CN108699014A

CN108699014A - A kind of indoles amine -2,3- dioxygenase inhibitors containing N-alkylation and arylation sulphoxide imine

Info

Publication number: CN108699014A
Application number: CN201780015261.2A
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: 2017-03-09
Publication date: 2018-10-23
Also published as: WO2017152857A1; CN107176933B; CN107176933A

Abstract

The invention discloses a kind of indoles amine -2,3- dioxygenase inhibitors and preparation method thereof.The inhibitor of the present invention, structure is as shown in logical formula (I), 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 methods of inhibitor.The logical formula (I) compound of the present invention can be used as indoles amine -2,3- dioxygenase inhibitor, be used to prepare prevention and/or treat the drug for the disease that indoles amine -2,3- dioxygenase mediates.

Description

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

Technical field

The invention belongs to field of pharmaceutical chemistry technology, and in particular to one kind is containing N-alkylation, arylation and is acylated sulphoxide imine and 1, the IDO inhibitor and preparation method thereof of 2,5- oxadiazoles structures.

Background technique

Indoles amine -2,3- dioxygenase (Indoleamine-2,3-dioxygenase, IDO) it is a kind of monomeric enzyme containing heme that Hayaishi group in 1967 finds in the cell for the first time, cDNA coding albumen is made of 403 amino acid, molecular weight is 45kDa, it is along tryptophan-kynurenine pathway catabolism rate-limiting enzyme, and there is extensive expression (Hayaishi O.et al Science in the tissue of a variety of mammals, 1969,164,389-396).In the cell of tumor patient, IDO generates important physiological action frequently as induction tumor microenvironment immune tolerance, its tryptophan (Tryptophan mediated, Trp)-kynurenin (Kynurenine, Kyn) metabolic pathway takes part in tumor immune escape, and IDO also generates important role as induction tumor microenvironment immune tolerance.

Tryptophan is one of necessary amino acid important in the mammalian body, needs the huge uptake from food, maintains the synthesis of cell activation and proliferation and protein and some neurotransmitters.Therefore, its shortage will lead to the malfunction of some important cells.IDO can be catalyzed tryptophan transfer in vivo and turn to N- formylkynurenine, the content for tryptophan of degrading and cause the intracorporal deficiency of tryptophan, lead oncogenic generation.And immunohistology researches show that, kynurenine pathway can result in increasing for excitotoxin quinolinic acid, also result in a variety of serious human diseases (Guillemin G.J.et al Neuropathol.and Appl.Neurobiol.2005 such as the nervous system diseases such as alzheimer, 31,395-404).

In the mammalian body there are mainly two types of tryptophan rate-limiting enzymes: tryptophan dioxygenase (TDO) and IDO.Nineteen thirty-seven, Kotake etc. are purified into albumen from rabbit intestines, and discovery TDO is mainly expressed in mammalian liver for the first time, not yet find that he and immune system have close ties at present.TDO can be catalyzed kynurenine pathway, make tryptophan transfer become N- formylkynurenine [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, identified is the dioxygenase (IDO) containing heme, IDO is the indoles oxicracking that can be uniquely catalyzed in tryptophan modules other than liver, and prolong the enzyme of kynurenine pathway catabolism, IDO is usually expressed in the more organ of mucous membrane, such as lung, small intestine and large intestine, rectum, spleen, kidney, stomach and brain etc., distribution is than wide (Hayaishi O.et al, Proceedings of the tenth FEBS meeting, 1975,131-144).Under certain special or pathological conditions, such as gestation, chronic infection, organ transplant and tumour etc., IDO expression can obviously increase, participate in mediate part immunosupress.

Studies have shown that IDO can inhibit local T cell to be immunoreacted in tumor microenvironment by following methods: tryptophan depletion, toxic metabolic and induction regulatory T cells proliferation.Many situations are that transition is expressed in tumour, to consume local tryptophan, generate the metabolites such as a large amount of kynurenin.In fact, Proliferation Ability can occur for T cell under the condition of culture of no tryptophan or kynurenin, activity reduces even apoptosis.And there are the horizontal very sensitive point of adjustment of tryptophan in T cell, under the action of IDO, tryptophan can be made to consume, stagnated so as to cause T cell in the G1 interim phase, to inhibit the proliferation of T cell, also inhibit the immune response of T cell.And T cell once stops being proliferated, and would not may be stimulated again effect, 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 field is it is still necessary to research and develop the Novel IDO inhibitor of high activity, present invention discover that a kind of novel containing N-alkylation and arylation sulphoxide imine and 1, the compound of 2,5- oxadiazoles structures has unexpected high IDO inhibitory activity.

Summary of the invention

The purpose of the present invention is to provide a kind of novel compounds for containing N-alkylation and arylation sulphoxide imine and 1,2,5- oxadiazoles structure as efficient IDO enzyme inhibitor.

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

The first aspect of the present invention provides a kind of logical formula (I) compound or its pharmaceutically acceptable salt, its stereoisomer or its tautomer or prodrug:

In formula,

R⁷And R⁸Respectively stand alone as hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀Naphthenic base, substituted or unsubstituted C₂-C₁₀Alkenyl, substituted or unsubstituted C₃-C₁₀Alkynyl, substituted or unsubstituted C₆-C₂₀Aryl or substituted or unsubstituted C₃-C₁₄Heteroaryl；R⁷And R⁸Three can be formed together to octatomic ring or three to eight circle heterocyclic rings, and wherein hetero atom can be sulphur, oxygen, NH or NR^f；

R⁹For C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl；R⁹It can be replaced by one or more groups selected from the group below: 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^bRespectively stand alone as hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀Naphthenic base, substituted or unsubstituted C₂-C₁₀Alkenyl, substituted or unsubstituted C₆-C₂₀Aryl or substituted or unsubstituted C₃-C₁₄Heteroaryl；R^aAnd R^bThree can be formed together to octatomic ring or four to eight circle heterocyclic rings, and 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^b、-C(O)NR^aR^bOr C₃-C₁₂Naphthenic base；

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

Ring A is 5- or 6-membered containing heterocycle；

R³And R⁴Respectively stand alone as hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl；R³And R⁴Three can be formed together to octatomic ring or three to eight circle heterocyclic rings, and 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-C₁₀Naphthenic base, C₆-C₂₀Aryl or C₃-C₁₄Heteroaryl；R¹It can be replaced by one or more groups selected from the group below: halogen, hydroxyl, amino, nitro, cyano, aldehyde radical, carboxyl, alkoxy ,-CF₃、-SF₅；

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

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；

The integer that n is 2 to 8；

M is 0,1 or 2.

In another preferred example, " substitution ", which refers to, has one or more substituent groups selected from the group below: halogen, hydroxyl ,-NH₂, nitro ,-CN, C₁-C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₃-C₆Naphthenic base, C₂-C₄Alkenyl, C₂-C₄Alkynyl, phenyl, benzyl.

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

In another preferred example, formula (I) structure is as shown in Formulas I a:

In another preferred example, R³And R⁴Respectively stand alone as hydrogen,

In another preferred example, n is 2 to 6.

In another preferred example, X NH.

In another preferred example, 0 m.

In another preferred example, the compound is as shown in logical formula (II),

In formula,

R⁹For C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl；R⁹It can be replaced by one or more groups selected from the group below: 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、-C(O)NR^aR^bOr C₃-C₁₂Naphthenic base；

N is 2-6.

It is another it is preferential select in example, compound as shown in logical formula (III),

In formula,

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

R²For C₁-C₁₂Alkyl, C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl ,-C (O) OR^e；-SO₂R^e、-SO₂NR^aR^bOr-C (O) NR^aR^b、C₃-C₁₂Naphthenic base；

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

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

N is 2-6.

