CN109928918A - Fluoro IDO inhibitor - Google Patents
Fluoro IDO inhibitor Download PDFInfo
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- CN109928918A CN109928918A CN201711359869.5A CN201711359869A CN109928918A CN 109928918 A CN109928918 A CN 109928918A CN 201711359869 A CN201711359869 A CN 201711359869A CN 109928918 A CN109928918 A CN 109928918A
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Abstract
Fluoro IDO inhibitor.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
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
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
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:
R1For
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 " in this article refers to mono- or polycyclic carbocyclic alkyl substituent.Including cyclic alkyl, alkenyl and
Alkynyl.Naphthenic base can make monocycle or polycyclic (such as containing condensed, bridging and/or spiro ring system), and wherein carbon atom is located at ring system
Inner or outer side.Any suitable ring position of naphthenic base can be covalently attached with defined chemical structure.
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 AlfaTCI、Splendid remote chemistry, the resistance to Jilin Chemical of peace, Ace special (Chengdu) bio-pharmaceuticals, Chengdu bass
Special reagent, Chengdu Hua Na chemicals Co., Ltd, Ai Qikang medicine science and technology (Shanghai) Co., Ltd., the vast fragrant biotechnology in Shanghai have
The companies such as limit company and Shanghai Yaoming Kangde New Medicine Development Co., Ltd are commercially available, or ripe by those skilled in the art institute
It is prepared by the method known.
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:442.2 [M+H]+。
Embodiment 2,
The compounds of this invention is synthesized referring to the method for process 1, obtains compound 2.ESI-MS m/z:424.3 [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 compounds of this invention 1 and the IDO1 intracellular to Hela of compound 2 have and is significantly better than BMS-
986205 inhibiting effect.
Claims (10)
1. a kind of formula (I) compound:
Its pharmaceutically acceptable salt, hydrate, solvate or stereoisomer, in which:
R1For
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
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
R2Selected from hydrogen, deuterium, halogen.
4. compound as claimed in claim 3, pharmaceutically acceptable salt, hydrate, solvate or stereoisomer,
Wherein:
R1For
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.
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