CN107176933B

CN107176933B - Indoleamine-2,3-dioxygenase inhibitor containing nitrogen alkylated and arylated sulfoximine

Info

Publication number: CN107176933B
Application number: CN201610134565.8A
Authority: CN
Inventors: 王召印; 郭巍; 朱继东; 胡新波
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 2016-03-09
Filing date: 2016-03-09
Publication date: 2020-10-09
Anticipated expiration: 2036-03-09
Also published as: WO2017152857A1; CN107176933A; CN108699014A

Abstract

The invention discloses an indoleamine-2,3-dioxygenase inhibitor and a preparation method thereof. The inhibitor has a structure shown in a general formula (I), wherein, X, R¹、R²、R³、R⁴、R⁷、R⁸、R⁹N and m are as defined in the description and claims. The invention also discloses a preparation method of the inhibitor. The compound of the general formula (I) can be used as an indoleamine-2,3-dioxygenase inhibitor and is used for preparing a medicament for preventing and/or treating indoleamine-2,3-dioxygenase mediated diseases.

Description

Indoleamine-2,3-dioxygenase inhibitor containing nitrogen alkylated and arylated sulfoximine

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an IDO inhibitor containing nitrogen alkylation, arylation and acylation sulfoxide imine and 1,2, 5-oxadiazole structures and a preparation method thereof.

Background

Indoleamine-2,3-dioxygenase (IDO) is a heme-containing monomeric enzyme first found intracellularly by the Hayaishi group in 1967, and the cDNA-encoded protein consists of 403 amino acids, has a molecular weight of 45kDa, is the rate-limiting enzyme for catabolism along the tryptophan-kynurenine pathway, and is widely expressed in various mammalian tissues (Hayaishi o.et al Science,1969,164, 389-396). In cells of tumor patients, IDO often plays an important physiological role in inducing tumor microenvironment immune tolerance, and the mediated Tryptophan (Trp) -Kynurenine (Kynurenine, Kyn) metabolic pathway participates in tumor immune escape, and IDO also plays an important role in inducing tumor microenvironment immune tolerance.

Tryptophan is one of the essential amino acids in mammals and requires large amounts of intake from food, maintenance of cell activation and proliferation, and synthesis of proteins and some neurotransmitters. Thus, its lack can lead to dysfunction of some important cells. IDO catalyzes the conversion of tryptophan into N-formyl kynurenine in vivo, degrades the content of tryptophan to cause the deficiency of tryptophan in vivo, and causes the occurrence of tumors. Immunohistological studies have shown that the kynurenine pathway can lead to an increase in the amount of the excitotoxin quinolinic acid and also to a number of serious human diseases such as neurological diseases such as alzheimer (Guillemin g. j. et al neuropathol. and appl. neurobiol.2005,31, 395-.

There are two major tryptophan rate-limiting enzymes in mammals: tryptophan Dioxygenase (TDO) and IDO. In 1937, Kotake et al purified proteins from rabbit intestine and found TDO to be expressed mainly in mammalian liver for the first time, and it has not been found that he is closely related to the immune system. TDO is able to catalyze the kynurenine pathway, converting tryptophan to N-formyl kynurenine [ Higuchi k.et al j. biochem.1937,25, 71-77; shimizu T.et J.biol.chem.1978,253,4700-4706 ]. In 1978, the enzyme purified from rabbit intestine was identified as heme-containing dioxygenase (IDO), which is the only enzyme outside the liver that catalyzes the oxidative cleavage of indole in tryptophan molecules and catabolizes via the kynurenine pathway, and is usually expressed in more mucosal organs, such as lung, small and large intestine, rectum, spleen, kidney, stomach and brain, etc., and is widely distributed (Hayaishi O.et al, Proceedings of the ten FEBS meetings, 1975, 131-. Under certain specific or pathological conditions, such as pregnancy, chronic infection, organ transplantation, tumor, etc., IDO expression is significantly increased and participates in mediating local immunosuppression.

Studies have shown that IDO can suppress local T cell immune responses in the tumor microenvironment in several ways: tryptophan depletion, toxic metabolism and induction of regulatory T cell proliferation. In many cases, it is excessively expressed in tumors, thereby consuming local tryptophan and producing a large amount of metabolites such as kynurenine. In fact, under culture conditions without tryptophan or kynurenine, T cells may undergo proliferation inhibition, decreased activity, or even apoptosis. And a regulatory point which is very sensitive to tryptophan level exists in the T cells, and under the action of IDO, tryptophan can be consumed, so that the T cells are arrested in the middle stage of G1, the proliferation of the T cells is inhibited, and the immune response of the T cells is also inhibited. However, once T cells cease to proliferate, they may not be stimulated any more, which is the mechanism of IDO in vivo immunization (Mellor A. et al biochem. Biophys. Res. Commun.2005,338(1):20-24) (LeRond S. et al J. exp. Med.2002,196(4): 447-.

There is a need in the art to develop novel IDO inhibitors with high activity, and the present invention has found that a novel class of compounds containing nitrogen alkylated and arylsulfoximine and 1,2, 5-oxadiazole structures have unexpectedly high IDO inhibitory activity.

Disclosure of Invention

The invention aims to provide a novel compound containing nitrogen alkylated and arylated sulfoximine and a 1,2, 5-oxadiazole structure as a high-efficiency IDO enzyme inhibitor.

Another object of the present invention is to provide a process for the preparation of the compound.

In a first aspect of the present invention, there is provided a compound of general formula (i) or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof:

in the formula (I), the compound is shown in the specification,

R⁷and R⁸Each independently hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₂-C₁₀Alkenyl, substituted or unsubstituted C₃-C₁₀Alkynyl, substituted or unsubstituted C₆-C₂₀Aryl, or substituted or unsubstituted C₃-C₁₄A heteroaryl group; r⁷And R⁸May together form a three-to eight-membered ring or a three-to eight-membered heterocyclic ring, wherein the heteroatom may be sulfur, oxygen, NH or NR^f；

R⁹Is C₆-C₂₀Aryl radical, C₅-C₂₀A heteroaryl group; r⁹May be substituted with one or more groups selected from: halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, amino, nitro, aldehyde, -CF₃、-CN、-SF₅、NR^aR^bCarboxy, -COR^a、-CO₂C₁-C₆Alkyl, -CONR^aR^b、-SO₂R^e、-SO₂NR^aR^b、-P(O)Me₂、-P(O)(OMe)₂(ii) a Wherein each R^aAnd each R^bEach independently hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₂-C₁₀Alkenyl, substituted or unsubstituted C₆-C₂₀Aryl, or substituted or unsubstituted C₃-C₁₄A heteroaryl group; r^aAnd R^bMay together form a three-to eight-membered ring or a four-to eight-membered heterocyclic ring, in which the heteroatom may be sulfur, oxygen, NH or NR^g；

R²Is C₁-C₁₂Alkyl radical, C₆-C₂₀Aryl radical, C₅-C₂₀Heteroaryl group, C₁-C₄Alkyl-phenyl, C₁-C₄alkyl-C5 heterocycles, -C (O) OR^e；-SO₂R^e、-SO₂NR^aR^bor-C (O) NR^aR^b；

X is a single bond, O, S, NH or NR^d；

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

R³and R⁴Each independently hydrogen, substituted or unsubstituted C₁-C₁₀An alkyl group; r³And R⁴May together form a three-to eight-membered ring or a three-to eight-membered heterocyclic ring, wherein the heteroatom may be sulfur, oxygen, NH or NR^h；

R¹、R^d、R^e、R^f、R^g、R^hIndependently is C₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl radical, C₆-C₂₀Aryl, or C₃-C₁₄A heteroaryl group; r¹May be substituted with one or more groups selected from: halogen, hydroxy, amino, nitro, cyano, aldehyde, carboxyl, alkoxy, -CF₃、-SF₅；

R¹And²may be substituted by one or more of halogen, alkoxy and cyano;

R¹and R^dMay be linked to form a six to eight membered ring;

R¹and R³May be linked to form a five to eight membered ring;

n is an integer of 2 to 8;

m is 0, 1 or 2.