In another preferred example, R¹For C₁-C₁₀Alkyl；

R²For C₁-C₁₂Alkyl, C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl ,-SO₂R^e、-SO₂NR^aR^b、-C(O)NR^aR^bOr C₃-C₁₂Naphthenic base；

R³And R⁴Respectively stand alone as hydrogen；

Ar is C₆-C₁₀Aryl, five yuan or six membered heteroaryl；R⁹It can be replaced by one or more groups selected from the group below: halogen, C₁-C₆Alkyl, C₁-C₆Alkoxy, hydroxyl, amino, nitro, aldehyde radical ,-CF₃、-CN、-SF₅。

In another preferred example, R¹For C₁-C₄Alkyl；

Ar is C₆-C₁₀Aryl, five yuan or six membered heteroaryl；R⁹It can be replaced by one or more groups selected from the group below: halogen, C₁-C₆Alkyl, C₁-C₆Alkoxy, hydroxyl ,-CF₃、-CN、-SF₅。

In another preferred example, the prodrug of the compound of Formula I, as shown in logical 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, substituted or unsubstituted C₁-C₁₂Alkyl, substituted or unsubstituted C₁-C₁₂Alkoxy, substituted or unsubstituted C₃-C₁₂Naphthenic base, C₃-C₁₂Cycloalkyloxy, NR^aR^b；Wherein, R^a、R^bIt is as defined above；

Wherein, " substitution ", which refers to, has one or more substituent groups selected from the group below: halogen, hydroxyl ,-NH_2、Nitro ,-CN, C₁-C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₃-C₆Naphthenic base, C₂-C₄Alkenyl, C₂-C₄Alkynyl, phenyl, benzyl.

In another preferred example, X, R¹、R²、R³、R⁴、R⁷、R⁸、R⁹、R^10aIt is separately the corresponding group in each particular compound of the formula (I), (II), (III) and (IV) prepared in embodiment etc. each group.

In another preferred example, the compound are as follows:

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (nitrogen, sulphur-dimethyl sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen ethyl-sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen isopropyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-azo-cycle propyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (2,2,2- trifluoroethyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (3,3,3- trifluoro propyl) sulphoxide imine) Ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (2- bis-fluoro ethyls) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (- 1 λ of 1- oxygen -3,4,5,6- tetrahydro⁶, 2- thiazine -1- base) and ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-azo-cycle butyl base sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-phenylsulfone imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- fluorophenyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- chlorophenyl imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(anilino- formyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(methylamino formyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(isopropyl carbamoyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl methyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl ethyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(formyl isopropyl ester) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(mesyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(benzenesulfonyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(nitrogen-phenylsulfamoyl base) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (nitrogen, sulphur-dimethyl sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidines

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen ethyl-sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen isopropyl sulphoxide imine) ethyl) ammonia Base) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-azo-cycle propyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (2,2,2- trifluoroethyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (3,3,3- trifluoro propyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (2- bis-fluoro ethyls) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (- 1 λ of 1- oxygen -3,4,5,6- tetrahydro⁶, 2- thiazine -1- base) and ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-azo-cycle butyl base sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-phenylsulfone imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- fluorophenyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- chlorophenyl imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(anilino- formyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(methylamino formyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(isopropyl carbamoyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- chlorine 4- fluorophenyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl methyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl ethyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(formyl isopropyl ester) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(mesyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- chlorine 4- fluorophenyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(benzenesulfonyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

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

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (nitrogen, sulphur-dimethyl sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidines

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen ethyl-sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen isopropyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-azo-cycle propyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (2,2,2- trifluoroethyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (3,3,3- trifluoro propyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (2- bis-fluoro ethyls) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (- 1 λ of 1- oxygen -3,4,5,6- tetrahydro⁶, 2- thiazine -1- base) and ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-azo-cycle butyl base sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-phenylsulfone imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- fluorophenyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- chlorophenyl imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(anilino- formyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(methylamino formyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(isopropyl carbamoyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl methyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl ethyl) sulphoxide imine) Ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(formyl isopropyl ester) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(mesyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(benzenesulfonyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(nitrogen-phenylsulfamoyl base) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

In another preferred example, the compound is compound 1-9 prepared in embodiment.

In another preferred example, the compound is racemic modification.

In another preferred example, the compound is enantiomter.

In another preferred example, the pharmaceutically acceptable salt is selected from the group: hydrochloride, hydrobromate, sulfate, phosphate, mesylate, fluoroform sulphonate, benzene sulfonate, tosilate (toluene fulfonate), 1-naphthalene sulfonic aicd salt, 2- naphthalene sulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalates, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, mandelate.

The second aspect of the present invention provides the preparation method of logical formula (I) compound described in first aspect, comprising the following steps:

(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 obtains final product P4 or P5, i.e., logical formula (I) compound.

Logical formula (I) compound of the invention can also be obtained by preparation method below, comprising 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 obtains final product P8 or P9, i.e., logical formula (I) compound.

Present invention provides the preparation methods that the third leads to formula (I) compound, comprising 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 loop under base hydrolysis conditions obtains final product and leads to formula (I) compound.

Present invention provides the preparation methods of the 4th kind of logical formula (I) compound, comprising 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 starting material in the present invention, by a series of oxidation, addition, the reactions such as cyclization, diazotising, substitution obtain compound P1.

The third aspect of the present invention provides the purposes of logical formula (I) compound described in first aspect, is used for:

(i) indoles amine -2,3- dioxygenase inhibitor is prepared；

(ii) drug for the disease that preparation prevention and/or treatment indoles amine -2,3- dioxygenase mediate；Or

(iii) anti-tumor drug or anti-inflammatory drug are prepared.

In another preferred example, the disease that indoles amine -2,3- dioxygenase mediates is the disease of the pathological characteristics for the tryptophan metabolic pathway that IDO is mediated.

In another preferred example, the disease that indoles amine -2,3- dioxygenase mediates is cancer, eye illness, at heart obstacle, depression, anxiety disorder, senile dementia and/or autoimmune disease.

In another preferred example, the cancer includes but is not limited to: colon cancer, breast cancer, gastric cancer, lung cancer, colorectal 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, including the metastasis in other tissues or organ far from tumour original site.

The fourth aspect of the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes:

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

Pharmaceutically acceptable carrier.

The fifth aspect of the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes:

Logical formula (I) compound described in first aspect or its pharmaceutically acceptable salt, its stereoisomer or its tautomer or its prodrug；And

Optionally, anti-tumor drug.

In another preferred example, the anti-tumor drug 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 target therapeutic agent, such as hdac inhibitor and EP4 antagonist.

The sixth aspect of the present invention, there is provided it is a kind of prevention and/or treatment indoles amine -2, the method for the disease that 3- dioxygenase mediates includes the steps that giving patient pharmaceutical composition described in logical formula (I) compound described in first aspect or the 4th or the 5th aspect.

In another preferred example, the disease that indoles amine -2,3- dioxygenase mediates is cancer, and the method further includes the step of applying additional anticancer agent (also referred to as anti-tumor drug, the anti-tumor drug are as described above) to patient.

Logical formula (I) compound of the invention has a variety of pharmacological activity such as antitumor, treatment neurological disease (Alzheimer disease), anti-inflammatory.

It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and it can be combined with each other between each technical characteristic specifically described in below (e.g. embodiment), to form a new or preferred technical solution.As space is limited, this is no longer going to repeat them.

Specific embodiment

The present inventor by depth studying extensively, it is unexpected for the first time develop it is a kind of novel comprising sulphoxide imine and 1,2, the compound of 5- oxadiazoles structure, the compound can be used as efficient IDO enzyme inhibitor, for preventing and/or treating the disease of indoles amine -2,3- dioxygenase mediation, anti-inflammatory drug use also can be used as.On this basis, the present invention is completed.

Definition

Term " alkyl " refers to monovalence radical of saturated aliphatic alkyl, has 1 to 10 carbon atom, including straight chain and branched hydrocarbyl, 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-), tert-butyl (i.e. (CH₃)₃C-), n-pentyl (i.e. CH₃CH₂CH₂CH₂CH₂), neopentyl (i.e. (CH₃)₃CCH₂-).In the present invention, which includes substituted or unsubstituted alkyl.

