WO2018184392A1 - 一种含有肼基的吲哚胺2,3-双加氧化酶抑制剂 - Google Patents

一种含有肼基的吲哚胺2,3-双加氧化酶抑制剂 Download PDF

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WO2018184392A1
WO2018184392A1 PCT/CN2017/112548 CN2017112548W WO2018184392A1 WO 2018184392 A1 WO2018184392 A1 WO 2018184392A1 CN 2017112548 W CN2017112548 W CN 2017112548W WO 2018184392 A1 WO2018184392 A1 WO 2018184392A1
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group
compound
reaction
pharmaceutically acceptable
alkoxy
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PCT/CN2017/112548
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French (fr)
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张孝清
宋志春
包金远
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南京华威医药科技集团有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the field belongs to the field of anti-tumor drugs, and particularly relates to an IDO inhibitor containing a thiol group, a preparation method thereof and use thereof.
  • IDO Indoleamine 2,3-dioxygenase
  • IDO Indoleamine 2,3-dioxygenase
  • IDO is the only rate-limiting enzyme outside the liver that catalyzes the catabolism of tryptophan along the kynurenine pathway. It is widely distributed in humans and animals. Many tissues and cells. IDO can inhibit the proliferation of pathogenic microorganisms by reducing the concentration of tryptophan in the microenvironment; IDO is also closely related to neurological diseases, which can reduce the level of serotonin and cause depression, and can also cause quinolinic acid in the brain. The accumulation of neurotoxic metabolites; some evidence suggests that IDO is involved in the induction of immune tolerance.
  • IDO-expressing cells can suppress T cell responses and promote tolerance, so IDO inhibits T-cell immunity and anti-tumor immunity, and induces maternal-fetal immunity. Both tolerance and graft immune tolerance play important metabolic immunomodulatory effects. At present, IDO is an important drug discovery target and has become the most important small molecule regulatory target for anti-tumor immunotherapy.
  • IDO inhibitors are WO2016071293, WO2010005958, WO2014066834, WO2016155545, CN 103130735A and the like.
  • IDO inhibitors can be used to treat various major diseases such as tumors, Alzheimer's disease, depression and cataract.
  • major diseases such as tumors, Alzheimer's disease, depression and cataract.
  • IDO inhibitors can be used to treat various major diseases such as tumors, Alzheimer's disease, depression and cataract.
  • Another object of the invention is to provide a pharmaceutical composition of the IDO inhibitor and uses thereof.
  • the object of the invention can be achieved by the following measures:
  • the R 1 group represents one of a hydrogen atom, a halogen, a C 1-10 alkyl group or a C 1-10 alkoxy group;
  • the R 2 group is optionally selected from a hydrogen atom, a C 1-10 alkyl group,
  • the R 3 group represents a C 1-10 alkyl group, a phenyl group or a substituted phenyl group, and the phenyl substituent group is optionally selected from the group consisting of halogen, C 1-10 alkyl group, C 1-10 alkoxy group, carboxyl group. One or more of a trifluoromethoxy group, an amino group, and a hydroxyl group;
  • R 4 represents an amino group, C 3 ⁇ 8 cycloalkyl, C 3 ⁇ 8 cycloalkyl substituted naphthyl, a substituted or unsubstituted phenyl group, wherein the phenyl substituent is optionally selected from the group consisting of halogen, C 1-10 alkyl, C 1-10 alkoxy, C 2-4 alkynyl, nitro, Wherein Ar represents a halogen-substituted phenyl group;
  • the R 5 groups represent C 2 ⁇ 6 alkenyl group, C 2 ⁇ 10 carboxyl group, C 2 ⁇ 6 alkylamino group, C 1 ⁇ 10 alkyl group, C 1 ⁇ 6 alkoxy group, a benzyl group, a C 5-8 heterocycloalkyl group having one or more N, O, S heteroatoms, Phenyl or substituted phenyl, or Any one of the above, wherein R 7 is optionally selected from the group consisting of a fluorenyl group, a hydroxyl group, a C 1-6 alkoxy group or an aniline group substituted with 1 to 3 F atoms, and n represents an arbitrary Arabic numeral of 0 to 5; R 8 is optionally selected from the group consisting of C 1-6 alkoxy, C 1-6 ester or C 1-4 alkyl substituted and unsubstituted benzopyrrolyl, and m represents any Arab of 0-5.
  • the phenyl substituent is optionally selected from the group consisting of halogen, C 1-10 alkyl, C 1-10 alkoxy, carboxy, hydroxy, One or more of the above; the X group is optionally selected from one or more of a hydrogen atom or a halogen.
  • C 5-8 heterocycloalkyl group having one or more N, O, S hetero atoms described in R 5 is optionally substituted with a C 1-6 alkyl group, a C 1-4 alkoxy group, or an amino group.
  • the R 4 group described in one embodiment is
  • the R 5 group described in one embodiment is optionally selected from One of them.
  • R 1 group is arbitrarily selected from one or more of a hydrogen atom, a halogen, a C 1-10 alkyl group, a C 1-10 alkoxy group; and the X group is optionally selected from a halogen or a hydrogen atom.
  • the R 1 group is arbitrarily selected from one or more of a hydrogen atom, a halogen, a C 1-10 alkyl group, a C 1-10 alkoxy group
  • the X group is optionally selected from a halogen or a hydrogen atom.
  • the R 1 group is arbitrarily selected from one or more of a hydrogen atom, a halogen, a C 1-10 alkyl group, a C 1-10 alkoxy group
  • the X group is optionally selected from a halogen or a hydrogen atom.
  • the present invention also provides a process for the preparation of a compound of the formula I and a salt thereof, but is not limited to the process described below. All starting materials are based on the group characteristics of the target molecule in accordance with the general formula and are prepared by methods in these routes, methods well known to those of ordinary skill in the art of organic chemistry, or purchased directly.
  • the compounds of the present invention can be synthesized by combining the following methods with synthetic methods known in the art of synthetic organic chemistry or related alteration methods recognized by those skilled in the art.
  • the preparation method of the compound of the formula I and the salt thereof comprises the following steps: in the step 5, a conventional oxidation reaction is carried out under the action of an oxidizing agent using the compound of the formula 4 as a starting material to obtain a compound of the formula 5.
  • the oxidizing agent used includes, but is not limited to, hydrogen peroxide, potassium permanganate and manganese dioxide, and the temperature of the oxidation reaction is from room temperature to 100 °C.
  • the compound of the formula 5 is dissolved in an organic solvent, and a 10% to 20% hydrazine hydrate solution is slowly added dropwise to obtain a compound of the formula 6. Further, the temperature of the reaction is from 15 ° C to 50 ° C.
  • the compound of the formula 6 is reacted with an acid chloride compound containing an R 2 group, a sulfonyl chloride compound, a carboxylic acid compound, an alkyl iodide or a urine forming reagent to obtain a compound of the formula 7.
  • Step 7 when R 2 is a C 1-10 alkyl group, the compound of the formula 6 is dissolved in an organic solvent and reacted with an alkyl iodide R 2 I to give the corresponding compound of the formula 7. Further, the reaction temperature is from 40 ° C to 100 ° C, and the molar ratio of R 2 I to the compound of the formula 6 is from 1:2 to 1:6.
  • Step 7 In one scheme, when R 2 is When the definition of R 3 is the same as defined above in the specification, the compound of the formula 6 is dissolved in an organic solvent, a catalytic amount of an organic base such as triethylamine is added, and then the sulfonyl chloride compound containing the R 3 group is slowly added. The reaction is carried out to obtain the corresponding compound of the formula 7. Further, the temperature of the reaction is -20 ° C to 20 ° C.
  • Step 7 In one scheme, when R 2 is When the definition of R 4 is the same as defined above in the specification, the ammonia compound R 4 —NH 2 containing the R 4 group is dissolved in an organic solvent, and triphosgene is slowly added at a low temperature to form an intermediate state of isocyanate, and then added. The compound of the formula 6 is reacted to obtain the corresponding compound of the formula 7; or the compound of the formula 6 is dissolved in an organic solvent, and phenyl chloroformate or N,N-carbonyldiimidazole (CDI) is slowly added at a low temperature to carry out the reaction, followed by addition. The R 4 group-containing amino compound R 4 —NH 2 is completely reacted to obtain the corresponding compound of the formula 7. Further, the temperature of the reaction is -10 ° C to 50 ° C.
  • Step 7 In one scheme, when R 2 is When the R 5 definition is the same as defined above in the specification, and the case where R 5 is one or more N, O, S C 5-8 heterocycloalkyl groups is selected, the carboxylic acid containing the R 5 group is selected. Acid compound The condensation reaction with the compound of the formula 6 gives the corresponding compound of the formula 7. Further, the condensing agent may be HBTU, HOBT, EDC.HCl or the like, and the base may be triethylamine, DIEA, N-methylmorpholine or the like, solvent. It is dichloromethane, DMF, DMSO, and the like.
  • Step 7 In one scheme, when R 2 is When the R 5 definition is the same as defined above in the specification, and excludes the case where R 5 is one or more N, O, S C 5-8 heterocycloalkyl, amino, alkylamino groups, Compound 6 is dissolved in an organic solvent, a catalytic amount of a base is added, and then an acid chloride compound containing an R5 group is slowly added. The reaction is carried out to obtain the corresponding compound of the formula 7.
  • the base may be an organic base such as triethylamine or DIEA, or an inorganic base such as potassium carbonate or sodium hydrogencarbonate.
  • the solvent may be dichloromethane, tetrahydrofuran, DMF, etc., temperature. -10 ° C to 50 ° C.
  • Step 7 In one scheme, when R 2 is (Definition of R 5 : C 2 to 6 alkenyl group, C 2 to 10 carboxyl group, C 1 to 10 alkyl group), the compound of the formula 6 is dissolved in an organic solvent, a catalytic amount of a base is added, and then slowly added Anhydride compound of R 5 group The reaction is carried out to obtain the corresponding compound of the formula 7.
  • the base may be an organic base such as triethylamine or DIEA, or an inorganic base such as potassium carbonate or sodium hydrogencarbonate.
  • the solvent may be dichloromethane, tetrahydrofuran, DMF, etc., temperature. -10 ° C to 50 ° C.
  • Step 7 In one scheme, when R 2 is (Definition of R 5 : when C 5-8 heterocycloalkyl having one or more N heteroatoms)
  • the compound of the formula 6 is dissolved in an organic solvent, and phenyl chloroformate or N,N-carbonyl is slowly added at a low temperature.
  • the diimidazole is reacted, and then a C 5-8 heterocycloalkyl compound containing one or more N hetero atoms is added to give a corresponding compound of the formula 7.
  • R 5 represents a C 2-6 alkylamino group
  • the compound of the formula 6 the amino group-protected R 5 group-containing carboxylic acid compound HBTU and DIEA are dissolved in DMSO or DMF solvent to carry out amidation reaction to obtain the corresponding intermediate compound, and then dissolved in methanol or ethanol solvent, and the amino protecting group is removed under strong acidity such as concentrated hydrochloric acid.
  • the corresponding compound of the formula 7 is obtained by treatment.
  • the amino protecting group may be a BOC protecting group.
  • the substrate which reacts with the compound of the formula 6 contains an amino group
  • the substrate can be subjected to conventional amino group protection to give the corresponding intermediate compound, and then the amino group can be removed to obtain the target molecule.
  • Methods of preparing compounds involve protecting and deprotecting various chemical groups. One skilled in the art can readily determine the need for protection and deprotection as well as selecting suitable protecting groups.
  • the compound of the formula 7 is dissolved in an organic solvent, and a ring-opening reaction is carried out under the action of an alkaline reagent such as hydrazine hydrate to obtain a compound of the formula I.
  • an alkaline reagent such as hydrazine hydrate
  • the temperature of the ring-opening reaction is from 10 ° C to 50 ° C
  • the alkaline agent is optionally selected from any one of hydrazine hydrate, potassium carbonate, sodium hydroxide, triethylamine and the like.
  • the low temperature means from minus 20 ° C to 10 ° C, more preferably about 0 ° C.
  • the organic solvent is optionally selected from the group consisting of N,N-dimethylformamide, toluene, acetic acid, methanol, ethanol, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, and 1,4-dioxane. .
  • the present invention also provides a process for the preparation of a compound of the general formula II and a salt thereof, but is not limited to the method described below.
  • the preparation method of the compound of the general formula II and a salt thereof comprises the following steps:
  • step a the compound of the formula 6 and the compound of the formula c are dissolved in an organic solvent, under the action of a catalytic amount of acetic acid, the reaction and post-treatment to obtain the Schiff base intermediate compound d;
  • the intermediate compound d is dissolved in a methanol or ethanol solvent, and the trityl (Trt) protecting group is removed by an acidic catalyst such as acetic acid to obtain an intermediate compound e; further, the reaction temperature is
  • the acidic catalyst is acetic acid, hydrochloric acid, trifluoroacetic acid or the like at 70 ° C to 100 ° C.
