WO2017152857A1 - Indoleamine-2,3-dioxygenase inhibitor containing nitrogen alkylated and arylated sulphoxide imines - Google Patents

Abstract

Disclosed in the present invention are an indoleamine-2,3-dioxygenase inhibitor and a preparation method therefor. The structure of the inhibitor of the present invention is shown in general formula (I), wherein the definitions of X, R¹, R², R³, R⁴, R⁷, R⁸, R⁹, n and m are as shown in the description and the claims. Also disclosed in the present invention is a preparation method for the inhibitor. The compound in general formula (I) of the present invention can be used as an indoleamine-2,3-dioxygenase inhibitor for the preparation of a drug for preventing and/or treating diseases mediated by indoleamine-2,3-dioxygenase.

Description

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

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

Background technique

Indoleamine-2,3-dioxygenase (IDO) is a monomeric enzyme containing heme found in the cell for the first time in 1967 by the Hayaishi group. The cDNA encodes a protein. 403 amino acid composition with a molecular weight of 45 kDa, which is the rate-limiting enzyme of the leucine-kynurenine pathway catabolism and has extensive expression in a variety of mammalian tissues (Hayaishi O. et al Science, 1969, 164, 389-396). In tumor cells, IDO often plays an important physiological role in inducing tumor microenvironmental immune tolerance, and its mediated tryptophan (Trp)-kynurenine (Kyn) metabolic pathway is involved in tumors. Immune escape, and IDO also plays an important role as an immune tolerance to induce tumor microenvironment.

Tryptophan is one of the important essential amino acids in mammals. It needs to be ingested in large quantities from food, maintain cell activation and proliferation, and synthesize proteins and some neurotransmitters. Therefore, its lack of dysfunction can lead to some important cells. IDO can catalyze the conversion of tryptophan to N-formyl kynurenine in vivo, degrading the content of tryptophan and causing deficiency of tryptophan in vivo, leading to tumor formation. Immunohistological studies have shown that the kynurenine pathway can lead to an increase in the excitotoxic quinolinic acid, as well as many serious human diseases such as Alzheimer's and other neurological diseases (Guillemin GJet al Neuropathol. and Appl. Neurobiol. 2005, 31, 395–404).

There are two main types of tryptophan rate-limiting enzymes in mammals: tryptophan dioxygenase (TDO) and IDO. In 1937, Kotake et al. purified proteins from rabbit intestines and found that TDO was mainly expressed in mammalian liver. It has not been found to be closely related to the immune system. TDO catalyzes the kynurenine pathway and converts tryptophan to N-formyl kynurenine [Higuchi K. et al J. Biochem. 1937, 25, 71-77; Shimizu T. et al J. Biol. Chem. 1978, 253, 4700-4706]. In 1978, the enzyme purified from the intestinal tract of rabbits was identified as a dioxygenase (IDO) containing heme, which is the only one outside the liver that can catalyze the oxidative cleavage of sputum in tryptophan molecules. An enzyme that catabolizes the lysine pathway. IDO is usually expressed in organs with more mucosa, such as the lung, small intestine and large intestine, rectum, spleen, kidney, stomach and brain. It is widely distributed (Hayaishi O. et al, Proceedings of the Tenth FEBS meeting, 1975, 131–144). Under certain special or pathological conditions, such as pregnancy, chronic infection, organ transplantation and tumors, IDO expression will increase significantly, and participate in mediating local immunosuppression.

Studies have shown that IDO can inhibit local T cell immune responses in the tumor microenvironment by: tryptophan depletion, toxic metabolism, and induction of regulatory T cell proliferation. In many cases, it is transiently expressed in tumors, thereby consuming local tryptophan and producing a large amount of metabolites such as kynurenine. In fact, in the absence of tryptophan or kynurenine culture conditions, T cells undergo proliferation inhibition, decreased activity, and even apoptosis. In T cells, there is a regulatory point that is very sensitive to the level of tryptophan. Under the action of IDO, tryptophan can be consumed, which leads to the arrest of T cells in the middle phase of G1, thereby inhibiting the proliferation of T cells and inhibiting the proliferation of T cells. The immune response of T cells. Once T cells stop proliferating, they may not be stimulated any more. This is IDO in vivo. Internal immune 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).

There is a need in the art to develop highly active novel IDO inhibitors, and the present inventors have discovered that a novel class of compounds containing nitrogen alkylated and arylated sulfoximines and 1,2,5-oxadiazole structures are unexpected. High IDO inhibitory activity.

Summary of the invention

It is an object of the present invention to provide a novel compound containing a nitrogen alkylated and arylated sulfoximine and a 1,2,5-oxadiazole structure as a highly potent 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 invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug:

In the formula,

R ⁷ and R ⁸ are each independently hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, a substituted or unsubstituted C ₃ -C ₁₀ alkynyl group, a substituted or unsubstituted C ₆ -C ₂₀ aryl group, or a substituted or unsubstituted C ₃ -C ₁₄ heteroaryl group; R ⁷ and R ⁸ may be formed together a three to eight membered ring or a three to eight membered heterocyclic ring wherein the hetero atom can be sulfur, oxygen, NH or NR ^f ;

R ⁹ is C ₆ -C ₂₀ aryl, C ₅ -C ₂₀ heteroaryl; R ⁹ may be substituted by one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxy, hydroxy, amino, nitro, aldehyde, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxy, -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, - CONR ^a R ^b , -SO ₂ R ^e , -SO ₂ NR ^a R ^b , -P(O)Me ₂ , -P(O)(OMe) ₂ ; wherein each R ^a and each R ^b are independently hydrogen, Substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, substituted or unsubstituted C ₆ -C ₂₀ An aryl group, or a substituted or unsubstituted C ₃ -C ₁₄ heteroaryl group; R ^a and R ^b may together form a three to eight membered ring or a four to eight membered heterocyclic ring, wherein the hetero atom may be sulfur, oxygen, NH or NR ^g ;

R ² is C ₁ -C ₁₂ alkyl, C ₆ -C ₂₀ aryl, C ₅ -C ₂₀ heteroaryl, C ₁ -C ₄ alkyl-phenyl, C ₁ -C ₄ alkyl-C5 heterocyclic , -C(O)OR ^e ; -SO ₂ R ^e , -SO ₂ NR ^a R ^b , -C(O)NR ^a R ^b , or a C ₃ -C ₁₂ cycloalkyl group;

X is a single bond, O, S, NH or NR ^d ;

Ring A is a 5- or 6-membered heterocyclic ring;

R ³ and R ⁴ are each independently hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl; R ³ and R ⁴ may together form a three to eight membered ring or a three to eight membered heterocyclic ring, wherein the hetero atom may be Sulfur, oxygen, NH or NR ^h ;

R ¹ , R ^d , R ^e , R ^f , R ^g , R ^{h are} independently C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₂₀ aryl, or C ₃ -C _C14 heteroaryl group; R ¹ may be substituted by one or more radicals from the group consisting of: halogen, hydroxy, amino, nitro, cyano, aldehyde, carboxyl, alkoxy, -CF _3, -SF ₅ ;

R ¹ and R ² may be substituted by one or more halogen, alkoxy and cyano groups;

R ¹ and R ² may be bonded to form a four to eight membered ring;

R ¹ and R ^d may be joined to form a six to eight membered ring;

R ¹ and R ³ may be bonded to form a five to eight membered ring;

n is an integer from 2 to 8;

m is 0, 1, or 2.

In another preferred embodiment, the "substitution" means having one or more substituents selected from the group consisting of halogen, hydroxy, -NH ₂ , nitro, -CN, C ₁ -C ₄ alkyl, C _1- C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, phenyl, benzyl.

In another preferred embodiment, R ² is C ₁ -C ₁₂ alkyl, C ₆ -C ₂₀ aryl, C ₅ -C ₂₀ heteroaryl, -SO ₂ R ^e , or -C(O)NR ^a R ^b .

In another preferred embodiment, the structure of formula (I) is as shown in formula Ia:

In another preferred embodiment, R ³ and R ⁴ are each independently hydrogen,

In another preferred embodiment, n is from 2 to 6.

In another preferred embodiment, X is NH.

In another preferred embodiment, m is zero.

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

In the formula,

R ⁹ is C ₆ -C ₂₀ aryl, C ₅ -C ₂₀ heteroaryl; R ⁹ may be substituted by one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxy, hydroxy, amino, nitro, aldehyde, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxy, -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, - CONR ^a R ^b , -SO ₂ R ^e , -SO ₂ NR ^a R ^b ;

Wherein R ^a , R ^b , R ³ , R ⁴ , R ¹ are as defined above;

R ² is C ₁ -C ₁₂ alkyl, C ₆ -C ₂₀ aryl, C ₅ -C ₂₀ heteroaryl, -C(O)OR ^e ; -SO ₂ R ^e , -SO ₂ NR ^a R ^b , -C(O)NR ^a R ^b , or a C ₃ -C ₁₂ cycloalkyl group;

n is 2-6.

In another preferred embodiment, the compound is as shown in the formula (III).

In the formula,

Wherein R ³ , R ⁴ , and R ¹ are as defined above;

R ² is C ₁ -C ₁₂ alkyl, C ₆ -C ₂₀ aryl, C ₅ -C ₂₀ heteroaryl, -C(O)OR ^e ; -SO ₂ R ^e , -SO ₂ NR ^a R ^b or -C(O)NR ^a R ^b , C ₃ -C ₁₂ cycloalkyl;

R ¹ and ² may be substituted by one or more halogen, alkoxy and cyano groups

Ar is a C ₆ -C ₁₀ aryl, five- or six-membered heteroaryl; Ar may be substituted by one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, hydroxy, -CF ₃ , -CN, -SF ₅ .

n is 2-6.

