JP2014531416A - PARP inhibitor - Google Patents

Abstract

This application discloses compounds of formula I that are PARP inhibitors, wherein variables R1 and R2 are as described herein, and provide compounds of formula I and compositions comprising them . The application further provides methods of using the disclosed PARP inhibitors for the treatment of PARP-mediated diseases and disorders.

Description

  Cancer is a disease characterized by a loss of proper control over cell proliferation. The American Cancer Society estimates that there are over 1.5 million new cases in the United States in 2010 and that approximately 570,000 deaths in that year are estimated to be due to cancer. The World Health Organization (WHO) estimates that cancer is the world's leading cause of death in 2010 and that cancer deaths will increase to 12 million each year by 2030.

  This has been suggested that there are six abilities that cells need to develop in order to result in the formation of cancerous lesions. These properties are self-sufficiency of proliferative signals, insensitivity to anti-proliferative signals, tissue invasion and metastasis, unlimited replication potential, persistent angiogenesis and avoidance of apoptosis. Proliferation signaling is required for cells to transition from a resting state to an active proliferative state. These signals are typically transmitted from transmembrane receptors through a signaling cascade involving numerous intracellular kinases that ultimately result in altered gene expression at the intracellular nuclear level. . In recent years, there has been much interest in the field of signal transduction inhibitors, particularly kinase inhibitors, and their use to treat cancer. Several examples of this class of compounds have been successfully evaluated in the clinical setting and are marketed for the treatment of certain forms of cancer, such as imatinib tosylate (of Philadefia chromosome positive chronic myeloid leukemia) Marketed as Gleevec® by Novartis for treatment), lapatinib ditosylate (sold as Tykerb® by GlaxoSmithKline for the treatment of HER2-positive breast cancer in combination with other chemotherapeutic agents) Sunitinib malate (sold by Pfizer as Sutent® and approved for the treatment of kidney cancer) and sorafenib (sold as Nexavar by Bayer for the treatment of kidney cancer).

  In addition to growth factor-related signaling pathways that primarily utilize kinase-catalyzed transfer of phosphate groups as a key component of the signaling pathway, a number of other signaling pathways are also present in the cell and their proper regulation Is important to maintain accurate levels of cell growth and replication. In the emerging field of cancer stem cell inhibition, the Wnt, Notch and hedgehog pathways have received much interest as potential methods for preventing tumor recurrence and metastasis. The Wnt pathway is in adults where the activity of individual components is within the pathway under tight regulation. Useful in embryonic development and tissue maintenance in adults with the activity of individual components. In cancer and other diseased cells, signaling pathways no longer show adequate levels of control. In the case of the Wnt pathway, signal transduction is controlled by the relative stability of the two proteins, axin and β-catenin. Excess β-catenin results in activation of nuclear transcription factors associated with increased Wnt signaling, while excess axin results in degradation of intracellular β-catenin and decreased signaling. Dysregulation of the canonical Wnt signaling pathway has been implicated in a range of human cancers such as, for example, colon cancer, hepatocellular carcinoma, endometrial ovarian cancer, papilloma skin cancer, prostate cancer, melanoma and Wilms tumor.

  In the canonical Wnt signaling pathway, signaling is initiated by the interaction of a Wnt ligand with a Frizzled family member and a receptor complex that includes a low density lipoprotein receptor-related protein. This results in the formation of the dished-Frizzled complex and the relocation of the axin from the disrupted complex to the cell membrane. Axin is a concentration limiting component of the destruction complex, and it is this complex that is formed with glycogen synthase kinase 3β, which is responsible for the regulation of intracellular levels of casein kinase 1α and β-catenin of the colorectal adenomatosis protein. In the presence of a functional disruption complex, β-catenin is phosphorylated in turn by a conserved set of amino-terminal serine and threonine residues by caseinase 1α and glycogen synthase kinase 3β. Phosphorylation facilitates the binding of β-catenin to β-transducin repeat-containing proteins, which in turn mediate ubiquitination and subsequent degradation of β-catenin by the proteasome. In the absence of a sufficiently high concentration of disruption complex, non-phosphorylated β-catenin migrates to the cell nucleus, interacts with T-cell factor protein, and is a powerful transcriptional activator via recruitment of coactivator protein You can switch them to.

  Intracellular axin levels have recently been reported that members of the poly (ADP-ribose) polymerase enzyme family are affected by tankyrase-1 and tankyrase-2 (also known as PARP5 and PARP5b) (Nature Chemical Biology 2009, 5, 100 and Nature 2009, 461, 614). The tankyrase enzyme can poly-ADP ribosylate the axin, which marks this protein for subsequent ubiquitination and proteasome degradation. Therefore, increasing the axin protein concentration in the presence of an inhibitor of tankyrase catalytic activity increases the concentration of the disrupted complex, decreases the concentration of non-phosphorylated intracellular β-catenin, and decreases Wnt signaling. It will be. Inhibitors of tankyrase-1 and -2 are also expected to affect other biological functions of tankyrase proteins, such as chromosome end protection (telomeres), insulin responsiveness and spindle formation during mitosis (Biochimie 2009, 5, 100).

  Therapies that are directed to the Wnt signaling pathway and can repair its dysregulation include bone density defects, coronary artery disease, late-onset Alzheimer's disease, familial exudative vitreoretinopathy, reticuloangiogenesis, tetraalimb disease, It is associated with symptoms such as Mueller duct regression and masculinization, SERKAL syndrome, type 2 diabetes, Fulman syndrome, skeletal dysplasia, partial skin hypoplasia and neural tube defects. Although the above foreword has focused on the relevance of Wnt signaling in cancer, the Wn signaling pathway is fundamentally important and covers a wide range of humans not necessarily limited to the examples provided above for illustrative purposes. Has potential relevance to the disease.

  The application provides a method of treating PARP-mediated symptoms (particularly tankyrases 1 and 2) comprising administering a therapeutically effective amount of a compound of formula I to a patient in need thereof.

（上式中、
Ｒ^１は、各々一又は複数のＲ^１’で置換されていてもよい、フェニル、フェニル−低級アルキル、シクロアルキル、又はシクロアルキル低級アルキルであり；
各Ｒ^１’は、独立して、低級アルキル、ハロ、低級アルコキシ、低級ハロアルキル、低級アルキルスルホニル、トリフルオロメトキシ、又はシアノであり；
Ｒ^２は、一又は複数のＲ^２’で置換されていてもよいフェニル、ナフチル、シクロヘキシル、又はピリダジニルであり；かつ
各Ｒ^２’は、独立して、ハロ、低級アルキル、低級アルコキシ、又は−Ｃ（＝Ｏ）ＯＣＨ_３である）
又はその薬学的に許容される塩を提供する。 The present application relates to a compound of formula I,

(In the above formula,
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 alkylsulfonyl, trifluoromethoxy, or cyano;
R ² is phenyl, naphthyl, cyclohexyl, or pyridazinyl optionally substituted with one or more R ^{2 ′} ; and each R ^{2 ′} is independently halo, lower alkyl, lower alkoxy, or — C (= O) OCH ₃ )
Or a pharmaceutically acceptable salt thereof.

The present application provides a method of treating tankyrase-mediated symptoms comprising administering a therapeutically effective amount of a compound of formula I to a patient in need of treatment.
The present application provides a method of treating cancer comprising administering a therapeutically effective amount of a compound of formula I to a patient in need of treatment.
The application provides a pharmaceutical composition comprising a compound of Formula I.

Definitions As used herein, the phrase “a” or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. Thus, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.

  As used herein, the terms “comprise (s)” and “comprising” have the open-ended meaning, whether in the transitional phrases or in the gist of the claims. Must be interpreted. That is, the term should be construed synonymously with the phrase “having at least” or “including at least”. As used in the context of a method, the term “comprising” means that the method includes at least the steps described, 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 described feature or component, but may also include additional features or components. To do.

  As used herein, unless otherwise defined, the word “or” is used in the “inclusive” sense of “and / or” and “any and / or” “exclusive” (Exclusive) ”does not mean.

  The term “independently” is used herein to indicate that a variable applies in any one case with or without a variable having the same or different definition within the same compound. The Thus, in compounds where R "appears twice and is defined as" independently carbon or nitrogen ", both R" can be carbon and both R "can be nitrogen, or R ″ can be carbon and the other can be nitrogen.

  When any variable appears more than once in any part or formula that indicates and describes a compound used or claimed in the present invention, its definition at each occurrence is independent of its definition at each other occurrence It is. Also, combinations of substituents and / or variables are permissible only when such compounds yield stable compounds.

である。 The symbol “*” at the end of a bond or “---” drawn through the bond means that each functional group or other chemical moiety binds to the rest of the molecule of which it is a part. To do. So, for example,

It is.

A bond drawn to a ring system (as opposed to being linked to a distinct vertex) indicates that the bond can be attached to any of its appropriate ring atoms.
The term “cyano”, alone or in combination with other groups, means N≡C— (NC—).
The term “halogen”, alone or in combination with other groups, denotes chloro (Cl), iodo (I), fluorine (F) and bromo (bromine). In particular, “halogen” is Cl and F. In particular, F.

  As used herein, the term “optional” or “optionally” refers to the event or situation that follows, may or may not occur Means that the description includes when an event or situation occurs and when it does not occur. For example, “optionally substituted” means that an optionally substituted moiety can include a hydrogen atom or a substituent.

  The term “optional bond” means that a bond may or may not be present, and the specification includes single, double, triple, or aromatic bonds. When a substituent is marked as “bonded” or “none”, the atoms bonded to the substituent are directly linked.

  The term “about” is used herein to mean approximately, around, or around. Where 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. Proton tautomers arise from the transfer of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium and attempts to separate individual tautomers usually give rise to mixtures where the chemical and physical properties are consistent with the mixture of compounds. The position of the equilibrium depends on the chemical characteristics within the molecule and the environment to which it is exposed, such as solvent, temperature, pH, etc. For example, for many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form is predominant, while for phenol, the enol form is predominant. Common proton tautomers include keto / enol (—C (═O) —CH— ← → —C (—OH) ═CH—), amide / imidic acid (—C (═O) —NH— ← → —C (—OH) ═N—) and amidine (—C (═NR) —NH— ← → —C (—NHR) ═N—) tautomers. The latter two are particularly common in heteroaryls and heterocycles, 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 ordinary skill in the art to which this invention pertains, unless otherwise defined. Reference is now made to various methodologies and materials known to those skilled in the art. Standard references describing the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th edition, McGraw Hill Companies Inc., New York (2001). Any suitable material and / or method known to those skilled in the art can be utilized in practicing the present invention. However, preferred materials and methods are described. Unless otherwise noted, the materials, reagents, etc. referenced in the following description and examples are available from commercial sources.

  The definitions described herein are added to form chemically related combinations such as “heteroalkylaryl”, “haloalkylheteroaryl”, “arylalkylheterocyclyl”, “alkylcarbonyl”, “alkoxyalkyl” and the like. May be. When the term “alkyl” is used as a suffix after another term, as in “phenylalkyl” or “hydroxyalkyl”, it is selected from other specifically named groups It is intended to mean an alkyl group as defined above that is substituted by one to two substituents. Thus, for example, “phenylalkyl” means an alkyl group having 1 to 2 phenyl substituents, and thus includes benzyl and phenylethyl. “Alkylaminoalkyl” is an alkyl group having 1 to 2 alkylamino substituents. “Hydroxyalkyl” includes 2-hydroxyethyl, 2-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, hydroxymethyl, 3-hydroxypropyl, and the like. . Thus, as used herein, the term “hydroxyalkyl” is used to define a subset of the heteroalkyl groups defined above.

  As used herein, “spirocycloalkyl” means a spirocyclic cycloalkyl group such as, for example, spiro [3.3] butane. The term spiheterocycloalkyl as used herein means a throcyclic heterocycloalkyl such as, for example, 2,6-diaza-spiro [3.3] heptane.

The term “acyl” as used herein refers to a group of formula —C (═O) R where R is hydrogen or lower alkyl as defined herein. The term “alkylcarbonyl” as used herein refers to a group of formula C (═O) R where R is as defined herein. The term C _1-6 acyl means a group —C (═O) R in which the R group contains up to 6 carbon atoms. The term “arylcarbonyl” as used herein refers to a group of formula C (═O) R where R is an aryl group; the term “benzoyl” as used herein refers to R being phenyl Certain “arylcarbonyl” groups are indicated.

  The term “ester” as used herein refers to a group of formula —C (═O) OR where R is lower alkyl, cycloalkyl, aryl or heteroaryl.

The term “alkyl” as used herein refers to 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. As used herein, "C ₁ - ₁₀ alkyl" refers to an alkyl composed of 10 carbons 1. Examples of alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl. A particular lower alkyl group is methyl.

  When the term “alkyl” is used as a suffix after another term, as in “phenylalkyl” or “hydroxyalkyl”, it is selected from other specifically named groups It is intended to mean an alkyl group as defined above that is substituted by one to two substituents. Thus, for example, “phenylalkyl” means a group R′R ″, where R ′ is a phenyl group and R ″ is an alkylene group as defined herein, and the point of attachment of the phenylalkyl moiety is on the alkylene group. It is understood. Examples of arylalkyl groups include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl. The terms “arylalkyl” or “aralkyl” are interpreted similarly except R ′ is an aryl group. “(Heta) arylalkyl” or “(Heta) aralkyl” is interpreted similarly except R ′ is optionally an aryl or heteroaryl group.

  The term “haloalkyl” or “halo-lower alkyl” or “lower haloalkyl” refers to a straight chain comprising 1 to 6 carbon atoms in which one or more carbon atoms are replaced by one or more halogen atoms or Means a branched chain hydrocarbon residue. A particular halogen is fluoro, in particular “haloalkyl” or “halo-lower alkyl” or “lower haloalkyl” means fluoroalkyl ”or“ fluoro-lower alkyl ”or“ lower fluoroalkyl ”.

“Alkylene” or “alkylenyl” as used herein, unless otherwise defined, is a divalent saturated straight chain hydrocarbon group of 1 to 10 carbon atoms (eg, (CH ₂ ) _n ) or 2 to 10 number of branched saturated divalent hydrocarbon radical of carbon atoms (e.g., -CHMe- or _{-CH 2 CH (i-Pr)} CH 2 -) means. Examples of alkylene groups 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 refers to —O-alkyl groups, including isomers thereof, wherein alkyl is as defined above, eg, methoxy, ethoxy, n-propyloxy, iso-propyloxy. N-butyloxy, iso-butyloxy, tert-butyloxy, pentyloxy, hexyloxy). “Lower alkoxy” as used herein refers to an alkoxy group with a “lower alkyl” group (C _1-6 alkoxy) as previously defined. “C _1-10 alkoxy” as used herein refers to O-alkyl wherein alkyl is C _1-10 . “C _1-6 alkoxy” as used herein means O-alkyl, especially methoxy (OMe), in which alkyl is C _1-6 .

  The term “aryl” refers to a monovalent aromatic carbocyclic monocyclic or bicyclic system containing 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl.

  The term “haloalkoxy” or “halo-lower alkoxy” or “lower haloalkoxy” means a lower alkoxy group in which one or more carbon atoms are replaced by one or more halogen atoms, in particular fluoro.

  The term “hydroxyalkyl” as used herein refers to an alkyl group in which 1 to 3 hydrogen atoms on different carbon atoms are replaced with hydroxy groups.

The terms “alkylsulfonyl” and “arylsulfonyl” as used herein are groups of the formula —S (═O) ₂ R where R is alkyl or aryl, respectively, and alkyl and aryl are as defined herein. Means. The term “heteroalkylsulfonyl” as used herein denotes a group of formula —S (═O) ₂ R wherein R is “heteroalkyl” as defined herein. Particular group is a _-SO 2 Me.

The terms “alkylsulfonylamino” and “arylsulfonylamino” as used herein are defined where R is alkyl or aryl, R ′ is hydrogen or C _1-3 alkyl, and alkyl and aryl are defined herein. Means a radical of the formula —NR ′S (═O) ₂ R as it is.

