CN107663159A - Polycyclic compound, its pharmaceutical composition and application - Google Patents

Polycyclic compound, its pharmaceutical composition and application Download PDF

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CN107663159A
CN107663159A CN201710633069.1A CN201710633069A CN107663159A CN 107663159 A CN107663159 A CN 107663159A CN 201710633069 A CN201710633069 A CN 201710633069A CN 107663159 A CN107663159 A CN 107663159A
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substituted
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利群
刘胜洋
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Shanghai de Novo Pharmatech Co Ltd
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Abstract

The invention discloses a kind of polycyclic compound, its preparation method, pharmaceutical composition and application.Polycyclic compound (I), its isomers, prodrug, solvated compoundses, hydrate, stable isotope derivatives or the pharmaceutically acceptable salt of the present invention has following structure.The polycyclic compound of the present invention has good IDO1 inhibitory action, can effectively treat, alleviates and/or prevent the various relevant diseases caused by immunosupress, such as tumour, virus infection or autoimmune disease etc..

Description

Polycyclic compound, its pharmaceutical composition and application
Technical field
The present invention relates to a kind of polycyclic compound, its pharmaceutical composition and application.
Background technology
Indole amine 2,3-dioxygenase (IDO) is by some alternative activated macrophages and other immunity regulatory cells Immunological regulation enzyme caused by (being also used as destroying immune strategy by many tumours), in the mankind is compiled by IDO genes Code.Its effect is to decompose required L-Trp to kynurenin (kynurenine).The exhaustion of tryptophan and its metabolism production Thing can cause the strong inhibition effect to immune response, cause the stopping of the growth of T cell, the activation of blocking t cell, induce T The generation of Apoptosis and increase regulatory T cells.By tryptophan inherent immunity has been asserted to kynurenine metabolism pathway With the crucial regulation path of adaptive immunity.
Substantial amounts of preclinical study shows this immune tolerance approach in tumour immunity, autoimmunity, infection, transplanting row Reprimand, and be all activation in allergy.Cancer cell IDO active increasing is presently considered to be a weight of increment and the transfer of cancer The factor wanted.Research shows that IDO causes tumor-specific cytotoxicity T lymphocyte functions to inactivate or can no longer attack patient Cancer cell, in fact, many human cancers, such as prostate cancer, colorectal cancer, cancer of pancreas, cervix cancer, stomach cancer, ovary Cancer, the cancer of the brain, lung cancer etc., all overexpression mankind IDO.IDO suppress can with suppression of the reversing tumor to immune function of human body, from And produce a kind of effective antitumour immune response.Because IDO inhibitor can activate T cell so as to strengthen the immune work(of human body Can, IDO inhibitor has therapeutic action, including drug resistance of tumor and repulsion, chronic infection, HIV and Chinese mugwort to many diseases Disease, autoimmune disease or illness, such as rheumatoid arthritis are grown, immune tolerance and prevention uterus fetus repel.IDO's Inhibitor can be used for treatment nerve or neuropsychiatric disease or obstacle, as depression (Protula et al., 2005, blood, 106:238290；Munn etc., 1998, science 281:11913).
A large amount of preclinical and clinical researches show that the immunocompetence of body can be strengthened by suppressing IDO, and be significantly improved various The antitumor drug effect of chemotherapeutic agent and (C.J.D.Austin and the effect of to disease caused by other immunosupress L.M.Rendina, Drug Discovery Today 2014,1-9).IDO-/- mice gene knockouts are feasible, Er Qie little Mouse is healthy, it means that IDO suppresses that the serious toxicity as caused by the mechanism of action may not be caused.
The IDO micromolecular inhibitors being currently being deployed treat and prevent the above-mentioned disease related to IDO, for example, PCT Patent application WO99/29310 discloses the method for changing T cell mediated immunity, including by giving a certain amount of 1- methyl DL Tryptophan or p- (3 benzofuranyl)-DL-Alanines change the extracellular concentration of local tryptophan and tryptophan metabolism thing (Munn, 1999).The chemical combination of indole amine 2,3-dioxygenase (IDO) activity can be suppressed by being disclosed in WO2004/0234623 Thing；U.S. Patent application 2004/0234623 discloses one kind by taking IDO inhibitor and combining other therapeutic modalities to control Treat cancer or the method for infected patient.
In view of lot of experimental data shows IDO inhibitor to immunosupress, tumor suppression, chronic infection, virus infection bag Including HIV, autoimmune disease or disorder and intrauterine fetal rejection etc. has good treatment and prevention, therefore, most It is good to use the treatment method for reaching suppression tryptophan degradation by suppressing IDO activity.As the HIV suppression such as malignant tumour or HIV T During cell, IDO inhibitor can be used for the activity for strengthening T cell.In addition, IDO chemistry has been studied clearer, and its X- ray crystal structures are also parsed, and this contributes to the structure optimization preferably with Structure-ba sed drug design and medicine.IDO It is a very attractive target currently used for therapeutic intervention.
The content of the invention
The technical problems to be solved by the invention are, there is provided a kind of novel multi-cyclic compounds, its preparation method, medicine Composition and application.The polycyclic compound of the present invention has good IDO inhibitory action, can effectively treat, alleviate and/or in advance The anti-various relevant diseases caused by immunosupress, such as tumour, communicable disease and autoimmunity class disease etc..
Although the activity of the compound disclosed by the invention as shown in formula (I) is showed by suppressing IDO, It suppresses the mechanism not yet thoroughly research of IDO activity, and is also not excluded for it with suppression TDO (tryptophan 2,3- dioxygenases) The possibility of activity.Therefore, relate to " IDO inhibitor " in the present invention and may each comprise following meanings：IDO inhibitor, TDO suppressions Preparation or IDO and TDO double inhibitors.
The invention provides a kind of polycyclic compound (I), its isomers, prodrug, stable isotope derivatives or pharmacy Upper acceptable salt；
Wherein, A rings are phenyl, naphthyl, 5-6 unit monocycles heteroaryl, 8-12 members and ring heteroaryl；
B rings are C6-12Bridged ring base or 6-12 member bridge heterocyclic radicals；
X is connecting key ,-NR4- or-CR5R5a-；
Z be-C (O)-,-S (O)1-2- or-S (O) (NCN)-；
Y is connecting key ,-O- ,-NR4- or-CR5R5a-；Also, it is connecting key during X with Y differences；
Or the Z group that X and Y is connected jointly by them forms 5-8 circle heterocycles alkyl together, the Heterocyclylalkyl is also Further N, O, S (O) can be selected from containing 1-20-2Hetero atom；
L1For connecting key or-(L)t-；
L2For connecting key, C2-6Alkenylene, C2-6Alkynylene or-(L)t-；
L is CR6R6a；
R1Selected from hydrogen, halogen, hydroxyl, alkyl, alkoxy, alkylthio group, haloalkyl, halogenated alkoxy, amino, C2-6Alkynes Base, C2-6Alkenyl ,-SH ,-CN ,-NO2、-ORb、-OC(O)Ra、-OC(O)ORb、-OC(O)N(Rb)2、-C(O)ORb、-C(O)Ra、-C (O)N(Rb)2、-N(Rb)2、-NRbC(O)Ra、-N(Rb)C(O)ORb、-N(Rb)C(O)N(Rb)2、-(CH2)tN(Rb)2、-NRbS(O)2Ra、-S(O)0-2Ra、-S(O)2N(Rb)2, cycloalkyl, Heterocyclylalkyl, substitution or be substitution aryl and substitution or be substitution One or more in heteroaryl；When the aryl or substituted heteroaryl, optionally by 1~3 selected from halogen, ammonia Base, cyano group, hydroxyl, C1-3Alkyl, C1-3Alkoxy, halo C1-3Alkoxy or halo C1-3The substituent of alkyl substitutes any position again Put；
R2Or R3Independently selected from hydrogen ,-NO2、-CN、-OH、-NH2、-SH、-OR8、-OC(O)R8、-OC(O)NR7R8、-OC (O)OR8、-OP(O)(O-R7)2、-B(O-R7)2、-OS(O)2(OH)、-OS(O)1-2R8、-S(O)1-2OR8、-S(O)2NR7R8、-S (O)0-2R8、-S(O)2N(R7)C(O)NR7R8、-C(O)OR8、-C(O)R8、-C(O)N(OH)R8,-C (=Rc)NR7R8、-NR7R8、- N(R7)C(O)OR8、-N(R7)C(O)N(R7)S(O)2R8、-N(R7) C (=Rc)NR7R8、-N(Rd)S(O)1-2R8、-N(R7)C(O) R8、-N(Rd)S(O)1-2NR7R8、-N(R7) C (=Rc)R8、-N(R7)OR8、-N(R7)C(O)NR7R8, oxo base, halogen, C2-6Alkynes Base, C2-6Alkenyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substitution Or the unsubstituted substituted or unsubstituted aryl of Heterocyclylalkyl；
R4For hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycle alkane Base；
R5And R6Separately selected from hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkanes Base, substituted or unsubstituted Heterocyclylalkyl, or substituted or unsubstituted alkoxy；
R5aAnd R6aSeparately selected from hydrogen, deuterium, halogen, hydroxyl, amino, alkyl ,-SRa、-ORb、-N(Rb)2、-NRbS (O)2Ra、-S(O)2N(Rb)2、-(CH2)tS(O)0-2CH3、-OS(O)3H、-OP(O)(O-Rb)2、-OC(O)Ra、-OC(O)N (Rb)2、-C(O)N(Rb)2、-(CH2)tC(O)OH、-(CH2)tOH、-(CH2)tN(Rb)2Or-(CH2)tC(O)N(Rb)2；
Or R5And R5a3-8 unit monocycle cycloalkyl is formed together with the C atoms connected jointly with them；
Or R6And R6a3-8 unit monocycle cycloalkyl is formed together with the C atoms connected jointly with them；
R7Selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkanes Base, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substitution do not take The cycloalkyl-alkyl in generation, substituted or unsubstituted hetercycloalkylalkyl, substituted or unsubstituted aryl alkyl or substitution do not take The heteroaryl alkyl in generation；
R8Selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkanes Base, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substitution do not take The cycloalkyl-alkyl in generation, substituted or unsubstituted hetercycloalkylalkyl, substituted or unsubstituted aryl alkyl or substitution do not take The heteroaryl alkyl in generation ,-(L)t-R7、-(L)u-OR7、-(L)u-N(R7)2、-(L)t-C(O)OR7、-(L)u-OC(O)R7、-(L)t- C(O)N(R7)2、-(L)u-N(R7)C(O)Rd、-(L)u-N(R7)C(O)N(R7)2、-(L)u-N(R7)C(S)N(R7)2、-(L)u-OS (O)1-2R7、-(L)u-S(O)1-2OR7、-(L)u-S(O)0-2R7、-(L)u-N(Rd)S(O)2N(R7)2、-(L)u-S(O)2N(R7)2、- (L)u-N(Rd)S(O)2R7Or-(L)u-OP(O)(O-R7)2；
Or R7And R8Single Heterocyclylalkyl of 3-8 members is formed together with the N atoms connected jointly with them；
RaAnd RbIt is each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, heterocycle Alkyl-alkyl, cycloalkyl-alkyl, aryl alkyl or aryl alkyl, or, two RbTogether with the N atoms connected jointly with them Form the monocyclic heterocycloalkyl of 3-8 members；
=RcSelected from=O ,=S ,=NH or=N (OH)；
N is 1,2 or 3；
M is 1 or 2；
T is 1,2,3,4,5 or 6；
U is 2,3,4,5 or 6.
In the A rings, the 5-6 unit's heteroaryls are preferably pyrrole radicals, pyrazolyl, thienyl, pyridine radicals or pyrimidine radicals；
In the A rings, simultaneously ring heteroaryl is preferably that A rings are indyl, isoindolyl, indazolyl, benzo to the 8-12 members Isoxazolyl, benzofuranyl or benzothienyl.
The R1Preferably hydrogen, halogen, hydroxyl, sulfydryl, cyano group, amino, C1-3Alkoxy, C1-3Alkylthio group, C1-3Alkyl (for example, methyl, ethyl, n-propyl or isopropyl), halo C1-3Alkyl and halo C1-3Alkoxy, substitution or the phenyl for substitution In one or more.
The R1More preferably：H、F、Cl、Br、-CH3、-CN、-OCH3、-OCF3, phenyl or be selected from fluoroform by 1 One or more in the phenyl that base, trifluoromethoxy, fluorine or chlorine arbitrarily substitute.
In the B rings, the C6-12The preferred C of bridged ring base7-10Bicyclic bridged ring base, or C8-12Three ring bridged ring bases；
In the B rings, the preferred 7-10 membered bicyclics bridge heterocyclic radical of 6-12 members bridge heterocyclic radical, or 8-12 membered tricyclic bridge heterocycles Base；
In the B rings, the C7-10Bicyclic bridged ring base preferably bicyclic [2.2.1] heptane base (including：)、(1R, 5S)-bicyclic [3.2.1] octylBicyclic [2.2.2] octylOr (1s, 5s)-bicyclic [3.3.1] nonane Base
In the B rings, the C8-12The three preferred C of ring bridged ring base9-10Three ring bridged ring bases, more preferably adamantyl
In the B rings, the bicyclic bridge heterocyclic radical of the 7-10 be preferably 2- azabicyclos [2.2.1] heptane base (including：), 2- oxabicyclos [2.2.1] heptane base (including：), 2,5- diazabicyclos [2.2.1] heptane base (including： ), (1S, 5S) -9- oxabicyclos [3.3.1] nonyl(1R, 5S) -9- azabicyclos [3.3.1] nonyl(1R, 5S) -3- azabicyclos [3.3.1] nonyl(1R, 5S) -8- oxa-s Bicyclic [3.2.1] octyl(1R, 5S) -3- oxabicyclos [3.2.1] octyl(1R, 5S) -3- nitrogen Miscellaneous bicyclic [3.2.1] octyl(1R, 5S) -8- azabicyclos [3.2.1] octylQuininuclidinyl2- azabicyclos [2.2.2] octyl(1R, 5S) -3,8- diazas [3.2.1] octylOr (1R, 5S) -3,9- diazas [3.3.1] nonyl
In the B rings, the preferred 8-10 membered tricyclics bridge heterocyclic radical of 7-10 membered tricyclics bridge heterocyclic radical, more preferably 2- azepines gold Firm alkyl
In the X or Y, the R4Preferably hydrogen, substituted or unsubstituted C1-4Alkyl, substituted or unsubstituted C3-8Cycloalkanes Base or substitution or the 3-8 circle heterocycles alkyl for substitution.