In another preferred embodiment, R ¹ is C ₁ -C ₁₀ alkyl;

R ² is C ₁ -C ₁₂ alkyl, C ₆ -C ₂₀ aryl, C ₅ -C ₂₀ heteroaryl, -SO ₂ R ^e , -SO ₂ NR ^a R ^b , -C(O)NR ^a R ^b or a C ₃ -C ₁₂ cycloalkyl group;

R ³ and R ⁴ are each independently hydrogen;

Ar is a C ₆ -C ₁₀ aryl, five- or six-membered heteroaryl; R ⁹ may be substituted by one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, amino, nitro, aldehyde, -CF ₃ , -CN, -SF ₅ .

In another preferred embodiment, R ¹ is C ₁ -C ₄ alkyl;

Ar is a C ₆ -C ₁₀ aryl, five- or six-membered heteroaryl; R ⁹ may be substituted by one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, -CF ₃ , -CN, -SF ₅ .

In another preferred embodiment, the prodrug of the compound of formula I is as shown in formula (IV),

In the formula,

R ¹ , R ² , R ³ , R ⁴ and R ⁹ are as defined above;

R ^10a is a substituted or unsubstituted C ₆ -C ₂₀ aryl group, a substituted or unsubstituted five- or six-membered heteroaryl group, a substituted or unsubstituted C ₁ -C ₁₂ alkyl group, a substituted or unsubstituted C ₁ -C ₁₂ alkoxy, substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkoxy, NR ^a R ^b ; wherein R ^a , R ^b are as defined above;

Wherein said "substituted" means having one or more substituents selected from the group consisting of halogen, hydroxy, -NH _2, nitro, -CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkane A C ₁ -C ₄ alkoxy group, a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₄ alkenyl group, a C ₂ -C ₄ alkynyl group, a phenyl group, a benzyl group.

In another preferred embodiment, each of groups such as X, R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , R ^10a and the like are independently the formula (I) prepared in the examples, Corresponding groups in each of the specific compounds of (II), (III) and (IV).

In another preferred embodiment, the compound is:

(±)(Z)-N-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(nitrogen, thio-dimethyl sulfoximine)ethyl)amino) -1,2,5-oxadiazole-3-carboquinone

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

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

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

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

(±)(Z)-N-(3-bromo-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro)(2,2,2-trifluoroethyl Sulfoxide imine) ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

(±)(Z)-N-(3-bromo-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro)(3,3,3-trifluoropropyl) Sulfimide Ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

(±)(Z)-N-(3-bromo-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro(2-difluoroethyl)) sulfoxide Amine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

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

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

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

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

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

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

(±)(Z)-N-(3-bromo-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(isopropylcarbamoyl)) Sulfimide imine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

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

(±)(Z)-N-(3-bromo-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(formylisopropyl)) sulfoxide) Amine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

(±)(Z)-N-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(sulfo-methyl-nitro-(nitro-phenylaminosulfonyl)) sulfoxide Imine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

(±)(Z)-N-(3-chloro-4-fluorophenyl)-nitro'-hydroxy-4-((2-(nitrogen, thio-dimethylsulfoxideimine)ethyl)amino) -1,2,5-oxadiazole-3-carboquinone

(±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitroethyl sulfoximine)ethyl)amino )-1,2,5-oxadiazole-3-carboquinone

(±)(Z)-N-(3-chloro-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methyl-nitroisopropyl sulfoximine) ethyl) Ammonia 1,1,2,5-oxadiazole-3-carboquinone

(±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-aza-isobutyl sulfoximine)ethyl) Amino)-1,2,5-oxadiazole-3-carboxamidine

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

(±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro(2,2,2-trifluoroethyl) Sulfoxide imine) ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

(±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro)(3,3,3-trifluoropropyl) Sulfoxide imine) ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

(±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro(2-difluoroethyl)) sulfoxide Amine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

(±)(Z)-N-(3-chloro-4-fluorophenyl)-nitro'-hydroxy-4-((2-(1-oxo-3,4,5,6-tetrahydro-1λ ^{6 )} ,2-thiazin-1-yl)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

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

(±)(Z)-N-(3-chloro-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methyl-nitro-(4-fluorophenylsulfoximine) Ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

(±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(methylaminocarbonyl) sulfoxide) Imine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

(±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(isopropylcarbamoyl))) Sulfimide imine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

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

(±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(formylisopropyl)) sulfoxide) Amine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

(±)(Z)-N-(3-chloro-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methyl-nitro-(phenylsulfonyl) sulfoximine)) Amino)-1,2,5-oxadiazole-3-carboxamidine

(±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(nitro-phenylaminosulfonyl)) sulfoxide Imine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

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

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

(±)(Z)-N-(3-trifluoromethylphenyl)-aza--hydroxy-4-((2-(thio-methyl-aza-isobutyl sulfoxide imine)ethyl)amino )-1,2,5-oxadiazole-3-carboquinone

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

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

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

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

(±)(Z)-N-(3-trifluoromethylphenyl)-nitro'-hydroxy-4-((2-(1-oxo-3,4,5,6-tetrahydro-1λ ⁶ , 2-thiazin-1-yl)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

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

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

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

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

(±)(Z)-N-(3-trifluoromethylphenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(methylaminocarbonyl) sulfoxide) Amine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

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

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

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

(±)(Z)-N-(3-trifluoromethylphenyl)-nitro'-hydroxy-4-((2-(thio-methyl-nitro-(methylsulfonyl) sulfoximine)) Amino)-1,2,5-oxadiazole-3-carboxamidine

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

(±)(Z)-N-(3-trifluoromethylphenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(nitro-phenylaminosulfonyl)) sulfoxide Amine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

(±)(Z)-N-(3-trifluoromethylphenyl)-nitro'-hydroxy-4-((2-(thio-methyl-nitro-(carbamoyl) sulfoximine)) Amino)-1,2,5-oxadiazole-3-carboxamidine

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

In another preferred embodiment, the compound is a racemate.

In another preferred embodiment, the compound is an enantiomer.

In another preferred embodiment, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, triflate, benzenesulfonic acid Salt, p-toluenesulfonate (tosylate), 1-naphthalenesulfonate, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, milk Acid, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, mandelate.

In a second aspect of the invention, there is provided a process for the preparation of a compound of formula (I) according to the first aspect, comprising the steps of:

(a) compound P1 is reacted with R ₃ OBF ₄ to give compound P2;

(b) compound P1 is reacted with ArB(OH) ₂ and Cu(OAc) ₂ to obtain compound P3;

(c) Compound P2 or P3 is ring-opened in the presence of sodium hydroxide (e.g., aqueous sodium hydroxide) to give the final product P4 or P5, a compound of formula (I).

The compound of the formula (I) of the present invention can also be obtained by the following production method, comprising the following steps:

(a) Compound P1 is reacted with RN=C=O or ClSO ₂ R ² to give compound P6 or P7;

(b) Compound P6 or P7 is ring-opened in the presence of sodium hydroxide (e.g., aqueous sodium hydroxide) to give the final product P8 or P9, a compound of formula (I).

The invention also provides a process for the preparation of a third compound of the general formula (I), comprising the steps of:

(a) Compound D is reacted with compound E and a reducing agent under acid catalysis to give compound F;

(b) Compound F is ring-opened under alkaline hydrolysis conditions (e.g., aqueous sodium hydroxide) to give the final compound of formula (I).

The invention also provides a method for preparing a fourth compound of the general formula (I), comprising the steps of:

In the formulae, R ¹ , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , n, m, X and ring A are as defined above.

In the present invention, starting from propylene propylene cyanide, a series of oxidation, addition, cyclization, diazotization, substitution and the like are carried out to obtain a compound P1.

In a third aspect of the invention, there is provided the use of a compound of formula (I) according to the first aspect, for:

(i) preparing a guanamine-2,3-dioxygenase inhibitor;

(ii) preparing a medicament for preventing and/or treating a guanamine-2,3-dioxygenase mediated disease; or

(iii) Preparation of an antitumor or anti-inflammatory drug.

In another preferred embodiment, the guanamine-2,3-dioxygenase mediated disease is a disease characterized by the pathology of an IDO-mediated tryptophan metabolism pathway.

In another preferred embodiment, the guanamine-2,3-dioxygenase mediated disease is cancer, eye disease, heart disorder, depression, anxiety, Alzheimer's disease, and/or autoimmune disease.

In another preferred embodiment, the cancer includes, but is not limited to, colon cancer, breast cancer, gastric cancer, lung cancer, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, liver cancer, brain cancer, melanoma, multiple Myeloma, chronic myeloid leukemia, hematological tumors, lymphoid tumors, including metastatic lesions in other tissues or organs remote from the primary site of the tumor.

According to a fourth aspect of the invention, a pharmaceutical composition comprising:

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

A pharmaceutically acceptable carrier.

According to a fifth aspect of the invention, a pharmaceutical composition comprising:

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

Optionally, an anti-tumor drug.

