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Title:
PARP INHIBITORS
Document Type and Number:
WIPO Patent Application WO/2013/030205
Kind Code:
A1
Abstract:
The present application disclosed compounds of Formula I wherein variables R1 and R2 are defined as described herein, which are inhibitors of PARP and provides compounds and compositions containing the compounds of Formula I. The present application further provides methods of using the disclosed PARP inhibitors for the treatment of PARP-mediated diseases and disorders.

Inventors:
HAYNES, Nancy-Ellen (508 Linden Place, Cranford, New Jersey, 07016, US)
HUBY, Nicholas John Silvester (1835 North Gate Road, Scotch Plains, New Jersey, 07076, US)
SCOTT, Nathan Robert (30 Symington Avenue, Livingston, New Jersey, 07039, US)
Application Number:
EP2012/066721
Publication Date:
March 07, 2013
Filing Date:
August 29, 2012
Export Citation:
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Assignee:
F. HOFFMANN-LA ROCHE AG (Grenzacherstrasse 124, Basel, CH-4070, CH)
HAYNES, Nancy-Ellen (508 Linden Place, Cranford, New Jersey, 07016, US)
HUBY, Nicholas John Silvester (1835 North Gate Road, Scotch Plains, New Jersey, 07076, US)
SCOTT, Nathan Robert (30 Symington Avenue, Livingston, New Jersey, 07039, US)
International Classes:
C07C317/44; A61K31/167; A61K31/495; A61P35/00; C07D237/18
Domestic Patent References:
WO2007144652A22007-12-21
WO2010139966A12010-12-09
Other References:
MOTOHIRO NISHIHO: "Nuclear Magnetic Resonance Studies of Sulfur Compounds. II. The Substituent Effect on Geminal Coupling Constants and on Magnetic Nonequivalence of the Methylene Protons of Sulfoxides", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 15, 1967, Tokyo JP, pages 1669 - 1676, XP008157882
GIUSEPPE GUANTI ET AL: "Stereoselective synthesis of 3-p-tolylsulphinyl-4-aryl-?-lactams", JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL COMMUNICATIONS, no. 13, 1 January 1984 (1984-01-01), pages 861, XP055043660, ISSN: 0022-4936, DOI: 10.1039/c39840000861
BRUCE P. BRANCHAUD ET AL: "Relative ease of transient acyl imine formation via selenoxide, sulfoxide, and sulfone .beta. N-H elimination. A feasibility study on the preparation of novel peptide analog", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 52, no. 24, 1 November 1987 (1987-11-01), pages 5475 - 5478, XP055043756, ISSN: 0022-3263, DOI: 10.1021/jo00233a036
HUANG C-G ET AL: "An efficient synthesis of gamma-substituted alpha,beta-unsaturated-delta-lactams. Formal synthesis of (+/-)-protoemetinol", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 43, no. 15, 8 April 2002 (2002-04-08), pages 2721 - 2723, XP004345879, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(02)00401-X
YOSHIMITSU NAGAO ET AL: "Highly Stereoselective Asymmetric Pummerer Reactions That Incorporate Intermolecular and Intramolecular Nonbonded S...O Interactions", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 128, no. 30, 1 August 2006 (2006-08-01), pages 9722 - 9729, XP055043771, ISSN: 0002-7863, DOI: 10.1021/ja056649r
NATURE CHEMICAL BIOLOGY, vol. 5, 2009, pages 100
NATURE, vol. 461, 2009, pages 614
BIOCHIMIE, vol. 5, 2009, pages 100
GOODMAN; GILMAN'S: "The Pharmacological Basis of Therapeutics", 2001, MCGRAW HILL COMPANIES INC.
BIOCHEM. PHARMACOL., vol. 22, 1973, pages 3099
"Compendium of Chemical Terminology", 1997, BLACKWELL SCIENTIFIC PUBLICATIONS
VLOON, W. J.; KRUK, C.; PANDIT, U.K.; HOFS, H. P.; MCVIE, J. G., J. MED. CHEM., vol. 30, no. 1, 1987, pages 20 - 24
ETUKALA, J. R.; YADAV, J. S., HETEROATOM CHEM., vol. 19, no. 2, 2008, pages 221 - 227
JIANG, S.; LIAO, C.; BINDU, L.; YIN, B.; WORTHY, K. W.; FISHER, R. J.; BURKE, T. R.; NICKLAUS, M. C.; ROLLER, P. P., BIOORG MED. CHEM. LETT, vol. 19, no. 10, 2009, pages 2693 - 2698
JIANG, S.; LIAO, C.; BINDU, L.; YIN, B.; WORTHY, K. W.; FISHER, R. J.; BURKE, T. R.; NICKLAUS, M. C.; ROLLLER, P. P., BIOORG MED. CHEM. LETT, vol. 19, no. 10, 2009, pages 2693 - 2698
NEW, J.S.; CHRISTOPHER, W.L.; JASS, P.A., J. ORG. CHEM., vol. 54, 1989, pages 990 - 992
MONTALBETTI, C. A. G. N.; FALQUE, V., TETRAHEDRON, vol. 61, 2005, pages 10827 - 10852
OZTURK, T.; ERTAS, E.; MERT, O., CHEM REV., 2010, pages 3419 - 3478
ISHIBASHI, H.; HARADA, S.; OKADA, M.; SOMEKAWA, M.; KIDO, M.; IKEDA, M., CHEM. PHARM. BULL., vol. 37, no. 4, 1989, pages 939 - 943
"Remington: The Science and Practice of Pharmacy", 1995, MACK PUBLISHING COMPANY
J. RIGAUDY; D. P. KLESNEY: "IUPAC", 1979, PERGAMON PRESS, article "Nomenclature in Organic Chemistry"
Attorney, Agent or Firm:
MÜLLER-AFRAZ, Simona (Grenzacherstrasse 124, Basel, CH-4070, CH)
Download PDF:
Claims:
WHAT IS CLAIMED IS:

1. A compound of Formula I, wherein: R1 is phenyl, phenyl-lower alkyl, cycloalkyl, or cycloalkyl-lower alkyl, each optionally substituted with one or more R1 ; each R1 is independently lower alkyl, halo, lower alkoxy, lower haloalkyl, lower alkyl sulfonyl, trifluoromethoxy, or cyano;

R 2 is phenyl, optionally substituted with one or more R 2' , napthyl, cyclohexyl, or pyridazinyl; and each R 2' is independently halo, lower alkyl, lower alkoxy, or -C(=0)OCH3; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein R is pheny, optionally substituted with one or more R1'.

3. The compound of claim 2, wherein R is phenyl, optionally substituted with one or more R2'.

The compound of claim 3, wherein R 2' is halo.

5. The compound of claim 4, wherein R1 is methoxy.

6. The compound of claim 4, wherein R1 is fluoro.

7. The compound of claim 4, wherein R1 is trifluoromethyl, cyano, methyl sulfonyl, or trifluoromethoxy.

8. The compound of claim 3, wherein R1 is methoxy.

2'

9. The compound of claim 8, wherein R is methoxy, methyl, or -C(=0)OCH3.

10. The compound of claim 1, wherein R is phenyl, optionally substituted with one or more R2'. 11. The compound of claim 10, wherein R1 is phenyl lower alkyl, cycloalkyl, or cycloalkyl lower alkyl, each optionally substituted with one or more R1 .

2'

12. The compound of claim 11, wherein R is halo.

13. The compound of claim 1, wherein R1 is phenyl and R1 is methoxy.

14. The compound of claim 13, wherein R is napthyl, cyclohexyl, or pyridazinyl.

15. The compound of claim 1 selected from the group consisting of:

2-(3-Methoxy-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetamide;

2-(3-Fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetamide;

2-((R)-3-Fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetamide;

2-((S)-3-Fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetamide;

N- (4-Methoxy-phenyl)-2- (toluene- 3 - sulf inyl) - acetamide ;

N-(4-Methoxy-phenyl)-2-((R)-toluene-3-sulfinyl)-acetamide;

N-(4-Methoxy-phenyl)-2-((S)-toluene-3-sulfinyl)-acetamide; WO 2013/030205 "6°- PCT/EP2012/066721

N-(4-Methoxy-phenyl)-2-(naphthalene-2-sulfinyl)-acetamide;

N-(4-Methoxy-phenyl)-2-(naphthalene-l-sulfinyl)-acetamide;

2- Cyclohexanesulfinyl-N-(4-methoxy-phenyl)-acetamide;

3- [(4-Methoxy-phenylcarbamoyl)-methanesulfinyl] -benzoic acid methyl ester;

2-(3-Chloro-4-fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetamide;

2-((R)-3-Chloro-4-fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetamide;

2-((S)-3-Chloro-4-fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetamide;

N- (4-Methoxy-phenyl)-2- (pyridazine- 3 - sulfinyl) - acetamide ;

2- (3 , 5 -Dichloro-benzene sulfinyl) -N- (4-methoxy-phenyl) - acetamide ;

2-(3,4-Difluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetamide;

2-(3-Chloro-benzenesulfinyl)-N-(4-methoxy-benzyl)-acetamide;

2-(3-Chloro-benzenesulfinyl)-N-(4-fluoro-phenyl)-acetamide;

2-((R)-3-Chloro-benzenesulfinyl)-N-(4-fluoro-phenyl)-acetamide;

2-((S)-3-Chloro-benzenesulfinyl)-N-(4-methanesulfonyl-phenyl)-acetamide;

2-(3-Chloro-benzenesulfinyl)-N-(4-methanesulfonyl-phenyl)-acetamide;

2-(3-Chloro-benzenesulfinyl)-N-(3-methoxy-phenyl)-acetamide;

2- (3 -Chloro-benzenesulf inyl) -N- (2-methoxy-phenyl) - acetamide ;

2-(3-Chloro-benzenesulfinyl)-N-cyclohexylmethyl-acetamide;

2-(3-Chloro-benzenesulfinyl)-N-(3-fluoro-phenyl)-acetamide;

2-(3-Chloro-benzenesulfinyl)-N-(4-trifluoromethyl-phenyl)-acetamide;

2-(3-Chloro-benzenesulfinyl)-N-(4-cyano-phenyl)-acetamide;

2-(3-Chloro-benzenesulfinyl)-N-(2-fluoro-phenyl)-acetamide;

2-(3-Chloro-benzenesulfinyl)-N-(4-trifluoromethoxy-phenyl)-acetamide;

2-(3-Chloro-benzenesulfinyl)-N-cyclohexyl-acetamide; and

2-(3-Chloro-benzenesulfinyl)-N-cyclopentylmethyl-acetamide.

16. A method for treating an PARP-mediated condition comprising administering to a patient in need thereof a therapeutically effective amount of the compound of any one of claims 1-15.

17. A method for treating a Tankyrase-mediated condition comprising administering to a patient in need thereof a therapeutically effective amount of the compound of any one of claims 1-15.

18. A method for treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of the compound of any one of claims 1-15.

19. A pharmaceutical composition comprising the compound of the compound of any one of claims 1-15.

20. The pharmaceutical composition of claim 19, admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.

21. The pharmaceutical composition of claim 19, further comprising an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an antiinflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, and an agent for treating immunodeficiency disorders.

Description:
PARP INHIBITORS

FIELD OF THE INVENTION Cancer is a disease characterized by the loss of appropriate control for cell growth. The

American Cancer Society has estimated that there were in excess of 1.5 million new cases of cancer within the United Stated of America in 2010 and approximately 570,000 deaths that year estimated to be attributable to cancer. The World Health Organization has estimated that cancer was the leading cause of death globally in 2010, with the number of deaths caused by cancer growing to 12 million per year by 2030.

It has been suggested that there are 6 capabilities which need to be developed by cells in order to lead to the formation of cancerous lesions. These traits are self-sufficiency in growth signals, insensitivity to anti-growth signals, tissue invasion and metastasis, limitless replication potential, sustained angiogenesis and evasion of apoptosis. Growth signaling is required for cells to transition from a quiescent state into an active proliferative state. These signals are typically transmitted from transmembrane receptors, through signal transduction cascades involving numerous intracellular kinases, eventually resulting in changes in gene expression at the nuclear level within the cell. In recent years there has been much interest in the area of signal transduction inhibitors, particularly kinase inhibitors, and their use for the treatment of cancer Several examples from this class of compounds have been successfully evaluated in clinical settings and are now commercially available and marketed for the treatment of specific forms of cancer e.g. imatinib tosylate (marketed as Gleevec® by Novartis for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia), lapatinib ditosylate (marketed as Tykerb® by GlaxoSmithKline for the treatment of HER2 positive breast cancer in combination with other chemo therapeutic agents), sunitinib malate (marketed as Sutent® by Pfizer and approved for the treatment of renal cancer) and sorafenib (marketed as Nexavar by Bayer for the treatment of renal cancer).

