CN103906730A

CN103906730A - Parp inhibitors

Info

Publication number: CN103906730A
Application number: CN201280053428.1A
Authority: CN
Inventors: N-E.海恩斯; N.J.S.休比; N.R.斯科特
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 2011-09-01
Filing date: 2012-08-29
Publication date: 2014-07-02
Also published as: KR20140062096A; WO2013030205A1; RU2014110624A; EP2758370A1; CA2846429A1; BR112014005011A2; MX2014002343A; JP2014531416A

Abstract

The present application disclosed compounds of Formula I wherein variables R1 and R2 are defined as described herein, which are inhibitors of PARP and provides compounds and compositions containing the compounds of Formula I. The present application further provides methods of using the disclosed PARP inhibitors for the treatment of PARP-mediated diseases and disorders.

Description

PARP inhibitor

Invention field

Cancer is that the disease as feature is lost in a kind of suitable control take Growth of Cells.ACS (American Cancer Society) estimates, in the U.S., within 2010, have and exceed 1,500,000 new cases of cancers and by inference, has about 570,000 examples dead owing to cancer in this year.World Health Organization's estimation, in 2010, cancer was the main cause of the death in the whole world, to the year two thousand thirty, the death toll being caused by cancer will be increased to annual 12000000.

Prove, in order to form cancer focus, need cell to develop 6 kinds of abilities.These characteristics be self-sustaining (self-sufficiency) of growth signals, anti-growth signals insensitive, organize intrusion and transfer, the unconfined potential, lasting blood vessel of copying occur and escape apoptosis.Cell is transitioned into active proliferative state from static state needs growth signals.Normally by relating in many cells, kinase whose signal transduction cascade amplification system sends these signals from transmembrane receptor, finally causes the variation of the genetic expression under intracellular nucleic level.In recent years, the purposes that people are used for the treatment of cancer to signal transduction inhibitor field, particularly kinase inhibitor and they has great interest.Several examples of this compounds are successfully evaluated under clinical setting, and can on market, buy and sell the cancer that is used for the treatment of specific form now, described inhibitor for for example toluenesulphonic acids imatinib (by Novartis with

sell and be used for the treatment of Philadelphia chromosome positive chronic myelocytic leukemia (Philadelphiachromosome-positive chronic myeloid leukemia)), xylene monosulfonic acid lapatinibditosylate (by GlaxoSmithKline with sell and for other chemotherapeutics coupling treatment HER2 positive breast cancer), Sunitinib malate (by Pfizer with

sell and be approved for treatment kidney) and Xarelto (sold with Nexavar by Baeyer and be used for the treatment of kidney).

Except somatomedin coherent signal approach (it mainly utilizes catalysis to shift the kinases of bound phosphate groups as the key ingredient of described signal pathway), in cell, also have many other signal pathways, and their suitable adjusting is important for maintaining the Growth of Cells of correct level and copying.In the cancer stem cell field occurring at present, suppress Wnt, Notch and Hedgehog approach and caused great interest as the potential approach of avoiding tumor recurrence and transfer.Described Wnt approach contributes to fetal development and adult's tissue to maintain, and has the activity of independent component in this approach under closely regulating.In cancer and Other diseases, Cell signal transduction pathway no longer shows suitable level of control.The in the situation that of Wnt approach, it is the control of the relative stability of axin and beta-catenin that signal transduction is subject to 2 kinds of protein.Beta-catenin too much causes the activation of the enhancing of Wnt signal and the nuclear factor of being correlated with, and excessive axin causes beta-catenin degraded and signal weakening in cell.The insufficiency of accommodation of regular Wnt signal pathway has been involved in the human cancer of certain limit, as colorectal carcinoma, hepatocellular carcinoma, uterine endometrium ovarian cancer, pilomatricoma skin carcinoma, prostate cancer, melanoma and the nephroblastoma.

In regular Wnt signal pathway, Signal origin is in the interaction of Wnt part and acceptor complex body, and described acceptor complex body contains curling family member (Frizzled family member) and low density lipoprotein receptor-related protein.This causes forming in disorder-curling complex body and axin from destroying complex body (destruction complex) relocating to cytolemma.Axin is the concentration limit component of described destruction complex body, and this complex body is to be formed by the glycogen synthase kinase 3 β of level in polyp of colon albumen, casein-kinases 1 α and the responsible cell of controlling beta-catenin of adenoma just.Under the existence of functional destruction complex body, beta-catenin in a conservative cocainine propylhomoserin and threonine residues at amino-end successively by casein-kinases 1 α and glycogen synthase kinase 3 β phosphorylation.Phosphorylation promotes beta-catenin and the protein binding that contains the repetition of β-transducer, then mediates the proteasome degraded of ubiquitination and beta-catenin subsequently.In the case of the described destruction complex body that lacks enough high densitys, unphosphorylated beta-catenin can move to nucleus and with T-cytokine protein-interacting and by raising co-activator albumen, they is transformed into effective activating transcription factor.

Report recently, in cell, axin level is gathered impact (the Nature ChemicalBiology2009 of (ADP-ribose) polysaccharase family member tankyrase-1 and tankyrase-2 (also claiming PARP5a and PARP5b), 5,100 and Nature2009,461,614).Tankyrase can make axin poly--ADP ribosylation (PARsylate), this mark this albumen, make its ubiquitination and proteasome degraded for subsequently.Therefore, can be expected that, under the existence of the inhibitor of tankyrase catalytic activity, axin protein concentration will increase, the Wnt signal that causes the described destruction complex body of higher concentration and reduce beta-catenin in the unphosphorylated cell of concentration and weaken.What it is further contemplated that is; the for example spindle body in end of chromosome protection (telomere), insulin response and mitotic division process of other biological function of tankyrase-1 and-2 inhibitor opposite end anchor polymerase protein is equipped with effect (Biochimie2009; 5,100).

The therapeutical agent that is intended to correct the insufficiency of accommodation of Wnt signal pathway and can correct Wnt signal pathway insufficiency of accommodation has been involved in such as in following illness: bone density deficiency (bone density defect), coronary heart disease, the Alzheimer of late onset, familial exudative vitreoretinopathy, retinal vessel occurs, congenital four limbs cut off disease (tetra-amelia), gyneduct (Mullerian-duct) is degenerated and is manlike, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, it is bad that bone is sent out shoulder, focal adermogenesis and neural tube defect.Concentrate the cognation of Wnt signal in cancer although more than introduce, Wnt signal pathway is very important and is involved in potentially in multiple human diseases, is not necessarily confined to the above example for illustration purpose.

The application provides the method for the illness (particularly tankyrase 1 and 2) of a kind of PARP-for the treatment of mediation, comprises to the formula I compound of patient's drug treatment significant quantity that has these needs.

Summary of the invention

The application provides formula I compound or its pharmacy acceptable salt, and formula I compound is:

Wherein:

R ¹for phenyl, phenyl-low alkyl group, cycloalkyl or cycloalkyl low-grade alkyl, they are separately optionally by one or more R ^{1 '}replace;

Each R ^{1 '}be low alkyl group, halogen, lower alkoxy, low-grade halogenated alkyl, low alkyl group alkylsulfonyl, trifluoromethoxy or cyano group independently;

R ²for phenyl, it is optionally by one or more R ^{2 '}, naphthyl, cyclohexyl or pyridazinyl replace; And

Each R ^{2 '}be halogen, low alkyl group, lower alkoxy, Huo – C (=O) OCH independently ₃.

The application provides a kind of method of illness for the treatment of tankyrase-mediation, comprises to the formula I compound of patient's drug treatment significant quantity that has these needs.

The application provides a kind of method for the treatment of cancer, comprises to the formula I compound of patient's drug treatment significant quantity that has these needs.

The application provides pharmaceutical composition, its contained I compound.

Detailed Description Of The Invention

definition

Phrase " one " entity refers to one or more these entities as used in this article; For example, a kind of compound refers to one or more compounds or at least one compound.Thereby term " ", " one or more " and " at least one " are used interchangeably in this article.

As this specification sheets uses, no matter be in the phrase of transition or in the text of claim, term " comprises " and is appreciated that as having open implication., this term will " at least have " or the synonym of " at least comprising " is understood as phrase.In the time using in the linguistic context in method, term " comprises " and refers to that the method at least comprises cited step, but can comprise other step.In the time using in the linguistic context of compound or composition, term " comprises " and refers to that this compound or composition at least comprise cited feature or component, but also can comprise other feature or component.

As used in this article, except as otherwise noted, word "or" with in "and/or", " comprise " implication use rather than with " the two one of/or " in " eliminating " implication use.

Term " independently " uses in this article, represents that variable is applied to any situation, and no matter there is or do not exist the variable of identical or different definition in identical compound.Therefore, R therein " occur twice and be defined as in the compound of " being carbon or nitrogen independently ", two R " can be carbon, two R " can be nitrogen, or a R " can be carbon and another is nitrogen.

When any variable is being described while occurring more than once in any part of compound used or claimed in the present invention or formula, its definition in the time at every turn occurring is independent of it in all other definition while occurring.And the combination of substituting group and/or variable only has be only permission in the time that this composition produces stable compound.

"------" of drawing at the symbol " * " of key end or through key refers to the tie point of the rest part of functional group or other chemical part and its affiliated molecule separately.Therefore, for example:

MeC (=O) OR ⁴wherein

or

Represent that through drawing the key (clear and definite summit is different from being connected in) being inserted in ring system key can be connected with any suitable annular atoms.

Term " cyano group ", separately or with other moiety combinations, refer to N ≡ C-(NC-).

Term " halogen ", separately or with other moiety combinations, represent chlorine (Cl), iodine (I), fluorine (F) and bromine (Br).Concrete " halogen " is Cl and F.Be in particular F.

Term " optional " or " optionally " refer to that event or the situation described subsequently may occur as used herein, but do not need to occur, and this description comprises the example of event or situation generation and the example that it does not occur.For example, " optional replacement " refer to optional replace part can be in conjunction with hydrogen atom or substituting group.

Phrase " optional key " refers to that this key may exist or may not exist, and this description comprises singly-bound, two key, three key or aromatic gp.If it is " key " or " not existing " that substituting group is designated as, the atom that is coupled to so substituting group connection directly connects.

Term " about " is used in this article and refers to approximately, approaches (in the region of), roughly or left and right (around).In the time that term " about " and numerical range are used in conjunction, it is by making envelope extension exceed given numerical value and modifying that scope lower than given numerical value.

Some formula I compound can show tautomerism.Tautomerism compound can exist by the form of two or more interchangeable kinds.Proton tautomerism body is produced by the migration of the covalently bound hydrogen atom between two atoms.Tautomer exists with equilibrium state conventionally, and in the time attempting to isolate independent tautomer, conventionally produces the chemistry mixture consistent with the mixture of compound with physical properties.The position of balance depends on environment such as solvent, temperature, the pH etc. that intramolecular chemical feature and it expose.For example, many fatty aldehyde and ketone as acetaldehyde in, ketone form is preponderated; And in phenol, enol form is preponderated.Common proton tautomerism body comprises ketone/enol (C (=O)-CH-

-C (OH)=CH-), acid amides/imido acid (C (=O)-NH-

-C (OH)=N-) and amidine (C (=NR)-NH-

-C (NHR)=N-) tautomer.Latter two is common especially in heteroaryl ring and heterocycle, the present invention includes all tautomeric forms of described compound.

Scientific and technical terminology used herein has the implication that the those skilled in the art under the present invention understand conventionally, unless otherwise defined.The whole bag of tricks known to those skilled in the art and material are mentioned herein.The canonical reference works of setting forth pharmacology General Principle comprises the ThePharmacological Basis of Therapeutics of Goodman and Gilman, 10 ^thed., McGraw Hill Companies Inc., New York (2001).Any suitable material known to the skilled and/or method can be utilized in enforcement of the present invention.But, description be preferred materials and methods.Material, the reagent etc. of mentioning in ensuing specification sheets and embodiment can obtain from commercial sources, except as otherwise noted.

Described definition herein can be through the relevant combination of additional formation chemistry, as " assorted alkylaryl ", " haloalkyl heteroaryl ", " arylalkyl heterocyclic radical ", " alkyl-carbonyl ", " alkoxyalkyl " etc.In the time that term " alkyl " uses as the suffix after another term, as in " phenylalkyl " or " hydroxyalkyl ", this is intended to refer to that the substituting group that alkyl group is selected from another group of mentioning especially by one or two as defined above replaces.Therefore, for example, " phenylalkyl " refers to have the alkyl group of one or two phenyl substituent, thereby comprises benzyl and phenylethyl." alkylamino alkyl " is for having the substituent alkyl group of one or two alkylamino." hydroxyalkyl " comprises 2-hydroxyethyl, 2-hydroxypropyl, 1-(hydroxymethyl)-2-methyl-propyl, 2-hydroxybutyl, 2,3-dihydroxyl butyl, hydroxymethyl, 3-hydroxypropyl etc.Therefore, as used herein, term " hydroxyalkyl " is for being defined in the subgroup of assorted alkyl group defined above.

Term " spiro cycloalkyl group ", refers to volution group of naphthene base as used herein, as, for example, spiroheptane.Term spiroheterocyclic alkyl used herein refers to Spirocyclic heterocyclic alkyl, for example, and 2,6-diaza spiroheptane.

The group of term " acyl group " expression-C (=O) R as used in this article, wherein R be hydrogen or herein definition low alkyl group.The group of this term or " alkyl-carbonyl " used herein expression C (=O) R, wherein R is the alkyl defining herein.Term C _1-6acyl group refers to group-C (=O) R, and wherein R group contains maximum 6 carbon atoms." aryl carbonyl " refers to the group of formula C (=O) R as used in this article, and wherein R is aromatic yl group; Term " benzoyl " expression " aryl carbonyl " group as used in this article, wherein R is phenyl.