R4In, can be as follows when the Heterocyclylalkyl of the substituted alkyl, the cycloalkyl of substitution or substitution is substituted One or more group substitutions are at an arbitrary position：Halogen, hydroxyl, alkyl, Heterocyclylalkyl, cycloalkyl, alkoxy, amino, aryl, Heteroaryl ,-SRa、-N(Rb)2、-S(O)2N(Rb)2、-NRbC(O)N(Rb)2、-NRbC(O)Ra、-C(O)Ra、-S(O)0-2Ra、-C (O)ORb、-(CH2)tOH or-(CH2)tN(Rb)2；
The R4More preferably hydrogen.
In the Y, the R5Preferably hydrogen, deuterium, halogen, substituted or unsubstituted C1-4It is alkyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-8 circle heterocycles alkyl, or substituted or unsubstituted C1-4Alkoxy；
R5In, the substituted alkyl, the cycloalkyl of substitution, the Heterocyclylalkyl of substitution, or the alkoxy of substitution are as follows One or more group substitutions are at an arbitrary position：Halogen, hydroxyl, alkyl, Heterocyclylalkyl, cycloalkyl, alkoxy, amino, aryl, Heteroaryl ,-SRa、-N(Rb)2、-S(O)2N(Rb)2、-NRbC(O)N(Rb)2、-NRbC(O)Ra、-C(O)Ra、-S(O)0-2Ra、-C (O)ORb、-(CH2)tOH or-(CH2)tN(Rb)2；
In the Y, the R5aIt is preferred that hydrogen, deuterium, halogen, hydroxyl, amino, C1-4Alkyl ,-SRa、-ORb、-N(Rb)2、-NRbS (O)2Ra、-S(O)2N(Rb)2、-(CH2)tS(O)0-2CH3、-OS(O)3H、-OP(O)(O-Rb)2、-OC(O)Ra、-OC(O)N (Rb)2、-C(O)N(Rb)2、-(CH2)tC(O)OH、-(CH2)tOH、-(CH2)tN(Rb)2Or-(CH2)tC(O)N(Rb)2；Or R5a And R53-8 unit monocycle cycloalkyl is formed together with the C atoms connected jointly with them.
The R5More preferably H ,-CH3、-CF3、-CH2CH3Or F.
The R5aMore preferably H ,-CH3、-CF3、-CH2CH3Or F.
Described X, Y, Z are preferably following any combination：
1) X is-NR4-, Y be connecting key, Z be-C (O)-；
2) X be connecting key, Y be-NR4-, Z be-C (O)-；
3) X is-NR4-, Y be-NR4-, Z be-C (O)-；
4) X is-NR4-, Y be connecting key, Z be-S (O)2-；
Or 5) X be connecting key, Y be-NR4-, Z be-S (O)2-。
In the L, the R6Preferably hydrogen, deuterium, halogen, substituted or unsubstituted C1-4It is alkyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-8 circle heterocycles alkyl, or substituted or unsubstituted C1-4Alkoxy；
R6In, the substituted alkyl, the cycloalkyl of substitution, the Heterocyclylalkyl of substitution, or the alkoxy of substitution are as follows One or more group substitutions are at an arbitrary position：Halogen, hydroxyl, alkyl, Heterocyclylalkyl, cycloalkyl, alkoxy, amino, aryl, Heteroaryl ,-SRa、-N(Rb)2、-S(O)2N(Rb)2、-NRbC(O)N(Rb)2、-NRbC(O)Ra、-C(O)Ra、-S(O)0-2Ra、-C (O)ORb、-(CH2)tOH or-(CH2)tN(Rb)2；
The R6In, the substituted alkyl, the cycloalkyl of substitution, the Heterocyclylalkyl of substitution, or the alkoxy of substitution are excellent Choosing is substituted at an arbitrary position by such as 1~3 group；
In the L, the R6aIt is preferred that hydrogen, deuterium, halogen, hydroxyl, amino, C1-4Alkyl ,-SRa、-ORb、-N(Rb)2、-NRbS (O)2Ra、-S(O)2N(Rb)2、-(CH2)tS(O)0-2CH3、-OS(O)3H、-OP(O)(O-Rb)2、-OC(O)Ra、-OC(O)N (Rb)2、-C(O)N(Rb)2、-(CH2)tC(O)OH、-(CH2)tOH、-(CH2)tN(Rb)2Or-(CH2)tC(O)N(Rb)2；Or R6a And R63-8 unit monocycle cycloalkyl is formed together with the C atoms connected jointly with them.
The R6Or R6aMore preferably hydrogen, fluorine, hydroxyl, amino, methyl, ethyl or trifluoromethyl.
The L is preferably-CH2-、-CH(CH3)-、-CH(CH2CH3)-、-C(CH3)2-、-CH(CF3)-、-CH(NH2)-、- CH (OH)-,-CHF- or-CF2-。
The L1Preferably connecting key ,-CH2-、-CH(CH3)-or-C (CH3)2-。
The L2Preferably connecting key.
The R1Preferably hydrogen, halogen, hydroxyl, sulfydryl, cyano group, amino, C1-3Alkoxy, C1-3Alkylthio group, C1-4Alkyl (for example, methyl, ethyl, n-propyl, isopropyl or tert-butyl group), halo C1-3Alkyl and halo C1-3One kind or more in alkoxy Kind.
The R1More preferably：H、F、Cl、Br、-CH3、-CN、-OCH3、-OCF3And-NH2In one or more.
R2Or R3In, the substituted or unsubstituted alkyl is preferably substituted or unsubstituted C1-4Alkyl, more preferably take Generation or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl group, substituted or unsubstituted isopropyl；
R2Or R3In, the substituted or unsubstituted aryl is preferably substituted or unsubstituted C6-10Aryl, more preferably benzene Base or naphthyl；
R2Or R3In, the substituted or unsubstituted heteroaryl is preferably substituted or unsubstituted 5-10 unit's heteroaryls, more excellent Elect substituted or unsubstituted pyridine radicals, substituted or unsubstituted pyrimidine radicals, quinolyl or isoquinolyl as；
R2Or R3In, the substituted or unsubstituted cycloalkyl is preferably substituted or unsubstituted C3-8Cycloalkyl, more preferably For substituted or unsubstituted C3-8Monocyclic cycloalkyl；
R2Or R3In, the substituted or unsubstituted Heterocyclylalkyl is preferably substituted or unsubstituted 5-8 circle heterocycles alkyl, The more preferably single Heterocyclylalkyl of substituted or unsubstituted 5-8 members；
As described R2Or R3For substituted alkyl, the cycloalkyl of substitution, the Heterocyclylalkyl of substitution, the aryl of substitution, substitution Heteroaryl when can be by following 1-3 RAGroup substitutes at an arbitrary position：-OH、-SH、-CN、-NO2、-NH2, halogen, alkane sulphur Base ,-C (=Rc)N(Rb)2、-OC(O)Ra、-OC(O)ORb、-OC(O)N(Rb)2、-C(O)ORb、-C(O)Ra、-C(O)N(Rb)2、-N (Rb)2、-NRbC(O)Ra、-NRbC (=Rc)Ra、-NRbC(O)ORa、-NRbC(O)N(Rb)2、-NRbC (=Rc)N(Rb)2、-(CH2)tN(Rb)2、-NRbS(O)2Ra、-NRbS(O)2N(Rb)2、-S(O)0-2Ra、-S(O)2N(Rb)2, substituted or unsubstituted alkyl, substitution Or unsubstituted alkoxy, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C2-6Alkenyl, substituted or unsubstituted virtue Base, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl or substituted or unsubstituted heteroaryl；RAIn, institute State alkyl, alkoxy, C2-6Alkynyl, C2-6, can be further when alkenyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl are substituted By 1-3 selected from halogen, hydroxyl, amino, C1-4Alkyl or halo C1-3The substituent substitution of alkoxy is at an arbitrary position；
R2Or R3In, the RAPreferably fluorine, chlorine, bromine ,-OH ,-SH ,-CN ,-NO2、-NH2, alkylthio group ,-C (=Rc)N (Rb)2、-OC(O)Ra、-OC(O)ORb、-OC(O)N(Rb)2、-C(O)ORb、-C(O)Ra、-C(O)N(Rb)2、-N(Rb)2、-NRbC (O)Ra、-NRbC (=Rc)Ra、-NRbC(O)ORa、-NRbC(O)N(Rb)2、-NRbC (=Rc)N(Rb)2、-(CH2)tN(Rb)2、- NRbS(O)2Ra、-NRbS(O)2N(Rb)2、-S(O)0-2Ra、-S(O)2N(Rb)2, substituted or unsubstituted C1-4Alkyl, substitution or not Substituted C1-4Alkoxy, C1-4Alkylthio group, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C2-6Alkenyl, phenyl, C3-8Cycloalkyl, 5-8 circle heterocycles alkyl, 5-6 unit's heteroaryls；
R2Or R3In, the RAIn, the alkyl, alkoxy, C2-6Alkynyl, C2-6Alkenyl, aryl, heteroaryl, cycloalkyl, Or Heterocyclylalkyl it is substituted when, can be further by 1-3 selected from halogen, hydroxyl, amino, C1-3Alkyl or halo C1-3Alkoxy Substituent substitution at an arbitrary position.
R2Or R3In, the R7Preferably hydrogen, substituted or unsubstituted C1-4Alkyl, substituted or unsubstituted C1-4Alkoxy, Substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 5-8 circle heterocycles alkyl, substituted or unsubstituted C6-10Aryl, take Generation or unsubstituted 5-6 unit's heteroaryls, substituted or unsubstituted C3-8Cycloalkyl C1-4Alkyl, substituted or unsubstituted 5-8 members are miscellaneous Cycloalkyl C1-4Alkyl, substituted or unsubstituted C6-10Aryl C1-4Alkyl, substituted or unsubstituted 5-6 unit's heteroaryls C1-4Alkyl；
R2Or R3In, the R8Preferably hydrogen, substituted or unsubstituted C1-4Alkyl, substituted or unsubstituted C1-4Alkoxy, Substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 5-8 circle heterocycles alkyl, substituted or unsubstituted C6-10Aryl, take Generation or unsubstituted 5-6 unit's heteroaryls, substituted or unsubstituted C3-8Cycloalkyl C1-4Alkyl, substituted or unsubstituted 5-8 members are miscellaneous Cycloalkyl C1-4Alkyl, substituted or unsubstituted C6-10Aryl C1-4Alkyl, substituted or unsubstituted 5-6 unit's heteroaryls C1-4Alkane Base ,-(L)t-R7、-(L)u-OR7、-(L)u-N(R7)2、-(L)t-C(O)OR7、-(L)u-OC(O)R7、-(L)t-C(O)N(R7)2、- (L)u-N(R7)C(O)Rd、-(L)u-N(R7)C(O)N(R7)2、-(L)u-N(R7)C(S)N(R7)2、-(L)u-OS(O)1-2R7、- (L)u-S(O)1-2OR7、-(L)u-S(O)0-2R7、-(L)u-N(Rd)S(O)2N(R7)2、-(L)u-S(O)2N(R7)2、-(L)u-N(Rd) S(O)2R7Or-(L)u-OP(O)(O-R7)2；
Or R7And R8Single Heterocyclylalkyl of 3-8 members is formed together with the N atoms connected jointly with them；
As described R7Or R8For substituted alkyl, substituted or unsubstituted alkoxy, substitution cycloalkyl, substitution it is miscellaneous Cycloalkyl, the aryl of substitution, the heteroaryl of substitution, the cycloalkyl-alkyl of substitution, the hetercycloalkylalkyl of substitution, the aryl of substitution Can be by following 1-3 R when alkyl or the heteroaryl alkyl of substitutionBGroup substitutes at an arbitrary position：-OH、-SH、-CN、-NO2、- NH2, halogen, alkylthio group ,-C (=Rc)N(Rf)2、-OC(O)Rf、-OC(O)ORf、-OC(O)N(Rf)2、-C(O)ORf、-C(O) Rf、-C(O)N(Rf)2、-N(Rf)2、-NRfC(O)Rg、-NRfC (=Rc)Rg、-NRfC(O)ORf、-NRfC(O)N(Rf)2、-NRfC (=Rc)N(Rf)2、-(CH2)tN(Rf)2、-NRfS(O)2Rg、-NRfS(O)2N(Rf)2、-S(O)0-2Rg、-S(O)2N(Rf)2, substitution Or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C2-6Alkene Base, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl or substitution or not Substituted heteroaryl；
R7Or R8In, described RBPreferably-OH ,-SH ,-CN ,-NO2、-NH2, fluorine, chlorine, bromine, C1-4Alkylthio group ,-C (= Rc)N(Rf)2、-OC(O)Rf、-OC(O)ORf、-OC(O)N(Rf)2、-C(O)ORf、-C(O)Rf、-C(O)N(Rf)2、-N(Rf)2、- NRfC(O)Rg、-NRfC (=Rc)Rg、-NRfC(O)ORf、-NRfC(O)N(Rf)2、-NRfC (=Rc)N(Rf)2、-(CH2)tN (Rf)2、-NRfS(O)2Rg、-NRfS(O)2N(Rf)2、-S(O)0-2Rg、-S(O)2N(Rf)2, substituted or unsubstituted C1-4Alkyl, take Generation or unsubstituted C1-4Alkoxy, substituted or unsubstituted C2-6Alkenyl, substituted or unsubstituted C2-6Alkynyl, substitution do not take The phenyl in generation, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 5-8 circle heterocycles alkyl or substituted or unsubstituted 5-6 unit's heteroaryls；
RBIn, the alkyl, alkoxy, C2-6Alkenyl, C2-6Alkynyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl quilt , can be further by 1-3 selected from hydroxyl, halogen, amino, C during substitution1-3Alkyl or halo C1-3The substituent of alkyl is substituted in Optional position；
The R2Or R3More preferably：Hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl group, isopropyl, the tert-butyl group, methoxyl group, second Epoxide, isopropoxy, cyclohexyl epoxide, phenyl epoxide, benzyl epoxide, difluoromethyl, phenyl, pyridine radicals, pyrimidine radicals, pyrazine Base, quinolyl, isoquinolyl, tetrazole ,-C (O) OH ,-OH ,-NO2、-NH2、-NHC(O)CH3、-CN、-OCH3、-OCF3、- CF3、-CH2OH、-CH2NH2、-OP(O)(OH)2、
The R2More preferably hydrogen, phenyl, pyridine radicals, quinolyl,
The R3More preferably hydrogen, hydroxyl or methyl.M is preferably 0 or 1.
