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WO2018113758A1 - 一种作为吲哚胺-2，3-双加氧酶抑制剂的砜脒及其制备方法和用途 - Google Patents

一种作为吲哚胺-2，3-双加氧酶抑制剂的砜脒及其制备方法和用途 Download PDF

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WO2018113758A1
WO2018113758A1 PCT/CN2017/117861 CN2017117861W WO2018113758A1 WO 2018113758 A1 WO2018113758 A1 WO 2018113758A1 CN 2017117861 W CN2017117861 W CN 2017117861W WO 2018113758 A1 WO2018113758 A1 WO 2018113758A1
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compound
substituted
group
unsubstituted
alkyl
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PCT/CN2017/117861
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English (en)
French (fr)
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王喆
曾志宏
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上海长森药业有限公司
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Priority to CN201780006575.6A priority Critical patent/CN108473449B/zh
Priority to EP17883113.7A priority patent/EP3560914A4/en
Priority to AU2017380492A priority patent/AU2017380492B2/en
Priority to JP2019555538A priority patent/JP6854497B2/ja
Priority to US16/472,077 priority patent/US11370766B2/en
Publication of WO2018113758A1 publication Critical patent/WO2018113758A1/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
    • C07D271/04—1,2,3-Oxadiazoles; Hydrogenated 1,2,3-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
    • A61P25/22—Anxiolytics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present application relates to a sulfone oxime as a guanamine-2,3-dioxygenase inhibitor, a preparation method and use thereof, and more particularly to a structure containing a sulfone oxime and a 1,2,5-oxadiazole structure.
  • IDO Indoleamine-2,3-dioxygenase
  • Indoleamine-2,3-dioxygenase is a monomeric enzyme containing heme found in the cell for the first time in 1967 by the Hayaishi group.
  • the cDNA encodes a protein. 403 amino acid composition with a molecular weight of 45 kDa, which is a rate-limiting enzyme that is catabolized along the tryptophan-kynurenine pathway and is widely expressed in many mammalian tissues (Hayaishi O. et al. Science, 1969, 164). , 389-396).
  • IDO In tumor cells, IDO often plays an important physiological role in inducing tumor microenvironmental immune tolerance, and its mediated tryptophan (Trp)-kynurenine (Kyn) metabolic pathway is involved in tumors. Immune escape, and IDO also plays an important role as an immune tolerance to induce tumor microenvironment.
  • Tryptophan is one of the important essential amino acids in mammals and needs to be taken in large quantities from food to maintain cell activation and proliferation, as well as the synthesis of proteins and some neurotransmitters. Therefore, its lack of dysfunction can lead to some important cells. IDO can catalyze the conversion of tryptophan to N-formyl kynurenine in vivo, degrading the content of tryptophan and causing deficiency of tryptophan in vivo, leading to tumor formation.
  • tryptophan dioxygenase TDO
  • IDO IDO
  • IDO dioxygenase
  • heme heme
  • IDO is usually expressed in organs with more mucosa, such as lung, small intestine, large intestine, rectum, spleen, kidney, stomach and brain, and is widely distributed (Hayaishi O. et al, Proceedings of the tenth FEBS meeting, 1975, 131). . Under certain special or pathological conditions, such as pregnancy, chronic infection, organ transplantation and tumors, IDO expression will increase significantly, and participate in mediating local immunosuppression.
  • IDO can inhibit local T cell immune responses in the tumor microenvironment by: tryptophan depletion, toxic metabolism, and induction of regulatory T cell proliferation. In many cases, it is overexpressed in tumors, thereby consuming local tryptophan and producing a large amount of metabolites such as kynurenine. In fact, in the absence of tryptophan or kynurenine culture conditions, T cells undergo proliferation inhibition, decreased activity, and even apoptosis. In T cells, there is a regulatory point that is very sensitive to the level of tryptophan. Under the action of IDO, tryptophan can be consumed, which leads to the arrest of T cells in the middle phase of G1, thereby inhibiting the proliferation of T cells and inhibiting the proliferation of T cells.
  • T cells The immune response of T cells. Once T cells stop proliferating, they may not be stimulated any more. This is the mechanism of IDO immunity in vivo (Mellor A. et al Biochem. Biophys. Res. Commun. 2005, 338(1): 20-24) (LeRond S. et al J. Exp. Med. 2002, 196(4): 447-457).
  • IDO inhibitors There is a need to develop new IDO inhibitors.
  • the purpose of the present application is to provide a novel compound containing a sulfone oxime and a 1,2,5-oxadiazole structure as a highly potent IDO inhibitor.
  • Another object of the present application is to provide a process for the preparation of the compound.
  • Such compounds are not easily synthesized, and an effective method for preparing such compounds has been developed by the inventors' efforts.
  • the application provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, a deuterated compound, a stereoisomer or a tautomer thereof:
  • R 1 is a substituted or unsubstituted C 1 -C 10 alkyl group, a substituted or unsubstituted C 3 -C 10 cycloalkyl group, a substituted or unsubstituted C 2 -C 10 alkenyl group, a substituted or unsubstituted C 3 a -C 10 alkynyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 14 heteroaryl group;
  • R 2 , R 3 , R 4 and R 6 are each independently hydrogen, Substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 3 -C 10 Alkynyl, substituted or unsub
  • R 5 is C 6 -C 20 aryl, 5- or 6-membered heteroaryl; R 5 may be substituted by one or more groups selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 - C 6 alkoxy, hydroxy, amino, nitro, aldehyde, -CF 3 , -CN, -SF 5 , NR a R b , carboxy, -COR a , -CO 2 C 1 -C 6 alkyl, - CONR a R b , -S(O)R a , -S(O) 2 R a , -S(O)(NH)R a , -S(O)(NR d )R a , -S(O) 2 NR a R b , -P(O)Me 2 , -P(O)(OMe) 2 ; wherein each R a and each R b are independently hydrogen, substituted or unsub
  • X is a single bond, O, S, NH or NR d ;
  • R d and R f are independently C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 20 aryl, or C 3 -C 14 heteroaryl;
  • n is an integer from 2 to 8.
  • the absence of a clear definition of the "substituted” refers to the group having one or more substituents selected from: halogen, hydroxy, -NH 2, nitro, -CN, C 1 -C 4 Alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, benzyl base.
  • X is NH
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl; R 3 and R 4 may together form a three to eight membered ring or a three to eight membered heterocyclic ring.
  • the hetero atom can be sulfur, oxygen, NH or NR f .
  • n is an integer from 2 to 6.
  • R 3 is hydrogen
  • R 4 is hydrogen
  • the compound is as shown in formula (II),
  • Ar is a benzene ring, and Ar may be substituted by one or more groups selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, amino, nitro, aldehyde, -CF 3 , -CN, -SF 3 , -SF 5 , NR a R b , carboxyl group, -COR a , -CO 2 C 1 -C 6 alkyl group, -CONR a R b , -S(O)R a , -S(O) 2 R a , -S(O)(NH)R a , -S(O)(NR d )R a , -S(O) 2 NR a R b ;
  • X, R a , R b , R d , R 3 , R 4 , R 6 , R 2 , R 1 are as defined above; the hydrogen atom in the alkyl group may be substituted by halogen; n is 2 to 6 Integer.
  • R 1 is C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 20 aryl, or C 3 -C 10 heteroaryl; R 1 may be taken as one or Multiple halogen substitutions.
  • R 1 is C 1 -C 10 alkyl
  • R 2 , R 6 are hydrogen, C 1 -C 10 alkyl
  • R 3 and R 4 are each independently hydrogen, C 1 -C 10 alkyl .
  • R 1 is selected from the group consisting of -CH 3 , -C 2 H 5 , -CH(CH 3 ) 2 , cyclopropyl, CH 2 F, CHF 2 , CF 3 , CH 2 Cl, CHCl 2 , CCl 3 , CHFCH 3 , CF 2 CH 3 , CHFCH 2 F, CF 2 CH 2 F, CHFCHF 2 , CF 2 CHF 2 , CHFCF 3 or CF 2 CF 3 .
  • Ar is a phenyl ring
  • the para position is substituted by F
  • the meta position is substituted by Br.
  • the compound is selected from the group consisting of:
  • the present application also provides a second preparation method comprising the following steps:
  • a pharmaceutical composition comprising: a compound described herein or a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof or a tautomer thereof Isomer; and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising: a compound described herein or a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof or a tautomer thereof Isomers; and antitumor drugs.
  • the anti-tumor drug and the compound described herein may be present in one dosage form or may be present separately in separate dosage forms.
  • the present application provides a compound described herein or a pharmaceutical composition thereof for use in the prevention and/or treatment of a guanamine-2,3-dioxygenase mediated disease.
