amino]methylphenyl]-benzamide (also known as ZM-336372) and sorafenib ted as r® by Bayer).

Intermediates and Examples The following es are intended to be illustrative only and not limiting in any way.

Abbreviations used are those conventional in the art or the following: AcOH acetic acid BOC ry butylcarboxy C s d doublet dd doublet of doublets DCM dichloromethane DIEA diethylisopropylamine DME 1,4-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxide EtOAc ethyl acetate EtOH ethanol EDCL 1-ethyl(3'-dimethylaminopropyl)carbodiimide 9 gram h hour(s) HBTU 1-[bis(dimethylamino)methylene]-1 H-benzotriazoliumhexafluorophosphate(1-) 3- oxide HOBt 1-hydroxyazabenzotriazole HPLC high pressure liquid chromatography IR ed spectroscopy kg kilogram L liter LCMS liquid chromatography and mass spectrometry MTBE methyl tert butyl either MeOH methanol MS mass spectrometry MW microwave m multiplet min minutes mL milliliter(s) uM micromolar m/z mass to charge ratio nm nanometer 2012/053613 nM nanomolar N normal NMR nuclear magnetic resonance Pa pascal Pd/C palladium on carbon rac c RP-HPLC reverse phase-high re liquid chromatography 3 singlet t triplet TEA triethylamine TLC thin layer chromatography TFA trifluoroacetic acid THF tetrahydrofuran Intermediate 1 4-Oxo-tetrahydro-pyrancarboxylic acid methyl ester 0 O 65*? To a solution of tetrahydro-pyranone (1.3 kg, 12.98 mol) and carbonic acid dimethyl ester (11.69 kg, 129.8 mol) was added solid potassium utoxide (1.89 kg, 16.08 mol) in portions at -10°C over 2 h under en protection. The suspension was stirred at room temperature 10 h after the addition. LCMS (215nm) indicated that tetrahydro-pyran- 4-one had been completely consumed. The reaction was acidified by HCI (2 N) to pH 6~7 and then the phases were separated. The organic phase was washed with water (3 Lx2) and the combined aqueous phases were extracted with MTBE (2.5 Lx2). The combined organic phase was concentrated under reduced pressure at 25°C to remove most of MTBE. The e was distilled out by oil pump (~200 Pa) at 74 °C to give the title compound as colorless oil (545 g, 26.3%). CHN analysis: calculated (results). C 53.16 (53.10), H 6.37 (6.245), N 0.00 (0.00).

Intermediate 2 2-Chloro-acetamidine HZNJK/CI W0 2013/008217 Sodium (18.39, ol) was completely dissolved in 2 L of MeOH at 25 °C and stirred for 1 hour. To the solution was then added chloro-acetonitrile (600 g, 7.95 mol) dropwise in 1 hour under the protection of N2. After being stirred at about 20 °C for an additional hour, NH4CI (514 g, 8.73 mol) was added in ns over 45 minutes (the solution turned to yellow and then red, and then a black liquid was obtained), the reaction mixture was then allowed to stir at 15-20 °C for 16 hours. After tion, the filtrate was concentrated to give a residue, which was triturated with MTBE (1 L x 2) to give the title compound as a black solid (988 g, 96%).

Intermediate 3 2-Chloromethyl-3,5, 7,8-tez‘rahydro—pyrano[4, 3-d]pyrimidin-4—one 0 NH I N/J\/Cl A mixture of crude 4-oxo-tetrahydro-pyrancarboxylic acid methyl ester (1780 g, 11 mol) and triethylamine (830 g, 8.2 mol) in MeOH (3560 mL) was cooled to 0°C under N2.

A solution of 2-chloro-acetamidine (567 g, 4.4 mol) in 890 mL of MeOH was added dropwise over 50 minutes. The reaction mixture was stirred at 0°C for 30 minutes and then at about 20°C for 16 hours. LCMS at 215nm and TLC (DCM:MeOH=10:1) analysis showed that most of 4-oxo-tetrahydro-pyrancarboxylic acid methyl ester was consumed. The mixture was then filtered and concentrated to give black oil, which was uently purified by flash column chromatography on silica gel and eluted with DCM to give yellow solid/oil mixture, which was further triturated with MTBE (~1200 mL) and H20: CH3CN: EA=1:1:2 (~600 mL) to give the title compound as a white solid (318 9).

MS m/z 201.2 (M+H). CHN analysis: calculated (results). C 47.89 (47.95), H 4.52 ), N 13.96 (13.76).

Intermediate 4 Bis-(2-bromo-ethyl)-carbamic acid ethyl ester BrNNwBr To a stirred on of bis-(2-bromo-ethyl)-amine (1 g, 3.21 mmol) in water (10 mL) at 0°C was added ethyl chloroformate (0.293 mL, 3.08 mmol) and then NaOH (4.01 mL, 8.02 mmol), and stirred for 10 min at 0°C. The on mixture was acidified by 2 N HCI to pH 5, and extracted three times with 20 mL of ethyl acetate, dried over Na2804 and concentrated in vacuo. The crude product was purified by flash tography (gradient of 85:15 to 70:30 heptane/ethyl e in 30 min) to give the title compound (287 mg, 0.947 mmol, 29.5 % yield). MS calculated for C7H14Br2N02 304.0, found (ESI) m/z 304.2 (M+H)", retention time 0.56 min.

Intermediate 5 Ethyl 5-fluorooxo- 1,3—dihydrospiro[indene-2,4 ’-piperidine]- 1 '-carboxylate \_:>‘"NC><:I::LF To a stirred solution of 5-fluoroindanone (302 mg, 2.013 mmol) and bis-(2-bromo- ethyl)-carbamic acid ethyl ester (610 mg, 2.01 mmol) in DMF (5 mL) at 50°C was added NaH (121 mg, 5.03 mmol) by small portions. After being stirred at 50°C for 16 hr, the reaction was cooled to 25°C. The on was diluted with 15 mL of ethyl acetate and washed twice with 10mL of water, dried over NaZSO4 and concentrated in vacuo. The crude product was purified by flash column (gradient of 85:15 to 60:40 heptane/ethyl acetate in 20 min to give the title compound (188 mg, 0.645 mmol, 32.1 % yield). MS (ESI) [m/e, (M+H)+] = 292.4. HPLC retention time = 1.46 minutes (Agilent 1100 HPLC system; 3.0 cm x 3.0 mm x 3.0 um C8 column; flow rate of 2.0 mL/ min; gradient of 5- 95% acetonitrile / water with 0.1% formic acid over 2 s).

Intermediate 6 -Fluorospiro[indene-2,4'-piperidin]- 1 (3H)-one mod)F To a stirred solution of ethyl 5—fluorooxo-1,3-dihydrospiro[indene-2,4'—piperidine]—1'- carboxylate (188 mg, 0.645 mmol) in HCI (19.61 uL, 0.645 mmol) was heated at 100°C over night. The on mixture was trated to dryness t any further purification to give the title compound (160 mg, 97% yield). MS (ESI) [m/e, (M+H)*] = 220.0 (M+H)*, HPLC retention time = 0.51 minutes (Agilent 1100 HPLC system; 3.0 cm x 3.0 mm x 3.0 um C8 column; flow rate of 2.0 mL / min; gradient of 5-95% acetonitrile/ water with 0.1% fomic acid over 2 minutes).

Intermediate 7 2,2-Diallyl—5—mez‘hoxy-indanone W0 2013/008217 To a stirred solution of 5-methoxyindanone (5.24 g, 32.3 mmol) and allyl bromide (9.77 g, 81 mmol) in DMF (80 mL) at ambient temperature was added NaH (3.23 g, 81 mmol) by small portions. After being stirred for 10 min, the reaction mixture was stirred at 50 °C for 8 h, the reaction solution was cooled to ambient temperature, then diluted with 15 mL of EtOAc and washed twice with water (10 mL). The organic phase was dried with anhydrous Na2804 and concentrated in vacuo. The crude product was purified by flash column (gradient of 85:15 to 60:40 heptane/ethyl acetate in 20 min) to give the title compound (6.72 g, 27.7 mmol) as colorless . MS (ESI) [m/e, (M+H)* = 243.7.

Retention time 1.79 min (Agilent 1100 HPLC ; 3.0 cm x 3.0 mm x 3.0 um C8 column; flow rate of 2.0 mL / min; nt of 5-95% acetonitrile / water with 0.1% formic acid over 2 minutes).

Intermediate 8 2,2-(5—Methoxy— 1-0xo-2,3-dihydro-1H-indene-2,2-diyl) a/dehyde :/\ 0/ A solution 2,2-diallylmethoxy-indanone (600 mg, 2.5 mmol) in CH2CI2 (10 mL) was bubbled with 0;; at - 78 °C for 10 min, then with N2 to remove excess 03. To the reaction solution was added PS-PhaP (2.75 mg, 4.95 mmol, 1.8 mmol/g) at -78 °C. After being stirred at ambient temperature for 1 hr, the reaction e was filtered. The te was concentrated in vacuo to give the title compound (535 mg, 2.17 mmol) used without purification in the next step. 1H NMR (400 MHz, MeOD) 8 ppm 9.61 (s, 2 H), 7.64 (d, J=8.6 Hz, 1H), 6.84 (m., 2 H), 3.81 (s, 3 H), 3.09 (s, 2H), 2.80 (dd, J=69.2 Hz, J=17.7 Hz, 4 H).

Intermediate 9 (S)Methoxy-1 '-(2-oxopyrro/idinyl)spiro[indene-2,4 '-piperidin]— 1(3H)-one A solution of 2,2-(5-methoxyoxo-2,3-dihydro-1H-indene-2,2-diyl) aldehyde (100 mg, 0.406 mmol), (S)aminopyrrolidin—2-one (41 mg, 0.41 mmol) and Pd(OH)2 (3 mg, 0.02 mmol) in MeOH (2 mL) was stirred under H2 from a balloon at ambient temperature for 5 h. The reaction e was filtered. The filtrate was trated. The crude product was purified by HPLC (Column: Sunfire Waters 50x50mm; mobile: acetonitrile % / H20 80% with 0.1% TFA to acetonitrile 50% / H20 50% in 10 min gradient, Flow rate: 65ml / min) to give the title compound (33 mg, 0.11 mmol). MS (ESI) [m/e, (M+H)* = 315.1. retention time = 0.64 min (Agilent 1100 HPLC system; 3.0 cm x 3.0 mm x 3.0 um C8 column; flow rate of 2.0 mL / min; gradient of 5-95% acetonitrile / water with 0.1% 1O formic acid over 2 minutes). 1H NMR (400 MHz, CDCI3) 8 ppm 7.58 (d, J=8.6 Hz, 1 H), 7.28 ( s, 1H), 6.86 (d, J=8.6 Hz, 1 H,), 6.80 (3., 1 H), 4.23 (t, J=9.1 Hz, 1H), 4.05 (br,s, 1H), 3.48 (m, 1H), 3.82 (s, 3H), 3.73 (s, 1H), 3.46 (m, 2H), 3.30 (br, s, 1H), 2.97 (s, 2H), 2.52 (m, 2H), 2.04 (br,s, 4H).

Intermediate 10 4-(4-Methoxymethyl—benzoyl)-piperidinecarboxylic acid tert-butyl ester O O A stirrred solution of 4-(methoxy—methyl-carbamoyl)—piperidinecarboxylic acid tert-butyl ester (3.0 g, 11.02 mmol) in 30 mL THF was cooled to 0°C, then (4-methoxy methylphenyl)magnesium bromide (6.21 g, 27.5 mmol) was added dropwise via a syringe under N2 and the reaction mixture was stirred at the same temperature for 1.5 h, then gradually warmed up to room temperature over 1 h when the reaction was judged complete by LCMS. To the reaction mixture was slowly added 40 mL of saturated aqueous NH4CI then the aqueous solution was extracted with ethyl acetate (2 x 50 mL).

The combined c phases were washed with brine, dried over NaQSO4 and the solvent was removed to yield the crude t. cation by flash chromatography gave the title compound as a white solid (1.97 g, 5.62 mmol, 51% yield). MS (ESI) m/z 334.4 (M + W); HPLC ak 150 X 3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) retention time = 1.57 min. 1H NMR (400 MHz, CDCLS) 6 ppm 1.48 (s, 9 H) 1.62 - 1.91 (m, 4 H) 2.27 (s, 3 H) 2.78 - 3.02 (m, 2 H) 3.27 - 3.46 (m, 1 H) 3.91 (s, 3 H) 4.12 - 4.27 (m, 2 H) 6.87 (d, J=8.59 Hz, 1 H) 7.77 (t, J=8.10 Hz, 2 H).

Alternative procedure To a solution of 4-(methoxy-methyl-carbamoyl)-piperidinecarboxylic acid tert-butyl ester (5.0 g, 18.36 mmol) in 50 mL dry THF at ambient temperature was added (4- ymethylphenyl)magnesiUm bromide (55.1 mL, 0.5 M) was added dropwise under N2, the reaction mixture was stirred at the same ature for 16 hours. The reaction was quenched with saturated sodium sulfate solution (10 mL) and partitioned between brine (150 mL) and 10% isopropyl alcohol/chloroform (200 mL), and the organic layer was removed to yield the crude product. Purification by flash chromatography (silica: 5—35% ethyl acetate/pentane) gave the title compound as a white solid (6.4 g, 19.21 mmol, >99 % yield). HPLC (Novapak 150 X 3.9 mm C-18 column: mobile phase: -90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) retention time = 4.131 Intermediate 11 (4-Mefhoxymethyl-phenyl)-piperidin-4—yI-methanone HN O/ Trifluoroacetic acid (5.55 mL, 72.0 mmol) was added to a solution of 4-(4-methoxy—3- methyl-benzoyl)-piperidinecarboxylic acid utyl ester (4.8 g, 14.4 mmol) in romethane (100 mL) and water (10 mL) and allowed to stir for 4 hours at room temperature. The reaction was concentrated under reduced pressure, dissolved in chloroform (200 mL), washed with a saturated sodium bicarbonate solution, dried over M9804 and the solvent was evaporated in vacuo to yield the crude product which was used crude in the next step (white . Calculated molecular formula = N02 = 233.3130, found MS (ESI) m/e 234.4 (M + H+); 1H NMR (400 MHz, CDCla) 8 ppm 1.22 (d, J=6.57 Hz, 6 H) 1.64 - 1.77 (m, 2 H) 1.83 (d, J=1.52 Hz, 2 H) .08 (br. s, 2H) 2.26 (s, 3 H) 2.79 (td, J=12.38, 3.03 Hz, 2 H) 3.21 (dt, 3, 3.79 Hz, 2 H) 3.33 - 3.44 (m, J=11.18, 11.18, 3.79, 3.66 Hz, 1 H) 3.91 (s, 3 H) 4.03 (dq, J=6.32, 6.15 Hz, 0.5 H) 6.87 (d, J=8.59 Hz, 1 H) 7.83 (dd, J=8.59, 2.53 Hz, 1 H) 7.77 (d, J=2.02 Hz, 1 H). Analytical RP-HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.444 min.

Alternative procedure 1 4-(4-methoxymethyl-benzoyl)-piperidinecarboxylic acid tert-butyl ester (6.4 g, 19.21 mmol) was treated with 90% trifluoroacetic acid/water (100 mL) and allowed to stir for 30 minutes at room temperature. The reaction was concentrated under reduced pressure, dissolved in 10% isopropanol/chloroform (200 mL), washed w/ saturated sodium bicarbonate solution, dried over MgSO4 and the t was removed to yield the crude product which was used crude in the next step (white solid). Calculated molecular formula = C14H19N02 = 233.3130, found MS (ESI) m/e 234.4 (M + H*); 1H NMR (400 MHz, form-d) Analytical RP-HPLC (Novapak 150 X 3.9 mm C18 : mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.514 min.

Alternative procedure 2 A suspension of 1-(4-(4-methoxy-S-methylbenzoyl)piperidinyl)ethanone (5.45 g, 19.8 mmol) in 6 N HCl (40 mL) was heated to reflux for 12 h then concentrated in vacuo to a light purple solid. The material was taken up in ~100 mL MeOH with heating and sonication, concentrated in vacuo to ~25 mL, added diethyl ether (~200 mL) to form white precipitate and a purple aqueous layer. The s layer was removed via a pipet and concentrated in vacuo. The suspension was decanted through filter to recover a white solid (1.30 g). The s material was concentrated in vacuo to form a purplish oil which was taken up in diethyl ether and the resulting suspension was filtered (0.82 g). The filtrate was concentrated in vacuo to a purple oil. The solid material was confirmed to be the title nd. Calculated molecular a = N02= 233.31, found MS (ESI) m/e 233.9 (M + H”) Intermediate 12 4-Phenylsulfanylcarbonyl-piperidinecarboxylic acid tert-butyl ester XO NOASPh for To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (5.0 g, 21.81 mmol), diisopropylethylamine (5.64 g, 43.6 mmol) in 40 mL of Dmolecular a were added HATU (9.2 g, 24.0 mmol) and benzenethiol (2.7 g, 24.0 mmol). The reaction mixture was stirred at ambient temperature for 15 hours. The reaction mixture was quenched with water (50 mL), then extracted with DCM (50 mL). The combined organic layers were washed with water and saturated aqueous NaCl solution, dried over NaQSO4, filtered and concentrated in vacuo to yield the crude product. (6.85g, 20.25 mmol) as a yellow oil. MS (ESI) m/z 321.8 (M + H”); HPLC (Novapak 150 X 3.9 mm C-18 column: W0 2013/008217 mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) retention time = 1.66 min.