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its general structure are preferably：
Wherein, U is NH or CH2；
A rings, R1、R2、R3、L1、L2, X, Y, Z and n be the same as those described above.
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its general structure are preferably：
Wherein, A rings, R1、R2、R3、L1、L2, X, Y, Z and n be the same as those described above.
Various situations are included in structural formula (IA) definition below：
In wherein a kind of preferred embodiment, X be-NH-, Y be connecting key, Z be-C (O)-；
In wherein a kind of preferred embodiment, X be-NH-, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y is that-NH-, Z are S (O)2。
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its general structure are preferably：
Wherein, A rings, R1、R2、R3、L1、L2, X, Y, Z and n be the same as those described above.
Various situations are included in structural formula (IB) definition below：
In wherein a kind of preferred embodiment, X be-NH-, Y be connecting key, Z be-C (O)-；
In wherein a kind of preferred embodiment, X be-NH-, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y is that-NH-, Z are S (O)2。
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its general structure are more preferably：
Wherein,The stereoisomeric configurations of the singly-bound of mark are respectively cis, trans, or the mixing of cis and trans, its Remaining each substituent is same as above.
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its formula are more preferably following structure：
Wherein,The stereoisomeric configurations of the singly-bound of mark are respectively cis, trans, or the mixing of cis and trans, its Remaining each substituent is same as above.
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its general structure are preferably：
Wherein, U is N or CH；
R1、R2、R3、L1、L2, X, Y, Z and n be the same as those described above.
Various situations are included in structural formula (IE) definition below：
In wherein a kind of preferred embodiment, X be-NH-, Y be connecting key, Z be-C (O)-；
In wherein a kind of preferred embodiment, X be-NH-, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y is that-NH-, Z are S (O)2。
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its general structure are preferably：
Wherein, U is N or CH；
R1、R2、R3、L1、L2, X, Y, Z and n be the same as those described above.
Various situations are included in structural formula (IF) definition below：
In wherein a kind of preferred embodiment, X be-NH-, Y be connecting key, Z be-C (O)-；
In wherein a kind of preferred embodiment, X be-NH-, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y is that-NH-, Z are S (O)2。
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its general structure are preferably：
Wherein, R1、R2、R3、L1、L2, X, Y, Z and n be the same as those described above.
Various situations are included in structural formula (IG) definition below：
In wherein a kind of preferred embodiment, X be-NH-, Y be connecting key, Z be-C (O)-；
In wherein a kind of preferred embodiment, X be-NH-, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y is that-NH-, Z are S (O)2。
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its general structure are preferably：
Wherein, R1、R2、R3、L1、L2, X, Y, Z and n be the same as those described above.
Various situations are included in structural formula (IH) definition below：
In wherein a kind of preferred embodiment, X be-NH-, Y be connecting key, Z be-C (O)-；
In wherein a kind of preferred embodiment, X be-NH-, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y is that-NH-, Z are S (O)2。
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its general structure are preferably：
Wherein, V is N or CH；R1、R2、R3、L1、L2, X, Y, Z and n be the same as those described above.
Various situations are included in structural formula (IJ) definition below：
In wherein a kind of preferred embodiment, X be-NH-, Y be connecting key, Z be-C (O)-；
In wherein a kind of preferred embodiment, X be-NH-, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y is that-NH-, Z are S (O)2。
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its general structure are preferably：
Wherein, V is N or CH；R1、R2、R3、L1、L2, X, Y, Z and n be the same as those described above.
Various situations are included in structural formula (IJ) definition below：
In wherein a kind of preferred embodiment, X be-NH-, Y be connecting key, Z be-C (O)-；
In wherein a kind of preferred embodiment, X be-NH-, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y is that-NH-, Z are S (O)2。
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its formula are more preferably following structure：
Wherein, M O or NH；V is N or CH；
R1、R2、R3、L1、L2, X, Y, Z and n be the same as those described above；
Various situations are included in structural formula (IL) definition below：
In wherein a kind of preferred embodiment, X be-NH-, Y be connecting key, Z be-C (O)-；
In wherein a kind of preferred embodiment, X be-NH-, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y is that-NH-, Z are S (O)2。
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its formula are more preferably following structure：
Wherein, M O or NH；V is N or CH；
R1、R2、R3、L1、L2, X, Y, Z and n be the same as those described above；
Various situations are included in structural formula (IM) definition below：
In wherein a kind of preferred embodiment, X be-NH-, Y be connecting key, Z be-C (O)-；
In wherein a kind of preferred embodiment, X be-NH-, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y is that-NH-, Z are S (O)2。
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its formula are more preferably following structure：
Wherein, M O or NH；V is N or CH；
R1、R2、R3、L1、L2, X, Y, Z and n be the same as those described above；
Various situations are included in structural formula (IN) definition below：
In wherein a kind of preferred embodiment, X be-NH-, Y be connecting key, Z be-C (O)-；
In wherein a kind of preferred embodiment, X be-NH-, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y is that-NH-, Z are S (O)2。
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its formula are more preferably following structure：
Wherein, M O or NH；V is N or CH；
R1、R2、R3、L1、L2, X, Y, Z and n be the same as those described above；
Various situations are included in structural formula (IP) definition below：
In wherein a kind of preferred embodiment, X be-NH-, Y be connecting key, Z be-C (O)-；
In wherein a kind of preferred embodiment, X be-NH-, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y be-NH-, Z be-C (O)-；
In wherein a kind of preferred embodiment, X is connecting key, Y is that-NH-, Z are S (O)2。
The polycyclic compound (I), its isomers, prodrug, stable isotope derivatives or pharmaceutically acceptable salt Most preferably it is following any structure：
Present invention also offers the polycyclic compound (I), its isomers, prodrug, stable isotope derivatives or medicine The preparation method of acceptable salt on, it is following either method：
Method 1：
Compound shown in Formulas I a can be obtained by the reaction equation 1 shown in method 1, wherein, A rings, B rings, R1、R2、L1、L2And n It is as defined above.
Method 1 comprises the following steps：Compound shown in 1-a and 1-b is obtained into Ia by condensation reaction in the basic conditions Shown compound, the condition and step of condensation reaction can be the condition and step of the conventional condensation reaction in this area, and the present invention is special Not not preferably following reaction condition：The preferred DMF of solvent (DMF), described condensing agent preferred 2- (7- azobenzenes And triazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU)；The preferred N of described alkali, N- diisopropylethylamine (DIPEA) or triethylamine (TEA), reaction temperature preferably 0 DEG C~room temperature.
Method 2：
Compound shown in Formulas I b can be obtained by the reaction equation 2 shown in method 2, wherein, A rings, B rings, R1、R2、L1、L2And n It is as defined above.
Method 2 comprises the following steps：Compound shown in 2-a and 2-b is obtained by nucleophilic substitution in the basic conditions To compound shown in Ib, the condition and step of reaction can be this area conventional condition and step, specifically preferred according to the invention following Reaction condition：The preferred dichloromethane of solvent (DCM)；The preferred N of described alkali, N- diisopropylethylamine (DIPEA) or triethylamine (TEA), generally for catalytic reaction process, the 4- methylamino pyridines of catalytic amount can be added in reaction system (DMAP), reaction temperature preferably 0 DEG C~room temperature.
Method 3：
Compound shown in Formulas I c can be obtained by the reaction equation 3 shown in method 3, wherein, A rings, B rings, R1、R2、L1、L2And n It is as defined above.
Method 3 comprises the following steps：Compound shown in 3-a and 3-b is obtained into Id by condensation reaction in the basic conditions Shown compound, the condition and step of condensation reaction can be the condition and step of the conventional condensation reaction in this area, and the present invention is special Not not preferably following reaction condition：The preferred DMF of solvent (DMF), the preferred 1- of described condensing agent (3- diformazan ammonia Base propyl group) -3- ethyl-carbodiimide hydrochlorides (EDCI)；The preferred N of described alkali, N- diisopropylethylamine (DIPEA) or three second Amine (TEA), reaction temperature preferably 0 DEG C~room temperature.
Method 4：
Compound shown in Formulas I d can be obtained by the reaction equation 4 shown in method 4, wherein, A rings, B rings, R1、R2、L1、L2And n It is as defined above.
Method 4 comprises the following steps：Compound shown in 4-a and 4-b is reacted to obtain chemical combination shown in Id in the basic conditions Thing, the condition and step of reaction can be this area conventional condition and step, following reaction condition specifically preferred according to the invention：Solvent It is preferred that dichloromethane (DCM)；The preferred DIPEA of described alkali (DIPEA) or triethylamine (TEA), reaction temperature is excellent Select 0 DEG C~room temperature.
In the above method 1~4, it be present in the compound as shown in formula 1-a, 1-b, 2-b, 3-a, 3-b, 4-a or 4-b When its amino group or oh group, the amino group or oh group can be protected from other side reactions by protection group Occur.Then needed after follow-up deprotection steps if there is above-mentioned amido protecting group or hydroxy-protective group, obtain as Compound shown in Formulas I a, Ib or Ic.Any suitable amido protecting group, such as：Tertbutyloxycarbonyl (Boc) group, can be with For protecting amino group.If using Boc as protection group, follow-up deprotection reaction can be in standard conditions, for example, right Toluenesulfonic acid/methanol system, dichloromethane/trifluoroacetic acid system, the ether solution of hydrogen chloride of saturation or trifluoromethanesulfonic acid front three Carried out in base estersil/2,6- lutidines/dichloromethane system；Any suitable hydroxy-protective group, such as：Benzyl, It can be used for protecting amino group, follow-up deprotection reaction can be in standard conditions, for example, palladium carbon/hydrogen.
The pharmaceutically acceptable salt of the polycyclic compound (I) can be chemically synthesized by general.
Generally, the preparation of salt can by free alkali or acid with etc. chemical equivalent or excess acid (inorganic acid or Organic acid) or alkali (inorganic base or organic base) reacted in suitable solvent or solvent compositions be made.
Present invention also offers a kind of pharmaceutical composition, and it includes the active component of therapeutically effective amount and can pharmaceutically connect The auxiliary material received；The active component includes polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable same One or more in the plain derivative in position and pharmaceutically acceptable salt.
In described pharmaceutical composition, the active component may also include its of cancer, virus infection or autoimmune disease Its therapeutic agent.
In described pharmaceutical composition, the pharmaceutically acceptable auxiliary material may include pharmaceutically acceptable carrier, dilution Agent and/or excipient.
According to therapeutic purposes, pharmaceutical composition can be made to various types of administration unit dosage forms, such as tablet, pill, powder Agent, liquid, suspension, emulsion, granule, capsule, suppository and injection (solution and suspension) etc., preferred liquid, suspension, breast Liquid, suppository and injection (solution and suspension) etc..
In order that the pharmaceutical composition shaping of tablet form, can be used any known and widely used figuration in this area Agent.For example, carrier, such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, avicel cellulose and silicon Acid etc.；Adhesive, such as water, ethanol, propyl alcohol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose Element, lac, methylcellulose and potassium phosphate, polyvinylpyrrolidone etc.；Disintegrant, such as dried starch, mosanom, agar powder and sea Band powder, sodium acid carbonate, calcium carbonate, the fatty acid ester of polyethylene sorbitan, lauryl sodium sulfate, stearic acid monoglycerides, Starch and lactose etc.；Disintegration inhibitor, such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil and fat；Adsorption enhancer, such as season Amine base and lauryl sodium sulfate etc.；Wetting agent, such as glycerine, starch；Adsorbent, such as starch, lactose, kaolin, bentonite With colloid silicic acid etc.；And lubricant, such as pure talcum, stearate, boric acid powder and polyethylene glycol etc..Can also be according to need To be made from common coated material sugar coated tablet, apply gelatin film tablet, enteric coated tablets, film coated tablets, duplicature tablet and Multilayer tablet.
In order that the pharmaceutical composition shaping of pill, it can be used this area any of and widely used figuration Agent, for example, carrier, such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talcum powder etc.；Adhesive, such as Arabic tree Rubber powder, tragacanth gum powder, gelatin and ethanol etc.；Disintegrant, such as agar and Kelp Powder.
