CN107108600A

CN107108600A - It is used as the heteroarylalkylenyl aryl sultam derivative of RORc conditioning agents

Info

Publication number: CN107108600A
Application number: CN201580068854.6A
Authority: CN
Inventors: B·法贝尔; T·拉杜瓦赫蒂; O·勒内
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 2014-12-17
Filing date: 2015-12-16
Publication date: 2017-08-29
Also published as: JP2017537966A; WO2016096936A1; EP3233849A1

Abstract

Formula (I) compound or pharmaceutically acceptable salt thereof is retinoid receptor related orphan acceptor RORc (RORy) conditioning agent, wherein m, n, p, q, Het, A, W, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸, R and R¹⁰As defined herein.Also disclose and prepare the compound and the use for example arthritic method of the compounds for treating inflammatory disease.

Description

It is used as the heteroarylalkylenyl aryl sultam derivative of RORc conditioning agents

Invention field

The present invention relates to regulation retinoid receptor related orphan acceptor RORc (RORγ) function compound and these change Compound is used for the purposes for treating autoimmune disease.

Background of invention

T helper cell 17 (Th17) is to participate in autoimmune disease such as rheumatoid arthritis, IBS, silver bits The CD4+T cells of the secreting leukocytes mesonium (IL) -17 of the pathogenesis of disease, psoriatic arthritis and arthritis vertebralis.Wei Jia Acid acceptor related orphan receptor y (ROR γ or RORc) is considered as transcription factor necessary to Th17 cell differentiations.RORc is The orphan member of nuclear hormone receptor subfamily comprising ROR α (RORa) and ROR β (RORb).RORc is by being combined as monomer DNA controls genetic transcription.RORc selective control has been proposed as finding itself related to development Th17 cells The approach of immunological diseases.

Accordingly, it would be desirable to which suppressing RORc is used to treat autoimmune disease such as rheumatoid arthritis, IBS, silver The compound of bits disease, psoriatic arthritis and arthritis vertebralis.

Invention summary

The present invention provides compound of formula I：

Or its officinal salt,

Wherein：

M is 0 or 1；

N is 0 or 1；

P is 0-3；

Q is 0-3；

Het is：

Five or six membered heteroaryl, it is selected from：

Pyrrole radicals；

Pyrazolyl；

Imidazole radicals；

Oxazolyl；

Thiazolyl；

Isoxazolyl；

Isothiazolyl；

Triazolyl；

Oxadiazolyl；

Thiadiazolyl group；

Tetrazole radical；

Thienyl；

Furyl；

Pyridine radicals；

Pyrimidine radicals；

Pyridazinyl；Or

Pyrazinyl；Or

Quinary heterocyclic radical, is selected from：

Pyrrolidinyl；

Oxazole alkyl；

Dioxolane base；Or

Imidazolidinyl；

A is：

C_1-6Alkylidene；Or

C_1-6Alkenylene,

It can be each unsubstituted or by R^aSubstitution is once or twice；

W is：-CR^bR^c-；-O-；-S-；-SO₂-；Or-NR^d-；

X¹、X²、X³And X⁴One of be N, and other is CR^e；Or X¹、X²、X³And X⁴In two be N, and other is CR^e； Or X¹、X²、X³And X⁴In three be N, and other is CR^e；Or X¹、X²、X³And X⁴Individually CR^e；

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷And R⁸It is independently of one another：Hydrogen；Or C_1-6Alkyl, it can be unsubstituted or by halogen Element substitution is one or many；

Or R³And R⁴Formed together with the atom that they are connected optionally can be selected from-O- ,-NR comprising one or two^d- Or-S- heteroatomic three, four, five, the ring of six or seven yuan of saturations or fractional saturation, and it can be unsubstituted or by R^f Substitution is one or many；

Or R⁵And R⁶Formed together with the atom that they are connected optionally can be selected from-O- ,-NR comprising one or two^d- Or-S- heteroatomic three, four, five, the ring of six or seven yuan of saturations or fractional saturation, and it can be unsubstituted or by R^f Substitution is one or many；

Or R⁷And R⁸Formed together with the atom that they are connected optionally can be selected from-O- ,-NR comprising one or two^d- Or-S- heteroatomic three, four, five, the ring of six or seven yuan of saturations or fractional saturation, and it can be unsubstituted or by R^f Substitution is one or many；

Or R³And R⁴One of and R⁵And R⁶One of formed together with the atom that it is connected can optionally comprising one or Two are selected from-O- ,-NR^d- or-S- heteroatomic three, four, five, the ring of six or seven yuan of saturations or fractional saturation, and it can To be unsubstituted or by R^fSubstitution is one or many；

Or R⁵And R⁶One of and R⁷And R⁸One of formed together with the atom that it is connected can optionally comprising one or Two are selected from-O- ,-NR^d- or-S- heteroatomic three, four, five, the ring of six or seven yuan of saturations or fractional saturation, and it can To be unsubstituted or by R^fSubstitution is one or many；

R⁹It is independently of one another：

C_1-6Alkyl；

Halogen；

C_1-6Alkoxy；Or

Cyano group；

Wherein C_1-6Moieties can be unsubstituted or be optionally substituted by halogen one or many；

R¹⁰It is independently of one another：

C_1-6Alkyl；

Oxo；

Hydroxyl

Halogen；

Cyano group；

Halo-C_1-6Alkyl；

Hydroxyl-C_1-6Alkyl；

C_1-6Alkoxy -C_1-6Alkyl；Or

Cyano group-C_1-6Alkyl,

R^aIt is：

C_1-6Alkoxy；

C_1-6Alkoxy -C_1-6Alkyl；

Hydroxyl-C_1-6Alkyl；

C_3-6Cycloalkyl；

C_3-6Cycloalkyl-C_1-6Alkyl；

C_3-6Cycloalkyl oxy；

C_3-6Cycloalkyl-C_1-6Alkoxy；

Heterocyclic radical；

Heterocyclic radical-C_1-6Alkyl；Or

Heterocyclic radical-C_1-6Alkoxy；

Wherein described heterocyclyl moieties are each independently selected from expoxy propane base, tetrahydrofuran base, THP trtrahydropyranyl, azepine Cyclobutane base, pyrrolidinyl and piperidyl, and wherein described heterocyclyl moieties and C_3-6Cycloalkyl moiety can be each unsubstituted Or by R^fSubstitution is one or many；

R^b、R^cAnd R^dIt is independently of one another：

Hydrogen；

C_1-6Alkyl；Or

Halo-C_1-6Alkyl；

Or R^bAnd R^cFormed together with the atom that it is connected optionally can be selected from-O- ,-NR comprising one or two^a- or- S- heteroatomic three, four, five, the ring of six or seven yuan of saturations or fractional saturation, and it can be unsubstituted or by R^fTake For one or many；

Or R^bAnd R^cOne of and R⁷And R⁸One of formed together with the atom that it is connected can optionally comprising one or Two are selected from-O- ,-NR^a- or-S- heteroatomic three, four, five, the ring of six or seven yuan of saturations or fractional saturation, and it can To be unsubstituted or by R^fSubstitution is one or many；

Or R^bAnd R^cOne of and R⁵And R⁶One of formed together with the atom that it is connected can optionally comprising one or Two are selected from-O- ,-NR^a- or-S- heteroatomic three, four, five, the ring of six or seven yuan of saturations or fractional saturation, and it can To be unsubstituted or by R^fSubstitution is one or many；

R^eIt is independently of one another：

Hydrogen；

C_1-6Alkyl；

Halogen；

C_1-6Alkoxy；Or

Cyano group；

Wherein C_1-6Moieties can be unsubstituted or be optionally substituted by halogen one or many；And

R^fIt is：C_1-6Alkyl；Halo-C_1-6Alkyl；Halogen；Oxo；Hydroxyl；Or C_1-6Alkoxy.

Present invention also offers the pharmaceutical composition comprising the compound, the method using the compound and preparation institute The method for stating compound.

Detailed description of the invention

Definition

Unless otherwise indicated, it is following fixed that the following term used in the application (including specification and claims) has Justice.It must be noted that as used in specification and appended book, singulative " one kind ", " one " and "the" includes plural referents, clearly specifies unless the context otherwise.In some cases, dash ("-") can be in definition Middle used interchangeably (such as " alkoxyalkyl " eliminates the dash found in equivalent terms " alkoxy-alkyl ").

" alkyl " refers to the monovalent straight chain or branched-chain saturated hydrocarbon that are only made up of carbon and hydrogen atom with 1 to 12 carbon atom Part." low alkyl group " refers to the alkyl group of 1 to 6 carbon atom, i.e. C₁-C₆Alkyl.The example of alkyl includes but is not limited to first Base, ethyl, propyl group, isopropyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, n-hexyl, octyl group, dodecyl etc..

" alkenyl " refers to the linear monovalent hydrocarbon radical or 3-6 carbon atom of the 2-6 carbon atom containing at least one double bond Branched monovalent hydrocarbon group, such as vinyl, acrylic.

" alkynyl " refers to the linear monovalent hydrocarbon radical or 3-6 carbon atom of the 2-6 carbon atom containing at least one three key Branched monovalent hydrocarbon group, such as acetenyl, propinyl.

" alkylidene " refers to the straight chain saturation bivalent hydrocarbon radical of 1 to 6 carbon atom or the side chain saturation two of 3 to 6 carbon atoms Valency alkyl, such as methylene, ethylidene, 2,2- dimethylethylenes, propylidene, 2- methyl propylenes, butylidene, pentylidene Deng.

" alkoxy " and " alkyl oxy ", it with used interchangeably, can refer to formula-OR part, and wherein R is as determined herein The moieties of justice.The example of alkoxy portion includes but is not limited to methoxyl group, ethyoxyl, isopropoxy etc..

" alkoxyalkyl " refers to formula R^a–O–R^b- part, wherein R^aIt is alkyl and R^bIt is alkylidene as herein defined. Exemplary alkoxy-alkyl group includes, for example 2- methoxy ethyls, 3- methoxy-propyls, 1- methyl -2- methoxy ethyls, 1- (2- methoxy ethyls) -3- methoxy-propyls and 1- (2- methoxy ethyls) -3- methoxy-propyls.

" alkyloxy-alkoxy " refers to formula-O-R-R ' groups, and wherein R is alkylidene, and R ' is alkoxy, as determined herein Justice.

" alkyl-carbonyl " refers to formula-C (O)-R-portion, and wherein R is alkyl as herein defined.

" alkoxy carbonyl " refers to formula-C (O)-R group, and wherein R is alkoxy, as defined herein.

" alkyl-carbonyl-amino " refers to formula-R-C (O)-NR '-group, and wherein R is alkyl, and R ' is hydrogen or alkyl.

" Alkylcarbonylalkyl " refers to formula-R-C (O)-R ' group, and wherein R is alkylidene, and R ' is as herein defined Alkyl.

" alkoxyalkylcarbonyl radicals " refer to formula-C (O)-R-R ' parts, and wherein R is alkylidene, and R ' is alkoxy, such as originally Text is defined.

" alkoxy carbonyl alkyl " refers to formula-R-C (O)-R ' group, and wherein R is alkylidene, and R ' is alkoxy, such as originally Text is defined.

" alkoxycarbonyl amino " refers to formula R-C (O)-NR '-part, and wherein R is alkoxy, and R ' is hydrogen or alkyl, such as It is defined herein.

" alkoxycarbonylamino " refers to formula R-C (O)-NR '-R "-part, wherein R is alkoxy, and R ' is hydrogen or alkane Base, and R " is alkylidene as herein defined.

" Alkoxycarbonylalkoxy " refers to formula-O-R-C (O)-R ' group, and wherein R is alkylidene, and R ' is alcoxyl Base, as defined herein.

" hydroxycarbonyl group alkoxy " refers to formula-O-R-C (O)-OH groups, and wherein R is alkylidene as herein defined.

" alkyl amino-carbonyl alkoxy " refers to formula-O-R-C (O)-NHR ' groups, and wherein R is alkylidene, and R ' is such as this Alkyl defined in literary.

" dialkyl amino carbonyl alkoxy " refers to formula-O-R-C (O)-NR ' R " groups, and wherein R is alkylidene, and R ' and R " is alkyl as herein defined.

" alkylaminoalkoxy " refers to formula-O-R-NHR ' groups, and wherein R is alkylidene, and R ' is as defined herein Alkyl.

" dialkylaminoalkoxy groups " refer to formula-O-R-NR ' R ' groups, and wherein R is alkylidene, and R ' and R " is as herein Defined alkyl.

" alkyl sulphonyl " refers to formula-SO₂- R-portion, wherein R are alkyl as herein defined.

" Alkylsulfonylalkyl " refers to formula-R'-SO₂- R " parts, wherein R ' are alkylidenes, and R " is as determined herein The alkyl of justice.

" alkyl sulphonyl alkoxy " refers to formula-O-R-SO₂- R ' group, wherein R are alkylidenes, and R ' is such as this paper institutes The alkyl of definition.

" amino " refers to-NRR' parts, and wherein R and R ' are hydrogen or alkyl independently of one another, as defined herein.Therefore, " amino " (wherein R and R ' are comprising alkyl amino (wherein one of R and R ' are alkyl, and other is hydrogen) and dialkyl amido Alkyl).

" amino carbonyl " refers to formula-C (O)-R group, and wherein R is amino, as defined herein.

" N- hydroxy-aminos carbonyl " refers to formula-C (O)-NR-OH groups, and wherein R is hydrogen or alkyl, as defined herein.

" N- alkoxies-amino carbonyl " refers to formula-C (O)-NR-R ' groups, and wherein R is hydrogen or alkyl, and R ' is alcoxyl Base, as defined herein.

" amino carbonyl amino alkyl " refers to formula R₂N-C (O)-NR '-R "-groups, wherein R is hydrogen or alkane independently of one another Base, R ' is hydrogen or alkyl, and R " is alkylidene as herein defined.

" N- alkyl-aminocarbonyls " refers to formula-C (O)-NH-R groups, and wherein R is alkyl as herein defined.

" N- hydroxy-ns-alkyl amino-carbonyl " refers to formula-C (O)-NRR ' groups, and wherein R is alkane as herein defined Base, and R ' is hydroxyl.

" N- alkoxy-N- alkyl amino-carbonyls " refers to formula-C (O)-NRR ' groups, and wherein R is alkyl, and R ' is alcoxyl Base, as defined herein.

"-the C of N, N- bis-_1-6Alkyl-aminocarbonyl " refers to formula-C (O)-NRR ' groups, and wherein R and R ' are as defined herein Alkyl.

" amino-sulfonyl " refers to formula-SO₂-NH₂Group.

" N- alkyl amino sulfonyls " refers to formula-SO₂- NHR groups, wherein R are alkyl as herein defined.

" N, N- dialkyl amino sulfonyl " refers to formula-SO₂- NRR ' groups, wherein R and R ' are alkane as herein defined Base.

" alkyl sulfonyl-amino " refers to formula-NR '-SO₂- R group, wherein R are alkyl and R ' is hydrogen or alkyl, such as herein Defined.

" N- (alkyl sulphonyl)-aminoalkyl " refers to formula-R-NH-SO₂- R ' group, wherein R are alkylidenes, and R ' is Alkyl as herein defined.

" N- (alkyl sulphonyl) amino carbonyl " refers to formula-C (O)-NH-SO₂- R group, wherein R are as defined herein Alkyl.

" N- (alkyl sulphonyl)-N- alkyl amino-carbonyls " refers to formula-C (O)-NR-SO₂- R ' group, wherein R and R ' are Alkyl as herein defined.

" N- alkoxyalkyls-amino carbonyl " refers to formula-C (O)-NR-R '-OR " group, wherein R is hydrogen or alkyl, and R ' is Alkylidene, and R " is alkyl as herein defined.

" N- hydroxyalkyl-aminos carbonyl " refers to formula-C (O)-NR-R '-OH groups, and wherein R is hydrogen or alkyl, and R ' is Alkylidene as herein defined.

" alkoxy amino " refers to formula-NR-OR' parts, and wherein R is hydrogen or alkyl, and R' is alkane as herein defined Base.

" alkyl sulfenyl " refers to formula-SR parts, and wherein R is alkyl as herein defined.

" aminoalkyl " refers to-R-R' groups, and wherein R' is amino, and R is alkylidene as herein defined.

" aminoalkyl " includes amino methyl, amino-ethyl, 1- aminopropyls, 2- aminopropyls etc.." aminoalkyl " Amino part can be replaced once or twice by alkyl, respectively obtain " alkylaminoalkyl group " and " dialkyl aminoalkyl "." alkane Base aminoalkyl " includes Methylaminomethyl, methylaminoethyl, dimethylaminopropyl, ethylaminoethyl etc.." dialkyl group Aminoalkyl " includes dimethylaminomethyl, dimethyl aminoethyl, dimethylaminopropyl, N- methyl-N-ethylamino second Base etc..

" aminoalkoxy " refers to-OR-R' groups, and wherein R' is amino, and R is alkylidene as herein defined.

" alkyl sulfonyl amino " refers to formula-NR'SO₂- R-portion, wherein R are alkyl, and R' is hydrogen or alkyl.

" amino carbonyl epoxide alkyl " or " carbamoyloxy group alkyl " refer to formula-R-O-C (O)-NR'R " groups, and wherein R is sub- Alkyl, and R', R " is hydrogen or alkyl independently of one another, as defined herein.

" alkynyl alkoxy " refers to formula-O-R-R' groups, and wherein R is alkylidene, and R' is alkynyl, as defined herein.

" aryl " refers to the monovalent cyclic aromatic moiety being made up of monocyclic, bicyclic or tricyclic aromatic ring.Aromatic yl group can appoint Choosing is replaced by substituent as herein defined.The example of aryl moiety includes but is not limited to phenyl, naphthyl, phenanthryl, fluorenyl, indenes Base, pentalene base, azulenyl, oxydiphenyl base, xenyl, methylenediphenyl, aminodiphenyl base, diphenylsulfidyl, two Phenyl sulfonyl, diphenyl isopropylidene, benzodioxan base, benzofuranyl, benzodioxole base, chromene Base, benzoxazinyl, benzoxazine ketone group, benzo piperidyl, benzo piperazinyl, benzopyrrolodinyl, benzo morpholinyl, methylene Methylenedioxyphenyl, ethylenedioxy phenyl etc., it optionally can be replaced by substituent as herein defined.

" aryl alkyl " and " aralkyl ", it can refer to group-R with used interchangeably^aR^b, wherein R^aIt is alkylidene group, And R^bIt is aromatic yl group as herein defined；For example, phenylalkyl such as benzyl, phenethyl, 3- (3- chlorphenyls) -2- methylpents Base etc. is the example of aryl alkyl.

" aryl sulfonyl " refers to formula-SO₂- R group, wherein R are aryl as herein defined.

" aryloxy group " refers to formula-O-R groups, and wherein R is aryl as herein defined.

" aralkoxy " refers to formula-O-R-R " groups, and wherein R is alkylidene, and R' is aryl as herein defined.

" carboxyl " or " hydroxycarbonyl group ", it can refer to formula-C (O)-OH groups with used interchangeably.

" cyanoalkyl " refers to formula-R '-R " group, wherein R ' is alkylidene as herein defined, and R " be cyano group or Nitrile.

" cycloalkyl " refer to by it is single-or two ring groups into monovalent saturated carbon ring part.Specific cycloalkyl is unsubstituted Or replaced by alkyl.Cycloalkyl can be optionally substituted, as defined herein.Unless otherwise defined, cycloalkyl can be optionally Be substituted by one or more substituents, wherein substituent be independently of one another hydroxyl, alkyl, alkoxy, halogen, haloalkyl, Amino, alkyl monosubstituted amino or dialkyl amido.The example of cycloalkyl moiety include but is not limited to cyclopropyl, cyclobutyl, cyclopenta, Cyclohexyl, suberyl etc., including unsaturated (cycloalkenyl group) derivative in its part.

" cycloalkenyl group " refers to the cycloalkyl as herein defined comprising at least one double bond or unsaturated bond.Exemplary Cycloalkenyl group includes cyclohexenyl group, cyclopentenyl, cyclobutane base etc..

" cycloalkyl-alkyl " refers to formula-R '-R " part, wherein R ' is alkylidene, and R " is cycloalkanes as herein defined Base.

" cycloalkyl alkoxy " is formula-O-R-R ' groups, and wherein R is alkylidene, and R ' is cycloalkanes as herein defined Base.

" naphthene base carbonyl " refers to formula-C (O)-R-portion, and wherein R is cycloalkyl as herein defined.

“C_3-6Cycloalkyl-C_1-6Alkyl-carbonyl " refers to formula-C (O)-R-portion, and wherein R is cycloalkyl as herein defined Alkyl.

" cyanoalkyl carbonyl " refers to formula-C (O)-R-R ' parts, and wherein R is alkylidene as herein defined, and R ' is Cyano group or nitrile.

" N- cyano group-amino carbonyl " refers to formula-C (O)-NHR parts, and wherein R is cyano group or nitrile.

" N- cyano group-N- alkyl-aminocarbonyls " refers to formula-C (O)-NRR '-R-portion, and wherein R ' is as herein defined Alkyl, and R is cyano group or nitrile.

" naphthene sulfamide base " refers to formula-SO₂- R group, wherein R are cycloalkyl as herein defined.

" cycloalkyl-alkyl sulfonyl " refers to formula-SO₂- R group, wherein R are cycloalkyl-alkyls as herein defined.

" formoxyl " refers to formula-C (O)-H parts.

" heteroaryl " refers to the monocyclic or bicyclic radicals of 5 to 12 annular atoms with least one aromatic ring, the aromatic ring N, O or S ring hetero atom are selected from containing one, two or three, remaining annular atom is C, while it should be appreciated that heteroaryl Tie point is on aromatic ring.The heteroaryl ring can be optionally substituted, as defined herein.The example of heteroaryl moieties include but It is not limited to optionally substituted imidazole radicals, oxazolyl, isoxazolyls, thiazolyl, isothiazolyl, oxadiazolyls, thiadiazolyl group, pyrrole Piperazine base, thienyl, benzothienyl, thienyl, furyl, pyranose, pyridine radicals, pyrrole radicals, pyrazolyl, pyrimidine radicals, quinoline Base, isoquinolyl, benzofuranyl, benzothienyl, benzothiopyran derivative base, benzimidazolyl, benzoxazolyl, Ben Bing oxadiazoles Base, benzothiazolyl, diazosulfide base, benzopyranyl, indyl, isoindolyl, triazolyl, triazine radical, quinoxalinyl, Purine radicals, quinazolyl, quinolizine base, naphthyridines base, pteridyl, carbazyl, azepineBase, diazaBase, acridinyl etc., its It is each optionally substituted, as defined herein.

" heteroaryl alkyl " or " heteroarylalkyl " refers to formula-R-R' groups, and wherein R is alkylidene, and R' is such as this paper institutes The heteroaryl of definition.

" heteroarylsulfonyl " refers to formula-SO₂- R group, wherein R are heteroaryls as herein defined.

" heteroaryloxy " refers to formula-O-R groups, and wherein R is heteroaryl as herein defined.

" heteroarylalkyl epoxide " refers to formula-O-R-R ' groups, and wherein R is alkylidene, and R' is miscellaneous as herein defined Aryl.

Term " halo ", " halogen " and " halide ", it can refer to substituent fluorine, chlorine, bromine or iodine with used interchangeably.

" haloalkyl " refers to alkyl as herein defined, and wherein one or more hydrogen are by identical or different halogen generation Replace.Exemplary haloalkyls include-CH₂Cl、–CH₂CF₃、–CH₂CCl₃, perfluoroalkyl (such as-CF₃) etc..

" halogenated alkoxy " refers to formula-OR parts, and wherein R is haloalkyl moiety as herein defined.Exemplary halogen It is difluoro-methoxy for alkoxy.

" heterocyclic amino group " refers to saturated rings, and wherein at least one annular atom is N, NH or N- alkyl, and remaining annular atom shape Into alkylidene group.

" heterocyclic radical " refer to by one to three ring group into monovalent saturation part, contain one, two or three or four Hetero atom (is selected from nitrogen, oxygen or sulphur).Heterocyclic radical can be optionally substituted, as defined herein.The example of heterocyclyl moieties includes But it is not limited to optionally substituted piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, azepineBase, pyrrolidinyl, azacyclo- Butane group, THP trtrahydropyranyl, tetrahydrofuran base, expoxy propane base etc..The heterocyclic radical can be optionally substituted, as determined herein Justice.

" cycloheteroalkylalkyl " refers to formula-R-R' parts, and wherein R is alkylidene, and R' is heterocyclic radical as herein defined.

" heterocyclic radical epoxide " refers to formula-OR parts, and wherein R is heterocyclic radical as herein defined.

" heterocyclylalkoxy " refers to formula-OR-R' parts, and wherein R is alkylidene, and R' is heterocycle as herein defined Base.

" hydroxy alkoxy base " refers to formula-OR parts, and wherein R is hydroxy alkyl as herein defined.

" hydroxyalkylamino " refers to formula-NR-R' parts, and wherein R is hydrogen or alkyl, and R' is hydroxyl as herein defined Base alkyl.

" hydroxyalkylaminoalkyl " refers to formula-R-NR'-R " parts, and wherein R is alkylidene, and R' is hydrogen or alkyl, and R " It is hydroxy alkyl as herein defined.

" hydroxycarbonylalkyl " or " carboxyalkyl " refers to formula-R- (CO)-OH groups, and wherein R is as herein defined Alkylidene.

" hydroxyalkylcarbonyl " refers to formula-C (O)-R-R ' groups, and wherein R is alkylidene as herein defined, and R ' is Hydroxyl.

" hydroxy alkyl Epoxide carbonyl alkyl " or " hydroxy alkoxy base carbonylic alkyl " refers to formula-R-C (O)-O-R-OH groups, Wherein R is individually alkylidene, and can be identical or different.

" hydroxy alkyl " refers to moieties as herein defined, and it is by one or more such as one, two or three Individual oh group substitution, condition is that same carbon atom does not carry more than one hydroxyl.Representative example includes but is not limited to hydroxyl Ylmethyl, 2- hydroxyethyls, 2- hydroxypropyls, 3- hydroxypropyls, 1- (hydroxymethyl) -2- methyl-propyls, 2- hydroxybutyls, 3- Hydroxybutyl, 4- hydroxybutyls, 2,3- dihydroxypropyls, 2- hydroxyl -1- hydroxymethylethyls, 2,3- dihydroxy butyl, 3,4- Dihydroxy butyl and 2- (hydroxymethyl) -3- hydroxypropyls.

" hydroxycycloalkyl " refers to cycloalkyl moiety as herein defined, wherein in group of naphthene base one, two or Three hydrogen atoms are optionally substituted by a hydroxyl group base replacement.Representative example includes but is not limited to 2-, 3- or 4- hydroxy-cyclohexyl etc..