In another preferred embodiment, the anti-tumor drug includes, but is not limited to, an immunotherapeutic drug for cancer: PD-1 antibody, CTLA-4 antibody, PD-L1 antibody, PD-L2 antibody, any other chemotherapeutic drug or target To therapeutic agents such as HDAC inhibitors and EP4 antagonists.

According to a sixth aspect of the present invention, a method for preventing and/or treating a guanamine-2,3-dioxygenase-mediated disease comprising administering a compound of the formula (I) according to the first aspect to a patient Or the step of the pharmaceutical composition of the fourth or fifth aspect.

In another preferred embodiment, the indoleamine-2,3-dioxygenase mediated disease is cancer, the method further comprising administering to the patient an additional anticancer agent (also known as an antitumor drug, The steps of the antitumor drug as described above).

The compound of the formula (I) of the present invention has various pharmacological activities such as antitumor, treatment of neurodegenerative diseases (Alzheimer's disease), and anti-inflammatory.

It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.

Specific implementation

The inventors have extensively and intensively studied, and for the first time, unexpectedly developed a novel compound containing a sulfoximine and a 1,2,5-oxadiazole structure, which can be used as a highly effective IDO enzyme inhibitor. Prevention and/or treatment of indoleamine-2,3-dioxygenase mediated diseases can also be used as an anti-inflammatory drug. On the basis of this, the present invention has been completed.

definition

The term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having from 1 to 10 carbon atoms, including straight-chain and branched hydrocarbon groups such as methyl (ie, CH ₃ -), ethyl (ie, CH ₃ CH ₂ -). , n-propyl (ie CH ₃ CH ₂ CH ₂ -), isopropyl (ie (CH ₃ ) ₂ CH-), n-butyl (ie CH ₃ CH ₂ CH ₂ CH ₂ -), isobutyl (ie (CH ₃ ) ₂ CHCH ₂ -), sec-butyl (ie (CH ₃ )(CH ₃ CH ₂ )CH-), tert-butyl (ie (CH ₃ ) ₃ C-), n-pentyl (ie CH _{3 )} CH ₂ CH ₂ CH ₂ CH ₂ -), neopentyl (ie (CH ₃ ) ₃ CCH ₂ -). In the present invention, the term includes a substituted or unsubstituted alkyl group.

The term "substituted or unsubstituted" as used herein means that the group may be unsubstituted or that H in the group is one or more (preferably 1-6, more preferably 1- Replaced by three substituents.

As used herein, "substituted" or "substituted" means that the group has one or more (preferably 1-6, more preferably 1-3) substituents selected from the group consisting of: Halogen, hydroxy, -NH ₂ , nitro, -CN, C1-C4 alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ alkynyl, phenyl, benzyl.

The term "cycloalkyl" as used herein refers to a substituted or unsubstituted C3-C12 cycloalkyl.

As used herein, the term "alkoxy" refers to -O-alkyl, wherein the alkyl group can be saturated or unsaturated, can be branched, straight chain, 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 which has a monocyclic (eg phenyl) or fused ring (eg naphthyl) Or sulfhydryl), if the point of attachment is on the aromatic carbon, the fused ring may be non-aromatic (eg 2-benzoxazolone, 2H-1,4-benzoxazine-3(4H)-one-7 - base, etc.). Preferred aryl groups include phenyl and naphthyl. The term includes substituted or unsubstituted forms wherein the substituents are as defined above.

The term "alkenyl" as used herein refers to an alkenyl group having 2 to 10 (eg 2 to 6 or 2 to 4) carbon atoms and having at least 1 (eg 1 to 2) unsaturated ethylenic bonds (>C) =C<). Examples of such groups are vinyl, allyl, but-3-enyl. As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having from 3 to 10 carbon atoms having a single or multiple ring (including fused systems, bridged ring systems, and spiro ring systems). In a fused ring system, one or more of the rings may be a cycloalkyl, heterocyclic, aryl or heteroaryl group as long as the attachment site is a ring through a 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 fluoro, chloro, bromo and iodo.

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

The term "substituted heteroaryl" as used herein refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the group consisting of The same substituent as defined by the aryl group.

As used herein, the term "heterocycle" or "heterocycle" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated, partially saturated or unsaturated group (but not aromatic), Has a single ring or a fused ring (including a bridged ring system and a spiro ring system having from 1 to 10 carbon atoms and from 1 to 4 (eg, three) heteroatoms selected from nitrogen, sulfur or oxygen in the ring, in a fused ring system Wherein one or more of the rings may be a cycloalkyl, aryl or heteroaryl group, as long as the point of attachment passes through the non-aromatic ring. In one embodiment, the nitrogen atom and/or the sulfur atom of the heterocyclic group is optionally It is oxidized to provide N-oxide, sulfinyl and sulfonyl moieties.

The term "substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclic" as used herein refers to a heterocyclic group substituted by 1 to 5 (eg, 1 to 3) substituents. a group, the substituent is defined by a substituted cycloalkyl group The substituents are the same.

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

As used herein, the term "tautomer" refers to an alternative form of a compound having a different proton position, such as an enol-ketone and an imine-enamine tautomer, or a tautomeric form of a heteroaryl group. The heteroaryl group comprises 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 an embodiment compound that, when administered to a subject, is capable of providing, directly or indirectly, a compound of the Examples, or an active metabolite or residue thereof. Particularly preferred derivatives and prodrugs are those which, when administered to a subject, increase the bioavailability of the compound of the example (eg, the compound administered orally is more readily absorbed into the blood) or the parent compound relative to the parent species Derivatives and prodrugs to the bioregional compartment (such as the brain or lymphatic system). Prodrugs include the ester form of the compounds of the invention.

Compound of the invention

The term "compound of the invention" as used herein, refers to a compound of formula (I) or formula (II), a racemate thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug, or a pharmaceutical thereof Acceptable salt. It is to be understood that the term also includes a compound of formula (III), a racemate thereof, a stereoisomer thereof or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

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

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

In the formula,

R ⁷ and R ⁸ are each independently hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, a substituted or unsubstituted C ₃ -C ₁₀ alkynyl group, a substituted or unsubstituted C ₆ -C ₂₀ aryl group, or a substituted or unsubstituted C ₃ -C ₁₄ heteroaryl group; R ⁷ and R ⁸ may be formed together a three to eight membered ring or a three to eight membered heterocyclic ring wherein the hetero atom can be sulfur, oxygen, NH or NR ^f ;

R ⁹ is C ₆ -C ₂₀ aryl, five- or six-membered heteroaryl; R ⁹ may be substituted by one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxy, hydroxy, amino, nitro, aldehyde, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxy, -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, - CONR ^a R ^b , -SO ₂ R ^a , -SO ₂ NR ^a R ^b , -P(O)Me ₂ , -P(O)(OMe) ₂ ; wherein each R ^a and each R ^b are independently hydrogen, Substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, substituted or unsubstituted C ₆ -C ₂₀ An aryl group, or a substituted or unsubstituted C ₃ -C ₁₄ heteroaryl group; R ^a and R ^b may together form a three to eight membered ring or a four to eight membered heterocyclic ring, wherein the hetero atom may be sulfur, oxygen, NH or NR ^g ;

R ² is C ₁ -C ₁₂ alkyl, C ₆ -C ₂₀ aryl, C ₅ -C ₂₀ heteroaryl, -SO ₂ R ^e , -SO ₂ NR ^a R ^b or -C(O)NR ^a R ^b ;

X is a single bond, O, S, NH or NR ^d ;

R ³ and R ⁴ are each independently hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl; R ³ and R ⁴ may together form a three to eight membered ring or a three to eight membered heterocyclic ring, wherein the hetero atom may be Sulfur, oxygen, NH or NR ^h ;

R ¹ , R ^d , R ^e , R ^f , R ^g , R ^{h are} independently C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₂₀ aryl, or C ₃ -C _C14 heteroaryl group; R ¹ may be substituted by one or more radicals from the group consisting of: halogen, hydroxy, amino, nitro, cyano, aldehyde, carboxyl, alkoxy, -CF _3, -SF ₅ ;

R ¹ and R ^d may be joined to form a six to eight membered ring;

R ¹ and R ³ may be bonded 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 (I) is:

Wherein R ¹ is C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₁₀ alkenyl, aryl, or heteroaryl, and R ¹ may be substituted by one or more halogens;

R ² is C ₁ -C ₁₂ alkyl, C ₆ -C ₂₀ aryl, C ₅ -C ₂₀ heteroaryl, -SO ₂ R ^e , -SO ₂ NR ^a R ^b or -C(O)NR ^a R ^b ;

R ¹⁰ and R ¹¹ are each independently hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkynyl, hydroxy, amino, nitro, cyano, aldehyde, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl group, -CO ₂ C ₁ -C ₆ alkyl group, -CONR ^a R ^b , -SO ₂ R ^a , SO ₂ NR ^a R ^b substitution; R The definitions of ^a and R ^b are as described above;

n is 1 to 8.

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

In the formula, each group is as defined above.

Where a compound of the invention is present as a stereoisomer, the invention includes all stereoisomers of the compound.

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

The invention also includes deuterated compounds resulting from the substitution of any one or more of the hydrogen atoms of the compound by its stable isotope oxime.

Pharmaceutical composition

The invention also provides a pharmaceutical composition comprising an active ingredient in a safe and effective amount, together with a pharmaceutically acceptable carrier.

The "active ingredient" as used in the present invention means a compound of the formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof.

