CN109928924A - One kind is used as IDO inhibitor - Google Patents

One kind is used as IDO inhibitor Download PDF

Info

Publication number
CN109928924A
CN109928924A CN201711359879.9A CN201711359879A CN109928924A CN 109928924 A CN109928924 A CN 109928924A CN 201711359879 A CN201711359879 A CN 201711359879A CN 109928924 A CN109928924 A CN 109928924A
Authority
CN
China
Prior art keywords
cancer
alkyl
carcinoma
disease
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201711359879.9A
Other languages
Chinese (zh)
Inventor
张磊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chengdu Huajian Future Technology Co Ltd
Original Assignee
Chengdu Huajian Future Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chengdu Huajian Future Technology Co Ltd filed Critical Chengdu Huajian Future Technology Co Ltd
Priority to CN201711359879.9A priority Critical patent/CN109928924A/en
Priority to PCT/CN2018/121870 priority patent/WO2019120199A1/en
Publication of CN109928924A publication Critical patent/CN109928924A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Hematology (AREA)
  • Rheumatology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Hospice & Palliative Care (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to a kind of quinolyl-4 cyclohexanes compounds, its pharmaceutically acceptable salt, hydrate, solvate or stereoisomer, and preparation method thereof and such compound individually or with other drugs be used in combination treatment have IDO mediate tryptophan metabolic pathway pathological characteristics disease.