" oxo " refers to formula=O groups (i.e. the oxygen with double bond).Thus, for example, 1- oxo-ethyl groups are acetyl group Group.

" alkoxy hydroxy alkyl " and " hydroxy alkoxy alkyl ", it can be referred to as herein defined with used interchangeably Alkyl, it is at least optionally substituted by a hydroxyl group once and is at least replaced once by alkoxy.

Therefore, " alkoxy hydroxy alkyl " and " hydroxy alkoxy alkyl " include, such as 2- hydroxy-3-methoxies -propyl- 1- Base etc..

" urea " or " urea groups " refers to formula-NR'-C (O)-NR " R " ' groups, wherein R', R " and R " ' be independently of one another hydrogen or Alkyl.

" carbamate " refers to formula-O-C (O)-NR'R " group, wherein R' and R " is hydrogen or alkyl independently of one another.

" carboxyl " refers to formula-O-C (O)-OH groups.

" sulfoamido " refers to formula-SO₂- NR'R " groups, wherein R', R " and R " ' it is hydrogen or alkyl independently of one another.

When " optionally substituted " uses with " aryl ", " phenyl ", " heteroaryl ", " cycloalkyl " or " heterocyclic radical " part combination When, it can be unsubstituted (that is, the chemical valence of all openings is occupied by hydrogen atom) or related by this paper to refer to the part Special groups replace.

" leaving group " refers to the group in synthetic organic chemistry with usual implication associated therewith, i.e., in substitution reaction Under the conditions of replaceable atom or group.The example of leaving group includes but is not limited to halogen, alkyl or aryl sulfonyl epoxide, Such as mesyl epoxide, ethylsulfonyl epoxide, sulfidomethyl, benzenesulfonyl epoxide, tosyl and thienyl epoxide, dihalo- For phosphino- epoxide, optionally substituted benzyl epoxide, isopropyl epoxide, acyloxy etc..

" conditioning agent " refers to the molecule interacted with target spot.Interaction includes but is not limited to activator, antagonist etc., As defined herein.

" optional " or " optionally " refers to that the event then described or situation need not may occur, and the term includes thing Part or situation situation about occurring and situation about not occurring.

" disease " and " morbid state " refers to any disease, illness, symptom, obstacle or indication.

" inert organic solvents " or " atent solvent " refer to that under the reaction condition related to its described the solvent is inertia , including such as benzene, toluene, acetonitrile, tetrahydrofuran, DMF, chloroform, dichloromethane, dichloroethanes, second Ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propyl alcohol, isopropanol, tert-butyl alcohol, dioxanes, pyridine etc..Unless another It is described, the solvent otherwise used in present invention reaction is atent solvent.

" pharmaceutically acceptable " refers to can be used for preparing pharmaceutical composition, and described pharmaceutical composition is typically safe and nontoxic and neither It is biologically, nor other side is undesirable, and including that can be connect for animal doctor and human pharmaceutical use The pharmaceutical composition received.

" officinal salt " of compound refers to pharmaceutically acceptable salt as herein defined, and it has parent Pharmacological activity needed for compound.

It should be appreciated that all refer to that officinal salt part includes the solvent addition form (solvate) of same acid-addition salts Or crystal form (polymorph) defined herein.

" blocking group " refers to optionally block the group of a reactive site in polyfunctional compound, and it makes Must chemically react can select in another the unprotected reaction site synthesized to it in chemistry under conventional related implication Carry out to property.Some methods of the present invention are dependent on active nitrogen and/or oxygen atom present in blocking group blocking reaction thing.Example Such as, term " amido protecting group " and " nitrogen-protecting group group " are used interchangeably herein, and refer to be intended to protect nitrogen-atoms not Participate in not expecting those organic groups of reaction in building-up process.Exemplary nitrogen-protecting group group includes but is not limited to trifluoroacetyl Base, acetylamino, benzyl (Bn), Benzyloxycarbonyl (carbonyl benzyl epoxide, CBZ), to methbxybenzyl-oxycarbonyl, to nitrobenzyl oxygen Carbonyl, tertbutyloxycarbonyl (BOC) etc..It will be apparent to one skilled in the art that how to select a group, its have be easily removed and It is resistant to the ability of subsequent reactions.

" solvate " refers to the solvent addition form of the solvent comprising stoichiometry or non-stoichiometry amount.Some chemical combination Thing tends to capture the solvent molecule of fixed molar ratio under crystalline solid state, so as to form solvate.If solvent is Water, the solvate of formation is hydrate, when solvent is alcohol, and the solvate of formation is alcoholates.Hydrate passes through one Or multiple hydrones are combined to form with a molecule in material, its reclaimed water keeps its molecular state H₂O, this combination being capable of shape Into one or more hydrates.

" arthritis " refers to cause the disease or illness of body joints damage and the pain related to the joint injury.Joint Inflammation includes rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, joint of vertebral column inflammation, gouty joint Scorching, systemic loupus erythematosus and juvenile arthritis, osteoarthritis and other arhritis conditions.

" respiratory disorder " refers to but is not limited to chronic obstructive pulmonary disease (COPD), asthma, bronchial spasm etc..

" individual " refers to mammal and nonmammalian.Mammal refers to mammiferous any member, including but not It is limited to people；Non-human primate such as chimpanzee and other apes and monkey class；Such as domestic animal of ox, horse, sheep, goat and pig； Such as performing animal of rabbit, dog and cat；Experimental animal, including rodent such as rat, mouse and cavy；Etc..Non- lactation The example of animal includes but is not limited to birds etc..Term " individual " does not indicate that given age or sex.

" therapeutically effective amount " refers to when being applied to individual to treat morbid state, it is sufficient to realize treat morbid state effect The amount of the compound of fruit." therapeutically effective amount " by according to compound, the morbid state treated, the severity for treating disease, The factors such as the judgement of individual age and relative healths, route of administration and form, attending doctor or animal doctor and change.

When referring to variable, term " definition as described above " and " those definition herein " are incorporated by reference into the variable Generalized definition and specific definitions (if any).

" treatment " of morbid state, particularly including suppressing morbid state, that is, prevents morbid state or its clinical symptoms Development and/or alleviation morbid state, i.e. cause morbid state or the temporarily or permanently regression of its clinical symptoms.

When referring to a chemical reaction, term " processing ", " contact " and " reaction " refers to add or mix under proper condition Product that two or more reagents are specified with producing and/or required.It should be appreciated that producing indicated and/or required product Reaction may not necessarily directly from two kinds of reagents being initially added combination, i.e. there may be in the mixture it is a kind of or A variety of intermediates produced in the mixture that may eventually lead to the formation of indicated and/or required product.

Name and structure

In general, name and chemical name use herein is to be based on CambridgeSoft^TM's ChembioOffice^TM.Unless otherwise indicated, the change of any opening on carbon, oxygen, sulphur or nitrogen-atoms is appeared in this paper structures Conjunction valency represents there is hydrogen atom.When nitrogenous heteroaryl ring is shown on nitrogen-atoms with open valence state, on heteroaryl ring Show such as R^a、R^bOr R^cVariable, these variables can combine or be connected to the nitrogen of open valence state.When there is hand in structure Property center but when the chiral centre does not show specific spatial chemistry, the two kind enantiomters related to the chiral centre It is included in the structure.If structure shown in this article can exist with a variety of tautomeric forms, all these changes Isomers is included in structure.The atom represented in this paper structures is intended to the naturally occurring same position of all these atoms Element.Thus, for example, the hydrogen atom represented herein is intended to include deuterium and tritium, and carbon atom is intended to include C¹³And C¹⁴Same position Element.One or more carbon atoms of the compounds of this invention can be replaced by silicon atom, and one of expected the compounds of this invention Or multiple oxygen atoms can be replaced by sulphur or selenium atom.

The compounds of this invention

The invention provides compound of formula I or its officinal salt：

Wherein：

M is 0 or 1；

N is 0 or 1；

P is 0-3；

Q is 0-3；

Het is：

Five or six membered heteroaryl, it is selected from：

Pyrrole radicals；

Pyrazolyl；

Imidazole radicals；

Oxazolyl；

Thiazolyl；

Isoxazolyl；

Isothiazolyl；

Triazolyl；

Oxadiazolyl；

Thiadiazolyl group；

Tetrazole radical；

Thienyl；

Furyl；

Pyridine radicals；

Pyrimidine radicals；

Pyridazinyl；Or

Pyrazinyl；Or

Quinary heterocyclic radical, is selected from：

Pyrrolidinyl；

Oxazole alkyl；

Dioxolane base；Or

Imidazolidinyl；

A is：

C_1-6Alkylidene；Or

C_1-6Alkenylene,

It can be each unsubstituted or by R^aSubstitution is once or twice；

W is：-CR^bR^c-；-O-；-S-；-SO₂-；Or-NR^d-；

X¹、X²、X³And X⁴One of be N, and other is CR^e；Or X¹、X²、X³And X⁴In two be N, and other is CR^e； Or X¹、X²、X³And X⁴In three be N, and other are CR^e；Or X¹、X²、X³And X⁴Individually CR^e；

Or R³And R⁴Can form three together with the atom that it is connected, four, five, six or seven yuan of saturations or fractional saturation Ring, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^d- or-S-, also, it can be not Substitution or by R^fSubstitution is one or many；

Or R⁵And R⁶Can form three together with the atom that it is connected, four, five, six or seven yuan of saturations or fractional saturation Ring, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^d- or-S-, also, it can be not Substitution or by R^fSubstitution is one or many；

Or R⁷And R⁸Can form three together with the atom that it is connected, four, five, six or seven yuan of saturations or fractional saturation Ring, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^d- or-S-, also, it can be not Substitution or by R^fSubstitution is one or many；

Or R³And R⁴One of and R⁵And R⁶One of can be formed together with the atom that it is connected three, four, five, six or The ring of seven yuan of saturations or fractional saturation, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^d- Or-S-, also, it can be unsubstituted or by R^fSubstitution is one or many；

Or R⁵And R⁶One of and R⁷And R⁸One of can be formed together with the atom that it is connected three, four, five, six or The ring of seven yuan of saturations or fractional saturation, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^d- Or-S-, also, it can be unsubstituted or by R^fSubstitution is one or many；

R⁹It is independently of one another

C_1-6Alkyl；

Halogen；

C_1-6Alkoxy；Or

Cyano group；

R¹⁰It is independently of one another：

C_1-6Alkyl；

Oxo；

Hydroxyl

Halogen；

Cyano group；

Halo-C_1-6Alkyl；

Hydroxyl-C_1-6Alkyl；

C_1-6Alkoxy -C_1-6Alkyl；Or

Cyano group-C_1-6Alkyl；

R^aIt is：

C_1-6Alkoxy；

C_1-6Alkoxy -C_1-6Alkyl；

Hydroxyl-C_1-6Alkyl；

C_3-6Cycloalkyl；

C_3-6Cycloalkyl-C_1-6Alkyl；

C_3-6Cycloalkyl oxy；

C_3-6Cycloalkyl-C_1-6Alkoxy；

Heterocyclic radical；

Heterocyclic radical-C_1-6Alkyl；Or

Heterocyclic radical-C_1-6Alkoxy；

R^b、R^cAnd R^dIt is independently of one another：

Hydrogen；

C_1-6Alkyl；Or

Halo-C_1-6Alkyl；

Or R^bAnd R^cCan form three together with the atom that it is connected, four, five, six or seven yuan of saturations or fractional saturation Ring, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^a- or-S-, also, it can be not Substitution or by R^fSubstitution is one or many；

Or R^bAnd R^cOne of and R⁷And R⁸One of can be formed together with the atom that it is connected three, four, five, six or The ring of seven yuan of saturations or fractional saturation, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^a- Or-S-, also, it can be unsubstituted or by R^fSubstitution is one or many；

Or R^bAnd R^cOne of and R⁵And R⁶One of can be formed together with the atom that it is connected three, four, five, six or The ring of seven yuan of saturations or fractional saturation, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^a- Or-S-, also, it can be unsubstituted or by R^fSubstitution is one or many；

R^eIt is independently of one another：

Hydrogen；

C_1-6Alkyl；

Halogen；

C_1-6Alkoxy；Or

Cyano group；

In some embodiments of Formulas I, m is 0.

In some embodiments of Formulas I, m is 1.

In some embodiments of Formulas I, n is 0.

In some embodiments of Formulas I, n is 1.

In some embodiments of Formulas I, p is 0-2.

In some embodiments of Formulas I, p is 0 or 1.

In some embodiments of Formulas I, p is 0.

In some embodiments of Formulas I, p is 1.

In some embodiments of Formulas I, p is 2.

In some embodiments of Formulas I, p is 3.

In some embodiments of Formulas I, q is 0.

In some embodiments of Formulas I, q is 1.

In some embodiments of Formulas I, q is 2.

In some embodiments of Formulas I, q is 0 or 1.

In some embodiments of Formulas I, q is 0,1 or 2.

In some embodiments of Formulas I, Het is five or six membered heteroaryl, is selected from：

Pyrrole radicals；

Pyrazolyl；

Imidazole radicals；

Oxazolyl；

Thiazolyl；

Isoxazolyl；

Isothiazolyl；

Triazolyl；

Oxadiazolyl；

Thiadiazolyl group；

Tetrazole radical；

Thienyl；

Furyl；

Pyridine radicals；

Pyrimidine radicals；

Pyridazinyl；Or

Pyrazinyl

In some embodiments of Formulas I, Het is：Oxadiazolyl；Or thiadiazolyl group；

In some embodiments of Formulas I, Het is imidazole radicals.

In some embodiments of Formulas I, Het is pyrazolyl.

In some embodiments of Formulas I, Het Shi isoxazolyls.

In some embodiments of Formulas I, Het Shi oxazolyls.

In some embodiments of Formulas I, Het is thiazolyl.

In some embodiments of Formulas I, Het Shi oxadiazolyls.

In some embodiments of Formulas I, Het is triazolyl.

In some embodiments of Formulas I, Het is tetrazole radical.

In some embodiments of Formulas I, Het is thienyl.

In some embodiments of Formulas I, Het is furyl.

In some embodiments of Formulas I, Het is pyridine radicals.

In some embodiments of Formulas I, Het is pyrimidine radicals.

In some embodiments of Formulas I, Het is pyridazinyl.

In some embodiments of Formulas I, Het is pyrazinyl.

In some embodiments of Formulas I, Het is 3H-1,3,4- oxadiazole -2- ketone -5- bases.

In some embodiments of Formulas I, Het is 2- hydroxymethyls -1,3,4- oxadiazole -5- bases.In some realities of Formulas I Apply in scheme, Het is quinary heterocyclic radical, is selected from：

Pyrrolidinyl；

Oxazole alkyl；

Dioxolane base；

Imidazolidinyl.

In some embodiments of Formulas I, Het is pyrrolidinyl.

In some embodiments of Formulas I, Het is oxazole alkyl.

In some embodiments of Formulas I, Het is dioxolane base.

In some embodiments of Formulas I, Het is imidazolidinyl.

In some embodiments of Formulas I, A is：C_1-6Alkylidene, it can be unsubstituted or by R^aSubstitution once or Twice.

In some embodiments of Formulas I, A is：C_1-6Alkenylene, it can be unsubstituted or by R^aSubstitution once or Twice.

In some embodiments of Formulas I, A is：Methylene；Or ethylidene；It is individually unsubstituted or by R^aSubstitution.

In some embodiments of Formulas I, A is：-CH₂-；-C(CH₃)₂-；-CHCH₃-；Or-CHR^a-。

In some embodiments of Formulas I, A is methylene, and it can be unsubstituted or by R^aSubstitution.

In some embodiments of Formulas I, A is ethylidene, and it can be unsubstituted or by R^aSubstitution.

In some embodiments of Formulas I, A is methylene.

In some embodiments of Formulas I, A is ethylidene.

In some embodiments of Formulas I, A is-CH₂--。

In some embodiments of Formulas I, A is-CHCH₃-。

In some embodiments of Formulas I, A is-C (CH₃)₂-。

In some embodiments of Formulas I, A is-CHR^a-。

In some embodiments of Formulas I, W is-CR^bR^c- or-O-.

In some embodiments of Formulas I, W is-CR^bR^c-。

In some embodiments of Formulas I, W is-O-.

In some embodiments of Formulas I, W is-NR^d-。

In some embodiments of Formulas I, W is-S-.

In some embodiments of Formulas I, W is-SO₂-。

In some embodiments of Formulas I, W is-CH₂-。

In some embodiments of Formulas I, X¹、X²、X³And X⁴In one or two be N, and other is CR^e。

In some embodiments of Formulas I, X¹、X²、X³And X⁴In three be CR^e, and other is N.

In some embodiments of Formulas I, X¹、X²、X³And X⁴It is CR^e。

In some embodiments of Formulas I, X¹It is N, and X²、X³And X⁴It is CR^e。

In some embodiments of Formulas I, X²It is N, and X¹、X³And X⁴It is CR^e。

In some embodiments of Formulas I, X¹And X⁴It is N, and X²And X³It is CR^a。

In some embodiments of Formulas I, X²And X³It is N, and X¹And X⁴It is CR^e。

In some embodiments of Formulas I, X¹And X²It is N, and X³And X⁴It is CR^e。

In some embodiments of Formulas I, R¹It is hydrogen.

In some embodiments of Formulas I, R¹It is C_1-6Alkyl.

In some embodiments of Formulas I, R²It is hydrogen.

In some embodiments of Formulas I, R²It is C_1-6Alkyl.

In some embodiments of Formulas I, R³It is hydrogen.

In some embodiments of Formulas I, R³It is C_1-6Alkyl.

In some embodiments of Formulas I, R⁴It is hydrogen.

In some embodiments of Formulas I, R⁴It is C_1-6Alkyl.

In some embodiments of Formulas I, R⁵It is hydrogen.

In some embodiments of Formulas I, R⁵It is C_1-6Alkyl.

In some embodiments of Formulas I, R⁶It is hydrogen.

In some embodiments of Formulas I, R⁶It is C_1-6Alkyl.

In some embodiments of Formulas I, R⁷It is hydrogen.

In some embodiments of Formulas I, R⁷It is C_1-6Alkyl.

In some embodiments of Formulas I, R⁸It is hydrogen.

In some embodiments of Formulas I, R⁸It is C_1-6Alkyl.

In some embodiments of Formulas I, R³And R⁴Form three together with the atom that it is connected, four, five, six or seven yuan The ring of saturation or fractional saturation, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^a- or-S-, And it can be optionally by RⁱSubstitution is one or many.

In some embodiments of Formulas I, R³And R⁴Form three together with the atom that it is connected, four or five yuan of saturated rings.

In some embodiments of Formulas I, R⁵And R⁶Form three together with the atom that it is connected, four, five, six or seven yuan The ring of saturation or fractional saturation, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^a- or-S-, And it can be optionally by RⁱSubstitution is one or many.

In some embodiments of Formulas I, R⁵And R⁶Form three together with the atom that it is connected, four or five yuan of saturated rings.

In some embodiments of Formulas I, R⁷And R⁸Form three together with the atom that it is connected, four, five, six or seven yuan The ring of saturation or fractional saturation, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^a- or-S-, And it can be optionally by RⁱSubstitution is one or many.

In some embodiments of Formulas I, R⁷And R⁸Form three together with the atom that it is connected, four or five yuan of saturated rings.

In some embodiments of Formulas I, R³And R⁴One of and R⁵And R⁶One of can together with the atom that it is connected To form three, four, five, six or heptatomic ring, it can optionally include and be selected from one or two following hetero atom：-O-、- NR^a- or-S-, and it can be optionally by RⁱSubstitution is one or many.

In some embodiments of Formulas I, R⁵And R⁶One of and R⁷And R⁸One of can together with the atom that it is connected With the ring of formation three, four, five, six or seven yuan of saturations or fractional saturation, it can optionally include and be selected from following one or two Individual hetero atom：-O-、-NR^a- or-S-, and it can be optionally by RⁱSubstitution is one or many.

In some embodiments of Formulas I, R⁹It is independently of one another：C_1-6Alkyl；Halogen；Or halo-C_1-6Alkyl.

In some embodiments of Formulas I, R⁹It is C_1-6Alkyl.

In some embodiments of Formulas I, R⁹It is halogen.

In some embodiments of Formulas I, R⁹It is C_1-6Alkoxy.

In some embodiments of Formulas I, R⁹It is cyano group.

In some embodiments of Formulas I, R⁹It is halo-C_1-6Alkyl.

In some embodiments of Formulas I, R⁹It is independently of one another：Fluorine；Chlorine；Or trifluoromethyl.

In some embodiments of Formulas I, R¹⁰It is：C_1-6Alkyl；Hydroxyl；Oxo；Or hydroxyl-C_1-6Alkyl.

In some embodiments of Formulas I, R¹⁰It is hydroxyl.

In some embodiments of Formulas I, R¹⁰It is oxo.

In some embodiments of Formulas I, R¹⁰It is cyano group.

In some embodiments of Formulas I, R¹⁰It is halogen.

In some embodiments of Formulas I, R¹⁰It is hydroxyl-C_1-6Alkyl.

In some embodiments of Formulas I, R¹⁰It is C_1-6Alkoxy -C_1-6Alkyl.

In some embodiments of Formulas I, R¹⁰It is C_1-6Alkyl.

In some embodiments of Formulas I, R¹⁰It is halo-C_1-6Alkyl.

In some embodiments of Formulas I, R¹⁰It is cyano group-C_1-6Alkyl.

In some embodiments of Formulas I, R^aIt is：C_1-6Alkoxy；C_3-6Cycloalkyl-C_1-6Alkyl；C_3-6Cycloalkyl oxy； C_3-6Cycloalkyl-C_1-6Alkoxy；Heterocyclic radical-C_1-6Alkyl；Or heterocyclic radical-C_1-6Alkoxy；Wherein heterocyclyl moieties are each independent Ground is selected from expoxy propane base, tetrahydrofuran base, THP trtrahydropyranyl, azetidinyl, pyrrolidinyl and piperidyl, wherein heterocycle Base section and C_3-6Cycloalkyl can be each unsubstituted or by R^fSubstitution is one or many.

In some embodiments of Formulas I, R^aIt is：C_1-6Alkoxy；Heterocyclic radical-C_1-6Alkyl；Or heterocyclic radical-C_1-6Alcoxyl Base；Wherein heterocyclyl moieties be each independently selected from expoxy propane base, tetrahydrofuran base, THP trtrahydropyranyl, azetidinyl, Pyrrolidinyl and piperidyl, and wherein heterocyclyl moieties can be each unsubstituted or by R^fSubstitution is one or many.

In some embodiments of Formulas I, R^aIt is：C_1-6Alkoxy；Heterocyclic radical-C_1-6Alkyl；Or heterocyclic radical-C_1-6Alcoxyl Base；Wherein heterocyclyl moieties are each independently selected from expoxy propane base, tetrahydrofuran base, THP trtrahydropyranyl and azetidine Base.

In some embodiments of Formulas I, R^aIt is C_1-6Alkoxy.

In some embodiments of Formulas I, R^aIt is C_1-6Alkoxy -C_1-6Alkyl.

In some embodiments of Formulas I, R^aIt is hydroxyl-C_1-6Alkyl.

In some embodiments of Formulas I, R^aIt is C_3-6Cycloalkyl, it can be unsubstituted or by R^fSubstitution is once or more It is secondary.

In some embodiments of Formulas I, R^aIt is C_3-6Cycloalkyl-C_1-6Alkyl, wherein C_3-6Cycloalkyl moiety can be not Substitution or by R^fSubstitution is one or many.

In some embodiments of Formulas I, R^aIt is C_3-6Cycloalkyl oxy；C_3-6Cycloalkyl-C_1-6Alkoxy；Heterocyclic radical；It is miscellaneous Ring group-C_1-6Alkyl；Or heterocyclic radical-C_1-6Alkoxy；Wherein heterocyclyl moieties are each independently selected from expoxy propane base, tetrahydrochysene furan Mutter base, THP trtrahydropyranyl, azetidinyl, pyrrolidinyl and piperidyl, and wherein heterocyclyl moieties and C_3-6Cycloalkyl is each Can be unsubstituted or by R^fSubstitution is one or many.

In some embodiments of Formulas I, R^aIt is C_3-6Cycloalkyl-C_1-6Alkoxy, wherein C_3-6Cycloalkyl moiety can be It is unsubstituted or by R^fSubstitution is one or many.

In some embodiments of Formulas I, R^aIt is heterocyclic radical, selected from expoxy propane base, tetrahydrofuran base, oxinane Base, azetidinyl, pyrrolidinyl and piperidyl, it can be each unsubstituted or by R^fSubstitution is one or many.

In some embodiments of Formulas I, R^aIt is heterocyclic radical-C_1-6Alkyl, wherein heterocyclyl moieties are selected from expoxy propane Base, tetrahydrofuran base, THP trtrahydropyranyl, azetidinyl, pyrrolidinyl and piperidyl, its can be each it is unsubstituted or By R^fSubstitution is one or many.

In some embodiments of Formulas I, R^aIt is heterocyclic radical-C_1-6Alkoxy, wherein heterocyclyl moieties are selected from expoxy propane Base, tetrahydrofuran base, THP trtrahydropyranyl, azetidinyl, pyrrolidinyl and piperidyl, its can be each it is unsubstituted or By R^fSubstitution is one or many.

In some embodiments of Formulas I, R^bIt is hydrogen.

In some embodiments of Formulas I, R^bIt is C_1-6Alkyl.

In some embodiments of Formulas I, R^cIt is hydrogen.

In some embodiments of Formulas I, R^cIt is C_1-6Alkyl.

In some embodiments of Formulas I, R^bAnd R^cForm three together with the atom that it is connected, four, five, six or seven yuan The ring of saturation or fractional saturation, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^a- or-S-, And it can be optionally by RⁱSubstitution is one or many.

In some embodiments of Formulas I, R^bAnd R^cOne of and R⁷And R⁸One of together with the atom that it is connected shape Into three, the ring of four, five, six or seven yuan of saturations or fractional saturation, it can optionally include miscellaneous selected from one or two following Atom：-O-、-NR^a- or-S-, and it can be optionally by RⁱSubstitution is one or many.

In some embodiments of Formulas I, R^bAnd R^cOne of and R⁵And R⁶One of together with the atom that it is connected shape Into three, the ring of four, five, six or seven yuan of saturations or fractional saturation, it can optionally include miscellaneous selected from one or two following Atom：-O-、-NR^a- or-S-, and it can be optionally by RⁱSubstitution is one or many.

In some embodiments of Formulas I, R^dIt is hydrogen.

In some embodiments of Formulas I, R^dIt is C_1-6Alkyl.

