CN109180649A - A kind of IDO inhibitor and preparation method thereof containing indole ring - Google Patents

A kind of IDO inhibitor and preparation method thereof containing indole ring Download PDF

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CN109180649A
CN109180649A CN201810945673.2A CN201810945673A CN109180649A CN 109180649 A CN109180649 A CN 109180649A CN 201810945673 A CN201810945673 A CN 201810945673A CN 109180649 A CN109180649 A CN 109180649A
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钟刚
李�杰
何桂佳
杨秀娟
李志勇
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Sichuan Baili Pharmaceutical Co Ltd
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Abstract

The IDO inhibitor and preparation method thereof containing indole ring that the invention discloses a kind of can be used for treating related immune activation, inflammation class disease and cardiovascular disease etc. with the activity of indoles amine -2,3- dioxygenase using such compound as the drug of active ingredient.

Description

A kind of IDO inhibitor and preparation method thereof containing indole ring
Technical field
The present invention relates to a kind of tetrazole Phenylindole analog derivatives can using such compound as the drug of active ingredient For treating related immune activation, inflammation class disease and cardiovascular disease etc. with the activity of indoles amine -2,3- dioxygenase.
Background technique
There are two the approach of decomposition for the intracorporal necessary amino acid of people --- tryptophan: serotonin approach (accounting for about 5%) and dog Urinary ammonia acid approach (accounting for about 95%) (Neuroch em Res, 1980,5 (3): 223-239).Indoles amine -2,3- dioxygenase (IDO) and tryptophan -2,3- dioxygenase (TDO) is tryptophan/kynurenine pathway rate-limiting enzyme, and IDO is widely present in the food in one's mouth In histocyte in addition to liver, TDO is then most of to express newborn animal in liver.
Indoles amine -2,3- dioxygenase is can be uniquely catalyzed indole ring oxicracking in tryptophan modules other than liver, To be decomposed into a variety of metabolins such as L- kynurenin, pyridine carboxylic acid and quinolinic acid along kynurenine approach.Enzyme generation related to its The expression for thanking to product is distributed mainly on the T cell area of thymic medulla and secondary lymphatic organ, and sporadically appear in some immune tolerances or In immune special pardon tissue, such as thymus gland, gastrointestinal tract mucous, placenta.
Under normal physiological conditions, IDO and TDO can be by immunosupress protective tissue, from the too drastic of immune system Reaction.The expression activation for INF- γ induction indoles amine -2,3- dioxygenase that activating T cell generates, thus reverse feedback regulation CD4+T cell, CD8+T cell and NK cell.However IDO and TDO has higher expression in kinds of tumors tissue, it is high Expression is one of the reason of causing tumour immunity to be resistant to, poor in close relations with the prognosis of tumor patient.IDO and TDO can be blunt Change the oncological surveillance effect of immune system and prevents tumor rejection.Tumour cell and specific type immunocyte are limited using the mechanism Anti tumor immune response processed.
Research shows that immune suppression function can be adjusted to the inhibition of indoles amine -2,3- dioxygenase, to reach inhibition Effect (the Nat.ReV.Immunol 2004,4,762-74 of tumour growth；Nat.ReV.Cancer,2006,6,613-625).
Numerous studies confirm that IDO and inflammation, cardiovascular disease, nervous system degeneration disease, psychotic disorder, virus feel It is also related in dye, autoimmune disease etc. other chronic diseases related with tryptophan degradation.
However, the IDO micromolecular inhibitor for entering clinical investigation phase most of at present, some to the inhibition of IDO all Only micromole's grade (such as Indoximod of NewLink Genetics company), some oral administration biaavailabilities are poor (such as The Epacadostat of Incyte Corporation company), so needing inhibition and the better drug of bioavilability Meet current clinical demand.
Meanwhile it being different at present into the mechanism of action of the IDO micromolecular inhibitor of clinical research, Epacadostat There is affinity to IDO holoenzyme；Indoximod can be released produced by the decline of the mTORC1 activity as caused by tryptophan depletion T cell function inhibitio；Navoximod is inhibited to the tumour for expressing IDO1/TDO simultaneously；PF-06840003 is The noncompetitive inhibitor of tryptophan, not in conjunction with the confactor ferroheme of IDO enzyme；BMS-986205 be then with without auxiliary because Son apo-IDO1 in conjunction with and generate inhibiting effect.
Definition
According to the standard convention of this field, the formula that chemical structure is represented in term used herein may includes list Dash "-", parallel dash "=" or symbolFor indicate chemical element or name substituent group and its parent fraction it Between chemical bonding structure: single dash "-" indicates that singly-bound, parallel dash "=" indicate double bond, symbolIndicate as part or The key of the tie point of the core or core of substituent group and compound structure.If representing in the formula of chemical structure does not have single or double break Folding number, then be interpreted as forming singly-bound between substituent group and its parent fraction.
It is miscellaneous (atom, alkyl, aryl, ring group) according to the standard convention of this field, refer to and contains its other than carbon atom The corresponding chemical structure of its atom.
Summary of the invention
The present invention provides a kind of tetrazole Phenylindole analog derivatives, are indoles amine -2,3- dioxygenase inhibitor, Their main function be by inhibit indoles amine -2,3- dioxygenase activity play adjust function of immune system and inflammation because The effect of son, the specially compound of structure formula (I):
And/or its stereoisomer, tautomer or officinal salt, solvate, In:
R1For the alkyl of the linear chain or branched chain optionally replaced, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, It is substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted with or without heteroatomic aromatic radical, substituted or unsubstituted cycloalkanes Base, substituted or unsubstituted heterocycle, substituted or unsubstituted alkanoyl, substituted or unsubstituted amide groups, substitution do not take The amidoalkyl group in generation, aforementioned hetero atom are oxygen, sulphur or nitrogen-atoms.
R2Selected from substituted or unsubstituted alkyl, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted alkoxy, take Generation or unsubstituted naphthenic base, substituted or unsubstituted heterocycle, substituted or unsubstituted alkynyl.
A is with or without heteroatomic carbochain, and structure is-(CH2)n, wherein n=0~5；Or-NH (CH2)n, n=0 ~5, wherein the end NH is connected with indole ring.
R3For substituted or unsubstituted aromatic radical, aromatic radical can be miscellaneous for full carbon skeleton or the oxygen containing one or more, sulphur, nitrogen etc. The skeleton of atom；Wherein the substitution on aryl can for one replace or it is polysubstituted, substituent group independently selected from halogen, hydroxyl, amino, Nitro, cyano, trifluoromethyl, azido, sulfonyl, sulfoamido, substituted or unsubstituted alkyl, substituted or unsubstituted alkene Base, substituted or unsubstituted alkynyl, substituted or unsubstituted miscellaneous alkyl, C1-C8Substituted or unsubstituted alkoxy, substitution or not Substituted aromatic radical, substituted or unsubstituted naphthenic base, substituted or unsubstituted heterocycle, substituted or unsubstituted alkanoyl, Substituted or unsubstituted amide groups, substituted or unsubstituted amidoalkyl group.
The substituent group is independently selected from halogen, hydroxyl, amino, nitro, cyano, trifluoromethyl, azido, sulphonyl thereon Base, acyl group.
The alkyl is C thereon1-C8Substituted or unsubstituted alkyl group ,-(CH2)n-Ar-、-(CH2)n- Cy-, wherein Ar is substituted or unsubstituted aryl or heteroaryl, and Cy is substituted or unsubstituted naphthenic base or Heterocyclylalkyl.
The alkenyl is the C containing one or more-(C=C)-thereon2-C8Alkyl group.
The alkynyl is the C containing one or more-(C ≡ C)-thereon2-C8Alkyl group.
The miscellaneous alkyl is the substitution or not of the atom (oxygen, sulphur or nitrogen-atoms) containing one or more in addition to carbon thereon Substituted C1-C8Alkyl group.
The alkoxy is-O-R thereon4, wherein R4For the substituted or unsubstituted C of linear chain or branched chain1-C8Alkyl, alkene Base or alkynyl.
Thereon the aromatic radical be can be full carbon skeleton or containing heteroatomic skeletons such as one or more oxygen, sulphur, nitrogen, On can have one or more substituent groups, in some circumstances, two substituent groups of arbitrary neighborhood can form C1-C6With or without miscellaneous The cyclic structure of atom (oxygen, sulphur or nitrogen).
The naphthenic base is C thereon3-C7Carbocylic radical.
The heterocycle is the substitution or not of the atom (oxygen, sulphur or nitrogen-atoms) containing one or more in addition to carbon thereon Substituted C3-C7Carbocylic radical.
The alkanoyl is-(C=O)-R thereon5, wherein R5For the substituted or unsubstituted C of linear chain or branched chain1-C7Alkane Base.
The amide groups is-(C=O)-NH-R thereon6, wherein R6For hydrogen, linear chain or branched chain it is substituted or unsubstituted C1-C7Alkyl.
The amidoalkyl group is-R thereon7(C=O)-NH-R8, wherein R7For the substituted or unsubstituted of linear chain or branched chain C1-C7Alkyl, R8For hydrogen, the substituted or unsubstituted C of linear chain or branched chain1-C5Alkyl.
The sulfonyl is substituted or unsubstituted C thereon1-C6Alkyl sulphonyl.
Compound (I) provided by the present invention, it is characterised in that R3For substituted or unsubstituted phenyl or containing one or more A heteroatomic six Yuans aromatic radicals, wherein hetero atom is N, O or S.