Description

One kind is used as IDO inhibitor
Technical field
The present invention relates to a kind of quinolyl-4 cyclohexanes compound, pharmaceutically acceptable salt, hydrate, solvents Compound or stereoisomer, and preparation method thereof and such compound be used in combination individually or with other drugs and have in treatment The disease for the tryptophan metabolic pathway pathological characteristics that IDO is mediated.
Background technique
Tryptophan is a kind of amino acid needed by human.The tryptophan obtained from diet, a part are used to synthetic proteins Matter and neurotransmitter serotonin, rest part are then mainly carried out by kynurenine pathway (kynurenine pathway) Metabolism.Indole amine 2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme for being catalyzed tryptophan and being metabolized along kynurenine pathway.When tissue is thin In born of the same parents, when IDO1 expression is high, a large amount of tryptophans are metabolized through kynurenine metabolism pathway, and tryptophane reduces, and are directly pressed down The activation and increment of effector T cell are made.And the metabolite that kynurenine pathway generates is to immune, reproduction and central nervous system System has a certain impact, in addition to the energy directly survival of depression effect T cell, also by the differentiation for promoting regulatory T cells Depression effect T cell.Studies have shown that the full uric acid metabolism approach of tryptophan is to cause tumour cell that the important of immunologic escape occurs Reason.
Recent studies have indicated that the formation for the Kynurenine metabolism that IDO is mediated is also related to other diseases.Such as kynurenin Approach and myelodysplastic syndrome (Leuk Res.2013；37(5):573-9)；Neurodegenerative disease, 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)；It inflammation and loses Mass formed by blood stasis (Nat.Med 2010；16(3):279-85)；AIDS (PLoS One.2013；8(9):e74551)；Etc. related.
Lot of experimental data shows that IDO inhibitor has treatment and prevention effect in a variety of disease areas such as tumour, has Good application prospect, but existing IDO inhibitor shows the deficient validity in clinical trial or has dose limiting toxicity, This field needs to develop Novel IDO inhibitor.
Summary of the invention
The purpose of the present invention is to provide a kind of formula (I) compound represented or its pharmaceutically acceptable salt, hydrate, Solvate or stereoisomer,
Wherein:
R1For-S-C1-6Alkyl；-S(O)-C1-6Alkyl；-S(O2)-C1-6Alkyl；
X is selected from O or S；
R2Selected from hydrogen, deuterium, halogen, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl ,-CN ,-CF3、-CHF2、-OCF3、-NH2、- NO2, wherein alkyl, alkenyl and alkynyl can be selected from halogen, C1-4The substituent group of alkyl replaces；
R3And R4It is separately hydrogen, halogen, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-6Naphthenic base；Alternatively,
R3And R43-6 member naphthenic base, 3-6 membered heterocycloalkyl are formed together with coupled carbon atom, wherein naphthenic base It can be by C with Heterocyclylalkyl1-4Alkyl replaces.
On the other hand, the present invention is supplied to formula (II) compound,
Wherein,
R1For-S-C1-6Alkyl；-S(O)-C1-6Alkyl；-S(O2)-C1-6Alkyl；
R2Selected from hydrogen, deuterium, halogen, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl ,-CN ,-CF3、-CHF2、-OCF3、-NH2、- NO2。
In further embodiment, the present invention provides formula (II) compound, pharmaceutically acceptable salt, hydration Object, solvate or stereoisomer, in which:
R1Selected from flowering structure:
R3Selected from fluorine.
The present invention relates to formula (I)-formula (II) typical compound is as shown in table 1, but it is not limited to following embodiment:
Table 1
Definition
As used above and elsewhere in this article, following term and abbreviation have meaning defined below.As undefined, Then all technical and scientific terms used in this specification all have the meaning that those of ordinary skill in the art are generally understood.
Abbreviation Meaning
IDO Indole amine 2,3-dioxygenase
TLC Thin-layer chromatography
Rf Rf value
CDI Carbonyl dimidazoles
EDCI 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride
DIC N, N'- diisopropylcarbodiimide
DCC Dicyclohexylcarbodiimide
HATU 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester
HBTU Benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester
PyBOP 1H- benzotriazole -1- base oxygen tripyrrole alkyl hexafluorophosphate