In some embodiments of Formulas I, R^eIt is independently of one another：Hydrogen；C_1-6Alkyl；Halogen；Or cyano group；Wherein C_1-6Alkane Base section can be unsubstituted or be optionally substituted by halogen one or many；

In some embodiments of Formulas I, R^eIt is independently of one another：Hydrogen；C_1-6Alkyl；Halogen；Or halo-C_1-6Alkyl.

In some embodiments of Formulas I, R^eIt is independently of one another：Hydrogen；C_1-6Alkyl；Or halogen.

In some embodiments of Formulas I, R^eIt is independently of one another：Hydrogen；Or halogen.

In some embodiments of Formulas I, R^eIt is independently of one another：Hydrogen；Or fluorine.

In some embodiments of Formulas I, R^eIt is hydrogen.

In some embodiments of Formulas I, R^eIt is C_1-6Alkyl.

In some embodiments of Formulas I, R^eIt is halogen.

In some embodiments of Formulas I, R^eIt is C_1-6Alkoxy.

In some embodiments of Formulas I, R^eIt is cyano group.

In some embodiments of Formulas I, R^eIt is halo-C_1-6Alkyl.

In some embodiments of Formulas I, R^fIt is：C_1-6Alkyl；Halogen；Oxo；Hydroxyl；Acetyl group；Or C_1-6Alkoxy.

In some embodiments of Formulas I, R^fIt is C_1-6Alkyl.

In some embodiments of Formulas I, R^fIt is halogen.

In some embodiments of Formulas I, R^fIt is C_1-6Alkoxy.

In some embodiments of Formulas I, R^fIt is halo-C_1-6Alkyl.

In some embodiments of Formulas I, R^fIt is oxo.

In some embodiments of Formulas I, R^fIt is hydroxyl.

In some embodiments of Formulas I, R^fIt is acetyl group.

In some embodiments of Formulas I, R^gIt is C_1-6Alkyl；

In some embodiments of Formulas I, R^gIt is oxo；

In some embodiments of Formulas I, R^gIt is halogen；

In some embodiments of Formulas I, R^gIt is halo-C_1-6Alkyl；

In some embodiments of Formulas I, R^gIt is hydroxyl-C_1-6Alkyl；

In some embodiments of Formulas I, R^gIt is C_1-6Alkoxy -C_1-6Alkyl；Or

In some embodiments of Formulas I, R^gIt is cyano group-C_1-6Alkyl.

In some embodiments of Formulas I, the compound can be Formula II：

Wherein s is 0-3, and m, n, p, q, Het, A, W, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹And R¹⁰As defined herein.

In some embodiments of Formula II, R^eIt is halogen.

In some embodiments of Formula II, R^eIt is fluorine.

In some embodiments of Formula II, s is 0 or 1.

In some embodiments of Formula II, s is 0.

In some embodiments of Formula II, s is 1.

In some embodiments of Formula II, s is 1 or 2.

In some embodiments of Formula II, s is 2.

In some embodiments of Formula II, s is 1,2 or 3.

In some embodiments of Formula II, s is 2 or 3.

In some embodiments of Formula II, s is 3.

In some embodiments of Formulas I, the compound can be Formula II.

In some embodiments of Formulas I, the compound can be formula III：

Wherein p, q, s, Het, A, R³、R⁹、R¹⁰And R^eAs defined herein.

In some embodiments of Formulas I, the compound can be formula IV:

Wherein p, q, s, Het, A, R³、R⁹、R¹⁰And R^eAs defined herein.

In some embodiments of Formulas I, the compound can be Formula V:

Wherein q, Het, A, R³、R¹⁰And R^eAs defined herein.

In certain embodiments, present invention also offers selected from following compound：

[5- [[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] methyl] -1,3,4- oxadiazole -2- bases] methanol；

5- [[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] methyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [(1R) -1- [fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] Methyl] phenyl] -2- (oxetanes -3- bases) ethyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [(R)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl]-(oxetanes -3- bases epoxide) methyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [(S)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl]-(oxetanes -3- bases epoxide) methyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6S) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] -1- methyl-ethyls] -3H-1,3,4- oxadiazole -2- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] -1- methyl-ethyls] -3H-1,3,4- oxadiazole -2- ketone；

5- [(R)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl]-tetrahydropyran -4-base epoxide-methyl] -3H-1,3,4- oxadiazole -2- ketone；

3- [[the fluoro- 4- of 2,5- bis- [[(3S, 6S) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] methyl] -1,4- dihydro -1,2,4- triazole -5- ketone；

3- [[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] methyl] -1,4- dihydro -1,2,4- triazole -5- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -1,2- pyrazoline -3- ketone；

3- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -2H- isoxazole -5- ketone；

3- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -1,4- dihydro -1,2,4- triazole -5- ketone；

3- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -4- methyl isophthalic acid H-1,2,4- triazole -5- ketone；

5- [(1S) -1- [fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] Methyl] phenyl] propyl group] -3H-1,3,4- oxadiazole -2- ketone；

5- [(1R) -1- [fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] Methyl] phenyl] propyl group] -3H-1,3,4- oxadiazole -2- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -2- methyl -4H-1,2,4- triazole -3- ketone；

3- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -2- methyl isophthalic acid H-1,2,4- triazole -5- ketone；

5- [(R)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl]-isopropoxy-methyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [(S)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl]-isopropoxy-methyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [(R)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl]-methoxymethyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [(S)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl]-methoxymethyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] isoxazole -3- ketone；

3- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -1H- imidazoles -2- ketone；

1- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] imidazolidine -2,4- diketone；

5- [(1S) -1- [fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] Methyl] phenyl] -3- methoxy-propvls] -3H-1,3,4- oxadiazole -2- ketone；

5- [(1R) -1- [fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] Methyl] phenyl] -3- methoxy-propvls] -3H-1,3,4- oxadiazole -2- ketone；

2- [5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] ethyl] -2- oxo -1,3,4- oxadiazole -3- bases] acetonitrile；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -3- (2- hydroxyethyls) -1,3,4- oxadiazole -2- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -3H- oxazole -2- ketone；

5- [(1S) -1- [fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] Methyl] phenyl] -3- hydroxyl-propyls] -3H-1,3,4- oxadiazole -2- ketone；

5- [(1R) -1- [fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] Methyl] phenyl] -3- hydroxyl-propyls] -3H-1,3,4- oxadiazole -2- ketone；

5- [(R)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl]-ethoxy-methyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [(S)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl]-ethoxy-methyl] -3H-1,3,4- oxadiazole -2- ketone；

2- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -4H-1,2,4- triazole -3- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -3- (2,2,2- trifluoroethyls) -1,3,4- oxadiazole -2- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -3- ethyl -1,3,4- oxadiazole -2- ketone；

2- [5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] ethyl] -2- oxo -1,3,4- oxadiazole -3- bases] acetamide；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -3- (2- methoxy ethyls) -1,3,4- oxadiazole -2- ketone；

1- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] imidazolidin-2-one；

2- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -1H- pyrazoles -3- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -3- methyl isophthalic acids, 3,4- oxadiazole -2- ketone；

2- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] isoxazole -5- ketone；

(3S, 6R) -2- [[the fluoro- 4- of 2,5- bis- [1- (3- first epoxides isoxazole -5-base) ethyl] phenyl] methyl] -3- first Base -6- phenyl-thiazan 1,1- dioxide；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl]-isoxazole -3- ketone of -2- methyl；

4- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethylidene] -1,3- dioxolane -2- ketone；

2- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -1H- pyrazoles -5- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl]-oxazole -2- ketone of -3- methyl；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] oxazolidine -2- ketone；

N- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -1H- pyrazole-4-carboxamides；

1- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -5,5- dimethyl-imidazol -4- ketone；Formic acid；

2- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -1H-1,2,4- triazole -5- ketone；

(3S, 6R) -2- [[the fluoro- 4- of 2,5- bis- [1- (3- methoxyl group -1,2,4- triazol-1-yls) ethyl] phenyl] methyl] - 3- methyl -6- phenyl-thiazan 1,1- dioxide；

4- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -3H- oxazole -2- ketone；

1- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -2- methyl isophthalic acids, 2,4- triazole -3- ketone；

(3S) -1- [1- [fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] Methyl] phenyl] ethyl] -3- hydroxy-pyrrolidine 2- ketone；

And its officinal salt.

Method

Present invention also offers for treating by RORc is receptor-mediated or the disease related to RORc acceptors or the side of illness Method, methods described includes applying the compounds of this invention of effective dose to individual in need.

The disease can be arthritis, such as rheumatoid arthritis or osteoarthritis.

The disease can be asthma or COPD.

The disease can be psoriasis.

The disease can be muscular dystrophy.

Shown in the representative compound following article EXPERIMENTAL EXAMPLE of the method according to the invention.

Synthesis

The compound of the present invention can be by various described in shown below and description illustrative synthetic reaction flow It is prepared by method.

Raw material and reagent for preparing these compounds can generally be obtained from commercial supplier, such as Aldrich Chemical Co., or prepared by method known to those skilled in the art according to the method described in bibliography, example Such as Fieser and Fieser ' s Reagents for Organic Synthesis；Wiley&Sons:New York, 1991, the 1-15 volumes；Rodd’s Chemistry of Carbon Compounds,Elsevier Science Publishers, 1989,1-5 volumes and supplementary issue；With Organic Reactions, Wiley＆Sons:New York, 1991, 1-40 volumes.Following synthetic reaction flow is only the explanation for the certain methods that can synthesize the compounds of this invention, can be to these Synthetic reaction flow carries out various modifications, and will be prompted to those skilled in the art with reference to the content being contained in the application.

When needed, routine techniques can be used to separate and purify the raw material and intermediate in the synthetic reaction flow, Including but not limited to filtering, distillation, crystallization, chromatogram etc..Conventional method can be used to characterize these materials, including physical constant And spectroscopic data.

Unless otherwise indicated, reaction described here can be under an inert atmosphere under atmospheric pressure at about -78 DEG C to about 150 DEG C, carried out in e.g., from about 0 DEG C to about 125 DEG C of range of reaction temperature, or easily at a temperature of about room temperature (or environment), example Carried out at such as from about 20 DEG C.

Following flow A illustrates the synthetic method that can be used for preparing specific compound of formula I, and wherein LG is leaving group Group, such as halogen, sulphonic acid ester, and m, n, p, q, X¹、X²、X³、X⁴、R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R^bAnd R^cSuch as It is defined herein.

In flow A step 1, by alkylamineaWith arylsulfonyl chloridebReaction, forms sulfonamide compoundsc.Step 1 Reaction can be in polar non-solute such as THF or dichloromethane, and in the presence of tertiary amine base or weak base such as potassium carbonate It is lower to carry out.In certain embodiments, compoundaLeaving group can be bromine.Similarly, chemical combination in certain embodiments ThingbCl radical can be replaced by other halogens or leaving group.

Cyclization is carried out in step 2, obtains thiazine hydride compoundsd.The cyclization can be in highly basic such as alkyl In the presence of lithium reagent, carried out in anhydrous conditions using polar non-solute.

In step 3, by thiazine hydride compoundscWith aralkyl halides compoundseReaction, obtains aralkyl thiazanf。 The reaction of step 3 can be carried out in the presence of highly basic such as sodium hydride under the conditions of anhydrous polar aprotic solvent.Compounde The other suitable leaving groups that can be used in the art of bromine group replace.

Then can be in step 4 by thiazine hydride compoundsfWith oxoethyl halogenation zincongReaction, obtains ester compoundsh.The reaction can be in the presence of suitable palladium catalyst, under polar aprotic conditions in solvent such as anhydrous tetrahydro furan Carry out.

In steps of 5, by ester compoundshWith hydrazine reaction, corresponding hydrazide compound is obtainedi。

In step 6, by hydrazide compound and acid halide reagentsjReaction, obtains acyl hydrazide compoundk。

In step 7, cyclization is carried out with shape into oxadiazole group, obtains compoundl, it is the Formulas I of the present invention Compound.

Many alternatives in the above method are all possible, and will provide enlightenment for those skilled in the art.Example Such as, reagentgIt can be replaced with corresponding monothioester, obtain the thiadiazoles group in final compound.Group R^aAlkyl can be used Group is replaced, or can be from reagentgIn omit and in step below introduce (if desired).Similarly, group R¹⁰Can be from Acyl reagentjIn omit, and can be introduced if desired in step below.

Hereafter flow B shows another synthetic method for preparing specific compound of formula I, and wherein TBS is three-(tertiary fourth Base)-silylation, and m, n, p, q, X¹、X²、X³、X⁴、Y、R¹、R²、R³、R⁴、R⁵、R⁶、R⁹And R¹⁰As defined herein.

In flow B step 1, by three-(tert-butyl group)-silylation epoxide aminemWith arylsulfonyl chloridebReaction, with reference to such as Flow A described above, forms sulfonamide compoundsn.In certain embodiments, described three-(tert-butyl group)-silylation epoxide Group can be replaced with other leaving groups.

In step 2, by sulfonamide compoundsnReacted with iodine chloromethanes, obtain alkenyl sulfonamide compoundso.The reaction It can carry out, be carried out in anhydrous conditions using polar non-solute such as THF in the presence of highly basic such as alkyl lithium reagents. In certain embodiments, iodine chloromethanes can be replaced with other methylene reagents.

In step 3, cyclization is carried out, oxa- thiazepine cycloheptyl hydride compounds are obtainedp.The cyclization can be Carried out in the presence of amine base under the conditions of polar non-solute.

In step 4, by oxa- thiazepine cycloheptyl hydride compoundspWith aralkyl halideeReaction, obtains aralkyl oxy Miscellaneous thiazepine cycloheptyl hydride compounds q, with reference to procedure described above A method.

Then method as described above described in flow A step 4-7 carries out step 5-8.In short, by oxa- sulphur Miscellaneous nitrogen heterocyclic heptane compound q and halogenation zincongReact in steps of 5, obtain ester compoundsr, it is then with hydrazine in step 6 Middle reaction, obtains corresponding hydrazide compounds.Then by hydrazide compoundsIt is acylated in step 7, obtains compoundt, then Ring closure is carried out in step 8, obtains sultam compoundu, it is the compound of formula I of the present invention.

Method flow B many work-around solutions are possible, and will provide enlightenment to those skilled in the art.Prepare this The detail of invention compound is described in the examples below.

Administration and pharmaceutical composition

The present invention includes pharmaceutical composition, and it includes at least one compound of the invention or its individual isomer, disappeared outside Rotation or the isomer mixture or officinal salt or solvate of non-racemic, and at least one pharmaceutical acceptable carrier and optional Other treatment and/or prevention compositions.

Generally, compound of the invention will pass through any received of the medicine for similar effectiveness with therapeutically effective amount Administering mode is applied.Suitable dosage range generally daily 1-500mg, such as daily 1-100mg, most preferably 1-30mg, this takes Certainly in many factors, such as the order of severity, individual age and the relative health of disease to be treated, the effect of compound used therefor The targeted indication of energy, method of administration and form, administration and the preference and experience for participating in doctor.Treat these diseases The those of ordinary skill of technical field is possible in no excessively experiment and relies on personal knowledge and present disclosure In the case of determine to give disease the compounds of this invention therapeutically effective amount.

The compound of the present invention can be applied as pharmaceutical preparation, including those be adapted to oral (including oral cavity and sublingual), Rectum, nose, part, lung, vagina or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous) administration or to be adapted to By the pharmaceutical preparation for the form for sucking or being blown into administration.A kind of specific administering mode is usually daily dose side easy to use Case is oral, and it can be adjusted according to extent.

The compound of the present invention can be placed with medicine group together with one or more standard adjuvants, carrier or diluent The form of compound and unit dose.Pharmaceutical composition and unit dosage form can be made up of the conventional ingredient of conventional ratio, tool Have or without other reactive compounds or material, and unit dosage forms can containing any suitable effective dose with it is used pre- The suitable active component of phase daily dose scope.Pharmaceutical composition can be used as solid, such as tablet or filling capsule, semisolid, powder End, sustained release preparation, or liquid, such as solution, suspension, emulsion, elixir or the filling capsule for being administered orally；Or with rectum Or the suppository form of vagina administration；Or in the form of the aseptic injectable solution that parenteral is used.Therefore, every contains about 1 milligram Active component or broadly about 0.01 to about 100 milligram of preparation is suitable typical flat dosage form.

The compound of the present invention can be configured to various oral administered dosage forms.Pharmaceutical composition and dosage form can be wrapped Compound or pharmaceutically acceptable salt thereof containing the present invention is used as active component.Pharmaceutical acceptable carrier can be solid or liquid.Solid form Preparation include powder, tablet, pill, capsule, cachet, suppository and dispersible granule.Solid carrier can be one Kind or it is a variety of also be used as diluent, flavouring, solubilizer, lubricant, suspending agent, adhesive, preservative, tablet disintegrant or The material of encapsulating material.In the powder, carrier is typically solid in small, broken bits, and it is the mixture with active component in small, broken bits.In piece In agent, active component is generally mixed in proper proportions with the carrier with necessary binding ability, and by required shape and chi Very little compacting.Powder and tablet can contain about 1% to about 70% reactive compound.Suitable carrier includes but is not limited to carbonic acid Magnesium, magnesium stearate, talcum, sugar, lactose, pectin, dextrin, starch, gelatin, bassora gum, methylcellulose, carboxymethyl cellulose Sodium, low melt wax, cocoa butter etc..Terms " formulation " is intended to include the preparation of reactive compound and the encapsulating material as carrier, It provides the active component capsule that (bag is with or without carrier) is surrounded by carrier in connection.Similarly, including cachet and Lozenge.Tablet, powder, capsule, pill, cachet and lozenge can be adapted for the solid form being administered orally.

The other forms for being adapted to be administered orally include liquid form preparation, including emulsion, syrup, elixir, the aqueous solution, water Property suspension it is contemplated that uses the Solid form preparations for not long ago changing into liquid form preparation.Emulsion can be made in the solution It is standby, such as in aqueous solution of propylene glycol, or emulsifying agent can be contained, such as lecithin, Arlacel-80 or Ah Draw primary glue.Active component can be by being dissolved in water and adding suitable colouring agent, spices, stabilizer and thickening by the aqueous solution It is prepared by agent.Water slurry can be by by active component in small, broken bits and stickum (such as natural or synthetic natural gum, resin, methyl Cellulose, sodium carboxymethylcellulose and other well known suspending agent) it is dispersed in water to prepare.The preparation of solid form includes molten Liquid, suspension and emulsion, can also be containing colouring agent, spices, stabilizer, buffer, artificial and natural in addition to active component Sweetener, dispersant, thickener, solubilizer etc..

The compound of the present invention can be formulated for parenteral (for example, by injection, such as injecting or continuous defeated Note), and can with the addition of preservative ampoule, Cartrix, small size be transfused or multi-dose container in unit Dosage form is provided.Said composition can take the form of suspension in oiliness or aqueous carrier, solution or emulsion, for example In Aqueous Solutions of Polyethylene Glycol.Oiliness or non-aqueous carrier, diluent, the example of solvent or carrier include propane diols, poly- second two Alcohol, vegetable oil (such as olive oil) and injectable organic ester (such as ethyl oleate), and preparaton can be contained, for example prevent Rotten, wetting, emulsification or suspension, stable and/or dispersant.Or, active component can be powder type, and it passes through sterile solid Sterile separation obtain, or from solution freeze-drying, to use preceding for example sterile with suitable carrier, pyrogen-free water Mixing carrys out wiring solution-forming.

The compound of the present invention can be configured to for topical application to epidermis, such as ointment, cream or lotion, or is made For transdermal patch.Ointment and cream can for example together with aqueous or oleaginous base, and add suitable thickener and/or Gelling agent is prepared.Lotion can use aqueous or oleaginous base to prepare, generally also containing one or more emulsifying agents, stabilizer, Dispersant, suspending agent, thickener or colouring agent.(it is usually sugarcane suitable for the preparation of local application is included in flavoured base in mouth Sugar and Arabic gum or bassora gum) in include the lozenge of active agent；Inert base (such as gelatin and glycerine or sucrose and Ah Draw uncle's natural gum) in include the lozenge of active component；And the mouth-wash of active component is included in suitable liquid-carrier.

The compound of the present invention can be prepared to be applied as suppository.First by wax (such as fatty glyceride of low melting point Or the mixture of cocoa butter) fusing, and active component is uniformly dispersed (such as by stirring).Then by the uniform mixed of melting Compound is poured into the mould of suitable dimension, is allowed to cool and is solidified.

The compound of the present invention can be formulated for vagina administration.Pessary, tampon, creme, gel, paste, foam Or spray includes suitable carrier known in the art in addition to the active ingredient (s.

The compound can be formulated for nasal-cavity administration.Solution or suspension are directly applied to nose by conventional method Chamber, such as with dropper, pipette or sprayer.Said preparation can be provided with single or multiple dose form.In latter dropper or shifting In the case of liquid device, this can be applied the solution or suspension of appropriate predetermined by patient to realize.In the situation of spraying Under, this for example can be realized by metering atomising atomizing pump.

The compound of the present invention can be formulated for aerosol drug delivery, particularly respiratory tract and including intranasal administration.The change Compound generally has such as five (5) microns or the more low particle size of decimal magnitude.Such granularity can be by this area The method known is obtained, for example, obtained by being micronized.Active component is provided with suitable propellant, such as chlorine in pressurized package Fluorine carbon (CFC), such as dicholorodifluoromethane, Arcton 11 or dichlorotetra-fluoroethane, or carbon dioxide or other suitable gas Body.Aerosol can also easily contain surfactant such as lecithin.The dosage of medicine can be controlled by metering valve.Or Person, active component can be provided in the form of dry powder, and such as compound is in suitable powdered substrate such as lactose, starch, starch Mixture of powders in derivative such as hydroxypropyl methyl cellulose and polyvinylpyrrolidine (PVP).Dust carrier will be in nasal cavity Form gel.The powder composition can exist in a unit, for example the cartridge case of capsule or such as gelatin or blister package, Powder can be therefrom administered by inhalator.

When needed, preparation can be prepared with the enteric coating of active component is applied suitable for lasting or control release.For example, The compound of the present invention can be configured to transdermal or subcutaneous drug delivery device.When the sustained release for needing compound and when trouble When person is most important to the compliance of therapeutic scheme, these delivery systems are favourable.Compound in transdermal delivery system is led to Often it is attached on the solid support of binding skin.Compound interested can also be combined with penetration enhancer, for example azone (Azone).Sustained release delivery system is subcutaneously inserted hypodermic layer by operation or injection.Subcutaneously Compound is encapsulated in lipid soluble film by implant, for example silicon rubber, or biodegradable polymer, for example PLA.

Pharmaceutical preparation can be unit dosage forms.In this form, preparation is subdivided into the list for including appropriate active component Position dosage.Unit dosage forms can be the preparation of packaging, and the packaging includes the preparation of dispersed number, tablet, the capsule of such as packaging With the powder in bottle or ampoule.In addition, unit dosage forms can be capsule, tablet, cachet or lozenge in itself, or they It can be an appropriate number of any packaged form.

Other suitable pharmaceutical carriers and other preparations such as Remington:The Science and Practice of Pharmacy 1995, E.W.Martin is edited, Mack Publishing Company, the 19th edition, Easton, Described in Pennsylvania.Representational pharmaceutical preparation includes the compounds of this invention as described below.

Purposes

The compound of the present invention is generally used for treating immunological diseases.The compound can be used for treatment of arthritis, including class Rheumathritis, osteoarthritis, psoriatic arthritis, septic arthritis, SpA, urarthritis, systematicness Lupus erythematosus and juvenile arthritis, osteoarthritis and other arhritis conditions.

The compound can be used for treatment respiratory disease such as chronic obstructive pulmonary disease (COPD), asthma, bronchus convulsion Contraction etc..

The compound can be used for treatment enterogastric diseases (" GI obstacles "), such as IBS (IBS), inflammatory Enteropathy (IBD), cholecystalgia and other disease of biliary tract, renal colic, the IBS based on diarrhoea, the pain related to GI expansions etc..

The compound can be used for treatment psoriasis, muscular sclerosis, Sjogren syndrome, lupus and pulmonary fibrosis.

General experimental

LCMS methods：

Carry out high pressure liquid chromatography-mass spectrum (LCMS) experiment to determine retention time (RT) and phase using one of following methods Close mass ion：

Method A：Use following condition analysis compound：With with UV PDADs and 100 positions from Carried out on the mono- quadrupole mass spectrometers of Waters ZMD of the Hewlett Packard HP1100LC systems connection of dynamic injector real Test.Spectrometer has the electrospray ionization source for being operated in cation and negative ion mode.The system is used at ambient temperature Phenomenex Luna3 μm C18 (2) 30x4.6mm chromatographic columns, flow velocity is 2.0mL/min.Initial solvent system is preceding 0.5 95% water (solvent orange 2 A) of the minute containing 0.1% formic acid and 5% acetonitrile (solvent B) containing 0.1% formic acid, then at following 4 points Clock rises to 5% solvent orange 2 A and 95% solvent B gradient.Kept for 1 minute, then returned to 95% in ensuing 0.5 minute molten Agent A and 5% solvent B.Total run time is 6 minutes.

Method B：Use following condition analysis compound：Experiment with the Waters Acquity with PDA UV detectors Carried out on the Waters Micromass ZQ2000 quadrupole mass spectrometers of UPLC systems connection.Spectrometer have be operated in just from The electrospray ionization source of son and negative ion mode.The system uses 1.7 μm of 100x2.1mm chromatographic columns of Acquity BEH C18, keeps At 40 DEG C, or Acquity BEH Shield 1.7 μm of 100x2.1mm chromatographic columns of RP18, it is maintained at 40 DEG C, flow velocity 0.4mL/ min.Initial solvent system is in first 0.4 minute 95% water (solvent orange 2 A) containing 0.1% formic acid and 5% second containing 0.1% formic acid Nitrile (solvent B), then rose to 5% solvent orange 2 A and 95% solvent B gradient at following 5.6 minutes.Kept for 0.8 minute, Ran Hou 95% solvent orange 2 A and 5% solvent B are returned in ensuing 1.2 minutes.Total run time is 8 minutes.

NMR methods：

Recorded at environment temperature or 80 DEG C¹H NMR spectras, wherein using one of following equipment record：With triple common Varian Unity Inova (400MHz) spectrometer of the 5mm that shakes probes, the Bruker popped one's head in triple resonant 5mm Avance DRX 400 (400MHz) spectrometer, equipped with for detecting the Bruker that 1H and 13C standard 5mm double frequencies are popped one's head in Avance DPX 300 (300MHz), the Bruker Fourier 300MHz systems popped one's head in equipped with standard 5mm 1H/13C, are used The Bruker AVIII (400MHz) of BBI Broad Band Inverse 5mm probes use QNP (Quad Nucleus inspections Survey) 5mm probe Bruker AVIII (500MHz).Chemical shift relative to interior target ppm to represent, tetramethylsilane (ppm =0.00).Use following abbreviation：Br=bandwidth signals, s=is unimodal, and d=is bimodal, dd=double doublets, t=triplets, td=tri- Weight is bimodal, dddd=double doublet, q=quartets, m=multiplets, or its any combinations in pairs.

