CN108017639B - IDO inhibitor and preparation method and application thereof - Google Patents

Abstract

The invention provides pharmaceutically acceptable salts, isomers, racemates, non-corresponding isomers and pharmaceutical compositions of formula I, formula II, formula III or formula IV, and application thereof in treating diseases related to indoleamine 2,3-dioxygenase (IDO), in particular application thereof in treating various major diseases such as tumors, Alzheimer's disease, depression, cataract and the like; r, R therein₂The definitions of the groups such as W and the like are shown in the specification. The results of preliminary drug activity studies show that the compound has significant IDO inhibitory activity. Simultaneously, SD rats are taken as tested animals, and LC/MS is appliedThe method determines the drug concentration in the blood plasma of a rat at different times after the rat is administrated with the compound by gavage, and researches the pharmacokinetic behavior of the compound in the rat body, and the result shows that the compound has obvious drug absorption effect and better clinical application prospect.

Description

IDO inhibitor and preparation method and application thereof

Technical Field

The field belongs to the field of antitumor drugs, and particularly relates to an IDO inhibitor, and a preparation method and application thereof.

Background

Indoleamine 2,3-dioxygenase (IDO) is the only rate-limiting enzyme outside the liver that catalyzes the catabolism of tryptophan along the kynurenine pathway, and is widely distributed in many tissues and cells in humans and animals. The IDO can achieve the effect of inhibiting the proliferation of pathogenic microorganisms by reducing the concentration of tryptophan in the microenvironment; IDO is also closely related to nervous system diseases, and can reduce the level of 5-hydroxytryptamine to cause depression and also cause accumulation of neurotoxic metabolites such as quinolinic acid in brain; some evidence suggests that IDO is involved in the induction of immune tolerance. The research of mammal pregnancy, tumor drug resistance, chronic infection and autoimmune diseases shows that the cell expressing IDO can inhibit T cell reaction and promote tolerance, so that ID O plays an important role in metabolic immunoregulation in inhibiting T cell immunity and anti-tumor immunity, inducing maternal and fetal immune tolerance and graft immune tolerance. At present, IDO is an important drug discovery target and has become the most important small molecule regulation target of anti-tumor immunotherapy.

Few IDO inhibitor compounds with IC50 on nanomolar scale before 2010 exist, and no IDO inhibitor medicine is on the market at home and abroad at present. Two compounds have been introduced into clinical trials abroad, namely the NLG919 compound from New link Genetics, usa, Indoximod (NLG-8189) and the INCB024360 compound from Incyte, usa, and patent applications relating to IDO inhibitors are WO2016071293, WO2010005958, WO2014066834, WO2016155545, and the like.

Indoximod (NLG-8189), a methylated tryptophan, developed by New Link Genetics, is used as an IDO (indoleamine- (2,3) -dioxygenase) pathway inhibitor, can reverse IDO-mediated immunosuppression, and has a very good clinical application prospect.

At present, a higher technical barrier still exists in the research and development of an IDO inhibitor, the inhibition effect of the existing IDO inhibitor is not ideal, the IDO inhibitor serving as a medicine with a new medicine target and a new mechanism can be applied to the treatment of a plurality of important diseases such as tumors, alzheimer disease, depression, cataract and the like, the IDO inhibitor has a very good market value, and in order to meet the clinical requirement on IDO regulation metabolites at present, a series of IDO inhibitors with medicine activity are to be researched, so that the IDO inhibitor has a great significance to the medicine field.

Disclosure of Invention

The invention aims to provide an IDO inhibitor and a preparation method thereof.

Another object of the present invention is to provide pharmaceutical compositions comprising IDO inhibitors described in formula I and uses thereof.

The object of the invention can be achieved by the following measures:

a compound shown in formula I, or pharmaceutically acceptable salt, isomer, racemate and diastereoisomer thereof,

wherein the content of the first and second substances,

R₂optionally selected from halogen, hydrogen atom, substituted or unsubstituted phenyl or p-fluoroanilino,

Wherein, the substituent of the phenyl is one or more of halogen, trifluoromethyl and amino;

r is selected from hydrogen atom,

Substituted or unsubstituted C_5～12Aryl, substituted or unsubstituted heteroaryl of 5 to 12 ring atoms, C_1～6Alkyl, amino, p-fluoroanilino,

In the formula (I), the R is₅Optionally selected from hydrogen atoms,

Or C_2～8An ether group, for example, is

Further, the substituent of the aryl or heteroaryl in the R group is independently selected from amino, dimethylamino, diethylamino and C_1～20Alkyl radical, C_1～10Alkoxy radical, C_2～6Acyl group, trifluoromethyl ether group, C_5～12Aryl, halogen, trifluoromethyl, aldehyde group, benzyloxy, phenoxy, phenyl, cyano, hydroxy, C_1～6Hydroxyalkyl, vinyl, C_2～8Sulfide radicals are, for example

C_1～6Alkoxy radical, C_2～8Carboxylic acid ester group, C_2～8Ether radical, C_1～8One of an amide group or a substituted amide group;

further, the substituted amido in R is optionally selected from the group consisting of:

or

Wherein Y is₁Represents C_1～6Alkyl radical, C_1～6Any one of alkoxy, phenyl, vinyl, methylamino, cyclopropylamino and anilino,

w is selected from

C_1～6Alkoxy, amino, p-fluoroanilino,

Wherein the Q group is a substituted or unsubstituted 4-to 8-membered heterocycloalkyl group containing at least one N atom, wherein the 5-to 8-membered heterocycle contains one or more N, O, S atoms, and the substituents of the Q group are optionally selected from

One or more of hydroxyl, in the group Q, Y represents aryl with 5-12 ring atoms, heteroaryl with 5-12 ring atoms, C_1～6Alkyl radical, C_3～6Cycloalkyl, benzyl, or a salt thereof,

C_1～4Alkyl substituted 5-6 ring atom heteroaryl, benzyloxy substituted phenyl, hydroxyl substituted 5-8 ring atom aryl, C_1～4Any one of alkoxy substituted aryl with 5-8 ring atoms, acrylamide substituted aryl with 5-8 ring atoms and amino substituted aryl with 5-8 ring atoms.