MS Mass spectrum
Term " hydrogen " in this article refers to-H.
Term " deuterium " in this article refers to-D.
Term " halogen " in this article refers to-F ,-Cl ,-Br and-I.
Term " alkyl " is in this article referred to without containing heteroatomic alkyl.Therefore, which includes straight chained alkyl such as first Base, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl etc..The term is also Branched isomer including branched alkyl, including but not limited to for example following group :-CH (CH3)2、-CH(CH3) (CH2CH3)、-CH(CH2CH3)2、-C(CH3)3、-C(CH2CH3)3、-CH2CH(CH3)2、-CH2CH(CH3)(CH2CH3)、-CH2CH (CH2CH3)2、-CH2C(CH3)3、-CH2C(CH2CH3)3、-CH(CH3)-CH(CH3)(CH2CH3)、-CH2CH2CH(CH3)2、- CH2CH2CH(CH3)(CH2CH3)、-CH2CH2CH(CH2CH3)2、-CH2CH2C(CH3)3、-CH2CH2C(CH2CH3)3、-CH(CH3) CH2CH(CH3)2、-CH(CH3)CH(CH3)CH(CH3)2、-CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3) etc..Therefore term Alkyl includes primary alkyl, secondary alkyl and tertiary alkyl.
Term " alkenyl " in this article refers to wherein have at least one unsaturation, that is, two of them adjacent carbon atom is logical It crosses double bond and connects alkyl as defined above, wherein the alkyl is as defined herein
Term " alkynyl " in this article refers to be related to the alkyl that two of them adjacent carbon atom passes through three key connections, wherein institute It is as defined herein to state alkyl.
Term " naphthenic base " refers to monocycle or polycyclic free radical, only contains carbon and hydrogen, and is optionally saturation , part is unsaturated or completely unsaturated.According to structure, group of naphthene base is single free radical or diradical (example Such as, ring alkylidene group).
Term " Heterocyclylalkyl " in this article refers to the hetero atom that at least one is selected from O, N and S and optionally contains one Or a plurality of double or triple bonds non aromatic cycloalkyl.Heterocyclylalkyl can have 3-14 annular atom as a whole and contain 1-5 A hetero atom (such as with 3-6 annular atom for monocyclic heterocycloalkyl, has 7-14 ring for polycyclic Heterocyclylalkyl Atom).Heterocyclylalkyl can be covalent with defined chemical structure in any heteroatom or carbon atom for generating rock-steady structure Connection.One or more N or S atom on Heterocyclylalkyl can be oxidized (such as morpholine N-Oxide, thiomorpholine S- oxidation Object, thiomorpholine S, S- dioxide).Heterocyclylalkyl can also contain one or more oxo groups, such as phthalyl imido Base, piperidone base, oxazolidine ketone group, 2,4 (1H, 3H)-dioxo-pyrimidine radicals, pyridine -2 (1H) -one base etc..Heterocyclylalkyl Example further includes morpholinyl, thiomorpholine base, pyranose, imidazolidinyl, imidazolinyl, oxazolidinyl, pyrazolidinyl, pyrazoline Base, pyrrolidinyl, pyrrolinyl, tetrahydrofuran base, tetrahydro-thienyl, tetrahydro-thiazoles base, piperidyl, azetidine, piperazine Base etc..
In each position of this specification, the substituent group of the compounds of this invention carries out disclosure in the form of group or range. This specifically means that the present invention includes the sub-combination of each of each member or member of such group and range individual.Such as Term " C1-6Alkyl " specifically means to separately disclose methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
Term " the compounds of this invention " (unless otherwise particularly pointing out) in this article refer to formula (I)-(II) compound and its All pure and mixed stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug and isotope The compound of label and any pharmaceutically acceptable salt.The solvate of the compounds of this invention refers to and stoichiometry and non-ization Learn the compound or its salt that the solvent of metering combines, such as hydrate, ethanolates, methanol solvate.Compound can also be a kind of Or a variety of crystalline states exist, i.e., as eutectic, polymorph or its can exist with amorphous solid.All such form It is covered by the claims.
" pharmaceutically acceptable " the expression substance of term or composition chemically and/or toxicologically must be with composition preparations Other ingredients and/or with its treat mammal it is compatible.
Term " stereoisomer " in this article refers to the different compound of the chirality with one or more Stereocenters, Including corresponding isomers and diastereoisomer.
