CN107176933A

CN107176933A - A kind of indoles amine -2,3- dioxygenase inhibitors containing N-alkylation and arylation sulphoxide imine

Info

Publication number: CN107176933A
Application number: CN201610134565.8A
Authority: CN
Inventors: 王召印; 郭巍; 朱继东; 胡新波
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 2016-03-09
Filing date: 2016-03-09
Publication date: 2017-09-19
Anticipated expiration: 2036-03-09
Also published as: CN107176933B; CN108699014A; WO2017152857A1

Abstract

The invention discloses a kind of indoleamine 2,3 dioxygenase inhibitors and preparation method thereof.The present invention inhibitor, structure as lead to formula (I) shown in, wherein, X, R¹、R²、R³、R⁴、R⁷、R⁸、R⁹, n and m definition as shown in specification and claims.The invention also discloses the preparation method of inhibitor.The logical formula (I) compound of the present invention, can be as indoleamine 2,3 dioxygenase inhibitors, for preparing prevention and/or treatment indoleamine 2, the medicine of the disease of 3 dioxygenases mediation.

Description

A kind of indoles amine -2,3- dioxygenase inhibitors containing N-alkylation and arylation sulphoxide imine

Technical field

The invention belongs to field of pharmaceutical chemistry technology, and in particular to one kind contains N-alkylation, arylation and acylation IDO inhibitor of sulphoxide imine and 1,2,5- oxadiazole structures and preparation method thereof.

Background technology

Indoles amine -2,3- dioxygenases (Indoleamine-2,3-dioxygenase, IDO) are that Hayaishi in 1967 is small A kind of monomeric enzyme containing heme that group is found in the cell first, cDNA encoding proteins are by 403 amino Acid composition, molecular weight is 45kDa, and it is the rate-limiting enzyme along tryptophan-kynurenine pathway catabolism, and And have in the tissue of a variety of mammals extensive expression (Hayaishi O.et al Science, 1969,164, 389-396).In the cell of tumor patient, IDO produces important frequently as induced tumor microenvironment immune tolerance Physiological action, its tryptophan (Tryptophan, Trp) mediated-kynurenin (Kynurenine, Kyn) metabolic pathway ginseng With tumor immune escape, and IDO also produces important effect as induced tumor microenvironment immune tolerance.

Tryptophan be in mammal body one of important necessary amino acid, it is necessary to from food huge uptake, maintenance Cell activation and propagation, and protein and some neurotransmitters synthesis.Therefore, its shortage can cause one The malfunction of a little important cells.IDO can be catalyzed tryptophan transfer and turn to N- formylkynurenines in vivo, drop Solve the content of tryptophan and cause the deficiency in tryptophan body, lead oncogenic generation.And immunohistology research is aobvious Show, kynurenine pathway can result in increasing for excitotoxin quinolinic acid, also result in the nervous systems such as alzheimer A variety of serious human diseases (Guillemin G.J.et al Neuropathol.and Appl.Neurobiol. such as disease 2005,31,395–404)。

Tryptophan rate-limiting enzyme mainly has two kinds in mammal body：Tryptophan dioxygenase (TDO) and IDO.1937 Year, Kotake etc. is purified into albumen from rabbit intestines, and finds the main tables in mammalian liver of TDO first Reach, not yet find that he there are close ties with immune system at present.TDO can be catalyzed kynurenine pathway, make color ammonia Acid is changed into N- formylkynurenines [Higuchi K.et al J.Biochem.1937,25,71-77；Shimizu T.et al J.Biol.Chem.1978,253,4700-4706].1978, the enzyme purified from rabbit enteron aisle was accredited It is the dioxygenase (IDO) containing heme, IDO is can be uniquely catalyzed beyond liver in tryptophan modules Indoles oxicracking, and prolong the enzyme of kynurenine pathway catabolism, IDO tables generally in the more organ of mucous membrane Reach, such as lung, small intestine and large intestine, rectum, spleen, kidney, stomach and brain etc., distribution than it is wide (Hayaishi O.et al, Proceedings of the tenth FEBS meeting,1975,131–144).Under some special or pathological conditions, Such as gestation, chronic infection, organ transplant and tumour etc., IDO expression can substantially increase, and participate in mediating local exempt from Epidemic disease suppresses.

Research shows that IDO can be suppressed local T cell by following several ways in tumor microenvironment and is immunized Reaction：Tryptophan depletion, toxic metabolic and induction regulatory T cells propagation.Many situations are the transition in tumour Expression, so as to consume local tryptophan, produces the metabolites such as substantial amounts of kynurenin.In fact, colourless Under the condition of culture of propylhomoserin or kynurenin, Proliferation Ability, activity reduction even apoptosis can occur for T cell.And T Exist in cell in the presence of the very sensitive point of adjustment of a tryptophan level, IDO, tryptophan can be made to disappear Consumption, so as to cause T cell to be stagnated in the G1 interim phases, so as to inhibit the propagation of T cell, also inhibits T thin The immune response of born of the same parents.And T cell once stops propagation, effect would not may be again stimulated, this is IDO in body Interior immunostimulation mechanism (Mellor A.et al Biochem.Biophys.Res.Commun.2005,338 (1):20- 24)(LeRond S.et al J.Exp.Med.2002,196(4):447-457)。

This area, which is still needed, researches and develops the Novel IDO inhibitor of high activity, present invention discover that a class is new to contain N-alkylation There is unexpected high IDO inhibitory activity with the compound of arylation sulphoxide imine and 1,2,5- oxadiazole structures.

The content of the invention

New contain N-alkylation and arylation sulphoxide imine and 1,2,5- Evil it is an object of the invention to provide a kind of The compound of diazole structure is used as efficient IDO enzyme inhibitors.

Another object of the present invention is to provide the preparation method of the compound.

The first aspect of the present invention there is provided a kind of formula (i) compound or its pharmaceutically acceptable salt, its stand Body isomers or its dynamic isomer or prodrug：

In formula,

R⁷And R⁸Each stand alone as hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀ Cycloalkyl, substituted or unsubstituted C₂-C₁₀Alkenyl, substituted or unsubstituted C₃-C₁₀Alkynyl, substitution or unsubstituted C₆-C₂₀Aryl or substituted or unsubstituted C₃-C₁₄Heteroaryl；R⁷And R⁸Can be formed together three to Octatomic ring or three to eight circle heterocycles, wherein hetero atom can be sulphur, oxygen, NH or NR^f；

R⁹For C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl；R⁹Can be by one or more substituent groups being selected from the group： Halogen, C₁-C₆Alkyl, C₁-C₆Alkoxy, hydroxyl, amino, nitro, aldehyde radical ,-CF₃、-CN、-SF₅、 NR^aR^b, carboxyl ,-COR^a、-CO₂C₁-C₆Alkyl ,-CONR^aR^b、-SO₂R^e、-SO₂NR^aR^b、-P(O)Me₂、 -P(O)(OMe)₂；Wherein each R^aWith each R^bEach stand alone as hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl, substitution Or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₂-C₁₀Alkenyl, substituted or unsubstituted C₆-C₂₀Virtue Base or substituted or unsubstituted C₃-C₁₄Heteroaryl；R^aAnd R^bThree can be formed together to octatomic ring or four To eight circle heterocycles, wherein hetero atom can be sulphur, oxygen, NH or NR^g；

R²For C₁-C₁₂Alkyl, C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl, C₁-C₄Alkyl-phenyl, C₁-C₄Alkyl-C5 Heterocycle ,-C (O) OR^e；-SO₂R^e、-SO₂NR^aR^bOr-C (O) NR^aR^b；

X is singly-bound, an O, S, NH or NR^d；

Ring A is 5 yuan or 6 yuan and contains heterocycle；

R³And R⁴Each stand alone as hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl；R³And R⁴Can together can be with shape Cheng Sanzhi octatomic rings or three to eight circle heterocycles, wherein hetero atom can be sulphur, oxygen, NH or NR^h；

R¹、R^d、R^e、R^f、R^g、R^hIt independently is C₁-C₁₀Alkyl, C₃-C₁₀Cycloalkyl, C₆-C₂₀Aryl, Or C₃-C₁₄Heteroaryl；R¹Can be by one or more substituent groups being selected from the group：Halogen, hydroxyl, amino, Nitro, cyano group, aldehyde radical, carboxyl, alkoxy ,-CF₃、-SF₅；

R¹With²It can be replaced by one or more halogens, alkoxy and cyano group；

R¹And R^dIt can connect to form six to octatomic ring；

R¹And R³It can connect to form five to octatomic ring；

N is 2 to 8 integer；

M is 0,1 or 2.

In another preference, described " substitution " refers to one or more substituents being selected from the group：Halogen, Hydroxyl ,-NH₂, nitro ,-CN, C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, C₃-C₆Cycloalkanes Base, C₂-C₄Alkenyl, C₂-C₄Alkynyl, phenyl, benzyl.

In another preference, R²For C₁-C₁₂Alkyl, C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl ,-SO₂R^eOr -C(O)NR^aR^b；

In another preference, R³And R⁴Each stand alone as hydrogen,

In another preference, n is 2 to 6.

In another preference, X is NH.

In another preference, m is 0.

In another preference, shown in the compound such as formula (ii),

In formula,

R⁹For C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl；R⁹Can be by one or more substituent groups being selected from the group： Halogen, C₁-C₆Alkyl, C₁-C₆Alkoxy, hydroxyl, amino, nitro, aldehyde radical ,-CF₃、-CN、-SF₅、 NR^aR^b, carboxyl ,-COR^a、-CO₂C₁-C₆Alkyl ,-CONR^aR^b、-SO₂R^e、-SO₂NR^aR^b；

Wherein, R^a、R^b、R³、R⁴、R¹It is as defined above；

R²For C₁-C₁₂Alkyl, C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl ,-C (O) OR^e；-SO₂R^e、-SO₂NR^aR^b Or-C (O) NR^aR^b；

N is 2-6.