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

As used herein, " substitution " or " substituted " refers to that the group has one or more (preferably 1-6, more preferably 1-3) substituent group selected from the group below: halogen, hydroxyl ,-NH₂, nitro ,-CN, C1-C4 alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₃-C₆Naphthenic base, C₂-C₄Alkenyl, C₂-C₄Alkynyl, phenyl, benzyl.

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

As used herein, term " alkoxy " refers to-O- alkyl, wherein the alkyl can be it is saturated or unsaturated, can be branch, straight chain or it is cricoid.Preferably, alkoxy has 1-10 carbon atom, preferably 1-6 carbon atom.Representative example includes (but being not limited to): methoxyl group, ethyoxyl, propoxyl group.

As used herein, term " aryl " refers to the monovalent aromatic carbocyclic group of 6 to 20 (preferable 6-14) carbon atoms, it has monocycle (such as phenyl) or condensed ring (such as naphthalene or anthryl), if tie point is in aromatic carbon original, condensed ring may be nonaromatic (such as 2- benzoxazolone, 2H-1,4- benzoxazine -3 (4H) -one -7- base etc.).Preferred aryl includes phenyl and naphthalene.The term includes substituted or unsubstituted form, and wherein substituent group 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) a carbon atoms, and has a unsaturated ethylene linkage (>C=C<) at least 1 (such as 1 to 2).This kind of group for example has vinyl, allyl, butyl- 3- alkenyl.As used herein, term " naphthenic base " refers to cyclic alkyl with 3 to 10 carbon atoms, with monocycle or polycyclic (including fused system, bridged-ring system and spiro ring system).In fused ring system, one or more rings can be naphthenic base, heterocycle, aryl or heteroaryl, as long as connection site is the ring by naphthenic base.The example of suitable naphthenic base includes: for example, adamantyl, cyclopropyl, cyclobutyl, cyclopenta and cyclooctyl.

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

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

As used herein, term " substituted heteroaryl " refers to that the heteroaryl replaced 1 to 5, preferably 1 to 3, more preferable 1 to 2 substituent group, the substituent group are selected from and identical substituent group defined in substituted aryl.

As used herein, term " heterocycle " or " heterocycle " or " Heterocyclylalkyl " or " heterocycle " refer to saturation, fractional saturation or unsaturated group (but not being armaticity), with monocycle or condensed ring (including bridged-ring system and spiro ring system, the hetero atom of nitrogen, sulphur or oxygen is selected from ring with 1 to 10 carbon atom and 1 to 4 (such as 3), in fused ring system, one or more rings can be naphthenic base, aryl or heteroaryl, as long as tie point passes through nonaro-maticity ring.In one embodiment, the nitrogen-atoms of heterocyclic group and/or sulphur atom are optionally oxidized, to provide N- oxide, sulfinyl and sulfonyl moieties.

As used herein, term " substituted heterocycle " or " substituted Heterocyclylalkyl " or " substituted heterocycle " refer to that heterocyclic group replaced a substituent group, the substituent group and substituted naphthenic base are defined (such as 1 to 3) by 1 to 5 Substituent group it is identical.

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

As used herein, term " tautomer " refers to the alternative form of the different compound in proton position, such as enol-keto and imine-enamine tautomers, or the tautomeric form of heteroaryl, the heteroaryl include with the part-NH- of ring and ring=annular atom that partially connect of N-, such as pyrazoles, imidazoles, benzimidazole, triazole and tetrazolium.

" prodrug " refers to any derivative of embodiment compound, when being applied to subject, can directly or indirectly provide the compound or its active metabolite or residue of embodiment.Particularly preferred derivative and prodrug are those, when being applied to subject, improves the bioavilability (as the compound of oral administration is easier to be rapidly absorbed into blood) of embodiment compound or improve the derivative and prodrug of the transport of parent compound to biological compartment (such as brain or lymphatic system) relative to parent species.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 logical formula (I) or logical formula (II) compound, its racemic modification, its stereoisomer or its tautomer or prodrug or its pharmaceutically acceptable salt.It should be understood that the term further includes formula (III) compound represented, its racemic modification, its stereoisomer or its tautomer or its pharmacy, upper acceptable salt.

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

Typically, the present invention provides logical formula (I) compound or its pharmaceutically acceptable salt, its stereoisomer or its tautomer or prodrug,

In formula,

R⁹For C₆-C₂₀Aryl, five yuan or six membered heteroaryl；R⁹It can be replaced by one or more groups selected from the group below: 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^bRespectively stand alone as hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀Naphthenic base, substituted or unsubstituted C₂-C₁₀Alkenyl, substituted or unsubstituted C₆-C₂₀Aryl or substituted or unsubstituted C₃-C₁₄Heteroaryl；R^aAnd R^bThree can be formed together to octatomic ring or four to eight circle heterocyclic rings, and wherein hetero atom can be sulphur, oxygen, NH or NR^g；

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

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

R³And R⁴Respectively stand alone as hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl；R³And R⁴It can together can be with shape Cheng Sanzhi octatomic ring or three to eight circle heterocyclic rings, wherein hetero atom can be sulphur, oxygen, NH or NR^h；

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- oxadiazoles ring；

M is 0 to 2.

In another preferred example, the logical formula (I) compound are as follows:

Wherein R¹For C₁-C₁₀Alkyl, C₃-C₁₀Naphthenic base, C₁-C₁₀Alkenyl, aryl or heteroaryl, R¹It can be replaced by one or more halogens；

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

N is 1 to 8.

In another preferred example, the present invention also provides the prodrugs of formula (III):

In formula, each group is as defined above.

In the presence of compound of the present invention has stereoisomer, the present invention includes all stereoisomers of compound.

In the presence of compound of the present invention has tautomer, the present invention includes all tautomers of compound.

The invention also includes any one or more of compound hydrogen atoms by its stable isotope deuterium replaces and generates deuterated compound.

Pharmaceutical composition

The present invention also provides a kind of pharmaceutical compositions, it includes active constituent and pharmaceutically acceptable carrier within the scope of safe and effective amount.

" active constituent " of the present invention refers to logical formula (I) compound of the present invention or its pharmaceutically acceptable salt, its stereoisomer or its tautomer or its prodrug.

" active constituent " of the present invention and pharmaceutical composition can be used as IDO inhibitor.In another preferred example, it is used to prepare prevention and/or treats the drug of tumour.In another preferred example, it is used to prepare prevention and/or treats the drug for the disease that IDO is mediated.

" safe and effective amount " refers to: the amount of active constituent is enough to be obviously improved the state of an illness, and is unlikely to generate serious side effect.In general, pharmaceutical composition contains 1-2000mg active constituent/agent, more preferably, contain 10-200mg active constituent/agent.Preferably, described is " one " for a tablet.

" pharmaceutically acceptable carrier " refers to: one or more biocompatible solids or liquid filler or gelatinous mass, they are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity.In " compatibility " referred to herein as composition each component energy and active constituent of the invention and they between mutually admix, and significantly reduce the drug effect of active constituent.

The compound of the preferred embodiment of the present invention can be used as independent active agents administration, can also be applied in combination with one or more of the other reagent for treating cancer.It is also effectively that the combination of the compound and other anticancer agents or chemotherapeutics that are currently known is within the scope of preferred embodiment that the compound of the preferred embodiment of the present invention and known therapeutic agent and anticancer agent, which are applied in combination,.The example of this kind of medicament can be found in " cancer theory and practice oncology " (Cancer Principles and Practice of Oncology), V.T.Devita and S.Hellman (editor), 6th edition (on 2 15th, 2001), Lippincott Williams&Wilkins publishing house.Special nature and related cancer based on drug, those of ordinary skill in the art can distinguish effective pharmaceutical agent combinations.This anticancer agent is including but not limited to as follows: estrogenic agents, androgen receptor modifier, retinoid receptor modulators, cytotoxicity/cytostatic agent, antiproliferative, prenyl protein transferase inhibitor, take acetyl enzyme (HDAC) inhibitor, HMG-CoA reductase inhibitor and other angiogenesis inhibitors, cell Proliferation and survival signaling inhibitor, 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 which the compound of embodiment will be applied with therapeutically effective amount, by any one acceptable mode of the medicament with similar effect.The actual amount of the compound (i.e. active constituent) of preferred embodiment is determined according to Multiple factors, such as the severity of disease to be treated, the age of patient and relative health, the effect for being used compound, the path of application and form and other factors.The drug can be applied repeatedly for one day, it is preferable that once or twice daily.All of these factors taken together all the attending physician the considerations of within the scope of.

