WO2019120202A1 - Cyclohexane derivatives and uses thereof - Google Patents

Cyclohexane derivatives and uses thereof Download PDF

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Publication number
WO2019120202A1
WO2019120202A1 PCT/CN2018/121873 CN2018121873W WO2019120202A1 WO 2019120202 A1 WO2019120202 A1 WO 2019120202A1 CN 2018121873 W CN2018121873 W CN 2018121873W WO 2019120202 A1 WO2019120202 A1 WO 2019120202A1
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cancer
alkyl
disease
group
pharmaceutically acceptable
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French (fr)
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张磊
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成都华健未来科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals

Definitions

  • the present invention relates to a class of quinolin-4-ylcyclohexane compounds, pharmaceutically acceptable salts, hydrates, solvates or stereoisomers thereof, and processes for their preparation and combinations thereof, alone or in combination with other drugs
  • a disease is used in the treatment of pathological features of the IDO-mediated tryptophan metabolism pathway.
  • Tryptophan is an essential amino acid in the human body. Part of the tryptophan obtained from the diet is used to synthesize proteins and the neurotransmitter serotonin, and the rest is mainly metabolized by the kynurenine pathway.
  • Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that catalyzes the metabolism of tryptophan along the kynurenine pathway. When the expression level of IDO1 is high in tissue cells, a large amount of tryptophan is metabolized by the kynurenine metabolic pathway, and the tryptophan content is decreased, which directly inhibits the activation and proliferation of effector T cells.
  • the metabolites produced by the kynurenine pathway have certain effects on immunity, reproduction and central nervous system. In addition to directly inhibiting the survival of effector T cells, they also inhibit effector T cells by promoting the differentiation of regulatory T cells. Studies have shown that the total uric acid metabolic pathway of tryptophan is an important cause of immune escape in tumor cells.
  • IDO-mediated kynurenine metabolism is also associated with other diseases.
  • diseases such as the kynurenine pathway and myelodysplastic syndrome (Leuk Res. 2013; 37 (5): 573-9); neurodegenerative diseases, schizophrenia and depression (Nat Rev Neurosci. 2012; 13 (7): 465 -77); Alzheimer's disease (J Neural Transm (Vienna). 2000; 107(3): 343-53); cataract (Curr Eye Res. 2009; 34(4): 274-81); inflammation and sepsis (Nat. Med 2010; 16 (3): 279-85); AIDS (PLoS One. 2013; 8 (9): e74551);
  • IDO inhibitors have therapeutic and preventive effects in various diseases such as tumors, and have good application prospects, but existing IDO inhibitors have shown insufficient effectiveness or dose-limiting toxicity in clinical trials, which is required in the art. Development of new IDO inhibitors.
  • L is a bond, -C 1-4 alkyl
  • R 1 is -OC 1-4 alkyl
  • R 5 and R 6 are each independently -C 1-4 alkyl
  • X is selected from O or S
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -CF 3 , -CHF 2 , -OCF 3 , - NH 2 , —NO 2 , wherein the alkyl, alkenyl and alkynyl groups may be substituted by a substituent selected from halogen, —C 1-4 alkyl;
  • R 3 and R 4 are each independently hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl; or
  • R 3 and R 4 together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, wherein the cycloalkyl group and the heterocycloalkyl group may be substituted by a -C 1-4 alkyl group.
  • the invention provides a compound of formula (II),
  • L is a bond, -C 1-4 alkyl
  • R 1 is -OC 1-4 alkyl
  • R 5 and R 6 are each independently -C 1-4 alkyl
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -CF 3 , -CHF 2 , -OCF 3 , - NH 2 , -NO 2 .
  • the invention provides a compound of formula (VIII), a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:
  • L is a bond, -CH 2 -CH 2 -;
  • R 1 is selected from the following structures:
  • R 3 is selected from fluorine.
  • ⁇ refers herein to -D.
  • halogen refers to -F, -Cl, -Br and -I.
  • alkyl refers to an alkyl group that does not contain a hetero atom.
  • the term includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl and the like.
  • the term also includes branched chain isomers of branched alkyl groups, including but not limited to, the following groups: -CH (CH 3) 2, -CH (CH 3) (CH 2 CH 3), - CH (CH 2 CH 3 ) 2 , -C(CH 3 ) 3 , -C(CH 2 CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), - CH 2 CH(CH 2 CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 C(CH 2 CH 3 ) 3 , -CH(CH 3 )-CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH
  • alkenyl refers to at least one point of unsaturation in which two adjacent carbon atoms are bonded to the alkyl group defined above by a double bond, wherein the alkyl group is as defined herein.
  • alkynyl refers to an alkyl group wherein two adjacent carbon atoms are joined by a triple bond, wherein the alkyl group is as defined herein.
  • cycloalkyl refers herein to a mono- or polycyclic carbocyclic alkyl substituent. These include cyclic alkyl, alkenyl and alkynyl groups.
  • the cycloalkyl group can be monocyclic or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems) wherein the carbon atoms are located on the inside or outside of the ring system.
  • the cycloalkyl group as a whole may have 3 to 14 ring atoms (for example, having 3 to 8 carbon atoms for a monocyclic cycloalkyl group and 7-14 carbon atoms for a polycyclic cycloalkyl group).
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norbornyl, norbornyl, adamantyl and spiro[4.5]decyl groups and their homologs and isomers.
  • heterocycloalkyl refers to at least one heteroatom selected from O, N and S and optionally contains one or more double or triple bond non-aromatic cycloalkyl groups.
  • the heterocycloalkyl group as a whole may have 3 to 14 ring atoms and contain 1 to 5 hetero atoms (for example, 3 to 6 ring atoms in the case of a monocyclic heterocycloalkyl group, in the case of a polycyclic heterocycloalkyl group) Has 7-14 ring atoms).
  • Heterocycloalkyl groups can be covalently attached to a defined chemical structure at any heteroatom or carbon atom that results in a stable structure.
  • heterocycloalkyl group can be oxidized (e.g., morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S, S-dioxide).
  • Heterocycloalkyl groups may also contain one or more oxo groups, such as phthalimido, piperidinone, oxazolidinone, 2,4(1H,3H)-dioxo-pyrimidinyl , pyridine-2(1H)-keto group and the like.
  • heterocycloalkyl groups also include morpholinyl, thiomorpholinyl, pyranyl, imidazolidinyl, imidazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrroline Base, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, piperidinyl, azetidine, piperazinyl and the like.
  • substituents of the compounds of the invention are disclosed in the form of groups or ranges. This specifically means that the invention encompasses subgroups of each of the members or members of such groups and ranges.
  • the term "C 1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • compound of the invention refers herein to compounds of formula (I)-(II) and all their pure and mixed stereoisomers, geometric isomers, tautomers. , solvates, hydrates, prodrugs and isotopically labeled compounds and any pharmaceutically acceptable salts.
  • the solvate of the compound of the present invention means a compound or a salt thereof, such as a hydrate, an ethanolate, a methanolate or the like, in combination with a stoichiometric and non-stoichiometric solvent.
  • the compound may also be present in one or more crystalline states, i.e., as a co-crystal, a polymorph, or it may be present as an amorphous solid. All such forms are covered by the claims.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients that make up the formulation and/or the mammal to which it is treated.
  • stereoisomer refers to a chiralally different compound having one or more stereocenters, including the corresponding isomers and diastereomers.
  • the compound of the present invention can be used in the form of a salt such as a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
  • a salt such as a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
  • a salt such as a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
  • a salt such as a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
  • basic nitrogen-containing groups can be quaternized with the following reagents to form quaternary ammonium salts: such as lower alkyl halides, including chlorides, bromides and iodines of methyl, ethyl, propyl and butyl groups.
  • a dialkyl sulfate including dimethyl, diethyl, dibutyl, and dipentyl sulfates; such as long chain halides, including sulfhydryl, lauryl, myristyl, and stearyl Chloride, bromide and iodide; such as aralkyl halides, such as benzyl and phenethyl bromide.
  • the invention also includes isotopically-labeled compounds of the invention, i.e., identical to those disclosed above, but in which one or more atoms are replaced by an atom having the same number of protons but a different number of neutrons.
  • isotopes incorporating compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl and 131 I, etc.
  • the compounds of the present invention are within the scope of the invention.
  • Certain isotopically-labeled compounds of the invention such as those labeled with 3 H or 14 C, can be used in drug tissue distribution assays, and therefore, these 3 H or 14 C isotopes are particularly preferred for their ease of preparation and detection.
  • certain compounds of the invention that are replaced by heavier isotopes such as 2 H have certain therapeutic advantages due to better metabolic stability, such as increased in vivo half-life and lower doses, etc., therefore, 2 H is in some It is also preferred in some cases.