In addition to the growth factor associated signaling pathways, which predominantly utilize kinase catalyzed transfer of phosphate groups as the key component of the signaling pathway, numerous other signaling pathways also exist within cells and their proper regulation is critical for maintaining correct levels of cell growth and replication. In the emerging area of cancer stem cell inhibition the Wnt, Notch and Hedgehog pathways have received much interest as potential ways in which to avoid tumor relapse and metastasis. The Wnt pathway is instrumental in embryonic development and in tissue maintenance in adults with the activity of individual components within the pathway under tight regulation. In cancer and other diseases cell signaling pathways no longer exhibit the appropriate level of control. In the case of the Wnt pathway, signal transduction is controlled by the relative stabilities of 2 proteins, axin and β- catenin. An over abundance of β-catenin leads to increased Wnt signaling and activation of associated nuclear transcription factors while excess axin results in the degradation of intracellular β-catenin and decreased signaling. Dysregulation of the canonical Wnt signaling pathway has been implicated in a range of human carcinomas such as colon cancer, hepatocellular carcinoma, endometrial ovarian cancer, pilomatricoma skin cancer, prostate cancer, melanoma and Wilms tumor. In the canonical Wnt signaling pathway signaling is initiated by interaction of a Wnt ligand with a receptor complex containing a Frizzled family member and low-density lipoprotein receptor-related protein. This leads to the formation of a disheveled-frizzled complex and relocation of axin from the destruction complex to the cell membrane. Axin is the concentration limiting component of the destruction complex, and it is this complex which is formed with adenomatous polyposis coli proteins, casein-kinase la and glycogen synthase kinase 3β which is responsible for controlling intracellular levels of β-catenin. In the presence of functional destruction complex, β-catenin is sequentially phosphorylated by casein-kinase la and glycogen synthase kinase 3β on a conserved set of serine and threonine residues at the amino-terminus. Phosphorylation facilitates binding of β-catenin to β-transducin repeat-containing protein which then mediates ubiquitination and subsequent proteasomal degradation of β-catenin. In the absence of sufficiently elevated concentrations of the destruction complex, un-phosphorylated β- catenin is able to migrate to the cell nucleus and interact with T-cell factor proteins and convert them into potent transcriptional activators through the recruitment of co-activator proteins.

It has recently been reported that intracellular axin levels are influenced by the poly(ADP-ribose) polymerase enzyme family members tankyrase-1 and tankyrase-2 (also known as PARP5a and PARP5b) {Nature Chemical Biology 2009, 5, 100 and Nature 2009, 461, 614). Tankyrase enzymes are able to poly-ADP ribosylate (PARsylate) axin, which marks this protein for subsequent ubiquitination and proteasomal degradation. Thus, it would be expected that in the presence of an inhibitor of tankyrase catalytic activity, axin protein concentration would be increased, resulting in higher concentration of the destruction complex and decreased concentrations of unphosphorylated intracellular β-catenin and decreased Wnt signaling. An inhibitor of tankyrase-1 and -2 would also be expected to have an effect on other biological functions of the tankyrase proteins e.g. chromosome end protection (telomeres), insulin responsiveness and spindle assembly during mitosis (Biochimie 2009, 5, 100). Therapeutics which are directed at and can correct dysregulation of the Wnt signaling pathway have been implicated in conditions such as bone density defects, coronary disease, late onset Alzheimer's disease, familial exudative vitreoretinopathy, retinal angiogenesis, tetra-amelia, Mullerian-duct regression and virilization, SERKAL syndrome, type 2 diabetes, Fuhrmann syndrome, skeletal dysplasia, focal dermal hypoplasia and neural tube defects. Although the above introduction has focused on the relevance of Wnt signaling in cancer, the Wnt signaling pathway is of fundamental importance and has potential implication in a broad range of human diseases, not necessarily limited to the examples provided above for illustrative purposes. The instant application provides a method for treating an PARP-mediated condition

(specifically Tankyrase 1 and 2) comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.

SUMMARY OF THE INVENTION

The application provides a compound of Formula I, wherein:

R 1 is phenyl, phenyl-lower alkyl, cycloalkyl, or cycloalkylllower alkyl, each optionally substituted with one or more R 1 ; each R 1 is independently lower alkyl, halo, lower alkoxy, lower haloalkyl, lower alkyl sulfonyl, trifluoromethoxy, or cyano;

R 2 is phenyl, optionally substituted with one or more R 2' , napthyl, cyclohexyl, or pyridazinyl; and each R 2' is independently halo, lower alkyl, lower alkoxy, or -C(=0)OCH 3 ; or a pharmaceutically acceptable salt thereof. The application provides a method for treating a Tankyrase-mediated condition comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.

The application provides a method for treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I. The application provides a pharmaceutical composition comprising the compound of

Formula I.

DETAILED DESCRIPTION OF THE INVENTION Definitions The phrase "a" or "an" entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms "a" (or "an"), "one or more", and "at least one" can be used interchangeably herein.

As used in this specification, whether in a transitional phrase or in the body of the claim, the terms "comprise(s)" and "comprising" are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

As used herein, unless specifically indicated otherwise, the word "or" is used in the "inclusive" sense of "and/or" and not the "exclusive" sense of "either/or".

The term "independently" is used herein to indicate that a variable is applied in any one instance without regard to the presence or absence of a variable having that same or a different definition within the same compound. Thus, in a compound in which R" appears twice and is defined as "independently carbon or nitrogen", both R"s can be carbon, both R"s can be nitrogen, or one R" can be carbon and the other nitrogen.

When any variable occurs more than one time in any moiety or formula depicting and describing compounds employed or claimed in the present invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such compounds result in stable compounds.

The symbols "*" at the end of a bond or " " drawn through a bond each refer to the point of attachment of a functional group or other chemical moiety to the rest of the molecule of which it is a part. Thus, for example:

MeC(=0)OR 4 wherein R 4 = *— | or -j-<] MeC(=0)0— <]

A bond drawn into a ring system (as opposed to connected at a distinct vertex) indicates that the bond may be attached to any of the suitable ring atoms.

The term "cyano", alone or in combination with other groups, refers to N≡C-(NC-). The term "halogen", alone or in combination with other groups, denotes chloro (CI), iodo

(I), fluoro (F) and bromo (Br). Particular "halogen" is CI and F. Specific is F. The term "optional" or "optionally" as used herein means that a subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optionally substituted" means that the optionally substituted moiety may incorporate a hydrogen atom or a substituent.

The phrase "optional bond" means that the bond may or may not be present, and that the description includes single, double, triple, or aromatic bonds. If a substituent is designated to be a "bond" or "absent", the atoms linked to the substituents are then directly connected.

The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth.

Certain compounds of Formula I may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertable species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate an individual tautomer usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule and the environment to which it is exposed e.g. solvent, temperature, pH, etc.. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates while; in phenols, the enol form predominates. Common prototropic tautomers include keto/enol (-C(=0)-CH-→ -C(-OH)=CH-), amide/imidic acid (-C(=0)-NH- ¾ -C(-OH)=N-) and amidine (-C(=NR)-NH- ¾ -C(-NHR)=N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings and the present invention encompasses all tautomeric forms of the compounds.

Technical and scientific terms used herein have the meaning commonly understood by one of skill in the art to which the present invention pertains, unless otherwise defined. Reference is made herein to various methodologies and materials known to those of skill in the art. Standard reference works setting forth the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10 th Ed., McGraw Hill Companies Inc., New York (2001). Any suitable materials and/or methods known to those of skill can be utilized in carrying out the present invention. However, preferred materials and methods are described. Materials, reagents and the like to which reference are made in the following description and examples are obtainable from commercial sources, unless otherwise noted.

The definitions described herein may be appended to form chemically-relevant combinations, such as "heteroalkylaryl," "haloalkylheteroaryl," "arylalkylheterocyclyl," "alkylcarbonyl," "alkoxyalkyl," and the like. When the term "alkyl" is used as a suffix following another term, as in "phenylalkyl," or "hydroxyalkyl," this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically-named group. Thus, for example, "phenylalkyl" refers to an alkyl group having one to two phenyl substituents, and thus includes benzyl and phenylethyl. An "alkylaminoalkyl" is an alkyl group having one to two alkylamino substituents. "Hydroxyalkyl" includes 2-hydroxyethyl, 2-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, hydroxymethyl, 3-hydroxypropyl, and so forth. Accordingly, as used herein, the term "hydroxyalkyl" is used to define a subset of heteroalkyl groups defined above.

The term "spirocycloalkyl", as used herein, means a spirocyclic cycloalkyl group, such as, for example, spiro[3.3]heptane. The term spiroheterocycloalkyl, as used herein, means a spirocyclic heterocycloalkyl, such as, for example, 2,6-diaza spiro[3.3]heptane.

The term "acyl" as used herein denotes a group of formula -C(=0)R wherein R is hydrogen or lower alkyl as defined herein. The term or "alkylcarbonyl" as used herein denotes a group of formula C(=0)R wherein R is alkyl as defined herein. The term Ci_6 acyl refers to a group -C(=0)R where the R group contains up to 6 carbon atoms. The term "arylcarbonyl" as used herein means a group of formula C(=0)R wherein R is an aryl group; the term "benzoyl" as used herein denotes an "arylcarbonyl" group wherein R is phenyl.

The term "ester" as used herein denotes a group of formula -C(=0)OR wherein R is lower alkyl, cycloalkyl, aryl or heteroaryl as defined herein. The term "alkyl" as used herein denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 10 carbon atoms. The term "lower alkyl" denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms. "Cno alkyl" as used herein refers to an alkyl composed of 1 to 10 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, i-propyl, n- butyl, j-butyl, i-butyl or pentyl, isopentyl, neopentyl, hexyl. A specific lower alkyl group is methyl.

When the term "alkyl" is used as a suffix following another term, as in "phenylalkyl," or "hydroxyalkyl," this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically-named group. Thus, for example, "phenylalkyl" denotes the radical R'R"-, wherein R' is a phenyl radical, and R" is an alkylene radical as defined herein with the understanding that the attachment point of the phenylalkyl moiety will be on the alkylene radical. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl. The terms "arylalkyl" or "aralkyl" are interpreted similarly except R' is an aryl radical. The terms "(het) arylalkyl" or "(het) aralkyl" are interpreted similarly except R' is optionally an aryl or a heteroaryl radical. The terms "haloalkyl" or "halo-lower alkyl" or "lower haloalkyl" refers to a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms wherein one or more carbon atoms are substituted with one or more halogen atoms. Particular halogen is fluoro, and particular "haloalkyl" or "halo-lower alkyl" or "lower haloalkyl" refers to fluoroalkyl" or "fluoro-lower alkyl" or "lower fluoroalkyl".

The term "alkylene" or "alkylenyl" as used herein denotes a divalent saturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g. , (CH 2 ) n )or a branched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms (e.g. , -CHMe- or -CH 2 CH(i-Pr)CH 2 -), unless otherwise indicated. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, 1, 1-dimethyl-ethylene, butylene, 2-ethylbutylene.

The term "alkoxy" as used herein means an -O-alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, w-propyloxy, i-propyloxy, w-butyloxy, i-butyloxy, i-butyloxy, pentyloxy, hexyloxy, including their isomers. "Lower alkoxy" as used herein denotes an alkoxy group with a "lower alkyl" group as previously defined (Ci-ealkoxy). "Cno alkoxy" as used herein refers to an-O-alkyl wherein alkyl is C 1-10 . "Q-ealkoxy" as used herein refers to an-O- alkyl wherein alkyl is C 1-6 , in particular methoxy (OMe).

The term "aryl" denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. The terms "haloalkoxy" or "halo-lower alkoxy" or "lower haloalkoxy" refers to a lower alkoxy group, wherein one or more carbon atoms are substituted with one or more halogen atoms, in particular fluoro.

The term "hydroxyalkyl" as used herein denotes an alkyl radical as herein defined wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups.

The terms "alkylsulfonyl" and "arylsulfonyl" as used herein refers to a group of formula -S(=0) 2 R wherein R is alkyl or aryl respectively and alkyl and aryl are as defined herein. The term "heteroalkylsulfonyl" as used herein denotes a group of formula -S(=0) 2 R wherein R is "heteroalkyl" as defined herein. A particular group is -S0 2 Me. The terms "alkylsulfonylamino" and "arylsulfonylamino" as used herein refers to a group of formula -NR'S(=0) 2 R wherein R is alkyl or aryl respectively, R' is hydrogen or Ci_3 alkyl, and alkyl and aryl are as defined herein.

The term "cycloalkyl" as used herein refers to a saturated or unsaturated carbocyclic ring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. "C3_7 cycloalkyl" or "lower cycloalkyl" as used herein refers to an cycloalkyl composed of 3 to 7 carbons in the carbocyclic ring. Particular groups are cyclohexyl and cyclopentyl.

The term carboxy-alkyl as used herein refers to an alkyl moiety wherein one, hydrogen atom has been replaced with a carboxyl with the understanding that the point of attachment is through a carbon atom. The term "carboxy" or "carboxyl" refers to a -C0 2 H moiety.