Microwave reactor：

Microwave reaction is used in the bottle of reaction scale is suitable for, and under the temperature and time described in experimental detailCarry out.

Purifier apparatus：

Use Teledyne ISCOOrIsoleraOn it is pre-filled Silicagel column is purified using compressed air application external pressure.Use the solvent and gradient shown in experimental detail.

Reverse-phase HPLC (HPLC) is used to purify shown compound.In the Phenomenex as stationary phase On Gemini C18 posts (250 × 21.2mm, 5 microns), using specified mobile phase, Gilson UV/Vis-155 binary channels is used Detector and Gilson GX-271 automated fluids processors are separated with 18mL/min operated in flow rate.

Phase separator post byConduct is providedPhase separator post.

Abbreviated list

AcOH acetic acid

AIBN 2,2 '-azo two (2- methyl propionitrile)

Atm. atmospheric pressure

BOC tert-butoxy carbonyl groups

(BOC)₂O di-tert-butyl dicarbonates

CrO₃Chromium oxide (VI)

CDCl₃Deuterochloroform

DavePhos 2- dicyclohexyls phosphino- -2 '-(N, N- dimethylamino) biphenyl

DCM dichloromethane/dichloromethane

DMA DMAC N,N' dimethyl acetamides

DIAD diisopropyl azodiformates

DIPEA DIPEA

DMAP 4-dimethylaminopyridines

DME 1,2- dimethoxy-ethanes

DMF N,N-dimethylformamides

DMSO dimethyl sulfoxide (DMSO)s

Double (diphenylphosphino) ferrocene of DPPF 1,1'-

ES electron sprays

Et₂O ether

Et₃N triethylamines

EtOH ethanol/ethyl alcohol

EtOAc ethyl acetate

H₂O water

H₂SO₄Sulfuric acid

HATU 2- (1H-7- azepine benzos triazol-1-yl) -- 1,1,3,3- tetramethylurea first ammonium hexafluorophosphates

HBTU O- BTA -1- bases-N, N, N ', N '-tetramethylurea hexafluorophosphate

HCO₂H formic acid

HCl hydrochloric acid

HOBT I-hydroxybenzotriazoles

HPLC high pressure liquid chromatographies

RP HPLC reverse-phase HPLCs

IBX 2- iodoso benzoic acid

IMS industrial methylated spirits

KOH potassium hydroxide

K₂CO₃Potassium carbonate

LDA lithium diisopropylamines

I-PrOH isopropanols/isopropyl alcohol/propan-2-ol

LCMS liquid chromatography/mass spectrometries

LiOH lithium hydroxides

MgSO₄Magnesium sulfate

MeOH methanol/methylol

MW microwaves

NaH sodium hydrides

NaCl sodium chloride

NaOH sodium hydroxides

Na₂SO₄Sodium sulphate

Na₂CO₃Sodium carbonate

NaHCO₃Sodium acid carbonate/sodium acid carbonate

NBS N- bromine succinimides

NH₄Cl ammonium chlorides

NMP 1-Methyl-2-Pyrrolidones

POCl₃Phosphoryl chloride phosphorus oxychloride

PhCH₃Toluene

Pd₂(dba)₃Three (dibenzalacetone) two palladium (0)

PSI pound per square inches

RT room temperatures

Sat. saturation

SCX-2 is pre-filledSilica base adsorbent, the propane sulfonic acid functional group with chemical bonding

SFC supercritical fluid chromatographies

TBDMS t-butyldimethylsilyis

TFA trifluoroacetic acids

THF tetrahydrofurans

TIPS tri isopropyl silane bases

TLC thin-layer chromatographys

TMSCl chlorine trimethyl silanes

Double (the diphenylphosphino) -9,9- dimethyl xanthenes of XantPhos 4,5-

Preparation method 1 and 2:(3R) -3- amino butyl- 1- alcohol and (3S) -3- amino butyl- 1- alcohol

Step 1：3- [[(benzyl epoxide) carbonyl] amino] butyric acid

Load 3- aminobutyric acids (100g, 969.75mmol, 1.00 equivalent) into 2000mL 4 neck round-bottom flasks in water Solution in (1000mL), then divides several to add potassium hydroxide (136g, 2.42mol, 2.50 equivalent).In 0-5 in stirring DEG C benzyl chloroformate (247g, 1.45mol, 1.50 equivalent) is added dropwise to it.Resulting solution is stirred 5 hours at 25 DEG C. The reaction process is monitored with LCMS.Resulting solution is extracted with 3x250mL dichloromethane, and combining water layer.Use hydrogen chloride The pH value of aqueous phase is adjusted to 3 by (2mol/L).Precipitation is collected by filtration, and dries, 3- [[(the benzyl oxygen of 102g (44%) is obtained Base) carbonyl] amino] butyric acid is white solid.

Step 2:N- [(2S) -4- hydroxyl butyl- 2- yls] carbamic acid benzyl esters and N- [(2R) -4- hydroxyl butyl- 2- yls] ammonia Base benzyl chloroformate

Load 3- [[(benzyl epoxide) carbonyls into 3 neck round-bottom flasks for the 2000mL for being filled with and keeping nitrogen inert gas Base] amino] solution of the butyric acid (102g, 429.92mmol, 1.00 equivalent) in THF (300mL), then in 0-5 in stirring BH is added dropwise at DEG C₃/ THF (1N) (645mL, 1.50 equivalents).Resulting solution is stirred 2 hours at 40 DEG C, by adding 200mL methanol is quenched, and is concentrated in vacuo.Residue is used into ethyl acetate on a silica gel column:Petroleum ether (1:2) it is purified by flash.Will Crude product (70g) is purified through Prep-SFC with following condition (prep SFC)：Post, Phenomenex Lux 5u Cellulose- 4,2.12*25,5um；Mobile phase, CO₂(85%), ethanol (15%)；Detector, UV254nm.Obtain 30g (31.5%) N- [(2R) -4- hydroxyl butyl- 2- yls] carbamic acid benzyl ester, is pale solid, and 30g (31.5%) N- [(2S) -4- hydroxyls Butyl- 2- yls] carbamic acid benzyl ester is pale solid.

Step 3:(3R) -3- amino butyl- 1- alcohol and (3S) -3- amino butyl- 1- alcohol

Into 1000mL round-bottomed flasks load N- [(2S) -4- hydroxyl butyl- 2- yls] carbamic acid benzyl ester (30g, 134.4mmol, 1.00 equivalents) solution in methanol (500mL) and palladium carbon (3g, 0.10 equivalent).By resulting solution at 25 DEG C Under in hydrogen stir 12 hours.Solid is filtered out, and filter vacuum is concentrated, 11.7g (92%) (3S) -3- amino is obtained Butyl- 1- alcohol, is grease.¹H NMR(300MHz,DMSO,ppm):δ4.48(3H,s),3.47(2H,s),2.96(1H,s), 1.47-1.41(2H,q),1.02-0.99(3H,d)；LCMS(ESI),m/z,90[M+H]⁺；Measure [α]_D ^20.2+ 11.65 ° of (C= Solution of the 1.22g/100mL in EtOH), lit. [α]_D ²⁰+ 16.3 ° (solution of c=4.5 in EtOH) (J.Org.Chem.1996,61,2293–2304.)。

Using the above method, separation 12.0g 12g (94%) (3R) -3- amino butyl- 1- alcohol, is grease.¹H NMR (300MHz,DMSO,ppm):δ4.48(3H,s),3.47(2H,s),2.96(1H,s),1.47-1.41(2H,q),1.02-0.99 (3H,d)；LCMS(ESI),m/z,90[M+H]⁺；Measure [α]_D ^20.2- 11.1 ° (solution of C=0.32g/100mL in EtOH), lit.[α]_D ²⁵- 25 ° of (solution of the c=1.25 in EtOH) (Tetrahedron:Asymmetry 1999,10,2213– 2224.)。

Preparation method 3:(R)-N- (4- neoprene -2- bases) -1- phenyl methanesulfonamide acid amides

Step 1:(R)-phenylmethane sulfonic acid 3- (Phenylmethylsulfonyl amino) butyl ester

To (3R) -3- amino butyl- 1- alcohol (1.0g, 11.2mmol) and triethylamine (3.3mL, 23.6mmol) four at 0 DEG C Phenyl methanesulfonamide acyl chlorides (4.49g, 23.6mmol) is slowly added in the solution of hydrogen furans (37mL), and reactant is stirred at room temperature Mix 16 hours.Then MTBE (100mL) is added, and Et is removed by filtration₃NHCl salt.Then filtrate is concentrated, obtains thick (R)-phenylmethane sulfonic acid 3- (Phenylmethylsulfonyl amino) butyl ester, it is not purified directly to use.LCMS(ESI),m/z, 398[M+H]+。

Step 2:(R)-N- (4- neoprene -2- bases) -1- phenyl methanesulfonamide acid amides

Sodium chloride is added into thick (R)-phenyl methanesulfonamide acid 3- (Phenylmethylsulfonyl amino) butyl esters (23.6mmol) (984mg, 16.8mmol) and dimethylformamide (37mL), and reactant is stirred 16 hours at 80 DEG C.Then by reactant Diluted with EtOAc, with water (x2) and salt water washing, use MgSO₄Dry, concentration, and through silica gel chromatography (0-50% acetone Solution in heptane, 216nM), obtain (R)-N- (4- neoprene -2- bases) -1- phenyl methanesulfonamide acid amides (1.71g, 6.53mmol, 2 The yield 58% of individual step).LCMS(ESI),m/z,261[M+H]+.

The other compounds prepared using the above method are as shown in table 1.

Table 1

Preparation method 7:N- (2- bromoethyls) (phenyl) Methanesulfomide

By K at 0 DEG C₂CO₃(8.7g, 62mmol) adds phenyl methanesulfonamide acyl chlorides (6g, 31mmol) and 2- bromine ethamine hydrobromides (6.4g, 31mmol) is in DCM (100mL) mixture.Gained mixture is stirred at room temperature 4 hours, and stood overnight. After reaction completely, water (100mL) is added, and separate DCM phases.Aqueous phase is extracted with DCM.By the organic phase Na of merging₂SO₄It is dry It is dry, filter and be concentrated in vacuo, obtain crude product, (200-300 mesh silica gel, 0-50% EtOAc is in stone through pillar layer separation by it Solution in oily ether), compound N-(2- bromoethyls) (phenyl) Methanesulfomide (7.0g, 80%) is obtained, is light yellow solid.¹H NMR(300MHz,CDCl₃)δ7.40(m,5H),4.58(m,1H),4.29(s,2H),3.34-3.29(m,4H)。LCMS(ESI), 300,302[M+Na]⁺, find Br collection of illustrative plates.

Preparation method 8：N- (2- bromoethyls) (4- fluorophenyls) Methanesulfomide

N- (2- bromoethyls) (4- fluorophenyls) Methanesulfomide is also prepared using the above method, by phenyl methanesulfonamide acyl chlorides 4- Fluoro-phenyl mesyl chloride is replaced.¹H NMR(300MHz,CDCl₃)δ7.43-7.38(m,2H),7.13-7.07(m,2H),4.62 (br s,1H),4.26(s,2H),3.41-3.32(m,4H)。

Preparation method 9:N- (3- bromopropyls) (phenyl) Methanesulfomide

At 0 DEG C by phenyl methanesulfonamide acyl chlorides (2.19g, 10mmol) add 3- bromine propyl- 1- amine hydrobromide (2.19g, 10mmol) and Et₃N (2.02g, 20mmol) is in THF (50mL) suspension.The mixture is stirred 5 minutes at 0 DEG C.TLC It is determined that reaction is complete.Solid is filtered out through suction, and filtrate is concentrated, compound N-(3- bromopropyls) (phenyl) Methanesulfomide is obtained (2.7g, quantitative), is light yellow solid, it is directly used in next step without further purification.¹H NMR(300MHz,CDCl₃) δ 7.40 (m, 5H), 4.48 (m, 1H), 4.27 (s, 2H), 3.41 (t, J=6.6Hz, 2H), 3.16 (q, 2H), 2.01 (m, 2H). LCMS (ESI), m/z, 314 and 316 [M+Na]⁺, find Br collection of illustrative plates.

Preparation method 10:N- (3- bromopropyls) (4- fluorophenyls) Methanesulfomide

N- (3- bromopropyls) (4- fluorophenyls) Methanesulfomide is prepared using the above method.¹H NMR(300MHz,CDCl₃)δ 7.42-7.37(m,2H),7.13-7.07(m,2H),4.26(m,1H),4.24(s,2H),3.46-3.42(m,2H),3.20- 3.16(m,2H),2.05-2.00(m,2H)。

Preparation method 11:6- phenyl -1,2- thiazan 1,1- dioxide

At -78 DEG C to N- (3- bromopropyls) -1- phenyl methanesulfonamides acid amides (2.3g, 7.9mmol), diisopropylamine (0.28mL, N-BuLi 2.0mmol) is added dropwise in tetrahydrofuran (26mL) solution with 1,10- phenanthroline (3.6mg, 0.02mmol) (6.8mL, 2.5M in hexane s), and the reactant is stirred 16 hours.It is subsequently added saturation NH₄Cl, and reactant is used EtOAc dilutes, and with water and salt water washing, uses MgSO₄Dry, concentration, and through silica gel chromatography (0-50%EtOAc/ heptan Alkane), obtain 6- phenyl -1,2-thiazines alkane 1,1- dioxide (1.3g, 80% yield).¹H NMR(300MHz,DMSO-d₆)δ 7.40-7.35(m,5H),6.98(m,1H),4.12(dd,1H),3.26-3.20(m,2H),2.40-2.30(m,1H),2.16- 2.12(m,1H),1.77-1.65(m,2H)。LCMS(ESI),m/z,234[M+Na]⁺.(bibliography:D.Askin etc. Org.Lett.2003,4175.)

The other compounds prepared using the above method are as shown in table 2.

Table 2

Preparation method 19:3- phenyl -1,4,5- oxa- thiazepine cycloheptane 4,4- dioxide

Step 1:N- (2- ((t-butyldimethylsilyi) epoxide) ethyl) -1- phenyl methanesulfonamide acid amides

To 2- ((t-butyldimethylsilyi) epoxide) ethamine (11.7g, 66.6mmol) and triethylamine at 0 DEG C (11.2mL, 79.9mmol) in tetrahydrofuran (222mL) solution it is slow be added portionwise phenyl methanesulfonamide acyl chlorides (12.7g, 66.6mmol), and by the reactant it is stirred at room temperature 16 hours.Then MTBE is added, and Et is removed by filtration₃N·HCl Salt.Then filtrate is concentrated, and through silica gel chromatography (solution of the 0-30% acetone in heptane, 216nM), obtains N- (2- ((t-butyldimethylsilyi) epoxide) ethyl) -1- phenyl methanesulfonamides acid amides (17.8g, 81% yield).LCMS(ESI), m/z,330.[M+H]+。

Step 2:N- (2- ((t-butyldimethylsilyi) epoxide) ethyl) -1- phenyl ethyl sulfonamides

Through sleeve pipe to N- [2- [tert-butyl group (dimethyl) silylation] epoxide ethyl] -1- phenyl-methane-sulfonamides at -78 DEG C (33g, 100.2mmol) is slowly added to n- BuLi (solution of 2.5M in hexane) in tetrahydrofuran (334mL) solution (100mL, 250mmol), and the reactant is stirred 2 hours at -78 DEG C.Be then slowly added to chloroiodomethane (8.3mL, 110mmol), and by the reactant stirred one hour at -78 DEG C, be then heated up to room temperature, and aging 16 hours.Then will reaction Thing saturation NH₄Cl is quenched, and is extracted with dichloromethane, uses MgSO₄Dry, concentration, and through silica gel chromatography (0-60% Solution of the EtOAc in heptane), obtain N- [2- [tert-butyl group (dimethyl) silylation] epoxide ethyl] -1- phenyl-ethylene sulphonyl Amine (24g, 70% yield).LCMS(ESI),m/z,342.[M+H]+.

Step 3:3- phenyl -1,4,5- oxa- thiazepine cycloheptane 4,4- dioxide

At 0 DEG C to N- (2- ((t-butyldimethylsilyi) epoxide) ethyl) -1- phenylethylenes sulfonamide (717mg, 2.1mmol) be added dropwise in tetrahydrofuran (7mL) solution tetrabutyl ammonium fluoride (1.0M in THF) (2.2mL, 2.2mmol), and by reactant it is stirred at room temperature 16 hours.Then saturation NH is added₄Cl, and by the product dichloromethane (x2) extract, use MgSO₄Dry, concentration, and through silica gel chromatography (solution of the 0-100%EtOAc in heptane), obtain 3- phenyl -1,4,5- oxa- thiazepine cycloheptane 4,4- dioxide (401mg, 84% yield).(24g, 70% yield). LCMS(ESI),m/z,228.[M+H]+.(bibliography：The Org.Lett.2008,2951 such as P.Hansen).

The other compounds prepared using the above method are as shown in table 3.

Table 3

The 2- of preparation method 24 (the bromo- 2- luorobenzyls of 4-) -6- phenyl -1,2- thiazan 1,1- dioxide

To 6- phenyl -1,2- thiazan 1,1- dioxide (300mg, 1.42mmol) and 4- bromo- 1- (bromine first at 0 DEG C Base) -2- fluorobenzene (456mg, 1.7mmol) adds sodium hydride in DMAC N,N' dimethyl acetamide (5mL) solution (60% in mineral Solution in oil) (68mg, 1.85mmol), and reactant is stirred at room temperature 2 hours.Water is added, and reactant is used EtOAc dilutes, and uses salt water washing, uses MgSO₄Dry, filter and through silica gel chromatography (0-60%EtOAc/ heptane), obtain To 2- (the bromo- 2- luorobenzyls of 4-) -6- phenyl -1,2-thiazines alkane 1,1- dioxide, be non-enantiomer mixture (396mg, 70% yield).LCMS(ESI),m/z,398[M+H]+.

(3S) -2- (the bromo- 2- luorobenzyls of 4-) -3- methyl -6- phenyl -1,2- thiazans 1,1- is prepared according to similarly method Dioxide.

Examples 1 and 2:[1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazans - 2- yls] methyl] phenyl] ethyl] -3H-1,3,4- oxadiazole -2- ketone (isomers A and isomers B)

Step 1:(3S, 6R) -2- (the bromo- 2,5- difluorobenzyls of 4-) -3- methyl -6- phenyl -1,2- thiazan 1,1- dioxies Compound

One mechanical stir is installed on a 3L flask, and load under a nitrogen (3S, 6R) -3- methyl -6- phenyl - Thiazan 1,1- dioxide (100g, 444mmol), 1- bromo- 4- (chloromethyl) -2,5- difluorobenzenes (122g, 488mmol) in N, Solution in dinethylformamide (800mL), 0 DEG C is cooled to by the solution.Under mechanical stirring, added and hydrogenated with small batch Sodium (60% solution in mineral oil, 18.6g, 466mmol), and reactant is stirred 30 minutes at 0 DEG C, then it is heated up to room Temperature.Reactant is stirred at such a temperature 2 hours.Then water (1.5L) is added, and precipitation, vacuum drying 16 is collected by filtration Hour, obtain thick material.The precipitation is suspended in 2.5L heptane:Ethyl acetate:Methanol (1:1:0.5) in, and by the suspension It is heated to backflow.Then acetone (100mL) is added to complete the dissolving of the material, and the solution was slowly cooled to after 1 hour Room temperature, is then stored 16 hours at -23 DEG C.Gained crystal is collected by filtration, obtaining (3S, 6R) -2-, [(bromo- 2, the 5- bis- of 4- are fluoro- Phenyl) methyl] -3- methyl -6- phenyl-thiazan 1,1- dioxide (145g, 76% yield).¹H NMR(400MHz, DMSO-d₆) δ 7.71 (dd, J=9.2,5.6Hz, 1H), 7.50-7.44 (m, 2H), 7.44-7.33 (m, 4H), 4.58 (dd, J= 12.8,3.5Hz, 1H), 4.51 (d, J=17.9Hz, 1H), 4.37 (d, J=17.8Hz, 1H), 4.20-4.06 (m, 1H), 2.48-2.38 (m, 1H), 2.15-2.07 (m, 1H), 1.90-1.73 (m, 1H), 1.72-1.62 (m, 1H), 1.12 (d, J= 6.8Hz,3H)。

Step 2:2- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] tert-butyl acetate

Load (3S, 6R) -2- [(the bromo- 2,5- difluorophenyls of 4-) methyl] -3- methyl -6- in a 500-mL flask Phenyl-thiazan 1,1- dioxide (10.0g, 23.2mmol), double (dibenzylidene) palladiums (352mg, 0.58mmol) and 1,2, 3,4,5- five phenyl -1'- (di-t-butyl phosphino-) ferrocene (435mg, 0.58mmol), 2 points are swept by flask nitrogen punching Clock.Then (0.5M is in Et for addition tetrahydrofuran (50mL) and 2- tert-butoxy -2- oxoethyls zinc chloride₂Solution in O, 60mL, 30mmol), reactant is stirred at room temperature 4 hours.After the completion of, by reactant saturation NH₄Cl solution is quenched, and (x2) is extracted with dichloromethane, MgSO is used₄Dry, filter, concentration, and (0%-60% acetone is in heptan through silica gel chromatography Solution in alkane), obtain 2- [2,5- bis- fluoro- 4- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] Methyl] phenyl] tert-butyl acetate (10.6g, 98% yield).¹H NMR(400MHz,CDCl₃)δ7.50–7.43(m,2H), 7.43-7.33 (m, 4H), 6.94 (dd, J=10.0,5.8Hz, 1H), 4.52 (d, J=17.0Hz, 1H), 4.39 (d, J= 17.1Hz, 1H), 4.33-4.20 (m, 1H), 3.98 (dd, J=13.0,3.5Hz, 1H), 3.53 (s, 2H), 2.74-2.58 (m, 1H), 2.28-2.18 (m, 1H), 1.81-1.72 (m, 2H), 1.44 (s, 9H), 1.14 (d, J=6.9Hz, 3H)

Step 3:2- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] methyl acetate

By 2- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] tert-butyl acetate (2.68g, 5.76mmol) is suspended in hydrogen chloride in methanol (100mL) solution.By by HCl gas Body (it is produced by the way that sulfuric acid is added slowly on sodium chloride) blasts in methanol 15 minutes to prepare HCl solution.By reactant plus Heat is stirred 16 hours to 55 DEG C, and at such a temperature, until the material is completely dissolved.Solvent is evaporated under reduced pressure, and by gained solid It is dissolved in ethyl acetate (250mL), and is washed with saturated sodium bicarbonate aqueous solution (100mL) and salt solution (100mL), uses MgSO₄ Dry, filtering, and concentrate, obtain 2- [2,5- bis- fluoro- 4- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazans - 2- yls] methyl] phenyl] methyl acetate (2.46g,>99% yield), it is directly used without further purification.LCMS(ESI), m/z,424.3[M+H]⁺。

Step 4:2- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] methyl propionate

Load 2- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazans-in the vial 2- yls] methyl] phenyl] methyl acetate (300mg, 0.71mmol) and DMF (3.5mL), and the solution is cold But to 0 DEG C.Sodium hydride (60% in mineral oil, 40mg, 0.99mmol) is added, and the solution is stirred 15 minutes at 0 DEG C.So Iodomethane (0.055mL., 0.89mmol) is added afterwards, and reactant is heated up to room temperature, is stirred 30 minutes at such a temperature.Will Reactant is quenched with saturated aqueous ammonium chloride (15mL), and product is extracted with ethyl acetate into (2x15mL), uses MgSO₄It is dry It is dry, filter, concentration, through silica gel chromatography (solution of the 0%-60%EtOAc in heptane), obtains 2- [2,5- bis- fluoro- 4- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] phenyl] methyl propionate (184mg, 59% Yield).LCMS(ESI),m/z,438.3[M+H]⁺。

Step 5:2- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] propionyl hydrazine

To 2- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] methyl propionate (184mg, 0.42mmol) adds hydrazine hydrate (0.13mL, 4.2mmol) in methanol (3mL) suspension, And stir reactant 48 hours at 65 DEG C.Then reactant is concentrated under reduced pressure, obtain 2- [2,5- bis- fluoro- 4- [[(3S, 6R)- 3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] phenyl] propionyl hydrazine (184mg,>99% yield), its without It is further purified and directly uses.LCMS(ESI),m/z,438.3[M+H]⁺。

Step 6:5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- Base] methyl] phenyl] ethyl] -3H-1,3,4- oxadiazole -2- ketone

By 2- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] propionyl hydrazine (184mg, 0.42mmol) and triethylamine (0.089mL, 0.63mmol) be at N,N-dimethylformamide (3mL) In solution be cooled to 0 DEG C.Then 1,1'- carbonyl dimidazoles (139mg, 0.84mmol) are added, and by reactant in 0 DEG C of stirring 1 hour, room temperature is heated up to, and is stirred at such a temperature one hour.Reactant mixture directly inverted preparation HPLC is pure Change, obtain 5- [1- [2,5- bis- fluoro- 4- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -3H-1,3,4- oxadiazole -2- ketone (91mg, 0.20mmol, 47% yield).Chiral pillar layer separation isomery Body, obtains 5- [1- [2,5- bis- fluoro- 4- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -3H-1,3,4- oxadiazole -2- ketone (35.1mg, 18% yield) (isomers A) and 5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] phenyl] ethyl] -3H-1,3,4- Evil bis- Azoles -2- ketone (isomers B) (40.0mg, 21% yield).