  • the present application also provides the use of the compound or a pharmaceutical composition thereof for the preparation of a medicament for the prevention and/or treatment of a guanamine-2,3-dioxygenase mediated disease.
  • the present application further provides a method of preventing and/or treating a guanamine-2,3-dioxygenase mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein or The step of the pharmaceutical composition.
  • the present application also provides a compound of the present application, or a pharmaceutically acceptable salt thereof, a deuterated compound, a stereoisomer or a tautomer thereof, in the preparation of cancer, eye diseases, heart disorders, depression, anxiety, and elderly Use in drugs for dementia and/or autoimmune diseases.
  • the indoleamine-2,3-dioxygenase mediated diseases described herein are diseases characterized by the pathology of an IDO-mediated tryptophan metabolism pathway.
  • the indoleamine-2,3-dioxygenase-mediated disease described herein is selected from the group consisting of cancer, eye disease, heart disorder, depression, anxiety, Alzheimer's disease, and/or autoimmunity Sexual disease.
  • the cancers described herein include, but are not limited to, colorectal cancer, breast cancer, gastric cancer, lung cancer, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer, renal cancer, liver cancer, brain cancer, melanoma. Multiple myeloma, chronic myeloid leukemia, hematological tumors, including metastatic lesions in other tissues or organs away from the primary site of the tumor.
  • a compound of the present application may be associated with additional anti-cancer when the disease being treated is cancer
  • the agent also known as an anti-tumor drug
  • two or more active ingredients may be formulated into one dosage form, or different active ingredients may be separately prepared into separate dosage forms.
  • the anti-tumor drug includes, but is not limited to, an immunotherapeutic agent for cancer: PD-1 antibody, CTLA-4 antibody, PD-L1 antibody, PD-L2 antibody, any other chemotherapeutic drug or targeting medicine.
  • Figure 1 shows the tumor growth inhibition effect of the compound LW105-1-1 of the present application in a mouse primary colorectal cancer tumor CT-26 model
  • 1A is a graph
  • 1B is a histogram.
  • alkyl refers to a monovalent saturated aliphatic hydrocarbon group having from 1 to 10 carbon atoms, including straight-chain and branched hydrocarbon groups such as methyl (ie, CH 3 -), ethyl (ie, CH 3 CH 2 -).
  • n-propyl ie CH 3 CH 2 CH 2 -
  • isopropyl ie (CH 3 ) 2 CH-
  • n-butyl ie CH 3 CH 2 CH 2 CH 2 -
  • isobutyl ie (CH 3 ) 2 CHCH 2 -
  • sec-butyl ie (CH 3 )(CH 3 CH 2 )CH-
  • tert-butyl ie (CH 3 ) 3 C-
  • n-pentyl ie CH 3 ) CH 2 CH 2 CH 2 CH 2 -
  • neopentyl ie (CH 3 ) 3 CCH 2 -
  • the term includes substituted or unsubstituted alkyl groups.
  • substituted or unsubstituted means that the group may be unsubstituted or substituted.
  • substituted means that the group has one or more (preferably 1 to 6, more preferably 1 to 3) substituents selected from the group consisting of the following groups. : halogen, hydroxy, -NH 2 , nitro, -CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2- C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, benzyl.
  • cycloalkyl refers to a substituted or unsubstituted C 3 -C 12 cycloalkyl, such as C 3 -C 6 cycloalkyl.
  • alkoxy refers to -O-alkyl, wherein the alkyl group can be saturated or unsaturated, can be branched, straight chain, or cyclic.
  • the alkoxy group has 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy.
  • aryl refers to an aromatic carbocyclic group of 6 to 20 (eg, 6-14, 6-10) carbon atoms which has a single ring (eg, phenyl) or a fused ring (such as naphthyl or anthracenyl), if the point of attachment is on an aromatic carbon atom, the fused ring may be non-aromatic (eg 2-benzoxazolone, 2H-1,4-benzoxazine-3(4H)- Keto-7-yl, etc.).
  • Preferred aryl groups include phenyl and naphthyl.
  • the term includes substituted or unsubstituted forms wherein the substituents are as defined above.
  • cycloalkyl refers to a cyclic alkyl group having from 3 to 10 carbon atoms having a single or multiple ring (including fused systems, bridged ring systems, and spiro ring systems).
  • one or more of the rings may be a cycloalkyl, heterocyclic, aryl or heteroaryl group as long as the attachment site is a ring through a cycloalkyl group.
  • suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • heteroaryl refers to an aromatic group having from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, such heteroaryl groups may be monocyclic (such as pyridyl or furyl) or a fused ring (such as benzothienyl), wherein the fused ring may be non-aromatic and/or contain a hetero atom as long as the point of attachment is through an aromatic heteroaryl atom .
  • the ring atom nitrogen and/or sulfur of the heteroaryl group is optionally oxidized to an N-oxide (N-O), a sulfinyl group or a sulfonyl group.
  • Preferred heteroaryl groups include pyridinyl, pyrrolyl, indolyl, thienyl and furanyl.
  • the term includes substituted or unsubstituted heteroaryl.
  • the substituted heteroaryl group means a heteroaryl group substituted by 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the same as defined for the substituted aryl group. Substituent.
  • heterocycle or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated, partially saturated or unsaturated group (but not aromatic), Has a single ring or a fused ring (including a bridged ring system and a spiro ring system having from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in the ring, in a fused ring system, one or more
  • the ring may be a cycloalkyl, aryl or heteroaryl group as long as the point of attachment passes through the non-aromatic ring.
  • the nitrogen and/or sulfur atom of the heterocyclic group is optionally oxidized to provide N-oxide, sulfinyl and sulfonyl moieties.
  • “Substituted heterocycle” or “substituted heterocycloalkyl” or “substituted heterocyclyl” means substituted by 1 to 5 (eg 1 to 3) a heterocyclic group substituted with a group, the substituent being as defined above.
  • stereoisomer refers to a chiralally different compound of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • tautomer refers to an alternative form of a compound having a different proton position, such as an enol-ketone, an imine-enamine, and an amide-imidic tautomer, or a heteroaryl group.
  • the compounds of the present application also include various geometric isomers. Wavy line The indicated bond means that the structure represents a cis or trans isomer or a mixture of cis and trans isomers in any ratio.
  • the term "compound of the present application” refers to a compound of formula (I), formula (II), or a compound of formula (I), (II), a deuterated compound, a racemate thereof. And a stereoisomer thereof or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present application relates to racemic mixtures of these compounds, enrichment of mixtures of any of the enantiomers, and any of the isolated enantiomers.
  • the present application also encompasses deuterated compounds produced by the replacement of any one or more of the hydrogen atoms of the compound by its stable isotope oxime.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • compositions described herein it comprises the active ingredient in a safe and effective amount, and a pharmaceutically acceptable carrier.
  • active ingredient refers to a compound described herein, or a pharmaceutically acceptable salt thereof, a deuterated compound, a stereoisomer thereof, or a tautomer thereof.
  • active ingredients and pharmaceutical compositions described herein are useful as IDO inhibitors.
  • safe and effective amount is meant that the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of active ingredient, for example from 10 to 200 mg of active ingredient.
  • “Pharmaceutically acceptable” means that the substance is suitable for use in tissues with humans and animals without undue toxicity, irritation, allergic reactions or other problems or complications.
  • a salt in a "pharmaceutically acceptable salt” refers to an acid addition salt or a base addition salt formed by the compound of the present application, for example, an acid addition salt formed with an inorganic or organic acid, and formed with an inorganic or organic base. Base addition salt.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. Each component of the pharmaceutical composition should be compatible with the active ingredient.
  • “compatibility” it is meant herein that the components of the carrier and the like in the composition and the active ingredients of the present application can be incorporated into each other without significantly reducing the efficacy of the active ingredient.
  • the compounds of the present application can be administered as separate active agents, or in combination with one or more other agents for treating cancer (i.e., anti-tumor drugs).
  • the compounds of the present application can be administered concurrently with radiation therapy.
  • the compounds of the present application are administered in a therapeutically effective amount, the actual amount of which is determined by a number of factors, such as the severity of the condition to be treated, the age and relative health of the patient, the potency of the compound being used, the route and form of administration, and other factors.
  • the drug can be administered multiple times a day, such as once or twice a day. All of these factors are within the consideration of the attending physician.
  • the therapeutically effective dose can generally be a total daily dose for a single or divided administration to a patient, for example, from about 0.001 to about 1000 mg/kg body weight per day, specifically such as from about 1.0 to about 30 mg/kg body weight per day.
  • the compounds of the present application can be administered as a pharmaceutical composition by any of the following routes: oral, systemic (eg, transdermal, intranasal or by suppository), or parenteral (eg, intramuscular, intravenous) Or subcutaneous).