It is another it is preferential select example, shown in the compound such as formula (iii),

In formula,

Wherein, R³、R⁴、R¹It is as defined above；

R¹With²It can be replaced by one or more halogens, alkoxy and cyano group

Ar is C₆-C₁₀Aryl, five yuan or six membered heteroaryl；Ar can be by one or more groups being selected from the group Substitution：Halogen, C₁-C₆Alkyl, C₁-C₆Alkoxy, hydroxyl ,-CF₃、-CN、-SF₅。

N is 2-6.

In another preference, R¹For C₁-C₁₀Alkyl；

R²For C₁-C₁₂Alkyl, C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl ,-SO₂R^e、-SO₂NR^aR^bOr-C (O) NR^aR^b；

R³And R⁴Each stand alone as hydrogen；

Ar is C₆-C₁₀Aryl, five yuan or six membered heteroaryl；Ar can be by one or more groups being selected from the group Substitution：Halogen, C₁-C₆Alkyl, C₁-C₆Alkoxy, hydroxyl, amino, nitro, aldehyde radical ,-CF₃、-CN、-SF₅。

In another preference, R¹For C₁-C₄Alkyl；

In another preference, shown in the prodrug of described formula i compounds, such as formula (iv),

In formula,

R¹、R²、R³、R⁴And R⁹It is as defined above；

R^10aFor substituted or unsubstituted C₆-C₂₀Aryl, substituted or unsubstituted five yuan or six membered heteroaryl, substitution Or unsubstituted C₁-C₁₂Alkyl, substituted or unsubstituted C₁-C₁₂Alkoxy, substituted or unsubstituted C₃-C₁₂Ring Alkyl, C₃-C₁₂Cycloalkyloxy, NR^aR^b；Wherein, R^a、R^bIt is as defined above；

Wherein, described " substitution " refers to one or more substituents being selected from the group：Halogen, hydroxyl ,-NH₂、 Nitro ,-CN, C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, C₃-C₆Cycloalkyl, C₂-C₄Alkene Base, C₂-C₄Alkynyl, phenyl, benzyl.

In another preference, X, R¹、R²、R³、R⁴、R⁷、R⁸、R⁹、R^10aEtc. each group independently Ground is formula (i), (ii), the corresponding group in (ii) and (iv) each particular compound prepared in embodiment.

In another preference, the compound is：

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (nitrogen, sulphur-dimethyl sulfoxide (DMSO) imines) ethyl) ammonia Base) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((3- (sulphur-methyl-nitrogen ethyl-sulfoxide imines) ethyl) ammonia Base) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((3- (sulphur-methyl-nitrogen isopropyl sulphoxide imine) ethyl) ammonia Base) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((3- (sulphur-methyl-azo-cycle propyl group sulphoxide imine) ethyl) ammonia Base) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen ' (((sulphur-methyl-nitrogen (2,2,2- trifluoroethyls) sulfoxide is sub- by 3- by-hydroxyl -4- Amine) ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((3- (sulphur-methyl-nitrogen (2- fluoro ethyls) sulphoxide imine) second Base) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (the λ 6,2- thiazine -1- bases of 1- oxygen -3,4,5,6- tetrahydrochysenes -1) second Base) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((3- (sulphur-methyl-azo-cycle butyl base sulphoxide imine) ethyl) Amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-phenylsulfone imines) ethyl) ammonia Base) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- fluorophenyls sulphoxide imines) Ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- chlorophenyls imines) Ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(anilino- formyl) sulphoxide imine) Ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen ' (((sulphur-methyl-nitrogen-(methylamino formyl) sulfoxide is sub- by 2- by-hydroxyl -4- Amine) ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(isopropyl carbamoyl) sulfoxide Imines) ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl methyl) sulphoxide imine) second Base) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl ethyl) sulphoxide imine) second Base) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(formyl isopropyl ester) sulphoxide imine) Ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(mesyl) sulphoxide imine) second Base) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(benzenesulfonyl) sulphoxide imine) second Base) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(nitrogen-phenylsulfamoyl base) sulfoxide Imines) ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamyl) sulphoxide imine) second Base) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (nitrogen, sulphur-dimethyl sulfoxide (DMSO) imines) ethyl) ammonia Base) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((3- (sulphur-methyl-nitrogen ethyl-sulfoxide imines) ethyl) ammonia Base) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(3- trifluoromethyls)-nitrogen '-hydroxyl -4- ((3- (sulphur-methyl-nitrogen isopropyl sulphoxide imine) ethyl) Amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(3- trifluoromethyls)-nitrogen '-hydroxyl -4- ((3- (sulphur-methyl-azo-cycle propyl group sulphoxide imine) ethyl) Amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((3- (sulphur-methyl-azo-cycle butyl base sulphoxide imine) ethyl) Amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-phenylsulfone imines) ethyl) ammonia Base) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(3- trifluoromethyls)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- fluorophenyls sulphoxide imines) Ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- chlorophenyls imines) Ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(anilino- formyl) sulphoxide imine) Ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyls of 3-)-nitrogen ' (((sulphur-methyl-nitrogen-(methylamino formyl) sulfoxide is sub- by 2- by-hydroxyl -4- Amine) ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(3- trifluoromethyls)-nitrogen ' (((sulphur-methyl-nitrogen-(isopropyl carbamoyl) is sub- by 2- by-hydroxyl -4- Sulfoximide) ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl methyl) sulphoxide imine) second Base) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(3- trifluoromethyls)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl ethyl) sulphoxide imine) Ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(formyl isopropyl ester) sulphoxide imine) Ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(mesyl) sulphoxide imine) second Base) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(3- trifluoromethyls)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(benzenesulfonyl) sulphoxide imine) Ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(nitrogen-phenylsulfamoyl base) sulfoxide Imines) ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamyl) sulphoxide imine) second Base) amino) -1,2,5- oxadiazole -3- carbonamidines

In another preference, described compound is prepared compound 1-9 in embodiment.

In another preference, described compound is racemic modification.

In another preference, described compound is enantiomter.

In another preference, the pharmaceutically acceptable salt is selected from the group：Hydrochloride, hydrobromate, sulfuric acid Salt, phosphate, mesylate, fluoroform sulphonate, benzene sulfonate, tosilate (toluene fulfonate), 1-naphthalene sulfonic aicd salt, 2- naphthalene sulfonates, acetate, trifluoroacetate, malate, tartrate, citrate, Lactate, oxalates, succinate, fumarate, maleate, benzoate, salicylate, phenylacetic acid Salt, mandelate.

The second aspect of the present invention there is provided the preparation method of formula (i) compound described in first aspect, including with Lower step：

(a) compound P1 and R₃OBF₄Reaction, obtains compound P2；

(b) compound P1 and ArB (OH)₂With Cu (OAc)₂Reaction, obtains compound P3；

(c) compound P2 or P3 (such as sodium hydrate aqueous solution) open loop in the presence of sodium hydroxide, obtain end-product P4 or P5, that is, lead to formula (I) compound.

Formula (i) compound of the present invention can also be obtained by following preparation method, be comprised the following steps：

(a) compound P1 and R-N=C=O or ClSO₂R²Reaction, obtains compound P6 or P7；

(b) compound P6 or P7 (such as sodium hydrate aqueous solution) open loop in the presence of sodium hydroxide, obtain end-product P8 or P9, that is, lead to formula (I) compound.

Present invention provides the preparation method of the third formula (i) compound, comprise the following steps：

(a) compound D reacts under the catalysis of acid with compound E and a reducing agent, obtains compound F；

(b) compound F (such as sodium hydrate aqueous solution) open loops under base hydrolysis conditions, obtain end-product and lead to formula (I) Compound.

Present invention provides the preparation method of the 4th kind of formula (i) compound, comprise the following steps：

In various, R¹、R³、R⁴、R⁷、R⁸、R⁹, shown in n, m, X and ring A be as defined above.

Using the third dicyan as initiation material in the present invention, by a series of oxidation, addition, takes cyclization, diazotising The reaction such as generation obtains compound P1.

The third aspect of the present invention is used for there is provided the purposes of formula (i) compound described in first aspect：

(i) indoles amine -2,3- dioxygenase inhibitors are prepared；

(ii) medicine of the disease of prevention and/or treatment indoles amine -2,3- dioxygenase mediations is prepared；Or

(iii) anti-inflammatory drug is prepared.

In another preference, the disease of indoles amine -2,3- dioxygenase mediation is the tryptophan generation that IDO is mediated Thank to the disease of the pathological characteristicses of approach.

In another preference, the disease of indoles amine -2,3- dioxygenase mediation is cancer, eye illness, hindered at heart Hinder, depression, anxiety disorder, senile dementia and/or autoimmune disease.

In another preference, the cancer includes but is not limited to：It is colon cancer, breast cancer, stomach cancer, lung cancer, big Intestinal cancer, cancer of pancreas, oophoroma, prostate cancer, kidney, liver cancer, the cancer of the brain, melanoma, Huppert's disease, Chronic granulocytic leukemia, neoplastic hematologic disorder, lympha tumour, are included in other tissues away from tumour original site Or the metastasis of organ.

The fourth aspect of the present invention is included there is provided a kind of pharmaceutical composition, described pharmaceutical composition：

The logical formula (I) compound of first aspect or its pharmaceutically acceptable salt, its stereoisomer or its mutually variation Structure body or its prodrug；And

Pharmaceutically acceptable carrier.

The fifth aspect of the present invention is included there is provided a kind of pharmaceutical composition, described pharmaceutical composition：

Formula (i) compound described in first aspect or its pharmaceutically acceptable salt, its stereoisomer or its is mutual Tautomeric or its prodrug；And

Antineoplastic.

In another preference, the antineoplastic includes but is not limited to the immunotherapy medicaments of cancer：PD-1 Antibody, CTLA-4 antibody, PD-L1 antibody, PD-L2 antibody, any other chemotherapeutics or targeting are controlled Treat medicine, such as hdac inhibitor and EP4 antagonists.

