WO2019141027A1 - 吲哚胺2,3-双加氧化酶抑制剂及其制备方法和用途 - Google Patents

吲哚胺2,3-双加氧化酶抑制剂及其制备方法和用途 Download PDF

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WO2019141027A1
WO2019141027A1 PCT/CN2018/120771 CN2018120771W WO2019141027A1 WO 2019141027 A1 WO2019141027 A1 WO 2019141027A1 CN 2018120771 W CN2018120771 W CN 2018120771W WO 2019141027 A1 WO2019141027 A1 WO 2019141027A1
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group
compound
added
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substituted
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PCT/CN2018/120771
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English (en)
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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Priority to US15/733,410 priority Critical patent/US11214554B2/en
Publication of WO2019141027A1 publication Critical patent/WO2019141027A1/zh

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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
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/08—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 carbon chain containing alicyclic rings
    • 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
    • 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

Definitions

  • the field belongs to the field of medical chemistry, and in particular relates to a highly efficient IDO inhibitor, 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 WO2006122150, WO2016071293, WO2010005958, WO2014066834, WO2016155545, CN 103130735A, CN102164902, and the like.
  • IDO inhibitors can be applied to treat many major diseases such as tumors, Alzheimer's disease, depression, cataract, etc., and have very good market value, in order to meet the current clinical regulation of IDO.
  • Another object of the invention is to provide a pharmaceutical composition of the guanamine 2,3-dioxygenase inhibitor and uses thereof.
  • the object of the invention can be achieved by the following measures:
  • a compound and a salt or isomer thereof characterized in that the structure is as shown in Formula I or Formula II:
  • the R 1 group is arbitrarily selected from one or more of a hydrogen atom, a halogen or a trifluoromethyl group;
  • n 0 or 1
  • Y is optionally selected from an oxygen atom, a sulfur atom, a nitrogen atom or One of them;
  • Z is optionally selected from an oxygen atom, a sulfur atom, a nitrogen atom or One of them;
  • the R 3 group is arbitrarily selected from a substituted or unsubstituted C 1-10 alkyl group, a C 3 ⁇ 10 cycloalkyl group, and the substituent is optionally selected from an amino group, an oxo group, a C 3-6 cycloalkyl group, One or more of C 2-6 ester group, C 1-6 alkyl group, and -CONH 2 ;
  • the R 4 group is optionally selected from a hydrogen atom, a substituted or unsubstituted C 1-10 alkyl group; further, the C 1-10 alkyl substituent is optionally selected from One or more of a C 1-4 alkyl substituted or unsubstituted phenyl group; the R 2 group is optionally selected from a hydrogen atom, a C 1-6 alkyl group, a C 2-4 ester group, a C 1-4 alkyl substituted sulfonyl group, an amino substituted sulfonyl group, an amino substituted sulfonylamino group, Substituted or unsubstituted C 4-8 aryl or heteroaryl, In one of the above, R 5 is optionally selected from a C 1-6 alkyl group, a C 1-6 alkoxy group, a substituted or unsubstituted anilino group, a substituted or unsubstituted C 5-12 aryl group or C.
  • the Z and R 3 groups together form a 5-8 membered heterocycloalkyl group
  • the Y, Z and R 3 groups together form a 5-8 membered heterocycloalkyl group
  • the R 2 group is or
  • n 1 and the R 2 group is
  • the R 4 group is selected from one of the substituted C 1-10 alkyl groups, and the C 1-10 alkyl group is optionally selected from the group consisting of One of C 1-4 alkyl substituted or unsubstituted phenyl groups.
  • the present invention also provides a process for the preparation of the compounds of Formula I, Formula II, and salts or isomers thereof, but is not limited to the methods 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 skilled 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 of the compound 1 can be carried out by referring to the method disclosed in the specification of the invention patent WO2010005958.
  • Step 1 using the compound of the formula 1 as a starting material, under the action of N, N'-carbonyldiimidazole, ring-closing reaction to obtain the compound of the formula 2;
  • Step 2 Compound 2 is subjected to a conventional oxidation reaction under the action of an oxidizing agent to obtain a compound of the formula 3, which 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.
  • R 4 is In the case of a group (the definition of the R 5 group is the same as defined above), the compound of the formula 3 is dissolved in an organic solvent, and the Y-NH 2 compound is slowly added dropwise, for example, 10% to 20% hydrazine hydrate, methyl One of an aqueous solution of hydrazine, hydroxylamine or thiamine is reacted to obtain a compound of the formula 4.
  • Compound 6 is reacted with an acid chloride or isocyanate compound containing an R 5 group to give Formula I, and the reaction temperature is from 15 ° C to 50 ° C.
  • R 4 is optionally selected from a hydrogen atom
  • the preparation of the compound of formula I further comprises the steps of:
  • Step 3 '
  • the compound of the formula 3 is dissolved in an organic solvent, and then an organic solution of the compound of R 4 -Y-NH 2 is added dropwise to obtain a compound of the formula 5.
  • step 1
  • the compound of the formula 7 is deprotected by the action of hydrochloric acid, trifluoroacetic acid, piperidine, palladium carbon/hydrogen or sodium hydroxide to obtain the compound of the formula 8;
  • Compound 9 is subjected to a ring opening reaction under the action of a base to give Formula II.
  • Another aspect of the 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 or isomer thereof, as an active ingredient, and one or more pharmaceutically acceptable Accepted carrier, diluent or excipient.
  • the pharmaceutical composition preferably contains, as an active ingredient, a pharmaceutically acceptable salt or isomer of the formula I, formula II in an amount of from 1% to 90% by weight, more preferably from 10% to 80% by weight of the active ingredient.
  • aryl denotes an all-carbon monocyclic or fused polycyclic group of 5 to 12 carbon atoms having a fully 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 to which the parent structure is attached is an aryl ring.
  • the aryl group can be substituted or unsubstituted.
  • the substituent is preferably one or more, more preferably one, two or three, still more preferably one or two, independently selected from lower alkyl, trihaloalkyl, halogen, hydroxy , lower alkoxy, fluorenyl, (lower alkyl)thio, cyano, acyl, thioacyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thioamino Formyl, C-amido, N-acylamino, nitro, N-sulfonylamino, S-sulfonylamino.
  • the aryl group is a 5-membered monocyclic aryl group, a 6-membered monocyclic aryl group.
  • heteroaryl denotes a monocyclic or fused ring radical 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, additionally having a fully conjugated ⁇ -electron system.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring.
  • Heteroaryl groups can 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 sites are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, indole, tetrazole, triazine and oxazole; preferably,
  • the heteroaryl group is a nitrogen-containing 5-membered monocyclic heteroaryl group and a nitrogen-containing 6-membered monocyclic heteroaryl group.
  • alkyl denotes a saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, and includes both straight-chain and branched-chain groups (the numerical ranges mentioned in the specification, such as “1-20", mean the group, In this case, it is an alkyl group which may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms or the like 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 denotes -O-(unsubstituted alkyl) and -O-(unsubstituted cycloalkyl), wherein the definition of alkyl is the same 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.
  • trifluoromethyl means -CF 3
  • halogen means fluoro, chloro, bromo or iodo.
  • amino means -NH 2 .
  • alkoxy denotes -R-OH, wherein R is as defined for alkyl.
  • mercapto means -SH.
  • cycloalkyl denotes 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 The 8 carbon atoms, most preferably the cycloalkyl ring contains 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.
  • heterocycloalkyl denotes a saturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur heteroatoms and the remaining ring atoms are carbon.
  • ester group denotes 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, a carbon atom of an alkyl group contained therein.
  • R is generally a non-H group such as an alkyl group, and the alkyl group is as defined above
  • the ester group may be abbreviated as a C 1 to 6 ester group.
  • salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
  • an inorganic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, or the like
  • organic acid such as, but not limited to, acetic acid, Malic acid, fumaric acid, maleic acid, p-toluenesulfonic acid, tartaric acid, citric acid, lactic acid, succinic acid or malonic acid.
  • Such salts are useful in mammals for safety, efficacy, and biological activity.