The compounds of this invention can be used in a salt form, such as from inorganic acid or organic acid it is derivative obtain " pharmaceutically Acceptable salt ".These include but is not limited to what follows: acetate, adipate, alginates, citrate, asparagus fern ammonia Hydrochlorate, benzoate, benzene sulfonate, disulfate, butyrate, camphor hydrochlorate, camsilate, digluconate, ring penta Alkane propionate, lauryl sulfate, esilate, glucose enanthate, glycerophosphate, Hemisulphate, enanthate, caproic acid Salt, fumarate, hydrochloride, hydrobromate, hydriodate, 2- isethionate, lactate, maleate, methylsulphur Hydrochlorate, hydrochloride, 2- naphthalene sulfonate, oxalates, pectinic acid salt, sulfate, 3- phenylpropionic acid salt, picrate, trimethyl Acetate, propionate, succinate, tartrate, rhodanate, tosilate and caprate.In addition, the nitrogenous base of alkalinity Group can occur quaternization reaction with following reagent and generate quaternary ammonium salt: such as low-carbon alkyl halide, including methyl, ethyl, propyl With the chloride, bromide and iodide of butyl；Such as dialkyl sulfate, including dimethyl, diethyl, dibutyl and diamyl Sulfate；Such as long chain halide, chloride, bromide and iodate including decyl, lauryl, myristyl and stearyl Object；Such as aralkyl halide, such as the bromide of benzyl and phenethyl.
The invention also includes the compounds of this invention of isotope labelling, i.e., identical as above-mentioned disclosed structure, but the knot One or more atoms are substituted from its atom with identical proton number but different neutron populations in structure.In conjunction with chemical combination of the present invention The isotope embodiment of object includes the isotope of hydrogen, carbon, nitrogen, oxygen, sulphur, fluorine, chlorine, iodine, respectively such as2H、3H、13C、14C、15N、18O 、17O、35S、18F、36Cl and131I etc..The compound of the present invention, stereoisomer, tautomer or pharmaceutically acceptable Salt, and the compound of the above form containing above-mentioned isotope and/or other atom isotopes, in the scope of the invention It is interior.The compounds of this invention of certain isotope labellings, such as quilt3H or14C those of marks compound to can be used for drug entities In distribution test, therefore, these3H or14C isotope is particularly preferred due to its easy preparation and detection.In addition, heavier Isotope such as2Certain the compounds of this invention that H is substituted with better metabolic stability due to having certain treatments excellent Gesture, such as Half-life in vivo and less dosage can be increased, therefore,2H is also preferred in some cases.Isotope labelling Formula (I) compound and its premise drug of the present invention can generally be prepared, carrying out following processes and/or embodiment and system When technique disclosed in standby example, isotope-labeled reagent is replaced with the reagent for the isotope labelling being easy to get.
Another aspect of the present invention relates to a kind of pharmaceutical compositions, and the logical formula (I)-(II) containing therapeutically effective amount is described Compound or its pharmaceutically acceptable carrier, diluent or excipient.
The invention further relates to compound described in logical formula (I)-(II) or its pharmaceutical salt, or the drug comprising it Disease of the composition in preparation for preventing and/or treating the pathological characteristics with the IDO tryptophan metabolic pathway mediated Purposes in drug.Disease with the IDO tryptophan metabolic pathway pathological characteristics mediated is selected from cancer, myeloproliferative disorder Syndrome, autoimmune disease, alzheimer's disease, depression, schizophrenia, anxiety disorder, mental handicape, neuropathy With pain, cataract, AIDS and pneumonia, wherein the cancer preferably is selected from prostate cancer, breast cancer, cervical carcinoma, intrauterine Film cancer, colon cancer, gastric cancer, lung cancer, liver cancer, bladder cancer, cancer of pancreas, the carcinoma of the rectum, cutaneum carcinoma (including melanoma and basal cell Cancer), carcinoma of mouth, osteocarcinoma, oophoroma, the cancer of the brain, head-neck carcinoma, mesothelium endometrial carcinomas, leukaemia, lymthoma, the cancer of the esophagus, kidney, first Shape gland cancer, myeloma, choriocarcinoma, carcinoma of testis, glioma, female glioma, fallopian tube cneoplasms.