The purpose of preferred embodiment, treatment effective dose usually can be every total daily dose to patient's one-time use or gradation application, for example, about 0.001 to about 1000 mg kg of body weight daily, it is preferable that daily about 1.0 to about 30 mg/kg weight.Units dosage composition (Dosage unit composition) may include its dosage factor to form daily dosage.The selection of dosage form depends on various factors, such as the bioavilability of mode of administration and drug substance.Pass through any one following route generally, it is preferred to which the compound of embodiment can be used as pharmaceutical composition and be administered: oral, Formulations for systemic administration (such as transdermal, intranasal or pass through suppository) or parenteral administration (such as intramuscular, intravenously or subcutaneously).Preferred administration mode be oral, daily dose that can be easy to adjust according to the degree of hardship.The form that composition can be taken is tablet, pill, capsule, semisolid, pulvis, sustained release preparation, solution, suspension, elixir, aerosol or any other composition appropriate.The mode of another preferred application preferred embodiment compound is sucking.This is a kind of 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: that such as inorganic agent and drug transport modifying agent and promotor, calcium phosphate, magnesium stearate, talcum, monosaccharide, disaccharides, starch, gelatin, cellulose, sodium carboxymethylcellulose pyce, carboxymethyl cellulose, glucose, hydroxypropyl-B- cyclodextrin, polyvinylpyrrolidone, low melt wax, ion exchange resin etc., and its any two or more of combinations.Liquid and semisolid excipient can be selected from glycerol, propylene glycol, water, ethyl alcohol and various oil, including petroleum, animal oil, vegetable oil or synthesis source, as peanut oil, Soya-bean oil, mineral oil, sesame oil etc..Preferred liquid-carrier is especially used for the carrier of Injectable solution, including water, salt water, glucose aqueous solution and ethylene glycol.At " Remington pharmaceutical science " (Remington ' s Pharmaceutical Sciences), Mack Pub.Co., New Jersey (1991) are described other suitable pharmaceutically acceptable excipient, are totally incorporated herein by reference.

As used herein, term " pharmaceutically acceptable salt " refers to the non-toxic acid or alkali salt of compound of Formula I.These salt can be made in situ when being finally recovered and purifying compound of Formula I or respectively react suitable organic or inorganic acid or alkali with alkalinity or acidic functionality and be made.Representative salt includes, but it is not limited to: acetate, adipate, alginates, citrate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, camphor hydrochlorate, camsilate, digluconate, cyclopentane propionate, lauryl sulfate, esilate, flucoheptanoate, glycerophosphate, Hemisulphate, enanthate, caproate, fumarate, hydrochloride, hydrobromate, hydriodate, 2- isethionate, lactate, maleate, mesylate, nicotinate, 2- naphthyl sulphonic acids salt, oxalates, embonate, pectate, rhodanate, 3- phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, sulfate, tartrate, rhodanate, tosilate and undecanoate.In addition, nitrogenous basic group can be by following reagent quaternization: alkyl halide, such as methyl, ethyl, propyl, the chloride of butyl, bromide and iodide；Dialkyl sulfate, such as dimethyl, diethyl, dibutyl and diamyl sulfates；The chloride, bromide and iodide of long chain halide such as decyl, lauryl, myristyl and stearyl；Aralkyl halide such as benzyl and phenylethyl bromide etc..Thus water-soluble or oil-soluble or dispersible product are obtained.May be used to form pharmaceutically acceptable acid-addition salts acid example include as hydrochloric acid, sulfuric acid, phosphoric acid inorganic acid, and as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, citric acid organic acid.Base addition salts can be made in situ when being finally recovered and purifying compounds of formula I or carboxylic moiety is made with suitable alkali (hydroxide of such as pharmaceutically acceptable metal cation, carbonate or bicarbonate) or ammonia or the reaction of organic primary, secondary or tertiary amine respectively.Pharmaceutically acceptable salt includes, but it is not limited to, cation based on alkali and alkaline earth metal ions, such as salt of sodium, lithium, potassium, calcium, magnesium, aluminium, 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..Other representative organic amines for being used to form base addition salts include diethylamine, ethylenediamine, ethanol amine, diethanol amine, piperazine etc..

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

Present invention will be further explained below with reference to specific examples.It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition such as Sambrook et al., molecular cloning: laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989) condition described in, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.

The invention has the beneficial effects that:

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

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

(3) synthetic method is mild, and operation is simple, and yield is higher, is easy to derivatization, is suitble to industry amplification quantity production；

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

Unless otherwise defined, all professional and scientific terms as used herein have the same meanings as commonly understood by one of ordinary skill in the art.In addition, any method similar to or equal to what is recorded and material can be applied to the method for the present invention.The preferred methods and materials described herein are for illustrative purposes only.

Embodiment 1

Step 1: 4- amino-nitrogen '-hydroxyl -1,2,5- oxadiazoles -3- carbonamidine

Third dicyan (3.2g, 48.5mmol) is dissolved in 70mL water, is heated to being completely dissolved.Under ice-water bath is cooling, sodium nitrite (3.8g, 55mmol) and 6N hydrochloric acid (0.6mL) is added.After reacting 0.5 hour under ice bath, it is warming up to room temperature reaction 2 hours.Reaction solution is continued into ice bath cooling, 50% hydroxylamine hydrochloride aqueous solution (9.9g, 150mmol) is added dropwise to reaction solution, after stirring half an hour, is warmed to room temperature reaction 1 hour.Heating reflux reaction 2 hours, after fully reacting, under ice bath, with 8mL 6N salt acid for adjusting pH to 7.0.Filtering precipitating, is respectively washed once with water and ethyl acetate, dry, obtains white compound 6.0g, yield 93%.

¹³C NMR(75MHz,DMSO-d₆):δ154.4,144.0,140.0。

MS ESI:m/z=144.0, [M+H]⁺.

Step 2: 4- amino-nitrogen-hydroxyl -1,2,5- oxadiazoles -3- carbonamidine chlorine

First step product (4.2g, 29.4mmol) is dissolved in 30mL acetic acid, is separately added into water 60mL, hydrochloric acid 15mL and sodium chloride (5.2g, 88.2mmol).Under ice bath, be added dropwise to the sodium nitrite (2.0g, 29.4mmol) for being dissolved in 7mL water, zero degree kept to react 1 hour, after be warming up to room temperature reaction 5 hours.After reaction, filtering precipitating, washing is primary, dry, obtains compound as white solid 2.6g, yield 55%.

¹³C NMR(75MHz,DMSO-d₆):δ154.4,142.3,126.9。

MS ESI:m/z=160.9, [M+H]^-.

Step 3: 4- amino-nitrogen '-(the bromo- 4- fluorophenyl of 3-) -1,2,5- oxadiazoles -3- carbonamidine

At 60 DEG C, the bromo- 4- fluoroaniline (54.179g, 285.12mmol) of 3- is added in batches into pure water (800ml) solution of second step product (41.99g, 259.2mmol).Reaction mixture stirs 10min at 60 DEG C, and Na is added into the mixed liquor₂CO₃Water (500ml) solution of (41.2g, 388.8mmol).LCMS shows fully reacting after being stirred to react 20min.Reaction mixture cooled and filtered, is washed with water, and drying obtains 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).

Step 4: 4- amino-nitrogen '-(the bromo- 4- fluorophenyl of 3-) -1,2,5- oxadiazoles -- 3- yl) -1,2-4- oxadiazoles ketone

At room temperature, third portion product (70g, 221.5mmol) and CDI (39.8g, 332.173mmol) are dissolved in ethyl acetate (600ml) and are warming up to 60 DEG C, be stirred to react 20 minutes；TLC monitors fully reacting, reaction mixture is cooled to room temperature, dense reaction solution, residue is beaten with PE:EA=4:1, obtain pale solid (55g, yield 72%).