Intermediate 13 methanesulfonic acid oxo-pyrrolidinyl ester HN 7,.HOMS To a stirred mixture of (R)—3-hydroxypyrroIidin-Z-one (19.5 g, 193 mmol) and triethylamine (90 mL) at 0°C was added a solution of methanesulfonic anhydride (33.6 g, 193 mmol) in DCM (90 mL) over 35 minutes maintaining an internal temperature below 5°C. After stirring at 0°C for 30 min the on was allowed to warm to room temperature and stirred for an additional 18 h and then concentrated in vacuo. This material was combined with 12 g crude material from previous batches and then purified via silica gel chromatography to yield 35 g of the title compound. ediate 14 methanesulfonic acid (S)oxo—pyrrolidin—3-yl ester HwaCl To a 10°C solution of (S)—3-hydroxypyrrolidin—2—one (120 g, 1.19 mol) in pyridine (38.4 mL, 475 mmol) and dichloromethane (3 L) at 10°C was added thionyl chloride (173 mL, 2.37 mol) se and the reaction was stirred for an additional 3 h. The reaction was concentrated in vacuo, taken up in dichloromethane and purified by filtering through a plug of silica gel, eluting with 10 L ethyl e. The material was concentrated in vacuo to approximately 1 L, diluted with 1.5 L l ether and heated gently for 15 min. The suspension was filtered, washed with diethyl ether (500 mL), dried in vacuo, taken up in diethyl ether (1 L) and heated at 45°C then filtered to afford 105 g of the title nd as a white solid.

Intermediate 15 Methanesulfonic acid 2-oxo-piperidinyl ester Hktj/OMS WO 08217 PCT/IBZOIZ/0536l3 To a suspension of 3-hydroxy-piperidin—2-one (500 mg, 4.34 mmol, 1.0 eq) and triethylamine (0.908 mL, 6.51 mmol, 1.5 eq) in dichloromethane (3 mL) at 0°C was added se methanesulfonyl chloride (497 mg, 4.34 mmol, 1.0 eq) dissolved in dichloromethane (1 mL). The reaction was complete within 30 min as judged by LCMS.

An orange precipitate was filtered, redissolved in dichloromethane and purified by column chromatography (MeOH/CHQCIQ) to give the title compound as a white waxy solid (204 mg, 1.056 mmol, 24.3% yield). 1H NMR (400 MHz, form-d) 8 ppm 5.78 (br. s, 1 H) 4.94 - 5.05 (m, 1 H) 3.30 - 3.44 (m, 2 H) 3.27 (s, 3 H) 2.24 - 2.37 (m, 1 H) 2.08 - 2.21 (m, 1 H) 1.98 — 2.08 (m, 1 H) 1.79 - 1.96 (m,1 H) MS (m/z, MH+): 193.7 Intermediate 16 3—[4—(4-Methoxy—benzoyI)-piperidinyl]—pyrrolidin-2—one 0 CW1 In a 1 L round bottom flask was added methanesulfonic acid (S)—2-oxo-pyrrolidinyl ester red according to procedure in Eur. Pat. Appl., 257602, 02 Mar 1988) (95 mmol, 17 g) and hoxy-phenyl)-piperidiny|—methanone (95 mmol, 20.8 g) in DIEA (379 mmol, 66.3 mL). The reaction mixture was heated at 85°C for 18 hours. The top layer was decanted off and silica gel flash column chromatography was performed on the remaining residue eluting with ethyl acetate to 20% MeOH/ethyl acetate to provide the title compound as a light beige solid (13 g, 49% yield). Calculated M8 = 302.4, found MS (ESI) m/e 303.4 (M + W); 1H NMR (400 MHz, MeOD) 8 ppm 1.69 - 1.89 (m, 4 H) 2.11 - 2.18 (m, 1 H) 2.18 - 2.30 (m, 1 H) 2.50 (td, J=11.29, 3.01 Hz, 1 H) 2.78 (td, J=11.54, 3.01 Hz, 1 H) 2.84 - 2.91 (m, 1 H) 3.13 (d, J=11.54 Hz, 1 H) 3.24 - 3.41 (m, 7 H) 3.49 (t, J=8.78 Hz, 1 H) 7.01 (d, J=9.00 Hz, 2 H) 7.96 (d, J=9.03 Hz, 2 H); HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.305 min.

Intermediate 17 4--(-4 Methoxy-benozoyl))-[1 3']bipiperidinyl——2'--one ..ng To a solution of methanesulfonic acid 2-oxo-piperidinyl ester (250 mg, 1/294 mmol, 1.0 eq) and (4-methoxy-phenyl)—piperidin-4—yl-methanone (312 mg, 1.423 mmol, 1.1 eq) in acetonitrile (2.5 mL) was added diisopropylethylamine (351 mg, 0.475 mL, 2.1 eq) and the reaction was heated at 85 °C for 3 hours. The reaction was cooled to room temperature and the solvent evaporated in vacuo. The resulting oily residue was purified by silica gel column chromatography (MeOH/CHQCIQ) to give the title compound as a clear oil (142 mg, 0.449 mmol, 34.7% yield). 1H NMR (400 MHz, s) 8 ppm 7.95 (d, J=9.09 Hz, 2 H) 7.39-7.43 (br. s, 1 H) 7.04 (d, J=8.59 Hz, 2 H) 3.84 (s, 3 H) 3.23 - 3.33 (m, 2 H) 2.97 - 3.14 (m, 4 H) 2.74 - 2.85 (m, 2 H) 1.75 - 1.91 (m, 2 H) 1.57 — 1.75 (m, 4 H) 1.47-1.54 (m, 2 H). MS (m/z, MH+): 316.8 Intermediate 18 (S)[4-(4-Methoxy—benzoyl)-piperidiny/]-pyrro/idin-2—one HNp"! N \ To a suspension of (4-methoxyphenyl)(piperidinyl)methanone (34 g, 155 mmol) and (R)—2-oxopyrrolidinyl esulfonate (34.7 g, 194 mmol) in acetonitrile (388 mL) at room temperature was added DIPEA (108 mL, 620 mmol) and the reaction was heated to 60 C for 29 h then allowed to cool to room ature and stirred for an additional 24 h. The reaction mixture was trated in vacuo to afford a waxy solid which was taken up in ethyl e (300 mL) and sonicated. The mixture was filtered and the resulting white solid was washed with ethyl acetate (200 mL) to yield 21.05 g. The combined filtrates were concentrated and purified via silica gel chromatography (330 g isco 0.01% NH4OH 5-10% MeOH/ethyl acetate). Pure ons were combined, concentrated in vacuo and then taken up in ethyl acetate (80-100 mL) and stirred. A white precipitate formed that was collected by filtration. The filtrate was concentrated to a gold oil, taken up in ethyl acetate to afford a white precipitate that was collected by filtration. A total of 27.7 g of the title material was obtained as a white solid. Calculated M8 = 302.4, found MS (ESI) m/e-303.4 (M + H’“) Intermediate 19 (R)-3—[4-(4-Methoxy—3-methyI-benzoyI)-piperidinyl]-pyrrolidinone 2012/053613 H6_‘\\N / In a 1 L round bottom flask was added methanesulfonic acid (S)oxo-pyrrolidinyl ester (prepared according to procedure in Eur. Pat. Appl., 257602, 02 Mar 1988) (18.75 mmol, 3.36 g) and (4-methoxymethyl-phenyl)—piperidin—4-yl-methanone (18.75 mmol, 4.37 g) in DIEA (75 mmol, 13.1 mL) and itrile (100 mL). The reaction mixture was heated at 85°C for 4 hours. The reaction was ated under a vacuum and silica gel flash column chromatography was performed on the remaining residue eluting with ethyl acetate to 20% MeOH/ethyl acetate to e the title compound as a white solid (4 g, 67.4% yield). Calculated for C18H24N203 M8 = 316.4036, found MS (ESI) m/e 317.1863 (M + H+)j1H NMR (400 MHz, MeOD) 5 ppm 1.69 — 1.89 (m, 4 H) 2.08 - 2.21 (m, 1 H) 2.24 - 2.30 (m, 1 H) 2.44 — 2.56 (m, 1 H) 2.73 — 2.84 (m, 1 H) 2.84 - 2.92 (m, 1 H) 3.08 — 3.17 (m, 1 H) 3.30 - 3.42 (m, 6 H) 3.45 — 3.54 (m, 1 H) 3.90 (s, 3 H) 6.95 — 7.04 (m, 1 H) 7.72 — 7.81 (m, 1 H) 7.83 — 7.90 (m, 1 H); analytical RP-HPLC retention time = 4.67 min.

Intermediate 20 (S)~3-[4-(4-Methoxy—B-methyl—benzoyl)-piperidiny/]-pyrrolidin-2—one m5N / In a 1 L round bottom flask was added methanesulfonic acid (R)oxo-pyrrolidinyl ester (19.72 mmol, 3.53 g) (4-methoxy—3-methyl-pheny|)-piperidin-4—yl-methanone (19.72 mmol, 4.60 g) in DIEA (79 mmol, 13.8 mL) and acetonitrile (75 mL). The reaction mixture was heated at 85°C for 13 hours. The reaction was evaporated under a vacuum and silica gel flash column tography was performed on the remaining residue eluting with 5% MeOH/ethyl acetate to 20% MeOH/ethyl e to provide the title compound as a white solid (4.6 g, 73.7% yield). Calculated for C18H24N203 MS = 316.4036, found MS (ESI) m/e 317.1876 (M + W); 1H NMR (400 MHz, CDCls) 8 ppm 1.82 - 1.97 (m, 4 H) 2.15 - 2.36 (m, 5 H) 2.48 - 2.59 (m, 1 H) 2.90 - 3.04 (m, 2 H) 3.07 - 3.15 (m, 1 H) 3.23 - 3.44 (m, 3 H) 3.48 - 3.56 (m, 1 H) 3.91 (s, 3 H) 6.08-6.13 (br. s, 1 H) 6.85 (s, 1 H) 7.77 (s, 1 H) 7.83 (dd, J=8.53, 2.01 Hz, 1 H), analytical RP-HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.557 min.

Intermediate 21 4-FIuoro-benzoyl)-piperidinyl]—pyrrolidin0ne . CW1 HNfi/N F To a 10 mL microwave vial was added methanesulfonic acid (S)—2-oxo-pyrrolidinyl ester (4.97 mmol, 890 mg) and (4-fluoro-phenyl)-piperidinyl-methanone hydrochloride (4.97 mmol, 1.21 g) in DIEA (24.8 mmol, 5 mL) was heated to 85°C for 105 min. The DIEA was ed and flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate afforded the title compound (1 12 mg, 7.8% yield). MS (ESI) m/e 291.2 (M + W), calculated 290.33; HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2mL/min over 5 min.) retention time = 2.303 min.

Intermediate 22 3-[4-(4-Chloro-benzoyI)-piperidinyI]-pyrrolidinone HN50GAO A 10 mL microwave vial ning methanesulfonic acid oxo-pyrrolidinyl ester (0.56 mmol, 100 mg) and (4-chloro-phenyl)-piperidinyl-methanone (0.56 mmol, 125 mg) in DIEA (2.8 mmol, 0.5 mL) was heated to 85°C for 105 min. The diisopropylethylamine was decanted off and flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate afforded the title compound (53 mg, 31% yield). MS (ESI) m/e 307.3 (M + H“), calculated 306.2; HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2mL/min over 5 min.) retention time = 2.506 min. ediate 23 -methoxy- 1 '-(2-oxopyrrolidinyl)spiro[indene-2,4 '-pl;oeridin]- 1(3H) -one HN: rN O/ WO 08217 To a 250 mL round bottom flask was added methanesulfonic acid (S)oxo-pyrrolidin yl ester (2) (4.76 mmol, 852 mg) and 5-methoxyspiro[indene-2,4'-piperidin]-1(3H)-one (3) (4.32 mmol, 1.00 g) in DIEA (17.29 mmol, 3.02 mL) and acetonitrile (20 mL). The solution was then heated to 85°C for 90 min. The reaction was concentrated in vacuo and flash column chromatography (silica) was med g with ethyl acetate to % MeOH/ethyl acetate afforded the title compound (1.05 g, 77% yield). Calculated M8 = 306.2, found MS (ESI) m/e 307.3 (M + H+); HPLC ak 150 X 3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2mL/min over 5 min.) retention time = 2.253 min.

Intermediate 24 momethyl)chlorobenzonitrile To a solution of 2-chloromethylbenzonitrile (2.0 g, 13 mmol) and N-bromosuccinimide (2.6 g, 15 mmol) in carbon tetrachloride (20 mL) was added azobisisobutyronitrile (0.20 g, 1.2 mmol). The mixture was refluxed for 3 h and then cooled, diluted with dichloromethane and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resultant oil was purified via flash column chromatography (ethyl acetaterhexane, 0:100 to 30:70) to yield white solid product (1.4 g, 46%). 1H NMR (400 MHz, CDCIs) 8 7.43 - 7.59 (m, 3 H), 4.64 (s, 2 H).

Intermediate 25 2-(3-bromo-2—oxopyrro/idin— 1 —yl)acetonitrile N0”)? 0 Br To a solution of 2,4-dibromobutanoyl chloride (3.6 g, 14 mmol) in DCM (100 mL) and 2- aminoacetonitrile hydrochloride (1.3 g, 14 mmol) was added triethylamine (5.7 mL, 41 mmol) at 0°C. The mixture was stirred at ambient temperature for 24 h. To the resulting material was added methylene chloride and it was washed with water and then brine.

The combined organic layers were dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The ing residue was taken up in toluene (130 mL) and at 0°C was added sodium hydride (545 mg, 13.6 mmol, 60% in mineral oil) portion-wise WO 08217 over 20 minutes. The reaction was d at ambient temperature for 60 h. The mixture was diluted with ethyl acetate and then poured into ice water. The organic layer was separated, washed with brine, dried over sodium sulfate, and purified via flash column chromatography (ethyl acetatezhexane, 0:100 to 100:0) to provide a brown oil (730 mg, 26% yield). 1H NMR (400 MHz, CDCla) 8 .50 (m, 2 H), 4.10-4.28 (m, 1 H), 3.70 (dq, J: 7.6, 2.0 Hz, 1 H), 3.51—3.59 (m, 1 H), 2.65-2.79 (m, J: 7.0 Hz, 1 H), 2.33-2.50 (m, 1 H).

Intermediate 26 2—(3-(4-(4-methoxybenzoy/)piperidin- 1 ~yl)oxopyrro/idin- 1 ~yl)acetonitrile N/b/N / N O To a solution of 2-(2-bromooxopyrrolidinyl)acetonitrile (730 mg, 3.6 mmol) and (4- methoxyphenyl)(piperidinyl)methanone hydrochloride (920 mg, 3.6 mmol) in acetonitrile (4 mL) was added triethylamine (1.5 mL, 11 mmol). The mixture was microwave at 130°C for 12 minutes. The solvent was d in vacuo and the residue was taken up in methylene chloride and water. The organic layer was ed via flash column chromatography (ethyl acetatezhexane, 10:90 to 100:0) to provide slightly yellow oil (950 mg, 74% yield). 1H NMR (400 MHz, CDCI3) 8 7.94 (d, J: 8.5 Hz, 2 H), 6.96 (d, J = 8.5 Hz, 2 H), 4.22—4.39 (m, 2 H), 3.90 (s, 3 H), 3.57 (dt, J: 22.6, 9.0 Hz, 2 H), 3.40— 3.51 (m, J: 8.5 Hz, 1 H), 3.23-3.39 (br s, 1 H), 2.93-3.20 (m, 3 H), 2.33-2.61 (m, 2 H), 2.13-2.31 (m, 1 H), 1.83-2.03 (m, 4 H). HRMS calculated for C19H23N303 342.1818, found (ESl, [M + H]*), 30.