The term "heteroaryl" or "heteroaromatic" as used herein means a monocyclic or bicyclic radical of 5 to 12 ring atoms in which there is at least one aromatic ring containing at least one hetero-atom drawn from the list of N, O, or S heteroatoms. Thus, for the purposes of the invention, a heteroaryl group need only have some degree of aromatic character. Heteroaryl may be optionally substituted as defined directly below. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms include, but is not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazole, thiazole, isothiazole, thiadiazole and which can optionally be substituted with one or more, preferably one or two substituents selected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, lower haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples of bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzoxazole, benzisoxazole, benzothiazole, naphthyridinyl, 5,6,7,8-Tetrahydro-[l,6]naphthyridinyl, and benzisothiazole. Bicyclic moieties can be optionally substituted on either ring. A particular group is pyridazinyl.

The term "heterocyclyl", "heterocycloalkyl" or "heterocycle" as used herein denotes a monovalent saturated or unsaturated cyclic radical, consisting of one or more rings, preferably one to two rings, including spirocyclic ring systems, of three to eight atoms per ring, incorporating one or more ring heteroatoms (chosen from N,0 or S(0)o -2 ), and which can optionally be independently substituted with one or more, preferably one or two substituents selected from hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, lower haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and ionic forms thereof, unless otherwise indicated. Examples of heterocyclic radicals include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl, and ionic forms thereof. Examples may also be bicyclic, such as, for example, 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza- bicyclo[2.2.2]octane, or octahydro-pyrazino[2,l-c][l,4]oxazine. The term "PARP" is used herein to mean a protein having ADP-ribosylation activity. Within the meaning of this term, PARP encompass all proteins encoded by a parp gene, mutants thereof, and alternative slice proteins thereof. Additionally, as used herein, the term "PARP" includes PARP analogues, homologues and analogues of other animals. The term "PARP", includes but is not limited to PARP- 1. Within the meaning of this term PARP-2, PARP 3, Vault-PARP (PARP-4), PARP-7 (TiPARP), PARP- 8. PARP 9 (Bal), PARP- 10, PARP-1 1, PARP- 12, PARP- 13, PARP-14, PARP- 15, PARP- 16, TNK-1, IN - 2, and may be encompassed.

The term. " I N *" or " I N S" is used to represent the word, Tankyrase. Compounds that inhibit tankyrase 1 and 2 can have advantageous properties in that they have growth inhibitory activity in cancer cells.

The term "pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and animals. Examples of suitable salts with inorganic and organic acids are, but are not limited to acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methane-sulfonic acid, nitric acid, phosphoric acid, p-toluenesulphonic acid, succinic acid, sulfuric acid, sulphuric acid, tartaric acid, trifluoroacetic acid and the like. Particular acids are formic acid, trifluoroacetic acid and hydrochloric acid.

The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable auxiliary substance" refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.

The term "pharmaceutical composition" encompasses a product comprising specified ingredients in pre-determined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. In particular it encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. The term "inhibitor" denotes a compound which competes with, reduces or prevents the binding of a particular ligand to particular receptor or which reduces or prevents the inhibition of the function of a particular protein.

The term "half maximal inhibitory concentration" (IC 50 ) denotes the concentration of a particular compound required for obtaining 50% inhibition of a biological process in vitro. IC 50 values can be converted logarithmically to pIC 5 o values (-log IC 50 ), in which higher values indicate exponentially greater potency. The IC 50 value is not an absolute value but depends on experimental conditions e.g. concentrations employed. The IC 50 value can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973) 22:3099). The term "inhibition constant" (Ki) denotes the absolute binding affinity of a particular inhibitor to a receptor. It is measured using competition binding assays and is equal to the concentration where the particular inhibitor would occupy 50% of the receptors if no competing ligand (e.g. a radioligand) was present. Ki values can be converted logarithmically to pKi values (-log Ki), in which higher values indicate exponentially greater potency.

"Therapeutically effective amount" means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors. The term "as defined herein" and "as described herein" when referring to a variable incorporates by reference the broad definition of the variable as well as in particular, more particular and most particular definitions, if any. The term "aromatic" denotes the conventional idea of aromaticity as defined in the literature, in particular in IUPAC - Compendium of Chemical Terminology, 2nd, A. D. McNaught & A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997).

The term "pharmaceutically acceptable excipient" denotes any ingredient having no therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products. Whenever a chiral carbon is present in a chemical structure, it is intended that all stereoisomers associated with that chiral carbon are encompassed by the structure.

Tankyrase Inhibitors

The application provides a compound of Formula I, wherein:

R 1 is phenyl, phenyl lower alkyl, cycloalkyl, or cycloalkyl lower alkyl, each optionally substituted with one or more R 1 ; each R 1 is independently lower alkyl, halo, lower alkoxy, lower haloalkyl, lower alkyl sulfonyl, trifluoromethoxy, or cyano;

R 2 is phenyl, optionally substituted with one or more R 2' , napthyl, cyclohexyl, or pyridazinyl; and each R 2' is independently halo, lower alkyl, lower alkoxy, or -C(=0)OCH 3 ; or a pharmaceutically acceptable salt thereof.

The application provides the compound of Formula I, wherein R 1 is phenyl, optionally substituted with one or more R 1 .

The application provides the compound of Formula I, wherein R is phenyl, optionally substituted with one or more R 2' .

The application provides the compound of Formula I, wherein R 1 is phenyl, optionally substituted with one or more R 1 ' , and R 2 is phenyl, optionally substituted with one or more R 2' .

The application provides the compound of Formula I, wherein R 2' is halo.

The application provides the compound of Formula I, wherein R 2' is halo and R 1 is phenyl, optionally substituted with one or more R 1 .

The application provides the compound of Formula I, wherein R 2 is phenyl and R 2' is halo.

The application provides the compound of Formula I, wherein R 2 is phenyl, R 2' is halo, and R 1 is phenyl, optionally substituted with one or more R 1 . The application provides the compound of Formula I, wherein R 1 is methoxy.

The application provides the compound of Formula I, wherein R 1 is phenyl and R 1 is methoxy.

The application provides the compound of Formula I, wherein R 1 ' is methoxy and R 2 is phenyl, optionally substituted with one or more R 2' . The application provides the compound of Formula I, wherein R 1 ' is methoxy, R 2 is phenyl, and R 2' is halo.

The application provides the compound of Formula I, wherein R 1 is phenyl, R 1 is methoxy, R 2 is phenyl, and R 2' is halo.

The application provides the compound of Formula I, wherein R 1 is fluoro. The application provides the compound of Formula I, wherein R 1 is phenyl and R 1 is fluoro.

The application provides the compound of Formula I, wherein R 1 ' is fluoro and R 2 is phenyl, optionally substituted with one or more R 2' . The application provides the compound of Formula I, wherein R 1 ' is fluoro, R 2 is phenyl, and R 2' is halo.

The application provides the compound of Formula I, wherein R 1 is phenyl, R 1 is fluoro,

R 2 is phenyl, and R 2' is halo.

The application provides the compound of Formula I, wherein R 1 is trifluoromethyl, cyano, methyl sulfonyl, or trifluoromethoxy.

The application provides the compound of Formula I, wherein R 1 is phenyl and R 1 is trifluoromethyl, cyano, methyl sulfonyl, or trifluoromethoxy.

The application provides the compound of Formula I, wherein R 1 is trifluoromethyl, cyano, methyl sulfonyl, or trifluoromethoxy and R is phenyl, optionally substituted with one or more R 2' .

The application provides the compound of Formula I, wherein R 1 is trifluoromethyl, cyano, methyl sulfonyl, or trifluoromethoxy, R 2 is phenyl, and R 2' is halo.

The application provides the compound of Formula I, wherein R 1 is phenyl, R 1 is fluoro,

R 2 is phenyl, and R 2' is halo. The application provides the compound of Formula I, wherein R is phenyl, optionally substituted with one or more R 2' , and R 1 ' is methoxy.

The application provides the compound of Formula I, wherein R 2' is methoxy, methyl, or -C(=0)OCH 3 .

The application provides the compound of Formula I, wherein R 2 is phenyl, R 2' is methoxy, methyl, or -C(=0)OCH , and R 1 is methoxy.

The application provides the compound of Formula I, wherein R is phenyl, optionally substituted with one or more R 2' , and R 1 is phenyl lower alkyl, cycloalkyl, or cycloalkyl lower alkyl, each optionally substituted with one or more R 1 .

The application provides the compound of Formula I, wherein R 2 is phenyl, R 2' is halo, and R 1 is phenyl lower alkyl, cycloalkyl, or cycloalkyl lower alkyl, each optionally substituted with one or more R 1 . The application provides the compound of Formula I, wherein R 1 is phenyl, R 1 is methoxy, and R is napthyl, cyclohexyl, or pyridazinyl.

The application provides the compound of Formula I, selected from the group consisting of:

2-(3-Methoxy-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetamide ;

2-(3-Fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetamide; 2-((R)-3-Fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetam ide;

2-((S)-3-Fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetam ide; N- (4-Methoxy-phenyl)-2- (toluene- 3 - sulf inyl) - acetamide ;

N-(4-Methoxy-phenyl)-2-((R)-toluene-3-sulfinyl)-acetamide; N-(4-Methoxy-phenyl)-2-((S)-toluene-3-sulfinyl)-acetamide;

N-(4-Methoxy-phenyl)-2-(naphthalene-2-sulfinyl)-acetamide; N-(4-Methoxy-phenyl)-2-(naphthalene-l-sulfinyl)-acetamide;

2- Cyclohexanesulfinyl-N-(4-methoxy-phenyl)-acetamide;

3- [(4-Methoxy-phenylcarbamoyl)-methanesulfinyl] -benzoic acid methyl ester;

2-(3-Chloro-4-fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-a cetamide; 2-((R)-3-Chloro-4-fluoro-benzenesulfinyl)-N-(4-methoxy-pheny l)-acetamide;

2-((S)-3-Chloro-4-fluoro-benzenesulfinyl)-N-(4-methoxy-pheny l)-acetamide; N- (4-Methoxy-phenyl)-2- (pyridazine- 3 - sulfinyl) - acetamide ;

2- (3 , 5 -Dichloro-benzene sulfinyl) -N- (4-methoxy-phenyl) - acetamide ;

2-(3,4-Difluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-ace tamide;

2-(3-Chloro-benzenesulfinyl)-N-(4-methoxy-benzyl)-acetamide;

2-(3-Chloro-benzenesulfinyl)-N-(4-fluoro-phenyl)-acetamid e;

2-((R)-3-Chloro-benzenesulfinyl)-N-(4-fluoro-phenyl)-acetami de;

2-((S)-3-Chloro-benzenesulfinyl)-N-(4-methanesulfonyl-phe nyl)-acetamide;

2-(3-Chloro-benzenesulfinyl)-N-(4-methanesulfonyl-phenyl)-ac etamide;

2-(3-Chloro-benzenesulfinyl)-N-(3-methoxy-phenyl)-acetami de;

2- (3 -Chloro-benzenesulf inyl) -N- (2-methoxy-phenyl) - acetamide ; 2- -(3- -Chloro- -benzenesulfinyl)--N-cyclohexylmethyl-acetamide;

2- -(3- -Chloro- -benzenesulfinyl)- -N-(3-fluoro-phenyl)-acetamide;

2- -(3- -Chloro- -benzenesulfinyl)- -N- (4- trifluoromethyl-phenyl) -acetamide ;

2- -(3- -Chloro- -benzenesulfinyl)- -N-(4-cyano-phenyl)-acetamide;

2- -(3- -Chloro- -benzenesulfinyl)- -N-(2-fluoro-phenyl)-acetamide;

2- -(3- -Chloro- -benzenesulfinyl)- -N-(4-trifluoromethoxy-phenyl)-acetamide;

2- -(3- -Chloro- -benzenesulfinyl)- -N-cyclohexyl-acetamide; and

2- -(3- -Chloro- -benzenesulfinyl)- -N-cyclopentylmethyl-acetamide.

The application provides a method for treating a Tankyrase-mediated condition comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.

The application provides a method for treating an Tankyrase-mediated condition comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.

The application provides a method for treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.

The application provides a pharmaceutical composition comprising the compound of Formula I.

The application provides the above pharmaceutical composition, admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.

In one variation, the above pharmaceutical composition further comprises an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti- inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

In one aspect, the application provides a use of the compound of formula I in the manufacture of a medicament for the treatment of a Tankyrase-mediated disorder. The application provides a compound or method as described herein.

Compounds of Formula I Examples of representative compounds encompassed by the present invention and within the scope of the invention are provided in the following Table I. These examples and preparations which follow are provided to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

In general, the nomenclature used in this Application is based on AUTONOM™ v.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. If there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.

TABLE I depicts examples of sulfoxide compounds according to generic Formula I:

TABLE I.