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

Step 5: 4- (the bromo- 4- fluorophenyl of 3-) -3-4- (((2- methyl sulphur) ethyl) amino) -1,2,5- oxadiazoles -3- base) preparation of -1,2-4- oxadiazoles ketone

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

¹H NMR(300MHz,acetone-d₆):δ8.08(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)。

Step 6: 4- (the bromo- 4- fluorophenyl of 3-) -3-4- (((2- methyl sulphur) ethyl) t-butoxycarbonyl amino) -1,2,5- oxadiazoles -3- base) -1,2-4- oxadiazoles ketone

By the 5th step product (50mg, it 0.120mmol) is dissolved in THF (2ml), di-tert-butyl dicarbonate (131mg is added, 0.601mmol), it is added catalytic amount 4-dimethylaminopyridine (2mg), it is stirred under ice bath, until fully reacting, water (10ml) is added, (10ml x 3) extraction is extracted with ethyl acetate, it is dry that (5ml) saturated common salt washing (5ml) sodium sulphate is washed with water, column chromatographic isolation and purification obtains white solid (60mg, 100% yield).

¹H NMR:(400MHz, CDCl₃):δ7.71-7.69(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)

Step 7: (±) 4- (the bromo- 4- fluorophenyl of 3-) -3-4- (((2- (methyl sulfoxide) ethyl) t-butoxycarbonyl amino) -1,2,5- oxadiazoles -3- base) -1,2,4- oxadiazoles ketone

6th step product (2.0g, 3.9mmol) is dissolved in 20mL methylene chloride and 2mL methanol, MMPP (1.06g, 2.15mmol) is added under ice bath, reacts at room temperature 1 hour.After reaction, 20mL water is added, is extracted with ethyl acetate 3 times, merges organic layer, water (10mL) is washed three times, and saturated sodium-chloride (10mL) is washed once, is spin-dried for solvent, and it is dry, obtain yellow solid 1.6g, yield 77%.

¹H NMR(400MHz,CDCl₃):δ7.71(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).

Step 8: (±) 4- (the bromo- 4- fluorophenyl of 3-) 3-4- (((2- (methyl trifluoro acetyl group sulphoxide imine) ethyl) t-butoxycarbonyl amino) -1; 2; 5- oxadiazoles -3- base) -1,2,4- oxadiazoles ketone

7th step product (330mg, 0.620mmol) is added in reaction flask, CF is added₃C(O)NH₂(140mg, 1.240mmol), MgO (99mg, 2.479mmol) and Rh (OAc)₂(10mg) is stirred at room temperature one minute, is added PhI (OAc)₂(309mg, 0.930mol) is stirred at room temperature until TLC monitors fully reacting.Water (10ml) is added in reaction, (10ml x 3) is extracted with ethyl acetate, (10ml) and saturated common salt washing (10ml) is washed with water, anhydrous sodium sulfate is dry.Column chromatographic isolation and purification obtains target compound (300mg, 75% yield).

Step 9: (±) 4- (the bromo- 4- fluorophenyl of 3-) 3-4- (((2- (methyl sulfoxide imines) ethyl) t-butoxycarbonyl amino) -1,2,5- oxadiazoles -3- base) -1,2,4- oxadiazoles ketone

8th step product (330mg, 0.513mmol) is dissolved in methanol (5ml), under ice bath, is added potassium carbonate (142mg, 1.026mmol), stirs 15 minutes.TLC shows fully reacting, n-hexane: ethyl acetate=1:1.Reaction solution filtering, filter cake are washed (10ml*2) with methylene chloride, obtain white (280mg, 99% yield) after filtrate concentration.

¹H NMR:(400MHz,DMSO-d₆):δ8.00(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)

Step 10: (±) 4- (the bromo- 4- fluorophenyl of 3-) 3-4- (((2- (methyl sulfoxide methylene imine) ethyl) T-butoxycarbonyl amino) -1,2,5- oxadiazoles -3- base) -1,2,4- oxadiazoles ketone

By the 9th step product (20mg, (2ml) 0.037mmol) is dissolved in methylene chloride, trimethyl oxygen tetrafluoroborate (8mg is added, 0.055mmol), it stirs 2 hours at room temperature, TLC shows fully reacting, water (10ml) is added in reaction solution, ethyl acetate (10ml), then (10ml x 2) is extracted with ethyl acetate and merges organic phase, then it is washed with water (10ml), saturated common salt washes (10ml), and sodium sulphate is dry.Column chromatographic isolation and purification after concentration obtains target compound (10mg, 48% yield).

¹H NMR:(400MHz,acetone-d6):δ7.96-7.94(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)

Step 11: ((±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (nitrogen, sulphur-dimethyl sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidines

By the tenth step product (20mg, (1ml) 0.037mmol) is dissolved in methylene chloride, hydrogen chloride/ethanol solution (2ml) of 10N is added, it stirs 2 hours at room temperature, after fully reacting, directly concentration is dry, and gained residue is dissolved in tetrahydrofuran (2ml), it is added 2M sodium hydrate aqueous solution (0.2ml), is stirred at room temperature 30 minutes.TLC shows fully reacting (methylene chloride: methanol=20:1), 2M hydrochloric acid is added and adjusts pH=5, water (10ml) is added in reaction solution, ethyl acetate (10ml), then (10ml x 2) is extracted with ethyl acetate and merges organic phase, then it is washed with water (10ml), saturated common salt washes (10ml), and sodium sulphate is dry.Column chromatographic isolation and purification after concentration obtains target compound (10mg, 52% yield).

¹H NMR:(400MHz,acetone-d₆):δ10.78(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 1 preparation method of embodiment, the reagent of the tenth step triethyl group oxygen tetrafluoroborate is replaced, then obtains target compound 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- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- (2- (sulphur-methyl-nitrogen-phenylsulfone imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

Step 1: (±) 4- (the bromo- 4- fluorophenyl of 3-) 3-4- (((2- (methyl sulfoxide phenyl imine) ethyl) t-butoxycarbonyl amino) -1,2,5- oxadiazoles -3- base) -1,2,4- oxadiazoles ketone

By the product (20mg of the 9th step of embodiment 1, (2ml) 0.037mmol) is dissolved in methylene chloride, phenyl boric acid (8mg is added, 0.055mmol), copper acetate (5mg) stirs 2 hours at room temperature, TLC shows fully reacting, water (10ml) is added in reaction solution, ethyl acetate (10mL), then (2x 10mL) is extracted with ethyl acetate and merges organic phase, then it is washed with water (10mL), saturated common salt washes (10mL), and sodium sulphate is dry.Column chromatographic isolation and purification after concentration obtains target compound (15mg, 66% yield)

¹HNMR (400MHz, acetone-d₆):δ7.93-7.91(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)

Step 2: (±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-nitrogen-phenylsulfone imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

By first step product (10mg, (1mL) 0.016mmol) is dissolved in methylene chloride, hydrogen chloride/ethanol solution (2mL) of 10M is added, it stirs 2 hours at room temperature, after fully reacting, directly concentration is dry, and gained residue is dissolved in tetrahydrofuran (2mL), it is added 2M sodium hydrate aqueous solution (0.2ml), is stirred at room temperature 30 minutes.TLC shows fully reacting, 2M hydrochloric acid is added and adjusts PH=5, water (10mL) is added in reaction solution, ethyl acetate (10mL), then (2x 10m L) is extracted with ethyl acetate and merges organic phase, then it is washed with water (10mL), saturated common salt washes (10mL), and sodium sulphate is dry.Column chromatographic isolation and purification after concentration obtains target compound (5mg, 63% yield)

¹HNMR(400MHz,acetone-d₆):δ10.80(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