Intermediate 27 2—(3-(4-(4-methoxybenzoyUp/peridinyI)oxopyrrolidinyl)acez‘imidamide hydrochloride {NM 0’ To a solution of 4-(4—methoxybenzoyl)piperidin-1—yl)oxopyrrolidinyl)acetonitrile (690 mg, 2.0 mmol) in methanol (15 mL) was added sodium methoxide (0.046 mL, 0.20 mmol, 25%) and the mixture was stirred at ambient temperature for 2 h. Ammonium WO 08217 l3 chloride (120 mg, 2.3 mmol) was added and the mixture was stirred at ambient temperature for 60 h. The on mixture was trated in vacuo, ethyl acetate in heptane (40%) was added, stirred at ambient temperature for 1 h then filtrated. the resulting solid was washed with ether to give a pale solid (800 mg, 100% yield). MS m/z 342.4 (M+1), retention time 0.79 Intermediate 28 2-(3-(4-(4-methoxybenzoyl)piperidinyl)oxopyrrolidiny/)acetonitrile (”9%O To a solution of 3-[4—(4—methoxy-benzoyl)-piperidinyl]-pyrrolidinone (1.65 mmol, 500 mg) and chloroacetonitrile (1.65 mmol, 0.125 g) in THF (30 mL) and DMF (5 mL) was added sodium hydride (60%, 2.48 mmol, 0.099 g) and heated to 70°C for 30 min. The on was allowed to cool to ambient temperature and dried under vacuum. Flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate and provided the title compound as an off-white residue (125 mg, 22.1% yield). Calculated MS = 341.4, found MS (ESI) m/e 342.9 (M + H“); HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10—90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.472 min.

Intermediate 29 {(S)[4-(4-Methoxymethyl-benzoyl)-piperidin- 1-yl]oxo-pyrrolidin- 1-y/}-acetonitrile ‘\3% To a solution of S()--[-(4(4--methoxy-methyl-benzoyl)-piperidin- 1-y|]—pyrrolidin--one (6.32 mmol, 2.0 g) and bromoacetonitrile (18.96 mmol, 2.275 g) in THF (60 mL) at 0°C was added sodium hydride (60%, 18.96 mmol, 0.76 g) and allowed to stir under N2 for 1 hour. Allowed to warm to ambient temperature and chloroacetonitrile (2 mL) was added.

After 30 min the reaction was cooled to 0°C and quenched with saturated ammonium de on. Flash column chromatography (silica) was performed eluting with 3% MeOH/ethyl acetate to 15% thyl acetate and provided the title compound as an own foam (1.6 g, 71.2% yield). Calculated molecular formula = 020H25N303 = 355.4406, found MS (ESI) m/e 356.6 (M + H“); analytical RP-HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) ion time = 2.831 min.

Intermediate 30 {(R)[4-(4-MethoxymethyI-benzoyl)-piperidiny/]oxo-pyrro/idin- 1-yl}-acez‘onitrile \\Nb‘‘0N / To a solution of (R)[4-(4-methoxy-3—methyl-benzoyl)-piperidiny|]-pyrro|idinone (6.32 mmol, 2.0 g) and chloroacetonitrile (6.32 mmol, 0.48 g) in THF (50 mL) was added sodium hydride (60%, 9.48 mmol, 0.38 g) and heated to 70°C for 30 min. The reaction was allowed to cool to ambient temperature and dried under vacuum. Flash column tography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate and provided the title compound as an off-white e (1.1 g, 49% yield).

Calculated molecular formula = C20H25N303 = 355.4406, found MS (ESI) m/e 356.1978 (M + H*); analytical RP-HPLC (Novapak 150 X 3.9 mm C18 : mobile phase: 10- 90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.591 ediate 31 2-{3—[4-(4—Methoxy-benzoyl)—piperidin-1—yl]—2-oxo-pyrrolidin— 1 -yl}-acez‘amidine “z”f“§”9bNH O 0’ To a solution of 2-(3-(4-(4-methoxybenzoyl)piperidin—1-y|)oxopyrrolidiny|)acetonitrile (125 mg, 0.366 mmol) in methanol (4 mL) was added sodium methoxide (2 mg, 0.037 mmol) and stirred at ambient temperature for 2 h. Ammonium chloride (23.5 mg, 0.439 mmol) was added and the mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated then ethyl acetate in pentane (1:1) was added and stirred at ambient temperature for 1 h. Filtration provided a solid that was washed with ether to give a pale solid (130 mg, 100%). MS m/z 360.0 (M+1), HPLC ak 150 X 3.9 mm C18 : mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.139 min.

Intermediate 32 2-{(S)[4—(4-Methoxymethyl-benzoyl)-piperidiny|]oxo-pyrrolidiny|}- acetamidine CIHHWCWOJE To a solution of({(S-[-44—(—m-ethoxy--3——methylbenzoyl)-piperidin- 1-yl]oxo-pyrrolidin y|}-acetonitri|e (1.60 g, 4.5 mmol) in methanol (40 mL) was added sodium methoxide (511 mg, 9.45 mmol) and d at 40°C for 3 hours. Ammonium chloride (265 mg, 9.45 mmol) was added and the mixture was stirred at 40°C ature for 2 h. The reaction mixture was concentrated then chloroform in ethyl acetate (volume of 1:2) was added and stirred at ambient temperature for 1 h. Centrifugation at 1500 rpm for 30 min. provided a beige solid (1.8 g, 98%). HRMS calculated for C20H29N403Cl 372.4712, found (ESI, [M + H]+), found 373.2242. 1H NMR (400 MHz, CDCIs-o) 8 ppm 1.75-1.98 (m, H) 2.19 - 2.40 (m, 7 H) 2.48 - 2.65 (m, 1 H) 2.76 - 3.01 (m, 3 H) 3.16 - 3.36 (m, 3 H) 3.46 - 3.64 (m, 3 H) 3.81 - 3.94 (m, 6 H) 4.34 (d, J=16.56 Hz, 1 H) 4.52 (d, 6 Hz, 1 H) 6.84 (d, J=8.53 Hz, 1 H) 7.28 (s, 1 H) 7.70 - 7.87 (m, 3 H) 8.51 (s, 1 H), HPLC (Novapak 150 X 3.9 mm C18 : mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.385 min.

Intermediate 33 Toluenesulfonic acid 7-oxo-cyclohepta-1,3,5-trienyl ester 0:3. o’ O The title material was synthesized according to the conditions found in Chem. Pharm.

Bull. 5_4(5), 703, (2006).

Intermediate 34 Ethyl 2—(2,4-dibromobutanamido)acetate NH/\[r Br 0 To a stirred mixture of ethyl 2-aminoacetate hydrochloride (1.568 g, 11.24 mmol) in dichloromethane (9 mL) and water (2 mL) at 0°C was added a solution of 2,4- dibromobutanoyl chloride (3.0 g, 10.21 mmol) in dichloromethane (2 mL). A solution of sodium hydroxide in water (11.5 M, 2 mL) was then added slowly. The reaction was stirred 1 hour at 0°C and then 15 minutes at room temperature. The reaction was then treated with dichloromethane (40 mL) and water (25 mL). The layers were separated, and the organic layer was brine—washed, dried over sodium sulfate, filtered, concentrated down, and dried under vacuum to afford the crude title racemic compound (3.165 g in 90% purity, 84% yield) as a clear oil. 1H NMR (400 MHz, chloroform-d) 8 ppm 6.81 (br s, 1 H), 4.58 (dd, J=8.84, 4.80 Hz, 1 H), 4.21 - 4.31 (m, 2 H), 4.07 (d, J=5.56 Hz, 2 H), 3.51 - 3.63 (m, 2 H), 2.62 - 2.75 (m, 1 H), 2.44 - 2.57 (m, 1 H), 1.28 - 1.36 (m, 3 H).

Intermediate 35 Ethyl 2-(3-bromooxopyrrolidin— 1 —y/)acetate OK,N?Br To a stirred on of crude ethyl 2-(2,4-dibromobutanamido)acetate (2.847 g, 8.60 mmol) in benzene (8.6 mL) at 5°C was added portionwise a 60% mineral oil dispersion (344 mg) of sodium hydride (206 mg, 8.60 mmol) over 20 minutes. The reaction was stirred an onal 10 minutes before being poured onto ice water and d with ethyl acetate. The layers were separated. The c phase was brine-washed, dried over sodium sulfate, filtered, concentrated down, and dried. The mixture of starting dibromide and product was purified by eluting through a silica gel column with a 0 to 100% ethyl acetate / heptane gradient to afford the title racemic compound (523 mg, 24% yield) as a clear oil. MS (ESl) [m/e, (M+H)+] = 251.5. 1H NMR (400 MHz, chloroform-d) 5 ppm 4.46 (dd, J=7.07, 3.03 Hz, 1 H), 3.96 - 4.28 (m, 4 H), 3.63 - 3.72 (m, 1 H), 3.43 - 3.53 (m, 1 H), 2.63 — 2.76 (m, 1 H), 2.34 - 2.43 (m, 1 H), 1.26 - 1.34 (m, 3 H). ediate 36 Ethyl 2-(3-(4-(4-methoxybenzoy/)piperidinyI)-2—oxopyrrolidin- cefate 139000“ (4-Methoxyphenyl)(piperidin-4—yl)methanone hydrochloride (524 mg, 2.05 mmol) was d at room temperature with triethylamine (0.657 mL, 477 mg, 4.71 mmol) in acetonitrile (80 mL). A solution of ethyl 2-(3-bromo—2-oxopyrrolidin—1-yl)acetate (513 mg, PCT/1B2012/053613 2.05 mmol) in acetonitrile (20 mL) was added to the mix. The reaction was d 3 hours at 40°C and then overnight at 50°C. After 24 hours the reaction was not complete and the reaction was stirred an additional 48 hours at 70°C then allowed to cool to room temperature. The solvents were d in vacuo. The crude orange solid was eluted through a silica gel column with a 0 to 10% methanol / dichloromethane nt to afford the title racemic compound (730 mg, 87% yield, 95% purity) as a thick amber oil. MS (ESI) [m/e, (M+H)+] = 389.5. 1H NMR (400 MHz, chloroform-d) 8 ppm 7.90 - 7.95 (m, 2 H), 6.91 - 6.96 (m, 2 H), 4.17 - 4.24 (m, 2 H), 3.95 - 4.17 (m, 2 H), 3.88 (s, 3 H), 3.56 3.64 (m, 1 H), 3.36 - 3.50 (m, 2 H), 3.18 - 3.29 (m, 1 H), 3.04 - 3.13 (m, 1 H), 2.93 - 3.04 1O (m, 2 H), 2.41 - 2.56 (m, 1 H), 2.20 - 2.35 (m, 1 H), 2.04 - 2.19 (m, 1 H), 1.80 - 1.95 (m, 4 H), 1.26 - 1.32 (m, 3 H).

Intermediate 37 2-(3-(4—(4-Methoxybenzoy/)piperidiny/)oxopyrrolidinyl)acetic acid o¢l\/N/P\l\| o\ To a solution of ethyl 2-(3-(4-(4—methoxybenzoyl)piperidinyl)oxopyrrolidin yl)acetate (727 mg, 1.778 mmol) in ethanol (36 mL) was added a 2 N aqueous NaOH on (1.8 mL). The mixture was stirred 1 hour at room temperature. The reaction was then neutralized to pH 7 with 1 N HCl. The solvents were removed in vacuo, then azeotroped 3 times with dichloromethane. The light yellow foamy solid was dried under high vacuum to afford the title racemic t (835 mg). MS (ESI) [m/e, (M+H)*] = 360.9. 1H NMR (400 MHz, DMSO-de) 6 ppm 7.89 - 8.01 (m, 2 H), 6.96 - 7.11 (m, 2 H), 3.85 (s, 3 H), 3.46 — 3.68 (rn, 2 H), 3.13 - 3.46 (m, 5 H), 2.93 - 3.04 (m, 1 H), 2.61 — 2.84 (m, 1 H), 2.30 - 2.42 (m, 1 H), 1.95 - 2.11 (m, 1 H), 1.81 -1.95(m, 1 H), 1.64 - 1.78 (m, 2 H), 1.44 - 1.63 (m, 2 H).

Intermediate 38 , 6-dihydrothiazolo[2,3-c][1,2,4]triazoIamine hydrobromide K/N/N_;<NNH2HBr.

The title compound was prepared in ance with the procedure exemplified in the ing citation: On triazoles XLVlll [1]. Synthesis of isomeric aminothiazolo[1,2,4]triazo|e, amino[1,2,4]triazolo[1,3]thiazine and -[1,3]thiazepine derivatives. Prauda, lbolya; Reiter, . Egis Pharmaceuticals Ltd., Budapest, Hung. Journal of Heterocyclic Chemistry (2003), 40(5), 6.

Intermediate 39 Ethyl 6-formyl-3,4-dihydro-2H-pyrancarboxylate 1O A mixture of ethyl 6-methyl-3,4-dihydro-2H-pyrancarboxylate (6.0 g, 35.3 mmol) and selenium dioxide (4.3 g, 38.8 mmol) was stirred in acetic acid (141 mL) 5 hours at 110°C.

The reaction was then cooled to room temperature and the solids were removed by filtration. The filtrate was concentrated down and purified by silica gel chromatography with 0 to 15% ethyl acetate / heptane gradient, ed by 15% to afford the title compound (1.710 g) as an amber oil in about 90% purity. MS (ESI) [m/e, (M+H)+] = 185.3. 1H NMR (400 MHz, chloroform-d) 8 ppm 10.22 (s, 1 H), 4.28 (q, J=7.24 Hz, 2 H), 4.12 - 4.19 (m, 2 H), 2.54 (t, J=6.57 Hz, 2 H), 1.88 - 1.98 (m, 2 H), 1.30 - 1.38 (m, 3 H).

Intermediate 40 3,4-Dihydro-2H-pyrano[2,3-d]pyridazin-5(6H)-one CgNH To a stirred 0°C mixture of ethyl 6-formyl—3,4-dihydro-2H-pyrancarboxylate (1.705 g, 9.26 mmol) in methanol (80 mL) was added very quickly 35% hydrazine hydrate (0.311 g, 9.72 mmol). After 20 s, the solvent was removed under reduced pressure, and the residue was treated with acetic acid (70 mL) and water (7 mL) and stirred at 110°C for 20 minutes. The solvents were d in vacuo. The crude residue was eluted by silica gel chromatography with a 0 to 25% gradient of methanol / dichloromethane to afford the title compound (1.384 g) as a light yellow solid in better than 90% purity. MS (ESI) [m/e, (M+H)*] = 153.2. 1H NMR (400 MHz, chloroform—d) 8 ppm 10.56 (br s, 1 H), 7.53 (s,1 H), 4.17 - 4.35 (m, 2 H), 2.57 (t, J=6.57 Hz, 2 H), 1.99 - 2.08 (m, 2 H).

Intermediate 41 -Ch/oro-3,4-dihydro-2H—pyrano[2,3—d]pyridazine hydro-2H-pyrano[2,3-d]pyridazin-5(6H)-one (400 mg, 2.63 mmol) was stirred in phosphorus oxychloride (4 mL, 6.58 g, 42.9 mmol) at 95°C for nearly 2 hours. The reaction was then cooled to room ature and excess phosphorus oxychloride was removed in vacuo. The residue was treated with ice (~15 g) and very slowly with solid potassium carbonate until pH > 7. A tan solid was isolated by filtration and dried under vacuum to afford the title compound (267 mg, 57% yield). MS (ESI) [m/e, (M)+] = 170.6. 1H NMR (400 MHz, chloroform-d) 8 ppm 8.68 (s, 1 H), 4.28 - 4.42 (m, 2 H), 2.78 (t, J=6.32 Hz, 2 H), 2.05 - 2.20 (m, 2 H).

Intermediate 42 N-(2,4-dimethoxybenzyl)-3,4-dihydro-2H-pyrano[2,3—d]pyridazinamine A mixture of 5-chloro-3,4-dihydro-2H-pyrano[2,3-d]pyridazine (150 mg, 0.879 mmol), N,N-diisopropylethylamine (0.154 mL, 114 mg, 0.879 mmol), and 2,4- dimethoxybenzylamine (294 mg, 1.76 mmol) in isopropanol (2 mL) was heated in a sealed tube 18 hours at 115°C and then 4.5 hours at 145°C before addition of excess 2,4—dimethoxybenzylamine (about 2 g, 12 mmol). The reaction was stirred at 145°C for 18 hours. After cooling to room temperature, isopropanol was removed in vacuo. The crude was then treated with diethyl ether (30 mL). A tan solid was removed by filtration.

The filtrate was washed twice with small amounts of saturated aqueous ammonium chloride. The organic layer was dried over sodium sulfate, ed, and concentrated down. The crude was purified by silica gel tography with a 0 to 10% methanol / romethane gradient to afford the title compound (159 mg) as an amber foamy oil.