In another preferred embodiment, the "substituted" refers to having one or more substituents selected from the group consisting of: halogen, hydroxy, -NH₂Nitro, -CN, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₃-C₆Cycloalkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, phenyl, benzyl.

In another preferred embodiment, R²Is C₁-C₁₂Alkyl radical, C₆-C₂₀Aryl radical, C₅-C₂₀Heteroaryl, -SO₂R^eor-C (O) NR^aR^b；

In another preferred embodiment, R³And R⁴Each independently is hydrogen,

In another preferred embodiment, n is 2 to 6.

In another preferred embodiment, X is NH.

In another preferred embodiment, m is 0.

In another preferred embodiment, the compound is represented by the general formula (ii),

in the formula (I), the compound is shown in the specification,

R⁹is C₆-C₂₀Aryl radical, C₅-C₂₀A heteroaryl group; r⁹May be substituted with one or more groups selected from: halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, amino, nitro, aldehyde, -CF₃、-CN、-SF₅、NR^aR^bCarboxy, -COR^a、-CO₂C₁-C₆Alkyl, -CONR^aR^b、-SO₂R^e、-SO₂NR^aR^b；

Wherein R is^a、R^b、R³、R⁴、R¹Is as defined above;

R²is C₁-C₁₂Alkyl radical, C₆-C₂₀Aryl radical, C₅-C₂₀Heteroaryl, -C (O) OR^e；-SO₂R^e、-SO₂NR^aR^bor-C (O) NR^aR^b；

n is 2 to 6.

In another preferred embodiment, the compound is represented by the general formula (iii),

in the formula (I), the compound is shown in the specification,

wherein R is³、R⁴、R¹Is as defined above;

R¹And²may be substituted by one or more of halogen, alkoxy and cyano

Ar is C₆-C₁₀Aryl, five or six membered heteroaryl; ar may be substituted with one or more groups selected from the group consisting of: halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, -CF₃、-CN、-SF₅。

n is 2 to 6.

In another preferred embodiment, R¹Is C₁-C₁₀An alkyl group;

R²is C₁-C₁₂Alkyl radical, C₆-C₂₀Aryl radical, C₅-C₂₀Heteroaryl, -SO₂R^e、-SO₂NR^aR^bor-C (O) NR^aR^b；

R³And R⁴Each independently is hydrogen;

ar is C₆-C₁₀Aryl, five or six membered heteroaryl; ar may be substituted with one or more groups selected from the group consisting of: halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, amino, nitro, aldehyde, -CF₃、-CN、-SF₅。

In another preferred embodiment, R¹Is C₁-C₄An alkyl group;

In another preferred embodiment, the prodrug of the compound of the general formula i is represented by a general formula (iv),

in the formula (I), the compound is shown in the specification,

R¹、R²、R³、R⁴and R⁹Is as defined above;

R^10ais substituted or unsubstituted C₆-C₂₀Aryl, substituted or unsubstituted five-or six-membered heteroaryl, substituted or unsubstituted C₁-C₁₂Alkyl, substituted or unsubstituted C₁-C₁₂Alkoxy, substituted or unsubstituted C₃-C₁₂Cycloalkyl radical, C₃-C₁₂Cycloalkoxy, NR^aR^b(ii) a Wherein R is^a、R^bIs as defined above;

wherein said "substituted" means having one or more substituents selected from the group consisting of: halogen, hydroxy, -NH₂Nitro, -CN, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₃-C₆Cycloalkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, phenyl, benzyl.

In another preferred embodiment, X, R¹、R²、R³、R⁴、R⁷、R⁸、R⁹、R^10aEach group is independently the corresponding group in each particular compound of formulae (i), (ii) and (iv) prepared in the examples.

In another preferred embodiment, the compound is:

(±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (N, S-dimethyl sulfoxide imine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((3- (thio-methyl-AZO ETHYL SULFOXIMIDE) Ethyl) amino) -1,2, 5-oxadiazole-3-Carboxamidine

(±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((3- (thio-methyl-N-isopropylsulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((3- (thio-methyl-N-cyclopropylsulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((3- (thio-methyl-aza (2,2, 2-trifluoroethyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((3- (thio-methyl-N (2-fluoroethyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (1-oxo-3, 4,5, 6-tetrahydro-1 λ 6, 2-thiazin-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((3- (thio-methyl-N-cyclobutyl sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methyl-N-phenylsulfoxide) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methyl-N- (4-fluorophenyl sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methyl-N- (4-chlorophenyl sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methyl-N- (anilino formyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methyl-N- (methylaminoformyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methyl-N- (isopropylaminoformyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methyl-aza- (formylmethyl ester) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methyl-N- (formyl ethyl ester) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methyl-aza- (formyl isopropyl ester) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methyl-aza- (methylsulfonyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methyl-aza- (benzenesulfonyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methyl-aza- (aza-phenylaminosulfonyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methyl-aza- (carbamoyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-chloro-4-fluorophenyl) -N' -hydroxy-4- ((2- (N, S-dimethyl sulfoxide imine) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine

(±) (Z) -N- (3-chloro-4-fluorophenyl) -N' -hydroxy-4- ((3- (thio-methyl-AZO ETHYL SULFOXIMIDE) Ethyl) amino) -1,2, 5-oxadiazole-3-Carboxamidine

(±) (Z) -N- (3-trifluoromethylphenyl) -N' -hydroxy-4- ((3- (thio-methyl-N-isopropylsulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-trifluoromethylphenyl) -N' -hydroxy-4- ((3- (thio-methyl-N-cyclopropylsulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-chloro-4-fluorophenyl) -N' -hydroxy-4- ((3- (thio-methyl-N-cyclobutyl sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-chloro-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methyl-aza-phenylsulfoxide) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-trifluoromethylphenyl) -N' -hydroxy-4- ((2- (thio-methyl-N- (4-fluorophenyl sulfoxide imine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-chloro-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methyl-aza- (4-chlorophenyl sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-chloro-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methyl-N- (anilino formyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-chloro-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methyl-N- (methylaminoformyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-trifluoromethylphenyl) -N' -hydroxy-4- ((2- (thio-methyl-N- (isopropylamido formyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-chloro-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methyl-aza- (formyl methyl ester) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-trifluoromethylphenyl) -N' -hydroxy-4- ((2- (thio-methyl-N- (formyl ethyl ester) sulfoxide imine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-chloro-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methyl-aza- (formyl isopropyl ester) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-chloro-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methyl-aza- (methylsulfonyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -N- (3-trifluoromethylphenyl) -N' -hydroxy-4- ((2- (thio-methyl-N- (phenylsulfonyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-chloro-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methyl-aza- (aza-phenylaminosulfonyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-chloro-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methyl-aza- (carbamoyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

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

In another preferred embodiment, the compound is a racemate.

In another preferred embodiment, the compounds are enantiomers.

In another preferred embodiment, the pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, hydrobromide, sulphate, phosphate, methanesulphonate, trifluoromethanesulphonate, benzenesulphonate, p-toluenesulphonate (toluenesulphonate), 1-naphthalenesulphonate, 2-naphthalenesulphonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, mandelate.

In a second aspect of the present invention, there is provided a process for the preparation of a compound of formula (i) as defined in the first aspect, comprising the steps of:

(a) compounds P1 and R₃OBF₄Reacting to obtain a compound P2;

(b) compound P1 with ArB (OH)₂And Cu (OAc)₂Reacting to obtain a compoundP3；

(c) The ring opening of the compound P2 or P3 in the presence of sodium hydroxide (such as aqueous sodium hydroxide) gives the final product P4 or P5, i.e. the compound of formula (I).

The compounds of general formula (i) according to the invention can also be obtained by a process for the preparation comprising the following steps:

(a) compound P1 with R-N ═ C ═ O or ClSO₂R²Reacting to obtain a compound P6 or P7;

(b) the ring opening of the compound P6 or P7 in the presence of sodium hydroxide (such as aqueous sodium hydroxide) gives the final product P8 or P9, i.e. the compound of formula (I).

The present invention also provides a process for the preparation of a third compound of formula (i) comprising the steps of:

(a) reacting the compound D with the compound E and a reducing agent under the catalysis of acid to obtain a compound F;

(b) the compound F is subjected to ring opening under the alkaline hydrolysis condition (such as aqueous sodium hydroxide solution) to obtain the final product, namely the compound shown in the general formula (I).