  • step c the intermediate compound e is dissolved in an organic solvent, and a ring-opening reaction is carried out under the action of an alkaline reagent such as hydrazine hydrate to obtain a compound of the formula II.
  • an alkaline reagent such as hydrazine hydrate
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, as an active ingredient, and one or more pharmaceutically acceptable carriers, Thinner or excipient.
  • the pharmaceutical composition preferably contains, as an active ingredient, a pharmaceutically acceptable salt of the formula I or the formula II in a weight ratio of from 1% to 99%, more preferably from 5% to 80% by weight of the active ingredient.
  • Alkyl means a saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, including both straight-chain and branched-chain groups (the range of numbers referred to in this application, such as “1-20", refers to the group, In the case of an alkyl group, it 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 contains an "alkylene group".
  • An alkyl group having 1 to 6 carbon atoms is referred to as a lower alkyl group. When the lower alkyl group has no substituent, it is referred to as an unsubstituted lower alkyl group.
  • the alkyl group is a medium size alkyl group having from 1 to 10 carbon atoms, such as methyl, ethyl, ethylene, propyl, propylene, 2-propyl, n-butyl, iso Butyl, butylene, tert-butyl, pentyl and the like.
  • the alkyl group is a lower alkyl group having 1 to 5 carbon atoms, such as a methyl group, an ethyl group, a propyl group, a 2-propyl group, a n-butyl group, a butylene group, an isobutyl group or a t-butyl group.
  • the alkyl group can be substituted or unsubstituted.
  • Alkoxy means -O-(unsubstituted alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • Alkoxy preferably includes alkoxy groups of 1 to 10 carbon atoms, more preferably alkoxy groups of 1 to 6 carbon atoms; representative examples include, but are not limited to, methoxy, ethoxy, propoxy, Butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • alkenyl group in the present invention means an unsaturated aliphatic hydrocarbon group having 2 to 20 carbon atoms and having at least one carbon-carbon double bond, and includes straight-chain and branched-chain groups. More preferably, the alkenyl group is a medium-sized alkenyl group having 2 to 10 carbon atoms, and more preferably a C 2 - 6 alkenyl group.
  • alkynyl group in the present invention means an unsaturated aliphatic hydrocarbon group having 2 to 20 carbon atoms and having at least one carbon-carbon triple bond, and includes straight-chain and branched-chain groups. More preferably, the alkynyl group is a medium-sized alkenyl group having 2 to 10 carbon atoms, and more preferably a C 2-6 alkynyl group.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Amino means -NH 2 .
  • Carboxyl means -COOH.
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises from 3 to 8 The carbon atom, most preferably the cycloalkyl ring contains from 3 to 6 carbon atoms, most preferably a cyclopropyl group.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • Niro means -NO 2 .
  • Alkylamino means an -alkyl-NH2 group, the alkyl group being as defined above.
  • Ester group means a functional group of an ester in a carboxylic acid derivative, -COOR (R is generally a non-H group such as an alkyl group, and the alkyl group is as defined above), for example, when a carbon atom of an alkyl group is contained therein When the number is from 1 to 6, the ester group may be abbreviated as a C 1-6 ester group.
  • “Pharmaceutically acceptable salt” means those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
  • a salt with an acid obtained by reacting a free base of a parent compound with an inorganic acid or an organic acid such as (but not limited to) Hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, etc., organic acids such as, but not limited to, acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, Fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid , p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or malonic acid,
  • “Pharmaceutical composition” refers to one or more of the compounds described herein, or pharmaceutically acceptable salts, isomers and prodrugs thereof, and other chemical ingredients, such as pharmaceutically acceptable carriers and a mixture of excipients.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • “Pharmaceutically acceptable carrier” refers to 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 administered compound.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound.
  • excipients include, without limitation, lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose. , water, syrup and methyl cellulose.
  • compositions may also contain: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners and flavoring Agent.
  • lubricants such as talc, magnesium stearate and mineral oil
  • wetting agents such as talc, magnesium stearate and mineral oil
  • emulsifying and suspending agents such as methyl benzoate and hydroxypropyl benzoate
  • preservatives such as methyl benzoate and hydroxypropyl benzoate
  • sweeteners and flavoring Agent sweeteners and flavoring Agent.
  • the present invention also provides the use of the compound of Formula I or Formula II, and a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the disease associated with indoleamine 2,3-dioxygenase (IDO), in particular It is used in the treatment of a variety of major diseases such as tumors, Alzheimer's disease, depression, cataracts.
  • the tumor is preferably liver cancer, lung cancer, or ovarian cancer.
  • the results of preliminary drug activity studies indicate that the compounds of the present invention have good IDO inhibitory activity against human hepatoma cell lines, human large cell lung cancer cell lines, human ovarian cancer cell lines, human small cell lung cancer cell lines, and human non-small cell lung cancer cell lines.
  • the growth of various human tumor cell lines has obvious inhibitory effects, and its comprehensive effect is better than INCB024360.
  • the pharmacokinetic test also showed that the compound of the present invention has good absorption of the drug and has obvious pharmacological absorption effect. Compared with INCB024360, the compound of the present invention has better pharmacokinetics in the case of a relatively higher or even higher drug effect.
  • Kinetic properties; Experimental results of acute oral toxicity studies indicate that the compounds of the present invention are non-toxic or low-toxic substances, have potential medicinal value and broad market prospects.
  • the second step 5.0g of compound 15 was dissolved in 100ml of tetrahydrofuran (THF), 3.2g of N,N-carbonyldiimidazole was added, and the temperature was raised to 70 ° C. The reaction was completed by TLC. The reaction was stopped, the reaction was stopped, the temperature was lowered to room temperature, and the pressure was reduced. Concentrate, add ethyl acetate and dilute hydrochloric acid, and separate. The organic phase was washed with aq. EtOAc (EtOAc)EtOAc.
  • EtOAc EtOAc
  • the third step 5.0g of compound 16 was dissolved in 90ml of TFA (trifluoroacetic acid), then added to 45ml of 30% hydrogen peroxide, and the temperature was raised to 50 ° C; TLC detection of the reaction of the starting material was complete, the reaction was stopped, and the hydrogen peroxide solution was quenched with saturated sodium sulfite solution. extracted with EA, the combined organic phases, the organic phase was washed with saturated NaCl solution and dried over anhydrous NaSO 4, filtered and concentrated under reduced pressure, by column chromatography to obtain 1.3g oil, compound 17;
  • TFA trifluoroacetic acid
  • Step 4 1.5 g of compound 10 was dissolved in 25 ml of THF, 1 ml of 85% hydrazine hydrate was diluted with 10 ml of THF and slowly added dropwise to the reaction system. The reaction of the starting material was completed by TLC, diluted with 50 ml of water, and most of the mixture was evaporated under reduced pressure. THF, a large amount of solid precipitated, suction filtration and rinse the filter cake with water to obtain 1.0 g of compound 18;
  • the fifth step 1.0g of compound 18 was dissolved in 10ml of tetrahydrofuran, 0.5g of triethylamine was added, and the temperature was lowered to below 0 °C, 0.8g of phenyl chloroformate was slowly added dropwise, and the reaction of the starting material was completely detected by TLC. In addition to most of the THF, ethyl acetate and water were added, and the organic phase was washed with a saturated NaCI solution and dried over anhydrous NaSO?
  • the sixth step The above compound 19 was dissolved in 10 ml of tetrahydrofuran, and 3 ml of 85% hydrazine hydrate was added. The reaction of the starting material was completely detected by TLC. Most of the THF was removed under reduced pressure, and a large amount of solid was precipitated, and filtered, and the filter cake was rinsed with water. Chromatography gave 100 mg of off-white solid compound I-1.
  • the first step is to take 5.0g of malononitrile, add 10ml of water to dissolve, and then cool to below 0 °C, add 6.0g of sodium nitrite, stir for 1.0h, then turn off the refrigeration, add 1.35ml of 4N hydrochloric acid, transfer to normal temperature and stir for 2.0h Then, the temperature is lowered to below 0 ° C, and 15.5 g of a 50% aqueous solution of hydroxylamine is slowly added dropwise. After the dropwise addition, the temperature is raised to reflux. After refluxing for 3 hours, the temperature is lowered to 6 ° C, and the mixture is stirred overnight, below 0 ° C, and slowly diluted with hydrochloric acid to adjust the pH. About 5, a large amount of solids were precipitated, and 10.0 g of compound 1 was obtained by suction filtration;
  • the second step 10.0g of compound 1 was dissolved in 50ml of acetic acid, then added with 100ml of water, 38ml of 6N HCl and 13.0g of sodium chloride, dissolved and reduced to below 0 ° C, slowly added 5.3g of sodium nitrite / 15ml Aqueous solution, and the temperature control is below 0 ° C, after the completion of the addition, the reaction is continued for 3 h, suction filtration and the filter cake is washed with water to neutral, and dried at 45 ° C to obtain 6.5 g of compound 2;
  • the third step Take 6.0g of compound 2 dissolved in 250ml of EA, add 4.8g of p-fluoroaniline in batches, react at room temperature until TLC detection is complete, add 0.5ml of triethylamine to quench the reaction, add ethyl acetate and water, solution, the organic phase is washed with saturated NaCl solution and dried over anhydrous NaSO 4, filtered and concentrated under reduced pressure and purified by column chromatography to give 5.2g white solid compound 8;
  • Step 4 Dissolve 4.8 g of compound 8 in 100 ml of THF, add 3.2 g of N,N-carbonyldiimidazole, and warm to 70 ° C. The reaction is completed until TLC. The reaction is stopped, the reaction is cooled to room temperature, concentrated under reduced pressure, and acetic acid is added. Ethyl ester and dilute hydrochloric acid, liquid separation. The organic phase was washed with a saturated NaCI solution and dried over anhydrous Na ⁇
  • the fifth step 5.0g of compound 9 was dissolved in 90ml of TFA, then added 45ml of 30% hydrogen peroxide, the temperature was raised to 50 ° C reaction; TLC detected the reaction of the starting material was complete, stop the reaction, quench the hydrogen peroxide solution with saturated sodium sulfite solution, EA extraction, combined organic The organic phase is washed with a saturated NaCl solution and dried over anhydrous NaSO.sub.4, filtered, filtered, and evaporated.
  • Step 6 1.5 g of compound 10 was dissolved in 25 ml of THF, 1 ml of 85% hydrazine hydrate was diluted with 10 ml of THF, and then slowly added dropwise to the reaction system. The reaction of the starting material was completed by TLC, diluted with 50 ml of water, and most of the mixture was evaporated under reduced pressure. THF, a large amount of solid precipitated, suction filtration and rinse the filter cake with water to obtain 1.2 g of compound 11;
  • the seventh step 200mg of the compound was dissolved in 5.0ml of THF, 1ml of 85% hydrazine hydrate was added dropwise, the reaction of the starting material was completely detected by TLC, most of the THF was removed under reduced pressure, a large amount of solid precipitated, and the filter cake was filtered with water and washed with water. Chromatography gave 30 mg of white solid compound I-38.
  • the first step is to dissolve 280 mg of compound 11 in 5 ml of tetrahydrofuran, add 120 mg of triethylamine, and then cool to below 0 ° C, slowly add 290 mg of p-trifluoromethoxybenzenesulfonyl chloride, detect by TLC until the starting material is completely reacted, and quench with 25 ml of water.
  • the organic phase is extracted with ethyl acetate.
  • the organic phase is washed with a saturated NaCI solution and dried over anhydrous NaSO?
  • the second step The above compound 12 was dissolved in 1 ml of tetrahydrofuran, and 1 ml of 85% hydrazine hydrate was added. The reaction of the starting material was completely detected by TLC. Most of the THF was removed under reduced pressure, and a large amount of solid was precipitated, filtered, and rinsed with water. Chromatography gave 50 mg of white solid compound I-34.
  • the second step The above compound 13 was dissolved in 3 ml of acetic acid, 6 ml of methanol, and the temperature was raised to 90 ° C. The reaction was completed by TLC until the reaction of the starting material was completely cooled to room temperature, the solvent was evaporated under reduced pressure, water and ethyl acetate were added, and the mixture was separated. The organic phase was reserved, the organic phase was washed with saturated NaCl solution and dried over anhydrous NaSO 4, filtered and concentrated under reduced pressure to give compound 14, administered directly to the next step;
  • the third step The above compound 14 was dissolved in 10 ml of tetrahydrofuran, 2 ml of 85% hydrazine hydrate was added, the reaction of the starting material was completely detected by TLC, most of the THF was removed under reduced pressure, a large amount of solid was precipitated, filtered, and the filter cake was rinsed with water. Chromatography gave 20 mg of off-white solid compound I-43.
  • Step 1 290 mg of compound 10-1 was dissolved in 5 ml of tetrahydrofuran, 120 mg of triethylamine was added, and the temperature was lowered to below 0 ° C. 300 mg of m-bromobenzenesulfonyl chloride was slowly added, and the reaction of the starting material was completed by TLC, and quenched by adding 25 ml of water. The ester is extracted, the organic phase is preserved, the organic phase is washed with a saturated NaCl solution and dried over anhydrous NaSO.sub.4, filtered, filtered, and the filtrate is concentrated under reduced pressure to give crude compound 12-1.