The group of term " ester " expression-C (=O) OR as used in this article, wherein R is low alkyl group, cycloalkyl, aryl or the heteroaryl defining herein.

Term " alkyl " represents the hydrocarbon residue containing 1 to 10 carbon atom non-side chain or side chain, saturated, unit price as used in this article.Term " low alkyl group " represents the hydrocarbon residue containing 1 to 6 carbon atom of straight or branched." C as used in this article _1-10alkyl " refer to by 1 to 10 alkyl that carbon forms.The example of alkyl group includes but not limited to low-grade alkyl group, comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl or amyl group, isopentyl, neo-pentyl, hexyl.Concrete low-grade alkyl group is methyl.

In the time that term " alkyl " uses as the suffix after another term, as in " phenylalkyl " or " hydroxyalkyl ", this is intended to refer to that alkyl group is selected from another substituting group of specially appointed group by one or two as defined above replaces.Thereby, for example, " phenylalkyl " expression radicals R ' R ", wherein R' is phenyl group, and R, and " be the alkylidene group defining herein, condition is that the tie point of phenylalkyl part will be on alkylidene group.The example of aromatic yl alkyl group includes but not limited to, benzyl, phenylethyl, 3-phenyl propyl.Term " arylalkyl " or " aralkyl " explain similarly, and different is that R' is aromatic yl group.Term " (mixing) arylalkyl " or " (mixing) aralkyl " explain similarly, and different is that R' is optionally aryl or heteroaryl groups.

Term " haloalkyl " or " halo-low alkyl group " or " low-grade halogenated alkyl " refer to the hydrocarbon residue that contains 1 to 6 carbon atom of straight or branched, and wherein one or more carbon atoms are replaced by one or more halogen atoms.Concrete halogen is fluorine, and concrete " haloalkyl " or " halo-low alkyl group " or " low-grade halogenated alkyl " refers to fluoro-alkyl " or " fluoro-low alkyl group " or " rudimentary fluoro-alkyl ".

Term " alkylidene group " or " alkylene (alkylenyl) " represent saturated straight chain hydrocarbyl group (for example, (CH of the divalence of 1 to 10 carbon atom as used in this article ₂) _n) or the saturated divalent hydrocarbyl mission of the side chain of 2 to 10 carbon atoms (for example ,-CHMe-or-CH ₂cH (i-Pr) CH ₂-), except as otherwise noted.The example of alkylidene group includes but not limited to, methylene radical, ethylidene, propylidene, 2-methyl-propylidene, 1,1-dimethyl-ethylidene, butylidene, 2-ethyl butylidene.

" alkoxyl group " refer to-O-alkyl group as used in this article, wherein alkyl as above defines, and as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, pentyloxy, hexyloxy, comprises their isomer." lower alkoxy " represents the alkoxy base (C containing " low alkyl group " group as previously defined as used in this article _1-6alkoxyl group)." C as used in this article _1-10alkoxyl group " refer to-O-alkyl, wherein alkyl is C _1-10." C as used in this article _1-6alkoxyl group " refer to-O-alkyl, wherein alkyl is C _1-6, be in particular methoxyl group (OMe).

Term " aryl " represents containing the unit price aromatic carbocyclic shape monocycle of 6 to 10 carboatomic ring atoms or bicyclic ring system.The example of aryl moiety comprises phenyl and naphthyl.

Term " halogenated alkoxy " or " halo-lower alkoxy " or " elementary halogenated alkoxy " refer to lower alkoxy groups, and wherein one or more carbon atoms are specially fluorine by one or more halogen atoms and replace.

Term " hydroxyalkyl " represents the alkyl of definition herein that one to three hydrogen atom on different carbon atoms is replaced by oh group as used in this article.

Term " alkyl sulphonyl " and " aryl sulfonyl " refer to formula-S (=O) as used in this article ₂the group of R, wherein R is respectively alkyl or aryl, and alkyl and aryl are as definition herein.Term " assorted alkyl sulphonyl " expression-S (=O) as used in this article ₂the group of R, wherein R is " the assorted alkyl " defining herein.Concrete group is-SO ₂me.

Term " alkyl sulfonyl amino " and " Arenesulfonyl amino " refer to formula-NR'S (=O) as used in this article ₂the group of R, wherein R is respectively alkyl or aryl, and R' is hydrogen or C _1-3alkyl, and alkyl and aryl are as definition herein.

Term " cycloalkyl " refers to the saturated or undersaturated carbocyclic ring that contains 3 to 8 carbon atoms as used in this article, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group." C as used in this article _3-7cycloalkyl " or " low-grade cycloalkyl " refer in carbocyclic ring by 3 to 7 cycloalkyl that carbon forms.Concrete group is cyclohexyl and cyclopentyl.

Term carboxy-alkyl refers to the moieties that one of them hydrogen atom has been replaced by carboxyl as used in this article, and condition is that tie point is to pass through carbon atom." carboxyl ” is Zhied – CO to term ₂h part.

Term " heteroaryl " or " heteroaromatic " refer to monocycle or the bicyclic groups of 5 to 12 annular atomses as used herein, wherein exist at least one to contain at least one and are selected from N, O or the heteroatomic aromatic nucleus of S.Therefore, for the purpose of the present invention, heteroaryl groups only need to have aromaticity to a certain degree.As being about to define below, heteroaryl can be optional replacement.The example of heteroaryl moieties comprises containing 5 to 6 annular atomses and 1 to 3 heteroatomic monocycle aromatic heterocycle, include but not limited to, pyridyl, pyrimidyl, pyrazinyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazole, thiazole, isothiazole, thiadiazoles, it is optionally by one or more, preferably one or two is selected from following substituting group replacement: hydroxyl, cyano group, alkyl, alkoxyl group, sulfenyl, elementary halogenated alkoxy, alkyl sulfenyl, halo, low-grade halogenated alkyl, alkyl sulphinyl, alkyl sulphonyl, halogen, amino, alkylamino, dialkyl amido, aminoalkyl, alkylamino alkyl, and dialkyl aminoalkyl, nitro, alkoxy carbonyl and carbamyl, alkylcarbamoyl group, dialkyl amino formyl radical, aromatic yl ammonia methanoyl, alkyl-carbonyl-amino and aryl-amino-carbonyl.The example of two loop sections includes but not limited to, quinolyl, isoquinolyl, benzofuryl, benzothienyl, benzoxazole, benzoisoxazole, benzothiazole, phthalazinyl, 5,6,7,8-tetrahydrochysene-[1,6] phthalazinyl and benzisothiazole.Two loop sections are optionally substituted on arbitrary ring.Concrete group is pyridazinyl.

As used in this article term " heterocyclic radical ", " Heterocyclylalkyl " or " heterocycle " represent the saturated or undersaturated cyclic group of unit price, it is by one or more rings, preferably one or two ring forms, comprise volution ring system, three to eight atoms of each ring, mix one or more ring hetero atoms and (are selected from N, O or S (O) _0-2), and it is optionally independently by one or more, preferably one or two is selected from following substituting group replacement: hydroxyl, oxo, cyano group, low alkyl group, lower alkoxy, elementary halogenated alkoxy, alkylthio, halogen, low-grade halogenated alkyl, hydroxyalkyl, nitro, carbalkoxy, amino, alkylamino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl amino, Arenesulfonyl amino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl, with their ionic species, except as otherwise noted.The example of heterocyclic radical includes but not limited to, morpholinyl, piperazinyl, piperidyl, azetidinyl, pyrrolidyl, six hydrogen azepines

base (hexahydroazepinyl), oxetanyl, tetrahydrofuran base, tetrahydro-thienyl, oxazolidinyl, thiazolidyl, isoxazole alkyl, THP trtrahydropyranyl, parathiazan base, quinuclidinyl and imidazolinyl and their ionic species.Example can be also two rings, as, for example, 3,8-diaza-bis-encircle [3.2.1] octane, 2,5-diaza-bis-ring [2.2.2] octane or also [2,1-c] [Isosorbide-5-Nitrae] oxazine of octahydro-pyrazine.

Term " PARP " has the albumen of ADP-ribosylation activity for this paper middle finger.In the intended scope of this term, PARP comprises by all albumen of parp gene, its mutant code and alternative sheet albumen (slice proteins) thereof.In addition, as used in this article, term " PARP " comprises the analogue of PARP analogue, homologue and other animal.

Term " PARP ", includes but not limited to PARP-1.In the intended scope of this term, can comprise 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.

Term " TNK " or " TNKS " are for representing tankyrase.

The compound that suppresses tankyrase 1 and 2 can have favourable character, because they have growth inhibitory activity in cancer cells.

Term " pharmacy acceptable salt " refers to be applicable to the salt contacting with the tissue of humans and animals.The salt that the example of the suitable salt forming with mineral acid and organic acid is and following acid forms, described acid for but be not limited to acetic acid, Citric Acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, toxilic acid, oxysuccinic acid, methylsulfonic acid, nitric acid, phosphoric acid, tosic acid, succsinic acid, sulfuric acid (sulfuric acid), sulfuric acid (sulphuric acid), tartrate, trifluoroacetic acid etc.Concrete acid is formic acid, trifluoroacetic acid and hydrochloric acid.

Term " pharmaceutically acceptable carrier " and " pharmaceutically acceptable auxiliary substance " refer to that the carrier compatible with other composition of preparation and auxiliary substance are as thinner or vehicle.

Term " pharmaceutical composition " comprises the product of the special component of predetermined amount or ratio, and comprises directly or indirectly and combine by the special component of specified quantitative any product obtaining.Particularly, it comprises the product containing one or more activeconstituentss and optional carrier (comprising inert component), and directly or indirectly by combination, compound (complexation) of two or more compositions arbitrarily or assemble any products that obtains or by dissociate any products that (dissociation) obtain or by the reaction of other type of composition described in one or more or any products that interaction obtains of one or more compositions.

Term " inhibitor " represents with concrete part and concrete receptors bind competition, reduces or stop the compound of the inhibition of concrete part and concrete receptors bind or minimizing or the function of prevention to concrete albumen.

Term " half maximum inhibition concentration " (IC ₅₀) represent that 50% of acquisition external biological process suppresses the concentration of needed particular compound.IC ₅₀value can be converted into pIC by logarithm ₅₀value (log IC ₅₀), its intermediate value is higher to be shown effect more exponentially ground is large.IC ₅₀value is not absolute value, but depends on for example concentration used of experiment condition.Available Cheng-Prusoff equation is by IC ₅₀value changes absolute inhibition constant (Ki) (Biochem.Pharmacol. (1973) 22:3099) into.Term " inhibition constant " (Ki) represents the absolute binding affinity of concrete inhibitor to acceptor.It is to adopt Competition binding assay to measure, and for example equals, in the situation that there is no competitive part (radioligand), concentration when concrete inhibitor occupies acceptor 50%.Ki value can be converted into pKi value (log Ki) by logarithm, and more exponentially ground is large for the higher expression effect of its intermediate value.

" treatment significant quantity " refers to be enough to the amount of the compound of obtaining the described illness effect for the treatment of in the time delivering medicine to experimenter with treatment illness." treatment significant quantity " is by different to the severity because of compound, the illness for the treatment of, the disease for the treatment of, experimenter's age and the approach of relative healthy state, administration and form, attending doctor or animal doctor's judgement and other factors.

In the time relating to variable, term " as defined herein " and " as described in this article " by reference to combine the generalized definition of described variable and (if any) concrete, more specifically and the most concrete definition.Term " aromatics " represents in document, especially at IUPAC-Compendium of ChemicalTerminology, 2nd, A.D.McNaught & A.Wilkinson (Eds) .Blackwell ScientificPublications, the tradition of the aromaticity of the definition meaning in Oxford (1997).

Term " pharmaceutically acceptable vehicle " represents not have therapeutic activity and nontoxic any composition as the disintegrating agent for compounding pharmaceutical product, tackiness agent, condiment, solvent, buffer reagent, tonicity agent (tonicityagents), stablizer, antioxidant, tensio-active agent or lubricant.

As long as there is chiral carbon in chemical structure, it means described structure and comprises all steric isomers relevant to this chiral carbon.

tankyrase inhibitor

The application provides formula I compound,

Wherein:

R ¹for phenyl, phenyl lower alkyl, cycloalkyl or cycloalkyl low-grade alkyl, these groups are separately optionally by one or more R ^{1 '}replace;

Each R ^{2 '}be halogen, low alkyl group, lower alkoxy, Huo – C (=O) OCH independently ₃;

Or its pharmacy acceptable salt.

The application provides formula I compound, wherein R ¹for phenyl, it is optionally by one or more R ^{1 '}replace.

The application provides formula I compound, wherein R ²for phenyl, it is optionally by one or more R ^{2 '}replace.

The application provides formula I compound, wherein R ¹for phenyl, it is optionally by one or more R ^{1 '}replace, and R ²for phenyl, it is optionally by one or more R ^{2 '}replace.

The application provides formula I compound, wherein R ^{2 '}for halogen.

The application provides formula I compound, wherein R ^{2 '}for halogen, and R ¹for phenyl, it is optionally by one or more R ^{1 '}replace.

The application provides formula I compound, wherein R ²for phenyl and R ^{2 '}for halogen.

The application provides formula I compound, wherein R ²for phenyl, R ^{2 '}for halogen, and R ¹for phenyl, it is optionally by one or more R ^{1 '}replace.

The application provides formula I compound, wherein R ^{1 '}for methoxyl group.

The application provides formula I compound, wherein R ¹for phenyl and R ^{1 '}for methoxyl group.

The application provides formula I compound, wherein R ^{1 '}for methoxyl group, and R ²for phenyl, it is optionally by one or more R ^{2 '}replace.