The invention further relates to the tryptophan metabolic pathway pathology that there is IDO to mediate for a kind of Prevention and/or Prevention The method for learning the disease of feature comprising apply compound described in the logical formula (I)-(II) of therapeutically effective amount to patient or it can Medicinal salt, or comprising its pharmaceutical composition, wherein the tryptophan metabolic pathway pathological characteristics mediated with IDO Disease is selected from cancer, myelodysplastic syndrome, autoimmune disease, alzheimer's disease, depression, schizophrenia Disease, anxiety disorder, mental handicape, neuropathy and pain, cataract, AIDS and pneumonia.
The invention further relates to the tryptophan metabolic pathway pathology that there is IDO to mediate for a kind of Prevention and/or Prevention The method for learning the disease of feature comprising apply compound described in the logical formula (I)-(II) of therapeutically effective amount to patient or it can Medicinal salt, or comprising its pharmaceutical composition, wherein the tryptophan metabolic pathway pathological characteristics mediated with IDO Disease is selected from cancer, wherein the cancer be selected from prostate cancer, breast cancer, cervical carcinoma, carcinoma of endometrium, colon cancer, gastric cancer, Lung cancer, liver cancer, bladder cancer, cancer of pancreas, the carcinoma of the rectum, cutaneum carcinoma (including melanoma and basal-cell carcinoma), carcinoma of mouth, osteocarcinoma, Oophoroma, the cancer of the brain, head-neck carcinoma, mesothelium endometrial carcinomas, leukaemia, lymthoma, the cancer of the esophagus, kidney, thyroid cancer, myeloma, suede Trichilemma cancer, carcinoma of testis, glioma, female glioma, fallopian tube cneoplasms.
Compound or intermediate preparation
For the description present invention, it is listed below specific embodiment.But it is to be understood that the present invention is not limited to these Examples, Following embodiment, which is only to provide, practices method of the invention, the scope not limiting the invention in any way.
Compound provided by the invention can be prepared by Standard synthetic methods well known in the art, and this specification provides Prepare the conventional method of the compounds of this invention.Starting material can usually be obtained by commercialization, such as pass through Alfa Sigma-TCI、Splendid remote chemistry, the resistance to Jilin Chemical of peace, special (Chengdu) bio-pharmaceuticals of Ace, Chengdu bass spy examination Agent, Chengdu Hua Na chemicals Co., Ltd, Ai Qikang medicine science and technology (Shanghai) Co., Ltd., the limited public affairs of the vast fragrant biotechnology in Shanghai The companies such as department and Shanghai Yaoming Kangde New Medicine Development Co., Ltd are commercially available, or by well-known to those skilled in the art It is prepared by method.
Following reaction methods and synthesis step provide the possibility for synthesizing the compounds of this invention and key intermediate Approach.About being described in more detail for individual reaction steps, referring to following embodiments.It will be understood by those skilled in the art that of the invention Compound can also be obtained by other route of synthesis.Although hereafter having used specific starting material and examination in reaction process Agent, but these starting materials can be replaced other similar starting materials or reagent, to provide various derivatives with reagent Object.In addition, many compounds as made from following methods can pass through those skilled in the art under the guidance of this specification Known conventional chemical processes are further modified.
The compounds of this invention and corresponding preparation method are hereafter explained further and enumerated with preparation by embodiment.Ying Liao Solution, although given in specific embodiment typical or preferred reaction condition (such as reaction temperature, the time, reactant molar ratio, Reaction dissolvent and pressure etc.), but other reaction conditions also can be used in those skilled in the art.Optimum reaction condition can be with Specific reaction substrate used or solvent and change, but the condition can be passed through by those skilled in the art it is conventional excellent Change and determines.
React starting material, intermediate and embodiment compound can by precipitating, filtering, crystallization, evaporation, distillation with And the routine techniques such as chromatography (such as column chromatography, TLC isolates and purifies) carry out isolation and purification.