  • routes e.g. oral, systemic (eg, transdermal, intranasal or by suppository), or parenteral (eg, intramuscular, intravenous) Or subcutaneous).
  • the compositions may take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols or any other suitable compositions.
  • Suitable pharmaceutically acceptable carriers or excipients or salts are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991).
  • Methanesulfonamide (9.50 g) was dissolved in THF (150 ml) under a nitrogen atmosphere, triethylamine (20.24 g) was added at room temperature, a solution of TBSCl (17.33 g) in toluene (50 ml) was added dropwise, and the reaction was carried out at room temperature. After the mixture was filtered, the solid was washed with diethyl ether (200 ml), and then diethyl ether (100 ml) was added to the filtrate, and the mixture was allowed to stand for 30 min, and then filtered again.
  • Triphenylphosphine (2.89g) and hexachloroethane (2.60g) were added to chloroform (30ml) under nitrogen atmosphere, heated to 70 ° C for 6 hours, a large amount of white solids were produced, cooled to 0 ⁇ 5 ° C, Add triethylamine (1.52 g), stir for 10 min, then add a solution of N-(tert-butyldimethylsilyl)methylsulfonamide (2.09 g) in chloroform (10 ml), stirring at 0 to 5 ° C for 20 min to give 0.25 M-N-(tert-butyldimethylsilyl)methylsulfone decanoyl chloride solution. This solution was used directly in the next step.
  • the third step synthesis of N-(2-benzyloxycarbonylamino)ethyl-N'-tert-butyldimethylsilyl-methylsulfone oxime
  • the fourth step synthesis of N-aminoethyl-N'-tert-butyldimethylsilyl-methylsulfone oxime
  • N-(2-Benzyloxycarbonylamino)ethyl-N-carbonyl-tert-butyldimethylsilyl-methylsulfone oxime (610 mg) was dissolved in methanol (10 ml), and three times of nitrogen was added, then Pd/C 10% was added. (Hydration 58%, 125 mg), after replacing with hydrogen, stirring at room temperature for 4 hours, TLC followed the disappearance of the starting material, filtration, concentration and column chromatography to give 119 mg of N-aminoethyl-N'-tert-butyldimethylsilyl- Methyl sulfone oxime.
  • Phenyl)-3-(4-amino-1,2,5-oxadiazolyl)-1,2,4-oxadiazol-5(4H)-one (1.0g), raised to room temperature for 2 days
  • add sodium carbonate solids to adjust the pH 8 ⁇ 9
  • Step 6 4-(3-Bromo-4-fluorophenyl)-3-(4-(2-(N'-tert-butyldimethylsilyl-methylsulfonylamino)ethyl)amino- 1,2,5-oxadiazolidine-1,2,4-oxadiazol-5(4H)-one
  • N-Aminoethyl-N'-tert-butyldimethylsilyl-methylsulfone oxime (110 mg) was dissolved in acetonitrile (2 ml), cooled to 0-5 ° C, and added 4-(3-bromo-4- Fluorophenyl)-3-(4-nitro-1,2,5-oxadiazole)-1,2,4-oxadiazol-5(4H)-one (150 mg), raised to room temperature for 3 hours It was diluted with ethyl acetate (20 ml), and the organic phase was washed with saturated brine, and concentrated, and then, then,,,
  • Step 7 4-((2-(methylsulfonyl)ethyl)amino)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadi Synthesis of oxazol-3-carboxamidine (LW105-1-1)
  • the compound 4-((2-(methylsulfonyl)ethyl)amino)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole- 3-methylhydrazine was formulated into a 60 mg/ml ethanol solution, and the injection volume was 2 ml.
  • the peak with a retention time of 14.3 min was LW105-1-18 (20 mg), and the peak with a retention time of 21.1 min was LW105-1-19. (17 mg).
  • test compound and the reference compound LW3018 were finally tested at concentrations ranging from 10 M to 0.51 nM, 3 fold dilutions, 10 concentrations, and two duplicate wells.
  • RPMI 1640 phenol red free medium (Invitrogen Cat. No. 11835030), fetal bovine serum (Invitrogen Cat. No. 10099141), penicillin (Invitrogen Gibco Cat. No. 15140-122), recombinant human interference ⁇ (R&D system, Cat. No. 285-IF-100).
  • 5% (w/v) trichloroacetic acid Alfa Aesar Cat. No. A11156
  • DMSO Sigma, Cat. No. D2650
  • 96 wells Plate_Compound Dilution Plate Axygen, Cat. No. WIPP02280
  • 96-well plate_Test Plate Gibiner, Cat. No. 655090
  • test compound and reference compound LW3018 were finally tested at concentrations ranging from 5M to 0.76 nM, 3-fold gradient dilution, 9 concentrations, and two replicate wells.
  • Hela cells were plated in 96-well cell culture plates at a number of 40,000 cells per well, incubated with RPMI 1640 containing 10% fetal bovine serum for 5-6 hours, and the diluted test compound was added to a final concentration of 100 ng. /mL recombinant human interferon gamma activates IDO1 expression.
  • the cells were cultured for 20 hours in a 37 ° C cell incubator rich in 5% carbon dioxide, and the reaction was stopped with 5% trichloroacetic acid and incubated at 50 ° C for 30 minutes. After the cell culture solution was precipitated, the supernatant was sent to LC/MS to detect the content of kynurenine. Data analysis and mapping according to XLfit5 software.
  • CT26 cells in the proliferative phase were harvested, adjusted for cell concentration after digestion, and inoculated into the right hind limb of the mouse. 1 ⁇ 10 5 CT26 cells were inoculated into each mouse, and the inoculation volume was 0.1 mL.
  • the average tumor volume was close to 20-30 mm 3 , and the cells were administered in random groups, and D0 was recorded on the day of administration, and the negative control was given the same amount of vehicle.
  • Co-administration of LW 105-1-1 with Anti-CTLA4 antibody was also tested in this experiment. After the start of administration, the tumor long diameter and short diameter were measured 3 times per week. The experimental grouping and dosing schedule are shown in Table 2.
  • N number of mice per group
  • the tumor inhibiting effect of the compound LW105-1-1 is shown in Fig. 1.
  • the results showed that the compound LW105-1-1 of the present invention has a dose-dependent anti-tumor growth effect in a mouse CT26 tumor model of colorectal cancer.
  • the tumor inhibition rate of LW105-1-1 was 40.6%
  • the combination of LW105-1-1 and Anti-CTLA4 antibody showed a tumor inhibition rate of up to 96.4%.
  • the preparation containing 5% DMA and 20% HPbCD aqueous solution as a vehicle was administered by intravenous administration, and a preparation containing a solution of 5% DMA, 20% HPbCD and 0.1% CREMOPHOR EL as a vehicle was intragastrically administered.
  • the animal strain was male C57BL/6 mice. Prior to the animal experiment, all animals were fasted and fed 4 hours after dosing; all animals were given free access to water.