In certain embodiments, the present invention provides the compounds of structure formula (II):
And/or its stereoisomer, tautomer or officinal salt, solvate, in which:
R1For the alkyl of the linear chain or branched chain optionally replaced, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, It is substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted with or without heteroatomic aromatic radical, substituted or unsubstituted cycloalkanes Base, substituted or unsubstituted heterocycle, substituted or unsubstituted alkanoyl, substituted or unsubstituted amide groups, substitution do not take The amidoalkyl group in generation, aforementioned hetero atom are oxygen, sulphur or nitrogen-atoms.
R2Selected from substituted or unsubstituted alkyl, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted alkoxy, take Generation or unsubstituted naphthenic base, substituted or unsubstituted heterocycle, substituted or unsubstituted alkynyl.
N=0~5.
R3For substituted or unsubstituted fragrant phenyl or six Yuans fragrance of the hetero atoms containing one or more (nitrogen, oxygen or sulphur) Base, wherein the substitution on aryl can be a substitution or polysubstituted, and substituent group is independently selected from halogen, hydroxyl, amino, nitro, cyanogen Base, trifluoromethyl, azido, sulfonyl, sulfoamido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substitution Or unsubstituted alkynyl, substituted or unsubstituted miscellaneous alkyl, C1-C8Substituted or unsubstituted alkoxy, substituted or unsubstituted virtue Perfume base, substituted or unsubstituted naphthenic base, substituted or unsubstituted heterocycle, substituted or unsubstituted alkanoyl, substitution or not Substituted amide groups, substituted or unsubstituted amidoalkyl group.
The substituent group is independently selected from halogen, hydroxyl, amino, nitro, cyano, trifluoromethyl, azido, sulphonyl thereon Base, acyl group.
The alkyl is C thereon1-C8Substituted or unsubstituted alkyl group ,-(CH2)n-Ar-、-(CH2)n- Cy-, wherein Ar is substituted or unsubstituted aryl or heteroaryl, and Cy is substituted or unsubstituted naphthenic base or Heterocyclylalkyl.
The alkenyl is the C containing one or more-(C=C)-thereon2-C8Alkyl group.
The alkynyl is the C containing one or more-(C ≡ C)-thereon2-C8Alkyl group.
The miscellaneous alkyl is the substitution or not of the atom (oxygen, sulphur or nitrogen-atoms) containing one or more in addition to carbon thereon Substituted C1-C8Alkyl group.
The alkoxy is-O-R thereon4, wherein R4For the substituted or unsubstituted C of linear chain or branched chain1-C8Alkyl, alkene Base or alkynyl.
Thereon the aromatic radical be can be full carbon skeleton or containing heteroatomic skeletons such as one or more oxygen, sulphur, nitrogen, On can have one or more substituent groups, in some circumstances, two substituent groups of arbitrary neighborhood can form C1-C6With or without miscellaneous The cyclic structure of atom (oxygen, sulphur or nitrogen).
The naphthenic base is C thereon3-C7Carbocylic radical.
The heterocycle is the substitution or not of the atom (oxygen, sulphur or nitrogen-atoms) containing one or more in addition to carbon thereon Substituted C3-C7Carbocylic radical.
The alkanoyl is-(C=O)-R thereon5, wherein R5For the substituted or unsubstituted C of linear chain or branched chain1-C7Alkane Base.
The amide groups is-(C=O)-NH-R thereon6, wherein R6For hydrogen, linear chain or branched chain it is substituted or unsubstituted C1-C7Alkyl.
The amidoalkyl group is-R thereon7(C=O)-NH-R8, wherein R7For the substituted or unsubstituted of linear chain or branched chain C1-C7Alkyl, R8For hydrogen, the substituted or unsubstituted C of linear chain or branched chain1-C5Alkyl.
The sulfonyl is substituted or unsubstituted C thereon1-C6Alkyl sulphonyl.
In certain embodiments, the present invention provides the compounds of structure formula (III):
And/or its stereoisomer, tautomer or officinal salt, solvate, Wherein:
R1For the alkyl of the linear chain or branched chain optionally replaced, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, It is substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted with or without heteroatomic aromatic radical, substituted or unsubstituted cycloalkanes Base, substituted or unsubstituted heterocycle, substituted or unsubstituted alkanoyl, substituted or unsubstituted amide groups, substitution do not take The amidoalkyl group in generation, aforementioned hetero atom are oxygen, sulphur or nitrogen-atoms.
R2Selected from substituted or unsubstituted alkyl, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted alkoxy, take Generation or unsubstituted naphthenic base, substituted or unsubstituted heterocycle, substituted or unsubstituted alkynyl.
N=0~5.
R3For substituted or unsubstituted fragrant phenyl or six Yuans fragrance of the hetero atoms containing one or more (nitrogen, oxygen or sulphur) Base, wherein the substitution on aryl can be a substitution or polysubstituted, and substituent group is independently selected from halogen, hydroxyl, amino, nitro, cyanogen Base, trifluoromethyl, azido, sulfonyl, sulfoamido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substitution Or unsubstituted alkynyl, substituted or unsubstituted miscellaneous alkyl, C1-C8Substituted or unsubstituted alkoxy, substituted or unsubstituted virtue Perfume base, substituted or unsubstituted naphthenic base, substituted or unsubstituted heterocycle, substituted or unsubstituted alkanoyl, substitution or not Substituted amide groups, substituted or unsubstituted amidoalkyl group.
The substituent group is independently selected from halogen, hydroxyl, amino, nitro, cyano, trifluoromethyl, azido, sulphonyl thereon Base, acyl group.
The alkyl is C thereon1-C8Substituted or unsubstituted alkyl group ,-(CH2)n-Ar-、-(CH2)n- Cy-, wherein Ar is substituted or unsubstituted aryl or heteroaryl, and Cy is substituted or unsubstituted naphthenic base or Heterocyclylalkyl.
The alkenyl is the C containing one or more-(C=C)-thereon2-C8Alkyl group.
The alkynyl is the C containing one or more-(C ≡ C)-thereon2-C8Alkyl group.
The miscellaneous alkyl is the substitution or not of the atom (oxygen, sulphur or nitrogen-atoms) containing one or more in addition to carbon thereon Substituted C1-C8Alkyl group.
The alkoxy is-O-R thereon4, wherein R4For the substituted or unsubstituted C of linear chain or branched chain1-C8Alkyl, alkene Base or alkynyl.
Thereon the aromatic radical be can be full carbon skeleton or containing heteroatomic skeletons such as one or more oxygen, sulphur, nitrogen, On can have one or more substituent groups, in some circumstances, two substituent groups of arbitrary neighborhood can form C1-C6With or without miscellaneous The cyclic structure of atom (oxygen, sulphur or nitrogen).
The naphthenic base is C thereon3-C7Carbocylic radical.
The heterocycle is the substitution or not of the atom (oxygen, sulphur or nitrogen-atoms) containing one or more in addition to carbon thereon Substituted C3-C7Carbocylic radical.
The alkanoyl is-(C=O)-R thereon5, wherein R5For the substituted or unsubstituted C of linear chain or branched chain1-C7Alkane Base.
The amide groups is-(C=O)-NH-R thereon6, wherein R6For hydrogen, linear chain or branched chain it is substituted or unsubstituted C1-C7Alkyl.
The amidoalkyl group is-R thereon7(C=O)-NH-R8, wherein R7For the substituted or unsubstituted of linear chain or branched chain C1-C7Alkyl, R8For hydrogen, the substituted or unsubstituted C of linear chain or branched chain1-C5Alkyl.
The sulfonyl is substituted or unsubstituted C thereon1-C6Alkyl sulphonyl.
The present invention surprisingly has found a kind of tetrazole Phenylindole analog derivative, can be by IDO enzyme in biological cell Inhibit the adjusting of progress IDO bioactivity, and because of the nuance of the mechanism of action, can press down with the IDO with other mechanism of action Preparation generates synergistic effect, to meet at present the needs of to IDO regulator.