In order that the pharmaceutical composition shaping of suppository form, can be used any known and widely used inborn nature in this area Agent, for example, polyethylene glycol, coconut oil, higher alcohol, the ester of higher alcohol, gelatin and semi-synthetic glyceride etc..
In order to prepare the pharmaceutical composition of injection form, (appropriate chlorine can will be preferably added after solution or suspension liquid disinfectant Change sodium, glucose or glycerine etc.), it is made and the isotonic injection of blood.When preparing injection, it is possible to use in the art any Conventional carrier.For example, water, ethanol, propane diols, the isooctadecanol of ethoxylation, the isooctadecanol and polyethylene of polyoxy Fatty acid ester of anhydro sorbitol etc..In addition, it can also add common lytic agent, buffer and anodyne etc..
In the present invention, content of the described composition in pharmaceutical composition, can be in a wide range without specifically limited Selected, generally can be the 5~95% of mass percent, preferably mass percent 30~80%.
In the present invention, the medication of described pharmaceutical composition is not particularly limited.Can according to patient age, sex and its Its condition and symptom, the preparation of various formulations is selected to be administered.For example, tablet, pill, solution, suspension, emulsion, granule or Capsule oral is administered；Injection can be administered alone, or mixed with injection conveying liquid (such as glucose solution and Freamine Ⅲ) Conjunction is injected intravenously；Suppository is to be administered into rectum.
Present invention also offers the polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable Isotope derivatives or pharmaceutically acceptable salt, or described pharmaceutical composition are preparing IDO inhibitor In application.Described indole amine 2,3-dioxygenase inhibitor (IDO inhibitor) refers to that IDO activity or expression can be suppressed (abnormal movement or the overexpression that include IDO), and the immunosuppressive compound for reversing IDO- to mediate.Described IDO inhibitor IDO can be suppressed.
Present invention also offers the polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable Isotope derivatives or pharmaceutically acceptable salt, or described pharmaceutical composition answering in stimulation T cell hyperproliferation agent is prepared With.
Present invention also offers the polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable Isotope derivatives or pharmaceutically acceptable salt, or described pharmaceutical composition are preparing treatment, alleviation and/or prevented by indoles Amine 2,3- dioxygenases mediation relevant disease medicine in application.The N- hydroxy amidino compounds (I), its isomers, Prodrug, solvate, hydrate, stable isotope derivatives or pharmaceutically acceptable salt, or described pharmaceutical composition is also Can combine with the therapeutic agent and/or treatment method for treating cancer of one or more other species be used to treating, alleviate and/ Or the relevant disease that prevention is mediated by IDO.The relevant disease of described 2,3- dioxygenases mediation refers to The disease caused by the immunosupress of 2,3- dioxygenases mediation, described disease may include：Viral or other infection (examples Such as：Skin infection, alimentary infection, urogenital infections, systemic infection etc.), cancer or autoimmune disease (such as：Rheumatoid arthritis, lupus erythematosus, psoriasis etc.).
The therapeutic agent for treating cancer of other species can be made with described polycyclic compound (I) it is single to The therapeutic dosage forms of medicine, or it is taken up in order of priority the therapeutic dosage forms of administration.
The therapeutic agent and/or treatment method for treating cancer of other species may include but be not limited to：Micro-pipe egg White inhibitor, alkylating agent, topological enzyme I/II inhibitor, platinum-like compounds, antimetabolitas, hormone and hormone analogs, letter Number transduction pathway inhibitors, angiogenesis inhibitors, targeted therapy (such as：Special kinase inhibitor), immunotherapeutic agent, rush One or more in apoptosis agent, cell cycle signalling pathways inhibitor and radiotherapy.
The Antitubulin may be selected from but be not limited to：Vincaleukoblastinum series (such as：Vincaleukoblastinum, vincristine, Changchun Rui Bin, eldisine), the one or more in taxanes (docetaxel, taxol) and methanesulfonic acid eribulin.
The alkylating agent may be selected from but be not limited to：Mustargen, ethylenimine derivatives, Loprazolam esters, nitrosourea and One or more in Triazenes.
The topological enzyme I/II inhibitor may be selected from but be not limited to：Irinotecan, TPT, adriamycin and dexrazoxane In one or more.
The platinum-like compounds may be selected from but be not limited to：Cis-platinum and/or carboplatin.
The antimetabolitas may be selected from but be not limited to：Antifol, pyrimidine analogue, purine analogue, adenosine Deaminase inhibitors, such as：Methotrexate (MTX), 5 FU 5 fluorouracil, fluridine, cytarabine, Ismipur, 6- thioguanines, One or more in fludarabine phosphate, Pentostatin and gemcitabine.
The immunotherapeutic agent may be selected from but be not limited to：Anti-tumor vaccine (such as：Synthetic peptide, DNA vaccination and restructuring disease Poison), oncolytic virus, immunostimulation antibody, novel adjuvant, cytokine therapy (such as：IL2 and GM-CSF), chimeric antigen by One in body T cell cure (CAR-T), Small molecule immunodulators, tumor microenvironment conditioning agent and anti-angiogenesis Kind is a variety of.Described immunostimulation antibody may include but be not limited to：1) suppress T cell activity protein antagonist (such as：Exempt from Epidemic disease checkpoint inhibitor)：CTLA4 (such as：Ipilimumab and tremelimumab), PD-1 (such as：pembrolizumab And nivolumab), PD-L1 (such as：Durvalumab, avelumab and atezolizumab), one kind in LAG3 and TIM3 It is or a variety of；1) protein agonist of T cell activity is stimulated：In GITR, OX40, OX40L, 4-1BB (CD137), CD27 and CD40 One or more.
The signal transduction pathway inhibitor (STI) may be selected from but be not limited to：BCR/ABL kinase inhibitors, epidermal growth Factor receptor inhibitor, her-2/neu acceptor inhibitors, AKT family kinase inhibitors, PI3K signal pathway inhibitors and thin Born of the same parents' cycle checkpoint inhibitors.
The angiogenesis inhibitors may be selected from but be not limited to：VEGF/VEGFR signal pathway inhibitors, Src family kinases One or more in inhibitor, Src signal pathway inhibitors and c-Fes kinase inhibitors.
The virus infection may include：By influenza, HCV (HCV), HPV (HPV), huge Cell virus (CMV), epstein-Barr virus (EBV), poliovirus, varicella virus, COxsackie Infected caused by the virus such as virus or human immunodeficiency virus (HIV).
Described cancer may include but be not limited to：Osteocarcinoma, lung cancer, stomach cancer, colon cancer, cancer of pancreas, breast cancer, prostate Cancer, lung cancer, the cancer of the brain, oophoroma, carcinoma of urinary bladder, cervix cancer, carcinoma of testis, kidney, head and neck cancer, lymph cancer, leukaemia and cutaneum carcinoma In one or more.
Described autoimmune disease may include but be not limited to：Rheumatoid arthritis, systemic lupus erythematosus, mixing Property CTD (MCTD), system chorionitis (including：CREST syndromes), dermatomyositis, nodular vasculitis, nephrosis (bag Include：Empsyxis nephrotic syndrome, acute glomerulonephritis, primary membranoproliferative glomerulonephtitis etc.), endocrine relevant disease (including：Type i diabetes, sexual gland insufficiency, pernicious anaemia, hyperthyroidism etc.), hepatopathy (including：Primary biliary Property hepatic sclerosis, autoimmune cholangitis, oneself immunity hepatitis, primary sclerotic cholangitis etc.) and because infection causes Autoimmune response (such as：AIDS, malaria etc.) in one or more.
Present invention also offers it is a kind of with the polycyclic compound (I), its isomers, prodrug, solvate, hydrate, Stable isotope derivatives or pharmaceutically acceptable salt, or in described pharmaceutical composition inhibition system tryptophan degradation side Method, it comprises the following steps：Mammal is suppressed by the compound as shown in formula (I) for giving mammalian therapeutic effective dose The degraded of internal tryptophan；Described system is expression IDO tissue, mammal or cell tissue.
The mammal, preferably people.
In the present invention, unless otherwise indicated, do not referred both to not labeled with what " substituted or unsubstituted " defined before substituent title Substituted situation, such as：" alkyl " refers to unsubstituted alkyl, and " cycloalkyl " refers to unsubstituted cycloalkyl.
In the present invention, unless otherwise indicated, term " being substituted at an arbitrary position by one or more groups " refers on group Any one or multiple hydrogen atoms of specified one or more atoms use specified group to substitute, and condition is no more than The normal chemical valence of specified atom, the substitution is the common reasonable substitution in this area.Such as：It is substituted in by 1~3 group Optional position, referring to can be by the rationally substitution of 1,2 or 3 identical or different substituent at an arbitrary position.
In the present invention, when the bonding display with substituent with connection ring two atoms be bonded intersect when, then so The bonding any bonding annular atom on ring of substituent.
Unless otherwise indicated, the following term occurred in description of the invention and claims has following implications：
Term " alkyl " refers to saturated straight chain or branched hydrocarbyl comprising 1-20 carbon atom, preferably 1~10 carbon atom, More preferably 1~8 carbon atom, the representative example of alkyl include but is not limited to：Methyl, ethyl, n-propyl, isopropyl, positive fourth Base, sec-butyl, the tert-butyl group, isobutyl group, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, 4,4- dimethyl amyl groups, 2,2,4- tri- Methyl amyl, undecyl, dodecyl, and their various isomers etc..
Term " cycloalkyl " refers to the saturation comprising 3-20 carbon atom or part unsaturation (including 1 or 2 double bond) Monocyclic or polycyclic moiety." monocyclic cycloalkyl " preferably 3-10 unit monocycle alkyl, more preferably 5-8 unit monocycles alkyl, such as：Ring third Base, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclodecyl, cyclo-dodecyl, cyclohexenyl group." polycyclic naphthene base " Including " fused cycloalkyl " and " spiro cycloalkyl group ", " fused cycloalkyl " includes the list being fused on aryl, cycloalkyl or heteroaryl Ring cycloalkyl ring, condensed-bicyclic cycloalkyl include but is not limited to：Benzocyclobutene, 2,3- dihydro -1-H- indenes, 2,3- cyclopentas Pyridine, 5,6- dihydro -4H- cyclopenta [B] thiophene, decahydronaphthalene etc.." spiro cycloalkyl group " refers to that two cycloalkyl share a carbon original The bicyclic radicals that son is formed, spiro cycloalkyl group include but is not limited to：Spiral shell [2.4] heptyl, spiral shell [4.5] decane etc..Monocyclic cycloalkyl or Bicyclic cycloalkyl can be connected on parent molecule by arbitrary carbon atom chain on ring.
Term " bridged ring base " includes " bicyclic bridged ring base " and " three ring bridged ring bases "." the bicyclic bridged ring base " refers to monocyclic ring The carbon atom that alkyl any two is not connected with connects (that is ,-(CH by the alkylidene bridge between 1-3 extra carbon atoms2)q- The bridge joint group of form, wherein q are 1,2 or 3).Term " three ring bridged ring bases " refers to that 1) bicyclic bridged ring base any two is not attached to The carbon atom connect connects formed group by the alkylidene bridge between 1-3 extra carbon atoms, or 2) from bicyclic alkyl A non-common annular atom is chosen in two rings of group respectively, and passes through the alkylidene bridge between 1-3 extra carbon atoms Formed group (that is, the-(CH of connection2)qThe bridge joint group of-form, wherein q are 1,2 or 3), described bicycloalkyl radicals by Two monocyclic cycloalkyl fusions form." bridged ring base " the preferred C6-15Bridged ring base, more preferably C7-12Bridged ring base, " bicyclic bridged ring The representative example of base " includes but is not limited to：It is bornyl, bicyclic [2.2.1] heptenyl, bicyclic [3.1.1] heptane base, bicyclic It is [2.2.1] heptane base, bicyclic [2.2.2] octyl, bicyclic [3.2.2] nonyl, bicyclic [3.3.1] nonyl, bicyclic [4.2.1] nonyl etc.；The representative example of " three ring bridged ring bases " includes but is not limited to adamantyl.Three ring bridged cyclic groups can lead to Arbitrary annular atom on ring is crossed to be linked on parent molecule.Above-mentioned annular atom refers in particular to form the carbon atom of ring skeleton.
Term " Heterocyclylalkyl " refers to by carbon atom and the saturation formed selected from hetero atoms such as nitrogen, oxygen or sulphur or part insatiable hunger The non-aromatic cyclic radical of the 3-20 members of (including 1 or 2 double bond), this cyclic group can be monocyclic or bicyclic radicals, at this In invention, hetero atom number preferably 1,2,3 or 4 in Heterocyclylalkyl, nitrogen, carbon or the sulphur atom in Heterocyclylalkyl are optionally by oxygen Change.Nitrogen-atoms optionally can further be substituted by other groups and form tertiary amine or quaternary ammonium salt." monocyclic heterocycloalkyl " preferred 3-10 Unit monocycle Heterocyclylalkyl, more preferably 5-8 unit monocycles Heterocyclylalkyl.Such as：'-aziridino, tetrahydrofuran -2- bases, morpholine -4- bases, Thiomorpholine -4- bases, thiomorpholine-S-oxide -4- bases, piperidin-1-yl, N- Alkylpiperidine -4- bases, pyrrolidin-1-yl, N- Alkyl pyrrolidine -2- bases, piperazine -1- bases, 4- alkyl piperazine -1- bases etc.." polycyclic Heterocyclylalkyl " includes " annelated heterocycles alkyl " " spiro heterocyclic radical "." annelated heterocycles alkyl " includes the monocyclic heterocycles alkane for being fused to phenyl, Heterocyclylalkyl, cycloalkyl or heteroaryl Basic ring, annelated heterocycles alkyl include but is not limited to：
2,3- dihydro benzo furyls, 1,3- dihydroisobenzofurans base, indolinyl, 2,3- dihydrobenzos [b] thiophene Fen base, dihydrobenzo piperazine mutter base, 1,2,3,4- tetrahydric quinoline groups,Deng." spiro heterocyclic radical " refer to two it is miscellaneous Cycloalkyl or a cycloalkyl and Heterocyclylalkyl share the bicyclic radicals that a carbon atom is formed, and spiro heterocyclic radical is included but not It is limited to：Deng.Monocyclic heterocycloalkyl and polycyclic Heterocyclylalkyl can be linked by arbitrary annular atom on ring Onto parent molecule.Above-mentioned annular atom refers in particular to form the carbon atom and/or nitrogen-atoms of ring skeleton.