  • Intravenous administration group 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours before administration
  • Oral administration group 0.25, 0.5, 1, 2, 4, 8 and 24 hours before administration

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Abstract

本申请提供了一种如式（I）所示的作为吲哚胺-2，3-双加氧酶抑制的砜脒及其制备方法和用途。本申请的式（I）化合物，可以作为吲哚胺-2，3-双加氧酶抑制剂，用于制备预防和/或治疗吲哚胺-2，3-双加氧酶介导的疾病的药物。

Description

一种作为吲哚胺-2，3-双加氧酶抑制剂的砜脒及其制备方法和用途 技术领域
本申请涉及一种作为吲哚胺-2，3-双加氧酶抑制剂的砜脒及其制备方法和用途，更具体涉及一种含有砜脒和1，2，5-噁二唑结构的吲哚胺-2，3-双加氧酶(IDO)抑制剂及其制备方法和用途。
背景技术
吲哚胺-2，3-双加氧酶(Indoleamine-2，3-dioxygenase，IDO)是1967年Hayaishi小组首次在细胞内发现的一种含有亚铁血红素的单体酶，cDNA编码蛋白由403氨基酸组成，分子量为45kDa，它是沿着色氨酸-犬尿氨酸途径分解代谢的限速酶，并且在多种哺乳动物的组织中具有广泛的表达(Hayaishi O.et alScience，1969，164，389-396)。在肿瘤患者的细胞中，IDO常作为诱导肿瘤微环境免疫耐受产生重要的生理作用，其介导的色氨酸(Tryptophan，Trp)-犬尿氨酸(Kynurenine，Kyn)代谢途径参与了肿瘤免疫逃逸，而IDO作为诱导肿瘤微环境免疫耐受也产生重要的作用。
色氨酸为哺乳动物体内重要的必须氨基酸之一，需要从食物中大量摄取，维持细胞活化和增殖，以及蛋白质和一些神经递质的合成。因此，它的缺乏会导致一些重要的细胞的功能失常。IDO在体内能够催化色氨酸转化为N-甲酰犬尿氨酸，降解色氨酸的含量而造成色氨酸体内的不足，导致肿瘤的发生。而免疫组织学研究显示，犬尿氨酸途径能够导致兴奋毒素喹啉酸的增多，还会导致阿兹海默等神经系统疾病等多种严重的人类疾病(Guillemin G.J.et al Neuropathol.andAppl.Neurobiol.2005，31，395)。
哺乳动物体内色氨酸限速酶主要有两种：色氨酸双加氧酶(TDO)和IDO。1937年，Kotake等从兔子肠中纯化出蛋白，并首次发现TDO主要在哺乳动物肝脏中表达，目前尚未发现他与免疫系统有密切联系。TDO能够催化犬尿氨酸途径，使色氨酸转变为N-甲酰犬尿氨酸[Higuchi K.et al J.Biochem.1937，25，71-77；Shimizu T.et al J.Biol.Chem.1978，253，4700-4706]。1978年，从兔子肠道中纯化的酶，被鉴定是含有亚铁血红素的双加氧酶(IDO)，IDO是肝脏以外唯一可以催化色氨酸分子中的吲哚氧化裂解，产生犬尿氨酸及其它代谢物的酶。IDO通常在粘膜较多的器官中表达，如肺、小肠、大肠、直肠、脾、肾、胃和脑等，分布比较广泛(Hayaishi O.et al，Proceedings of the tenth FEBS meeting，1975，131)。在某些特殊或病理条件下，如妊娠，慢性感染，器官移植和肿瘤等，IDO表达会明显增加，参与介导局部的免疫抑制。
研究表明，IDO在肿瘤微环境中可以通过以下几种方式来抑制局部T细胞免疫反应：色氨酸耗竭、毒性代谢和诱导调节性T细胞增殖。很多情况是在肿瘤中过度表达，从而消耗局部的色氨酸，产生大量的犬尿氨酸等代谢产物。事实上，在无色氨酸或犬尿氨酸的培养条件下，T细胞会发生增殖抑制、活性降低甚至凋亡。而T细胞中存在一个对色氨酸水平非常敏感的调节点，IDO的作用下，能够使色氨酸消耗，从而导致T细胞停滞于G1期中期，从而抑制了T细胞的增殖，也抑制了T细胞的免疫应答。而T细胞一旦停止增殖，可能就不会再被刺激作用，这是IDO在体内免疫作用机制(Mellor A.etal Biochem.Biophys.Res.Commun.2005，338(1)：20-24)(LeRond S.et al J.Exp.Med.2002，196(4)：447-457)。目前，尚需研发新型的IDO抑制剂。
发明内容
本申请的目的在于提供一种新型的含有砜脒和1，2，5-噁二唑结构的化合物作为高效的IDO抑制剂。
本申请的另一目的在于提供该化合物的制备方法。该类化合物不易合成，经本发明人的努力探索，研发出制备该类化合物的有效方法。
本申请的第一方面，本申请提供了一种通式(I)化合物或其药学上可接受的盐、其氘代化合物、立体异构体或其互变异构体：
Figure PCTCN2017117861-appb-000001
式中，
R 1为取代或未取代的C 1-C 10烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 2-C 10烯基、取代或未取代的C 3-C 10炔基、取代或未取代的C 6-C 20芳基、或取代或未取代的C 3-C 14杂芳基；R 2，R 3，R 4和R 6各自独立为氢、取代或未取代的C 1-C 10烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 2-C 10烯基、取代或未取代的C 3-C 10炔基、取代或未取代的C 6-C 20芳基、或取代或未取代的C 3-C 14杂芳基；R 1和R 2，R 1和R 3，R 1和R 6，R 2和R 6，R 3和R 4或R 3和R 6可以形成三至八元碳环或三至八元杂环，其中杂原子可以是硫、氧、NH或NR f；
R 5为C 6-C 20芳基、五元或六元杂芳基；R 5可以被一个或多个选自下组的基团取代：卤素、C 1-C 6烷基、C 1-C 6烷氧基、羟基、氨基、硝基、醛基、-CF 3、-CN、-SF 5、NR aR b、羧基、-COR a、-CO 2C 1-C 6烷基、-CONR aR b、-S(O)R a，-S(O) 2R a、-S(O)(NH)R a、-S(O)(NR d)R a、-S(O) 2NR aR b、-P(O)Me 2、-P(O)(OMe) 2；其中各R a和各R b各自独立为氢、取代或未取代的C 1-C 10烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 2-C 10烯基、取代或未取代的C 6-C 20芳基、或取代或未取代的C 3-C 14杂芳基；R a和R b可以一起可以形成三至八元环或四至八元杂环，其中杂原子可以是硫、氧、NH或NR f；
X为一个单键、O、S、NH或NR d；
R d和R f独立地为C 1-C 10烷基、C 3-C 10环烷基、C 6-C 20芳基、或C 3-C 14杂芳基；
n为2至8的整数。
在一些实施方式中，如无明确定义，所述的“取代”指具有一个或多个选自下组的取代基：卤素、羟基、-NH 2、硝基、-CN、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 3-C 6环烷基、C 2-C 4链烯基、C 2-C 4炔基、苯基、苄基。
在一些实施方式中，X为NH。
在一些实施方式中，R 3和R 4各自独立为氢、取代或未取代的C 1-C 10烷基；R 3和R 4可以一起可以形成三至八元环或三至八元杂环，其中杂原子可以是硫、氧、NH或NR f。
在一些实施方式中，n为2至6的整数。
在一些实施方式中，R 3为氢。
在一些实施方式中，R 4为氢。
在一些实施方式中，所述化合物如通式(II)所示，
Figure PCTCN2017117861-appb-000002
式中，
Ar为苯环，Ar可以被一个或多个选自下组的基团取代：卤素、C 1-C 6烷基、C 1-C 6烷氧基、羟基、氨基、硝基、醛基、-CF 3、-CN、-SF 3、-SF 5、NR aR b、羧基、-COR a、-CO 2C 1-C 6烷基、-CONR aR b、-S(O)R a，-S(O) 2R a、-S(O)(NH)R a、-S(O)(NR d)R a、-S(O) 2NR aR b；
其中，X、R a、R b、R d、R 3、R 4、R 6、R 2、R 1的定义如上所述；烷基中的氢原子可被卤素取代；n为2至6的整数。
在一些实施方式中，R 1为C 1-C 10烷基、C 3-C 10环烷基、C 6-C 20芳基、或C 3-C 10杂芳基；R 1可以被一个或多个卤素取代。
在一些实施方式中，R 1为C 1-C 10烷基；R 2、R 6为氢、C 1-C 10烷基；R 3和R 4各自独立为氢、C 1-C 10烷基。