There is provided the disease of a kind of prevention and/or the dioxygenase mediation for the treatment of indoles amine -2,3- for the sixth aspect of the present invention Method, including the medicine described in formula (i) compound or the 4th or the 5th aspect described in first aspect is given to patient The step of composition.

In another preference, the disease of indoles amine -2,3- dioxygenase mediation is cancer, and methods described enters one Step, which is included, applies extra anticancer (being also referred to as antineoplastic, the antineoplastic is as described above) to patient Step.

Formula (i) compound of the present invention, with antitumor, treatment neurological disease (Alzheimer disease), resists A variety of pharmacological activity such as inflammation.

It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and in below (eg embodiment) It can be combined with each other between each technical characteristic specifically described, so as to constitute new or preferred technical scheme.Limit In length, this is no longer going to repeat them.

Specific embodiment

The present inventor by extensively and in depth studying, it is unexpected first develop it is a kind of it is new comprising sulphoxide imine with The compound of 1,2,5- oxadiazole structure, the compound can as efficient IDO enzyme inhibitors, for preventing and/or The disease of indoles amine -2,3- dioxygenase mediation is treated, can also be used as anti-inflammatory drug.On this basis, complete The present invention.

Definition

Term " alkyl " refers to monovalence radical of saturated aliphatic alkyl, with 1 to 10 carbon atom, including straight chain and branched-chain hydrocarbons Base, such as methyl (i.e. CH₃-), ethyl (i.e. CH₃CH₂-), n-propyl (i.e. CH₃CH₂CH₂-), isopropyl (i.e. (CH₃)₂CH-), normal-butyl (i.e. CH₃CH₂CH₂CH₂-), isobutyl group (i.e. (CH₃)₂CHCH₂-), sec-butyl (i.e. (CH₃)(CH₃CH₂) CH-), the tert-butyl group (i.e. (CH₃)₃C-), n-pentyl (i.e. CH₃CH₂CH₂CH₂CH₂-), new penta Base (i.e. (CH₃)₃CCH₂-).In the present invention, the term includes substituted or unsubstituted alkyl.

As used herein, it can be unsubstituted, or described that term " substituted or unsubstituted ", which refers to the group, H in group is replaced by one or more (preferably 1-6, more preferably 1-3) substituents.

As used herein, described " substitution " or " substituted " refer to the group have it is one or more (preferably Ground 1-6, more preferably 1-3) substituent that is selected from the group：Halogen, hydroxyl ,-NH₂, nitro ,-CN, C1-C4 Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, C₃-C₆Cycloalkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, benzene Base, benzyl.

As used herein, term " cycloalkyl " refers to substituted or unsubstituted C3-C12 cycloalkyl.

As used herein, term " alkoxy " refers to-O- alkyl, wherein the alkyl can be saturation or unsaturation , can be side chain, straight chain or ring-type.Preferably, alkoxy has 1-10 carbon atom, preferably 1-6 carbon atom.Representational example includes (but being not limited to)：Methoxyl group, ethyoxyl, propoxyl group.

As used herein, term " aryl " refers to the monovalent aromatic carbocyclic of 6 to 20 (preferable 6-14) carbon atoms Group, it has monocyclic (such as phenyl) or condensed ring (such as naphthyl or anthryl), if tie point is in aromatic carbon original, condensed ring It is probably nonaromatic (such as 2- benzoxazolones, 2H-1,4- benzoxazines -3 (4H) -one -7- bases etc.).It is preferred that virtue Base includes phenyl and naphthyl.The term includes substituted or unsubstituted form, and wherein substituent is as defined above.

As used herein, term " alkenyl " refers to the alkenyl with 2 to 10 (such as 2 to 6 or 2 to 4) individual carbon atoms, And with the individual unsaturated ethylene linkage (＞ C=C ＜) at least 1 (such as 1 to 2).This kind of group for example have vinyl, pi-allyl, Butyl- 3- alkenyls.As used herein, term " cycloalkyl " refer to it is with 3 to 10 carbon atoms, with monocyclic or The cyclic alkyl of polycyclic (including fused system, bridged-ring system and spiro ring system).In fused ring system, one or many Individual ring can be cycloalkyl, heterocycle, aryl or heteroaryl, as long as connection site is the ring by cycloalkyl.Close The example of suitable cycloalkyl includes：For example, adamantyl, cyclopropyl, cyclobutyl, cyclopenta and cyclooctyl.

As used herein, term " halo " or " halogen " refer to fluorine, chlorine, bromine and iodine.

As used herein, term " heteroaryl " be have in finger ring 1 to 10 carbon atom and 1 to 4 selected from oxygen, The heteroatomic aromatic group of nitrogen and sulphur, such heteroaryl can be monocyclic (such as pyridine radicals or furyl) or thick Ring (such as indolizine base (indolizinyl) or benzothienyl), wherein, the condensed ring can be nonaromatic and/or contain There is a hetero atom, as long as tie point is the atom by armaticity heteroaryl.In one embodiment, heteroaryl Annular atom nitrogen and/or sulphur are optionally oxidized to N- oxides (N-O), sulfinyl or sulfonyl.Preferably heteroaryl Base includes pyridine radicals, pyrrole radicals, indyl, thienyl and furyl.The term includes substituted or unsubstituted miscellaneous Aryl.

As used herein, term " substituted heteroaryl " refer to by 1 to 5, preferably 1 to 3, more preferably 1 The heteroaryl replaced to the substituents of 2, the substituent is selected from substitution identical with defined in substituted aryl Base.

As used herein, term " heterocycle " or " heterocycle " or " Heterocyclylalkyl " or " heterocyclic radical " refer to saturation, portion Point saturated or unsaturated group (but not being armaticity), with monocyclic or condensed ring (including bridged-ring system and loop coil With 1 to 10 carbon atom and 1 to 4 hetero atom for being selected from nitrogen, sulphur or oxygen in system, ring, in condensed ring body In system, one or more rings can be cycloalkyl, aryl or heteroaryl, as long as tie point passes through nonaro-maticity ring. In one embodiment, the nitrogen-atoms and/or sulphur atom of heterocyclic group optionally be oxidized, with provide N- oxides, Sulfinyl and sulfonyl moieties.

As used herein, term " substituted heterocycle " or " substituted Heterocyclylalkyl " or " substituted heterocyclic radical " refer to The heterocyclic group replaced by 1 to 5 (such as 1 to 3) individual substituents, the substituent is defined with the cycloalkyl replaced Substituent it is identical.

As used herein, term " stereoisomer " refers to the chiral different compound of one or more Stereocenters. Stereoisomer includes enantiomter and diastereoisomer.

As used herein, term " dynamic isomer " refers to the alternative form of the different compound in proton position, such as alkene Alcohol -one and imine-enamine tautomers, or heteroaryl tautomeric form, the heteroaryl include and ring - NH- part and ring=N- part connection annular atom, such as pyrazoles, imidazoles, benzimidazole, triazole and tetrazolium.

" prodrug " refers to any derivative of embodiment compound, when being applied to subject, its can directly or The compound or its active metabolite or residue of embodiment are provided indirectly.Particularly preferred derivative and prodrug are Those, when being applied to subject, improve the bioavilability of embodiment compound (such as the compound being administered orally It is easier to be rapidly absorbed into blood) or relative to parent species raising parent compound to biological compartment (such as brain or lymph System) transport derivative and prodrug.Prodrug includes the esters form of the compounds of this invention.

The compounds of this invention

As used herein, term " the compounds of this invention " refers to the compound with formula of the present invention, including logical Formula (i) or formula (ii) compound, its racemic modification, its stereoisomer or its dynamic isomer or prodrug or its Pharmaceutically acceptable salt.It should be understood that the term also includes in formula (iii) and description of the invention and claim Compound, its racemic modification, its stereoisomer or its dynamic isomer or its pharmacy shown in other formulas, Upper acceptable salt.

The present invention relates to：The racemic mixture of these compounds, is enriched with the mixture of any enantiomer, and The enantiomer of any separation.For the scope of the present invention, it should be appreciated that the racemic mixture refers to two kinds R and S enantiomers 50%:50% mixture.The enantiomer of the separation is interpreted as pure enantiomer (i.e. 100%) Or highly enriched certain enantiomer (purity >=98%, >=95%, >=93%, >=90%, >=88%, >=85%, >=mixture 80%).

Typically, the present invention provide formula (i) compound or its pharmaceutically acceptable salt, its stereoisomer or Its dynamic isomer or prodrug,

In formula,

R⁹For C₆-C₂₀Aryl, five yuan or six membered heteroaryl；R⁹Can be by one or more groups being selected from the group Substitution：Halogen, C₁-C₆Alkyl, C₁-C₆Alkoxy, hydroxyl, amino, nitro, aldehyde radical ,-CF₃、-CN、-SF₅、 NR^aR^b, carboxyl ,-COR^a、-CO₂C₁-C₆Alkyl ,-CONR^aR^b、-SO₂R^a、-SO₂NR^aR^b、-P(O)Me2、 -P(O)(OMe)₂；Wherein each R^aWith each R^bEach stand alone as hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl, substitution Or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₂-C₁₀Alkenyl, substituted or unsubstituted C₆-C₂₀Virtue Base or substituted or unsubstituted C₃-C₁₄Heteroaryl；R^aAnd R^bThree can be formed together to octatomic ring or four To eight circle heterocycles, wherein hetero atom can be sulphur, oxygen, NH or NR^g；

X is singly-bound, an O, S, NH or NR^d；

R¹And R^dIt can connect to form six to octatomic ring；

R¹And R³It can connect to form five to octatomic ring；

N is 2 to 8；

Ring A is 1,2,5- oxadiazole rings；

M is 0 to 2.