  • Isotopically labeled compounds of the formula (I) according to the invention and their presuppositions can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopic labels when carrying out the processes disclosed in the following schemes and/or examples and preparations. Reagents.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I)-(II), or a pharmaceutically acceptable carrier, diluent or excipient thereof.
  • the invention further relates to a compound of the formula (I)-(II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same for use in the prevention and/or treatment of IDO-mediated tryptophan metabolism
  • a pathway for the pathology of a drug in a disease The use of a pathway for the pathology of a drug in a disease.
  • the disease having the pathological characteristics of the IDO-mediated tryptophan metabolism pathway is selected from the group consisting of cancer, myelodysplastic syndrome, autoimmune disease, Alzheimer's disease, depression, schizophrenia, anxiety, psychological disorder, nerve Lesions and pain, cataracts, AIDS and pneumonia, wherein the cancer is preferably selected from prostate cancer, breast cancer, cervical cancer, endometrial cancer, colon cancer, stomach cancer, lung cancer, liver cancer, bladder cancer, pancreatic cancer, rectal cancer, and skin.
  • Cancer including melanoma and basal cell carcinoma
  • oral cancer including melanoma and basal cell carcinoma
  • bone cancer ovarian cancer
  • brain cancer head and neck cancer
  • mesothelioma leukemia, lymphoma, esophageal cancer
  • kidney cancer thyroid cancer
  • myeloma choriocarcinoma
  • testicular cancer glioma
  • maternal glioma fallopian tube tumor.
  • the present invention also relates to a method of treating a disease preventing and/or treating a disease having an IDO-mediated pathology of a tryptophan metabolism pathway comprising administering to a patient a therapeutically effective amount of the formula (I)-(II) The compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolic pathway is selected from the group consisting of cancer, myelodysplastic syndrome, autoimmune Disease, Alzheimer's disease, depression, schizophrenia, anxiety, psychological disorders, neuropathy and pain, cataracts, AIDS and pneumonia.
  • the present invention also relates to a method of treating a disease preventing and/or treating a disease having an IDO-mediated pathology of a tryptophan metabolism pathway comprising administering to a patient a therapeutically effective amount of the formula (I)-(II) The compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolic pathway is selected from the group consisting of cancer, wherein the cancer is selected from the group consisting of prostate cancer , breast cancer, cervical cancer, endometrial cancer, colon cancer, stomach cancer, lung cancer, liver cancer, bladder cancer, pancreatic cancer, rectal cancer, skin cancer (including melanoma and basal cell carcinoma), oral cancer, bone cancer, ovarian cancer , brain cancer, head and neck cancer, mesothelioma, leukemia, lymphoma, esophageal cancer, kidney cancer, thyroid cancer, myeloma, choriocarcinoma, test
  • the compounds provided herein can be prepared by standard synthetic methods well known in the art, and the present specification provides general methods for preparing the compounds of the invention.
  • Starting materials are usually commercially available, for example by Alfa TCI, Suiyuan Chemical, An Naiji Chemical, Ester (Chengdu) Biopharmaceutical, Chengdu Best Reagent, Chengdu Huana Chemical Preparation Co., Ltd., Aiqi Kang Pharmaceutical Technology (Shanghai) Co., Ltd., Shanghai Yuxiang Biotechnology Co., Ltd. It is commercially available from companies such as Shanghai WuXi PharmaTech Development Co., Ltd. or by methods well known to those skilled in the art.
  • reaction temperature e.g., reaction temperature, time, molar ratio of reactants, reaction solvent, and pressure, etc.
  • Optimum reaction conditions may vary depending on the particular reaction substrate or solvent employed, but such conditions can be determined by one of ordinary skill in the art by routine optimization.
  • reaction starting materials, intermediates, and example compounds can be isolated and purified by conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography (e.g., column chromatography, TLC separation, etc.).
  • TLC was extracted from Yantai Huanghai HSGF254 thin-layer chromatography silica gel plate (0.2 ⁇ 0.03 mm) by TLC.
  • the Yantai Yellow Sea HSGF254 thin layer chromatography thick preparation plate (0.9-1 mm) was purchased from Qingdao Ocean Chemical Plant.
  • reaction temperature reaction temperature
  • reaction solvent reactant molar ratio or/and reaction duration
  • the purification conditions of the compound may also vary.
  • the appropriate column chromatography eluent is selected according to the Rf value of TLC, or the corresponding compound is isolated and purified by preparative TLC.
  • the compound of the formula (I) of the present invention can be produced according to the following Scheme 1.
  • the condensation of A and B gives the compound of formula (I), which typically employs a condensing agent such as CDI, EDCI, DIC, DCC, HATU, HBTU, PyBOP, and the like.
  • a condensing agent such as CDI, EDCI, DIC, DCC, HATU, HBTU, PyBOP, and the like.
  • the compound of the formula (I) of the present invention can be produced according to the following Scheme 2.
  • Reaction of A with thionyl chloride in a suitable solvent such as dichloromethane affords intermediate C.
  • Intermediates C and B in the presence of a base such as pyridine, triethylamine, diisopropylethylamine, DBU, etc. in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, In the hexacyclic or the like, the reaction gives a compound of the formula (I).
  • a base such as pyridine, triethylamine, diisopropylethylamine, DBU, etc.
  • dichloromethane tetrahydrofuran
  • N,N-dimethylformamide N,N-dimethylformamide
  • HeLa cells were purchased from ATCC and cultured in DMEM containing L-glutamine (2 mM), non-essential amino acids (84 mg/L) and fetal bovine serum (10% FBS) at 95% humidity, 5% CO 2 , 37 ° C. Incubator. One day before the test, the cells were continuously passaged and grown well. More than 90% of the fused Hela cells were digested with EDTA/trypsin, resuspended in DMEM complete medium, and seeded in 96-well culture plates at a density of 5000/well. Cultivate overnight.
  • 96-well plate cell culture medium was replaced, and 200 ⁇ l of IFN- ⁇ (final concentration 50 ng/mL, purchased from R&D) and serial dilutions of the compound medium were added to each well. The highest concentration of the compound was 1000 nM, and 7 concentration gradients were diluted 5 times.
  • 150 ⁇ l of the supernatant/well was transferred to a new 96-well plate, 7.5 ⁇ l of trichloroacetic acid was added to each well, and the mixture was incubated at 50 ° C for 30 min to produce N.
  • - Formyl kynurenine is hydrolyzed to kynurenine.
  • the precipitate was then removed by centrifugation at 12000 rpm for 10 minutes.
  • the supernatant was analyzed by liquid/triple quadrupole mass spectrometry (LC/MS/MS, LC-20AD high performance liquid chromatography system, Shimadzu, Japan; API4000 triple quadrupole mass spectrometer, Applied Biosystem, USA) for analysis of L-kynurenine concentration.
  • a standard curve was established with a concentration gradient of 2-5000 ng/ml L-kynurenine; the concentration of L-kynurenine in the cell culture supernatant was measured to calculate the activity of each compound to inhibit IDO by fitting with original 7.5.
  • IC 50 of uridine
  • test results indicate that the compound of the present invention has a significantly better inhibitory effect on IDO1 in Hela cells than BMS-986205.

Abstract

Provided is a quinoline-4-base cyclohexane compound, a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, as well as a preparation method therefor. Said compound alone or in combination with other drugs is used for treating pathological features of a tryptophan metabolic pathway disorder mediated by IDO.

Description

一类环己烷类衍生物及其用途A class of cyclohexane derivatives and uses thereof 技术领域Technical field
本发明涉及一类喹啉-4-基环己烷类化合物，其药学上可接受的盐、水合物、溶剂化物或立体异构体，及其制备方法以及该类化合物单独或与其他药物联合使用在治疗具有IDO介导的色氨酸代谢途径病理学特征的疾病。The present invention relates to a class of quinolin-4-ylcyclohexane compounds, pharmaceutically acceptable salts, hydrates, solvates or stereoisomers thereof, and processes for their preparation and combinations thereof, alone or in combination with other drugs A disease is used in the treatment of pathological features of the IDO-mediated tryptophan metabolism pathway.