在一些实施方式中，R 1选自-CH 3、-C 2H 5、-CH(CH 3) 2、环丙烷基、CH 2F、CHF 2、CF 3、CH 2Cl、CHCl 2、CCl 3、CHFCH 3、CF 2CH 3、CHFCH 2F、CF 2CH 2F、CHFCHF 2、CF 2CHF 2、CHFCF 3或CF 2CF 3。
在一些实施方式中，Ar为苯环，其对位被F取代，且间位被Br取代。
在一些实施方式中，所述化合物选自下述化合物：
Figure PCTCN2017117861-appb-000003
Figure PCTCN2017117861-appb-000004
Figure PCTCN2017117861-appb-000005
本申请的第二方面，提供本申请所述化合物的制备方法，包括以下步骤：
Figure PCTCN2017117861-appb-000006
(a)化合物A与化合物C反应，得到化合物B；
(b)化合物B在碱水解条件下(如氢氧化钠水溶液)开环，得到终产物通式I化合物；各式中，R 1、R 2、R 3、R 4、R 5、R 6、n的定义如上所示。
本申请也提供了第二种制备方法，包括以下步骤：
Figure PCTCN2017117861-appb-000007
(a)化合物D在硫酸的催化下被双氧水氧化成化合物E；
(b)化合物E和化合物F发生取代反应得到化合物B；
(c)化合物B在碱水解条件下(如氢氧化钠水溶液)开环，得到终产物通式(I)化合物。
本申请的第三方面，提供一种药物组合物，所述药物组合物包含：本申请所述的化合物或其药学上可接受的盐、其氘代化合物、其立体异构体或其互变异构体；以及药学上可接受的载体。
本申请的第四方面，提供一种药物组合物，所述药物组合物包含：本申请所述的化合物或其药学上可接受的盐、其氘代化合物、其立体异构体或其互变异构体；以及抗肿瘤药物。所述抗肿瘤药物与本申请所述的化合物可以存在于一个剂型中，也可以以分别剂型而独立存在。
本申请的第五方面，本申请提供了本申请所述的化合物或其药物组合物，其用于预防和/或治疗吲哚胺-2，3-双加氧酶介导的疾病。本申请还提供了所述的化合物或其药物组合物在制备用于预防和/或治疗吲哚胺-2，3-双加氧酶介导的疾病的药物中的应用。本申请又提供了一种预防和/或治疗吲哚胺-2，3-双加氧酶介导的疾病的方法，包括对有此需求的患者给予治疗有效量的本申请所述的化合物或所述的药物组合物的步骤。本申请也提供本申请所述化合物或其药学上可接受的盐、其氘代化合物、立体异构体或其互变异构体在制备癌症、眼疾、心里障碍、抑郁症、焦虑症、老年痴呆症和/或自身免疫性疾病的药物中的应用。
在一些实施方式中，本申请所述的吲哚胺-2，3-双加氧酶介导的疾病为IDO介导的色氨酸代谢途径的病理学特征的疾病。
在一些实施方式中，本申请所述的吲哚胺-2，3-双加氧酶介导的疾病选自癌症、眼疾、心里障碍、抑郁症、焦虑症、老年痴呆症和/或自身免疫性疾病。
在一些实施方式中，本申请所述的癌症包括但不限于：结直肠癌、乳腺癌、胃癌、肺癌、大肠癌、胰腺癌、卵巢癌、前列腺癌、肾癌、肝癌、脑癌、黑色素瘤、多发性骨髓瘤、慢性粒细胞性白血病、血液肿瘤，包括在其他远离肿瘤原发部位的组织或器官的转移病变。
在一些实施方式中，当治疗的疾病为癌症时，本申请的化合物或其药学上可接受的盐、其氘代化合物、其立体异构体或其互变异构体可以与额外的抗癌剂(也称为抗肿瘤药物)联合使用。当联合使用时，可以将两种或多种活性成分制成一个剂型，也可以是不同的活性成分分别制成独立的剂型。
在一些实施方式中，所述抗肿瘤药物包括但不限于癌症的免疫治疗药物：PD-1抗体，CTLA-4抗体，PD-L1抗体，PD-L2抗体，任何一种其它化疗药物或靶向治疗药物。
附图说明
图1显示本申请化合物LW105-1-1在小鼠原代结直肠癌肿瘤CT-26模型中的肿瘤生长抑制作用，1A为曲线图，1B为柱状图。
具体实施方式
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本申请所属领域的普通技术人员通常理解的相同含义。如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。
术语定义
术语“烷基”是指一价饱和脂族烃基，具有1至10个碳原子，包括直链和支链烃基，如甲基(即CH 3-)、乙基(即CH 3CH 2-)、正丙基(即CH 3CH 2CH 2-)、异丙基(即(CH 3) 2CH-)、正丁基(即CH 3CH 2CH 2CH 2-)、异丁基(即(CH 3) 2CHCH 2-)、仲丁基(即(CH 3)(CH 3CH 2)CH-)、叔丁基(即(CH 3) 3C-)、正戊基(即CH 3CH 2CH 2CH 2CH 2-)、新戊基(即(CH 3) 3CCH 2-)。在本申请中，该术语包括取代或未取代的烷基。
如本文所用，术语“取代或未取代的”、“任选取代”或“任选被取代”指所述基团可以是未取代的，或者是被取代的。
所述“取代”、“被取代的”或“取代的”指所述基团具有一个或多个(较佳地1-6个，更佳地1-3个)选自下组的取代基：卤素、羟基、-NH 2、硝基、-CN、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 3-C 6环烷基、C 2-C 4链烯基、C 2-C 4炔基、苯基、苄基。
如本文所用，术语“环烷基”指取代或未取代的C 3-C 12环烷基，例如C 3-C 6环烷基。
如本文所用，术语“烷氧基”指-O-烷基，其中所述烷基可以是饱和或不饱和的、可以是支链、直链的、或环状的。优选地，烷氧基具有1-10个碳原子，较佳地1-6个碳原子。代表性的例子包括(但并不限于)：甲氧基、乙氧基、丙氧基。
如本文所用，术语“芳基”是指6至20个(如6-14个、6-10个)碳原子的芳香族碳环基团，它具有单环(如苯基)或稠环(如萘基或蒽基)，如果连接点在芳香碳原子上，稠环可能是非芳香性的(如2-苯并噁唑酮，2H-1，4-苯并噁嗪-3(4H)-酮-7-基等)。优选的芳基包括苯基和萘基。该术语包括取代或未取代的形式，其中取代基的定义如上。
如本文所用，术语“烯基”是指具有2至10(如2至6或2至4)个碳原子的烯基，且具有至少1(如1至2)个不饱和烯键(＞C＝C＜)。这类基团的例如有乙烯基、烯丙基、丁-3-烯基。如本文所用，术语“环烷基”是指具有3至10个碳原子的、具有单环或多环(包括稠合体系，桥环体系和螺环体系)的环状烷基。在稠环体系中，一个或多个环可以是环烷基、杂环的、芳基或杂芳基，只要连接位点是通过环烷基的环。合适的环烷基的例子包括：例如，金刚烷基、环丙基、环丁基、环戊基和环辛基。
如本文所用，术语“卤代”或“卤素”是指氟、氯、溴和碘。
如本文所用，术语“杂芳基”是指环内具有1至10个碳原子和1至4个选自氧、氮和硫的杂原子的芳香基团，这样的杂芳基可以是单环的(如吡啶基或呋喃基)或稠环(如苯并噻吩基)，其中，所述稠环可以是非芳香性的和/或含有一个杂原子，只要连接点是通过芳香性杂芳基的原子。在一实施例中，杂芳基的环原子氮和/或硫任选地被氧化为N-氧化物(N-O)，亚磺酰基或磺酰基。优选的杂芳基包括吡啶基、吡咯基、吲哚基、噻吩基和呋喃基。该术语包括取代或未取代的杂芳基。取代的杂芳基是指被1至5个、优选1至3个、更优选1至2个的取代基所取代的杂芳基，所述取代基选自与取代的芳基所定义的相同取代基。
如本文所用，术语“杂环”或“杂环的”或“杂环烷基”或“杂环基”是指饱和的、部分饱和的或不饱和的基团(但不是芳香性的)，具有单环或稠环(包括桥环体系和螺环体系，环内具有1至10个碳原子和1至4个选自氮、硫或氧的杂原子，在稠环体系中，一个或多个环可以是环烷基、芳基或杂芳基，只要连接点通过非芳香性环。在一些实施例中，杂环基团的氮原子和/或硫原子任选地被氧化，以提供N-氧化物、亚磺酰基和磺酰基部分。“取代的杂环”或“取代的杂环烷基”或“取代的杂环基”是指被1到5(如1至3)个取代基所取代的杂环基团，所述取代基如上所定义。
如本文所用，术语“立体异构体”是指一个或多个立体中心的手性不同的化合物。立体异构体包括对映异构体和非对映异构体。
如本文所用，术语“互变异构体”是指质子位置不同的化合物的替代形式，如烯醇-酮、亚胺-烯胺和酰胺-亚胺酸互变异构体，或杂芳基的互变异构形式，所述杂芳基包含与环的-NH-部分和环的＝N-部分连接的环原子，如吡唑、咪唑、苯并咪唑、三唑和四唑。
本申请的化合物还包括各种几何异构体。波浪线
Figure PCTCN2017117861-appb-000008
表示的键意指该结构表示顺式或反式异构体或任意比例的顺式和反式异构体混合物。
如本文所用，术语“本申请的化合物”指通式(I)、通式(II)的化合物，或泛指通式(I)、(II)的化合物、其氘代化合物、外消旋体、其立体异构体或其互变异构体、或其药学上可接受的盐。本申请涉及：这些化合物的外消旋混合物，富集任种对映体的混合物，以及任一种分离的对映体。