  • Step 2 The above compound 12-1 was dissolved in 10 ml of tetrahydrofuran, and 1 ml of 85% hydrazine hydrate was added. The reaction of the starting material was completely detected by TLC. Most of the THF was removed under reduced pressure, and a large amount of solid was precipitated, filtered, and the cake was rinsed with water. Column chromatography gave 50 mg of white solid compound 1-2.
  • Step 1 2.5 g of compound 13-1 was dissolved in 45 ml of TFA, then added with 45 ml of 30% hydrogen peroxide, and the temperature was raised to 50 ° C; TLC was used to detect the completion of the reaction, the reaction was stopped, the hydrogen peroxide solution was quenched with saturated sodium sulfite solution, and EA was extracted and combined. The organic phase is washed with a saturated NaCl solution and dried over anhydrous NaSO 4 and filtered with suction.
  • Step 2 The above compound 14-1 was dissolved in 10 ml of tetrahydrofuran, and 1 ml of 85% hydrazine hydrate was added, and the reaction of the starting material was completely detected by TLC. Most of the THF was removed under reduced pressure, and a large amount of solid was precipitated, filtered, and the cake was rinsed with water. Column chromatography gave 300 mg of off-white solid compound I-5.
  • Step 1 Take 290 mg of compound 10-1, dissolve it with 10 ml of dichloromethane, add 120 mg of succinic anhydride, raise the temperature to 35 ° C, react with TLC to detect the starting material, add 10 ml of water, separate the liquid, and wash the organic phase with saturated NaCl solution. Drying anhydrous NaSO 4 , suction filtration, and concentrating the filtrate under reduced pressure to give crude compound 15-1
  • Step 2 The above compound 15-1 was dissolved in 10 ml of tetrahydrofuran, and 1 ml of 85% hydrazine hydrate was added thereto. The reaction of the starting material was completely detected by TLC, and most of the THF was removed under reduced pressure, and a large amount of solid was precipitated, filtered, and the cake was rinsed with water. Column chromatography gave 25 mg of the white solid compound I-7.
  • Step 1 5.0 g of compound 16-1 was dissolved in 90 ml of TFA, then added with 45 ml of 30% hydrogen peroxide, and the temperature was raised to 50 ° C; TLC was used to detect the completion of the reaction, the reaction was stopped, the hydrogen peroxide solution was quenched with saturated sodium sulfite solution, and EA was extracted and combined. The organic phase is washed with a saturated NaCl solution and dried over anhydrous NaSO 4 and filtered with suction.
  • Step 2 1.0 g of compound 17-1 was dissolved in 25 ml of THF, and 1 ml of 85% hydrazine hydrate was diluted with 10 ml of THF and slowly added dropwise to the reaction. The solution of the system was tested by TLC until the reaction of the starting material was complete, diluted with 50 ml of water, and most of the THF was removed under reduced pressure. A large amount of solid was precipitated, filtered, and the cake was rinsed with water to obtain 850 mg of compound 18-1;
  • Step 3 Dissolve 165 mg of p-fluoroaniline in 10 ml of dichloromethane, stir at 0 ° C, slowly add 445 mg of triphosgene, stir the reaction for 30 min, then add 310 mg of compound 18-1 in dichloromethane (10 ml) and transfer to The reaction is carried out at room temperature until the reaction of the starting material is complete. 10 ml of water is added and the mixture is separated. The organic phase is washed with a saturated NaCI solution and dried over anhydrous NaSO 4 and filtered, and the filtrate is concentrated under reduced pressure to give crude compound 19-1.
  • Step 4 The above compound 19-1 was dissolved in 10 ml of tetrahydrofuran, and 1 ml of 85% hydrazine hydrate was added, and the reaction of the starting material was completely detected by TLC. Most of the THF was removed under reduced pressure, and a large amount of solid was precipitated, filtered, and the cake was rinsed with water. Column chromatography gave 28 mg of white solid compound I-8.
  • Step 1 5.0 g of compound 20 was dissolved in 90 ml of TFA, then added with 45 ml of 30% hydrogen peroxide, and the temperature was raised to 80 ° C. The reaction was completed by TLC, the reaction was stopped, the hydrogen peroxide solution was quenched with saturated sodium sulfite solution, and the organic phase was combined. The organic phase is washed with a saturated NaCl solution and dried over anhydrous NaSO 4 and filtered with suction.
  • Step 2 0.65 g of compound 21 was dissolved in 10 ml of THF, 1 ml of 85% hydrazine hydrate was diluted with 10 ml of THF, and then slowly added dropwise to the reaction system solution. The reaction of the starting material was completed by TLC, diluted with 50 ml of water, and most of the mixture was evaporated under reduced pressure. THF, a large amount of solid precipitated, suction filtration and rinse the filter cake with water to obtain 480 mg of compound 22;
  • Step 3 Take 450 mg of 22,300 mg of N-tert-butoxycarbonyl-2-methylalanine, 680 mg of O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU), 230 mg of N,N- Diisopropylethylamine (DIEA), dissolved in 10 ml of DMF, and allowed to react at room temperature.
  • the reaction of the starting material was completed by TLC, the reaction was stopped, poured into 100 ml of water, solid precipitated, suction filtered, and filtered to obtain 350 mg of compound 23 ;
  • Step 5 The above compound 24 was dissolved in 10 ml of tetrahydrofuran, and 1 ml of 85% hydrazine hydrate was added, and the reaction of the starting material was completely determined by TLC. Most of the THF was spun off, a large amount of solid was precipitated, filtered, and the filter cake was rinsed with water.
  • Step 1 295 mg of compound 10-1 was dissolved in 10 ml of dichloromethane, 120 mg of triethylamine was added, and the mixture was stirred at 0 ° C, and 140 mg of isopropyl chloroformate was slowly added. The reaction of the starting material was completely detected by TLC, the reaction was stopped, and water was added. and dichloromethane solution was separated, washed with saturated NaCl solution and the organic phase was dried over anhydrous NaSO 4, filtered and concentrated under reduced pressure to afford crude compound 25, administered directly to the next step;
  • Step 2 The above compound 25 was dissolved in 10 ml of tetrahydrofuran, and 1 ml of 85% hydrazine hydrate was added. The reaction of the starting material was completely detected by TLC. Most of the THF was removed under reduced pressure, and a large amount of solid was precipitated, and filtered, and the filter cake was rinsed with water. Analysis gave 32 mg of the white solid compound I-13.
  • Step 1 Take a 100 ml single-mouth bottle, add 300 mg of 2-formylbenzeneboronic acid, 1090 mg of 1-trityl-4-iodoimidazole, 848 mg of K 3 PO 4 , 23 mg of Pd(PPh 3 ) 4 , and 2 ml of water, 10 ml of DMF. The reaction was carried out at 100 ° C overnight under N 2 , and the reaction was taken to room temperature. The mixture was poured into water and extracted with EA. The organic phase was washed with saturated NaCI solution and dried over anhydrous NaSO 4 , filtered and filtered. Light gray compound 26;
  • Step 2 Take 620 mg of compound 26, 1.0 g of ethoxyformylmethylenetriphenylphosphine, 30 ml of tetrahydrofuran, and let it react at 50 ° C overnight, then cool to room temperature, and then remove tetrahydrofuran under reduced pressure to obtain 470 mg of white compound. 27;
  • Step 4 Take 204 mg of compound 28, 70 mg of sodium hydroxide, 15 ml of methanol, 2d of water, and let the reaction be carried out at 30 ° C. The reaction of the starting material is completely detected by TLC, the reaction is stopped, the solvent is removed under reduced pressure, and the mixture is stirred with ethyl acetate and filtered. The filtrate was spun dry to give 150 mg of compound 29;
  • Step 5 Take 150 mg of compound 29, 200 mg of compound 11, 380 mg of HBTU, 130 mg of DIEA, 10 ml of DMF, and react at 30 ° C. The reaction of the starting material is complete by TLC, the reaction is stopped, poured into 150 ml of water, a large amount of solid is precipitated, suction filtration, and the filter cake is retained. , that is, compound 31, directly into the next step;
  • Step 6 The above compound 31 was dissolved in 10 ml of tetrahydrofuran, and 1 ml of 85% hydrazine hydrate was added, and the reaction of the starting material was completely detected by TLC. Most of the THF was removed under reduced pressure, and a large amount of solid was precipitated, and filtered, and the filter cake was rinsed with water. Analysis gave 60 mg of off-white solid compound I-18.
  • Step 1 312 mg of compound 22 was dissolved in 10 ml of tetrahydrofuran, 414 mg of compound 26 was added, 2 drops of acetic acid were added dropwise, and the reaction was completed at room temperature until the reaction of the starting material was completed. Most of the THF was removed under reduced pressure, water and ethyl acetate were added, and the mixture was separated. The organic phase, the organic phase was washed with saturated NaCl solution and dried over anhydrous NaSO 4, filtered and concentrated under reduced pressure, to give compound 32, administered directly to the next step;
  • Step 2 The above compound 33 was dissolved in 6 ml of acetic acid, 6 ml of methanol, and the temperature was raised to 90 ° C. The reaction was completed by TLC until the reaction of the starting material was completely cooled to room temperature, solvent was evaporated under reduced pressure, water and ethyl acetate were added, and the solution was separated. The organic phase, the organic phase was washed with saturated NaCl solution and dried over anhydrous NaSO 4, filtered and concentrated under reduced pressure, to give compound 33, administered directly to the next step;
  • Step 3 The above compound 33 was dissolved in 10 ml of tetrahydrofuran, 2 ml of 85% hydrazine hydrate was added, and the reaction of the starting material was completely detected by TLC. Most of the THF was removed under reduced pressure, and a large amount of solid was precipitated, and filtered, and the filter cake was rinsed with water. Analysis revealed 50 mg of off-white solid compound 1-32.
  • Step 1 Take 500 mg of 2,3-difluoroaniline, 614 mg of monomethyl 1 ,1-cyclopropyldicarboxylate, 680 mg of 1-hydroxybenzotriazole (HOBT), 964 mg of 1-ethyl-(3-dimethylaminopropyl) Carboxyl diimide hydrochloride (EDC.HCl), and 15 ml of DMF, placed at 30 ° C reaction, TLC detection until the reaction of the starting material is complete, poured into water, a large amount of solid precipitation, suction filtration, filter cake drying, to get 890mg Compound 34;
  • HOBT 1-hydroxybenzotriazole
  • EDC.HCl 1-ethyl-(3-dimethylaminopropyl) Carboxyl diimide hydrochloride
  • Step 2 Take 890mg of compound 34, 280mg of sodium hydroxide, 40ml of methanol, and let the reaction be carried out at 50 ° C.
  • Step 3 Take 260 mg of compound 35, 200 mg of compound 30, 127 mg of HOBT, 180 mg of EDC.HCl, 116 mg of N-methylmorpholine, and 20 ml of DMF, and react at 30 ° C. The reaction of the starting material was completed by TLC, poured into water, and a large amount of solid precipitated. Filtering to give 100 mg of compound 36;
  • Step 4 The above compound 36 was dissolved in 10 ml of tetrahydrofuran, 2 ml of 85% hydrazine hydrate was added, and the reaction of the starting material was completely detected by TLC. Most of the THF was removed under reduced pressure, and a large amount of solid was precipitated, and filtered, and the cake was rinsed with water. 40 mg of off-white solid compound I-39 was obtained.
  • Step 1 Take 2.7 g of compound 34-1, 1.4 g of methyl iodide, 50 ml of tetrahydrofuran, and react at 50 ° C overnight, and then remove the solvent under reduced pressure to prepare a liquid phase to obtain 50 mg of compound 35-1;
  • Step 2 Take compound 35-1, dissolve it with 5 ml of tetrahydrofuran, add 1 ml of 85% hydrazine hydrate, check the reaction of the starting material by TLC, remove most of the THF under reduced pressure, precipitate a large amount of solid, filter with suction and rinse the filter cake with water. Column chromatography gave 10 mg of white solid compound I-48.
  • Step 1 Take 200 mg of compound 22 and dissolve it with 15 ml of tetrahydrofuran, add 220 mg of potassium carbonate, stir at 0 ° C, slowly add 130 mg of phenyl chloroformate dropwise, and then react at room temperature for 1 h after the completion of the addition, and then remove the solvent under reduced pressure, add water and ethyl acetate, and liquid separation, the organic phase is washed with saturated NaCl solution and dried over anhydrous NaSO 4, filtered and concentrated under reduced pressure, to give compound 36-1, administered directly next;
  • Step 2 Take the above compound 36-1, dissolve it with 20 ml of tetrahydrofuran, add 278 mg of morpholine, warm to 50 ° C for 5 h, remove the solvent under reduced pressure, add water and ethyl acetate, separate the liquid, and wash the organic phase with saturated NaCl solution. Drying with anhydrous NaSO 4 , suction filtration, concentration of the filtrate under reduced pressure, column chromatography to give 85 mg of compound 37;
  • Step 3 Take compound 37, dissolve it with 5 ml of tetrahydrofuran, add 1 ml of 85% hydrazine hydrate, check the reaction of the starting material by TLC, remove most of the THF under reduced pressure, precipitate a large amount of solid, filter with water and rinse the filter cake with water, column layer 13 mg of off-white solid compound I-50 was obtained.