背景技术Background technique
色氨酸是人体必需的一种氨基酸。从饮食中获得的色氨酸，一部分用来合成蛋白质以及神经递质5-羟色胺，其余部分则主要通过犬尿氨酸途径(kynurenine pathway)进行代谢。吲哚胺2,3-双加氧酶1(IDO1)是催化色氨酸沿犬尿氨酸途径代谢的限速酶。当组织细胞中，IDO1表达水平高时，大量色氨酸经犬尿氨酸代谢途径代谢，色氨酸含量降低，直接抑制了效应T细胞的活化与增值。而犬尿氨酸途径产生的代谢产物对免疫、生殖及中枢神经***均有一定的影响，除能直接抑制效应T细胞的存活外，也通过促进调节性T细胞的分化而抑制效应T细胞。研究表明，色氨酸的全尿酸代谢途径是导致肿瘤细胞发生免疫逃逸的重要原因。Tryptophan is an essential amino acid in the human body. Part of the tryptophan obtained from the diet is used to synthesize proteins and the neurotransmitter serotonin, and the rest is mainly metabolized by the kynurenine pathway. Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that catalyzes the metabolism of tryptophan along the kynurenine pathway. When the expression level of IDO1 is high in tissue cells, a large amount of tryptophan is metabolized by the kynurenine metabolic pathway, and the tryptophan content is decreased, which directly inhibits the activation and proliferation of effector T cells. The metabolites produced by the kynurenine pathway have certain effects on immunity, reproduction and central nervous system. In addition to directly inhibiting the survival of effector T cells, they also inhibit effector T cells by promoting the differentiation of regulatory T cells. Studies have shown that the total uric acid metabolic pathway of tryptophan is an important cause of immune escape in tumor cells.
近期的研究表明，IDO介导的犬尿氨酸代谢的形成还与其他疾病相关。如犬尿氨酸途径与骨髓增生异常综合征(Leuk Res.2013；37(5):573-9)；神经变性疾病、精神***症和抑郁(Nat Rev Neurosci.2012；13(7):465-77)；阿尔兹海默症(J Neural Transm(Vienna).2000；107(3):343-53)；白内障(Curr Eye Res.2009；34(4):274-81)；炎症和败血症(Nat.Med 2010；16(3):279-85)；艾滋病(PLoS One.2013；8(9):e74551)；等有关。Recent studies have shown that IDO-mediated kynurenine metabolism is also associated with other diseases. Such as the kynurenine pathway and myelodysplastic syndrome (Leuk Res. 2013; 37 (5): 573-9); neurodegenerative diseases, schizophrenia and depression (Nat Rev Neurosci. 2012; 13 (7): 465 -77); Alzheimer's disease (J Neural Transm (Vienna). 2000; 107(3): 343-53); cataract (Curr Eye Res. 2009; 34(4): 274-81); inflammation and sepsis (Nat. Med 2010; 16 (3): 279-85); AIDS (PLoS One. 2013; 8 (9): e74551);
大量实验数据表明IDO抑制剂在肿瘤等多种疾病领域具有治疗和预防作用，具有良好的应用前景，但现有IDO抑制剂在临床实验中显示了有效性不足或具有剂量限制毒性，本领域需要开发新型IDO抑制剂。A large number of experimental data indicate that IDO inhibitors have therapeutic and preventive effects in various diseases such as tumors, and have good application prospects, but existing IDO inhibitors have shown insufficient effectiveness or dose-limiting toxicity in clinical trials, which is required in the art. Development of new IDO inhibitors.
发明内容Summary of the invention
本发明的目的在于提供一种式(I)所示的化合物或其药学上可接受的盐、水合物、溶剂化物或立体异构体，It is an object of the present invention to provide a compound of the formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof,
Figure PCTCN2018121873-appb-000001
Figure PCTCN2018121873-appb-000001
其中：among them:
L为键、-C 1-4烷基； L is a bond, -C 1-4 alkyl;
R 1为-O-C 1-4烷基、
Figure PCTCN2018121873-appb-000002
R 1 is -OC 1-4 alkyl,
Figure PCTCN2018121873-appb-000002
R 5和R 6分别独立地为-C 1-4烷基； R 5 and R 6 are each independently -C 1-4 alkyl;
X选自O或S；X is selected from O or S;
R 2选自氢、氘、卤素、-C 1-6烷基、-C 2-6烯基、-C 2-6炔基、-CN、-CF 3、-CHF 2、-OCF 3、-NH 2、-NO 2，其中烷基、烯基和炔基可被选自卤素、-C 1-4烷基的取代基取代； R 2 is selected from the group consisting of hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -CF 3 , -CHF 2 , -OCF 3 , - NH 2 , —NO 2 , wherein the alkyl, alkenyl and alkynyl groups may be substituted by a substituent selected from halogen, —C 1-4 alkyl;
R 3和R 4分别独立地为氢、卤素、-C 1-6烷基、-C 2-6烯基、-C 2-6炔基、-C 3-6环烷基；或者， R 3 and R 4 are each independently hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl; or
R 3和R 4和与其相连的碳原子一起形成3-6元环烷基、3-6元杂环烷基，其中，环烷基和杂环烷基可被-C 1-4烷基取代。 R 3 and R 4 together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, wherein the cycloalkyl group and the heterocycloalkyl group may be substituted by a -C 1-4 alkyl group. .
在另一个方面，本发明提供给式(II)化合物，In another aspect, the invention provides a compound of formula (II),
Figure PCTCN2018121873-appb-000003
Figure PCTCN2018121873-appb-000003
其中，among them,
L为键、-C 1-4烷基； L is a bond, -C 1-4 alkyl;
R 1为-O-C 1-4烷基、
Figure PCTCN2018121873-appb-000004
R 1 is -OC 1-4 alkyl,
Figure PCTCN2018121873-appb-000004
R 5和R 6分别独立地为-C 1-4烷基； R 5 and R 6 are each independently -C 1-4 alkyl;
R 2选自氢、氘、卤素、-C 1-6烷基、-C 2-6烯基、-C 2-6炔基、-CN、-CF 3、-CHF 2、-OCF 3、-NH 2、-NO 2。 R 2 is selected from the group consisting of hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -CF 3 , -CHF 2 , -OCF 3 , - NH 2 , -NO 2 .
在进一步的实施方式中，本发明提供式(VIII)化合物，其药学上可接受的盐、水合物、溶剂化物或立体异构体，其中：In a further embodiment, the invention provides a compound of formula (VIII), a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:
L为键、-CH 2-CH 2-； L is a bond, -CH 2 -CH 2 -;
R 1选自以下结构： R 1 is selected from the following structures:
Figure PCTCN2018121873-appb-000005
Figure PCTCN2018121873-appb-000005
R 3选自氟。 R 3 is selected from fluorine.
本发明涉及式(I)-式(II)的典型化合物如表1所示，但并不限于以下实施例：Typical compounds of the present invention relating to formula (I)-formula (II) are shown in Table 1, but are not limited to the following examples:
表1Table 1
Figure PCTCN2018121873-appb-000006
Figure PCTCN2018121873-appb-000006
定义definition
如上文和本文其它地方所用，下列术语和缩写具有下面所定义的含义。如未定义，则本说明书所使用的所有技术和科学术语均具有本领域普通技术人员通常所理解的含义。As used above and elsewhere herein, the following terms and abbreviations have the meanings defined below. If not defined, all technical and scientific terms used in the specification have the meaning commonly understood by one of ordinary skill in the art.
缩写abbreviation 含义meaning
IDOIDO 吲哚胺2,3-双加氧酶Indoleamine 2,3-dioxygenase
TLCTLC 薄层色谱TLC
R f R f 比移值Ratio shift
CDICDI 羰基二咪唑Carbonyldiimidazole
EDCIEDCI 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
DICDIC N,N'-二异丙基碳二亚胺N,N'-diisopropylcarbodiimide
DCCDCC 二环己基碳二亚胺Dicyclohexylcarbodiimide
HATUHATU 2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate
HBTUHBTU 苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯Benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate
PyBOPPyBOP 1H-苯并***-1-基氧三吡咯烷基六氟磷酸盐1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate
MSMS 质谱Mass spectrometry
IFN-γIFN-γ γ-干扰素Γ-interferon
EDTAEDTA 乙二胺四乙酸Ethylenediaminetetraacetic acid
FBSFBS 胎牛血清Fetal bovine serum
术语“氢”在本文中是指-H。The term "hydrogen" as used herein refers to -H.
术语“氘”在本文中是指-D。The term "氘" refers herein to -D.
术语“卤素”在本文中是指-F、-Cl、-Br和-I。The term "halogen" as used herein refers to -F, -Cl, -Br and -I.