在本申请所述的化合物有立体异构体存在的情况下，本申请包括化合物的所有立体异构体。
在本申请所述的化合物有互变异构体存在的情况下，本申请包括化合物的所有互变异构体。
本申请还包括所述化合物中的任何一个或多个氢原子被其稳定同位素氘取代而产生的氘代化合物。
除特别说明之处，本申请的所有化合物之中，各手性碳原子(手性中心)可以任选地为R构型或S构型，或R构型和S构型的混合物。
关于本申请所述的药物组合物，它包含安全有效量范围内的活性成分，以及药学上可接受的载体。
本申请所述的“活性成分”是指本申请所述的化合物或其药学上可接受的盐、其氘代化合物、其立体异构体或其互变异构体。本申请所述的“活性成分”和药物组合物可用作IDO抑制剂。“安全有效量”指的是：活性成分的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg活性成分，例如含有10-200mg活性成分。
“药物上可接受的”表示所述物质适用于与人和动物的组织，而没有过度的毒性、刺激、过敏反应或其他问题或并发症。
“药学上可接受的盐”中的盐是指本申请化合物形成的酸加成盐或碱加成盐，例如与无机酸或有机酸形成的酸加成盐，与无机碱或有机碱形成的碱加成盐。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。药物组合物中的各组分与活性成分应具有相容性。“相容性”在此指的是组合物中的载体等组分和本申请的活性成分可相互掺和，而不明显降低活性成分的药效。
本申请的化合物可以作为单独活性药剂给药，也可以与一个或多个其它用于治疗癌症的药剂(即，抗肿瘤药物)组合使用。本申请的化合物可与放射治疗同时施用。
通常，本申请的化合物以治疗有效量施用，其实际用量根据多个因素确定，如待治疗疾病的严重程度、患者的年龄和相对健康程度、被使用化合物的效力、施用的路径和形式，以及其他因素。该药物可一天施用多次，如每天一次或两次。所有这些因素都在主治医生的考虑范围内。治疗有效剂量通常可以是对患者一次性施用或分次施用的每日总剂量，例如，每日约0.001至约1000毫克/公斤体重，具体如每日约1.0至约30毫克/千克体重。通常，本申请的化合物可作为药物组合物通过以下任意一种途径给药：口服、全身给药(如透皮、鼻内或通过栓剂)、或胃肠外给药(如肌内、静脉内或皮下)。组合物可 采取的形式为片剂、丸剂、胶囊、半固体、粉剂、缓释制剂、溶液、悬浮液、酏剂、气雾剂或任何其他适当的组合物。
合适的药学上可接受的载体或赋形剂或盐在《雷明顿药物科学》(Remington’s Pharmaceutical Sciences)，Mack Pub.Co.，新泽西(1991)有描述。
下面结合具体实施例，进一步阐述本申请。应理解，这些实施例仅用于说明本申请而不用于限制本申请的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(NewYork：ColdSpringHarborLaboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本申请方法中。文中所述的实施方法与材料仅作示范之用。
实施例1
Figure PCTCN2017117861-appb-000009
第一步：N-(叔丁基二甲基硅基)甲基磺酰胺的合成
Figure PCTCN2017117861-appb-000010
氮气保护下将甲基磺胺(9.50g)溶于THF(150ml)，室温下加入三乙胺(20.24g)，滴加TBSCl(17.33g)的甲苯(50ml)溶液，滴完在室温下反应18小时，过滤，固体用乙醚(200ml)洗涤，向滤液中加入乙醚(100ml)，放置30min后，再次过滤，滤液浓缩后得到固体，向该固体中加入正庚烷(300ml)，室温打浆1小时后过滤，固体室温真空干燥后得到15.13g，收率72.3％。
第二步：N-(叔丁基二甲基硅基)甲基砜脒酰氯的合成
Figure PCTCN2017117861-appb-000011
氮气保护下将三苯基膦(2.89g)和六氯乙烷(2.60g)加入到氯仿(30ml)中，加热至70℃反应6小时，有大量白色固体产生，冷却至0～5℃，加入三乙胺(1.52g)，搅拌10min，然后加入N-(叔丁基二甲基硅基)甲基磺酰胺(2.09g)的氯仿(10ml)溶液，在0～5℃搅拌20min得到0.25M的N-(叔丁基二甲基硅基)甲基砜脒酰氯溶液。该溶液直接用于下步反应。
第三步：N-(2-苄氧羰基氨基)乙基-N’-叔丁基二甲基硅基-甲基砜脒的合成
Figure PCTCN2017117861-appb-000012
氮气保护下将N-(叔丁基二甲基硅基)甲基砜脒酰氯的(0.25M，40ml)溶液冷却至0～5℃，加入单CBz乙二胺(1.94g)的氯仿(10ml)溶液。加完升至室温反应1小时，直接柱层析分离得到含三苯氧膦的产物610mg N-(2-苄氧羰基氨基)乙基-N’-叔丁基二甲基硅基-甲基砜脒。
第四步：N-氨基乙基-N’叔丁基二甲基硅基-甲基砜脒的合成
Figure PCTCN2017117861-appb-000013
将N-(2-苄氧羰基氨基)乙基-N羰基叔丁基二甲基硅基-甲基砜脒(610mg)溶于甲醇(10ml)中，氮气置换三次后加入Pd/C 10％(含水58％，125mg)，用氢气置换后，室温搅拌4小时，TLC跟踪原料消失，过滤，浓缩后柱层析分离得到119mgN-氨基乙基-N’-叔丁基二甲基硅基-甲基砜脒。
1HNMR(400MHz，CDCl 3)：3.13(m，2H)，2.95(s，3H)，2.88(t，2H，J＝6.0Hz)，1.75(br，3H)，0.90(s，9H)，0.11(s，3H)，0.10(s，3H).
第五步：4-(3-溴-4-氟苯基)-3-(4-硝基-1，2，5-噁二唑)基-1，2，4-噁二唑-5(4H)-酮的合成
Figure PCTCN2017117861-appb-000014
将钨酸钠(1.0g)加入35％双氧水(25ml)中，冷却至0～5℃，滴加浓硫酸(25ml)，滴完搅拌10min，一次性加入4-(3-溴-4-氟苯基)-3-(4-氨基-1，2，5-噁二唑)基-1，2，4-噁二唑-5(4H)-酮(1.0g)，升至室温反应2天，将反应液倒入冰水(200g)，加入碳酸钠固体调pH＝8～9，DCM萃取，浓缩后柱层析，流动相为正庚烷/乙酸乙酯＝3∶1，得白色固体0.80g，收率74％。
1HNMR(400MHz，d6-DMSO)：8.02(dd，1H，J＝2.4，6.0Hz)，7.64(m，1H，)，7.54(t，1H，J＝8.4Hz).
第六步：4-(3-溴-4-氟苯基)-3-(4-(2-(N’-叔丁基二甲基硅基-甲基砜脒氨基)乙基)氨基-1，2，5-噁二唑)基-1，2，4-噁二唑-5(4H)-酮
Figure PCTCN2017117861-appb-000015
将N-氨基乙基-N’-叔丁基二甲基硅基-甲基砜脒(110mg)溶于乙腈(2ml)，冷却至0～5℃，加入4-(3-溴-4-氟苯基)-3-(4-硝基-1，2，5-噁二唑)-1，2，4-噁二唑-5(4H)-酮(150mg)，升至室温反应3小时，加入乙酸乙酯(20ml)稀释，有机相用饱和食盐水洗涤，浓缩后柱层析得70mg，收率30％。
1HNMR(400MHz，d6-DMSO)：8.09(dd，1H，J＝2.0，6.0Hz)，7.72(m，1H)，7.60(t，1H，J＝8.8Hz)，6.54(t，1H，J＝5.6Hz)，6.43(t，1H，J＝6.0Hz)，3.38(q，2H，J＝6.0Hz)，3.14(q，2H，J＝6.8Hz)，2.86(s，3H)，0.84(s，9H)，0.02(s，3H)，0.00(s，3H).
第七步：4-((2-(甲基砜脒基)乙基)氨基)-N-(3-溴-4-氟苯基)-N′-羟基-1，2，5-噁二唑-3-甲脒(LW105-1-1)的合成
Figure PCTCN2017117861-appb-000016
将4-(3-溴-4-氟苯基)-3-(4-(2-(N’-叔丁基二甲基硅基-甲基砜脒氨基)乙基)氨基-1，2，5-噁二唑)基-1，2，4-噁二唑-5(4H)-酮(40mg)溶于甲醇(5ml)，室温下加入2N氢氧化钠溶液(0.44ml)，搅拌1小时，加乙酸中和pH至6～7，浓缩后用制备层析板分离得到12mg固体，收率39％。
1HNMR(400MHz，d6-DMSO)：11.49(s，1H)，8.88(s，1H)，7.19(t，1H，J＝4.8Hz)，7.12(dd，1H，J＝2.4，5.2Hz)，6.77(dd，1H，J＝2.0，9.6Hz)，6.28(t，1H，J＝6.0Hz)，3.33(q，2H，J＝6.0Hz)，3.15(q，2H，J＝6.4Hz)，2.86(s，3H).