In one embodiment, formula I represents a compound of formula II below and salts, isomers, racemates, diastereomers thereof:

R₁optionally self-substituted or non-substitutedSubstituted C_5～12Aryl, substituted or unsubstituted heteroaryl with 5 to 12 ring atoms, wherein the substituents are respectively and independently selected from amino, dimethylamino, diethylamino and C_1～20Alkyl radical, C_1～10Alkoxy radical, C_2～6Acyl group, trifluoromethyl ether group, C_5～12Aryl, halogen, trifluoromethyl, aldehyde group, benzyloxy, phenoxy, phenyl, cyano, hydroxy, C_1～6Hydroxyalkyl, vinyl, C_2～8Sulfide radicals are, for example

C_1～6Alkoxy radical, C_2～8Carboxylic acid ester group, C_2～8Ether radical, C_1～8One of an amide group or a substituted amide group;

further, R₁Wherein said substituted amido group is optionally selected from the group consisting of:

or

Wherein Y is₁Represents C_1～6Alkyl radical, C_1～6Any one of alkoxy, phenyl, vinyl, methylamino, cyclopropylamino and anilino;

R₂the definitions of (A) and (B) are the same as those of the specification.

In one embodiment, formula I represents a compound of formula III below and salts, isomers, racemates, diastereomers thereof:

wherein the content of the first and second substances,

R₂the definitions of the components are the same as those in the specification;

R₅optionally selected from hydrogen atoms,

Or C_2～8An ether group, for example, is

Q is a substituted or unsubstituted 4-to 8-membered heterocycloalkyl group containing at least one N atom, wherein the 5-to 8-membered heterocycle contains one or more N, O, S atoms; the substituents of the Q group are optionally selected from

One or more of hydroxyl, in the group Q, Y represents aryl with 5-12 ring atoms, heteroaryl with 5-12 ring atoms, C_1～6Alkyl radical, C_3～6Cycloalkyl, benzyl, or a salt thereof,

C_1～4Alkyl substituted 5-6 ring atom heteroaryl, benzyloxy substituted phenyl, hydroxyl substituted 5-8 ring atom aryl, C_1～4Any one of alkoxy substituted 5-6 membered aryl, vinylamide substituted 5-8 ring atom aryl, and amino substituted 5-8 ring atom aryl.

In one embodiment, formula I represents a compound of formula IV below and salts, isomers, racemates, diastereomers thereof:

wherein the content of the first and second substances,

R₂and R₅The definitions of the components are the same as those in the specification;

R₆is optionally selected fromC_1～6Alkoxy, amino, p-fluoroanilino,

One kind of (1).

The invention also provides a preparation method of the compound in the general formula I and salts, isomers, racemates and non-corresponding isomers thereof, but the invention is not limited to the methods described below. All starting materials are prepared or purchased directly according to the radical characteristics of the target molecule according to the general formula and by the schemes in these schemes, methods well known to the person skilled in the art of organic chemistry:

scheme I Synthesis route for Compounds of formula I

W, R, R in the synthetic route to the compounds of formula I₂The definition of the groups is the same as that in the general formula I on the specification, and the synthetic route comprises the following steps:

(1) taking a compound a as a starting material, and reacting with a corresponding W-H amine compound containing a W group or C in a proper alcohol solvent_1～6And (3) reacting and refining the sodium alkyl alkoxide compound under the catalytic action of organic base to obtain a compound b.

(2) And (3) carrying out coupling reaction on the compound b and a boric acid compound containing an R group under the action of alkali and a palladium catalyst to obtain a compound c.

(3) When R is₂Optionally from substituted or unsubstituted phenyl,

When the compound c is reacted with the corresponding compound containing R₂Boronic acid compounds of the group

Performing coupling reaction under the action of inorganic base and palladium catalyst to obtain the catalystA target molecule of formula I;

when R is₂In the case of para-fluoroaniline radical, the compound c is reacted directly with R₂Reacting with an H-ammonia compound, and catalyzing with trifluoroacetic acid to obtain a corresponding target molecule.

R₂When it is a hydrogen atom, it is selected from

Further reacting the starting materials to obtain the corresponding target molecules.

When W C_1～6Alkoxy can be started from compound a with the corresponding C_1～6And (3) reacting and refining the sodium alkyl alkoxide compound under the catalytic action of organic base to obtain a compound b.

Further, the alcohol solvent in step (1) may be methanol, ethanol, isopropanol, etc., and the organic base may be triethylamine, N-diisopropylethylamine, etc., at-10 deg.C to 30 deg.C, preferably 20 deg.C to 25 deg.C.

Further, in the step (2) and the step (3), the reaction solvent is one or more selected from DME, dioxane, DMF, methanol, ethanol and isopropanol; the alkali is selected from one or more of potassium phosphate, potassium acetate and potassium carbonate; the palladium catalyst is one or more of palladium tetratriphenylphosphine, (palladium tetratriphenylphosphine) palladium dichloride, ferrocene palladium dichloride and palladium acetate; the reaction temperature is 50 ℃ to 120 ℃.

In one scheme, when R represents a hydrogen atom, the compound b is directly subjected to debromination reaction, and corresponding sites are changed into hydrogen atoms under the action of a catalytic amount of palladium catalyst, so that target molecules are obtained through the reaction.