术语“烷基”在本文中是指不含有杂原子的烷基。因此，该术语包括直链烷基如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基等。该术语还包括支链烷基的支链异构体，包括但不限于例如下面的基团：-CH(CH 3) 2、-CH(CH 3)(CH 2CH 3)、-CH(CH 2CH 3) 2、-C(CH 3) 3、-C(CH 2CH 3) 3、-CH 2CH(CH 3) 2、-CH 2CH(CH 3)(CH 2CH 3)、-CH 2CH(CH 2CH 3) 2、-CH 2C(CH 3) 3、-CH 2C(CH 2CH 3) 3、-CH(CH 3)-CH(CH 3)(CH 2CH 3)、-CH 2CH 2CH(CH 3) 2、-CH 2CH 2CH(CH 3)(CH 2CH 3)、-CH 2CH 2CH(CH 2CH 3) 2、-CH 2CH 2C(CH 3) 3、-CH 2CH 2C(CH 2CH 3) 3、-CH(CH 3)CH 2CH(CH 3) 2、-CH(CH 3)CH(CH 3)CH(CH 3) 2、-CH(CH 2CH 3)CH(CH 3)CH(CH 3)(CH 2CH 3)等。因此 术语烷基包括伯烷基、仲烷基和叔烷基。 The term "alkyl" as used herein refers to an alkyl group that does not contain a hetero atom. Thus, the term includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl and the like. The term also includes branched chain isomers of branched alkyl groups, including but not limited to, the following groups: -CH (CH 3) 2, -CH (CH 3) (CH 2 CH 3), - CH (CH 2 CH 3 ) 2 , -C(CH 3 ) 3 , -C(CH 2 CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), - CH 2 CH(CH 2 CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 C(CH 2 CH 3 ) 3 , -CH(CH 3 )-CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 2 CH 3 ) 2 , -CH 2 CH 2 C(CH 3 ) 3 , -CH 2 CH 2 C(CH 2 CH 3 ) 3 , -CH(CH 3 )CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH(CH 3 )CH(CH 3 ) 2 , -CH(CH 2 CH 3 )CH(CH 3 )CH(CH 3 )(CH 2 CH 3 ), and the like. Thus the term alkyl includes primary alkyl, secondary alkyl and tertiary alkyl.
术语“烯基”在本文中是指其中有至少一个不饱和点，即，其中两个相邻碳原子通过双键连接上面所定义的烷基，其中所述烷基如本文中所定义The term "alkenyl" as used herein refers to at least one point of unsaturation in which two adjacent carbon atoms are bonded to the alkyl group defined above by a double bond, wherein the alkyl group is as defined herein.
术语“炔基”在本文中是指涉及其中两个相邻碳原子通过三键连接的烷基，其中所述烷基如本文中所定义。The term "alkynyl" as used herein refers to an alkyl group wherein two adjacent carbon atoms are joined by a triple bond, wherein the alkyl group is as defined herein.
术语“环烷基”在本文中是指单-或多环的碳环烷基取代基。包括环状烷基、烯基和炔基。环烷基可以使单环或多环(例如含有稠合、桥连和/或螺环系)，其中碳原子位于环系内侧或外侧。环烷基作为整体可以具有3-14个环原子(例如就单环环烷基而言具有3-8个碳原子，就多环环烷基而言具有7-14个碳原子)。环烷基的任意适当的环位置可以与所定义的化学结构共价连接。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环己二烯基、环庚三烯基、降冰片基、降蒎烷基、降蒈烷基、金刚烷基和螺[4.5]癸基及其同系物和异构体等。The term "cycloalkyl" refers herein to a mono- or polycyclic carbocyclic alkyl substituent. These include cyclic alkyl, alkenyl and alkynyl groups. The cycloalkyl group can be monocyclic or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems) wherein the carbon atoms are located on the inside or outside of the ring system. The cycloalkyl group as a whole may have 3 to 14 ring atoms (for example, having 3 to 8 carbon atoms for a monocyclic cycloalkyl group and 7-14 carbon atoms for a polycyclic cycloalkyl group). Any suitable ring position of the cycloalkyl group can be covalently attached to the defined chemical structure. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norbornyl, norbornyl, adamantyl and spiro[4.5]decyl groups and their homologs and isomers.
术语“杂环烷基”在本文中是指至少有一个选自O、N和S的杂原子且任选含有一条或多条双键或三键非芳族环烷基。杂环烷基作为整体可以具有3-14个环原子并且含有1-5个杂原子(例如就单环杂环烷基而言具有3-6个环原子，就多环杂环烷基而言具有7-14个环原子)。杂环烷基可以在产生稳定结构的任意杂原子或碳原子上与所定义的化学结构共价连接。杂环烷基上的一个或多个N或S原子可以被氧化(例如吗啉N-氧化物、硫吗啉S-氧化物、硫吗啉S,S-二氧化物)。杂环烷基还可以含有一个或多个氧代基团，例如邻苯二酰亚氨基、哌啶酮基、恶唑烷酮基、2,4(1H,3H)-二氧代-嘧啶基、吡啶-2(1H)-酮基等。杂环烷基的实例还包括吗啉基、硫吗啉基、吡喃基、咪唑烷基、咪唑啉基、恶唑烷基、吡唑烷基、吡唑啉基、吡咯烷基、吡咯啉基、四氢呋喃基、四氢噻吩基、四氢噻唑基、哌啶基、氮杂环丁烷、哌嗪基等。The term "heterocycloalkyl" as used herein refers to at least one heteroatom selected from O, N and S and optionally contains one or more double or triple bond non-aromatic cycloalkyl groups. The heterocycloalkyl group as a whole may have 3 to 14 ring atoms and contain 1 to 5 hetero atoms (for example, 3 to 6 ring atoms in the case of a monocyclic heterocycloalkyl group, in the case of a polycyclic heterocycloalkyl group) Has 7-14 ring atoms). Heterocycloalkyl groups can be covalently attached to a defined chemical structure at any heteroatom or carbon atom that results in a stable structure. One or more N or S atoms on the heterocycloalkyl group can be oxidized (e.g., morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S, S-dioxide). Heterocycloalkyl groups may also contain one or more oxo groups, such as phthalimido, piperidinone, oxazolidinone, 2,4(1H,3H)-dioxo-pyrimidinyl , pyridine-2(1H)-keto group and the like. Examples of heterocycloalkyl groups also include morpholinyl, thiomorpholinyl, pyranyl, imidazolidinyl, imidazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrroline Base, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, piperidinyl, azetidine, piperazinyl and the like.
在本说明书的各个位置，本发明化合物的取代基以基团或范围的形式进行公开。这具体意味着本发明包括这样的基团和范围的每个成员或成员中的每个个体的亚组合。如术语“C 1-6烷基”具体意味着单独公开了甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。 At various points in the specification, substituents of the compounds of the invention are disclosed in the form of groups or ranges. This specifically means that the invention encompasses subgroups of each of the members or members of such groups and ranges. The term "C 1-6 alkyl" is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
术语“本发明化合物”(除非另有具体指明)在本文中是指式(I)-(II)化合物及其所有纯的和混合的立体异构体、几何异构体、互变异构体、溶剂合物、水合物、前药及同位素标记的化合物和任何药学上可接受的盐。本发明化合物 的溶剂合物是指与化学计量和非化学计量的溶剂结合的化合物或其盐，如水合物、乙醇合物、甲醇合物等。化合物也可以一种或多种结晶状态存在，即作为共晶体、多晶型物，或其可以无定形固体存在。所有此种形式均被权利要求所涵盖。The term "compound of the invention" (unless otherwise specifically indicated) refers herein to compounds of formula (I)-(II) and all their pure and mixed stereoisomers, geometric isomers, tautomers. , solvates, hydrates, prodrugs and isotopically labeled compounds and any pharmaceutically acceptable salts. The solvate of the compound of the present invention means a compound or a salt thereof, such as a hydrate, an ethanolate, a methanolate or the like, in combination with a stoichiometric and non-stoichiometric solvent. The compound may also be present in one or more crystalline states, i.e., as a co-crystal, a polymorph, or it may be present as an amorphous solid. All such forms are covered by the claims.
术语“药学上可接受”表示物质或组合物在化学上和/或毒理学上必须与构成制剂的其它成分和/或用其治疗的哺乳动物相容。The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients that make up the formulation and/or the mammal to which it is treated.
术语“立体异构体”在本文中是指具有一个或多个立体中心的手性不同的化合物，包括对应异构体和非对映异构体。The term "stereoisomer" as used herein refers to a chiralally different compound having one or more stereocenters, including the corresponding isomers and diastereomers.