  • “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, microcrystalline cellulose, sorbitol, polyvinylpyrrolidone, cellulose, water, and methylcellulose.
  • 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 invention also provides the use of a compound of formula I or formula II, and a pharmaceutically acceptable salt or isomer thereof, for:
  • the compounds of the present invention can be used for the preparation of various major diseases such as tumors, Alzheimer's disease, depression, cataracts and the like.
  • the preliminary pharmacological activity study results indicate that the compound of the present invention has a good IDO inhibitory activity and can be used for the preparation of a medicament for preventing and/or treating a pathological characteristic disease having an IDO-mediated tryptophan metabolism pathway.
  • the pharmacokinetic test also showed that the compound of the present invention has good absorption of the drug and has obvious pharmacological absorption effect.
  • the compound of the present invention has better pharmacokinetics in the case of a relatively higher or even higher drug effect.
  • the dynamic nature, great medicinal value and broad market prospects are expected to develop a new generation of immunosuppressants.
  • Step 1 632 mg of compound I-24-1 was dissolved in 20 ml of tetrahydrofuran, 486 mg of carbonyldiimidazole (CDI) was added, and the reaction was carried out at 50 ° C for 0.5 h. After the reaction was completed, the solvent was removed under reduced pressure, and 30 ml of water was added to dilute hydrochloric acid. The pH was adjusted to 4-5, and the mixture was extracted twice with ethyl acetate. The organic phase was combined and washed twice with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness. White solid)
  • Step 2 650 mg of compound I-24-2 was added to a mixed solvent of 20 ml of trifluoroacetic acid and 12 ml of hydrogen peroxide, and the reaction was allowed to stand at 70 ° C overnight. After the reaction was completed, 20 ml of water was added, and a large amount of solid was precipitated and dried by suction filtration.
  • Compound I-24-3 (315 mg, pale yellow solid);
  • Step 3 315 mg of the compound I-24-3 was dissolved in 20 ml of tetrahydrofuran, and 224 mg/10 ml of the compound 1 tetrahydrofuran solution was added dropwise, and the reaction was carried out for 12.0 h at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, and ethyl acetate and water were added thereto. The organic phase was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dry
  • Step 4 Dissolve 320 mg of compound I-24-4 in 20 ml of dichloromethane, add 4 ml of trifluoroacetic acid, and react at room temperature for 2.0 h. After the reaction is completed, the solvent is removed under reduced pressure, 20 ml of water is added, and the pH is adjusted with saturated sodium hydrogencarbonate. The mixture was extracted with ethyl acetate. The organic phase was combined and washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to afford compound I-24-5 (205 mg, white solid) ;
  • Step 5 15 ml of methylene chloride was cooled to below 0 ° C, 108 mg of chlorosulfonic acid isocyanate was added, then 56 mg of t-butanol was added dropwise and the temperature was controlled below 0 ° C. After the completion of the dropwise addition, the reaction was incubated for 15 min and moved to room temperature for 2.0 h. , the reaction liquid A was obtained.
  • Step 6 Dissolve 225 mg of compound I-24-6 in 20 ml of dichloromethane, add 4 ml of trifluoroacetic acid, and react at room temperature for 2.0 h. After the reaction is completed, the solvent is removed under reduced pressure, 20 ml of water is added, and the pH is adjusted with saturated sodium hydrogencarbonate. The mixture was extracted with ethyl acetate for 2 times, and the organic phase was combined and washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give compound I-24-7 (160 mg, white solid) ;
  • Step 7 Dissolve 160 mg of compound I-24-7 in 20 ml of tetrahydrofuran, add 1 ml of 2.5 M sodium hydroxide solution, and react at room temperature for 2.0 h. After the reaction is completed, add saturated ammonium chloride solution and ethyl acetate, and separate the organic phase. The mixture was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 1 320 mg of the compound I-24-3 was dissolved in 20 ml of tetrahydrofuran, and 262 mg/10 ml of the compound 2 tetrahydrofuran solution was added dropwise, and the reaction was carried out at room temperature for 6.0 h. After the reaction was completed, the solvent was evaporated under reduced pressure, and ethyl acetate and water were added thereto. The organic phase is washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dry
  • Step 2 364 mg of compound I-20-1 was dissolved in 20 ml of dichloromethane, and 4 ml of trifluoroacetic acid was added thereto, and the mixture was reacted at room temperature for 2.0 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 20 ml of water was added, and pH was adjusted with saturated sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The organic phase was combined and washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to afford compound I-20-2 (235 mg, white solid) ;
  • Step 3 15 ml of methylene chloride was cooled to below 0 ° C, 118 mg of chlorosulfonic acid isocyanate was added, then 60 mg of t-butanol was added dropwise and the temperature was controlled below 0 ° C. After the completion of the dropwise addition, the reaction was incubated for 15 min and moved to room temperature for 2.0 h. , the reaction liquid A was obtained.
  • Step 4 260 mg of compound I-20-3 was dissolved in 20 ml of dichloromethane, and 4 ml of trifluoroacetic acid was added thereto, and the mixture was reacted at room temperature for 2.0 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 20 ml of water was added, and the mixture was adjusted with saturated sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The organic phase was combined and washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give compound I-20-4 (184 mg, white solid) ;
  • Step 5 184 mg of compound I-20-4 was dissolved in 20 ml of tetrahydrofuran, and 1 ml of 2.5 M sodium hydroxide solution was added thereto, and reacted at room temperature for 2.0 h. After the reaction was completed, saturated ammonium chloride solution and ethyl acetate were added, and the organic phase was separated. The mixture was washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate.
  • Step 1 200 mg of compound I-24-3 was dissolved in 20 ml of tetrahydrofuran, 97 mg/10 ml of compound 3 tetrahydrofuran solution was added dropwise, and reacted at room temperature for 6.0 h. After the reaction was completed, the solvent was evaporated under reduced pressure, and ethyl acetate and water were added thereto. The organic phase was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated
  • Step 2 180 mg of compound I-1-1 was dissolved in 20 ml of tetrahydrofuran, and 1 ml of 2.5 M sodium hydroxide solution was added thereto, and reacted at room temperature for 2.0 h. After the reaction was completed, saturated ammonium chloride solution and ethyl acetate were added, and the organic phase was separated. The mixture was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 1 200 mg of compound I-24-3 was dissolved in 20 ml of tetrahydrofuran, 128 mg/10 ml of compound 4 tetrahydrofuran solution was added dropwise, and reacted at room temperature for 6.0 h. After the reaction was completed, the solvent was removed under reduced pressure, and ethyl acetate and water were added thereto. The organic phase was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dry
  • Step 2 196 mg of compound I-15-1 was dissolved in 20 ml of dichloromethane, cooled to -70 ° C, and 220 mg of boron tribromide was slowly added dropwise. After the addition was completed, the temperature was slowly raised to -10 ° C for 0.5 h, and the reaction was completed. After that, it was stirred to room temperature, quenched with saturated sodium hydrogencarbonate, and extracted with dichloromethane. The organic phase was washed twice with saturated sodium chloride solution and dried over anhydrous sodium sulfate. -2 (120 mg, oil);
  • Step 3 120 mg of compound I-15-2 was dissolved in 20 ml of tetrahydrofuran, and 1 ml of 2.5 M sodium hydroxide solution was added thereto, and reacted at room temperature for 2.0 h. After the reaction was completed, saturated ammonium chloride solution and ethyl acetate were added, and the organic phase was separated. The mixture was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 1 200 mg of compound I-24-5 was dissolved in 20 ml of dichloromethane, 100 mg of triethylamine was added, 115 mg of methanesulfonyl chloride was added dropwise at 0 ° C, and the reaction was continued for 2.0 h after the completion of the addition. Water, and the pH was adjusted to 4-5 with dilute hydrochloric acid.