The present invention also provides a fourth process for the preparation of a compound of formula (i), comprising the steps of:

in the formulae, R¹、R³、R⁴、R⁷、R⁸、R⁹N, m, X and Ring A are as defined above.

In the invention, the compound P1 is obtained by taking propylene dicyan as an initial raw material and carrying out a series of reactions such as oxidation, addition, cyclization, diazotization, substitution and the like.

In a third aspect of the invention, there is provided the use of a compound of formula (i) as defined in the first aspect for:

(i) preparing indoleamine-2,3-dioxygenase inhibitor;

(ii) preparing a medicament for the prevention and/or treatment of indoleamine-2,3-dioxygenase mediated diseases; or

(iii) Preparing the anti-inflammatory medicine.

In another preferred embodiment, the indoleamine-2,3-dioxygenase mediated disease is a disease that is pathologically characteristic of the IDO-mediated tryptophan metabolic pathway.

In another preferred embodiment, the indoleamine-2,3-dioxygenase mediated disease is cancer, an eye disease, a mood disorder, depression, anxiety, senile dementia and/or an autoimmune disease.

In another preferred example, the cancer includes, but is not limited to: colon cancer, breast cancer, stomach cancer, lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, liver cancer, brain cancer, melanoma, multiple myeloma, chronic myelogenous leukemia, hematologic tumors, lymphoid tumors, including metastatic lesions in other tissues or organs remote from the site of tumor origin.

In a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising:

a compound of general formula (I) of the first aspect or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof; and

a pharmaceutically acceptable carrier.

In a fifth aspect of the present invention, there is provided a pharmaceutical composition comprising:

a compound of the general formula (i) according to the first aspect or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof; and

an antitumor drug.

In another preferred embodiment, the anti-tumor drugs include, but are not limited to, cancer immunotherapeutic drugs: PD-1 antibody, CTLA-4 antibody, PD-L1 antibody, PD-L2 antibody, any one of the other chemotherapeutic or targeted therapeutic agents, such as HDAC inhibitors and EP4 antagonists.

In a sixth aspect of the present invention, there is provided a method for the prophylaxis and/or treatment of indoleamine 2,3-dioxygenase mediated diseases comprising the step of administering to a patient a compound of formula (i) according to the first aspect or a pharmaceutical composition according to the fourth or fifth aspect.

In another preferred embodiment, the indoleamine-2,3-dioxygenase mediated disease is cancer, and the method further comprises the step of administering to the patient an additional anti-cancer agent (also referred to as an anti-tumor agent, said anti-tumor agent being as described above).

The compound of the general formula (i) has various pharmacological activities of resisting tumors, treating neurodegenerative diseases (Alzheimer disease), resisting inflammation and the like.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. For reasons of space, they will not be described in detail.

Detailed description of the preferred embodiments

The present inventors have conducted extensive and intensive studies and, for the first time, have unexpectedly developed a novel sulfoximine-and 1,2, 5-oxadiazole-containing compound which is useful as a highly effective IDO enzyme inhibitor for the prevention and/or treatment of indoleamine-2, 3-dioxygenase-mediated diseases and as an anti-inflammatory agent. On the basis of this, the present invention has been completed.

Definition of

The term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group of 1 to 10 carbon atoms, including straight and branched chain hydrocarbon groups, such as methyl (i.e., CH)₃-, ethyl (i.e. CH)₃CH₂-, n-propyl (i.e., CH)₃CH₂CH₂-), isopropyl (i.e., (CH)₃)₂CH-), n-butyl (i.e. CH)₃CH₂CH₂CH₂-, isobutyl (i.e., (CH)₃)₂CHCH₂-, sec-butyl (i.e., (CH)₃)(CH₃CH₂) CH-), tert-butyl (i.e., (CH)₃)₃C-), n-pentyl (i.e. CH)₃CH₂CH₂CH₂CH₂-, neopentyl (i.e. (CH))₃)₃CCH₂-). In the present invention, the term includes substituted or unsubstituted alkyl groups.

The term "substituted or unsubstituted" as used herein means that the group may be unsubstituted or that H in the group is substituted with one or more (preferably 1 to 6, more preferably 1 to 3) substituents.

As used herein, the term "substituted" or "substituted" means that the group has one or more (preferably 1 to 6, more preferably 1 to 3) substituents selected from the group consisting of: halogen, hydroxy, -NH₂Nitro, -CN, C1-C4 alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₃-C₆Cycloalkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, phenyl, benzyl.

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

As used herein, the term "alkoxy" refers to an-O-alkyl group, wherein the alkyl group may be saturated or unsaturated, may be branched, linear, or cyclic. Preferably, the alkoxy group has 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Representative examples include (but are not limited to): methoxy, ethoxy, propoxy.

As used herein, the term "aryl" refers to a monovalent aromatic carbocyclic group of 6 to 20 (preferably 6 to 14) carbon atoms having a single ring (e.g., phenyl) or a fused ring (e.g., naphthyl or anthryl) which may be non-aromatic if the point of attachment is at an aromatic carbon atom (e.g., 2-benzoxazolone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, etc.). Preferred aryl groups include phenyl and naphthyl. The term includes substituted and unsubstituted forms wherein the substituents are as defined above.

As used herein, the term "alkenyl" refers to alkenyl groups having 2 to 10 (e.g., 2 to 6 or 2 to 4) carbon atoms and having at least 1 (e.g., 1 to 2) ethylenically unsaturated bonds (> C ═ C <). Examples of such radicals are vinyl, allyl, but-3-enyl. As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms with a single ring or multiple rings (including fused systems, bridged ring systems, and spiro ring systems). In fused ring systems, one or more rings may be cycloalkyl, heterocyclic, aryl or heteroaryl, provided that the attachment site is through the ring of the cycloalkyl group. Examples of suitable cycloalkyl groups include: for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl.

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

As used herein, the term "heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring, such heteroaryl groups can be monocyclic (e.g., pyridyl or furyl) or fused rings (e.g., indolizinyl or benzothienyl), wherein the fused rings can be non-aromatic and/or contain one heteroatom, so long as the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the ring atoms nitrogen and/or sulfur of the heteroaryl group are optionally oxidized to the N-oxide (N-O), sulfinyl, or sulfonyl. Preferred heteroaryl groups include pyridyl, pyrrolyl, indolyl, thienyl and furyl. The term includes substituted or unsubstituted heteroaryl groups.

The term "substituted heteroaryl" as used herein refers to heteroaryl substituted with 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the same substituents as defined for substituted aryl.

As used herein, the term "heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated, partially saturated or unsaturated group (but not aromatic) having a single or fused ring (including bridged ring systems and spiro ring systems, with 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen within the ring, in the fused ring system, one or more rings may be cycloalkyl, aryl or heteroaryl, so long as the point of attachment is through a non-aromatic ring.

As used herein, the term "substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclic group that is substituted with from 1 to 5 (e.g., 1 to 3) substituents as defined for substituted cycloalkyl.

As used herein, the term "stereoisomer" refers to a compound in which the chirality of one or more stereocenters is different. Stereoisomers include enantiomers and diastereomers.

As used herein, the term "tautomer" refers to alternative forms of compounds that differ in the position of the proton, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups that contain a ring atom attached to the-NH-moiety of the ring and the ═ N-moiety of the ring, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

"prodrug" refers to any derivative of a compound of the examples which, when administered to a subject, is capable of providing, directly or indirectly, the compound of the examples or an active metabolite or residue thereof. Particularly preferred derivatives and prodrugs are those that, when administered to a subject, enhance the bioavailability of the compounds of the examples (e.g., the compounds administered orally are more readily absorbed into the blood) or enhance the transport of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Prodrugs include ester forms of the compounds of the present invention.

Compounds of the invention

As used herein, the term "compound of the present invention" refers to a compound having the general structure of the present invention, including a compound of general formula (i) or general formula (ii), its racemate, its stereoisomer or its tautomer, or a prodrug, or a pharmaceutically acceptable salt thereof. It is to be understood that the term also includes compounds of formula (iii) and other general formulae in the description and claims of the invention, racemates, stereoisomers or tautomers thereof, or pharmaceutically acceptable salts thereof.