The term “cycloalkyl” as used herein refers to a saturated or unsaturated carbocycle containing from 3 to 8 carbon atoms, ie cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. “C _3-7 cycloalkyl” or “lower cycloalkyl” as used herein refers to a cycloalkyl composed of 3 to 7 carbons in the carbocycle.

The term carboxy-alkyl as used herein refers to an alkyl moiety in which one hydrogen atom is replaced by a carboxyl, and the point of attachment is understood to be through a carbon atom. The term “carboxy” or “carboxyl” means a —CO ₂ H moiety.

As used herein, “heterocyclyl”, “heterocycloalkyl” or “heterocycle” includes one or more ring heteroatoms (selected from N, O or S (═O) _0-2 ), Means a monovalent saturated or unsaturated cyclic group consisting of one or more rings, preferably 1 to 2 rings of 3 to 8 atoms per ring, optionally independently 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, arylamino Carbonyl, alkylcarbonylamino, arylcarbonylamino, and one or more selected from the ionic form, preferably may be substituted with 1 or 2 substituents. Examples of heterocyclic groups include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, tetrahydropyranyl, Includes thiomorpholinyl, quinuclidinyl and imidazolinyl, and their ionic forms. Examples are also bicyclic, for example 3,8-diazabicyclo [3.2.1] octane, 2,5-diazabicyclo [2.2.2] octane, or octahydro-pyrazino [2,1-c]. [1,4] Oxazine.

  The term “PARP” is used herein to mean a protein having ADP-ribosylation activity. In the meaning of this term, PARP includes all proteins encoded by their parp genes, variants thereof, and alternative splice proteins thereof. The term “PARP” as used herein also includes PARP analogs, homologues and analogs of other animals.

The term “PARP” includes, but is not limited to, PARP-1. In the meaning of this term, PARP-2, PARP-3, Vault-PARP (PARP-4), PARP-7 (TiPARP), PARP-8, PARP-9 (Bal), PARP-10, PARP-11, PARP -12, PARP-13, PARP-14, PARP-15, PARP-16, TNK-1, TNK-2 may be included.
The term “TNK” or “TNKS” is used to represent the term tankyrase.
Compounds that inhibit tankyrase 1 and 2 may 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 human and animal tissues. Examples of suitable salts with inorganic and organic acids include, but are not limited to, acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluene Sulfonic acid, succinic acid, sulfuric acid, sulfuric acid, tartaric acid and trifluoroacetic acid. Particular acids are formic acid, trifluoroacetic acid and hydrochloric acid.

  The terms “pharmaceutically acceptable carrier” and “pharmaceutically acceptable auxiliary substances” 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” refers to any product obtained directly or indirectly from combining a specified amount of a specified ingredient, as well as a product containing the specified component in a predetermined amount or ratio. Includes products. In particular, it comprises a product comprising one or more active ingredients and an optional carrier comprising inactive ingredients, as well as any two or more combinations, conjugations or collections of ingredients, or one or more ingredients. Any product that results directly or indirectly from the dissociation of, or from one or more other types of reactions or interactions of the components.

  The term “inhibitor” refers to a compound that reduces or prevents binding of a particular ligand to a particular receptor, or reduces or prevents inhibition of the function of a particular protein.

The term “half inhibitory concentration” (IC ₅₀ ) refers to the concentration of a particular compound required to obtain 50% inhibition of a biological process in vitro. IC ₅₀ values can be logarithmically converted to pIC ₅₀ values (-log IC ₅₀ ) where higher values show exponentially greater efficacy. IC ₅₀ values are not absolute but depend on experimental conditions such as concentration used. IC ₅₀ values can be converted to absolute inhibition constants (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973) 22: 3099). The term “inhibition constant” (Ki) indicates the absolute binding affinity of a particular inhibitor to the receptor. It is measured using a competitive binding assay and is equal to the concentration at which a particular inhibitor will occupy 50% of the receptor if no competing ligand (eg, radioligand) is present. Ki values can be logarithmically converted to pKi values (-logKi) where higher values indicate exponentially higher potency.

  “Therapeutically effective amount” means the 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. “Therapeutically effective amount” refers to the compound, the disease state being treated, the severity or disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and others Varies depending on the factors.

  When referring to a variable, the terms “as defined herein” and “as described herein” refer to the broad definition of that variable, as well as the more specific and most specific if present. Is taken in by reference. The term “aromatic” is a general term for aromaticity as defined in the literature, in particular IUPAC-Compendium of Chemical Terminology, 2nd, AD McNaught and A. Wilkinson (ed.). Blackwell Scientific Publications, Oxford (1997). Show the way of thinking.

（上式中、
Ｒ^１は、各々一又は複数のＲ^１’で置換されていてもよい、フェニル、フェニル低級アルキル、シクロアルキル、又はシクロアルキル低級アルキルであり；
各Ｒ^１’は、独立して、低級アルキル、ハロ、低級アルコキシ、低級ハロアルキル、低級アルキルスルホニル、トリフルオロメトキシ、又はシアノであり；
Ｒ^２は、一又は複数のＲ^２’で置換されていてもよいフェニル、ナフチル、シクロヘキシル、又はピリダジニルであり；
各Ｒ^２’は、独立して、ハロ、低級アルキル、低級アルコキシ、又は−Ｃ（＝Ｏ）ＯＣＨ_３である）
の化合物又はその薬学的に許容される塩を提供する。 The term “pharmaceutically acceptable excipient” refers to any ingredient that has no therapeutic activity and is non-toxic, such as a disintegrant, binder, filler, used to formulate a pharmaceutical product, Solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant or lubricant.
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

(In the above formula,
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 alkylsulfonyl, trifluoromethoxy, or cyano;
R ² is phenyl, naphthyl, cyclohexyl, or pyridazinyl optionally substituted with one or more R ² ′;
Each R ² ′ is independently halo, lower alkyl, lower alkoxy, or —C (═O) OCH ₃ )
Or a pharmaceutically acceptable salt thereof.

The application provides a compound of Formula I, wherein R ¹ is phenyl optionally substituted with one or more R ¹ ′.
The application provides a compound of Formula I, wherein R ² is phenyl optionally substituted with one or more R ² ′.
The application relates to a 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 ′. Of the compound.
The application provides compounds of Formula I, wherein R ² ′ is halo.

The application provides a 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 a compound of Formula I, wherein R ² is phenyl and R ² ′ is halo.
The application provides a 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 compounds of Formula I, wherein R ¹ ′ is methoxy.
The application provides compounds of Formula I, wherein R ¹ is phenyl and R ¹ ′ is methoxy.
The application provides a 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 compounds of Formula I, wherein R ¹ ′ is methoxy, R ² is phenyl, and R ² ′ is halo.

The application provides compounds of Formula I, wherein R ¹ is phenyl, R ¹ ′ is methoxy, R ² is phenyl, and R ² ′ is halo.
The application provides compounds of Formula I, wherein R ¹ ′ is fluoro.
The application provides compounds of Formula I, wherein R ¹ is phenyl and R ¹ ′ is fluoro.
The application provides a 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 compounds of Formula I, wherein R ¹ ′ is fluoro, R ² is phenyl, and R ² ′ is halo.

The application provides compounds of Formula I, wherein R ¹ is phenyl, R ¹ ′ is fluoro, R ² is phenyl, and R ² ′ is halo.
The application provides compounds of formula I, wherein R ¹ ′ is trifluoromethyl, cyano, methylsulfonyl, or trifluoromethoxy.
The application provides compounds of Formula I, wherein R ¹ ′ is trifluoromethyl, cyano, methylsulfonyl, or trifluoromethoxy, and R ² is phenyl optionally substituted with one or more R ² ′. To do.

The application provides compounds of Formula I, wherein R ¹ ′ is trifluoromethyl, cyano, methylsulfonyl, or trifluoromethoxy, R ² is phenyl, and R ² ′ is halo.
The application provides compounds of Formula I, wherein R ² is phenyl optionally substituted with one or more R ² ′, and R ¹ ′ is methoxy.
The application provides compounds of formula I, wherein R ² ′ is methoxy, methyl, or —C (═O) OCH ₃ .
The application provides compounds of Formula I, wherein R ² is phenyl, R ² ′ is methoxy, methyl, or —C (═O) OCH ₃ , and R ¹ ′ is methoxy.

The application relates to phenyl lower alkyl, cyclalkyl, wherein R ² is phenyl optionally substituted with one or more R ² ′, and R ¹ is each optionally substituted with one or more R ¹ ′. Or a compound of formula I, which is a cycloalkyl lower alkyl.
The application relates to phenyl lower alkyl, cycloalkyl, or cycloalkyl lower alkyl, wherein R ² is phenyl, R ² ′ is halo, and R ¹ is each optionally substituted with one or more R ¹ ′. A compound of formula I is provided.
The application provides a compound of Formula I, wherein R ² is phenyl, R ¹ ′ is methoxy, and R ² is naphthyl, cyclohexyl, or pyridazinyl.

This application
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-sulfinyl) -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-1-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-benzenesulfinyl) -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-benzenesulfinyl) -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;
There is provided a compound of formula I selected from the group consisting of 2- (3-chloro-benzenesulfinyl) -N-cyclohexyl-acetamide; and 2- (3-chloro-benzenesulfinyl) -N-cyclopentylmethyl-acetamide.

The present application provides a method for treating a PARP-mediated condition comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.
The present application provides a method for treating tankyrase-mediated conditions comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.
The present application provides a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.
The application provides a pharmaceutical composition comprising a compound of Formula I.
The application provides the above pharmaceutical composition mixed with at least one pharmaceutically acceptable carrier, excipient or diluent.
In one variation, the pharmaceutical composition comprises a chemotherapy or antiproliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, a cardiovascular disease therapeutic agent, a diabetes therapeutic agent, and an immunodeficiency disease therapeutic agent. And further comprising an additional therapeutic agent selected from.
In one aspect, the application provides the use of a compound of formula I in the manufacture of a medicament for the treatment of tankyrase-mediated disorders.
The application provides a compound or method as described herein.

Compounds of Formula I Examples of representative compounds encompassed by and within the scope of the present invention are set forth in Table I below. These examples and the following preparative examples are provided to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be construed as limiting the invention, but merely as exemplary and representative thereof.
In general, the nomenclature used in this application is the AUTONOM ^™ v. Of Beilstein Institute computer system for the creation of IUPAC systematic nomenclature. Based on 4.0. If there is a discrepancy between the indicated structure and the name given to that structure, the indicated structure will be weighted. In addition, if the stereochemistry of a structure or part of a structure is not indicated by, for example, bold or wavy lines, the structure or part of the structure should be interpreted as encompassing all stereoisomers thereof .

Table I shows examples of sulfoxide compounds according to general formula I.

Synthesis General synthesis scheme

R ₁ is aryl, substituted aryl, CH ₂ - aryl, cycloalkyl or CH ₂ - compound of formula I is a cycloalkyl, in the presence of a base, _{R 1} is aryl, substituted aryl, CH ₂ - aryl, cycloalkyl Alternatively, it can be prepared by reacting a suitable amine that is CH ₂ -cycloalkyl with commercially available 2-bromoacetyl chloride (eg Vloon, WJ, Kruk, C., Pandit, UK, Hofs, HP, McVie , JG, J. Med. Chem., 1987, 30 (1), 20-24).

A compound of Formula II wherein R ₁ is aryl, substituted aryl, CH ₂ -aryl, cycloalkyl or CH ₂ -cycloalkyl, and R ₂ is aryl or substituted aryl, R ₁ is aryl, substituted aryl, CH ₂ — A bromide of formula I that is aryl, cycloalkyl or CH ₂ -cycloalkyl can be prepared from a compound of formula I by replacing R ₂ with an appropriate thiol compound where aryl is substituted with aryl, substituted aryl, or cycloalkyl. (See, for example, Etukala, JR, Yadav, JS, Heteroatom Chem., 2008, 19 (2), 221-227).

A compound of formula III wherein R ₁ is aryl, substituted aryl, CH ₂ -aryl, cycloalkyl or CH ₂ -cycloalkyl, and R ₂ is aryl, substituted aryl, or cycloalkyl, wherein R ₁ is aryl, substituted aryl CH ₂ -aryl, cycloalkyl or CH ₂ -cycloalkyl, by oxidizing a sulfide to the corresponding sulfoxide under standard conditions from a compound of formula II where R ₂ is aryl, substituted aryl, or cycloalkyl. Can be prepared from compounds of formula II (eg, Jiang, S., Liao, C., Bindu, L., Yin, B., Worthy, KW, Fisher, RJ, Burke, TR, Nicklaus, MC, Roller, PP, Bioorg Med. Chem. Lett, 2009, 19 (10), 2693-2698).

R ₂ is aryl, substituted aryl, or a compound of formula IV cycloalkyl are prepared by R ₂ is aryl, to replace the commercially available 2-bromo-acetate with a substituted aryl, or a suitable thiol compound cycloalkyl (See, for example, Etukala, JR, Yadav, JS, Heteroatom Chem., 2008, 19 (2), 221-227).

R ₂ is aryl, substituted aryl, or a compound of formula V is a cycloalkyl, by oxidizing the sulfide to the corresponding sulfoxide under standard conditions, R ₂ is aryl, substituted aryl, or of formula IV cycloalkyl (E.g. Jiang, S., Liao, C., Bindu, L., Yin, B., Worthy, KW, Fisher, RJ, Burke, TR, Nicklaus, MC, Rolller, PP, Bioorg Med. Chem. Lett, 2009, 19 (10), 2693-2698).

R ₂ is aryl, substituted aryl, or a compound of formula VI is cycloalkyl, by hydrolysis of the ester to the corresponding acid under standard conditions, wherein R ₂ is aryl, substituted aryl, or cycloalkyl V (See, for example, New, JS, Christopher, WL, Jass, PA, J. Org. Chem., 1989, 54, 990-992).

A compound of formula III wherein R ₁ is aryl, substituted aryl, CH ₂ -aryl, cycloalkyl or CH ₂ -cycloalkyl, and R ₂ is aryl, substituted aryl, or cycloalkyl, wherein R ₁ is aryl, substituted aryl CH ₂ -aryl, cycloalkyl or CH ₂ -cycloalkyl, from a compound of formula VI where R ₂ is aryl, substituted aryl, or cycloalkyl, the acid R ₁ is aryl under standard amide bond formation conditions , Substituted aryl, CH ₂ -aryl, cycloalkyl or CH ₂ -cycloalkyl can be prepared by coupling to a suitable amine (eg Montalbetti, CAGN, Falque, V., Tetrahedron, 2005, 61, 10827-10852). Amines are commercially available or can be prepared by synthesizing amines from various commercially available substrates under standard conditions.

  Compounds 5a-x can be synthesized according to the reactions outlined in Scheme 2. A commercially available or synthetically obtainable alkyl or arylamine 1a-x and 2-bromoacetyl chloride can be reacted in the presence of a base to give compound 2a-x (eg, Vloon, WJ, Kruk , C., Pandit, UK, Hofs, HP, McVie, JG, J. Med. Chem., 1987, 30 (1), 20-24). The bromide of compound 2a-x can be substituted with thiol 3a-x which is commercially available under standard conditions or can be obtained synthetically to give compound 4a-x (eg, Etukala, JR, Yadav, JS , Heteroatom Chem., 2008, 19 (2), 221-227). Thiols 3a-x are either commercially available or can be prepared from the corresponding phenols using reagents such as phosphorous pentasulfide (eg, Ozturk, T., Ertas, E., Mert, O., Chem Rev 2010, (110), 3419-3478). The resulting sulfide 4a-x can be oxidized to the corresponding sulfoxide under standard conditions to give compound 5a-x (eg, Jiang, S., Liao, C., Bindu, L., Yin, B., Worthy, KW, Fisher, RJ, Burke, TR, Nicklaus, MC, Rolller, PP, 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).