Compound Nomenclature Structure

2-(3-Methoxy- benzenesulfinyl) -N- (4-

I-l

methoxy-phenyl) - acetamide ON

2-(3-Fluoro- benzenesulfinyl) -N- (4-

1-2

methoxy-phenyl) - acetamide F

2-((R)-3-Fluoro- ft ft

benzenesulfinyl)-N-(4-

1-3

methoxy-phenyl) - acetamide F 2-Cyclohexanesulfinyl-

I- 10 N- (4-methoxy-phenyl) - acetamide H

3-[(4-Methoxy- phenylcarbamoyl)-

1-11 methanesulfinyl] - benzoic acid methyl

ester

2-(3-Chloro-4-fluoro- benzenesulfinyl) -N- (4-

1-12

methoxy-phenyl) - u H acetamide

2-((R)-3-Chloro-4- fluoro-

1-13 benzenesulfinyl)-N-(4- methoxy-phenyl) - acetamide

2-((S)-3-Chloro-4- fluoro-

1-14 benzenesulfinyl)-N-(4- u H

methoxy-phenyl) - acetamide

N-(4-Methoxy-

1-15 phenyl)-2-(pyridazine- 3 - sulfinyl) -acetamide w H 2-(3,5-Dichloro- benzenesulfinyl) -N- (4--16

methoxy-phenyl) - K H acetamide Cl

2-(3,4-Difluoro- benzenesulfinyl) -N- (4--17

methoxy-phenyl) - acetamide F

2-(3-Chloro- benzenesulfinyl) -N- (4--18

methoxy-benzyl) - acetamide Cl

2-(3-Chloro- benzenesulfinyl) -N- (4--19

fluoro-phenyl)- acetamide Cl

2-((R)-3-Chloro- benzenesulfinyl)-N-(4--20

fluoro-phenyl)- acetamide Cl

2-((S)-3-Chloro- benzenesulfinyl)-N-(4--21

fluoro-phenyl)- acetamide Cl 2-(3-Chloro- benzenesulfinyl) -N- (4--22

methanesulfonyl- phenyl) - acetamide Cl o

2-(3-Chloro- benzenesulfinyl) -N-(3--23

methoxy-phenyl) -

Cl

acetamide

2-(3-Chloro- benzenesulfinyl) -N- (2--24

methoxy-phenyl) - acetamide Cl

2-(3-Chloro- benzenesulfinyl)-N--25

cyclohexylmethyl- acetamide Cl

2-(3-Chloro- benzenesulfinyl) -N-(3--26

fluoro-phenyl)- acetamide Cl

2-(3-Chloro- benzenesulfinyl)-N-

1-32

cyclopentylmethyl- acetamide CI

Synthesis

General Synthetic Schemes

Scheme 1

III

VI

IV

The compounds of formula I where Ri is aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 -cycloalkyl can be prepared by reacting commercially available 2-bromoacetyl chloride with an appropriate amine where Ri is aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 -cycloalkyl in the presence of base (see for example, Vloon, W. J., Kruk, C, Pandit, U.K., Hofs, H. P., McVie, J. G., /. Med. Chem. , 1987, 30(1 ), 20-24).

The compounds of formula II where Ri is aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 -cycloalkyl and R 2 is aryl or substituted aryl can be prepared from the compounds of formula I by displacing the bromide of formula I where Ri is aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 -cycloalkyl with the appropriate thiol compound where R 2 is aryl, substituted aryl, or cycloalkyl (see for example, Etukala, J. R., Yadav, J. S., Heteroatom Chem., 2008, 19(2), 221-227).

The compounds of formula III where Ri is a aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 -cycloalkyl and R 2 is aryl, substituted aryl, or cycloalkyl can be prepared from the compounds of formula II where Ri is a aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 - cycloalkyl and R 2 is aryl, substituted aryl, or cycloalkyl by oxidizing the sulfide to the corresponding sulfoxide under standard conditions (see for example, Jiang, S., Liao, C, Bindu, L., Yin, B., Worthy, K. W., Fisher, R. J., Burke, T. R., Nicklaus, M. C, Roller, P. P., Bioorg Med. Chem. Lett, 2009, 19(10), 2693-2698).

The compounds of formula IN where R 2 is aryl, substituted aryl, or cycloalkyl can be prepared by displacing the bromide of commercially available 2-bromoacetic acid methyl ester with the appropriate thiol compound where R 2 is aryl, substituted aryl, or cycloalkyl (see for example, Etukala, J. R., Yadav, J. S., Heteroatom Chem., 2008, 19(2), 221-227). The compounds of formula V where R 2 is aryl, substituted aryl, or cycloalkyl can be prepared from the compounds of formula IN where R 2 is aryl, substituted aryl, or cycloalkyl by oxidizing the sulfide to the corresponding sulfoxide under standard conditions (see for example, Jiang, S., Liao, C, Bindu, L., Yin, B., Worthy, K. W., Fisher, R. J., Burke, T. R., Nicklaus, M. C, Rolller, P. P., Bioorg Med. Chem. Lett, 2009, 19(10), 2693-2698). The compounds of formula VI where R 2 is aryl, substituted aryl, or cycloalkyl can be prepared from the compounds of formula V where R 2 is aryl, substituted aryl, or cycloalkyl by hydrolyzing the ester to the corresponding acid using standard conditions (see for example, New, J.S., Christopher, W.L., Jass, P.A., /. Org. Chem., 1989, 54, 990-992).

The compounds of formula III where Ri is aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 -cycloalkyl and R 2 is aryl, substituted aryl, or cycloalkyl can be prepared from the compounds of formula VI where Ri is aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 - cycloalkyl and R 2 is aryl, substituted aryl, or cycloalkyl by coupling the acid to the appropriate amines Ri is aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 -cycloalkyl under standard amide bond formation conditions (see for example, Montalbetti, C. A. G. N., Falque, V., Tetrahedron, 2005, 61, 10827-10852). The amines can be commercially available or prepared under standard conditions to synthesize amines from various commercially available substrates.

Scheme 2

4a-x 5a-x

Compounds 5a-x can be synthesized following the reactions outlined in Scheme 2. Commercially available or synthetically accessible alkyl or aryl amines, la-x, and 2-bromoacetyl chloride can be reacted in the presence of base to afford compounds 2a-x (see for example, Vloon, W. J., Kruk, C, Pandit, U.K., Hofs, H. P., McVie, J. G., /. Med. Chem., 1987, 30(1 ), 20- 24). The bromide of compounds 2a-x can be displaced with the commercially available or synthetically accessible thiol, 3a-x, under standard conditions to afford compounds 4a-x (see for example, Etukala, J. R., Yadav, J. S., Heteroatom Chem., 2008, 19(2), 221-227). The thiols, 3a- x, can be commercially available or prepared from the corresponding phenol using such reagents as phosphorous pentasulfide (see for example, Ozturk, T., Ertas, E., Mert, O., Chem Rev. 2010, (110), 3419-3478). The resulting sulfide, 4a-x, can be oxidized to the corresponding sulfoxide, 5a-x, under standard conditions to afford compounds 5a-x (see for example, Jiang, S., Liao, C, Bindu, L., Yin, B., Worthy, K. W., Fisher, R. J., Burke, T. R., Nicklaus, M. C, Rolller, P. P., Bioorg Med. Chem. Lett, 2009, 19(10), 2693-2698 and Ishibashi, H., Harada, S., Okada, M., Somekawa, M., Kido, M., Ikeda, M., Chem. Pharm. Bull., 1989, 37(4), 939-943).

Scheme 3

3a-x 6a-x 7 a -x

^ O Amide coupling O

Base R2 -S^ 0H + H 2 N. R1 conditions R2 ^^ N ' R1

' H

8a-x la-x 5a . x

Compounds 5a-x can be synthesized following the reactions outlined in Scheme 3. Commercially available bromo-acetic acid methyl ester and the appropriate thiol, 3a-x, can be reacted in the presence of base to afford compounds 6a-x (see for example, Etukala, J. R., Yadav, J. S., Heteroatom Chem., 2008, 19(2), 221-227). The thiols, 3a-x, can be commercially available or easily prepared from the corresponding phenol using such reagents as phosphorous pentasulfide (see for example, Ozturk, T., Ertas, E., Mert, O., Chem Rev. 2010, (110), 3419- 3478). The resulting sulfides of compounds 6a-x can be oxidized to the corresponding sulfoxide under standard conditions to afford compounds 7a-x (see for example, Jiang, S., Liao, C, Bindu, L., Yin, B., Worthy, K. W., Fisher, R. J., Burke, T. R., Nicklaus, M. C, Rolller, P. P., Bioorg Med. Chem. Lett, 2009, 19(10), 2693-2698 and Ishibashi, H., Harada, S., Okada, M., Somekawa, M., Kido, M., Ikeda, M., Chem. Pharm. Bull, 1989, 37(4), 939-943). The ester of compounds 7a-x can be hydrolysed to the corresponding acid using standard conditions to afford compounds 8a-x (see for example, New, J.S., Christopher, W.L., Jass, P.A., /. Org. Chem., 1989, 54, 990- 992). Compounds 8a-x can be coupled to the appropriate amines, la-x, under standard amide bond formation conditions to afford compounds 5a-x (see for example, Montalbetti, C. A. G. N., Falque, V., Tetrahedron, 2005, 61, 10827-10852). The amines, la-x, can be commercially available or prepared under standard conditions to synthesize amines from various commercially available substrates.

PHARMACEUTICAL COMPOSITION AND ADMINISTRATION The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms and carriers. Oral administration can be in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, syrups, or suspensions. Compounds of the present invention maybe efficacious when administered by other routes of administration including continuous (intravenous drip) topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal, nasal, inhalation and suppository administration, among other routes of administration. The preferred manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the degree of affliction and the patient's response to the active ingredient. A compound or compounds of the present invention, as well as their pharmaceutically useable salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. A typical preparation will contain from about 5% to about 95% active compound or compounds (w/w). The term "preparation" or "dosage form" is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the target organ or tissue and on the desired dose and pharmacokinetic parameters.

The term "excipient" as used herein refers to a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. The compounds of this invention can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice. "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

A "pharmaceutically acceptable salt" form of an active ingredient may also initially confer a desirable pharmacokinetic property on the active ingredient which was absent in the non-salt form, and may even positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body. The phrase "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene- l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g. , an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.

The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi- dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water. The compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g. , gelatin or blister packs from which the powder may be administered by means of an inhaler.

When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylaza- cycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into to the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polyactic acid. Suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. A skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity.

The modification of the present compounds to render them more soluble in water or other vehicle, for example, may be easily accomplished by minor modifications (salt formulation, esterification, etc.), which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.

The term "therapeutically effective amount" as used herein means an amount required to reduce symptoms of the disease in an individual. The dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved. For oral administration, a daily dosage of between about 0.01 and about 1000 mg/kg body weight per day should be appropriate in monotherapy and/or in combination therapy. A preferred daily dosage is between about 0.1 and about 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg body weight and most preferred 1.0 and about 10 mg/kg body weight per day. Thus, for administration to a 70 kg person, the dosage range would be about 7 mg to 0.7 g per day. The daily dosage can be administered as a single dosage or in divided dosages, typically between 1 and 5 dosages per day. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect for the individual patient is reached. One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient.

The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. INDICATIONS AND METHODS OF TREATMENT

The application provides a method for treating an PARP-mediated condition comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.

The application provides a method for treating an Tankyrase-mediated condition comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.

The application provides a method for treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.

PHARMACEUTICAL COMPOSITIONS The compounds of formula I and the pharmaceutically acceptable salts can be used as therapeutically active substances, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula I and the pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.

The following examples illustrate the present invention without limiting it, but serve merely as representative thereof. The pharmaceutical preparations conveniently contain about 1- 500 mg, in particular 1-100 mg, of a compound of formula I. Examples of compositions according to the invention are:

Example A

Tablets of the following composition are manufactured in the usual manner:

Table 1: possible tablet composition Manufacturing Procedure

1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

2. Dry the granules at 50°C.

3. Pass the granules through suitable milling equipment.

4. Add ingredient 5 and mix for three minutes; compress on a suitable press. Example B-l Capsules of the following composition are manufactured:

Table 2: possible capsule ingredient composition

Manufacturing Procedure

1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add ingredients 4 and 5 and mix for 3 minutes.

3. Fill into a suitable capsule.

The compound of formula I, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer; the talc is added thereto and mixed thoroughly. The mixture is filled by machine into suitable capsules, e.g. hard gelatine capsules.

Example B-2

Soft Gelatine Ca sules of the following composition are manufactured:

Table 3: possible soft gelatine capsule ingredient composition ingredient mg/capsule

Gelatin 75

Glycerol 85 % 32

Karion 83 8 (dry matter) Titan dioxide 0.4

Iron oxide yellow 1.1

Total 116.5

Table 4: possible soft gelatine capsule composition

Manufacturing Procedure

The compound of formula I is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.

Example C

Suppositories of the following composition are manufactured:

Table 5: possible suppository composition

Manufacturing Procedure The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to

45 °C. Thereupon, the finely powdered compound of formula I is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool; the suppositories are then removed from the moulds and packed individually in wax paper or metal foil. Example D

Injection solutions of the following composition are manufactured:

Table 6: possible injection solution composition

Manufacturing Procedure The compound of formula I is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized. Example E

Sachets of the following composition are manufactured:

Table 7: possible sachet composition

Manufacturing Procedure

The compound of formula I is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granulate is mixed with magnesium stearate and the flavoring additives and filled into sachets.