  • Step 2 180 mg of compound I-13-1 was dissolved in 20 ml of tetrahydrofuran, 1 ml of 2.5 M sodium hydroxide solution was added, and reacted at room temperature for 2.0 h. After the reaction was completed, saturated ammonium chloride solution and ethyl acetate were added. The organic phase was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 1 370 mg of compound I-24-3 was dissolved in 20 ml of tetrahydrofuran, and 496 mg/10 ml of compound 6 tetrahydrofuran solution was added dropwise, and reacted at room temperature for 6.0 h. After the reaction was completed, the solvent was removed under reduced pressure, and ethyl acetate and water were added thereto. The organic phase was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dry
  • Step 2 430 mg of compound I-16-1 was dissolved in 20 ml of dichloromethane, 4 ml of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 2.0 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 20 ml of water was added, and pH was adjusted with saturated sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The organic phase was combined and washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to afford compound I-16-2 (284 mg, white solid) ;
  • Step 3 284 mg of compound I-16-2 was dissolved in 20 ml of tetrahydrofuran, and 1 ml of 2.5 M sodium hydroxide solution was added thereto, and reacted at room temperature for 2.0 h. After the reaction was completed, saturated ammonium chloride solution and ethyl acetate were added, and the organic phase was separated. The mixture was washed twice with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 1 542 mg of compound I-5-1 was dissolved in 20 ml of tetrahydrofuran, 486 mg of CDI was added, and the reaction was carried out at 50 ° C for 0.5 h. After the reaction was completed, the solvent was removed under reduced pressure, 30 ml of water was added, and the pH was adjusted to 4- with dilute hydrochloric acid. 5, extraction with ethyl acetate 2 times, the organic phase was combined, washed twice with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness to give compound I-5-2 (564 mg, white solid);
  • Step 2 564 mg of compound I-5-2 was added to a mixed solvent of 20 ml of trifluoroacetic acid and 12 ml of hydrogen peroxide, and reacted at 70 ° C overnight. After the reaction was completed, 20 ml of water was added, and a large amount of solid was precipitated, and dried by suction filtration.
  • Compound I-5-3 (402 mg, pale yellow solid);
  • Step 3 Dissolve 402 mg of compound I-5-3 in 20 ml of tetrahydrofuran, add 324 mg/10 ml of compound 1 tetrahydrofuran solution, and react at room temperature for 12.0 h. After the reaction is completed, the solvent is removed under reduced pressure, ethyl acetate and water are added, and the mixture is separated. The organic phase was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dry
  • Step 4 465 mg of compound I-5-4 was dissolved in 20 ml of dichloromethane, and 4 ml of trifluoroacetic acid was added thereto, and the mixture was reacted at room temperature for 2.0 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 20 ml of water was added, and pH was adjusted with saturated sodium hydrogen carbonate. The mixture was extracted with ethyl acetate for 2 times, and the organic phase was combined and washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give compound I-5-5 (308 mg, white solid) ;
  • Step 5 308 mg of compound I-5-4 was dissolved in 20 ml of tetrahydrofuran, and 1 ml of 2.5 M sodium hydroxide solution was added thereto, and reacted at room temperature for 2.0 h. After the reaction was completed, saturated ammonium chloride solution and ethyl acetate were added, and the organic phase was separated. The mixture was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness to give the compound I-7-5 (256 mg, white solid)
  • Step 6 256 mg of compound I-5-5 was dissolved in 20 ml of ethanol, 115 mg of maleic anhydride was added, and the reaction was refluxed for 6.0 h. After the reaction was completed, the solvent was evaporated under reduced pressure, water and ethyl acetate were added, and the organic phase was separated. The mixture was washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate.
  • Step 1 740 mg of the compound I-24-3 was dissolved in 20 ml of tetrahydrofuran, and 738 mg/10 ml of the compound 7 tetrahydrofuran solution was added dropwise, and the reaction was carried out at room temperature for 6.0 h. After the reaction was completed, the solvent was evaporated under reduced pressure, and ethyl acetate and water were added thereto. The organic phase was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dry
  • Step 2 855 mg of the compound I-23-1 was dissolved in 20 ml of methanol, and 115 mg of p-toluenesulfonic acid-hydrate was added thereto, and the mixture was reacted at room temperature for 12.0 h. After the reaction was completed, the saturated sodium hydrogencarbonate solution was added to neutralize the acid, and concentrated under reduced pressure. The organic phase is washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 3 395 mg of compound I-23-2 was dissolved in 20 ml of dichloromethane, 148 mg of triethylamine was added, cooled to below 0 ° C, 116 mg of acetyl chloride was added dropwise, and the reaction was carried out for 1.0 h. After the reaction was completed, saturated sodium hydrogencarbonate was added. The liquid phase was separated, and the organic phase was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give compound I-23-3 (400 mg, oil).
  • Step 4 400 mg of compound I-23-3 was dissolved in 20 ml of dichloromethane, and 4 ml of trifluoroacetic acid was added thereto, and the mixture was reacted at room temperature for 2.0 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 20 ml of water was added, and pH was adjusted with saturated sodium hydrogen carbonate. The mixture was extracted with ethyl acetate for 2 times, and the organic phase was combined and washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give compound I-23-4 (284 mg, white solid) ;
  • Step 5 15 ml of dichloromethane was cooled to below 0 ° C, 127 mg of chlorosulfonic acid isocyanate was added, then 65 mg of t-butanol was added dropwise and the temperature was controlled below 0 ° C. After the completion of the dropwise addition, the reaction was incubated for 15 min and moved to room temperature for 2.0 h. , the reaction liquid A is prepared;
  • Step 6 293 mg of compound I-23-5 was dissolved in 20 ml of dichloromethane, and 4 ml of trifluoroacetic acid was added thereto, and the mixture was reacted at room temperature for 2.0 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 20 ml of water was added, and pH was adjusted with saturated sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The organic phase was combined and washed twice with saturated sodium chloride solution and dried over anhydrous sodium sulfate. ;
  • Step 7 198 mg of compound I-23-6 was dissolved in 20 ml of methanol, 248 mg of potassium carbonate was added, and reacted at 50 ° C for 2.0 h. After the reaction was completed, saturated ammonium chloride solution and ethyl acetate were added, and the organic phase was saturated with chlorine. The sodium solution was washed twice, dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 1 710 mg of compound I-7-1 was dissolved in 20 ml of tetrahydrofuran, 486 mg of CDI was added, and the reaction was carried out at 50 ° C for 0.5 h. After the reaction was completed, the solvent was removed under reduced pressure, 30 ml of water was added, and the pH was adjusted to 4- with dilute hydrochloric acid. 5, extraction with ethyl acetate 2 times, the organic phase was combined, washed twice with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness to give compound I-7-2 (610 mg, white-white solid);
  • Step 2 610 mg of compound I-7-2 was added to a mixed solvent of 20 ml of trifluoroacetic acid and 12 ml of hydrogen peroxide, and reacted at 70 ° C overnight. After the reaction was completed, 20 ml of water was added, and a large amount of solid was precipitated, and dried by suction filtration.
  • Compound I-7-3 (365 mg, pale yellow solid);
  • Step 3 365 mg of compound I-7-3 was dissolved in 20 ml of tetrahydrofuran, and 215 mg/10 ml of compound 5 tetrahydrofuran solution was added dropwise, and the reaction was carried out for 12.0 h at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, and ethyl acetate and water were added thereto. The organic phase was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dry
  • Step 7 375 mg of compound I-7-4 was dissolved in 20 ml of tetrahydrofuran, and 1 ml of 2.5 M sodium hydroxide solution was added thereto, and reacted at room temperature for 2.0 h. After the reaction was completed, saturated ammonium chloride solution and ethyl acetate were added, and the organic phase was separated. The mixture was washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate.
  • Step 1 494 mg of compound I-27-1 was dissolved in 20 ml of tetrahydrofuran, 486 mg of CDI was added, and the reaction was carried out at 50 ° C for 0.5 h. After the reaction was completed, the solvent was removed under reduced pressure, 30 ml of water was added, and the pH was adjusted to 4- with dilute hydrochloric acid. 5, extraction with ethyl acetate 2 times, the organic phase was combined, washed twice with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness to give compound I-27-2 (518 mg, white-white solid);
  • Step 2 518 mg of compound I-27-2 was added to a mixed solvent of 20 ml of trifluoroacetic acid and 12 ml of hydrogen peroxide, and reacted at 70 ° C overnight. After the reaction was completed, 20 ml of water was added, and a large amount of solid was precipitated, and dried by suction filtration.