本发明化合物可以以盐的形式被使用，如从无机酸或有机酸衍生得到的“医药上可接受的盐”。这些包括但并不限于下列所述：乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡萄糖酸盐、环戊烷丙酸盐、十二烷基硫酸盐、乙磺酸盐、葡糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、延胡索酸盐、氢氯化物、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、盐酸盐、2-萘磺酸盐、草酸盐、果胶酯酸盐、硫酸盐、3-苯基丙酸盐、苦味酸盐、三甲基乙酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐和癸酸盐。另外，碱性含氮基团可以与以下试剂发生季铵化反应生成季铵盐：如低碳烷基卤化物，包括甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物；如二烷基硫酸盐，包括二甲基、二乙基、二丁基和二戊基的硫酸盐；如长链卤化物，包括癸基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物；如芳烷基卤化物，如苯甲基和苯乙基的溴化物等。The compound of the present invention can be used in the form of a salt such as a "pharmaceutically acceptable salt" derived from an inorganic or organic acid. These include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate , camphorate, camphor sulfonate, digluconate, cyclopentane propionate, lauryl sulfate, ethanesulfonate, glucoheptanoate, glycerol phosphate, hemisulfate, heptanoic acid Salt, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, hydrochloride, 2 -naphthalene sulfonate, oxalate, pectate ester, sulfate, 3-phenylpropionate, picrate, trimethylacetate, propionate, succinate, tartrate, sulfur Cyanate, p-toluenesulfonate and decanoate. In addition, basic nitrogen-containing groups can be quaternized with the following reagents to form quaternary ammonium salts: such as lower alkyl halides, including chlorides, bromides and iodines of methyl, ethyl, propyl and butyl groups. a dialkyl sulfate, including dimethyl, diethyl, dibutyl, and dipentyl sulfates; such as long chain halides, including sulfhydryl, lauryl, myristyl, and stearyl Chloride, bromide and iodide; such as aralkyl halides, such as benzyl and phenethyl bromide.
本发明还包括同位素标记的本发明化合物，即与上述所公开的结构相同，但该结构中一个或多个原子被与其具有相同质子数但不同中子数的原子所替代。结合本发明化合物的同位素实施例包括氢、碳、氮、氧、硫、氟、氯、碘的同位素，分别如 2H、 3H、 13C、 14C、 15N、 18O、 17O、 35S、 18F、 36Cl和 131I等。本发明的化合物，其立体异构体、互变异构体或医药上可接受的盐，以及含有上述同位素和/或其他原子同位素的所述以上形式的化合物，均在本发明范围内。某些同位素标记的本发明化合物，如被 3H或 14C所标记的那些化合物可以用于药物组织分布试验中，因此，这些 3H或 14C同位素由于其容易制备和检测是特别优选的。此外，被较重的同位素如 2H所替代的某些本发明化合物由于具有更好的代谢稳定性而具有某些治疗优势，如可以增加体内半衰期和较少剂量等，因此， 2H在某些情况下也是优选的。同位素标记的本发明式(I)化合物及其前 提药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。 The invention also includes isotopically-labeled compounds of the invention, i.e., identical to those disclosed above, but in which one or more atoms are replaced by an atom having the same number of protons but a different number of neutrons. Examples of isotopes incorporating compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl and 131 I, etc. The compounds of the present invention, their stereoisomers, tautomers or pharmaceutically acceptable salts, as well as the compounds of the above forms containing the above isotopes and/or other atomic isotopes, are within the scope of the invention. Certain isotopically-labeled compounds of the invention, such as those labeled with 3 H or 14 C, can be used in drug tissue distribution assays, and therefore, these 3 H or 14 C isotopes are particularly preferred for their ease of preparation and detection. In addition, certain compounds of the invention that are replaced by heavier isotopes such as 2 H have certain therapeutic advantages due to better metabolic stability, such as increased in vivo half-life and lower doses, etc., therefore, 2 H is in some It is also preferred in some cases. Isotopically labeled compounds of the formula (I) according to the invention and their presuppositions can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopic labels when carrying out the processes disclosed in the following schemes and/or examples and preparations. Reagents.
本发明的另一方面涉及一种药物组合物，其含有治疗有效量的通式(I)-(II)所述的化合物，或其药学上可接受的载体、稀释剂或赋形剂。Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I)-(II), or a pharmaceutically acceptable carrier, diluent or excipient thereof.
本发明进一步涉及通式(I)-(II)所述的化合物或其可药用的盐，或包含其的药物组合物在制备用于预防和/或治疗具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物中的用途。具有IDO介导的色氨酸代谢途径病理学特征的疾病选自癌症、骨髓增生异常综合征、自身免疫性疾病、阿尔兹海默症、抑郁症、精神***症、焦虑症、心理障碍、神经病变和疼痛、白内障、艾滋病和肺炎，其中所述的癌症优选自***癌、乳腺癌、***、子宫内膜癌、结肠癌、胃癌、肺癌、肝癌、膀胱癌、胰腺癌、直肠癌、皮肤癌(包括黑色素瘤和基底细胞癌)、口腔癌、骨癌、卵巢癌、脑癌、头颈部癌、间皮内膜癌、白血病、淋巴瘤、食管癌、肾癌、甲状腺癌、骨髓瘤、绒毛膜癌、睾丸癌、神经胶质瘤、母神经胶质瘤、输卵管肿瘤。The invention further relates to a compound of the formula (I)-(II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same for use in the prevention and/or treatment of IDO-mediated tryptophan metabolism The use of a pathway for the pathology of a drug in a disease. The disease having the pathological characteristics of the IDO-mediated tryptophan metabolism pathway is selected from the group consisting of cancer, myelodysplastic syndrome, autoimmune disease, Alzheimer's disease, depression, schizophrenia, anxiety, psychological disorder, nerve Lesions and pain, cataracts, AIDS and pneumonia, wherein the cancer is preferably selected from prostate cancer, breast cancer, cervical cancer, endometrial cancer, colon cancer, stomach cancer, lung cancer, liver cancer, bladder cancer, pancreatic cancer, rectal cancer, and skin. Cancer (including melanoma and basal cell carcinoma), oral cancer, bone cancer, ovarian cancer, brain cancer, head and neck cancer, mesothelioma, leukemia, lymphoma, esophageal cancer, kidney cancer, thyroid cancer, myeloma , choriocarcinoma, testicular cancer, glioma, maternal glioma, fallopian tube tumor.
本发明还涉及一种治疗预防和/或治疗预防具有IDO介导的色氨酸代谢途径病理学特征的疾病的方法，其包括向患者施用治疗有效量的通式(I)-(II)所述的化合物或其可药用的盐，或包含其的药物组合物，其中所述具有IDO介导的色氨酸代谢途径病理学特征的疾病选自癌症、骨髓增生异常综合征、自身免疫性疾病、阿尔兹海默症、抑郁症、精神***症、焦虑症、心理障碍、神经病变和疼痛、白内障、艾滋病和肺炎。The present invention also relates to a method of treating a disease preventing and/or treating a disease having an IDO-mediated pathology of a tryptophan metabolism pathway comprising administering to a patient a therapeutically effective amount of the formula (I)-(II) The compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolic pathway is selected from the group consisting of cancer, myelodysplastic syndrome, autoimmune Disease, Alzheimer's disease, depression, schizophrenia, anxiety, psychological disorders, neuropathy and pain, cataracts, AIDS and pneumonia.
本发明还涉及一种治疗预防和/或治疗预防具有IDO介导的色氨酸代谢途径病理学特征的疾病的方法，其包括向患者施用治疗有效量的通式(I)-(II)所述的化合物或其可药用的盐，或包含其的药物组合物，其中所述具有IDO介导的色氨酸代谢途径病理学特征的疾病选自癌症，其中所述的癌症选自***癌、乳腺癌、***、子宫内膜癌、结肠癌、胃癌、肺癌、肝癌、膀胱癌、胰腺癌、直肠癌、皮肤癌(包括黑色素瘤和基底细胞癌)、口腔癌、骨癌、卵巢癌、脑癌、头颈部癌、间皮内膜癌、白血病、淋巴瘤、食管癌、肾癌、甲状腺癌、骨髓瘤、绒毛膜癌、睾丸癌、神经胶质瘤、母神经胶质瘤、输卵管肿瘤。The present invention also relates to a method of treating a disease preventing and/or treating a disease having an IDO-mediated pathology of a tryptophan metabolism pathway comprising administering to a patient a therapeutically effective amount of the formula (I)-(II) The compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolic pathway is selected from the group consisting of cancer, wherein the cancer is selected from the group consisting of prostate cancer , breast cancer, cervical cancer, endometrial cancer, colon cancer, stomach cancer, lung cancer, liver cancer, bladder cancer, pancreatic cancer, rectal cancer, skin cancer (including melanoma and basal cell carcinoma), oral cancer, bone cancer, ovarian cancer , brain cancer, head and neck cancer, mesothelioma, leukemia, lymphoma, esophageal cancer, kidney cancer, thyroid cancer, myeloma, choriocarcinoma, testicular cancer, glioma, maternal glioma, Tubal tumors.