Synthetic method
In compound (II) according to the present invention, as n=0, the bromo- 2- Iodoaniline of 4- and R can be used2Substituted acyl group second Acetoacetic ester carries out the building of indoles skeleton, then successively obtains by alkyl substitution, amidation process and the suzuki reaction of hydrogen on N, Synthetic route sees below formula:
It, can also be successively anti-through suzuki reaction and amidation after alkyl substitution on indoles N as n=0 in compound (II) Target compound should be prepared:
Indole ring is constructed with 1,4-benzoquinone after cyclohexylamine and ethyl acetoacetate coupling, then successively passes through suzuki reaction and amide Change reaction, compound (II) (wherein n=0) also can be obtained:
In compound (II), as n >=1, indole acid intermediate can be prepared into acyl chlorides, be reacted through Arndt-Eister To the carboxylic acid for increasing a carbochain, tetrazole phenyl is coupled by suzuki reaction with after the condensation of corresponding amine, obtains target product；? Can after constructing indole ring by ester through reduction and oxidative synthesis aldehyde, obtain the carboxylic acid of 2~5 carbon of growth through Ylide reaction, then Target compound is obtained through amidation and suzuki reaction, synthetic route sees below formula:
In compound (III) according to the present invention, as n=0, can by cyclohexylamine and ethyl acetoacetate coupling after with 1,4-benzoquinone constructs indole ring, then successively resets and obtain by suzuki reaction, Cruise, and synthetic route sees below formula:
In compound (III), as n=0, it is also possible to which the bromo- 2- Iodoaniline of 4- and ethyl acetoacetate carry out indoles skeleton Building, then tetrazole phenyl segments are connected by suzuki reaction, Cruise resets building urea bond, synthetic route is seen below Formula:
In compound (III), as n=1~5, it can be reset by indoxyl carboxylic acid ester's intermediate through hydrolysis, Cruise and generate amine Afterwards, connect with the brominated esters containing different length methylene straight chain, after ester hydrolysis with corresponding amine coupling, most afterwards through suzuki reaction It obtains, synthetic route sees below formula:
Application method
The activity of adjustable indoles amine -2, the 3- dioxygenase (IDO) of compound in the present invention.It is above-described " to adjust Section " refers to the active ability for increasing or decreasing enzyme or receptor.The compound that the present invention describes can be used for by by enzyme and the present invention Any one or more of compound or composition contact of description and the method that adjusts IDO.In certain embodiments, the present invention The compound of description can be used as the inhibitor of IDO.In further embodiment, the compound that the present invention describes can be used for leading to Cross the IDO activity of giving and adjust the compound of the present invention of dosage (as inhibited) to the cell or individual that need to adjust the enzyme into Row is adjusted.
The present invention is provided to be changed in the system (such as tissue, cell or living organism culture) of the IDO expressed containing cell Become the method for the extracellular tryptophan levels in mammal (as increased), including gives a effective amount of chemical combination provided by the invention Object or ingredient.The method of tryptophan levels and tryptophan degradation is measured as the conventional method in this field.
The present invention provides inhibited in patient by the compound or ingredient of the present invention for giving patient effective amounts The method of immunosupress (immunosupress that such as IDO is mediated).The immunosupress and cancer, tumour growth, transfer, biography that IDO is mediated Catch an illness (such as virus infection), virus replication it is related.
The present invention treats individual (such as patient) and giving the compound or ingredient of the present invention of patient effective amounts Middle IDO activity or the related disease of abnormal expression.Disease includes directly or indirectly related abnormal with IDO expression of enzymes or activity What disease, disorder or illness.The example of disease in relation to IDO includes cancer, neurodegenerative disorders (such as alzheimer's disease, henry Court of a feudal ruler Dun Shi chorea etc.), virus infection (such as HIV infection etc.), depression, wound, cataract, autoimmune disease (such as Rheumatoid arthritis, asthma, multiple sclerosis, psoriasis, systemic loupus erythematosus, inflammatory bowel disease etc.), organ transplant (such as organ-graft refection etc.).
The embodiment of the medicable tumor-specific immunity inhibition related with cancer of the method includes through the invention With colon, pancreas, breast, prostate, lung, brain, ovary, uterine neck, testis, kidney, head and neck cancer disease, lymthoma, leukaemia, black The related immunosupress such as plain tumor.
The immunosupress that IDO related with viral infection of the present invention is mediated is felt with the virus selected from the following group It is infected with pass: Hepatitis C Virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), poliovirus, varicellazoster virus, Coxsackie virus, human immunodeficiency virus (HIV).
In another embodiment, and the immunosupress that mediates of the related IDO of infectious disease is related with tuberculosis or leishmaniasis.
For example, the trouble of a kind of positive chemotherapy for carrying out or having completed treating morbid state (such as cancer) and/or the radiotherapy course for the treatment of Person can be from a effective amount of compound of the present invention or ingredient be given in patient's treatment to inhibit to exempt from caused by because of morbid state Benefit in epidemic disease inhibition and/or its treatment.
Further provide by give need associated treatment individual (such as patient) therapeutically effective amount it is of the present invention Compound or its pharmaceutical composition, treatment are related with IDO activity or expression (including abnormal activity and/or overexpression) with individual The method of disease.The embodiment of disease may include it is any directly or indirectly with the expression of IDO enzyme or the related disease of activity, barrier Hinder or situation, such as overexpression or activity are abnormal.The related disease of IDO may also comprise can by adjust enzymatic activity prevention, alleviate or Any disease, obstacle or the situation cured.
" contact " described herein, which refers to, links together specified portions and vitro system or vivo system.For example, making IDO enzyme and compound of the present invention or ingredient " contact " include giving individual or patient (such as people) present invention with IDO Compound, or the compounds of this invention is introduced into the sample of the cell containing IDO enzyme or pure preparations.
Signified " individual " or " patient " refers to any animal or people including mammal in the present invention, preferably small Mouse, rat, other rodents, rabbit, dog, cat, pig, ox, sheep, horse or primate, it is optimal to choose.
Signified " therapeutically effective amount " refers to researcher, doctor or animal doctor in tissue, system, animal, individual in the present invention Or the amount for the reactive compound for causing biology or medical response or drug found in people, including prevention disease, alleviate disease, Inhibit one or more in disease.
Combination therapy
Compound of the present invention can (such as antiviral agent, chemotherapeutics be other with one or more other treatment methods Anticancer drug, immunopotentiator, immunosuppressor, radiation, antitumor and antiviral vaccine, cytokine therapy (such as IL2, GM- CSF etc.) and/or tyrosine kinase inhibitor) Drug combination, to treat the relevant disease of IDO, obstacle or situation (such as It is upper described) or improve the curative effect for the treatment of morbid state or situation (such as cancer).These drugs can be with the compound of the present invention one It is used in combination in kind of dosage form or these drugs can be in different dosage form simultaneously or consecutive administration.
It is contemplated that the suitable antiviral drugs being used in combination with compound of the present invention may include ucleosides and nucleotide Reverse transcriptase inhibitor (NRTIs), non-nucleoside reverse transcriptase inhibitor (NNRTIs), protease inhibitors and other disease-resistant Cytotoxic drug.
The embodiment of suitable efabirenz includes but is not limited to Zidovudine (AZT)；Didanosine (ddI)；Zalcitabine (ddC)；Stavudine (d4T)；Lamivudine (3TC)；Abacavir (1592U89)；Aldoforwe ester [bisacrylamide (POM)-PMEA]；Lobucavir (BMS-180194)；BCH-10652；Emtricitabine [(-)-FTC]；β-L- FD4 (also known as β-L-D4C and entitled β-L-2 ', 3 '-double deoxidation -5- fluoro-cytidine)；DAPD ((-)-β-D-2,6- diamino- Purine dioxolane)；And lodenosine (FddA).Typically how suitable non-nucleoside reverse transcriptase inhibitor includes but is not limited to Wei Laping (BI-RG-587)；Delavirdine (BHAP, U-90152)；Efavirenz (DMP-266)；PNU-142721；AG- 1549；MKC-442 [1- (ethoxy-methyl) -5- (1- Methylethyl) -6- (benzyl)-(2,4- (1H, 3H)-pyrimidine-two Ketone]；And (+)-Calanolide A (NSC-675451) and B.Typically suitable protease inhibitors includes but is not limited to inverase (Ro31-8959)；Ritonavir (ABT-538)；Indinavir (MK-639)；Nai Feinawei (AG-1343)；Amprenavir (141W94)；Lasinavir (BMS-234475)；DMP-450；BMS-2322623；ABT-378；And AG-1549.It is other disease-resistant Cytotoxic drug includes but is not limited to hydroxycarbamide, virazole, IL-2, IL-12, pentafuside and Yissum (project number 11607).
Suitable chemotherapy or other anticancer drugs include but is not limited to that alkylating agent (unlimitedly includes mustargen, azacyclo- third Alkane derivatives, alkylsulfonate, nitroso ureas and triazenes), such as uracil mustard, pipobroman, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, Chlorambucil, pipobroman, triethylene-melamine, triethylene are thio Phosphamide, busulfan, Carmustine, lomustine, streptozocin, Dacarbazine and Temozolomide；Antimetabolite is (unlimitedly Including f antifol, pyrimidine analogue, purine analogue and adenosine deaminase inhibitors), as methotrexate (MTX), 5- fluoro are urinated Pyrimidine, floxuridine, cytarabine, 6-MP, 6-thioguanine, fludarabine phosphate, Pentostatin and gemcitabine；One A little natural prodcuts and its derivative (such as vinca alkaloids, antitumor antibiotics, enzyme, lymphokine and epipodophyllotoxin), Such as vincaleukoblastinum, vincristine, eldisine, bleomycin, dactinomycin D, daunorubicin, adriamycin, Epi-ADM, remove methoxy Daunorubicin, cytarabine, taxol (TaxolTM), mithramycin, deoxycoformycin, Mitomycin-C, left-handed asparagus fern Amidase, interferon, Etoposide and Teniposide.
Other suitable cytotoxic drugs include but is not limited to Noviburn, CPT-11, Anastrozole, Letrozole, card training His shore, Raloxifene, cyclophosphamide, ifosfamide and Droloxifene.
Following cytotoxic drug (drug including same mechanism) is equally also suitble to: such as epidophylltoxin；Tumour enzyme；Topology is different Structure enzyme inhibitor；Procarbazine；Mitoxantrone；Platinum complexes such as cis-platinum and carboplatin；Biological response modifiers；Growth inhibition Agent；Antihormonal therapy agents；Calciumlevofolinate；Tegafur；And hemopoieticgrowth factor.