  Compounds 5a-x can be synthesized according to the reactions outlined in Scheme 3. Commercially available bromoacetic acid methyl ester and the appropriate thiol 3a-x can be reacted in the presence of a base to give compound 6a-x (eg Etukala, JR, Yadav, JS, Heteroatom Chem., 2008, 19 (2 ), 221-227). Thiols 3a-x are either commercially available or can be prepared from the corresponding phenols using reagents such as phosphorous pentasulfide (eg, Ozturk, T., Ertas, E., Mert, O., Chem Rev 2010, (110), 3419-3478). The resulting sulfide of compound 6a-x can be oxidized to the corresponding sulfoxide under standard conditions to give compound 7a-x (eg, Jiang, S., Liao, C., Bindu, L., Yin, B., Worthy, KW, Fisher, RJ, Burke, TR, Nicklaus, MC, Rolller, PP, 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). Ester of compound 7a-x can be hydrolyzed to the corresponding acid using standard conditions to give compound 8a-x (eg, New, JS, Christopher, WL, Jass, PA, J. Org. Chem., 1989, 54, 990-992). Compound 8a-x can be coupled with the appropriate amine 1a-x under standard amide bond forming conditions to give compound 5a-x (eg Montalbetti, CAGN, Falque, V., Tetrahedron, 2005, 61, 10827-10852). Amines 1a-x are commercially available or can be prepared by synthesizing amines from various commercially available substrates under standard conditions.

Pharmaceutical Compositions and Administration The compounds of the present invention can be formulated into a wide variety of oral dosage forms and carriers. Oral administration may be in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, syrups, or suspensions. The compounds of the present invention are continuous (intravenous infusion), topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain penetration enhancers) buccal, transdermal, among other routes of administration. It may also be effective by other routes of administration including nasal, inhalation and suppository administration. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction and the patient's response to the active ingredient.

  One or more compounds of the present invention, and pharmaceutically usable salts thereof, together with one or more common excipients, carriers, or diluents, are in the form of pharmaceutical compositions and unit dosages. be able to. The pharmaceutical compositions and unit dosage forms can be comprised of a general proportion of the general ingredients, with or without additional active compounds or ingredients, and the unit dosage forms are intended for daily use to be used. An appropriate effective amount of the active ingredient may be included to meet a specified dosage range. The pharmaceutical composition may be a solid, semi-solid, powder, sustained release formulation, or solution, such as a tablet or filled capsule for oral use, such as a solution, suspension, emulsion, elixir, or filled capsule; Or in the form of a suppository for rectal or vaginal administration; or in the form of a sterile injectable solution for parenteral use. A typical preparation will contain from about 5% to about 95% of one or more active compounds (w / w). The term “preparation” or “dosage form” is intended to include both solid and liquid formulations of the active compound, and those skilled in the art will recognize that the active ingredient is the target organ or tissue, the desired dosage and It will be appreciated that it can be present in different preparations depending on the pharmacokinetic parameters.

  The term “excipient” as used herein is useful in preparing pharmaceutical compositions, is generally safe, non-toxic, and not biologically or otherwise undesirable. Meaning no compounds, including excipients acceptable for veterinary use as well as human pharmaceutical use. While the compounds of the invention can be administered alone, they are generally mixed with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice. Administered.

  “Pharmaceutically acceptable” means one that is generally safe, non-toxic, and useful for preparing a pharmaceutical composition that is not biologically or otherwise undesirable. And those acceptable for veterinary use as well as human pharmaceutical use.

  The “pharmaceutically acceptable salt” form of the active ingredient may also initially impart the desired pharmacokinetic properties to the active ingredient that was not present in the non-salt form, and the active ingredient's active activity in the body. Can even positively affect pharmacodynamics. The phrase “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that retains the desired pharmacological activity of the parent compound. Such salts include (1) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or 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, methane Sulfonic 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-1-carboxylic acid, glucoheptonic acid, 3-phenyl Acid addition salts formed with lopionic acid, trimethylacetic acid, tertbutylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc .; or (2) the acid present in the parent compound Formed when a proton is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion; or with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine Salts that coordinate are included.

  Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can 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 ingredient is generally mixed in a suitable proportion with a carrier having the requisite binding ability and consolidated into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like. Not. Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

  Liquid formulations are also suitable for oral administration, including liquid formulations including emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions. These include solid form preparations that are intended to be converted to liquid form preparations immediately prior to use. Emulsions can be prepared in solution, for example in an aqueous propylene glycol solution, or may contain emulsifiers such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active ingredient in water with viscous materials, such as natural or synthetic rubbers, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. it can.

  The compounds of the present invention can be formulated for parenteral administration (eg, by injection such as bolus injection or continuous infusion) and are unit dosages in multi-dose containers with ampoules, prefilled syringes, small volume injections or preservatives added It can be provided in the form. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, such as a solution in aqueous polyethylene glycol. Examples of oils or non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (eg olive oil), and injectable organic esters (eg ethyl oleate) such as storage, wetting, Formulation agents such as emulsifying, stabilizing and / or dispersing agents may be included. Alternatively, the active ingredient is in powder form, eg, obtained by aseptic isolation of sterile solids or lyophilization from solution, for constitution with a suitable vehicle, eg, sterile pyrogen-free water, prior to use. Also good.

  The compounds of the present invention can be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams can be formulated, for example, using aqueous or oily bases with the addition of suitable bulking agents and / or gelling agents. Lotions can be formulated with an aqueous or oily base and will in general contain one or more emulsifying agents, stabilizing agents, dispersing agents, agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges containing active agents in flavor bases, usually sucrose and acacia or tragacanth; active ingredients in inert bases such as gelatin and glycerin or sucrose and acacia Mouthwashes including the active ingredients in a suitable liquid carrier; and pastilles;

  The compounds of the present invention can 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 solidify.

  The compounds of the present invention can be formulated for vaginal administration. It is known in the art that pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers in addition to the active ingredient are suitable.

  The compounds of the present invention can be formulated for nasal administration. Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulation can be provided in single or multiple dose forms. In the latter case of a dropper or pipette, this can be accomplished by administering an appropriate and predetermined volume of solution or suspension to the patient. In the case of a spray, this can be achieved, for example, by a metering atomizing spray pump.

  The compounds of the present invention may be formulated for aerosol administration, particularly including respiratory tract and intranasal administration. The compound will generally have a small particle size, for example of the order of 5 microns or less. Such a particle size can 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 The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug can be controlled by a metering valve. Alternatively, the active ingredient can be provided in the form of a dry powder, for example, a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition can be provided in unit dosage form, for example by capsules or cartridges of eg gelatin or blister packs where the powder can be administered by inhaler.

  If 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 required and when patient compliance with a treatment regimen is important. Compounds in transdermal delivery systems are often bound to a skin adhesive solid support. The subject compounds can also be combined with penetration enhancers such as azone (1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into the subcutaneous layer by surgery or injection. Subcutaneous implants encapsulate the compound in a fat soluble film such as silicone rubber or a biodegradable polymer such as polylactic acid.

  Suitable formulations 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 pharmaceutical scientist will modify the formulation within the teachings of the present specification and will recognize a number of specific administration routes without destabilizing the composition of the present invention or impairing its therapeutic activity. A formulation can be provided.

  For example, modifications of the compounds of the present invention to make them more soluble in water or other vehicles can be readily accomplished by minor modifications (salt formation, esterification, etc.) that are within the skill of the artisan. . It is also within the skill of the artisan to alter the route of administration and regimen of a particular compound to manage the pharmacokinetics of the compound for maximizing beneficial effects in the patient.

  The term “therapeutically effective amount” as used herein refers to an amount necessary to reduce the symptoms of the disease in an individual. The dose will be adjusted to the individual requirements in each particular case. The dosage will vary depending on the severity of the disease being treated, the age and general health of the patient, the other drugs the patient is treating, the route and form of administration and the preferences and experiences of the healthcare professional involved. It can vary within a wide range depending on the factors. For oral administration, a daily dose of about 0.01 to about 1000 mg / kg body weight per day should be appropriate in monotherapy and / or combination therapy. A preferred daily dosage is about 0.1 to about 500 mg / kg body weight, more preferably 0.1 to about 100 mg / kg body weight, most preferably 1.0 to about 10 mg / kg body weight. Thus, for administration to a 70 kg human, the dosage range would be about 7 mg to 0.7 g per day. Daily dosages can be administered as a single dosage or in divided dosages, typically in dosages of 1 to 5 dosages per day. Generally, treatment is initiated with 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. Those skilled in the art of treating the diseases described herein will be able to therapeutically treat the compounds of the present invention for a given disease and patient, without undue experimentation, relying on personal knowledge, experience and disclosure of the present application. An effective amount could be confirmed.

  The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be in a packaged preparation, the package containing discrete quantities of preparation, such as, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet, or troche itself, or it can be any suitable number of these in package form.

Indications and Methods of Treatment The present application provides a method of treating PARP-mediated symptoms comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.
The present application provides a method of treating tankyrase-mediated symptoms comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.
The application provides a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.

Pharmaceutical Compositions The compounds of formula I and pharmaceutically acceptable salts can be used as therapeutically active substances, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration can also take place rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

  The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used as such carriers for eg tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like. However, depending on the nature of the active substance, no carrier is usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils 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 preparation further comprises pharmaceuticals such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants flavors, salts for changing osmotic pressure, buffers, masking agents or antioxidants. Auxiliary substances which can be accepted as acceptable. They can also contain still other therapeutically valuable substances.

  A medicament comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier is also desired with one or more compounds of formula I and / or a pharmaceutically acceptable salt thereof. As well as its method of manufacture comprising the formation of a galenic dosage form together with one or more other therapeutically valuable substances together with one or more therapeutically inert carriers. Is the purpose.

  The dosage can vary within wide limits and of course must be adapted to the individual requirements in each particular case. For oral administration, the dosage for adults can vary from about 0.01 mg to about 1000 mg of compound of general formula I or a pharmaceutically acceptable salt thereof per day. The daily dose may be administered as a single dose or in divided doses and may exceed the upper limit when it is found to be indicated.

製造手順
１．成分１、２、３、４を混合し、精製水で顆粒にする。
２．５０℃で顆粒を乾燥させる。
３．適当な粉砕装置に顆粒を通す。
４．成分５を加え、３分間混合する；適切な成形機で圧縮する。 The following examples illustrate the invention without limiting it, but are merely representative thereof. The pharmaceutical preparation conveniently contains about 1-500 mg, especially 1-100 mg of the compound of formula I. Examples of compositions according to the invention are as follows:
Example A
Tablets of the following composition are produced by conventional methods:

Manufacturing procedure Ingredients 1, 2, 3, 4 are mixed and granulated 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 3 minutes; compress in a suitable machine.

製造手順
１．適切なミキサーで成分１、２及び３を３０分間混合する。
２．成分４と５を加え、３分間混合する。
３．適切なカプセルに充填する。
式Ｉの化合物、ラクトース及びコーンスターチを最初にミキサーで、ついで粉砕機で混合する。混合物をミキサーに戻す；タルクをそれに加え、十分に混合する。混合物を機械により適切なカプセル、例えば、ハードゼラチンカプセル中に充填する。 Example B-1
Produce capsules with the following composition:

Manufacturing procedure Mix ingredients 1, 2 and 3 with a suitable mixer for 30 minutes.
2. Add ingredients 4 and 5 and mix for 3 minutes.
3. Fill into suitable capsules.
The compound of formula I, lactose and corn starch are mixed first in a mixer and then in a grinder. Return the mixture to the mixer; add talc to it and mix well. The mixture is filled by machine into suitable capsules, for example hard gelatin capsules.

製造手順
式Ｉの化合物を他の成分の加温溶融物に溶解させ、混合物を適切なサイズのソフトゼラチンプセルに充填する。充填したソフトゼラチンカプセルを通常の手順に従って処理する。 Example B-2
A soft gelatin capsule of the following composition is produced:

Manufacturing Procedure The compound of formula I is dissolved in a warm melt of the other ingredients and the mixture is filled into appropriately sized soft gelatin pusels. The filled soft gelatin capsules are processed according to normal procedures.

製造手順
座薬塊をガラス又はスチール容器中で溶解し、十分に混合し、４５℃に冷却する。その後直ぐに、式Ｉの化合物の微粉末化化合物をそれに加え、それが完全に分散するまで撹拌する。混合物を適切なサイズの坐剤成形型に注ぎ、放置して冷却する；坐剤はついで成形型から取り外し、ワックスペーパー又は金属ホイルで個別に包装する。 Example C
Produce a suppository with the following composition:

Manufacturing Procedure The suppository mass is dissolved in a glass or steel container, mixed well and cooled to 45 ° C. Immediately thereafter, a micronized compound of the compound of formula I is added to it and stirred until it is completely dispersed. The mixture is poured into an appropriately sized suppository mold and allowed to cool; the suppository is then removed from the mold and individually packaged with wax paper or metal foil.

製造手順
式Ｉの化合物を、ポリエチレングリコール４００と注射用水（一部）の混合物に溶解させる。酢酸によりｐＨを５．０に調整する。残りの水を加えて体積を１．０ｍｌに調整する。溶液を濾過し、適切な過剰量を使用してバイアルに充填し、滅菌する。 Example D
An injection solution of the following composition is produced:

Manufacturing Procedure The compound of formula I is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). Adjust the pH to 5.0 with acetic acid. Add remaining water to adjust volume to 1.0 ml. The solution is filtered, filled into vials using an appropriate excess and sterilized.

製造手順
式Ｉの化合物を、ラクトース、微結晶性セルロース及びナトリウムカルボキシメチルセルロースと混合し、水中のポリビニルピロリドンの混合物と共に造粒する。顆粒をステリン酸マグネシウム及び風味添加剤と混合し、小袋（サッシェ）に充填する。 Example E
Produce a sachet of the following composition:

Manufacturing Procedure The compound of formula I is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavor additives and filled into sachets.

Examples Commonly used abbreviations are acetyl (Ac), azo-bis-isobutyrylnitrile (AIBN), atmospheric pressure (Atm), 9-borabicyclo [3.3.1] nonane (9-BBN or BBN). 2,2′-bis (diphenphosphino) -1,1′-binaphthyl (BINAP), tert-butoxycarbonyl (Boc), di-tert-butylpyrocarbonate or boc anhydride (BOC ₂ O), benzyl (Bn), butyl (Bu), chemical abstract registration number (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyldiimidazole (CDI), 1,4-diazabicyclo [2.2.2] octane (DABCO), Diethylaminosulfur trifluoride (DAST), dibenzylideneacetone (dba), 1,5-diaza Chlo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), NN'-dicyclohexylcarbodiimide (DCC), 1,2 -Dichloroethane (DCE), dichloromethane (DCM), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), diethyl azodicarboxylate (DEAD), di-iso-propyl azodicarboxylate ( DIAD), di-iso-butylaluminum hydride (DIBAL or DIBAL-H), di-iso-propylethylamine (DIPEA), NN-dimethylacetamide (DMA), 4-N, N-dimethylaminopyridine (DMAP), N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,1′-bis (Differphosphino) ethane (dppe), 1,1′-bis- (diphenylphosphino) ferrocene (dppf), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 2- Ethoxy-1 ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H-quinoline-1-carboxylic acid ethyl ester (EEDQ), Diethyl ether (Et ₂ O), ethyl isopropyl ether (EtOiPr), O- (7-azabenzotriazol-1-yl) -N, N, N′N′-tetramethyluronium hexafluorophosphate acetic acid (HATU), Acetic acid (HOAc), 1-N-hydroxybenzotriazole (HOBt) , High pressure liquid chromatography (HPLC), iso-propanol (IPA), isopropyl magnesium chloride (iPrMgCl), hexamethyldisilazane (HMDS), hexane (hex), liquid chromatography mass spectrometry (LCMS), lithium hexamethyldi silazanes (LiHMDS), meta - chloroperoxybenzoic acid (m-CPBA), methanol (MeOH), melting point (mp), MeSO ₂ - (mesyl or Ms), methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic Benzoic acid (MCPBA), mass spectrum (ms), methyl t-butyl ether (MTBE), meltetrahydrofuran (MeTHF), N-bromosuccinimide (NBS), n-butyllithim (nBuLi), N-carboxy anhydride (NCA) N-chlorosuccinimide (NCS), N-melmorpholine (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), iso-propyl (i-Pr), pounds per square inch (psi), pyridine (pyr), 1,2,3,4,5-pentaphenyl-1,3 ′-(di -Tert-butylphosphino) ferrocene (Q-Phos), room temperature (ambient temperature, rt or RT), sec-butyllithi Um (sBuLi), tert-butyldimethylsilyl or t-BuMe ₂ Si (TBDMS), tetra-n-butylammonium fluoride (TBAF), triethylamine (TEA or Et ₃ N), 2,2,6,6-tetra methyl-1-oxyl (TEMPO), triflate or _{CF 3 SO 2 - (Tf)} , trifluoroacetic acid (TFA), 1,1'-bis-2,2,6,6-tetramethyl-heptane-2,6 -One (TMHD), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU), thin layer chromatography (TLC), tetrahydrofuran (THF), trimethylsilyl Or Me ₃ Si (TMS), p-toluenesulfonic acid monohydrate (TsOH or pTs _{OH), 4-Me-C} 6 H 4 SO 2 - containing or tosyl (Ts), and N- urethane -N- carboxyanhydride (UNCA). When used with an alkyl moiety, common nomenclatures including the prefix normal (n), iso (i-), secondary (sec-), tertiary (tert-) and neo are their conventional Has meaning. (J. Rigaudy and DP Klesney, Nomenclature in Organic Chemistry, IUPA 1979 Pergamon Press, Oxford).