EXAMPLES

Commonly used abbreviations include: acetyl (Ac), azo-bis-isobutyrylnitrile (AIBN), atmospheres (Atm), 9-borabicyclo[3.3.1]nonane (9-BBN or BBN), 2,2'-bis(diphenylphosphino)- Ι,Γ-binaphthyl (BINAP), iert-butoxycarbonyl (Boc), di-iert-butyl pyrocarbonate or boc anhydride (BOC 2 0), benzyl (Bn), butyl (Bu), Chemical Abstracts Registration Number (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI), 1,4- diazabicyclo[2.2.2]octane (DABCO), diethylamino sulfur trifluoride (DAST), dibenzylideneacetone (dba), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), Ν,Ν'-dicyclohexylcarbodiimide (DCC), 1,2- dichloroethane (DCE), dichloromethane (DCM), 2,3-Dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), diethyl azodicarboxylate (DEAD), di-isopropylazodicarboxylate (DIAD), di-iso- butylaluminumhydride (DIBAL or DIBAL-H), di-iso-propylethylamine (DIPEA), N,N-dimethyl acetamide (DMA), 4-N,N-dimethylaminopyridine (DMAP), Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), l,l'-bi5'-(diphenylphosphino)ethane (dppe), l,V-bis- (diphenylphosphino)ferrocene (dppf), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline (EEDQ), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H-quinoline-l-carboxylic acid ethyl ester (EEDQ), diethyl ether (Et 2 0), ethyl isopropyl ether (EtOiPr), 0-(7-azabenzotriazole-l-yl)-N, Ν,Ν'Ν'-tetramethyluronium hexafluorophosphate acetic acid (HATU), acetic acid (HOAc), 1-N- hydroxybenzotriazole (HOBt), high pressure liquid chromatography (HPLC), isopropanol (IPA), isopropylmagnesium chloride (iPrMgCl), hexamethyl disilazane (HMDS), hexanes (hex), liquid chromatography mass spectrometry (LCMS), lithium hexamethyl disilazane (LiHMDS), meta- chloroperoxybenzoic acid (m-CPBA), methanol (MeOH), melting point (mp), MeS0 2 - (mesyl or Ms), methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrum (ms), methyl i-butyl ether (MTBE), methyl tetrahydrofuran (MeTHF), N-bromosuccinimide (NBS), n-Butyllithium (nBuLi), N-carboxyanhydride (NCA), N-chlorosuccinimide (NCS), N- methylmorpholine (NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), Dichloro-((bis-diphenylphosphino)ferrocenyl) palladium(II) (Pd(dppf)Cl 2 ), palladium(II) acetate (Pd(OAc) 2 ), tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ), pyridinium dichromate (PDC), phenyl (Ph), propyl (Pr), isopropyl (i-Pr), pounds per square inch (psi), pyridine (pyr), 1,2,3,4,5- Pentaphenyl-l'-(di-tert-butylphosphino)ferrocene (Q-Phos), room temperature (ambient temperature, rt or RT), sec-Butyllithium (sBuLi), iert-butyldimethylsilyl or i-BuMe 2 Si (TBDMS), tetra-n-butylammonium fluoride (TBAF), triethylamine (TEA or Et 3 N), 2,2,6,6- tetramethylpiperidine 1-oxyl (TEMPO), triflate or CF 3 S0 2 - (Tf), trifluoroacetic acid (TFA), 1,1'- bis-2,2,6,6-tetramethylheptane-2,6-dione (TMHD), O-benzotriazol- l-yl-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU), thin layer chromatography (TLC), tetrahydrofuran (THF), trimethylsilyl or Me Si (TMS), p-toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C 6 H 4 S0 2 - or tosyl (Ts), and N-urethane-N-carboxyanhydride (UNCA). Conventional nomenclature including the prefixes normal (n), iso (i-), secondary (sec-), tertiary (tert-) and neo have their customary meaning when used with an alkyl moiety. (J. Rigaudy and D. P. Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford.).

Preparation 1.

Pyridazine-3-thiol

A solution of pyridazin-3-ol (1.0 g, 10.4 mmol) in pyridine (15 mL) was treated with phosphorous pentasulfide (924 mg, 4.16 mmol) at room temperature. This solution was then stirred at reflux temperature for 1 h. At this time, the resulting mixture was cooled to room temperature and concentrated in vacuo to afford pyridazine-3-thiol as a yellow solid (560 mg, 48%). This material was used without further purification. 1H NMR (300 MHz, DMSO- 6 ) δ 14.74 (s, 1H), 8.26 (del, J = 4.1, 1.6 Hz, 1H), 7.61 - 7.58 (m, 1H), 7.23 - 7.27 (dd, J = 9.1, 4.1 Hz, 1H).

Preparation 2.

N-(4-Methoxy-phenyl)-2-(3-methoxy-phenylsulfanyl)-acetami de

A solution of 4-methoxyaniline (5.00 g, 40.7 mmol) in tetrahydrofuran (50 mL) at - 78°C was treated with triethylamine (4.19 g, 41.5 mmol) followed by 2-bromoacetyl chloride (6.38 g, 40.7 mmol) which upon addition formed a precipitate. The reaction was allowed to slowly warm up to 25 °C where it was stirred overnight. At this time, the mixture was poured into water (100 mL), extracted with methylene chloride (2 x 50 mL), washed with a saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate and concentrated. The resulting residue was purified by a chromatography (petroleum ethenethyl acetate = 8 : 1) to afford 2-bromo-N-(4-methoxy-phenyl)-acetamide as a light brown solid (8.1 g, 82%). 1H NMR (300 MHz, DMSO- ): δ ppm 8.67 (s, 1H), 7.18 - 6.85 (m, 4H), 4.20 (m, 2H), 4.08 -3.87 (m, 2H), 3.72 (s, 3H). LC-MS: 244 [M+l] + , R t = 1.400 min.

A solution of 2-bromo-N-(4-methoxy-phenyl)-acetamide (200 mg, 0.82 mmol) in tetrahydrofuran (4 mL) and water (4 mL) was treated with N-methylmorpholine (190 mg, 1.89 mmol) and then treated quickly dropwise with a solution of 3-methoxy-benzenethiol (230 mg, 1.65 mmol) in tetrahydrofuran (3 mL). The reaction solution was stirred at 25 °C overnight. At this time, the resulting mixture was concentrated in vacuo. The residue was diluted with water (30 mL) and extracted with a solution of 10% methanol in methylene chloride (2 x 30 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 8: 1) to afford N-(4-methoxy- phenyl)-2-(3-methoxy-phenylsulfanyl)-acetamide as a yellow solid (510 mg, 85%). LC-MS: 304 [M+l] + , R t = 1.515 min.

In an analogous manner the following compounds were synthesized following the above procedure:

Preparation 3. From 2-bromo-N-(4-methoxy-phenyl)-acetamide and 3-fluoro-benzenethiol: 2-(3- Fluoro-phenylsulfanyl)-N-(4-methoxy-phenyl)-acetamide was obtained as a yellow solid (510 mg, 85%). LC-MS: 292 [M+l] + , R t = 1.529 min.

Preparation 4. From 2-bromo-N-(4-methoxy-phenyl)-acetamide and 3-methyl-benzenethiol: N-(4-

Methoxy-phenyl)-2-m-tolylsulfanyl-acetamide was obtained as a yellow solid (500 mg, 85%). LC-MS: 288 [M+l] + , R t = 1.575 min.

Preparation 5.

From 2-bromo-N-(4-methoxy-phenyl)-acetamide and naphthalene-2-thiol: N-(4- Methoxy-phenyl)-2-(naphthalen-2-ylsulfanyl)-acetamide was obtained as yellow solid (480 mg, 90%) .LC-MS: 324 [M+l] + , R t = 1.623 min.

Preparation 6.

From 2-bromo-N-(4-methoxy-phenyl)-acetamide and naphthalene- 1 -thiol: N-(4- Methoxy-phenyl)-2-(naphthalen- l-ylsulfanyl)-acetamide was obtained as white solid (500mg, 93%). LC-MS: 324 [M+l] + , R t = 1.622 min.

Preparation 7.

From 2-bromo-N-(4-methoxy-phenyl)-acetamide and cyclohexanethiol: 2- Cyclohexylsulfanyl-N-(4-methoxy-phenyl)-acetamide was obtained as a white solid (260 mg, 57%). LC-MS: 280 [M+l] + , R t = 1.630 min. Preparation 8.

From 2-bromo-N-(4-methoxy-phenyl)-acetamide and 3-mercapto-benzoic acid methyl ester: 3- [(4-Methoxy-phenylcarbamoyl)-methylsulfanyl] -benzoic acid methyl ester was obtained as a white solid (500 mg, 91%). LC-MS: 304 [M+l] + , R t = 1.515 min.

Preparation 9. From 2-bromo-N-(4-methoxy-phenyl)-acetamide and 3-chloro-4-fluoro-benzenethiol: 2-

(3-Chloro-4-fluoro-phenylsulfanyl)-N-(4-methoxy-phenyl)-a cetamide was obtained as a yellow solid (400 mg, 75%). LC-MS: 304 [M+l] + , R t = 1.599 min.

Preparation 10.

From 2-bromo-N-(4-methoxy-phenyl)-acetamide and pyridazine-3-thiol: N-(4- Methoxy-phenyl)-2-(pyridazin-3-ylsulfanyl)-acetamide was obtained as a yellow solid (400 mg, 88%). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 10.20 (s, 1H), 8.98 (m, 1H), 7.74 - 7.71 (m, 1H), 7.56 - 7.50 (m, 3H), 6.86 - 6.59 (m, 2H), 4.22 (m, 2H), 3.72 (s, 3H). LC-MS: 276 [M+l] + , R t = 1.303 min.

Preparation 11. From 2-bromo-N-(4-methoxy-phenyl)-acetamide and 3,5-dichloro-benzenethiol: 2-(3,5- dichloro-phenylsulfanyl)-N-(4-methoxy-phenyl)-acetamide was obtained as an off-white solid (0.26 g, 74.2%). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 3.71 (s, 3 H) 3.95 (s, 2 H) 6.89 (d, J=9.04 Hz, 2 H) 7.28 - 7.59 (m, 5 H) 10.13 (s, 1 H).

Preparation 12. From 2-bromo-N-(4-methoxy-phenyl)-acetamide and 3,4-difluoro-benzenethiol: 2-(3,4- difluoro-phenylsulfanyl)-N-(4-methoxy-phenyl)-acetamide was obtained as an off-white solid (302.2 mg, 95.4%). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 3.72 (s, 3 H) 3.85 (s, 2 H) 6.88 (d, J=9.04 Hz, 2 H) 7.20 - 7.31 (m, 1 H) 7.34 - 7.50 (m, 3 H) 7.51 - 7.63 (m, 1 H) 10.07 (s, 1 H).

Example 1.

2-(3-Methoxy-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetamide (1-1)

A solution of N-(4-methoxy-phenyl)-2-(3-methoxy-phenylsulfanyl)-acetamide (200 mg, 0.66 mmol) in acetic acid (4 mL) was treated with 30% aqueous hydrogen peroxide (224 mg, 6.60 mmol) at room temperature. This solution was then stirred at 40°C for 1 h. At this time, the resulting mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with a IN aqueous hydrochloric acid solution (30 mL), water (30 mL), a saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5 : 1) to afford compound 2-(3-methoxy-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetamide as a white solid (200 mg, 95%). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 10.08 (s, 1H), 7.52 - 7.43 (m, 3H), 7.27 - 7.25 (m, 2H), 7.11 - 7.08 (m, 1H), 6.91 - 6.86 (m, 2H), 4.03 - 3.83 (m, 2H), 3.71 (s, 3H). LC-MS: 320 [M+l] + , Rt = 1.368 min. HPLC: 98.34 % at 214 nm, 99.30 % at 254 nm, R t = 3.333 min.

In an analogous manner the following sulfoxides were synthesized following the above procedure: Example 2.

2-(3-Fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetami de (1-2)

From 2-(3-fluoro-phenylsulfanyl)-N-(4-methoxy-phenyl)-acetamide: 2-(3-Fluoro- benzenesulfinyl)-N-(4-methoxy-phenyl)-acetamide was obtained as a white solid (200 mg, 63%). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 10.09 (s, 1H), 7.63 - 7.54 (m, 3H), 7.44 - 7.41 (m, 3H), 6.89 - 6.86 (m, 2H), 4.09 - 3.85 (m, 2H), 3.71 (s, 3H). LC-MS: 308 [M+l] + , R t = 1.371 min. HPLC: 99.1 % at 214 nm, 99.7 % at 254 nm, R t = 4.470 min.

Example 3. 2-((R)-3-Fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetam ide (1-3)

Isomer 1 ; Supercritical fluid chromatography; Chiralpak AS-H, 40°C, Flow rate 60 mL/min, 40% methanol; UV wavelength: 260 nM; R t = 2.21 min; white solid (47.1 mg). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 3.72 (s, 3 H) 3.83 - 3.97 (m, 1 H) 3.99 - 4.16 (m, 1 H) 6.90

(d, J=8.85 Hz, 2 H) 7.44 (d, J=9.04 Hz, 3 H) 7.57 (d, J=7.72 Hz, 2 H) 7.61 - 7.73 (m, 1 H) 10.08 (s, 1 H).