In another preference, formula (a) compound is：

Wherein R¹For C₁-C₁₀Alkyl, C₃-C₁₀Cycloalkyl, C₁-C₁₀Alkenyl, aryl or heteroaryl, R¹Can To be replaced by one or more halogens；

R¹⁰And R¹¹It is each independently hydrogen, halogen, C₁-C₆Alkyl, C₁-C₆Alkoxy, C₂-C₆Alkynyl, hydroxyl, Amino, nitro, cyano group, aldehyde radical ,-CF₃、-CN、-SF₅、NR^aR^b, carboxyl ,-CO₂C₁-C₆Alkyl ,-CONR^aR^b、 -SO₂R^a、SO₂NR^aR^bSubstitution；R^aAnd R^bIt is defined as described above；

N is 1 to 8.

In another preference, present invention also offers the prodrug of formula (a)：

In formula, each group is as defined above.

The present invention one be preferably carried out in mode, the invention provides a kind of logical formula (I) compound or its Pharmaceutically acceptable salt, its stereoisomer or its dynamic isomer or prodrug：

In formula,

R²For C₁-C₁₂Alkyl, C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl, C₁-C₄Alkyl-phenyl, C₁-C₄Alkyl-C₅ Heterocycle ,-C (O) OR^e；-SO₂R^e、-SO₂NR^aR^bOr-C (O) NR^aR^b；

X is singly-bound, an O, S, NH or NR^d；

R¹、R^d、R^e、R^f、R^g、R^hIt independently is C₁-C₁₀Alkyl, C₃-C₁₀Cycloalkyl, C₆-C₂₀Aryl, Or C₃-C₁₄Heteroaryl；R¹And R²Can be by one or more substituent groups being selected from the group：Halogen, hydroxyl, Amino, nitro, cyano group, aldehyde radical, carboxyl, alkoxy ,-CF₃、-SF₅；

R¹And R²It can be replaced by one or more halogens, alkoxy and cyano group；

R¹And R²It can connect to form four to octatomic ring；

R¹And R^dIt can connect to form six to octatomic ring；

R¹And R³It can connect to form five to octatomic ring；

N is 2 to 8 integer；

M is 0,1 or 2.

Be preferably carried out at another in mode, the compound that provides of the present invention as led to shown in formula (II),

In formula,

Wherein, R^a、R^b、R³、R⁴、R¹Definition it is as claimed in claim 1；

R¹And R²It can be replaced by one or more halogens, alkoxy and cyano group；

R¹And R²It can connect to form four to octatomic ring；

N is 2-6 integer.

In presently preferred ground embodiment, the compound that provides of the present invention as led to shown in formula (III),

In formula,

Ar is phenyl ring, and five yuan or six membered heteroaryl, Ar can be by one or more substituent groups being selected from the group： Halogen, C₁-C₆Alkyl, C₁-C₆Alkoxy, hydroxyl, amino, nitro, aldehyde radical ,-CF₃、-CN、-SF₅、 NR^aR^b, carboxyl ,-COR^a、-CO₂C₁-C₆Alkyl ,-CONR^aR^b、-SO₂R^e、-SO₂NR^aR^b；

R^a、R^b、R³、R⁴、R¹Definition it is as claimed in claim 1；

R¹And R²It can be replaced by one or more halogens, alkoxy and cyano group；

R¹And R²It can connect to form four to octatomic ring；

N is 2-6 integer.

In presently preferred ground embodiment, R¹For C₁-C₄Alkyl；

R²For C₁-C₆Alkyl, phenyl, C₅-C₂₀Heteroaryl ,-C (O) OR^e；-SO₂R^e、-SO₂NR^aR^bOr -C(O)NR^aR^b；

R^a、R^bDefinition it is as claimed in claim 1；

R¹And R²It can connect to form four to octatomic ring；

R³And R⁴Each stand alone as hydrogen；

N is 2-6 integer.

In presently preferred ground embodiment, before described logical formula (I) compound Medicine, as shown in logical formula (IV),

In formula,

R¹、R²、R³、R⁴And R⁹Definition it is as claimed in claim 1；

R^10aFor substituted or unsubstituted C₆-C₂₀Aryl, substituted or unsubstituted five yuan or six membered heteroaryl, substitution Or unsubstituted C₁-C₁₂Alkyl, substituted or unsubstituted C₁-C₁₂Alkoxy, substituted or unsubstituted C₃-C₁₂Ring Alkyl, C₃-C₁₂Cycloalkyloxy, NR^aR^b；Wherein, R^a、R^bDefinition as claimed in claim 1,

Wherein, described " substitution " refers to one or more substituents being selected from the group：Halogen, hydroxyl ,-NH₂、 Nitro ,-CN, C1-C4 alkyl, C1-C4 haloalkyls, C1-C4 alkoxies, C3-C6 cycloalkyl, C2-C4 Alkenyl, C2-C4 alkynyls, phenyl, benzyl.

In the presence of compound of the present invention has stereoisomer, the present invention is all including compound Stereoisomer.

In the presence of compound of the present invention has dynamic isomer, the present invention is all including compound Dynamic isomer.

Replaced present invention additionally comprises any one or more hydrogen atoms in the compound by its stable isotope deuterium And the deuterated compound produced.

Pharmaceutical composition

Present invention also offers a kind of pharmaceutical composition, it includes the active component in the range of safe and effective amount, and Pharmaceutically acceptable carrier.

" active component " of the present invention refer to logical formula (I) compound of the present invention or its can pharmaceutically connect Salt, its stereoisomer or its dynamic isomer for receiving or its prodrug.

" active component " of the present invention and pharmaceutical composition can be used as IDO inhibitor.In another preference, Medicine for preparing prevention and/or treatment tumour.In another preference, for preparing prevention and/or treatment IDO The medicine of the disease of mediation.

" safe and effective amount " is referred to：The amount of active component is enough to be obviously improved the state of an illness, and is unlikely to produce seriously Side effect.Generally, pharmaceutical composition contains 1-2000mg active components/agent, more preferably, contains 10-200mg Active component/agent.It is preferred that described is " one " for a tablet.

" pharmaceutically acceptable carrier " is referred to：One or more biocompatible solids or liquid filler or jello Matter, they are suitable for people and used and it is necessary to have enough purity and sufficiently low toxicity." compatibility " herein Refer to each component energy in composition and the active component of the present invention and they between mutually admix, without substantially drop The drug effect of low activity composition.

The compound of the preferred embodiment of the present invention can be administered as independent active agents, can also with it is one or more Other agent combinations for treating cancer are used.The compound of the preferred embodiment of the present invention and known therapeutic agent and It is also effective that anticancer, which is applied in combination, and the compound being currently known and the combination of other anticancers or chemotherapeutics are excellent Select within scope of embodiments.The example of this kind of medicament can be found in《Cancer theory and put into practice oncology》(Cancer Principles and Practice of Oncology), V.T.Devita and S.Hellman (editor), the 6th edition (2001 15 days 2 months year), Lippincott Williams ＆Wilkins publishing houses.Special nature based on medicine and involved And cancer, those of ordinary skill in the art can distinguish effective pharmaceutical agent combinations.This anticancer includes (but not limiting In) as follows：Estrogenic agents, androgen receptor modifier, retinoid receptor modulators, cytotoxicity / cytostatic agent, antiproliferative, prenyl protein transferase inhibitor, take acetyl enzyme (HDAC) press down Preparation, HMG-CoA reductase inhibitor and other angiogenesis inhibitors, cell propagation and survival signaling suppress Agent, the reagent of inducer of apoptosis and interference cell cycle checkpoint (cell cycle checkpoint), CTLA4 antibody, PD-1 antibody, PD-L1 antibody etc..It is also effective when the compound of preferred embodiment is administered simultaneously with radiotherapy.

Generally, it is preferred to the compound of embodiment by with therapeutically effective amount, pass through any of the medicament with similar effect A kind of acceptable pattern is applied.The actual amount of the compound (i.e. active component) of preferred embodiment according to it is multiple because Element determines, the age of the order of severity, patient such as disease to be treated and relative health, by use compound Effect, the path applied and form, and other factors.The medicine can be applied multiple for one day, it is preferable that daily Once or twice.All of these factors taken together is all in the limit of consideration of the doctor in charge.

The purpose of preferred embodiment, treatment effective dose generally can be to patient's one-time use or administration by several times Per total daily dose, for example, daily about 0.001 to about 1000 mg kg of body weight, it is preferable that daily about 1.0 to About 30 mg/kg body weight.Units dosage composition (Dosage unit composition) can comprising its dosage factor with Form daily dosage.The selection of formulation depends on various factors, the biological utilisation of such as mode of administration and drug substance Degree.Generally, it is preferred to which the compound of embodiment can be administered as pharmaceutical composition by any one following route：Mouthful Clothes, Formulations for systemic administration (such as transdermal, intranasal or by suppository) or parenteral administration (such as intramuscular, intravenously or subcutaneously).It is excellent The administering mode of choosing be it is oral, can be according to bitter degree daily dose easy to adjust.The form that composition can be taken is Tablet, pill, capsule, semisolid, pulvis, sustained release preparation, solution, suspension, elixir, aerosol are appointed What his appropriate composition.The mode of another preferred administration preferred embodiment compound is suction.This is one Plant the effective ways that therapeutic agent is shipped directly to respiratory tract (referring to such as U.S. Patent number 5,607,915).

Suitable pharmaceutically acceptable carrier or excipient include：As inorganic agent and medicine transport modifying agent and promotion Agent, such as calcium phosphate, magnesium stearate, talcum, monose, disaccharides, starch, gelatin, cellulose, Methyl cellulose Plain sodium, carboxymethyl cellulose, glucose, hydroxypropyl-B- cyclodextrin, polyvinylpyrrolidone, low melt wax, from Sub-exchange resin etc., and its any combination of two or more.Liquid and semisolid excipient can selected from glycerine, Propane diols, water, ethanol and various oil, including oil, animal oil, vegetable oil or synthesis source, such as peanut oil, Soya-bean oil, mineral oil, sesame oil etc..It is preferred that liquid-carrier, the particularly carrier for Injectable solution, including Water, salt solution, glucose aqueous solution and ethylene glycol.Other suitable pharmaceutically acceptable excipient exist《Lei Ming Pause pharmaceutical science》(Remington ' s Pharmaceutical Sciences), Mack Pub.Co., New Jersey (1991) have Description, is totally incorporated herein by reference.