The present invention relates to: racemic mixtures of these compounds, mixtures enriched in any one of the enantiomers, and any one of the isolated enantiomers. For the scope of the present invention, it is understood that the racemic mixture refers to a 50% to 50% mixture of the two R and S enantiomers. The isolated enantiomer is understood to be a pure enantiomer (i.e.100%) or a mixture highly enriched in a certain enantiomer (purity ≥ 98%, ≥ 95%, ≥ 93%, ≥ 90%, ≥ 88%, ≥ 85%, ≥ 80%).

Typically, the present invention provides a compound of general formula (i) or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof,

in the formula (I), the compound is shown in the specification,

R⁹Is C₆-C₂₀Aryl, five or six membered heteroaryl; r⁹May be substituted with one or more groups selected from: halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, amino, nitro, aldehyde, -CF₃、-CN、-SF₅、NR^aR^bCarboxy, -COR^a、-CO₂C₁-C₆Alkyl, -CONR^aR^b、-SO₂R^a、-SO₂NR^aR^b、-P(O)Me2、-P(O)(OMe)₂(ii) a Wherein each R^aAnd each R^bEach independently hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₂-C₁₀Alkenyl, substituted or unsubstituted C₆-C₂₀Aryl, or substituted or unsubstituted C₃-C₁₄A heteroaryl group; r^aAnd R^bMay together form a three-to eight-membered ring or a four-to eight-membered heterocyclic ring, in which the heteroatom may be sulfur, oxygen, NH or NR^g；

X is a single bond, O, S, NH or NR^d；

R¹And R^dMay be linked to form a six to eight membered ring;

R¹and R³May be linked to form a five to eight membered ring;

n is 2 to 8;

ring a is a 1,2, 5-oxadiazole ring;

m is 0 to 2.

In another preferred embodiment, the compound of formula (a) is:

wherein R is¹Is C₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl radical, C₁-C₁₀Alkenyl, aryl, or heteroaryl, R¹May be substituted by one or more halogens;

R¹⁰And R¹¹Are each independently hydrogen, halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₂-C₆Alkynyl, hydroxy, amino, nitro, cyano, aldehyde, -CF₃、-CN、-SF₅、NR^aR^bCarboxy, -CO₂C₁-C₆Alkyl, -CONR^aR^b、-SO₂R^a、SO₂NR^aR^bSubstitution; r^aAnd R^bAs defined above;

n is 1 to 8.

In another preferred embodiment, the present invention also provides a prodrug of formula (a):

in the formula, each group is as defined above.

In a preferred embodiment of the present invention, the present invention provides a compound of general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof:

in the formula (I), the compound is shown in the specification,

R⁷and R⁸Each is independentImmediately hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₂-C₁₀Alkenyl, substituted or unsubstituted C₃-C₁₀Alkynyl, substituted or unsubstituted C₆-C₂₀Aryl, or substituted or unsubstituted C₃-C₁₄A heteroaryl group; r⁷And R⁸May together form a three-to eight-membered ring or a three-to eight-membered heterocyclic ring, wherein the heteroatom may be sulfur, oxygen, NH or NR^f；

R²Is C₁-C₁₂Alkyl radical, C₆-C₂₀Aryl radical, C₅-C₂₀Heteroaryl group, C₁-C₄Alkyl-phenyl, C₁-C₄alkyl-C₅Heterocycle, -C (O) OR^e；-SO₂R^e、-SO₂NR^aR^bor-C (O) NR^aR^b；

X is a single bond, O, S, NH or NR^d；

R¹、R^d、R^e、R^f、R^g、R^hIndependently is C₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl radical, C₆-C₂₀Aryl, or C₃-C₁₄A heteroaryl group; r¹And R²May be substituted with one or more groups selected from: halogen, hydroxy, amino, nitro, cyano, aldehyde, carboxyl, alkoxy, -CF₃、-SF₅；

R¹And R²May be substituted by one or more of halogen, alkoxy and cyano;

R¹and R²May be linked to form a four to eight membered ring;

R¹and R^dMay be linked to form a six to eight membered ring;

R¹and R³May be linked to form a five to eight membered ring;

n is an integer of 2 to 8;

m is 0, 1 or 2.

In another preferred embodiment, the compounds provided by the present invention are represented by general formula (II),

in the formula (I), the compound is shown in the specification,

R⁹is C₆-C₂₀Aryl radical, C₅-C₂₀A heteroaryl group; r⁹May be substituted with one or more groups selected from: halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, aminoNitro, aldehyde, -CF₃、-CN、-SF₅、NR^aR^bCarboxy, -COR^a、-CO₂C₁-C₆Alkyl, -CONR^aR^b、-SO₂R^e、-SO₂NR^aR^b；

Wherein R is^a、R^b、R³、R⁴、R¹As defined in claim 1;

R¹And R²May be substituted by one or more of halogen, alkoxy and cyano;

R¹and R²May be linked to form a four to eight membered ring;

n is an integer of 2 to 6.

In another preferred embodiment of the present invention, the compound provided by the present invention is represented by the general formula (III),

in the formula (I), the compound is shown in the specification,

ar is a benzene ring, a five-or six-membered heteroaryl group, which Ar may be substituted with one or more groups selected from: halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, amino, nitro, aldehyde, -CF₃、-CN、-SF₅、NR^aR^bCarboxy, -COR^a、-CO₂C₁-C₆Alkyl, -CONR^aR^b、-SO₂R^e、-SO₂NR^aR^b；

R^a、R^b、R³、R⁴、R¹As defined in claim 1;

R¹and R²May be substituted by one or more of halogen, alkoxy and cyano;

R¹and R²May be linked to form a four to eight membered ring;

n is an integer of 2 to 6.

In another preferred embodiment of the invention, R¹Is C₁-C₄An alkyl group;

R²is C₁-C₆Alkyl, phenyl, C₅-C₂₀Heteroaryl, -C (O) OR^e；-SO₂R^e、-SO₂NR^aR^bor-C (O) NR^aR^b；

R^a、R^bAs defined in claim 1;

R¹and R²May be linked to form a four to eight membered ring;

R³and R⁴Each independently is hydrogen;

n is an integer of 2 to 6.

In another preferred embodiment of the present invention, the present invention provides a prodrug of said compound of formula (I), as shown in formula (IV),

in the formula (I), the compound is shown in the specification,

R¹、R²、R³、R⁴and R⁹As defined in claim 1;

R^10ais substituted or unsubstituted C₆-C₂₀Aryl, substituted or unsubstituted five-or six-membered heteroaryl, substituted or unsubstituted C₁-C₁₂Alkyl, substituted or unsubstituted C₁-C₁₂Alkoxy, substituted or unsubstituted C₃-C₁₂Cycloalkyl radical, C₃-C₁₂Cycloalkoxy, NR^aR^b(ii) a Wherein R is^a、R^bAs defined in claim 1, in accordance with claim 1,

wherein said "substituted" means having one or more substituents selected from the group consisting of: halogen, hydroxy, -NH₂Nitro, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, benzyl.

Where the compounds of the present invention exist as stereoisomers, the present invention includes all stereoisomers of the compounds.

In the case where the compounds of the present invention exist as tautomers, the present invention includes all tautomers of the compounds.

The invention also includes deuterated compounds produced by replacement of any one or more hydrogen atoms in said compounds with deuterium, which is a stable isotope thereof.

Pharmaceutical composition

The invention also provides a pharmaceutical composition comprising a safe and effective amount of the active ingredient, and a pharmaceutically acceptable carrier.

The "active ingredient" of the present invention refers to the compound of general formula (I) of the present invention or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof.

The "active ingredients" and pharmaceutical compositions described herein are useful as IDO inhibitors. In another preferred embodiment, the compound is used for preparing medicaments for preventing and/or treating tumors. In another preferred embodiment, the compound is used for preparing a medicament for preventing and/or treating IDO mediated diseases.

"safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of active ingredient per dose, more preferably, 10-200mg of active ingredient per dose. Preferably, said "dose" is a tablet.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being combined with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredient.