Term " bridge heterocyclic radical " includes " bicyclic bridge heterocyclic radical " and " three ring bridge heterocyclic radicals ".Described " bicyclic bridge heterocyclic radical " Refer to that the annular atom that monocyclic heterocycloalkyl any two is not connected with is extra by 1-3 extra carbon atoms and hetero atom, 1-3 Carbon atom or the straight chain group bridging that is formed of 1 extra hetero atom obtained by group (described straight chain group be selected from but It is not limited to：-CH2-、-O-、-NH-、-S-、-CH2CH2-、-CH2O-、-CH2S-、-CH2NH-、-CH2CH2CH2-、-CH2OCH2-、- CH2CH2O-、-CH2CH2NH-、-CH2NHCH2-).Described " three ring bridge heterocyclic radicals " refers to 1) bicyclic bridge heterocyclic radical any two The annular atom not being linked is by the 1-3 extra carbon atoms of extra carbon atom and hetero atom, 1-3 or 1 extra miscellaneous original Group obtained by the straight chain group bridging that son is formed, or 2) choose respectively in two rings of double heterocycloalkyls one it is non-common With annular atom, and pass through 1-3 extra carbon atoms and hetero atom, 1-3 extra carbon atoms or 1 extra hetero atom Group obtained by the straight chain group bridging of formation, described straight chain group are selected from, but not limited to,：-CH2-、-O-、-NH-、- S-、-CH2CH2-、-CH2O-、-CH2S-、-CH2NH-、-CH2CH2CH2-、-CH2OCH2-、-CH2CH2O-、-CH2CH2NH-、- CH2NHCH2-, described double heterocycloalkyls by two monocyclic heterocycloalkyls, or a monocyclic heterocycloalkyl and one it is monocyclic It is Cycloalkylfused to form." the bridge heterocyclic radical " preferably 6-15 member bridge heterocyclic radicals, more preferably 7-12 members bridge heterocyclic radical, " bicyclic bridge The representative example of heterocyclic radical " includes but is not limited to：
Deng；The representative of " three ring bridge heterocyclic radicals " Property example includes but is not limited to：Deng.Bridge heterocyclic radical can be connected to parent molecule by arbitrary annular atom on ring On.Above-mentioned annular atom refers in particular to form the carbon atom and/or nitrogen-atoms of ring skeleton.
Term " cycloalkyl-alkyl " refers to connect by alkyl between cycloalkyl and mother nucleus structure.Thus, " cycloalkyl alkane Base " includes the definition of abovementioned alkyl and cycloalkyl.
Term " hetercycloalkylalkyl " refers to connect by alkyl between Heterocyclylalkyl and mother nucleus structure.Thus, " heterocycle alkane Base alkyl " includes the definition of abovementioned alkyl and Heterocyclylalkyl.
Term " alkoxy " refers to has the carbon number purpose ring-type or acyclic alkyl groups, bag by what oxygen bridge connected Containing alkyl oxy, cycloalkyl oxy and Heterocyclylalkyl epoxide.Thus, " alkoxy " includes abovementioned alkyl, Heterocyclylalkyl and cycloalkanes The definition of base.
Term " alkylthio group " refers to, and ring-type or acyclic alkyl groups are connected with each other by sulphur atom and parent molecule, include alkane Base sulfydryl, cycloalkyl sulfydryl and Heterocyclylalkyl sulfydryl.Thus, " alkylthio group " includes abovementioned alkyl, Heterocyclylalkyl and cycloalkyl Definition.
Term " hydroxyalkyl " refers to that any one hydrogen atom is substituted by hydroxyl on alkyl, includes but is not limited to：- CH2OH、-CH2CH2OH、-CH2CH2C(CH3)2OH。
Term " alkenyl " refers to the straight chain containing at least one carbon-carbon double bond, side chain or the non-aromatic alkyl of ring-type.Wherein can be with 1-3 carbon-carbon double bond be present, preferably in the presence of 1 carbon-carbon double bond.Term " C2-4Alkenyl " refers to the alkenyl with 2-4 carbon atom, Term " C2-6Alkenyl " refers to the alkenyl with 2-6 carbon atom, including vinyl, acrylic, cyclobutenyl, 2- methyl butene bases And cyclohexenyl group.Described alkenyl can be substituted.
Term " alkynyl " refers to the straight chain containing at least one triple carbon-carbon bonds, side chain or cyclic hydrocarbon group.Wherein there may be 1-3 triple carbon-carbon bonds, preferably in the presence of 1 triple carbon-carbon bonds.Term " C2-6Alkynyl " refers to the alkynyl with 2-6 carbon atom, including Acetenyl, propinyl, butynyl and 3- methylbutynyls.
Term " aryl " refers to the 6-10 unit monocycles or bicyclic aromatic groups of any stabilization, such as：Phenyl, naphthyl, four Hydrogen naphthyl, indanyl or xenyl etc..
Term " heteroaryl " refers to that the carbon atom at least one ring is formed by the hetero atom displacement selected from nitrogen, oxygen or sulphur Aromatic group, it can be 5-6 unit monocycles structure or 7-12 membered bicyclic structures, preferably 5-6 unit's heteroaryls.In the present invention, Hetero atom number preferably 1,2 or 3, include but is not limited to：Pyridine radicals, pyrimidine radicals, (2H) -one of pyridazine -3 base, furyl, thiophene Base, thiazolyl, pyrrole radicals, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,4- triazol radicals, 1,2,3- triazol radicals, tetrazole base, indazolyl, iso indazolyl, indyl, isoindolyl, benzo furan Mutter base, benzothienyl, benzo [d] [1,3] dioxolanyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, Quinazolyl etc..
Term " and ring heteroaryl " refers to bicyclic heteroaryl and a group selected from bicyclic heteroaryl or monocyclic aryl The group that two adjacent cyclic atoms are formed is shared, described " and ring heteroaryl " is bicyclic radicals.Described and ring heteroaryl is preferred For 8-12 membered bicyclic groups, include but is not limited to：Indazolyl, iso indazolyl, indyl, isoindolyl, benzofuranyl, benzo Thienyl, benzothiazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolyl, 1,8- naphthyridines base, 1,5- naphthyridines base, 4- azaindolyls, 5- azaindolyls, 2- azaindolyls, 6- azaindolyls, 7- azaindolyls, 1H- pyrrolo-es [2,3-B] pyridine radicals, 4- azaindazoles base, 7- azaindazoles base, 6- azaindazoles base, 1H- pyrazolos [3,4- C] pyridine etc..
Term " aryl alkyl " refers to connect by alkyl between aryl and mother nucleus structure.Thus, " aryl alkyl " includes The definition of abovementioned alkyl and aryl.
Term " heteroaryl alkyl " refers to connect by alkyl between Heterocyclylalkyl and mother nucleus structure.Thus, " heteroaryl alkane Base " includes the definition of abovementioned alkyl and heteroaryl.
Term " halogen " represents fluorine, chlorine, bromine or iodine.
Term " haloalkyl " refers to the alkyl arbitrarily substituted by halogen.Thus, " haloalkyl " include above halogen and The definition of alkyl.
Term " halogenated alkoxy " refers to the alkoxy arbitrarily substituted by halogen.Thus, more than " halogenated alkoxy " includes The definition of halogen and alkoxy.
Term " amino " refers to-NH2, term " alkyl amino " refers to that at least one hydrogen atom is taken by alkyl on amino In generation, include but is not limited to：-NHCH2、-NHCH2CH3.Term " aminoalkyl " refers to that any one hydrogen atom is by amino institute on alkyl Substitution, include but is not limited to：-CH2NH2、-CH2CH2NH2.Thus, " alkyl amino " and " aminoalkyl " includes abovementioned alkyl and ammonia The definition of base.
Term " alkylidene ", " alkenylene " or " alkynylene " refers to can be as the alkane of other two groups of connection key connection Base, alkenyl or alkynyl, the alkylidene can be that straight chain can also be branched structure, such as-(CH2)q-；The alkenylene or Alkynylene can be side chain, straight chain or cyclic structure.
Term " adamantyl " refers to：
Term " 2-aza-adamantane base " refers to：
Symbol "=" represents double bond；
" room temperature " of the present invention refers to 15-30 DEG C.
Described isotope substitutive derivative includes：Arbitrary hydrogen atom substitutes to obtain same by 1-5 D-atom in Formulas I Isotope substitutive derivative or the formula that arbitrary carbon atom substitutes to obtain by the 1-3 atom of carbon 14 in the plain substitutive derivative in position, Formulas I The isotope substitutive derivative that arbitrary oxygen atom substitutes to obtain by the 1-3 atom of oxygen 18 in I.
Described " prodrug " refers to that compound is converted into original activity compound after being metabolized in vivo.Typically say, it is preceding Medicine is inert matter, or specific activity parent compound activity is small, but can provide convenient operation, is administered or improve generation Thank to characteristic.
" pharmaceutically acceptable salt " of the present invention is in Berge, et al., " Pharmaceutically Acceptable salts ", J.Pharm.Sci., 66,1-19 are discussed in (1977), and for Pharmaceutical Chemist be it is aobvious and Be clear to, described salt is substantially avirulent, and pharmacokinetic property needed for providing, palatability, absorption, distribution, Metabolism or excretion etc..Compound of the present invention can have acidic-group, basic group or amphiprotic group, typically pharmaceutically Acceptable salt includes the salt being prepared by the compounds of this invention and acid reaction, such as：Hydrochloride, hydrobromate, sulfuric acid Salt, pyrosulfate, disulfate, sulphite, bisulfites, phosphate, dibasic alkaliine, dihydric phosphate, metaphosphoric acid Salt, pyrophosphate, nitrate, acetate, propionate, caprate, caprylate, formates, acrylates, isobutyrate, caproic acid Salt, enanthate, oxalates, malonate, succinate, suberate, benzoate, methyl benzoic acid salt, phthalic acid Salt, maleate, mesylate, tosilate, (D, L)-tartaric acid, citric acid, maleic acid, (D, L)-malic acid are rich Horse acid, succinic acid, succinate, lactate, fluoroform sulphonate, naphthalene -1- sulfonate, mandelate, acetonate, stearic acid Salt, ascorbate, salicylate.When the compounds of this invention contains acidic-group, its pharmaceutically acceptable salt can be with Including：Alkali metal salt, such as sodium or sylvite；Alkali salt, such as calcium or magnesium salts；Organic alkali salt, for example, with ammonia, alkyl ammonia The salt of the formation such as class, hydroxy alkyl Ammonia, amino acid (lysine, arginine), N-METHYL-ALPHA-L-GLUCOSAMINE.
" isomers " of the present invention refer to formula (I) compound of the present invention can have asymmetric center and racemic modification, Racemic mixture and single diastereoisomer, all these isomers, including stereoisomer, geometric isomer include In the present invention.In the present invention, compound of formula I or its salt in the form of stereomeric (for example, its contain it is one or more not Symmetric carbon atom) in the presence of, single stereoisomer (enantiomter and diastereoisomer) and their mixture It is included within the scope of the invention.The compound or the independent isomers of salt represented present invention additionally comprises Formulas I, and with wherein one The mixture of the isomers of individual or multiple chiral centers reversion.The scope of the present invention includes：The mixture of stereoisomer, and The mixture of the enantiomter or enantiomter of purifying/diastereoisomer enrichment.The present invention includes all enantiomerisms The mixture of the stereoisomer of body and all possible various combination of non-corresponding isomers.The present invention includes institute defined above There are whole combinations and the subset of the stereoisomer of specific group.Present invention additionally comprises compound of formula I or the geometrical isomerism of its salt Body, the geometric isomer include cis-trans-isomer.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and it is each preferably to produce the present invention Example.
Agents useful for same and raw material of the present invention are commercially available.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality Apply among a scope.The experimental method of unreceipted actual conditions in the following example, conventionally and condition, or according to business Product specification selects.
The structure of all compounds of the present invention can by nuclear magnetic resonance (1H NMR) and/or Mass Spectrometer Method (MS) identification.
1H nmr chemicals displacement (δ) records (10 with PPM-6).NMR is carried out by Bruker AVANCE-400 spectrometers.Close Suitable solvent is deuterochloroform (CDCl3), deuterated methanol (CD3OD), deuterated dimethyl sulfoxide (DMSO-d6), tetramethylsilane conduct Internal standard (TMS).
Algorithm (MS) is determined by Agilent 1200HPLC/6120 mass spectrographs, using XBridge C18,4.6 × 50mm, 3.5 μm, condition of gradient elution one：80-5% solvent orange 2 As1With 20-95% solvents B1(1.8 minutes), then 95% solvent B1With 5% solvent orange 2 A1(more than 3 minutes), percentage are the percentage by volume that a certain solvent accounts for total solvent volume.Solvent orange 2 A1： The aqueous solution of 0.01% trifluoroacetic acid (TFA)；Solvent B1：The acetonitrile solution of 0.01% trifluoroacetic acid；Percentage accounts for molten for solute The percentage by volume of liquid.Condition of gradient elution two：80-5% solvent orange 2 As2With 20-95% solvents B2(1.5 minutes), then 95% is molten Agent B2With 5% solvent orange 2 A2(more than 2 minutes), percentage are the percentage by volume that a certain solvent accounts for total solvent volume.Solvent orange 2 A2： The aqueous solution of 10mM ammonium hydrogen carbonate；Solvent B2：Acetonitrile.