  • Compound I-27-3 (345 mg, pale yellow solid);
  • Step 3 345mg of compound I-27-3 was dissolved in 20ml of tetrahydrofuran, 300mg/10ml of compound 1 tetrahydrofuran solution was added dropwise, and reacted at room temperature for 12.0h. After the reaction was completed, the solvent was removed under reduced pressure, and ethyl acetate and water were added. The organic phase was washed twice with a saturated sodium chloride solution and dried over anhydrous sodium sulfate.
  • Step 4 Dissolve 334 mg of compound I-27-4 in 20 ml of dichloromethane, add 4 ml of trifluoroacetic acid, and react at room temperature for 2.0 h. After the reaction is completed, the solvent is removed under reduced pressure, 20 ml of water is added, and the pH is adjusted with saturated sodium hydrogencarbonate. To a solution of about 2, ethyl acetate was added for 2 times, and the organic phase was combined and washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give compound I-27-5 (225 mg, white solid) ;
  • Step 5 15 ml of dichloromethane was cooled to below 0 ° C, 150 mg of chlorosulfonic acid isocyanate was added, then 73 mg of t-butanol was added dropwise and the temperature was controlled below 0 ° C. After the completion of the dropwise addition, the reaction was incubated for 15 min and moved to room temperature for 2.0 h. , the reaction liquid A was obtained.
  • Step 6 263 mg of compound I-27-6 was dissolved in 20 ml of dichloromethane, and 4 ml of trifluoroacetic acid was added thereto, and the mixture was reacted at room temperature for 2.0 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 20 ml of water was added, and pH was adjusted with saturated sodium hydrogen carbonate. The mixture was extracted with ethyl acetate for 2 times, and the organic phase was combined and washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give compound I-27-7 (180 mg, white solid) ;
  • Step 7 180 mg of compound I-27-7 was dissolved in 20 ml of tetrahydrofuran, and 1 ml of 2.5 M sodium hydroxide solution was added thereto, and reacted at room temperature for 2.0 h. After the reaction was completed, saturated ammonium chloride solution and ethyl acetate were added, and the organic phase was separated. The mixture was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 1 981 mg of the compound I-5 was dissolved in 20 ml of tetrahydrofuran, and 10 ml of a 20% methylhydrazine tetrahydrofuran solution was added dropwise thereto, and the mixture was reacted at room temperature for 2.0 h. After the reaction was completed, the solvent was evaporated under reduced pressure, and ethyl acetate and water were added, and the mixture was separated. The organic phase was washed twice with a saturated sodium chloride solution and dried over anhydrous sodium sulfate.
  • Step 2 780 mg of the compound I-36-1 was dissolved in 20 ml of tetrahydrofuran, and 405 mg of phenylacetyl chloride/5 ml of tetrahydrofuran solution was added dropwise, and 263 mg of triethylamine was added thereto, and the mixture was reacted at room temperature for 0.5 h. After the reaction was completed, the solvent was removed under reduced pressure, and 30 ml was added. The mixture was extracted twice with ethyl acetate. EtOAc (EtOAc m.
  • Step 3 818 mg of compound I-36-2 was dissolved in 20 ml of tetrahydrofuran, and 1 ml of 2.5 M sodium hydroxide solution was added thereto, and reacted at room temperature for 2.0 h. After the reaction was completed, saturated ammonium chloride solution and ethyl acetate were added, and the organic layer was separated. The mixture was washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate.
  • Step 1 401 mg of compound I-24-5, 198 mg of 3,5-difluorophenylisocyanate, 200 mg of triethylamine were dissolved in 10 ml of DMF, and reacted at room temperature overnight. After the reaction was completed, 50 ml of water was added, and ethyl acetate was added to extract 2 The organic phase was combined, washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate
  • Step 2 283 mg of compound I-40-1 was dissolved in 20 ml of tetrahydrofuran, and 1 ml of 2.5 M sodium hydroxide solution was added thereto, and reacted at room temperature for 2.0 h. After the reaction was completed, saturated ammonium chloride solution and ethyl acetate were added, and the organic layer was separated. The mixture was washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate.
  • 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 the IDO1 enzyme.
  • 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 is to test the inhibitory activity of the test compound on IDO1 enzyme. Each dilution concentration is the re-pore test. The final concentration of DMSO in the control reaction system is 1%. The inhibition rate is tested twice and averaged. The experimental results are shown in the following table. The results indicate that the compound of the present application exhibits a good inhibitory activity against the IDO1 protease.
  • This experiment detects the inhibitory activity of the test compound on IDO1 enzyme.
  • This method is used to determine the inhibitory effect of the compounds of the present invention on IDO protease inhibitory activity in highly expressed HeLa cells.
  • Multi-function microplate reader (Cat: M5, Molecular Devices)
  • tumor cell growth inhibition rate % [(Ac-As) / (Ac-Ab)] ⁇ 100%
  • the pharmacokinetic tests of the compounds I-20, I-24, I-40 and the compound INCB024360 of the present application were carried out to study their pharmacokinetic behavior in rats, and their pharmacokinetic characteristics were evaluated.
  • Blood was collected by jugular vein puncture, and each sample was collected about 0.25 mL.
  • the 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 after administration. 8h, 24h.
  • Blood 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 WinConlin5.2 non-compartment model were used to calculate the pharmacokinetic parameters AUC 0-t , Cmax, Tmax, T 1/2d and other parameters of the test sample and their parameters. Average 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-20, I-24, I-40, 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 and has broad market prospect.