The "active ingredient" and pharmaceutical compositions described herein are useful as IDO inhibitors. In another preferred embodiment, a medicament for the preparation and prevention or/or treatment of a tumor is prepared. In another preferred embodiment, a medicament for the preparation of a disease preventing and/or treating IDO mediated diseases.

By "safe and effective amount" is meant that the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. In general, the pharmaceutical compositions contain from 1 to 2000 mg of active ingredient per dose, more preferably from 10 to 200 mg of active ingredient per dose. Preferably, the "one dose" is a tablet.

"Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By "compatibility" it is meant herein that the components of the composition are capable of intermingling with the active ingredients of the present invention and with respect to each other without significantly reducing the efficacy of the active ingredients.

The compounds of the preferred embodiments of the invention may be administered as separate active agents or in combination with one or more other agents useful in the treatment of cancer. The use of the compounds of the preferred embodiments of the invention in combination with known therapeutic agents and anticancer agents is also effective, and combinations of currently known compounds with other anticancer or chemotherapeutic agents are within the scope of the preferred embodiments. Examples of such agents can be found in "Cancer Principles and Practice of Oncology", VT Devita and S. Hellman (editor), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Press . One of ordinary skill in the art will be able to discern effective combinations of agents based on the particular nature of the drug and the cancer involved. Such anticancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinol receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, iseswagen Alkenyl protein transferase inhibitors, acetylase (HDAC) inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, cell proliferation and survival signal inhibitors, apoptosis inducers, and interfering cell cycle checkpoints ( Cell cycle checkpoint), CTLA4 antibody, PD-1 antibody, PD-L1 antibody, 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 of the accepted modes of administration of agents having similar effects. The actual amount of the compound (i.e., active ingredient) of the preferred embodiment is determined by a number of factors, such as the severity of the condition to be treated, the age and relative health of the patient, the potency of the compound being used, the route and form of administration, and other factors. . The drug can be administered multiple times a day, preferably once or twice a day. All of these factors are within the consideration of the attending physician.

For the purposes of the preferred embodiment, the therapeutically effective dose can generally be the total daily dose administered to the patient in a single or divided dose, for example, from about 0.001 to about 1000 mg/kg body weight per day, preferably from about 1.0 to about daily. 30 mg / kg body weight. A Dosage unit composition can include its dosage factor to form a daily dose. The choice of dosage form will depend on various factors such as the mode of administration and the bioavailability of the drug substance. In general, the compounds of the preferred embodiments can be administered as a pharmaceutical composition 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 a convenient daily dose can be adjusted depending on the degree of bitterness. The compositions may take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols or any other suitable compositions. Another preferred mode of administration of the preferred embodiment compounds is inhalation. This is an effective method of delivering a therapeutic agent directly to the respiratory tract (see, e.g., U.S. Patent No. 5,607,915).

Suitable pharmaceutically acceptable carriers or excipients include, for example, treatment and drug delivery modifiers and accelerators such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starches, gelatin, cellulose , sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting wax, ion exchange resin, and the like, and combinations of any two or more thereof. The liquid and semi-solid excipients may be selected from the group consisting of glycerin, propylene glycol, water, ethanol, and various oils, including petroleum, animal, vegetable, or synthetic sources, such as peanut oil, Soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly carriers for injectable solutions, include water, saline, aqueous dextrose and ethylene glycol. Other suitable pharmaceutically acceptable excipients are described in Remington&apos;s Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991), incorporated herein by reference.

The term "pharmaceutically acceptable salt," as used herein, refers to a non-toxic acid or alkaline earth metal salt of a compound of formula I. These salts can be prepared in situ by final isolation and purification of the compound of formula I, or by separately reacting a suitable organic or inorganic acid or base with a basic or acidic functional group. Representative salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate , camphorate, camphor sulfonate, digluconate, cyclopentane propionate, lauryl sulfate, ethanesulfonate, glucose heptanoate, glycerol phosphate, hemisulfate, heptanoic acid Salt, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate , 2-naphthyl sulfonate, oxalate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, Succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Further, the nitrogen-containing basic group can be quaternized by the following reagents: alkyl halides such as methyl, ethyl, propyl, butyl chloride, bromide and iodide; dialkyl sulfate Such as dimethyl, diethyl, dibutyl and dipentyl sulfate; long chain halides such as sulfhydryl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl Base halides such as benzyl and phenethyl bromide. A water soluble or oil soluble or dispersible product is thus obtained. Examples of the acid which can be used to form a pharmaceutically acceptable acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, and citric acid. The base addition salt can be prepared in situ upon final isolation and purification of the compound of formula I, or by separately reacting the carboxylic acid moiety with a suitable base such as a hydroxide, carbonate or carbonate of a pharmaceutically acceptable metal cation. Hydrogen salt) or ammonia, or organic primary, secondary or tertiary amine reaction. Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including However, it is not limited to: ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. Other representative organic amines useful for the formation of 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 a compound of those preferred embodiments, which is rapidly converted in vivo to a parent compound of the above formula, for example, hydrolyzed in blood. In "T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, 14 volumes of the ACS15Symposium Series" and "Edward B. Roche, Bioreversible Vectors in Drug Design" A complete discussion is provided in Bioreversible Carriers in Drug Design, The American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually carried out according to the conditions described in conventional conditions such as Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer. The suggested conditions. Percentages and parts are by weight unless otherwise stated.

The invention is advantageous in that:

(1) providing a novel structure of the compound of the formula (I);

(2) The compound of the present invention can be used as a highly potent IDO enzyme inhibitor;

(3) The synthesis method is mild, the operation is simple and easy, the yield is high, and the derivatization is easy, and it is suitable for industrial scale production;

(4) It has various pharmacological activities such as anti-tumor, neurodegenerative diseases (Alzheimer's disease), anti-inflammatory and the like.

Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described may be employed in the methods of the invention. The preferred embodiments and materials described herein are for illustrative purposes only.

Example 1

(±)(Z)-N-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(nitrogen, thio-dimethyl sulfoximine)ethyl)amino) -1,2,5-oxadiazole-3-carboquinone

First step: 4-amino-nitro&apos;-hydroxy-1,2,5-oxadiazol-3-carboxamidine

Propyl cyanohydrin (3.2 g, 48.5 mmol) was dissolved in 70 mL of water and heated to complete dissolution. Under ice cooling, sodium nitrite (3.8 g, 55 mmol) and 6N hydrochloric acid (0.6 mL) were added. After reacting for 0.5 hour in an ice bath, the mixture was heated to room temperature for 2 hours. The reaction solution was cooled in an ice bath, and a 50% aqueous solution of hydroxylamine hydrochloride (9.9 g, 150 mmol) was added dropwise to the reaction mixture, and the mixture was stirred for half an hour, and then allowed to react at room temperature for 1 hour. The reaction was heated to reflux for 2 hours. After completion of the reaction, the mixture was adjusted to pH 7.0 with 8 mL of 6N hydrochloric acid. The precipitate was filtered, washed once with water and ethyl acetate and dried to yield white crystals (yield:

¹³ C NMR (75 MHz, DMSO-d ₆ ): δ 154.4, 144.0, 140.0.

MS ESI: m/z = 144.0, [M+H] ⁺ .

The second step: 4-amino-nitro-hydroxy-1,2,5-oxadiazole-3-carboxamidine

The first step product (4.2 g, 29.4 mmol) was dissolved in 30 mL of acetic acid, and then water, 60 mL, 15 mL of hydrochloric acid and sodium chloride (5.2 g, 88.2 mmol) were added. Under ice cooling, sodium nitrite (2.0 g, 29.4 mmol) dissolved in 7 mL of water was added dropwise, and the reaction was kept at zero temperature for 1 hour, and then the temperature was raised to room temperature for 5 hours. After completion of the reaction, the precipitate was filtered, washed with water and dried to give 2.6 g of white solid compound.

¹³ C NMR (75 MHz, DMSO-d ₆ ): δ 154.4, 142.3, 126.9.

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

The third step: 4-amino-nitro&apos;-(3-bromo-4-fluorophenyl)-1,2,5-oxadiazole-3-carboxamidine

To a solution of the second step product (41.99 g, 259.2 mmol) in purified water (800 ml), 3-bromo-4-fluoroaniline (54.179 g, 285.12 mmol). The reaction mixture was stirred at 60 ° C for 10 min, and a solution of Na ₂ CO ₃ (41.2 g, 388.8 mmol) in water (500 ml) was added to the mixture. LCMS showed complete reaction after stirring the reaction for 20 min. The reaction mixture was cooled, filtered, washed with water and dried then evaporated.

¹ H NMR (400 MHz, Acetone-d ₆ ): δ 8.10 (dd, 1H), 7.78 (m, 1H), 7.56 (t, 1H), 6.15 (s, 1H).

Fourth step: 4-amino-nitro&apos;-(3-bromo-4-fluorophenyl)-1,2,5-oxadiazol-3-yl)-1,2-4-oxadiazolone

The third product (70 g, 221.5 mmol) and CDI (39.8 g, 332.173 mmol) were dissolved in ethyl acetate (600 ml) and warmed to 60 ° C and stirred for 20 min. The reaction mixture was cooled to rt. EtOAc (EtOAc m.

¹ H NMR (400 MHz, acetone-d ₆ ): δ 8.09 (dd, 1H), 7.83 (m, 1H), 6.79 (t, 1H).