  • Step 1 Take 312 mg of compound 18-1, 243 mg of CDI, 300 mg of triethylamine, and 15 ml of tetrahydrofuran, and let it react at 50 ° C for 5 h, remove the solvent under reduced pressure, add water and ethyl acetate, separate the liquid, and wash the organic phase with saturated NaCl solution. Drying with anhydrous NaSO 4 , suction filtration, concentration of the filtrate under reduced pressure, column chromatography to give 150 mg of compound 38;
  • Step 2 Take compound 38, dissolve it with 5 ml of tetrahydrofuran, add 1 ml of 85% hydrazine hydrate, and judge the reaction of the starting material completely by TLC. Most of the THF had a large amount of solid precipitated, which was suction filtered and rinsed with water and then purified by column chromatography to afford 13 mg of white solid compound I-53.
  • Step 1 Take 0.58 g of compound 39, 0.51 g of compound 18-1, 0.38 g of EDCI.HCl, 0.3 g of HOBT, and 30 ml of DMF, and drop to 0 ° C, slowly add 0.26 g of N-methylmorpholine, and heat up. The reaction to 30 °C, TLC detection until the reaction was complete, poured into water, extracted with EA, the organic phase was washed with saturated NaCl solution and dried over anhydrous NaSO 4, filtered off with suction, the filtrate was concentrated under reduced pressure to give 0.6g of compound 40 as a yellow oil; Step 2.
  • Step 3 Take 0.46 g of chlorosulfonic acid isocyanate dissolved in 10 ml of DCM and set to below -4 ° C, slowly add 0.24 g of t-butanol and keep stirring for 1 h to prepare reaction solution A, and dissolve 0.3 g of compound 41 in 10 ml of DCM. Add 0.82g of triethylamine and reduce to below -4 °C, slowly add the reaction solution A and keep the reaction for 6h, quench the reaction with saturated sodium bicarbonate solution, extract with EA, wash the organic phase with saturated NaCl solution and use Drying anhydrous NaSO 4 , suction filtration, concentration of the filtrate under reduced pressure, column chromatography to give 0.17 g of a yellow solid as compound 42;
  • Step 5 The above compound 43 was dissolved in 10 ml of tetrahydrofuran, 2 ml of 85% hydrazine hydrate was added, and the reaction of the starting material was completely detected by TLC. Most of the THF was removed under reduced pressure, and a large amount of solid was precipitated, and filtered, and the filter cake was rinsed with water. Analysis revealed 23 mg of off-white solid compound I-59.
  • Step 1 Take 650mg of 3,4-difluoroaniline, 500mg of succinic anhydride, 20ml of DMF, reacted at 50 ° C for 3h, poured into water, a large amount of solids were precipitated, suction filtration, filter cake dried to obtain 980mg of compound 44;
  • Step 3 The above compound 45 was dissolved in 10 ml of tetrahydrofuran, 2 ml of 85% hydrazine hydrate was added, and the reaction of the starting material was completely detected by TLC. Most of the THF was removed under reduced pressure, a large amount of solid was precipitated, filtered, and the filter cake was rinsed with water. Analysis gave 60 mg of off-white solid compound I-60.
  • Step 1 810 mg of compound 6 was dissolved in 15.0 ml of DMF, 750 mg of p-carboxyaniline was added in portions, and the reaction was completed by TLC. The reaction was quenched by dropwise addition of 0.25 ml of triethylamine, ethyl acetate and water were added, and the organic layer was separated. phases were washed with saturated NaCl solution and dried 4, filtered and concentrated under reduced pressure and was dried over anhydrous NaSO4, purified by column chromatography to give 0.9g white solid compound 46;
  • Step 2 Dissolve 0.9 g of compound 46 in 30 ml of THF, add 660 mg of N,N-carbonyldiimidazole, and warm to 70 ° C until the reaction of TLC is complete. Stop the reaction, cool to room temperature, concentrate under reduced pressure, and add ethyl acetate. And dilute hydrochloric acid, liquid. The organic phase was washed with saturated NaCl solution and dried over anhydrous NaSO 4, filtered and concentrated under reduced pressure, ethyl acetate and n-hexane to give 0.75g beating to give compound 47;
  • Step 3 Take 145 mg of compound 47, 155 mg of compound 18-1, 228 mg of HBTU, 80 mg of DIEA, and 20 ml of DMF, and react at 30 ° C. The reaction of the starting material by TLC is complete, stirred with water, and suction filtered to give compound 48 directly to the next step;
  • Step 4 The above compound 48 was dissolved in tetrahydrofuran, 2 ml of 85% hydrazine hydrate was added, and the reaction of the starting material was completely detected by TLC. Most of the THF was removed under reduced pressure, and a large amount of solid was precipitated, filtered, and rinsed with water. 35 mg of off-white solid compound I-67 were obtained.
  • Test Example 1 Determination of the inhibitory activity of the compound on IDO1:
  • test examples are not intended to limit the present invention, and the following are the inhibitory activities of some of the compounds of the present invention against IDO1 enzyme at a concentration of 10 ⁇ M and 1 ⁇ M.
  • the structural formula of the compound is as shown in the above examples of the specification.
  • Multi-function microplate reader (Cat: M5, Molecular Devices)
  • Inhibition rate (OD positive - OD sample ) / (OD positive - OD negative ) * 100%
  • This experiment detects the inhibitory activity of the test compound on IDO1 enzyme at 10 ⁇ M and 1 ⁇ M. Each dilution concentration is a duplicate well test. The final concentration of DMSO in the control reaction system is 1%, and the inhibition rates at two concentrations are tested twice. The average value and the experimental results are shown in the following table. The results show that the compound of the present application shows a good inhibitory activity against the IDO1 protease.
  • This experiment detects the inhibitory activity of the test compound on IDO1 enzyme.
  • Test Example 2 Determination of IC50 value of compound in vitro cytotoxicity
  • Cytotoxicity IC50 values of the compounds of the present application against eight tumor cell lines were tested using the CCK-8 assay kit.
  • NCI-H460 human large cell lung cancer cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • SMMC-7721 human liver cancer cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • SK-OV-3 human ovarian cancer cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • NCI-H446 human small cell lung cancer cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • A549 human non-small cell lung cancer cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • HepG2 human hepatoma cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • OVCAR-3 human ovarian cancer cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • the compound was diluted with DMSO to a final concentration of 10 mM.
  • test compound was diluted with the medium to the corresponding concentration of action set, and the cells were added at 25 ⁇ l/well.
  • the final concentration of the compound was started from 100 ⁇ M, diluted 4 fold, 10 concentration points, and duplicate wells were tested.
  • tumor cell growth inhibition rate % [(Ac-As) / (Ac-Ab)] ⁇ 100%
  • the compounds of the present invention have obvious inhibitory effects on the growth of various human tumor cell lines, and the effect is better than INCB024360.
  • the pharmacokinetic tests of the compounds I-18, I-32 and the compound INCB024360 of the present application were carried out to study their pharmacokinetic behavior in rats, and their pharmacokinetic characteristics were evaluated.
  • mice 36 (male and female) SPF-class SD rats were purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., among which 30 (male and female) healthy SD rats with good physical examination and no abnormality were used. In the study.
  • Blood was collected by jugular vein puncture, and each sample was collected about 0.25 mL. Heparin sodium was anticoagulated. The time of blood collection was as follows:
  • Oral administration group before administration, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h after administration.
  • Plasma samples were collected and placed on ice, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ° C). The collected plasma was stored at -80 °C prior to analysis. The plasma samples were analyzed by the laboratory analysis department using LC-MS/MS for the content of the test compound in the rat plasma. The LLOQ of the test substance was 1 ng/mL.
  • the pharmacokinetic parameters ANU 0-t , AUC 0-C , MRT 0-T and Cmax of the test sample were calculated using the non-compartment model of the pharmacokinetic calculation software WinNonlin5.2. Parameters such as Tmax, T 1/2 and V d and their mean and standard deviation.
  • samples taken prior to reaching C max should be calculated as zero values when calculating the pharmacokinetic parameters. Samples at the sampling point should be incapable of quantification (BLQ) after C max is reached.
  • the pharmacokinetic parameters of I-18, I-32, INCB024360 were calculated using the non-compartment model of the pharmacokinetic calculation software WinNonlin5.2, as shown in the following table.
  • the compound of the present invention has good pharmacological absorption and obvious pharmacological absorption effect. Compared with INCB024360, the compound of the present invention has better pharmacokinetic properties in the case of relatively higher or even higher efficacy. Broad market prospects.
  • the toxic reaction of the compound of the present invention was orally administered to SD rats in order to fully expose the possible toxicity of the compound, and preliminary acute oral toxicity data were obtained.
  • Test substance purity Molecular weight Traits Storage conditions I-18 96.9% 560.47 Off-white solid -20 ° C I-32 99.2% 448.14 White solid -20 ° C
  • the solvent is initially scheduled to be 0.5% CMC-Na (800-1200 CPS)
  • mice ICR, SPF grade, 18 ⁇ 24g, 12, male and female.
  • Laboratory animal inventory 999M-018
  • the experimental animals were randomly divided into 2 groups, 4 in each group, half male and half female.
  • the doses of the animals in each group were designed to be 2000 mg/kg, the concentration was 100 mg/mL, the dosage volume was 20 mL/kg, and the observation period was 14 days.
  • mice All animals were observed at least twice a day (upper and afternoon) during the experiment, including but not limited to morbidity, mortality, damage, and water supply.
  • the experiment was performed 3 times on the first day (before administration, 0.5 and 3 hours after administration), and once every day on the 2nd to 14th day.
  • Observations include, but are not limited to, morbidity, mortality, damage, and water supply, skin, hair, eyes, ears, nose, mouth, chest, abdomen Department, external genitalia, limbs, respiratory and circulatory systems, autonomic effects (such as salivation), nervous system (such as tremor, convulsions, stress response, and abnormal behavior).
  • the compound of the formula I or the formula II of the present invention and a pharmaceutically acceptable salt thereof have good IDO inhibitory activity and have significant inhibitory effects on the growth of various human tumor cell lines, and the pharmacological agent thereof The absorption is good, and the absorption effect of the drug is good.
  • the results of the experimental study on acute oral toxicity indicate that the compound of the present invention is non-toxic or low-toxic, and its comprehensive effect is superior to INCB024360, so it has good medicinal value and a broad market. Prospects.