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Abstract

本发明提供一种新型吲哚胺2,3-双加氧化酶抑制剂及其制备方法、药物组合物，其中n、Y、Z、R 1、R 2、R 3、R 4的定义如说明书所示。同时提供了所述的化合物及其的药学上可接受的盐和异构体在制备与吲哚胺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。本发明的化合物活性较好，具有潜在的药用价值和广阔的市场化前景。

Description

吲哚胺2,3-双加氧化酶抑制剂及其制备方法和用途 技术领域
本领域属于医药化学领域，具体涉及一种高效的IDO抑制剂及其制备方法和用途。
背景技术
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***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 PCTCN2018120771-appb-000001
INCB024360结构式
Figure PCTCN2018120771-appb-000002
INCB024360类似物结
涉及IDO抑制剂的发明专利申请有WO2006122150、WO2016071293、WO2010005958、WO2014066834、WO2016155545、CN 103130735A、CN102164902等。
发明专利申请CN102164902中公开了化合物，获得了较好的临床研究效果：
Figure PCTCN2018120771-appb-000003
CN106883193A中公开了以下化合物：
Figure PCTCN2018120771-appb-000004
CN 105646389A中公开了下了化合物：
Figure PCTCN2018120771-appb-000005
其中各取代基的定义如其说明书所述。
目前，IDO抑制剂的研发仍存在较高的技术壁垒，现有的me-too类IDO抑制剂分子均尚未应用于临床治疗。IDO抑制剂作为具有新药靶、新机制的药物，可应用于***、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，达到更好的疾病治疗效果，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新型吲哚胺2,3-双加氧化酶抑制剂及其制备方法。
本发明的另一个目的是提供所述吲哚胺2,3-双加氧化酶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：
一种化合物及其盐或异构体，其特征在于结构如式I或式II所示：
Figure PCTCN2018120771-appb-000006
其中，
R 1基团任意选自氢原子、卤素或者三氟甲基中的一种或几种；
n代表0或1；
Y任意选自氧原子、硫原子、氮原子或
Figure PCTCN2018120771-appb-000007
中的一种；
Z任意选自氧原子、硫原子、氮原子或
Figure PCTCN2018120771-appb-000008
中的一种；
R 3基团任意选自取代或非取代的C 1～10烷基、C 3～10环烷基，所述的取代基任意选 自氨基、氧代基团、C 3～6环烷基、C 2～6酯基、C 1～6烷羟基、-CONH 2的一种或几种；
R 4基团任意选自氢原子、
Figure PCTCN2018120771-appb-000009
取代或非取代的C 1～10烷基中的一种；进一步地，所述的C 1～10烷基的取代基任意选自
Figure PCTCN2018120771-appb-000010
Figure PCTCN2018120771-appb-000011
C 1～4烷基取代或非取代的苯基中的一种或几种；R 2基团任意选自氢原子、C 1～6烷基、C 2～6酯基、
Figure PCTCN2018120771-appb-000012
Figure PCTCN2018120771-appb-000013
C 1～4烷基取代的磺酰基、氨基取代的磺酰基、氨基取代的磺酰胺基、
Figure PCTCN2018120771-appb-000014
取代或非取代的C 4～8的芳基或 杂芳基、
Figure PCTCN2018120771-appb-000015
中的一种，所述的R 5任意选自C 1～6烷基、C 1～6烷氧基、取代或非取代的苯胺基、取代或非取代的C 5～12的芳基或C 4～10杂芳基中的一种，所述的苯胺基、芳基、杂芳基的取代基为卤素、氨基中的任意一种或几种。
在一种情况下，Z和R 3基团一起形成5～8元杂环烷基；
在一种情况下，Y、Z和R 3基团一起形成5～8元杂环烷基；
在一种情况下,R 2基团为
Figure PCTCN2018120771-appb-000016
或者
Figure PCTCN2018120771-appb-000017
在一种方案中，n代表1，R 2基团为
Figure PCTCN2018120771-appb-000018
在一种方案中，R 4基团选自取代的C 1～10烷基中的一种，所述的C 1～10烷基被任意选自
Figure PCTCN2018120771-appb-000019
Figure PCTCN2018120771-appb-000020
C 1～4烷基取代或非取代的苯基中的一种封端。
本发明还提供通式I、式II化合物及其盐或异构体的制备方法，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。
式I的制备方案：
Figure PCTCN2018120771-appb-000021
式I的制备方案
上述式I制备方案中，n、R 1、R 4和Y基团的定义与说明书上文定义相同。
其中，化合物1的制备可以参照发明专利WO2010005958中说明书公开的方法进行。
式I化合物及其盐或异构体的制备方法包含以下步骤：
步骤1：以通式化合物1为起始原料，在N,N'-羰基二咪唑的作用下关环反应得到通式化合物2；
步骤2：化合物2在氧化剂的作用下进行常规的氧化反应，得到通式化合物3，所述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3：
在一种方案中，当R 4为
Figure PCTCN2018120771-appb-000022
基团时(R 5基团的定义与说明书上文定义相同)，将通式化合物3溶解在有机溶剂中，缓慢滴加Y-NH 2类化合物例如是10％-20％水合肼、甲基肼、羟胺或硫胺等水溶液中的一种，反应得到通式化合物4。
步骤4：
将化合物4在碱的作用下开环反应得到通式化合物6；
步骤6：
将化合物6与含有R 5基团的酰氯类或者异氰酸酯类化合物反应，得到通式式I，所述的反应的温度为15℃至50℃。
在另一种方案中，当R 4任意选自氢原子、
Figure PCTCN2018120771-appb-000023
取代或非取代的C 1～10烷基时，式I化合物的制备还包含如下步骤：
步骤3‘：
将通式化合物3溶解在有机溶剂中，然后滴加R 4-Y-NH 2化合物的有机溶液，反应得到通式化合物5。
步骤5：
将化合物5溶解在有机溶剂中，然后在碱的作用下开环得到通式式I化合物。
式II的制备方案：
Figure PCTCN2018120771-appb-000024
式II的制备方案
上述式II制备方案中，n、R 1、R 3、Z和Y基团的定义与说明书上文定义相同。式II化合物及其盐或异构体的制备方法包含以下步骤：
步骤1：
选择合适的化合物3，在有机溶剂中，滴加
Figure PCTCN2018120771-appb-000025
的有机溶液，反应得到通式化合物7，其中，Pg为羟基、巯基或者氨基的保护基，例如Boc、Cbz、Fmoc、甲基或乙酰基等保护基；
步骤2：
通式化合物7在盐酸、三氟乙酸、哌啶、钯碳/氢气或者氢氧化钠等作用下脱除保护基，得到通式化合物8；
步骤3：
根据目标分子的结构特征选择合适的含有R 2基团的羧酸类化合物、含有R 2基团的酰氯或磺酰氯类化合物，含有R 2基团的卤代物或者含有R 2基团的异氰酸酯中的任意一种与化合物8在碱性条件反应，得到通式化合物9；
步骤4：
化合物9在碱的作用下进行开环反应得到通式式II。
在上述制备方法中，当各中间体的制备过程的稳定性需要而进行基团保护时，需先将相应的中间体进行脱保护基反应，最终得到目标分子化合物。制备化合物的方法如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。所述的脱保护反应可以在三氟乙酸或者盐酸的催化作用下进行。
本发明提到的上述特征，或实施例提到的特征可以在符合药学规律基础上任意组合，说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。除有特别说明，所揭示的特征仅为相同或形似特征的一般性例子。
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或者式II化合物或其药学上可接受的盐或异构体作为活性成分，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％-90％的式I、式II的药学上可接受的盐或异构体作为活性成分，更优选含有重量比为10％-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或特征：
术语“芳基”表示5至12个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子***。芳基的非限制性实例有苯基、萘基和蒽基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环。芳基可以是取代的或未取代的。当被取代时，取代基优选为一个或多个，更优选为一个、两个或三个，进而更优选为一个或两个，独立地选自由低级烷基、三卤烷基、卤素、羟基、低级烷氧基、巯基、(低级烷基)硫基、氰基、酰基、硫代酰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、硝基、N-磺酰氨基、S-磺酰氨基。优选地，芳基为5元单环芳基、6元单环芳基。
术语“杂芳基”表示5至12个环原子的单环或稠合环基团，含有一个、两个、三个或四个选自N、O或S的环杂原子，其余环原子是C，另外具有完全共轭的π电子***。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是取代的或未取代的。当被取代时，取代基优选为一个或多个，更为优选为一个、两个或三个，进而更为优选一个或两个。未取代的杂芳基地非限制性实例有吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、嘧啶、喹啉、异喹啉、嘌呤、四唑、三嗪和咔唑；优选地，杂芳基为含氮5元单环杂芳基、含氮6元单环杂芳基。
术语“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。
术语“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。