The application provides formula I compound, wherein R ^{1 '}for methoxyl group, R ²for phenyl, and R ^{2 '}for halogen.

The application provides formula I compound, wherein R ¹for phenyl, R ^{1 '}for methoxyl group, R ²for phenyl, and R ^{2 '}for halogen.

The application provides formula I compound, wherein R ^{1 '}for fluorine.

The application provides formula I compound, wherein R ¹for phenyl and R ^{1 '}for fluorine.

The application provides formula I compound, wherein R ^{1 '}for fluorine, and R ²for phenyl, it is optionally by one or more R ^{2 '}replace.

The application provides formula I compound, wherein R ^{1 '}for fluorine, R ²for phenyl, and R ^{2 '}for halogen.

The application provides formula I compound, wherein R ¹for phenyl, R ^{1 '}for fluorine, R ²for phenyl, and R ^{2 '}for halogen.

The application provides formula I compound, wherein R ^{1 '}for trifluoromethyl, cyano group, methyl sulphonyl or trifluoromethoxy.

The application provides formula I compound, wherein R ¹for phenyl and R ^{1 '}for trifluoromethyl, cyano group, methyl sulphonyl or trifluoromethoxy.

The application provides formula I compound, wherein R ^{1 '}for trifluoromethyl, cyano group, methyl sulphonyl or trifluoromethoxy, and R ²for phenyl, it is optionally by one or more R ^{2 '}replace.

The application provides formula I compound, wherein R ^{1 '}for trifluoromethyl, cyano group, methyl sulphonyl or trifluoromethoxy, R ²for phenyl, and R ^{2 '}for halogen.

The application provides formula I compound, and wherein R1 is phenyl, R ^{1 '}for fluorine, R ²for phenyl, and R ^{2 '}for halogen.

The application provides formula I compound, wherein R ²for phenyl, it is optionally by one or more R ^{2 '}replace, and R ^{1 '}for methoxyl group.

The application provides formula I compound, wherein R ^{2 '}for methoxyl group, methyl, Huo – C (=O) OCH ₃.

The application provides formula I compound, wherein R ²for phenyl, R ^{2 '}for methoxyl group, methyl, Huo – C (=O) OCH ₃, and R ^{1 '}for methoxyl group.

The application provides formula I compound, wherein R ²for phenyl, it is optionally by one or more R ^{2 '}replace, and R ¹for phenyl lower alkyl, cycloalkyl or cycloalkyl low-grade alkyl, they are separately optionally by one or more R ^{1 '}replace.

The application provides formula I compound, wherein R ²for phenyl, R ^{2 '}for halogen, and R ¹for phenyl lower alkyl, cycloalkyl or cycloalkyl low-grade alkyl, they are separately optionally by one or more R ^{1 '}replace.

The application provides formula I compound, wherein R ¹for phenyl, R ^{1 '}for methoxyl group, and R ²for naphthyl, cyclohexyl or pyridazinyl.

The application provides formula I compound, is selected from:

2-(3-methoxyl group-benzenesulfinyl)-N-(4-methoxyl group-phenyl)-ethanamide;

2-(the fluoro-benzenesulfinyl of 3-)-N-(4-methoxyl group-phenyl)-ethanamide;

2-(the fluoro-benzenesulfinyl of (R)-3-)-N-(4-methoxyl group-phenyl)-ethanamide;

2-(the fluoro-benzenesulfinyl of (S)-3-)-N-(4-methoxyl group-phenyl)-ethanamide;

N-(4-methoxyl group-phenyl)-2-(Toluene-3,4-dithiol-sulfinyl)-ethanamide;

N-(4-methoxyl group-phenyl)-2-((R)-Toluene-3,4-dithiol-sulfinyl)-ethanamide;

N-(4-methoxyl group-phenyl)-2-((S)-Toluene-3,4-dithiol-sulfinyl)-ethanamide;

N-(4-methoxyl group-phenyl)-2-(naphthalene-2-sulfinyl)-ethanamide;

N-(4-methoxyl group-phenyl)-2-(naphthalene-1-sulfinyl)-ethanamide;

2-hexanaphthene sulfinyl-N-(4-methoxyl group-phenyl)-ethanamide;

3-[(4-methoxyl group-phenyl amino formyl radical)-methanesulfinyl]-methyl benzoate;

2-(the fluoro-benzenesulfinyl of the chloro-4-of 3-)-N-(4-methoxyl group-phenyl)-ethanamide;

2-(the fluoro-benzenesulfinyl of the chloro-4-of (R)-3-)-N-(4-methoxyl group-phenyl)-ethanamide;

2-(the fluoro-benzenesulfinyl of the chloro-4-of (S)-3-)-N-(4-methoxyl group-phenyl)-ethanamide;

N-(4-methoxyl group-phenyl)-2-(pyridazine-3-sulfinyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3,5-bis-)-N-(4-methoxyl group-phenyl)-ethanamide;

2-(the fluoro-benzenesulfinyl of 3,4-bis-)-N-(4-methoxyl group-phenyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(4-methoxyl group-benzyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(the fluoro-phenyl of 4-)-ethanamide;

2-(the chloro-benzenesulfinyl of (R)-3-)-N-(the fluoro-phenyl of 4-)-ethanamide;

2-(the chloro-benzenesulfinyl of (S)-3-)-N-(4-methylsulfonyl-phenyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(4-methylsulfonyl-phenyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(3-methoxyl group-phenyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(2-methoxyl group-phenyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-cyclohexyl methyl-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(the fluoro-phenyl of 3-)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(4-trifluoromethyl-phenyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(4-cyano group-phenyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(the fluoro-phenyl of 2-)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(4-trifluoromethoxy-phenyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-cyclohexyl-ethanamide; With

2-(the chloro-benzenesulfinyl of 3-)-N-cyclopentyl-methyl-ethanamide.

The application provides a kind of pharmaceutical composition of contained I compound.

The application provides aforementioned pharmaceutical compositions, and it is mixed with at least one pharmaceutically acceptable carrier, vehicle or thinner.

In a version, aforementioned pharmaceutical compositions further comprises other therapeutical agent of the medicine that is selected from chemotherapeutic or anti-proliferative agent, anti-inflammatory agent, immunomodulatory or immunosuppressor, neurotrophic factor, the medicine for the treatment of cardiovascular diseases, the medicine for the treatment of diabetes or treatment immune deficiency obstacle.

On the other hand, the application provides the purposes of formula I compound in the medicine of the illness of preparation treatment tankyrase-mediation.

The application provides compound described herein or method.

formula I compound

The present invention includes and example representative compound within the scope of the present invention provides in lower Table I.Provide these embodiment and preparation subsequently to enable those skilled in the art to more clearly understand and implement the present invention.They should not be considered to limit the scope of the invention, and are only exemplary with representational.

Conventionally, nomenclature used in the application is based on AUTONOMTM the 4.0th edition, a kind of Beilstein Institute computerized system for generation of IUPAC systematic naming method.If there are differences in described structure with between with regard to the given title of this structure, be as the criterion with the structure of being described.In addition,, as a part for fruit structure or structure does not represent with for example thick line or dotted line, a part for structure or this structure is appreciated that to be all steric isomers that comprise it.

Table I has been described the example of the sulfoxide compound of general formula I:

table I.

synthetic

general synthetic schemes

Scheme 1

Wherein R ₁for aryl, the CH of aryl, replacement ₂-aryl, cycloalkyl or CH ₂the formula I compound of-cycloalkyl can be by making the 2-bromoacetyl chloride of commercially available acquisition and R wherein under the existence of alkali ₁for aryl, the CH of aryl, replacement ₂-aryl, cycloalkyl or CH ₂the suitable amine of-cycloalkyl react to prepare (referring to, for example Vloon, W.J., Kruk, C., Pandit, U.K., Hofs, H.P., McVie, J.G., J.Med.Chem., 1987,30 (1), 20-24).

Wherein R ₁for aryl, the CH of aryl, replacement ₂-aryl, cycloalkyl or CH ₂-cycloalkyl and R ₂for the formula II compound of the aryl of aryl or replacement can be by with R wherein ₂replacing wherein R1 for the aryl of aryl, replacement or the suitable mercaptan compound of cycloalkyl is aryl, the CH of aryl, replacement ₂-aryl, cycloalkyl or CH ₂the bromine of the formula I of-cycloalkyl is prepared (for example referring to, Etukala, J.R., Yadav, J.S., Heteroatom Chem., 2008,19 (2), 221-227) from formula I compound.

Wherein R ₁for aryl, the CH of aryl, replacement ₂-aryl, cycloalkyl or CH ₂-cycloalkyl and R ₂for the aryl of aryl, replacement or the formula III compound of cycloalkyl can be by being oxidation of the sulfide into corresponding sulfoxide from R under standard conditions ₁for aryl, the CH of aryl, replacement ₂-aryl, cycloalkyl or CH ₂-cycloalkyl and R ₂for the aryl of aryl, replacement or the formula II compound of cycloalkyl prepare (for example referring to, Jiang, S., Liao, C., Bindu, L., Yin, B., Worthy, K.W., Fisher, R.J., Burke, T.R., Nicklaus, M.C., Roller, P.P., Bioorg Med.Chem.Lett, 2009,19 (10), 2693-2698).

Wherein R ₂for the formula IV compound of aryl, aryl or the cycloalkyl of aryl, replacement can be by with R wherein ₂the suitable mercaptan compound of the aryl of aryl, replacement or cycloalkyl replace the bromine of commercially available 2-bromoacetic acid methyl ester prepare (for example referring to, Etukala, J.R., Yadav, J.S., Heteroatom Chem., 2008,19 (2), 221-227).

Wherein R ₂for the aryl of aryl, replacement or the formula V compound of cycloalkyl can be by being oxidation of the sulfide into corresponding sulfoxide from R wherein under standard conditions ₂for the aryl of aryl, replacement or the formula IV compound of cycloalkyl prepare (for example referring to, Jiang, S., Liao, C., Bindu, L., Yin, B., Worthy, K.W., Fisher, R.J., Burke, T.R., Nicklaus, M.C., Rolller, P.P., Bioorg Med.Chem.Lett, 2009,19 (10), 2693-2698).

Wherein R ₂for the aryl of aryl, replacement or the formula VI compound of cycloalkyl can be by making ester be hydrolyzed into corresponding acid from R wherein by standard conditions ₂for example, for the aryl of aryl, replacement or the formula V compound of cycloalkyl are prepared (referring to, New, J.S., Christopher, W.L., Jass, P.A., J.Org.Chem., 1989,54,990-992).

Wherein R ₁for aryl, the CH of aryl, replacement ₂-aryl, cycloalkyl or CH ₂-cycloalkyl and R ₂for the aryl of aryl, replacement or the formula III compound of cycloalkyl can by under the amido linkage formation condition of standard from R wherein ₁for aryl, the CH of aryl, replacement ₂-aryl, cycloalkyl or CH ₂-cycloalkyl and R ₂for the aryl of aryl, replacement or the formula VI compound of cycloalkyl start, by making this acid and suitable R ₁for aryl, the CH of aryl, replacement ₂-aryl, cycloalkyl or CH ₂(for example referring to, Montalbetti, C.A.G.N., Falque, V., Tetrahedron, 2005,61,10827-10852) prepared in the amine coupling of-cycloalkyl.The commercially available acquisition of amine or prepare under the standard conditions of the synthetic amine of the substrate by various commercially available acquisitions.

Scheme 2

Compound 5a-x can synthesize according to the reaction of general introduction in scheme 2.Commercially available acquisition maybe can synthesize the alkyl or aryl amine, 1a-x and the 2-bromoacetyl chloride that obtain can under the existence of alkali, react obtain compound 2a-x (for example referring to, Vloon, W.J., Kruk, C., Pandit, U.K., Hofs, H.P., McVie, J.G., J.Med.Chem., 1987,30 (1), 20-24).Under standard conditions, the bromine of compound 2a-x can be 3a-x displacement with the mercaptan obtaining that maybe can synthesize of commercially available acquisition, obtains compound 4a-x (for example, referring to, Etukala, J.R., Yadav, J.S., Heteroatom Chem., 2008,19 (2), 221-227).Mercaptan 3a-x, commercially available acquisition or use such as the such reagent of thiophosphoric anhydride and be prepared from (for example referring to, Ozturk, T., Ertas, E., Mert, O., Chem Rev.2010, (110), 3419-3478) by corresponding phenol.The sulfide 4a-x obtaining can be oxidized to corresponding sulfoxide 5a-x under standard conditions, obtains compound 5a-x (for example, referring to, Jiang, S., Liao, C., Bindu, L., Yin, B., Worthy, K.W., Fisher, R.J., Burke, T.R., Nicklaus, M.C., Rolller, P.P., Bioorg Med.Chem.Lett, 2009,19 (10), 2693-2698and Ishibashi, H., Harada, S., Okada, M., Somekawa, M., Kido, M., Ikeda, M., Chem.Pharm.Bull., 1989,37 (4), 939-943).