MS(ESI)：正离子436(M+H) +，负离子434(M-H) -。
实施例2
LW105-1-1的手性拆分
用制备型液相色谱仪对外消旋体LW105-1-1进行手性拆分
手性柱：大赛璐AD柱，4.6*250mm，5μm；流速1.0ml/min；检测波长：220nm；洗脱剂(正己烷∶乙醇＝65∶35，体积比)。
将化合物4-((2-(甲基砜脒基)乙基)氨基)-N-(3-溴-4-氟苯基)-N′-羟基-1，2，5-噁二唑-3-甲脒配制成60mg/ml的乙醇溶液，每次进样量为2ml，收集保留时间14.3min的峰为LW105-1-18(20mg)，保留时间21.1min的峰为LW105-1-19(17mg)。
实施例3
4-((2-(甲基砜脒基)乙基)氨基)-N-(3-溴-4-氟苯基)-N′-乙酰氧基-1，2，5-噁二唑-3-甲脒
Figure PCTCN2017117861-appb-000017
将化合物4-((2-(甲基砜脒基)乙基)氨基)-N-(3-溴-4-氟苯基)-N′-羟基-1，2，5-噁二唑-3-甲脒(50mg)溶于二氯甲烷(2ml)，加入三乙胺(0.1ml)，冷却至0℃，加入醋酐(0.1ml)，搅拌30min，水洗，干燥浓缩后柱层析得4-((2-(甲基砜脒基)乙基)氨基)-N-(3-溴-4-氟苯基)-N′-乙酰氧基-1，2，5-噁二唑-3-甲脒。
利用本申请所述的制备方法合成了本申请的化合物(见如下表格)。
Figure PCTCN2017117861-appb-000018
Figure PCTCN2017117861-appb-000019
Figure PCTCN2017117861-appb-000020
Figure PCTCN2017117861-appb-000021
实施例4活性测试
1.I DO1酶活性测试方法(NFK green)
研究内容：检测化合物对IDO1酶活性的抑制效应。
材料与方法
试剂和耗材
IDO assay kit(NTRC，Cat.No.NTRC-hTDO-1K)，DMSO(Sigma，Cat.No.D2650)，384孔板_化合物稀释板(Greiner，Cat.No.781280)，384孔板_测试板(Perkin Elmer，Cat.No.6007299)
实验方法
将10nM IDO1与化合物或DMSO于23℃孵育30分钟，加入终浓度为100uM的L型色氨酸反应1.5小时。加入NFK green于37℃孵育4小时，Envision采集荧光信号数据(激 发波段，400/25；发射波段，510/20)。根据XLfit5软件进行数据分析及拟图。
化合物最终测试浓度：
受试化合物和参考化合物LW3018最终测试浓度从10M到0.51nM，3倍梯度稀释，10个浓度，两复孔。
酶活性检测：
将10nM IDO1与化合物或DMSO于23℃孵育30分钟，加入终浓度为100uM的L型色氨酸反应1.5小时。加入NFK green于37℃孵育4小时，Envision采集荧光信号数据(激发波段，400/25；发射波段，510/20)。根据XLfit5软件进行数据分析及拟图。
2.I DO细胞学测试方法(LC-MS)
研究内容：检测化合物对Hela细胞IDO1活性的抑制效应。
材料与方法
试剂和耗材
RPMI 1640(无酚红)培养基(Invitrogen Cat.No.11835030)，胎牛血清(Invitrogen Cat.No.10099141)，青链霉素(Invitrogen Gibco Cat.No.15140-122)，重组人源干扰素γ(R&D system，Cat.No.285-IF-100).5％(w/v)三氯乙酸(Alfa Aesar Cat.No.A11156)，DMSO(Sigma，Cat.No.D2650)，96孔板_化合物稀释板(Axygen，Cat.No.WIPP02280)，96孔板_测试板(Greiner，Cat.No.655090)
实验方法
化合物最终测试浓度：
受试化合物和参考化合物LW3018最终测试浓度从5M到0.76nM，3倍梯度稀释，9个浓度，两复孔。
细胞学检测：
将Hela细胞以每孔40，000个细胞的数目铺于96孔细胞培养板中，用含10％胎牛血清的RPMI 1640培养5-6小时，加入稀释好的待测化合物和终浓度为100ng/mL重组人源干扰素γ激活IDO1表达。细胞于富含5％二氧化碳的37℃细胞培养箱中培养20小时后，用5％三氯乙酸终止反应，并于50℃孵育30分钟。细胞培养液经沉淀后，上清送LC/MS检测其中的犬尿氨酸含量。根据XLfit5软件进行数据分析及拟图。
本申请化合物的IDO酶抑制活性和细胞抑制活性的测试结果如表1所示。
表1 IDO酶和细胞抑制活性测试结果
代号 IDO IC 50(nM) Hela IC 50(nM)
LW105-1-1 22.3 11.5
LW105-1-2 25.2 15.6
LW105-1-3 19.4 12.7
LW105-1-4 29.4 7.2
LW105-1-11 26.5 11.1
LW105-1-18 22.8 7.6
LW105-1-19 22.3 6.7
LW3018(阳性对照) 59.9 14.8
上述结果表明，本申请化合物(包括外消旋体和对映异构体)均具有优异地针对IDO酶和细胞的抑制。
实施例5小鼠结直肠癌CT26移植肿瘤的体内药效试验
在无菌条件下，取处于生长增殖期的CT26细胞，消化后调整细胞浓度，接种于小鼠的右侧后肢背部。在每只小鼠接种1×10 5个CT26细胞，接种体积为0.1mL。接种4天后，肿瘤平均体积接近20-30mm 3，随机分组给药，给药当天记为D0，阴性对照给予等量溶媒。LW 105-1-1与Anti-CTLA4抗体的联合给药也在本实验中做了测试。开始给药以后，每周测量3次肿瘤长径和短径。实验分组和给药方案见表2。
表2动物实验分组和给药方案
Figure PCTCN2017117861-appb-000022
1注：N：每组小鼠数量；
化合物LW105-1-1对肿瘤抑制效果如图1所示。结果表明，本发明化合物LW105-1-1在鼠结直肠癌CT26移植肿瘤模型有着剂量依赖性的抗肿瘤生长效果。在300mg/kg的剂量，LW105-1-1的肿瘤抑制率为40.6％，LW105-1-1与Anti-CTLA4抗体的联合显示了高达96.4％的肿瘤抑制率。
实施例6化合物LW105-1-1在小鼠内的药代动力学研究
1.给药方案
雄性C57BL/6小鼠18只，灌胃或静脉给予化合物LW105-1-1(表3)
表3
Figure PCTCN2017117861-appb-000023
静脉注射给药以含有5％DMA以及20％HPbCD水溶液为溶媒的制剂，灌胃给药以含5％DMA、20％HPbCD以及0.1％CREMOPHOR EL的水溶液为溶媒的制剂。动物品系为雄 性C57BL/6小鼠。动物实验前，所有动物均禁食，并于给药后4小时喂食；所有动物可以自由饮水。
2.采血时间点以及样品处理：
静脉注射给药组：给药前、0.083、0.25、0.5、1、2、4、8以及24小时
灌胃给药组：给药前、0.25、0.5、1、2、4、8以及24小时
3.样品测试和数据分析：
通过隐静脉在规定的时间采集(或其他合适的采血位点)全血样品(0.03mL)，所有血样均加入预先加好K2-EDTA抗凝剂并标记好的塑料离心管中。血样采集后，2到8℃，3000g离心10分钟吸取上清血浆，迅速至于干冰中，保持-20℃或更低温度，用于LC-MS/MS分析。
所有样品的浓度均使用LC-MS/MS进行分析。采用WinNonlin TM Version 6.3(Pharsight，Mountain View，CA)药动学软件的非房室模型处理血浆均值浓度，使用线性对数梯形法方法计算药动学参数。
4实验结果：
雄性C57BL/6小鼠静脉注射给药3mg/kg后以及口服灌胃给药30和100mg/kg的药代动力学参数见表4和表5。
表4雄性C57BL/6小鼠静脉注射给药3mg/kg LW105-1-1后药代参数表
Figure PCTCN2017117861-appb-000024
表5雄性C57BL/6小鼠口服灌胃给药30和100mg/kg LW105-1-1后药代参数表
Figure PCTCN2017117861-appb-000025
结果表明，静脉注射给药后，化合物LW105-1-1在小鼠体内清除率(CL)为34.5mL/min/kg，稳态分布容积(Vdss)为1.87L/kg，暴露量(AUC 0-last)为1427ng/mL h。在100mg/kg剂量灌胃LW105-1-1后，在小鼠体内的血浆达峰时间Tmax为0.25h，暴露量(AUC 0-last)为39342ng/mL h，剂量标准化后，绝对生物利用度为81.4％。
在本申请提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本申请的上述讲授内容之后，本领域技术人员可以对本申请作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (16)