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -3H-1,3,4- oxadiazole -2- ketone (isomers A):¹H NMR(400MHz,DMSO-d₆)δ12.21(s,1H), 7.49–7.44(m,2H),7.44–7.34(m,3H),7.31–7.23(m,2H),4.60–4.48(m,2H),4.42–4.30(m, 2H),4.19–4.06(m,1H),2.48–2.37(m,1H),2.18–2.04(m,1H),1.89–1.72(m,1H),1.72–1.61 (m, 1H), 1.52 (d, J=7.1Hz, 3H), 1.12 (d, J=6.9Hz, 3H)；LCMS(ESI),m/z,464.2[M+H]⁺。

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -3H-1,3,4- oxadiazole -2- ketone (isomers B):¹H NMR(400MHz,DMSO-d₆)δ12.21(s,1H), 7.50-7.44 (m, 2H), 7.44-7.33 (m, 3H), 7.27 (dd, J=10.0,6.5Hz, 2H), 4.63-4.48 (m, 2H), 4.43–4.29(m,2H),4.20–4.08(m,1H),2.47–2.37(m,1H),2.16–2.04(m,1H),1.88–1.73(m, 1H), 1.72-1.63 (m, 1H), 1.52 (d, J=7.2Hz, 3H), 1.13 (d, J=6.8Hz, 3H)；LCMS(ESI),m/z, 464.2[M+H]⁺。

Embodiment 3:5- [the fluoro- 4- of 2,5- bis- ((3S, 6R)-3- methyl isophthalic acids, the λ * 6*- [1,2] of 1- dioxo-6- phenyl-1- Thiazan -2- ylmethyls)-benzyl) -3H- [1,3,4] oxadiazole -2- ketone

Step 1:[the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazine Alkane -2- ylmethyls)-phenyl]-acetic acid

By [the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazan -2- Ylmethyl)-phenyl]-tert-butyl acetate (embodiment 1, step 2)；300mg, 0.64mmol) and p-methyl benzenesulfonic acid monohydrate The mixture of (25mg, 0.13mmol) in toluene (15mL) is stirred and in 90 DEG C of heating.Solvent is removed in vacuum after 1.5 hours, And by residue H₂O is ground.Solid is removed by filtration, H is then used₂O wash, and dry, obtain white solid (245mg, 93% yield).¹H NMR(300MHz,CDCl₃) δ 7.49-7.34 (6H, m), 7.00-6.92 (1H, m), 4.52 (1H, d, J= 17.2Hz), 4.39 (1H, d, J=17.1Hz), 4.33-4.19 (1H, m), 3.98 (1H, dd, J=12.9,3.5Hz), 3.67 (2H, s), 2.73-2.56 (1H, m), 2.28-2.17 (1H, m), 1.82-1.71 (2H, m), 1.14 (3H, d, J=6.9Hz). LCMS (method A), m/z, 432 [M+Na]⁺。

Step 2:N'- { 2- [the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, the λ * 6*- [1,2] of 1- dioxo -6- phenyl -1 Thiazan -2- ylmethyls)-phenyl]-acetyl group }-hydrazine t-butyl formate

At room temperature by stirred [the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- benzene in argon gas Base -1 λ * 6*- [1,2] thiazan -2- ylmethyls)-phenyl] the solution use of-acetic acid (0.32g, 0.78mmol) in DCM (7mL) DMF (1 drop) processing, is then handled with oxalyl chloride (136 μ L, 1.56mmol).After 1 hour, solvent is removed in vacuum, and gained is consolidated Body is dissolved in DCM (5mL).By the solution add hydrazine t-butyl formate (155mg, 1.17mmol) and triethylamine (327 μ L, 2.35mmol) in DCM (5mL) solution, in stirring at 0 DEG C in argon gas.The mixture is heated up to room temperature, after 2 hours Solvent is removed in vacuum.By residue in EtOAc and H₂Between O distribute, and by EtOAc extracts 0.5M aqueous citric acid solutions, H₂O、NaHCO₃, salt water washing, use MgSO₄Dry, filtering, and concentrate.By residue be purified by flash chromatography with MeOH in DCM Solution (0-4%) gradient elution purifying, obtain the title compound (0.35g, 85% yield) of pale solid.LCMS (sides Method A), m/z, 522 [M-1]^-。

Step 3:[the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazine Alkane -2- ylmethyls)-phenyl]-acethydrazide

At room temperature by stirred N'- { 2- [the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazan -2- ylmethyls)-phenyl]-acetyl group }-hydrazine t-butyl formate (0.35g, 0.67mmol) is in MeOH Solution in (8mL) is handled with HCl (solution of the 4N in the dioxane of Isosorbide-5-Nitrae-, 3mL).Solvent is removed in vacuum after 2 hours, by remnants Thing is again dissolved in MeOH, applied to SCX-2 posts, is washed with MeOH, then the ammonia solution recovery product with 2M in MeOH.Steam Hair, obtains the title compound (0.18g, 64% yield) of yellow solid.LCMS (method A), m/z, 424 [M+H]⁺。

Step 4:5- [the fluoro- 4- of 2,5- bis- ((3S, 6R)-3- methyl isophthalic acids, the λ * 6*- [1,2] of 1- dioxo-6- phenyl-1-thiophene Piperazine -2- ylmethyls)-benzyl) -3H- [1,3,4] oxadiazole -2- ketone

At 0 DEG C in argon gas by it is stirred [the fluoro- 4- of 2,5- bis- (and (3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl - 1 λ * 6*- [1,2] thiazan -2- ylmethyls)-phenyl]-acethydrazide (90mg, 0.21mmol) and triethylamine (45 μ L, 0.32mmol) 1,1 '-carbonyl dimidazoles of solution (69mg, 0.42mmol) processing in DMF (1.5mL).Should after 1 hour Mixture is in EtOAc and H₂Distributed between O, and by EtOAc extracts H₂O, salt water washing, use MgSO₄Dry, filtering, and Concentration.Residue be purified by flash chromatography solution (0-10%) gradient elutions of EtOAc in DCM are purified, white are obtained solid The title compound (38mg, 40% yield) of body.¹H NMR(400MHz,DMSO-d₆)δ12.20(1H,br s),7.44(2H, M), 7.36 (3H, m), 7.26 (2H, m), 4.52 (2H, m, J=13.9Hz), 4.36 (1H, d, J=16.2Hz), 4.14-4.06 (1H, m), 3.96 (2H, s), 2.41 (1H, m), 2.08 (1H, m), 1.78 (1H, m), 1.64 (1H, m), 1.09 (3H, d, J= 5.0Hz)；LCMS (method B), m/z, 450.1 [M+H]⁺。

Embodiment 4:{ 5- [the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, the λ * 6*- [1,2] of 1- dioxo -6- phenyl -1 Thiazan -2- ylmethyls)-benzyl]-[1,3,4] oxadiazole -2- bases) methanol

Step 1:Acetic acid 2- (N'- { 2- [the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, the λ * of 1- dioxo -6- phenyl -1 6*- [1,2] thiazan -2- ylmethyls)-phenyl]-acetyl group }-diazanyl) -2- oxo-ethyl esters

At room temperature by stirred [the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- benzene in argon gas Base -1 λ * 6*- [1,2] thiazan -2- ylmethyls)-phenyl]-acethydrazide (embodiment 1, step 5)；228mg, 0.54mmol) and Solution of the triethylamine (150 μ L, 1.07mmol) in DCM (7mL) is with acetoxy acetyl chloride (60 μ L, 0.54mmol).1.5 it is small Shi Hou, is removed in vacuum solvent, and residue is distributed between EtOAc and 0.5M aqueous citric acid solutions.EtOAc extracts are used H₂O, salt water washing, use MgSO₄Dry, filtering, and concentrate.Solution by residue be purified by flash chromatography with MeOH in DCM (0-2.5%) gradient elution is purified, and obtains the title compound (0.10g, 35% yield) of white solid.LCMS (method A), m/ z,522[M-1]^-。

Step 2:Acetic acid 5- [the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, the λ * 6*- [1,2] of 1- dioxo -6- phenyl -1 Thiazan -2- ylmethyls)-benzyl]-[1,3,4] oxadiazole -2- ylmethyl esters

In argon gas by acetic acid 2- (N'- 2- [the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl - 1 λ * 6*- [1,2] thiazan -2- ylmethyls)-phenyl]-acetyl group }-diazanyl) -2- oxo-ethyls ester (0.10g, 0.19mmol), triethylamine (55 μ L, 0.39mmol) and paratoluensulfonyl chloride (73mg, 0.38mmol) are mixed in DCM (4mL) Compound is stirred at room temperature 18 hours.Solvent is removed in vacuum, and residue is divided between EtOAc and 0.5M aqueous citric acid solutions Match somebody with somebody.By EtOAc extracts H₂O, salt water washing, use MgSO₄Dry, filtering, and concentrate.Residue be purified by flash chromatography is used Solution (0-25%) gradient elution purifying of the EtOAc in DCM, obtains title compound (61mg, 63% production of white solid Rate).LCMS (method A), m/z, 506 [M+H]⁺。

Step 3:{ 5- [the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiophene Piperazine alkane -2- ylmethyls)-benzyl]-[1,3,4] oxadiazole -2- bases) methanol

At room temperature by stirred acetic acid 5- [the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazan -2- ylmethyls)-benzyl]-[1,3,4] oxadiazole -2- ylmethyls esters (61mg, 0.12mmol) exist Solution in MeOH (3mL) is handled with the 1M NaOH aqueous solution (130 μ L, 0.13mmol).After 1 hour, 0.5M citric acid waters are added Solution, and solvent is removed in vacuum.The residue is distributed between EtOAc and 0.5M aqueous citric acid solutions.By EtOAc extracts Use H₂O, salt water washing, use MgSO₄It is dried, filtered and concentrated.Solution by crude product through flash chromatography with EtOAc in DCM (0-20%) gradient elution is purified, and obtains the title compound (37mg, 66% yield) of white solid.¹H NMR(400MHz, DMSO-d₆) δ 7.43 (2H, m), 7.36 (3H, m), 7.27 (2H, m), 5.79 (1H, t, J=7.1Hz), 4.53 (4H, m), 4.36 (1H, d, J=17.2Hz), 4.27 (2H, s), 4.09 (1H, m), 2.43 (1H, m), 2.06 (1H, m), 1.78 (1H, m), 1.65 (1H, m), 1.10 (3H, d, J=6.7Hz)；LCMS (method B), m/z, 464.1 [M+H]⁺。

Embodiment 5 and 6:5- { (R)-[the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, the λ * of 1- dioxo -6- phenyl -1 6*- [1,2] thiazan -2- ylmethyls)-phenyl]-oxetanes -3- bases-methyl -3H- [1,3,4] oxadiazole -2- ketone and 5- { (S)-[the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazan -2- Ji Jia Base)-phenyl] oxetanes -3- bases-methyl } -3H- [1,3,4] oxadiazole -2- ketone

Stirring [the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazan - 2- ylmethyls)-phenyl]-tert-butyl acetate (300mg, 0.64mmol) and p-methyl benzenesulfonic acid monohydrate (25mg, 0.13mmol) In PhCH₃Mixture in (15mL) and in 90 DEG C of heating.It is removed in vacuum solvent after 1.5 hours, and by residue H₂O is ground. Solid is removed by filtration, H is used₂O is washed, and uses MgSO₄Dry, obtain title compound, be white solid (245mg, 93%).¹H NMR(300MHz,CDCl₃) δ 7.49-7.34 (6H, m), 7.00-6.92 (1H, m), 4.52 (1H, d, J=17.2Hz), 4.39 (1H, d, J=17.1Hz), 4.33-4.19 (1H, m), 3.98 (1H, dd, J=12.9,3.5Hz), 3.67 (2H, s), 2.73- 2.56 (1H, m), 2.28-2.17 (1H, m), 1.82-1.71 (2H, m), 1.14 (3H, d, J=6.9Hz).LCMS (method A):m/ z,432[M+Na]⁺。

Step 2:[the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazine Alkane -2- ylmethyls)-phenyl]-methyl acetate

At room temperature by stirred solution of the product (1.0g, 2.2mmol) of step 1 in DCM (15mL) in argon gas With DMF (1 drop) processing, then handled with oxalyl chloride (220 μ L, 2.6mmol).After 1 hour, solvent is removed in vacuum, gained is consolidated Body is again dissolved in DCM (5mL), and is added dropwise in anhydrous MeOH (10mL).After stirring 0.5 hour, solvent is removed in vacuum Afterwards, by gained solid triturated under ether, and filter, obtain title compound, be brown solid (780mg, 84%, 2 step) 。¹H NMR(300MHz,CDCl₃)δ7.49-7.43(2H),7.41-7.36(3H,m),6.99-6.93(2H,m),4.46(2H, Dd, J=16.6,39.9), 4.26 (1H, m), 3.99 (1H, dd, J=3.7,13.0Hz), 3.72 (3H, s), 3.62 (2H, s), 2.65 (1H, m), 2.23 (1H, m), 1.77 (2H, m), 1.15 (3H, d, J=7.3Hz).

Step 3:Diazo-[the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, the λ * 6*- of 1- dioxo -6- phenyl -1 [1, 2] thiazan -2- ylmethyls)-phenyl]-methyl acetate

To the product (0.360g, 0.85mmol) and acetylaminobenzene sulfuryl azide of step 2 in argon gas (0.245g, 1.02mmol) is in CH₃DBU (0.18mL, 1.2mmol) is added dropwise in stirred solution in CN (8mL).Will be anti- Answer thing to stir 4 hours, be concentrated in vacuo, and purified through silica gel column chromatography (5%-40%EtOAc/ hexamethylenes), obtain title compound Thing, is yellow solid (0.350g, 92%).

Step 4:[the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazine Alkane -2- ylmethyls)-phenyl]-oxetanes -3- bases-methyl acetate

To 3- hydroxyls oxetanes (0.065g, 0.88mmol) and Rh (OAc) in argon gas₄(9mg, 0.02mmol's) De gassed solution of the product of step 3 (0.200g, 0.44mmol) in DCM (3mL) is added dropwise in de gassed solution.By the green Solution is stirred 1 hour, is concentrated in vacuo, and is purified through silica gel column chromatography (7%-40%EtOAc/ hexamethylenes), obtains title compound Thing (product A) and accessory substance (product B) (combined yield：0.180g,A:B-2.5:1).LC/MS (method A):Product A, m/z, 518[M+Na]⁺；Product B, m/z, 462 [M+Na]⁺。

Step 5:[the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazine Alkane -2- ylmethyls)-phenyl]-oxetanes -3- bases-acethydrazide

Hydrazine monohydrate (0.1mL) is added into solution of the product (0.102g) of step 4 in IMS (5mL), and should Solution is heated to 80 DEG C and continues 16 hours.Solvent is removed in vacuum, and by residue in 10%MeOH/EtOAc and water (3:1, Distributed between 100mL).By organic layer H₂O, salt water washing, use MgSO₄Dry, filtering, and be concentrated in vacuo, obtain white solid (0.1g), it is directly used in next step.LC/MS (method A):m/z,518[M+Na]⁺。

Step 6:5- (R)-[the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, the λ * 6*- of 1- dioxo -6- phenyl -1 [1, 2] thiazan -2- ylmethyls)-phenyl]-oxetanes -3- bases-methyl } -3H- [1,3,4] oxadiazole -2- ketone and 5- (S) - [the fluoro- 4- of 2,5- bis- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazan -2- ylmethyls)-benzene Base] oxetanes -3- bases-methyl } -3H- [1,3,4] oxadiazole -2- ketone

Solution Et at 0 DEG C by the product (0.1g) of step 5 in DMF (5mL)₃N (0.04mL, 0.3mmol) and 1, 1 '-carbonyl dimidazoles (0.1g, 0.6mmol) processing.After stirring 1 hour, by the mixture in EtOAc and H₂Distributed between O, and By EtOAc extracts H₂O, salt water washing, use MgSO₄Dry, filtering, and be concentrated in vacuo.By residue through silica gel column chromatography (0%-10%EtOAc/DCM) is purified, and is obtained title compound, is non-enantiomer mixture (32mg), and it is with SFC points From.

Stereoisomer A：¹H NMR(400MHz,DMSO-d₆)δ12.5(1H,br s),7.48-7.45(2H,m),7.42- 7.37(3H,m),7.33-7.29(2H,m),5.72(1H,s),4.84-4.78(1H,m),4.68-4.54(4H,m),4.47- 4.38(3H,m),4.17-4.09(1H,m),2.45(1H,m),2.11(1H,m),1.86-1.75(1H,m),1.70-1.65 (1H, m), 1.13 (3H, d, J=6.9Hz).LC/MS (method B):m/z,522[M+H]⁺,521[M-H]^-。

Stereoisomer B：¹H NMR(400MHz,DMSO-d₆)δ12.5(1H,br s),7.47-7.45(2H,m),7.40- 7.35(3H,m),7.32-7.28(2H,m),5.71(1H,s),4.84-4.78(1H,m),4.68-4.52(4H,m),4.47- 4.39(3H,m),4.18-4.08(1H,m),2.45(1H,m),2.11(1H,m),1.87-1.76(1H,m),1.70-1.60 (1H, m), 1.12 (3H, d, J=6.9Hz).LC/MS (method B):m/z,522[M+H]⁺,521[M-H]^-。

Embodiment 7 and 8:5- (2- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiophenes Piperazine alkane -2- bases) methyl) phenyl) propyl- 2- yls) (3H) -one of -1,3,4- oxadiazoles -2 and 5- (2- (the fluoro- 4- of 2,5- bis- (((3S, 6S) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazan -2- bases) methyl) phenyl) propyl- 2- yls) -1,3,4- oxadiazoles - 2 (3H) -one

Step 1:2- (the fluoro- 4- of 2,5- bis- (((3S) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazan -2- bases) Methyl) phenyl) -2 Methylpropionic acid methyl esters

Load 2- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazine in a bottle Alkane -2- bases] methyl] phenyl] methyl acetate (300mg, 0.71mmol) and DMF (3.5mL), and this is molten Liquid is cooled to 0 DEG C.Sodium hydride (60% solution in mineral oil, 142mg, 3.5mmol) is added, and the solution is stirred at 0 DEG C Mix 15 minutes.Then iodomethane (0.266mL, 4.2mmol) is added, and reactant is heated up to room temperature, and is stirred at such a temperature Mix 30 minutes.Reactant is quenched with saturated aqueous ammonium chloride (15mL), and (2x15mL) is extracted with ethyl acetate in product, Use MgSO₄Dry, filtering concentrates and through silica gel chromatography, obtains title compound (203mg, 63% yield).LCMS (ESI):M/z=452 [M+H]⁺。

Step 2:2- (the fluoro- 4- of 2,5- bis- (((3S) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazan -2- bases) Methyl) phenyl) -2- methyl-prop hydrazides

The product of step 1 is reacted as described in the step 5 of embodiment 1, title compound is obtained.LCMS(ESI):M/z= 452[M+H]⁺。

Step 3:5- (2- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) propyl- 2- yls) (3H) -one of -1,3,4- oxadiazoles -2 and 5- (2- (the fluoro- 4- of 2,5- bis- (((3S, 6S) -3- Methyl isophthalic acid, 1- dioxo -6- phenyl -1,2- thiazan -2- bases) methyl) phenyl) propyl- 2- yls) -1,3,4- oxadiazoles -2 (3H) - Ketone

The product of step 2 is reacted as described in the step 6 of embodiment 1, title compound is obtained.Two kinds of epimer warps Chiral SFC separation.5- (2- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) propyl- 2- yls) -1,3,4- oxadiazoles -2 (3H) -one:¹H NMR(400MHz,DMSO-d₆)δ11.21(s, 1H), 7.50-7.44 (m, 2H), 7.43-7.35 (m, 3H), 7.32 (dd, J=11.1,6.6Hz, 1H), 7.22 (dd, J= 12.2,6.3Hz, 1H), 4.64-4.47 (m, 2H), 4.38 (d, J=17.8Hz, 1H), 4.21-4.04 (m, 1H), 2.47-2.36 (m, 1H), 2.18-2.06 (m, 1H), 1.89-1.75 (m, 1H), 1.72-1.52 (m, 7H), 1.13 (d, J=6.8Hz, 3H).5- (2- (the fluoro- 4- of 2,5- bis- (((3S, 6S) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazan -2- bases) methyl) phenyl) Propyl- 2- yls) -1,3,4- oxadiazoles -2 (3H) -one:¹H NMR(400MHz,DMSO-d₆)δ12.24(s,1H),7.50–7.44(m, 2H), 7.43-7.32 (m, 4H), 7.25 (dd, J=11.8,6.2Hz, 1H), 4.54 (dd, J=12.6,3.3Hz, 1H), 4.48 (s,2H),3.73–3.56(m,1H),2.83–2.66(m,1H),2.28–2.12(m,1H),2.12–2.02(m,1H),1.73– 1.55 (m, 7H), 1.41 (d, J=7.0Hz, 3H).

Embodiment 9:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazines Alkane -2- bases) methyl) phenyl) ethyl) -1,2- dihydro -3H- pyrazoles -3- ketone

Step 1:2- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) acetic acid

To 2- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazan -2- bases) first Base) phenyl) propanoic acid tert-butyl ester (5g, 10.4mmol) adds trifluoroacetic acid (10mL) in DCM (100mL) solution, and incite somebody to action anti- Thing is answered to be stirred at room temperature 2 hours.Reactant is concentrated, and is dissolved in methyl tertiary butyl ether(MTBE) (20mL) and DCM (2mL).By heptan Alkane (500mL) is added in the solution, and the precipitation to be formed is collected by filtration, vacuum drying, obtain title compound (4.20g, 95% yield).¹H NMR(400MHz,DMSO-d₆)δ12.54(s,1H),7.50–7.43(m,2H),7.43–7.33(m,3H), 7.26-7.15 (m, 2H), 4.63-4.45 (m, 2H), 4.36 (d, J=17.8Hz, 1H), 4.19-4.05 (m, 1H), 3.87 (q, J =7.2Hz, 1H), 2.48-2.37 (m, 1H), 2.16-2.04 (m, 1H), 1.87-1.72 (m, 1H), 1.71-1.62 (m, 1H), 1.39 (dd, J=7.5,1.3Hz, 3H), 1.12 (dd, J=7.0,3.5Hz, 3H).

Step 2:4- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) -3- oxopentanoics

1,1'- carbonyl dimidazoles are added in THF (20mL) solution to the product (2.73g, 6.4mmol) of step 1 (1.12g, 6.7mmol), and reactant is stirred at room temperature 2 hours.Then magnesium chloride (706mg, 7.4mmol) and 3- are added Methoxyl group -3- oxopropanoic acids potassium (1.18g, 7.4mmol), and reactant is stirred 16 hours at 50 DEG C.By reactant mixture mistake Filter, in evaporated onto silica gel, and through silica gel chromatography, obtains title compound (1.78g, 58% yield), is white solid. LCMS(ESI):M/z=480 [M+H]⁺。

Step 3:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) ethyl) -1,2- dihydro -3H- pyrazoles -3- ketone

Added to the product (75mg, 0.16mmol) of step 2 in methanol (0.5mL) solution hydrazine hydrate (0.04mL, 0.8mmol), the solution is stirred 2 hours at 60 DEG C.Then reactant mixture is purified through preparation HPLC, obtains titled Compound (9mg, 0.020mmol, 12% yield).¹H NMR(400MHz,DMSO-d₆)δ11.42(br s,1H),9.45(br s, 1H), 7.50-7.43 (m, 2H), 7.43-7.34 (m, 3H), 7.20 (dd, J=10.2,6.5Hz, 1H), 7.08-6.99 (m, 1H),5.30(s,1H),4.59–4.45(m,2H),4.40–4.30(m,1H),4.29–4.21(m,1H),4.18–4.06(m, 1H),2.46–2.38(m,1H),2.14–2.05(m,1H),1.86–1.72(m,1H),1.71–1.61(m,1H),1.49(d,J =6.7Hz, 3H), 1.10 (dd, J=6.9,4.3Hz, 3H).

Embodiment 10:3- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazines Alkane -2- bases) methyl) phenyl) ethyl) isoxazoles -5 (2H) -one

To 4- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazan -2- bases) first Base) phenyl) -3- oxopentanoics (110mg, 0.23mmol) and hydroxylamine hydrochloride (42mg, 0.57mmol) be in methanol (1mL) Triethylamine (0.08mL, 0.6mmol) is added in solution, and reactant is stirred 16 hours at 60 DEG C.Then by reactant through system Standby type HPLC purifying, obtains title compound (10mg, 9% yield).¹H NMR(400MHz,DMSO-d₆)δ7.50–7.44(m, 2H),7.44–7.35(m,3H),7.26–7.13(m,2H),6.51(s,1H),4.59–4.46(m,2H),4.41–4.31(m, 1H),4.20–4.05(m,2H),2.47–2.37(m,1H),2.15–2.04(m,1H),1.88–1.74(m,1H),1.71–1.63 (m, 1H), 1.49-1.41 (m, 3H), 1.11 (d, J=7.0Hz, 3H).

Embodiment 11:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazines Alkane -2- bases) methyl) phenyl) ethyl) -2,4- dihydro -3H-1,2,4- triazole -3- ketone

Step 1:2- (2- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) propiono) hydrazine -1- formamides

To 2- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] at 0 DEG C Methyl] phenyl] propionic acid (300mg, 0.71mmol) and triethylamine (0.5mL 3.5mmol) add in DMF (3.5mL) solution HATU (416mg, 1.1mmol), and reactant is stirred 10 minutes at such a temperature.Then semicarbazides hydrochloride is added (118mg, 1.1mmol), and reactant is stirred at room temperature 1 hour.Add saturation NaHCO₃The aqueous solution, and by the mixture Diluted with isopropyl acetate, with water and salt water washing, concentration, and through silica gel chromatography, obtain title compound (216mg, 64% yield).LCMS(ESI):M/z=481 [M+H]⁺。

Step 2:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) ethyl) -2,4- dihydro -3H-1,2,4- triazole -3- ketone

The product (216mg, 0.45mmol) of step 1 is dissolved in 1M NaOH (10mL), and reactant is stirred at 110 DEG C Mix 3 hours.Reactant is acidified to pH=1 with dense HCl, and extracted (x3) with DCM, MgSO is used₄Dry, filter, concentration is used in combination Silica gel chromatography, obtains title compound (31mg, 15% yield).¹H NMR(400MHz,DMSO-d₆)δ11.33(s, 1H), 11.25-11.20 (m, 1H), 7.49-7.45 (m, 2H), 7.42-7.36 (m, 3H), 7.23 (dd, J=10.6,6.2Hz, 1H), 7.14-7.06 (m, 1H), 4.58-4.46 (m, 2H), 4.36 (d, J=17.8Hz, 1H), 4.20-4.09 (m, 2H), 2.47-2.42 (m, 1H), 2.13-2.06 (m, 1H), 1.85-1.73 (m, 1H), 1.72-1.60 (m, 1H), 1.48 (dd, J= 7.3,5.0Hz, 3H), 1.12 (d, J=6.9Hz, 3H).