In one scheme, when R in the target formula I is a pyrazole group, the intermediate acid containing the pyrazole protecting group needs to be subjected to catalytic deprotection reaction conditions, the reaction solvent is selected from tetrahydrofuran, methanol and the like, hydrochloric acid can be selected for catalytic deprotection reaction, and the concentration of hydrochloric acid can be 1-12 mol/L, preferably 4-5 mol/L.

In one embodiment, when R and R are₂When both are pyrazole groups, it is first necessary to synthesize R and R₂All are protected pyrazole groups, and the target compound is obtained by removing a protective agent from the compound through acidity.

The preparation method of the compound of the general formula II or the pharmaceutically acceptable salt, the isomer, the racemate and the diastereoisomer thereof comprises the following steps:

scheme two

Wherein R is₂And R₁The definitions are the same as in formula II.

Dissolving a compound 1 in an organic solvent, adding organic base such as triethylamine, pyridine and the like under the protection of nitrogen, dissolving a compound 2 in the organic solvent, dropwise adding the mixture into a reaction system, and continuously reacting until the compound 3 is completely obtained after the dropwise adding is finished; and (2) performing coupling reaction on the compound 3 and the compound 4 under the action of a catalyst to obtain a compound shown in a formula II, wherein the catalyst is one or more of tetratriphenylphosphine palladium, ferrocene palladium dichloride, (bis (triphenylphosphine) palladium dichloride and palladium acetate, and the organic base is one or more of potassium phosphate, potassium acetate and potassium carbonate.

The preparation method of the compound of the general formula III and the salt, the isomer, the racemate and the non-corresponding isomer thereof comprises the following steps:

scheme three

Dissolving the compound 1 in an organic solvent, adding an organic base such as triethylamine, pyridine and the like, dissolving the compound 4 in the organic solvent, dropwise adding the mixture into a reaction system, and continuously reacting the mixture until the compound 5 is completely obtained after the dropwise adding is finished;

and (2) carrying out coupling reaction on the compound 5 and the compound 6 under the action of inorganic base and palladium catalysts to obtain a compound in a formula III, wherein the catalysts are one or more of palladium tetratriphenylphosphine, palladium ferrocene dichloride, (bis (triphenylphosphine) palladium dichloride and palladium acetate, and the inorganic base is one or more of potassium phosphate, potassium acetate and potassium carbonate.

The preparation method of the compound of the general formula IV and the salt, the isomer, the racemate and the non-corresponding isomer thereof comprises the following steps:

scheme four

Dissolving compound 1 in organic solvent, adding organic base such as triethylamine, pyridine, etc., and selecting appropriate R₆-H type amino derivatives or containing C_1～6Alkyl alcohol compounds (when R is₆Represents C_1～6Alkoxy) is dissolved in an organic solvent, the mixture is dripped into a reaction system, and the reaction is continued until the intermediate compound 1' is completely obtained after the dripping is finished;

reacting the intermediate compound 1' with R₅The protected pyrazole boronic acid pinacol ester compound is subjected to coupling reaction under the action of inorganic base and palladium catalysts to obtain a compound in a formula, wherein the catalysts are one or more of palladium tetratriphenylphosphine, palladium ferrocene dichloride, (bis (triphenylphosphine) palladium dichloride and palladium acetate, and the inorganic base is one or more of potassium phosphate, potassium acetate and potassium carbonate.

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt, isomer, racemate, diastereoisomer, or mixture thereof of formula I, formula II, formula III, or formula IV as an active ingredient, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.

The pharmaceutical composition preferably contains 0.1-99.5% by weight of pharmaceutically acceptable salts, isomers, racemates, diastereoisomers or mixtures thereof of formula I, formula II, formula III or formula IV as active ingredients, more preferably 1-90% by weight of active ingredients.

The pharmaceutical compositions containing the active ingredient compounds may be in a form suitable for oral administration, for example as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water soluble taste masking substances such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose, or time extending substances such as ethyl cellulose, cellulose acetate butyrate may be used.

Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water soluble carrier, for example polyethylene glycol, or an oil vehicle, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol (heptadecaethyleneoxy cetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyethylene oxide sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl paraben, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrative of the examples given above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyethylene oxide sorbitol monooleate. The emulsions may also contain sweetening agents, flavouring agents, preservatives and antioxidants. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding to a mixture of water and glycerol. The injection solution or microemulsion may be injected into the bloodstream of a patient by local bulk injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.

As is well known to those skilled in the art, the dosage of a drug to be administered depends on a variety of factors, including but not limited to: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dose of the pharmaceutical composition having the pharmaceutically acceptable salt, isomer, racemate, diastereoisomer or mixture thereof of formula I, formula II, formula III or formula IV as an active ingredient or the kind of the pharmaceutically acceptable salt may be verified according to the conventional treatment protocol.

Unless otherwise indicated, the following terms used in the claims and specification have the following meanings:

"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

"amino" means-NH₂。

"trifluoromethyl" means-CF₃。

"aryl" means an all-carbon monocyclic or fused polycyclic group of 5 to 12 carbon atoms having a completely conjugated pi-electron system. Non-limiting examples of aryl groups are phenyl, naphthyl and anthracenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, even more preferably one or two, independently selected from the group consisting of lower alkyl, trihaloalkyl, halogen, hydroxy, lower alkoxy, mercapto, (lower alkyl) thio, cyano, acyl, thioacyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, nitro, N-sulphonylamino, S-sulphonylamino. Preferably, aryl is 5-membered monocyclic aryl, 6-membered monocyclic aryl.