  1. 一种通式I化合物或其药学上可接受的盐、其氘代化合物、其立体异构体或其互变异构体：
    Figure PCTCN2017117861-appb-100001
    式中，
    R 1为取代或未取代的C 1-C 10烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 2-C 10烯基、取代或未取代的C 3-C 10炔基、取代或未取代的C 6-C 20芳基、取代或未取代的C 3-C 14杂芳基、氨基；
    R 2，R 3，R 4和R 6各自独立为氢、取代或未取代的C 1-C 10烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 2-C 10烯基、取代或未取代的C 3-C 10炔基、取代或未取代的C 6-C 20芳基、或取代或未取代的C 3-C 14杂芳基；R 1和R 2，R 1和R 3，R 1和R 6，R 2和R 6，R 3和R 4或R 3和R 6可以一起可以形成三至八元碳环或三至八元杂环，其中杂原子可以是硫、氧、氮，如果杂环上有氮原子，该氮原子任选被C 1-C 6烷基或C 3-C 6环烷基取代；
    R 5为C 6-C 20芳基、五元或六元杂芳基；R 5可以被一个或多个选自下组的基团取代：卤素、C 1-C 6烷基、C 1-C 6烷氧基、羟基、氨基、硝基、醛基、-CF 3、-CN、-SF 5、NR aR b、羧基、-COR a、-CO 2C 1-C 6烷基、-CONR aR b、-S(O)R a，-S(O) 2R a、-S(O)(NH)R a、-S(O)(NR d)R a、-S(O) 2NR aR b、-P(O)Me 2、-P(O)(OMe) 2；其中各R a和各R b各自独立为氢、取代或未取代的C 1-C 10烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 2-C 10烯基、取代或未取代的C 6-C 20芳基、或取代或未取代的C 3-C 14杂芳基；R a和R b可以一起可以形成三至八元环或四至八元杂环，其中杂原子可以是硫、氧、氮，如果杂环上有氮原子，该氮原子任选被C 1-C 6烷基或C 3-C 6环烷基取代；
    X为一个单键、O、S或NH或NR d；
    R d选自C 1-C 10烷基、C 3-C 10环烷基、C 6-C 20芳基、或C 3-C 14杂芳基；
    n为2至8的整数。
  2. 如权利要求1所述的化合物或其药学上可接受的盐、其氘代化合物、其立体异构体或其互变异构体，其中所述化合物如式(II)所示，
    Figure PCTCN2017117861-appb-100002
    式中，
    Ar为苯环，Ar可以被一个或多个选自下组的基团取代：卤素、C 1-C 6烷基、C 1-C 6烷氧基、羟基、氨基、硝基、醛基、-CF 3、-CN、-SF 3、-SF 5、NR aR b、羧基、-COR a、-CO 2C 1-C 6 烷基、-CONR aR b、-S(O)R a，-S(O) 2R a、-S(O)(NH)R a、-S(O)(NR d)R a、-S(O) 2NR aR b；
    R a、R b、R d、R 3、R 4、R 6、R 2、R 1和X的定义如上所述；
    n为2至6的整数。
  3. 如权利要求2所述的化合物或其药学上可接受的盐、其氘代化合物、其立体异构体或其互变异构体，其中，式(II)中，
    Ar为苯环，其被一个或两个选自以下的基团取代：卤素、羟基、氨基、硝基、-CF 3和-CN；
    R 1为C 1-C 6烷基、C 3-C 6环烷基、C 6-C 10芳基、或含至少一个杂原子的C 3-C 8杂芳基；R 1可以被一个或多个卤素取代
    R 2、R 6为H、C 1-C 6烷基；
    R 1和R 2、R 1和R 6R 2和R 6可以一起可以形成三至八元碳环或三至八元杂环；
    上述杂原子选自硫、氧和氮；如果杂环上有氮原子，该氮原子任选被C 1-C 6烷基或C 3-C 6环烷基取代；
    R 3和R 4各自独立为氢、C 1-C 6烷基；
    n为2或3；
    X为NH或NR d；R d选自C 1-C 6烷基。
  4. 如权利要求3所述的化合物或其药学上可接受的盐、其氘代化合物、其立体异构体或其互变异构体，其中，在式(II)中，
    Ar为苯环，其被两个卤素原子取代；
    R 1为C 1-C 6烷基或C 3-C 6环烷基，R 1可以被一个或多个卤素取代；
    R 2和R 6各自独立地为H；
    R 3和R 4各自独立为氢；
    n为2或3；
    X为NH。
  5. 如权利要求4所述的化合物或其药学上可接受的盐、其氘代化合物、其立体异构体或其互变异构体，其中，在式(II)中，
    R 1为C 1-C 3烷基或环丙烷基，R 1可以被一个或多个卤素取代；
    R 2和R 6各自独立为氢；
    R 3和R 4各自独立为氢；
    n为2或3；
    X为NH；
    Ar为苯环，其被位于对位和问位的两个卤素原子取代。
  6. 如权利要求5所述的化合物或其药学上可接受的盐、其氘代化合物、其立体异构体或其互变异构体，其中，在式(II)中，
    R 1选自-CH 3、-C 2H 5、-CH(CH 3) 2、环丙烷基、CH 2F、CHF 2、CF 3、CH 2Cl、CHCl 2、CCl 3、CHFCH 3、CF 2CH 3、CHFCH 2F、CF 2CH 2F、CHFCHF 2、CF 2CHF 2、CHFCF 3或CF 2CF 3；
    Ar为苯环，其对位被F取代，且问位被Br取代。
  7. 如权利要求1-6所述的化合物或其药学上可接受的盐、其氘代化合物、其立体异构体或其互变异构体，其中，所述化合物选自以下化合物：
    Figure PCTCN2017117861-appb-100003
    Figure PCTCN2017117861-appb-100004
  8. 权利要求1-7中任一项所述的化合物的制备方法，其包括以下步骤：
    Figure PCTCN2017117861-appb-100005
    (a)化合物A与化合物C反应，得到化合物B；
    (b)化合物B在碱水解条件下(如氢氧化钠水溶液)开环，得到终产物通式I化合物；
    各式中，X、R 1、R 2、R 3、R 4、R 5、R 6、n的定义如上所示。
  9. 权利要求1-7中任一项所述的化合物的制备方法，其包括以下步骤：
    Figure PCTCN2017117861-appb-100006
    (a)化合物D在硫酸的催化下被双氧水氧化成化合物E；
    (b)化合物E和化合物F发生取代反应得到化合物B；
    (c)化合物B在碱水解条件下(如氢氧化钠水溶液)开环，得到终产物通式(I)化合物；
    各式中，X、R 1、R 2、R 3、R 4、R 5、R 6、n的定义如上所示。
  10. 权利要求1-7中任一项所述的化合物、其药学上可接受的盐、其氘代化合物、其立体异构体或其互变异构体在制备预防或治疗吲哚胺-2，3-双加氧酶介导的疾病的药物中的应用。
  11. 如权利要求10所述的应用，其中所述疾病选自癌症、神经退行疾病、眼疾、心里障碍、抑郁症、焦虑症、老年痴呆症和/或自身免疫性疾病。
  12. 如权利要求1-7中任一项所述的化合物、其药学上可接受的盐、其氘代化合物、其立体异构体或其互变异构体在制备预防或治疗以下疾病的药物中的应用，其中所述疾病选自癌症、神经退行疾病、眼疾、心里障碍、抑郁症、焦虑症、老年痴呆症和/或自身免疫性疾病。
  13. 如权利要求11或12所述的应用，其中所述癌症选自结直肠癌、乳腺癌、胃癌、肺癌、大肠癌、胰腺癌、卵巢癌、前列腺癌、肾癌、肝癌、脑癌、黑色素瘤、多发性骨髓瘤、慢性粒细胞性白血病、血液肿瘤，以及远离肿瘤原发部位的组织或器官的转移病变。
  14. 一种药物组合物，其中所述药物组合物包含权利要求1-7中任一项所述的化合物或其药学上可接受的盐、其氘代化合物、其立体异构体或其互变异构体以及药学上可接受的载体。
  15. 一种药物组合物，其中所述药物组合物包含权利要求1-7中任一项所述的化合物或其药学上可接受的盐、其氘代化合物、其立体异构体或其互变异构体以及一种或多种抗肿瘤药物。
  16. 如权利要求15所述的药物组合物，其中所述抗肿瘤药物选自PD-1抗体、CTLA-4抗体、PD-L1抗体、PD-L2抗体。
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US20200207728A1 (en) 2020-07-02
AU2017380492B2 (en) 2020-12-24
EP3560914A1 (en) 2019-10-30
AU2017380492A1 (en) 2019-08-08

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