Step 1: (±) 4- (the bromo- 4- fluorophenyl of 3-) 3-4- (((2- sulphur-methyl-nitrogen-(anilino- formyl) sulphoxide imine) ethyl) t-butoxycarbonyl amino) -1,2,5- oxadiazoles -3- base) -1,2,4- oxadiazoles ketone

By the product (20mg of the 9th step of embodiment 1, (2mL) 0.037mmol) is dissolved in tetrahydrofuran, phenyl isocyanate (9mg is added, it 0.073mmol) is stirred overnight at room temperature, sodium bicarbonate aqueous solution (10mL) ethyl acetate (10mL) is added, (10mL x 2) is extracted with ethyl acetate, merge organic phase, it is washed with water (10mL), saturated common salt washes (10mL), and organic phase is concentrated.Column chromatographic isolation and purification obtains target compound (20mg, 82% yield)

¹H NMR(400MHz,acetone-d₆):δ8.24(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)

Step 2: (±) 4- (the bromo- 4- fluorophenyl of 3-) 3-4- (((2- sulphur-methyl-nitrogen-(anilino- formyl) sulphoxide imine) ethyl) t-butoxycarbonyl amino) -1,2,5- oxadiazoles -3- base) -1,2,4- oxadiazoles ketone

10N HCL/EtOH (3ml) is added in first step product (20mg, 0.030mmol), is stirred at room temperature 3 hours.After fully reacting, directly concentration is dry, obtains target compound (20mg, 100% yield)

¹HNMR (400MHz, acetone-d₆):δ8.10(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)

Step 3: (±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(anilino- formyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

Second step product (20mg, 0.035mmol) is dissolved in tetrahydrofuran (2mL), is added 2M sodium hydrate aqueous solution (0.2mL), is stirred at room temperature 30 minutes.TLC shows fully reacting, 2mol/L hydrochloric acid is added and adjusts pH=5, water (10mL) is added in reaction solution, ethyl acetate (10mL), then (2x10mL) is extracted with ethyl acetate and merges organic phase, then it is washed with water (10mL), saturated common salt washes (10mL), and sodium sulphate is dry.Column chromatographic isolation and purification after concentration obtains target compound (10mg, 52% yield)

¹H NMR(400MHz,acetone-d₆):δ10.70(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

Step 1: (±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbonylic imidazole) sulphoxide imine) ethyl) amino) -1, the preparation of 2,5- oxadiazoles -3- carbonamidine (compound R):

At room temperature, by (±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) ethyl) amino) -1, 2, 5- oxadiazoles -3- carbonamidine (500mg, 1.19mol) it is dissolved in 20mL ethyl acetate, carbonyl dimidazoles (579mg is added, 3.57mmol), then it stirs 5 hours for 60 °, solvent is evaporated, 20mL water is added, (3x 30mL) is extracted with ethyl acetate, merge organic layer, saturated common salt water system, anhydrous sodium sulfate is dry, filtering, concentration, cross column (methylene chloride: methanol=100:5), concentration, it is 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)。

Step 2: (±)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl methyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

First step product (30mg, 0.055mmol) is dissolved in 3mL methanol, under ice bath, 2N hydroxide is added Sodium solution 1mL.1h is stirred at room temperature, pH=7. is adjusted with 6N hydrochloric acid solution, and 20mL water is added, (3x 20mL) is extracted with ethyl acetate, organic layer merges, and water, saturated salt solution is respectively washed once, concentrated solvent, pillar layer separation (DCM:MeOH=20:1) is prepared, target compound (10mg, 38%) is obtained

¹H NMR(400MHz,acetone-d₆):δ10.76(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 5 preparation method of embodiment, 5 first step product (30mg, 0.055mmol) of embodiment is dissolved in 3mL ethyl alcohol, under ice bath, 2N sodium hydroxide solution 1mL is added.1h is stirred at room temperature, pH=7. is adjusted with 6N hydrochloric acid solution, and 20mL water is added, (3x 20mL) is extracted with ethyl acetate, organic layer merges, and water, saturated salt solution is respectively washed once, concentrated solvent, pillar layer separation (DCM:MeOH=20:1) is prepared, target compound (14mg, 51%) is obtained

¹H NMR(400MHz,CDCl₃):δ9.96(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 5 preparation method of embodiment, 5 first step product (30mg, 0.055mmol) of embodiment is dissolved in 3mL isopropanol, under ice bath, 2N sodium hydroxide solution 1mL is added.1h is stirred at room temperature, pH=7. is adjusted with 6N hydrochloric acid solution, and 20mL water is added, (3x 20mL) is extracted with ethyl acetate, organic layer merges, and water, saturated salt solution is respectively washed once, concentrated solvent, pillar layer separation (DCM:MeOH=20:1) is prepared, compound TM (10mg, 37%) is obtained

¹H NMR(400MHz,CDCl₃):δ10.07(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) of the 9th step of COMPOUNDS EXAMPLE 1 and triethylamine (15uL) are dissolved in 3mL methylene chloride, under ice bath, it is added methylsufonyl chloride (6.4uL), reaction ten minutes later, is added 20mL water quenching and goes out, (3x 20mL) is extracted with dichloromethane, merge organic layer, salt washing is primary, dry, filtering, it is spin-dried for solvent, crosses column (DCM:MeOH=100:5), obtains crude product 35mg.By crude product, (35mg, 0.056mmol are dissolved in 1mL methylene chloride and 1mL trifluoroacetic acid, are reacted at room temperature three hours.Be spin-dried for solvent, water 20mL be added, is extracted with dichloromethane (3x 20mL), merge organic layer, salt washing, anhydrous sodium sulfate is dried, filtered, is spin-dried for, crude product (25mg).Previous step crude product is dissolved in 2mL tetrahydrofuran solution, 0.5mL2N sodium hydrate aqueous solution is added, is stirred at room temperature 0.5 hour, it is adjusted to pH=7 with 2NHCl, adds water 20mL, ethyl acetate extracts (3x 20mL), with simultaneously organic layer, salt washing, anhydrous sodium sulfate dry, filter, it is spin-dried for, column (DCM:MeOH=100:5) is crossed, white solid (20mg, 84%) is obtained

¹H NMR(400MHz,CDCl₃):δ9.28(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- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-cyanosulfoximine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine (20mg, it 0.045mmol) is dissolved in 2mL DMSO solution, Anhydrous potassium carbonate (63mg, 0.45mmol) then is added, it is slowly added dropwise into 0.5mL hydrogen peroxide, reacts at room temperature 0.5 hour.Sodium thiosulfate solution 20mL is added, it after being quenched, is extracted with dichloromethane (3x 20mL), merges organic layer, saturated common salt washing, anhydrous sodium sulfate dries, filters, and is spin-dried for, cross column (DCM:MeOH=100:5), it is spin-dried for, obtains 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

Embodiment 10

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen propyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

By the 9th step product (50mg of embodiment 1,0.09mmol), it is dissolved in tetrahydrofuran (10mL), propionic aldehyde (11mg is added, 0.18mmol), it is added acetoxyl group sodium borohydride (58mg, 0.27mmol), catalytic amount acetic acid, 40 degree are stirred 2 hours, saturated sodium bicarbonate solution (20mL) and methylene chloride (20mL) is added in TLC monitoring, raw material fully reacting, extraction, organic phase is collected, water phase is extracted with dichloromethane (10mL) again, merges organic phase, sodium sulphate is dry, concentration, column chromatographic isolation and purification obtain compound (50mg, 94%yield).(1ml) is dissolved in methylene chloride, hydrogen chloride/ethanol solution (2ml) of 10N is added, it stirs 2 hours at room temperature, after fully reacting, directly concentration is dry, gained residue is dissolved in tetrahydrofuran (2ml), is added 2M sodium hydrate aqueous solution (0.2ml), is stirred at room temperature 30 minutes.TLC shows fully reacting (methylene chloride: methanol=20:1), 2M hydrochloric acid is added and adjusts pH=5, water (10ml) is added in reaction solution, ethyl acetate (10ml), then (10ml x 2) is extracted with ethyl acetate and merges organic phase, then it is washed with water (10ml), saturated common salt washes (10ml), and sodium sulphate is dry.Column chromatographic isolation and purification after concentration obtains target compound (10mg, 25% yield).