As used herein, term " pharmaceutically acceptable salt " refers to the non-toxic acid or alkaline earth gold of compound of Formula I Belong to salt.These salt can be made when being finally recovered and purifying compound of Formula I or respectively will be suitable organic in original position Or inorganic acid or alkali are made with alkalescence or acidic functionality reaction.Representational salt includes, but are not limited to：Acetate, Adipate, alginates, citrate, aspartate, benzoate, benzene sulfonate, disulfate, fourth Hydrochlorate, camphor hydrochlorate, camsilate, digluconate, cyclopentane propionate, lauryl sulfate, second Sulfonate, flucoheptanoate, glycerophosphate, Hemisulphate, enanthate, caproate, fumarate, salt Hydrochlorate, hydrobromate, hydriodate, 2- isethionates, lactate, maleate, mesylate, cigarette Hydrochlorate, 2- naphthyl sulphonic acids salt, oxalates, embonate, pectate, rhodanate, 3- phenylpropionic acids salt, Picrate, Pivalate, propionate, succinate, sulfate, tartrate, rhodanate, to toluene Sulfonate and hendecane hydrochlorate.In addition, nitrogenous basic group can be by following reagent quaternization：Alkyl halide, Such as methyl, ethyl, propyl group, the chloride of butyl, bromide and iodide；Dialkyl sulfate, such as dimethyl, Diethyl, dibutyl and diamyl sulfates；Long chain halide such as decyl, lauryl, myristyl and stearyl Chloride, bromide and iodide；Aralkyl halide such as benzyl and phenylethyl bromide etc..Thus water is obtained Dissolubility or oil-soluble or dispersible product.It may be used to form the sour example bag of pharmaceutically acceptable acid-addition salts Include as hydrochloric acid, sulfuric acid, phosphoric acid inorganic acid, and such as oxalic acid, maleic acid, methanesulfonic acid, butanedioic acid, citric acid Organic acid.Base addition salts in situ when being finally recovered and purifying compounds of formula I can be made or make carboxylic moiety Respectively with suitable alkali (hydroxide of such as pharmaceutically acceptable metal cation, carbonate or bicarbonate) or Ammonia or organic primary, secondary or tertiary amine reaction are made.Pharmaceutically acceptable salt includes, but not limited to based on alkali gold The salt of the cation, such as sodium, lithium, potassium, calcium, magnesium, aluminium of category and alkaline-earth metal, and nontoxic ammonium, quaternary ammonium And amine cation, include, but are not limited to：Ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethylamine, trimethylamine, Triethylamine, ethamine etc..It is other it is representational be used for formed base addition salts organic amines include diethylamine, ethylenediamine, Monoethanolamine, diethanol amine, piperazine etc..

As used herein, term " pharmaceutically acceptable prodrug " refers to the prodrug of the compound of those preferred embodiments, The compound for the parent compound being quickly converted in vivo shown in above-mentioned formula, for example, hydrolyze in blood.In " T. Higuchi and V.Stella, is used as prodrug (the Pro-drugs as Novel Delivery of new delivery system Systems), A.C.S.15Symposium Series volume 14 " and " Edward B.Roche volumes, drug design In bio-reversible carrier (Bioreversible Carriers in Drug Design), American Pharmaceutical Association and Pergamon Complete discussion is provided in publishing house, 1987 ", both of which is incorporated herein by reference.

With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate this Invention rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally According to normal condition such as Sambrook et al., molecular cloning：Laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989) described in condition, or according to the condition proposed by manufacturer.Unless Illustrate in addition, otherwise percentage and number are calculated by weight.

The present invention is advantageous in that：

(1) provide a kind of structure novel logical formula (I) compound；

(2) compound of the invention can be used as efficient IDO enzyme inhibitors；

(3) synthetic method is gentle, and operation is simple, and yield is higher, it is easy to derivatization, is adapted to industry amplification quantity Production；

(4) there are a variety of pharmacological activity such as antitumor, nerve degenerative diseases (Alzheimer disease), anti-inflammatory.

Unless otherwise defined, all specialties used in text with known to scientific words and one skilled in the art Meaning is identical.In addition, any method similar or impartial to described content and material all can be applied to present invention side In method.Preferable implementation described in text only presents a demonstration with material to be used.

Embodiment 1

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (nitrogen, sulphur-dimethyl sulfoxide (DMSO) imines) second Base) amino) -1,2,5- oxadiazole -3- carbonamidines

The first step：4- amino-nitrogen '-hydroxyl -1,2,5- oxadiazole -3- carbonamidines

Third dicyan (3.2g, 48.5mmol) is dissolved in 70mL water, is heated to being completely dissolved.Under ice-water bath cooling, Add natrium nitrosum (3.8g, 55mmol) and 6N hydrochloric acid (0.6mL).After being reacted 0.5 hour under ice bath, heating To room temperature reaction 2 hours.Reaction solution is continued into ice bath cooling, by 50% the hydroxylamine hydrochloride aqueous solution (9.9g, 150 Mmol reaction solution) is added dropwise to, after stirring half an hour, reaction 1 hour is warmed to room temperature.Heating reflux reaction 2 hours, After reaction completely, under ice bath, with 8mL 6N salt acid for adjusting pH to 7.0.Filtering precipitation, with water and acetic acid second Ester is respectively washed once, is dried, is obtained white compound 6.0g, yield 93%.

¹³C NMR(75MHz,DMSO-d₆):δ 154.4,144.0,140.0。

MS ESI:M/z=144.0, [M+H]⁺.

Second step：4- amino-nitrogen-hydroxyl -1,2,5- oxadiazole -3- carbonamidine chlorine

First step product (4.2g, 29.4mmol) is dissolved in 30mL acetic acid, water 60mL, hydrochloric acid 15mL is separately added into With sodium chloride (5.2g, 88.2mmol).Under ice bath, natrium nitrosum (2.0g, 29.4 for being dissolved in 7mL water are added dropwise to Mmol), keep zero degree react 1 hour, after be warming up to room temperature reaction 5 hours.After reaction terminates, filtering precipitation, Washing once, is dried, obtains compound as white solid 2.6g, yield 55%.

¹³C NMR(75MHz,DMSO-d₆):δ 154.4,142.3,126.9。

MS ESI：M/z=160.9, [M+H]^-.

3rd step：4- amino-nitrogen '-(the bromo- 4- fluorophenyls of 3-) -1,2,5- oxadiazole -3- carbonamidines

At 60 DEG C, criticized into second step product (41.99g, 259.2mmol) pure water (800ml) solution Amount adds the bromo- 4- fluoroanilines (54.179g, 285.12mmol) of 3-.Reaction mixture stirs 10min at 60 DEG C, Na is added into the mixed liquor₂CO₃Water (500ml) solution of (41.2g, 388.8mmol).Stirring reaction 20min LCMS displays reaction is complete afterwards.Reaction mixture cooled and filtered, is washed with water, drying obtain gray solid (70g, 85%).

¹H NMR(400MHz,Acetone-d₆)：δ 8.10(dd,1H),7.78(m,1H),7.56(t,1H),6.15(s, 1H)。

4th step：4- amino-nitrogen '-(the bromo- 4- fluorophenyls of 3-) -1,2,5- oxadiazoles -- 3- yls) -1,2-4- oxadiazole ketone

At room temperature, by the 3rd product (70g, 221.5mmol) and CDI (39.8g, 332.173mmol) It is dissolved in ethyl acetate (600ml) and is warming up to 60 DEG C, stirring reaction 20 minutes；TLC monitorings have been reacted Entirely, reaction mixture is cooled to room temperature, dense reaction solution, by residue PE:EA=4:1 mashing, obtains greyish white (72%) 55g, yield is to color solid.

¹H NMR(400MHz,acetone-d₆)：δ 8.09(dd,1H),7.83(m,1H),6.79(t,1H).

5th step：4- (the bromo- 4- fluorophenyls of 3-) -3-4- (((2- methyl sulphur) ethyl) amino) -1,2,5- oxadiazoles - 3- bases) -1,2-4- oxadiazoles ketone preparation

At room temperature, by 4- amino-nitrogen '-(the bromo- 4- fluorophenyls of 3-) -1,2,5- oxadiazoles -- 3- yls) -1,2-4- oxadiazoles ketone (3.0g, 8.8mmol) it is dissolved in DCM (20ml) and adds triethyl silicane (3.1g, 26.3mmol) and methanesulfonic acid (2.4g, 26.3 Mmol), ice bath is cooled to 0 DEG C, and 2,2- dimethoxy methyl mercapto ethane (2.4g, 17.5mmol) is added dropwise.Drop finishes, in room The lower reaction reaction in 2 hours of temperature is finished, and PH=7 is transferred to saturated sodium bicarbonate aqueous solution, (20mL × 3) are washed with water in organic phase, Saturated common salt washes (20mL × 3), separates organic item, dries concentration, obtains brown solid (3.5g, 96%).

¹H NMR(300MHz,acetone-d₆):δ 8.08(d,1H),7.80(dd,1H),7.57(t,1H),6.14(s, 1H),3.66(m,2H),2.80(m,2H),2.13(s,3H)。

6th step：4- (the bromo- 4- fluorophenyls of 3-) -3-4- (((2- methyl sulphur) ethyl) t-butoxycarbonyl amino) - 1,2,5- oxadiazoles -3- bases) -1,2-4- oxadiazoles ketone

5th step product (50mg, 0.120mmol) is dissolved in THF (2ml), di-tert-butyl dicarbonate (131 is added Mg, 0.601mmol), add under catalytic amount DMAP (2mg), ice bath and stir, until having reacted Entirely, add water (10ml) and (10ml x3) extraction is extracted with ethyl acetate, (5ml) saturation food is washed with water Salt washing (5ml) sodium sulphate is dried, and column chromatographic isolation and purification obtains white solid (60mg, 100% yield).