Scheme 3

Compound 5a-x can synthesize according to the reaction of general introduction in scheme 3.Bromo-acetic acid methyl ester and the suitable mercaptan of commercially available acquisition, 3a-x can under the existence of alkali, react obtain compound 6a-x (for example referring to, Etukala, J.R., Yadav, J.S., Heteroatom Chem., 2008,19 (2), 221-227).Mercaptan 3a-x, commercially available acquisition or use such as the such reagent of thiophosphoric anhydride by corresponding phenol be prepared from easily (for example referring to, Ozturk, T., Ertas, E., Mert, O., Chem Rev.2010, (110), 3419-3478).The sulfide compound 6a-x obtaining can be oxidized to corresponding sulfoxide under standard conditions, obtain compound 7a-x (for example referring to, Jiang, S., Liao, C., Bindu, L., Yin, B., Worthy, K.W., Fisher, R.J., Burke, T.R., Nicklaus, M.C., Rolller, P.P., Bioorg Med.Chem.Lett, 2009,19 (10), 2693-2698and Ishibashi, H., Harada, S., Okada, M., Somekawa, M., Kido, M., Ikeda, M., Chem.Pharm.Bull., 1989,37 (4), 939-943).Can adopt standard conditions that ester cpds 7a-x is hydrolyzed into corresponding acid, obtain compound 8a-x (for example referring to, New, J.S., Christopher, W.L., Jass, P.A., J.Org.Chem., 1989,54,990-992).Compound 8a-x can be under the amido linkage formation condition of standard obtains compound 5a-x (for example referring to, Montalbetti, C.A.G.N., Falque, V., Tetrahedron, 2005,61,10827-10852) with suitable amine 1a-x coupling.The commercially available acquisition of amine 1a-x or prepare under the standard conditions of the synthetic amine of the substrate by various commercially available acquisitions.

Pharmaceutical composition and administration

Compound of the present invention can be formulated in multiple oral administered dosage form and carrier.Oral administration can be tablet form, coated tablet form, dragee form, hard and soft gelatin capsule form, solution form, emulsion form, syrup form or suspensoid form.When by other route of administration administration, compound of the present invention may be effectively, and described its route of administration comprises continuous (intravenous drip) administration, topical, administered parenterally, intramuscular administration, intravenous administration, subcutaneous administration, transdermal administration (can comprise penetration enhancer), containing taking administration, intranasal administration, inhalation and suppository dosing.Preferred administering mode is generally the oral application of easy to use every day of dosage regimen, and it can be adjusted the reaction of activeconstituents according to painful degree and patient.

Compound of the present invention and their pharmacologically acceptable salt, together with vehicle, carrier or the thinner conventional with one or more, can be made into the form of pharmaceutical composition and unitary dose.Pharmaceutical composition and unit dosage can be made up of the conventional ingredient of conventional ratio, contain or do not contain other active compound or composition, and unit dosage form can, containing the activeconstituents of any suitable significant quantity, match with adopted expection dosage range every day.Pharmaceutical composition can adopt the form of solid, and as tablet or filled capsules, semisolid, powder, sustained release preparation, or the form of liquid is as solution, suspensoid, emulsion, elixir, or for the filled capsules of oral application; Or be the suppository form for rectum or vagina administration; Or be the sterile injectable solution agent form for parenteral application.Typical preparation will be containing approximately 5% to approximately 95% active compound (w/w).Terms " formulation " or " formulation " are intended to comprise solid and the liquid preparation of active compound, and it will be appreciated by those skilled in the art that activeconstituents can be present in different preparations, depend on target organ or tissue and depend on dosage and the pharmacokinetic parameter of expectation.

Term " vehicle " refers to the compound for the preparation of pharmaceutical composition as used herein, normally safety, nontoxic and biologically and be not less desirable in other side, comprise and can be veterinary applications and medicinal the accepted vehicle of people.The compounds of this invention can be administered alone, but conventionally with one or more for the route of administration of expecting and the selected suitable drug excipient of pharmacy practice, the diluent or carrier mixing administration of standard.

" pharmaceutically acceptable " refer to preparation normally safety, nontoxic and biologically and in other side be not less desirable and comprising in can be veterinary science and medicinal the accepted pharmaceutical composition of people it being useful.

" pharmacy acceptable salt " form of activeconstituents also can start to make activeconstituents have the pharmacokinetic property not having at the activeconstituents of salt-independent shape most, and even can with regard to activeconstituents therapeutic activity in vivo, affect the pharmacodynamics of activeconstituents forward." pharmacy acceptable salt " of phrase compound refers to pharmaceutically acceptable and has the salt of pharmacologically active of the parent compound of expectation.This type of salt comprises: (1) acid salt, and with all example hydrochloric acids, Hydrogen bromide, sulfuric acid, nitric acid, the acid salt that the mineral acids such as phosphoric acid form, or with organic acid such as acetic acid, propionic acid, caproic acid, pentamethylene propionic acid, oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid, succsinic acid, oxysuccinic acid, toxilic acid, fumaric acid, tartrate, Citric Acid, phenylformic acid, 3-(4-hydroxy benzoyl) phenylformic acid, styracin, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, 1, 2-second-disulfonic acid, 2-isethionic acid, Phenylsulfonic acid, 4-chlorobenzenesulfonic acid, naphthalene-2-sulfonic acid, toluene-4-sulfonic acid acid, camphorsulfonic acid, 4-methyl bicyclic [2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert.-butylacetic acid, lauryl sulfate, glyconic acid, L-glutamic acid, carbonaphthoic acid, Whitfield's ointment, stearic acid, the acid salt that the organic acids such as muconic acid form, or (2) when the acid proton existing in parent compound by metal ion for example, alkalimetal ion, alkaline-earth metal ions or aluminum ion are replaced the salt forming, or the salt forming during as coordinations such as thanomin, diethanolamine, trolamine, Trometamol, N-methylglucamines with organic bases.

Solid form preparation comprises powder, tablet, pill, capsule, cachet (cachets), suppository and dispersible granule.Solid carrier can be one or more materials that also can be used as thinner, correctives, solubilizing agent, lubricant, suspending agent, tackiness agent, sanitas, tablet disintegrant or coating material.In powder, carrier is generally the solid of fine pulverizing, and it is and mixture together with the activeconstituents of fine pulverizing.In tablet, activeconstituents conventionally mixes in the proper ratio with the carrier with necessary adhesive capacity and is pressed into desired shape and size.Suitable carrier includes but not limited to magnesiumcarbonate, Magnesium Stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragakanta, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.Solid form preparation also can contain tinting material, seasonings, stablizer, buffer reagent, artificial and natural sweeting agent, dispersion agent, thickening material, solubilizing agent etc. except activeconstituents.

Liquid preparation is to be also suitable for oral administration, and liquid preparation comprises emulsion, syrup, elixir, aqueous solution agent, aqueous suspension.These comprise wants changing before use the solid form preparation of liquid form preparation into.Emulsion can be prepared in solution, for example, in aqueous solution of propylene glycol, prepare, maybe can be containing emulsifying agent as Yelkin TTS, dehydrated sorbitol mono-fatty acid ester or gum arabic.Aqueous solution agent can be by being dissolved in the water activeconstituents and adding suitable tinting material, correctives, stablizer and thickening material to prepare.Aqueous suspension can be by by the activeconstituents of fine pulverizing and viscous substance, as natural or synthetic colloidal substance, resin, methylcellulose gum, Xylo-Mucine and other known suspending agent are scattered in water and prepare together.

Compound of the present invention (for example can be formulated for administered parenterally, by injection, for example bolus injection or continuous infusion), and can be present in the form of unitary dose in the infusion vessel or multi-dose container of ampoule, pre-filled syringe, small volume together with the sanitas adding.Composition can adopt the form such as the suspensoid in oiliness or aqueous vehicles, solution or emulsion, for example the solution in Aqueous Solutions of Polyethylene Glycol.Oiliness or non-aqueous carrier, thinner, solvent or vectorial example (for example comprise propylene glycol, polyoxyethylene glycol, vegetables oil, sweet oil) and injectable organic ester is (for example, ethyl oleate), and can contain preparaton (formulatory agent) as sanitas, wetting agent, emulsifying agent or suspending agent, stablizer and/or dispersion agent.Or activeconstituents can be powder type, it is by the solid of aseptic separation sterilizing or by solution lyophilize is obtained, for using before use suitable vehicle, for example, sterilized, pyrogen-free water structure.

Compound of the present invention can be mixed with for the form with ointment, ointment or lotion or with transdermal patch form topical in epidermis.Ointment and ointment can be for example, and use or oleaginous base are formulated and add suitable thickening material and/or jelling agent.Lotion can be formulated by water-based or oleaginous base, and conventionally also containing one or more emulsifying agents, stablizer, dispersion agent, suspending agent, thickening material or tinting material.Be suitable for the preparation of topical in oral cavity and comprise lozenge (lozenges), pastille (pastilles) and mouth wash shua, wherein lozenge comprises activeconstituents in flavoring matrix (being generally sucrose and gum arabic or tragakanta); Pastille comprises activeconstituents at inert base in as gelatin and glycerine or sucrose and gum arabic; Mouth-washes comprises activeconstituents in suitable liquid vehicle.

Compound of the present invention can be formulated for the form administration with suppository.First by the wax of low melting point as the mixture melting of glycerin fatty acid ester or theobroma oil, and by for example stirring activeconstituents is disperseed equably.Then the uniform mixture of melting is poured in the mould of suitable size, made it cooling and curing.

Compound of the present invention can be formulated for vagina administration.It is suitable carrier that vaginal suppository, sanitary tampons (tampons), ointment, gelifying agent, paste, foaming agent or sprays also contain known in the state of the art except containing activeconstituents.

Compound of the present invention can be formulated for nose administration.Can be by solution or suspensoid by conventional methods, for example, directly deliver medicine to nasal cavity with dropper, valinche or atomizer.Said preparation can provide with the form of single dose or multiple doses.In the situation that the latter is dropper or valinche, this can by patient by administration suitable, solution or the suspensoid of pre-determined volume realize.The in the situation that of atomizer, this can for example realize with atomisation pump by means of metering.

Compound of the present invention can be mixed with for aerosol drug delivery, especially delivers medicine to respiratory tract, comprises intranasal administration.Compound has little granularity conventionally, for example, be about five (5) microns or less.Such granularity can for example obtain by micronization by manner known in the art.Activeconstituents is contained in the packing of pressurization with together with suitable propelling agent, and described suitable propelling agent is as cfc (CFC), for example, and Refrigerant 12, trichlorofluoromethane or dichloro tetrafluoro ethane or carbonic acid gas or other suitable gas.Aerosol also can contain tensio-active agent as Yelkin TTS easily.The dosage of medicine can be by metering valve control.Selectively, described activeconstituents can provide with the form of dry powder, for example described compound in suitable powder matrix as the powdered mixture in lactose, starch, starch derivative (as Vltra tears) and polyvinylpyrrolidine (PVP).Powder carrier will form gel at nasal cavity.Powder composition can exist with the form of unitary dose, for example be present in as in the capsule of gelatin or cartridge case (cartridges), or be present in Blister Package (blister packs), powder can be by sucker from wherein administration.

When expectation, preparation can be through preparation with the enteric coating that is suitable for activeconstituents slowly-releasing or controlled release drug administration.For example, compound of the present invention can be formulated in transdermal or subcutaneous medicament delivery apparatus.When the slowly-releasing of compound is necessary and in the time that patient is very crucial to the compliance for the treatment of plan, these drug delivery systems are favourable.Compound in transdermal drug delivery system is attached on the solid support that adheres to skin conventionally.Important compound also can combine with for example Azone of penetration enhancer (1-dodecyl azepine-ring heptan-2-ketone).Slowly-releasing delivery system is by surgical operation or inject subcutaneous being implanted in subcutaneous layer.Hypodermic implant is encapsulated in compound for example, for example, in fat-soluble film (silicon rubber) or biodegradable polymkeric substance (poly(lactic acid) (polyactic acid)).

Suitable preparation and pharmaceutical carrier, thinner and vehicle are described in The Science and Practice of Pharmacy1995, and E.W.Martin compiles, Mack Publishing Company, and the 19 edition, Easton, in Pennsylvania.Skilled formulation art scientist can be in the scope of specification sheets instruction improves do not make composition of the present invention unstable or many preparations for specific administration approach are provided do not damage their therapeutic activities in the situation that to preparation.

The compounds of this invention is modified to make their more soluble in water or other vehicle, for example, can easily realize by small modification (salt pref, esterification etc.), this belongs to the ordinary skill of this area completely.Ordinary skill also comprises and changes the route of administration of particular compound and dosage regimen to control the pharmacokinetics of the compounds of this invention, thereby makes the compounds of this invention have maximum beneficial effect.

Term " treatment significant quantity " refers to reduce the needed amount of symptom of individual disease as used herein.In each concrete case, dosage will be adjusted to individual demand.Dosage can change in the larger context, depends on other medicines, route of administration and form that patient that many factors as the severity for the treatment of disease, patient's age and general health, are receiving treatment uses and preference and experience about medical practitioner.For oral administration, in single therapy and/or in combination therapy, every day approximately 0.01 to the per daily dose between about 1000mg/kg body weight will be suitable.Preferred per daily dose in every day approximately 0.1 between about 500mg/kg body weight, preferred per daily dose in every day 0.1 between about 100mg/kg body weight, most preferred per daily dose in every day 1.0 between about 10mg/kg body weight.Therefore,, for the people who delivers medicine to 70kg, dosage range is about 7mg to 0.7g every day.Per daily dose can single dose or with the form administration of broken dose, typically between every day 1 to 5 dosage.Conventionally, treatment is from the smaller dose lower than compound optimal dose.After this, the little increment of dosage ground increases until reach the best effect of individual patient.The those of ordinary skill for the treatment of disease described herein, will not need excessive experiment and rely on the individual disclosed content of knowledge, experience and the application, just can determine the treatment significant quantity for given disease and patient's the compounds of this invention.

Pharmaceutical preparation is preferably unit dosage form.In this class form, preparation is subdivided into the unitary dose containing appropriate activeconstituents.Unit dosage form can be the preparation of packing, and described packing is containing the many preparations that separate, as complete tablet, capsule and the powder in bottle or ampoule.In addition, unit dosage form can be capsule, tablet, cachet or lozenge (lozenge) itself, can be maybe any in these packaged form preparations of proper amt.

Indication and methods for the treatment of

The application provides the method for the illness of a kind of PARP-for the treatment of mediation, comprises to the formula I compound of patient's drug treatment significant quantity that has these needs.