术语“三氟甲基”表示-CF 3
术语“异构体”选自其顺式异构体、反式异构体或者顺反异构体的混合物。
术语“卤素”表示氟、氯、溴或碘。
术语“氨基”表示-NH 2。
羰基作取代基时称为氧代基团。
术语“烷羟基”表示-R-OH,其中R的定义如烷基所述。
术语“磺酰基”表示
Figure PCTCN2018120771-appb-000026
术语“磺酰胺基”表示
Figure PCTCN2018120771-appb-000027
术语“巯基”表示-SH。
术语“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。
术语“杂环烷基”表示饱和的单环或多环环状烃取代基，其中一个或多个环原子选择氮、氧或硫的杂原子，其余环原子为碳。
术语“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C 1～6酯基。
术语“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、氢溴酸等，有机酸例如(但不限于)乙酸、苹果酸、富马酸、马来酸、对甲苯磺酸、酒石酸、柠檬酸、乳酸、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、微晶纤维素、山梨醇、聚乙烯吡咯烷酮、纤维素、水、和甲基纤维素等。
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或异构体的用途，用于：
(1)制备与吲哚胺2,3-双加氧化酶(IDO)相关疾病的药物；
(2)制备色氨酸代谢紊乱相关疾病的药物。
进一步地，本发明的化合物可以用于制备肿瘤、阿尔茨海默病、抑郁症、白内障等多种重大疾病的药物。
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，可以用于制备预防和/或治疗具有IDO介导的色氨酸代谢途径的病理学特征疾病的药物。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，有较大的药用价值和广阔的市场化前景，有望开发新一代免疫抑制剂。
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
Figure PCTCN2018120771-appb-000028
步骤1：将632mg化合物I-24-1溶于20ml四氢呋喃，加入486mg羰基二咪唑(CDI)，置于50℃反应0.5h，反应结束后，减压旋除溶剂，加入30ml水，用稀盐酸调PH至4-5，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠水溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-24-2(650mg，类白色固体)；
步骤2：将650mg化合物I-24-2加入到20ml三氟乙酸与12ml双氧水的混合溶剂中，置于70℃反应过夜，反应结束后，加入20ml水，有大量固体析出，抽滤烘干得化合物I-24-3(315mg，淡黄色固体)；
步骤3：将315mg化合物I-24-3溶于20ml四氢呋喃，滴加224mg/10ml化合物1四氢呋喃溶液，室温反应12.0h，反应结束后，减压旋除溶剂，加入乙酸乙酯 与水，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干柱层析得化合物I-24-4(320mg，类白色固体)；
步骤4：将320mg化合物I-24-4溶于20ml二氯甲烷，加入4ml三氟乙酸，室温反应2.0h，反应结束后，减压旋除溶剂，加入20ml水，用饱和碳酸氢钠调PH至8左右，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-24-5(205mg，类白色固体)；
步骤5：将15ml二氯甲烷冷却至0℃以下，加入108mg氯磺酸异氰酸酯，然后滴加56mg叔丁醇并控温在0℃以下，滴加完毕后保温反应15min，移至室温反应2.0h，制得反应液A。
将205mg化合物I-24-5溶于20ml二氯甲烷，降温至0℃以下，滴加反应液A，滴加完毕后，滴加155mg三乙胺，反应2.0h，反应结束后，加入饱和碳酸氢钠淬灭，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析纯化得化合物I-24-6(225mg，类白色固体)；
步骤6：将225mg化合物I-24-6溶于20ml二氯甲烷，加入4ml三氟乙酸，室温反应2.0h，反应结束后，减压旋除溶剂，加入20ml水，用饱和碳酸氢钠调PH至8左右，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-24-7(160mg，类白色固体)；
步骤7：将160mg化合物I-24-7溶于20ml四氢呋喃，加入1ml 2.5M氢氧化钠溶液，室温反应2.0h，反应结束后，加入饱和氯化铵溶液和乙酸乙酯，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析得化合物I-24(18mg，类白色固体，纯度：98.2％)；
实施例2
Figure PCTCN2018120771-appb-000029
步骤1：将320mg化合物I-24-3溶于20ml四氢呋喃，滴加262mg/10ml化合物2四氢呋喃溶液，室温反应6.0h，反应结束后，减压旋除溶剂，加入乙酸乙酯与水，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干柱层析得化合物I-20-1(364mg，类白色固体)；
步骤2：将364mg化合物I-20-1溶于20ml二氯甲烷，加入4ml三氟乙酸，室温反应2.0h，反应结束后，减压旋除溶剂，加入20ml水，用饱和碳酸氢钠调PH至8左右，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-20-2(235mg，类白色固体)；
步骤3：将15ml二氯甲烷冷却至0℃以下，加入118mg氯磺酸异氰酸酯，然后滴加60mg叔丁醇并控温在0℃以下，滴加完毕后保温反应15min，移至室温反应2.0h，制得反应液A。
将235mg化合物I-20-2溶于20ml二氯甲烷，降温至0℃以下，滴加反应液A，滴加完毕后，滴加166mg三乙胺，反应2.0h，反应结束后，加入饱和碳酸氢钠淬灭，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析纯化得化合物I-20-3(260mg，类白色固体)；
步骤4：将260mg化合物I-20-3溶于20ml二氯甲烷，加入4ml三氟乙酸，室温反应2.0h，反应结束后，减压旋除溶剂，加入20ml水，用饱和碳酸氢钠调PH 至8左右，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-20-4(184mg，类白色固体)；
步骤5：将184mg化合物I-20-4溶于20ml四氢呋喃，加入1ml 2.5M氢氧化钠溶液，室温反应2.0h，反应结束后，加入饱和氯化铵溶液和乙酸乙酯，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析得化合物I-20(25mg，类白色固体，纯度：97.8％)。
实施例3
Figure PCTCN2018120771-appb-000030
步骤1：将200mg化合物I-24-3溶于20ml四氢呋喃，滴加97mg/10ml化合物3四氢呋喃溶液，室温反应6.0h，反应结束后，减压旋除溶剂，加入乙酸乙酯与水，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干柱层析得化合物I-1-1(180mg，类白色固体)；
步骤2：将180mg化合物I-1-1溶于20ml四氢呋喃，加入1ml 2.5M氢氧化钠溶液，室温反应2.0h，反应结束后，加入饱和氯化铵溶液和乙酸乙酯，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析得化合物I-1(15mg，类白色固体，纯度：96.4％)；
实施例4
Figure PCTCN2018120771-appb-000031
步骤1：将200mg化合物I-24-3溶于20ml四氢呋喃，滴加128mg/10ml化合物4四氢呋喃溶液，室温反应6.0h，反应结束后，减压旋除溶剂，加入乙酸乙 酯与水，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干柱层析得化合物I-15-1(196mg，类白色固体)；
步骤2：将196mg化合物I-15-1溶于20ml二氯甲烷，降温冷却至-70℃，缓慢滴加220mg三溴化硼，滴加完毕后缓慢升温至-10℃反应0.5h，反应结束后，移至室温，加入饱和碳酸氢钠淬灭，加入二氯甲烷萃取，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干柱层析得化合物I-15-2(120mg，油状物)；
步骤3：将120mg化合物I-15-2溶于20ml四氢呋喃，加入1ml 2.5M氢氧化钠溶液，室温反应2.0h，反应结束后，加入饱和氯化铵溶液和乙酸乙酯，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析得化合物I-15(11mg，类白色固体，纯度：96.5％)；
实施例5
Figure PCTCN2018120771-appb-000032
步骤1：将200mg化合物I-24-5溶于20ml二氯甲烷，加入100mg三乙胺，置于0℃下滴加115mg甲磺酰氯，滴加完毕后继续反应2.0h，反应结束后，加入水，并用稀盐酸调PH至4-5，分液有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干得粗品化合物I-13-1(180mg，油状物)，直接头下一步；步骤2：将180mg化合物I-13-1溶于20ml四氢呋喃，加入1ml 2.5M氢氧化钠溶液，室温反应2.0h，反应结束后，加入饱和氯化铵溶液和乙酸乙酯，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析得化合物I-13(19mg，类白色固体，纯度：96.8％)；
实施例6
Figure PCTCN2018120771-appb-000033
步骤1：将370mg化合物I-24-3溶于20ml四氢呋喃，滴加496mg/10ml化合物6四氢呋喃溶液，室温反应6.0h，反应结束后，减压旋除溶剂，加入乙酸乙酯与水，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干柱层析得化合物I-16-1(430mg，类白色固体)；
步骤2：将430mg化合物I-16-1溶于20ml二氯甲烷，加入4ml三氟乙酸，室温反应2.0h，反应结束后，减压旋除溶剂，加入20ml水，用饱和碳酸氢钠调PH至8左右，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-16-2(284mg，类白色固体)；