化合物或中间体制备方法Compound or intermediate preparation method
为描述本发明，以下列出了具体实施例。但需要理解，本发明不限于这些实施例，以下实施例只是提供实践本发明的方法，并不以任何方式限制本发明 的范畴。For the purpose of describing the invention, specific embodiments are set forth below. However, it is to be understood that the invention is not limited to the embodiments, and the following examples are merely intended to provide a method of practicing the invention and are not intended to limit the scope of the invention.
本发明提供的化合物可以通过本领域公知的标准合成方法来制备，本说明书提供了制备本发明化合物的一般方法。起始原料通常可通过商业化获得，例如通过Alfa
Figure PCTCN2018121873-appb-000007
TCI、
Figure PCTCN2018121873-appb-000008
韶远化学、安耐吉化学、爱斯特(成都)生物制药、成都贝斯特试剂、成都华娜化学制剂有限公司、艾琪康药科技(上海)有限公司、上海瀚香生物科技有限公司和上海药明康德新药开发有限公司等公司购买得到，或者通过本领域技术人员所熟知的方法进行制备。 The compounds provided herein can be prepared by standard synthetic methods well known in the art, and the present specification provides general methods for preparing the compounds of the invention. Starting materials are usually commercially available, for example by Alfa
Figure PCTCN2018121873-appb-000007
TCI,
Figure PCTCN2018121873-appb-000008
Suiyuan Chemical, An Naiji Chemical, Ester (Chengdu) Biopharmaceutical, Chengdu Best Reagent, Chengdu Huana Chemical Preparation Co., Ltd., Aiqi Kang Pharmaceutical Technology (Shanghai) Co., Ltd., Shanghai Yuxiang Biotechnology Co., Ltd. It is commercially available from companies such as Shanghai WuXi PharmaTech Development Co., Ltd. or by methods well known to those skilled in the art.
下述反应方法及合成步骤提供了用于合成本发明化合物以及关键中间体的可能途径。关于个别反应步骤的更详细说明，参见下述实施例。本领域技术人员应理解，本发明化合物也可以通过其它的合成途径获得。虽然下文反应流程中使用了特定的起始原料和试剂，但是这些起始原料和试剂可以被其它类似的起始原料或试剂所取代，以提供各种衍生物。此外，在本说明书的指导下，通过下述方法制得的许多化合物可以通过本领域技术人员所熟知的常规化学方法进行进一步修饰。The following reaction methods and synthetic procedures provide possible routes for the synthesis of the compounds of the invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the examples below. Those skilled in the art will appreciate that the compounds of the invention may also be obtained by other synthetic routes. While specific starting materials and reagents are used in the reaction schemes below, these starting materials and reagents can be replaced by other similar starting materials or reagents to provide various derivatives. Furthermore, many of the compounds produced by the methods described below can be further modified by conventional chemical methods well known to those skilled in the art under the teachings of the present specification.
下文通过实施例与制备进一步解释并列举本发明化合物及相应的制备方法。应了解，尽管具体实施例中给出了典型或优选的反应条件(如反应温度、时间、反应物的摩尔比、反应溶剂以及压力等)，但是本领域技术人员也可以使用其它反应条件。最佳反应条件可随所用的特定反应底物或溶剂而发生改变，但所述条件可由所属领域的技术人员通过常规优化而确定。The compounds of the invention and the corresponding methods of preparation are further explained and exemplified below by way of examples and preparations. It will be appreciated that while typical or preferred reaction conditions (e.g., reaction temperature, time, molar ratio of reactants, reaction solvent, and pressure, etc.) are given in the specific examples, other reaction conditions can be used by those skilled in the art. Optimum reaction conditions may vary depending on the particular reaction substrate or solvent employed, but such conditions can be determined by one of ordinary skill in the art by routine optimization.
反应起始原料、中间体以及实施例化合物可以通过沉淀、过滤、结晶、蒸发、蒸馏以及色谱法(如柱层析法、TLC分离纯化等)等常规技术进行分离与纯化。The reaction starting materials, intermediates, and example compounds can be isolated and purified by conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography (e.g., column chromatography, TLC separation, etc.).
TLC使用烟台黄海HSGF254薄层层析硅胶板(0.2±0.03mm)，TLC分离纯化使用烟台黄海HSGF254薄层层析厚制备板(0.9～1mm)，均购自青岛海洋化工厂。TLC was extracted from Yantai Huanghai HSGF254 thin-layer chromatography silica gel plate (0.2±0.03 mm) by TLC. The Yantai Yellow Sea HSGF254 thin layer chromatography thick preparation plate (0.9-1 mm) was purchased from Qingdao Ocean Chemical Plant.
柱层析以烟台黄海300～400目硅胶为载体，购自青岛海洋化工厂。Column chromatography was purchased from Qingdao Ocean Chemical Plant using Yantai Yellow Sea 300-400 mesh silica gel as carrier.
试验中使用的商品化溶剂及试剂如无特殊说明，购买后均无需进一步纯化或处理直接使用。参考其它实施例或合成方法时，反应条件(反应温度、反应溶剂、反应物摩尔比或/和反应持续时间)可能不同。一般而言，可通过TLC监测反应进程，据此选择合适的时间终止反应并进行后处理。化合物的纯化条件 也可能发生变化，一般而言，依据TLC的R f值选择合适的柱层析洗脱剂，或通过制备TLC分离纯化相应化合物。 The commercial solvents and reagents used in the test are used without any further explanation after purchase and without further purification or treatment. The reaction conditions (reaction temperature, reaction solvent, reactant molar ratio or/and reaction duration) may be different with reference to other examples or synthetic methods. In general, the progress of the reaction can be monitored by TLC, and the appropriate time is selected to terminate the reaction and post-treat. The purification conditions of the compound may also vary. In general, the appropriate column chromatography eluent is selected according to the Rf value of TLC, or the corresponding compound is isolated and purified by preparative TLC.
本发明式(I)化合物可以按照以下流程1加以制备。A和B缩合得到式(I)化合物，该反应一般使用缩合剂，如CDI、EDCI、DIC、DCC、HATU、HBTU、PyBOP等。应了解，这些反应条件并不是限制性的，所述的方法能够通过合理变化反应条件用于制备式(I)化合物。其中R 1、R 2、R 3和R 4具有如本发明所述的定义。 The compound of the formula (I) of the present invention can be produced according to the following Scheme 1. The condensation of A and B gives the compound of formula (I), which typically employs a condensing agent such as CDI, EDCI, DIC, DCC, HATU, HBTU, PyBOP, and the like. It will be appreciated that these reaction conditions are not limiting and that the process can be used to prepare compounds of formula (I) by rationally varying the reaction conditions. Wherein R 1 , R 2 , R 3 and R 4 have the definitions as described in the present invention.
流程1Process 1
Figure PCTCN2018121873-appb-000009
Figure PCTCN2018121873-appb-000009
本发明式(I)化合物可以按照以下流程2加以制备。A与氯化亚砜在合适的溶剂如二氯甲烷中，反应得到中间体C。中间体C和B在碱，如吡啶、三乙胺、二异丙基乙胺、DBU等存在下，在合适的溶剂，如二氯甲烷、四氢呋喃、N，N-二甲基甲酰胺、二氧六环等中，反应得到式(I)化合物。应了解，这些反应条件并不是限制性的，所述的方法能够通过合理变化反应条件用于制备式(I)化合物。其中R 1、R 2、R 3和R 4具有如本发明所述的定义。 The compound of the formula (I) of the present invention can be produced according to the following Scheme 2. Reaction of A with thionyl chloride in a suitable solvent such as dichloromethane affords intermediate C. Intermediates C and B in the presence of a base such as pyridine, triethylamine, diisopropylethylamine, DBU, etc. in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, In the hexacyclic or the like, the reaction gives a compound of the formula (I). It will be appreciated that these reaction conditions are not limiting and that the process can be used to prepare compounds of formula (I) by rationally varying the reaction conditions. Wherein R 1 , R 2 , R 3 and R 4 have the definitions as described in the present invention.
流程2Process 2
Figure PCTCN2018121873-appb-000010
Figure PCTCN2018121873-appb-000010
下列实施例打算阐述特定的发明实施方式，决不打算限制本发明说明书或权利要求书的范围。本领域技术人员将认可的是，原料可以不同，可以采用额外步骤来生成本发明涵盖的化合物，正如下列实施例所证明的。下列实施例仅供阐述目的，既不打算、也不应当以任意方式被解释为限制发明。本领域技术人员将认识到的是，可以进行变化和修改，而不违背本发明的精神或范围。The following examples are intended to illustrate the specific embodiments of the invention, and are not intended to limit the scope of the invention. Those skilled in the art will recognize that the starting materials may vary and additional steps may be employed to generate the compounds encompassed by the present invention, as demonstrated by the following examples. The following examples are for illustrative purposes only and are not intended to be construed as limiting the invention in any way. A person skilled in the art will recognize that variations and modifications can be made without departing from the spirit or scope of the invention.