Suitable other anticancer drugs include antibody therapy, such as trastuzumab (Trastuzumab), costimulatory molecules antibody, such as CTLA-4,4-1BB and PD-1 or cytokine antibodies (IL-10, TGF-β etc.)；The drug of blocking immunity cell migration, such as becomes Change cytokine receptor antagonist (CCR2, CCR4 and CCR6) etc.；Enhance the drug of immune system, such as complementary or adaptability T cell Transfer.
Suitable anti-cancer vaccine includes dendritic cells, synthetic peptide, DNA vaccination and recombinant virus.
It is familiar with this technology person and knows the method for safely and effectively giving these most of chemotherapeutics.In addition, its administration exists Normative document is always described.For example, the medication of many chemotherapeutics is at " Physicians ' Desk Reference " It is described in (PDR, such as version in 1996, Medical Economics Company, Meng Teweier, New Jersey), disclosing should Document is incorporated herein by reference, as listed by its full text.
Pharmaceutical formulation and dosage form
Compound of the present invention is as drug in use, can be administered by the form of pharmaceutical composition, said medicine group Close the combination that object is compound of the present invention and pharmaceutically acceptable carrier.These compositions can be with ripe in pharmaceutical field Prepared by the mode known, and according to the region for part or systemic therapy and treatment, be administered by all means. Administration can be part (including ophthalmic administration and the mucosa deliveries such as intranasal, vagina and rectum), lung (as by atomizer, gas In pipe, intranasal, epidermis and the approach sucking such as percutaneous or spray into powder or aerosol), it is eyes, oral or extra-parenteral.
The method of ophthalmic administration may include under local administration (eye drops), conjunctiva, eye circumference or intravitreal injection, pass through gas Ball conduit or operation are placed on ophthalmic insert importing of conjunctival sac etc..
The method of parenteral includes vein, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion；Or encephalic, such as The administration of the intrathecal or ventricles of the brain.Parenteral can for single bolus dosage or can pass through continuous pouring pump etc. forms.
The method of local administration may include transdermal skin patches, ointment, lotion, emulsifiable paste, gel, drops, suppository, spray, frost Agent, powder, liquid agent and powder.It may be necessary to or needing using Conventional pharmaceutical carriers, water, powder or oleaginous base, thickening Agent etc..
Pharmaceutical composition of the present invention can be containing as above-mentioned one or moreization in the present invention of active constituent Object is closed, and combines one or more pharmaceutically acceptable carriers.When making composition of the present invention, active constituent is general It mixes, is diluted by adjuvant or in the carrier of the forms such as capsule, anther sac, paper or other containers with adjuvant.When adjuvant conduct When diluent, adjuvant can be solid, semisolid or liquid substance, the excipient, carrier or medium as active constituent.Combination The form of object can be tablet, pill, powder, pastille, wafer, cachet, elixir, suspending agent, emulsion, solution, syrup, aerosol Agent (as solid or liquid medium), containing the up to ointment of reactive compound weight 10%, soft or hard gel capsule, suppository, nothing Bacterium injection and aseptic packaging powder.
Carry out preparation preparation when, reactive compound of the present invention can be clayed into power, with other ingredients Particle size appropriate is provided before merging.If reactive compound is substantially insoluble, can wear into micro- less than 200 meshes Grain size.If reactive compound can be dissolved in water, granule size can be adjusted by crushing, can be substantially evenly distributed In formula, such as from about 40 mesh.
The some embodiments for the excipient that the present invention uses include lactose, dextrose, sucrose, sorbierite, mannitol, shallow lake Powder, Arabic gum, calcium phosphorus, alginates, bassora gum, gelatin, calcium silicates, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, Water, syrup and methylcellulose.Pharmaceutical formulation can also include but is not limited to: lubricant (such as talcum powder, magnesium stearate, mineral Oil etc.), wetting agent, emulsification and suspending agent, preservative (such as methyl p-hydroxybenzoate, propyl ester), sweetener and flavoring agent.This The invention composition can be prepared using program as known in the art, so that active constituent is fast after patient is administered Speed, slow or sustained release.
Formula can also be made in heretofore described composition by unit dosage forms, and every dosage is made to contain about 5 to about 200mg, More typical is about 10 active constituents for arriving about 100mg.Described above " unit dosage forms ", which refer to, is suitable as people experimenter and other The physically separated unit of the single dose of mammal, per unit, which contains to be computed, can produce the pre- of required therapeutic effect Quantitative active material.
Reactive compound in the present invention can be within the scope of various dosage forms effectively, and are generally administered by medicinal effective quantity. The exact practical dosage of compound that is interpreted as usually determines by doctor according to related situation, including need to treat illness, selection Administration route, give practical compound, age, weight and the reaction of individual patients, the severity of patient symptom etc..
When preparing solid composite (such as tablet), main active is mixed with pharmaceutical adjuvants, is formed containing the present invention The pre-preparation composition of the homogeneous mixture of the compound." homogeneous " alleged by appeal refers to that active constituent usually equably divides It dissipates in the composition, so that composition is easy to be further divided into equivalent unit dosage forms, such as tablet, pill, capsule.This solid preformulation The unit dosage forms of the above-mentioned type of the reactive compound of the present invention containing such as 0.1 to about 500mg are further divided into after agent.
Tablet or pill can be coated or otherwise compound, have the dosage form for extending effect beneficial to obtain.For example, Tablet or pill may include interior dosage and external dose component, the latter for the former by form membrane.Two kinds of components can be by enteric Layer separation, enteric layer is for preventing from being disintegrated in stomach and interior component being made completely to pass through duodenum or sustained release.There are many Material can be used for this enteric layer or coating agent, including but not limited to various polymeric acids and polymeric acid and shellac, hexadecane The mixture of pure and mild cellulose acetate.
Can be added the compounds of this invention and composition with the liquid form for oral or injection administration include: aqueous solution, The cream of suitable seasoning syrup, water or oil suspension and edible oil (such as cottonseed oil, sesame oil, coconut oil or peanut oil) seasoning Agent, elixir and similar pharmaceutical carrier etc..
Sucking or the composition sprayed into include that the compounds of this invention is dissolved in pharmaceutically acceptable solution, suspension, water Or organic solvent, or mixtures thereof and powder.Pharmaceutically acceptable tax appropriate may be contained in liquid or solid composition Shape agent.In some embodiments, composition is locally or systemically acted on by mouth or the administration of nasal airways approach to generate.It can be with Composition is atomized using inert gas.It can be directly sucked in atomized soln by atomising device, or atomising device is connected to Mask or intermittent positive pressure breathing machine use.Solution, suspension or powder composition can setting with release formulation in a suitable manner Standby oral or nasal administration.
The amount of the compound or composition of patient is given according to administration ingredient, administration purpose (as prevented or treating), patient State, administration mode etc. and it is different.In treatment use, composition can by it is enough cure or at least partly stop disease symptoms and The content of its complication gives the patient for having suffered from certain disease.Effective dose depends on treated disease condition and attending physician's root According to the judgement of the factors such as disease severity, patient age, weight and general status.
The composition for giving patient can be the form of aforementioned pharmaceutical compositions.It can be by conventional sterilization techniques to these Composition carries out sterilizing or sterile filtration.Aqueous solution can be packed and use or be made lyophilized formulation with original state, low pressure is frozen Dry preparation uses after mixing before administration with sterile water carrier.The pH value of compound formulation is generally between 3 to 11, and more preferable 5 To 9 and most preferably 7 to 8.It is deposited in a salt form it should be appreciated that will lead to drug using above-mentioned some excipient, carrier or stabilizer ?.
The therapeutic dose of compound of the present invention can be according to the special-purpose for the treatment of, the mode for giving compound, trouble Judgement of the health and situation of person and the doctor that writes a prescription etc. and it is different.Ratio of the compound of the present invention in pharmaceutical composition or Concentration can be different because of various factors, including dosage, chemical characteristic (such as hydrophobicity), administration route.For example, of the present inventionization Closing object can provide in the physiological buffer aqueous solution of the compound containing about 0.1 to about 10%w/v, be used for parenteral.One A little typical dosage ranges are in about 1 μ g/kg daily between about 1g/kg weight.In some embodiments, dosage range exists Daily about 0.01mg/kg is between about 100mg/kg weight.How much dosage is likely to be dependent on the type and progress of disease or obstacle Degree, the overall health of particular patient, the Relative biological curative effect of the compound of selection, the formula of adjuvant and administration route etc. Factor.Can by from vitro or the dose-effect curve of animal model test system infer effective dose.
Compound of the present invention can also combine one or more other active constituents and formula, other active constituents are made It may include any drug, such as antiviral drugs, vaccine, antibody, immunopotentiator, immunosuppressor, anti-inflammatory drug.
Labeled compound and measurement method
Another aspect for the present invention is related to fluorescent dye, spin labeling, heavy metal or the radiation mark of the compound Remember that derivative, these substances cannot be only used for iconography, it may also be used for in vivo outer detection, with positioning and quantitative tissue mark IDO enzyme in this (including people) and for by with labeled compound inhibit in conjunction with and identification id O enzyme ligand.The present invention is into one Step provides the detection of the IDO enzyme containing such labeled compound.