ピリジン（１５ｍＬ）中のピリダジン−３−オール（１．０ｇ、１０．４ｍｍｏｌ）の溶液を室温で五硫化二リン（９２４ｍｇ、４．１６ｍｍｏｌ）で処理した。ついで、この溶液を１時間還流温度で撹拌した。このとき、得られた混合物を室温に冷却し、真空下で濃縮してピリダジン−３−チオールを黄色固形物（５６０ｍｇ、４８％）として得た。この物質さらに精製することなく使用した。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ１４．７４（ｓ，１Ｈ），８．２６（ｄｄ，Ｊ＝４．１，１．６Ｈｚ，１Ｈ），７．６１−７．５８（ｍ，１Ｈ），７．２３−７．２７（ｄｄ，Ｊ＝９．１，４．１Ｈｚ，１Ｈ）。 Preparation Example 1
Pyridazine-3-thiol

A solution of pyridazin-3-ol (1.0 g, 10.4 mmol) in pyridine (15 mL) was treated with diphosphorus pentasulfide (924 mg, 4.16 mmol) at room temperature. The solution was then stirred at reflux temperature for 1 hour. At this time, the resulting mixture was cooled to room temperature and concentrated in vacuo to give pyridazine-3-thiol as a yellow solid (560 mg, 48%). This material was used without further purification. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 14.74 (s, 1H), 8.26 (dd, 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).

−７８℃のテトラヒドロフラン（５０ｍＬ）中の４−メトキシアニリン（５．００ｇ、４０．７ｍｍｏｌ）の溶液をトリエチルアミン（４．１９ｇ、４１．５ｍｍｏｌ）と続いて２−ブロモアセチルクロリド（６．３８ｇ、４０．７ｍｍｏｌ）で処理し、添加時に沈殿物を生じた。反応物をゆっくりと２５℃まで温め、そこでそれを一晩撹拌した。この時点で、混物を水（１００ｍＬ）に注ぎ、塩化メチレン（２×５０ｍＬ）で抽出し、飽和塩化ナトリウム水溶液（１００ｍＬ）で洗浄し、硫酸ナトリウムで乾燥し、濃縮した。得られた残留物をクロマトグラフィー（石油エーテル：酢酸エチル＝８：１）によって精製して、２−ブロモ−Ｎ−（４−メトキシ−フェニル）−アセトアミドを淡褐色の固形物として得た（８．１ｇ、８２％）。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）：δｐｐｍ８．６７（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＋１］^＋，Ｒ_ｔ＝１．４００ｍｉｎ。 Preparation Example 2
N- (4-methoxy-phenyl) -2- (3-methoxy-phenylsulfanyl) -acetamide

A solution of 4-methoxyaniline (5.00 g, 40.7 mmol) in tetrahydrofuran (50 mL) at −78 ° C. was triethylamine (4.19 g, 41.5 mmol) followed by 2-bromoacetyl chloride (6.38 g, 40 0.7 mmol), a precipitate formed upon addition. The reaction was slowly warmed to 25 ° C. where it was stirred overnight. At this point, the mixture was poured into water (100 mL), extracted with methylene chloride (2 × 50 mL), washed with saturated aqueous sodium chloride (100 mL), dried over sodium sulfate, and concentrated. The resulting residue was purified by chromatography (petroleum ether: ethyl acetate = 8: 1) to give 2-bromo-N- (4-methoxy-phenyl) -acetamide as a light brown solid (8 .1 g, 82%). ¹ HNMR (300 MHz, DMSO-d ₆ ): 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 + 1] ⁺ , 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, 1.8 mmol). Then it was treated quickly with a solution of 3-methoxy-benzethiol (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 × 30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 8: 1) to give N- (4-methoxy-phenyl) -2- (3-methoxy-fersulfanyl) -acetamide as yellow Obtained as a solid (510 mg, 85%). LC-MS: 304 [M + 1] ⁺ , R _t = 1.515 min.

The following compounds were synthesized in an analogous manner according to the above procedure:
Preparation Example 3
2- (3-Fluoro-phenylsulfanyl) -N- (4-methoxy-phenyl) -aceamide as a yellow solid from 2-bromo-N- (4-methoxy-phenyl) -acetamide and 3-fluorobenzenethiol Obtained. LC-MS: 292 [M + 1] ⁺ , R _t = 1.529 min.

Preparation Example 4
From 2-bromo-N- (4-methoxy-phenyl) -acetamide and 3-methylbenzenethiol, N- (4-methoxy-phenyl) -2-m-tolylsulfanyl-acetamide was converted to a yellow solid (500 mg, 85 %). LC-MS: 288 [M + 1] ⁺ , R _t = 1.575 min.

Preparation Example 5
From 2-bromo-N- (4-methoxy-phenyl) -acetamide and naphthalene-2-thiol, N4- (4-methoxy-phenyl) -2- (naphthalen-2-ylsulfanyl) -acetamide is a yellow solid. (480 mg, 90%). LC-MS: 324 [M + 1] ⁺ , R _t = 1.623 min.

Preparation Example 6
2-Bromo-N- (4-methoxy-phenyl) -acetamide and naphthalene-1-thiol to N- (4-methoxy-phenyl) -2- (naphthalen-1-ylsulfanyl) -acetamide as a white solid Obtained (500 mg, 93%). LC-MS: 324 [M + 1] ⁺ , R _t = 1.622 min.

Preparation Example 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 + 1] ⁺ , R _t = 1.630 min.

Preparation Example 8
2-[(4-Methoxy-phenylcarbamoyl) -methyl] -benzoic acid methyl ether is obtained as a white solid from 2-bromo-N- (4-methoxy-phenyl) -acetamide and 3-mercapto-benzoic acid mel ester (500 mg, 91%). LC-MS: 304 [M + 1] ⁺ , R _t = 1.515 min.

Preparation Example 9
2-Bromo-N- (4-methoxy-phenyl) -acetamide and 3-chloro-4-fluoro-bezenthiol to 2- (3-chloro-4-fluoro-phenylsulfanyl) -N- (4-methoxy-phenyl) -Acetamide was obtained as a yellow solid (400 mg, 75%). LC-MS: 304 [M + 1] ⁺ , R _t = 1.599 min.

Preparation Example 10
Obtaining N- (4-methoxy-phenyl) -2- (pyridazin-3-ylsulfanyl) -acetamide as a yellow solid from 2-bromo-N- (4-methoxy-phenyl) -acetamide and pyridazine-3-thiol (400 mg, 88%). ¹ HNMR (300 MHz, DMSO-d ₆ ) dppm 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 + 1] ⁺ , R _t = 1.303 min.

Preparation Example 11
2- (3,5-dichloro-phenylsulfanyl) -N- (4-methoxy-phenyl) -atamide from 2-bromo-N- (4-methoxy-phenyl) -acetamide and 3,5-dichloro-benzeneyl Obtained as an off-white solid (0.26 g, 74.2%). ¹ HNMR (300 MHz, DMSO-d ₆ ) dppm 3.71 (s, 3H) 3.95 (s, 2H) 6.89 (d, J = 9.04 Hz, 2H) 7.28-7.59 (m, 5H) 10.13 (s, 1H).

Preparation Example 12
2- (3,4-Difluoro-phenylsulfanyl) -N- (4-methoxy-phenyl) -acetamide from 2-bromo-N- (4-methoxy-phenyl) -acetamide and 3,4-difluorobenzenethyl Obtained as an off-white solid (302.2 mg, 95.4%). ¹ HNMR (300 MHz, DMSO-d ₆ ) dppm 3.72 (s, 3H) 3.85 (s, 2H) 6.88 (d, J = 9.04 Hz, 2H) 7.20-7.31 (m, 1H) 7.34-7.50 (m, 3H) 7.51-7.63 (m, 1H) 10.07 (s, 1H).

酢酸（４ｍＬ）中のＮ−（４−メトキシ−フェニル）−２−（３−メトキシ−フェニルスルファニル）−アセトアミド（２００ｍｇ、０．６６ｍｍｏｌ）の溶液を室温で３０％の過酸化水素水溶液（２２４ｍｇ、６．６０ｍｍｏｌ）で処理した。ついで、この溶液を１時間４０℃で撹拌した。の時点で、得られた混合物を、室温まで冷却し、酢酸エチル（３０ｍＬ）で希釈し、１Ｎの塩酸水溶液（３０ｍＬ）、水（３０ｍＬ）、飽和塩化ナトリウム水溶液（３０ｍＬ）で洗浄し、硫酸ナトリウムで乾燥させ、減圧下で濃縮した。得られた残留物をシリカゲルクロマトグラフィー（石油エーテル：酢酸エチル＝５：１）により精製し、白色固形物として２−（３−メトキシ−ベンゼンスルフィニル）−Ｎ−（４−メトキシ−フェニル）−アセトアミドを得た（２００ｍｇ、９５％）。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ１０．０８（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＋１］^＋，Ｒｔ＝１．３６８ｍｉｎ．ＨＰＬＣ：９８．３４％（２１４ｎｍ），９９．３０％（２５４ｎｍ），Ｒ_ｔ＝３．３３３ｍｉｎ。 Example 1
2- (3-Methoxy-benzenesulfinyl) -N- (4-methoxy-phenyl) -acetamide (I-1)

A solution of N- (4-methoxy-phenyl) -2- (3-methoxy-phenylsulfanyl) -acetamide (200 mg, 0.66 mmol) in acetic acid (4 mL) at room temperature with 30% aqueous hydrogen peroxide (224 mg, 6.60 mmol). The solution was then stirred at 40 ° C. for 1 hour. At this point, the resulting mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with 1N aqueous hydrochloric acid (30 mL), water (30 mL), saturated aqueous sodium chloride (30 mL), and sodium sulfate. And concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5: 1) to give 2- (3-methoxy-benzenesulfinyl) -N- (4-methoxy-phenyl) -acetamide as a white solid. (200 mg, 95%) was obtained. ¹ HNMR (300 MHz, DMSO-d 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 + 1] ⁺ , Rt = 1.368 min. HPLC: 98.34% (214 nm), 99.30% (254 nm), R _t = 3.333 min.

２−（３−フルオロ−フェニルスルファニル）−Ｎ−（４−メトキシ−フェニル）−アセトアミドから、２−（３−フルオロ−ベンゼンスルフィニル）−Ｎ−（４−メトキシ−フェニル）−アセアミドを白色の固形物（２００ｍｇ、６３％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ１０．０９（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＋１］^＋，Ｒ_ｔ＝１．３７１ｍｉｎ．ＨＰＬＣ：９９．１％（２１４ｎｍ），９９．７％（２５４ｎｍ），Ｒ_ｔ＝４．４７０ｍｉｎ。 In an analogous manner, the following sulfoxides were synthesized according to the above procedure:
Example 2
2- (3-Fluoro-benzenesulfinyl) -N- (4-methoxy-phenyl) -acetimide (I-2)

2- (3-Fluoro-phenylsulfanyl) -N- (4-methoxy-phenyl) -acetamide from 2- (3-fluoro-benzenesulfinyl) -N- (4-methoxy-phenyl) -aceamide as a white solid Obtained as a product (200 mg, 63%). ¹ HNMR (300 MHz, DMSO-d 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 + 1] ⁺ , R _t = 1.371 min. HPLC: 99.1% (214 nm), 99.7% (254 nm), R _t = 4.470 min.

異性体１；超臨界流体クロマトグラフィー；キラルパックＡＳ−Ｈ、４０℃、流量６０ｍＬ／分、４％メタノール；ＵＶ波長：２６０ｎＭ；Ｒ_Ｔ＝２．２１分；白色固形物（４７．１ｍｇ）。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）ｄｐｐｍ３．７２（ｓ，３Ｈ）３．８３−３．９７（ｍ，１Ｈ）３．９９−４．１６（ｍ，１Ｈ）６．９０（ｄ，Ｊ＝８．８５Ｈｚ，２Ｈ）７．４４（ｄ，Ｊ＝９．０４Ｈｚ，３Ｈ）７．５７（ｄ，Ｊ＝７．７２Ｈｚ，２Ｈ）７．６１−７．７３（ｍ，１Ｈ）１０．０８（ｓ，１Ｈ）。 Example 3
2-((R) -3-Fluoro-benzenesulfinyl) -N- (4-methoxy-phenyl) -atamide (I-3)

Isomer 1; supercritical fluid chromatography; Chiralpak AS-H, 40 ° C., flow rate 60 mL / min, 4% methanol; UV wavelength: 260 nM; R _T = 2.21 min; white solid (47.1 mg). ¹ HNMR (300 MHz, DMSO-d ₆ ) dppm 3.72 (s, 3H) 3.83-3.97 (m, 1H) 3.99-4.16 (m, 1H) 6.90 (d, J = 8.85 Hz, 2H) 7.44 (d, J = 9.04 Hz, 3H) 7.57 (d, J = 7.72 Hz, 2H) 7.61-7.73 (m, 1H) 10.08 ( s, 1H).

異性体２；キラルパックＡＳ−Ｈ、４０℃、流量６０ｍＬ／分、４０％メタノール；ＵＶ波長：２６０ｎ；Ｒ_Ｔ＝２．９１分；白色固形物（４４．９ｍｇ）；^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）ｄｐｐｍ３．７２（ｓ，３Ｈ）３．８２−３．９７（ｍ，１Ｈ）３．９８−４．１９（ｍ，１Ｈ）６．８９（ｄ，Ｊ＝８．６７Ｈｚ，２Ｈ）７．４４（ｄ，Ｊ＝８．６７Ｈｚ，３Ｈ）７．５７（ｄ，Ｊ＝８．２９Ｈｚ，２Ｈ）７．６１−７．７３（ｍ，１Ｈ）１０．０８（ｓ，１Ｈ）。 Example 4
2-((S) -3-Fluoro-benzenesulfinyl) -N- (4-methoxy-phenyl) -atamide (I-4)

Isomer 2; Chiralpak AS-H, 40 ° C., flow rate 60 mL / min, 40% methanol; UV wavelength: 260 n; R _T = 2.91 min; white solid (44.9 mg); ¹ HNMR (300 MHz, DMSO) −d ₆ ) dppm 3.72 (s, 3H) 3.82-3.97 (m, 1H) 3.98-4.19 (m, 1H) 6.89 (d, J = 8.67 Hz, 2H) 7.44 (d, J = 8.67 Hz, 3H) 7.57 (d, J = 8.29 Hz, 2H) 7.61-7.73 (m, 1H) 10.08 (s, 1H).