TLC uses Yantai Huanghai Sea HSGF254 tlc silica gel plate (0.2 ± 0.03mm), and TLC is isolated and purified using Yantai Huanghai Sea HSGF254 thin-layer chromatography thickness prepares plate (0.9~1mm), is purchased from Haiyang Chemical Plant, Qingdao.
Column is chromatographed using 300~400 mesh silica gel of the Yantai Huanghai Sea as carrier, is purchased from Haiyang Chemical Plant, Qingdao.
Commercialization solvent and reagent used in test unless otherwise specified, are not necessarily to be further purified or handle after purchase Directly use.When with reference to other embodiments or synthetic method, reaction condition (reaction temperature, reaction dissolvent, reactant molar ratio Or/and duration of the reaction) may be different.In general, reaction process can be monitored by TLC, the suitable time is selected accordingly It terminates and reacts and post-processed.The purification condition of compound is it can also happen that variation, it is however generally that, the R according to TLCfValue choosing Suitable column chromatographic elution agent is selected, or isolates and purifies respective compound by preparing TLC.
Formula (I) compound of the present invention can be prepared according to following scheme 1.A and B is condensed to yield formula (I) compound, should Reaction generally uses condensing agent, such as CDI, EDCI, DIC, DCC, HATU, HBTU, PyBOP.It will be appreciated that these reaction conditions are simultaneously It is not limiting, the method can be used to prepare formula (I) compound by reasonable change reaction condition.Wherein R1、R2、 R3And R4With definition as described in the present invention.
Process 1
The following example intends to illustrate specific invention embodiment, is in no way intended to limit description of the invention or right is wanted Seek the range of book.Those skilled in the art will recognize that raw material can be different, can generate the present invention using additional step The compound covered, as the following example is proved.The following example is both not intended to or should not only for purposes of illustration It is interpreted limitation invention in any way.Those skilled in the art will appreciate that can be changed and modify, without Violate the spirit or scope of the present invention.
Embodiment 1,
The compounds of this invention is synthesized referring to the method for process 1, obtains compound 1.ESI-MS m/z:423.4 [M+H]+。
Biological test
1. compound tests IDO inhibitory activity
HeLa cell is purchased from ATCC, containing L-Glutamine (2mM), nonessential amino acid (84mg/L) and fetal calf serum 95% humidity, 5%CO are incubated in the DMEM of (10%FBS)2, 37 ° of incubators.Test the previous day grows continuous passage good It is good, after 90% or more the Hela cell EDTA/ trypsin digestion merged, it is resuspended in DMEM complete medium, by 5000/ hole Density, be seeded in 96 well culture plates, and overnight incubation.Second day, 96 orifice plate cell culture mediums are replaced, are added in every hole Compound culture medium of the 200 μ l containing IFN-γ (final concentration 50ng/mL is purchased from R&D) and serial dilutions.Compound is most highly concentrated 1000nM is spent, by 5 times of dilutions, 7 concentration gradients.Culture plate is put back to cell incubator and is continued after being incubated for 48h, by 150 μ l supernatants Liquid/hole moves in 96 new orifice plates, and 7.5 μ l trichloroacetic acids are added in every hole, and incubating 30min at 50 DEG C after mixing makes the N- first generated Acyl group kynurenin is hydrolyzed to kynurenin.Then 10 minutes removal sediments are centrifuged with 12000rpm.Supernatant is with liquid phase/triple Level four bars matter general (LC/MS/MS, LC-20AD highly effective liquid phase chromatographic system, Japanese Shimadzu；API4000 triple quadrupole mass spectrometer, U.S. Applied Biosystem) analysis L- kynurenin concentration.With the foundation of 2-5000ng/ml concentration gradient L- kynurenin Standard curve；It measures in cell culture supernatant L- kynurenin concentration and IDO is inhibited with each compound of origin7.5 the Fitting Calculation Activity/(generate kynurenin IC50)。
The inhibitory activity test result of compound IDO1 intracellular to Hela is listed in Table 1 below.
Test result shows that the IDO1 intracellular to Hela of the compounds of this invention 1 has the inhibition for being significantly better than BMS-986205 Effect.