All compounds of the present invention can pass through high performance liquid chromatograph, silica gel column chromatography, thin layer silica gel plate or quick separating Machine separates.
Fast selector (Flash column chromatographies) (flash system/CheetahTM) use Agela Technologies MP200, matching used splitter are Flash columm Silica-CS (80g), Cat No.CS140080-0。
High performance liquid chromatograph (prep-HPLC) uses Shimadzu LC-20 preparative liquid chromatographies, chromatographic column：X BridgeTM Prep C18,10um, 19*250mm column S/N, Detection wavelength：214,254nm.
Thin layer silica gel plate is Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates.Column chromatography typically uses the Yantai Huanghai Sea 200-300 mesh silica gel is as carrier.
Embodiment 1：The synthesis of compound 1.1
Benzene (30mL) solution of 5- hydroxyl -2- Buddha's warrior attendants alkanones (2g, 12mmol), instillation trifluoromethanesulfonic acid (1.1mL, 12mmol).The system stirs 16 hours in 80 DEG C.Vacuum rotary steam removes solvent, residue silica gel column chromatography (petroleum ether：Acetic acid Ethyl ester=100:1~4:1) isolated compound 1.1 (1.48g, yield：55%) it is white solid.
m/z:[M+H]+227
Embodiment 2：The synthesis of compound 2.2
Step 1：The synthesis of compound 2.1
4- oxo adamantane -1- carboxylic acids (5.0g, 25.8mmol) are dissolved in dichloromethane (75mL), add oxalyl chloride (6.5g, 51.2mmol) and two drop DMFs.After stirring at normal temperature 30 minutes, it is evaporated under reduced pressure and removes solvent, obtain Acyl chlorides dissolving in acetone, and add excessive saturation aqueous sodium azide.Reaction system stirs 1 hour at normal temperatures. Add water, be extracted with ethyl acetate (150mL × 3) aqueous phase, merge organic phase, with saturated common salt water washing, anhydrous sodium sulfate drying, Filtering, solvent is distilled off in filtrate decompression, and obtained residue purifies (petroleum ether with silica gel column chromatography：Ethyl acetate=4:1) Obtain compound 2.1 (4.3g, yield：76%) it is white solid.
Step 2：The synthesis of compound 2.2
Compound 2.1 (4.2g, 19.2mmol) is added in toluene (120mL), then add the tert-butyl alcohol (7.0g, 95.9mmol).After reaction system return stirring 3 hours, vacuum rotary steam removes solvent, adds water in residue, is extracted with ethyl acetate (150mL × 2), merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, filtering, filtrate decompression distillation Remove solvent, obtained residue silica gel column chromatography (petroleum ether：Ethyl acetate=3:1) purify compound 2.2 (4.3g, Yield：84%) it is white solid.
m/z:[M+H]+266
Embodiment 3：The synthesis of compound 2.3
The ammonium persulfate aqueous solution being dissolved in (18.3g, 0.08mol, 40mL) is added drop-wise to 4- oxo adamantane -1- carboxylic acids 10% sulfuric acid water of (15.55g, 0.08mol), 6- fluorine quinoline (5.89g, 0.04mol) and silver nitrate (2.72g, 0.016mol) In solution (40mL) and acetonitrile (80mL).Reactant mixture stirs 1.5 hours at 80 DEG C, is then cooled to room temperature, and use is dense Ammoniacal liquor adjusts pH value to 8-9, ethyl acetate (200mL × 2) extraction, merges organic phase, anhydrous sodium sulfate drying, filtering, filtrate It is concentrated under reduced pressure, residue is isolated and purified to obtain compound 2.3 (4.3g, production with flash column chromatography (petrol ether/ethyl acetate=10/1) Rate：36%) it is white solid.
m/z:[M+H]+296
Embodiment 4：The synthesis of compound 2.4
With the synthetic method of compound 2.3,6- fluorine quinoline is replaced with into pyridine and obtains compound 2.4：
m/z:[M+H]+228
Embodiment 5：Compound 3.3 synthesizes
Step 1：The synthesis of compound 3.1
Potassium tert-butoxide (4.48g, 40mmol) is suspended in tetrahydrofuran (100mL), after ice bath is cooled to 0 DEG C, is added dropwise The tetrahydrofuran solution (50mL) of phosphine acyl acetic acid three ethyl (8.95g, 40mmol).After about 30 minutes are added dropwise, reactant Tie up at 0 DEG C stir 1 hour obtain white suspension.By the tetrahydrofuran (50mL) of 2- Buddha's warrior attendants alkanone (5.0g, 33mmol) Solution is instilled in this suspension.After about 1 hour is added dropwise, ice-water bath is removed, is stirred at room temperature 2 hours.Sediment is filtered out, is filtered Cake is eluted with ethyl acetate (200mL).It is dissolved in after filtrate decompression concentration in ethyl acetate (150mL), adds saturated ammonium chloride water Solution (300mL), stirring, liquid separation.Aqueous phase is extracted with ethyl acetate (150mL).Merge organic phase, organic phase saturated aqueous common salt Wash, be concentrated under reduced pressure after anhydrous sodium sulfate drying.Crude product silica gel column chromatography (petroleum ether：Ethyl acetate=50:1) must change after separating Compound 3.1 (7.1g, yield：98%) it is colourless oil liquid.
Step 2：The synthesis of compound 3.2
Compound 3.1 (7.1g, 32.2mmol) is dissolved in ethanol (150mL), add wet palladium charcoal (Pd/C) (10%, 300mg), after reaction system is replaced three times with hydrogen, hydrogenated over night is stirred at room temperature.Reaction solution is filtered with diatomite, filter cake Eluted with ethanol (50mL), it is colourless oil liquid that filtrate decompression, which is concentrated to give compound 3.2 (5.02g, yield 70%),.
Step 3：The synthesis of compound 3.3
Compound 3.2 (5.02g, 22.6mmol) is dissolved in the in the mixed solvent of ethanol (80mL) and water (20mL), adds After one hydronium(ion) lithia (3.80g, 90.4mmol), reaction system is heated to 40 DEG C and stirred 4 hours.Reaction solution water After (100mL) dilution, it is concentrated under reduced pressure after evaporating most of ethanol and filters off sediment.Filtrate adjusts pH with hydrochloric acid (1.0M)<Continue after 6 Stirring 10 minutes.Filtering, filter cake are washed with water, and compound 3.3 (3.50g, yield are obtained after obtained filter cake vacuum drying 79.7%) it is white solid.
m/z:[M+H]+195
Embodiment 6：The synthesis of compound 3.4~3.7
With embodiment 3 be compound 1.1 synthetic method, by 2- Buddha's warrior attendant alkanones replace with compound 1.1,2.2,2.3 or 2.4 obtain compound 3.4~3.7.
Embodiment 7：The synthesis of compound 4.6
Step 1：The synthesis of compound 4.1
4- oxo adamantane -1- carboxylic acids (5.0g, 26mmol) are dissolved in anhydrous tetrahydro furan (100mL), ice-water bath Lower dropwise addition phenylmagnesium bromide solution (22mL, 3.0M diethyl ether solution, 65mmol).It is stirred overnight at 10 DEG C of the reaction system, salt Aqueous acid is quenched, and ethyl acetate extraction (100mL × 2), organic phase is washed with saline solution (50mL), anhydrous sodium sulfate drying, Filtering, filtrate decompression concentration, residue Flash column chromatography (petroleum ethers：Ethyl acetate=3：1) isolate and purify to obtain compound 4.1 (4.1g, yields：58%) it is off-white powder.
1H NMR(400MHz,CDCl3):δ7.56-7.58(m,2H),7.40-7.44(m,2H),7.30-7.34(m,1H), 2.71 (s, 2H), 2.65 (d, J=12.4Hz, 2H), 1.90-1.92 (m, 5H), 1.17 (s, 4H).
Step 2：The synthesis of compound 4.2
Compound 4.1 (1.68g, 6.17mmol) is dissolved in chloroform (40mL), is separately added into triethyl silicane (2.03g, 12.3mmol) and trifluoroacetic acid (2.46g, 21.59mmol).65 DEG C of the reaction system is stirred overnight, reaction solution decompression Concentration, residue Flash column chromatography (petroleum ethers：Ethyl acetate=5：1) isolate and purify to obtain compound 4.2 (1.37g, yield： 87%) it is off-white powder.
1H NMR(400MHz,CDCl3):δ7.35-7.40(m,4H),7.20-7.24(m,1H),3.03(s,1H),2.64 (s, 2H), 2.17-2.22 (m, 3H), 1.98 (s, 4H), 1.87 (d, J=13.2Hz, 2H), 1.55 (d, J=12.4Hz, 2H).
Step 3：The synthesis of compound 4.3
Compound 4.2 (2.2g, 8.58mmol) is dissolved in anhydrous tetrahydro furan (50mL), is slowly added dropwise under ice-water bath The tetrahydrofuran solution (6.86mL, 17.2mmol, 2.5M) of Lithium Aluminium Hydride.After the stirring 3 hours of 80 DEG C of the reaction system, it is cooled to Room temperature, sodium hydroxide solution are quenched, and ethyl acetate extraction (100mL × 2), organic phase is washed with saline solution (50mL), anhydrous sulphur Sour sodium is dried, and filtering, filtrate decompression is concentrated to give compound 4.3 (2.2g, yield：100%) it is pale yellow oil.
1H NMR(400MHz,CDCl3):δ7.34-7.42(m,4H),7.21-7.23(m,1H),3.33(s,2H),2.97 (s,1H),2.60(s,2H),1.73-1.94(m,7H),1.47-1.58(m,4H)。
Step 4：The synthesis of compound 4.4
Compound 4.3 (2.15g, 8.58mmol) is dissolved in dichloromethane (60mL), is added portionwise and wears under ice-water bath This-Martin's oxidant (5.64g, 13.3mmol).Stirred 3 hours under the reaction system ice-water bath, saturated sodium bicarbonate solution is quenched Go out, ethyl acetate extraction (100mL × 2), organic phase is washed with saline solution (50mL), anhydrous sodium sulfate drying, and filtering, filtrate subtracts Pressure concentration, residue Flash column chromatography (petroleum ethers：Ethyl acetate=10：1) it is faint yellow to isolate and purify to obtain compound 4.4 Grease (1.67g, yield：78%).
1H NMR(400MHz,CDCl3):δ9.46(s,0.85H),9.24(s,0.16H),7.35-7.41(m,4H), 7.21-7.25(m,1H),3.06(s,0.22H),3.01(s,0.88H),2.68(s,2H),1.98-2.02(m,5H),1.84- 1.93(m,2H),1.77-1.79(m,2H),1.53-1.58(m,2H)。
Step 5：The synthesis of compound 4.5
Compound 4.4 (600mg, 2.5mmol) is dissolved in dimethyl ether (50mL) and ethanol (2.5mL), under ice-water bath Sequentially add to Methyl benzenesulfonyl methyl isocyanide (635mg, 3.25mmol) and potassium tert-butoxide (701mg, 6.3mmol).The reaction Stir 4 hours, filter under system ice-water bath, filter cake is washed with dimethyl ether, filtrate decompression concentration, residue Flash column chromatography (stones Oily ether：Ethyl acetate=10:1) isolate and purify to obtain compound 4.5 (115mg, yield：18%) it is brown solid.
1H NMR(400MHz,CDCl3):δ7.34-7.39(m,4H),7.21-7.24(m,1H),2.98(s,1H),2.63 (s,2H),2.22(s,2H),1.97-1.98(m,1H),1.91-1.93(m,1H),1.85-1.88(m,5H),1.70(s,2H), 1.50 (d, J=13.2Hz, 2H).
Step 6：The synthesis of compound 4.6
Compound 2.5 (115mg, 0.46mmol) is suspended in the mixed solution of acetic acid (2.0mL) and hydrobromic acid (4.0mL) In, the reaction system is stirred overnight at 120 DEG C.Reactant mixture is cooled to room temperature, and compound 4.6 is obtained after being concentrated under reduced pressure (120mg, yield：97%) it is brown solid.
m/z:[M+H]+271
Embodiment 8：The synthesis of compound 5.1
It is added dropwise after compound 3.4 (400mg, 1.48mmol) adds carbon tetrachloride (20mL), under ice bath and is pre-mixed cooling Nitric acid (1.5mL) sulfuric acid (1.5mL) mixed liquor.Reaction system is dilute with 40mL dichloromethane after being stirred at room temperature 4 hours Release, 50mL washings, the washing of 50mL saturated common salts, be concentrated under reduced pressure after anhydrous sodium sulfate drying.Crude product silica gel column chromatography separation (two Chloromethanes：Methanol=100:1~10:1) compound 5.1 (440mg, yield are obtained：94%) it is white solid.
Embodiment 9：The synthesis of compound 6.2
Step 1：The synthesis of compound 6.1
Compound 1.1 (1.0g, 4.4mmol) is dissolved in the in the mixed solvent of glycol dimethyl ether (20mL) and ethanol (2mL), Sequentially add to after Methyl benzenesulfonyl methyl isocyanide (TosMIC) (1.12g, 5.7mmol) and potassium tert-butoxide (1.23g, 11mmol) 16 hours are stirred at room temperature.Water (100mL) is added into reaction system, and is extracted with ethyl acetate (100mL × 2).It is associated with Machine phase, organic phase are washed with saturated common salt, are concentrated under reduced pressure after anhydrous sodium sulfate drying.Crude product silica gel column chromatography (petroleum ether：Acetic acid Ethyl ester=100:1~10:1) isolated compound 6.1 (720mg, yield：70%) it is white solid.