Step 5: 4-(3-Bromo-4-fluorophenyl)-3-4-(((2-methylthio)ethyl)amino)-1,2,5-oxadiazol-3-yl Preparation of-1,2-4-oxadiazolone

4-Amino-nitro-(3-bromo-4-fluorophenyl)-1,2,5-oxadiazol-3-yl)-1,2-4-oxadiazolone (at room temperature) 3.0 g, 8.8 mmol), dissolved in DCM (20 ml), added triethylsilane (3.1 g, 26.3 mmol) and methanesulfonic acid (2.4 g, 26.3 mmol), cooled to 0 ° C in ice bath, 2, 2 - Dimethoxymethylthioethane (2.4 g, 17.5 mmol). After the completion of the reaction, the reaction was completed at room temperature for 2 hours, and the mixture was adjusted to pH = 7 with a saturated aqueous solution of sodium hydrogen carbonate. The organic phase was washed with water (20 mL×3), and brine (20 mL×3) Obtained as a brown solid (3.5 g, 96%).

¹ H NMR (300 MHz, acetate-d ₆ ): δ 8.08 (d, 1H), 7.80 (dd, 1H), 7.57 (t, 1H), 6.14 (s, 1H), 3.66 (m, 2H), 2.80 (m, 2H), 2.13 (s, 3H).

Step 6: 4-(3-Bromo-4-fluorophenyl)-3-4-(((2-methylthio)ethyl)-tert-butoxycarbonylamino)-1,2,5-oxadiazole -3-yl)-1,2-4-oxadiazolone

The product of the fifth step (50 mg, 0.120 mmol) was dissolved in THF (2 ml), di-tert-butyl dicarbonate (131 mg, 0.601 mmol) was added, and a catalytic amount of 4-dimethylaminopyridine (2 mg) was added and stirred in an ice bath. After the reaction was completed, water (10 ml) was extracted with EtOAc (EtOAc (EtOAc) (EtOAc) Yield).

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

Step 7: (±) 4-(3-Bromo-4-fluorophenyl)-3-4-(((2-(methylsulfoxide)ethyl)-tert-butoxycarbonylamino)-1,2, 5-oxadiazol-3-yl)-1,2,4-oxadiazolone

The product of the sixth step (2.0 g, 3.9 mmol) was dissolved in 20 mL dichloromethane and 2 mL methanol. MMPP (1.06 g, 2. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with EtOAc (3 mL). EtOAc (EtOAc) The rate is 77%.

_{^{1 H NMR (400MHz, CDCl 3}} ): 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-(3-Bromo-4-fluorophenyl)3-4-(((2-(methyltrifluoroacetylsulfoximine)ethyl)tert-butoxycarbonylamino) -1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazolone

The product from the seventh step (330 mg, 0.620 mmol) was added to a reaction flask, and CF ₃ C(O)NH ₂ (140 mg, 1.240 mmol), MgO (99 mg, 2.449 mmol) and Rh(OAc) ₂ (10 mg) were added. After stirring for one minute at room temperature, PhI(OAc) ₂ (309 mg, 0.930 mol) was added and stirred at room temperature until the reaction was completed by TLC. Water (10 ml) was added to the reaction, and the mixture was evaporated. Purification by column chromatography gave the title compound (300 mg, 75% yield).

Step 9: (±) 4-(3-Bromo-4-fluorophenyl)3-4-(((2-(methyl sulfoximine)ethyl)-tert-butoxycarbonylamino)-1,2 , 5-oxadiazol-3-yl)-1,2,4-oxadiazolone

The product of the eighth step (330 mg, 0.513 mmol) was dissolved in methanol (5 ml). TLC showed the reaction was complete, n-hexane: ethyl acetate = 1:1. The reaction mixture was filtered, and the filtered cake was washed with methylene chloride (10ml*2).

¹ H NMR: (400 MHz, DMSO-d ₆ ): δ 8.00 (s, 1H), 7.64-7.60 (m, 2H), 4.03 - 3.99 (m, 2H), 3.88 (s, 1H), 3.42-3.40 (m, 2H), 2.96 (s, 3H), 1.48 (s, 9H)

Step 10: (±) 4-(3-Bromo-4-fluorophenyl)3-4-(((2-(methylsulfoxidemethylimine)ethyl)) Tert-Butoxycarbonylamino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazolone

The product of the ninth step (20 mg, 0.037 mmol) was dissolved in dichloromethane (2 ml), and trimethyloxonium tetrafluoroborate (8 mg, 0.055 mmol) was added and stirred at room temperature for 2 hr. Water (10 ml), ethyl acetate (10 ml), and ethyl acetate (10 ml) were evaporated. After concentration and column chromatography, the title compound (10 mg, 48% yield) was obtained.

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

The eleventh step: ((±)(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(nitrogen, thio-dimethyl sulfoximine) Ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

The product of the tenth step (20 mg, 0.037 mmol) was dissolved in dichloromethane (1 ml), and a 10N hydrogen chloride / ethanol solution (2 ml) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to dryness and the residue was dissolved. To a solution of 2M aqueous sodium hydroxide (0.2 ml), TLC showed that the reaction was complete (dichloromethane:methanol = 20:1), and the mixture was adjusted to pH=5 with 2M hydrochloric acid, and water (10 ml), ethyl acetate (10 ml), and then ethyl acetate (10 ml) The combined organic phases were washed with water (10 ml), brine (10 ml) After concentration and column chromatography, the title compound (10 mg, 52% yield) was obtained.

¹ H NMR: (400 MHz, acetone-d ₆ ): δ 10.78 (s, 1H), 8.10 (s, 1H), 7.31-7.29 (m, 1H), 7.17-7.13 (m, 1H), 7.02-6.98 (m, 1H), 4.28-4.27 (m, 2H), 4.02-4.04 (m, 2H), 3.84 (s, 3H), 2.92 (s, 3H)

MS (ESI): [M+H] ⁺ m/z =435.0

Example 2

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

According to the preparation method of Example 1, the reagent of the tenth step was substituted with triethyloxonium tetrafluoroborate, and the target compound was obtained by using the conditions of the eleventh step.

¹ H NMR: (400 MHz, acetone-d ₆ ): δ 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)-N-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-(2-(thio-methyl-nitro-phenylsulfoxideimine)ethyl)amino )-1,2,5-oxadiazole-3-carboquinone

First step: (±) 4-(3-bromo-4-fluorophenyl)3-4-(((2-(methyl sulfoxide phenylimine)ethyl)-tert-butoxycarbonylamino)-1 , 2,5-oxadiazol-3-yl)-1,2,4-oxadiazolone

The product of the ninth step of Example 1 (20 mg, 0.037 mmol) was dissolved in dichloromethane (2 ml), benzene boronic acid (8 mg, 0.055 mmol) was added, and copper acetate (5 mg) was stirred at room temperature for 2 hr. Water (10 ml), ethyl acetate (10 mL), EtOAc (EtOAc)EtOAc. After concentration and purification by column chromatography, the title compound (15 mg, 66% yield)

¹ H NMR (400 MHz, acetone-d ₆ ): δ 7.93-7.91 (m, 1H), 7.62-7.58 (m, 1H), 7.51-7.47 (m, 1H), 7.23-7.12 (m, 2H), 6.96 (d, 2H), 6.92-6.89 (m, 1H), 4.29 (s, 2H), 3.87-3.80 (m, 1H), 3.76-3.68 (m, 1H), 3.21 (s, 3H), 1.51 (s) , 9H)

Second step: (±)(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-nitro-phenyl sulfoximine)ethyl) )amino)-1,2,5-oxadiazole-3-carboxamidine

The first step product (10 mg, 0.016 mmol) was dissolved in dichloromethane (1 mL), then 10M hydrogen chloride / ethanol solution (2 mL) was added and stirred at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to dryness. Aqueous 2M aqueous sodium hydroxide (0.2 ml) was added to tetrahydrofuran (2 mL) and stirred at room temperature for 30 min. TLC showed the reaction was completed. EtOAc (EtOAc) (EtOAc (EtOAc) (EtOAc) The mixture was washed with saturated brine (10 mL) and dried over sodium sulfate. After concentration and column chromatography, the title compound (5 mg, 63% yield) was obtained.