Example 4.

2-((S)-3-Fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-ace tamide (1-4)

Isomer 2; Chiralpak AS-H, 40°C, Flow rate 60 mL/min, 40% methanol; UV wavelength:

260 nM; R t = 2.91 min; white solid (44.9 mg); 1H NMR (300 MHz, DMSO- 6 ) δ ppm 3.72 (s, 3 H) 3.82 - 3.97 (m, 1 H) 3.98 - 4.19 (m, 1 H) 6.89 (d, J=8.67 Hz, 2 H) 7.44 (d, J=8.67 Hz, 3 H) 7.57 (d, J=8.29 Hz, 2 H) 7.61 - 7.73 (m, 1 H) 10.08 (s, 1 H).

Example 5.

N-(4-Methoxy-phenyl)-2-(toluene-3-sulfinyl)-acetamide (1-5)

From N- (4-Methoxy-phenyl) -2-m-tolylsulf anyl- acetamide : N- (4-Methoxy-phenyl) -2- (toluene-3-sulfinyl)-acetamide was obtained as a white solid (260 mg, 82%). 1H NMR (300 MHz, DMSO- ) δ ppm 10.07 (s, 1H), 7.52 - 7.42 (m, 6H), 6.89 - 6.82 (m, 2H), 4.20 - 4.18 (s, 2H), 3.97 - 3.82 (m, 2H), 3.71 (s, 3H). LC-MS: 304 [M+l] + , R t = 1.390 min. HPLC: 99.10 % at 214 nm, 99.63 % at 254 nm, R t = 3.370 min.

Example 6.

N-(4-Methoxy-phenyl)-2-((R)-toluene-3-sulfinyl)-acetamide (1-6)

Isomer 1 ; Supercritical fluid chromatography; Chiralpak AS-H, 40°C, Flow rate 60 mL/min, 40% methanol; UV wavelength: 260 nM; R t = 2.36 min; off-white solid (40.3 mg); 1H NMR (300 MHz, DMSO- 6 ) δ ppm 2.38 (s, 3 H) 3.72 (s, 3 H) 3.77 - 4.08 (m, 2 H) 6.89 (d, J=9.04 Hz, 2 H) 7.29 - 7.65 (m, 6 H) 10.06 (s, 1 H).

Example 7.

N-(4-Methoxy-phenyl)-2-((S)-toluene-3-sulfinyl)-acetamide (1-7)

Isomer 2; Supercritical fluid chromatography; Chiralpak AS-H, 40°C, Flow rate 60 mL/min, 40% methanol; UV wavelength: 260 nM; R t = 3.34 min; off-white solid (43.6 mg); 1H NMR (300 MHz, DMSO- 6 ) δ ρρηι 2.38 (s, 3 H) 3.72 (s, 3 H) 3.79 - 4.07 (m, 2 H) 6.90 (d, J=8.48 Hz, 2 H) 7.28 - 7.68 (m, 6 H) 10.06 (s, 1 H).

Example 8.

N-(4-Methoxy-phenyl)-2-(naphthalene-2-sulfinyl)-acetamide (1-8)

From N-(4-methoxy-phenyl)-2-(naphthalen-2-ylsulfanyl)-acetamide: N-(4-Methoxy- phenyl)-2-(naphthalene-2-sulfinyl)-acetamide was obtained as a white solid (180 mg, 57%). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 10.11 (s, 1H), 8.31 - 8.30 (m, 1H), 8.03 - 8.01 (m, 3H), 7.78 - 7.62 (m, 3H), 7.44 - 7.41 (m, 2H), 6.89 - 6.81 (m, 2H), 4.12 - 3.91 (m, 2H), 3.71 (s, 3H). LC- MS: 340 [M+l] + , R t = 1.447 min. HPLC: 98.89 % at 214 nm, 99.23 % at 254 nm, R t = 3.720 min.

Example 9.

N-(4-Methoxy-phenyl)-2-(naphthalene-l-sulfinyl)-acetamide (1-9)

From N-(4-methoxy-phenyl)-2-(naphthalen- 1 -ylsulfanyl)-acetamide: N-(4-Methoxy- phenyl)-2-(naphthalene- l-sulfinyl)-acetamide was obtained as a white solid (210 mg, 67%). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 10.15 (s, 1H), 8.18 - 8.05 (m, 4H), 7.77 - 7.66 (m, 3H), 7.45 - 7.42 (m, 2H), 6.90 - 6.87 (m, 1H), 4.12 - 3.91 (m, 2H), 3.71 (s, 3H). LC-MS: 340 [M+l] + , R t = 1.447 min. HPLC: 95.32 % at 214 nm, 97.72 % at 254 nm, R t = 5.270 min.

Example 10. 2-Cyclohexanesulfinyl-N-(4-methoxy-phenyl)-acetamide (1-10) From 2-cyclohexylsulfanyl-N-(4-methoxy-phenyl)-acetamide: 2-Cyclohexanesulfinyl- N- (4-methoxy-phenyl) -acetamide was obtained as a white solid (190 mg, 69%). 1 H NMR (300 MHz, DMSO- ) δ ppm 10.16 ( , 1H), 7.53 - 7.46 ( , 2H), 6.92 - 6.87 (m, 2H), 3.85 - 3.64 (m, 4H), 2.86 - 2.72 (m, 1H), 1.98 - 1.76 ( , 4H), 1.69 - 1.60 ( , 1H), 1.48 - 1.13 ( , 5H). LC-MS: 340 [M+l] + , R t = 1.376 min. HPLC: 96.87% at 214 nm, 97.30% at 254 nm, R t =5.213 min.

Example 11.

3-[(4-Methoxy-phenylcarbamoyl)-methanesulfinyl]-benzoic acid methyl ester (I-ll)

From 3-[(4-methoxy-phenylcarbamoyl)-methylsulfanyl]-benzoic acid methyl ester: 3- [(4-Methoxy-phenylcarbamoyl)-methanesulfinyl] -benzoic acid methyl ester was obtained as a white solid (180 mg, 43%). 1 H NMR (300 MHz, DMSO- 6 ) δ ppm 10.07 (s, 1H), 8.29 (d, J = 1.5 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.74 (i, J = 7.8 Hz, 1H), 7.42 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 4.06 (d, J = 13.2 Hz, 1H), 3.95 - 3.86 (m, 3H), 3.72 (s, 3H). LC-MS: 348 [M+l] + , R t = 1.402 min. HPLC: 95.05 % at 214 nm, 96.05 % at 254 nm, R t = 4.387 min.

Example 12.

2-(3-Chloro-4-fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl )-acetamide (1-12)

From 2-(3-chloro-4-fluoro-phenylsulfanyl)-N-(4-methoxy-phenyl)-ac etamide: 2-(3- Chloro-4-fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetam ide was obtained as a white solid (130 mg, 31%). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 10.06 (s, 1H), 7.95 - 7.89 (m, 1H), 7.73 (m, 1H), 7.70 - 7.62 (m, 1H), 7.41 (d, J = 9.1 Hz, 2H), 6.92 - 6.84 (m, 2H), 4.10 - 4.04 (m, 1H), 3.90 (d, J = 13.3 Hz, 1H), 3.71 (s, 3H). LC-MS: 342 [M+l] + , R t = 1.478 min. HPLC: 100 % at 214 nm, 100 % at 254 nm, R t = 0.742 min. Example 13.

2-((R)-3-Chloro-4-fluoro-benzenesulfinyl)-N-(4-methoxy-ph enyl)-acetamide (1-13)

Isomer 1 ; Supercritical fluid chromatography; Chiralpak AS-H, 40°C, Flow rate 60 mL/min, 40% methanol; UV wavelength: 260 nM; R t = 2.53 min; white solid (45.8 mg); 1H NMR (300 MHz, DMSO- 6 ) δ ppm 3.72 (s, 3 H) 3.91 (m, 1 H) 4.01 - 4.19 (m, 1 H) 6.89 (d, J=9.04 Hz, 2 H) 7.43 (d, J=8.67 Hz, 2 H) 7.57 - 7.82 (m, 2 H) 7.94 (d, J=6.78 Hz, 1 H) 10.07 (s, 1 H).

Example 14.

2-((S)-3- Chloro-4-fluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetam ide (1-14) Isomer 2; Supercritical fluid chromatography; Chiralpak AS-H, 40°C, Flow rate 60 mL/min, 40% methanol; UV wavelength: 260 nM; R t = 3.68 min; white solid (47.8 mg); 1H NMR (300 MHz, DMSO- 6 ) δ ppm 3.72 (s, 3 H) 3.83 - 3.98 (m, 1 H) 4.00 - 4.17 (m, 1 H) 6.90 (d, J=8.67 Hz, 2 H) 7.43 (d, J=8.85 Hz, 2 H) 7.56 - 7.84 (m, 2 H) 7.94 (d, J=6.78 Hz, 1 H) 10.08 (s, 1 H). Example 15.

N-(4-Methoxy-phenyl)-2-(pyridazine-3-sulfinyl)-acetamide (1-15)

From N-(4-methoxy-phenyl)-2-(pyridazin-3-ylsulfanyl)-acetamide: /V-(4-Methoxy- phenyl)-2-(pyridazine-3-sulfinyl)-acetamide (400 mg) was obtained as a yellow solid (80 mg, 19%). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 10.21 (s, 1H), 9.38 (del, J = 5.0, 1.6 Hz, 1H), 8.16 (del, J = 8.5, 1.6 Hz, 1H), 8.03 (dd, J = 8.5, 5.0 Hz, 1H), 7.44 (d, J = 9.1 Hz, 2H), 6.88 (d, J = 9.1 Hz, 2H), 4.31 (d, J = 13.6 Hz, 1H), 4.04 (d, J = 13.6 Hz, 1H), 3.72 (s, 3H). LC-MS: 292 [M+l] + , R t = 1.198 min. HPLC: 99.20 % at 214 nm, 99.65 % at 254 nm, R t = 4.617 min.

Example 16. 2-(3,5-Dichloro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetam ide (1-16)

From 2- (3 , 5 -dichloro -phenylsulf anyl) -N- (4-methoxy-phenyl)- acetamide : 2- (3 , 5 - Dichloro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetamide (0.26 g) was obtained as an off- white solid (49.8 mg, 18.3%). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 3.72 (s, 3 H) 3.93 (d, J=13.38 Hz, 1 H) 4.15 (d, J=13.37 Hz, 1 H) 6.90 (d, J=9.04 Hz, 2 H) 7.43 (d, J=9.04 Hz, 2 H) 7.75 (d, J=1.88 Hz, 2 H) 7.85 (t, J=1.88 Hz, 1 H) 10.08 (s, 1 H)

Example 17.

2-(3,4-Difluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetam ide (1-17)

From 2-(3,4-difluoro-phenylsulfanyl)-N-(4-methoxy-phenyl)-acetami de: 2-(3,4- Difluoro-benzenesulfinyl)-N-(4-methoxy-phenyl)-acetamide (302 mg) was obtained as a white solid (244.6 mg, 77%). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 3.72 (s, 3 H) 3.80 - 3.96 (m, 1 H) 4.07 (d, J=13.37 Hz, 1 H) 6.80 - 6.96 (m, 2 H) 7.35 - 7.50 (m, 2 H) 7.55 - 7.65 (m, 1 H) 7.72 (dt, J=10.36, 8.10 Hz, 1 H) 7.83 (ddd, J=9.89, 7.63, 2.07 Hz, 1 H) 10.09 (s, 1 H).

Preparation 13.

2-Bromo-N-(4-methoxy-benzyl)-acetamide

A solution of tetrahydrofuran (60 mL) at -78°C was treated with compound 4-methoxy- benzylamine (1.0 g, 7.3 mmol) followed by triethylamine (838 mg, 8.29 mmol). This solution was then treated with 2-bromoacetyl chloride (1.28 g, 8.13 mmol) which upon addition resulted in the formation of a precipitate. The reaction was allowed to slowly warm to 25°C where upon it was stirred overnight. At this time, the reaction was poured into water (100 mL), extracted with methylene chloride (2 x 100 mL), washed with a saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5 : 1) to afford 2- bromo-N-(4-methoxy-benzyl)-acetamide as a yellow solid (630 mg, 34%). 1H NMR (300 MHz, DMSO- ) δ ppm 8.67 (s, 1H), 6.85 - 7.18 (m, 4H), 4.20 (m, 2H), 3.87 - 4.08 (m, 2H), 3.72 (s, 3H). LC-MS: 258 [M+l] + , R t = 1.393 min. In an analogous manner the following compounds were synthesized following the above procedure:

Preparation 14.

From 2-bromoacetyl chloride and 4-fluoro-phenylamine: 2-Bromo-N-(4-fluoro-phenyl)- acetamide was obtained as a white solid (1.20 g, 85%). LC-MS: 232 [M+l] + , R t = 1.425 min. Preparation 15.