"heteroaryl" denotes a monocyclic or fused ring group of 5 to 12 ring atoms, containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C, and additionally having a completely conjugated pi-electron system. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined to the parent structure is a heteroaryl ring. Heteroaryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and still more preferably one or two. Non-limiting examples of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine, and carbazole; preferably, the heteroaryl is a nitrogen-containing 5-membered monocyclic heteroaryl, a nitrogen-containing 6-membered monocyclic heteroaryl.

"alkyl" means a saturated aliphatic radical of 1 to 20 carbon atoms, including straight and branched chain radicals (a numerical range referred to herein, e.g., "1 to 20", means that the radical, in this case alkyl, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). The alkyl group in the present invention includes an "alkylene group". Alkyl groups having 1 to 6 carbon atoms are referred to as lower alkyl groups. When a lower alkyl group has no substituent, it is referred to as unsubstituted lower alkyl. More preferably, the alkyl group is a medium size alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, ethylene, propyl, propylene, 2-propyl, n-butyl, isobutyl, butylene, t-butyl, pentyl, and the like. Preferably, the alkyl group is a lower alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, butylene, isobutyl, tert-butyl, etc. Alkyl groups may be substituted or unsubstituted.

"cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably a cycloalkyl ring comprising 3 to 10 carbon atoms, most preferably a cycloalkyl ring comprising 3 to 6 carbon atoms, most preferably cyclopropyl. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like, with cyclopropyl, cyclohexenyl being preferred. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxylic acid groups, carboxylic acid ester groups.

"P-fluoroanilino" means

"Ether" means an aliphatic ether group having two alkyl groups connected by an oxygen atom, wherein the alkyl groups are as defined above.

"alkoxy" means-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl). Alkoxy groups comprising 1 to 8 carbon atoms are preferred, and representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.

"dimethylamino" refers to a monovalent radical remaining after removal of a hydrogen atom from an imino group in a dimethylamine molecule.

"diethylamino" refers to a monovalent radical remaining in the diethylamine molecule after removal of the hydrogen atom from the imino group.

The remaining monovalent radicals of an organic or inorganic oxyacid molecule of the "acyl group" after removal of the hydroxyl group are collectively referred to as acyl groups.

"hydroxy" means-OH

"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

"aldehyde" means-CHO.

"cyano" means-CN.

"alkenyl" means-CH ═ CH-

"thioether group" means a linkage of two carbons by a sulfur atom_1～6The number of carbon atoms in the aliphatic thioether group of the alkyl group is preferably 2 to 8.

"carboxylate" means-C (O) O (alkyl) or C (O) O (cycloalkyl), wherein alkyl or cycloalkyl is as defined herein above.

The "amide group" refers to a compound group formed by substituting a hydroxyl group in a carboxylic acid with an amino group (or an amine group), and may be considered as a derivative group in which a hydrogen of ammonia (or an amine) is substituted with an acyl group.

"acrylamido" means

"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:

(1) salts with acids are formed by reaction of the free base of the parent compound with inorganic acids such as, but not limited to, hydrochloric, hydrobromic, nitric, phosphoric, metaphosphoric, sulfuric, sulfurous, and perchloric acids or organic acids such as, but not limited to, acetic, propionic, acrylic, oxalic, (D) or (L) malic, fumaric, maleic, hydroxybenzoic, γ -hydroxybutyric, methoxybenzoic, phthalic, methanesulfonic, ethanesulfonic, naphthalene-1-sulfonic, naphthalene-2-sulfonic, p-toluenesulfonic, salicylic, tartaric, citric, lactic, mandelic, succinic, or malonic acids, and the like. The salt has safety, effectiveness and bioactivity in mammalian body.

"pharmaceutical composition" refers to a mixture of one or more compounds described herein or their pharmaceutically acceptable salts, isomers, prodrugs, etc. with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.

By "pharmaceutically acceptable carrier" is meant a carrier or diluent that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the compound being administered.

"excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound. Examples of excipients include, without limitation, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

The invention also provides application of pharmaceutically acceptable salts, isomers, racemates and non-corresponding isomers of the formula I, the formula II, the formula III or the formula IV in treating diseases related to indoleamine 2,3-dioxygenase (IDO), in particular application of the pharmaceutically acceptable salts, isomers, racemates and non-corresponding isomers in treating various major diseases such as tumors, Alzheimer's disease, depression, cataract and the like, and preliminary medicinal activity research results show that the pharmaceutically acceptable salts, isomers, racemates and non-corresponding isomers have obvious IDO inhibition activity. Meanwhile, SD rats are used as tested animals, the LC/MS/MS method is used for measuring the drug concentration in blood plasma of the rats at different moments after the rats are subjected to intragastric administration of the compound, and the pharmacokinetic behavior of the compound in the rats is researched.

Detailed Description

The following examples further illustrate the invention, but are intended to be illustrative only and not limiting as to the scope of the invention.

Example 1: preparation of Compound I-1

Synthesis of Compound 7:

adding 1.23g of 5-bromo-2, 4-dichloropyrimidine into a 100ml three-necked bottle, adding 5ml of ethanol, dissolving, placing the three-necked bottle into a refrigerator under the protection of nitrogen, adding 0.54g of triethylamine at 0 ℃, taking 1.5g of 2,4,5, 6-tetrahydro-2- (methylsulfonyl) pyrrolo [3,4-C ] pyrazole, adding 20ml of ethanol, dropwise adding into the reaction solution at 0 ℃, separating out solids in the reaction solution, continuing to perform low-temperature reaction for 2 hours after dropwise addition, detecting by TLC that raw materials are completely reacted, stopping the reaction, and performing suction filtration to obtain 1.74g of similar white solids, wherein the yield is 85%.