Embodiment 12:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazines Alkane -2- bases) methyl) phenyl) ethyl) -4- methyl -2,4- dihydro -3H-1,2,4- triazole -3- ketone

Step 1:2- (2- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) propiono)-N- methyl hydrazine -1- formamides

By 2- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazan -2- bases) first Base) phenyl) propionic acid reacted with N- methyl Hydrazinecarboxamidederivatives as described in the step 1 of embodiment 5, obtains title compound.LCMS (ESI):M/z=495 [M+H]⁺。

Step 2:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) ethyl) -4- methyl -2,4- dihydro -3H-1,2,4- triazole -3- ketone

The product of step 1 is reacted as described in the step 2 of embodiment 5, title compound is obtained.¹H NMR (400MHz,DMSO-d₆) δ 11.58 (s, 1H), 7.50-7.43 (m, 2H), 7.43-7.33 (m, 3H), 7.27 (dd, J=10.6, 6.1Hz, 1H), 6.98 (dd, J=10.3,6.0Hz, 1H), 4.60-4.44 (m, 2H), 4.43-4.26 (m, 2H), 4.18-4.03 (m, 1H), 2.88 (d, J=2.5Hz, 3H), 2.47-2.37 (m, 1H), 2.15-2.04 (m, 1H), 1.86-1.73 (m, 1H), 1.70-1.62 (m, 1H), 1.49 (d, J=6.9Hz, 3H), 1.11 (d, J=6.8Hz, 3H).

Embodiment 13:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazines Alkane -2- bases) methyl) phenyl) ethyl) -2- methyl -2,4- dihydro -3H-1,2,4- triazole -3- ketone

Step 1:2- (2- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) propiono) -1- methyl hydrazine -1- formamides

By 2- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazan -2- bases) first Base) phenyl) propionic acid reacted with 1- methyl hydrazine -1- formamides as described in the step 1 of embodiment 5, obtains title compound. LCMS(ESI):M/z=495 [M+H]⁺。

Step 2:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) ethyl) -2- methyl -2,4- dihydro -3H-1,2,4- triazole -3- ketone

The product of step 1 is reacted as described in the step 2 of embodiment 5, title compound is obtained.¹H NMR (400MHz,DMSO-d₆) δ 11.51 (s, 1H), 7.53-7.43 (m, 2H), 7.43-7.33 (m, 3H), 7.24 (dd, J=10.6, 6.1Hz, 1H), 7.13 (dd, J=10.5,6.0Hz, 1H), 4.66-4.45 (m, 2H), 4.41-4.28 (m, 1H), 4.26-4.02 (m, 2H), 3.22 (d, J=2.4Hz, 3H), 2.44-2.35 (m, 1H), 2.21-2.03 (m, 1H), 1.94-1.72 (m, 1H), 1.72-1.55 (m, 1H), 1.48 (d, J=7.3Hz, 3H), 1.12 (d, J=6.9Hz, 3H).

Embodiment 14:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazines Alkane -2- bases) methyl) phenyl) ethyl) -1- methyl isophthalic acids, 2- dihydro -3H-1,2,4- triazole -3- ketone

Step 1:2- (2- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) propiono) -2- methyl hydrazine -1- formamides

By 2- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazan -2- bases) first Base) phenyl) propionic acid reacted with 2- methyl hydrazine -1- formamides as described in the step 1 of embodiment 5, obtains title compound. LCMS(ESI):M/z=495 [M+H]⁺。

Step 2:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) ethyl) -1- methyl isophthalic acids, 2- dihydro -3H-1,2,4- triazole -3- ketone

The product of step 1 is reacted as described in the step 2 of embodiment 5, title compound is obtained.¹H NMR (400MHz,DMSO-d₆)δ10.77(s,1H),7.49–7.43(m,2H),7.42–7.34(m,3H),7.27–7.20(m,1H), 7.15-7.07 (m, 1H), 4.62-4.45 (m, 3H), 4.35 (dd, J=17.8,4.0Hz, 1H), 4.18-4.05 (m, 1H), 3.53 (d, J=2.8Hz, 3H), 2.47-2.37 (m, 1H), 2.15-2.06 (m, 1H), 1.86-1.72 (m, 1H), 1.70-1.62 (m, 1H), 1.53 (dd, J=7.0,1.3Hz, 3H), 1.11 (dd, J=7.0,2.4Hz, 3H).

Embodiment 15:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazines Alkane -2- bases) methyl) phenyl) ethyl) isoxazoles -3 (2H) -one

Step 1:4- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl)-N- hydroxyl -3- oxo pentanamides

To -30 DEG C of 4- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- Base] methyl] phenyl] -3- oxo-pentanoates (1.78g, 3.7mmol) add hydroxide in methanol (15mL) suspension Sodium (solution of 16mL, 0.25M in MeOH), and reactant is stirred 10 minutes at -30 DEG C.Then it is added dropwise at -30 DEG C Hydroxylamine hydrochloride (672mg, 9.3mmol), sodium hydroxide (solution of 37mL, 0.25M in MeOH) and water (5mL), and will reaction Thing is stirred 2 hours at such a temperature.Reactant is diluted with water, and is acidified with dense HCl, is extracted with DCM (x3), is concentrated, and pass through Silica gel chromatography, obtains title compound (1.06g, 59% yield).LCMS(ESI):M/z=481 [M+H]⁺。

Step 2:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) ethyl) isoxazoles -3 (2H) -one

The product (150mg, 0.31mmol) of step 1 is dissolved in MeOH (5mL) and dense HCl (1.5mL).Reactant is existed 80 DEG C are stirred 2 hours.After cooling, the mixture is diluted with water, (x3) is extracted with isopropyl acetate, MgSO is used₄Dry, mistake Filter, and purified through preparation HPLC, obtain title compound (93.5mg, 65% yield).¹H NMR(400MHz,DMSO-d₆)δ 11.18 (s, 1H), 7.50-7.43 (m, 2H), 7.43-7.30 (m, 3H), 7.25 (dd, J=10.4,6.4Hz, 1H), 7.21- 7.11 (m, 1H), 5.87 (d, J=6.0Hz, 1H), 4.62-4.46 (m, 2H), 4.45-4.32 (m, 2H), 4.19-4.06 (m, 1H),2.47–2.37(m,1H),2.15–2.06(m,1H),1.86–1.73(m,1H),1.71–1.62(m,1H),1.54(d,J =7.2Hz, 3H), 1.12 (d, J=6.8Hz, 3H).

Embodiment 16:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazines Alkane -2- bases) methyl) phenyl) ethyl) oxazoles -2 (3H) -one

To 4- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] at 0 DEG C Methyl] phenyl] -3- oxos-pentane hydroxamic acid (1.1g, 2.2mmol) adds N, N- diisopropyls in THF (22mL) solution Ethylamine (0.97mL, 5.5mmol), then adds 4- nitrobenzene sulfonyl chlorides (598mg, 2.4mmol), and will be anti-after 3 hours Thing is answered in 0 DEG C of stirring to room temperature.By reactant saturation NH₄The Cl aqueous solution is quenched, and (x3) is extracted with DCM, MgSO is used₄Dry, mistake Filter, and purified through preparation HPLC, obtain title compound (390mg, 38% yield).¹H NMR(400MHz,DMSO-d₆)δ 10.41 (s, 1H), 7.51-7.44 (m, 2H), 7.44-7.31 (m, 3H), 7.24 (dd, J=10.6,6.1Hz, 1H), 7.16- 7.05 (m, 1H), 6.73 (dd, J=9.1,1.3Hz, 1H), 4.61-4.46 (m, 2H), 4.36 (dd, J=17.8,3.1Hz, 1H),4.18–4.07(m,2H),2.48–2.37(m,1H),2.15–2.06(m,1H),1.87–1.73(m,1H),1.71–1.61 (m, 1H), 1.41 (dd, J=7.1,3.0Hz, 3H), 1.12 (dd, J=7.0,3.0Hz, 3H).

Embodiment 17:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazines Alkane -2- bases) methyl) phenyl) ethyl) -3- methyl isophthalic acids, 3,4- oxadiazoles -2 (3H) -one

To 5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] ethyl] -3H-1,3,4- oxadiazole -2- ketone (150mg, 0.32mmol) adds potassium carbonate in DMF solution (112mg, 0.81mmol) and iodomethane (91mg, 0.64mmol), and reactant is stirred at room temperature 2 hours.By filtering out Lixiviating, and filtrate is purified through preparation HPLC, obtain title compound (34mg, 22% yield).1H NMR(400MHz, DMSO-d₆)δ7.50–7.43(m,2H),7.43–7.34(m,3H),7.34–7.23(m,2H),4.61–4.47(m,2H), 4.43-4.33 (m, 2H), 4.20-4.06 (m, 1H), 3.29 (d, J=1.8Hz, 3H), 2.48-2.36 (m, 1H), 2.15-2.05 (m, 1H), 1.87-1.73 (m, 1H), 1.72-1.62 (m, 1H), 1.52 (dd, J=7.2,2.1Hz, 3H), 1.13 (dd, J= 6.9,2.6Hz,3H)。

Embodiment 18:2- (5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- Thiazan -2- bases) methyl) phenyl) ethyl) -3 (2H)-yl of -2- oxo -1,3,4- oxadiazoles) acetonitrile

By 5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] ethyl] -3H-1,3,4- oxadiazole -2- ketone and the reaction of 2- bromoacetonitriles, described in embodiment 11, obtain titled Compound.¹H NMR(400MHz,DMSO-d₆) δ 7.49-7.43 (m, 2H), 7.43-7.25 (m, 5H), 5.03 (d, J=1.7Hz, 2H),4.61–4.47(m,2H),4.47–4.32(m,2H),4.19–4.05(m,1H),2.48–2.35(m,1H),2.15–2.03 (m, 1H), 1.86-1.72 (m, 1H), 1.71-1.62 (m, 1H), 1.54 (dd, J=7.1,2.4Hz, 3H), 1.13 (dd, J= 7.0,2.6Hz,3H)。

Embodiment 19:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazines Alkane -2- bases) methyl) phenyl) ethyl) -3- (2- hydroxyethyls) -1,3,4- oxadiazoles -2 (3H) -one

By 5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] ethyl] -3H-1,3,4- oxadiazole -2- ketone and ethylene bromohyrin reaction, as described in embodiment 11, obtain title compound Thing.¹H NMR(400MHz,DMSO-d₆)δ7.49–7.44(m,2H),7.43–7.35(m,3H),7.32–7.19(m,2H),4.87 (s,1H),4.63–4.47(m,2H),4.44–4.31(m,2H),4.19–4.06(m,1H),3.76–3.55(m,4H),2.47– 2.38 (m, 1H), 2.16-2.04 (m, 1H), 1.87-1.72 (m, 1H), 1.73-1.62 (m, 1H), 1.53 (dd, J=7.1, 2.4Hz,3H),1.17–1.07(m,3H)。

Embodiment 20:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazines Alkane -2- bases) methyl) phenyl) ethyl) -3- (2,2,2- trifluoroethyls) -1,3,4- oxadiazoles -2 (3H) -one

By 5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] ethyl] -3H-1,3,4- oxadiazole -2- ketone and 2,2,2- trifluoroethyl triflates reaction, by embodiment 11 It is described, obtain title compound.¹H NMR(400MHz,DMSO-d₆)δ7.49–7.43(m,2H),7.43–7.35(m,3H), 7.35–7.25(m,2H),4.71–4.61(m,2H),4.61–4.49(m,2H),4.48–4.34(m,2H),4.19–4.07(m, 1H),2.47–2.37(m,1H),2.15–2.05(m,1H),1.88–1.72(m,1H),1.72–1.62(m,1H),1.53(dd,J =7.2,2.4Hz, 3H), 1.13 (dd, J=7.0,2.5Hz, 3H).

Embodiment 21:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazines Alkane -2- bases) methyl) phenyl) ethyl) -2 (3H) -one of -3- ethyl -1,3,4- oxadiazoles

By 5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] ethyl] -3H-1,3,4- oxadiazole -2- ketone and bromoethane reaction, as described in embodiment 11, obtain title compound 。¹H NMR(400MHz,DMSO-d₆)δ7.51–7.43(m,2H),7.43–7.33(m,3H),7.33–7.23(m,2H),4.62– 4.47(m,2H),4.44–4.33(m,2H),4.22–4.04(m,1H),3.73–3.60(m,2H),2.48–2.36(m,1H), 2.16-2.04 (m, 1H), 1.89-1.73 (m, 1H), 1.72-1.62 (m, 1H), 1.53 (dd, J=7.0,2.2Hz, 3H), 1.21 (td, J=7.2,2.3Hz, 3H), 1.13 (dd, J=6.8,2.6Hz, 3H).

Embodiment 22:2- (5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- Thiazan -2- bases) methyl) phenyl) ethyl) -3 (2H)-yl of -2- oxo -1,3,4- oxadiazoles) acetamide

By 5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] ethyl] -3H-1,3,4- oxadiazole -2- ketone and the reaction of 2- acetbromamides, as described in embodiment 11, obtain titled Compound.¹H NMR(400MHz,DMSO-d₆)δ7.62(s,1H),7.53–7.43(m,2H),7.43–7.35(m,3H),7.35– 7.22 (m, 3H), 4.61-4.48 (m, 2H), 4.44-4.33 (m, 2H), 4.26 (d, J=2.7Hz, 2H), 4.19-4.06 (m, 1H),2.48–2.38(m,1H),2.15–2.08(m,1H),1.88–1.72(m,1H),1.72–1.63(m,1H),1.52(dd,J =7.1,2.6Hz, 3H), 1.13 (dd, J=6.8,3.2Hz, 3H).

Embodiment 23:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazines Alkane -2- bases) methyl) phenyl) ethyl) -3- (2- methoxy ethyls) -1,3,4- oxadiazoles -2 (3H) -one

By 5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] ethyl] -3H-1,3,4- oxadiazole -2- ketone and the bromo- 2- methoxyl groups of 1--ethane reaction, as described in embodiment 11, obtain To title compound.¹H NMR(400MHz,DMSO-d₆)δ7.49–7.43(m,2H),7.43–7.34(m,3H),7.31–7.23 (m, 2H), 4.61-4.48 (m, 2H), 4.46-4.31 (m, 2H), 4.20-4.06 (m, 1H), 3.79 (td, J=5.2,1.9Hz, 2H), 3.56 (td, J=5.3,2.3Hz, 2H), 3.23 (d, J=1.0Hz, 3H), 2.47-2.35 (m, 1H), 2.17-2.03 (m, 1H), 1.89-1.72 (m, 1H), 1.72-1.62 (m, 1H), 1.53 (dd, J=7.1,2.0Hz, 3H), 1.13 (dd, J=7.0, 2.4Hz,3H)。

Embodiment 24:5- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazines Alkane -2- bases) methyl) phenyl) ethyl) (2H) -one of -2- methyl-isoxazoles -3 and (3S, 6R) -2- (fluoro- 4- (1- (3- first of 2,5- bis- Epoxide isoxazole -5-base) ethyl) benzyl) -3- methyl -6- phenyl -1,2- thiazan 1,1- dioxide

To 5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] ethyl] isoxazole -3- ketone (93.5mg, 0.20mmol) in the solution of methanol (1mL) and tetrahydrofuran (1mL) by (trimethylsilyl) diazomethane (solution of 2.0M in hexane, about 0.5mL) is added dropwise to, until yellow is continued above 10 Second.Reactant is stirred 30 minutes under RT, then distributed between water and isopropyl acetate, and extracted with isopropyl acetate. By organic extract MgSO₄Dry, concentrate and purified through supercritical fluid chromatography, obtain 5- [1- [2,5- bis- fluoro- 4- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] phenyl] ethyl]-isoxazole of -2- methyl - 3- ketone (11.6mg, 12% yield):¹H NMR(400MHz,DMSO-d6)δ7.51–7.43(m,2H),7.43–7.32(m,3H), 7.31-7.17 (m, 2H), 5.81 (s, 1H), 4.62-4.48 (m, 2H), 4.37 (d, J=18.0Hz, 1H), 4.30 (q, J= 7.1Hz,1H),4.19–4.05(m,1H),3.32(s,3H),2.48–2.36(m,1H),2.15–2.05(m,1H),1.90– 1.72 (m, 1H), 1.72-1.62 (m, 1H), 1.52 (dd, J=7.3,1.4Hz, 3H), 1.12 (dd, J=6.8,3.3Hz, 3H)； (3S, 6R) -2- [[the fluoro- 4- of 2,5- bis- [1- (3- first epoxides isoxazole -5-base) ethyl] phenyl] methyl] -3- methyl -6- benzene Base-thiazan 1,1- dioxide (17.7mg, 18% yield):¹H NMR(400MHz,DMSO-d₆)δ7.50–7.43(m,2H), 7.43-7.33 (m, 3H), 7.29-7.11 (m, 2H), 6.14 (d, J=6.5Hz, 1H), 4.59-4.47 (m, 2H), 4.43 (q, J =7.1Hz, 1H), 4.36 (dd, J=17.6,2.5Hz, 1H), 4.18-4.07 (m, 1H), 3.85 (d, J=3.6Hz, 3H), 2.47-2.37 (m, 1H), 2.14-2.05 (m, 1H), 1.88-1.72 (m, 1H), 1.71-1.62 (m, 1H), 1.56 (dd, J= 7.2,1.6Hz, 3H), 1.12 (d, J=6.9Hz, 3H).

Embodiment 25:3- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazans - 2- yls] methyl] phenyl] ethyl] -1H- imidazoles -2- ketone

Step 1:N- (1- (4- (((t-butyldimethylsilyi) epoxide) methyl) -2,5- difluorophenyls) ethyl) -2- Methylpropane -2- sulfenamides

To ((the bromo- 2,5- difluorobenzyls of 4-) epoxide) (tert-butyl group) dimethylsilane (10g, 29.8mmol) at -78 DEG C N-BuLi (2.5M, 14.2mL, 35.6mmol) is added dropwise in ether (200mL) solution.By gained mixture -78 DEG C stirring 1 hour, be then added dropwise at -78 DEG C (E)-N- ethylidene -2- methylpropane -2- sulfenamides (5.8g, 39.4mmol) the solution in ether (30mL), reactant mixture is stirred 30 minutes at -78 DEG C.By reactant saturation chlorine Change ammonium salt solution (100mL) quenching, (2 × 100mL) is extracted with EtOAc, is dried with sodium sulphate, filter, and be concentrated under reduced pressure.By remnants Thing is purified through the quick posts of Biotage (40g silica gel, UV254,0-30%PE/EA), obtains title product (10g, 83% yield), For colorless oil.LCMS(ESI):M/z=406.2 [M+H]⁺。

Step 2:N- (1- (2,5- bis- fluoro- 4- (hydroxymethyl) phenyl) ethyl) -2- methylpropane -2- sulfenamides

TBAF (38mL, 38mmol) is added in THF (100mL) solution to the product (7.7g, 19mmol) of step 1, Reactant mixture is stirred 1 hour at 25 DEG C.Solvent is removed, and is diluted with EtOAc (100mL), be then washed with water (50mL × 3), with anhydrous sodium sulfate drying, filtering, and be concentrated in vacuo.By residue be purified by flash chromatography with 0-50%EtOAc in PE Solution is purified by flash, and is obtained title compound (4.9g, 76% yield), is colorless oil.LCMS(ESI):M/z=292.1 [M+H]⁺。

Step 3:N- (1- (4- (chloromethyl) -2,5- difluorophenyls) ethyl) -2- methylpropane -2- sulfenamides

Added at 0 DEG C in DCM (100mL) solution to the product (4.9g, 16.8mmol) of step 2 triethylamine (5.1g, 50.5mmol) with mesyl chloride (3.9g, 33.6mmol).Reactant mixture is stirred overnight at 25 DEG C, then with water (50mL) Quenching, (2 × 50mL) is extracted with DCM, is dried with sodium sulphate, is filtered, and be concentrated under reduced pressure.By residue through the quick posts of Biotage Purify (40g silica gel, UV254, PE/EA=1:0-2:3) title compound (3.4g, 65% yield), is obtained, is white solid. LCMS(ESI):M/z=310.0 [M+H]⁺。

Step 4:N- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) ethyl) -2- methylpropane -2- sulfenamides

(3S, 6R) -3- methyl -6- benzene is added in DMF (50mL) solution to the product (3.4g, 11mmol) of step 3 Base-thiazan 1,1- dioxide (2.9g, 13mmol) and cesium carbonate (12.4g, 38mmol).Reactant is stirred 16 at 25 DEG C Hour, use saturation NH₄Cl solution (100mL) is quenched, and (50mL × 3) are extracted with EtOAc, are dried with sodium sulphate, is filtered, and depressurize Concentration.By residue through Biotage flash columns (40g silica gel, UV254,0-50%PE/EA), title compound is obtained (4.6g, 84% yield), is light yellow oil.LCMS(ESI):M/z=499.2 [M+H]⁺。

Step 5:1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) second -1- ammonium chlorides

Anhydrous HCl is added dropwise in MeOH (20mL) solution to the product (4.6g, 9.2mmol) of step 4 at 0 DEG C to exist Solution (4M, 6.9mL, 27.7mmol) in 1,4- dioxanes.Reactant is stirred 30 minutes at 0 DEG C.Solvent is removed in vacuum, and By crude product triturated under ether, filtering is washed with more ether, is dried 1 hour under high vacuum system, obtain title compound (3.8g, 96% yield), is white solid.LCMS(ESI):M/z=395.2 [M+H]⁺；¹H NMR(400MHz,DMSO-d₆)δ 8.46(s,3H),7.54-7.50(m,1H),7.47-7.46(m,2H),7.40-7.31(m,4H),4.61-4.52(m,3H), 4.43-4.37(m,1H),4.16-4.10(m,1H),2.47-2.44(m,1H),2.13-2.08(m,1H),1.82-1.79(m, 1H),1.69-1.66(m,1H),1.52-1.50(m,3H),1.15-1.11(m,3H)。

Step 6:N- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) ethyl) -1H- imidazoles -1- formamides

Added to the product (150mg, 0.38mmol) of step 5 in THF (10mL) solution CDI (74mg, 0.46mmol).Reactant is stirred 2 hours at 20 DEG C, is then quenched with water (20mL), (2 × 30mL) is extracted with EA, sulfuric acid is used Sodium is dried, filtering, and is concentrated under reduced pressure.Residue be purified by flash chromatography is purified by flash with solution of the 0-30%EtOAc in PE, Title compound (250mg, 98% yield) is obtained, is colorless oil.LCMS(ESI):M/z=489.1 [M+H]⁺。

Step 7:3- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- Base] methyl] phenyl] ethyl] -1H- imidazoles -2- ketone

2,2- dimethoxy second -1- is added in THF (15mL) solution to the product (250mg, 0.45mmol) of step 6 Amine (568mg, 5.4mmol).Reactant is stirred 2 hours at 20 DEG C, then removal of solvent under reduced pressure, MeOH is dissolved in by residue In (4mL) and water (2mL), and add the solution (1.1mL, 4.2mmol) of anhydrous HCl in methyl alcohol.By reactant mixture 25 DEG C stirring 48 hours.Solvent is removed, with EA and H₂O(20mL,1:1) dilute, (20mL × 2) extracted with EA, are dried with sodium sulphate, And be concentrated under reduced pressure.By residue through preparative-HPLC 25-55%CH₃CN/H₂O (0.1%NH₄HCO₃In H₂Solution in O) wash De- purifying, obtains title compound (180mg, 93% yield), is white solid.LCMS(ESI):M/z=462.0 [M+H]⁺；¹H NMR(400MHz,DMSO-d₆)δ10.02(s,1H),7.47-7.45(m,2H),7.41-7.36(m,3H),7.25-7.21(m, 1H),7.11-7.06(m,1H),6.68-6.65(m,1H),6.42-6.39(m,1H),5.42-5.37(m,1H),4.59-4.48 (m,2H),4.38-4.33(m,1H),4.15-4.08(m,1H),2.46-2.39(m,1H),2.11-2.08(m,1H),1.81- 1.73 (m, 1H), 1.68-1.63 (m, 1H), 1.59 (d, J=7.2Hz, 3H), 1.11 (d, J=6.8Hz, 3H).

Embodiment 26:1- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazans - 2- yls] methyl] phenyl] ethyl] imidazolidin-2-one

To 1- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) ethyl) -1,3- dihydro-2 H-imidazol-2-ones (150mg, 0.33mmol) are in MeOH (10mL) solution Pd/C (50mg) is added, reactant is stirred 12 hours in nitrogen atmosphere (1atm) in 25 DEG C.By reactant mixture through diatomite Pad filtering, and filtrate decompression is concentrated.By residue through preparative-HPLC 25-55%CH₃CN/H₂O (0.1%NH₄HCO₃ H₂Solution in O) it is purified by flash, title product (70mg, 46% yield) is obtained, is white solid.LCMS(ESI):M/z= 464.1[M+H]⁺；¹H NMR(400MHz,DMSO-d₆)δ7.47-7.46(m,2H),7.42-7.36(m,3H),7.28-7.22 (m, 2H), 6.35 (d, J=3.2Hz, 1H), 5.16-5.11 (m, 1H), 4.59-4.49 (m, 2H), 4.39-4.35 (m, 1H), 4.15-4.10(m,1H),3.43-3.37(m,1H),3.23-3.18(m,2H),3.14-3.05(m,1H),2.47-2.39(m, 1H), 2.12-2.07 (m, 1H), 1.82-1.75 (m, 1H), 1.68-1.65 (m, 1H), 1.42 (d, J=6.8Hz, 3H), 1.13- 1.10(m,3H)；

Embodiment 27：1- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazans - 2- yls] methyl] phenyl] ethyl] imidazolidine -2,4- diketone

Step 1:N- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) ethyl) cyanamide

To (3S, 6R) -2- (4- (1- amino-ethyls) -2,5- difluorobenzyls) -3- methyl -6- phenyl -1,2- thiazans 1, 1- dioxide (120mg, 0.3mmol) adds BrCN (35mg, 0.33mmol) and NaOAc in MeOH (20mL) solution (50mg,0.61mmol).Reactant mixture is stirred 16 hours at 25 DEG C.Solvent is removed, by residue through silica gel chromatograph 0- Solution of the 5%MeOH in DCM is purified by flash, and is obtained title compound (100mg, 78%), is white solid.LCMS(ESI): M/z=437 [M+Na]⁺。

Step 2:N- cyano group-N- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- Thiazan -2- bases) methyl) phenyl) ethyl) glycine methyl ester

Added to the product (100mg, 0.24mmol) of step 1 in THF (10mL) solution NaH (60%, 10.4mg, 0.26mmol), reactant mixture is stirred 1 hour at 0 DEG C, then adds 2- methyl bromoacetates (36mg, 0.24mmol), will be anti- Mixture is answered to be stirred 16 hours at 25 DEG C.By reactant H₂O (2mL) is quenched, and (2 × 10mL) is extracted with EA, anhydrous slufuric acid is used Sodium is dried, filtering, and is concentrated under reduced pressure.Residue is purified through silica gel chromatograph with 0-5%MeOH/DCM as eluting solvent, obtained Title compound (115mg, 98%), is white solid.LCMS(ESI):M/z=509 [M+Na]⁺。

Step 3:1- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- Base] methyl] phenyl] ethyl] imidazolidine -2,4- diketone

To the product (80mg, 0.16mmol) of step 2 H is added in THF (10mL) solution₂SO₄(32mg, 0.16mmol), and by reactant mixture stirred 16 hours at 25 DEG C.Then the mixture is diluted with EA (20mL), uses saturation NaHCO₃Solution washs (50mL × 2), with anhydrous sodium sulfate drying, filters and is concentrated under reduced pressure.Residue is used through preparation HPLC 25-55%CH₃CN/H₂O (0.1%NH₄HCO₃In H₂Solution in O) it is purified by flash, obtain title product (40mg, 52% production Rate).LCMS(ESI):M/z=495.2 [M+NH₄]⁺；¹H NMR(400MHz,CD₃OD):δ7.52-7.50(m,2H),7.40- 7.34(m,4H),7.24-7.19(m,1H),5.46-5.44(m,1H),4.59-4.46(m,2H),4.38-4.34(m,1H), 4.28-4.23(m,1H),4.13-4.07(m,1H),3.80-3.73(m,1H),2.64-2.60(m,1H),2.24-2.19(m, 1H), 1.91-1.87 (m, 1H), 1.79-1.74 (m, 1H), 1.61 (d, J=7.2Hz, 3H), 1.18 (d, J=6.8Hz, 3H).