Ｎ−（４−メトキシ−フェニル）−２−ｍ−トリルスルファニル−アセトアミドから、Ｎ−（４−メトキシ−フェニル）−２（トルエン−３−スルフィニル）−アセトアミドを白色固形物（２６０ｍｇ、８２％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ１０．０７（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＋１］^＋，Ｒ_ｔ＝１．３９０ｍｉｎ．ＨＰＬＣ：９９．１０％（２１４ｎｍ），９９．６３％（２５４ｎｍ），Ｒ_ｔ＝３．３７０ｍｉｎ。 Example 5
N- (4-Methoxy-phenyl) -2- (toluene-3-sulfinyl) -acetamide (I-5)

From N- (4-methoxy-phenyl) -2-m-tolylsulfanyl-acetamide, N- (4-methoxy-phenyl) -2 (toluene-3-sulfinyl) -acetamide was obtained as a white solid (260 mg, 82%) Got as. ¹ HNMR (300 MHz, DMSO-d ₆ ) 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 + 1] ⁺ , R _t = 1.390 min. HPLC: 99.10% (214 nm), 99.63% (254 nm), R _t = 3.370 min.

異性体１；超臨界流体クロマトグラフィー；キラルパックＡＳ−Ｈ、４０℃、流量６０ｍＬ／分、４％メタノール；ＵＶ波長：２６０ｎＭ；Ｒ_Ｔ＝２．３６分；オフホワイトの固形物（４０．３ｍｇ）；^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）ｄｐｐｍ２．３８（ｓ，３Ｈ）３．７２（ｓ，３Ｈ）３．７７−４．０８（ｍ，２Ｈ）６．８９（ｄ，Ｊ＝９．０４Ｈｚ，２Ｈ）７．２９−７．６５（ｍ，６Ｈ）１０．０６（ｓ，１Ｈ）。 Example 6
N- (4-methoxy-phenyl) -2-((R) -toluene-3-sulfinyl) -acetoami (I-6)

Isomer 1; supercritical fluid chromatography; Chiralpak AS-H, 40 ° C., flow rate 60 mL / min, 4% methanol; UV wavelength: 260 nM; R _T = 2.36 min; off-white solid (40.3 mg ¹ HNMR (300 MHz, DMSO-d ₆ ) dppm 2.38 (s, 3H) 3.72 (s, 3H) 3.77-4.08 (m, 2H) 6.89 (d, J = 9. 04 Hz, 2H) 7.29-7.65 (m, 6H) 10.06 (s, 1H).

異性体２；超臨界流体クロマトグラフィー；キラルパックＡＳ−Ｈ、４０℃、流量６０ｍＬ／分、４％メタノール；ＵＶ波長：２６０ｎＭ；Ｒ_Ｔ＝３．３４分；オフホワイトの固形物（４３．６ｍｇ）；^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）ｄｐｐｍ２．３８（ｓ，３Ｈ）３．７２（ｓ，３Ｈ）３．７９−４．０７（ｍ，２Ｈ）６．９０（ｄ，Ｊ＝８．４８Ｈｚ，２Ｈ）７．２８−７．６８（ｍ，６Ｈ）１０．０６（ｓ，１Ｈ）。 Example 7
N- (4-methoxy-phenyl) -2-((S) -toluene-3-sulfinyl) -acetoami (I-7)

Isomer 2; supercritical fluid chromatography; Chiralpak AS-H, 40 ° C., flow rate 60 mL / min, 4% methanol; UV wavelength: 260 nM; R _T = 3.34 min; off-white solid (43.6 mg ¹ HNMR (300 MHz, DMSO-d ₆ ) dppm 2.38 (s, 3H) 3.72 (s, 3H) 3.79-4.07 (m, 2H) 6.90 (d, J = 8. 48 Hz, 2H) 7.28-7.68 (m, 6H) 10.06 (s, 1H).

Ｎ−（４−メトキシ−フェニル）−２−（ネフタレン−２−イルスルファニル）−アセトアミドから、Ｎ−（４−メトキシ−フェニル）−２（ネフタレン−２−スルフィニル）−アセトアミドを白色固形物（１８０ｍｇ、５７％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ１０．１１（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＋１］^＋，Ｒ_ｔ＝１．４４７ｍｉｎ．ＨＰＬＣ：９８．８９％（２１４ｎｍ），９９．２３％（２５４ｎｍ），Ｒ_ｔ＝３．７２０ｍｉｎ。 Example 8
N- (4-Methoxy-phenyl) -2- (naphthalene-2-sulfinyl) -acetamide (I-8)

From N- (4-methoxy-phenyl) -2- (nephthalen-2-ylsulfanyl) -acetamide, N- (4-methoxy-phenyl) -2 (nephthalene-2-sulfinyl) -acetamide was obtained as a white solid (180 mg 57%). ¹ HNMR (300 MHz, DMSO-d 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 + 1] ⁺ , R _t = 1.447 min. HPLC: 98.89% (214 nm), 99.23% (254 nm), R _t = 3.720 min.

Ｎ−（４−メトキシ−フェニル）−２−（ネフタレン−１−イルスルファニル）−アセトアミドから、Ｎ−（４−メトキシ−フェニル）−２（ネフタレン−１−スルフィニル）−アセトアミドを白色の固形物（２１０ｍｇ、６７％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ１０．１５（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＋１］^＋，Ｒ_ｔ＝１．４４７ｍｉｎ．ＨＰＬＣ：９５．３２％（２１４ｎｍ），９７．７２％（２５４ｎｍ），Ｒ_ｔ＝５．２７０ｍｉｎ．。 Example 9
N- (4-methoxy-phenyl) -2- (naphthalene-1-sulfinyl) -acetamide (I-9)

From N- (4-methoxy-phenyl) -2- (nephthalen-1-ylsulfanyl) -acetamide, N- (4-methoxy-phenyl) -2 (nephthalene-1-sulfinyl) -acetamide was converted to a white solid ( 210 mg, 67%). ¹ HNMR (300 MHz, DMSO-d 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 + 1] ⁺ , R _t = 1.447 min. HPLC: 95.32% (214 nm), 97.72% (254 nm), R _t = 5.270 min. .

２−シクロヘキシル−Ｎ−（４−メトキシ−フェニル）−アセトアミドから、２−シクロヘキサンスルフィニル−Ｎ−（４−メトキシ−フェニル）−アセトアミドを白色の固形物（１９０ｍｇ、６９％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ１０．１６（ｍ，１Ｈ），７．５３−７．４６（ｍ，２Ｈ），６．９２−６．８７（ｍ，２Ｈ），３．８５−３．６４（ｍ，４Ｈ），２．８６−２．７２（ｍ，１Ｈ），１．９８−１．７６（ｍ，４Ｈ），１．６９−１．６０（ｍ，１Ｈ），１．４８−１．１３（ｍ，５Ｈ）．ＬＣ−ＭＳ：３４０［Ｍ＋１］^＋，Ｒ_ｔ＝１．３７６ｍｉｎ．ＨＰＬＣ：９６．８７％（２１４ｎｍ），９７．３０％（２５４ｎｍ），Ｒ_ｔ＝５．２１３ｍｉｎ。 Example 10
2-Cyclohexanesulfinyl-N- (4-methoxy-phenyl) -acetamide (I-10)

2-Cyclohexanesulfinyl-N- (4-methoxy-phenyl) -acetamide was obtained as a white solid (190 mg, 69%) from 2-cyclohexyl-N- (4-methoxy-phenyl) -acetamide. ¹ HNMR (300 MHz, DMSO-d ₆ ) δ ppm 10.16 (m, 1H), 7.53-7.46 (m, 2H), 6.92-6.87 (m, 2H), 3.85-3 .64 (m, 4H), 2.86-2.72 (m, 1H), 1.98-1.76 (m, 4H), 1.69-1.60 (m, 1H), 1.48 -1.13 (m, 5H). LC-MS: 340 [M + 1] ⁺ , R _t = 1.376 min. HPLC: 96.87% (214 nm), 97.30% (254 nm), R _t = 5.213 min.

３−［（４−メトキシ−フェニルカルバモイル）−メチル］−安息香酸メチルエステルから３−［（４−メトキシ−フェニルカルバモイル）−メタンスルフィニル］−安息香酸メチルエテルを白色の固形物（１８０ｍｇ、４３％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ１０．０７（ｓ，１Ｈ），８．２９（ｄ，Ｊ＝１．５Ｈｚ，１Ｈ），８．１１（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．９７（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．７４（ｔ，Ｊ＝７．８Ｈｚ，１Ｈ），７．４２（ｄ，Ｊ＝９．０Ｈｚ，２Ｈ），６．８８（ｄ，Ｊ＝９．０Ｈｚ，２Ｈ），４．０６（ｄ，Ｊ＝１３．２Ｈｚ，１Ｈ），３．９５−３．８６（ｍ，３Ｈ），３．７２（ｓ，３Ｈ）．ＬＣ−ＭＳ：３４８［Ｍ＋１］^＋，Ｒ_ｔ＝１．４０２ｍｉｎ．ＨＰＬＣ：９５．０５％（２１４ｎｍ），９６．０５％（２５４ｎｍ），Ｒ_ｔ＝４．３８７ｍｉｎ。 Example 11
3-[(4-Methoxy-phenylcarbamoyl) -methanesulfinyl] -benzoic acid methyl ester (I-11)

3-[(4-Methoxy-phenylcarbamoyl) -methyl] -benzoic acid methyl ester from 3-[(4-methoxy-phenylcarbamoyl) -methanesulfinyl] -benzoic acid methyl ether to a white solid (180 mg, 43%) Got as. ¹ HNMR (300 MHz, DMSO-d 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 (t, 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 + 1] ⁺ , R _t = 1.402 min. HPLC: 95.05% (214nm), 96.05% (254nm), R t = 4.387min.

２−（３−クロロ−４−フルオロ−フェニルスルファニル）−Ｎ−（４−メトキシ−フェニル）−アトアミドから２−（３−クロロ−４−フルオロ−ベンゼンスルフィニル）−Ｎ−（４−メトキシ−フニル）−アセトアミドを白色の固形物（１３０ｍｇ、３１％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ１０．０６（ｓ，１Ｈ），７．９５−７．８９（ｍ，１Ｈ），７．７３（ｍ，１Ｈ），７．７０−７．６２（ｍ，１Ｈ），７．４１（ｄ，Ｊ＝９．１Ｈｚ，２Ｈ），６．９２−６．８４（ｍ，２Ｈ），４．１０−４．０４（ｍ，１Ｈ），３．９０（ｄ，Ｊ＝１３．３Ｈｚ，１Ｈ），３．７１（ｓ，３Ｈ）．ＬＣ−ＭＳ：３４２［Ｍ＋１］^＋，Ｒ_ｔ＝．４７８ｍｉｎ．ＨＰＬＣ：１００％（２１４ｎｍ），１００％（２５４ｎｍ），Ｒ_ｔ＝０．７４２ｍｉｎ。 Example 12
2- (3-Chloro-4-fluoro-benzenesulfinyl) -N- (4-methoxy-phenyl) -acetamide (I-12)

2- (3-Chloro-4-fluoro-phenylsulfanyl) -N- (4-methoxy-phenyl) -atamide to 2- (3-chloro-4-fluoro-benzenesulfinyl) -N- (4-methoxy-funil) ) -Acetamide was obtained as a white solid (130 mg, 31%). ¹ HNMR (300 MHz, DMSO-d 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 + 1] ⁺ , R _t =. 478 min. HPLC: 100% (214 nm), 100% (254 nm), R _t = 0.742 min.

異性体１；超臨界流体クロマトグラフィー；キラルパックＡＳ−Ｈ、４０℃、流量６０ｍＬ／分、４％メタノール；ＵＶ波長：２６０ｎＭ；Ｒ_Ｔ＝２．５３分；白色固形物（４５．８ｍｇ）；^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）ｄｐｐｍ３．７２（ｓ，３Ｈ）３．９１（ｍ，１Ｈ）４．０１−４．１９（ｍ，１Ｈ）６．８９（ｄ，Ｊ＝９．０４Ｈｚ，２Ｈ）７．４３（ｄ，Ｊ＝８．６７Ｈｚ，２Ｈ）７．５７−７．８２（ｍ，２Ｈ）７．９４（ｄ，Ｊ＝６．７８Ｈｚ，１Ｈ）１０．０７（ｓ，１Ｈ）。 Example 13
2-((R) -3-Chloro-4-fluoro-benzenesulfinyl) -N- (4-methoxy-phenyl) acetamide (I-13)

Isomer 1; supercritical fluid chromatography; Chiralpak AS-H, 40 ° C., flow rate 60 mL / min, 4% methanol; UV wavelength: 260 nM; R _T = 2.53 min; white solid (45.8 mg); ¹ HNMR (300 MHz, DMSO-d ₆ ) dppm 3.72 (s, 3H) 3.91 (m, 1H) 4.01-4.19 (m, 1H) 6.89 (d, J = 9.04 Hz, 2H) 7.43 (d, J = 8.67 Hz, 2H) 7.57-7.82 (m, 2H) 7.94 (d, J = 6.78 Hz, 1H) 10.07 (s, 1H) .

異性体２；超臨界流体クロマトグラフィー；キラルパックＡＳ−Ｈ、４０℃、流量６０ｍＬ／分、４％メタノール；ＵＶ波長：２６０ｎＭ；Ｒ_Ｔ＝３．６８分；白色固形物（４７．８ｍｇ）；^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）ｄｐｐｍ３．７２（ｓ，３Ｈ）３．８３−３．９８（ｍ，１Ｈ）４．００−４．１７（ｍ，１Ｈ）６．９０（ｄ，Ｊ＝８．６７Ｈｚ，２Ｈ）７．４３（ｄ，Ｊ＝８．８５Ｈｚ，２Ｈ）７．５６−７．８４（ｍ，２Ｈ）７．９４（ｄ，Ｊ＝６．７８Ｈｚ，１Ｈ）１０．０８（ｓ，１Ｈ）。 Example 14
2-((S) -3-Chloro-4-fluoro-benzenesulfinyl) -N- (4-methoxy-ferle) -acetamide (I-14)

Isomer 2; supercritical fluid chromatography; Chiralpak AS-H, 40 ° C., flow rate 60 mL / min, 4% methanol; UV wavelength: 260 nM; R _T = 3.68 min; white solid (47.8 mg); ¹ HNMR (300 MHz, DMSO-d ₆ ) dppm 3.72 (s, 3H) 3.83-3.98 (m, 1H) 4.00-4.17 (m, 1H) 6.90 (d, J = 8.67 Hz, 2H) 7.43 (d, J = 8.85 Hz, 2H) 7.56-7.84 (m, 2H) 7.94 (d, J = 6.78 Hz, 1H) 10.08 ( s, 1H).

Ｎ−（４−メトキシ−フェニル）−２−（ピリダジン−３−イルスルファニル）−アセトアミドからＮ−（４−メトキシ−フェニル）−２（ピリダジン−３−スルフィニル）−アセトアミド（４００ｍｇ）を黄色固形物（８０ｍｇ、１９％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ１０．２１（ｓ，１Ｈ），９．３８（ｄｄ，Ｊ＝５．０，１．６Ｈｚ，１Ｈ），８．１６（ｄｄ，Ｊ＝８．５，１．６Ｈｚ，１Ｈ），８．０３（ｄｄ，Ｊ＝８．５，５．０Ｈｚ，１Ｈ），７．４４（ｄ，Ｊ＝９．１Ｈｚ，２Ｈ），６．８８（ｄ，Ｊ＝９．１Ｈｚ，２Ｈ），４．３１（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），４．０４（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），３．７２（ｓ，３Ｈ）．ＬＣ−ＭＳ：２９２［Ｍ＋１］^＋，Ｒ_ｔ＝１．１９８ｍｉｎ．ＨＰＬＣ：９９．２０％（２１４ｎｍ），９９．６５％（２５４ｎｍ），Ｒ_ｔ＝４．６１７ｍｉｎ。 Example 15
N- (4-Methoxy-phenyl) -2- (pyridazine-3-sulfinyl) -acetamide (I-15)

N- (4-methoxy-phenyl) -2- (pyridazin-3-ylsulfanyl) -acetamide to N- (4-methoxy-phenyl) -2 (pyridazine-3-sulfinyl) -acetamide (400 mg) as a yellow solid (80 mg, 19%). ¹ HNMR (300 MHz, DMSO-d ₆ ) δ ppm 10.21 (s, 1H), 9.38 (dd, J = 5.0, 1.6 Hz, 1H), 8.16 (dd, 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 + 1] ⁺ , R _{t =} 1.198 min. HPLC: 99.20% (214 nm), 99.65% (254 nm), R _t = 4.617 min.