Synthesis of Compound I-1:

a100 ml single-neck flask was charged with 0.20g of Compound 1, 0.13g of 4-fluoro, 3-trifluoromethylphenylboronic acid, and 0.06g of Pd (dppf) Cl in that order₂0.22g of potassium carbonate, 10ml of DMA and 1ml of water react for 2 hours under the protection of nitrogen, TLC detects that the raw materials completely react and stops the reaction, the reaction liquid is poured into water, 100ml of EA is added for extraction, 50ml of saturated sodium chloride is used for washing, anhydrous sodium sulfate is used for drying, decompression and spin-drying are carried out, column chromatography (ethyl acetate/petroleum ether) is carried out to obtain 50mg of white solid, namely the compound I-1, and the yield is 21%.

¹H NMR(400MHz,d6-DMSO):＝8.06(s,1H),8.02(s,1H),7.91-7.89(m,1H),7.86-7.82(m,1H),7.83-7.61(m,1H),4.35-4.31(m,4H),3.50(s,3H)ppm.HRMS(ESI)(M+H)⁺＝462.29.

EXAMPLE 2 Synthesis of Compound I-48

Preparation of intermediate 8 compound:

0.60g of Compound 1 is weighed into a 100mL reaction flask, and 0.26g of 3-thiopheneboronic acid, 0.14g of Pd (dppf) Cl₂And 0.66g of potassium carbonate, and finally 10mL of DMA and 1mL of water were added, and the mixture was replaced with nitrogen three times, placed in an oil bath, and allowed to rise to 80 ℃ to react for 1 hour. TLC to check the reaction was complete, quenched with 100mL of water, extracted with 50mL of 2EA, combined organic layers and dried over anhydrous sodium sulfate, spin-dried under reduced pressure, and column chromatographed (petroleum ether: ethyl acetate) to give 300mg of the final product as intermediate 2, 99% pure.

Synthesis of Compounds I-48:

0.29g of intermediate 8 was weighed into a 100mL reaction flask, and 0.28g of 4-fluoro-3-trifluoromethylphenylboronic acid, 0.10g of Pd (dppf) Cl was weighed in₂And 0.36g of potassium carbonate, finally 10mL of GME and 1mL of water were added, nitrogen was replaced three times and placed in an oil bath, and the temperature was raised to 80 ℃ to react for 1 hour. TLC to detect the reaction is complete, adding 100mL water to quench, extracting with 50mL 2EA, combining organic layers and drying with anhydrous sodium sulfate, drying under reduced pressure, and performing column chromatography (petroleum ether: ethyl acetate) to obtain 40mg of product, namely compound I-48.

EXAMPLE 3 Synthesis of Compound I-52

Synthesis of Compound 9: taking a 100ml single-mouth bottle, sequentially adding 5.0g of Fmoc proline, 0.5g of methylamine, 3.2g of EDCI, 3.0g of triethylamine and 50ml of dichloromethane, reacting at room temperature for 3 hours, detecting by TLC that raw materials completely react, stopping the reaction, adding 50ml of DCM for dilution, washing with 25ml of 2 diluted HCl, washing with 50ml of 2 saturated sodium chloride, drying with anhydrous sodium sulfate, performing reduced pressure spin-drying to obtain a crude product, and performing column chromatography to obtain 4.5g of a white solid.

Synthesis of Compound 10: and (3) adding 4.5g of compound 3, 2ml of pyridine and 10ml of DMF into a 100ml single-neck bottle in sequence, reacting at room temperature for 2h, detecting that the raw materials completely react by TLC, stopping the reaction, adding 50ml of DCM for dilution, washing by 50ml of 2 saturated sodium chloride, drying by anhydrous sodium sulfate, performing reduced pressure spin drying to obtain a crude product, and performing column chromatography to obtain 1.5g of an off-white solid.

Compound 10' synthesis: adding 1.23g of 5-bromo-2, 4-dichloropyrimidine into a 100ml three-necked bottle, adding 5ml of ethanol for dissolving, placing the three-necked bottle into a refrigerator under the protection of nitrogen after 5ml of ethanol is dissolved, adding 0.54g of triethylamine at 0 ℃, adding 1.0g of compound 4 into 20ml of ethanol for dissolving, dropwise adding the compound 4 into the reaction solution at 0 ℃, separating out solids in the reaction solution, continuing low-temperature reaction for 2 hours after dropwise adding, detecting that the raw materials are completely reacted by TLC, stopping the reaction, and obtaining 1.2g of white-like solids by suction filtration.

Synthesis of Compound I-52: a100 ml single-neck bottle was taken, and 1.0g of the compound 10', 0.71g of 1- (1-ethoxyethyl) -4-pyrazoleboronic acid pinacol ester, 0.19g of Pd (dppf) Cl₂0.92g of potassium carbonate, 20ml of DME and 2ml of water are reacted for 2 hours at 80 ℃ under the protection of nitrogen, TLC detects that the raw materials are completely reacted, the reaction is stopped and cooled to room temperature, the reaction liquid is poured into 100ml of water and is extracted by 50ml of 2EA, the organic phase is washed by saturated sodium chloride, dried by anhydrous sodium sulfate, decompressed and dried by spinning, and column chromatography separation is carried out to obtain 0.56g of white solid.

Example 4: synthesis of Compound I-65

Synthesis of Compound 11:

taking a 100ml single-mouth bottle, adding 1.13g of 5-bromo-2, 4-dichloropyrimidine, adding 5ml of ethanol for dissolving, placing at 0 ℃, then adding 0.50g of triethylamine, dissolving 1.96g of 4- (4-trifluoromethoxy phenoxy) piperidine in 10ml of ethanol, slowly dripping into the reaction solution for reaction for 3 hours, detecting that the raw materials are completely reacted by TLC, performing suction filtration, and leaching by a little ethanol to obtain 1.5g of off-white solid.