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Abstract

本发明提供一种式I和式II所示的IDO抑制剂及其制备方法，其中R1、R2、X基团的定义如说明书所示。本发明同时提供了包含式I或式II化合物的药物组合物及其用途。所述的化合物及其的药学上可接受的盐在制备与吲哚胺2,3-双加氧化酶（IDO）相关的疾病药物方面的用途，具体而言其在治疗癌症、阿尔茨海默病、抑郁症、白内障等多种重大疾病方面的应用。本发明的化合物高效低毒，具有潜在的药用价值和广阔的市场化前景。

Description

一种含有肼基的吲哚胺2,3-双加氧化酶抑制剂
相关申请的交叉引用
本申请要求于2017年04月05日提交中国专利局的申请号为CN201710218159.4、名称为“一种含有肼基的吲哚胺2,3-双加氧化酶抑制剂”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本领域属于抗肿瘤药物领域，具体涉及一种含有肼基基团的IDO抑制剂及其制备方法和用途。
背景技术
传统的肿瘤疗法都是大分子或细胞疗法，它们是针对细胞表面受体，无法直接调控庞大复杂的免疫细胞内免疫应答体系。肿瘤微环境中有许多免疫抑制分子存在，通过调节这些抑制分子的功能进而改善肿瘤免疫微环境的免疫治疗策略被称为免疫疗法，这个涉及数百个蛋白的调控体系有一些节点可能会和PD-1类似功能或和PD-1抗体有协同作用，而这些靶点最适合用小分子药物调控。因此免疫疗法也被称为是肿瘤治疗史上的一个突破性进展。
吲哚胺2,3-双加氧化酶(indoleamine 2,3-dioxygenase,IDO)是肝脏以外唯一的催化色氨酸沿犬尿氨酸途径分解代谢的限速酶，广泛分布于人和动物的许多组织和细胞中。IDO可通过降低微环境中色氨酸的浓度而达到抑制病原微生物增殖的作用；IDO与神经系统疾病也密切相关,它能降低5-羟色胺的水平而导致抑郁,也可造成脑中喹啉酸等具有神经毒性的代谢产物的累积；一些证据表明，IDO参与免疫耐受的诱导。哺乳动物妊娠、肿瘤耐药性、慢性感染和自身免疫性疾病的研究表明，表达IDO的细胞能抑制T细胞反应，促进耐受性，因此IDO在抑制T细胞免疫和抗肿瘤免疫、诱导母胎免疫耐受和移植物免疫耐受中均发挥重要的代谢性免疫调节作用。目前，IDO是一个重要的药物发现靶标，已经成为抗肿瘤免疫疗法最重要的小分子调控靶点。
目前国内外尚无IDO抑制剂药物上市，在国外进入临床试验分别化合物分别是美国New link Genetics公司的NLG919化合物、Indoximod(NLG-8189)与美国Incyte公司的INCB024360(Epacadostat)化合物，其中Epacadostat和免疫哨卡抑制剂(Yervoy)联合使用显示出了良好疗效，目前Epacadostat已经处于三期临床研究阶段。Epacadostat类似物也处于二期临床阶段，有研究表明二者将成为极具市场潜力的上市IDO抑制剂药物。
Figure PCTCN2017112548-appb-000001
INCB024360结构式
Figure PCTCN2017112548-appb-000002
INCB024360类似物结
涉及IDO抑制剂的发明专利申请有WO2016071293、WO2010005958、WO2014066834、WO2016155545、CN 103130735A等。
目前，IDO抑制剂的研发仍存在较高的技术壁垒，IDO抑制剂作为具有新药靶、新机制的药物，可应用于治疗肿瘤、阿尔茨海默病、抑郁症、白内障等多种重大疾病，具有非常好的市场价值，为了满足目前临床上对IDO调控代谢物的需要，达到更好的肿瘤治疗效果，我们致力于一系列高效低毒的IDO抑制剂的研究开发，这对于医药领域具有重大的意义。
发明内容
本发明的目的在于提供一种含有肼基的IDO抑制剂及其制备方法。
本发明的另一个目的是提供所述IDO抑制剂的药物组合物及其用途。
本发明的目的可以通过以下措施达到：
一种式I所示的化合物，或其药学上可接受的盐，
Figure PCTCN2017112548-appb-000003
其中，
R1基团代表氢原子、卤素、C1～10烷基或者C1～10烷氧基中的一种；
R2基团任意选自氢原子、C1～10烷基、
Figure PCTCN2017112548-appb-000004
所述的R3基团代表C1～10烷基、苯基或者取代苯基，所述的苯基取代基任意选自卤素、C1～10烷基、C1～10烷氧基、羧基、三氟甲氧基、氨基、羟基中的一种或几种；
所述的R4基团代表氨基、C3～8环烷基、C3～8环烷基取代的萘基、
Figure PCTCN2017112548-appb-000005
取代或非取代的苯基，其中所述的苯基取代基任意选自卤素、C1～10烷基、C1～10烷氧基、C2～6炔基、硝基、
Figure PCTCN2017112548-appb-000006
其中所述的Ar代表卤素取代的苯基；
所述的R5基团代表C2～6烯基、C2～10羧基、C2～6烷氨基、C1～10烷基、C1～6烷氧基、苄基、
Figure PCTCN2017112548-appb-000007
Figure PCTCN2017112548-appb-000008
具有一个或多个N、O、S杂原子的C5～8杂环烷基、
Figure PCTCN2017112548-appb-000009
Figure PCTCN2017112548-appb-000010
Figure PCTCN2017112548-appb-000011
苯基或者取代苯基、
Figure PCTCN2017112548-appb-000012
或者
Figure PCTCN2017112548-appb-000013
中的任意一种，其中所述的R7任意选自肼基、羟基、C1～6烷氧基或者1～3个F原子取代的苯胺基，n代表0～5的任意阿拉伯数字；所述的R8任意选自C1～6烷氧基、C1～6酯基或C1～4烷基取代及非取代的苯并吡咯基中的一种，m代表0～5的任意阿拉伯数字；所述的苯基取代基任意选自卤素、C1～10烷基、C1～10烷氧基、羧基、羟基、
Figure PCTCN2017112548-appb-000014
中的一种或几种；所述的X基团任意选自氢原子或者卤素中的一种或几种。
进一步地，R5中所述的具有一个或多个N、O、S杂原子的C5～8杂环烷基被C1～6烷基、C1～4烷氧基、氨基任意取代。
在一种方案中所述的R4基团为
Figure PCTCN2017112548-appb-000015
在一种方案中所述的R5基团任意选自
Figure PCTCN2017112548-appb-000016
Figure PCTCN2017112548-appb-000017
Figure PCTCN2017112548-appb-000018
中的一种。
一种式II所示的化合物，或其药学上可接受的盐，
Figure PCTCN2017112548-appb-000019
其中R1基团任意选自氢原子、卤素、C1～10烷基、C1～10烷氧基中的一种或几种；所述的X基团任选自卤素或氢原子中的一种或几种。
本发明还提供通式I化合物及其盐的制备方法，但不仅限于以下描述的方法。所有的原料都是根据符合通式规律的目标分子的基团特征，并通过这些路线中的方案、有机化学领域普通技术人员熟知的方法制备或者直接购买的。可将用下述方法和合成有机化学领域中已知的合成方法或本领域技术人员意识到的有关改变方法结合在一起，合成本发明化合物。
Figure PCTCN2017112548-appb-000020
上述式I制备方案中，化合物4的制备可以参照发明专利WO2010005958中说明书公开的方法进行。R1的定义与说明书上文定义相同。
通式I化合物及其盐的制备方法包含以下步骤：步骤5中，以通式化合物4为起始原料，在氧化剂的作用下进行常规的氧化反应，得到通式化合物5。进一步地，所用的氧化剂包括但不限于：双氧水、高锰酸钾和二氧化锰，氧化反应的温度为室温至100℃。
步骤6中，将通式化合物5溶解在有机溶剂中，缓慢滴加10％-20％水合肼溶液，反应得到通式化合物6。进一步地，反应的温度为15℃至50℃。
步骤7中，将通式化合物6与含有R2基团的酰氯类化合物、磺酰氯类化合物、羧酸类化合物、烷基碘化物或者成尿试剂反应，得到通式化合物7。
进一步地，
步骤7在一种方案中，当R2为C1～10烷基时，将通式化合物6溶解在有机溶剂中，与烷基碘化物R2I反应，得到对应的通式化合物7。进一步地，反应的温度为40℃至100℃，R2I与通式化合物6的投料 摩尔比为1:2-1:6。
步骤7在一种方案中，当R2为
Figure PCTCN2017112548-appb-000021
时(R3的定义与说明书上文定义相同)，将通式化合物6溶解在有机溶剂中，加入催化量的三乙胺等有机碱，然后缓慢加入含R3基团的磺酰氯类化合物
Figure PCTCN2017112548-appb-000022
进行反应，得到对应的通式化合物7。进一步地，反应的温度为-20℃至20℃。
步骤7在一种方案中，当R2为
Figure PCTCN2017112548-appb-000023
时(R4的定义与说明书上文定义相同)，将含有R4基团的氨类化合物R4-NH2在有机溶剂中溶解，低温下缓慢加入三光气，生成异氰酸酯中间态，然后加入通式化合物6反应，得到对应的通式化合物7；或者将通式化合物6溶解在有机溶剂中，低温下缓慢加入氯甲酸苯酯或N,N-羰基二咪唑(CDI)，进行反应，然后加入含R4基团的氨类化合物R4-NH2，反应完全，得到对应的通式化合物7。进一步地，反应的温度为-10℃至50℃。
步骤7在一种方案中，当R2为
Figure PCTCN2017112548-appb-000024
时(此时R5定义与说明书上文定义相同，并排除R5为一个或多个N，O,S的C5-8的杂环烷基时的情况)选择含R5基团的羧酸类化合物
Figure PCTCN2017112548-appb-000025
与通式化合物6进行缩合反应，得到对应的通式化合物7，进一步，缩合剂可以为HBTU、HOBT、EDC.HCl等，碱可以为三乙胺，DIEA，N-甲基吗啉等，溶剂为二氯甲烷，DMF，DMSO等。
步骤7在一种方案中，当R2为
Figure PCTCN2017112548-appb-000026
时(此时R5定义与说明书上文定义相同，并排除R5为一个或多个N，O,S的C5-8的杂环烷基、氨基、烷氨基的情况)，将通式化合物6溶解在有机溶剂中，加入催化量的碱，然后缓慢加入含有R5基团的酰氯类化合物
Figure PCTCN2017112548-appb-000027
进行反应，得到对应的通式化合物7，进一步，碱可以为三乙胺，DIEA等有机碱，也可以碳酸钾，碳酸氢钠等无机碱，溶剂可以是二氯甲烷，四氢呋喃，DMF等，温度-10℃至50℃。
步骤7在一种方案中，当R2为
Figure PCTCN2017112548-appb-000028
(R5的定义：C2～6烯基、C2～10羧基、C1～10烷基、)时，将通式化合物6溶解在有机溶剂中，加入催化量的碱，然后缓慢加入含有R5基团的酸酐类化合物
Figure PCTCN2017112548-appb-000029
进行反应，得到对应的通式化合物7，进一步，碱可以为三乙胺，DIEA等有机碱，也可以碳酸钾，碳酸氢钠等无机碱，溶剂可以是二氯甲烷，四氢呋喃，DMF等，温度-10℃至50℃。
步骤7在一种方案中，当R2为
Figure PCTCN2017112548-appb-000030
(R5的定义：具有一个或多个N杂原子的C5～8杂环烷基时)将通式化合物6溶解在有机溶剂中，低温缓慢下加入氯甲酸苯酯或N,N-羰基二咪唑，进行反应，然后加入含一个或多个N杂原子的C5～8杂环烷基类化合物反应，得到对应的通式化合物7。
在一种情况中，当R5代表C2～6烷氨基时，将通式化合物6、氨基保护的含R5基团的羧酸类化合物
Figure PCTCN2017112548-appb-000031
HBTU、DIEA溶解在DMSO或者DMF溶剂中，进行酰胺化反应，得到对应的中间体化合物，然后溶解在甲醇或者乙醇溶剂中，在强酸性例如是浓盐酸条件下，脱掉氨基保护基团，后处理得到对应的通式化合物7。进一步地，氨基保护基可以为BOC保护基团。
当与通式化合物6进行反应的底物中含有氨基时，可以先将该底物进行常规的氨基保护，得到对应的中间体化合物，然后再脱去氨基保护基团，得到目标分子。制备化合物的方法涉及将各种化学基团保护和脱保护。本领域技术人员可容易地确定保护和脱保护的需要以及选择适宜的保护基团。
步骤8中，将通式化合物7溶解在有机溶剂中，在水合肼等碱性试剂的作用下进行开环反应，得到目标分子式I化合物。进一步地，开环反应的温度为10℃至50℃，所述的碱性试剂任意选自水合肼、碳酸钾、氢氧化钠、三乙胺等中的任意一种。
上述反应条件中，所述的低温是指零下20℃至10℃，进一步优选0℃左右。
所述的有机溶剂任意选自N,N-二甲基甲酰胺、甲苯、醋酸、甲醇、乙醇、四氢呋喃、二氯甲烷、二甲基亚砜、1,4-二氧六环中的一种。
本发明还提供通式II化合物及其盐的制备方法，但不仅限于以下描述的方法。
Figure PCTCN2017112548-appb-000032
通式II化合物及其盐的制备方法包含以下步骤：
步骤a中，将通式化合物6和通式化合物c溶解在有机溶剂中，在催化量的醋酸的作用下，反应并后处理得到希夫碱类的中间体化合物d；
步骤b中，将中间体化合物d溶解在甲醇或者乙醇溶剂中，在酸性催化剂例如是醋酸的作用下脱掉三苯甲基(Trt)保护基，得到中间体化合物e；进一步地，反应温度为70℃至100℃，酸性催化剂为醋酸、盐酸、三氟乙酸等。
步骤c中，将中间体化合物e溶解在有机溶剂中，在水合肼等碱性试剂的作用下进行开环反应，得到目标分子式II化合物。反应条件可参照上述步骤8。
本发明另一方面提供了一种药物组合物，其中含有治疗有效量的式I或式II化合物或其药学上可接受的盐作为活性成分，以及一种或多种药学上可接受的载体、稀释剂或赋型剂。
该药物组合物优选含有重量比为1％-99％的式I或式II的药学上可接受的盐作为活性成分，更优选含有重量比为5％-80％的活性成分。
除非另有说明，下列用在权利要求书和说明书中的术语有如下含义：
“烷基”表示1-20个碳原子的饱和的脂烃基，包括直链和支链基团(本申请书中提到的数字范围，例如“1-20”，是指该基团，此时为烷基，可以含1个碳原子、2个碳原子、3个碳原子等，直至包括20个碳原子)。本发明中的烷基包含“亚烷基”。含1－6个碳原子的烷基称为低级烷基。当低级烷基没有取代基时，称其为未取代的低级烷基。更优选的是，烷基是有1-10个碳原子的中等大小的烷基，例如甲基、乙基、亚乙基、丙基、亚丙基、2-丙基、正丁基、异丁基、亚丁基、叔丁基、戊基等。最好是，烷基为有1-5个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、亚丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的。
“烷氧基”表示-O-(未取代的烷基)和-O-(未取代的环烷基)，其中烷基的定义与说明书上文定义相同。“烷氧基”优选包括1至10个碳原子的烷氧基，更优选1至6个碳原子的烷氧基；代表性实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