２−（３，５−ジクロロ−フェニルスルファニル）−Ｎ−（４−メトキシ−フェニル）−アセトアミドから２−（３，５−ジクロロ−ベンゼンスルフィニル）−Ｎ−（４−メトキシ−フェニル）−アセアミド（０．２６ｇ）をオフホワイトの固形物（４９．８ｍｇ、１８．３％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）ｄｐｐｍ３．７２（ｓ，３Ｈ）３．９３（ｄ，Ｊ＝１３．３８Ｈｚ，１Ｈ）４．１５（ｄ，Ｊ＝１３．３７Ｈｚ，１Ｈ）６．９０（ｄ，Ｊ＝９．０４Ｈｚ，２Ｈ）７．４３（ｄ，Ｊ＝９．０４Ｈｚ，２Ｈ）７．７５（ｄ，Ｊ＝１．８８Ｈｚ，２Ｈ）７．８５（ｔ，Ｊ＝１．８８Ｈｚ，１Ｈ）１０．０８（ｓ，１Ｈ） Example 16
2- (3,5-Dichloro-benzenesulfinyl) -N- (4-methoxy-phenyl) -aceamide (I-16)

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

２−（３，４−ジフルオロ−フェニルスルファニル）−Ｎ−（４−メトキシ−フェニル）−アセトミドから２−（３，４−ジフルオロ−ベンゼンスルフィニル）−Ｎ−（４−メトキシ−フェニル）−セトアミド（３０２ｍｇ）を白色固形物（２４４．６ｍｇ、７７％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）ｄｐｐｍ３．７２（ｓ，３Ｈ）３．８０−３．９６（ｍ，１Ｈ）４．０７（ｄ，Ｊ＝１３．３７Ｈｚ，１Ｈ）６．８０−６．９６（ｍ，２Ｈ）７．３５−７．５０（ｍ，２Ｈ）７．５５−７．６５（ｍ，１Ｈ）７．７２（ｄｔ，Ｊ＝１０．３６，８．１０Ｈｚ，１Ｈ）７．８３（ｄｄｄ，Ｊ＝９．８９，７．６３，２．０７Ｈｚ，１Ｈ）１０．０９（ｓ，１Ｈ）。 Example 17
2- (3,4-Difluoro-benzenesulfinyl) -N- (4-methoxy-phenyl) -atamide (I-17)

2- (3,4-Difluoro-phenylsulfanyl) -N- (4-methoxy-phenyl) -acetamide to 2- (3,4-difluoro-benzenesulfinyl) -N- (4-methoxy-phenyl) -cetamide ( 302 mg) was obtained as a white solid (244.6 mg, 77%). ¹ HNMR (300 MHz, DMSO-d ₆ ) dppm 3.72 (s, 3H) 3.80-3.96 (m, 1H) 4.07 (d, J = 13.37 Hz, 1H) 6.80-6. 96 (m, 2H) 7.35-7.50 (m, 2H) 7.55-7.65 (m, 1H) 7.72 (dt, J = 10.36, 8.10 Hz, 1H) 83 (ddd, J = 9.89, 7.63, 2.07 Hz, 1H) 10.09 (s, 1H).

−７８℃のテトラヒドロフラン（６０ｍＬ）の溶液を、化合物４−メトキシ−ベンジルアミン（１．０ｇ、７．３ｍｍｏｌ）と続いてトリエチルアミン（８３８ｍｇ、８．２９ｍｍｏｌ）で処理した。ついで、この溶液を２−ブロモセチルクロリド（１．２８ｇ、８．１３ｍｍｏｌ）で処理し、添加時点で沈殿物が形成された。反応物を２５℃までゆっくり温め、その時点でそれを一晩撹拌した。この時点で、反応物を水（１００ｍＬ）に注ぎ、塩化メチレン（２×１００ｍＬ）で抽出し、飽和塩化ナトリウム水溶液（１００ｍＬ）で洗浄し、硫酸ナトリウムで乾燥させ、減圧下で濃縮した。得られた残留物をシリゲルクロマトグラフィー（石油エーテル：酢酸エチル＝５：１）によって精製して、２−ブロモ−Ｎ−（４−メトキシ−ベンジル）−アセトアミドを黄色固形物（６３０ｍｇ、３４％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ８．６７（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＋１］^＋，Ｒ_ｔ＝１．３９３ｍｉｎ。 Preparation Example 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-bromocetyl chloride (1.28 g, 8.13 mmol) and a precipitate formed at the time of addition. The reaction was slowly warmed to 25 ° C. at which point it was stirred overnight. At this time, the reaction was poured into water (100 mL), extracted with methylene chloride (2 × 100 mL), washed with saturated aqueous sodium chloride (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by siligel chromatography (petroleum ether: ethyl acetate = 5: 1) to give 2-bromo-N- (4-methoxy-benzyl) -acetamide as a yellow solid (630 mg, 34% ). ¹ HNMR (300 MHz, DMSO-d ₆ ) 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 + 1] ⁺ , Rt ₌ 1.393 min.

The following compounds were synthesized in an analogous manner according to the procedure described above:
Preparation Example 14
2-Bromo-N- (4-fluoro-phenyl) -acetamide was obtained as a white solid (1.20 g, 85%) from 2-bromoacetyl chloride and 4-fluoro-phenylamine. LC-MS: 232 [M + 1] ⁺ , R _{t =} 1.425 min.

Preparation Example 15
2-Bromo-N- (4methanesulfonyl-phenyl) -acetamide was obtained as a white solid (1.20 g, 88%) from 2-bromoacetyl chloride and 4-methanesulfonyl-phenylamine. LC-MS: 292 [M + 1] ⁺ , Rt ₌ 1.256 min.

Preparation Example 16
2-Bromo-N- (3-methoxy-phenyl) -acetamide was obtained as a white solid (1.56 g, 78%) from 2-bromoacetyl chloride and 3-methoxy-phenylamine. LC-MS: 244 [M + 1] ^< +>, Rt ₌ 1.388min.

Preparation Example 17
2-Bromo-N2- (2-Mexyl-phenyl) -acetamide was obtained as a yellow solid (800 mg, 42%) from 2-bromoacetyl chloride and 2-methoxy-phenylamine. LC-MS: 244 [M + 1] ^< +>, Rt ₌ 1.455min.

Preparation Example 18
2-Bromo-N-cyclohexyl-acetamide was obtained as a white solid (1.00 g, 48%) from 2-bromoacetyl chloride and cycloxanmethylamine. LC-MS: 234 [M + 1] ^< +>, Rt ₌ 1.485min.

テトラヒドロフラン（６ｍＬ）及び水（６ｍＬ）中の化合物２−ブロモ−Ｎ−（４−メトキシ−ベンジル）−アセトアミド（５０ｍｇ、１．９５ｍｍｏｌ）の溶液をＮ−メチルモルホリン（４５６ｍｇ、４．５０ｍｍｏｌ）で処理し、ついでテトラヒドロフラン（３ｍＬ）中の３−クロロチオフェノール（５６０ｍｇ、３．８７ｍｍｏｌ）の溶液で速やかに滴下処理した。反応溶液を２５℃で一晩撹拌した。この時点で、得られた混合物を真空中で濃縮した。残留物を水（３０ｍＬで希釈し、塩化メチレン（２×３０ｍＬ）中の１０％メタノール溶液で抽出した。一緒にした有機物を飽和塩化ナトリウム水液（３０ｍＬ）で洗浄し、硫酸ナトリウムで乾燥させ、減圧下で濃縮した。得られた残留物をシリカゲルクロマトグラフィー（石油エーテル：酢酸エチル＝５：１）により精製し、２−（３−クロロ−フェニルスルファニル）−Ｎ−（４−メトキシ−ベンジル）−アセトアミドを白色の固形物（６２０ｍｇ、９９％）として得た。ＬＣ−ＭＳ：３２２［Ｍ＋１］^＋，Ｒ_ｔ＝１．５６２ｍｉｎ。 Preparation Example 19
2- (3-Chloro-phenylsulfanyl) -N- (4-methoxy-benzyl) -acetamide

Treatment of a solution of compound 2-bromo-N- (4-methoxy-benzyl) -acetamide (50 mg, 1.95 mmol) in tetrahydrofuran (6 mL) and water (6 mL) with N-methylmorpholine (456 mg, 4.50 mmol). And then quickly added dropwise with a solution of 3-chlorothiophenol (560 mg, 3.87 mmol) in tetrahydrofuran (3 mL). The reaction solution was stirred at 25 ° C. overnight. At this point, the resulting mixture was concentrated in vacuo. The residue was diluted with water (30 mL and extracted with a 10% methanol solution in methylene chloride (2 × 30 mL). The combined organics were washed with saturated aqueous sodium chloride (30 mL), dried over sodium sulfate, The residue obtained was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5: 1) and 2- (3-chloro-phenylsulfanyl) -N- (4-methoxy-benzyl). Acetamide was obtained as a white solid (620 mg, 99%) LC-MS: 322 [M + 1] ⁺ , R _{t =} 1.562 min.

The following compounds were synthesized in an analogous manner according to the procedure described above:
Preparation Example 20
2- (3-Chloro-phenylsulfanyl) -N- (4-fluoro-phenyl) -acetamide as a white solid from 3-chlorothioenol and 2-bromo-N- (4-fluoro-phenyl) -acetamide Obtained (560 mg, 86%). LC-MS: 296 [M + 1] ⁺ , R _{t =} 1.646 min.

Preparation Example 21
2- (3-Chloro-phenylsulfanyl) -N- (4-methanesulfonyl-phenyl-acetamide) from 3-chlorothiophenol and 2-bromo-N- (4-methanesulfonyl-phenyl) -aceamide as a yellow solid (450 mg, 74%) LC-MS: 356 [M + 1] ⁺ , R _{t =} 1.508 min.

Preparation Example 22
2- (3-Chloro-phenylsulfanyl) -N- (3-methoxy-phenyl) -acetamide from 3-chlorothioenol and 2-bromo-N- (3-methoxy-phenyl) -acetamide as a yellow solid (530 mg, 84%). LC-MS: 308 [M + 1] ^< +>, Rt ₌ 1.620min.

Preparation Example 23
3-Chlorothioenol and 2-bromo-N- (2-methoxy-phenyl) -acetamide from 2- (3-chloro-phenylsulfanyl) -N- (2-methoxy-phenyl) -acetamide as a white solid ( 550 mg, 87%). LC-MS: 308 [M + 1] ⁺ , R _{t =} 1.694 min.

Preparation Example 24
2- (3chloro-phenylsulfanyl) -N-cyclohexyl-acetamide was obtained as a white solid (1.05 g, 8%) from 3-chlorothiophenol and 2-bromo-N-cyclohexyl-acetamide. LC-MS: 298 [M + 1] ⁺ , R _{t =} 1.686 min.

酢酸（５ｍＬ）中の化合物２−（３−クロロ−フェニルスルファニル）−Ｎ−（４−メトキシ−ベンジル）−アセアミド（３００ｍｇ、０．９４ｍｍｏｌ）の溶液を室温で３０％過酸化水素水溶液（３１８ｍｇ、９．４ｍｍｏｌ）で処理した。ついで、この溶液を１時間４０℃で撹拌した。得られた混合物を室温に冷却し、酢酸エチル（３０ｍＬ）で希釈し、１Ｎの塩酸水溶液（３０ｍＬ）、水（３０ｍＬ）、飽和塩化ナトリウム水溶液（３０ｍＬ）で洗浄し、硫酸ナトリウムで乾燥させ、真空中で濃縮した。残留物をシリカゲルクロマトグラィー（石油エーテル：酢酸エチル＝５：１）によって精製して、２−（３−クロロ−ベンゼンスルフィニル）−Ｎ−（４−メトキシ−ベンジル）−アセトアミドを白色の固形物（２００ｍｇ、６３％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ８．５６−８．５３（ｍ，１Ｈ），７．７０−７．５５（ｍ，３Ｈ），７．１３−７．０８（ｍ，２Ｈ），６．８８−６．８３（ｍ，２Ｈ），４．１９（ｄ，Ｊ＝５．８Ｈｚ，２Ｈ），３．９５−３．７７（ｍ，２Ｈ），３．７２（ｓ，３Ｈ）．ＬＣ−ＭＳ：３０８［Ｍ＋１］^＋，Ｒ_ｔ＝１．４１２ｍｉｎ．ＨＰＬＣ：９９．７９％（２１４ｎｍ），９９．５２％（２５４ｎｍ），Ｒ_ｔ＝３．４９８ｍｉｎ。 Example 18
2- (3-Chloro-benzenesulfinyl) -N- (4-methoxy-benzyl) -acetamide (I-18)

A solution of compound 2- (3-chloro-phenylsulfanyl) -N- (4-methoxy-benzyl) -aceamide (300 mg, 0.94 mmol) in acetic acid (5 mL) at room temperature with 30% aqueous hydrogen peroxide (318 mg, 9.4 mmol). The solution was then stirred at 40 ° C. for 1 hour. The resulting mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with 1N aqueous hydrochloric acid (30 mL), water (30 mL), saturated aqueous sodium chloride (30 mL), dried over sodium sulfate, and vacuum Concentrated in. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5: 1) to give 2- (3-chloro-benzenesulfinyl) -N- (4-methoxy-benzyl) -acetamide as a white solid (200 mg, 63%). ¹ H NMR (300 MHz, DMSO-d 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 + 1] ⁺ , R _{t =} 1.412 min. HPLC: 99.79% (214 nm), 99.52% (254 nm), Rt ₌ 3.498 min.

２−（３−クロロ−フェニルスルファニル）−Ｎ−（４−フルオロ−フェニル）−アセトアミドから２−（３−クロロ−ベンゼンスルフィニル）−Ｎ−（４−フルオロ−フェニル）−アセトアミドを白色の固形物（１２０ｍｇ、２０％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）：δｐｐｍ１０．１０（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＋１］^＋，Ｒ_ｔ＝１．５１３ｍｉｎ．ＨＰＬＣ：９８．５９％（２１４ｎｍ），９９．３７％（２５４ｎｍ），Ｒ_ｔ＝５．４８７ｍｉｎ。 The following compounds were synthesized in an analogous manner according to the procedure described above:
Example 19
2- (3-Chloro-benzenesulfinyl) -N- (4-fluoro-phenyl) -acetamide (I-19)

2- (3-Chloro-phenylsulfanyl) -N- (4-fluoro-phenyl) -acetamide to 2- (3-chloro-benzenesulfinyl) -N- (4-fluoro-phenyl) -acetamide as a white solid (120 mg, 20%). ¹ HNMR (300 MHz, DMSO-d 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 + 1] ⁺ , R _t = 1.513 min. HPLC: 98.59% (214 nm), 99.37% (254 nm), R _t = 5.487 min.

異性体１；超臨界流体クロマトグラフィー；キラルパックＡＳ−Ｈ、４０℃、流量６０ｍＬ／分、４％メタノール；ＵＶ波長：２６０ｎＭ；Ｒ_Ｔ＝２．４３分；白色固形物（３４．８ｍｇ）。^１１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）ｄｐｐｍ３．８３−４．０１（ｍ，１Ｈ）４．０３−４．２４（ｍ，１Ｈ）６．８５−７．００（ｍ，１Ｈ）７．２３（ｄ，Ｊ＝８．１０Ｈｚ，１Ｈ）７．３０−７．４３（ｍ，１Ｈ）７．５３（ｄ，Ｊ＝１０．９３Ｈｚ，１Ｈ）７．５８−７．７３（ｍ，３Ｈ）７．７８（ｓ，１Ｈ）１０．４３（ｓ，１Ｈ）。 Example 20
2-((R) -3-Chloro-benzenesulfinyl) -N- (4-fluoro-phenyl) -aceamide (I-20)

Isomer 1; supercritical fluid chromatography; Chiralpak AS-H, 40 ° C., flow rate 60 mL / min, 4% methanol; UV wavelength: 260 nM; R _T = 2.43 min; white solid (34.8 mg). ¹¹ H NMR (300 MHz, DMSO-d ₆ ) dppm 3.83-4.01 (m, 1H) 4.03-4.24 (m, 1H) 6.85-7.00 (m, 1H) 7.23 ( d, J = 8.10 Hz, 1H) 7.30-7.43 (m, 1H) 7.53 (d, J = 10.93 Hz, 1H) 7.58-7.73 (m, 3H) 78 (s, 1H) 10.43 (s, 1H).