Synthesis of Compound 12:

a100 ml single-neck bottle was taken, and 1.0g of Compound 11, 0.71g of 1- (1-ethoxyethyl) -4-pyrazoleboronic acid pinacol ester, and 0.19g of Pd (dppf) Cl were added in this order₂0.92g of potassium carbonate,and 20ml of DME and 2ml of water, reacting for 2 hours at 80 ℃ under the protection of nitrogen, detecting by TLC that the raw materials completely react, stopping the reaction, cooling to room temperature, pouring the reaction liquid into 100ml of water, extracting by 50ml of 2EA, washing an organic phase by saturated sodium chloride, drying by anhydrous sodium sulfate, performing reduced pressure spin-drying, and performing column chromatography separation to obtain 0.96g of colorless transparent liquid.

Synthesis of Compound I-65:

taking 0.3g of the compound 12, dissolving the compound with 10ml of THF, adding 2ml of 4N hydrochloric acid, stirring at room temperature for three hours, detecting that the raw materials completely react by TLC, removing THF in a spinning mode, adding ammonia water to adjust the raw materials to be alkalescent, extracting with 25ml of 2EA, drying with anhydrous sodium sulfate, drying in a spinning mode under reduced pressure, and separating by column chromatography to obtain 50mg of white solid, namely the compound I-65.

Example 5: synthesis of Compound I-76

0.51g of compound 11, 0.74g of 1- (1-ethoxyethyl) -4-pyrazoleboronic acid pinacol ester, 0.10g of Pd (dppf) Cl2, 0.46g of potassium carbonate, 20ml of DME and 2ml of water are sequentially added into a 100ml single-neck bottle, the mixture reacts for 5 hours at 80 ℃ under the protection of nitrogen, TLC detects that raw materials completely react, the reaction is stopped, the reaction solution is poured into water and added with EA for extraction, saturated sodium chloride is washed, dried and spin-dried, column chromatography separation is carried out to obtain a colorless transparent liquid compound 16, the compound 11 is directly dissolved by THF, 2ml of 4N hydrochloric acid is added, after stirring for three hours at room temperature, the raw materials completely react, THF is spin-removed, ammonia water is added to adjust to alkalescence, EA is added for extraction, and after drying and spin-drying, column chromatography separation is carried out to obtain a.

Example 6: synthesis of Compound I-67

A100 ml single-necked flask was charged with 0.25g of Compound 12, 0.18g of 4-fluoro-3-trifluoromethylphenylboronic acid, and 0.07g of Pd (dppf) Cl in that order₂0.20g of potassium carbonate, 20ml of DME and 2ml of water react for 2 hours at 80 ℃ under the protection of nitrogen, TLC detects that the raw materials completely react,stopping the reaction, pouring the reaction liquid into water, adding EA for extraction, washing with saturated sodium chloride, drying and spin-drying, performing column chromatography separation to obtain a colorless transparent liquid compound 17, dissolving the compound 17 with THF, adding 2ml of 4N hydrochloric acid, stirring at room temperature for three hours, detecting that the raw materials react completely by TLC (thin layer chromatography), spinning off the THF, adding ammonia water to adjust to alkalescence, adding EA for extraction, drying and spin-drying, and performing column chromatography separation to obtain 50mg of a white solid compound I-67.

Example 7: synthesis of Compound I-81

Synthesis of Compound 13:

6.6g of 5-bromo-2, 4-dichloropyrimidine was added to a 100mL reaction flask, dissolved in 10mL of methanol, stirred at-3 ℃, 2.99g of triethylamine was added, 5g of proline was weighed and dissolved in 50mL of methanol, slowly added dropwise to the reaction flask, and stirred overnight. TLC detection reaction is complete, adding 200mL water quenching reaction, a small amount of EA extraction, removing unreacted A and removing part of product, the aqueous phase pH value is 5-6, and EA extraction. The organic layer was dried over anhydrous sodium sulfate and dried to give 3.0g of white solid 13.

Compound 14 synthesis:

a100 mL reaction vessel was charged with 3.0g of Compound 13, 1.8g of DIC, 2.0g of HOBT and 10mL of acetonitrile, and stirred at room temperature for 30 min. 1.4g of p-anisidine was weighed in and stirred for 1 hour. TLC detection reaction is complete, suction filtration is carried out, and the filter cake is washed twice with acetonitrile to obtain 3.77g of white solid.

Synthesis of Compound 15:

0.74g of Compound 14 was weighed into a 100mL reaction flask, and 0.64g of 1- (1-ethoxyethyl) -4-pyrazoleboronic acid pinacol ester, 0.16g Pd (dppf) Cl₂And 0.76g of potassium carbonate were added thereto, 10mL of GME and 1mL of water were further added thereto, the mixture was placed in an oil bath after nitrogen substitution was carried out three times, the temperature was raised from 30 ℃ to 80 ℃ and the reaction was carried out for 2 hours. TLC detection of the starting material essentially reacted completely, quenched with 100mL of water, extracted with EA, dried organic layer over anhydrous sodium sulfate, and column chromatography dried to yield 260mg of Compound 15.

Synthesis of Compound I-81:

0.19g of Compound 15 is weighed into a 100mL reaction flask and 0.18g of 1- (1-ethoxyethyl) -4-pyrazoleboronic acid pinacol ester, 0.05g Pd (dppf) Cl₂And 0.30g of potassium carbonate were added thereto, 10mL of dime and 1mL of water were further added thereto, the mixture was placed in an oil bath after nitrogen substitution was carried out three times, the temperature was raised from 30 ℃ to 80 ℃ and the reaction was carried out overnight. TLC detection of material residue, addition of 100mL water quenching, EA extraction, organic layer dried with anhydrous sodium sulfate, spin-dry column chromatography, 50mg compound I-81.