MS (ESI) [m/e, (M)+] = 301.8. 1H NMR (400 MHz, chloroform-d) 5 ppm 8.22 (s, 1 H), 7.35 (d, J=8.08 Hz, 1 H), 6.36 - 6.56 (m, 2 H), 4.73 (d, J=5.56 Hz, 2 H), 4.37 - 4.56 (m, 1 H), 4.11 - 4.24 (m, 2 H), 3.86 (s, 3 H), 3.81 (s, 3 H), 2.27 - 2.31 (m, 2 H), 2.04 - 2.11 (m, 2 Intermediate 43 3,4-Dihydro-2H-pyrano[2,3—djpyridazinamine hydrobromide 'HBr A mixture of N-(2,4—dimethoxybenzyl)-3,4—dihydro-2H-pyrano[2,3—d]pyridazinamine (158, 0.524 mmol) and 30% by weight hydrobromic acid / acetic acid (0.3 mL, 0.4 g, 1.5 mmol) in acetic acid (3 mL) was stirred nearly 2 hours at 90°C. The reaction was then cooled to room temperature and the solvents were removed in vacuo. The dark red solid was washed with diethyl ether and then dried to afford the crude title compound (122 mg) in about 65% purity. MS (ESI) [m/e, (M)*] = 151.7. 1H NMR (400 MHz, DMSO-de) 5 ppm 8.22 (s, 1 H), 8.11 (br s, 2 H), 4.36 - 4.40 (m, 2 H), 2.47 (1, J=6.32 Hz, 2 H), 1.98 - 2.06 (m, 2 H).

Example 1: 2—Chloro-6—{3—[4-(4-methoxy—benzoyl)-piper1'din— 1 -y/]-2—oxo—pyrro/idinylmethyl} — benzonitrile ~Q§OA©L To a solution of 3--(-(4(4methoxybenzoyl)piperidin-yl)pyrro|idin-o-ne (70 mg, 0.23 mmol) and 2-(bromomethyl)chlorobenzonitrile (80 mg, 0.35 mmol) in tetrahydrofuran (1 mL) and dimethylformamide (0.1 mL) was added sodium hydride (46 mg, 1.2 mmol, 60% in mineral oil). The mixture was stirred at ambient temperature for 30 minutes.

Dichloromethane and ol were added slowly to quench the reaction. Then the mixture was filtered through a short pad of l gel column, the t was removed in vacuo, and the residue was purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) first and then (methanol: dichloromethane, 1:99 to :90) to give brown oil which is further purified by HPLC to give a colorless product. 1H NMR (400 MHz, CDCI3) 8 7.85 (m, 2 H), 7.45 (t, J=8.0 Hz, 1 H), 7.35 - 7.41 (m, 1 H), 7.30 (d, J=7.5 Hz, 1 H), 6.87 (m, J=9.0 Hz, 2 H), 4.62 (q, J=15.6 Hz, 2 H), 3.80 (s, 3 H), 3.50 (t, J=9.0 Hz, 1 H), 3.11 - 3.37 (m, 3 H), 2.94 - 3.11 (m, 1 H), 2.75 - 2.94 (m, 2 H), 2.28 - 2.54 (m, 1 H), 2.09 - 2.28 (m, 1 H), 1.90 - 2.09 (m, 1 H), 1.66 - 1.90 (m, 4 H).

HRMS calculated for C25H26C|N303 41, found (ESl, [M + H]*), 452.1760.

W0 2013/008217 e 2: 2-{3—[4-(4-Methoxy—benzoyl)-piperidinyI]oxo-pyrro/idinylmethyl}-3,5, 7,8- tetrahydro-pyrano[4,3-d]pyrimidinone o NH 0 To a solution of 3-[4-(4-methoxy-benzoyl)—piperidinyl]-pyrrolidinone (43.7 mmol, 13.2 g) and 2-chloromethyl-3,5,7,8—tetrahydro-pyrano[4,3-d]pyrimidinone (48 mmol, 9.6 g) in THF (400 mL) and DMF formula (20 mL) was added sodium hydride (60%, 153 mmol, 6.1 g) and heated to 70°C for 1 hour. The reaction was allowed to cool to ambient temperature, diluted with 1 L of ether, and the resulting solid in suspension was filtered and dried under vacuum ed the title compound as an off-white solid (22 g, 95.3% yield). HRMS ated for C25H30N405 466.5417, found (ESI, [M + H]*) 05. 1H NMR (400 MHz, MeOD) 5 ppm 1.67 - 1.92 (m, 4 H) 2.05 - 2.24 (m, 2 H) 2.47 - 2.64 (m, 3 H) 2.72 - 2.82 (m, 1 H) 2.84 - 2.93 (m, 1 H) 3.06 - 3.15 (m, 1 H) 3.26 - 3.47 (m, 10 H) 3.68 (t, J=8.78 Hz, 1 H) 3.83 - 3.99 (m, 5 H) 4.16 (d, J=15.56 Hz, 1 H) 4.40 - 4.58 (m, 3 H) 7.01 (d, J=9.03 Hz, 2 H) 7.97 (d, J=9.03 Hz, 2 H), ical RP-HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.455 min.

Example 3: 2-{(S)[4-(4—Methoxy-benzoyl)-piperidiny/]—2—oxo-pyrrolidin- 1-yImethyI}-3,5, 7,8- ydro-pyrano[4,3-d]pyrimidinone 2-{3-[4-(4-Methoxy—benzoyI)-piperidinyl]oxo-pyrrolidinylmethyl}-3,5,7,8- tetrahydro-pyrano[4,3-d]pyrimidinone (21 g) was dissolved in methanol (2.1 L) and sonicated for 30 min and the undissolved material was removed by filtration. Chiral separation via SFC chromatography on a 3.0 x 25.0 cm (8,8) Whelk0-1 column eluting 50% MeOH/1% isopropylamine/COz (v/v) at 70 mL/min at 125 bar afforded 7.91 g of material. The material was codistilled with chloroform (10 x 1L) under vacuum until dry.

The dried sample was dissolved in acetonitrile/water and frozen by immersing in liquid N2 PCT/IBZOIZ/0536l3 and put under vacuum (0.014 torr) for 3 days. The lyophilized material was dissolved in acetonitrile and treated with K2C03 (6.3 g) and heated to 80°C for 45 min., filtered and dried (9.1 g). The salt (8 g) was dissolved in 40 mL of water and d to 0°C, aqueous HCI (5 mL of a 15% solution chilled to 0°C) was added dropwise until pH 9.5 whereupon the on became cloudy. The on was extracted with dichloromethane (2 x 50 mL) and concentrated to dryness. The compound was further dried in a tube under vacuum at 65°C resulted in the free base of (4.246 g, 40.4% yield). HRMS calculated for C25H30N4O5 466.5417, found (ESI, [M + H]+) 4672305.; 1H NMR (400 MHz, MeOD) 8 ppm 1.67 - 1.91 (m, 4 H) 2.08 - 2.31 (m, 2 H) 2.48 — 2.58 (m, 1 H) 2.59 - 2.66 (m, 2 H) 1O 2.78 - 2.87 (m, 1 H) 2.89 - 2.98 (m, 1 H) 3.11 - 3.19 (m, 1 H) 3.27 - 3.41 (m, 12 H) 3.45 - 3.52 (m, 2 H) 3.64 (t, J=8.53 Hz, 1 H) 3.87 (s, 3 H) 3.91 (t, J=5.52 Hz, 2 H) 4.38 (d, J=10.54 Hz, 2 H) 4.48 (s, 2 H) 7.01 (d, J=9.03 Hz, 2 H) 7.96 (d, J=9.03 Hz, 2 H). HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.455 min ative procedure A solution of (S)(4-(4—methoxybenzoyl)piperidinyl)pyrrolidinone (25.66 g, 85 mmol) in THF (283 mL) was cooled to -1.7 °C and to this was slowly added NaH (10.18 g, 255 mmol) and 2-chIoromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidinone (89 mmol, 17.88 g) maintaining the temperature below 5 °C. The reaction vessel was immersed into an ice-water bath and allowed bath to expire overnight. When reaction was complete by LCMS (approximately 15 h), the reaction was cooled to 1.7 °C and ted NH4Cl was slowly added, keeping the internal temperature below 10 °C. The mixture was diluted with romethane (500 mL) and 1 N NaOH (500 mL) and split into tWo batches that were processed identically. Additional 1 N NaOH (500 mL) was added and the aqueous layer was washed with dichloromethane (2 x 500 mL). The aqueous layer was adjusted to pH 7 using approximately 250 mL 3 N HCl and extracted with dichloromethane (4 x 500 mL), dried over Na2804, filtered and concentrated in vacuo. The crude material was taken up in dichloromethane (500 mL) and ethyl acetate (500 mL) was added. The ing solution was concentrated to an approximate volume of 300 mL and seeded with pure title compound and concentrated further in vacuo. To this stirred solution was added ethyl acetate (500 mL) and a seed of pure title compound. tion of the sion provided the title compound as a white solid (32.87 g, 70.5 mmol).

Example 4: 2012/053613 2-{(R)—3-[4—(4-Methoxy—benzoyl)-piperidin— 1 -yI]oxo-pyrrolidinylmethy/}-3,5, 7,8- tetrahydro-pyrano[4,3-d]pyrimidinone 2-{3-[4-(4-Methoxy-benzoyl)-piperidinyl]oxo-pyrrolidinylmethyl}-3,5,7,8— tetrahydro-pyrano[4,3-d]pyrimidinone (37 mg) was purified via chiral SFC chromatography on an AS-H column (60g/min, 21 x 250 mm) eluting 40% IPA/0.2% DEA/002 (v/v) ing 19 mg of crude material which was further purified by HPLC (300 x 50 mm) eluting with a gradient of 25-35% acetonitrile/water over 45 min., followed by lyophilization of the pure fractions provided the TFA salt of the desired al.

Neutralization of the TFA salt by filtration through a bicarbonate MP resin cartridge eluting with methanol (2 mL), DCM (3 mL), and methanol (2 mL) afforded the title nd (5 mg, 26% yield). MW calculated for 025H30N405 466.5417, HRMS m/z found 467.2305 (M+H)*; 1H NMR (400 MHz, MeOD) 8 ppm 1.69 - 1.90 (m, 4 H) 2.09 - 2.32 (m, 2 H) 2.48 — 2.58 (m, 1 H) 2.59 - 2.66 (m, 2 H) 2.77 - 2.87 (m, 1 H) 2.90 - 2.99 (m, 1 H) 3.11 - 3.20 (m, 1 H) 3.26 - 3.42 (m, 12 H) 3.50 (s, 2 H) 3.63 (s, 1 H) 3.87 (s, 3 H) 3.91 (t, J=5.77 Hz, 2 H) 4.39 (s, 2 H) 4.47 (s, 2 H) 7.01 (d, J=9.03 Hz, 2 H) 7.96 (d, J=9.03 Hz, 2 H).; HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2mL/min over 5 min.) retention time = 2.455 min Alternative procedure To a solution of (R)[4-(4-methoxy-benzoyl)-piperidinyl]-pyrrolidinone (0.165 mmol, 50 mg), which was prepared in a similar manner as (R)[4-(4-methoxy-benzoyl)- piperidiny|]-pyrro|idinone from (S)hydroxypyrrolidinone and 2-chloromethyl- 3,5,7,8—tetrahydro—pyrano[4,3-d]pyrimidinone (0.165 mmol, 33.2 mg) in THF (5 mL) was added 1 M solution of potassium hexamethyldilsilylamide in THF (0.331 mmol, 0.331 mL) at -78°C for 2 hours. The reaction was allowed to warm to 0°C for 16 hours and evaporated under . The remaining residue was purified by flash column chromatography a) g over a gradient of 0-50% MeOH/ethyl acetate ed the title compound as an off—white solid (20 mg, 25.9% yield). HRMS calculated for C25H30N405 466.5417, found (ESI, [M + H]+) 467.2296. 1H NMR (400 MHz, MeOD) 5 ppm 1.69 - 1.91 (m, 4 H) 2.10 - 2.33 (m, 2 H) 2.49 - 2.59 (m, 1 H) 2.59 — 2.67 (m, 2 H) 2.76 - 2.89 (m, 1 H) 2.91 — 3.01 (m, 1 H) 3.11 - 3.22 (m, 1 H) 3.32 - 3.44 (m, 2 H) 3.46 - 3.58 (m, 2 H) 3.59 — 3.71 (t, J=8.78 Hz, 1 H) 3.88 - 3.96 (m, 2 H) 4.04 - 4.14 (d, J=15.56 2012/053613 Hz, 2 H) 4.36 — 4.42 (m, 2 H) 4.44 - 4.51 (m, 2 H) 6.97 (d, J=9.03 Hz, 2 H) 7.92 (d, J=9.03 Hz, 2 H), analytical RP-HPLC retention time = 4.02 min.

Exampie 5: 2-Chloro((3-(4-(4-methoxybenzoyl)piperidinyI)oxopyrrolidin y/)methyl)benzonitrile @5011) To a mixture of 3-(-(4-(m-ethoxybenzoyl)piperidin- 1--yl)pyrro|idin--one (70 mg, 0.232 mmol) and momethyl)chlorobenzonitrile (80 mg, 0.347 mmol) in THF (1 mL) and 1O DMF (0.1 mL) was added NaH (46.3 mg, 1.16 mmol, 60%). The reaction was concentrated in vacuo then taken up in dichlormethane and MeOH and filtered through a short plug of silica gel. The pooled fractions containing the title material were pooled, concentrated and neutralized with NaHCO3. MeOH was added and the on was cooled in a freezer. The title compound was obtained by collecting the white solid via filtration (45 mg). HRMS calculated for C25H25CIN303 451.1671, found (ESI, [M + H]*) 452.1744.

Example 6: 6—{3—[4-(4-Mez‘hoxy-benzoyl)-piperidin- 1-yl]oxo-pyrrolidinylmethy/}methy/— 1, 3a, 5, 7:-tetrahydro-pyrazo/o[3,4-d]pyrimidinone To a solution of 3-[4-(4-methoxy-benzoyl)—piperidin—1-yl]-pyrrolidinone (0.165 mmol, 50 mg) and 6-chloromethylmethyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidinone (0.165 mmol, 33 mg) in THF (2 mL) was added sodium hydride (60%, 0.331 mmol, 23 mg) and heated to 70°C for 1 hour. The reaction was allowed to cool to ambient temperature, diluted with 10 mL of ether, and the resulting solid in suspension was ed and dried under vacuum provided the title compound as an off-white solid (66.4 mg, 87% .

HRMS ated for C24H28N604 464.5286, found (ESI, [M + H]*) 465.2256. 1H NMR (400 MHz, MeOD) 5 ppm 1.70 - 1.93 (m, 4 H) 2.09 - 2.31 (m, 2 H) 2.53 - 2.66 (m, 1 H) PCT/lBZOlZ/053613 2.80 - 2.91 (m, 1 H) 2.93 — 3.02 (m, 1 H) 3.10 - 3.21 (m, 1 H) 3.33 - 3.43 (m, 2 H) 3.48 — 3.57 (m, 2 H) 3.65 - 3.75 (m, 1 H) 3.83 — 3.90 (m, 6 H) 4.37 - 4.51 (m, 2 H) 6.97 (d, J=9.03 Hz, 2 H) 7.83 — 7.91 (m, 1 H) 7.97 (d, J=9.03 Hz, 2 H), analytical RP-HPLC retention time = 2.77 min Example 7: 2—{3—[4-(4-ll/lethoxy-benzoyl)-piperidinyl]—2-oxo-pyrro/idiny/methyl}-4a, ydro- 3H-thieno[3,2—d]pyrimidinone S NH \ Nan| N To a solution of 3-[4-(4-methoxy-benzoyl)-piperidinyl]-pyrrolidinone (0.165 mmol, 50 mg) and 2-chloromethyl-3H-thieno[3,2-d]pyrimidinone (0.165 mmol, 33 mg) in THF (2 mL) was added sodium hydride (60%, 0.331 mmol, 23 mg) and heated to 70°C for 1 hour. The reaction was d to cool to ambient temperature, diluted with 10 mL of ether, and the resulting solid in suspension was filtered and dried under vacuum provided the title compound as an ite solid (70.5 mg, 95.4% yield). HRMS calculated for C24H26N4O4S 466.5632, found (ESl, [M + H]+) 467.1740. 1H NMR (400 MHz, MeOD) 5 ppm 1.65 - 1.92 (m, 4 H) 2.06 - 2.29 (m, 2 H) 2.48 - 2.62 (m, 1 H) 2.78 - 2.89 (m, 1 H) 2.89 — 3.00 (m, 1 H) 3.09 - 3.18 (m, 1 H) 3.34 - 3.53 (m, 4 H) 3.55 — 3.65 (m, 1 H) 3.68 - 3.77 (m, 1 H) 4.23 — 4.32 (m, 1 H) 4.60 - 4.69 (m, 1 H) 6.97 (d, J=9.03 Hz, 2 H) 7.17 — 7.24 (m, 1 H) 7.73 — 7.81 (m, 1 H) 7.96 (d, J=9.03 Hz, 2 H), analytical RP-HPLC retention time = 2.77 min Example 8: 2-{3-[4-(4-Methoxy-benzoyl)-piperidinyl]—2-0xo-pyrrolidinyImethy/}methy/—4a, 7a- dihydro-3H-thieno[2,3-d]pyrimidinone To a solution of 3-[4—(4-methoxy-benzoyl)—piperidinyl]-pyrrolidinone (0.165 mmol, 50 mg) and 2-chloromethylmethyl-3H-thieno[2,3-d]pyrimidinone (0.165 mmol, 33 mg) in THF (2 mL) was added sodium hydride (60%, 0.331 mmol, 23 mg) and heated to 70°C for 1 hour. The on was allowed to cool to ambient temperature, diluted with 10 mL PCT/IBZOIZ/053613 of ether, and the resulting solid in sion was filtered and dried under vacuum provided the title compound as an off-white solid (70.5 mg, 95.4% yield). HRMS calculated for C25H25N4O4S 480.5903, found (ESI, [M + H]+) 481.1907. 1H NMR (400 MHz, MeOD) 6 ppm 1.66 - 1.93 (m, 4 H) 2.05 - 2.30 (m, 2 H) 2.51 - 2.63 (m, 1 H) 2.79 - 2.90 (m, 1 H) 2.90 — 2.98 (m, 1 H) 3.03 - 3.18 (m, 1 H) 3.33 - 3.54 (m, 4 H) 3.65 - 3.75 (m, 1 H) 3.87 (s, 3 H) 4.20 —4.31 (m, 1 H) 4.51 - 4.62 (m, 1 H) 6.94 — 7.06 (m, 3 H) 7.98 (d, J=9.03 Hz, 2 H), analytical RP-HPLC retention time = 3.22 min Example 9: 1O 2—{3—[4"(4-Chloro-benzoyl)-piperidiny/]—2~oxo-pyrrolidiny/methyl}-3, 5, 7, 8-tetrahydro- pyrano[4,3-d]pyrimidinone 0 0143330CI NH To a solution of 3-[4-(4-chloro-benzoyl)-piperidinyl]-pyrrolidinone (0.17 mmol, 53 mg) and 2—chloromethyl-3,5,7,8—tetrahydro-pyrano[4,3-d]pyrimidinone (0.17 mmol, 35 mg) in THF (15 mL and DMF (2.5 mL) was added sodium hydride (60%, (0.6 mmol, 14 mg) and heated to 70°C for 15 min. The reaction was concentrated in vacuo and the remainder of the DMF was removed via a stream of N2. The crude material was purified by preparative reverse-phase HPLC (300 x 50 mm) eluting with a gradient of 25-35% acetonitrile/water over 45 min. Lyophilization of the pure ons provided the TFA salt of the desired material. Neutralization of the TFA salt by filtration through a bicarbonate MP resin cartridge eluting with methanol (2 mL), DCM (3 mL), and methanol (2 mL) afforded the title compound (7 mg, 8.6% . HR-MS m/z (M+H)*: measured 471.1823 ated for C24H27CIN4O4 = 466.5417; 1H NMR (400 MHz, MeOD) 8 ppm 1.66 - 1.92 (m, 6 H) 2.05 - 2.28 (m, 3 H) 2.47 - 2.67 (m, 5 H) 2.75 — 2.87 (m, 2 H) 2.88 — 2.97 (m, 2 H) 3.08 - 3.18 (m, 2 H) 3.24 - 3.51 (m, 22 H) 3.61 - 3.70 (m, 2 H) 3.91 (t, J=5.52 Hz, 2 H) 4.20 - 4.32 (m, 1 H) 4.38 - 4.54 (m, 3 H) 7.51 (d, J=8.53 Hz, 2 H) 7.96 (d, J=8.53 Hz, 2 H). HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2mL/min over 5 min.) ion time = 2.666 min.