異性体２；超臨界流体クロマトグラフィー；キラルパックＡＳ−Ｈ、４０℃、流量６０ｍＬ／分、４％メタノール；ＵＶ波長：２６０ｎＭ；Ｒ_Ｔ＝３．２４分；白色固形物（３５ｍｇ）。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）ｄｐｐｍ３．７９−４．０１（ｍ，１Ｈ）４．０３−４．２５（ｍ，１Ｈ）６．８６−７．００（ｍ，１Ｈ）７．２３（ｄ，Ｊ＝７．９１Ｈｚ，１Ｈ）７．３０−７．４４（ｍ，１Ｈ）７．５３（ｄ，Ｊ＝１１．４９Ｈｚ，１Ｈ）７．５９−７．７４（ｍ，３Ｈ）７．７８（ｓ，１Ｈ）１０．４３（ｓ，１Ｈ）。 Example 21
2-((S) -3-Chloro-benzenesulfinyl) -N- (4-fluoro-phenyl) -aceamide (I-20)

Isomer 2; supercritical fluid chromatography; Chiralpak AS-H, 40 ° C., flow rate 60 mL / min, 4% methanol; UV wavelength: 260 nM; R _T = 3.24 min; white solid (35 mg). ¹ HNMR (300 MHz, DMSO-d ₆ ) dppm 3.79-4.01 (m, 1H) 4.03-4.25 (m, 1H) 6.86-7.00 (m, 1H) 7.23 ( d, J = 7.91 Hz, 1H) 7.30-7.44 (m, 1H) 7.53 (d, J = 11.49 Hz, 1H) 7.59-7.74 (m, 3H) 78 (s, 1H) 10.43 (s, 1H).

２−（３−クロロ−フェニルスルファニル）−Ｎ−（４−メタンスルホニル−フェニル）−アトアミドから２−（３−クロロ−ベンゼンスルフィニル）−Ｎ−（４−メタンスルホニル−フェル）−アセトアミドを白色の固形物（３００ｍｇ、６４％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ１０．１０（ｓ，１Ｈ），７．８８−７．５７（ｍ，８Ｈ），４．２０−３．９５（ｍ，２Ｈ），３．３０（ｓ，３Ｈ）．ＬＣ−ＭＳ：３７２［Ｍ＋１］^＋，Ｒ_ｔ＝１．３４２ｍｉｎ．ＨＰＬＣ：９９．６５％（２１４ｎｍ），９９．６５％（２５４ｎｍ），Ｒ_ｔ＝４．１７３ｍｉｎ。 Example 22
2- (3-Chloro-benzenesulfinyl) -N- (4-methanesulfonyl-phenyl) -cetamide (I-22)

2- (3-Chloro-phenylsulfanyl) -N- (4-methanesulfonyl-phenyl) -atamide is converted to 2- (3-chloro-benzenesulfinyl) -N- (4-methanesulfonyl-ferle) -acetamide on white Obtained as a solid (300 mg, 64%). ¹ HNMR (300 MHz, DMSO-d 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 + 1] ⁺ , R _t = 1.342 min. HPLC: 99.65% (214 nm), 99.65% (254 nm), R _t = 4.173 min.

２−（３−クロロ−フェニルスルファニル）−Ｎ−（３−メトキシ−フェニル）−アセトアミドから２−（３−クロロ−ベンゼンスルフィニル）−Ｎ−（３−メトキシ−フェニル）−アセトアミドを白色の固形物（２００ｍｇ、３５％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）：δｐｐｍ１０．２０（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＋１］^＋，Ｒ_ｔ＝１．４４９ｍｉｎ．ＨＰＬＣ：９９．０２％（２１４ｎｍ），９９．３４％（２５４ｎｍ），Ｒ_ｔ＝３．３７９ｍｉｎ。 Example 23
2- (3-Chloro-benzenesulfinyl) -N- (3-methoxy-phenyl) -acetamide (I-23)

2- (3-Chloro-phenylsulfanyl) -N- (3-methoxy-phenyl) -acetamide to 2- (3-chloro-benzenesulfinyl) -N- (3-methoxy-phenyl) -acetamide as a white solid (200 mg, 35%). ¹ HNMR (300 MHz, DMSO-d 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 + 1] ⁺ , R _t = 1.449 min. HPLC: 99.02% (214 nm), 99.34% (254 nm), R _t = 3.379 min.

２−（３−クロロ−フェニルスルファニル）−Ｎ−（２−メトキシ−フェニル）−アセトアミドから２−（３−クロロ−ベンゼンスルフィニル）−Ｎ−（２−メトキシ−フェニル）−アセトアミドを白色の固形物（２５０ｍｇ、４４％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ９．４５（ｓ，１Ｈ），７．９３−７．９０（ｄｄ，Ｊ＝７．９，１．４Ｈｚ，１Ｈ），７．７７（ｄｄｄ，Ｊ＝５．８，２．９，１．６Ｈｚ，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−ＭＳ３２４［Ｍ＋１］^＋，Ｒ_ｔ＝１．４７２ｍｉｎ．ＨＰＬＣ：９９．１４％（２１４ｎｍ），９９．４２％（２５４ｎｍ），Ｒ_ｔ＝３．５６１ｍｉｎ。 Example 24
2- (3-Chloro-benzenesulfinyl) -N- (2-methoxy-phenyl) -acetamide (I-24)

2- (3-Chloro-phenylsulfanyl) -N- (2-methoxy-phenyl) -acetamide to 2- (3-chloro-benzenesulfinyl) -N- (2-methoxy-phenyl) -acetamide as a white solid (250 mg, 44%). ¹ HNMR (300 MHz, DMSO-d ₆ ) δ ppm 9.45 (s, 1H), 7.93-7.90 (dd, J = 7.9, 1.4 Hz, 1H), 7.77 (ddd, J = 5.8, 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 + 1] ⁺ , R _t = 1.472 min. HPLC: 99.14% (214 nm), 99.42% (254 nm), R _t = 3.561 min.

２−（３−クロロ−フェニルスルファニル）−Ｎ−シクロヘキシルメチル−アセトアミドから２−（３−クロロ−フェニルスルファニル）−Ｎ−シクロヘキシルメチル−アセトアミドを白色の固（８００ｍｇ、７２％）として得た^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ８．０７（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），７．７０−７．６０（ｍ，４Ｈ），３．８９−３．７８（ｑ，Ｊ＝１３．２Ｈｚ，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＋１］^＋，Ｒ_ｔ＝１．５１６ｍｉｎ．ＨＰＬＣ：９７．９３％（２１４ｎｍ），９８．４４％（２５４ｎｍ），Ｒ_ｔ＝６．３１０ｍｉｎ。 Example 25
2- (3-Chloro-benzenesulfinyl) -N-cyclohexylmethyl-acetamide (I-25)

¹ HNMR obtained 2- (3-chloro-phenylsulfanyl) -N-cyclohexylmethyl-acetamide as a white solid (800 mg, 72%) from 2- (3-chloro-phenylsulfanyl) -N-cyclohexylmethyl-acetamide (300 MHz, DMSO-d ₆ ) δ ppm 8.07 (d, J = 2.0 Hz, 1H), 7.70-7.60 (m, 4H), 3.89-3.78 (q, J = 13. 2Hz, 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 + 1] ⁺ , R _t = 1.516 min. HPLC: 97.93% (214 nm), 98.44% (254 nm), R _t = 6.310 min.

テトラヒドロフラン（１００ｍＬ）中のブロモ−酢酸メチルエステル（１０ｇ、６９ｍｍｏｌ）及び３−クロベンゼンチオール（１１．６ｇ、７６ｍｍｏｌ）の溶液をＮ−メチルモルホリン（１７．４ｍＬ）で処理した。得られた混合物を２０時間２０℃で撹拌した。この時点で、混合物を濾過し、濾液を真空下で濃縮して（３−クロロ−フェニルスルファニル）−酢酸メチルエステルを黄色油状物（１５．６８ｇ、１００％）として得た。その物質を更に精製せずに直接使用した。ＬＣ−ＭＳ：２１７［Ｍ＋１］^＋，Ｒ_ｔ＝１．６５８ｍｉｎ。 Preparation Example 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 for 20 hours at 20 ° C. At this point, the mixture was filtered and the filtrate was concentrated in vacuo to give (3-chloro-phenylsulfanyl) -acetic acid methyl ester as a yellow oil (15.68 g, 100%). The material was used directly without further purification. LC-MS: 217 [M + 1] ⁺ , R _t = 1.658 min.

酢酸（１５６ｍＬ）中の粗（３−クロロフェニルスルファニル）−酢酸メチルエステル（１５．６ｇ、６９ｍｍｏｌ）の溶液を３０％過酸化水素水溶液（７８ｍｌ、６９０ｍｍｏｌ）で処理した。得れた混合物を１時間４０℃で撹拌した。この時点で、溶液を室温に冷却し、塩化メチレン（２×３００ｍＬ）で抽出した。一緒にした有機層を飽和炭酸水素ナトリウム水溶液（２×５００ｍＬ）で洗浄し、硫酸ナトリウムで乾燥し、濾過した。濾液を真空下で濃縮して、黄色油（１５．９ｇ、１００％）として、（３−クロロ−ベンゼンスルフィニル）−酢酸メチルエステルを得た。その物質を更に精製せずに直接使用した。ＬＣ−ＭＳ：２３３［Ｍ＋１］^＋，Ｒ_ｔ＝１．３５８ｍｉｎ。 Preparation Example 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 hour. At this point, the solution was cooled to room temperature and extracted with methylene chloride (2 × 300 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2 × 500 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give (3-chloro-benzenesulfinyl) -acetic acid methyl ester as a yellow oil (15.9 g, 100%). The material was used directly without further purification. LC-MS: 233 [M + 1] ⁺ , R _t = 1.358 min.

１，４−ジオキサン（１６０ｍＬ）及び水（１６０ｍＬ）中の粗（３−クロロ−ベンゼンスフィニル）−酢酸メチルエステル（１５．９ｇ、６９ｍｍｏｌ）の溶液を水酸化ナトリウム水溶液（４．１４ｇ、水中１０３．５ｍｍｏｌ、１０ｍＬ）で処理した。ついで、この溶液を１０分間２０℃で撹拌した。この時点で、得られた混合物を塩化メチレン（５００ｍＬ）で抽出した。有機層を廃棄した。水性層を塩酸水溶液でをｐＨ＝１−２に酸性化し、塩化メチレン（２×２００ｍＬ）で抽出した。一緒にした有機層を硫酸ナトリウムで乾燥し、濾過し、真空下で濃縮し、（３−クロロ−ンゼンスルフィニル）−酢酸を白色の固形物（１２．６７ｇ、８４％）として得た。その物質を更に精製せずに直接使用した。ＬＣ−ＭＳ：２１９［Ｍ＋１］^＋，Ｒ_ｔ＝１．２０９ｍｉｎ。 Preparation Example 27
(3-Chloro-benzenesulfinyl) -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 dissolved in aqueous sodium hydroxide (4.14 g, 103 in water). .5 mmol, 10 mL). The solution was then stirred at 20 ° C. for 10 minutes. At this point, the resulting mixture was extracted with methylene chloride (500 mL). The organic layer was discarded. The aqueous layer was acidified with aqueous hydrochloric acid to pH = 1-2 and extracted with methylene chloride (2 × 200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give (3-chloro-zenzenesulfinyl) -acetic acid as a white solid (12.67 g, 84%). The material was used directly without further purification. LC-MS: 219 [M + 1] ⁺ , R _t = 1.209 min.

０℃溶液に冷却した塩化メチレン（２０ｍＬ）中の（３−クロロ−ベンゼンスルフィニル）−酢酸（６００ｍｇ、２．７４ｍｍｏｌ）の溶液を（２−（７−アザ−１Ｈ−ベンゾトリアゾール−１イル）−１，１，３，３−テトラメチルウロニウムヘキサフルオロホスフェート）（１．１５ｇ、３．０ｍｍｏｌ）及びＮ，Ｎ−ジイソプロピルエチルアミン（１．０６ｇ、８．２２ｍｍｏｌ）で処理した。反応物を０．５時間０℃で撹拌した。この時点で、反応物を３−フルオロ−フェニルアミン（３０５ｍｇ、２．７４ｍｍｏｌ）で処理した。反応混合物を室温に温め、一撹拌した。この時点で、得られた混合物を真空中で濃縮した。残留物を酢酸エチル（３０ｍＬ）で希釈し、１Ｎの塩酸水溶液（３０ｍＬ）、飽和重炭酸ナトリウム水溶液（３０ｍＬ）、水（３０ｍＬ）及び飽和塩化ナトリウム水溶液（３０ｍＬ）で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、真空中で濃縮した。シリカゲルクロマトグラフィー（石油エーテル：酢酸エチル＝５：１）に供して、白色の固形物（１００ｍｇ、１２％）として２−（３−クロロ−ベンゼンスルフィニル）−Ｎ−（３−フルオロ−フェニル）−アセトアミドを得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ１０．４１（ｓ，１Ｈ），７．７４−６．８７（ｍ，８Ｈ），３．９１−４．１５（ｍ，２Ｈ）．ＬＣ−ＭＳ：３１２［Ｍ＋１］^＋，Ｒ_ｔ＝１．４７４ｍｉｎ．ＨＰＬＣ：９８．８９％（２１４ｎｍ），９９．７４％（２５４ｎｍ），Ｒ_ｔ＝５．５７７ｍｉｎ。 Example 26
2- (3-Chloro-benzenesulfinyl) -N- (3-fluoro-phenyl) -acetamide (I-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 (2- (7-aza-1H-benzotriazol-1yl)- Treated with 1,1,3,3-tetramethyluronium hexafluorophosphate (1.15 g, 3.0 mmol) and N, N-diisopropylethylamine (1.06 g, 8.22 mmol). The reaction was stirred at 0 ° C. for 0.5 hour. At this time, the reaction was treated with 3-fluoro-phenylamine (305 mg, 2.74 mmol). The reaction mixture was warmed to room temperature and stirred. At this point, the resulting mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (30 mL), washed with 1N aqueous hydrochloric acid (30 mL), saturated aqueous sodium bicarbonate (30 mL), water (30 mL) and saturated aqueous sodium chloride (30 mL), and dried over sodium sulfate. , Filtered and concentrated in vacuo. Subject to silica gel chromatography (petroleum ether: ethyl acetate = 5: 1) to give 2- (3-chloro-benzenesulfinyl) -N- (3-fluoro-phenyl)-as a white solid (100 mg, 12%). Acetamide was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.41 (s, 1H), 7.74-6.87 (m, 8H), 3.91-4.15 (m, 2H). LC-MS: 312 [M + 1] ⁺ , R _t = 1.474 min. HPLC: 98.89% (214 nm), 99.74% (254 nm), R _t = 5.577 min.

（３−クロロ−ベンゼンスルフィニル）−酢酸及び４−トリフルオロメチル−フェニルアミから２−（３−クロロ−ベンゼンスルフィニル）−Ｎ−（４−トリフルオロメチル−フェニル−アセトアミドを白色の固形物（６６０ｍｇ、４０％）として得た。^１１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ１０．５７（ｓ，１Ｈ），７．７８−７．５９（ｍ，８Ｈ），４．２０−３．９５（ｍ，２Ｈ）．ＬＣ−ＭＳ：３６２［Ｍ＋１］^＋，Ｒ_ｔ＝１．５５９ｍｉｎ．ＨＰＬＣ：９２．１２％（２１４ｎｍ），９９．０６％（２５４ｎｍ），Ｒ_ｔ＝４．４７８ｍｉｎ。 The following compounds were synthesized in an analogous manner according to the procedure described above:
Example 27
2- (3-Chloro-benzenesulfinyl) -N- (4-trifluoromethyl-phenyl) -acetamide (I-27)

2- (3-Chloro-benzenesulfinyl) -N- (4-trifluoromethyl-phenyl-acetamide from white (3-chloro-benzenesulfinyl) -acetic acid and 4-trifluoromethyl-phenylami (660 mg, ¹¹ HNMR (300 MHz, DMSO-d 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% (214 nm), 99.06% (254 nm), R _t = 4.478 min.