实施例1、制备化合物1Example 1. Preparation of Compound 1
Figure PCTCN2018121873-appb-000011
Figure PCTCN2018121873-appb-000011
将(R)-2-((1S,4S)-4-(6-氟喹啉-4-基)环己基)丙酸(制备方法参考WO2016073774A2)30mg、5mL二氯甲烷加入至干燥的反应瓶中，搅拌下加入1ml二氯亚砜，再升至40℃反应1小时。减压浓缩至干后冷至室温，向浓缩物中依次加入1.2当量4-(2-甲氧基乙氧基)苯胺，5mL二氯甲烷，0.5mL吡啶，室温搅拌反应30分钟，TLC监测。反应完全后，加入二氯甲烷、水萃取分层，有机层用无水硫酸钠干燥，过滤，减压浓缩至干，柱层析纯化(先用EA:PE＝1：1洗脱，再用EA洗脱)得化合物1 25mg。 1H NMR(CDCl 3,400MHz,ppm):δ＝8.80-8.78(d,J＝4.5Hz,1H),8.13-8.09(m,1H),7.66-7.63(dd,J＝10.5,2.5Hz,1H),7.53(s,1H),7.46-7.44(m,3H),7.32-7.30(d,J＝4.4Hz,1H),6.89-6.87(m,2H),4.10-4.08(m,2H),3.74-3.70(m,2H),3.44(s,3H),3.29(br s,1H),2.62-2.57(m,1H),2.14-2.11(m,1H),1.93-1.78(m,7H),1.70-1.62(m,1H),1.28-1.26(d,J＝6.8Hz,3H).ESI MS(M+H) +＝451.3. Add (R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propionic acid (preparation method reference WO2016073774A2) 30mg, 5mL dichloromethane to the dry reaction bottle The mixture was added with 1 ml of thionyl chloride under stirring, and further raised to 40 ° C for 1 hour. After concentration under reduced pressure to dryness and then cooled to room temperature, to the concentrate was added to the residue, then, toluene, toluene, toluene (5 eq. After the reaction is completed, the mixture is separated by dichloromethane and water, and the organic layer is dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to dryness and purified by column chromatography eluting with EA:PE=1:1 EA elution) gave compound 1 25 mg. 1 H NMR (CDCl 3 , 400 MHz, ppm): δ = 8.80 - 8.78 (d, J = 4.5 Hz, 1H), 8.13 - 8.09 (m, 1H), 7.66 - 7.63 (dd, J = 10.5, 2.5 Hz, 1H), 7.53 (s, 1H), 7.46-7.44 (m, 3H), 7.32-7.30 (d, J = 4.4 Hz, 1H), 6.89-6.87 (m, 2H), 4.10-4.08 (m, 2H) , 3.74-3.70 (m, 2H), 3.44 (s, 3H), 3.29 (br s, 1H), 2.62-2.57 (m, 1H), 2.14-2.11 (m, 1H), 1.93-1.78 (m, 7H) ), 1.70-1.62 (m, 1H), 1.28-1.26 (d, J = 6.8 Hz, 3H). ESI MS (M+H) + = 451.3.
实施例2、制备化合物2Example 2, Preparation of Compound 2
Figure PCTCN2018121873-appb-000012
Figure PCTCN2018121873-appb-000012
本发明化合物参照流程2的方法合成，得到化合物2。ESI-MS m/z：465.2[M+H] +。 The compound of the present invention was synthesized by the method of Scheme 2 to give Compound 2. ESI-MS m/z: 465.2 [M+H] + .
生物测试Biological test
1.化合物对IDO抑制活性测试1. Compound test for IDO inhibition activity
HeLa细胞购自ATCC，在含L－谷氨酰胺(2mM)、非必需氨基酸(84mg/L)和胎牛血清(10％FBS)的DMEM中培养于95％湿度，5％CO 2，37℃培养箱。测试前一天，将连续传代，生长良好，90％以上融合的Hela细胞用EDTA/胰蛋白酶消化后，重悬于DMEM完全培养基，按5000/孔的密度，接种在96孔培养板中，并培养过夜。第二天，更换96孔板细胞培养基，在每孔加入200μl含IFN-γ(终浓度50ng/mL，购自R&D)和系列稀释浓度的化合物培养基。化合物最高浓度1000nM，按5倍稀释7个浓度梯度。培养板放回细胞培养箱继续孵育48h后，将150μl上清液/孔移至新的96孔板中，每孔加入7.5μl三氯乙酸，混匀后在50℃温育30min使产生的N-甲酰基犬尿氨酸水解为犬尿氨酸。然后以12000rpm离心10分钟去除沉淀物。上清以液相/三重四级杆质谱(LC/MS/MS，LC-20AD高效液相色谱***，日本岛津；API4000三重四极杆质谱仪，美国Applied Biosystem)分析L-犬尿氨酸浓度。以2－5000ng/ml浓度梯度L-犬尿氨酸建立标准曲线；测得细胞培养上清液中L-犬尿氨酸浓度以origin7.5拟合计算各化合物抑制IDO的活性/(生成犬尿氨酸的IC 50)。 HeLa cells were purchased from ATCC and cultured in DMEM containing L-glutamine (2 mM), non-essential amino acids (84 mg/L) and fetal bovine serum (10% FBS) at 95% humidity, 5% CO 2 , 37 ° C. Incubator. One day before the test, the cells were continuously passaged and grown well. More than 90% of the fused Hela cells were digested with EDTA/trypsin, resuspended in DMEM complete medium, and seeded in 96-well culture plates at a density of 5000/well. Cultivate overnight. On the next day, 96-well plate cell culture medium was replaced, and 200 μl of IFN-γ (final concentration 50 ng/mL, purchased from R&D) and serial dilutions of the compound medium were added to each well. The highest concentration of the compound was 1000 nM, and 7 concentration gradients were diluted 5 times. After the culture plate was returned to the cell culture incubator for 48 hours, 150 μl of the supernatant/well was transferred to a new 96-well plate, 7.5 μl of trichloroacetic acid was added to each well, and the mixture was incubated at 50 ° C for 30 min to produce N. - Formyl kynurenine is hydrolyzed to kynurenine. The precipitate was then removed by centrifugation at 12000 rpm for 10 minutes. The supernatant was analyzed by liquid/triple quadrupole mass spectrometry (LC/MS/MS, LC-20AD high performance liquid chromatography system, Shimadzu, Japan; API4000 triple quadrupole mass spectrometer, Applied Biosystem, USA) for analysis of L-kynurenine concentration. A standard curve was established with a concentration gradient of 2-5000 ng/ml L-kynurenine; the concentration of L-kynurenine in the cell culture supernatant was measured to calculate the activity of each compound to inhibit IDO by fitting with original 7.5. IC 50 of uridine;
将化合物对Hela细胞内IDO1的抑制活性测试结果列于表1中。The test results of the inhibitory activity of the compound against IDO1 in HeLa cells are shown in Table 1.
Figure PCTCN2018121873-appb-000013
Figure PCTCN2018121873-appb-000013
测试结果表明本发明化合物对Hela细胞内IDO1具有显著优于BMS-986205的抑制作用。The test results indicate that the compound of the present invention has a significantly better inhibitory effect on IDO1 in Hela cells than BMS-986205.

Claims (10)

  1. 一种式(I)化合物：A compound of formula (I):
    Figure PCTCN2018121873-appb-100001
    Figure PCTCN2018121873-appb-100001
    其药学上可接受的盐、水合物、溶剂化物或立体异构体，其中：a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:
    L为键、-C 1-4烷基； L is a bond, -C 1-4 alkyl;
    R 1为-O-C 1-4烷基、
    Figure PCTCN2018121873-appb-100002
    R 1 is -OC 1-4 alkyl,
    Figure PCTCN2018121873-appb-100002
    R 5和R 6分别独立地为-C 1-4烷基； R 5 and R 6 are each independently -C 1-4 alkyl;
    X选自O或S；X is selected from O or S;
    R 2选自氢、氘、卤素、-C 1-6烷基、-C 2-6烯基、-C 2-6炔基、-CN、-CF 3、-CHF 2、-OCF 3、-NH 2、-NO 2，其中烷基、烯基和炔基可被选自卤素、-C 1-4烷基的取代基取代； R 2 is selected from the group consisting of hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -CF 3 , -CHF 2 , -OCF 3 , - NH 2 , —NO 2 , wherein the alkyl, alkenyl and alkynyl groups may be substituted by a substituent selected from halogen, —C 1-4 alkyl;
    R 3和R 4分别独立地为氢、卤素、-C 1-6烷基、-C 2-6烯基、-C 2-6炔基、-C 3-6环烷基；或者， R 3 and R 4 are each independently hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl; or
    R 3和R 4和与其相连的碳原子一起形成3-6元环烷基、3-6元杂环烷基，其中，环烷基和杂环烷基可被C 1-4烷基取代。 R 3 and R 4 together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, wherein the cycloalkyl group and the heterocycloalkyl group may be substituted by a C 1-4 alkyl group.