Example 10: 2—{3—[4-(4-Fluoro-benzoy/)-piperidin- 2-oxo-pyrrolidinylmethyI}-3,5, trahydro- pyrano[4,3—d]pyrimidinone To a solution of 3-[4-(4-fluoro-benzoyI)-piperidinyl]-pyrrolidinone (0.39 mmol, 112 mg) and 2-chloromethyI-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidinone (0.39 mmol, 76 mg) in THF (15 mL and DMF (2.5 mL) was added sodium e (60%, (1.35 mmol, 54 mg) and heated to 70°C for 15 min. The reaction was concentrated in vacuo and the remainder of the DMF was removed via a stream of N2. The crude material was purified by preparative reverse-phase HPLC (300 x 50 mm) eluting with a gradient of 25-35% acetonitriIe/water over 45 min., ed by lyophilization of the pure fractions provided the TFA salt of the desired material. Neutralization of the TFA salt by filtration h a bicarbonate MP resin dge g with methanol (2 mL), DCM (3 mL), and methanol (2 mL) afforded the title compound (100 mg, 57% yield). HR-MS m/z (M+H)+: measured 455.2111, calculated for molecular formula Cz4H27FN4O4 = 454.5056; 1H NMR (400 MHz, MeOD) 8 ppm 1.58 — 1.85 (m, 4 H) 1.99 - 2.24 (m, 2 H) 2.42 - 2.57 (m, 3 H) 2.67 - 2.81 (m, 1 H) 2.84 - 2.93 (m, 1 H) 3.11-3.17 (m, 1 H) 3.36 - 3.47 (m, 2 H) 3.52 - 3.62 (m, 1 H) 3.76 - 3.86 (m, 2 H) 4.26 - 4.40 (m, 4 H) 7.09 - 7.18 (m, 2 H) 7.91 - 8.00 (m, 2 H); HPLC (Novapak 150 X 3.9 mm 018 : mobile phase: 10—90% acetonitrile/water with 0.1% TFA, at 2mL/min over 5 min.) retention time = 2.461 min.

Example 11 : 2-{(S)[4-(4-Fluoro-benzoyl)-piperidinyI]oxo-pyrrolidinylmethyl}-3,5, 7, 8- tetrahydro-pyrano[4,3-d]pyrimidinone Chiral tion 2-{3-[4-(4-fluoro-benzoyI)-piperidinyl]oxo-pyrro|idinylmethyi}- 3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidinone (90 mg) via chiral SFC chromatography on a AS-H column (60 g/min, 21 x 250 mm) eluting 40% IPA/0.2% DEA/002 (v/v) afforded 48 mg of crude material which was further purified by RP-HPLC (300 x 50 mm) eluting with a gradient of 25-35% acetonitrile/water over 45 min., followed by lization of the pure fractions provided the TFA salt of the desired material.

Neutralization of the TFA salt by filtration through a bicarbonate MP resin cartridge eluting with methanol (2 mL), DCM (3 mL), and methanol (2 mL) afforded the title compound (5 mg, 10.4% yield). HRMS m/z : measured 455.2101 calculated for molecular a C24H27FN4O4 = 454.5056; 1H NMR (400 MHz, MeOD) 8 ppm 1.87 - 2.10 (m, 2 H) 2.11 - 2.29 (m, 3 H) 2.34 - 2.53 (m, 1 H) 2.53 - 2.70 (m, 3 H) 3.23 — 3.43 (m, 14 H) 3.43 - 3.71 (m, 5 H) 3.71 - 3.84 (m, 1 H) 3.86 - 4.01 (m, 3 H) 4.37 - 4.57 (m, 5 H) 7.22 - 7.33 (m, 2 H) 8.07 - 8.16 (m, 2 H). HPLC (Novapak 150 X 3.9 mm C18 : mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2mL/min over 5 min.) retention time = 2.461 min Example 12: 2—{(R)[4-(4-Fluoro-benzoyI)-piperidinyl]—2—oxo-pyrrolidin- 1-ylmethyl] -3,5, 7,8- tetrahydro—pyrano[4,3-d]pyrimidin—4—one Chiral resolution of 2-{3-[4—(4-fluoro-benzoyl)-piperidinyl]oxo-pyrrolidinylmethyl}- 3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidinone (90 mg) via SFC chromatography on a AS—H column (609/min, 21 x 250 mm) eluting 40% IPA/0.2% 2 (v/v) afforded 48 mg of crude material which was further purified by RP-HPLC (300 x 50 mm) g with a gradient of 25-35% acetonitrile/water over 45 min., followed by lyophilization of the pure fractions provided the TFA salt of the desired al. Neutralization of the TFA salt by filtration through a bicarbonate MP resin cartridge eluting with methanol (2 mL), DCM (3 mL), and methanol (2 mL) resulted in the free base of the title compound (27 mg, 56% yield). HRMS m/z (M+H)+: measured 455.2088, calculated for molecular formula C24H27FN4O4 = 454.505; 1H NMR (400 MHz, MeOD) 8 ppm 1.66 - 1.93 (m, 4 H) 2.07 - 2.32 (m, 2 H) 2.47 - 2.58 (m, 1 H) 2.58 - 2.66 (m, 2 H) 2.75 - 2.87 (m, 1 H) 2.89 — 2.99 (m, 1 H) 3.10 - 3.21 (m, 1 H) 3.22 - 3.43 (m, 13 H) 3.44 - 3.53 (m, 2 H) 3.60 - 3.70 (m, 1 H) 3.91 (t, J=5.52 Hz, 2 H) 4.29 - 4.53 (m, 4 H) 7.17 - 7.30 (m, 2 H) 8.00 - 8.12 (m, 2 H). HPLC ak 150 X 3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2mL/min over 5 min.) retention time = 2.461 min Example 13: 2-{(S)[4—(4-Methoxymethyl—benzoyl)-piperidin- 1-y/]oxo-pyrrolidiny/methyl} — 3,5, 7,8-tetrahydro-pyrano[4,3-d]pyrimidinone W0 2013/008217 2012/053613 To a solution of (R)~3-[4-(4—methoxymethyl-benzoyl)—piperidiny|]-pyrrolidinone (0.79 mmol, 250 mg) and 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidinone (0.87 mmol, 174 mg) in THF (10 mL ) was added sodium hydride (60%, 2.77 mmol, 111 mg) and heated to 70°C for 1 hour. The reaction was allowed to cool to ambient temperature, diluted with 100 mL of ether, and the resulting solid in sion was filtered and dried under vacuum provided the title compound as an off-white solid (300 mg). Chiral resolution of 2[4—(4—methoxymethyl-benzoyl)-piperidin-1—yl]oxo— idinylmethyl}—3,5,7,8—tetrahydro-pyrano[4,3-d]pyrimidin-4—one (300 mg) via chiral 1O SFC chromatography on a AS-H column (60 g/min, 21 x 250 mm) eluting 40% IPA/0.2% DEA/002 (v/v) afforded 77 mg of pure al. HRMS calculated for CZSH32N405 = 480.5687, found (ESI, [M + H]+) 481.2455. 1H NMR (400 MHz, MeOD) 5 ppm 1.69 - 1.90 (m, 4 H) 2.10 - 2.20 (m, 1 H) 2.20 - 2.31 (m, 4 H) 2.48 - 2.58 (m, 1 H) 2.59 - 2.65 (m, 2 H) 2.77 - 2.88 (m, 1 H) 2.90 - 3.06 (m, 1 H) 3.10 — 3.20 (m, 1 H) 3.32 - 3.42 (m, 3 H) 3.46 - 3.54 (m, 2 H) 3.63 (t, J=8.53 Hz, 1 H) 3.88 - 3.94 (m, 5 H) 4.39 (s, 2 H) 4.47 (s, 2 H) 6.99 (d, J=8.53 Hz, 1 H) 7.77 (s, 1 H) 7.87 (dd, J=8.53, 2.01 Hz, 1 H), analytical RP-HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.731 min.

Example 14: 2-{(R)—3—[4—(4—Methoxy—3—methyl-benzoyl)-piperidinyI]oxo-pyrrolidin— 1 —ylmethyl}- 3,5, 7,8-tetrahydro-pyrano[4,3—d]pyrimidinone This material was obtained from 2—3-[4-(4-methoxymethyl-benzoyl)—piperidiny|] oxo-pyrrolidinylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidinone (300 mg) via chiral SFC chromatography on a AS—H column (60 g/min, 21 x 250 mm) eluting 40% IPA/0.2% DEA/C02 (v/v) afforded 125 mg of pure material. HRMS calculated for C25H32N4O5 480.5687, found (ESI, [M + H]+) 481.2463. 1H NMR (400 MHz, MeOD) 8 ppm 1.69 - 1.91 (m, 4 H) 2.10 - 2.21 (m, 1 H) 2.20 - 2.31 (m, 4 H) 2.59 - 2.66 (m, 2 H) 2.78 - 2.87 (m, 1 H) 2.90 - 2.98 (m, 1 H) 3.11 - 3.20 (m, 1 H) 3.33 - 3.42 (m, 2 H) 3.46 - 3.55 (m, 2 H) 3.63 (t, J=8.78 Hz, 1 H) 4.39 (s, 2 H) 4.47 (s, 2 H) 6.99 (d, J=8.53 Hz, 1 H) 7.77 (s, 1 H) 7.87 (dd, , 2.01 Hz, 1 H), analytical RP-HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.693 min. e 1 5: 2-((3-(5—methoxyoxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1 '-yl)oxopyrrolidin— 1- yl)meth):3I)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one Off/W@3090 To a solution of 5-methoxy-1'-(2-oxopyrrolidinyl)spiro[indene-2,4'-piperidin]-1(3H)—one (3.34 mmol, 1.05 g) and 2-chloromethyl-3,5,7,8-tetrahydro—pyrano[4,3—d]pyrimidinone (3.67 mmol, 0.737 g) in THF (40 mL) and DMF (5 mL) was added sodium hydride (60%, 11.69 mmol, 0.468 g) and the suspension was heated at 70°C for 45 min. The reaction was allowed to cool to ambient ature, diluted with 100 mL of ether, an off—white solid was collected by filtration and was dried in vacuo. Recrystallization from isopropyl alcohol/methyl alcohol provided the title compound as an off-white solid (661 mg, 41.4% yield). Calculated M8 = 478.6, MS (ESI) m/e 479.0 (M + H”); 1H NMR (400 MHz, MeOD) ppm 1.33 - 1.46 (m, 2 H) 1.92 - 2.07 (m, 2 H) 2.07 - 2.27 (m, 2 H) 2.49 - 2.65 (m, 3 H) 2.89 (dd, , 2.51 Hz, 2 H) 3.02 - 3.15 (m, 3 H) 3.35 - 3.50 (m, 2 H) 3.70 (t, J=8.78 Hz, 1 H) 3.85 - 3.98 (m, 6 H) 4.16 (d, J=15.06 Hz, 1 H) 4.44 - 4.53 (m, 3 H) 6.96 (dd, , 2.51 Hz, 1 H) 7.05 (s, 1 H) 7.62 (d, J=9.03 Hz, 1 H). HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10—90% acetonitriIe/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.391 min.

Example 16 (Peak 1) and Example 17 (Peak 2) Chiral resolution of 2-((3-(5—methoxy-1—oxo-1,3-dihydrospiro[indene—2,4'-piperidine]-1'-y|)- 2-oxopyrrolidiny|)methyl)—7,8-dihydro-3H—pyrano[4,3-d]pyrimidin-4(5H)-one (650 mg) via chiral SFC chromatography on a AS-H column (60 g/min, 21 x 250 mm) g 40% IPA/0.2% DEA/C02 (v/v) afforded two enantiomers (S)((3-(5-methoxy—1-oxo-1,3- dihydrospiro[indene-2,4 '-piperidine]-1 '-yl)oxopyrrolidin- 1-y/)methyl)- 7,8-dihydro-3H- pyrano[4,3-d]pyrimidin-4(5H)-one and (H)((3-(5—methoxy- 1-oxo- 7,3- W0 2013/008217 PCT/lBZOlZ/0536l3 dihydrospiro[indene-2,4 '-piperidine]-1 '-yI)oxopyrrolidin- 1-yl)methyl)- 7, 8-dihydro-3H— pyran0[4,3-d]pyrimidin-4(5H)-one.

Peak 1: 145 mg, HRMS calculated for C26H30N4O5 28, found (ESl, [M + H]+) 479.2291. 1H NMR (400 MHz, MeOD) 5 ppm 1.39 (dd, J=11.29, 7.78 Hz, 3 H) 1.91 - 2.05 (m, 2 H) 2.06 - 2.26 (m, 2 H) 2.50 - 2.65 (m, 3 H) 3.02 - 3.14 (m, 3 H) 3.23 - 3.32 (m, 3 H) 3.34 (s, 1 H) 3.40 - 3.47 (m, 2 H) 3.68 (t, J=8.78 Hz, 1 H) 3.87 - 3.94 (m, 4 H) 4.18 (d, J=15.56 Hz, 1 H) 4.44 - 4.52 (m, 3 H) 6.96 (d, J=8.53 Hz, 1 H) 7.04 (s, 1 H) 7.61 (d, J=8.53 Hz, 1 H). HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10-90% 1O acetonitrile/water with 0.1% TFA, at 2mL/min over 5 min.) retention time = 2.430 min.

Peak 2: 177 mg, HRMS calculated for CZSH30N4O5 478.5528, found (ESI, [M + H]+) 479.2294. 1H NMR (400 MHz, MeOD) 8 ppm 1.36 - 1.52 (m, 10 H) 1.91 - 2.06 (m, 3 H) 2.08 - 2.30 (m, 3 H) 2.50 - 2.65 (m, 6 H) 2.76 - 2.95 (m, 6 H) 3.03 - 3.14 (m, 5 H) 3.25 - 3.36 (m, 16 H) 3.38 - 3.51 (m, 4 H) 3.58 - 3.74 (m, 3 H) 3.86 - 3.94 (m, 8 H) 4.20 (d, J=15.56 Hz, 2 H) 4.44 - 4.54 (m, 5 H) 6.92 - 6.97 (m, 1 H) 7.05 (s, 2 H) 7.62 (d, J=8.53 Hz, 2 H). HPLC (Novapak 150 X 3.9 mm C18 : mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at n over 5 min.) retention time = 2.432 min.