（３−クロロ−ベンゼンスルフィニル）−酢酸及び４−アミノ−ベンゾニトリルから２−（３クロロ−ベンゼンスルフィニル）−Ｎ−（４−シアノ−フェニル）−アセトアミドを白色固形物（２００ｍｇ、１４％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）：δｐｐｍ１０．６４（ｓ，１Ｈ），７．８６−７．６３（ｍ，８Ｈ），４．２１−３．９５（ｍ，２Ｈ）．ＬＣ−ＭＳ：３４１［Ｍ＋１］^＋，Ｒ_ｔ＝１．４２６ｍｉｎ．ＨＰＬＣ：９９．７４％（２１４ｎｍ），９９．６９％（２５４ｎｍ），Ｒ_ｔ＝５．１３０ｍｉｎ。 Example 28
2- (3-Chloro-benzenesulfinyl) -N- (4-cyano-phenyl) -acetami (I-28)

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

（３−クロロ−ベンゼンスルフィニル）−酢酸及び２−フルオロ−フェニルアミンから２−（３−クロロ−ベンゼンスルフィニル）−Ｎ−（２−フルオロ−フェニル）−アセトアミドを白色固形物（４００ｍｇ、２８％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ１０．２０（ｓ，１Ｈ），７．９１−７．５９（ｍ，５Ｈ），７．３４−７．１０（ｍ，３Ｈ），４．２４−４．０９（ｍ，２Ｈ）．ＬＣ−ＭＳ：３１２［Ｍ＋１］^＋，Ｒ_ｔ＝１．４６３ｍｉｎ．ＨＰＬＣ：９６．４１％（２１４ｎｍ），９９．３２％（２５４ｎｍ），Ｒ_ｔ＝５．１４７ｍｉｎ。 Example 29
2- (3-Chloro-benzenesulfinyl) -N- (2-fluoro-phenyl) -acetamide (I-29)

2- (3-Chloro-benzenesulfinyl) -N- (2-fluoro-phenyl) -acetamide from white (3-chloro-benzenesulfinyl) -acetic acid and 2-fluoro-phenylamine (400 mg, 28%) Got as. ¹ HNMR (300 MHz, DMSO-d ₆ ) δ ppm 10.20 (s, 1H), 7.91-7.59 (m, 5H), 7.34-7.10 (m, 3H), 4.24-4 .09 (m, 2H). LC-MS: 312 [M + 1] ⁺ , R _t = 1.463 min. HPLC: 96.41% (214 nm), 99.32% (254 nm), R _t = 5.147 min.

（３−クロロ−ベンゼンスルフィニル）−酢酸及び４−トリフルオロメトキシ−フェニルアンから２−（３−クロロ−ベンゼンスルフィニル）−Ｎ−（４−トリフルオロメトキシ−フニル）−アセトアミドを白色の固形物（４００ｍｇ、２３％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ１０．４３（ｓ，１Ｈ），７．７７−７．７０（ｍ，１Ｈ），７．７２−７．５７（ｍ，５Ｈ），７．３４（ｄ，Ｊ＝９．０Ｈｚ，２Ｈ），４．１７−３．９２（ｍ，２Ｈ）．ＬＣ−ＭＳ：３７８［Ｍ＋１］^＋，Ｒ_ｔ＝１．５６１ｍｉｎ．ＨＰＬＣ：９６．７７％（２１４ｎｍ），９９．４２％（２５４ｎｍ），Ｒ_ｔ＝４．５４７ｍｉｎ。 Example 30
2- (3-Chloro-benzenesulfinyl) -N- (4-trifluoromethoxy-phenyl) -acetamide (I-30)

(3-Chloro-benzenesulfinyl) -acetic acid and 4-trifluoromethoxy-phenylan convert 2- (3-chloro-benzenesulfinyl) -N- (4-trifluoromethoxy-funil) -acetamide to a white solid ( 400 mg, 23%). ¹ HNMR (300 MHz, DMSO-d 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% (214 nm), 99.42% (254 nm), Rt ₌ 4.547 min.

（３−クロロ−ベンゼンスルフィニル）−酢酸及びシクロヘキシルアミンから、２−（３−ロロ−ベンゼンスルフィニル）−Ｎ−シクロヘキシル−アセトアミドを白色の固形物（７００ｍｇ、５％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ７．９７−７．９４（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＋１］^＋，Ｒ_ｔ＝１．４９５ｍｉｎ．ＨＰＬＣ：９６．２９％（２１４ｎｍ），９８．２８％（２５４ｎｍ），Ｒ_ｔ＝３．５９７ｍｉｎ。 Example 31
2- (3-Chloro-benzenesulfinyl) -N-cyclohexyl-acetamide (I-31)

2- (3-Lolo-benzenesulfinyl) -N-cyclohexyl-acetamide was obtained as a white solid (700 mg, 5%) from (3-chloro-benzenesulfinyl) -acetic acid and cyclohexylamine. ¹ HNMR (300 MHz, DMSO-d 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 + 1] ⁺ , R _t = 1.495 min. HPLC: 96.29% (214 nm), 98.28% (254 nm), R _t = 3.597 min.

（３−クロロ−ベンゼンスルフィニル）−酢酸とシクロペンタンメチルアミンから２−（３−クロロ−ベンゼンスルフィニル）−Ｎ−シクロペンチルメチル−アセトアミドを白色の固（５００ｍｇ、４５％）として得た。^１ＨＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ８．１３−８．０９（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＋１］^＋，Ｒ_ｔ＝１．４６４ｍｉｎ．ＨＰＬＣ：９５．３０％（２１４ｎｍ），９７．８５％（２５４ｎｍ），Ｒ_ｔ＝３．６９８ｍｉｎ。 Example 32
2- (3-Chloro-benzenesulfinyl) -N-cyclopentylmethyl-acetamide (I-32)

2- (3-Chloro-benzenesulfinyl) -N-cyclopentylmethyl-acetamide was obtained as a white solid (500 mg, 45%) from (3-chloro-benzenesulfinyl) -acetic acid and cyclopentanemethylamine. ¹ HNMR (300 MHz, DMSO-d 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 + 1] ⁺ , R _t = 1.464 min. HPLC: 95.30% (214 nm), 97.85% (254 nm), R _t = 3.698 min.

Example 33
μHTS-TNKS-IWR2 TR-FRET binding assay (10 μL / well in BD1536 well plate, single point)
Reagents and stock solutions Tankyrase 1 (TNKS1): 184.3 μM = 5.2 mg / mL His6-TNKS1, MW = 28.2 KDa (construct: 1088-1327, I266M), 20 mM Tris pH 8, 150 mM NaCl, 10% glycerol, and 0.5 mM Alternatively, His6-tankylase 2 (construct: 934-1166) or His6-PARP1 (full length) instead of His6-TNKS1.
2. 2. Biotin-IWR2: 10 mM biotin-IWR2 stock in DMSO, stored at −20 ° C. Positive control: 10 mM XAV939 in DMSO, stored at −20 ° C. Eu-Streptavidin: 38.1 μM (2.1 mg / mL) Eu-SA (Bio # Eu-2212, lot # N18001-BDHO2)
5. APC-anti-HisAb: 8.50 [mu] M SL-APC, 8.26 [mu] M anti-6His antibody-SureLight AP (Columia Bioscience, Catalog # D3-1711, Lot # N01010-AAH04)
6). Assay plate: BD 1536 well, clear / black plate (Catalog # 353255)
7). NP-40: 10% NP-40 solution (PIERCE, catalog # 28324, lot # 97101671)

Preparation of assay buffer Assay buffer 1a for dilution of TNKS (AB1a): 50 mM Tris, pH 7.4, 100 mM thorium chloride solution, 1 mM magnesium chloride solution, 1 mM DL-dithiothreitol solution, 0.2 mg / mL bovine serum albumin solution, 0.025% NP-40.
2. Biotin-IWR2 dilution assay buffer 1b (AB1b): 50 mM Tris, pH 7.4, 100 mM sodium chloride solution, 1 mM magnesium chloride solution, 1 mM DL-dithiothreitol solution, 0.2 mg / mL bovine serum albumin Solution, 0.05% NP-40
3. Assay buffer 1c (AB1c) for compound dilution: 50 mM Tris, pH 7.4, 100 mM sodium chloride solution, 1 mM magnesium chloride solution, 1 mM DL-dithiothreitol solution, 0.2 mg / mL bovine serum albumin solution 4). Assay buffer 2 for Eu / APC (AB2): 50 mM Tris, pH 7.4, 100 mM sodium chloride solution, 1 mM magnesium chloride solution, 0.2 mg / mL bovine serum albumin solution

1. Preparation of reagent stock solution 1. Biotinylated IWR2 stock solution (3.33 × stock solution) for TOTL and cpd wells: Prepare 200 nM biotin-IWR2 in 5% DMSO / AB1b buffer. Blank well stock solution: Prepare 5% DMSO / AB1b buffer 3. 3. Positive control well stock solution (3.33 × stock solution): Prepare 200 nM XAV939 in 200 nM biotin IWR2 / 5% DMSO / AB1b buffer. TNKS1 stock solution (5 × stock solution): Prepare 300 nM TNKS in AB1a buffer (or use TNKS2 or PARP1 stock solution)
5. Eu / APC stock solution (5 × stock solution): Prepare 3.5 nM Eu-SA / 50 nM APC-His6Ab in AB2 buffer

Assay Procedure 1. Compound preparation:
25 μL / well of 1.5% DMSO / AB1c in each compound to a concentration of 74 μM compound in 8.8% DMSO / AB1c buffer or 2 μL DMSO control wells (BLANK, TOTAL and POSITIVE wells) in compound plates Add buffer.
2. Transfer 3 μL / well of the above solution (solutions 1, 2, 3) to an empty assay plate (BD1536-well plate) as follows.
TOTL and cpd wells: Solution 1 (Biotin-IWR2):
BLNK well: Solution 2 (without biotin-IWR2):
POSITIVE CONTROL well: Solution 3 (Biotin-IWR2 + XAV939)
3. Transfer 3 μL / well of the diluted compound solution or compound dilution buffer to the assay plate.
4). Add 2 μL / well of 300 nM TNKS stock solution (4) to each well in the assay plate.
5. Centrifuge assay plate at 2100 rpm for 2 minutes.
6. Incubate assay plate at 26 ° C. for 30 minutes.
7). Add 2 μL / well of 3.5 nMEu / 50 nMAPC solution (5) to each well in the assay plate.
8. Centrifuge assay plate at 2100 rpm for 2 minutes.
9. Incubate assay plate at 26 ° C. for 60 minutes.
10. Read the assay plate immediately with 330 nm excitation wavelength and 615 and 665 nm emission wavelengths in time-resolved fluorescence mode.

Final assay conditions:
Biotin-IWR2: 60 nM
TNKS: 60nM
Eu-SA: 0.7 nM
APC-HisAb: 10 nM
XAV939 (+ ve control): 60 nM with ~ 70% inhibition
General library compound: 22.23 μM in 4% DMSO
Representative compound data for the assay are listed in Table II below.

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

  All patents, patent applications and publications cited in this application are incorporated by reference in their entirety for all purposes as if each individual patent, patent application or publication was individually designated. Is incorporated herein by reference.

The term “pharmaceutically acceptable excipient” refers to any ingredient that has no therapeutic activity and is non-toxic, such as a disintegrant, binder, filler, used to formulate a pharmaceutical product, Solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant or lubricant.
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.

（上式中、
Ｒ^１は、各々一又は複数のＲ^１’で置換されていてもよい、フェニル、フェニル低級アルキル、シクロアルキル、又はシクロアルキル低級アルキルであり；
各Ｒ^１’は、独立して、低級アルキル、ハロ、低級アルコキシ、低級ハロアルキル、低級アルキルスルホニル、トリフルオロメトキシ、又はシアノであり；
Ｒ^２は、一又は複数のＲ^２’で置換されていてもよいフェニル、ナフチル、シクロヘキシル、又はピリダジニルであり；
各Ｒ^２’は、独立して、ハロ、低級アルキル、低級アルコキシ、又は−Ｃ（＝Ｏ）ＯＣＨ_３である）
の化合物又はその薬学的に許容される塩を提供する。
本出願は、Ｒ^１が一又は複数のＲ^１’で置換されていてもよいフェニルである、式Ｉの化合物を提供する。
本出願は、Ｒ^２が、一又は複数のＲ^２’で置換されていてもよいフェニルである、式Ｉの化合物を提供する。
本出願は、Ｒ^１が、一又は複数のＲ^１’で置換されていてもよいフェニルであり、Ｒ^２が、一又は複数のＲ^２’で置換されていてもよいフェニルである、式Ｉの化合物を提供する。
本出願は、Ｒ^２’がハロである式Ｉの化合物を提供する。 Tankyrase inhibitors

(In the above formula,
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 alkylsulfonyl, trifluoromethoxy, or cyano;
R ² is phenyl, naphthyl, cyclohexyl, or pyridazinyl optionally substituted with one or more R ² ′;
Each R ² ′ is independently halo, lower alkyl, lower alkoxy, or —C (═O) OCH ₃ )
Or a pharmaceutically acceptable salt thereof.
The application provides a compound of Formula I, wherein R ¹ is phenyl optionally substituted with one or more R ¹ ′.
The application provides a compound of Formula I, wherein R ² is phenyl optionally substituted with one or more R ² ′.
The application relates to a 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 ′. Of the compound.
The application provides compounds of Formula I, wherein R ² ′ is halo.

Claims (21)

Formula I

(In the above formula,
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 alkylsulfonyl, trifluoromethoxy, or cyano;
R ² is phenyl, naphthyl, cyclohexyl, or pyridazinyl optionally substituted with one or more R ² ′;
Each R ² ′ is independently halo, lower alkyl, lower alkoxy, or —C (═O) OCH ₃ )
Or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein R ¹ is phenyl optionally substituted with one or more R ¹ ′. The compound according to claim 2, wherein R ² is phenyl optionally substituted with one or more R ² ′. A compound according to claim 3 R 2 ^'is halo. The compound according to claim 4, wherein R ¹ 'is methoxy. The compound according to claim 4, wherein R ¹ ′ is fluoro. The compound according to claim 4, wherein R ¹ 'is trifluoromethyl, cyano, methylsulfonyl, or trifluoromethoxy. The compound according to claim 3, wherein R ¹ 'is methoxy. Methoxy R ² ', methyl, or -C (= O) A compound according to claim 8 is OCH _3. The compound according to claim 1, wherein R ² is phenyl optionally substituted with one or more R ² ′. 11. The compound according to claim 10, wherein R ¹ is phenyl lower alkyl, cycloalkyl, or cycloalkyl lower alkyl, each optionally substituted with one or more R ¹ ′. A compound according to claim 11 R 2 ^'is halo. The compound of claim ¹ , wherein R ¹ is phenyl and R ¹ ′ is methoxy. R ² is naphthyl, cyclohexyl, or pyridazinyl, The compound according to claim 13. 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-sulfinyl) -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-1-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-benzenesulfinyl) -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-benzenesulfinyl) -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;
The compound of claim 1 selected from the group consisting of 2- (3-chloro-benzenesulfinyl) -N-cyclohexyl-acetamide; and 2- (3-chloro-benzenesulfinyl) -N-cyclopentylmethyl-acetamide.   16. A method for treating a PARP-mediated condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1-15.   16. A method for treating a tankyrase-mediated condition comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1-15.   16. A method for treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1-15.   A pharmaceutical composition comprising a compound according to any one of claims 1 to 15.   20. A pharmaceutical composition according to claim 19, mixed with at least one pharmaceutically acceptable carrier, excipient or diluent.   Further comprising an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, a cardiovascular disease therapeutic agent, a diabetes therapeutic agent, and an immunodeficiency disease therapeutic agent, 20. A pharmaceutical composition according to claim 19.