MS (ESI): [M+H]+m/z=465.0

The fractionation of 11 chiral isomer of embodiment

Chiral resolution (chiral atom is sulphur atom) is carried out using 1260 semi-preparative liquid chromatography instrument of Agilent:

The fractionation of 1 compound of embodiment:

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: 1 sample 1mg of embodiment is dissolved in 1ml n-hexane and isopropyl alcohol mixture (hexane:iPrOH=8:2), sample volume 10 μ l, eluent Hexane:EtOH=88:12 (volume ratio)；Two optical isomer appearance times are respectively 14.251 minutes and 16.905 minutes；

1 sample 1mg of embodiment: will be dissolved in 1ml n-hexane and isopropyl alcohol mixture (hexane:iPrOH=8:2) by condition 2, sample volume 10 μ l, eluent Hexane:iPrOH=75:25 (volume ratio)；Two optical isomer appearance times are respectively 11.180 minutes and 13.978 minutes.

The fractionation of 2 compound of embodiment:

Condition 1: by DMSO solution (10mmol/L) isopropanol to 1mL of 200 microlitres of embodiments 2, sample volume 10 μ l, eluent Hexane:EtOH=88:12 (volume ratio)；Two optical isomer compound 11A and compound 11B appearance time are respectively 11.188 minutes and 13.786 minutes；

Condition 2: by DMSO solution (10mmol/L) isopropanol to 1mL of 200 microlitres of embodiments 2, sample volume 10 μ l, eluent Hexane:iPrOH=80:20 (volume ratio)；Two optical isomer appearance times are respectively 11.655 minutes and 15.261 minutes.

The fractionation of 3 compound of embodiment:

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: 3 sample 1mg of embodiment is dissolved in 1ml n-hexane and isopropyl alcohol mixture (hexane:iPrOH=8:2), sample volume 5 μ l, eluent Hexane:EtOH=60:40 (volume ratio)；Two optical isomer appearance times are respectively 9.842 minutes and 16.879 minutes.

Embodiment 12

Active testing

(1) inducing expression and purification process of IDO albumen

PCR amplification IDO gene first, the PCR product of amplification recycles, then pET28a plasmid (being purchased from the graceful Biotechnology Co., Ltd of upper Hypon) and IDO glue recovery product are carried out (37 DEG C of digestion with two kinds of restriction enzymes of EcoR I and Xho I, digestion 2h), run glue, recycling, T4 ligase links connection product overnight and is added to DH5 α competence, places 30min, 42 DEG C of thermal shock 90s on ice, shake bacterium coated plate, picking monoclonal, PCR identification, sequencing identification, it is all correct, i.e. pET28a-IDO plasmid construction success.

The BL21 containing pET28a-IDO plasmid that will be built, 37 DEG C are shaken to OD greatly₆₀₀For 0.6-0.8, it is added to the IPTG (isopropyl-β-D-thiogalactoside), 28 DEG C of induction 4h of final concentration of 7 μM of hemin and 1mM；After induction, 4 DEG C, thalline were collected by centrifugation by 6000rpm, and the thallus of collection is cleaned once with 20mM PBS (pH6.5), then thalline were collected by centrifugation.

The thallus of collection lysate (20mM PBS pH6.5) is hanged again, ultrasound cracking (power 40% cracks 20min, places on ice), by the bacterium after cracking, 13000rpm is centrifuged 15min, discards precipitating, retains supernatant；Nickel column is balanced into 3 column volumes with lysate (20mM PBS pH6.5), then cracking supernatant is loaded in nickel column, after loading, with rinsing liquid (20mM PBS pH6.5,20mM imidazoles) 4 column volumes of cleaning, finally albumen is eluted with eluent (20mM PBS pH6.5,250mM imidazoles)；The protein solution of elution is subjected to dialysis 4h, dialysis solution is 20mM PBS pH6.5, and protein sample is concentrated after dialysis, and packing, liquid nitrogen flash freezer is put into -80 DEG C and saves backup.

(2) IDO enzyme inhibition activity test method

Compound is subjected to 3 times of gradient dilutions first, each concentration takes 1 μ L to be added in 96 orifice plates；The IDO enzyme solutions (final concentration 600ng/100 μ L) that 50 μ L are prepared are added: 25 μ L substrate, 1 mixed solution is added, 2 mixed solution of substrate that 25 μ L are added originates reaction.Last OD₃₂₁Nm reads 60min.

(3) cell activity test method

Hela cell (100 μ L) is seeded on 96 orifice plates, and inoculum concentration is each hole 5 × 10³, growth is overnight.Second day, after diluted chemical compound, 1 μ L is taken to be added in 96 orifice plates, then the 100 μ L of culture medium of the interferon gamma (final concentration 50ng/mL) containing someone is added in 96 orifice plates, makes 200 μ L of final volume.After hatching in 48 hours, each hole takes 140 μ L supernatants to be transferred on a 96 new orifice plates.Each hole mixing is added in 10 μ L 6.1N trichloroacetic acids, and 50 DEG C hatch 30 minutes, and it is cynruin that IDO, which is catalyzed N formyl cynruin,.2500 turns of reaction mixture centrifugations remove sediment in 10 minutes.Each 100 μ L supernatant of hole is transferred to a 96 new orifice plates and mixes with 100 μ L2% dimethylaminobenzaldehyde acetic acid solutions.After cynruin separation, with SPECTRAmax i3reader 480 Nm measures numerical value.

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

Table 1IDO enzyme and cell inhibitory activity test result

The above results show that the compounds of this invention (including racemic modification and enantiomter) all has the excellent inhibitory activity for IDO enzyme and cell, and especially compound 2 has the high activity expected out in IDO cell inhibitory activity.

Claims

A kind of logical formula (I) compound or its pharmaceutically acceptable salt, its stereoisomer or its tautomer or prodrug:

In formula,

R⁷And R⁸Respectively stand alone as hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀Naphthenic base, substituted or unsubstituted C₂-C₁₀Alkenyl, substituted or unsubstituted C₃-C₁₀Alkynyl, substituted or unsubstituted C₆-C₂₀Aryl or substituted or unsubstituted C₃-C₁₄Heteroaryl；R⁷And R⁸Three can be formed together to octatomic ring or three to eight circle heterocyclic rings, and wherein hetero atom can be sulphur, oxygen, NH or NR^f；

R⁹For C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl；R⁹It can be replaced by one or more groups selected from the group below: 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^bRespectively stand alone as hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀Naphthenic base, substituted or unsubstituted C₂-C₁₀Alkenyl, substituted or unsubstituted C₆-C₂₀Aryl or substituted or unsubstituted C₃-C₁₄Heteroaryl；R^aAnd R^bThree can be formed together to octatomic ring or four to eight circle heterocyclic rings, and wherein hetero atom can be sulphur, oxygen, NH or NR^g；

R²For C₁-C₁₂Alkyl, C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl, C₁-C₄Alkyl-phenyl, C₁-C₄Alkyl-C₅Heterocycle ,-C (O) OR^e；-SO₂R^e、-SO₂NR^aR^b、-C(O)NR^aR^bOr C₃-C₁₂Naphthenic base；

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

Ring A is five yuan or hexa-member heterocycle；

R³And R⁴Respectively stand alone as hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl；Or R³And R⁴Three can be formed together to octatomic ring or three to eight circle heterocyclic rings, and 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-C₁₀Naphthenic base, C₆-C₂₀Aryl or C₃-C₁₄Heteroaryl；R¹And R²It can be replaced by one or more groups selected from the group below: halogen, hydroxyl, amino, nitro, cyano, aldehyde radical, carboxyl, alkoxy ,-CF₃、-SF₅；