From 2-bromoacetyl chloride and 4-methanesulfonyl-phenylamine: 2-Bromo-N-(4- methanesulfonyl-phenyl)-acetamide was obtained as a white solid (1.20 g, 88%). LC-MS: 292 [M+l] + , R t = 1.256 min.

Preparation 16. From 2-bromoacetyl chloride and 3-methoxy-phenylamine: 2-Bromo-N-(3-methoxy- phenyl)-acetamide was obtained as a white solid (1.56 g, 78%). LC-MS: 244 [M+l] + , R t = 1.388 min.

Preparation 17.

From 2-bromoacetyl chloride and 2-methoxy-phenylamine: 2-Bromo-N-(2-methoxy- phenyl)-acetamide was obtained as a yellow solid (800 mg, 42%). LC-MS: 244 [M+l] + , R t = 1.455 min.

Preparation 18.

From 2-bromoacetyl chloride and cyclohexanemethylamine: 2-Bromo-N- cyclohexylmethyl-acetamide was obtained as a white solid (1.00 g, 48%). LC-MS: 234 [M+l] + , R t = 1.485 min.

Preparation 19.

2-(3-Chloro-phenylsulfanyl)-N-(4-methoxy-benzyl)-acetamid e

A solution of compound 2-bromo-N-(4-methoxy-benzyl)-acetamide (500 mg, 1.95 mmol) in tetrahydrofuran (6 mL) and water (6 mL) was treated with N-methylmorpholine (456 mg, 4.50 mmol) and then treated quickly dropwise with a solution of 3-chlorothiophenol (560 mg, 3.87 mmol) in tetrahydrofuran (3 mL). The reaction solution stirred at 25 °C overnight. At this time, the resulting mixture was concentrated in vacuo. The residue was diluted with water (30 mL) and extracted with a solution of 10% methanol in methylene chloride (2 x 30 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5 : 1) to afford 2-(3-chloro-phenylsulfanyl)- N-(4-methoxy-benzyl)-acetamide as a white solid (620 mg, 99%). LC-MS: 322 [M+l] + , R t = 1.562 min.

In an analogous manner the following compounds were synthesized following the above procedure: Preparation 20.

From 3-chlorothiophenol and 2-bromo-N-(4-fluoro-phenyl)-acetamide: 2-(3-Chloro- phenylsulfanyl)-N-(4-fluoro-phenyl)-acetamide was obtained as a white solid (560 mg, 86%). LC-MS: 296 [M+l] + , R t = 1.646 min.

Preparation 21. From 3-chlorothiophenol and 2-bromo-N-(4-methanesulfonyl-phenyl)-acetamide: 2-(3-

Chloro-phenylsulfanyl)-N-(4-methanesulfonyl-phenyl)-aceta mide was obtained as a yellow solid (450 mg, 74%). LC-MS: 356 [M+l] + , R t = 1.508 min.

Preparation 22.

From 3-chlorothiophenol and 2-bromo-N-(3-methoxy-phenyl)-acetamide: 2-(3-Chloro- phenylsulfanyl)-N-(3-methoxy-phenyl)-acetamide was obtained as a yellow solid (530 mg, 84%). LC-MS: 308 [M+l] + , R t = 1.620 min.

Preparation 23.

From 3-chlorothiophenol and 2-bromo-N- (2-methoxy-phenyl) -acetamide : 2- (3 -Chloro- phenylsulfanyl)-N-(2-methoxy-phenyl) i-acetamide was obtained as a white solid (550 mg, 87%). LC-MS: 308 [M+l] + , R t = 1.674 min. Preparation 24.

From 3-chlorothiophenol and 2-bromo-N-cyclohexylmethyl-acetamide: 2-(3-Chloro- phenylsulfanyl)-N-cyclohexylmethyl-acetamide was obtained as a white solid (1.05 g, 82%). LC- MS: 298 [M+l] + , R t = 1.686 min. Example 18.

2-(3-Chloro-benzenesulfinyl)-N-(4-methoxy-benzyl)-acetami de (1-18)

A solution of compound 2-(3-chloro-phenylsulfanyl)-N-(4-methoxy-benzyl)-acetamide (300 mg, 0.94 mmol) in acetic acid (5 mL) was treated with 30% aqueous hydrogen peroxide (318 mg, 9.4 mmol) at room temperature. This solution was then stirred at 40°C for 1 h. The resulting mixture was cooled to room temperature and diluted with ethyl acetate (30 mL), washed with a IN aqueous hydrochloric acid solution (30 mL), water (30 mL), a saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5 : 1) to afford 2-(3-chloro-benzenesulfinyl)-N-(4-methoxy-benzyl)-acetamide as a white solid (200 mg, 63%). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 8.56 - 8.53 (m, 1H), 7.70 - 7.55 (m, 3H), 7.13 - 7.08 (m, 2H), 6.88 - 6.83 (m, 2H), 4.19 (d, J = 5.8 Hz, 2H), 3.95 - 3.77 (m, 2H), 3.72 (s, 3H). LC- MS: 308 [M+l] + , R t = 1.412 min. HPLC: 99.79 % at 214 nm, 99.52 % at 254 nm, R t = 3.498 min.

In an analogous manner the following compounds were synthesized following the above procedure:

Example 19.

2-(3-Chloro-benzenesulfinyl)-N-(4-fluoro-phenyl)-acetamid e (1-19)

From 2-(3-chloro-phenylsulfanyl)-N-(4-fluoro-phenyl)-acetamide: 2-(3-Chloro- benzenesulfinyl)-N-(4-fluoro-phenyl)-acetamide was obtained as a white solid (120 mg, 20%). 1H NMR (300 MHz, DMSO- 6 ): δ ppm 10.10 (s, 1H), 7.77 - 7.76 (m, 1H), 7.70 - 7.60 (m, 3H), 7.54 - 7.49 (m, 1H), 7.39 - 7.32 (m, 1H), 7.23 - 7.20 (m, 1H), 6.96 - 6.94 (m, 1H), 4.16 - 3.91(m, 2H). LC-MS: 312 [M+l] + , R t = 1.513 min. HPLC: 98.59 % at 214 nm, 99.37 % at 254 nm, R t = 5.487 min.

Example 20. 2-((R)-3-Chloro-benzenesulfinyl)-N-(4-fluoro-phenyl)-acetami de (1-20)

Isomer 1; Supercritical fluid chromatography; Chiralpak AS-H, 40°C, Flow rate 60 mL/min, 40% methanol; UV wavelength: 260 nM; R t = 2.43 min; white solid (34.8 mg). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 3.83 - 4.01 (m, 1 H) 4.03 - 4.24 (m, 1 H) 6.85 - 7.00 (m, 1 H) 7.23 (d, J=8.10 Hz, 1 H) 7.30 - 7.43 (m, 1 H) 7.53 (d, J=10.93 Hz, 1 H) 7.58 - 7.73 (m, 3 H) 7.78 (s, 1 H) 10.43 (s, 1 H).

Example 21.

2-((S)-3-Chloro-benzenesulfinyl)-N-(4-fluoro-phenyl)-acet amide (1-20)

Isomer 2; Supercritical fluid chromatography; Chiralpak AS-H, 40°C, Flow rate 60 mL/min, 40% methanol; UV wavelength: 260 nM; R t = 3.24 min; white solid (35 mg). 1H NMR (300 MHz, DMSO- ) δ ppm 3.79 - 4.01 (m, 1 H) 4.03 - 4.25 (m, 1 H) 6.86 - 7.00 (m, 1 H) 7.23 (d, J=7.91 Hz, 1 H) 7.30 - 7.44 (m, 1 H) 7.53 (d, J=11.49 Hz, 1 H) 7.59 - 7.74 (m, 3 H) 7.78 (s, 1 H) 10.43 (s, 1 H). Example 22.

2-(3-Chloro-benzenesulfinyl)-N-(4-methanesulfonyl-phenyl) -acetamide (1-22)

From 2-(3-chloro-phenylsulfanyl)-N-(4-methanesulfonyl-phenyl)-ace tamide: 2-(3- Chloro-benzenesulfinyl)-N-(4-methanesulfonyl-phenyl)-acetami de was obtained as a white solid (300 mg, 64 ). 1 H NMR (300 MHz, DMSO- 6 ) δ ppm 10.10 (s, 1H), 7.88 - 7.57 (m, 8H), 4.20 - 3.95 (m, 2H), 3.30 (s, 3H). LC-MS: 372 [M+l] + , R t = 1.342 min. HPLC: 99.65 % at 214 nm, 99.65 % at 254 nm, R t = 4.173 min.

Example 23.

2-(3-Chloro-benzenesulfinyl)-N-(3-methoxy-phenyl)-acetami de (1-23)

From 2-(3-chloro-phenylsulfanyl)-N-(3-methoxy-phenyl)-acetamide: 2-(3-Chloro- benzenesulfinyl)-N-(3-methoxy-phenyl)-acetamide was obtained as a white solid (200 mg, 36%).1H NMR (300 MHz, DMSO- 6 ): δ ppm 10.20 (s, 1H), 7.77 - 7.61 (m, 4H), 7.25 - 7.03 (m, 3H), 6.69 - 6.65 (m, 1H), 4.14 - 3.89 (m, 2H), 3.72 (s, 3H). LC-MS: 324 [M+l] + , R t = 1.449 min. HPLC: 99.02 % at 214 nm, 99.34 % at 254 nm, R t = 3.379 min.

Example 24. 2-(3-Chloro-benzenesulfinyl)-N-(2-methoxy-phenyl)-acetamide (1-24)

From 2-(3-chloro-phenylsulfanyl)-N-(2-methoxy-phenyl)-acetamide: 2-(3-Chloro- benzenesulfinyl)-N-(2-methoxy-phenyl)-acetamide was obtained as a white solid (250 mg, 44%). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 9.45 (s, 1H), 7.93 - 7.90 (del, J = 7.9, 1.4 Hz, 1H), 7.77 (ddd, J = 5.&, 2.9, 1.6 Hz, 1H), 7.69 - 7.65 (m, 1H), 7.63 - 7.61 (m, 2H), 7.08 - 7.04 (m, 2H), 6.91 - 6.86 (m, 1H), 4.25 - 4.12 (m, 2H), 3.82 (s, 3H). LC-MS 324 [M+l] + , R t = 1.472 min. HPLC: 99.14 % at 214 nm, 99.42 % at 254 nm, R t = 3.561 min.

Example 25.

2-(3-Chloro-benzenesulfinyl)-N-cyclohexylmethyl-acetamide (1-25)

From 2-(3-chloro-phenylsulfanyl)-N-cyclohexylmethyl-acetamide: 2-(3-Chloro- phenylsulfanyl)-N-cyclohexylmethyl-acetamide was obtained as a white solid (800 mg, 72%).1H NMR (300 MHz, DMSO- 6 ) δ ppm 8.07 (d, J = 2.0 Hz, 1H), 7.70 - 7.60 (m, 4H), 3.89 - 3.78 (q, J = 13.2 Hz, 2H), 2.99 - 2.76 (m, 2H), 1.68 - 1.52 (m, 5H), 1.30 - 1.06 (m, 4H), 0.87 - 0.73 (m, 2H). LC-MS: 314 [M+l] + , R t = 1.516 min. HPLC: 97.93 % at 214 nm, 98.44 % at 254 nm, R t = 6.310 min.

Preparation 25.

3-Chloro-phenylsulfanyl)-acetic acid methyl ester

A solution of bromo-acetic acid methyl ester (10 g, 69 mmol) and 3-chlorobenzenethiol (11.6 g, 76 mmol) in tetrahydrofuran (100 mL) was treated with N-methylmorpholine (17.4 mL). The resulting mixture was stirred at 20°C for 20 h. At this time, the mixture was filtered and the filtrate was concentrated in vacuo to afford (3-chloro-phenylsulfanyl)-acetic acid methyl ester as yellow oil (15.68 g, 100%). The material was used directly without further purification. LC-MS: 217 [M+l] + , R t = 1.658 min.

Preparation 26.

(3-Chloro-benzenesulfinyl)-acetic acid methyl ester

A solution of crude (3-chlorophenylsulfanyl)-acetic acid methyl ester (15.6 g, 69 mmol) in acetic acid (156 mL) was treated with 30% aqueous hydrogen peroxide (78 ml, 690 mmol). The resulting mixture was stirred at 40°C for 1 h. At this time, the solution was cooled to room temperature and was extracted with methylene chloride (2 x 300 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (2 x 500 mL) and dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford (3- chloro-benzenesulfinyl)-acetic acid methyl ester as yellow oil (15.9 g, 100%). The material was used directly without further purification. LC-MS: 233 [M+l] + , R t = 1.358 min. Preparation 27.