Claims (10)

1. a kind of formula (I) compound:
Its pharmaceutically acceptable salt, hydrate, solvate or stereoisomer, in which:
R1For-S-C1-6Alkyl；-S(O)-C1-6Alkyl；-S(O2)-C1-6Alkyl；
X is selected from O or S；
R2Selected from hydrogen, deuterium, halogen, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl ,-CN ,-CF3、-CHF2、-OCF3、-NH2、-NO2, Middle alkyl, alkenyl and alkynyl can be selected from halogen, C1-4The substituent group of alkyl replaces；
R3And R4It is separately hydrogen, halogen, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-6Naphthenic base；Alternatively,
R3And R43-6 member naphthenic base, 3-6 membered heterocycloalkyl are formed together with coupled carbon atom, wherein naphthenic base and miscellaneous Naphthenic base can be by C1-4Alkyl replaces.
2. compound as described in claim 1, pharmaceutically acceptable salt, hydrate, solvate or stereoisomer, Wherein shown in the compound such as formula (II):
R1For-S-C1-6Alkyl；-S(O)-C1-6Alkyl；-S(O2)-C1-6Alkyl；
R2Selected from hydrogen, deuterium, halogen, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl ,-CN ,-CF3、-CHF2、-OCF3、-NH2、-NO2。
3. compound as claimed in claim 2, pharmaceutically acceptable salt, hydrate, solvate or stereoisomer, Wherein:
R1For-S-C1-6Alkyl；-S(O)-C1-6Alkyl；-S(O2)-C1-6Alkyl；
R2Selected from hydrogen, deuterium, halogen.
4. compound as claimed in claim 3, pharmaceutically acceptable salt, hydrate, solvate or stereoisomer, Wherein:
R1Selected from flowering structure:
R2Selected from fluorine.
5. the compound as described in Claims 1-4, pharmaceutically acceptable salt, hydrate, solvate or alloisomerism Body is selected from:
6. a kind of pharmaceutical composition, the compound described in any one of -5 according to claim 1 containing therapeutically effective amount, Or its pharmaceutically acceptable carrier, diluent or excipient.
7. according to claim 1 any one of in -5 described in compound or its pharmaceutical salt or according to claim 6 institute The pharmaceutical composition stated is in preparation for preventing and/or treating the pathological characteristics with the IDO tryptophan metabolic pathway mediated Disease drug in purposes.
8. according to the purposes in claim 7, wherein the disease of the tryptophan metabolic pathway pathological characteristics mediated with IDO Disease selected from cancer, myelodysplastic syndrome, autoimmune disease, alzheimer's disease, depression, schizophrenia, Anxiety disorder, mental handicape, neuropathy and pain, cataract, AIDS and pneumonia, wherein the cancer preferably is selected from prostate Cancer, breast cancer, cervical carcinoma, carcinoma of endometrium, colon cancer, gastric cancer, lung cancer, liver cancer, bladder cancer, cancer of pancreas, the carcinoma of the rectum, cutaneum carcinoma (including melanoma and basal-cell carcinoma), carcinoma of mouth, osteocarcinoma, oophoroma, the cancer of the brain, head-neck carcinoma, mesothelium endometrial carcinomas, white blood Disease, lymthoma, the cancer of the esophagus, kidney, thyroid cancer, myeloma, choriocarcinoma, carcinoma of testis, glioma, female neuroglia Tumor, fallopian tube cneoplasms.
9. a kind of disease for the tryptophan metabolic pathway pathological characteristics that there is IDO to mediate for Prevention and/or Prevention Method comprising apply compound described in any one of claim 1-5 of therapeutically effective amount to patient or its is pharmaceutically acceptable Salt or pharmaceutical composition according to claim 6, wherein the tryptophan metabolic pathway pathology mediated with IDO are special The disease of sign is selected from cancer, myelodysplastic syndrome, autoimmune disease, alzheimer's disease, depression, spirit point Split disease, anxiety disorder, mental handicape, neuropathy and pain, cataract, AIDS and pneumonia.
10. a kind of disease for the tryptophan metabolic pathway pathological characteristics that there is IDO to mediate for Prevention and/or Prevention Method comprising apply compound described in any one of claim 1-5 of therapeutically effective amount to patient or its is pharmaceutically acceptable Salt or pharmaceutical composition according to claim 6, wherein the tryptophan metabolic pathway pathology mediated with IDO are special The disease of sign is selected from cancer, wherein the cancer be selected from prostate cancer, breast cancer, cervical carcinoma, carcinoma of endometrium, colon cancer, Gastric cancer, lung cancer, liver cancer, bladder cancer, cancer of pancreas, the carcinoma of the rectum, cutaneum carcinoma (including melanoma and basal-cell carcinoma), carcinoma of mouth, Osteocarcinoma, oophoroma, the cancer of the brain, head-neck carcinoma, mesothelium endometrial carcinomas, leukaemia, lymthoma, the cancer of the esophagus, kidney, thyroid cancer, marrow Tumor, choriocarcinoma, carcinoma of testis, glioma, female glioma, fallopian tube cneoplasms.
CN201711359879.9A 2017-12-18 2017-12-18 One kind is used as IDO inhibitor Pending CN109928924A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201711359879.9A CN109928924A (en) 2017-12-18 2017-12-18 One kind is used as IDO inhibitor
PCT/CN2018/121870 WO2019120199A1 (en) 2017-12-18 2018-12-18 Quinoline derivatives and bioactivity thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201711359879.9A CN109928924A (en) 2017-12-18 2017-12-18 One kind is used as IDO inhibitor