Pharmaceutical composition

Formula I compound and pharmacy acceptable salt can be used as therapeutic active substance, for example, be the form of pharmaceutical preparation.Pharmaceutical preparation Orally-administrable, for example, with the form oral administration of tablet, coated tablet, dragee, hard and soft gelatin capsule, solution, emulsion or suspensoid.But, also can rectal administration the form of suppository (for example with) or the parenteral admin form of injection solution (for example with).

Formula I compound and pharmacy acceptable salt thereof can be processed together with pharmacy inertia for the production of pharmaceutical preparation, inorganic or organic carrier.Can use lactose, W-Gum or derivatives thereof, talcum, stearic acid or its salt etc., for example, they are used as the carrier of tablet, coated tablet, dragee and hard gelatin capsule.For the suitable carrier of soft gelatin capsule be, for example, vegetables oil, wax, fat, semisolid and liquid polyol etc.But, according to the character of active substance, the in the situation that of soft gelatin capsule, conventionally do not need carrier.Suitable carrier for the production of solution and syrup is, for example, and water, polyvalent alcohol, glycerine, plant wet goods.For the suitable carrier of suppository be, for example, natural oil or winterized stearin, wax, fat, semiliquid or liquid polyol etc.

In addition, pharmaceutical preparation can contain pharmaceutically acceptable auxiliary substance as salt, buffer reagent, sequestering agent or the antioxidant of sanitas, solubilizing agent, stablizer, wetting agent, emulsifying agent, sweeting agent, tinting material, spices, change osmotic pressure.They also can be containing the upper valuable material of other treatment.

The medicine that contains formula I compound or its pharmacy acceptable salt and treatment inert support is also object of the present invention, its production method is also object of the present invention, comprises and makes one or more formulas I compound and/or its pharmacy acceptable salt become galenical form of medication with the upper valuable material of (if expectation) one or more other treatment together with one or more treatment inert supports.

Dosage can change in the larger context, and in each concrete case, dosage must be adjusted to individual demand certainly.The dosage of being grown up the in the situation that of oral administration can change at about 0.01mg every day between the compound of Formula I of about 1000mg or its pharmacy acceptable salt of respective amount.Per daily dose can single dose or with the form administration of broken dose, in addition, also can exceed this upper limit according to indication.

Following examples illustrate the present invention and do not limit the present invention, but as just its representative.Pharmaceutical preparation contains easily about 1-500mg, is in particular the formula I compound of 1-100mg.The example of composition of the present invention is:

embodiment A

The tablet of the following composition of preparation in a usual manner:

Table 1: possible tablet composition

Preparation process

1. composition 1,2,3 and 4 mixed and use the granulation of purifying waste water.

Particle is dry at 50 ℃ 2..

3. make particle pass through suitable grinding plant.

4. add composition 5 and mix three minutes; On suitable tabletting machine, suppress.

embodiment B-1

The capsule of the following composition of preparation:

Table 2: possible capsule becomes to be grouped into

Preparation process

1. composition 1,2 and 3 is mixed 30 minutes in suitable mixing tank.

2. add composition 4 and 5 and mix 3 minutes.

3. pack in suitable capsule

First formula I compound, lactose and W-Gum are mixed and then in pulverizer, mixed in mixing tank.Mixture is put back in mixing tank; Add wherein talcum powder and fully mix.Mixture is encased in to suitable capsule for example in hard gelatin capsule by machine.

embodiment B-2

The soft gelatin capsule of the following composition of preparation:

Composition	Mg/ capsule
		Formula I compound	5
Yellow wax	8
		Hydrogenated soybean oil	8
Partially hydrogenated vegetables oil	34
		Soya-bean oil	110
Amount to	165

Table 3: possible soft gelatin capsule becomes to be grouped into

Composition	Mg/ capsule
		Gelatin	75
Glycerine 85%	32
		Karion83	8 (dry-matteies)
Titanium dioxide	0.4
		Iron oxide yellow	1.1
Amount to	116.5

Table 4: possible soft gelatin capsule composition

Preparation process

By formula I compound dissolution in other composition of warm fusing and mixture is packed in the soft gelatin capsule of suitable size.Filled out the soft gelatin capsule of material according to conventional steps processing.

embodiment C

The suppository of the following composition of preparation:

Composition	Mg/ suppository
		Formula I compound	15
Suppository material	1285
		Amount to	1300

Table 5: possible suppository composition

Preparation process

Suppository material is melted in glass or Steel Vessel, fully mix and be cooled to 45 ℃.Immediately, add wherein the formula I compound of finely powdered and stir until it disperses completely.Mixture is poured in the suppository mould of suitable size, made it cooling; Then from model, take out suppository and be packaged in separately in paraffin paper or tinsel.

embodiment D

The injection solution of the following composition of preparation:

Composition	Mg/ injection solution
		Formula I compound	3
Poly(oxyethylene glycol) 400	150
		Acetic acid	Add in right amount to pH5.0
The water of injection solution	Add to 1.0ml

Table 6: possible injection solution composition

Preparation process

By formula I compound dissolution in the mixture of poly(oxyethylene glycol) 400 and water for injection (part).PH is adjusted to 5.0 with acetic acid.By the water that adds residual content, volume is adjusted to 1.0ml.By solution filter, pack in the bottle of suitable overaging and sterilizing.

embodiment E

The wafer (sachet) of the following composition of preparation:

Composition	Mg/ wafer
		Formula I compound	50
Lactose, fine powder	1015
		Microcrystalline Cellulose (AVICEL PH102)	1400
Xylo-Mucine	14
		PVP K30	10
Magnesium Stearate	10
		Flavoring additive	1
Amount to	2500

Table 7: possible wafer composition

Preparation process

Formula I compound and lactose, Microcrystalline Cellulose and Xylo-Mucine are mixed and use to the mixture pelleting of polyvinylpyrrolidone/water.Particle is mixed and packed in wafer with Magnesium Stearate and flavoring additive.

Embodiment

Conventional abbreviation comprises: ethanoyl (Ac), azo-bis-isobutyryl nitrile (AIBN), normal atmosphere (Atm), assorted two ring [3.3.1] nonanes (9-BBN or BBN) of 9-boron, 2,2'-bis-(diphenylphosphino)-1,1'-dinaphthalene (BINAP), tertbutyloxycarbonyl (Boc), two-tertiary butyl pyrocarbonate or tertbutyloxycarbonyl acid anhydrides (BOC ₂o), benzyl (Bn), butyl (Bu), chemical abstracts registry no (CASRN), carbobenzoxy-(Cbz) (CBZ or Z), carbonyl dimidazoles (CDI), 1, 4-diazabicylo [2.2.2] octane (DABCO), diethylamino sulphur trifluoride (DAST), dibenzalacetone (dba), 1, 5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN), 1, 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), N, N '-dicyclohexylcarbodiimide (DCC), 1, 2-ethylene dichloride (DCE), methylene dichloride (DCM), 2, 3-bis-chloro-5, 6-dicyano-1, 4-benzoquinones (DDQ), azoformic acid diethyl ester (DEAD), azoformic acid two-isopropyl esters (DIAD), Di-Isobutyl aluminum hydride (DIBAL or DIBAL-H), two-sec.-propyl ethylamine (DIPEA), N, N-N,N-DIMETHYLACETAMIDE (DMA), 4-N, N-Dimethylamino pyridine (DMAP), N, dinethylformamide (DMF), methyl-sulphoxide (DMSO), 1, 1'-bis-(diphenylphosphino) ethane (dppe), 1, 1'-bis-(diphenylphosphino) ferrocene (dppf), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI), 2-oxyethyl group-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-oxyethyl group-2H-quinoline-1-ethyl formate (EEDQ), ether (Et ₂o), ethyl isopropyl ether (EtOiPr), O-(7-azepine benzo triazol-1-yl)-N, N, N ' N '-tetramethyl-urea hexafluorophosphate acetic acid (HATU), acetic acid (HOAc), 1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography (HPLC), Virahol (iPA), isopropylmagnesium chloride (iPrMgCl), hexamethyldisilazane (HMDS), hexane (hex), liquid chromatography mass (LCMS), hexamethyl dimethyl silanyl Lithamide (LiHMDS), m-chloroperoxybenzoic acid (m-CPBA), methyl alcohol (MeOH), fusing point (mp), MeSO ₂-(methylsulfonyl or Ms), methyl (Me), acetonitrile (MeCN), m-chlorine peroxybenzoic acid (MCPBA), mass spectrum (ms), methyl tertiary butyl ether (MTBE), methyltetrahydrofuran (MeTHF), N-bromosuccinimide (NBS), n-Butyl Lithium (nBuLi), N-carboxylic acid (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine (NMM), N-Methyl pyrrolidone (NMP), pyridinium chlorochromate (PCC), two chloro-((2-2 phenyl phosphine base) ferrocenyl) palladium (II) (Pd (dppf) Cl ₂), acid chloride (II) (Pd (OAc) ₂), three (dibenzalacetone) two palladiums (0) (Pd ₂(dba) ₃), dichromic acid pyridine (PDC), phenyl (Ph), propyl group (Pr), sec.-propyl (i-Pr), pound/square inch (psi), pyridine (pyr), 1,2,3,4,5-pentapheneyl-1 '-(two-tertiary butyl phosphino-) ferrocene (Q-Phos), room temperature (envrionment temperature, rt or RT), s-butyl lithium (sBuLi), tertiary butyl dimethylsilane or t-BuMe ₂si (TBDMS), four-n-butyl ammonium fluoride (TBAF), triethylamine (TEA or Et ₃n), 2,2,6,6-tetramethyl piperidine 1-oxygen base (TEMPO), trifluoromethanesulfonic acid root or CF ₃sO ₂-(Tf), trifluoroacetic acid (TFA), 1,1'-bis--2,2,6,6-tetramethyl-heptane-2,6-diketone (TMHD), O-benzotriazole-1-base-N, N, N', N'-tetramethyl-urea a tetrafluoro borate (TBTU), tlc (TLC), tetrahydrofuran (THF) (THF), trimethyl silyl or Me ₃si (TMS), tosic acid monohydrate (TsOH or pTsOH), 4-Me-C ₆h ₄sO ₂-or tosyl group (Ts), and N-urethane-N-carboxylic acid (UNCA).Traditional name comprises just (n), different (i-), secondary (sec-), uncle (tert-) and newly have their common implications together with moieties in the time using of prefix.(J.Rigaudy?and?D.P.Klesney,Nomenclature?in?Organic?Chemistry,IUPAC1979Pergamon?Press,Oxford.)。

preparation 1.

Pyridazine-3-mercaptan

Thiophosphoric anhydride for solution (924mg, 4.16mmol) by pyridazine-3-alcohol (1.0g, 10.4mmol) in pyridine (15mL) is in room temperature treatment.Then this solution is stirred to 1h in reflux temperature.Now, gained mixture be cooled to room temperature and concentrate in a vacuum the pyridazine-3-mercaptan (560mg, 48%) that obtains yellow solid form.This material uses without being further purified. 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 2.

N-(4-methoxyl group-phenyl)-2-(3-methoxyl group-phenyl sulfanyl)-ethanamide

By 4-anisidine (5.00g, 40.7mmol) solution in tetrahydrofuran (THF) (50mL) in-78 ℃ with triethylamine (4.19g, 41.5mmol) process, use afterwards 2-bromoacetyl chloride (6.38g, 40.7mmol) process, in the time adding 2-bromoacetyl chloride, form precipitation.Reaction mixture is slowly warmed to 25 ℃, it is spent the night 25 ℃ of stirrings.At this moment, mixture is poured in water (100mL), with methylene dichloride (2x50mL) extraction, with saturated sodium-chloride water solution (100mL) washing, through dried over sodium sulfate concentrated.Gained resistates obtains the bromo-N-of 2-(4-methoxyl group-phenyl)-ethanamide (8.1g, 82%) of light brown solid form through chromatogram purification (sherwood oil: ethyl acetate=8:1). ¹H?NMR(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。

By bromo-2-N-(4-methoxyl group-phenyl)-ethanamide (200mg, 0.82mmol) N-methylmorpholine (the 190mg for solution in tetrahydrofuran (THF) (4mL) and water (4mL), 1.89mmol) process, then process by dripping rapidly the solution of 3-methoxyl group-thiophenol (230mg, 1.65mmol) in tetrahydrofuran (THF) (3mL).Reaction soln is spent the night in 25 ℃ of stirrings.At this moment, gained mixture is concentrated in a vacuum.Resistates water (30mL) is diluted and use the solution extraction of 10% methyl alcohol in methylene dichloride (2X30mL).By saturated sodium-chloride water solution for organic layer (30mL) washing merging, through dried over sodium sulfate concentrated in a vacuum.Gained resistates is obtained to N-(4-methoxyl group-phenyl)-2-(3-methoxyl group-phenyl sulfenyl)-ethanamide (510mg, 85%) of yellow solid form through silica gel chromatography purifying (sherwood oil: ethyl acetate=8:1).LC-MS:304[M+1] ⁺,R _t＝1.515min。

In a similar fashion according to the synthetic following compounds of above-mentioned steps:

preparation 3.

By the bromo-N-of 2-(4-methoxyl group-phenyl)-ethanamide and the fluoro-thiophenol of 3-: 2-(the fluoro-phenyl sulfenyl of 3-)-N-(4-methoxyl group-phenyl)-ethanamide (510mg, 85%) that obtains yellow solid form.LC-MS:292[M+1] ⁺,R _t＝1.529min。

preparation 4.

By the bromo-N-of 2-(4-methoxyl group-phenyl)-ethanamide and 3-methyl-thiophenol: the m-tolyl sulfenyl-ethanamide of N-(4-methoxyl group-phenyl)-2-(500mg, 85%) that obtains yellow solid form.LC-MS:288[M+1] ⁺,R _t＝1.575min。

preparation 5.