步骤3：将284mg化合物I-16-2溶于20ml四氢呋喃，加入1ml 2.5M氢氧化钠溶液，室温反应2.0h，反应结束后，加入饱和氯化铵溶液和乙酸乙酯，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析得化合物I-16(20mg，类白色固体，纯度：98.5％)；
实施例7
Figure PCTCN2018120771-appb-000034
步骤1：将542mg化合物I-5-1溶于20ml四氢呋喃，加入486mg CDI，置于50℃反应0.5h，反应结束后，减压旋除溶剂，加入30ml水，用稀盐酸调PH至4-5，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠水溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-5-2(564mg，类白色固体)；
步骤2：将564mg化合物I-5-2加入到20ml三氟乙酸与12ml双氧水的混合溶剂中，置于70℃反应过夜，反应结束后，加入20ml水，有大量固体析出，抽滤烘干得化合物I-5-3(402mg，淡黄色固体)；
步骤3：将402mg化合物I-5-3溶于20ml四氢呋喃，滴加324mg/10ml化合物1四氢呋喃溶液，室温反应12.0h，反应结束后，减压旋除溶剂，加入乙酸乙酯与水，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干柱层析得化合物I-5-4(465mg，类白色固体)；
步骤4：将465mg化合物I-5-4溶于20ml二氯甲烷，加入4ml三氟乙酸，室温反应2.0h，反应结束后，减压旋除溶剂，加入20ml水，用饱和碳酸氢钠调PH至8左右，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-5-5(308mg，类白色固体)；
步骤5：将308mg化合物I-5-4溶于20ml四氢呋喃，加入1ml 2.5M氢氧化钠溶液，室温反应2.0h，反应结束后，加入饱和氯化铵溶液和乙酸乙酯，分液，有机 相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，得化合物I-7-5(256mg，类白色固体)，直接投下一步；
步骤6：将256mg化合物I-5-5溶于20ml乙醇，加入115mg马来酸酐，回流反应6.0h，反应结束后，减压旋除溶剂，加入水和乙酸乙酯，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析得化合物I-5(13mg，类白色固体，纯度：97.2％)。
实施例8
Figure PCTCN2018120771-appb-000035
步骤1：将740mg化合物I-24-3溶于20ml四氢呋喃，滴加738mg/10ml化合物7四氢呋喃溶液，室温反应6.0h，反应结束后，减压旋除溶剂，加入乙酸乙酯 与水，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干柱层析得化合物I-23-1(855mg，类白色固体)；
步骤2：将855mg化合物I-23-1溶于20ml甲醇，加入115mg对甲苯磺酸-水合物，于室温反应12.0h，反应结束后，加入饱和碳酸氢钠溶液中和酸，减压浓缩，加入乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干柱层析得化合物I-23-2(395mg，油状物)；
步骤3：将395mg化合物I-23-2溶于20ml二氯甲烷中，加入148mg三乙胺，冷却至0℃以下，滴加116mg乙酰氯，反应1.0h，反应结束后，加入饱和碳酸氢钠，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-23-3(400mg，油状物)，直接投下一步；
步骤4：将400mg化合物I-23-3溶于20ml二氯甲烷，加入4ml三氟乙酸，室温反应2.0h，反应结束后，减压旋除溶剂，加入20ml水，用饱和碳酸氢钠调PH至8左右，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-23-4(284mg，类白色固体)；
步骤5：将15ml二氯甲烷冷却至0℃以下，加入127mg氯磺酸异氰酸酯，然后滴加65mg叔丁醇并控温在0℃以下，滴加完毕后保温反应15min，移至室温反应2.0h，制得反应液A；
将284mg化合物I-23-4溶于20ml二氯甲烷，降温至0℃以下，滴加反应液A，滴加完毕后，滴加240mg三乙胺，反应2.0h，反应结束后，加入饱和碳酸氢钠淬灭，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析纯化得化合物I-23-5(293mg，类白色固体)；
步骤6：将293mg化合物I-23-5溶于20ml二氯甲烷，加入4ml三氟乙酸，室温反应2.0h，反应结束后，减压旋除溶剂，加入20ml水，用饱和碳酸氢钠调PH至8左右，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-23-6(198mg，类白色固体)；
步骤7：将198mg化合物I-23-6溶于20ml甲醇，加入248mg碳酸钾，50℃反应2.0h，反应结束后，加入饱和氯化铵溶液和乙酸乙酯，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析得化合物I-23(18mg，类白色固体，纯度：97.6％)。
实施例9
Figure PCTCN2018120771-appb-000036
步骤1：将710mg化合物I-7-1溶于20ml四氢呋喃，加入486mg CDI，置于50℃反应0.5h，反应结束后，减压旋除溶剂，加入30ml水，用稀盐酸调PH至4-5，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠水溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-7-2(610mg，类白色固体)；
步骤2：将610mg化合物I-7-2加入到20ml三氟乙酸与12ml双氧水的混合溶剂中，置于70℃反应过夜，反应结束后，加入20ml水，有大量固体析出，抽滤烘干得化合物I-7-3(365mg，淡黄色固体)；
步骤3：将365mg化合物I-7-3溶于20ml四氢呋喃，滴加215mg/10ml化合物5四氢呋喃溶液，室温反应12.0h，反应结束后，减压旋除溶剂，加入乙酸乙酯与水，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干柱层析得化合物I-7-4(375mg，类白色固体)；
步骤7：将375mg化合物I-7-4溶于20ml四氢呋喃，加入1ml 2.5M氢氧化钠溶液，室温反应2.0h，反应结束后，加入饱和氯化铵溶液和乙酸乙酯，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析得化合物I-7(26mg，类白色固体，纯度：97.6％)。
实施例10
Figure PCTCN2018120771-appb-000037
步骤1：将494mg化合物I-27-1溶于20ml四氢呋喃，加入486mg CDI，置于50℃反应0.5h，反应结束后，减压旋除溶剂，加入30ml水，用稀盐酸调PH至4-5，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠水溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-27-2(518mg，类白色固体)；
步骤2：将518mg化合物I-27-2加入到20ml三氟乙酸与12ml双氧水的混合溶剂中，置于70℃反应过夜，反应结束后，加入20ml水，有大量固体析出，抽滤烘干得化合物I-27-3(345mg，淡黄色固体)；
步骤3：将345mg化合物I-27-3溶于20ml四氢呋喃，滴加300mg/10ml化合物1四氢呋喃溶液，室温反应12.0h，反应结束后，减压旋除溶剂，加入乙酸乙酯与水，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干柱 层析得化合物I-27-4(334mg，类白色固体)；
步骤4：将334mg化合物I-27-4溶于20ml二氯甲烷，加入4ml三氟乙酸，室温反应2.0h，反应结束后，减压旋除溶剂，加入20ml水，用饱和碳酸氢钠调PH至8左右，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-27-5(225mg，类白色固体)；
步骤5：将15ml二氯甲烷冷却至0℃以下，加入150mg氯磺酸异氰酸酯，然后滴加73mg叔丁醇并控温在0℃以下，滴加完毕后保温反应15min，移至室温反应2.0h，制得反应液A。
将225mg化合物I-27-5溶于20ml二氯甲烷，降温至0℃以下，滴加反应液A，滴加完毕后，滴加205mg三乙胺，反应2.0h，反应结束后，加入饱和碳酸氢钠淬灭，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析纯化得化合物I-27-6(263mg，类白色固体)；
步骤6：将263mg化合物I-27-6溶于20ml二氯甲烷，加入4ml三氟乙酸，室温反应2.0h，反应结束后，减压旋除溶剂，加入20ml水，用饱和碳酸氢钠调PH至8左右，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-27-7(180mg，类白色固体)；
步骤7：将180mg化合物I-27-7溶于20ml四氢呋喃，加入1ml 2.5M氢氧化钠溶液，室温反应2.0h，反应结束后，加入饱和氯化铵溶液和乙酸乙酯，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析得化合物I-27(22mg，类白色固体，纯度：96.9％)；
实施例11
Figure PCTCN2018120771-appb-000038
步骤1：将981mg化合物I-5溶于20ml四氢呋喃，滴加20％甲基肼四氢呋喃溶液10ml，室温反应2.0h，反应结束后，减压旋除溶剂，加入乙酸乙酯与水，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干柱层析得化合物I-36-1(780mg，类白色固体)；
步骤2：将780mg化合物I-36-1溶于20ml四氢呋喃，滴加405mg苯乙酰氯/5ml四氢呋喃溶液，加入263mg三乙胺，室温反应0.5h，反应结束后，减压旋除溶剂，加入30ml水，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠水溶液洗涤2次，无水硫酸钠干燥，减压旋干得化合物I-36-2(818mg，类白色固体)；