Example 18: 2-[4-(4-Methoxy-benzoyl)-2'-oxo-[1,37bipiperidinyl— 1 ’-ylmethyI]-3, 5, 7,8-fez‘rahydro- pyrano[4,3—d]pyrimidinone To a stirred solution of NaH (23.8 mg, 0.942 mmol, 2.1 eq) in THF (10 mL) were added 4-(4-methoxy-benzoyl)-[1,3’]bipiperidinyl-2’-one (142 mg, 0.449 mmol, 1.0 eq) and 2— methyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidinone (90 mg, 0.449 mmol, 1.0 eq). The reaction was let to stir at 70°C for 3 h. The solid precipitate was filtered off and washed with CHZCI2. The solvent of the mother liquor was evaporated and the residue purified by flash chromatography on silica gel (0-15% HgClg) to afford the title compound as an off-white powder (60 mg, 0.139 mmol, 31.1% yield). 1H NMR (400 MHz, DMSO-de) 5 ppm 12.34 (br s, 1 H) 7.94 (d, J=8.59 Hz, 2 H) 7.03 (d, J=8.59 Hz, 2 H) 4.14 - 4.54 (m, 5 H) 4.06-4.10 (m, 1 H) 3.45 (br s, 1 H) 3.18 (d, J=5.05 Hz, 3 H) 3.03 (br s, 1 H) 2.85 (br s, 2 H) 2.30 - 2.65 (m, 5 H) 1.30 - 2.05 (m, 9 H). HR-MS (m/z, MH+): 61, 482.2471. HPLC ion time: 2.78 min (Agilent column 3.0 x 100 mm 3 um C18 colum; flow rate of 1.0 mL/min with with gradient from 5% to 95% acetonitrile in 10 min, 0.1% FA) Example 19 (Peak 1) and Example 20 (Peak 2): Chiral resolution of 2-[4-(4-methoxy-benzoyl)-2'-oxo-[1,3']bipiperidinyI-1'-y|methyl]- 3,5,7,8—tetrahydro-pyrano[4,3-d]pyrimidinone using an OD-H column by SFC with mobile phase of 30% MeOH gave two enantiomers (4-Methoxy-benzoyl)-2'-oxo- [1,37bipiperidinyl- 1 '-ylmethy/]-3, 5, 7, 8-tetrahydro-pyrano[4,3—d]pyrimidinone and 2-[(Fi)- 4-(4-Methoxy-benzoyl)-2'—oxo-[1,37bipiperidinyl- 1 '-y/methyIJ-3,5, 7,8-tetrahydro- pyrano[4,3-d]pyrimidinone.

Peak 1 retention time = 2.31 min.

Peak 2 retention time = 3.17 min.

Example 21: 2-((3—(4-(4-methoxybenzoyl)p/;oeridin- 1-yI)0X0pyrro/idiny/)methyl)-6, 7—dihydro-3H— enta[d]pyrimidin-4(5H)-one To a solution of 4-(4-methoxybenzoyl)piperidinyl)oxopyrrolidin yl)acetimidamide hydrochloride (140 mg, 0.37 mmol) and methyl 2- oxocyclopentanecarboxylate (0.060 mL, 0.47 mmol) in l (4 mL) was added sodium ethoxide (0.160 mL, 0.44 mmol, 21%). The mixture was heated at 100°C for 24 h. The resulting mixture was purified via flash column chromatography (methanol: dichloromethane, 1:99 to 10:90) and then crystalized out from methanol to provide slighly yellow solid (33 mg, 20% yield). 1H NMR (400 MHz, CDCIa) 6 10.85 (s, 1H), 7.95 (d, J=8.5 Hz, 2 H), 6.96 (d, J: 8.5 Hz, 2 H), 4.32 - 4.47 (m, 2 H), 3.89 (s, 3 H), 3.60 - 3.73 (m, 1 H), 3.40 - 3.56 (m, 2 H), 3.23-3.37 (br. s, 1 H), 3.00-3.20 (br. s, 3 H), 2.84 (ddd, 4 H, J=14.7, 7.5, 7.4 Hz), 2.46-2.62 (br. s, 1 H), 2.38 (d, 1 H, J=7.0 Hz), 2.15-2.25 (br. s, 1 H), 2.10 (dq, 2 H, J=7.8, 7.6 Hz), 1.82-2.01 (br. s, 4 H) HRMS calculated for C25H30N4O4 451.2345, found (ESI, [M + H]*), 451.2362.

Example 22: 2-{3-[4-(4-Methoxy-benzoyI)-piperidinoxo-pyrrolidin— 1 -yImethy/}-3H—pyrimidin The title compound (1.8 mg, 1% yield) was ed using a similar method to the one described in Example 21 from (E)-methyl 3-methoxyacrylate (0.055 mL, 0.47 mmol). 1H NMR (400 MHz, CD30D) 8 8.03 (d, J=9.0 Hz, 2 H), 7.92 (d, J=6.5 Hz, 1 H), 7.05 (d, J=9.0 Hz, 2 H), 6.33 (d, J=7.0 Hz, 1 H), 4.48 - 4.58 (m, 2 H), 4.36 - 4.48 (m, 1 H), 3.93- 4.05 (br. s. 1 H), 3.89 (s, 3 H), 3.70-3.83 (br. s, 1H), 3.66 (d, J=8.0 Hz, 2 H), 3.51-3.63 (br. s, 2 H), 3.25 - 3.39 (m, 1 H), 2.54 - 2.71 (m, 1 H), 2.47 (d, J=10.0 Hz, 1 H), 2.19 (d, J=14.1 Hz, 2 H), 2.03-2.15 (br. s, 2 H). HRMS calculated for C22H26N4O4 411.2032, found (ESl, [M + H]+), 411.2047.

Example 23: 2-{3-[4-(4-Methoxy-benzoyl)-piperidinyl]oxo-pyrrolidiny/methyl}methyI-3H- pyrimidinone The title compound (73 mg, 47% yield) was prepared using a similar method to the one described in Example 21 from (E)-methyl butenoate (0.044 mL, 0.47 mmol). 1H NMR (400 MHz, CDCla) 6 11.30 (s, 1H), 7.95 (d, J=9.0 Hz, 2 H), 6.96 (d, J=9.0 Hz, 2 H), 6.20 (s, 1 H), 4.40 (s, 2 H), 3.89 (s, 3 H), 3.70 (d, J=9.0 Hz, 1 H), 3.40 - 3.57 (m, 2 H), 3.22 - 3.40 (m, 1 H), 2.98-3.21 (br. s, 3 H), 2.45-2.60 (br. s, 1 H), 2.30-2.43 (br. s, 1 H), 2.28 (s, 3 H), 2.11-2.25 (br. s, 1 H), 1.82-1.99 (br. s, 4 H). HRMS calculated for C23H28N4O4 89, found (ESI, [M + H]+), 425.2186.

Example 24: 6-Ethyl—2-{3—[4-(4-methoxy-benzoyl)-piperidin- 1-yl]oxo-pyrrolidin- 1—y/methyI}-3H- pyrimidinone The title compound (64 mg, 40% yield) was prepared using a similar method to the one described in Example 21 from ethyl 3-oxopentanoate (0.067 mL, 0.47 mmol). 1H NMR (400 MHz, CDCI3) 8 11.67 (s, 1H), 7.95 (d, J=9.0 Hz, 2 H), 6.96 (d, J=8.5 Hz, 2 H), 6.19 (s, 1 H), 4.42 (s, 2 H), 3.89 (s, 3 H), 3.68 (t, J=8.3 Hz, 1 H), 3.40 - 3.55 (m, 2 H), 3.22— 3.35 (br. s, 1 H), 3.07-3.18 (br. s, 1 H), 2.98-3.07 (br. s, 2 H), 2.54 (q, J=7.5 Hz, 3 H), 2.25 - 2.43 (m, 1 H), 2.08-2.24 (br. s, 1 H), 1.81-1.97 (br. s, 4 H), 1.15 - 1.33 (m, 3 H).

HRMS calculated for CZ4H30N4O4 439.2345, found (ESI, [M + H]*), 439.2356.

Example 25: 2—{3—[4-(4-Methoxy-benzoyl)-piperidinyI]oxo—pyrro/idin- 1 hyl}-5—methyl—3H— pyrimidinone The title compound (96 mg, 62% yield) was ed using a similar method to the one described in Example 21 from ethyl 2-methyIoxopropanoate (0.057 mL, 0.47 mmol). 1H NMR (400 MHz,CDCI3)81O.65(s, 1H), 7.95 (d, J=9.0 Hz, 2 H), 7.74 (s, 1 H), 6.96 (d, J=8.5 Hz, 2 H), 4.25 - 4.51 (m, 2 H), 3.89 (s, 3 H), 3.65 (t, J=8.5 Hz, 1 H), 3.39 - 3.58 (m, 2 H), 3.17 - 3.37 (m, 1 H), 3.10 (d, J=10.5 Hz, 1 H), 2.99 (br. s, 2 H), 2.47 (br. s, 1H), 2.22 - 2.40 (m, 1 H), 2.14 (dd, , 8.3 Hz, 1 H), 2.07 (s, 3 H), 1.88 (br. s, 4 H). HRMS calculated for C23H28N4O4 425.2189, found (ESI, [M + H]*), 425.2191.

Example 26: 2-{3—[4-(4-Methoxy-benzoyD-piperidinyI]oxo-pyrrolidiny/methyl}-5, 6-dimethyl-3H- pyrimidinone The title compound (40 mg, 19% yield) was prepared using a similar method to the one described in e 21 from (Z)-ethy| 3-hydroxymethylbut-2—enoate (0.081 mL, 0.56 mmol). 1H NMR (400 MHz, CDCI3) 8 10.65 (s, 1H), 7.86 (d, J=9.1 Hz, 2 H), 6.87 (d, J=9.1 Hz, 2 H), 4.27 (s, 2 H), 3.80 (s, 3 H), 3.54 (t, J=8.6 Hz, 1 H), 3.31 - 3.47 (m, 2 H), 3.18 (ddd, J=9.5, 5.3, 4.9 Hz, 1 H), 2.95 - 3.06 (m, 1 H), 2.87 - 2.95 (m, 2 H), 2.33 - 2.45 (m, 1 H), 2.17 - 2.31 (m, 4 H), 1.94 - 2.10 (m, 4 H), 1.70 - 1.88 (m, 4 H). HRMS calculated for CZ4H30N4O4 439.2345, found (ESl, [M + H]*), 439.2347.

Example 27: (4-(4-methoxybenzopriperid/n- 1-y/)oxopyrrolidin yl)methyl)cyclohepta[d]imidazol-4(3H)-one Cit/“$39NH 0.. 1O O Toluenesulfonic acid 7-oxo-cyclohepta—1,3,5-trienyl ester (0.33 mmol. 91 mg), 2-{3-[4— hoxy-benzoyl)-piperidin—1-yl]oxo—pyrrolidin—1-y|}-acetamidine (0.33 mmol, 130 mg) and tetrabutylammonium bromide (0.132 mmol, 42.4 mg) were added to a solution of 30% NaOH (13.1 mg, 1 mL) and toluene (5 mL) and stirred for 16 hours. The reaction was treated with an excess of brine and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were concentrated in vacuo. The crude material was purified by preparative reverse-phase HPLC (300 x 50 mm) eluting with a gradient of 25-35% acetonitrile/water over 45 min., followed by lyophilization of the pure fractions provided the TFA salt of the title compound (23.6 mg, 14% . HRMS calculated for .20 N4O4 460.4375, found (ESI, [M + H]+), found 00. 1H NMR (400 MHz, MeOD) 8 ppm 1.91 - 2.26 (m, 4 H) 2.33 - 2.50 (m, 1 H) 2.54 - 2.68 (m, 1 H) 3.24 - 3.43 (m, 8 H) 3.45 - 3.82 (m, 6 H) 3.88 (s, 3 H) 3.92 ~ 4.12 (m, 1 H) 4.32 - 4.48 (m, 1 H) 4.72 - 4.92 (m, 2 H) 7.04 (d, J=9.03 Hz, 2 H) 7.14 - 7.33 (m, 1 H) 7.42 - 7.65 (m, 1 H) 7.69 - 7.88 (m, 1 H) 8.02 (d, J=9.03 Hz, 2 H). HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.572 min.

Example 28: 2—{(S) [4-(4-Methoxy—3—methyl—benzoyl)-piperidin- 1-yI]oxo-pyrrolidiny/methyl]-3H- cycloheptaimidazoIone \fN .— esulfonic acid 7-oxo-cyclohepta-1,3,5-trienyl ester (0.86 mmol. 236 mg), 2- {(S)[4-(4-methoxymethyl-benzoyl)-piperidinyl]oxo-pyrrolidiny|}-acetamidine (0.86 mmol, 350 mg) and tetrabutylammonium bromide (0.34 mmol, 110 mg) were added to a solution of 30% NaOH (13.1 mg, 1 mL) and toluene (5 mL) and stirred for 16 hours.

The reaction was treated with an excess of saturated ammonium chloride, d w/ % isopropanol/chloroform, washed with brine, dried, concentrated in vacuo. Chiral resolution of 2-((3—(4—(4—methoxybenzoyl)piperidinyl)—2—oxopyrrolidinyl)methyl) cyclohepta[d]imidazol-4(3H)-one (405 mg) via SFC chromatography on a AS-H column (60g/min, 21 x 250 mm) eluting 40% IPA/0.2% DEA/C02 (v/v) afforded 21 mg of pure material. (21 mg, 9% yield). HRMS calculated for C27H30N4O4 474.5646, found (ESl, [M + H]+), found 475.2354. 1H NMR (400 MHz, CDCla-d) 8 ppm 1.85 (d, 4 H) 2.00 - 2.15 (m, 1 H) 2.16 - 2.33 (m, 4 H) 2.39 - 2.52 (m, 1 H) 2.90 - 3.00 (m, 2 H) 3.02 - 3.12 (m, 1 H) 3.18-3.31 (br. s, 1 H) 3.38 - 3.55 (m, 8 H) 3.57 - 3.67 (m, 1 H) 3.91 (s, 3 H) 4.68 - 4.86 (m, 2 H) 6.83 - 6.91 (m, 1 H) 6.98 - 7.10 (m, 1 H) 7.25 - 7.34 (m, 3 H) 7.35 - 7.45 (m, 2 H) 7.72 - 7.86 (m, 6 H). HPLC (Novapak 150 X 3.9 mm C18 : mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.920 min.

Example 29: 2—{(R)-3—[4—(4-Methoxy—3—methyl-benzoyl)-piperidin—1—y/]—2—oxo-pyrrolidiny/mez‘hyl]-3H- cycloheptaimidazol—(j-one Mfg-«Ob The title compound( 18 mg))was prepared ing the general ures of Example 28 starting with 2-{(R)[4—(4-methoxy—3-methyl-benzoyl)-piperidiny|]oxo-pyrrolidin- 1-yl}-acetamidine (405 mg, 0.85 mmol). HRMS calculated for C27H30N4O4 474.5646, found (ESI, [M + H]+), found 475.2345. 1H NMR (400 MHz, CDCls-d) 5 ppm 1.74 - 2.11 (m, 4 H) 2.22 - 2.44 (m, 5 H) 2.57 (d, J=8.03 Hz, 1 H) 3.09 (d, J=6.53 Hz, 3 H) 3.28 - 3.40 (m, 1 H) 3.50 (t, J=8.28 Hz, 2 H) 3.62 - 3.83 (m, 1 H) 3.89 - 3.97 (m, 3 H) 4.82 (br. s, 2 H) 6.87 (d, J=8.53 Hz, 1 H) 7.00 - 7.11 (m, 1 H) 7.26 - 7.36 (m, 5 H) 7.38 - 7.47 (m, 1 H) 7.72 - 7.86 (m, 3 H) HPLC (Novapak 150 X 3.9 mm C18 column: mobile phase: 10- PCT/1B2012/053613 90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.874 min.