By the bromo-N-of 2-(4-methoxyl group-phenyl)-ethanamide and naphthalene-2-mercaptan: N-(4-methoxyl group-phenyl)-2-(naphthalene-2-base sulfenyl)-ethanamide (480mg, 90%) that obtains yellow solid form.LC-MS:324[M+1] ⁺,R _t＝1.623min。

preparation 6.

By the bromo-N-of 2-(4-methoxyl group-phenyl)-ethanamide and naphthalene-1-mercaptan: N-(4-methoxyl group-phenyl)-2-(naphthalene-1-base sulfenyl)-ethanamide (500mg, 93%) that obtains white solid form.LC-MS:324[M+1] ⁺,R _t＝1.622min。

preparation 7.

By the bromo-N-of 2-(4-methoxyl group-phenyl)-ethanamide and hexanaphthene mercaptan: 2-cyclohexyl sulfenyl-N-(4-methoxyl group-phenyl)-ethanamide (260mg, 57%) that obtains white solid form.LC-MS:280[M+1] ⁺,R _t＝1.630min。

preparation 8.

By the bromo-N-of 2-(4-methoxyl group-phenyl)-ethanamide and 3-sulfydryl-methyl benzoate: the 3-[(4-methoxyl group-phenyl amino formyl radical that obtains white solid form)-methyl sulfenyl]-methyl benzoate (500mg, 91%).LC-MS:304[M+1] ⁺,R _t＝1.515min。

preparation 9.

By the bromo-N-of 2-(4-methoxyl group-phenyl)-ethanamide and the fluoro-thiophenol of the chloro-4-of 3-: 2-(the fluoro-phenyl sulfenyl of the chloro-4-of 3-)-N-(4-methoxyl group-phenyl)-ethanamide (400mg, 75%) that obtains yellow solid form.LC-MS:304[M+1] ⁺,R _t＝1.599min。

preparation 10.

By the bromo-N-of 2-(4-methoxyl group-phenyl)-ethanamide and pyridazine-3-mercaptan: N-(4-methoxyl group-phenyl)-2-(pyridazine-3-base sulfenyl)-ethanamide (400mg, 88%) that obtains yellow solid form. ¹H?NMR(300MHz,DMSO-d ₆)δppm10.20(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＝1.303min.

preparation 11.

By the bromo-N-of 2-(4-methoxyl group-phenyl)-ethanamide and 3, the chloro-thiophenol of 5-bis-: the 2-(3 that obtains pale solid form, the chloro-phenyl sulfenyl of 5-bis-)-N-(4-methoxyl group-phenyl)-ethanamide (0.26g, 74.2%). ¹HNMR(300MHz,DMSO-d ₆)δppm3.71(s,3H)3.95(s,2H)6.89(d,J＝9.04Hz,2H)7.28-7.59(m,5H)10.13(s,1H).

preparation 12.

By the bromo-N-of 2-(4-methoxyl group-phenyl)-ethanamide and 3, the fluoro-thiophenol of 4-bis-: the 2-(3 that obtains pale solid form, the fluoro-phenyl sulfenyl of 4-bis-)-N-(4-methoxyl group-phenyl)-ethanamide (302.2mg, 95.4%). ¹H?NMR(300MHz,DMSO-d ₆)δppm3.72(s,3H)3.85(s,2H)6.88(d,J＝9.04Hz,2H)7.20-7.31(m,1H)7.34-7.50(m,3H)7.51-7.63(m,1H)10.07(s,1H).

Embodiment 1.

2-(3-methoxyl group-benzenesulfinyl)-N-(4-methoxyl group-phenyl)-ethanamide (I-1)

By N-(4-methoxyl group-phenyl)-2-(3-methoxyl group-phenyl sulfenyl)-ethanamide (200mg, 0.66mmol) solution in acetic acid (4mL) with 30% aqueous hydrogen peroxide solution (224mg, 6.60mmol) in room temperature treatment.Then this solution is stirred to 1h in 40 ℃.At this moment, gained mixture is cooled to room temperature, with ethyl acetate (30mL) dilution, with 1N aqueous hydrochloric acid (30mL), water (30mL), saturated sodium-chloride water solution (30mL) washing, through dried over sodium sulfate concentrated in a vacuum.Gained resistates is obtained to compound 2-(3-methoxyl group-benzenesulfinyl)-N-(4-methoxyl group-phenyl)-ethanamide (200mg, 95%) of white solid form through silica gel chromatography purifying (sherwood oil: ethyl acetate=5:1). ¹H?NMR(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: being 98.34% at 214nm, is 99.30%, R at 254nm _t=3.333min.

In a similar fashion according to the synthetic following sulfoxide of above-mentioned steps:

Embodiment 2.

2-(the fluoro-benzenesulfinyl of 3-)-N-(4-methoxyl group-phenyl)-ethanamide (I-2)

By 2-(the fluoro-phenyl sulfenyl of 3-)-N-(4-methoxyl group-phenyl)-ethanamide: 2-(the fluoro-benzenesulfinyl of 3-)-N-(4-methoxyl group-phenyl)-ethanamide (200mg, 63%) that obtains white solid form. ¹H?NMR(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: being 99.1% at 214nm, is 99.7%, R at 254nm _t=4.470min.

Embodiment 3.

2-(the fluoro-benzenesulfinyl of (R)-3-)-N-(4-methoxyl group-phenyl)-ethanamide (I-3)

Isomer 1; Supercritical fluid chromatography; Chiralpak AS-H, 40 ℃, flow velocity 60mL/min, 40% methyl alcohol; UV wavelength: 260nM; Rt=2.21min; White solid (47.1mg). ¹H?NMR(300MHz,DMSO-d ₆)δppm3.72(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).

Embodiment 4.

2-(the fluoro-benzenesulfinyl of (S)-3-)-N-(4-methoxyl group-phenyl)-ethanamide (I-4)

Isomer 2; Chiralpak AS-H, 40 ℃, flow velocity 60mL/min, 40% methyl alcohol; UV wavelength: 260nM; Rt=2.91min; White solid (44.9mg); ¹h NMR (300MHz, DMSO-d ₆) δ ppm3.72 (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).

Embodiment 5.

N-(4-methoxyl group-phenyl)-2-(Toluene-3,4-dithiol-sulfinyl)-ethanamide (I-5)

By the m-toluene sulfenyl-ethanamide of N-(4-methoxyl group-phenyl)-2-: N-(4-methoxyl group-phenyl)-2-(Toluene-3,4-dithiol-sulfinyl)-ethanamide (260mg, 82%) that obtains white solid form. ¹H?NMR(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: being 99.10% at 214nm, is 99.63%, R at 254nm _t=3.370min.

Embodiment 6.

N-(4-methoxyl group-phenyl)-2-((R)-Toluene-3,4-dithiol-sulfinyl)-ethanamide (I-6)

Isomer 1; Supercritical fluid chromatography; Chiralpak AS-H, 40 ℃, flow velocity 60mL/min, 40% methyl alcohol; UV wavelength: 260nM; Rt=2.36min; Pale solid (40.3mg); ¹h NMR (300MHz, DMSO-d ₆) δ ppm2.38 (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).

Embodiment 7.

N-(4-methoxyl group-phenyl)-2-((S)-Toluene-3,4-dithiol-sulfinyl)-ethanamide (I-7)

Isomer 2; Supercritical fluid chromatography; Chiralpak AS-H, 40 ℃, flow velocity 60mL/min, 40% methyl alcohol; UV wavelength: 260nM; Rt=3.34min; Pale solid (43.6mg); ¹h NMR (300MHz, DMSO-d ₆) 2.38 (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).

Embodiment 8.

N-(4-methoxyl group-phenyl)-2-(naphthalene-2-sulfinyl)-ethanamide (I-8)

By N-(4-methoxyl group-phenyl)-2-(naphthalene-2-base sulfenyl)-ethanamide: N-(4-methoxyl group-phenyl)-2-(naphthalene-2-sulfinyl)-ethanamide (180mg, 57%) that obtains white solid form. ¹H?NMR(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% is in 214nm, and 99.23% in 254nm, Rt=3.720min.

Embodiment 9.

N-(4-methoxyl group-phenyl)-2-(naphthalene-1-sulfinyl)-ethanamide (I-9)

By N-(4-methoxyl group-phenyl)-2-(naphthalene-1-base sulfenyl)-ethanamide: N-(4-methoxyl group-phenyl)-2-(naphthalene-1-sulfinyl)-ethanamide (210mg, 67%) that obtains white solid form. ¹H?NMR(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% is in 214nm, and 97.72% in 254nm, Rt=5.270min.

Embodiment 10.

2-hexanaphthene sulfinyl-N-(4-methoxyl group-phenyl)-ethanamide (I-10)

By 2-cyclohexyl sulfenyl-N-(4-methoxyl group-phenyl)-ethanamide: 2-hexanaphthene sulfinyl-N-(4-methoxyl group-phenyl)-ethanamide (190mg, 69%) that obtains white solid form. ¹h NMR (300MHz, DMSO-d ₆) δ ppm10.16 (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% is in 214nm, and 97.30% in 254nm, Rt=5.213min.

Embodiment 11.

3-[(4-methoxyl group-phenyl amino formyl radical)-methanesulfinyl]-methyl benzoate (I-11)

By 3-[(4-methoxyl group-phenyl amino formyl radical)-methyl sulfenyl]-methyl benzoate: the 3-[(4-methoxyl group-carbaniloyl,phenylcarbamoyl that obtains white solid form)-methanesulfinyl]-methyl benzoate (180mg, 43%). ¹H?NMR(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% is in 214nm, and 96.05% in 254nm, Rt=4.387min.

Embodiment 12.

2-(the fluoro-benzenesulfinyl of the chloro-4-of 3-)-N-(4-methoxyl group-phenyl)-ethanamide (I-12)

By 2-(the fluoro-phenyl sulfenyl of the chloro-4-of 3-)-N-(4-methoxyl group-phenyl)-ethanamide: 2-(the fluoro-benzenesulfinyl of the chloro-4-of 3-)-N-(4-methoxyl group-phenyl)-ethanamide (130mg, 31%) that obtains white solid form. 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＝1.478min。HPLC:100% is in 214nm, and 100% in 254nm, Rt=0.742min.

Embodiment 13.

2-(the fluoro-benzenesulfinyl of the chloro-4-of (R)-3-)-N-(4-methoxyl group-phenyl)-ethanamide (I-13)

Isomer 1; Supercritical fluid chromatography; Chiralpak AS-H, 40 ℃, flow velocity 60mL/min, 40% methyl alcohol; UV wavelength: 260nM; Rt=2.53min; White solid (45.8mg); ¹h NMR (300MHz, DMSO-d ₆) δ ppm3.72 (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).

Embodiment 14.

2-(the fluoro-benzenesulfinyl of the chloro-4-of (S)-3-)-N-(4-methoxyl group-phenyl)-ethanamide (I-14)

Isomer 2; Supercritical fluid chromatography; Chiralpak AS-H, 40 ℃, flow velocity 60mL/min, 40% methyl alcohol; UV wavelength: 260nM; Rt=3.68min; White solid (47.8mg); ¹h NMR (300MHz, DMSO-d ₆) δ ppm3.72 (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).

Embodiment 15.

N-(4-methoxyl group-phenyl)-2-(pyridazine-3-sulfinyl)-ethanamide (I-15)

By N-(4-methoxyl group-phenyl)-2-(pyridazine-3-base sulfenyl)-ethanamide: N-(4-methoxyl group-phenyl)-2-(pyridazine-3-sulfinyl)-ethanamide (400mg) (80mg, 19%) that obtains yellow solid form. ¹h NMR (300MHz, DMSO-d ₆) δ ppm10.21 (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% is in 214nm, and 99.65% in 254nm, Rt=4.617min.

Embodiment 16.

2-(the chloro-benzenesulfinyl of 3,5-bis-)-N-(4-methoxyl group-phenyl)-ethanamide (I-16)

By 2-(3; the chloro-phenyl sulfenyl of 5-bis-)-N-(4-methoxyl group-phenyl)-ethanamide: the 2-(3 that obtains pale solid form; the chloro-benzenesulfinyl of 5-bis-)-N-(4-methoxyl group-phenyl)-ethanamide (0.26g) (49.8mg, 18.3%). ¹H?NMR(300MHz,DMSO-d ₆)δppm3.72(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)

Embodiment 17.

2-(the fluoro-benzenesulfinyl of 3,4-bis-)-N-(4-methoxyl group-phenyl)-ethanamide (I-17)

By 2-(3; the fluoro-phenyl sulfenyl of 4-bis-)-N-(4-methoxyl group-phenyl)-ethanamide: the 2-(3 that obtains white solid form; the fluoro-benzenesulfinyl of 4-bis-)-N-(4-methoxyl group-phenyl)-ethanamide (302mg) (244.6mg, 77%). ¹H?NMR(300MHz,DMSO-d ₆)

3.72(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).

preparation 13.

The bromo-N-of 2-(4-methoxyl group-benzyl)-ethanamide

In-78 ℃, the solution of tetrahydrofuran (THF) (60mL) is processed with compound 4-methoxyl group-benzylamine (1.0g, 7.3mmol), use afterwards triethylamine (838mg, 8.29mmol) to process.Then this solution is processed with 2-bromoacetyl chloride (1.28g, 8.13mmol), in the time adding 2-bromoacetyl chloride, formed precipitation.Reaction mixture is slowly warmed to 25 ℃, will spends the night in its stirring.At this moment, reaction mixture is poured in water (100mL), with methylene dichloride (2x100mL) extraction, with saturated sodium-chloride water solution (100mL) washing, through dried over sodium sulfate concentrated in a vacuum.Gained resistates is obtained to the bromo-N-of 2-(4-methoxyl group-benzyl)-ethanamide (630mg, 34%) of yellow solid form through silica gel chromatography purifying (sherwood oil: ethyl acetate=5:1). ¹H?NMR(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 14.