¹H NMR:(400MHz, CDCl₃):δ 7.71-7.69(m,1H),7.39-7.35(m,1H),7.22-7.14 (m,1H),3.97-3.94(m,2H),2.83-2.80(m,2H),2.12(s,3H),1.53(s,9H)

7th step：(±) 4- (the bromo- 4- fluorophenyls of 3-) -3-4- (((2- (methyl sulfoxide) ethyl) tertiary butyloxycarbonyls Base amino) -1,2,5- oxadiazoles -3- bases) -1,2,4- oxadiazoles ketone

6th step product (2.0g, 3.9mmol) is dissolved under 20mL dichloromethane and 2mL methanol, ice bath and added Enter MMPP (1.06g, 2.15mmol), react at room temperature 1 hour.After reaction terminates, 20mL water is added, is used Ethyl acetate is extracted 3 times, merges organic layer, and water (10mL) is washed three times, and saturated sodium-chloride (10mL) is washed once, Solvent is spin-dried for, dries, obtains yellow solid 1.6g, yield 77%.

¹H NMR(400MHz,CDCl₃):δ 7.71(dd,1H),7.38(m,1H),7.22(t,1H),3.95(t,2H), 2.82(t,2H),2.12(s,3H),1.50(s,9H).

8th step：(±) 4- (the bromo- 4- fluorophenyls of 3-) 3-4- (((2- (methyl trifluoro acetyl group sulphoxide imine) Ethyl) t-butoxycarbonyl amino) -1,2,5- oxadiazoles -3- bases) -1,2,4- oxadiazoles ketone

7th step product (330mg, 0.620mmol) is added in reaction bulb, CF is added₃C(O)NH₂(140 Mg, 1.240mmol), MgO (99mg, 2.479mmol) and Rh (OAc)₂(10mg), is stirred at room temperature one point Clock, adds PhI (OAc)₂(309mg, 0.930mol), is stirred at room temperature until TLC monitoring reactions are complete.Instead Middle water (10ml) should be added, (10ml x3) is extracted with ethyl acetate, (10ml) and saturation food is washed with water Salt washes (10ml), anhydrous sodium sulfate drying.Column chromatographic isolation and purification, obtains target compound (300mg, 75% Yield).

9th step：(±) 4- (the bromo- 4- fluorophenyls of 3-) 3-4- (((2- (methyl sulfoxide imines) ethyl) tertiary fourths Oxygen carbonyl amino) -1,2,5- oxadiazoles -3- bases) -1,2,4- oxadiazoles ketone

8th step product (330mg, 0.513mmol) is dissolved in methanol under (5ml), ice bath, carbonic acid is added Potassium (142mg, 1.026mmol), is stirred 15 minutes.TLC display reactions are complete, n-hexane：Acetic acid second Ester=1:1.Reacting liquid filtering, filter cake is washed (10ml*2) with dichloromethane, and white (280 is obtained after filtrate concentration Mg, 99% yield).

¹H NMR:(400MHz,DMSO-d₆):δ 8.00(s,1H),7.64-7.60(m,2H),4.03-3.99(m, 2H),3.88(s,1H),3.42-3.40(m,2H),2.96(s,3H),1.48(s,9H)

Tenth step：(±) 4- (the bromo- 4- fluorophenyls of 3-) 3-4- (((2- (methyl sulfoxide methylene imine) ethyl) T-butoxycarbonyl amino) -1,2,5- oxadiazoles -3- bases) -1,2,4- oxadiazoles ketone

9th step product (20mg, 0.037mmol) is dissolved in dichloromethane (2ml), trimethyl oxygen four is added Borofluoride (8mg, 0.055mmol), is stirred 2 hours at room temperature, and TLC display reactions are complete, reaction solution (10ml x 2) merging is then extracted with ethyl acetate in middle addition water (10ml), ethyl acetate (10ml) Organic phase, is then washed with water (10ml), and saturated common salt washing (10ml), sodium sulphate is dried.Concentrate rear pillar Chromatography is purified, and obtains target compound (10mg, 48% yield).

¹H NMR:(400MHz,acetone-d6):δ 7.96-7.94(m,1H),7.66-7.62(m,1H), 7.53-7.49(m,1H),4.17(s,2H),3.64-3.57(m,1H),3.50-3.42(s,1H),2.97(s,3H),2.64(s, 3H),1.54(s,9H)

11st step：((±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (nitrogen, sulphur-diformazan Base sulphoxide imine) ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

Tenth step product (20mg, 0.037mmol) is dissolved in dichloromethane (1ml), adds 10N's Hydrogen chloride/ethanol solution (2ml), is stirred 2 hours at room temperature, after reaction completely, is directly concentrated and is done, gained is residual Stay thing to be dissolved in tetrahydrofuran (2ml), add 2M sodium hydrate aqueous solutions (0.2ml), be stirred at room temperature 30 Minute.TLC displays reaction (dichloromethane completely：Methanol=20:1) 2M hydrochloric acid regulation pH=5, is added, instead Answer and water (10ml) is added in liquid, ethyl acetate (10ml) is then extracted with ethyl acetate (10ml x2) Merge organic phase, be then washed with water (10ml), saturated common salt washing (10ml), sodium sulphate is dried.Concentration Column chromatographic isolation and purification, obtains target compound (10mg, 52% yield) afterwards.

¹H NMR:(400MHz,acetone-d₆):δ 10.78(s,1H),8.10(s,1H),7.31-7.29(m,1H), 7.17-7.13(m,1H),7.02-6.98(m,1H),4.28-4.27(m,2H),4.02-4.04(m,2H),3.84(s,3H), 2.92(s,3H)

MS(ESI):[M+H]⁺M/z=435.0

Embodiment 2

According to the preparation method of embodiment 1, the reagent of the tenth step is replaced with triethyl group oxygen tetrafluoroborate, then transports Target compound is obtained with the condition of the 11st step.

¹H NMR:(400MHz,acetone-d₆):δ10.85(s,1H),8.12(s,1H),7.28-7.26(m,1H), 7.17-7.13(m,1H),7.02-6.98(m,1H),6.64(s,1H),3.81(s,2H),3.57(s,1H), 3.43-3.40(m,1H),3.31-3.06(m,5H),1.11-1.05(m,3H).

MS(ESI):[M+H]⁺M/z=449.0

Embodiment 3

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- (2- (sulphur-methyl-nitrogen-phenylsulfone imines) ethyl) ammonia Base) -1,2,5- oxadiazole -3- carbonamidines

The first step：(±) 4- (the bromo- 4- fluorophenyls of 3-) 3-4- (((2- (methyl sulfoxide phenyl imine) ethyl) T-butoxycarbonyl amino) -1,2,5- oxadiazoles -3- bases) -1,2,4- oxadiazoles ketone

The product (20mg, 0.037mmol) of the step of embodiment 1 the 9th is dissolved in dichloromethane (2ml), added Phenyl boric acid (8mg, 0.055mmol), copper acetate (5mg) is stirred 2 hours at room temperature, TLC display reactions Completely, water (10ml) is added in reaction solution, (2x 10 is then extracted with ethyl acetate in ethyl acetate (10mL) ML) merge organic phase, be then washed with water (10mL), saturated common salt washing (10mL), sodium sulphate is dried. Column chromatographic isolation and purification after concentration, obtains target compound (15mg, 66% yield)

¹HNMR (400MHz, acetone-d₆):δ 7.93-7.91(m,1H),7.62-7.58(m,1H), 7.51-7.47(m,1H),7.23-7.12(m,2H),6.96(d,2H),6.92-6.89(m,1H),4.29(s,2H), 3.87-3.80(m,1H),3.76-3.68(m,1H),3.21(s,3H),1.51(s,9H)

Second step：(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-nitrogen-phenylsulfone imines) ethyl) Amino) -1,2,5- oxadiazole -3- carbonamidines

First step product (10mg, 0.016mmol) is dissolved in dichloromethane (1mL), 10M chlorine is added Change hydrogen/ethanol solution (2mL), stir 2 hours at room temperature, after reaction completely, directly concentrate dry, gained residual Thing is dissolved in tetrahydrofuran (2mL), is added 2M sodium hydrate aqueous solutions (0.2ml), is stirred at room temperature 30 points Clock.TLC display reactions are complete, add in 2M hydrochloric acid regulation PH=5, reaction solution and add water (10mL), second Acetoacetic ester (10mL), is then extracted with ethyl acetate (2x10mL) and merges organic phase, be then washed with water (10 ML), saturated common salt washing (10mL), sodium sulphate is dried.Column chromatographic isolation and purification after concentration, obtains target Compound (5mg, 63% yield)

¹HNMR(400MHz,acetone-d₆):δ 10.80(s,1H),8.13(s,1H),7.29-7.27(m,1H), 7.19-7.13(m,3H),7.04-7.01(m,3H),6.89-6.85(m,1H),6.55(s,1H),3.91-3.87(m,2H), 3.72-3.61(m,2H),3.20(s,3H)

MS(ESI):[M+H]⁺M/z=497.0

Embodiment 4

The first step：(±) 4- (the bromo- 4- fluorophenyls of 3-) 3-4- (((2- sulphur-methyl-nitrogen-(anilino- formyl) sulfoxides Imines) ethyl) t-butoxycarbonyl amino) -1,2,5- oxadiazoles -3- bases) -1,2,4- oxadiazoles ketone