Example 30: 2—{(S)[4-(4-Mez‘h0xy—benzoyl)-piperidiny/]oxo-pyrrolidinylmethy/}-3H- cyc/oheptaimidazoIone H \O Chiral resolution of 2-((3-(4-(4-methoxybenzoyl)piperidinyl)oxopyrro|idin yl)methyl)cyc|ohepta[d]imidazol-4(3H)-one (300 mg, 0.65 mmol) via SFC chromatography on a AS-H column (60g/min, 21 x 250 mm) eluting 40% IPA/0.2% DEA/002 (v/v) ed 35 mg of pure material. HRMS calculated for C26H28N4O4 460.5375, found (ESI, [M + H]+) 461.2195. 1H NMR (400 MHz, MeOD) 1H NMR (400 MHz, chloroform-d) 8 ppm 1.17-1.39 (br. s, 2 H) 1.41 - 1.50 (m, 1 H) 1.63 - 1.73 (m, 1 H) 1.76-1.96 (br. s, 4 H) 2.06 - 2.19 (m, 1 H) 2.23 - 2.35 (m, 1 H) 2.42 - 2.55 (m, 1 H) 2.93 - 3.03 (m, 2 H) 3.06 - 3.15 (m, 1 H) 3.22 - 3.32 (m, 1 H) 3.41 - 3.55 (m, 2 H) 3.60 - 3.70 (m, 1 H) 3.89 (s, 3 H) 4.76 - 4.89 (m, 2 H) 6.95 (d, J=9.03 Hz, 2 H) 7.02 — 7.11 (m, 1 H) 7.28 (s, 2 H) 7.32 - 7.40 (m, 1 H) 7.40 - 7.50 (m, 1 H) 7.78 (d, J=10.54 Hz, 1 H) 7.94 (d, J=8.53 Hz, 2 H), analytical RP-HPLC (Novapak 150 X 3.9 mm C18 : mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time = 2.638 min.

Example 31 : 2—{(R)[4-(4-Methoxy—benzoyl)-piperidin— 1 -yl]oxo—pyrr0/idin- 1 hyI}-3H- eptaimidazol—4-one thfioHN \O "'Nfl O Chiral resolution of 2-((3-(4-(4—methoxybenzoyl)piperidiny|)oxopyrrolidin yl)methyl)cyc|ohepta[d]imidazoI-4(3H)-one (300 mg) via SFC chromatography on a AS-H column (609/min, 21 x 250 mm) eluting 40% IPA/0.2% DEA/002 (v/v) afforded 35 mg of pure material. HRMS ated for 026H28N4O4 460.5375, found (ESI, [M + H]+) 461.2181. 1H NMR (400 MHz, MeOD) 1H NMR (400 MHz, chloroform-d) 6 ppm 0.81 - 0.95 (m, 1 H) 1.18 - 1.35 (m, 2 H) 1.78 - 1.93 (m, 4 H) 2.13 (dd, J=11.80, 7.28 Hz, 1 H) 2.22 - 2.34 (m, 1 H) 2.49 (d, J=3.51 Hz, 1 H) 2.91-3.04 (br. s, 2 H) 3.10 (d, J=10.54 Hz, 1 H) 3.21 - 3.31 (m, 1 H) 3.40 - 3.55 (m, 3 H) 3.65 (t, J=8.78 Hz, 1 H) 3.89 (s, 3 H) 4.76 - 4.91 (m, 2 H) 6.95 (d, J=9.03 Hz, 2 H) 7.06 (dd, J=10.54, 8.53 Hz, 1 H) 7.34 - 7.49 (m, 2 H) 7.78 (d, J=11.04 Hz, 1 H) 7.94 (d, J=8.53 Hz, 2 H). ical RP-HPLC ion time = 4.55 min Example 32: N-(5, 6-dihydrothiazolo[2,3-c][1,2,4]triazol-3—yl)~2-(3-(4-(4— methoxybenzoyl)piperidinyl)—2-oxopyrro/idin- 1~y/)acetamide N- N S N NH \_/ OMQN O O\H/©/o.

A mixture of 500 mg of 76.5% pure 2-(3-(4-(4-methoxybenzoyl)piperidinyl) oxopyrrolidinyl)acetic acid (382 mg, 1.061 mmol) and 5,6-dihydrothiazolo[2,3- c][1,2,4]triazolamine hydrobromide (237 mg, 1.061 mmol) was d in diisopropylethylamine (0.741 mL, 549 mg, 4.25 mmol) and dichloromethane (10 mL) before addition of HATU reagent (444 mg, 1.161 mmol). The reaction was d over 45 hours at room temperature. A small amount of off—white solid was removed by filtration. The filtrate was eluted through a silica gel column with 0 to 15% ol / dichloromethane, then 15% to 30%, followed by 30%. The fractions ning contaminated product were concentrated down and eluted through a second silica gel column with 5% to 12% methanol / dichloromethane gradient followed by 12% to afford the title compound (177 mg) as a white solid. Calculated mass for C23H28N504S = 484.57. HR-MS [m/z, (M+H)+] = 485.1956. HPLC retention time = 2.73 minutes (Agilent 1100 HPLC system; 3.0 x 100 nm 3 urn C18 column; flow rate of 1.0 mL/ min; gradient of 5-95% acetonitrile / water with 0.1% formic acid over 10 minutes). 1H NMR (400 MHz, DMSO-ds) 5 ppm 11.06 (br s, 1 H), 7.94 (d, J=9.09 Hz, 2 H), 7.03 (d, J=8.59 Hz, 2 H), 3.92 - 4.21 (m, 6 H), 3.83 (s, 3 H), 3.39 - 3.51 (m, 1 H), 3.21 - 3.37 (m, 3 H), 2.99 (d, J=13.14 Hz, 1 H), 2.64 - 2.84 (m, 2 H), 2.28 - 2.42 (m, 1 H), 2.03 - 2.18 (m, 1 H), 1.85 - 2.02 (m, 1H), 1.65 - 1.78 (m, 2 H), 1.44- 1.60 (m, 2 H).

Example 33 (Peak 1) and e 34 (Peak 2): N-(5,6-Dihydrothiazolo[2,3-c][1 ,2,4]triazolyl)(3-(4-(4— methoxybenzoyl)piperidin- 1-yl)oxopyrrolidinyl)acetamide (166 mg, 0.343 mmol) was eluted through a SCF column (70 mL / min flow rate) with 60% C02 and 40% modifier (composed of 70% dichloromethane / ethanol and 0.2% diethylamine) to yield two enantiomerically enriched peaks N-(5,6-dihydrothiazolo[2,3-c][1,2,4]triazolyI)((S)(4-(4- methoxybenzoyl)piperidin- 1-y0oxopyrrolidinyl)acetamide and N-(5, 6- dihydrothiazolo[2,3-c][1,2,4]triazolyl)((R)(4-(4-methoxybenzoyl)piperidin- 2- oxopyrrolidinyl)acetamide.

Peak 1 (54.5 mg), SFC retention time = 3.87 minutes (Instrument: 250; Column: Whelko (RR); Mobile Phase: 40%(70% DCM / 30% EtOH) 0.2% DEA).

Peak 2 (60 mg) SFC retention time = 6.85 minutes (Instrument: sfc_a—250; Column: Whelko (R,R); Mobile Phase: 40%(70% DCM/ 30% EtOH) 0.2% DEA).

Example 35: N-([1 ,2,4]triazolo[4,3-a]pyridinyl)—2-(3-(4-(4-methoxybenzoyl)piperidin-1 -yl) rolidinyl)acetamide N- N , W5; / N O N O\ 0 Following the l procedure of Example 32, the title compound (115 mg) was prepared from [1,2,4]triazolo[4,3-a]pyridinamine (101 mg, 0.472 mmol). The reaction was run 1 hour at room ature, 5.5 hours at 50°C, then 62 hours at room temperature before workup and purification. Calculated Mass for CQ5H23N604 = 476.53.

HR-MS [m/z, (M+H)+] = 477.2269. HPLC retention time = 2.70 minutes (Agilent 1100 HPLC system; 3.0 x 100 nm 3 urn C18 column; flow rate of 1.0 mL/ min; gradient of 5— 95% acetonitrile / water with 0.1% formic acid over 10 minutes). 1H NMR (400 MHz, DMSO-de) 8 ppm 11.06 (br s, 1 H), 8.06 (d, J=7.07 Hz, 1 H), 7.94 (d, J=8.59 Hz, 2 H), 7.75 (d, J=9.09 Hz, 1 H), 7.37 - 7.43 (m, 1 H), 6.98 - 7.07 (m, 3 H), 4.16 - 4.29 (m, 2 H), 3.84 (s, 3 H), 3.37 - 3.50 (m, 3 H), 3.26 - 3.30 (m, 2 H), 2.95 - 3.06 (m, 1 H), 2.75 - 2.81 (m, 1 H), 2.31 - 2.43 (m, 1 H), 2.07— 2.20 (m, 1 H), 1.93 - 2.04 (m, 1 H), 1.63 - 1.77 (m, 2 H), 1.45 - 1.60 (m, 2 H).

Example 36: 2-(3-(4-(4-methoxybenzoyl)piperidinyI)oxopyrrolidin( 1 -methyl- 1 H-tetrazol yl)acetamide --N‘N 0AA?!“ o\ 0 Following the general procedure of Example 32, the title compound (21 mg) was prepared from 1-me1hy|-1H-tetrazolamine (12.7 mg, 0.128 mmol). The reaction was run 1 hour at room ature followed at 50°C. ated Mass for C21H27N7O4 = 441.48. HR-MS [m/z, (M+H)“] = 09. HPLC retention time = 2.73 minutes (Agilent 1100 HPLC system; 3.0 x 100 nm 3 um C18 column; flow rate of 1.0 mL / min; gradient of 5-95% acetonitrile / water with 0.1% formic acid over 10 minutes). 1H NMR (400 MHz, chloroform—d) 8 ppm 7.91 (d, J=8.08 Hz, 2 H), 6.93 (d, J=8.08 Hz, 2 H), 4.09 - 4.57 (m, 2 H), 3.75 - 4.06 (m, 6 H), 3.40 - 3.73 (m, 3 H), 3.03 - 3.31 (m, 2 H), 2.75 - 3.02 (m, 2 H), 2.38 - 2.61 (m, 1 H), 2.03 - 2.36 (m, 2 H), 1.66 - 1.95 (m, 4 H). e 37: N-(3, 4-dihydro-2H—pyrano[2,3-d]pyridazinyl)(3-(4-(4-methoxybenzoyl)piperidinyl)- 2-oxopyrrolidinyl)ace1amide 055w?“/N\|N O\ o 0 Following the general procedure of Example 32, the title compound (98.7 mg) was prepared from 3,4-dihydro-2H—pyrano[2,3-d]pyridazinamine hydrobromide (186 mg, 0.521 mmol). Calculated Mass for 025H3}N505 = 493.55. HR-MS [m/z, (M+H)*] = 494.2390. HPLC retention time = 2.82 minutes (Agilent 1100 HPLC system; 3.0 x 100 nm 3 um C18 column; flow rate of 1.0 mL / min; gradient of 5-95% acetonitrile / water with 0.1% formic acid over 10 minutes). 1H NMR (400 MHz, chloroform-d) 8 ppm 8.5-8.8 (br s, 1 H), 7.88 - 7.98 (m, 2 H), 6.89 — 7.00 (m, 2 H), 4.28 - 4.39 (m, 2 H), 4.19 - 4.28 (m, 2 H), 3.88 (s, 3 H), 3.57 - 3.66 (m, 1 H), 3.42 - 3.58 (m, 2 H), 3.19 - 3.32 (m, 1 H), 3.08 - 3.19 (m, 1 H), 2.93 - 3.06 (m, 2 H), 2.59 - 2.72 (m, 2 H), 2.46 - 2.59 (m, 1 H), 2.22 - 2.37 (m, 1 H), 2.10 — 2.22 (m, 1 H), 1.99 - 2.10 (m, 2 H), 1.78 - 1.97 (m, 4 H).

Example 38: N-(isoxazo/o[5,4-b]pyridinyl)-2—(3-(4-(4-methoxybenzopriperid/n- 1-yl)oxopyrrolidinyl)acetamide __ 0AA Hop 0 0 Following the general procedure of Example 32, the title compound (23.9 mg) was prepared from isoxazo|o[5,4-b]pyridinamine (100 mg, 0.740 mmol). The reaction was run 1 hour at room temperature and 72 hours at 60°C before workup and purification.

Calculated Mass for 025H27N505 = . HR-MS [m/z, (M+H)*] = 478.2094. HPLC retention time = 2.68 minutes (Agilent 1100 HPLC system; 3.0 x 100 nm 3 um C18 column; flow rate of 1.0 mL / min; gradient of 5-95% acetonitrile / water with 0.1% ammonium formate over 10 minutes). 1H NMR (400 MHz, DMSO-de) 8 ppm 12.11-12.25 (br. s, 1 H), 8.18 (dd, J=7.07, 2.53 Hz, 1 H), 7.96 (d, J=8.59 Hz, 2 H), 7.62 - 7.67 (m, 1 H), 7.04 (d, J=8.59 Hz, 2 H), 6.36 (t, J=6.82 Hz, 1 H), 4.73 - 4.85 (m, 2 H), 3.84 (s, 3 H), 3.38 - 3.54 (m, 3 H), 3.29 — 3.31 (m, 2 H), 2.98 - 3.05 (m, 1 H), 2.77 - 2.82 (m, 1 H), 2.35 - 2.44 (m, 1 H), 2.13 — 2.24 (m, 1 H), 1.97 - 2.05 (m, 1 H), 1.68 - 1.79 (m, 2 H), 1.47 - 1.63 (m, 2 H). ical Assays and Data 2O Biochemical Assay to Determine Compound Inhibition of TNKS Enzyme ty The human tankyrase 1 PARP catalytic domain, TNKS1 P, was cloned into a pDONR221 vector using the lnvitrogen Gateway Technology. This entry clone was then subcloned into the destination vector 0 to obtain the N-terminal Glutathione S- transferase (GST)-tagged fusion n. GST-TNKS1 P was then expressed in Sf21 cells using the lnvitrogen baculovirus expression system (lnvitrogen-Bac-to-Bac® virus Expression System, Version D). The protein was purified by a GSTrap column (GE Healthcare). The N-terminal gged tankyrase 2 protein PARP domain, , was cloned, expressed, and purified in a similar manner. Human PARP1 (Cat. No. 4668- 100-01) and activated DNA (Cat. No. 4671-09606) were purchased from en, Inc.

PARP2 (Cat. No. ALX-201—O64-CO20) was purchased from Alexis Biochemical.

The rsylation activity of the TNKS 1/2 or PARP1/2 enzymes was measured by the liquid chromatography—mass spectrometry (LC/MS) detection of nicotinamide as readout. Compound activity in inhibiting the TNKS and PARP autoparsylation was W0 2013/008217 evaluated by |C50 ements. In the compound screening assays, the reaction is ed of 5 uL of nd in 8-point serial ons with trations ranging from 0.0086 to 18.75 uM, 20 nM of purified enzyme, and 250 ”M of B'NAD+ in the 1x Assay Buffer. After 60 min incubation at room temperature, the reactions were quenched by the addition of 10 uL of 5x quenching solution (20% formic acid and 500 nM icotinamide in water). For the background control wells, 10 uL of the 5x quenching solution per well was added prior to the addition of B-NAD+. The % Inhibition was calculated as: (Control — Sample)/(Control — Background)*100. “Control” is the average value of 8 wells without compound; and "Background" is the average of 8 wells mixed with 5x quenching solution measured prior to initiation of the reaction.

Examples 1-38 were tested in one or more of the above enzymatic assays, the results of which are given in Table 1.

Table 1 TNKS2 TNKS1 PARP1 PARP2 Example AP IC50 (uM) AP IC50 (uM) |C50(uM) —_——— ——_—— -—-— _—_-_ 7 0.083i0.005 —-—0.21 1:0.063 mi 0.141i0.04 i0.0280023:0001 0030:0002 16614.2 4.62:0.95 0.006i0.001 0.027i0.001 23.6:27 9.20i2.2 0.017i0.002 0.037i0.005 37.4i0.3 10.2i4.2 2.12i0.05 5.34i0.34 0.003i0.001 0.006i0.001 24i3 4 OJ+ 1.. 0.206i0.02 0.71 1:0.02 0.018i0.002 0.033i0.002 16 <0.0086 0.012i0.001 17 1 12 3.85i0.48 18 001510.001 0.046i0.001 19 0.009i0.001 0.024i0.001 0218:0002 0.483i0.01 W0 2013/008217 2012/053613 TNKSZ TNKS1 PARP1 PARP2 Example AP |C5o (uM) AP [(350 (HM) ICso (HM) IC50(lJM) 21 002 0.034i0.001 29.6:23 10.7iO.2 22 056 _- 23 0137:0022 _- 0036:0006 >19 27 0019:0001 —- m0007:0001 2.9:03 001 —- 039:0.07 101:2.6 0021:0001 5.09:0.12 33 0374:0002 _- 6.3iO.7 0636:0036 _- 1 .48i0.02 3.08:0.23 - 0971006 3.01 i006 - 4.56i0.04 6.5i0.8 - Cellular Reporter Gene Assay to Determine Compound Inhibition of Wnt signaling Activity Compound activity in ting Wnt ligand-induced signaling was measured using a Wnt—responsive Super-TOpFlash (STF) luciferase reporter gene assay in HEK293 cells.