By 2-bromoacetyl chloride and the fluoro-aniline of 4-: the bromo-N-of 2-(the fluoro-phenyl of the 4-)-ethanamide (1.20g, 85%) that obtains white solid form.LC-MS:232[M+1] ⁺,R _t＝1.425min。

preparation 15.

By 2-bromoacetyl chloride and 4-methylsulfonyl-aniline: the bromo-N-of 2-(4-methylsulfonyl-phenyl)-ethanamide (1.20g, 88%) that obtains white solid form.LC-MS:292[M+1] ⁺,R _t＝1.256min。

preparation 16.

By 2-bromoacetyl chloride and 3-methoxyl group-aniline: the bromo-N-of 2-(3-methoxyl group-phenyl)-ethanamide (1.56g, 78%) that obtains white solid form.LC-MS:244[M+1] ⁺,R _t＝1.388min.

preparation 17.

By 2-bromoacetyl chloride and 2-methoxyl group-aniline: the bromo-N-of 2-(2-methoxyl group-phenyl)-ethanamide (800mg, 42%) that obtains yellow solid form.LC-MS:244[M+1] ⁺,R _t＝1.455min.

preparation 18.

By 2-bromoacetyl chloride and hexanaphthene methylamine: the bromo-N-cyclohexyl methyl-ethanamide of 2-(1.00g, 48%) that obtains white solid form.LC-MS:234[M+1] ⁺,R _t＝1.485min.

preparation 19.

2-(the chloro-phenyl sulfenyl of 3-)-N-(4-methoxyl group-benzyl)-ethanamide

By bromo-compound 2-N-(4-methoxyl group-benzyl)-ethanamide (500mg, 1.95mmol) N-methylmorpholine (the 456mg for solution in tetrahydrofuran (THF) (6mL) and water (6mL), 4.50mmol) process, then by dripping rapidly the solution-treated of 3-chlorothio-phenol (560mg, 3.87mmol) in tetrahydrofuran (THF) (3mL).Reaction soln is spent the night in 25 ℃ of stirrings.At this moment, gained mixture is concentrated in a vacuum.Resistates water (30mL) is diluted and use the solution extraction of 10% methyl alcohol in methylene dichloride (2x30mL).By saturated sodium-chloride water solution for organism (30mL) washing merging, through dried over sodium sulfate concentrated in a vacuum.Gained resistates is obtained to 2-(the chloro-phenyl sulfenyl of 3-)-N-(4-methoxyl group-benzyl)-ethanamide (620mg, 99%) of white solid form through silica gel chromatography purifying (sherwood oil: ethyl acetate=5:1).LC-MS:322[M+1] ⁺,R _t＝1.562min.

preparation 20.

By 3-chlorothio-phenol and the bromo-N-of 2-(the fluoro-phenyl of 4-)-ethanamide: 2-(the chloro-phenyl sulfenyl of 3-)-N-(the fluoro-phenyl of the 4-)-ethanamide (560mg, 86%) that obtains white solid form.LC-MS:296[M+1] ⁺,R _t＝1.646min.

preparation 21.

By 3-chlorothio-phenol and the bromo-N-of 2-(4-methylsulfonyl-phenyl)-ethanamide: 2-(the chloro-phenyl sulfenyl of 3-)-N-(4-methylsulfonyl-phenyl)-ethanamide (450mg, 74%) that obtains yellow solid form.LC-MS:356[M+1] ⁺,R _t＝1.508min.

preparation 22.

By 3-chlorothio-phenol and the bromo-N-of 2-(3-methoxyl group-phenyl)-ethanamide: 2-(the chloro-phenyl sulfenyl of 3-)-N-(3-methoxyl group-phenyl)-ethanamide (530mg, 84%) that obtains yellow solid form.LC-MS:308[M+1] ⁺,R _t＝1.620min.

preparation 23.

From 3-chlorothio-phenol and the bromo-N-of 2-(2-methoxyl group-phenyl)-ethanamide: 2-(the chloro-phenyl sulfenyl of 3-)-N-(2-methoxyl group-phenyl)-ethanamide (550mg, 87%) that obtains white solid form.LC-MS:308[M+1] ⁺,R _t＝1.674min.

preparation 24.

By 3-chlorothio-phenol and the bromo-N-cyclohexyl methyl-ethanamide of 2-: 2-(the chloro-phenyl sulfenyl of the 3-)-N-cyclohexyl methyl-ethanamide (1.05g, 82%) that obtains white solid form.LC-MS:298[M+1] ⁺,R _t＝1.686min.

Embodiment 18.

2-(the chloro-benzenesulfinyl of 3-)-N-(4-methoxyl group-benzyl)-ethanamide (I-18)

In room temperature, by compound 2-(the chloro-phenyl sulfenyl of 3-)-N-(4-methoxyl group-benzyl)-ethanamide (300mg, 0.94mmol) solution in acetic acid (5mL) is processed with 30% aqueous hydrogen peroxide solution (318mg, 9.4mmol).Then this solution is stirred to 1h in 40 ℃.This is cooled to gained mixture room temperature and uses ethyl acetate (30mL) dilution, with 1N aqueous hydrochloric acid (30mL), water (30mL), saturated sodium-chloride water solution (30mL) washing, through dried over sodium sulfate concentrated in a vacuum.Resistates is obtained to 2-(the chloro-benzenesulfinyl of 3-)-N-(4-methoxyl group-benzyl)-ethanamide (200mg, 63%) of white solid form through silica gel chromatography purifying (sherwood oil: ethyl acetate=5:1). ¹h NMR (300MHz, DMSO-d ₆) δ ppm8.56-8.53 (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% is in 214nm, and 99.52% in 254nm, Rt=3.498min.

Embodiment 19.

2-(the chloro-benzenesulfinyl of 3-)-N-(the fluoro-phenyl of 4-)-ethanamide (I-19)

By 2-(the chloro-phenyl sulfenyl of 3-)-N-(the fluoro-phenyl of 4-)-ethanamide: 2-(the chloro-benzenesulfinyl of 3-)-N-(the fluoro-phenyl of the 4-)-ethanamide (120mg, 20%) that obtains white solid form. ¹H?NMR(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% is in 214nm, and 99.37% in 254nm, Rt=5.487min.

Embodiment 20.

2-(the chloro-benzenesulfinyl of (R)-3-)-N-(the fluoro-phenyl of 4-)-ethanamide (I-20)

Isomer 1; Supercritical fluid chromatography; Chiralpak AS-H, 40 ℃, flow velocity 60mL/min, 40% methyl alcohol; UV wavelength: 260nM; Rt=2.43min; White solid (34.8mg). ¹H?NMR(300MHz,DMSO-d ₆)δppm3.83-4.01(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).

Embodiment 21.

2-(the chloro-benzenesulfinyl of (S)-3-)-N-(the fluoro-phenyl of 4-)-ethanamide (I-20)

Isomer 2; Supercritical fluid chromatography; Chiralpak AS-H, 40 ℃, flow velocity 60mL/min, 40% methyl alcohol; UV wavelength: 260nM; Rt=3.24min; White solid (35mg). ¹H?NMR(300MHz,DMSO-d ₆)

3.79-4.01(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).

Embodiment 22.

2-(the chloro-benzenesulfinyl of 3-)-N-(4-methylsulfonyl-phenyl)-ethanamide (I-22)

By 2-(the chloro-phenyl sulfenyl of 3-)-N-(4-methylsulfonyl-phenyl)-ethanamide: 2-(the chloro-benzenesulfinyl of 3-)-N-(4-methylsulfonyl-phenyl)-ethanamide (300mg, 64%) that obtains white solid form. ¹H?NMR(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% is in 214nm, and 99.65% in 254nm, Rt=4.173min.

Embodiment 23.

2-(the chloro-benzenesulfinyl of 3-)-N-(3-methoxyl group-phenyl)-ethanamide (I-23)

By 2-(the chloro-phenyl sulfenyl of 3-)-N-(3-methoxyl group-phenyl)-ethanamide: 2-(the chloro-benzenesulfinyl of 3-)-N-(3-methoxyl group-phenyl)-ethanamide (200mg, 36%) that obtains white solid form. ¹H?NMR(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% is in 214nm, and 99.34% in 254nm, Rt=3.379min.

Embodiment 24.

2-(the chloro-benzenesulfinyl of 3-)-N-(2-methoxyl group-phenyl)-ethanamide (I-24)

By 2-(the chloro-phenyl sulfenyl of 3-)-N-(2-methoxyl group-phenyl)-ethanamide: 2-(the chloro-benzenesulfinyl of 3-)-N-(2-methoxyl group-phenyl)-ethanamide (250mg, 44%) that obtains white solid form. ¹H?NMR(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% is in 214nm, and 99.42% in 254nm, Rt=3.561min.

Embodiment 25.

2-(the chloro-benzenesulfinyl of 3-)-N-cyclohexyl methyl-ethanamide (I-25)

By 2-(the chloro-phenyl sulfenyl of 3-)-N-cyclohexyl methyl-ethanamide: 2-(the chloro-phenyl sulfenyl of the 3-)-N-cyclohexyl methyl-ethanamide (800mg, 72%) that obtains white solid form. ¹H?NMR(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% is in 214nm, and 98.44% in 254nm, Rt=6.310min.

preparation 25.

The chloro-phenyl sulfenyl of 3-)-acetic acid methyl ester

By bromo-acetic acid methyl ester (10g, 69mmol) and 3-chlorothio-phenol (11.6g, 76mmol), the N-methylmorpholine for solution (17.4mL) in tetrahydrofuran (THF) (100mL) is processed.Gained mixture is stirred to 1h in 20 ℃.At this moment, mixture is filtered and filtrate is concentrated to (the chloro-phenyl sulfenyl of the 3-)-acetic acid methyl ester (15.68g, 100%) that obtains yellow oily in a vacuum.This material directly uses without being just further purified.LC-MS:217[M+1] ⁺,R _t＝1.658min。

preparation 26.

(the chloro-benzenesulfinyl of 3-)-acetic acid methyl ester

The solution of crude product (3-chloro-phenyl-sulfenyl)-acetic acid methyl ester (15.6g, 69mmol) in acetic acid (156mL) is processed with 30% aqueous hydrogen peroxide solution (78ml, 690mmol).Gained mixture is stirred to 1h in 40 ℃.At this moment, solution be cooled to room temperature and use methylene dichloride (2x300mL) extraction.By saturated sodium bicarbonate aqueous solution for organic layer (2x500mL) washing merging and through dried over sodium sulfate and filtration.By filtrate concentrated (the chloro-benzenesulfinyl of the 3-)-acetic acid methyl ester (15.9g, 100%) that obtains yellow oily in a vacuum.This material directly uses without being just further purified.LC-MS:233[M+1] ⁺,R _t＝1.358min.

preparation 27.

(the chloro-benzenesulfinyl of 3-)-acetic acid

By rough (the chloro-benzenesulfinyl of 3-)-acetic acid methyl ester (15.9g; 69mmol) 1; aqueous sodium hydroxide solution (4.14g for solution in 4-diox (160mL) and water (160mL); 103.5mmol in water, 10mL) process.Then this solution is stirred to 10min in 20 ℃.At this moment, by gained methylene dichloride (500mL) extraction for mixture.Discard organic layer.Water layer is acidified to pH=1-2 and uses methylene dichloride (2x200mL) extraction with aqueous hydrochloric acid.The organic layer merging, through dried over sodium sulfate, is filtered and concentrates in a vacuum (the chloro-benzenesulfinyl of the 3-)-acetic acid (12.67g, 84%) that obtains white solid form.This material directly uses without being just further purified.LC-MS:219[M+1] ⁺,R _t＝1.209min.

Embodiment 26.

2-(the chloro-benzenesulfinyl of 3-)-N-(the fluoro-phenyl of 3-)-ethanamide (I-26)

By (the chloro-benzenesulfinyl of 3-)-acetic acid (600mg; 2.74mmol) solution in methylene dichloride (20mL) is cooled to 0 ℃; (2-(7-azepine-1H-benzotriazole-1-yl)-1 for solution; 1; 3,3-tetramethyl-urea hexafluorophosphate) (1.15g, 3.01mmol) and N; N-diisopropyl ethyl amine (1.06g, 8.22mmol) is processed.Reaction mixture is stirred to 0.5h in 0 ℃.At this moment, reaction mixture is processed with the fluoro-aniline of 3-(305mg, 2.74mmol).Reaction mixture is warmed to room temperature and stirs and spend the night.At this moment, gained mixture is concentrated in a vacuum.Ethyl acetate for resistates (30mL) is diluted and use 1N aqueous hydrochloric acid (30mL), saturated sodium bicarbonate aqueous solution (30mL), water (30mL) and saturated sodium-chloride water solution (30mL) to wash, through dried over sodium sulfate, filter and concentrate in a vacuum.Obtain 2-(the chloro-benzenesulfinyl of 3-)-N-(the fluoro-phenyl of the 3-)-ethanamide (100mg, 12%) of white solid form through silica gel chromatography (sherwood oil: ethyl acetate=5:1). 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% is at 214nm, and 99.74% at 254nm, R _t=5.577min.

Embodiment 27.

2-(the chloro-benzenesulfinyl of 3-)-N-(4-trifluoromethyl-phenyl)-ethanamide (I-27)

By (the chloro-benzenesulfinyl of 3-)-acetic acid and 4-trifluoromethyl-aniline: 2-(the chloro-benzenesulfinyl of 3-)-N-(4-the trifluoromethyl-phenyl)-ethanamide (660mg, 40%) that obtains white solid form. ¹H?NMR(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% is in 214nm, and 99.06% in 254nm, Rt=4.478min.