Publications (1)

Publication Number Publication Date
CN109928924A true CN109928924A (en) 2019-06-25

Family

ID=66982027

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201711359879.9A Pending CN109928924A (en) 2017-12-18 2017-12-18 One kind is used as IDO inhibitor

Country Status (2)

Country Link
CN (1) CN109928924A (en)
WO (1) WO2019120199A1 (en)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UY36390A (en) * 2014-11-05 2016-06-01 Flexus Biosciences Inc MODULATING COMPOUNDS OF INDOLAMINE ENZYME 2,3-DIOXYGENASE (IDO), ITS SYNTHESIS METHODS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
EP3452451A4 (en) * 2016-05-04 2019-11-13 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
JP2019516682A (en) * 2016-05-04 2019-06-20 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Indoleamine 2,3-dioxygenase inhibitors and methods of use thereof
KR20190003686A (en) * 2016-05-04 2019-01-09 브리스톨-마이어스 스큅 컴퍼니 Inhibitors of indoleamine 2,3-dioxygenase and methods of use thereof
US10323004B2 (en) * 2016-05-04 2019-06-18 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use

Also Published As

Publication number Publication date
WO2019120199A1 (en) 2019-06-27

Similar Documents

Publication Publication Date Title
JP7033141B2 (en) Condensation bicyclic inhibitor of menin-MLL interaction
CN104470921B (en) Thiophene miazines derivate, preparation method therefor, and medical application thereof
JP6296985B2 (en) Use of (2R, 6R) -hydroxynorketamine, (S) -dehydronorketamine and other (R, S) -ketamine stereoisomeric dehydro and hydroxylated metabolites in the treatment of depression and neuropathic pain
EP4331668A2 (en) Compounds for inhibiting nlrp3 and uses thereof
TW201124378A (en) Indole compounds and pharmaceutical use thereof
BR112021005044A2 (en) antibacterial compounds
EP3471830A1 (en) Ezh2 inhibitors for treating cancer
CN108495618A (en) New compound and application thereof
CN107814798A (en) 3 substitutional crylic acid class compounds and its production and use
US20240174616A1 (en) Hdac6 inhibitors and uses thereof
CN109928916A (en) A kind of quinolyl-4 cyclohexanes compound as IDO inhibitor
CN109928924A (en) One kind is used as IDO inhibitor
CN109928923A (en) One kind is used as IDO inhibitor compound
CN109928917A (en) A kind of IDO inhibitor compound
CN109928990A (en) The quinolyl-4 cyclohexanes compound of IDO inhibitor
CN109928918A (en) Fluoro IDO inhibitor
CN109928919A (en) Cyclohexanes compound as IDO inhibitor
Andricopulo et al. Synthesis and analgesic properties of cyclic imides: Naphthalimide and bis-Naphthalimide derivatives
CN109928920A (en) Cyclohexanes compound
CN109928921A (en) IDO inhibitor
CN109928922A (en) A kind of cyclohexanes compound
WO2009126335A2 (en) Ant2 inhibitor compounds and methods of use thereof
WO2019032961A1 (en) Trioxacarcin-antibody conjugates and uses thereof
CN109665992A (en) A kind of quinolyl-4 cyclohexanes compound as IDO inhibitor
CN112645955A (en) [1,2,4] triazolo [4,3-b ] pyridazine compound and preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20190625

WD01 Invention patent application deemed withdrawn after publication