Embodiment 28:2- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazans - 2- yls] methyl] phenyl] ethyl] -4H-1,2,4- triazole -3- ketone

Step 1:(3S, 6R) -2- (4- (1- ethoxy ethylenes base) -2,5- difluorobenzyls) -3- methyl -6- phenyl -1,2- Thiazan 1,1- dioxide

To (3S, 6R) -2- [(the bromo- 2,5- difluorophenyls of 4-) methyl] -3- methyl -6- phenyl-thiazan 1,1- titanium dioxides Thing (6.8g, 15.8mmol) and double (triphenylphosphine) palladiums (II) (1.66g, 2.37mmol) of dichloro are in DMF (200mL) solution Tributyl (1- ethoxy ethylenes base) tin (8.56g, 23.7mmol) is added, and the mixture is stirred 16 in nitrogen in 80 DEG C Hour.Reactant is quenched with saturation KF (300mL), and stirred 6 hours at 25 DEG C.Gained black solid is removed by elimination, And filtrate is extracted into (50mL × 3) with EtOAc, with salt water washing (50mL × 3), dried, filtered, and depressurize dense with sodium sulphate Contracting.By gained residue Biotage quick post (40g silica gel, UV254, PE/EA=1:0~1:1) purify, obtain titled Compound (6g, 79% yield), is brown oil.LCMS(ESI):M/z=422.2 [M+Na]⁺。

Step 2:1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) second -1- ketone

2M HCl/water solution is added in THF (200mL) solution to the product (6.0g, 14.2mmol) of step 1 (200mL), and the solution is stirred 16 hours at 10 DEG C.Use saturation NaHCO₃PH is adjusted to 8 by solution, is then extracted with EtOAc (40mL × 3), are dried with sodium sulphate, filtering, and are concentrated under reduced pressure, and are obtained required product (5.5g, 96.2% yield), are brown oil Shape thing.LCMS(ESI):M/z=394.2 [M+Na]⁺。

Step 3:(3S, 6R) -2- (2,5- bis- fluoro- 4- (1- hydroxyethyls) benzyl) -3- methyl -6- phenyl -1,2- thiazines Alkane 1,1- dioxide

It is added portionwise to the product (5.8g, 14.7mmol) of step 2 in THF (60mL) and MeOH (60mL) solution NaBH₄(1.4g, 36.9mmol), and the mixture is stirred 1 hour at 10 DEG C.By reactant H₂O (40mL) is quenched, and is used EtOAc extracts (30mL × 3), by organic phase Na₂SO₄Dry, filtering, and evaporate.By residue through the quick posts of Biotage (40g silica gel, UV254, PE/EtOAc 1:0~1:1) purify, obtain title compound (5.1g, 85% yield), be light yellow Grease.LCMS(ESI):M/z=418.2 [M+Na]⁺。

Step 4:1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) ethyl methane sulfonate ester

At 0 DEG C NEt is added to the product (800mg, 2.0mmol) of step 3 in DCM (40mL) solution₃(0.84mL, 6.1mmol), mesyl chloride (0.31mL, 4.1mmol) is then added dropwise.By the mixture 15 DEG C stir 2 hours, then Use saturation NaHCO₃Solution (20mL) is quenched, and (2 × 30mL) is extracted with DCM, is dried with sodium sulphate, is filtered, and is concentrated under reduced pressure, and is obtained It is light yellow oil to crude product, it is directly used in next step without further purification.LCMS(ESI):M/z=496.1 [M+Na]⁺。

Step 5:2- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) ethyl) hydrazine -1- t-butyl formates

Hydrazine t-butyl formate is added in acetonitrile (30mL) solution to the product (500mg, 1.1mmol) of step 4 (277mg, 2.1mmol) and Cs₂CO₃(1g,3.1mmol).The mixture is stirred 3 hours at 130 DEG C.Solid is removed by filtration, And evaporate filtrate.By gained residue through Biotage quick post (20g silica gel, UV254, PE/EtOAc=1:0-2:1) purify, Title compound (279mg, 50% yield) is obtained, is white solid.LCMS(ESI):M/z=510.1 [M+Na]⁺.

Step 6:2- carbamyls -2- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl - 1,2- thiazan -2- bases) methyl) phenyl) ethyl) hydrazine -1- t-butyl formates

At 0 DEG C triethylamine is added to the product (120mg, 0.24mmol) of step 5 in DCM (10mL) solution (0.1mL, 0.71mmol), is then added dropwise two (trichloromethyl) carbonic esters (22.8mg, 0.08mmol) in DCM (1mL) Solution.The mixture is stirred 1 hour at 0 DEG C, NH is then added₃In 1,4- dioxanes solution (6.0mL, 12mmol), and by the mixture stirred 2 hours at 15 DEG C.By reactant saturation NaHCO₃Solution is quenched (3mL), is extracted with DCM (2 × 10mL) is taken, with anhydrous sodium sulfate drying, and is concentrated under reduced pressure.By crude product through the quick posts of Biotage (12g silica gel, UV254, DCM/MeOH=1:0-20:1) purify, obtain title compound (116mg, 42% yield), be brown solid.LCMS (ESI):M/z=575.0 [M+Na]⁺。

Step 7:1- (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) ethyl) hydrazine -1- formamides

4M HCl are added into the solution of the product (116mg, 0.21mmol) of step 6 in MeOH (4.0mL, 16mmol) Solution.The mixture is stirred 16 hours at 15 DEG C, then evaporation solvent, and with DCM and H₂O(20mL,1:1) dilute, use Saturation NaHCO₃PH is adjusted to 8~9 by solution, and (20mL × 2) are extracted with DCM, are dried with sodium sulphate, filtering, and is concentrated under reduced pressure, and is obtained It is brown solid to product (89mg, 94% yield).LCMS(ESI):M/z=453.1 [M+1]⁺。

Step 8:2- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- Base] methyl] phenyl] ethyl] -4H-1,2,4- triazole -3- ketone

Into the solution of the product (100mg, 0.22mmol) of step 7 add acton (6.0mL, 0.22mmol), reactant mixture is stirred 6 hours at 85 DEG C.Removal of solvent under reduced pressure, and by residue through the quick posts of Biotage (12g silica gel, UV254, DCM/MeOH=1:0-10:1) purify, obtain crude product.By the crude product through preparation HPLC 25- 55%CH₃CN/H₂O (0.1%NH₄HCO₃In H₂Solution in O) it is purified by flash, title compound (35mg, 34% yield) is obtained, For white solid.LCMS(ESI):M/z=463.1 [M+Na]⁺；¹H NMR(400MHz,DMSO-d₆)δ7.89-7.88(m,1H), 7.47-7.36(m,5H),7.26-7.23(m,1H),7.19-7.14(m,1H),5.54-5.49(m,1H),4.59-4.33(m, 3H),4.14-4.10(m,1H),2.50-2.40(m,2H),2.11-2.08(m,1H),1.86-1.73(m,1H),1.68-1.59 (m,4H),1.12-1.10(m,3H)。

Embodiment 29:2- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazans - 2- yls] methyl] phenyl] ethyl] isoxazole -5- ketone

Step 1:((tert-butoxycarbonyl) epoxide) (1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxos - 6- phenyl -1,2- thiazan -2- bases) methyl) phenyl) ethyl) t-butyl carbamate

To methanesulfonic acid 1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) ethyl ester (500mg, 1.1mmol) adds tert-butoxy carbonyloxy group ammonia in acetonitrile (30mL) solution Base t-butyl formate (492mg, 2.1mmol) and Cs₂CO₃(1g,3.1mmol).The mixture is stirred 3 hours at 130 DEG C.Through Solid is filtered to remove, and evaporates filtrate.By gained residue through Biotage quick post (20g silica gel, UV254, PE/EA=1:0- 2:1) purify, obtain title compound (363mg, 50% yield), be white solid.LCMS(ESI):M/z=633.0 [M+Na ]⁺。

Step 2:(1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) ethyl) (hydroxyl) t-butyl carbamate

7M NH are added in the solution of sealing test tube to the product (100mg, 0.16mmol) of step 1₃It is molten in middle MeOH Liquid (6.3mL, 43.8mmol).Reactant mixture is sealed, and stirred 2 hours at 100 DEG C.Removal of solvent under reduced pressure, obtains thick Title compound (80mg, 85% yield), is light yellow solid, crude product is directly used in into next step without further purification Suddenly.LCMS(ESI):M/z=533.0 [M+Na]⁺。

Step 3:(1- (the fluoro- 4- of 2,5- bis- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) ethyl) (propine acyloxy) t-butyl carbamate

DCC (80mg, 0.39mmol) and step are added in DCM (10mL) solution to propiolic acid (22mg, 0.31mmol) Rapid 2 product (80mg, 0.16mmol).Reactant mixture is stirred 16 hours at 20 DEG C.Then solvent is removed, and by residue Through Biotage flash columns (12g silica gel, UV254, PE/EA=1:0-1:1) title compound (60mg, 56% production, are obtained Rate), it is light yellow solid.LCMS(ESI):M/z=585.1 [M+Na]⁺。

Step 4:2- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- Base] methyl] phenyl] ethyl] isoxazole -5- ketone

The product (60mg, 0.11mmol) of step 3 is added into formic acid solution (2mL), and by reactant mixture at 20 DEG C Stirring 3 hours.Solvent is removed, and by gained residue saturation NaHCO₃The aqueous solution (10mL) and EA (10mL) dilutions, then (30mL × 2) are extracted with EA, are dried with sodium sulphate, are filtered, and be concentrated under reduced pressure.By residue through Biotage flash columns (12g silica gel, UV254, PE/EtOAc=1:0-1:1) crude product, is obtained.By the crude product through preparative-HPLC 25-55% CH₃CN/H₂O (0.1%NH₄HCO₃In H₂Solution in O) it is purified by flash, title compound (40mg, 78% yield) is obtained, is white Color solid.LCMS(ESI):M/z=463.1 [M+H]⁺；¹H NMR(400MHz,DMSO-d₆)δ8.69-8.63(m,1H),7.46- 7.24(m,7H),5.43-5.37(m,1H),5.32-5.30(m,1H),4.62-4.56(m,2H),4.40-4.39(m,1H), 4.17-4.08(m,1H),2.50-2.38(m,1H),2.11-2.06(m,1H),1.82-1.77(m,1H),1.68-1.62(m, 4H),1.13-1.09(m,3H)。

Above-claimed cpd and the other compounds prepared using the above method and the IC to RORc₅₀Value is such as institute in table 4 below Show.

Table 4

The Proton NMR data of selected compounds is as follows in table 4, and compound number corresponds to shown in table 4.

Compound 17:¹H NMR(400MHz,DMSO)7.48-7.23(6H,m),4.60-4.49(2H,m),4.41-4.35 (1H,m),4.16-4.08(2H,m),2.47-2.33(1H,m),2.14-2.05(2H,m),1.90-1.75(2H,m),1.67 (1H, dd, J=2.2,14.3Hz), and 1.14-1.10 (3H, m), 0.86 (3H, t, J=7.3Hz).

Compound 18:¹H NMR(400MHz,DMSO)7.48-7.23(6H,m),4.60-4.50(2H,m),4.38(1H, D, J=17.9Hz), 4.16-4.08 (2H, m), 2.14-2.05 (2H, m), 1.91-1.74 (2H, m), 1.70-1.63 (1H, m), 1.12 (3H, d, J=6.9Hz), 0.85 (3H, t, J=7.3Hz).

Compound 24:¹H NMR(400MHz,DMSO)12.56-12.46(1H,m),7.49-7.28(6H,m),5.56 (1H, s), 4.62-4.53 (2H, m), 4.40 (1H, d, J=18.0Hz), 4.17-4.09 (1H, m), 3.40 (3H, s), 2.48- 2.38 (1H, m), 2.14-2.07 (1H, m), 1.87-1.74 (1H, m), 1.67 (1H, dd, J=2.3,14.2Hz), 1.13 (3H, D, J=6.9Hz).

Compound 25:¹H NMR(400MHz,DMSO)7.49-7.27(6H,m),5.56(1H,s),4.61-4.52(2H, M), 4.41 (1H, d, J=17.9Hz), 4.17-4.08 (1H, m), 3.29 (1H, s), 3.23-3.22 (1H, m), 2.48-2.39 (1H, m), 2.08-2.07 (2H, m), 1.91-1.75 (1H, m), 1.67 (1H, dd, J=2.2,14.2Hz), 1.12 (3H, d, J =6.9Hz).

Compound 29:¹H NMR(400MHz,DMSO)7.48-7.24(6H,m),4.60-4.50(2H,m),4.41-4.28 (2H,m),4.17-4.09(1H,m),3.40-3.35(1H,m),3.26-3.19(2H,m),3.17(3H,s),2.48-2.27 (2H, m), 2.14-2.04 (2H, m), 1.91-1.74 (1H, m), 1.67 (1H, dd, J=2.2,14.2Hz), 1.12 (3H, d, J =6.8Hz).

Compound 30:¹H NMR(400MHz,DMSO)7.48-7.24(6H,m),4.60-4.49(2H,m),4.41-4.28 (2H,m),4.17-4.08(1H,m),3.26-3.19(2H,m),3.16(3H,s),2.48-2.28(2H,m),2.14-2.02 (2H, m), 1.91-1.74 (2H, m), 1.71-1.63 (1H, m), 1.12 (3H, d, J=6.8Hz).

Compound 36:¹H NMR(400MHz,DMSO)7.49-7.27(6H,m),5.63-5.61(1H,m),4.62-4.52 (2H, m), 4.40 (1H, d, J=17.9Hz), 4.17-4.02 (1H, m), 3.66-3.53 (3H, m), 2.48-2.39 (1H, m), 2.14-2.06 (1H, m), 1.86-1.74 (1H, m), 1.67 (1H, dd, J=2.2,14.1Hz), 1.20-1.11 (6H, m).

Compound 37:¹H NMR(400MHz,DMSO)7.48-7.26(6H,m),5.60(1H,s),4.61-4.51(2H, M), 4.40 (1H, d, J=17.9Hz), 4.17-4.09 (1H, m), 3.65-3.53 (3H, m), 2.48-2.39 (1H, m), 2.13- 2.08(1H,m),1.88-1.75(1H,m),1.71-1.63(1H,m),1.20-1.10(6H,m)。

The external RORc ligand bindings experiment of embodiment 30

By determining Ki_app、IC₅₀Or percentage inhibiting value determines the chemical combination in RORc activity is suppressed using this experiment Thing efficiency.

Table 5

It is prepared by filter plate

On the day of experiment, by 100 μ L 0.05%CHAPS (in deionization H₂In O) it is added to GFB Unifilter flat boards All holes in, and soaked 1 hour.Prepare 50mM HEPES (pH7.4), 150mM NaCl and 5mM MgCl₂Washing Buffer solution carrys out washing and filtering flat board.In order to prepare experiment buffer solution, BSA is added in lavation buffer solution to reach 0.01%, and DTT is added to reach 1mM.

Compound

For IC₅₀Pattern, DMSO serial dilutions are used by 10mM compound stock solutions in DMSO, are obtained in DMSO (15 μ L The μ L of compound+30 DMSO) in 20 times needed for ultimate density.20 times of compound stock solutions are delayed in DMSO with 4 times of experiments Fliud flushing dilutes, to reach 5 times of final experimental concentrations in 25%DMSO (the μ L of 10 μ L compounds+30 test buffer solution).With setting The pipette put in 50 μ L volumes repeatedly mixes solution by imbibition.For the experiment, by 5 times of 10 μ L in 25%DMSO Compound stock solution is added in test panel in duplicate.

For 2 points of screenings, 10mM storage compound solution is diluted in DMSO to obtain 200uM (20 times of high experiments Concentration), 10 times are then further diluted to reach 20uM (20 times of low experimental concentrations).20 times of storing solutions are buffered with experiment 4 times of liquid (10uL compounds+30uL test buffer solution) dilution, to reach 5 times of experimental concentrations (50uM and 5uM), and by 10uL mono- Two parts of formula is added in two test panels.Each concentration is tested on 2 flat boards, and every group of 80 compounds are flat using 4 experiments Plate (1uM and 10uM, n=2).

Non-specific binding (NSB) sample, total binding (TB) sample and without acceptor (No R) sample

25-HYDROXY CHOLESTEROL (1uM) for the signal level that determines NSB is as above made described in cultural compound in DMSO It is standby, then diluted in experiment buffer solution, obtain 5uM final concentration.It is molten in 25%DMSO for 25-HYDROXY CHOLESTEROL Liquid/75% tests buffer solution, and 10uL is used for NSB samples per hole.Contain 10 μ L for total binding and without the hole that acceptor sample is determined 25%DMSO/75% tests buffer solution/hole.

Radioligand (25- [³H] hydroxy cholesterol) prepare

By 25- [³H] hydroxy cholesterol dilution in experiment buffer solution, obtain 15nM, and vortex mixed.To each Kong Zhongjia Enter 20uL, to reach the final concentration of 6nM in the experiment.

It is prepared by acceptor

It was found that the optium concentration of RORc acceptors is 0.6ug/mL.Spare receptor solution is diluted in experiment buffer solution, obtained To solution of the 1.5ug/mL in experiment buffer solution.20uL is added in each hole.For without acceptor sample, being tested and being buffered with 20uL Liquid replaces receptor solution.

Sample is added into flat board and is incubated

Test panel is 96 hole polypropylene V- base plates.10uL 5x compounds are tested in 25%DMSO/75% and buffered Solution in liquid is added in test hole.10uL 25%DMSO/75% experiment buffer solutions are added into total binding or without in receptor hole. Solution of the 10uL 5uM25- hydroxy cholesterols in 25%DMSO/75% tests buffer solution is added in NSB holes.Will be in experiment The 20uL prepared in buffer solution 15nM 25- [³H] hydroxy cholesterol added in each hole.By 20uL 1.5ug/mL RORc by Body is added in each hole (or adding 40uL experiment buffer solutions without in receptor hole).Add behind each hole, the flat board is incubated 3 at 25 DEG C Hour.

Filtering

Using Packard Filtermate Harvester, filter is washed 4 times after the sample of transfer culture.Will The thorough dry filter of flat board (at 50 DEG C 2 hours or stay overnight at room temperature).50uL Microscint 0 is added in all holes, And on Topcount protocol Inverted reading.

Final concentration

Final concentration is as follows：50mM HEPES buffer solutions (pH 7.4)；150mM NaCl；1mM DTT；5mM MgCl₂； 0.01%BSA；5%DMSO；0.6ug/mL RORc acceptors；6nM25-[³H] hydroxy cholesterol.For NSB holes, also there is 1uM 25-HYDROXY CHOLESTEROL.

Embodiment 31:RORc coactivator peptide binding tests

Experiment is to be reacted in black 384Plus F Proxiplates (Perkin-Elmer 6008269) with 16uL Volume is carried out.By the total Test component in addition to part is tested in the counselor work buffer solution D comprising 5mM DTT Mix, and be added to 8mL volumes with twice of its ultimate density in flat board in (Invitrogen PV4420).Then will be with 2 The 8 μ L that the experiment part of times final concentration is added in each hole contain 5mM DTT and 4%DMSO counselor work buffer solution D.Finally Incubating Solution comprising 1x counselor work buffer solution D, 5mM DTT, experiment part, 2%DMSO, 50nM biotinyl- CPSSHSSLTERKHKILHRLLQEGSPS(American Peptide Company；Vista, CA), the anti-GST of 2nM europiums (Cisbio 61GSTKLB), 12.5nM streptavidins-D2 (Cisbio 610SADAB), 50mM KF and 10nM bacteriums The residue 262-507 comprising N- ends 6xHis-GST- labels and accession number NP_005051 of expression people's RORc ligand bindings Domain albumen.Ten ligand concentrations are tested in duplicate.By reaction plate, (22-23 DEG C) is incubated 3 in the dark at room temperature After hour, according to europium/D2HTRF schemes (μ s lag times of ex 320, em 615 and 665,100,100 flickers, 500 μ s windows Mouthful) read flat board on EnVision plate readers (PerkinElmer).The FRET of time resolution at 665nm is believed Number divided by 615nm at signal, to produce the signal ratio in each hole.By the hole containing RORc and peptide but without experiment part Signal is set as 0% effect than carrying out mean deviation, and by the signal of the blank well containing auxiliary activating peptide but without RORc than carrying out Mean deviation is set as -100% effect.RORc shows basic (composing type) signal in this experiment, and relative to the basis Signal level, experiment part can increase or decrease signal ratio.RORc activators increase signal ratio in this experiment, and produce just % effect values.Inverse agonist reduces signal ratio, and produces negative % effect values.EC₅₀Value is to provide the (increasing of half ceiling effect Plus or reduction stimulus) test compound concentration, pass through GenedataSoftware (Genedata； Basel, Switzerland) calculated with below equation：

% effects=S₀+{(S_inf–S₀)/[1+(10^logEC ₅₀/10^c)ⁿ]}

Wherein S₀Equal to the activity level under the test compound of zero-dose, S_infIt is in the unlimited dense of test compound Activity level under degree, EC₅₀It is 50% concentration that activity reaches ceiling effect, c corresponds to the x of dose-response curve figure The concentration of the log unit of the value of axle, and n is Hill coefficients (EC₅₀The slope of curve at place).

Embodiment 32:Arthritis mouse model

Old Male DBA/1 (DBA/1OlaHsd, Harlan Laboratories) mouse of 8 to 10 week old is placed in In specific pathogen-free domestic (SPF) animal facility.Collagen-induced arthritis twice is subcutaneously injected by the base portion in afterbody.For the first time Injection uses the ox II type glue emulsified in isometric CFA containing 4mg/ml mycobacterium tuberculosis (Chondrex) in (the 0th day) Former (2mg/ml, from Chondrex, Redmond, Wash.).The CII booster shots liquid of the 29th day is in incomplete Freund's adjuvant (IFA) emulsified in.Every animal receives 0.1 milliliter by subcutaneous/intracutaneous injection in the afterbody apart from 2 to 3 centimetres of mouse body Emulsion.Strengthen injection site in the position neighbouring but different from initial injection position, and apart from animal bodies closer to.OR- 1050 prepare in HRC-6 as described above.On ordinary days, animal receive HRC-6 or 50mg/kg OR-1050 twice orally to Medicine (morning and afternoon) (2.5ml/kg).At weekend, using 100mg/kg single-dose (5ml/kg).

CIA clinical symptoms based on following qualitative scale, daily observation mouse.Every claw of individual inspiration is simultaneously given a mark.0 Level, normally；1 grade, ankle or wrist are slight but clearly rubescent and swelling, or are limited to the obvious rubescent and swelling of indivedual toes, Regardless of impacted toes；2 grades, ankle or wrist moderate are rubescent；3 grades, including toes whole pawl severe redness and Swelling；4 grades, with the limbs of the at utmost inflammation in multiple joints.In order to assess the accumulation disease severity of every animal, Add up to calculate the TG-AUC score of every animal by the summation for measuring the daily rear solid end between the 24th and 48 day.

Embodiment 33:Muscular sclerosis mouse model I

Experiment is carried out in the body weight 17-20g for belonging to C57BL/6 plants of 4-6 week old female mice.It is experimental itself Allergic encephalomyelitis (EAE) uses 95% pure synthesis myelin oligodendrocyte glycoprotein peptide 35-55 (MOG_35-55) (Invitrogen) actively induction.By every mouse anesthesia, and receive 200ug MOG_35-55Peptide and 15ug carry out comfortable 100uL phosphorus The saponin extract of the Quilija barks emulsified in hydrochlorate buffered saline.One 25uL dimensions subcutaneous is expelled to four flanks Region.Mouse is also used in the 200ng pertussis toxin intraperitoneal injections in 200 μ L PBS.Given after 48 hours identical for the second time Pertussis toxin injection.

The compound of the present invention is applied with the dosage of selection.Control-animal receives 25uL DMSO.It is daily to treat from immune Extend within the 26th day the 36th day afterwards.Clinical score was obtained daily from immune latter 0th day to the 60th day.Clinical sign is used with lower section Case is scored：0, without detectable symptom；0.5, distal end tail limp, arciform outward appearance and behavior are quiet；1, complete afterbody without Power；1.5, tail limp and hind limb weakness (instability of gait is fixed, and hind leg grasps bad)；2, unilateral partial hind paralysis；2.5, it is double Side hindlimb paralysis；3, complete bilateral hindlimb paralysis；3.5, complete hindlimb paralysis and unilateral fore limb paralysis；4, hind leg and forelimb pamplegia (Eugster et al., Eur J Immunol 2001,31,2302-2312).

Inflammation and demyelinate can be by Histological assessment EAE mouse CNS sections.Mouse was put to death after 30 or 60 days, The excision of full spinal cord is placed in 4 DEG C of 0.32M sucrose solutions overnight.Prepare tissue and cut into slices.The fast indigo plants of Luxol are dyed for seeing Examine demyelination.H and E is dyed for protruding areas of inflammation by contaminating the nucleus of black staining mononuclear cells. The immunocyte dyed with H＆E is counted with blind with light microscope.Section is divided into grey and whiteness, and by each portion Divide manual count before the combining, obtain the sum of the section.T cell is marked with AntiCD3 McAb+monoclonal antibody immunity.After washing, Section is incubated with goat anti-rat HRP secondary antibodies.Then section is washed and uses methyl green counterstain.The after immune The splenocyte lysis buffer separated from mouse is handled with 60 days to remove red blood cell within 30 days.Then cell is suspended again In PBS and count.With about 3 × 10⁶The cell of cell/mL density is incubated overnight with 20 μ g/mL MOG peptides.Using suitable Mouse IFN-γ immunoassay system determines the IFN γ protein level of the supernatant from stimulated cell.