Embodiment 28.

2-(the chloro-benzenesulfinyl of 3-)-N-(4-cyano group-phenyl)-ethanamide (I-28)

By (the chloro-benzenesulfinyl of 3-)-acetic acid and 4-amino-cyanobenzene: 2-(the chloro-benzenesulfinyl of 3-)-N-(4-cyano group-phenyl)-ethanamide (200mg, 14%) that obtains white solid form. ¹h NMR (300MHz, DMSO-d ₆): δ ppm10.64 (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% is in 214nm, and 99.69% in 254nm, Rt=5.130min.

Embodiment 29.

2-(the chloro-benzenesulfinyl of 3-)-N-(the fluoro-phenyl of 2-)-ethanamide (I-29)

By (the chloro-benzenesulfinyl of 3-)-acetic acid and the fluoro-aniline of 2-: 2-(the chloro-benzenesulfinyl of 3-)-N-(the fluoro-phenyl of the 2-)-ethanamide (400mg, 28%) that obtains white solid form. ¹H?NMR(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% is in 214nm, and 99.32% in 254nm, Rt=5.147min.

Embodiment 30.

2-(the chloro-benzenesulfinyl of 3-)-N-(4-trifluoromethoxy-phenyl)-ethanamide (I-30)

By (the chloro-benzenesulfinyl of 3-)-acetic acid and 4-trifluoromethoxy-aniline: 2-(the chloro-benzenesulfinyl of 3-)-N-(4-trifluoromethoxy-phenyl)-ethanamide (400mg, 23%) that obtains white solid form. ¹H?NMR(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% is in 214nm, and 99.42% in 254nm, Rt=4.547min.

Embodiment 31.

2-(the chloro-benzenesulfinyl of 3-)-N-cyclohexyl-ethanamide (I-31)

By (the chloro-benzenesulfinyl of 3-)-acetic acid and hexahydroaniline: 2-(the chloro-benzenesulfinyl of the 3-)-N-cyclohexyl-ethanamide (700mg, 51%) that obtains white solid form. ¹H?NMR(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% is in 214nm, and 98.28% in 254nm, Rt=3.597min.

Embodiment 32.

2-(the chloro-benzenesulfinyl of 3-)-N-cyclopentyl-methyl-ethanamide (I-32)

By (the chloro-benzenesulfinyl of 3-)-acetic acid and pentamethylene methylamine: 2-(the chloro-benzenesulfinyl of the 3-)-N-cyclopentyl-methyl-ethanamide (500mg, 45%) that obtains white solid form. ¹h NMR (300MHz, DMSO-d ₆) δ ppm8.13-8.09 (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% is in 214nm, and 97.85% in 254nm, Rt=3.698min.

Embodiment 33.

μ HTS-TNKS-IWR2TR-FRET is in conjunction with mensuration

(10 μ L/ holes in BD1536-orifice plate, single-point)

Reagent and stoste

1. tankyrase 1 (TNKS1): 184.3 μ M=5.2mg/mL His6-TNKS1, MW=28.2KDa (structure: 1088-1327, I266M), in 20mM Tris (pH8), 150mMNaCl, 10% glycerine and 0.5mM TCEP

As an alternative, can use His6-tankyrase 2 (structure: 934-1166) (His6-TNKS2) or His6-PARP1 (total length) replace His6-TNKS1.

2. vitamin H-IWR2: the 10mM vitamin H-IWR2 stoste in DMSO, in-20 ℃ of storages.

3. positive control: the 10mM XAV939 in DMSO, in-20 ℃ of storages

4.Eu-streptavidin: 38.1 μ M (2.1mg/mL) Eu-SA (Bio#Eu-2212, Lot#N18001-BDHO2)

The anti-His antibody of 5.APC-: 8.50 μ M SL-APC, 8.26 μ M anti-6His antibody-SureLight APC (Columia Bioscience, Cat#D3-1711, Lot#N01010-AAH04)

6. assay plate: BD1536-hole, transparent/black plate (Cat#353255)

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

Measure damping fluid

1. the mensuration damping fluid 1a (AB1a) diluting for TNKS: 50mM Tris (pH7.4), 100mM sodium chloride solution, 1mM magnesium chloride solution, 1mM DL-dithiothreitol (DTT) solution, 0.2mg/mL bovine serum albumin solution, 0.025%NP-40.

2. the mensuration damping fluid 1b (AB1b) diluting for vitamin H-IWR2: 50mM Tris (pH7.4), 100mM sodium chloride solution, 1mM magnesium chloride solution, 1mM DL-dithiothreitol (DTT) solution, 0.2mg/mL bovine serum albumin solution, 0.05%NP-40.

3. for the mensuration damping fluid 1c (AB1c) of diluted chemical compound: 50mM Tris (pH7.4), 100mM sodium chloride solution, 1mM magnesium chloride solution, 1mM DL-dithiothreitol (DTT) solution, 0.2mg/mL bovine serum albumin solution.

4. for the mensuration damping fluid 2 (AB2) of Eu/APC: 50mM Tris (pH7.4), 100mM sodium chloride solution, 1mM magnesium chloride solution, 0.2mg/mL bovine serum albumin solution.

The former liquid formulation of reagent

1. for the preparation of the former liquor of biotinylation IWR2 (3.33x stoste) in TOTL and compound hole: the 200nM vitamin H-IWR2 in 5%DMSO/AB1b damping fluid

2. the former liquor of preparation blank well: 5%DMSO/AB1b damping fluid

3. prepare the former liquor in positive control hole (3.33x stoste): the 200nM XAV939 in 200nM vitamin H-IWR2/5%DMSO/AB1b damping fluid

4. the preparation former liquor of TNKS1 (5x stoste): the 300nM TNKS in AB1a damping fluid

(as an alternative, use TNKS2 or PARP1 stoste.)

5. the preparation former liquor of Eu/APC (5x stoste): the 3.5nMEu-SA/50nM APC-His6Ab in AB2 damping fluid

Determination step

1. compound formulation:

In compound plate, in each compound hole, add 25 μ L/ hole 1.5%DMSO/AB1c damping fluids to compound concentration and add (blank well, total hole and positive hole) for 74 μ M in 8.8%DMSO/AB1c damping fluid or in 2 μ L DMSO control wells.

2. the above-mentioned solution (solution 1,2,3) in transfer as follows 3 μ l/ holes is to empty assay plate (BD1536-orifice plate):

TOTL and compound hole: solution 1 (vitamin H-IWR2):

Blank well: solution 2 (lifeless matter element-IWR2):

Positive control hole: solution 3 (vitamin H-IWR2+XAV939)

3. the compound solution of the above-mentioned dilution in transfer 3 μ L/ holes or diluted chemical compound damping fluid are to above-mentioned assay plate.

4. to the former liquor of 300nM TNKS (4) that adds 2 μ L/ holes in the each hole in said determination plate.

5. by assay plate under 2100rpm centrifugal 2 minutes.

By assay plate in 26 ℃ of incubations 30 minutes.

7. to the 3.5nMEu/50nM APC solution (5) that adds 2 μ L/ holes in the each hole in said determination plate.

8. by assay plate under 2100rpm centrifugal 2 minutes.

By assay plate in 26 ℃ of incubations 60 minutes.

Immediately with time resolved fluorescence pattern under the excitation wavelength of 330nM and 615 and the emission wavelength of 665nM to assay plate reading.

Final testing conditions:

List in Table II below for the representative compound of measuring.

Table II.

Compound	TNKS1(uM)	TNKS2(uM)	PARP1(uM)
				I-1	0.489	0.575	>50
I-2	0.181	0.203	>50
				I-3	0.141	0.126	>50
I-4	>50	>50	>50
				I-5	0.155	0.157	45.620
I-6	0.112	0.102	24.170
				I-7	>50	>50	>50
I-8	4.361	>50	>50
				I-9	2.558	3.744	36.800
I-10	2.450	2.431	>50

I-11	14.020	11.220	>50
				I-12	0.941	3.706	>50
I-13	0.876	2.575	>50
				I-14	>50	>50	>50
I-15	>50	>50	>50
				I-16	1.270	3.093	>50
I-17	0.872	1.289	>50
				I-18	11.600	13.700	>50
I-19	0.281	0.439	>50
				I-20	0.204	0.328	>50
I-21	>50	>50	>50
				I-22	4.451	5.769	>50
I-23	0.421	0.574	>50
				I-24	21.800	43.880	>50
I-25	2.438	2.515	>50
				I-26	0.398	0.627	>50
I-27	1.875	2.557	>50
				I-28	0.984	2.029	>50
I-29	1.026	2.586	>50
				I-30	1.099	1.660	>50
I-31	1.707	3.733	>50
				I-32	4.408	5.143	>50

Understand in order to know and to be convenient to, explanation and embodiment have done more detailed description to foregoing invention by way of example.Can change and change within the scope of the appended claims will be apparent to those skilled in the art.Therefore, be to be understood that above explanation is intended to example rather than restriction the present invention.Therefore, scope of the present invention should not determine according to above explanation, and should replace appended claim, the gamut of the coordinator (equivalents) given together with these claims comes together to determine.

All patents of quoting in this application, patent application and open for all objects, which is hereby incorporated by reference, its degree is equivalent to each independent patent, patent application or is openly mentioned individually.

Claims

1. formula I compound or its pharmacy acceptable salt, formula I compound is:

Wherein:

R ¹for phenyl, phenyl-low alkyl group, cycloalkyl or cycloalkyl-low alkyl group, these groups are separately optionally by one or more R ^{1 '}replace;

Each R ^{2 '}be halogen, low alkyl group, lower alkoxy Huo – C (=O) OCH independently ₃.

2. the compound of claim 1, wherein R ¹for phenyl, it is optionally by one or more R ^{1 '}replace.

3. the compound of claim 2, wherein R ²for phenyl, it is optionally by one or more R ^{2 '}replace.

4. the compound of claim 3, wherein R ^{2 '}for halogen.

5. the compound of claim 4, wherein R ^{1 '}for methoxyl group.

6. the compound of claim 4, wherein R ^{1 '}for fluorine.

7. the compound of claim 4, wherein R ^{1 '}for trifluoromethyl, cyano group, methyl sulphonyl or trifluoromethoxy.

8. the compound of claim 3, wherein R ^{1 '}for methoxyl group.

9. the compound of claim 8, wherein R ^{2 '}for methoxyl group, methyl, Huo – C (=O) OCH ₃.

10. the compound of claim 1, wherein R ²for phenyl, it is optionally by one or more R ^{2 '}replace.

The compound of 11. claims 10, wherein R ¹for phenyl lower alkyl, cycloalkyl or cycloalkyl low-grade alkyl, these groups are separately optionally by one or more R ^{1 '}replace.

The compound of 12. claims 11, wherein R ^{2 '}for halogen.

The compound of 13. claims 1, wherein R ¹for phenyl and R ^{1 '}for methoxyl group.

The compound of 14. claims 13, wherein R ²for naphthyl, cyclohexyl or pyridazinyl.

The compound of 15. claims 1, is selected from:

2-(3-methoxyl group-benzenesulfinyl)-N-(4-methoxyl group-phenyl)-ethanamide;

2-(the fluoro-benzenesulfinyl of 3-)-N-(4-methoxyl group-phenyl)-ethanamide;

N-(4-methoxyl group-phenyl)-2-(Toluene-3,4-dithiol-sulfinyl)-ethanamide;

N-(4-methoxyl group-phenyl)-2-((R)-Toluene-3,4-dithiol-sulfinyl)-ethanamide;

N-(4-methoxyl group-phenyl)-2-((S)-Toluene-3,4-dithiol-sulfinyl)-ethanamide;

N-(4-methoxyl group-phenyl)-2-(naphthalene-2-sulfinyl)-ethanamide;

N-(4-methoxyl group-phenyl)-2-(naphthalene-1-sulfinyl)-ethanamide;

2-hexanaphthene sulfinyl-N-(4-methoxyl group-phenyl)-ethanamide;

N-(4-methoxyl group-phenyl)-2-(pyridazine-3-sulfinyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(4-methoxyl group-benzyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(the fluoro-phenyl of 4-)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(4-methylsulfonyl-phenyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(3-methoxyl group-phenyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(2-methoxyl group-phenyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-cyclohexyl methyl-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(the fluoro-phenyl of 3-)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(4-trifluoromethyl-phenyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(4-cyano group-phenyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(the fluoro-phenyl of 2-)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-(4-trifluoromethoxy-phenyl)-ethanamide;

2-(the chloro-benzenesulfinyl of 3-)-N-cyclohexyl-ethanamide; With

2-(the chloro-benzenesulfinyl of 3-)-N-cyclopentyl-methyl-ethanamide.

Treat the method for the illness of PARP-mediation for 16. 1 kinds, comprise to the compound that has any one in the claim 1-15 of patient's drug treatment significant quantity of these needs.

Treat the method for the illness of tankyrase-mediation for 17. 1 kinds, comprise to the compound that has any one in the claim 1-15 of patient's drug treatment significant quantity of these needs.

Treat the method for cancer for 18. 1 kinds, comprise to the compound that has any one in the claim 1-15 of patient's drug treatment significant quantity of these needs.

19. pharmaceutical compositions, the compound that it comprises claim 1-15 any one.

The pharmaceutical composition of 20. claims 19, it is mixed with at least one pharmaceutically acceptable carrier, vehicle or thinner.

The pharmaceutical composition of 21. claims 19, further comprises and is selected from other following therapeutical agent: the medicine of the medicine of chemotherapeutic or anti-proliferative agent, anti-inflammatory agent, immunomodulatory or immunosuppressor, neurotrophic factor, Cardiovarscular, the medicine for the treatment of diabetes and treatment immune deficiency obstacle.