Step 2：The synthesis of compound 6.2
Compound 6.1 (175mg, 1.0mmol) is dissolved in tetrahydrofuran (10mL), and Lithium Aluminium Hydride is added dropwise under blanket of nitrogen (2.5M tetrahydrofuran solution, 1.2mL, 3mmol), reaction system are stirred at room temperature 3 hours.Add successively into reaction system Enter water (0.5mL), 15% sodium hydrate aqueous solution (0.5mL), water (0.5mL) and anhydrous magnesium sulfate (about 20g), stir 15 minutes After filter off solid.Filtrate decompression is concentrated to give compound 6.2 (171mg, yield：96%) it is white solid.
m/z:[M+H]+242
Embodiment 10：The synthesis of compound 7.4
Step 1：The synthesis of compound 7.2
Compound 4.3 (1.8g, 7.6mmol) and triethylamine (2.3g, 22.9mmol) are added in dichloromethane (30mL), cold But to 0 DEG C, mesyl chloride (0.95g, 8.4mmol) is added dropwise into reaction system.After being added dropwise, it is stirred overnight at room temperature.Reaction Then system uses saturated sodium bicarbonate aqueous solution and saturated common salt water washing with dchloromethane (50mL) respectively.Anhydrous sulphur Sour sodium is dried, and filtering, filtrate decompression is concentrated to give compound 7.2 (2.4g, yield：100%) it is, not purified to be directly used in next step Reaction.
m/z:[M+H]+321
Step 2：The synthesis of compound 7.3
Compound 7.2 (2.4g, 7.6mmol) and sodium azide (1.0g, 15.3mmol) are added separately to N, N- dimethyl In formamide (15mL), reaction system is stirred 4 hours at 150 DEG C, is subsequently cooled to room temperature, and reaction solution is slowly added into water In (50mL), ethyl acetate (50mL × 2) extraction.Merge organic phase, then with saturated common salt water washing, being concentrated under reduced pressure to give Compound 7.3 (2.0g, yield：100%), not purified be directly used in is reacted in next step.
m/z:[M+H]+268
Step 3：The synthesis of compound 7.4
Compound 7.3 (2.0g, 7.6mmol) and palladium charcoal (500mg) are added separately in ethanol (15mL), are replaced with hydrogen Reaction system, the system are stirred at room temperature 2 hours in nitrogen atmosphere.Filtering, filtrate decompression concentration, crude product silica gel column chromatography (dichloro Methane：Methanol=10:1) purifying obtains compound 7.4 (720mg, yield：40%) it is pale yellow oil.
m/z:[M+H]+242
Embodiment 11：The synthesis of compound 8.1
Compound 4.2 (1.0g, 3.91mmol) and diphenyl phosphate azide (5.4g, 19.5mmol) are added separately to toluene In (50mL), triethylamine (2g, 19.5mmol) is added into reaction system.The system is stirred overnight at room temperature, and reaction solution is successively With water, saturated common salt water washing.Organic phase is concentrated under reduced pressure, and dichloromethane (50mL), trifluoroacetic acid are added into residue (20mL) continues to stir 3 hours, is concentrated under reduced pressure and removes solvent, and residue with using unsaturated carbonate successively after dchloromethane Sodium, saturated common salt water washing.Organic phase is concentrated under reduced pressure, residue silica gel column chromatography (petroleum ether:Ethyl acetate=90:10~ 20:80) purifying obtains compound 8.1 (500mg, yield：56%) it is white solid.
m/z:[M+H]+228
Embodiment 12：The synthesis of compound 8.1
Step 1：The synthesis of compound 9.1
Bicyclic [2.2.2] octane -1- formic acid of 4- (methoxycarbonyl) is added portionwise in sodium borohydride (5.8g, 0.15mol) In the aqueous solution (120mL) of (6.5g, 0.03mol), reactant mixture is stirred overnight at room temperature.Ice-water bath cools down, and watery hydrochloric acid is water-soluble Liquid (1.0M) adjusts pH value to 2-3, solid filtering, filter cake and washed with cold water (20mL), and compound 9.1 is obtained after being dried under reduced pressure (5.66g, yield：100%) it is white solid.
m/z:[M+H]+185
Step 2：The synthesis of compound 9.2
By the ammonium persulfate aqueous solution being dissolved in (4.56g, 0.02mol, 10mL) be added drop-wise to compound 9.1 (3.68g, 0.02mol), 10% aqueous sulfuric acid of 2- picolines (1.86g, 0.02mol) and silver nitrate (340mg, 2.0mmol) In (30mL) and acetonitrile (40mL).Reactant mixture is heated to 80 DEG C, stirs 1 hour, is then cooled to environment temperature, use is dense Ammoniacal liquor adjusts pH value to 8-9, ethyl acetate (100mL × 2) extraction, merges organic phase, anhydrous sodium sulfate drying, filtering, filtrate It is concentrated under reduced pressure, residue is isolated and purified to obtain compound 9.2 (200mg, production with flash column chromatography (petrol ether/ethyl acetate=1/1) Rate：7%) it is faint yellow solid.
m/z:[M+H]+232
Step 3：The synthesis of compound 9.3
Methylsufonyl chloride (297mg, 2.59mmol) be slowly dropped under ice-water bath compound 9.2 (500mg, In dichloromethane solution (30mL) 2.16mmol), reaction solution stirs 1 hour at this temperature.Dichloromethane (30mL) is dilute Release, frozen water (20mL) is quenched, and organic phase is washed with saline solution (20mL), anhydrous sodium sulfate drying, filtering, after filtrate decompression concentration Obtain compound 9.3 (668mg, yield：100%) it is faint yellow solid.
m/z:[M+H]+310
Step 4：The synthesis of compound 9.4
Compound 9.2 (668mg, 2.16mmoL) and sodium azide (702mg, 10.8mmol) are added to N, N- dimethyl methyls 100 DEG C are heated in amide solution (15mL), under nitrogen protection to be stirred overnight.Reaction solution is cooled to environment temperature, frozen water (20mL) is diluted, and ethyl acetate (50mL) extraction, organic phase is washed with saline solution (20mL), anhydrous sodium sulfate drying, filtering, filter Liquid obtains compound 9.4 (560mg, yield after being concentrated under reduced pressure：100%) it is pale yellow oil.
m/z:[M+H]+257
Step 5：The synthesis of compound 9.5
Methanol solution (30mL) is added under compound 9.4 (560mg, 2.18mmoL) and palladium carbon (500mg, 10%) nitrogen In, hydrogenated over night.Reactant mixture is filtered, and compound 9.5 (400mg, yield are obtained after filtrate decompression concentration：80%) to be yellowish Color grease.
m/z:[M+H]+231
Embodiment 13：Compound 1-1 synthesis
Compound 4.6 (120mg, 0.44mmol) and para-fluoroaniline (50mg, 0.44mmol) are dissolved in N, N- dimethyl In formamide (10mL), then sequentially add HATU (201mg, 0.53mmol) and diisopropyl ethyl amine (114mg, 0.88mmol), the reaction system is stirred overnight at room temperature.Reactant mixture is quenched with frozen water (30mL), ethyl acetate extraction (50mL × 2), organic phase is separated, brine It (20mL).Anhydrous sodium sulfate drying, after filtering, filtrate decompression concentration, residue With Flash column chromatography (petroleum ethers：Ethyl acetate=8：1) isolate and purify to obtain compound 1-1 (cis-trans isomerism mixture, 128mg, yield：79%) it is faint yellow solid.
1H NMR(400MHz,CDCl3):δ7.50-7.53(m,2H),7.33-7.39(m,4H),7.20-7.23(m,1H), 7.03-7.09 (m, 3H), 2.98 (s, 1H), 2.59 (s, 2H), 2.21 (s, 2H), 1.91-1.96 (m, 5H), 1.85 (d, J= 12.8Hz, 2H), 1.76 (s, 2H), 1.49 (d, J=12.4Hz, 2H).
m/z:[M+H]+364
Embodiment 14：Compound 1-2~1-18 synthesis
With embodiment 13 be compound 1-1 synthetic method, with adamantane -1- carboxylic acids, compound 1.2, compound 3.4, Compound 3.5, compound 3.6, compound 3.7, compound 4.1, compound 4.2, compound 4.6 or compound 5.1 and to fluorine Aniline, parachloroanilinum, p-ethoxyaniline, to cyano-aniline, the chloro- 4- fluoroanilines of 3-, 3- aminopyridines, the fluoro- 5- amino pyrroles of 2- Pyridine, the chloro- 5- aminopyridines of 2- are that initiation material reacts to obtain compound 1-2~1-18 to Methoxyamino.
1H NMR(400MHz,CDCl3):δ7.46-7.51(m,2H),7.07-7.17(m,1H),6.99-7.05(m,2H), 2.11(s,2H),2.01(s,3H),1.62-1.75(m,12H)。
m/z:[M+H]+288
1H NMR(400MHz,CDCl3):δ7.46-7.54(m,2H),7.32-7.42(m,4H),7.19-7.26(m,1H), 7.16,7.12 (two s, 1H), 7.00-7.09 (m, 2H), 2.57,2.51 (two d, J=7.6Hz, 2H), 2.38-2.46 (m, 1H),2.09-2.16(m,1H),1.82-2.09(m,12H)。
m/z:[M+H]+364
m/z:[M+H]+350
1H NMR(400MHz,DMSO-d6):δ9.28(s,0.85H),9.12(s,0.15H),7.57-7.71(m,2H), 7.34-7.41(m,4H),7.12-7.20(m,3H),2.99(s,0.85H),2.94(s,0.15H),2.61(s,2H),2.10- 2.17(m,4H),1.93(br,s,3H),1.70-1.72(m,2H),1.50-1.54(m,2H)。
By compound 1-5 (180mg, cis-trans isomerism mixture) Flash column chromatography (petroleum ethers：Ethyl acetate=5：1) Isolate and purify to obtain the less compound 1-5a of polarity (36.1mg, single spatial configuration) and the larger compound 4-5b of polarity (32.8mg, single spatial configuration) is off-white powder.
m/z:[M+H]+366
1-5a：1H NMR(400MHz,DMSO-d6):δ 9.20 (s, 1H), 7.67-7.71 (m, 2H), 7.52 (d, J= 7.6Hz, 2H), 7.37 (t, J=7.6Hz, 2H), 7.24 (t, J=7.2Hz, 1H), 7.13 (t, J=8.8Hz, 2H), 4.73 (s, 1H),2.62(s,2H),2.51(s,2H),1.82-1.85(m,5H),1.64-1.68(m,2H),1.54-1.57(m,2H)。
1-5b：1H NMR(400MHz,DMSO-d6):δ 9.12 (s, 1H), 7.50-7.58 (m, 4H), 7.36 (d, J= 7.2Hz, 2H), 7.24-7.25 (m, 1H), 7.07 (t, J=8.8Hz, 2H), 4.73 (s, 1H), 2.60 (s, 2H), 2.38 (d, J =11.2Hz, 2H), 1.89-2.00 (m, 5H), 1.59-1.68 (m, 4H).
m/z:[M+H]+425
m/z:[M+H]+380
1H NMR(400MHz,CDCl3):δ 7.49 (d, J=8.8Hz, 2H), 7.28-7.36 (m, 6H), 7.16-7.20 (m, 1H), 7.12 (s, 1H), 2.95 (s, 1H), 2.56 (s, 2H), 2.19 (s, 2H), 1.81-1.96 (m, 9H), 1.47 (d, J= 12.8Hz,2H)。
m/z:[M+H]+390
1H NMR(400MHz,CDCl3):δ 7.44 (dd, J=9.2,2.4Hz, 2H), 7.33-7.39 (m, 4H), 7.19- 7.22 (m, 1H), 7.06 (s, 1H), 6.88 (dd, J=7.2,2.0Hz, 2H), 4.03 (q, J=7.2Hz, 2H), 2.98 (s, 1H), 2.59 (s, 2H), 2.19 (s, 2H), 1.94-1.96 (m, 5H), 1.85 (d, J=12.8Hz, 2H), 1.76 (s, 2H), 1.49 (d, J=12.4Hz, 2H), 1.42 (t, J=6.8Hz, 3H).
m/z:[M+H]+398
1H NMR(400MHz,CDCl3):δ 7.74 (dd, J=2.8,6.4Hz, 1H), 7.31-7.36 (m, 5H), 7.16- 7.20 (m, 2H), 7.08 (t, J=8.8Hz, 1H), 2.95 (s, 1H), 2.57 (s, 2H), 2.18 (s, 2H), 1.81-1.92 (m, 7H), 1.72 (s, 2H), 1.47 (d, J=12.4Hz, 2H).
By compound 1-10 (150mg, cis-trans isomerism mixture) Flash column chromatography (petroleum ethers：Ethyl acetate=10: 1) isolate and purify to obtain the less compound 1-10a of polarity (66.1mg, single spatial configuration) and the larger compound 1- of polarity 10b (35.7mg, single spatial configuration) is off-white powder.
m/z:[M+H]+380
1-10a：1H NMR(400MHz,DMSO-d6):δ 10.04 (s, 1H), 7.62 (d, J=8.8Hz, 2H), 7.31- 7.41(m,6H),7.18-7.20(m,1H),2.47-2.50(m,2H),2.24-2.26(m,1H),2.03-2.06(m,3H), 1.68-1.86(m,10H)。
1-10b：1H NMR(400MHz,DMSO-d6):δ 10.07 (s, 1H), 7.64 (dd, J=2.0Hz, J=6.8Hz, 2H),7.28-7.38(m,6H),7.14-7.18(m,1H),2.50-2.53(m,2H),2.24-2.26(m,1H),1.88-2.02 (m, 11H), 1.53 (d, J=12.4Hz, 2H).