Invention further provides the compound isotopically labelleds of the compound." isotope labelling " or " radiation mark Note " compound is the original that one or more atoms are generally found (i.e. present in nature) in atomic weight or mass number and nature The compound of the present invention of son is measured or mass number is different atom substitution or substitution.Suitable radioactive nucleus includes but unlimited In2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、18F、35S、36Cl、82Br、75Br、76Br、77Br、123I、124I、125I and131I.It include the concrete application that radionuclide in radiolabeled compound will depend on radiolabeled compound.For example, To in vitro IDO enzyme label and competitive assay, generally using containing3H、14C、82Br、125I、131I or35The compound of S.To putting Projection picture application, generally using containing11C、18F、125I、123I、124I、131I、75Br、76Br or77The compound of Br.
It is above to tell that " radio-labeled " or " labeled compound " is the compound comprising at least one radionuclide.One In a little embodiments, radionuclide is selected from the following group:3H、14C、125I、35S or82Br。
The method that radioactive isotope covers organic compound is suitable for compound of the present invention, and in ability It is known in domain.
Radiolabeled compound of the present invention can be used for identifying or evaluating the selective mechanisms of compound.In general may be used The new compound (i.e. test-compound) for synthesizing or finding of evaluation reduces radiolabeled compound and IDO enzyme knot of the present invention The ability of conjunction.Test-compound has with the ability affinity directly in connection that radiolabeled compound competes in conjunction with IDO enzyme It closes.
Kit
The invention also includes the kit for treating disease, for example, treat or prevent disease related with IDO or illness, Fat, diabetes and Other diseases according to the present invention.This kit is comprising one or more of the present invention medicinal The container of composition, the pharmaceutical composition contained have effective therapeutic dose.Such medicine box may also include suitable one or more Various conventional dose box ingredients, such as the container containing one or more pharmaceutically acceptable carriers, those skilled in the art Other containers being clear to etc..Can also include in kit as inset or label illustrate compound dosage, medication guide, And/or the specification of compound mixing guidance.
Common abbreviation and symbol
G: gram
Mg: milligram
ML: milliliter
Mol: mole
DEG C: degree Celsius
BINOL:1,1'- binaphthol
BOP: three (dimethylamino) phosphorus hexafluorophosphate of benzotriazole -1- base oxygroup
DCM: methylene chloride
DMAP:4- dimethylamino naphthyridine
DMF: dimethylformamide
DMSO: dimethyl sulfoxide
DPBS: Du Shi phosphate buffer
EA: ethyl acetate
EDTA: ethylenediamine tetra-acetic acid
H2O: water
LDA: lithium diisopropylamine
NBS:N- bromo-succinimide
Min: minute
PCC: pyridine chlorochromate ester
SOCl2: thionyl chloride
TEA: triethylamine
THF: tetrahydrofuran
TLC: thin-layered chromatography
Trypan Blue: trypan blue
Trypsin: trypsase
Detailed description of the invention
Fig. 1 is compound tumor killing effect figure.
Specific embodiment
Reagent and solvent are bought from commercial source, are monitored and are reacted with 0.25mm HSGF254 tlc silica gel plate, are used The tlc silica gel of 200-300 mesh particle size carries out flash column chromatography.With Bruker Avance III Nuclear Magnetic Resonance into The detection of row NMR spectrum.Mass Spectrometer Method is carried out with Agilent LC-MS chromatograph 1260-6110 and 1260-6120.It removes Non- to be otherwise noted, all reactions carry out magnetic agitation at normal temperature.
Following specific embodiment only supplies in detail that the present invention will be described, and not limits this hair in any way It is bright.Those skilled in the art, which will easily recognize, various changes or adjusts nonessential parameter to generate roughly the same knot Fruit.One or more detection methods according to the present invention find that the compound of following embodiment is IDO inhibitor.
Embodiment 1: 5- (2- (1H-TETRAZOLE -5- base) phenyl)-N- (4- aminomethyl phenyl) -1- isobutyl group -2- methyl-1 H- Yin Diindyl -3- formamide
The bromo- 2- Methyl-1H-indole -3- carboxylic acid, ethyl ester of 1A, 5-
By the bromo- 2- Iodoaniline (10g, 33.57mmol) of 4-, ethyl acetoacetate (6.55g, 50.35mmol), cuprous iodide (640mg, 3.36mmol), BINOL (1.922g, 6.71mmol), cesium carbonate (10.94g, 33.57mmol) and DMSO (60mL) It is added in reaction flask.It is heated to 55 DEG C to be stirred to react, TLC monitoring.After completion of the reaction, into reaction solution, increasing amount water dilutes, It is extracted with EA (200mL × 4), merges organic phase, washed away with a large amount of clear water after remaining DMSO with saturated common salt water washing, nothing Aqueous sodium persulfate is dry, and reaction mixture is concentrated to give crude brown grease, is made by using the solvent mixture of EA and hexane Product 3.12g, yield 21% are purified to obtain for the silica gel column chromatography of eluant, eluent.1H NMR (400MHz, CDCl3) δ ppm:8.41 (s,1H)；8.10(d,1H)； 7.14(d,1H)；4.40(q,2H)；2.38(s,3H)；1.39(t,3H).LCMS (ES-API): M/z=282 [M+H]+
The bromo- 1- isobutyl group -2- Methyl-1H-indole -3- carboxylic acid, ethyl ester of 1B, 5-
Compound 2A (3g, 11.5mmol) and DMF (50mL) is added in reaction flask, reacting liquid temperature drops in ice-water bath It is low, sodium hydride (1.1g, 46mmol), the bromo- 2- methylpropane (6.3g, 46mmol) of 1- and potassium iodide (100mg) is added, removes ice Water-bath rises to 50 DEG C of reactions, TLC monitoring.After completion of the reaction, water quenching reaction is added into reaction solution, adds a large amount of water dilutions, It is extracted with EA (150 mL × 4), merges organic phase, wash away DMF with a large amount of clear water, then with saturated common salt water washing, anhydrous slufuric acid Sodium is dry, reaction mixture is concentrated to give yellow oil, by using the solvent mixture of EA and hexane as eluant, eluent Silica gel column chromatography purifies to obtain product 2.85g, yield 79.3%.1H NMR (400MHz, CDCl3) δ ppm:7.86 (d, 1H)； 7.63(s,1H)；7.34(m,2H)；7.18 (d,1H)；4.40(q,2H)；4.13(d,2H)；2.71(s,3H)；2.15(m, 1H)；1.39(t,3H)；1.01(d,6H).LCMS (ES-API): m/z=338 [M+H]+
The bromo- 1- isobutyl group -2- Methyl-1H-indole -3- carboxylic acid of 1C, 5-
Compound 2B (800mg, 2.37mmol) and 50% potassium hydroxide solution (15mL, methanol: water=4:1v/v) are added Enter into reaction flask, is warming up to back flow reaction, TLC monitoring.Reaction solution is down to room temperature after the reaction was completed, is adjusted with 10N hydrochloric acid PH to 5-6 has a large amount of white solids to be precipitated, with EA (100mL × 3) extraction, merge organic phase, successively uses clear water, saturation food Salt water washing, anhydrous sodium sulfate is dry, and reaction mixture is concentrated to give white solid 760mg.1H NMR (400MHz, CDCl3)δ Ppm:11.2 (s, 1H)；7.97(d,1H)；7.49(m,2H)；4.23(d,2H)；2.81(s,3H)；2.25(m,1H)；1.11 (d,6H).LCMS (ES-API): m/z=308 [M-H]-
The bromo- N- of 1D, 5- (4- aminomethyl phenyl) -1- isobutyl group -2- Methyl-1H-indole -3- formamide
Compound 1C (400mg, 1.29mmol) is added in reaction flask, thionyl chloride is added after ice-water bath cooling (6mL), is stirred to react, TLC monitoring.Reaction mixture is concentrated after completion of the reaction.Dissolve the residue in dry THF (10mL) In, TEA (1mL), para-totuidine (346mg, 3.23mmol) is added in ice-water bath cooling, is warmed to room temperature reaction, TLC monitoring.Reaction After the completion, reaction solution is spin-dried for, is extracted after adding enough water-soluble solutions with EA (50mLx3), merges organic phase, successively with clear water, saturation Brine It, anhydrous sodium sulfate is dry, and reaction mixture is concentrated, and is used as and is washed by using the solvent mixture of EA and hexane The silica gel column chromatography of de- agent to obtain product 479mg, yield 80% after purification.1H NMR (400MHz, CDCl3) δ ppm:9.25 (s, 1H)；7.87(d,1H)；7.66 (d,2H)；7.40(d,1H)；7.31(d,2H)；4.13(d,2H)；2.71(s,3H)；2.44 (s,3H)；2.15(m,1H)；1.01(m,6H).LCMS (ES-API): m/z=399 [M+H]+
1,5- (2- (1H-TETRAZOLE -5- base) phenyl)-N- (4- aminomethyl phenyl) -1- isobutyl group -2- Methyl-1H-indole -3- Formamide
By compound 1D (200mg, 0.548mmol), 2- (tetra- pyrazoles of 5-) phenyl boric acid (200mg, 1.096mmol), seven water Solvent (the DMF:H that conjunction potassium phosphate (920mg, 2.74mmol) and 10mL degassing process are crossed2O=10:1 it) is added in tube sealing, uses nitrogen After gas in gas displacement tube sealing is primary, it is rapidly added tetra-triphenylphosphine palladium (60mg, 0.05mmol), in nitrogen displacement tube sealing Gas 3 times or more after be sealed, be heated to 90 DEG C react 7 hours.Reaction solution is down to room temperature, with the KOH solution of 10g/L Dilution has a small amount of solid to be precipitated, is washed with EA (100mL), and organic phase is in buff, and water phase color is shallower.Contact plate organic phase produces Object is less, retains water phase.Water phase adjusts pH to 4-5 with 1N HCl, has a large amount of white solids to be precipitated, and is extracted with EA (60mLx3), Merging organic phase, successively uses clear water, saturated common salt water washing, anhydrous sodium sulfate is dry, reaction mixture is concentrated, by using The solvent mixture of EA and hexane comes to obtain product 142mg, yield 49% after purification as the silica gel column chromatography of eluant, eluent.1H NMR (400MHz, CDCl3) δ ppm:7.97 (dd, 1H)；7.72(s,1H)；7.53(m,2H)；7.41(dd,1H)；7.18(t,3H)； 6.89(d,2H)；6.77(dd,1H)；3.81(d,2H)； 2.43(s,3H)；2.24(s,3H)；2.12(m,1H)；0.90(m, 6H).LCMS (ES-API): m/z=465 [M+H]+
Embodiment 2~5: compound below use the synthetic method similar with compound 1, by midbody compound 1C with Corresponding amine reaction, then obtained through suzuki reaction.