¹ H NMR (400 MHz, acetate-d ₆ ): δ 10.80 (s, 1H), 8.13 (s, 1H), 7.29-7.27 (m, 1H), 7.19-7.13 (m, 3H), 7.04-7.01 (m) , 3H), 6.89-6.85 (m, 1H), 6.55 (s, 1H), 3.91-3.87 (m, 2H), 3.72-3.61 (m, 2H), 3.20 (s, 3H)

MS (ESI): [M+H] ⁺ m/z =497.0

Example 4

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

First step: (±) 4-(3-bromo-4-fluorophenyl)3-4-(((2-thio-methyl-nitro-(anilinoyl) sulfoximine)) ethyl) Tert-Butoxycarbonylamino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazolone

The product of the ninth step of Example 1 (20 mg, 0.037 mmol) was dissolved in THF (2 mL), EtOAc EtOAc (EtOAc (EtOAc) The organic phase was combined with ethyl acetate (10 mL×2). Purification by column chromatography to give the title compound (20 mg, 82% yield)

¹ H NMR (400 MHz, acetate-d ₆ ): δ 8.24 (s, 1H), 7.96-7.95 (m, 1H), 7.66-7.58 (m, 3H), 7.50-7.46 (m, 1H), 7.26- 7.22 (m, 2H), 6.97-6.93 (m, 1H), 4.36 (s, 2H), 4.09-4.02 (m, 1H), 3.96-3.86 (m, 1H), 3.41 (s, 3H), 1.51 ( s, 9H)

Second step: (±) 4-(3-bromo-4-fluorophenyl)3-4-(((2-thio-methyl-nitro-(anilinoyl) sulfoximine)) ethyl) Tert-Butoxycarbonylamino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazolone

The first step product (20 mg, 0.030 mmol) was added to 10N HCI /EtOAc (3 mL). After the reaction was completed, it was directly concentrated to dryness to give the title compound (20 mg, 100% yield)

¹ H NMR (400 MHz, acetate-d ₆ ): δ 8.10 (s, 1H), 7.98-7.97 (m, 1H), 7.72-7.68 (m, 1H), 7.60 (d, 2H), 7.54-7.50 (m) , 1H), 6.61 (s, 1H), 4.03-4.00 (m, 2H), 3.94-3.88 (m, 2H), 3.64-3.60 (m, 1H), 3.46 (s, 3H)

Step 3: (±)(Z)-N-(3-bromo-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(anilinoyl)) Sulfoxide imine) ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

The second product (20 mg, 0.035 mmol) was dissolved in THF (2 mL). TLC showed that the reaction was completed, and the mixture was adjusted to pH=5 with 2 mol/L hydrochloric acid, and water (10 mL), ethyl acetate (10 mL), and then ethyl acetate (2×10 mL), and the organic phase was combined and washed with water (10 mL) The mixture was washed with saturated brine (10 mL) and dried over sodium sulfate. After concentration and purification by column chromatography, the title compound was obtained (10 mg, 52% yield)

¹ H NMR (400 MHz, acetate-d ₆ ): δ 10.70 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.61 (d, 2H), 7.30-7.28 (m, 4H) , 7.26-7.22 (m, 2H), 7.16-7.12 (m, 1H), 7.02-6.98 (m, 1H), 6.96-6.93 (m, 1H), 6.57 (s, 1H), 3.95-3.85 (m, 3H), 3.81-3.74 (m, 1H), 3.44 (s, 3H)

MS (ESI): [M+H] ⁺ m/z = 540.1

Example 5

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

First step: (±)(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(sulfo-methyl-nitro-(carbonylimidazole)) sulfoxide Preparation of imine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine (Compound R):

(±)(Z)-N-(3-bromo-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl sulfoximine)ethyl)amino group at room temperature -1,2,5-oxadiazol-3-carboxamidine (500 mg, 1.19 mol) was dissolved in 20 mL of ethyl acetate, carbonyldiimidazole (579 mg, 3.57 mmol) was added, then stirred at 60 ° for 5 hours, and the solvent was evaporated. The mixture was combined with EtOAc EtOAc (EtOAc)EtOAc. Dry to give a white solid.

¹ H NMR (400 MHz, acetone-d ₆ ): δ 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).

Second step: (±)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(sulfo-methyl-nitro-(formylmethyl)) sulfoxide) Amine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

The first step product (30 mg, 0.055 mmol) was dissolved in 3 mL of methanol. 1 mL of sodium solution. The mixture was stirred at room temperature for 1 h, and the pH was adjusted with a 6N hydrochloric acid solution. The mixture was extracted with ethyl acetate (3×20 mL), and the organic layer was combined, washed with water and brine, and concentrated to give a column chromatography (DCM: MeOH = 20:1) to give the title compound (10mg, 38%).

¹ H NMR (400 MHz, acetone-d ₆ ): δ 10.76 (s, 1H), 8.10 (s, 1H), 7.30 (m, 1H), 7.16 (t, 1H), 7.02 (m, 1H), 3.93 (m, 2H), 3.89 (s, 1H), 3.79 (s, 1H), 3.64 (s, 3H), 3.47 (s, 3H), 3.65 (s, 3H).

MS (ESI): [M+H] ⁺ m/z = 480.7

Example 6

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

According to the preparation method of Example 5, the first step product of Example 5 (30 mg, 0.055 mmol) was dissolved in 3 mL of ethanol, and ice-bath, and 1 mL of 2N sodium hydroxide solution was added. The mixture was stirred at room temperature for 1 h, and the pH was adjusted with a 6N hydrochloric acid solution. The mixture was extracted with ethyl acetate (3×20 mL), and the organic layer was combined, washed with water and brine, and concentrated to give a column chromatography (DCM: MeOH = 20:1) to give the title compound (14 mg, 51%).

_{^{1 H NMR (400MHz, CDCl 3}} ): 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

Example 7

(±)(Z)-N-(3-bromo-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(formylisopropyl)) sulfoxide) Amine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

According to the preparation method of Example 5, the first step product of Example 5 (30 mg, 0.055 mmol) was dissolved in 3 mL of isopropanol, and an ice bath was added, and 1 mL of a 2N sodium hydroxide solution was added. The mixture was stirred at room temperature for 1 h, and the pH was adjusted with a 6N hydrochloric acid solution. The mixture was extracted with ethyl acetate (3×20 mL), and the organic layer was combined, washed with water and brine, and concentrated to give a column chromatography (DCM: MeOH = 20:1) gave Compound TM (10 mg, 37%).

_{^{1 H NMR (400MHz, CDCl 3}} ): 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

Example 8

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

The product of the ninth step of the compound example 1 (30 mg, 0.055 mmol) and triethylamine (15 uL) were dissolved in 3 mL of dichloromethane, and then, under ice-cooling, methanesulfonyl chloride (6.4 uL) was added, and after reacting for ten minutes, It was quenched by the addition of 20 mL of EtOAc EtOAc (EtOAc)EtOAc. The crude product (35 mg, 0.056 mmol) was dissolved in 1 mL of dichloromethane and 1 mL of trifluoroacetic acid, and was allowed to react at room temperature for three hours. The solvent was evaporated to dryness, water (20 mL), and dichloromethane (3×20 mL). The dried product was dried over anhydrous sodium sulfate, filtered and evaporated to dryness eluted eluted eluted eluted eluted eluted eluted 7 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; , 84%)

_{^{1 H NMR (400MHz, CDCl 3}} ): 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

Example 9

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

Under the ice bath, (±)-nitro-(3-bromo-4-fluorophenyl)-nitro--hydroxy-4-((2-(thio-methyl-nitro-cyanosulfoximine)) Base)amino)-1,2,5-oxadiazol-3-carboxamidine (20 mg, 0.045 mmol) was dissolved in 2 mL of DMSO solution, then anhydrous potassium carbonate (63 mg, 0.45 mmol) was added, and 0.5 mL was slowly added dropwise. Hydrogen peroxide was reacted at room temperature for 0.5 hours. After adding 20 mL of aqueous sodium thiosulfate solution, the mixture was extracted with dichloromethane (3×20 mL), EtOAcjjjjjjjj 5), spin dry to give a white solid (14 mg, 67%)

_{^{1 H NMR (400MHz, CDCl 3}} ): δ9.45 (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

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

The product of the ninth step of Example 1 (50 mg, 0.09 mmol) was dissolved in tetrahydrofuran (10 mL), propionaldehyde (11 mg, 0.18 mmol) was added, and sodium acetoxyborohydride (58 mg, 0.27 mmol) was added. The mixture was stirred at 40 °C for 2 hours, and the reaction was completed with EtOAc. EtOAc (EtOAc) (EtOAc) The organic phase was dried over sodium sulfate, concentrated and purified by column chromatography to afford compound (50 mg, 94% yield). This was dissolved in dichloromethane (1 ml), and then added with a 10N hydrogen chloride / ethanol solution (2 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the residue was concentrated to dryness, and the residue was dissolved in THF (2 ml). Aqueous sodium hydroxide (0.2 ml) was stirred at room temperature for 30 minutes. TLC showed that the reaction was complete (dichloromethane:methanol = 20:1), and the mixture was adjusted to pH=5 with 2M hydrochloric acid, and water (10 ml), ethyl acetate (10 ml), and then ethyl acetate (10 ml) The combined organic phases were washed with water (10 ml), brine (10 ml) After concentration and column chromatography, the title compound (10 mg, 25% yield) was obtained.

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

Example 11 Resolution of Chiral Isomers

Chiral resolution using a Agilent 1260 semi-preparative liquid chromatograph (chiral atom is a sulfur atom):

Resolution of the compound of Example 1:

Chiral column: 赛 璐 RAL RAL RAL RAL 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐

Condition 1: 1 mg of the sample of Example 1 was dissolved in 1 ml of a mixed solution of n-hexane and isopropanol (hexane: iPrOH = 8:2), the injection amount was 10 μl, and the eluent Hexane: EtOH = 88:12 (volume ratio) The peak time of the two optical isomers was 14.251 minutes and 16.905 minutes, respectively;

Condition 2: 1 mg of the sample of Example 1 was dissolved in 1 ml of a mixed solution of n-hexane and isopropanol (hexane: iPrOH = 8:2), the injection amount was 10 μl, and the eluent Hexane: iPrOH = 75: 25 (volume ratio) The peak time of the two optical isomers was 11.180 minutes and 13.978 minutes, respectively.