The compounds of the preferred embodiments of the present invention may be administered as the sole active agent or in combination with one or more other agents useful in the treatment of cancer. The compounds of the preferred embodiments of the present invention are also effective for use in combination with known therapeutic and anti-cancer agents, and combinations of presently known compounds with other anti-cancer or chemotherapeutic agents are within the scope of the preferred embodiments. Examples of such agents are found in Cancer Principles and practice Oncology, v.t. devita and s.hellman (editor), 6 th edition (2.15.2001), lippincott williams & Wilkins press. One of ordinary skill in the art will be able to identify effective combinations of agents based on the particular nature of the drug and the cancer involved. Such anti-cancer agents include (but are not limited to) the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl protein transferase inhibitors, acetylase (HDAC) inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, cell proliferation and survival signaling inhibitors, apoptosis inducing agents and agents that interfere with cell cycle checkpoints (cell cycle checkpoints), CTLA4 antibodies, PD-1 antibodies, PD-L1 antibodies, and the like. The compounds of the preferred embodiments are also effective when administered concurrently with radiation therapy.

In general, the compounds of the preferred embodiments will be administered in a therapeutically effective amount by any acceptable mode of administration of the agents having a similar effect. The actual amount of the compound (i.e., active ingredient) of the preferred embodiment will depend on a number of factors, such as the severity of the condition being treated, the age and relative health of the patient, the potency of the compound being administered, the route and form of administration, and other factors. The medicament may be administered multiple times a day, preferably once or twice a day. All of these factors are considered by the attending physician.

For purposes of the preferred embodiments, a therapeutically effective dose will generally be a total daily dose administered to a patient in one dose or in divided doses, e.g., from about 0.001 to about 1000 mg/kg body weight per day, preferably from about 1.0 to about 30 mg/kg body weight per day. A unit dose composition (Dosage unit composition) may include its Dosage factors to form a daily dose. The choice of dosage form depends on various factors, such as the mode of administration and the bioavailability of the drug substance. In general, the compounds of the preferred embodiments may be administered as pharmaceutical compositions by any of the following routes: oral, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous). The preferred mode of administration is oral, and convenient daily dosages may be adjusted to the bitter taste. The composition may take the form of a tablet, pill, capsule, semi-solid, powder, sustained release formulation, solution, suspension, elixir, aerosol, or any other suitable composition. Another preferred mode of administering the compounds of the preferred embodiments is by inhalation. This is an effective method of delivering therapeutic agents directly to the respiratory tract (see, e.g., U.S. patent No. 5,607,915).

Suitable pharmaceutically acceptable carriers or excipients include: such as treatment agents and drug delivery modifiers and enhancers, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, sodium methyl cellulose, carboxymethyl cellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting waxes, ion exchange resins, and the like, and combinations of any two or more thereof. The liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol, and various oils, including petroleum, animal oils, vegetable oils, or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose solutions, and glycols. Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, MackPub.Co., New Jersey (1991), which is incorporated herein by reference.

As used herein, the term "pharmaceutically acceptable salt" refers to a non-toxic acid or alkaline earth metal salt of a compound of formula I. These salts can be prepared in situ during the final isolation and purification of the compounds of formula I or by reacting a suitable organic or inorganic acid or base, respectively, with a basic or acidic functional group. Representative salts include, but are not limited to: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthylsulfonate, oxalate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. In addition, the nitrogen-containing basic groups may be quaternized with the following agents: alkyl halides such as methyl, ethyl, propyl, butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromide, and the like. Thus obtaining a water-soluble or oil-soluble or dispersible product. Examples of acids which may be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulphonic acid, succinic acid, citric acid. Base addition salts can be prepared in situ during the final isolation and purification of the compounds of formula I, or by reacting the carboxylic acid moiety with a suitable base (e.g., a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation) or ammonia, or an organic primary, secondary or tertiary amine, respectively. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to: ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

As used herein, the term "pharmaceutically acceptable prodrug" refers to a prodrug of the compound of those preferred embodiments, a compound that is rapidly converted in vivo to the parent compound represented by the general formula above, e.g., by hydrolysis in blood. A complete discussion is provided in "t.higuchi and v.stella, prodrugs as Novel delivery systems (Pro-drugs as Novel delivery systems), volume 14 of a.c.s.15symposium Series" and "Edward b.roche eds," Bioreversible Carriers in Drug Design, american pharmaceutical association and Pergamon press, 1987, "both of which are incorporated herein by reference.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: the conditions described in the laboratory Manual (New York: Cold Spring Harbor laboratory Press,1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are by weight.

The invention has the advantages that:

(1) provides a compound with a novel structure and a general formula (I);

(2) the compound of the invention can be used as a high-efficiency IDO enzyme inhibitor;

(3) the synthesis method is mild, simple and feasible in operation, high in yield, easy to derivatize and suitable for industrial mass production;

(4) has various pharmacological activities such as tumor resistance, neurodegenerative diseases (Alzheimer disease), anti-inflammation and the like.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

Example 1

The first step is as follows: 4-amino-nitrogen' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidines

Malonic-cyanide (3.2g,48.5mmol) was dissolved in 70mL of water and heated to complete dissolution. While cooling in an ice-water bath, sodium nitrite (3.8g,55mmol) and 6N hydrochloric acid (0.6mL) were added. After the reaction was carried out for 0.5 hour in an ice bath, the temperature was raised to room temperature and the reaction was carried out for 2 hours. The reaction solution was further cooled in an ice bath, and 50% aqueous hydroxylamine hydrochloride solution (9.9g,150mmol) was added dropwise to the reaction solution, and after stirring for half an hour, the reaction solution was warmed to room temperature and reacted for 1 hour. The reaction was heated under reflux for 2 hours, and after completion of the reaction, the pH was adjusted to 7.0 with 8mL of 6N hydrochloric acid under ice bath. The precipitate was filtered, washed once with water and once with ethyl acetate, and dried to obtain 6.0g of a white compound in a yield of 93%.

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

MS ESI:m/z＝144.0,[M+H]⁺.

The second step is that: 4-amino-nitrogen-hydroxy-1, 2, 5-oxadiazole-3-carboxamidine chloride

The first step product (4.2g,29.4mmol) was dissolved in 30mL of acetic acid, and 60mL of water, 15mL of hydrochloric acid and sodium chloride (5.2g,88.2mmol) were added, respectively. Sodium nitrite (2.0g,29.4mmol) dissolved in 7mL of water was added dropwise under ice-bath, and the reaction was maintained at zero temperature for 1 hour, after which the reaction was warmed to room temperature for 5 hours. After the reaction was completed, the precipitate was filtered, washed once with water, and dried to obtain 2.6g of a white solid compound with a yield of 55%.

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

MS ESI：m/z＝160.9,[M+H]^-.

The third step: 4-amino-nitrogen' - (3-bromo-4-fluorophenyl) -1,2, 5-oxadiazole-3-carboxamidine

To a solution of the second-step product (41.99g, 259.2mmol) in pure water (800ml) was added 3-bromo-4-fluoroaniline (54.179g, 285.12mmol) in portions at 60 ℃. The reaction mixture was stirred at 60 ℃ for 10min, and Na was added to the mixture₂CO₃(41.2g,388.8mmol) in water (500 ml). After stirring the reaction for 20min LCMS showed the reaction was complete. The reaction mixture was cooled and filtered, washed with water and dried to give a grey solid (70g, 85%).

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

The fourth step: 4-amino-nitrogen' - (3-bromo-4-fluorophenyl) -1,2, 5-oxadiazol-3-yl) -1, 2-4-oxadiazolone

The third product (70g, 221.5mmol) and CDI (39.8g, 332.173mmol) were dissolved in ethyl acetate (600ml) at room temperature and the reaction was stirred for 20min at 60 ℃; TLC monitored the reaction complete, cooled the reaction mixture to room temperature, concentrated the reaction, and slurried the residue with PE: EA ═ 4:1 to give an off-white solid (55g, 72% yield).