Figure PCTCN2017112548-appb-000033
代表化合物选自其顺式异构体、反式异构体或者顺反异构体的混合物。本发明中的“烯基”，表示2-20个碳原子的含有至少一个碳碳双键的不饱和的脂烃基，包括直链和支链基团。更优选的是，烯基是有2-10个碳原子的中等大小的烯基，进一步优选C2-6烯基。
本发明中的“炔基”，表示2-20个碳原子的含有至少一个碳碳三键的不饱和的脂烃基，包括直链和支链基团。更优选的是，炔基是有2-10个碳原子的中等大小的烯基，进一步优选C2-6炔基。
“卤素”表示氟、氯、溴或碘。
“氨基”表示-NH2。
“羧基”表示-COOH。
“羟基”表示-OH。
“环烷基”表示饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个碳原子，优选包括3至12个碳原子，更优选环烷基环包含3至8个碳原子，最优选环烷基环包含3至6个碳原子，最佳为环丙基。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环己烯基。
“硝基”表示-NO2。
“肼基”表示-NH-NH2。
“烷氨基”表示-烷基-NH2基团,烷基定义如上文所述。
“酯基”表示羧酸衍生物中酯的官能团，-COOR(R一般为烷基等其他非H基团，烷基定义同如上文所述)，例如当其中所含烷基的碳原子个数为1～6时，所述酯基可以简称C1～6酯基。
“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：
(1)与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸例如(但不限于) 盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸例如(但不限于)乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。这类盐用于哺乳动物体内具有安全性、有效性和应有的生物活性。
“药用组合物”指的是在此描述的一种或多种化合物或者它们的药学上可接受的盐、异构体和前药等与其它的化学成分，例如药学上可接受的载体和赋形剂的混合物。药用组合物的目的是促进化合物对生物体的给药。
“药学上可接受的载体”指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的载体或稀释剂。
“赋形剂”指的是加入到药用组合物中以进一步便利于给予化合物的惰性物质。赋形剂的实例包括(不局限于)乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。
药物组合物还可含有：润滑剂例如滑石粉、硬脂酸镁和矿物油；湿润剂；乳化剂和悬浮剂；防腐剂例如苯甲酸甲酯和苯甲酸羟基丙酯；甜味剂和矫味剂。可通过使用本领域中已知的方法配制本发明组合物，以便在给予患者后提供速释、缓释或延迟释放活性成分的作用。
本发明还提供了所述的式I或式II化合物及其药学上可接受的盐在制备与吲哚胺2,3-双加氧化酶(IDO)相关的疾病药物方面的用途，具体而言其在治疗肿瘤、阿尔茨海默病、抑郁症、白内障等多种重大疾病方面的应用。所述的肿瘤优选为肝癌、肺癌、卵巢癌。
初步药物活性研究结果表明本发明的化合物具有较好的IDO抑制活性，对人肝癌细胞株、人大细胞肺癌细胞株、人卵巢癌细胞株、人小细胞肺癌细胞株、人非小细胞肺癌细胞株等多种人肿瘤细胞株的生长均具有明显的抑制作用，其综合效果比INCB024360更优。药代动力学试验还显示，本发明的化合物药代吸收良好，具有明显的药代吸收效果，与INCB024360相比，本发明化合物在药效相当甚至更高的情况下，具有更好的药代动力学性质；急性经口毒性实验研究结果表明本发明的化合物属于无毒或低毒物质，具有潜在的药用价值和广阔的市场化前景。
具体实施方式
以下实施例进一步描述本发明，但是，这些实施例仅是用于说明本发明，而不是对本发明范围的限制。
实施例1 化合物I-1合成
Figure PCTCN2017112548-appb-000034
第一步.将5.0g化合物2用25.0ml乙酸乙酯(EA)溶清，分批加入4.7g对氯苯胺，TLC检测至反应完全，滴加0.5ml三乙胺淬灭反应，加入乙酸乙酯和水，分液，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析纯化，得到6.2g类白色固体化合物15；
第二步.将5.0g化合物15溶于100ml四氢呋喃(THF)中，加入3.2g N,N-羰基二咪唑，升温至70℃反应至TLC检测原料反应完全，停止反应，降温至室温，减压浓缩，加入乙酸乙酯和稀盐酸，分液。有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩用乙酸乙酯与正己烷打浆得到得到5.4g化合物16。
第三步.将5.0g化合物16用90ml TFA(三氟乙酸)溶清，然后加入45ml 30％双氧水，升温至50℃反应；TLC检测原料反应完全，停止反应，用饱和亚硫酸钠溶液淬灭双氧水，EA萃取，合并有机相，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析得1.3g油状物，为化合物17；
第四步.将1.5g化合物10用25mlTHF溶清，将1ml 85％的水合肼用10mlTHF稀释后缓慢滴加至反应体系，TLC检测至原料反应完全，加入50ml水稀释，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，得到1.0g化合物18；
第五步.将1.0g化合物18用10ml四氢呋喃溶清，加入0.5g三乙胺，降温至降温至0℃以下，缓慢滴加0.8g氯甲酸苯酯，TLC检测至原料反应完全，减压旋除大部分THF，加入乙酸乙酯和水，分液，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，得到化合物19，直接投下一步；
第六步.将上述化合物19用10ml四氢呋喃溶清，加入3ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到100mg类白色固体化合物I-1。
实施例2 化合物I-38合成
Figure PCTCN2017112548-appb-000035
第一步.取5.0g丙二腈，加入10ml水溶清，然后降温至0℃以下，加入6.0g亚硝酸钠，搅拌1.0h后关闭制冷，加入1.35ml 4N盐酸，移至常温反应搅拌2.0h，然后降温至0℃以下，缓慢滴加15.5g 50％的羟胺水溶液，滴加完后升温至回流，回流3h后降温至6℃，搅拌过夜，至于0℃以下，缓慢滴加稀盐酸调PH＝5左右，有大量固体析出，抽滤得到10.0g化合物1；
第二步.将10.0g化合物物1用50ml醋酸溶清，然后加入100ml水，38ml 6N HCl以及13.0g氯化钠，溶清后降至0℃以下，缓慢滴加5.3g亚硝酸钠/15ml水溶液，并控温在0℃以下，滴加完毕后继续反应3h，抽滤并用水淋洗滤饼至中性，45℃烘干得6.5g化合物2；
第三步.取6.0g化合物2用250mlEA溶清，分批加入4.8g对氟苯胺，室温反应至TLC检测反应完全，滴加0.5ml三乙胺淬灭反应，加入乙酸乙酯和水，分液，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析纯化，得到5.2g类白色固体化合物8；
第四步.将4.8g化合物8溶于100mlTHF中，加入3.2g N,N-羰基二咪唑，升温至70℃反应至TLC检测原料反应完全，停止反应，降温至室温，减压浓缩，加入乙酸乙酯和稀盐酸，分液。有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，所得粗品用乙酸乙酯与正己烷(1:5)打浆纯化，得到5.1g化合物9；
第五步.将5.0g化合物9用90ml TFA溶清，然后加入45ml 30％双氧水，升温至50℃反应；TLC检测原料反应完全，停止反应，用饱和亚硫酸钠溶液淬灭双氧水，EA萃取，合并有机相，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析得1.5g油状物，为化合物10；
第六步.将1.5g化合物10用25mlTHF溶清，将1ml 85％的水合肼用10mlTHF稀释后缓慢滴加至反应体系，TLC检测至原料反应完全，加入50ml水稀释，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，得到1.2g化合物11；
第七步.将200mg化合物用5.0mlTHF溶清，滴加1ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到30mg类白色固体化合物I-38。
实施例3 化合物I-34合成：
Figure PCTCN2017112548-appb-000036
第一步.将280mg化合物11溶于5ml四氢呋喃，加入120mg三乙胺后降温至0℃以下，缓慢加入290mg对三氟甲氧基苯磺酰氯，TLC检测至原料反应完全，加入25ml水淬灭，乙酸乙酯萃取，保留有机相，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，得粗品化合物12，直接投下一步；
第二步.将上述化合物12用1ml四氢呋喃溶清，加入1ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到50mg类白色固体化合物I-34。
实施例4 化合物I-43合成
Figure PCTCN2017112548-appb-000037
化合物13-1合成:取100ml单口瓶，加入335mg 2-氟-4-甲酰基苯硼酸，1144mg 1-三苯甲基-4-碘咪唑，848mg K3PO4，23mg Pd(PPh3)4，以及2ml水，10mlDMF，N2保护下100℃反应过夜，反应完全降至室温，倒入水中，用EA萃取，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析得到淡灰色520mg化合物13-1，备用；
第一步.将278mg化合物11用10ml四氢呋喃溶清，加入435mg化合物13-1，滴加2滴醋酸，室温反应至原料反应完全，减压旋除大部分THF，加入水和乙酸乙酯，分液，保留有机相，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，得到化合物13，直接投下一步；
第二步.将上述化合物13用3ml醋酸，6ml甲醇溶清，升温至90℃反应，TLC检测至原料反应完全，降至室温，减压旋除溶剂，加入水和乙酸乙酯，分液，保留有机相，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，得到化合物14，直接投下一步；
第三步.将上述化合物14用10ml四氢呋喃溶清，加入2ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到20mg类白色固体化合物I-43。
实施例5 化合物I-2合成
Figure PCTCN2017112548-appb-000038
步骤1.将290mg化合物10-1溶于5ml四氢呋喃，加入120mg三乙胺后降温至0℃以下，缓慢加入300mg间溴苯磺酰氯，TLC检测至原料反应完全，加入25ml水淬灭，乙酸乙酯萃取，保留有机相，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，得粗品化合物12-1，直接投下一步；
步骤2.将上述化合物12-1用10ml四氢呋喃溶清，加入1ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到50mg类白色固体化合物I-2。
实施例6 化合物I-5合成
Figure PCTCN2017112548-appb-000039
化合物13-1的合成方法参照化合物9的合成方法
步骤1.将2.5g化合物13-1用45ml TFA溶清，然后加入45ml 30％双氧水，升温至50℃反应；TLC检测原料反应完全，停止反应，用饱和亚硫酸钠溶液淬灭双氧水，EA萃取，合并有机相，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析得0.65g油状物，为化合物14-1；
步骤2.将上述化合物14-1用10ml四氢呋喃溶清，加入1ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到300mg类白色固体化合物I-5。
实施例7 化合物I-6合成
Figure PCTCN2017112548-appb-000040
步骤1.取234mg化合物I-5用10ml二氯甲烷溶清，加入150mg三乙胺，置于T＝0℃下，缓慢滴加100mg丙烯酰氯/10ml二氯甲烷溶液，TLC检测原料反应完全，加入10ml水，分液，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析得到30mg类白色固体化合物I-6。
实施例8 化合物I-7合成
Figure PCTCN2017112548-appb-000041
步骤1.取290mg化合物10-1用10ml二氯甲烷溶清，加入120mg丁二酸酐，升温至35℃反应，TLC检测原料反应完全，加入10ml水，分液，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，得到粗品化合物15-1，直接投下一步；
步骤2.将上述化合物15-1用10ml四氢呋喃溶清，加入1ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到25mg类白色固体化合物I-7。
实施例9 化合物I-8合成
Figure PCTCN2017112548-appb-000042
化合物16-1的合成方法参照化合物9的合成方法
步骤1.将5.0g化合物16-1用90ml TFA溶清，然后加入45ml 30％双氧水，升温至50℃反应；TLC检测原料反应完全，停止反应，用饱和亚硫酸钠溶液淬灭双氧水，EA萃取，合并有机相，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析得1.0g油状物，为化合物17-1；
步骤2.将1.0g化合物17-1用25mlTHF溶清，将1ml 85％的水合肼用10mlTHF稀释后缓慢滴加至反应 体系溶液，TLC检测至原料反应完全，加入50ml水稀释，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，得到850mg化合物18-1；
步骤3.将165mg对氟苯胺用10ml二氯甲烷溶清，置于0℃下搅拌，缓慢加入445mg三光气，搅拌反应30min后加入310mg化合物18-1的二氯甲烷(10ml)溶液，移至室温反应至原料反应完全，加入10ml水，分液，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，得到粗品化合物19-1，直接投下一步；