The product (20mg, 0.037mmol) of the step of embodiment 1 the 9th is dissolved in tetrahydrofuran (2mL), added Phenyl isocyanate (9mg, 0.073mmol) is stirred overnight at room temperature, and adds sodium bicarbonate aqueous solution (10mL) Ethyl acetate (10mL), is extracted with ethyl acetate (10mL x2), merges organic phase, (10mL) is washed with water, Saturated common salt washes (10mL), concentrates organic phase.Column chromatographic isolation and purification obtains target compound (20mg, 82% Yield)

¹H NMR(400MHz,acetone-d₆):δ 8.24(s,1H),7.96-7.95(m,1H),7.66-7.58(m,3H), 7.50-7.46(m,1H),7.26-7.22(m,2H),6.97-6.93(m,1H),4.36(s,2H),4.09-4.02(m,1H), 3.96-3.86(m,1H),3.41(s,3H),1.51(s,9H)

Second step:(((2- sulphur-methyl-nitrogen-(anilino- formyl) sulfoxide is sub- by (±) 4- (the bromo- 4- fluorophenyls of 3-) 3-4- Amine) ethyl) t-butoxycarbonyl amino) -1,2,5- oxadiazoles -3- bases) -1,2,4- oxadiazoles ketone

First step product (20mg, 0.030mmol) is added into 10N HCL/EtOH (3ml), 3 are stirred at room temperature Hour.After reaction completely, directly concentrate and do, obtain target compound (20mg, 100% yield)

¹HNMR (400MHz, acetone-d₆):δ 8.10(s,1H),7.98-7.97(m,1H),7.72-7.68(m,1H), 7.60(d,2H),7.54-7.50(m,1H),6.61(s,1H),4.03-4.00(m,2H),3.94-3.88(m,2H), 3.64-3.60(m,1H),3.46(s,3H)

3rd step:(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen ' (((sulphur-methyl-nitrogen-(anilino- formyl) is sub- by 2- by-hydroxyl -4- Sulfoximide) ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

Second step product (20mg, 0.035mmol) is dissolved in tetrahydrofuran (2mL), 2M hydroxides are added Sodium water solution (0.2mL), is stirred at room temperature 30 minutes.TLC display reactions are complete, add the regulation of 2mol/L hydrochloric acid Water (10mL) is added in pH=5, reaction solution, (2x is then extracted with ethyl acetate in ethyl acetate (10mL) 10mL) merge organic phase, be then washed with water (10mL), saturated common salt washing (10mL), sodium sulphate is done It is dry.Column chromatographic isolation and purification after concentration, obtains target compound (10mg, 52% yield)

¹H NMR(400MHz,acetone-d₆):δ 10.70(s,1H),8.19(s,1H),8.14(s,1H),7.61(d, 2H),7.30-7.28(m,4H),7.26-7.22(m,2H),7.16-7.12(m,1H),7.02-6.98(m,1H), 6.96-6.93(m,1H),6.57(s,1H),3.95-3.85(m,3H),3.81-3.74(m,1H),3.44(s,3H)

MS(ESI):[M+H]⁺M/z=540.1

Embodiment 5

The first step：(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen ' (((sulphur-methyl-nitrogen-(carbonylic imidazole) is sub- by 2- by-hydroxyl -4- Sulfoximide) ethyl) amino) and -1,2,5- oxadiazole -3- carbonamidines (compound R) preparation：

At room temperature, by (±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) ethyl) Amino) -1,2,5- oxadiazoles -3- carbonamidines (500mg, 1.19mol) are dissolved in 20mL ethyl acetate, add carbonyl dimidazoles (579mg, 3.57mmol), then 60 ° are stirred 5 hours, and solvent is evaporated, and are added 20mL water, are used second Acetoacetic ester extracts (3x 30mL), merges organic layer, and saturated common salt water system, anhydrous sodium sulfate drying, filtering is dense Contracting, crosses post (dichloromethane:Methanol=100:5), concentrate, dry, obtain white solid.

¹H NMR(400MHz,acetone-d₆):δ8.09(m,2H),7.78(m,1H),7.55(t,1H),7.46(s, 1H),6.93(s,1H),6.46(t,1H),4.20(m,2H),4.10(m,2H),3.65(s,3H)。

Second step：(±)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen ' (((sulphur-methyl-nitrogen-(carbamoyl methyl) sulfoxide is sub- by 2- by-hydroxyl -4- Amine) ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines

First step product (30mg, 0.055mmol) is dissolved under 3mL methanol, ice bath, 2N hydroxides are added Sodium solution 1mL.1h is stirred at room temperature, adds 20mL water with 6N hydrochloric acid solutions regulation pH=7., uses acetic acid Ethyl ester extracts (3x 20mL), and organic layer merges, and water, saturated aqueous common salt is respectively washed once, concentrated solvent, system Standby pillar layer separation (DCM:MeOH=20:1) target compound (10mg, 38%), is obtained

¹H NMR(400MHz,acetone-d₆):δ 10.76(s,1H),8.10(s,1H),7.30(m,1H),7.16(t, 1H),7.02(m,1H),3.93(m,2H),3.89(s,1H),3.79(s,1H),3.64(s,3H),3.47(s,3H), 3.65(s,3H)。

MS(ESI):[M+H]⁺M/z=480.7

Embodiment 6

According to the preparation method of embodiment 5, the first step product (30mg, 0.055mmol) of embodiment 5 is dissolved in 3mL Under ethanol, ice bath, 2N sodium hydroxide solutions 1mL is added.1h is stirred at room temperature, is adjusted with 6N hydrochloric acid solutions PH=7. 20mL water is added, is extracted with ethyl acetate (3x20mL), organic layer merges, water, saturation food Salt solution is respectively washed once, concentrated solvent, prepares pillar layer separation (DCM:MeOH=20:1) target compound (14, is obtained Mg, 51%)

¹H NMR(400MHz,CDCl₃):δ 9.96(s,1H),7.82(t,1H),7.26(dd,1H),7.05(t,1H), 6.94(m,1H),6.84(s,1H),4.29(m,2H),4.00(m,1H),3.90(m,1H),3.64(m,1H), 3.52(m,1H),3.41(s,3H)。

MS(ESI):[M+H]⁺M/z=494.7

Embodiment 7

According to the preparation method of embodiment 5, the first step product (30mg, 0.055mmol) of embodiment 5 is dissolved in 3mL Under isopropanol, ice bath, 2N sodium hydroxide solutions 1mL is added.1h is stirred at room temperature, is adjusted with 6N hydrochloric acid solutions PH=7. 20mL water is added, is extracted with ethyl acetate (3x20mL), organic layer merges, water, saturation food Salt solution is respectively washed once, concentrated solvent, prepares pillar layer separation (DCM:MeOH=20:1) compound TM (10, is obtained Mg, 37%)

¹H NMR(400MHz,CDCl₃):δ 10.07(s,1H),7.96(s,1H),7.24(m,1H),7.05(t, 1H),6.93(m,1H),6.81(s,1H),5.03(m,1H),4.04(m,1H),3.89(m,1H),3.62(m,1H), 3.58(m,1H),3.42(s,3H),1.34(d,3H),1.26(m,3H)。

MS(ESI):[M+H]⁺M/z=506.7

Embodiment 8

The product (30mg, 0.055mmol) and triethylamine (15uL) of the step of COMPOUNDS EXAMPLE 1 the 9th is molten In 3mL dichloromethane, under ice bath, methylsufonyl chloride (6.4uL) is added, after reacting ten minutes, 20mL is added Water quenching is gone out, and is extracted with dichloromethane (3x20mL), merges organic layer, and salt is washed once, is dried, and is filtered, rotation Dry solvent, crosses post (DCM:MeOH=100:5) crude product 35mg, is obtained.By crude product (35mg, 0.056 Mmol is dissolved in 1mL dichloromethane and 1mL trifluoroacetic acids, is reacted at room temperature three hours.Solvent is spin-dried for, is added Water 20mL, is extracted (3x20mL) with dichloromethane, merges organic layer, and salt is washed, anhydrous sodium sulfate drying, Filtering, be spin-dried for, crude product (25mg).Previous step crude product is dissolved in 2mL tetrahydrofuran solutions, added 0.5mL2N sodium hydrate aqueous solutions, are stirred at room temperature 0.5 hour, are adjusted with 2NHCl to pH=7, add water 20mL, Ethyl acetate extracts (3x20mL), and simultaneously organic layer, and salt washing, anhydrous sodium sulfate drying, filtering is spin-dried for, Cross post (DCM:MeOH=100:5) white solid (20mg, 84%), is obtained

¹H NMR(400MHz,CDCl₃):δ 9.28(s,1H),8.34(s,1H),7.52(,1H),7.01(t,1H), 6.95(m,1H),6.87(s,1H),3.98(m,2H),3.95(m,1H),3.92(m,1H),3.54(m,1H), 3.23(s,3H)。

MS(ESI):[M+H]⁺M/z=499.0

Embodiment 9

Under ice bath, by (±)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-cyanosulfoximine) Ethyl) amino) -1,2,5- oxadiazole -3- carbonamidines (20mg, 0.045mmol) are dissolved in 2mL DMSO solutions, then Anhydrous potassium carbonate (63mg, 0.45mmol) is added, is slowly added dropwise into 0.5mL hydrogen peroxide, room temperature reaction 0.5 is small When.Sodium thiosulfate solution 20mL is added, after being quenched, is extracted with dichloromethane (3x20mL), is merged organic Layer, saturated common salt washing, anhydrous sodium sulfate drying, filtering is spin-dried for, and crosses post (DCM:MeOH=100:5), revolve It is dry, obtain white solid (14mg, 67%)

¹H NMR(400MHz,CDCl₃):δ 9.45(s,1H),7.52(,1H),7.01(t,1H),6.92(m, 1H), 5.00 (s, 2H), 3.96 (m, 2H), 3.75 (m, 1H), 3.66 (m, 1H), 3.32 (s, 3H).