Embodiment 34:Muscular sclerosis mouse model II

In the model, by female rodent isoflurane anesthesia, and at the 0th day of this research in two, back position Point injection contains 1mg/mL neurons antigen (such as myelin alkaline protein, myelin oligodendrocyte glycoprotein, proteolipin Matter protein) and 4mg/mL mycobacterium tuberculosis incomplete Freund's adjuvant.Then from the 0th day up to treatment end when, daily Purpose compound is applied with effective dose with subcutaneous, intraperitoneal or oral way.Daily observation degree of paralysis is used as curative effect evaluation.

Embodiment 35:Psoriasis mouse model I

Serious combined immunodeficiency (SCID) mouse model can be used for the effect for assessing compounds for treating people's psoriasis (Boehncke,Ernst Schering Res Found Workshop 2005,50,213-34；With Bhagavathula etc. People, J Pharmacol Expt'l Therapeutics 2008,324 (3), 938-947).In short, SCID mice is used as group Knit receptor.The biopsy of each normal or psoriasis volunteer (people) is transplanted in the back surfaces of recipient mice. Treatment starts for 1-2 weeks after the transfer.The animal for transplanting application on human skin is assigned into each treatment group.Animal is treated daily and continues 14 twice My god.In treatment end, animal is shot, is then euthanized.The tissue of surgery excision transplanting and the mouse of surrounding Skin, is fixed in 10% formalin, and by gained sample microexamination.Measure epidermal thickness.Tissue is cut Piece is dyed with Proliferation marker Ki-67 antibody and anti-human CD3+ monoclonal antibodies, to detect people's T lymphs in transplanting tissue Cell.Also with the antibody detection section of c-myc and beta-catenin.The reduction of the mean epidermal thickness of psoriatic skin graft Reflect the active response to treatment.Active response is also relevant with the expression decline of Ki-67 in keratinocyte.

Embodiment 36:Psoriasis mouse model II

Use imiquimod model (Fits et al., the Journal of Immunology, 2009,182 of scytitis: 5836-5845), by 10-12 week old BALB/c, Il17c+ /+or Il17c-/- or Il17re+ /+or Il17re-/- mouse shaving The back of light and auris dextra continue 5 days using 50mg Aldaras emulsifiable paste (5% imiquimod in Graceway, 3M) daily.Often It carries out clinical score and ear thickness measurement.Scoring is the performance based on psoriasis symptom, such as erythema, the scales of skin that peel off and thickness：0, no disease Disease.1, with the very slight erythema slightly thickened very much, and the small area scales of skin that peel off.2, it is slight red with what is slightly thickened Spot, and the small area scales of skin that peel off.3, the moderate erythema thickened with moderate, and small area (<25%) scales of skin that peel off (irregular and patch Shape).4, with the Severe erythema significantly thickened, and account for moderate area (25-50%) scales of skin that peel off (irregular and patch shape).5, With the Severe erythema significantly thickened, and large area (>50%) scales of skin that peel off (irregular and patch shape).Ear was gathered at the 5th day Histological assessment is carried out with back tissue.Effect of comparative compound in imiquimod (IMQ) mouse model of psoriasis.Such as Described above, Balb/c mouse (10 male/groups) are controlled shaving the back of light and auris dextra and receive daily local I MQ (5% emulsifiable paste) Treatment continues 5 days.From the -5th day to the+5th day, animal received the representative compound or DMF (45 or 90mg-eq of oral dose MMF/kg, twice daily) or carrier.Scores of erythema is main result index.With oral dose in male Balb/C mouse The erythema score value that 90mg-eq MMF/kg BID continue the compound tested for 10 days is listed in the table below in 3.This Shen of data display Compound please and DMF are equivalent.

Embodiment 37:IBS mouse model I

The therapeutic effect of IBD can by Jurjus et al. J Pharmaocol Toxicol Methods 2004, 50,81-92；Villegas et al., Int'l Immunopharmacol 2003,3,1731-1741；With Murakami et al., Description in Biochemical Pharmacol 2003,66,1253-1261 is estimated.In short, by Female ICR mice Assign to each treatment group, test start when to its 5%DSS in applying water (control), running water with inducing colitis, or administration The test compound of various concentration.After test compound 1 week, the 5%DSS in running water is also applied to reception test The group of compound continues 1 week.At the end of experiment, all mouse are put to death, large intestine is removed.Obtain mucous membrane of colon sample and homogenize Processing.It is quantitative to pro-inflammatory mediator (such as IL-1 α, IL-1 β, TNF α, PGE2 and PGF2 α) and protein concentration.To each it cut off Large intestine carry out histological examination, and the damage of colon is scored.

Embodiment 38:Chronic obstructive pulmonary disease mouse model

Martorana et al., Am J Respir Crit Care Med 2005,172,848-835；With Cavarra etc. People, Am J Respir Crit Care Med 2001,164,886-890 smoke extract models can be used for assessing treatment pulmonary emphysema Efficiency.In short, by the C57B1/6J male mices of six week old 20 points in room air or the smog of five cigarette Clock.For acute study, mouse is divided into three groups, every group 40.Then these groups are divided into 4 Asias of 10 following mouse Group：(1) it is untreated/to be exposed to air；(2) it is untreated/to be exposed to smog；(3) test compound for the first time administration+be exposed to cigarette Mist；(4) second of administration of test compound.In the first set, in assessment bronchoalveolar lavage fluid at the end of exposure The equivalent antioxidant capacities of trolox.In the second set, the combination of cytokines of commodity in use was determined in broncho-pulmonary at 4 hours Steep the cell factor and chemotactic factor (CF) in irrigating solution；And in the 3rd group, BAL fluid was assessed at 24 hours Cell count.

In a chronic research, by mouse exposed to room air or the smog of daily three cigarette, 5 days weekly, hold It is continuous 7 months.Use five groups of animals：(1) it is untreated/to be exposed to air；(2) test compound for the first time administration+be exposed to air； (3) it is untreated/to be exposed to smog；(4) test compound second be administered+be exposed to smog；And (5) test compound first Secondary administration+be exposed to smog.Room air or smoke from cigarette are chronicly exposed to after seven months, every group of 5-12 animal is put to death, And fix intrapulmonary tracheae with formalin.Pulmonary volume is determined by Water Displacement.Lung is dyed.Pulmonary emphysema, which are assessed, includes average linear Intercept and internal surface area.The macrophage marked by a counting measure with anti-mouse Mac-3 monoclonal antibody immunities histochemistry is thin The bulk density of born of the same parents.When the positive periodic acid-schiff dyeing of at least one or more medium sized bronchus/lung display (is used In measure desmosine) when, it is believed that mouse has goblet cell metaplasia, and fresh lung is homogenized, processing, and passes through high pressure liquid phase color Analysis of spectrum.

Embodiment 39:Asthma mouse model

Exciting for A Single Intake by Inhalation anaphylactogen may result in some individual airway reactivities with animal models drastically Enhancing.However, anaphylactogen suction repeatedly is had confirmed with more notable, consistent and extension airway reactivity enhancing.For a long time The mouse model of suction anaphylactogen has been used for the long-term influence for studying lung's anaphylactia repeatedly, and describes participation induction people Cell, mechanism, molecule and the medium of the airway hyperreactivity of lung.

Crystallize OVA and be obtained from Pierce Chem.Co. (Rockford, Ill.), aluminum potassium sulfate (alum) is obtained from Sigma Chem.Co. (St.Louis, Mo.), apyrogenic distilled water comes from Baxter, Healthcare Corporation (Deerfield, Ill.), 0.9% sodium chloride (physiological saline) from Lymphomed (Deerfield, Ill.) and Trappsol.TM.HPB-L100 (the hydroxypropyl beta cyclodextrin aqueous solution；The 45w/v% aqueous solution) come from Cyclodextrin Technologies Development,Inc.(Gainesville,Fla.).By OVA (500ug/ml is in physiological saline) with 10% isometric (w/v) alum is mixed in distilled water.By the mixture, (pH 6.5 is used after being incubated 60 minutes at room temperature 10N NaOH) centrifuged 5 minutes in 750g；The pellet is resuspended in the distilled water of initial volume, and it is small one When interior use.By selective 5- lipoxidase inhibitors Zileuton (N- [1- benzos [b] thiophene -2- bases ethyl]-N- hydroxycarbamides； J.Pharmacol Exp Ther.1991；256:929-937) it is dissolved in Trappsol.TM.Histatek, Inc. (Seattle, Wash. in), mast cell degranulation inhibitor f-Met-Leu-Phe-Phe (" HK-X ") is obtained.

Scheme (J.Exp Med.1996 according to different standards；184:1483-1494) by female BAl BIc/c once (6-8 Week old) receive intraperitoneal injection 0.2ml (100ug) OVA and alum.With 0.2ml intraperitoneal injection ketamines (0.44mg/ Ml then solution of the)/Xylazine (6.3mg/ml) in physiological saline individually receive mouse anesthesia on the different dates Solution of the 100ug OVA in 0.05ml physiological saline intranasal (i.n.) is administered and 50ug OVA are in 0.05ml physiological saline Solution intranasal administration.Use two control groups：The aluminated physiological saline intraperitoneal injection of first group of receiving, and it is not aluminated Physiological saline intranasal administration；The aluminated OVA intraperitoneal injections of second group of receiving, not aluminated OVA and single physiology salt Water intranasal administration.

Tracheae and left lung (right lung can be used for bronchoalveolar lavage (" BAL ") as described below) are obtained, and at room temperature It is fixed about 15 hours in 10% neutral formalin solution.After being embedded in paraffin, tissue is cut into 5 μm of sections, and further use Different dyeing immune labeled is handled.Discombe eosinophil, which is dyed, uses methylene blue counterstain Cell count.Unit air flue area (2,200um²) eosinophil quantity determined by morphometry (J.Pathol.1992；166:395-404；Am Rev Respir Dis.1993；147:448-456).Fibrosis passes through Masson trichrome stain is determined.Air way mucus is determined by following colouring method：Methylene blue, h and E, mucus Carmine, alcian blue and alcian blue/periodic acid-schiff (PAS) reaction (Troyer, H., " Carbohydrates " in Principles and Techniques of Histochemistry,Little,Brown and Company,Boston, Mass.,1980:89-121；Sheehan, D.C. et al., " Carbohydrates " in Theory and Practice of Histotechnology,Battle Press,Columbus,Ohio,1980:159-179).Mucoprotein is contaminated with mucus famille rose Color；Use the yellow counterstain of soap.Acid mucoprotein and sulphation mucosal mass are dyed with alcian blue, pH 2.5；Rapidly become popular soon using core Colour contrast is dyed.Neutral and acidic mucosubstance is identified with alcian blue (pH 2.5) and PAS reactions.Air flue chocking-up degree (diameter 0.5-0.8mm) it is estimated also by morphometry.Airway diameter is classified by mucus plugging percentage according to sxemiquantitative scale For 0 to 4+.Histology and morphological analysis can be by the unwitting personal progress of conceptual design.

28th day, after last time intranasal administration physiological saline or OVA 24 hours, intravenous infusion vinegar methylcholine Mechanics of lung can determine (10,1958 in mouse in vivo by foregoing plethysmography；192:364-368； J.Appl.Physiol.1988；64:2318-2323；J.Exp.Med.1996；184:1483-1494).

After closing left lung at main bronchus, right lung can be three times with the lavation of 0.4ml physiological saline.Use hemacytometer The fluid cell of the BAL fluid (BAL) of the 0.05ml aliquots from total elution samples is counted, and by residue Liquid at 4 DEG C 200g centrifuge 10 minutes.Supernatant can be in 70 DEG C of storages until carrying out eicosanoid analysis.Containing In the physiological saline of 10% bovine serum albumin(BSA) (" BSA ") after settling flux cell precipitation, BAL cells are prepared on a glass slide Smear.In order to dye eosinophil, dyeing 5-8 minutes is carried out to dry slide with Discombe dilutions (the solution of 0.05% Yihong aqueous solution and 5% acetone (v/v) in distilled water；J.Exp.Med.1970；131:1271- 1287), rinsed 0.5 minute with water, and with 0.07% methylene blue counterstain 2 minutes.

Although describing the present invention with reference to specific embodiments of the present invention, those skilled in the art should manage Solution, in the case where not departing from the true spirit and scope of the present invention, can carry out various changes and can use equivalence Replace.Furthermore, it is possible to carry out many modifications are so that concrete condition, material, material composition, method, method and step are adapted to this hair Bright spirit and scope.All such modifications are all covered by scope of the following claims.

Claims

1. compound of formula I or its officinal salt,

Wherein：

M is 0 or 1；

N is 0 or 1；

P is 0-3；

Q is 0-3；

Het is：

Five or six membered heteroaryl, it is selected from：

Pyrrole radicals；

Pyrazolyl；

Imidazole radicals；

Oxazolyl；

Thiazolyl；

Isoxazolyl；

Isothiazolyl；

Triazolyl；

Oxadiazolyl；

Thiadiazolyl group；

Tetrazole radical；

Thienyl；

Furyl；

Pyridine radicals；

Pyrimidine radicals；

Pyridazinyl；Or

Pyrazinyl；Or

Quinary heterocyclic radical, is selected from：

Pyrrolidinyl；

Oxazole alkyl；

Dioxolane base；Or

Imidazolidinyl；

A is：

C_1-6Alkylidene；Or

C_1-6Alkenylene,

It can be each unsubstituted or by R^aSubstitution is once or twice；

W is：-CR^bR^c-；-O-；-S-；-SO₂-；Or-NR^d-；

X¹、X²、X³And X⁴One of be N, and other is CR^e；Or X¹、X²、X³And X⁴In two be N, and other is CR^e；Or X¹、 X²、X³And X⁴In three be N, and other are CR^e；Or X¹、X²、X³And X⁴Individually CR^e；

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷And R⁸It is independently of one another：Hydrogen；Or C_1-6Alkyl, it can be unsubstituted or be taken by halogen For one or many；

Or R³And R⁴Can form three together with the atom that it is connected, the ring of four, five, six or seven yuan of saturations or fractional saturation, its It can optionally include and be selected from one or two following hetero atom：-O-、-NR^d- or-S-, also, it can be unsubstituted Or by R^fSubstitution is one or many；

Or R⁵And R⁶Can form three together with the atom that it is connected, the ring of four, five, six or seven yuan of saturations or fractional saturation, its It can optionally include and be selected from one or two following hetero atom：-O-、-NR^d- or-S-, also, it can be unsubstituted Or by R^fSubstitution is one or many；

Or R⁷And R⁸Can form three together with the atom that it is connected, the ring of four, five, six or seven yuan of saturations or fractional saturation, its It can optionally include and be selected from one or two following hetero atom：-O-、-NR^d- or-S-, also, it can be unsubstituted Or by R^fSubstitution is one or many；

Or R³And R⁴One of and R⁵And R⁶One of can form three together with the atom that it is connected, four, five, six or seven yuan it is full And/or the ring of fractional saturation, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^d- or-S-, and And, it can be unsubstituted or by R^fSubstitution is one or many；

Or R⁵And R⁶One of and R⁷And R⁸One of can form three together with the atom that it is connected, four, five, six or seven yuan it is full And/or the ring of fractional saturation, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^d- or-S-, and And, it can be unsubstituted or by R^fSubstitution is one or many；

R⁹It is independently of one another

C_1-6Alkyl；

Halogen；

C_1-6Alkoxy；Or

Cyano group；

R¹⁰It is independently of one another：

C_1-6Alkyl；

Oxo；

Hydroxyl

Halogen；

Cyano group；

Halo-C_1-6Alkyl；

Hydroxyl-C_1-6Alkyl；

C_1-6Alkoxy -C_1-6Alkyl；Or

Cyano group-C_1-6Alkyl；

R^aIt is：

C_1-6Alkoxy；

C_1-6Alkoxy -C_1-6Alkyl；

Hydroxyl-C_1-6Alkyl；

C_3-6Cycloalkyl；

C_3-6Cycloalkyl-C_1-6Alkyl；

C_3-6Cycloalkyl oxy；

C_3-6Cycloalkyl-C_1-6Alkoxy；

Heterocyclic radical；

Heterocyclic radical-C_1-6Alkyl；Or

Heterocyclic radical-C_1-6Alkoxy；

Wherein heterocyclyl moieties are each independently selected from expoxy propane base, tetrahydrofuran base, THP trtrahydropyranyl, azetidine Base, pyrrolidinyl and piperidyl, and wherein heterocyclyl moieties and C_3-6Cycloalkyl moiety can be each unsubstituted or by R^fTake For one or many；

R^b、R^cAnd R^dIt is independently of one another：

Hydrogen；

C_1-6Alkyl；Or

Halo-C_1-6Alkyl；

Or R^bAnd R^cCan form three together with the atom that it is connected, the ring of four, five, six or seven yuan of saturations or fractional saturation, its It can optionally include and be selected from one or two following hetero atom：-O-、-NR^a- or-S-, also, it can be unsubstituted Or by R^fSubstitution is one or many；

Or R^bAnd R^cOne of and R⁷And R⁸One of can form three together with the atom that it is connected, four, five, six or seven yuan it is full And/or the ring of fractional saturation, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^a- or-S-, and And, it can be unsubstituted or by R^fSubstitution is one or many；

Or R^bAnd R^cOne of and R⁵And R⁶One of can form three together with the atom that it is connected, four, five, six or seven yuan it is full And/or the ring of fractional saturation, it can optionally include and be selected from one or two following hetero atom：-O-、-NR^a- or-S-, and And, it can be unsubstituted or by R^fSubstitution is one or many；

R^eIt is independently of one another：

Hydrogen；

C_1-6Alkyl；

Halogen；

C_1-6Alkoxy；Or

Cyano group；

2. compound as claimed in claim 1, wherein n are 0.

3. compound as claimed in claim 1 or 2, wherein R¹、R²、R⁴、R⁵、R⁶、R⁷And R⁸It is hydrogen.

4. the compound as any one of claim 1-3, wherein W are-CR^bR^c-, and R^bAnd R^cIt is hydrogen.

5. the compound as any one of claim 1-4, wherein X¹、X²、X³And X⁴It is CR^e。

6. the compound as any one of claim 1-5, wherein p are 0.

7. the compound as any one of claim 1-6, wherein q are 0 or 1.

8. the compound as any one of claim 1-7, wherein p are 0.

9. the compound as any one of claim 1-8, wherein Het are five or six membered heteroaryl, it is selected from：

Pyrrole radicals；

Pyrazolyl；

Imidazole radicals；

Oxazolyl；

Thiazolyl；

Isoxazolyl；

Isothiazolyl；

Triazolyl；

Oxadiazolyl；

Thiadiazolyl group；

Tetrazole radical；

Thienyl；

Furyl；

Pyridine radicals；

Pyrimidine radicals；

Pyridazinyl；Or

Pyrazinyl.

10. compound as claimed in any one of claims 1-9 wherein, wherein A are C_1-6Alkylidene, its can be it is unsubstituted or By R^aSubstitution.

11. the compound as any one of claim 1-10, wherein A are：-CH₂-；-CHCH₃-；-C(CH₃)₂-；Or- CHR^a-。

12. the compound as any one of claim 1-11, wherein R³It is C_1-6Alkyl.

13. the compound as any one of claim 1-12, wherein R¹⁰It is：C_1-6Alkyl；Hydroxyl；Oxo；Or hydroxyl- C_1-6Alkyl.

14. the compound as any one of claim 1-13, wherein R^aIt is：C_1-6Alkoxy；Heterocyclic radical-C_1-6Alkyl；Or Heterocyclic radical-C_1-6Alkoxy；Wherein heterocyclyl moieties are each independently selected from expoxy propane base, tetrahydrofuran base, oxinane Base, azetidinyl, pyrrolidinyl and piperidyl, and wherein heterocyclyl moieties can be each unsubstituted or by R^fTake For one or many.

15. compound as claimed in claim 1, wherein compound are formula III compounds；

Wherein s is 1 or 2, and R^eIt is halogen.

16. compound as claimed in claim 15, wherein compound are formula IV compounds；

17. compound as claimed in claim 16, wherein compound are Formula V compounds；

18. the compound as any one of claim 1-16, wherein compound are selected from：

5- [[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] phenyl] Methyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [(1R) -1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] -2- (oxetanes -3- bases) ethyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [(R)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base]-(oxetanes -3- bases epoxide) methyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [(S)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base]-(oxetanes -3- bases epoxide) methyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6S) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] -1- methyl-ethyls] -3H-1,3,4- oxadiazole -2- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] -1- methyl-ethyls] -3H-1,3,4- oxadiazole -2- ketone；

5- [(R)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base]-tetrahydropyran -4-base epoxide-methyl] -3H-1,3,4- oxadiazole -2- ketone；

3- [[the fluoro- 4- of 2,5- bis- [[(3S, 6S) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] phenyl] Methyl] -1,4- dihydro -1,2,4- triazole -5- ketone；

3- [[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] phenyl] Methyl] -1,4- dihydro -1,2,4- triazole -5- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -1,2- pyrazoline -3- ketone；

3- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -2H- isoxazole -5- ketone；

3- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -1,4- dihydro -1,2,4- triazole -5- ketone；

3- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -4- methyl isophthalic acid H-1,2,4- triazole -5- ketone；

5- [(1S) -1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] propyl group] -3H-1,3,4- oxadiazole -2- ketone；

5- [(1R) -1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] propyl group] -3H-1,3,4- oxadiazole -2- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -2- methyl -4H-1,2,4- triazole -3- ketone；

3- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -2- methyl isophthalic acid H-1,2,4- triazole -5- ketone；

5- [(R)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base]-isopropoxy-methyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [(S)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base]-isopropoxy-methyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [(R)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base]-methoxymethyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [(S)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base]-methoxymethyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] isoxazole -3- ketone；

3- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -1H- imidazoles -2- ketone；

1- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] imidazolidine -2,4- diketone；

5- [(1S) -1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] -3- methoxy-propvls] -3H-1,3,4- oxadiazole -2- ketone；

5- [(1R) -1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] -3- methoxy-propvls] -3H-1,3,4- oxadiazole -2- ketone；

2- [5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -2- oxo -1,3,4- oxadiazole -3- bases] acetonitrile；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -3- (2- hydroxyethyls) -1,3,4- oxadiazole -2- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -3H- oxazole -2- ketone；

5- [(1S) -1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] -3- hydroxyl-propyls] -3H-1,3,4- oxadiazole -2- ketone；

5- [(1R) -1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] -3- hydroxyl-propyls] -3H-1,3,4- oxadiazole -2- ketone；

5- [(R)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base]-ethoxy-methyl] -3H-1,3,4- oxadiazole -2- ketone；

5- [(S)-[the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base]-ethoxy-methyl] -3H-1,3,4- oxadiazole -2- ketone；

2- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -4H-1,2,4- triazole -3- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -3- (2,2,2- trifluoroethyls) -1,3,4- oxadiazole -2- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -3- ethyl -1,3,4- oxadiazole -2- ketone；

2- [5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] Phenyl] ethyl] -2- oxo -1,3,4- oxadiazole -3- bases] acetamide；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -3- (2- methoxy ethyls) -1,3,4- oxadiazole -2- ketone；

1- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] imidazolidin-2-one；

2- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -1H- pyrazoles -3- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -3- methyl isophthalic acids, 3,4- oxadiazole -2- ketone；

2- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] isoxazole -5- ketone；

(3S, 6R) -2- [[the fluoro- 4- of 2,5- bis- [1- (3- first epoxides isoxazole -5-base) ethyl] phenyl] methyl] -3- methyl -6- Phenyl-thiazan 1,1- dioxide；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl]-isoxazole -3- ketone of -2- methyl；

4- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethylidene] -1,3- dioxolane -2- ketone；

2- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -1H- pyrazoles -5- ketone；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl]-oxazole -2- ketone of -3- methyl；

5- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] oxazolidine -2- ketone；

N- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -1H- pyrazole-4-carboxamides；

1- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -5,5- dimethyl-imidazol -4- ketone；Formic acid；

2- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -1H-1,2,4- triazole -5- ketone；

(3S, 6R) -2- [[the fluoro- 4- of 2,5- bis- [1- (3- methoxyl group -1,2,4- triazol-1-yls) ethyl] phenyl] methyl] -3- first Base -6- phenyl-thiazan 1,1- dioxide；

4- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -3H- oxazole -2- ketone；

1- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] benzene Base] ethyl] -2- methyl isophthalic acids, 2,4- triazole -3- ketone；

(3S) -1- [1- [the fluoro- 4- of 2,5- bis- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] ethyl] -3- hydroxy-pyrrolidine 2- ketone；

And its officinal salt.

19. composition, comprising：

(a) pharmaceutical acceptable carrier；With

(b) compound as any one of claim 1-18.

20. for treating the method selected from following diseases：Rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic are closed Save inflammation, SpA, urarthritis, juvenile arthritis, chronic obstructive pulmonary disease (COPD), asthma, bronchus convulsion Contraction, IBS (IBS), IBD (IBD), psoriasis, cholecystalgia, renal colic, the IBS based on diarrhoea, muscle Hardening, Sjogren syndrome, lupus and pulmonary fibrosis, this method are included to individual administration effective dose in need such as claim Compound any one of 1-18.

21. the compound as any one of claim 1-18, it is used as therapeutic active substance.

22. the compound as any one of claim 1-18, which is used to treat, is selected from rheumatoid arthritis, osteoarthritis, silver The sick arthritis of bits, septic arthritis, SpA, urarthritis, juvenile arthritis, chronic obstructive pulmonary disease (COPD), asthma, bronchial spasm, IBS (IBS), IBD (IBD), psoriasis, cholecystalgia, kidney are twisted Bitterly, the purposes of IBS, muscular sclerosis, Sjogren syndrome, lupus and the disease of pulmonary fibrosis based on suffering from diarrhoea.

23. the compound as any one of claim 1-18, it, which is used to treat, is selected from rheumatoid arthritis, Bones and joints Inflammation, psoriatic arthritis, septic arthritis, SpA, urarthritis, juvenile arthritis, chronic obstructive Tuberculosis (COPD), asthma, bronchial spasm, IBS (IBS), IBD (IBD), psoriasis, cholecystalgia, kidney IBS, muscular sclerosis, Sjogren syndrome, lupus and the disease of pulmonary fibrosis based on angina, diarrhoea.

24. the compound as any one of claim 1-18 is being prepared for treating selected from rheumatoid arthritis, bone pass Save inflammation, psoriatic arthritis, septic arthritis, SpA, urarthritis, juvenile arthritis, COPD Property tuberculosis (COPD), asthma, bronchial spasm, IBS (IBS), IBD (IBD), psoriasis, cholecystalgia, IBS, muscular sclerosis, Sjogren syndrome, lupus based on renal colic, diarrhoea and the purposes in the medicine of the disease of pulmonary fibrosis.

25. the present invention as described above.