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

The fifth step: preparation of 4- (3-bromo-4-fluorophenyl) -3-4- (((2-methylthio) ethyl) amino) -1,2, 5-oxadiazol-3-yl) -1, 2-4-oxadiazolone

4-amino-nitrogen' - (3-bromo-4-fluorophenyl) -1,2, 5-oxadiazol-3-yl) -1, 2-4-oxadiazolone (3.0g, 8.8mmol) was dissolved in DCM (20ml) at room temperature, triethylsilane (3.1g, 26.3mmol) and methanesulfonic acid (2.4g,26.3mmol) were added, the temperature was reduced to 0 ℃ in an ice bath, and 2, 2-dimethoxymethylthioethane (2.4g, 17.5mmol) was added dropwise. After completion of the reaction at room temperature for 2 hours, the reaction solution was adjusted to pH 7 with saturated aqueous sodium bicarbonate, the organic phase was washed with water (20 mL. times.3) and saturated brine (20 mL. times.3), the organic phase was separated, dried and concentrated to give a brown solid (3.5g, 96%).

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

And a sixth step: 4- (3-bromo-4-fluorophenyl) -3-4- (((2-methylthio) ethyl) tert-butoxycarbonylamino) -1,2, 5-oxadiazol-3-yl) -1, 2-4-oxadiazolone

The product of the fifth step (50mg,0.120mmol) was dissolved in THF (2ml), di-tert-butyl dicarbonate (131mg,0.601mmol) was added, a catalytic amount of 4-dimethylaminopyridine (2mg) was added, the reaction was stirred in an ice bath until completion, water (10ml) was added and extracted with ethyl acetate (10 ml. times. 3), washed with water (5ml) and saturated brine (5ml) and dried over sodium sulfate, and purified by column chromatography to give a white solid (60mg, 100% yield).

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

The seventh step: (±)4- (3-bromo-4-fluorophenyl) -3-4- (((2- (methyl sulfoxide) ethyl) tert-butyloxycarbonylamino) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazolone

The product of the sixth step (2.0g,3.9mmol) was dissolved in 20mL of dichloromethane and 2mL of methanol, MMPP (1.06g,2.15mmol) was added under ice bath, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, 20mL of water was added, extraction was performed 3 times with ethyl acetate, the organic layers were combined, washed three times with water (10mL), once with saturated sodium chloride (10mL), the solvent was spin-dried, and drying was performed to obtain 1.6g of a yellow solid with a yield of 77%.

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

Eighth step: (±)4- (3-bromo-4-fluorophenyl) 3-4- (((2- (methyl trifluoroacetyl sulfoxide imine) ethyl) tert-butyloxycarbonylamino) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazolone

The product of the seventh step (330mg,0.620mmol) was added to a reaction flask, and CF was added₃C(O)NH₂(140mg,1.240mmol), MgO (99mg,2.479mmol) and Rh (OAc)₂(10mg), stirred at room temperature for one minute, PhI (OAc) added₂(309mg,0.930mol), stirred at room temperature until completion of the reaction as monitored by TLC. Water (10ml) was added to the reaction, which was extracted with ethyl acetate (10 ml. times. 3), washed with water (10ml) and saturated brine (10ml), and dried over anhydrous sodium sulfate. Column chromatography separation and purification gave the title compound (300mg, 75% yield).

The ninth step: (±)4- (3-bromo-4-fluorophenyl) 3-4- (((2- (methyl sulfoxide imine) ethyl) tert-butyloxycarbonylamino) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazolone

The product of the eighth step (330mg,0.513mmol) was dissolved in methanol (5ml), and potassium carbonate (142mg,1.026mmol) was added under ice-bath and stirred for 15 min. TLC showed reaction complete, n-hexane: ethyl acetate 1: 1. The reaction was filtered, the filter cake was washed with dichloromethane (10ml x2), and the filtrate was concentrated to give a white color (280mg, 99% yield).

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

The tenth step: (±)4- (3-bromo-4-fluorophenyl) 3-4- (((2- (methyl sulfoxide methyl imine) ethyl) tert-butyloxycarbonylamino) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazolone

The product of the ninth step (20mg,0.037mmol) was dissolved in dichloromethane (2ml), trimethyloxonium tetrafluoroborate (8mg,0.055mmol) was added and stirred at room temperature for 2 hours, TLC showed reaction completion, water (10ml), ethyl acetate (10ml) were added to the reaction solution, then the organic phases were combined by extraction with ethyl acetate (10ml x2), then washed with water (10ml), brine (10ml) and dried over sodium sulphate. After concentration, column chromatography separation and purification, the target compound (10mg, 48% yield) was obtained.

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

The eleventh step: (±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (N, S-dimethyl sulfoxide imine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

The product of the tenth step (20mg,0.037mmol) was dissolved in dichloromethane (1ml), 10N hydrogen chloride/ethanol solution (2ml) was added and stirred at room temperature for 2 hours, after completion of the reaction, it was directly concentrated to dryness, the residue was dissolved in tetrahydrofuran (2ml), 2M aqueous sodium hydroxide solution (0.2ml) was added and stirred at room temperature for 30 minutes. TLC showed the reaction was complete (dichloromethane: methanol 20:1), pH 5 was adjusted by addition of 2M hydrochloric acid, water (10ml), ethyl acetate (10ml) was added to the reaction solution, the organic phases were combined and extracted with ethyl acetate (10ml x2), then washed with water (10ml), washed with saturated brine (10ml) and dried over sodium sulphate. After concentration, column chromatography separation and purification, the target compound (10mg, 52% yield) was obtained.

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

MS(ESI):[M+H]⁺m/z＝435.0

Example 2

The procedure of example 1 was followed, substituting the reagent of the tenth step with triethyloxonium tetrafluoroborate, and applying the conditions of the tenth step to obtain the target compound.

¹H NMR:(400MHz,acetone-d₆):10.85(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

Example 3

(±) (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- (2- (thio-methyl-aza-phenylsulfoxide) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

The first step is as follows: (±)4- (3-bromo-4-fluorophenyl) 3-4- (((2- (methyl sulfoxide phenyl imine) ethyl) tert-butyloxycarbonylamino) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazolone

The product of the ninth step of example 1 (20mg,0.037mmol) was dissolved in dichloromethane (2mL), phenylboronic acid (8mg,0.055mmol) was added, copper acetate (5mg) was stirred at room temperature for 2h, TLC showed completion of the reaction, water (10mL), ethyl acetate (10mL) was added to the reaction, the combined organic phases were extracted with ethyl acetate (2 × 10mL), then washed with water (10mL), brine (10mL) and dried over sodium sulfate. Concentrating, separating and purifying by column chromatography to obtain target compound (15mg, 66% yield)

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

The second step is that: (±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-N-phenylsulfoxylimine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

The first step product (10mg,0.016mmol) was dissolved in dichloromethane (1mL), 10M hydrogen chloride/ethanol solution (2mL) was added and stirred at room temperature for 2 hours, after completion of the reaction, the mixture was directly concentrated to dryness, the residue was dissolved in tetrahydrofuran (2mL), 2M aqueous sodium hydroxide solution (0.2mL) was added and stirred at room temperature for 30 minutes. TLC showed the reaction was complete, 2M hydrochloric acid was added to adjust PH to 5, water (10mL), ethyl acetate (10mL) was added to the reaction solution, then the organic phases were combined and extracted with ethyl acetate (2 × 10mL), then washed with water (10mL), brine saturated (10mL) and dried over sodium sulfate. Concentrating, separating and purifying by column chromatography to obtain the target compound (5mg, 63% yield)

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

MS(ESI):[M+H]⁺m/z＝497.0

Example 4

The first step is as follows: (±)4- (3-bromo-4-fluorophenyl) 3-4- (((2-thio-methyl-N- (anilino formyl) sulfoxide imine) ethyl) tert-butyloxycarbonylamino) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazolone

The product of the ninth step of example 1 (20mg,0.037mmol) was dissolved in tetrahydrofuran (2mL), phenyl isocyanate (9mg,0.073mmol) was added and stirred overnight at room temperature, aqueous sodium bicarbonate (10mL) ethyl acetate (10mL) was added, extraction was performed with ethyl acetate (10mL x2), the organic phases were combined, washed with water (10mL), brine (10mL) and the organic phase was concentrated. Column chromatography separation and purification to give the title compound (20mg, 82% yield)