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

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；

The integer that n is 2 to 8；

M is 0,1 or 2.
Logical formula (I) compound as described in claim 1, which is characterized in that R²For C₁-C₁₂Alkyl, C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl ,-SO₂R^e、-C(O)NR^aR^bOr C₃-C₁₂Naphthenic base.
Logical formula (I) compound as described in claim 1, which is characterized in that R³And R⁴Respectively stand alone as hydrogen or R³And R⁴Three can be formed together to octatomic ring or three to eight circle heterocyclic rings, and wherein hetero atom can be sulphur, oxygen, NH or NR^h, R^hDefinition is as described in claim 1.
Logical formula (I) compound as described in claim 1, which is characterized in that the integer that n is 2 to 6.
Logical formula (I) compound as described in claim 1, which is characterized in that the compound as led to shown in formula (II),

In formula,

R⁹For C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl；R⁹It can be replaced by one or more groups selected from the group below: 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、R¹Definition it is as described in claim 1；

R²For C₁-C₁₂Alkyl, C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl, C₁-C₄Alkyl-phenyl, C₁-C₄Alkyl-C5 heterocycle ,-C (O) OR^e；-SO₂R^e、-SO₂NR^aR^b、-C(O)NR^aR^bOr C₃-C₁₂Naphthenic base；

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

R¹And R²It can connect to form four to octatomic ring；

N is the integer of 2-6.
Logical formula (I) compound as described in claim 1, which is characterized in that the compound as led to shown in formula (III),

In formula,

Ar is phenyl ring, five yuan or six membered heteroaryl, and Ar can be replaced by one or more groups selected from the group below: 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；

R²For C₁-C₁₂Alkyl, C₆-C₂₀Aryl, C₅-C₂₀Heteroaryl, C₁-C₄Alkyl-phenyl, C₁-C₄Alkyl-C5 heterocycle ,-C (O) OR^e；-SO₂R^e、-SO₂NR^aR^b、-C(O)NR^aR^bOr C₃-C₁₂Naphthenic base；

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

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

R¹And R²It can connect to form four to octatomic ring；

N is the integer of 2-6.
Logical formula (III) compound as claimed in claim 3, which is characterized in that 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 described in claim 1；

R¹And R²It can connect to form four to octatomic ring；

R³And R⁴Respectively stand alone as hydrogen or R³And R⁴Three can be formed together to octatomic ring or three to eight circle heterocyclic rings, and wherein hetero atom can be sulphur, oxygen, NH or NR^h, R^hDefinition is as described in claim 1；

N is the integer of 2-6.
Logical formula (I) compound or its pharmaceutically acceptable salt, its stereoisomer or its tautomer as described in claim 1, which is characterized in that the prodrug as led to shown in formula (IV),

In formula,

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

R^10aFor substituted or unsubstituted C₆-C₂₀Aryl, substituted or unsubstituted five yuan or six membered heteroaryl, substituted or unsubstituted C₁-C₁₂Alkyl, substituted or unsubstituted C₁-C₁₂Alkoxy, substituted or unsubstituted C₃-C₁₂Naphthenic base, C₃-C₁₂Cycloalkyloxy, NR^aR^b；Wherein, R^a、R^bDefinition it is as described in claim 1,

Wherein, " substitution ", which refers to, has one or more substituent groups selected from the group below: halogen, hydroxyl ,-NH₂, nitro ,-CN, C₁-C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₃-C₆Naphthenic base, C₂-C₄Alkenyl, C₂-C₄Alkynyl, phenyl, benzyl.
Logical formula (I) compound as described in claim 1, which is characterized in that the compound are as follows:

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (nitrogen, sulphur-dimethyl sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidines

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen ethyl-sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen isopropyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-azo-cycle propyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (2,2,2- trifluoroethyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (3,3,3- trifluoro propyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (2- bis-fluoro ethyls) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (- 1 λ of 1- oxygen -3,4,5,6- tetrahydro⁶, 2- thiazine -1- base) and ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-azo-cycle propyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-azo-cycle butyl base sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-phenylsulfone imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- fluorophenyl sulphoxide imine) Ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- chlorophenyl imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(anilino- formyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(methylamino formyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(isopropyl carbamoyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-phenylsulfone imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl methyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl ethyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(formyl isopropyl ester) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(mesyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(benzenesulfonyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(nitrogen-phenylsulfamoyl base) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (nitrogen, sulphur-dimethyl sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidines

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen ethyl-sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen isopropyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-azo-cycle propyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (2,2,2- trifluoroethyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (3,3,3- trifluoro propyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (2- bis-fluoro ethyls) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (- 1 λ of 1- oxygen -3,4,5,6- tetrahydro⁶, 2- thiazine -1- base) and second Base) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-azo-cycle propyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-azo-cycle butyl base sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-phenylsulfone imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- fluorophenyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- chlorophenyl imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(anilino- formyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(methylamino formyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(isopropyl carbamoyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-phenylsulfone imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- chlorine 4- fluorophenyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl methyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl ethyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(formyl isopropyl ester) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(mesyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- chlorine 4- fluorophenyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(benzenesulfonyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(nitrogen-phenylsulfamoyl base) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(the chloro- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (nitrogen, sulphur-dimethyl sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidines

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen ethyl-sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen isopropyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen sulfoxide imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-azo-cycle propyl sulphoxide imine) ethyl) Amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (2,2,2- trifluoroethyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (3,3,3- trifluoro propyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen (2- bis-fluoro ethyls) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (- 1 λ of 1- oxygen -3,4,5,6- tetrahydro⁶, 2- thiazine -1- base) and ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-azo-cycle propyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-azo-cycle butyl base sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-phenylsulfone imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- fluorophenyl sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(4- chlorophenyl imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(anilino- formyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(methylamino formyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(isopropyl carbamoyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-phenylsulfone imines) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl methyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamoyl ethyl) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(formyl isopropyl ester) sulphoxide imine) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(mesyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(benzenesulfonyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(nitrogen-phenylsulfamoyl base) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine

(±) (Z)-nitrogen-(3- trifluoromethyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl-nitrogen-(carbamyl) sulphoxide imine) ethyl) amino) -1; 2,5- oxadiazoles -3- carbonamidine.
Logical formula (I) compound as described in claim 1, which is characterized in that described pharmaceutically acceptable Salt is selected from the group: hydrochloride, hydrobromate, sulfate, phosphate, mesylate, fluoroform sulphonate, benzene sulfonate, tosilate (toluene fulfonate), 1-naphthalene sulfonic aicd salt, 2- naphthalene sulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalates, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, mandelate.
The purposes of logical formula (I) compound as described in claim 1, which is characterized in that be used for:

(i) indoles amine -2,3- dioxygenase inhibitor is prepared；

(ii) drug for the disease that preparation prevention and/or treatment indoles amine -2,3- dioxygenase mediate；Or

(iii) anti-tumor drug or anti-inflammatory drug are prepared.
Purposes as claimed in claim 11, it is characterized in that, the disease that indoles amine -2,3- dioxygenase mediates is cancer, neurological disease, HIV infection, eye illness, at heart obstacle, depression, anxiety disorder, senile dementia and/or autoimmune disease.
A kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes:

Logical formula (I) compound described in claim 1 or its pharmaceutically acceptable salt, its stereoisomer or its tautomer or its prodrug；Preferably described pharmaceutical composition further includes other anti-tumor drugs, the anti-tumor drug 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 target therapeutic agent, such as hdac inhibitor and EP4 antagonist.
The preparation method of logical formula (I) compound as described in claim 1, which comprises the following steps:

(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, obtains final product P4 or P5, i.e., logical formula (I) compound；

Alternatively, the described method comprises 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 obtains final product P8 or P9, i.e., logical formula (I) compound；

Or meeting, it the described method comprises 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 loop under base hydrolysis conditions obtains final product and leads to formula (I) compound；

Alternatively, the described method comprises the following steps:

In various, R¹、R³、R⁴、R⁷、R⁸、R⁹, shown in n, m, X and ring A be as defined above.
A kind of method of prevention and/or the disease for treating the mediation of indoles amine -2,3- dioxygenase, includes the steps that giving patient pharmaceutical composition described in logical formula (I) compound described in claim 1 or claim 13.