(3- Chloro-benzenesulf inyl) -acetic acid

A solution of crude (3-chloro-benzenesulfinyl)-acetic acid methyl ester (15.9 g, 69 mmol) in 1,4-dioxane (160 mL) and water (160 mL) was treated with an aqueous sodium hydroxide solution (4.14 g, 103.5 mmol in water, 10 mL). This solution was then stirred at 20°C for 10 min. At this time, the resulting mixture was extracted with methylene chloride (500 mL). The organic layer was discarded. The aqueous layer was acidified to pH = 1 - 2 with an aqueous hydrochloric acid solution and extracted with methylene chloride (2 x 200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford (3- chloro-benzenesulfinyl)-acetic acid as a white solid (12.67 g, 84%). The material was used directly without further purification. LC-MS: 219 [M+l] + , R t = 1.209 min.

Example 26.

2-(3-Chloro-benzenesulfinyl)-N-(3-fluoro-phenyl)-acetamid e (1-26)

A solution of (3-chloro-benzenesulfinyl)-acetic acid (600 mg, 2.74 mmol) in methylene chloride (20 mL) cooled to 0°C solution was treated with (2-(7-aza-lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate) (1.15 g, 3.01 mmol) and N,N- diisopropylethylamine (1.06 g, 8.22 mmol). The reaction was stirred at 0°C for 0.5 h. At this time, the reaction was treated with 3-fluoro-phenylamine (305 mg, 2.74 mmol). The reaction mixture was allowed to warm to room temperature and was stirred overnight. At this time, the resulting mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (30 mL) and was washed with a IN aqueous hydrochloric acid solution (30 mL), a saturated aqueous sodium bicarbonate solution (30 mL), water (30 mL) and a saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (petroleum ether: ethyl acetate = 5 : 1) afforded 2-(3-chloro-benzenesulfinyl)-N- (3-fluoro-phenyl)-acetamide as a white solid (100 mg, 12%). 1HNMR (300 MHz, DMSO- 6 ) δ ppm 10.41 (s, 1H), 7.74 - 6.87 (m, 8H), 3.91 - 4.15 (m, 2H). LC-MS: 312 [M+l] + , R t = 1.474 min. HPLC: 98.89 % at 214 nm, 99.74% at 254 nm, R t = 5.577 min.

In an analogous manner the following compounds were synthesized following the above procedure:

Example 27. 2-(3-Chloro-benzenesulfinyl)-N-(4-trifluoromethyl-phenyl)-ac etamide (1-27)

From (3-chloro-benzenesulfinyl)-acetic acid and 4-trifluoromethyl-phenylamine: 2-(3- Chloro-benzenesulfinyl)-N-(4-trifluoromethyl-phenyl)-acetami de was obtained as a white solid (660 mg, 40%). 1 H NMR (300 MHz, DMSO- 6 ) δ ppm 10.57 (s, 1H), 7.78 - 7.59 (m, 8H), 4.20 - 3.95 (m, 2H). LC-MS: 362[M+1] + , R t = 1.559 min. HPLC: 92.12 % at 214 nm, 99.06 % at 254 nm, R t = 4.478 min.

Example 28.

2-(3-Chloro-benzenesulfinyl)-N-(4-cyano-phenyl)-acetamide (1-28)

From (3-chloro-benzenesulfinyl)-acetic acid and 4-amino-benzonitrile: 2-(3-Chloro- benzenesulfinyl)-N-(4-cyano-phenyl)-acetamide was obtained as a white solid (200 mg, 14%). 1H NMR (300 MHz, DMSO- 6 ): δ ppm 10.64 (s, 1H), 7.86 - 7.63 (m, 8H), 4.21 - 3.95 (m, 2H). LC-MS: 341 [M+l] + , R t = 1.426 min. HPLC: 99.74 % at 214 nm, 99.69 % at 254 nm, R t = 5.130 min. Example 29.

2-(3-Chloro-benzenesulfinyl)-N-(2-fluoro-phenyl)-acetamid e (1-29)

From (3-chloro-benzenesulfinyl)-acetic acid and 2-fluoro-phenylamine: 2-(3-Chloro- benzenesulfinyl)-N-(2-fluoro-phenyl)-acetamide was obtained as a white solid (400 mg, 28%). 1H NMR (300 MHz, DMSO-d 6 ) δ ppm 10.20 (s, 1H), 7.91 - 7.59 ( , 5H), 7.34 - 7.10 ( , 3H), 4.24 - 4.09 ( , 2H). LC-MS: 312[M+1] + , R t = 1.463 min. HPLC: 96.41 % at 214 nm, 99.32% at 254 nm, R t = 5.147 min.

Example 30. 2-(3-Chloro-benzenesulfinyl)-N-(4-trifluoromethoxy-phenyl)-a cetamide (1-30)

From (3-chloro-benzenesulfinyl)-acetic acid and 4-trifluoromethoxy-phenylamine: 2-(3- Chloro-benzenesulfinyl)-N-(4-trifluoromethoxy-phenyl)-acetam ide was obtained as a white solid (400 mg, 23%). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 10.43 (s, 1H), 7.77 - 7.70 (m, 1H), 7.72 - 7.57 (m, 5H), 7.34 (d, J = 9.0 Hz, 2H), 4.17 - 3.92 (m, 2H). LC-MS: 378[M+1] + , R t = 1.561 min. HPLC: 96.77 % at 214 nm, 99.42 % at 254 nm, R t = 4.547 min.

Example 31.

2-(3-Chloro-benzenesulfinyl)-N-cyclohexyl-acetamide (1-31)

From (3-chloro-benzenesulfinyl)-acetic acid and cyclohexylamine: 2-(3-Chloro- benzenesulfinyl)-/V-cyclohexyl-acetamide was obtained as a white solid (700 mg, 51%). 1H NMR (300 MHz, DMSO- 6 ) δ ppm 7.97 - 7.94 (m, 1H), 7.68 - 7.60 (m, 4H), 3.78 (s, 2H), 3.50 - 3.40 (m, 1H), 1.70 - 1.41 (m, 5H), 1.27 - 0.92 (m, 5H). LC-MS: 300 [M+l] + , R t = 1.495 min. HPLC: 96.29 % at 214 nm, 98.28 % at 254 nm, R t = 3.597 min.

Example 32.

2-(3-Chloro-benzenesulfinyl)-N-cyclopentylmethyl-acetamid e (1-32)

From (3-chloro-benzenesulfinyl)-acetic acid and cyclopentanemethylamine: 2-(3- Chloro-benzenesulfinyl)-N-cyclopentylmethyl-acetamide was obtained as a white solid (500 mg, 45%). 1 H NMR (300 MHz, DMSO- 6 ) δ ppm 8.13 - 8.09 (m, 1H), 7.70 - 7.60 (m, 4H), 3.88 - 3.77 (m, 2H), 2.88 - 2.30 (m, 2H), 1.93 - 1.81 (m, 1H), 1.64 - 1.40 (m, 6H), 1.14 - 1.03 (m, 2H). LC-MS: 300 [M+l] + , R t = 1.464 min. HPLC: 95.30 % at 214 nm, 97.85% at 254 nm, R t = 3.698 min. Example 33. ΗΤ8-ΤΝΚ8-Ι\¥Κ2 TR-FRET Binding Assay

(10 μίΛνεΙΙ in BD 1536- well plate, a single point)

Reagents and Stock Solutions

1. Tankyrase 1 (TNKS 1): 184.3 μΜ= 5.2 mg/mL His6-TNKS 1, MW=28.2 KDa (construct: 1088- 1327, 1266M ) in 20 mM Tris pH 8, 150 mM NaCl, 10 % glycerol, and 0.5 mM TCEP

Alternatively, in place of His6-TNKS 1 can use either His6-tankyrase 2 (construct: 934 - 1166) (His6-TNKS2) or His6-PARP1 (full length).

2. Biotin-IWR2: 10 mM Biotin-IWR2 stock in DMSO, stored at -20 °C. 3. Positive control: 10 mM XAV 939 in DMSO, stored at -20 °C

4. Eu-Streptavidin: 38.1 μΜ (2.1 mg/mL) Eu-SA (Bio# Eu-2212, Lot# N 18001-BDHO2) 5. APC-anti-His Ab: 8.50 μΜ SL-APC, 8.26 μΜ anti-6His antibody-SureLight APC (Columia Bioscience, Cat# D3-1711, Lot# N01010-AAH04)

6. Assay plate: BD 1536-well, clear/black plate (Cat# 353255)

7. NP-40: 10% NP-40 solution (PIERCE, Cat# 28324, Lot # 97101671) Assay Buffer Preparation

1. Assay buffer la (ABla) for TNKS dilution: 50 mM Tris, pH 7.4, 100 mM sodium chloride solution, ImM magnesium chloride solution, 1 mM DL-dithiothreitol solution, 0.2 mg/mL bovine serum albumin solution, 0.025% NP-40.

2. Assay buffer lb (ABlb) for Biotin- VR2 dilution: 50 mM Tris, pH 7.4, 100 mM sodium chloride solution, ImM magnesium chloride solution, 1 mM DL-dithiothreitol solution, 0.2 mg/mL bovine serum albumin solution, 0.05% NP-40

3. Assay buffer lc (ABlc) for compound dilution: 50 mM Tris, pH 7.4, 100 mM sodium chloride solution, ImM magnesium chloride solution, 1 mM DL-dithiothreitol solution, 0.2 mg/mL bovine serum albumin solution 4. Assay buffer 2 (AB2) for Eu/APC: 50 mM Tris, pH 7.4, 100 mM sodium chloride solution, ImM magnesium chloride solution, 0.2 mg/mL bovine serum albumin solution

Reagent Stock Solution Preparation

1. Prepare Biotinylated IWR2 stock solution (3.33x stock) for TOTL and cpd wells : 200 nM Biotin- VR2 in 5% DMSO/ABlb buffer 2. Prepare BLANK well stock solution: 5% DMSO/ABlb buffer

3. Prepare POSITIVE CONTROL well stock solution (3.33x stock): 200 nM XAV939 in 200 nM Biotin- VR2/5% DMSO/ABlb buffer

4. Prepare TNKS1 stock solution (5x stock): 300 nM TNKS in ABla buffer

(Alternatively, use TNKS2 or PARP1 stock solutions.) 5. Prepare Eu/APC stock solution (5x stock): 3.5 nM Eu-SA/50 nM APC-His6Ab in AB2 buffer

Assay Procedure

1. Compound preparations: Add 25 1.5% DMSO /ABlc buffer in each compound well to the compound concentration at 74 μΜ in 8.8 % DMSO /ABlc buffer or in the 2 μΐ. DMSO CONTROL wells (BLANK, TOTAL and POSITIVE wells) in the compound plate.

2. Transfer 3 μΐ/well of above solution (solution 1,2,3) to an empty assay plate (BD 1536- well plate) as follows:

TOTL and cpd wells: Solution 1 (Biotin-IWR2):

BLNK wells: Solution 2 (No Biotin-IWR2):

POSITIVE CONTROL wells: Solution 3 (Biotin-IWR2 + XAV939)

3. Transfer 3 μίΛνεΙΙ of the above diluted compound solutions or compound dilution buffer to the above assay plate.

4. Add 2 μL· /well of 300 nM TNKS stock solution (4) to every well in the above assay plate.

5. Centrifuge the assay plate at 2100 rpm for 2 minutes.

6. Incubate the assay plate at 26 °C for 30 minutes.

7. Add 2 μίΛνεΙΙ 3.5 nMEu/50 nM APC solution (5) to every well in the above assay plate. 8. Centrifuge the assay plate at 2100 rpm for 2 minutes.

9. Incubate the assay plate at 26 °C for 60 minutes.

10. Read the assay plate immediately at excitation wavelength of 330 nM and emission wavelength of 615 and 665 nM in time resolved fluorescence mode.

Final Assay Conditions: Biotin- VR2: 60 nM

TNKS: 60 nM

Eu-SA: 0.7 nM

APC-His Ab: 10 nM

XAV939 (+ve control): 60 nM at -70 % Inhibition General Library compounds: 22.23 μΜ in 4% DMSO

Representative compound data for assays are listed below in Table II. TABLE II.

Compound TNKSl (uM) TNKS2 (uM) PARP1 (uM)

1-1 0.489 0.575 >50

1-2 0.181 0.203 >50

1-3 0.141 0.126 >50

1-4 >50 >50 >50

1-5 0.155 0.157 45.620

1-6 0.112 0.102 24.170

1-7 >50 >50 >50

1-8 4.361 >50 >50

1-9 2.558 3.744 36.800

I- 10 2.450 2.431 >50

111 14.020 11.220 >50

1-12 0.941 3.706 >50

1-13 0.876 2.575 >50

1-14 >50 >50 >50

1-15 >50 >50 >50

1-16 1.270 3.093 >50

1-17 0.872 1.289 >50

1-18 11.600 13.700 >50

1-19 0.281 0.439 >50

1-20 0.204 0.328 >50

1-21 >50 >50 >50

1-22 4.451 5.769 >50 1-23 0.421 0.574 >50

1-24 21 .800 43.880 >50

1-25 2.438 2.51 5 >50

1-26 0.398 0.627 >50

1-27 1 .875 2.557 >50

1-28 0.984 2.029 >50

1-29 1 .026 2.586 >50

1-30 1 .099 1 .660 >50

1-31 1 .707 3.733 >50

1-32 4.408 5.143 >50

The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.