On day 1 of the assay, cells were plated at a density of 8000 cells per well of 384-well plate in 25 0| medium containing 5% fetal bovine serum (FBS). On the second day, 20 0L Wnt3A condition medium (CM) produced from mouse L cells was added to the cells to induce Wnt signaling, followed by addition of 5 0L of compounds each well in 10-point serial dilution. On the third day, the luciferase activity was measured by the Bright-GloTM rase Assay System following cture’s protocol (Promega, E2620). The % Inhibition was calculated as: (Maximum Wnt-induced signaling — Sample)/( Maximum Wnt- induced signaling — Background)*100. “Maximum Wnt-induced signaling” is the STF signal level induced by 20% Wnt3A CM without nd; and ”Background” is the STF signal level without the addition of Wnt3A CM or compound.

W0 2013/008217 Cellular ELISA Assay to Determine Compound Effect on Stabilizing the Axin2 Protein Compound activity in stabilizing the Axin2 protein was measured by Sandwich Enzyme-Linked Immuosorbent (ELISA) assay in the colorectal cell line SW480. 30,000 SW480 cells were seeded per well in l plate and incubated overnight prior to nd ent. Cells were then treated with compounds in 6-point dilution starting at pM for 24 hrs. Cells were then washed with 100 pL of cold Phosphate Buffer Saline (PBS), and lysed in 125 pl of cold 1X lysis buffer (Cell Signaling Technology, 9803) supplemented with Protease inhibitor (Roche, 11836170) and atase inhibitors (Sigma, P2850, P5726). For the ELISA assay, anti Axin-2 capture antibody (Strategic Diagnostics) antibody was diluted to a concentration of 1 pg/ml (121000) in ate Coating buffer, pH 9.2 (Sigma, 03041-5OCAP). 100 p of the diluted anti Axin-2 capture antibody per well was then used to coat the 96-well ELISA plate (Thermo on Corp, MicroLite 1 flat bottom plate # 7571) overnight at 4°C. Plates were then washed three times with 300 pI/well of wash solution, PBST20 (PBS + 0.05% Tween), and blocked with 300 pllwell 1% BSA/PBS (BSA, Millipore Probumin # 821) for 1.5 hours at room temperature while shaking gently. After blocking, plates were then washed three times with 300 pl/well of wash solution. 100 pL of prepared SW480 cell Iysate was then added to each well and incubated at room temperature for 2 hours while shaking . After washing, 100 pL of Biotinylated anti-Axin2 antibody (CST, 2151) was added to each well and ted room temperature for 2 hours. 100 uL of Streptavidin-HRP (R&D systems, DY998 ) diluted 1:200 in 1% BSA/PBS was then added in each well and incubate for 30 mins at Rfl' in the dark. Signal was detected by Chemiluminescence (Pierce SuperSignal ELISA Femto # 3704), and measured on PerkinEImer Wallac 1420 plate reader.

Cellular Proliferation Assay to Determine Compound Inhibition of Cancer Cell Growth Non-small lung cancer ABC-1 cells were plated at 5000 cells per well in 96-well plates and d with 8 serial compound dilutions starting from 10 uM as the highest tration. Viable cells were measured after 3 days of compound ent using the CeIITiter-Glo assay (Promega, G7570). Assay was performed following the manufacture protocol. Excel XLfit 4 was used for plotting of the growth curves and calculation of IC50 values. % growth following compound treatment was calculated as: ed sample/(DMSO control)*100. IC50 values are concentrations of the compound at which cell growth is inhibited by 50%.

Examples 1-38 were tested in one or more of the above cellular assays, the results of which are given in Table 2.

Table 2 STF Axin ABC-1 leo (HM) A050 (HM) I050 (HM) 0099:0011 0 239+0 031 0.408 003131000 0000000000 000000005 000631-000 3 0.0011i00004 0012:0003 _|. CO 0.095i0011 0.31 10.27 1.02i0.34 0017:0003 0066:0001 0.156 0.0059i00015 0023:0003 0.043 \I 0054:0012 0018:0004 0003:0003 _L O 0010:0001 +O 00 13 0001210001 0.003 -o.396:o010 1.79:0.14 0.0056:0.0007 007 0.oooao:0.oooos 0.0011o:000017 l\) l\) 0 0032+0 00 000040000000 00015 000046i00 0.0008i000 28 00015i00005 002 09 STF Axin ABC-1 Example 1050 (MM) A050 (11M) 1050 (NM) 0.004 0.009i0.001 0 010- 0.00060i0.0 0.00086i0.0 3O 0.0011i0.0001 001 001 0065:0014 0089:0002 0.085 00059:00089 0131:0008 0.076 0379:0067 1.34:011 0.012 0078:0006 o 049 0.94:0. 1 .891016 2.63 7.6i0.

PCT/lBZOlZ/053613

Claims (21)

What is claimed is:

1. A compound according to formula (I) wherein: R1 is R2 or (O)-; R2 is phenyl optionally substituted with one or two tuents each independently selected from the group consisting of: halo, OH, CN, N02, C1_6 alkyl, 01-6 alkoxy, 01-5 haloalkyl, C(O)Ra, coona, NRaRb, NHC(O)Ra, and aRb; R2 is a 5 ed heteroaryl having one to four heteroatoms selected from the group consisting of N, O, and S, or R2 is a 6 membered heteroaryl having one or two N, said 5 and 6 membered heteroaryl rings being optionally substituted with one to three substituents each independently selected from the group consisting of: halo, oxo, OH, CN, N02, 01-6 alkyl, c1_6 alkoxy, 01-6 haloalkyl, C(O)Ra, coona, NRaRb, NHC(O)Ra, and C(O)NRaRb; R2 is an 8-10 membered bicyclic heteroaryl having 3 or 4 heteroatoms selected from the group consisting of N, O, and 8, said 8-10 membered heteroaryl being optionally substituted with one to three substituents each ndently ed from the group consisting of: (a) halo, (b) oxo, (O) OH, (0') CN, (6) N02, (f) C1-6alkyl optionally substituted with one hydroxy or one 01—6 alkoxy, (9) 01-5 alkoxy, (h) C1 -6 haloalkyl, (i) C(O)Ra, (j) COORa, (k) NRaRb, (I) NHC(O)Ra, and (m) C(O)NRaRb; R3 is H and R4 is phenyl optionally substituted with one to three substituents each independently ed from the group consisting of: halo, OH, CN, N02, C1 -6alkyl, C1—6 alkoxy, C1_6 haloalkyl, C(O)Ra, COORa, NRaRb, NHC(O) Ra, and C(O)NRaF{b; R3 and R4 together with the atoms to which they are attached form optionally substituted 1-one, said indanone is attached to the dine ring of formula (I) h spiro carbon 4 and is optionally substituted with one to three substituents each independently selected from the group consisting of: halo and C1_5 alkoxy; Ra is H or C1_6 alkyl; Rb is H or 01-6 alkyl; and n is 1 or 2; or a pharmaceutically acceptable salt thereof.

2. The compound ing to claim 1 having the following formula O R4 (II); or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2 wherein R3 is H; or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1-3 wherein R4 is optionally substituted phenyl; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4 wherein R4 is substituted phenyl; or a pharmaceutically acceptable salt thereof. PCT/IBZOIZ/0536l3

6. The compound ing to claim 5 wherein R4 is phenyl substituted by one or two substituents each independently selected from the group consisting of halo, C1_6 alkyl, and C1 -6 alkoxy; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 or 2 wherein R3 and R4 together with the atoms to which they are attached form optionally substituted indan-f-one; or a pharmaceutically acceptable salt thereof.

8. The compound ing to any one of claims 1—7 wherein n is 1; or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of claims 1-7 wherein n is 2; or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of claims 1-9 wherein R1 is R2; or a pharmaceutically acceptable salt thereof.

11. The compound according to any one of claims 1-10 n R2 is ally substituted phenyl; or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of claims 1-10 wherein R2 is an optionally substituted 5 or 6 membered heteroaryl; or a pharmaceutically acceptable salt thereof.

13. The compound ing to any one of claims 1-10 wherein R2 is an optionally tuted 8-10 membered bicyclic aryl; or a pharmaceutically acceptable salt thereof.

14. The compound according to any one of claims 1—1 0 wherein R2 is O O 0 O 0 NH / NH 3 / NH N NH 'NA 'N/& NJ\/ N N/J\ \ N»\* 8 *(a), (b) , (C), (d), NH QH N~N / N /Nw N/J\* N’)\* SK/Nk.‘/</ \ i (6), (f). (9). (h), (I), / N 0‘ \ V1 ’/N\N (j), (k). or H wherein each of (a)-(l) is optionally substituted with one or two substituents each independently selected from the group consisting of halo, OH, CN, N02, 01—6 alkyl, C1_6 alkoxy, 01-6 kyl, C(O)Ra, COORa, NRaRb, NHC(O)Ra, and C(O)NRaRb; or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 which is: 2-Chloro{3-[4-(4-methoxy-benzoyl)—piperidinyl]oxo-pyrro|idiny|methy|}- benzonitrile; 2-{3—[4-(4-Methoxy-benzoyl)-piperidiny|]oxo-pyrro|idiny|methy|}-3,5,7,8— tetrahyd ro-pyrano[4,3-d]pyrimidinone; 2-{(R)—3-[4—(4-Methoxy—benzoyl)-piperidiny|]-2—oxo-pyrrolidinylmethy|}-3,5,7,8- tetrahydro-pyrano[4,3-d1pyrimidinone; 2-Chloro((3-(4-(4—methoxybenzoyl)piperidin—1-y|)—2—oxopyrrolidin hyl)benzonitrile; 6-{3-[4-(4—Methoxy—benzoyl)-piperidin—1-y|]oxo-pyrro|idinylmethyI}methyl- 10 1 ,3a,5,7a-tetrahydro-pyrazolo[3,4-d]pyrimidin-4—one; 2—{3-[4-(4—Methoxy—benzoyl)-piperidinyl]—2-oxo-pyrro|idiny|methy|}-4a,7a—dihydro- 3H-thieno[3,2-d]pyrimidin—4—one; 2-{3-[4-(4-Methoxy-benzoyl)-piperidiny|]-2—oxo-pyrro|idinylmethyl}-6—methyI-4a,7a- dihydro-3H-thieno[2,3-d]pyrimidin-4—one; 15 2-{3-[4—(4—Chloro-benzoyl)-piperidiny|]oxo-pyrro|idinylmethy|}-3,5,7,8-tetrahydro- pyrano[4,3-d]pyrimidin-4—one; 2-{3-[4—(4-FIuoro-benzoyl)-piperidinyI]oxo-pyrrolidiny|methy|}-3,5,7,8—tetrahydro- pyrano[4,3-d]pyrimidin-4—one; 2-{(S)—3-[4-(4-F|uoro-benzoyl)-piperidinyl]-2—oxo-pyrrolidiny|methy|}-3,5,7,8- tetrahydro-pyrano[4,3-d]pyrimidin-4—one; 2-{(R)—3-[4-(4-F|uoro-benzoyl)-piperidiny|]oxo-pyrrolidinylmethyl}-3,5,7,8- tetrahyd ano[4,3-d]pyrimidin-4—one; 2-{(R)—3-[4-(4-Methoxy—3-methyl—benzoyI)-piperidiny|]oxo-pyrrolidiny|methy|}- 3,5, 7,8-tetrahydro-pyrano[4,3-d]pyrimidinone; 2-((3-(5-methoxy-1—oxo-1,3-dihydrospiro[indene—2,4'-piperidine]—1'-y|)oxopyrrolidin hy|)-7, 8—dihyd ro-3H-pyrano[4,3-d]pyrimidin-4(5H)—one; (S)—2—((3-(5-methoxyoxo-1 ,3-dihydrospiro[indene-2,4'—piperidine]-1'-yl)oxopyrrolidin- 1O 1-y|)methy|)-7, 8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)—one; (R)—2-((3-(5-methoxyoxo-1 ,3—dihydrospiro[indene-2,4’-piperidine]-1'-y|)oxopyrrolidin- 1-yl)methyl)-7, 8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one; 2—[4-(4—Methoxy—benzoyl)-2'-oxo—[1 piperidinyl-1'-y|methyI]-3,5,7,8—tetrahydro— pyrano[4,3-d]pyrimidin-4—one; 15 2-[(S)-4—(4-Methoxy—benzoyl)-2'-oxo—[1 ,3']bipiperidinyl-1'-ylmethyI]-3,5,7,8-tetrahydro- pyrano[4,3—d]pyrimidin-4—one; 2-[(R)-4—(4—Methoxy—benzoy|)-2'-oxo-[1 ,3']bipiperidinyl-1'-ylmethyI]-3,5,7,8—tetrahydro- pyrano[4,3-d]pyrimidin-4—one; 2-((3-(4—(4—methoxybenzoyl)piperidinyl)oxopyrrolidiny|)methyl)-6,7-dihydro-3H- 20 cyclopenta[d]pyrimidin-4(5H)—one; 2-{3—[4—(4—Methoxy-benzoyl)-piperidiny|]oxo-pyrro|idiny|methyI}-3H-pyrimidin-4— one; 2-{3-[4-(4-Methoxy-benzoyl)-piperidinyl]oxo-pyrrolidiny|methy|}methyI-3H- pyrimidin-4—one; 25 6-Ethyl—2—{3-[4—(4-methoxy-benzoyl)-piperidinyI]—2-oxo-pyrro|idiny|methyl}-3H- pyrimidin-4—one; 2-{3-[4-(4-Methoxy—benzoyl)-piperidinyl]oxo-pyrrolidiny|methyl}methyI-3H- pyrimidinone; 2-{3-[4-(4—Methoxy—benzoyl)-piperidin-1—yl]oxo-pyrrolidinylmethyI}-5,6-dimethyI-3H- 30 pyrimidin-4—one; (4—(4-methoxybenzoyl)piperidiny|)—2-oxopyrrolidin-1 - yl)methyl)cyc|ohepta[d]imidazoI-4(3H)—one; 2-{(R)[4—(4—Methoxy—3—methyl-benzoyl)—piperidiny|]oxo-pyrrolidinyImethyI}-3H- cycloheptaimidazol-4—one; 35 2-{(S)-3—[4-(4-Methoxy—benzoyl)-piperidiny|]oxo—pyrro|idiny|methyl}-3H- cycloheptaimidazol-4—one; 2-{(R)—3-[4—(4—Methoxy-benzoyl)-piperidin—1-yl]oxo-pyrrolidinylmethyl}-3H- cycloheptaimidazol-4—one; N-(5,6-dihydrothiazolo[2,3-c][1 riazolyl)(3-(4-(4— methoxybenzoyl)piperidin- 1-y|)oxopyrrolidiny|)acetamide; N-(5,6-Dihydro-thiazolo[2,3-c][1,2,4]triazoly|){(S)[4-(4-methoxy-benzoyl)- piperidiny|]-2—oxo-pyrro|idin-1—yl}-acetamide; N-(5,6-Dihydro-thiazolo[2,3-c][1,2,4]triazolyl){(R)[4-(4-methoxy-benzoyl)- piperidinyl]oxo-pyrrolidiny|}-acetamide; N-([1,2,4]triazolo[4,3-a]pyridinyl)-2—(3-(4—(4—methoxybenzoyl)piperidiny|) 10 oxopyrrolidin-1—yl)acetamide; 2—(3-(4-(4-methoxybenzoyl)piperidinyl)—2-oxopyrro|idiny|)-N-(1-methyl-1 H-tetrazol yl)acetamide; N-(3,4—dihydro-2H-pyrano[2,3-d]pyridazin—5-yl)(3-(4-(4—methoxybenzoyl)piperidin-1 -y|)- 2-oxopyrrolidinyl)acetamide; or 15 N-lsoxazolo[5,4—b]pyridin-3—yl-2—{3-[4-(4—methoxy-benzoyl)-piperidinyl]—2-oxo- pyrrolidinyl}-acetamide; or a pharmaceutically acceptable salt thereof.

16. A compound which is 2-{(S)-3—[4-(4-methoxy-benzoyl)-piperidinyl]oxopyrrolidiny |methyl}-3,5,7,8-tetrahydro—pyrano[4,3-d]pyrimidinone having the following formula 20 o ; or a pharmaceutically acceptable salt thereof.

17. A compound which is 2-{(S)[4-(4—methoxy—3-methyl-benzoyl)-piperidin-1—yl]-2—oxo- pyrrolidinylmethyl}-3,5,7,8—tetrahydro-pyrano[4,3-d]pyrimidin-4—one having the 25 following a ; or a pharmaceutically acceptable salt thereof.

18. A compound which is 2-{(S)[4-(4—methoxymethyl-benzoyl)-piperidiny|]oxo- pyrrolidiny|methyl}-3H-cycloheptaimidazol-4—one having the following formula ; or a ceutically acceptable salt thereof.

19. A pharmaceutical ition comprising a compound according to any one of claims 1—18 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

20. A method for the treatment of cancer comprising administration of an effective amount of a compound according to any one of claims 1-18 or a pharmaceutically acceptable salt thereof to a non-human subject in need thereof.

21. Use of an effective amount of a compound according to any one of claims 1-18 or a pharmaceutically able salt thereof in the manufacture of a medicament for the treatment of cancer.