Resolution of the compound of Example 2:

Chiral column: 赛 璐 RAL RAL RAL RAL 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐

Condition 1: 200 μl of the DMSO solution of Example 2 (10 mmol/L) was diluted to 1 mL with isopropanol, the injection volume was 10 μl, and the eluent Hexane: EtOH = 88:12 (volume ratio); The peak times of the compound 11A and the compound 11B were 11.188 minutes and 13.786 minutes, respectively;

Condition 2: 200 μl of the DMSO solution of Example 2 (10 mmol/L) was diluted to 1 mL with isopropanol, the injection volume was 10 μl, and the eluent Hexane: iPrOH = 80:20 (volume ratio); The peak time of the structures was 11.655 minutes and 15.261 minutes, respectively.

Resolution of the compound of Example 3:

Chiral column: 赛 璐 RAL RAL RAL RAL RAL 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐 璐

Conditions: 1 mg of the sample of Example 3 was dissolved in 1 ml of a mixed solution of n-hexane and isopropanol (hexane: iPrOH = 8:2), the injection amount was 5 μl, and the eluent Hexane: EtOH = 60: 40 (volume ratio); The peak time of the two optical isomers was 9.842 minutes and 16.879 minutes, respectively.

Example 12

Activity test

(1) Inducible expression and purification method of IDO protein

First, the IDO gene was amplified by PCR, and the amplified PCR product was recovered. Then, the pET28a plasmid (purchased from Shanghai Baoman Biotechnology Co., Ltd.) and the IDO gel recovery product were digested with EcoR I and Xho I restriction enzymes. (37 ° C, digestion 2h), running gelatin, recovery, T4 ligase linkage overnight ligation product added to DH5α competent state, placed on ice for 30min, 42 °C heat shock 90s, shaken plate, pick monoclonal, PCR identification , sequencing identification, all correct, that is, the pET28a-IDO plasmid was successfully constructed.

The constructed BL21 containing the pET28a-IDO plasmid was shaken at 37 ° C to an OD ₆₀₀ of 0.6-0.8, and added to a final concentration of 7 μM hemin and 1 mM IPTG (isopropyl-β-D-thio Galactoside was induced at 28 ° C for 4 h; after induction, the cells were collected by centrifugation at 6000 ° C at 4 ° C, and the collected cells were washed once with 20 mM PBS (pH 6.5), and the cells were collected by centrifugation.

The collected cells were resuspended with lysate (20 mM PBS pH 6.5), sonicated (40% lysis for 20 min, placed on ice), and the lysed bacteria were centrifuged at 13,000 rpm for 15 min, the precipitate was discarded, and the supernatant was retained. The nickel column was equilibrated with lysate (20 mM PBS pH 6.5) for 3 column volumes, and then the lysed supernatant was applied to a nickel column. After loading, it was washed with a rinse solution (20 mM PBS pH 6.5, 20 mM imidazole). 4 column volumes, finally eluted with eluate (20 mM PBS pH 6.5, 250 mM imidazole); the eluted protein solution was dialyzed for 4 h, the dialysis solution was 20 mM PBS pH 6.5, and the protein sample was concentrated after dialysis. Packed, liquid nitrogen frozen, placed at -80 ° C for storage.

(2) IDO enzyme inhibitory activity test method

The compound was firstly diluted 3-fold, and 1 μL of each concentration was added to a 96-well plate; 50 μL of the formulated IDO enzyme solution (final concentration 600 ng/100 μL) was added: 25 μL of the substrate 1 mixed solution was added, and 25 μL of the substrate was added. The mixed solution initiates the reaction. The final OD ₃₂₁ nm reading was 60 min.

(3) Cell activity test method

Hela cells (100 μL) were seeded in 96-well plates in an amount of 5 × 10 ³ per well and grown overnight. On the next day, after the compound was diluted, 1 μL was added to a 96-well plate, and then 100 μL of a medium containing human interferon γ (final concentration: 50 ng/mL) was added to a 96-well plate to give a final volume of 200 μL. After 48 hours of incubation, 140 μL of supernatant from each well was transferred to a new 96-well plate. 10 μL of 6.1 N trichloroacetic acid was added to each well and mixed at 50 ° C for 30 minutes. IDO catalyzed N-formyl canine urea as canine urea. The reaction mixture was centrifuged at 2500 rpm for 10 minutes to remove the precipitate. 100 μL of the supernatant from each well was transferred to a new 96-well plate and mixed with 100 μL of a 2% dimethylaminobenzaldehyde acetic acid solution. After canine urea separation, the values were determined at 480 nm using a SPECTRAmax i3 reader.

The test results of 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) have excellent inhibitory activities against IDO enzymes and cells, and in particular, Compound 2 has an unexpectedly high activity in IDO cell inhibitory activity.

Claims (15)

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

   

   In the formula,

   R ⁷ and R ⁸ are each independently hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, a substituted or unsubstituted C ₃ -C ₁₀ alkynyl group, a substituted or unsubstituted C ₆ -C ₂₀ aryl group, or a substituted or unsubstituted C ₃ -C ₁₄ heteroaryl group; R ⁷ and R ⁸ may be formed together a three to eight membered ring or a three to eight membered heterocyclic ring wherein the hetero atom can be sulfur, oxygen, NH or NR ^f ;

   R ⁹ is C ₆ -C ₂₀ aryl, C ₅ -C ₂₀ heteroaryl; R ⁹ may be substituted by one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxy, hydroxy, amino, nitro, aldehyde, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxy, -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, - CONR ^a R ^b , -SO ₂ R ^e , -SO ₂ NR ^a R ^b , -P(O)Me ₂ , -P(O)(OMe) ₂ ; wherein each R ^a and each R ^b are independently hydrogen, Substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, substituted or unsubstituted C ₆ -C ₂₀ An aryl group, or a substituted or unsubstituted C ₃ -C ₁₄ heteroaryl group; R ^a and R ^b may together form a three to eight membered ring or a four to eight membered heterocyclic ring, wherein the hetero atom may be sulfur, oxygen, NH or NR ^g ;

   R ² is C ₁ -C ₁₂ alkyl, C ₆ -C ₂₀ aryl, C ₅ -C ₂₀ heteroaryl, C ₁ -C ₄ alkyl-phenyl, C ₁ -C ₄ alkyl-C ₅ Ring, -C(O)OR ^e ; -SO ₂ R ^e , -SO ₂ NR ^a R ^b , -C(O)NR ^a R ^b or C ₃ -C ₁₂ cycloalkyl;

   X is a single bond, O, S, NH or NR ^d ;

   Ring A is a five- or six-membered heterocyclic ring;

   R ³ and R ⁴ are each independently hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl; or R ³ and R ⁴ may together form a three to eight membered ring or a three to eight membered heterocyclic ring, wherein the hetero atom may Is sulfur, oxygen, NH or NR ^h ;

   R ¹ , R ^d , R ^e , R ^f , R ^g , R ^{h are} independently C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₂₀ aryl, or C ₃ -C _C14 heteroaryl group; R ¹ and R ² may be substituted with one or more groups selected from the group consisting of: halogen, hydroxy, amino, nitro, cyano, aldehyde, carboxyl, alkoxy, -CF _3, -SF ₅ ;

   R ¹ and R ² may be substituted by one or more halogen, alkoxy and cyano groups;

   R ¹ and R ² may be bonded to form a four to eight membered ring;

   R ¹ and R ^d may be joined to form a six to eight membered ring;

   R ¹ and R ³ may be bonded to form a five to eight membered ring;

   n is an integer from 2 to 8;

   m is 0, 1, or 2.
2. The compound of the formula (I) according to claim 1, wherein R ² is C ₁ -C ₁₂ alkyl, C ₆ -C ₂₀ aryl, C ₅ -C ₂₀ heteroaryl, -SO ₂ R ^e , -C(O)NR ^a R ^b or C ₃ -C ₁₂ cycloalkyl.
3. The compound of the formula (I) according to claim 1, wherein R ³ and R ⁴ are each independently hydrogen or R ³ and R ⁴ may together form a three to eight membered ring or a three to eight membered heterocyclic ring. Wherein the hetero atom may be sulfur, oxygen, NH or NR ^h , and ^Rh is as defined in claim 1.
4. The compound of the formula (I) according to claim 1, wherein n is an integer of from 2 to 6.
5. The compound of the formula (I) according to claim 1, wherein the compound is represented by the formula (II).

   

   In the formula,

   R ⁹ is C ₆ -C ₂₀ aryl, C ₅ -C ₂₀ heteroaryl; R ⁹ may be substituted by one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxy, hydroxy, amino, nitro, aldehyde, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxy, -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, - CONR ^a R ^b , -SO ₂ R ^e , -SO ₂ NR ^a R ^b ;

   Wherein R ^a , R ^b , R ³ , R ⁴ , R ¹ are as defined in claim 1;

   R ² is C ₁ -C ₁₂ alkyl, C ₆ -C ₂₀ aryl, C ₅ -C ₂₀ heteroaryl, C ₁ -C ₄ alkyl-phenyl, C ₁ -C ₄ alkyl-C5 heterocyclic , -C(O)OR ^e ; -SO ₂ R ^e , -SO ₂ NR ^a R ^b , -C(O)NR ^a R ^b , or a C ₃ -C ₁₂ cycloalkyl group;

   R ¹ and R ² may be substituted by one or more halogen, alkoxy and cyano groups;

   R ¹ and R ² may be bonded to form a four to eight membered ring;

   n is an integer of 2-6.
6. The compound of the formula (I) according to claim 1, wherein the compound is represented by the formula (III).