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

The second step is (+/-) 4- (3-bromo-4-fluorophenyl) 3-4- (((2-sulfur-methyl-nitrogen- (anilino formyl) sulfoxide imine) ethyl) tert-butyloxycarbonylamino) -1,2, 5-oxadiazole-3-yl) -1,2, 4-oxadiazolone

The first step product (20mg,0.030mmol) was added to 10N HCl/EtOH (3ml) and stirred at room temperature for 3 hours. After completion of the reaction, it was directly concentrated to dryness to give the objective compound (20mg, 100% yield)

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

The third step is (+/-) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methyl-N- (anilino formyl) sulfoxide imine) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine

The second step product (20mg,0.035mmol) was dissolved in tetrahydrofuran (2mL), and 2M aqueous sodium hydroxide (0.2mL) was added and stirred at room temperature for 30 minutes. TLC showed the reaction was complete, pH was adjusted to 5 by addition of 2mol/L hydrochloric acid, water (10mL), ethyl acetate (10mL) was added to the reaction solution, the organic phases were combined and extracted with ethyl acetate (2 × 10mL), then washed with water (10mL), brine saturated (10mL) and dried over sodium sulfate. Concentrating, separating and purifying by column chromatography to obtain target compound (10mg, 52% yield)

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

MS(ESI):[M+H]⁺m/z＝540.1

Example 5

The first step is as follows: preparation of (+ -) - (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methyl-aza- (carbonylimidazole) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (compound R):

(±) (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methylsulfoxide) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (500mg,1.19mol) was dissolved in 20mL ethyl acetate at room temperature, carbonyldiimidazole (579mg,3.57mmol) was added, followed by stirring at 60 ° for 5 hours, the solvent was evaporated to dryness, 20mL water was added, extraction was performed with ethyl acetate (3 × 30mL), the organic layers were combined, saturated brine system, dried over anhydrous sodium sulfate, filtered, concentrated, passed through a column (dichloromethane: methanol ═ 100:5), concentrated, and dried to give a white solid.

¹H NMR(400MHz,acetone-d₆):8.09(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)。

The second step is that: (±) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methyl-N- (formyl methyl ester) sulfoxide imine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

The first step product (30mg,0.055mmol) was dissolved in 3mL of methanol and 1mL of 2N sodium hydroxide solution was added under ice bath. After stirring at room temperature for 1 hour, pH was adjusted to 7 with 6N hydrochloric acid solution, 20mL of water was added, extraction was performed with ethyl acetate (3 × 20mL), organic layers were combined, water and saturated brine were washed once each, the solvent was concentrated, and preparative column chromatography (DCM: MeOH ═ 20:1) was performed to obtain the objective compound (10mg, 38%).

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

MS(ESI):[M+H]⁺m/z＝480.7

Example 6

The preparation process according to example 5 was followed by dissolving the product of the first step of example 5 (30mg,0.055mmol) in 3mL of ethanol and adding 1mL of 2N sodium hydroxide solution under ice bath. After stirring at room temperature for 1 hour, pH was adjusted to 7 with 6N hydrochloric acid solution, 20mL of water was added, extraction was performed with ethyl acetate (3 × 20mL), organic layers were combined, water and saturated brine were washed once each, the solvent was concentrated, and preparative column chromatography (DCM: MeOH ═ 20:1) was performed to obtain the objective compound (14mg, 51%).

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

MS(ESI):[M+H]⁺m/z＝494.7

Example 7

The procedure of example 5 was followed, the product of the first step of example 5 (30mg,0.055mmol) was dissolved in 3mL of isopropanol and 1mL of 2N sodium hydroxide solution was added under ice bath. After stirring at room temperature for 1h, pH was adjusted to 7 with 6N hydrochloric acid solution, 20mL of water was added, extraction was performed with ethyl acetate (3 × 20mL), organic layers were combined, water and saturated brine were washed once each, the solvent was concentrated, and preparative column chromatography (DCM: MeOH ═ 20:1) gave compound TM (10mg, 37%).

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

MS(ESI):[M+H]⁺m/z＝506.7

Example 8

The product of the ninth step of compound example 1 (30mg,0.055mmol) and triethylamine (15uL) were dissolved in 3mL dichloromethane and methanesulfonyl chloride (6.4uL) was added under ice bath and after ten minutes of reaction, 20mL water was added and quenched, extracted with dichloromethane (3 × 20mL), the organic layers were combined, washed once with brine, dried, filtered, the solvent was spun dry and the column was passed (DCM: MeOH ═ 100:5) to give 35mg crude product. The crude product (35mg,0.056mmol in 1mL dichloromethane and 1mL trifluoroacetic acid reacted at room temperature for three hours. spin dry solvent, add water 20mL, extract with dichloromethane (3 × 20mL), combine organic layers, wash with brine, dry over anhydrous sodium sulfate, filter, spin dry crude product (25 mg). the previous step crude product was dissolved in 2mL tetrahydrofuran solution, add 0.5mL2N aqueous sodium hydroxide, stir at room temperature for 0.5 hours, adjust to pH 7 with 2NHCl, add water 20mL, extract with ethyl acetate (3 × 20mL), and combine organic layer, wash with brine, dry over anhydrous sodium sulfate, filter, spin dry, column (DCM: MeOH 100:5) to give a white solid (20mg, 84%)

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

MS(ESI):[M+H]⁺m/z＝499.0

Example 9

(±) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methyl-N-cyanosulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (20mg,0.045mmol) was dissolved in 2mL of DMSO solution under ice bath, and anhydrous potassium carbonate (63mg,0.45mmol) was added thereto, and 0.5mL of hydrogen peroxide was slowly added dropwise and reacted at room temperature for 0.5 hour. After addition of 20mL of aqueous sodium thiosulfate solution, after quenching, extraction with dichloromethane (3 × 20mL) was performed, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, spun-dried, column-passed (DCM: MeOH ═ 100:5), spun-dried to give a white solid (14mg, 67%)

¹H NMR(400MHz,CDCl₃): 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

EXAMPLE 10 resolution of chiral isomers

Chiral resolution was performed using an agilent 1260 semi-preparative liquid chromatograph:

resolution of example 1:

chiral column: xylonite CHIRALCEL IC 4.6.6 × 250mm, filler particle size 5 μm; the flow rate is 1 ml/min; the detection wavelength is 254 nm; collecting the single enantiomer;

condition 1: 1mg of the sample of example 1 was dissolved in 1ml of a mixed solution of n-Hexane and isopropyl alcohol (Hexane: iPrOH 8:2) in an amount of 10 μ l, and Hexane: EtOH 88:12 (volume ratio) was eluted; the peak emergence times of the two optical isomers are 14.251 minutes and 16.905 minutes respectively;

condition 2: 1mg of the sample of example 1 was dissolved in 1ml of a mixed solution of n-Hexane and isopropyl alcohol (Hexane: iPrOH: 8:2) in an amount of 10 μ l, and the eluate (Hexane: iPrOH: 75:25 by volume) was added; the peak times of the two optical isomers were 11.180 minutes and 13.978 minutes, respectively.

Resolution of example 2:

condition 1: 200 microliters of the DMSO solution of example 2 (10mmol/L) was diluted to 1mL with isopropanol, and the sample was taken in an amount of 10 μ L, and the eluent Hexane: EtOH 88:12 (volume ratio); the peak emergence times of the two optical isomers are 11.188 minutes and 13.786 minutes respectively;

condition 2: 200 microliters of the DMSO solution of example 2 (10mmol/L) was diluted to 1mL with isopropanol, and the sample was taken in an amount of 10 μ L, and the eluate, Hexane: iPrOH, was 80:20 (volume ratio); the peak times of the two optical isomers were 11.655 minutes and 15.261 minutes, respectively.

Resolution of example 3:

chiral column: xylonite CHIRALCEL OD-H4.6 x 250mm, filler particle size 5 μm; the flow rate is 1 ml/min; the detection wavelength is 254 nm; collecting the single enantiomer;

conditions are as follows: 1mg of the sample of example 3 was dissolved in 1ml of a mixed solution of n-Hexane and isopropyl alcohol (Hexane: iPrOH: 8:2) in an amount of 5 μ l, and the eluate (Hexane: EtOH: 60: 40) (volume ratio); the peak times of the two optical isomers were 9.842 minutes and 16.879 minutes, respectively.