步骤4.将上述化合物19-1用10ml四氢呋喃溶清，加入1ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到28mg类白色固体化合物I-8。
实施例10 化合物I-10合成
Figure PCTCN2017112548-appb-000043
化合物20的合成方法参照化合物9的合成方法
步骤1.将5.0g化合物20用90ml TFA溶清，然后加入45ml 30％双氧水，升温至80℃反应，TLC检测原料反应完全，停止反应，用饱和亚硫酸钠溶液淬灭双氧水，EA萃取，合并有机相，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析得0.65g油状物，为化合物21；
步骤2.将0.65g化合物21用10mlTHF溶清，将1ml 85％的水合肼用10mlTHF稀释后缓慢滴加至反应体系溶液，TLC检测至原料反应完全，加入50ml水稀释，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，得到480mg化合物22；
步骤3.取450mg化合22，300mg N-叔丁氧羰基-2-甲基丙氨酸，680mg O-苯并三氮唑-四甲基脲六氟磷酸盐(HBTU)，230mg N,N-二异丙基乙胺(DIEA)，用10mlDMF溶清，置于室温反应，TLC检测原料反应完全，停止反应，倒入100ml水中，有固体析出，抽滤，滤饼柱层析得到350mg化合物23；
步骤4.将350mg化合物23用10ml甲醇溶清，加入3.5ml浓盐酸，置于50℃反应，TLC检测原料反应完全，停止反应，加入20ml水稀释，用氨水调PH＝7-8，加入乙酸乙酯，分液，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析得120mg油状物，为化合物24；
步骤5.将上述化合物24用10ml四氢呋喃溶清，加入1ml 85％水合肼，TLC检测原料反应完全，减压 旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到36mg类白色固体化合物I-10。
实施例11 化合物I-13合成
Figure PCTCN2017112548-appb-000044
步骤1.将295mg化合物10-1用10ml二氯甲烷溶清，加入120mg三乙胺，置于0℃下搅拌，缓慢加入140mg氯甲酸异丙酯，TLC检测原料反应完全，停止反应，加入水和二氯甲烷，分液，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，得到粗品化合物25，直接投下一步；
步骤2.将上述化合物25用10ml四氢呋喃溶清，加入1ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到32mg类白色固体化合物I-13。
实施例12 化合物I-18合成
Figure PCTCN2017112548-appb-000045
步骤1.取100ml单口瓶，加入300mg 2-甲酰基苯硼酸，1090mg 1-三苯甲基-4-碘咪唑，848mg K3PO4，23mg Pd(PPh3)4，以及2ml水，10mlDMF，N2保护下100℃反应过夜，反应完全降至室温，倒入水中，用EA萃取，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析得到650mg淡灰色化合物26；
步骤2.取620mg化合物26，1.0g乙氧甲酰基亚甲基三苯基膦，30ml四氢呋喃，置于50℃反应过夜，降至室温，减压旋除四氢呋喃，柱层析得到470mg类白色化合物27；
步骤3.将470mg化合物27用50ml MeOH/AcOH(V1:V2＝1:1)溶液溶清，升温至90℃反应过夜，降至室温，减压旋除溶剂，加入水和乙酸乙酯，分液，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析得到204mg油状物，即为化合物28；
步骤4.取204mg化合物28，70mg氢氧化钠，15ml甲醇，2d水，置于30℃反应，TLC检测原料反应完全，停止反应，减压旋除溶剂，加入乙酸乙酯搅拌，抽滤，取滤液旋干得到150mg化合物29；
步骤5.取150mg化合物29，200mg化合物11，380mgHBTU，130mg DIEA，10mlDMF，置于30℃反应，TLC检测原料反应完全，停止反应，倒入150ml水中，有大量固体析出，抽滤，保留滤饼，即为化合物31，直接投入下一步；
步骤6.将上述化合物31用10ml四氢呋喃溶清，加入1ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到60mg类白色固体化合物I-18。
实施例13 化合物I-32合成
Figure PCTCN2017112548-appb-000046
步骤1.将312mg化合物22用10ml四氢呋喃溶清，加入414mg化合物26，滴加2滴醋酸，室温反应至原料反应完全，减压旋除大部分THF，加入水和乙酸乙酯，分液，保留有机相，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，得到化合物32，直接投下一步；
步骤2.将上述化合物33用6ml醋酸，6ml甲醇溶清，升温至90℃反应，TLC检测至原料反应完全，降至室温，减压旋除溶剂，加入水和乙酸乙酯，分液，保留有机相，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，得到化合物33，直接投下一步；
步骤3.将上述化合物33用10ml四氢呋喃溶清，加入2ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到50mg类白色固体化合物I-32。
实施例14 化合物I-39合成
Figure PCTCN2017112548-appb-000047
步骤1.取500mg2,3-二氟苯胺，614mg1,1-环丙基二甲酸单甲酯，680mg1-羟基苯并三唑(HOBT)，964mg1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC.HCl)，以及15mlDMF，置于30℃反应，TLC检测至原料反应完全，倒入水中，有大量固体析出，抽滤，滤饼烘干，得到890mg化合物34；
步骤2.取890mg化合物34，280mg氢氧化钠，40ml甲醇，置于50℃反应，TLC检测至原料反应完全，减压旋除甲醇，加入水，用稀盐酸调PH＝3-4，析出大量固体，抽滤，滤饼烘干得到400mg，即为化合物35；
步骤3.取260mg化合物35,200mg化合物30，127mgHOBT，180mg EDC.HCl，116mgN-甲基吗啉，以及20mlDMF，置于30℃反应，TLC检测至原料反应完全，倒入水中，有大量固体析出，抽滤，得到100mg化合物36；
步骤4.将上述化合物36用10ml四氢呋喃溶清，加入2ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到40mg类白色固体化合物I-39。
实施例15 化合物I-48合成
Figure PCTCN2017112548-appb-000048
化合物34-1的合成方法参照化合物10-1的合成方法
步骤1.取2.7g化合物34-1，1.4g碘甲烷，50ml四氢呋喃，置于50℃反应过夜，减压旋除溶剂，制备液相制得50mg化合物35-1；
步骤2.取化合物35-1，用5ml四氢呋喃溶清，加入1ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到10mg类白色固体化合物I-48。
实施例16 化合物I-50合成
Figure PCTCN2017112548-appb-000049
步骤1.取,200mg化合物22用15ml四氢呋喃溶清，加入220mg碳酸钾，置于0℃搅拌，缓慢滴加130mg氯甲酸苯酯，滴加完毕后室温反应1h，减压旋除溶剂，加水和乙酸乙酯，分液，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，得到化合物36-1，直接投下一步；
步骤2.取上述化合物36-1，用20ml四氢呋喃溶清，加入278mg吗啡啉，升温至50℃反应5h，减压旋除溶剂，加水和乙酸乙酯，分液，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析得到85mg化合物37；
步骤3.取化合物37，用5ml四氢呋喃溶清，加入1ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到13mg类白色固体化合物I-50。
实施例17 化合物I-53合成
Figure PCTCN2017112548-appb-000050
步骤1.取312mg化合物18-1，243mgCDI，300mg三乙胺，以及15ml四氢呋喃，置于50℃反应5h，减压旋除溶剂，加水和乙酸乙酯，分液，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析得到150mg化合物38；
步骤2.取化合物38，用5ml四氢呋喃溶清，加入1ml 85％水合肼，TLC检测原料反应完全，减压旋除 大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到13mg类白色固体化合物I-53。
实施例18 化合物I-59合成
Figure PCTCN2017112548-appb-000051
步骤1.取0.58g化合物39，0.51g化合物18-1，0.38g EDCI.HCl，0.3g HOBT，以及30ml DMF，降至0℃下，缓慢加入0.26g N-甲基吗啉，加完升温至30℃反应，TLC检测至反应完全，倒入水中，用EA萃取，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，得0.6g黄色油状物化合物40；步骤2.取0.6g化合物40，加入12ml 2N HCl/MeOH溶液，升温至45℃反应，TLC检测至反应完全，减压浓缩干，加入10ml甲基叔丁基醚/己烷(1:1)有大量固体析出，打浆20min，抽滤得0.3g类白色固体，即为化合物41；
步骤3.取0.46g氯磺酸异氰酸酯用10ml DCM溶解并置于-4℃以下，缓慢滴加0.24g叔丁醇并保温搅拌1h，制得反应液A，将0.3g化合物41溶于10ml DCM，加入0.82g三乙胺并降至-4℃以下，将反应A液缓慢滴入并保温反应6h，用饱和碳酸氢钠溶液将反应淬灭，用EA萃取，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析得0.17g黄色固体，为化合物42；
步骤4.取0.17g化合物42用20ml DCM，降温至-3℃，缓慢滴加4ml TFA，滴加完毕后置于室温反应3h，TLC检测反应完全，加水稀释并用氨水调节PH＝8-9，萃取，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，得到化合物43，直接投下一步；
步骤5.将上述化合物43用10ml四氢呋喃溶清，加入2ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到23mg类白色固体化合物I-59。
实施例19 化合物I-60合成
Figure PCTCN2017112548-appb-000052
步骤1.取650mg3,4-二氟苯胺，500mg丁二酸酐，20mlDMF，置于50℃反应3h，倒入水中，有大量固体析出，抽滤，滤饼烘干得到980mg化合物44；
步骤2.230mg化合物44，280mg化合物11，455mgHBTU，155mg DIEA，以及20mlDMF，30℃反应，TLC检测原料反应完全，加水搅拌，抽滤，直接投下一步；
步骤3.将上述化合物45用10ml四氢呋喃溶清，加入2ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到60mg类白色固体化合物I-60。
实施例20 化合物I-67合成
Figure PCTCN2017112548-appb-000053
步骤1.将810mg化合物6用15.0ml DMF溶清，分批加入750mg对羧基苯胺，TLC检测至反应完全，滴加0.25ml三乙胺淬灭反应，加入乙酸乙酯和水，分液，有机相用饱和NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，柱层析纯化，得到0.9g类白色固体化合物46；
步骤2.将0.9g化合物46溶于30mlTHF中，加入660mg N,N-羰基二咪唑，升温至70℃反应至TLC检测原料反应完全，停止反应，降温至室温，减压浓缩，加入乙酸乙酯和稀盐酸，分液。有机相用饱和 NaCl溶液洗涤并用无水NaSO4干燥，抽滤，滤液减压浓缩，用乙酸乙酯与正己烷打浆得到得到0.75g化合物47；
步骤3.取145mg化合物47,155mg化合物18-1，228mg HBTU，80mg DIEA，以及20mlDMF，30℃反应，TLC检测原料反应完全，加水搅拌，抽滤，得化合物48直接投下一步；
步骤4.取上述化合物48用四氢呋喃溶清，加入2ml 85％水合肼，TLC检测原料反应完全，减压旋除大部分THF，有大量固体析出，抽滤并用水淋洗滤饼，柱层析得到35mg类白色固体化合物I-67。
参照上述化合物的制备方法例，在合适的溶剂及反应温度下，通过一系列反应制备得到下列化合物，测试核磁及质谱,包括但不限于下表所示化合物。
Figure PCTCN2017112548-appb-000054
Figure PCTCN2017112548-appb-000055
Figure PCTCN2017112548-appb-000056
Figure PCTCN2017112548-appb-000057
Figure PCTCN2017112548-appb-000058
Figure PCTCN2017112548-appb-000059
Figure PCTCN2017112548-appb-000060
Figure PCTCN2017112548-appb-000061
Figure PCTCN2017112548-appb-000062
Figure PCTCN2017112548-appb-000063
Figure PCTCN2017112548-appb-000064
Figure PCTCN2017112548-appb-000065
Figure PCTCN2017112548-appb-000066
生物学评价
测试例一 化合物对IDO1的抑制活性测定：
以下结合测试例进一步解释本发明，但这些测试例并非意味着限制本发明，下面是本发明部分化合物在作用浓度为10μM和1μM时对IDO1酶的抑制活性。化合物的结构式如说明书上文实施例所示。
1、材料，试剂盒及仪器
L-抗坏血酸钠(Cat:A4034-100G,SIGMA)
4-(二甲基氨基)苯甲醛(Cat:156477-25g,SIGMA)