   

   In the formula,

   Ar is a benzene ring, a five- or six-membered heteroaryl group, and Ar may be substituted by one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy , amino, nitro, aldehyde, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, -CONR ^a R ^b , -SO ₂ R ^e , -SO ₂ NR ^a R ^b ;

   R ² is C ₁ -C ₁₂ alkyl, C ₆ -C ₂₀ aryl, C ₅ -C ₂₀ heteroaryl, C ₁ -C ₄ alkyl-phenyl, C ₁ -C ₄ alkyl-C5 heterocyclic , -C(O)OR ^e ; -SO ₂ R ^e , -SO ₂ NR ^a R ^b , -C(O)NR ^a R ^b , or a C ₃ -C ₁₂ cycloalkyl group;

   R ^a , R ^b , R ³ , R ⁴ , R ¹ are as defined in claim 1;

   R ¹ and R ² may be substituted by one or more halogen, alkoxy and cyano groups;

   R ¹ and R ² may be bonded to form a four to eight membered ring;

   n is an integer of 2-6.
7. The compound of the formula (III) according to claim 3, wherein R ¹ is a C ₁ -C ₄ alkyl group;

   R ² is C ₁ -C ₆ alkyl, phenyl, C ₅ -C ₂₀ heteroaryl, -C(O)OR ^e ; -SO ₂ R ^e , -SO ₂ NR ^a R ^b or -C(O) NR ^a R ^b ;

   R ^a , R ^b are defined as defined in claim 1;

   R ¹ and R ² may be bonded to form a four to eight membered ring;

   R ³ and R ⁴ are each independently hydrogen or R ³ and R ⁴ may together form a three to eight membered ring or a three to eight membered heterocyclic ring, wherein the hetero atom may be sulfur, oxygen, NH or NR ^h , and ^Rh is as defined above. Claimed in claim 1;

   n is an integer of 2-6.
8. The compound of the formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, according to claim 1, wherein the prodrug is as defined in the formula (IV) Show,

   

   In the formula,

   R ¹ , R ² , R ³ , R ⁴ and R ⁹ are as defined in claim 1;

   R ^10a is a substituted or unsubstituted C ₆ -C ₂₀ aryl group, a substituted or unsubstituted five- or six-membered heteroaryl group, a substituted or unsubstituted C ₁ -C ₁₂ alkyl group, a substituted or unsubstituted C ₁ -C ₁₂ alkoxy, substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkoxy, NR ^a R ^b ; wherein R ^a , R ^b are as defined in claim 1 Said,

   Wherein said "substituted" means having one or more substituents selected from the group consisting of halogen, hydroxy, -NH ₂ , nitro, -CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkane A C ₁ -C ₄ alkoxy group, a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₄ alkenyl group, a C ₂ -C ₄ alkynyl group, a phenyl group, a benzyl group.
9. The compound of the formula (I) according to claim 1, wherein the compound is:

   (±)(Z)-N-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(nitrogen, thio-dimethyl sulfoximine)ethyl)amino) -1,2,5-oxadiazole-3-carboquinone

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

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

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

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

   (±)(Z)-N-(3-bromo-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro)(2,2,2-trifluoroethyl Sulfoxide imine) ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

   (±)(Z)-N-(3-bromo-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro)(3,3,3-trifluoropropyl) Sulfoxide imine) ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

   (±)(Z)-N-(3-bromo-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro(2-difluoroethyl)) sulfoxide Amine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

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

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

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

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

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

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

   (±)(Z)-N-(3-bromo-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(isopropylcarbamoyl)) Sulfimide imine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

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

   (±)(Z)-N-(3-bromo-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(formylisopropyl)) sulfoxide) Amine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

   (±)(Z)-N-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(sulfo-methyl-nitro-(nitro-phenylaminosulfonyl)) sulfoxide Imine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

   (±)(Z)-N-(3-chloro-4-fluorophenyl)-nitro'-hydroxy-4-((2-(nitrogen, thio-dimethylsulfoxideimine)ethyl)amino) -1,2,5-oxadiazole-3-carboquinone

   (±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitroethyl sulfoximine)ethyl)amino )-1,2,5-oxadiazole-3-carboquinone

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

   (±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-aza-isobutyl sulfoximine)ethyl) Amino)-1,2,5-oxadiazole-3-carboxamidine

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

   (±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro(2,2,2-trifluoroethyl) Sulfoxide imine) ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

   (±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro)(3,3,3-trifluoropropyl) Sulfoxide imine) ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

   (±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro(2-difluoroethyl)) sulfoxide Amine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

   (±)(Z)-N-(3-chloro-4-fluorophenyl)-nitro'-hydroxy-4-((2-(1-oxo-3,4,5,6-tetrahydro-1λ ^{6 )} ,2-thiazin-1-yl)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

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

   (±)(Z)-N-(3-chloro-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methyl-nitro-(4-fluorophenylsulfoximine) Ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

   (±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(methylaminocarbonyl) sulfoxide) Imine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

   (±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(isopropylcarbamoyl))) Sulfimide imine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

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

   (±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(formylisopropyl)) sulfoxide) Amine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

   (±)(Z)-N-(3-chloro-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methyl-nitro-(phenylsulfonyl) sulfoximine)) Amino)-1,2,5-oxadiazole-3-carboxamidine

   (±)(Z)-N-(3-chloro-4-fluorophenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(nitro-phenylaminosulfonyl)) sulfoxide Imine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

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

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

   (±)(Z)-N-(3-trifluoromethylphenyl)-aza--hydroxy-4-((2-(thio-methyl-aza-isobutyl sulfoxide imine)ethyl)amino )-1,2,5-oxadiazole-3-carboquinone

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

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

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

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

   (±)(Z)-N-(3-trifluoromethylphenyl)-nitro'-hydroxy-4-((2-(1-oxo-3,4,5,6-tetrahydro-1λ ⁶ , 2-thiazin-1-yl)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

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

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

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

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

   (±)(Z)-N-(3-trifluoromethylphenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(methylaminocarbonyl) sulfoxide) Amine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

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

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

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

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

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

   (±)(Z)-N-(3-trifluoromethylphenyl)-nitro'-hydroxy-4-((2-(thio-methyl-nitro-(methylsulfonyl) sulfoximine)) Amino)-1,2,5-oxadiazole-3-carboxamidine

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

   (±)(Z)-N-(3-trifluoromethylphenyl)-aza--hydroxy-4-((2-(thio-methyl-nitro-(nitro-phenylaminosulfonyl)) sulfoxide Amine)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine

   (±)(Z)-N-(3-trifluoromethylphenyl)-nitro'-hydroxy-4-((2-(thio-methyl-nitro-(carbamoyl) sulfoximine)) Base)amino)-1,2,5-oxadiazol-3-carboxamidine.
10. A compound of formula (I) according to claim 1 wherein said pharmaceutically acceptable The salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, triflate, besylate, p-toluenesulfonate (tosylate), 1-naphthalenesulfonate, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalate, succinate, fumaric acid Salt, maleate, benzoate, salicylate, phenylacetate, mandelate.
11. Use of a compound of the formula (I) according to claim 1 for:

    (i) preparing a guanamine-2,3-dioxygenase inhibitor;

    (ii) preparing a medicament for preventing and/or treating a guanamine-2,3-dioxygenase mediated disease; or

    (iii) Preparation of an antitumor or anti-inflammatory drug.
12. The use according to claim 11, wherein the indoleamine-2,3-dioxygenase-mediated disease is cancer, neurodegenerative disease, HIV infection, eye disease, mental disorder, depression, Anxiety disorders, Alzheimer's disease, and/or autoimmune diseases.
13. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises:

    A compound of the formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof, according to claim 1; preferably the pharmaceutical composition further comprises other antibiotics a tumor drug, including but not limited to a cancer immunotherapy drug: PD-1 antibody, CTLA-4 antibody, PD-L1 antibody, PD-L2 antibody, any other chemotherapeutic drug or targeted therapeutic drug, For example, HDAC inhibitors and EP4 antagonists.
14. A method of preparing a compound of the formula (I) according to claim 1, comprising the steps of:

    

    (a) compound P1 is reacted with R ₃ OBF ₄ to give compound P2;

    (b) compound P1 is reacted with ArB(OH) ₂ and Cu(OAc) ₂ to obtain compound P3;

    (c) Compound P2 or P3 is ring-opened in the presence of sodium hydroxide (such as aqueous sodium hydroxide) to give the final product. P4 or P5, that is, a compound of the formula (I);

    Alternatively, the method comprises the steps of:

    

    (a) Compound P1 is reacted with RN=C=O or ClSO ₂ R ² to give compound P6 or P7;

    (b) Compound P6 or P7 is ring-opened in the presence of sodium hydroxide (such as aqueous sodium hydroxide) to give the final product P8 or P9, a compound of formula (I);

    Or, the method includes the following steps:

    

    (a) Compound D is reacted with compound E and a reducing agent under acid catalysis to give compound F;

    (b) Compound F is ring-opened under alkaline hydrolysis conditions (such as aqueous sodium hydroxide) to give the final product of formula (I);

    Alternatively, the method comprises the steps of:

    

    In the formulae, R ¹ , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , n, m, X and ring A are as defined above.
15. A method for preventing and/or treating a guanamine-2,3-dioxygenase mediated disease comprising administering a compound of the formula (I) according to claim 1 or a drug according to claim 13 to a patient The step of the composition.