步骤3：将818mg化合物I-36-2用20ml四氢呋喃溶清，加入1ml 2.5M氢氧化钠溶液，室温反应2.0h，反应结束后，加入饱和氯化铵溶液和乙酸乙酯，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析得化合物I-36(38mg，类白色固体，纯度：98.9％)。
实施例12
Figure PCTCN2018120771-appb-000039
步骤1：将401mg化合物I-24-5，198mg 3,5-二氟苯异氰酸酯，200mg三乙胺溶于10ml DMF中，室温反应过夜，反应结束后，加入50ml水，加入乙酸乙酯萃取2次，合并有机相，用饱和氯化钠水溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析得化合物I-40-1(283mg，类白色固体)；
步骤2：将283mg化合物I-40-1用20ml四氢呋喃溶清，加入1ml 2.5M氢氧化钠溶液，室温反应2.0h，反应结束后，加入饱和氯化铵溶液和乙酸乙酯，分液，有机相用饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压旋干，柱层析得化合物I-40(12mg，类白色固体，纯度：95.8％)。
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 PCTCN2018120771-appb-000040
Figure PCTCN2018120771-appb-000041
Figure PCTCN2018120771-appb-000042
Figure PCTCN2018120771-appb-000043
Figure PCTCN2018120771-appb-000044
Figure PCTCN2018120771-appb-000045
Figure PCTCN2018120771-appb-000046
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 M5 Microplate 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，PH6.5
30％三氯乙酸
30％三氯乙酸的ddH  2O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＝(OD positive―OD sample)/(OD positive―OD negative)*100％
5.结果与讨论
本实验检测待测化合物对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％，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
化合物编号 IC 50(nm)
I-1 80
I-2 43
I-3 108
I-4 96
I-5 32
I-6 162
I-7 113
I-8 94
I-9 85
I-10 90
I-11 120
I-12 35
I-13 124
I-14 81
I-15 93
I-16 42
I-17 85
I-18 183
I-19 140
I-20 18
I-21 82
I-22 64
I-23 36
I-24 8
I-25 68
I-26 92
I-27 42
I-28 184
I-29 80
I-30 65
I-31 42
I-32 125
I-33 99
I-34 104
I-35 94
I-36 82
I-37 53
I-38 78
I-39 142
I-40 12
I-41 69
I-42 36
I-43 35
I-44 78
I-45 92
I-46 65
I-47 48
I-48 72
I-49 66
I-50 28
I-51 83
INCB024360 32
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 化合物对高表达的HeLa细胞内IDO蛋白酶抑制活性的测定
该方法用来测定本发明中的化合物对高表达的HeLa细胞内IDO蛋白酶抑制活性的抑制作用
1、试剂和耗材：
台式酶标仪SpectraMax M5 Microplate Reader(Molecular Devices)
多功能酶标仪(Cat:M5,Molecular Devices)
L-色氨酸(Cat:T8941-25G,SIGMA)
4-(二甲基氨基)苯甲醛(Cat:156477-25g,SIGMA)
三氯乙酸(Cat:T0699-100ML,SIGMA)
高表达的HeLa细胞株
2、测试方法
a.)加入50μL 30％三氯乙酸。
b.)52℃恒温水槽中反应30min。
c.)室温下12000g离心10min。
d.)混合100μL上清和100μL Ehrlich试剂。
e.)用M5酶标仪在480nm测定吸光。
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％
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：
化合物编号 IC 50(nm)
I-2 38
I-5 58
I-12 43
I-16 35
I-20 8
I-23 38
I-24 5
I-27 26
I-40 12
I-42 28
I-43 38
I-47 47
I-50 21
INCB024360 33
结论：试验结果显示，本发明的化合物对HeLa细胞内IDO蛋白酶具有显著的抑制作用。
测试例三 药代动力学评价
对本申请的化合物I-20、I-24、I-40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100只(雌雄各半)SPF级SD大鼠，其中体检合格、无异常的72只(雌雄各半)健康SD大鼠用于该研究。
2、动物给药
SD大鼠72只(雌雄各半)，给药前搅拌至少10min，按下表进行实验。
Figure PCTCN2018120771-appb-000047
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AUC 0-t、Cmax、Tmax、T 1/2d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C max以前取样的样品应以零值计算，在达到C max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-20、I-24、I-40,INCB024360的药代动力学参数，见下表。
SD大鼠单次灌胃口服化合物后血浆化合物的主要药代动力学参数
Figure PCTCN2018120771-appb-000048
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，本发明化合物具有更好的药代动力学性质，具有广阔的市场前景。

Claims (10)

  1. 一种化合物及其盐或异构体，其特征在于结构如式I或式II所示：
    Figure PCTCN2018120771-appb-100001
    其中，
    R 1基团任意选自氢原子、卤素或者三氟甲基中的一种或几种，例如一种或两种；n代表0或1；
    Y任意选自氧原子、硫原子、氮原子或
    Figure PCTCN2018120771-appb-100002
    中的一种；
    Z任意选自氧原子、硫原子、氮原子或
    Figure PCTCN2018120771-appb-100003
    中的一种；
    R 3基团任意选自取代或非取代的C 1～10烷基、C 3～10环烷基，所述的取代基任意选自氨基、氧代基团、C 3～6环烷基、C 2～6酯基、C 1～6烷羟基、-CONH 2的一种或几种；
    R 4基团任意选自氢原子、
    Figure PCTCN2018120771-appb-100004
    取代或非取代的C 1～10烷基中的一种；进一步地，所述的C 1～10烷基的取代基任意选自
    Figure PCTCN2018120771-appb-100005
    Figure PCTCN2018120771-appb-100006
    C 1～4烷基取代或非取代的苯基中的一种或几种；R 2基团任意选自氢原子、C 1～6烷基、C 2～6酯基、
    Figure PCTCN2018120771-appb-100007
    Figure PCTCN2018120771-appb-100008
    C 1～4烷基取代的磺酰基、氨基取代的磺酰基、氨基取代的磺酰胺基、
    Figure PCTCN2018120771-appb-100009
    取代或非取代的C 4～8的芳基或杂芳基、
    Figure PCTCN2018120771-appb-100010
    中的一种，所述的R 5任意选自C 1～6烷基、C 1～6烷氧基、取代或非取代的苯胺基、取代或非取代的C 5～12的芳基或C 4～10杂芳基中的一种，所述的苯胺基、芳基、杂芳基的取代基为卤素、氨基中的任意一种或几种。
  2. 如权利要求1所述的化合物及其盐或异构体，其特征在于所述的Z和R 3基团一起形成5～8元杂环烷基。
  3. 如权利要求1所述的化合物及其盐或异构体，其特征在于Y、Z和R 3基团一起形成5～8元杂环烷基。
  4. 如权利要求1所述的化合物及其盐或异构体，其特征在于R 2基团为
    Figure PCTCN2018120771-appb-100011
    或者
    Figure PCTCN2018120771-appb-100012
  5. 如权利要求1所述的化合物及其盐或异构体，其特征在于n代表1，R 2基团为
    Figure PCTCN2018120771-appb-100013
  6. 如权利要求1所述的化合物及其盐或异构体，其特征在于R 4基团选自取代的C 1～10烷基中的一种，所述的C 1～10烷基被任意选自
    Figure PCTCN2018120771-appb-100014
    Figure PCTCN2018120771-appb-100015
    C 1～4烷基取代或非取代的苯基中的一种封端。
  7. 一种化合物及其盐或异构体，其特征在于选自：
    Figure PCTCN2018120771-appb-100016
    Figure PCTCN2018120771-appb-100017
    Figure PCTCN2018120771-appb-100018
    Figure PCTCN2018120771-appb-100019
    及其盐或异构体。
  8. 一种药物组合物，其特征在于其中含有治疗有效量的式I或者式II化合物或其药学上可接受的盐或异构体作为活性成分，以及一种或多种药学上可接受的载体、稀释剂或赋型剂。
  9. 一种治疗与吲哚胺2,3-双加氧化酶相关的疾病的方法，所述方法包括向受治疗者施用治疗有效量的如权利要求1至7中任意一项所述的化合物或如权利要求8所述的药物组合物。
  10. 如权利要求9所述的方法，其中所述疾病为肿瘤、阿尔茨海默病、抑郁 症、白内障等。
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