MS(ESI):[M+H]⁺M/z=466.0

The fractionation of the chiral isomer of embodiment 10

Chiral resolution is carried out using the semi-preparative liquid chromatography instrument of Agilent 1260：

The fractionation of embodiment 1：

Chiral column：Daicel CHIRALCEL IC 4.6*250mm, 5 μm of packing material size；Flow velocity 1ml/min； Detection wavelength 254nm；Collect single enantiomer；

Condition 1：The sample 1mg of embodiment 1 is dissolved in 1ml n-hexanes and isopropyl alcohol mixture (hexane:IPrOH=8:2), sample size 10 μ l, eluent Hexane:EtOH=88:12 (volume ratios)；Two light It is respectively 14.251 minutes and 16.905 minutes to learn isomers appearance time；

Condition 2：The sample 1mg of embodiment 1 will be dissolved in 1ml n-hexanes and isopropyl alcohol mixture (hexane:IPrOH=8:2), sample size 10 μ l, eluent Hexane:IPrOH=75:25 (volume ratios)；Two light It is respectively 11.180 minutes and 13.978 minutes to learn isomers appearance time.

The fractionation of embodiment 2：

Condition 1：By the DMSO solution (10mmol/L) of 200 microlitres of embodiments 2 with isopropanol to 1mL, Sample size 10 μ l, eluent Hexane:EtOH=88:12 (volume ratios)；Two optical isomer appearance times point Wei not be 11.188 minutes and 13.786 minutes；

Condition 2：By the DMSO solution (10mmol/L) of 200 microlitres of embodiments 2 with isopropanol to 1mL, Sample size 10 μ l, eluent Hexane:IPrOH=80:20 (volume ratios)；Two optical isomer appearance times point Wei not be 11.655 minutes and 15.261 minutes.

The fractionation of embodiment 3：

Chiral column：Daicel CHIRALCEL OD-H 4.6*250mm, 5 μm of packing material size；Flow velocity 1ml/min；Detection wavelength 254nm；Collect single enantiomer；

Condition：The sample 1mg of embodiment 3 is dissolved in 1ml n-hexanes and isopropyl alcohol mixture (hexane:IPrOH=8:2), sample size 5 μ l, eluent Hexane:EtOH=60:40 (volume ratios)；Two optics Isomers appearance time is respectively 9.842 minutes and 16.879 minutes.

Embodiment 11

Active testing

(1) induced expression and purification process of IDO albumen

PCR first expands IDO genes, and the PCR primer of amplification is reclaimed, then by pET28a plasmids (purchased from upper The graceful bio tech ltd of Hypon) and IDO glue reclaims product two kinds of restriction enzymes of EcoR I and Xho I Digestion (37 DEG C, digestion 2h) is carried out, glue is run, reclaimed, the link of T4 ligases stays overnight connection product and is added to DH5 α Competence, places 30min, 42 DEG C of thermal shock 90s on ice, shakes bacterium coated plate, and picking monoclonal, PCR identifications are surveyed Sequence is identified, all correct, i.e. pET28a-IDO plasmid constructions success.

By the BL21 containing pET28a-IDO plasmids built, 37 DEG C are shaken to OD greatly₆₀₀For 0.6-0.8, add To final concentration of 7 μM of hemin and 1mM IPTG (isopropyl-β-D-thiogalactoside), 28 DEG C induction 4h；After induction, 4 DEG C, 6000rpm is collected by centrifugation thalline, and the thalline of collection is with 20mM PBS (pH6.5) Once, then thalline is collected by centrifugation in cleaning.

The thalline of collection lysate (20mM PBS pH6.5) is hanged again, (power 40% is cracked ultrasonic degradation 20min, is placed on ice), by the bacterium after cracking, 13000rpm centrifugation 15min discard precipitation, retain supernatant； Nickel post is balanced into 3 column volumes with lysate (20mM PBS pH6.5), cracking supernatant is then loaded to nickel post On, after loading, 4 column volumes are cleaned with rinsing liquid (20mM PBS pH6.5,20mM imidazoles), finally Albumen is eluted with eluent (20mM PBS pH6.5,250mM imidazoles)；The protein solution of elution is dialysed 4h, dialysis solution is 20mM PBS pH6.5, and protein sample is concentrated after dialysis, and packing, liquid nitrogen flash freezer is put Enter -80 DEG C to save backup.

(2) IDO enzyme inhibition activities method of testing

Compound is subjected to 3 times of gradient dilutions first, each concentration takes 1 μ L to be added in 96 orifice plates；Add 50 The IDO enzyme solutions (final concentration 600ng/100 μ L) that μ L are prepared：The mixed solution of 25 μ L substrates 1 is added, 25 are added The μ L mixed solution initial action of substrate 2.Last OD321nm readings 60min.

(3) cytoactive method of testing

Hela cells (100 μ L) are seeded on 96 orifice plates, and inoculum concentration is each hole 5 × 10³, growth stays overnight.Second My god, after diluted chemical compound, take 1 μ L to be added in 96 orifice plates, then by the interferon gamma (final concentration 50 containing someone Ng/mL the μ L of culture medium 100) are added in 96 orifice plates, and it is 200 μ L to make final volume.After hatching in 48 hours, Each hole takes 140 μ L of supernatant liquid to be transferred on a 96 new orifice plates.10 μ L 6.1N trichloroacetic acids add each Hole is mixed, and 50 DEG C hatch 30 minutes, and IDO catalysis N formyls cynruins are cynruin.Reactant mixture 2500 Leave the heart and remove sediment in 10 minutes.Each hole 100 μ L of supernatant liquid is transferred to new 96 orifice plates and 100 μ L 2% dimethylaminobenzaldehyde acetic acid solution is mixed.After cynruin separation, with SPECTRAmax i3reader 480 Nm determines numerical value.

The IDO enzyme inhibition activities of each compound and the test result of cell inhibitory activity are as shown in table 1.

The IDO enzymes of table 1 and cell inhibitory activity test result

The above results show that the compounds of this invention (including racemic modification and enantiomter) is respectively provided with excellent be directed to The inhibitory activity of IDO enzymes and cell, particularly compound 2 have the height of expectation living in IDO cell inhibitory activities Property.

Claims

1. a kind of logical formula (I) compound or its pharmaceutically acceptable salt, its stereoisomer or its mutually variation Structure body or prodrug：

In formula,

X is singly-bound, an O, S, NH or NR^d；

R¹And R²It can be replaced by one or more halogens, alkoxy and cyano group；

R¹And R²It can connect to form four to octatomic ring；

R¹And R^dIt can connect to form six to octatomic ring；

R¹And R³It can connect to form five to octatomic ring；

N is 2 to 8 integer；

M is 0,1 or 2.

2. lead to formula (I) compound as claimed in claim 1, it is characterised in that the compound such as logical formula (II) It is shown,

In formula,

Wherein, R^a、R^b、R³、R⁴、R¹Definition it is as claimed in claim 1；

R¹And R²It can be replaced by one or more halogens, alkoxy and cyano group；

R¹And R²It can connect to form four to octatomic ring；

N is 2-6 integer.

3. lead to formula (I) compound as claimed in claim 1, it is characterised in that the compound such as logical formula (III) It is shown,

In formula,

R^a、R^b、R³、R⁴、R¹Definition it is as claimed in claim 1；

R¹And R²It can be replaced by one or more halogens, alkoxy and cyano group；

R¹And R²It can connect to form four to octatomic ring；

N is 2-6 integer.

4. lead to formula (III) compound as claimed in claim 3, it is characterised in that R¹For C₁-C₄Alkyl；

R^a、R^bDefinition it is as claimed in claim 1；

R¹And R²It can connect to form four to octatomic ring；

R³And R⁴Each stand alone as hydrogen；

N is 2-6 integer.

5. as claimed in claim 1 logical formula (I) compound or its pharmaceutically acceptable salt, stereoisomer, Dynamic isomer or prodrug, it is characterised in that the prodrug as shown in logical formula (IV),

In formula,

R¹、R²、R³、R⁴And R⁹Definition it is as claimed in claim 1；

6. logical formula (I) compound as claimed in claim 1, it is characterised in that the compound is：

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyls of 3-)-nitrogen ' the-hydroxyl -4- ((2- (λ of 1- oxygen -3,4,5,6- tetrahydrochysenes -1⁶, 2- thiazine -1- bases) and second Base) amino) -1,2,5- oxadiazole -3- carbonamidines

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyls of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamyl) sulphoxide imine) second Base) amino) -1,2,5- oxadiazole -3- carbonamidines.

7. lead to formula (I) compound as claimed in claim 1, it is characterised in that the pharmaceutically acceptable salt It is selected from the group：Hydrochloride, hydrobromate, sulfate, phosphate, mesylate, fluoroform sulphonate, benzene sulphur Hydrochlorate, tosilate (toluene fulfonate), 1-naphthalene sulfonic aicd salt, 2- naphthalene sulfonates, acetate, trifluoroacetate, Malate, tartrate, citrate, lactate, oxalates, succinate, fumarate, maleic acid Salt, benzoate, salicylate, phenylacetate, mandelate.

8. lead to the purposes of formula (I) compound as claimed in claim 1, it is characterised in that be used for：

(i) indoles amine -2,3- dioxygenase inhibitors are prepared；

(iii) anti-inflammatory drug is prepared.

9. purposes as claimed in claim 8, it is characterised in that the disease of indoles amine -2,3- dioxygenase mediation Disease for cancer, neurological disease, eye illness, at heart obstacle, depression, anxiety disorder, senile dementia and/or from Body immunity disease.

10. a kind of pharmaceutical composition, it is characterised in that described pharmaceutical composition is included：

Logical formula (I) compound described in claim 1 or its pharmaceutically acceptable salt, its stereoisomer or its Dynamic isomer or its prodrug；And pharmaceutically acceptable carrier and/or antineoplastic.