Example 8: synthesis of Compound I-94

A100 mL reaction flask was charged with 50mg of Compound 15, 0.01g of para-fluoroaniline and 2d of trifluoroacetic acid, 10mL of acetonitrile, and left to react overnight at 50 ℃. TLC detects that the raw material is basically reacted completely, stops the reaction, adds 100mL water to quench the reaction, extracts with EA, dries with anhydrous sodium sulfate, and carries out spin-dry column chromatography to obtain 18mg of compound I-94.

Example 9: synthesis of Compound I-86

1.0g of 5-bromo-2-methoxy-4-chloropyrimidine, 1.44g of 1- (1-ethoxyethyl) -4-pyrazoleboronic acid pinacol ester and 0.40g of Pd (dppf) Cl were added in this order to a 100ml single-neck flask₂Reacting 1.85g of potassium carbonate, 20ml of DME and 2ml of water at 80 ℃ for 2 hours under the protection of nitrogen, monitoring the reaction by TLC, pouring the reaction liquid into water, adding EA for extraction, washing with saturated sodium chloride, drying and spin-drying, carrying out column chromatography separation to obtain colorless transparent oily liquid, dissolving the liquid by THF, adding 3ml of 4N hydrochloric acid, stirring at room temperature to obtain a crude product, and carrying out column chromatography to obtain 200mg of a compound I-86.

According to the preparation method of the compound I-1, the compounds I-2-51, the compounds I-90 and the compounds I-91 are prepared under proper solvent and reaction temperature, and the results of nuclear magnetic resonance and mass spectrometry are shown in the following table.

TABLE 1

The compounds corresponding to the general formulas III and IV are prepared by the preparation method according to the third scheme and the fourth scheme in the specification, and the structure is verified by adopting a nuclear magnetic and mass spectrometry detection method, and the method is as follows:

TABLE 2

Biological evaluation

Test example 1 determination of the inhibitory activity of the compounds on IDO 1:

the present invention is further explained below with reference to test examples, which are not intended to limit the present invention, and pharmacodynamic tests and results of some compounds of the present invention are as follows. The structural formula of the compound is shown in the above examples in the specification.

1. Materials, kits and apparatus

L-ascorbic acid sodium salt

4- (dimethylamino) benzaldehyde

Trichloroacetic acid

L-tryptophan (Cat: T8941-25G, SIGMA)

Methylene blue (Cat: M9140-25G, SIGMA)

Potassium dihydrogen phosphate (Cat:10017618, national chemical reagent)

Disodium hydrogen phosphate (Cat:20040618, national medicine chemical reagent)

Constant temperature water tank (Cat: DK-8D, Shanghai sperm macro experimental facility)

Multifunctional enzyme mark instrument (Cat: M5, Molecular Devices)

96-well reaction plate (Cat:3590, costar)

IDO1 protease (commercially available)

Desktop Microplate reader SpectraMax M5Microplate reader (molecular devices)

Test compounds: self-made

Positive control drug: indoximod (NLG-8189) (commercially available)

2. Reagent preparation

100mM PBS：

Mix 100mM disodium hydrogen phosphate and 100mM potassium dihydrogen phosphate at pH6.5 at 3:5

IDO1 assay buffer:

100mM PBS, pH6.5, containing 400. mu.L-tryptophan, 20mM ascorbate, 20. mu.M methylene blue and 1000U/ML catalase

30% trichloroacetic acid

ddH of 30% trichloroacetic acid₂O solution

Ehrlich reagent

1% (w/v) dilution of 4- (dimethylamino) benzaldehyde compound

All compounds were dissolved in DMSO and assayed by diluting each compound at the required concentration, each concentration being duplicate wells, with DMSO being controlled to a final concentration of 1%.

3. Test method

a.) preparing a reaction mixture: add 50nM IDO1 and desired concentration of assay to 100. mu.L IDO1 assay buffer

A compound (I) is provided. IDO1 and assay buffer required preheating to 37 ℃.

b.) reaction in a constant temperature water tank at 37 ℃ for 30 min.

c.) add 50. mu.L of 30% trichloroacetic acid.

d.) reaction in a constant temperature water tank at 52 ℃ for 30 min.

e.) centrifugation at 12000g for 10min at room temperature.

f.) mix 100. mu.L of supernatant with 100. mu.L of Ehrlich reagent.

g.) absorbance was measured at 480nm with an M5microplate reader.

4. Data analysis

Inhibition rate (OD)_positive―OD_sample)/(OD_positive―OD_negative)*100％

5. Results and discussion

The test detects the inhibitory activity of the compound to be tested on IDO1 enzyme at 10 mu M and 1 mu M, each dilution concentration is a multi-hole test, the final concentration of DMSO in a reaction system is controlled to be 1%, the inhibition rates of the two concentrations are respectively tested twice, an average value is taken, the test result is shown in the following table, wherein the compound NLG8189 is a positive reference compound, and the result shows that the compound to be tested shows stronger inhibitory activity on IDO1 protease.

Inhibitory Activity of the Compounds of Table 3 against IDO1 enzyme at 10. mu.M (% inhibition Rate Unit)

TABLE 4 inhibitory Activity of the Compounds on IDO1 enzyme at 1. mu.M

Test example 2:

pharmacokinetic evaluation

SD rats are used as test animals, the LC/MS/MS method is used for measuring the drug concentration in blood plasma of the rats at different moments after the rats are administered with the compounds I-31, I-66, I-82 and I-83 by gavage, the pharmacokinetic behavior of the compounds in the rats is researched, and the pharmacokinetic characteristics of the compounds are evaluated.