1 compound list of table
Embodiment 6: 5- (2- (1H-TETRAZOLE -5- base) phenyl)-N- (4- aminomethyl phenyl) -1- cyclohexyl -2- methyl-1 H- Yin Diindyl -3- formamide
6A, (3- cyclohexyl amido) butenoic acid ethyl
Ethyl acetoacetate (4.85mL, 38.4mmol) is added in 50mL single port bottle, at room temperature, cyclohexylamine is added dropwise (5.50mL, 48.0mmol) is finished into reaction solution, stirs 5h under equality of temperature.TLC shows raw material fully reacting, into reaction solution 100mL petroleum ether is added, separates organic layer, then successively respectively washed once with water, saturated salt solution, anhydrous sodium sulfate dries, filters, It is concentrated under reduced pressure at 50 DEG C, obtains light yellow oil 8.25g, crude product is not purified, is directly used in and reacts in next step.1H NMR (400MHz, CDCl3) δ ppm:4.82 (s, 1H)；4.40(q,2H)；2.77(m,1H)；2.46(s,3H)；1.94(m,2H)； 1.69(m,4H)；1.56(t,3H)；1.37 (m,4H).LCMS (ES-API): m/z=212 [M+H]+
6B, 1- cyclohexyl -5- hydroxy-2-methyl -1H- indole -3-carboxylic acid's ethyl ester
1,4-benzoquinone (14.52g, 134.3mmol) and dehydrated alcohol 200mL, stirring and dissolving are added in 500mL single port bottle Afterwards, the mixture of intermediate 6A (8.25g, 39.0mmol) and dehydrated alcohol (25mL) are added dropwise in the case where ice-water bath is cooling, then moves Raw material fully reacting is shown to room temperature reaction 18h, TLC.Reaction solution is moved on under condition of ice bath and stirs 30min, a large amount of coffees are precipitated Coffee color solid, filtering, filter cake are dried in vacuo at 50 DEG C with a small amount of cold ethanol washing, solid, obtain 5.42g coffee color solid, Crude product is not purified, is directly used in and reacts in next step.1H NMR (400MHz, CDCl3) δ ppm:7.17 (s, 1H)；7.29(d, 1H)；7.12(d,2H)；4.05(q,2H)；3.38(m, 1H)；2.33(s,3H)；1.82(m,2H)；1.55(m,2H)；1.31 (m,6H)；1.02(t,3H).LCMS (ES-API): m/z=302 [M+H]+
6C, 1- cyclohexyl -2- methyl -5- trifyl -1H- indole -3-carboxylic acid's ethyl ester
Intermediate 6B (5.4g, 17.9mmol) and 60mL methylene chloride are added in 250mL single port bottle, is added with stirring The mixing of trifluoromethanesulfanhydride anhydride (6.0mL, 35.7mmol) and methylene chloride (30mL) are added dropwise in the case where ice-water bath is cooling for 9mL pyridine Then reaction solution is moved on to and reacts 18h at room temperature by object, TLC shows raw material fully reacting.Organic layer is separated, successively with 10% HCl, water, saturated salt solution are respectively washed once, and anhydrous sodium sulfate dries, filters, and are concentrated under reduced pressure at 50 DEG C, are obtained brown oil 11.5g to obtain product 6.2g after purification, receive by using the solvent mixture of EA and hexane as the silica gel column chromatography of eluant, eluent Rate 72.0%.1H NMR (400MHz, CDCl3) δ ppm:7.84 (s, 1H)；7.29(d,1H)；7.12(d,2H)；4.05(q, 2H)；3.38(m,1H)；2.33(s,3H)；1.82(m,2H)；1.55 (m,2H)；1.31(m,6H)；1.02(t,3H).LCMS (ES-API): m/z=434 [M+H]+
6D, 5- (2- (1H-TETRAZOLE -5- base) phenyl) -1- cyclohexyl -2- Methyl-1H-indole -3- carboxylic acid, ethyl ester
Intermediate 6C (2.0g, 4.62mmol), 2- (tetrazole -5- base) benzene boron are sequentially added in Schlenk bottles of 50mL Acid (1.05g, 5.6mmol), cesium carbonate (4.52g, 13.9mmol), tetra-triphenylphosphine palladium (0.53g, 0.46mmol), 20mL DMF and 2mL water, then in N290 DEG C of reaction 3h are warming up under protection.Reaction solution is poured into 80mL water, with 10%HCl tune pH To 1, extracted with 100mL ethyl acetate, organic layer successively uses water, saturated common salt washing, and anhydrous sodium sulfate dries, filters, in 50 It is concentrated under reduced pressure at DEG C, obtains yellow oil 3.44g, the silica gel by using the solvent mixture of EA and hexane as eluant, eluent Column chromatography to obtain product 1.39g, yield 70.2% after purification.1H NMR (400MHz, CDCl3) δ ppm:8.39 (d, 1H)；7.55 (m,2H)；7.28(s,1H)；7.17(d,2H)； 6.95(d,1H)；4.01(q,2H)；3.37(m,1H)；2.35(s,3H)； 1.78(m,2H)；1.51(m,2H)；1.29(m,6H)；0.99(t, 3H).LCMS (ES-API): m/z=430 [M+H]+
6E, 5- (2- (1H-TETRAZOLE -5- base) phenyl) -1- cyclohexyl -2- Methyl-1H-indole -3- carboxylic acid
Intermediate 6D (1.3g, 3.03mmol) and 15mL methanol are added in 100mL single port bottle, is added after stirring and dissolving 5mL 50%KOH solution then heats to 65 DEG C of reactions 2h, TLC and shows raw material fully reacting.First is removed under reduced pressure at 45 DEG C Alcohol has solid precipitation, and 20mL water, which is added, dissolves solid, and with 10%HCl tune pH to 5-6, a large amount of white solids are precipitated, and filters, Filter cake is washed with 30mL, and solid is dried in vacuo at 45 DEG C, obtains white solid 0.95g, yield 78.0%.1H NMR (400MHz, CDCl3) δ ppm:12.89 (s, 1H)；7.97(d,1H)；7.55(d,2H)；7.17(m,3H)；7.05(s,1H)； 3.34(m,1H)；2.31(s,3H)；1.70(m,2H)；1.45 (m,2H)；1.48(m,6H).LCMS (ES-API): m/z=400 [M-H]-
6,5- (2- (1H-TETRAZOLE -5- base) phenyl)-N- (4- aminomethyl phenyl) -1- cyclohexyl -2- Methyl-1H-indole -3- Formamide
Intermediate 6E (0.15g, 0.37mmol) and 5ml anhydrous methylene chloride are added in 25ml single port bottle, under stirring according to Secondary addition open-chain crown ether (0.05g, 0.45mmol), three (dimethylamino) phosphorus hexafluoro phosphorus of benzotriazole -1- base oxygroup Hydrochlorate (bop reagent, 0.25g, 0.56mmol) and diisopropylethylamine (0.15ml, 0.89mmol), then react at room temperature 4h, TLC show raw material fully reacting.15ml methylene chloride is added, separates organic layer, successively uses 10%HCl, water, saturated common salt Washing, anhydrous sodium sulfate are dried, filtered, are concentrated under reduced pressure at 40 DEG C, and crude product is made by using the solvent mixture of EA and hexane To obtain yellow solid 0.16g, yield 87.4% after purification for the silica gel column chromatography of eluant, eluent.1H NMR (400MHz, CDCl3)δ Ppm:9.30 (s, 1H)；8.42(d,1H)；8.01(m,2H)；7.71 (d,2H)；7.63(m,2H)；7.60(d,1H)；7.50 (s,1H)；7.36(d,2H)；3.79(m,1H)；2.76(s,3H)；2.49(s,3H)；2.02 (m,4H)；1.63(m,5H). LCMS (ES-API): m/z=491 [M+H]+
Embodiment 7: by the bromo- 2- Iodoaniline of 4- with it is correspondingCarry out cyclization after, using with 6 class of compound As synthetic method, obtained by midbody compound 6E with corresponding amine coupling.