  2. 如权利要求1所述的化合物，其药学上可接受的盐、水合物、溶剂化物或立体异构体，其中所述化合物如式(II)所示：A compound, a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, according to claim 1, wherein the compound is as shown in formula (II):
    Figure PCTCN2018121873-appb-100003
    Figure PCTCN2018121873-appb-100003
    L为键、-C 1-4烷基； L is a bond, -C 1-4 alkyl;
    R 1为-O-C 1-4烷基、
    Figure PCTCN2018121873-appb-100004
    R 1 is -OC 1-4 alkyl,
    Figure PCTCN2018121873-appb-100004
    R 5和R 6分别独立地为-C 1-4烷基； R 5 and R 6 are each independently -C 1-4 alkyl;
    R 2选自氢、氘、卤素、-C 1-6烷基、-C 2-6烯基、-C 2-6炔基、-CN、-CF 3、-CHF 2、-OCF 3、-NH 2、-NO 2。 R 2 is selected from the group consisting of hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -CF 3 , -CHF 2 , -OCF 3 , - NH 2 , -NO 2 .
  3. 如权利要求2所述的化合物，其药学上可接受的盐、水合物、溶剂化物或立体异构体，其中：A compound according to claim 2, which is a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:
    L为键、-C 1-4烷基； L is a bond, -C 1-4 alkyl;
    R 1为-O-C 1-4烷基、
    Figure PCTCN2018121873-appb-100005
    R 1 is -OC 1-4 alkyl,
    Figure PCTCN2018121873-appb-100005
    R 5和R 6分别独立地为-C 1-4烷基； R 5 and R 6 are each independently -C 1-4 alkyl;
    R 2选自氢、氘、卤素。 R 2 is selected from the group consisting of hydrogen, helium, and halogen.
  4. 如权利要求3所述的化合物，其药学上可接受的盐、水合物、溶剂化物或立体异构体，其中：A compound according to claim 3, which is a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:
    L为键、-CH 2-CH 2-； L is a bond, -CH 2 -CH 2 -;
    R 1选自以下结构： R 1 is selected from the following structures:
    Figure PCTCN2018121873-appb-100006
    Figure PCTCN2018121873-appb-100006
    R 2选自氟。 R 2 is selected from fluorine.
  5. 如权利要求1至4中任一项所述的化合物，其药学上可接受的盐、水合物、溶剂化物或立体异构体，其选自：A compound, a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, according to any one of claims 1 to 4, which is selected from the group consisting of:
    Figure PCTCN2018121873-appb-100007
    Figure PCTCN2018121873-appb-100007
  6. 一种药物组合物，其含有治疗有效量的根据权利要求1-5中任意一项所 述的化合物，或其药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable carrier, diluent or excipient thereof.
  7. 根据权利要求1-5中任意一项所述的化合物或其可药用的盐或根据权利要求6所述的药物组合物在制备用于预防和/或治疗具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物中的用途。The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 6, prepared for the prevention and/or treatment of IDO-mediated tryptophan metabolism The use of a pathway for the pathology of a drug in a disease.
  8. 根据权利要求7中的用途，其中所述具有IDO介导的色氨酸代谢途径病理学特征的疾病选自癌症、骨髓增生异常综合征、自身免疫性疾病、阿尔兹海默症、抑郁症、精神***症、焦虑症、心理障碍、神经病变和疼痛、白内障、艾滋病和肺炎，其中所述的癌症优选自***癌、乳腺癌、***、子宫内膜癌、结肠癌、胃癌、肺癌、肝癌、膀胱癌、胰腺癌、直肠癌、皮肤癌(包括黑色素瘤和基底细胞癌)、口腔癌、骨癌、卵巢癌、脑癌、头颈部癌、间皮内膜癌、白血病、淋巴瘤、食管癌、肾癌、甲状腺癌、骨髓瘤、绒毛膜癌、睾丸癌、神经胶质瘤、母神经胶质瘤、输卵管肿瘤。The use according to claim 7, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolism pathway is selected from the group consisting of cancer, myelodysplastic syndrome, autoimmune disease, Alzheimer's disease, depression, Schizophrenia, anxiety, psychological disorders, neuropathy and pain, cataracts, AIDS and pneumonia, wherein the cancer is preferably selected from prostate cancer, breast cancer, cervical cancer, endometrial cancer, colon cancer, stomach cancer, lung cancer, liver cancer , bladder cancer, pancreatic cancer, rectal cancer, skin cancer (including melanoma and basal cell carcinoma), oral cancer, bone cancer, ovarian cancer, brain cancer, head and neck cancer, mesothelioma, leukemia, lymphoma, Esophageal cancer, renal cancer, thyroid cancer, myeloma, choriocarcinoma, testicular cancer, glioma, maternal glioma, fallopian tube tumor.
  9. 一种治疗预防和/或治疗预防具有IDO介导的色氨酸代谢途径病理学特征的疾病的方法，其包括向患者施用治疗有效量的权利要求1-5中任意一项所述的化合物或其可药用盐或根据权利要求6所述的药物组合物，其中所述具有IDO介导的色氨酸代谢途径病理学特征的疾病选自癌症、骨髓增生异常综合征、自身免疫性疾病、阿尔兹海默症、抑郁症、精神***症、焦虑症、心理障碍、神经病变和疼痛、白内障、艾滋病和肺炎。A method of treating a disease which prevents and/or treats a disease having a pathological feature of an IDO-mediated tryptophan metabolism pathway, comprising administering to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 5 or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolism pathway is selected from the group consisting of cancer, myelodysplastic syndrome, autoimmune disease, Alzheimer's disease, depression, schizophrenia, anxiety, psychological disorders, neuropathy and pain, cataracts, AIDS and pneumonia.
  10. 一种治疗预防和/或治疗预防具有IDO介导的色氨酸代谢途径病理学特征的疾病的方法，其包括向患者施用治疗有效量的权利要求1-5中任意一项所述的化合物或其可药用盐或根据权利要求6所述的药物组合物，其中所述具有IDO介导的色氨酸代谢途径病理学特征的疾病选自癌症，其中所述的癌症选自***癌、乳腺癌、***、子宫内膜癌、结肠癌、胃癌、肺癌、肝癌、膀胱癌、胰腺癌、直肠癌、皮肤癌(包括黑色素瘤和基底细胞癌)、口腔癌、骨癌、卵巢癌、脑癌、头颈部癌、间皮内膜癌、白血病、淋巴瘤、食管癌、肾癌、甲状腺癌、骨髓瘤、绒毛膜癌、睾丸癌、神经胶质瘤、母神经胶质瘤、输卵管肿瘤。A method of treating a disease which prevents and/or treats a disease having a pathological feature of an IDO-mediated tryptophan metabolism pathway, comprising administering to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 5 or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolic pathway is selected from the group consisting of cancer, wherein the cancer is selected from the group consisting of prostate cancer, breast Cancer, cervical cancer, endometrial cancer, colon cancer, stomach cancer, lung cancer, liver cancer, bladder cancer, pancreatic cancer, rectal cancer, skin cancer (including melanoma and basal cell carcinoma), oral cancer, bone cancer, ovarian cancer, brain Cancer, head and neck cancer, mesothelioma, leukemia, lymphoma, esophageal cancer, kidney cancer, thyroid cancer, myeloma, choriocarcinoma, testicular cancer, glioma, maternal glioma, fallopian tube tumor .
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WO2003099266A2 (en) * 2002-05-23 2003-12-04 Abbott Laboratories Acetamides and benzamides that are useful in treating sexual dysfunction
CN106999450A (en) * 2014-11-05 2017-08-01 弗莱塞斯生物科学公司 immunomodulator
CN107427499A (en) * 2014-11-05 2017-12-01 弗莱塞斯生物科学公司 Immunomodulator

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003099266A2 (en) * 2002-05-23 2003-12-04 Abbott Laboratories Acetamides and benzamides that are useful in treating sexual dysfunction
CN106999450A (en) * 2014-11-05 2017-08-01 弗莱塞斯生物科学公司 immunomodulator
CN107427499A (en) * 2014-11-05 2017-12-01 弗莱塞斯生物科学公司 Immunomodulator

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