The experimental scheme is as follows:

1. test animal

The test rats were given an environmental acclimation period of 2 days prior to the experiment.

24 SD rats were obtained, half male and half female, and the body weight was about 200 g. The groups of male/female rats were randomly divided into 4 test groups (6 per group, half male/female) based on average body weight.

2. Plasma sample processing

Collecting rat plasma 50 μ l, adding 200 μ l protein precipitant, shaking for 3min to precipitate protein, centrifuging at 20000rcf for 10min, transferring 80 μ l supernatant to sample injection bottle, and analyzing 2 μ l sample injection.

3. Preparing the medicine:

weighing appropriate amount of the medicine, adding 0.5ml of dimethylacetamide to dissolve, adding 10% 2-hydroxypropyl-beta-cyclodextrin to the final volume, and performing ultrasonic treatment to obtain 1.5mg/ml suspension.

4. Procedure of experiment

Rats were fasted for 12h and 10ml/kg of Compound I-1, Compound I-11, Compound I-12, Compound I-20 and Olaparib were administered sequentially by gavage (i.g.). After administration to rats, about 200. mu.l of venous blood from rats before (0) and 15min, 30min, 45min, 1h, 2h, 4h, 6h, 8h, 12h and 24h after administration were collected from orbital venous plexus into blood collection tubes (blood collection tubes were anticoagulated with 0.5% heparin sodium in advance), supernatant plasma was transferred after centrifugation at 4000rpm for 5min, plasma samples were pretreated with precipitated protein and analyzed to determine the chronological concentration of the compound in the plasma.

5. Pharmacokinetic parameter results

After SD rats are subjected to single intragastric administration of 10ml/kg of the compound, the in vivo actual measurement of the blood concentration of the drug in the course of time is carried out by using DAS software to calculate the pharmacokinetic parameters of the drug in the SD rats, and the results are respectively listed as the following table:

TABLE 5 pharmacokinetic parameters of the Compounds of the invention

And (4) conclusion: the compound of the invention has good drug absorption and obvious drug absorption effect.

Claims (7)

1. A compound of formula II or a pharmaceutically acceptable salt thereof,

R₂optionally selected from halogen, hydrogen atom, substituted or unsubstituted phenyl or p-fluoroanilino,

Wherein, the substituent of the phenyl is one or more of halogen, trifluoromethyl and amino;

R₁optionally self-substituted or non-substituted C_5～12Aryl or substituted or unsubstituted heteroaryl of 5 to 12 ring atoms, said aryl being phenyl, naphthyl or anthracenyl, said heteroaryl being pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl or carbazolyl,

the substituents of the aryl or the heteroaryl are respectively and independently selected from amino, dimethylamino, diethylamino and C_1～20Alkyl radical, C_1～10Alkoxy radical, C_2～6Acyl group, trifluoromethyl ether group, C_5～12Aryl, halogen, trifluoromethyl, aldehyde group, benzyloxy, phenoxy, cyano, hydroxy, C_1～6Hydroxyalkyl, vinyl, C_2～8A thioether group,

C_2～8Carboxylic acid ester group, C_2～8Ether radical, C_1～8Amide or

Wherein Y is₁Represents C_1～6Any one of alkoxy, phenyl, vinyl, methylamino, cyclopropylamino and anilino.

2. A compound of formula III or a pharmaceutically acceptable salt thereof:

wherein R is₂Optionally selected from halogen, hydrogen atom, substituted or unsubstituted phenyl or p-fluoroanilino,

Wherein, the substituent of the phenyl is one or more of halogen, trifluoromethyl and amino;

R₅optionally selected from hydrogen atoms,

Or C_2～8An ether group;

q is a substituted or unsubstituted 4-to 8-membered heterocycloalkyl group containing at least one N atom; the substituents of the Q group are optionally selected from

One or more of hydroxyl, in the group Q, Y represents aryl with 5-12 ring atoms, heteroaryl with 5-12 ring atoms, C_1～6Alkyl radical, C_3～6Cycloalkyl, benzyl, or a salt thereof,

C_1～4Alkyl substituted 5-6 ring atom heteroaryl, benzyloxy substituted phenyl, hydroxyl substituted 5-8 ring atom aryl, C_1～4Any one of alkoxy substituted 5-6 membered aryl, vinylamide substituted 5-8 ring atom aryl, and amino substituted 5-8 ring atom aryl.

3. A compound of formula IV:

wherein the content of the first and second substances,R₂optionally selected from halogen, hydrogen atom, substituted or unsubstituted phenyl or p-fluoroanilino,

Wherein, the substituent of the phenyl is one or more of halogen, trifluoromethyl and amino;

R₅optionally selected from hydrogen atoms,

Or C_2～8An ether group;

R₆is optionally selected from C_1～6Alkoxy, amino, p-fluoroanilino,

One kind of (1).

4. A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

5. A pharmaceutical composition characterized by comprising as active ingredient a therapeutically effective amount of a compound as defined in any one of claims 1 to 4, in free form or in pharmaceutically acceptable salt form, in association with one or more pharmaceutically acceptable carriers, diluents or excipients.

6. Use of a compound as defined in any one of claims 1 to 4 in the manufacture of a medicament for the treatment of a disease associated with indoleamine 2, 3-bis-oxidase.

7. Use of a compound as defined in any one of claims 1 to 4 for the manufacture of a medicament for the treatment of tumors, alzheimer's disease, depression, cataract disorders.