Embodiment 8: 1- (5- (2- (1H-TETRAZOLE -5- base) phenyl) -1- cyclohexyl -2- Methyl-1H-indole -3- base) -3- Tolyl urea
By the synthetic method of compound 6, midbody compound 6E and DPPA is generated into isocyanates, then with open-chain crown ether Reaction generates compound 8, yield 23.8%.1H NMR (400MHz, CDCl3) δ ppm:7.87 (d, 1H)；7.39(m,4H)；7.07 (d,2H)；6.97 (m,3H)；6.72(d,1H)；4.07(m,1H)；2.28(s,3H)；2.23(s,3H)；2.10(m,2H)； 1.93(m,2H)；1.80(m,2H)； 1.42(m,2H)；1.27(m,2H).LCMS (ES-API): m/z=506 [M+H]+
The biological evaluation of compound
Experimental material and instrument
Positive drug INCB024360 is purchased from MedChem Express company, and Hela cell origin is in Chinese Academy of Sciences's cell Library, complete medium are prepared by our company laboratory, and DPBS, 0.25%Trypsin~EDTA, Trypan Blue are Sai Mo Fly the Gibco of your scientific and technological (China) Co., Ltd of generationTM, microplate reader is the SpectraMax of Molecular Device company 190, cell counter is the Countstar of Shanghai Rui Yu biotechnology company, and cytospin is Town in Shanghai pavilion scientific instrument The TDL-40B of factory.
Reagent
It is 0.2mg/mL that INF- γ (R&D, 28-IF-100), which is dissolved into concentration with axenic purification water,；
4- dimethylaminobenzaldehyde solution (Sigma, CAT#100107) is configured to glacial acetic acid (section dragon, CAT#64197) Concentration is 2% (m/v)；
It is 10mM that sample DMSO (Amresco, CAT#N182), which is dissolved into concentration,；
6.1N trichloroacetic acid (Sigma, CAT#76039).
Cell line and condition of culture
Hela cell culture is at MEM culture medium (Gibco), and 90%；
Sodium Pyruvate (Gibco), 1mM；
Fetal calf serum (Hyclone), 10%；
Mycillin solution (100 ×, Hyclone), 1%；
Gas phase: air, 95%；Carbon dioxide, 5%；
37 DEG C of temperature.
The measurement of IDO enzyme inhibition rate
Hela cell is laid in 96 orifice plates (2500/ hole, the hole 200ul/), after adherent overnight, dilutes INF- γ with culture medium To final concentration of 50ng/mL, then it is arranged simultaneously with the culture medium dilution drug of the γ of INF- containing 50ng/mL to 1uM and 0.1nM Control: culture medium+cell negative control of the 50ng/mL INF- γ containing 0.1%DMSO and blank control: only 0.1% The culture medium of the 50ng/mL INF- γ of DMSO；The former culture medium of 96 orifice plates is sucked, the medicine group and control of 200ul is added in every hole 3 multiple holes are arranged in group, each concentration, and cell is incubated for 48h under regular culture conditions.The cell training in the hole 140ul/ is drawn after 48h Supernatant is supported in 96 hole round bottom plates, the 6.1N trichloroacetic acid of 10ul is added, is mixed, in 50 DEG C of storing 30min；Then with 2500rpm is centrifuged 10min；100ul supernatant is drawn in 96 new hole flat undersides；It is eventually adding the 4- dimethylamino of 100ul 2% Benzaldehyde solution mixes, room temperature avoid light place 10min, detects at microplate reader 480nm.
IDO inhibiting rate=[1- (OD medicine group-OD blank control group)/(OD negative control group-OD blank control group)] × 100%,
Wherein OD medicine group is medicine feeding hole；The 50ng/mL INF- γ culture medium that OD negative control group is 0.1%DMSO is trained Feeding cell；OD blank control group is the 50ng/mL INF- γ culture medium of the not 0.1%DMSO of cell.
2 part of compounds of table and positive drug are in various concentration to the inhibition percentage of IDO
The IDO kynurenin of employment IDO cell measures
Hela cell is laid in 96 orifice plates (2500/ hole, the hole 200ul/), after adherent overnight, dilutes INF- γ with culture medium To final concentration of 50ng/mL, then diluting drug with the culture medium of the γ of INF- containing 50ng/mL, (10 times dilute 5 down to 1uM Control is arranged to 0.1nM) in concentration: culture medium+cell negative control of the 50ng/mL INF- γ containing 0.1%DMSO And blank control: the only culture medium of the 50ng/mL INF- γ of 0.1%DMSO；The former culture medium of 96 orifice plates is sucked, every hole adds Enter the medicine group and control group of 200ul, 3 multiple holes are arranged in each concentration, and cell is incubated for 48h under regular culture conditions.After 48h The cells and supernatant in the hole 140ul/ is drawn in 96 hole round bottom plates, the 6.1N trichloroacetic acid of 10ul is added, mixes, is set in 50 DEG C Put 30min；Then 10min is centrifuged with 2500rpm；100ul supernatant is drawn in 96 new hole flat undersides；It is eventually adding 100ul 2% 4- dimethylaminobenzaldehyde solution mixes, room temperature avoid light place 10min, detects at microplate reader 480nm, uses 5 software of GraphPad prism calculates IC50。
The IDO inhibition measurement result of 3 compound 2,8 of table
The measurement of IDO enzyme inhibitor joint inhibiting rate
Hela cell is laid in 96 orifice plates (2500/ hole, the hole 200ul/), after adherent overnight, dilutes INF- γ with culture medium To final concentration of 50ng/mL, then with the culture medium of the γ of INF- containing 50ng/mL dilute drug, BL0019 and BL0030 from 120nM 2 times of dilutions, 5 concentration down, INCB 024360 is from 60nM 2 times of dilutions, 5 concentration down；It is administered in combination: BL0019: BL0030=1:1, BL00 19:INCB 024360=2:1, BL0030:INCB 024360=2:1, initial concentration is according to single medicine Concentration starts, 2 times of dilutions, in total 6 concentration；Control is set simultaneously: the culture medium of the 50ng/mL INF- γ containing 0.1%DMSO The negative control of+cell and blank control: the only culture medium of the 50ng/mL INF- γ of 0.1%DMSO；Suck 96 orifice plates The medicine group and control group of 200ul is added in former culture medium, every hole, and 3 multiple holes are arranged in each concentration, and cell is in regular culture conditions Lower incubation 48h.The cells and supernatant in the hole 140ul/ is drawn after 48h in 96 hole round bottom plates, and tri- chloroethene of 6.1N of 10ul is added Acid mixes, in 50 DEG C of storing 30min；Then 10min is centrifuged with 250 0rpm；It is flat in 96 new holes to draw 100ul supernatant Plate；It is eventually adding the 4- dimethylaminobenzaldehyde solution of 100ul 2%, is mixed, room temperature avoid light place 10min, in microplate reader It is detected at 480nm, the CI value of drug combination is calculated using Calcusyn software.
The measurement result that table 4 is administered in combination
Embodiment number The corresponding CI of Fa=50%
2:8 0.92
2:INCB 024360 0.89
8:INCB 024360 0.80
Detection to the inhibiting effect for the T cell proliferation for being expressed IDO mediation
Person monocytic cell is collected from peripheral mononuclear cells with leukapheresis, by 1 × 106The density of cells/well, will Person monocytic cell is on 96 well culture plates added in 1640 culture medium of 10% fetal calf serum and the RPMI of 2mM L-Glutamine It is incubated overnight.After retaining attached cell, cultivated 7 days with 250ng/ml IL-4,100ng/ml GM-CSF.With containing 50ng/mL INF- γ, 50 μ g/mL LPS combination of cytokines are accelerated the ripening cell 2 days, with inducing dendritic cell maturation.100-200U/mL is used again The IDO compound of IL-2,100ng/mL anti-cd 3 antibodies and people's allogeneic T cells and different dilutions from Normal donor Complete RPMI 1640 replace culture medium, obtain IDO inhibitor of the final concentration between 500 and 1 μM, cultivate other two days. Impact overnight is added in BrdU, with colorimetric cell proliferation ELISA kit measurement T cell proliferation.In 10 μM of BrdU label solutions In, cell is continuously cultivated 18 hours, removes label culture medium, 200 holes μ L FixDenat/ are added, be incubated for 30 points at room temperature Clock removes FixDenat solution, grips polymer solution with the 100 anti-BrdU-POD antibody in the hole μ L/ and is incubated for 90 minutes, removes antibody and grips conjunction Object is washed cell 3 times with 200 hole μ L/ cleaning solutions, and 100 200 hole μ L/ substrate solutions are added, and reads culture plate number with microplate reader According to, record in different time points it is multiple reading to ensure within the scope of online data.IC50 is less than about to 100 μM of the present inventionization It closes object and is considered as reactive compound.
The vivo detection of IDO inhibition
Mouse colorectal cancer CT26 Transplanted tumor model is established, and gives certain density compound 5, compound 161 respectively With INCB024360 (positive drug), each compound is evaluated to the curative effect of CT26 mice-transplanted tumor.By the CT26 cell of in vitro culture It is inoculated in nude mice dorsal sc, after tumour is grown, 6 groups is randomly divided into, every group 7~8, gives different pharmaceutical (except special theory It is bright outer, be administered 2 times within 1st), it periodically weighs, measure gross tumor volume, by indexs such as the tumor suppression curative effects of each compound of investigation, come Evaluate the drug effect for CT26 model.As the result is shown: compound 8 is better than compound 2 and positive drug, there is certain tumor killing effect.