三氯乙酸(Cat:T0699-100ML,SIGMA)
L-色氨酸(Cat:T8941-25G,SIGMA)
亚甲基蓝(Cat:M9140-25G,SIGMA)
磷酸二氢钾(Cat:10017618,国药化学试剂)
磷酸氢二钠(Cat:20040618,国药化学试剂)
恒温水槽(Cat:DK-8D,上海精宏实验设备)
多功能酶标仪(Cat:M5,Molecular Devices)
96孔反应板(Cat:3590,costar)
IDO1蛋白酶(市售)
台式酶标仪SpectraMax M5Microplate Reader(Molecular Devices)
待测化合物：自制
阳性对照药：INCB024360(市售)
2、试剂配制
100mM PBS：
按照3:5混合100mM磷酸氢二钠和100mM磷酸二氢钾，PH6.5
IDO1测定缓冲液：
含有400μML-色氨酸，20mM抗坏血酸盐，20μM亚甲蓝和1000U/ml过氧化氢酶的100mM PBS，PH6.530％三氯乙酸
30％三氯乙酸的ddH2O溶液
Ehrlich试剂
1％(w/v)4-(二甲基氨基)苯甲醛化合物稀释
用DMSO溶解所有化合物，测定时，按需要的浓度对各个化合物进行稀释，每个浓度为复孔，控制DMSO的终浓度为1％。
3.测试方法
a.)配制反应混合物：在100μL IDO1测定缓冲液中加入50nM IDO1和所需浓度的待测化合物。IDO1和测定缓冲液需要预热到37℃。
b.)37℃恒温水槽中反应30min。
c.)加入50μL 30％三氯乙酸。
d.)52℃恒温水槽中反应30min。
e.)室温下12000g离心10min。
f.)混合100μL上清和100μL Ehrlich试剂。
g.)用M5酶标仪在480nm测定吸光。
4.数据分析
抑制率＝(ODpositive―ODsample)/(ODpositive―ODnegative)*100％
5.结果与讨论
本实验检测待测化合物在10μM和1μM时对IDO1酶的抑制活性，每个稀释浓度为复孔测试，控制反应体系的DMSO终浓度为1％，在两个浓度的抑制率分别测试两次，取平均值，实验结果如下表所示，结果表明本申请的化合物对IDO1蛋白酶表现出较好的抑制活性。
本实验检测待测化合物对IDO1酶的抑制活性
Figure PCTCN2017112548-appb-000067
Figure PCTCN2017112548-appb-000068
Figure PCTCN2017112548-appb-000069
结论：试验结果显示，本发明的化合物对IDO具有显著的抑制作用，效果与INCB024360相当甚至更优。
测试例二 化合物体外细胞毒性的IC50值测定
应用CCK-8检测试剂盒检测本申请的化合物对8个肿瘤细胞株的细胞毒性IC50值测试。
1、材料和方法
细胞株:
NCI-H460人大细胞肺癌细胞株(订购于中科院上海细胞资源中心)
BEL-7402人肝癌细胞株(订购于中科院上海细胞资源中心)
SMMC-7721人肝癌细胞株(订购于中科院上海细胞资源中心)
SK-OV-3人卵巢癌细胞株(订购于中科院上海细胞资源中心)
NCI-H446人小细胞肺癌细胞株(订购于中科院上海细胞资源中心)
A549人非小细胞肺癌细胞株(订购于中科院上海细胞资源中心)
HepG2人肝癌细胞株(订购于中科院上海细胞资源中心)
OVCAR-3人卵巢癌细胞株(订购于中科院上海细胞资源中心)
2、试剂和耗材：
Cell Counting Kit-8(Cat#CK04-13，Dojindo)
96孔培养板(Cat#3599，Corning Costar)
培养基和胎牛血清(GIBCO)
台式酶标仪SpectraMax M5Microplate Reader(Molecular Devices)
待测化合物:I-18,I-32
3.1培养基的配制
Figure PCTCN2017112548-appb-000070
Figure PCTCN2017112548-appb-000071
化合物的制备：
用DMSO稀释化合物使终浓度为10mM。
3.2IC50实验(CCK-8检测)
a)收集对数生长期细胞，计数，用完全培养基重新悬浮细胞，调整细胞浓度至合适浓度(依照细胞密度优化试验结果确定)，接种96孔板，每孔加100μl细胞悬液。细胞在37℃，100％相对湿度，5％CO2培养箱中孵育24小时。
b)用培养基将待测化合物稀释至所设置的相应作用浓度，按25μl/孔加入细胞。化合物的作用终浓度从100μM开始，4倍梯度稀释，10个浓度点，复孔测试。
c)细胞置于37℃，100％相对湿度，5％CO2培养箱中孵育72小时。
d)吸弃培养基，加入含10％CCK-8的完全培养基置于37℃培养箱中孵育1-4小时。
e)轻轻震荡后在SpectraMax M5Microplate Reader上测定450nm波长处的吸光度，以650nm处吸光度作为参比，计算抑制率。
3.3数据处理
按下式计算药物对肿瘤细胞生长的抑制率：肿瘤细胞生长抑制率％＝[(Ac-As)/(Ac-Ab)]×100％
As:样品的OA(细胞+CCK-8+待测化合物)
Ac:阴性对照的OA(细胞+CCK-8+DMSO)
Ab:阳性对照的OA(培养基+CCK-8+DMSO)
运用软件Graphpad Prism 5并采用计算公式log(inhibitor)vs.normalized response进行IC50曲线拟合并计算出IC50值，结果如下表所示：
Figure PCTCN2017112548-appb-000072
Figure PCTCN2017112548-appb-000073
结论：本发明化合物对多种人肿瘤细胞株的生长均具有明显的抑制作用，其效果比INCB024360更优。
测试例三 药代动力学评价
对本申请的化合物I-18、I-32和化合物INCB024360进行药代动力学测试，研究其在大鼠体内的药代动力学行为，评价其药代动力学特征。
1、实验动物：从上海西普尔-必凯实验动物有限公司购入36只(雌雄各半)SPF级SD大鼠，其中体检合格、无异常的30只(雌雄各半)健康SD大鼠用于该研究。
2、动物给药
SD大鼠30只(雌雄各半)，按下表进行实验。
Figure PCTCN2017112548-appb-000074
注：*在口服给药前，所有动物禁食过夜(10-14小时)，给药后4小时给食。
3、样品采集与处理
经颈静脉穿刺采血，每个样品采集约0.25mL，肝素钠抗凝，采血时间点如下：
口服给药组：给药前，给药后0.25h，0.5h，1h，2h，4h，6h，8h，24h。
血液样本采集后置于冰上，离心分离血浆(离心条件：8000转/分钟，6分钟，2-8℃)。收集的血浆分析前存放于-80℃。血浆样品由实验机构分析部门采用LC-MS/MS进行分析大鼠血浆中的待测化合物含量，检测物检测的LLOQ均为1ng/mL。
4、药物代谢动力学分析
根据药物的血药浓度数据，使用药代动力学计算软件WinNonlin5.2非房室模型分别计算供试品的药代动力学参数AUC0-t、AUC0-C、MRT0-T、Cmax、Tmax、T1/2和Vd等参数及其平均值和标准差。
对于浓度低于定量下限的样品，在进行药代动力学参数计算时，在达到Cmax以前取样的样品应以零值计算，在达到Cmax以后取样点样品应以无法定量(BLQ)计算。
5、结果与讨论
主要药代动力学参数
根据药物的血药浓度数据，使用药代动力学计算软件WinNonlin5.2非房室模型分别计算I-18,I-32,INCB024360的药代动力学参数，见下表。
SD大鼠单次灌胃口服I-18后血浆I-18的主要药代动力学参数
Figure PCTCN2017112548-appb-000075
SD大鼠单次灌胃口服I-32后血浆I-32的主要药代动力学参数
Figure PCTCN2017112548-appb-000076
SD大鼠单次灌胃口服INCB024360后血浆INCB024360的主要药代动力学参数
Figure PCTCN2017112548-appb-000077
结论：本发明化合物的药代吸收良好，具有明显的药代吸收效果，与INCB024360相比，本发明化合物在药效相当甚至更高的情况下，还具有更好的药代动力学性质，具有广阔的市场前景。
测试例四急性经口毒性实验研究
1、目的
观察SD大鼠单次经口给予本发明的化合物的毒性反应，以期充分暴露化合物可能存在的毒性，初步获得急性经口毒性资料。
2、材料和动物
2.1受试物
受试物 纯度 分子量 性状 储存条件
I-18 96.9％ 560.47 灰白色固体 -20℃
I-32 99.2％ 448.14 白色固体 -20℃
2.2配置
溶媒初步预定为0.5％CMC-Na(800-1200CPS)
2.3实验动物
小鼠，ICR，SPF级，18～24g，12只，雌雄各半。实验机构动物储备库：999M-018
原始来源：上海西普尔-必凯实验动物有限公司
3、实验方法
给药前禁食10～18小时，一次灌胃染毒。将实验动物随机分为2组，每组4只，雌雄各半。各组动物染毒设计的给药剂量均为2000 mg/kg，给药浓度均为100mg/mL，给药体积均为20mL/kg，观察期14天。
实验期间所有动物每天至少进行2次(上、下午各一次)笼边观察，观察内容包括但不限于发病、死亡率、损害和供食供水情况。实验第1天进行3次(给药前，给药后0.5及3小时)，第2～14天每天1次。观察内容包括但不限于发病、死亡率、损害和供食供水情况，皮肤，毛，眼，耳，鼻，口腔，胸部，腹 部，外生殖器，四肢，呼吸及循环系统，自主效应(如流涎)，神经系统(如震颤，抽搐，应激反应以及反常行为)。
4、实验结果
Figure PCTCN2017112548-appb-000078
中毒表现:无明显中毒现象。
死亡情况:无死亡
病理检查:各组所有动物脏器和组织未发现明显异常
结果评价：初步提示两个候选化合物毒性较低。
工业实用性：
根据本发明的实施方案，本发明式I或式II化合物及其药学上可接受的盐具有较好的IDO抑制活性，对多种人肿瘤细胞株的生长均显著的抑制作用，其物药代吸收良好，药代吸收效果较好，急性经口毒性实验研究结果表明本发明的化合物属于无毒或低毒物质，其综合效果比INCB024360更优，因此具有较好的药用价值和广阔的市场化前景。

Claims (9)

  1. 一种式I所示的化合物，或其药学上可接受的盐，
    Figure PCTCN2017112548-appb-100001
    其中，
    R1基团代表氢原子、卤素、C1～10烷基或者C1～10烷氧基中的一种；
    R2基团任意选自氢原子、C1～10烷基、
    Figure PCTCN2017112548-appb-100002
    所述的R3基团代表C1～10烷基、苯基或者取代苯基，所述的苯基取代基任意选自卤素、C1～10烷基、C1～10烷氧基、羧基、三氟甲氧基、氨基和羟基中的一种或几种；
    所述的R4基团代表氨基、C3～8环烷基、C3～8环烷基取代的萘基、
    Figure PCTCN2017112548-appb-100003
    或者取代或非取代的苯基，其中所述的苯基取代基任意选自卤素、C1～10烷基、C1～10烷氧基、C2～6炔基、硝基或
    Figure PCTCN2017112548-appb-100004
    其中所述的Ar代表卤素取代的苯基；
    所述的R5基团代表C2～6烯基、C2～10羧基、C2～6烷氨基、C1～10烷基、C1～6烷氧基、苄基、
    Figure PCTCN2017112548-appb-100005
    Figure PCTCN2017112548-appb-100006
    具有一个或多个N、O、S杂原子的C5～8杂环烷基、
    Figure PCTCN2017112548-appb-100007
    Figure PCTCN2017112548-appb-100008
    Figure PCTCN2017112548-appb-100009
    苯基或者取代苯基、
    Figure PCTCN2017112548-appb-100010
    或者
    Figure PCTCN2017112548-appb-100011
    中的任意一种，其中所述的R7任意选自肼基、羟基、C1～6烷氧基或者1～3个F原子取代的苯胺基，n代表0～5的任意阿拉伯数字；所述的R8任意选自C1～6烷氧基、C1～6酯基或C1～4烷基取代及非取代的苯并吡咯基中的一种，m代表0～5的任意阿拉伯数字；所述的苯基取代基任意选自卤素、C1～10烷基、C1～10烷氧基、羧基、羟基和
    Figure PCTCN2017112548-appb-100012
    中的一种或几种；所述的X基团任意选自氢原子或者卤素中的一种或几种。
  2. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于R5中所述的具有一个或多个N、O、S杂原子的C5～8杂环烷基被C1～6烷基、C1～4烷氧基或氨基任意取代。
  3. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于所述的R5基团任意选自
    Figure PCTCN2017112548-appb-100013
    中的一种。
  4. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于所述的所述的R4基团为
    Figure PCTCN2017112548-appb-100014
  5. 一种式II所示的化合物，或其药学上可接受的盐，
    Figure PCTCN2017112548-appb-100015
    其中R1基团任意选自氢原子、卤素、C1～10烷基和C1～10烷氧基中的一种或几种；所述的X基团任选自卤素或氢原子中的一种或几种。
  6. 如权利要求1或5所述的化合物或其药学上可接受的盐，其特征在于选自：
    Figure PCTCN2017112548-appb-100016
    Figure PCTCN2017112548-appb-100017
    Figure PCTCN2017112548-appb-100018
    Figure PCTCN2017112548-appb-100019
    Figure PCTCN2017112548-appb-100020
    Figure PCTCN2017112548-appb-100021
    Figure PCTCN2017112548-appb-100022
    或其药学上可接受的盐。
  7. 一种药物组合物，其特征在于包含治疗有效量的游离形式或可药用盐形式的权利要求1至6中任意一项所定义的化合物作为活性成分，以及一种或多种药学上可接受的载体、稀释剂或赋型剂。
  8. 含有权利要求1至6中任意一项所定义的化合物在与吲哚胺2,3-双加氧化酶(IDO)相关的疾病药物中的应用。
  9. 含有权利要求1至6中任意一项所定义的化合物在肿瘤、阿尔茨海默病、抑郁症以及白内障等多种重大疾病方面的应用。
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