Example 11

Activity assay

(1) Induced expression and purification method of IDO protein

Firstly, amplifying an IDO gene by PCR, recovering an amplified PCR product, then carrying out enzyme digestion (37 ℃ and 2h) on pET28a plasmid (purchased from Shanghai Baumann Biotechnology Co., Ltd.) and an IDO gel recovery product by two restriction enzymes of EcoR I and Xho I, running gel, recovering, linking a T4 ligase and connecting the overnight ligation product to DH5 alpha competent state, placing on ice for 30min, carrying out heat shock at 42 ℃ for 90s, carrying out bacteria shaking and plate coating, selecting a single clone, carrying out PCR identification and sequencing identification, and ensuring that the product is all correct, namely the construction of pET28a-IDO plasmid is successful.

The constructed plasmid BL21 containing pET28a-IDO was shaken up to OD at 37 ℃₆₀₀0.6-0.8, adding hemin and 1mM IPTG (isopropyl- β -D-thiogalactoside) to a final concentration of 7 μ M, inducing at 28 deg.C for 4 hr, centrifuging at 4 deg.C and 6000rpm, collecting thallus, washing with 20mM PBS (pH6.5), and centrifuging to collect thallus.

Resuspending the collected thallus with lysis solution (20mM PBS pH6.5), ultrasonically lysing (power 40% lysis for 20min, placing on ice), centrifuging the lysed bacteria at 13000rpm for 15min, discarding the precipitate, and retaining the supernatant; the nickel column was equilibrated with lysis buffer (20mM PBS ph6.5) for 3 column volumes, then the lysis supernatant was loaded onto the nickel column, after which the 4 column volumes were washed with rinsing solution (20mM PBS ph6.5, 20mM imidazole), and finally the protein was eluted with eluent (20mM PBS ph6.5, 250mM imidazole); dialyzing the eluted protein solution for 4h, wherein the dialyzed solution is 20mM PBS pH6.5, concentrating the protein sample after dialysis, subpackaging, quick-freezing with liquid nitrogen, and storing at-80 ℃ for later use.

(2) Method for testing IDO enzyme inhibitory activity

Firstly, carrying out 3-time gradient dilution on a compound, and adding 1 mu L of each concentration into a 96-well plate; add 50. mu.L of the prepared IDO enzyme solution (final concentration 600 ng/100. mu.L): the reaction was initiated by adding 25. mu.L of the substrate 1 mixture and 25. mu.L of the substrate 2 mixture. Finally the OD321nm was read for 60 min.

(3) Cell activity test method

Hela cells (100. mu.L) were seeded in 96-well plates in an amount of 5 × 10 per well³And grown overnight. The following day, 1. mu.L of the diluted compound was added to a 96-well plate, and then 100. mu.L of a medium containing human interferon γ (final concentration 50ng/mL) was added to the 96-well plate to make a final volume of 200. mu.L. After 48 hours incubation, 140 μ L of supernatant was taken from each well and transferred to a new 96-well plate. mu.L of 6.1N trichloroacetic acid was added to each well and mixed, incubated at 50 ℃ for 30 minutes and the IDO catalyzed the N formyl canine urea to canine urea. The reaction mixture was centrifuged at 2500 rpm for 10 minutes to remove the precipitate. 100 μ L of supernatant per well was transferred to a new 96 well plate and mixed with 100 μ L of 2% dimethylaminobenzaldehyde acetic acid solution. After isolation of the canine urea, values were determined at 480nm using SPECTRAMaxi3 reader.

The results of the test for IDO enzyme inhibitory activity and cytostatic activity of each compound are shown in table 1.

TABLE 1 IDO enzyme and cytostatic Activity test results

The above results indicate that the compounds of the present invention (including racemates and enantiomers) all have excellent inhibitory activity against IDO enzyme and cells, and particularly that compound 2 has unexpectedly high activity in IDO cell inhibitory activity.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer thereof:

in the formula (I), the compound is shown in the specification,

R⁷and R⁸Each independently hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₂-C₁₀Alkenyl, substituted or unsubstituted C₃-C₁₀Alkynyl, substituted or unsubstituted C₆-C₂₀Aryl, or substituted or unsubstituted C₃-C₁₄A heteroaryl group; r⁷And R⁸May together form a three to eight membered ring wherein the heteroatom may be sulfur, oxygen, NH or NR^f；R⁹Is C₆-C₂₀Aryl radical, C₅-C₂₀A heteroaryl group; r⁹May be substituted with one or more groups selected from: halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, amino, nitro, aldehyde, -CF₃、-CN、-SF₅、NR^aR^bCarboxy, -COR^a、-CO₂C₁-C₆Alkyl, -CONR^aR^b、-SO₂R^e、-SO₂NR^aR^b、-P(O)Me₂、-P(O)(OMe)₂(ii) a Wherein each R^aAnd each R^bEach independently hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₂-C₁₀Alkenyl, substituted or unsubstituted C₆-C₂₀Aryl, or substituted or unsubstituted C₃-C₁₄A heteroaryl group; r^aAnd R^bMay together form a four to eight membered heterocyclic ring in which the heteroatom may be sulfur, oxygen, NH or NR^g；

R²is-C (O) OR^e、-SO₂R^e、-SO₂NR^aR^bor-C (O) NR^aR^b；

X is a single bond, OS, NH or NR^d；

R³And R⁴Each independently hydrogen, substituted or unsubstituted C₁-C₁₀An alkyl group; r³And R⁴May together form a three to eight membered ring wherein the heteroatom may be sulfur, oxygen, NH or NR^h；

n is an integer of 2 to 8;

m is 0, 1 or 2;

wherein said "substituted" or "substituted" means that said group has one or more substituents selected from the group consisting of: halogen, hydroxy, -NH₂Nitro, -CN, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₃-C₆Cycloalkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, phenyl, benzyl.

2. The compound of formula (I) according to claim 1, wherein the compound is of formula (II),

in the formula (I), the compound is shown in the specification,

Wherein R is^a、R^b、R^e、R³、R⁴、R¹As defined in claim 1;

R²is-C (O) OR^e、-SO₂R^e、-SO₂NR^aR^bor-C (O) NR^aR^b；

n is an integer of 2 to 6.

3. The compound of formula (I) according to claim 1, wherein the compound is of formula (III),

in the formula (I), the compound is shown in the specification,

R²is-C (O) OR^e、-SO₂R^e、-SO₂NR^aR^bor-C (O) NR^aR^b；

R^a、R^b、R^e、R³、R⁴、R¹As defined in claim 1;

n is an integer of 2 to 6.

4. A compound of formula (III) according to claim 3, wherein R is¹Is C₃-C₄An alkyl group;

R²is-C (O) OR^e、-SO₂R^e、-SO₂NR^aR^bor-C (O) NR^aR^b；

R^a、R^b、R^eAs defined in claim 1;

R³and R⁴Each independently is hydrogen;

n is an integer of 2 to 6.

5. A compound or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, wherein the compound is:

(±) (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (1-oxo-3, 4,5, 6-tetrahydro-1. lambda.)⁶2-thiazin-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

(±) (Z) -aza- (3-chloro-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methyl-aza- (carbamoyl) sulfoximine) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine.

6. The compound of claim 1 or claim 5, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, hydrobromide, sulphate, phosphate, methanesulphonate, trifluoromethanesulphonate, benzenesulphonate, p-toluenesulphonate, 1-naphthalenesulphonate, 2-naphthalenesulphonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, mandelate.

7. Use of a compound as claimed in claim 1 or claim 5 for:

(i) preparing indoleamine-2,3-dioxygenase inhibitor;

(iii) Preparing the anti-inflammatory medicine.

8. The use according to claim 7, wherein the indoleamine-2,3-dioxygenase mediated disease is cancer, a neurodegenerative disease, an eye disease, a psychogenic disorder and/or an autoimmune disease.

9. The use of claim 8, wherein the neurodegenerative disease is senile dementia.

10. The use according to claim 8, wherein the disorder of the heart is depression, anxiety.

11. A pharmaceutical composition, comprising:

a compound of claim 1 or claim 5, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof; and a pharmaceutically acceptable carrier and/or an anti-tumor drug.