Claims (19)

1. the compound of structure formula (I) or its stereoisomer, tautomer or officinal salt, solvate:
Wherein:
R1For the alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substitution of the linear chain or branched chain optionally replaced Or unsubstituted miscellaneous alkyl, it is substituted or unsubstituted with or without heteroatomic aromatic radical, substituted or unsubstituted naphthenic base, take Generation or unsubstituted heterocycle, substituted or unsubstituted alkanoyl, substituted or unsubstituted amide groups, substituted or unsubstituted acyl Amine alkyl, the hetero atom are oxygen, sulphur or nitrogen-atoms；
R2Selected from substituted or unsubstituted alkyl, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted alkoxy, substitution or Unsubstituted naphthenic base, substituted or unsubstituted heterocycle, substituted or unsubstituted alkynyl；
A is with or without heteroatomic carbochain, and structure is-(CH2)n, wherein n=0~5；Or-NH (CH2)n, n=0~5, Wherein the end NH is connected with indole ring.
R3For substituted or unsubstituted aromatic radical, aromatic radical can be for full carbon skeleton or containing hetero atoms such as one or more oxygen, sulphur, nitrogen Skeleton；Wherein the substitution on aryl can be a substitution or polysubstituted, and substituent group is independently selected from halogen, hydroxyl, amino, nitre Base, cyano, trifluoromethyl, azido, sulfonyl, sulfoamido, substituted or unsubstituted alkyl, substituted or unsubstituted alkene Base, substituted or unsubstituted alkynyl, substituted or unsubstituted miscellaneous alkyl, C1-C8Substituted or unsubstituted alkoxy, substitution or not Substituted aromatic radical, substituted or unsubstituted naphthenic base, substituted or unsubstituted heterocycle, substituted or unsubstituted alkanoyl, Substituted or unsubstituted amide groups, substituted or unsubstituted amidoalkyl group.
2. compound described in claim 1 or its stereoisomer, tautomer or officinal salt, solvate, special Sign is, the substituent group independently selected from halogen, hydroxyl, amino, nitro, cyano, trifluoromethyl, azido, sulfonyl or Acyl group.
3. compound described in claim 1 or its stereoisomer, tautomer or officinal salt, solvate, special Sign is that wherein alkyl is C1-C8Substituted or unsubstituted alkyl group ,-(CH2)n-Ar-、-(CH2)n- Cy-, wherein Ar is to replace Or unsubstituted aryl or heteroaryl, Cy are substituted or unsubstituted naphthenic base or Heterocyclylalkyl.
4. compound described in claim 1 or its stereoisomer, tautomer or officinal salt, solvate, special Sign is that wherein alkenyl is the C containing one or more-(C=C)-2-C8Alkyl group.
5. compound described in claim 1 or its stereoisomer, tautomer or officinal salt, solvate, special Sign is that wherein alkynyl is the C containing one or more-(C ≡ C)-2-C8Alkyl group.
6. compound described in claim 1 or its stereoisomer, tautomer or officinal salt, solvate, special Sign is that wherein miscellaneous alkyl is the substituted or unsubstituted of the atom (oxygen, sulphur or nitrogen-atoms) containing one or more in addition to carbon C1-C8Alkyl group.
7. compound described in claim 1 or its stereoisomer, tautomer or officinal salt, solvate, special Sign is that wherein alkoxy is-O-R4, wherein R4For the substituted or unsubstituted C of linear chain or branched chain1-C8Alkyl, alkenyl or alkynes Base.
8. compound described in claim 1 or its stereoisomer, tautomer or officinal salt, solvate, special Sign is that wherein aromatic radical can have thereon for that can be the heteroatomic skeleton such as full carbon skeleton or the oxygen containing one or more, sulphur, nitrogen One or more substituent groups, in some circumstances, two substituent groups of arbitrary neighborhood can form C1-C6With or without hetero atom The cyclic structure of (oxygen, sulphur or nitrogen).
9. compound described in claim 1 or its stereoisomer, tautomer or officinal salt, solvate, special Sign is that wherein naphthenic base is C3-C7Carbocylic radical.
10. compound described in claim 1 or its stereoisomer, tautomer or officinal salt, solvate, special Sign is that wherein heterocycle is the substituted or unsubstituted of the atom (oxygen, sulphur or nitrogen-atoms) containing one or more in addition to carbon C3-C7Carbocylic radical.
11. compound described in claim 1 or its stereoisomer, tautomer or officinal salt, solvate, special Sign is that wherein alkanoyl is-(C=O)-R5, wherein R5For the substituted or unsubstituted C of linear chain or branched chain1-C7Alkyl.
12. compound described in claim 1 or its stereoisomer, tautomer or officinal salt, solvate, special Sign is that wherein amide groups is-(C=O)-NH-R6, wherein R6For hydrogen, the substituted or unsubstituted C of linear chain or branched chain1-C7Alkane Base.
13. compound described in claim 1 or its stereoisomer, tautomer or officinal salt, solvate, special Sign is that wherein amidoalkyl group is-R7(C=O)-NH-R8, wherein R7For the substituted or unsubstituted C of linear chain or branched chain1-C7Alkane Base, R8For hydrogen, the substituted or unsubstituted C of linear chain or branched chain1-C5Alkyl.
14. compound described in claim 1 or its stereoisomer, tautomer or officinal salt, solvate, special Sign is that wherein sulfonyl is substituted or unsubstituted C1-C6Alkyl sulphonyl.
15. compound described in claim 1 or its stereoisomer, tautomer or officinal salt, solvate, special Sign is, it is characterised in that R3For substituted or unsubstituted phenyl or containing one or more heteroatomic hexa-atomic aromatic radicals, wherein Hetero atom is N, O or S.
16. compound described in any one of claim 10 or its stereoisomer, tautomer or officinal salt, solvate, It is characterized by having the structural formula such as formula (II):
Wherein:
R1For the alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substitution of the linear chain or branched chain optionally replaced Or unsubstituted miscellaneous alkyl, it is substituted or unsubstituted with or without heteroatomic aromatic radical, substituted or unsubstituted naphthenic base, take Generation or unsubstituted heterocycle, substituted or unsubstituted alkanoyl, substituted or unsubstituted amide groups, substituted or unsubstituted acyl Amine alkyl, aforementioned hetero atom are oxygen, sulphur or nitrogen-atoms；
R2Selected from substituted or unsubstituted alkyl, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted alkoxy, substitution or Unsubstituted naphthenic base, substituted or unsubstituted heterocycle, substituted or unsubstituted alkynyl；
N is selected from 0~5；
R3For substituted or unsubstituted fragrant phenyl or six Yuans aromatic radicals containing one or more hetero atoms (nitrogen, oxygen or sulphur), wherein Substitution on aryl can be a substitution or polysubstituted, and substituent group is independently selected from halogen, hydroxyl, amino, nitro, cyano, trifluoro Methyl, azido, sulfonyl, sulfoamido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substitution do not take The alkynyl in generation, substituted or unsubstituted miscellaneous alkyl, C1-C8Substituted or unsubstituted alkoxy, substituted or unsubstituted aromatic radical, It is substituted or unsubstituted naphthenic base, substituted or unsubstituted heterocycle, substituted or unsubstituted alkanoyl, substituted or unsubstituted Amide groups, substituted or unsubstituted amidoalkyl group.
17. compound described in claim 11 or its stereoisomer, tautomer or officinal salt, solvate, It is characterized by having the structural formula such as formula (III):
Wherein:
R1For the alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substitution of the linear chain or branched chain optionally replaced Or unsubstituted miscellaneous alkyl, it is substituted or unsubstituted with or without heteroatomic aromatic radical, substituted or unsubstituted naphthenic base, take Generation or unsubstituted heterocycle, substituted or unsubstituted alkanoyl, substituted or unsubstituted amide groups, substituted or unsubstituted acyl Amine alkyl, aforementioned hetero atom are oxygen, sulphur or nitrogen-atoms；
R2Selected from substituted or unsubstituted alkyl, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted alkoxy, substitution or Unsubstituted naphthenic base, substituted or unsubstituted heterocycle, substituted or unsubstituted alkynyl；
N is selected from 0~5；.
R3For substituted or unsubstituted fragrant phenyl or six Yuans aromatic radicals containing one or more hetero atoms (nitrogen, oxygen or sulphur), wherein Substitution on aryl can be a substitution or polysubstituted, and substituent group is independently selected from halogen, hydroxyl, amino, nitro, cyano, trifluoro Methyl, azido, sulfonyl, sulfoamido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substitution do not take The alkynyl in generation, substituted or unsubstituted miscellaneous alkyl, C1-C8Substituted or unsubstituted alkoxy, substituted or unsubstituted aromatic radical, It is substituted or unsubstituted naphthenic base, substituted or unsubstituted heterocycle, substituted or unsubstituted alkanoyl, substituted or unsubstituted Amide groups, substituted or unsubstituted amidoalkyl group.
18. a kind of compound or its stereoisomer, tautomer or officinal salt as described in claim 1-17 is any, Solvate, treating cancer, cardiovascular disease, nervous system degeneration disease, psychotic disorder, virus infection, itself are exempted from inflammation The purposes of epidemic disease or other chronic diseases related with tryptophan metabolism disorder.
19. a kind of includes the compound as described in claim 1-17 is any or its stereoisomer, tautomer or can medicine With the pharmaceutical composition of salt, solvate.
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