By compound 1-11 (182mg, cis-trans isomerism mixture) silica gel Flash column chromatography (petroleum ethers：Ethyl acetate= 10:1) isolate and purify to obtain the less compound 1-11a of polarity (9.8mg, single spatial configuration) and the larger compound of polarity 1-11b (4.8mg, single spatial configuration) is off-white powder.
1-11a：1H NMR(400MHz,CDCl3):δ7.59-7.67(m,4H),7.32-7.38(m,5H),7.20-7.22 (m, 1H), 2.53 (d, J=7.6Hz, 2H), 2.39-2.41 (m, 1H), 2.12 (s, 1H), 1.98-2.01 (m, 4H), 1.83- 1.89(m,8H)。
1-11b：1H NMR(400MHz,CDCl3):δ7.63-7.71(m,4H),7.33-7.40(m,5H),7.20-7.24 (m, 1H), 2.62 (d, J=7.6Hz, 2H), 2.41-2.43 (m, 1H), 1.92-2.12 (m, 11H), 1.65 (d, J=12.8Hz, 2H)。
Compound 1-12 (1.35g, cis-trans isomerism mixture) is used into silica gel column chromatography (petroleum ether：Ethyl acetate=2:1) Separate the less compound 1-12a of polarity (615mg, single spatial configuration) and the larger compound 1-12b of polarity (570mg, Single spatial configuration) it is white solid.
m/z:[M+H]+403
Compound 1-13 (100mg, cis-trans isomerism mixture) is used into silica gel column chromatography (petroleum ether：Ethyl acetate=1:1) Separate the less compound 1-13a of polarity (4mg, single spatial configuration) and the larger compound 1-13b of polarity (21mg, it is single One spatial configuration) it is white solid.
m/z:[M+H]+365
13a：1H NMR(400MHz,CDCl3):δ8.15-8.19(m,1H),8.09-8.10(m,1H),7.35-7.38(m, 3H),7.20-7.23(m,1H),7.02(br.s,1H),6.90-6.93(m,1H),3.00(s,1H),2.63(s,2H),2.13- 2.15(m,1H),2.04(s,2H),1.93-1.94(m,4H),1.78-1.79(m,2H),1.71-1.74(m,2H),1.53- 1.57(m,2H)。
13b：1H NMR(400MHz,CDCl3):δ8.27-8.32(m,1H),8.19-8.20(m,1H),7.34-7.38(m, 3H),7.19-7.23(m,2H),7.02(br.s,1H),6.94-6.93(m,1H),2.98(s,1H),2.60(s,2H),2.24 (s,1H),1.85-1.98(m,7H),1.76(s,2H),1.48-1.51(m,2H)。
Compound 1-14 (300mg, cis-trans isomerism mixture) is (single by the isolated compound 1-14a of prep-HPLC Spatial configuration, 115mg, appearance time：28.6-29.3min) and compound 1-14b (single spatial configuration, 45mg, during appearance Between：27.3-27.9min) it is off-white powder.
(separation method：Mobile phase A：70%-20% (v/v%), Mobile phase B：30%-80% (v/v%), mobile phase A: 0.02% ammonium bicarbonate aqueous solution, Mobile phase B：Acetonitrile)
Compound 1-14a or 1-14b are dissolved in methanol and dichloromethane mixed solution, make that 1-14a's or 1-14b is dense Spend for 5~10mL/mmol, hydrogen chloride-methanol solution (2eq., 4.0M) is added dropwise under ice-water bath, after being stirred 10 minutes under ice-water bath The hydrochloride for being concentrated under reduced pressure to give 1-14a or 1-14b is white solid.
m/z:[M+H]+347
1-14a (hydrochloride)：1H NMR(400MHz,DMSO-d6):δ 11.24 (s, 1H), 9.24 (d, J=2.4Hz, 1H), 8.57 (d, J=5.2Hz, 1H), 8.51 (dd, J=7.6,1.2Hz, 1H), 7.94 (dd, J=8.8,5.6Hz, 1H), 7.30- 7.43 (m, 4H), 7.19 (t, J=7.2Hz, 1H), 2.63 (d, J=7.6Hz, 2H), 2.28 (t, J=7.6Hz, 1H), 2.06- 2.09 (m, 3H), 1.71-1.89 (m, 8H), 1.68 (d, J=12.4Hz, 2H).
1-14b (hydrochloride)：1H NMR(400MHz,DMSO-d6):δ 11.06 (s, 1H), 9.20 (d, J=2.4Hz, 1H), 8.54 (d, J=5.2Hz, 1H), 8.45-8.48 (m, 1H), 7.88 (dd, J=8.8,5.2Hz, 1H), 7.29-7.39 (m, 4H), 7.17 (t, J=7.2Hz, 1H), 2.64 (d, J=7.2Hz, 2H), 2.31 (t, J=8.0Hz, 1H), 1.87-2.03 (m, 11H), 1.54 (d, J=12.4Hz, 2H).
Compound 1-15 (88mg, cis-trans isomerism mixture) is used into silica gel column chromatography (dichloromethane：Methanol=100/1~ 10/1) the less compound 1-15a of polarity (2.1mg, single spatial configuration) and the larger compound 1-15b of polarity is separated to obtain (17.3mg, single spatial configuration) is white solid.
m/z:[M+H]+376
1H NMR(400MHz,CDCl3):δ7.33-7.38(m,6H),7.19-7.24(m,1H),6.83-6.89(m,3H), 3.80(s,3H),2.96-3.02(m,1H),2.57-2.65(m,2H),2.12-2.13(m,1H),1.99(s,2H),1.93(s, 4H),1.78-1.83(m,2H),1.67-1.73(m,2H),1.55-1.60(m,2H)。
1H NMR(400MHz,CDCl3):δ7.42-7.48(m,2H),7.33-7.39(m,4H),7.16-7.22(m,2H), 6.85-6.91(m,2H),3.81(s,3H),2.98(s,1H),2.59(s,2H),2.19(s,2H),1.76-1.96(m,9H), 1.48-1.51(m,2H)。
Compound 1-16 (234mg, cis-trans isomerism mixture) is used into silica gel column chromatography (petroleum ether：Ethyl acetate=5:1) Separate the less compound 1-16a of polarity (15mg, single spatial configuration) and the larger compound 1-16b of polarity (16mg, it is single One spatial configuration) it is white solid.
m/z:[M+H]+449
1H NMR(400MHz,DMSO-d6):δ 11.05 (s, 1H), 8.31 (d, J=9.2Hz, 1H), 8.02 (dd, J= 5.6,9.2Hz, 1H), 7.73 (d, J=2.8,9.2Hz, 2H), 7.65-7.60 (m, 3H), 7.33 (dd, J=2.0,6.8Hz, 2H),3.32-3.30(m,1H),2.30-1.78(m,15H)。
1H NMR(400MHz,DMSO-d6):δ 11.09 (s, 1H), 8.28 (d, J=8.4Hz, 1H), 8.00 (dd, J= 5.6,9.2Hz, 1H), 7.74-7.58 (m, 5H), 7.34 (dd, J=2.0,7.2Hz, 2H), 3.32-3.30 (m, 1H), 2.55 (d, J=7.6Hz, 2H), 2.34-2.31 (m, 1H), 2.14-1.91 (m, 10H), 1.57 (d, J=12.4Hz, 2H).
Compound 1-17 (321mg, cis-trans isomerism mixture) is used into silica gel column chromatography (dichloromethane：Methanol=50:1) divide From the less compound 1-17a of polarity (60.4mg, single spatial configuration) and the larger compound 1-18b of polarity (60.1mg, Single spatial configuration) it is white solid.
m/z:[M+H]+381
1-17a,1H NMR(400MHz,DMSO-d6):δ 10.07 (s, 1H), 8.63 (d, J=6.8Hz, 2H), 8.00 (d, J =6.8Hz, 2H), 7.62 (dd, J=2.0,6.8Hz, 2H), 7.35 (dd, J=2.0,6.8Hz, 2H), 2.49-2.52 (m, 2H),2.25-2.27(m,1H),2.06-2.09(m,3H),1.78-1.94(m,10H)。
1-17b,1H NMR(400MHz,DMSO-d6):δ 10.11 (s, 1H), 8.76 (br.s, 2H), 7.89 (d, J= 6.0Hz, 2H), 7.64 (dd, J=2.0,6.8Hz, 2H), 7.35 (dd, J=2.0,6.8Hz, 2H), 2.52-2.55 (m, 2H), 2.30-2.32 (m, 1H), 2.07 (br.s, 1H), 1.91-1.98 (m, 10H), 1.56 (d, J=12.4Hz, 2H).
Compound 1-18 (234mg, cis-trans isomerism mixture) is used into silica gel column chromatography (dichloromethane：Methanol=50:1 bag Containing 0.1% ammoniacal liquor) separate to obtain the less compound 1-18a of polarity (17.8mg, single spatial configuration) and the larger change of polarity Compound 1-18b (20.8mg, single spatial configuration) is white solid.
m/z:[M+H]+382
1-18a,1H NMR(400MHz,DMSO-d6):δ 10.29 (s, 1H), 8.60 (d, J=2.8Hz, 1H), 8.49- 8.52 (m, 2H), 8.09 (dd, J=2.8Hz, J=8.4Hz, 1H), 7.45 (d, J=8.8Hz, 1H), 7.36-7.41 (m, 2H), 2.51-2.54 (m, 2H), 2.26 (t, J=7.6Hz, 1H), 2.00-2.06 (m, 3H), 1.70-1.89 (m, 10H).
1-18b,1H NMR(400MHz,DMSO-d6):δ 10.33 (s, 1H), 8.62 (d, J=2.4Hz, 1H), 8.48 (dd, J=1.6,4.8Hz, 2H), 8.10 (dd, J=2.8,8.8Hz, 1H), 7.46 (d, J=8.8Hz, 1H), 7.37 (dd, J=1.6, 4.4Hz, 2H), 2.57 (d, J=7.2Hz, 2H), 2.29 (t, J=3.2Hz, 1H), 2.04 (s, 1H), 1.86-1.97 (m, 10H), 1.54 (d, J=12.0Hz, 2H).
Embodiment 15：Compound 1-22 synthesis
Step 1：Compound 1-20 synthesis
By compound 1-6 (80mg, 0.19mmol), palladium charcoal (5mg) is added in ethyl acetate (10mL), hydrogen displacement gas Body is stirred at room temperature 16 hours afterwards three times, Filtration of catalyst, and filtrate decompression is concentrated to give compound 1-20 (67mg, yield： 89%) it is white solid.
m/z:[M+H]+395
Step 2：Compound 1-21 synthesis
Nitrogen protect and ice-water bath under, by the tert-butyl alcohol (38mg, 0.51mmol) instill chlorosulphonyl isocyanate (72mg, In dichloromethane (10mL) solution 0.51mmol).Compound 1-20 (67mg, 0.17mmol) is added dropwise after stirring 30 minutes in ice bath With dichloromethane (10mL) solution of triethylamine (70mg, 0.68mmol).It is stirred at room temperature after being added dropwise 2 hours.Reaction solution is used Dchloromethane (50mL), washed respectively with water (20mL) and saturated aqueous common salt (20mL).Organic phase is separated, organic phase is with anhydrous Sodium sulphate is concentrated under reduced pressure after drying.Crude product silica gel column chromatography (petroleum ether：Ethyl acetate=10:1~2:1) purifying obtains chemical combination Thing 1-21 (40mg, yield：41%) it is white solid.
m/z:[M+H]+574
Step 3：Compound 1-22 synthesis
Compound 1-21 (40mg, 0.07mmol) is dissolved in dichloromethane (8mL) and trifluoroacetic acid (2mL), is stirred at room temperature 2 Hour.It is concentrated under reduced pressure, crude product silica gel column chromatography (dichloromethane：Methanol=100:1~10:1) purifying obtains compound 1-22 (14mg, yield：42%) it is white solid.
m/z:[M+H]+474
1H NMR(400MHz,DMSO-d6):δ 10.05 (br.s, 1H), 9.36 (s, 1H), 7.62 (dd, J=8.8, 2.0Hz, 2H), 7.34 (dd, J=8.8,2.0Hz, 2H), 7.29 (d, J=8.8Hz, 2H), 7.12 (d, J=8.4Hz, 2H), 7.01 (s, 2H), 2.47 (d, J=7.2Hz, 2H), 2.23 (t, J=7.2Hz, 1H), 1.96-2.07 (m, 3H), 1.71-1.90 (m,8H),1.63-1.71(m,2H)。
Embodiment 16：Compound 1-23 synthesis
Compound 1-20 (100mg, 0.25mmol), DIPEA (65mg, 0.51mmol) and 4- diformazan ammonia Yl pyridines (5mg, 0.044mmol) are dissolved in dichloromethane, and it is small to be stirred at room temperature 2 after addition mesyl chloride (35mg, 0.30mmol) When.Decompression boils off solvent, crude product silica gel column chromatography (petroleum ether：Ethyl acetate=5:1~1:1) purifying obtains compound 1-23 (7.8mg, yield：26%) it is white solid.
m/z:[M+H]+473
1H NMR(400MHz,CDCl3):δ 7.49 (br.d, J=8.8Hz, 2H), 7.31 (br.d, J=8.8Hz, 2H), 7.22 (br.d, J=8.8Hz, 2H), 7.15 (br.d, J=8.8Hz, 2H), 3.43 (s, 1H), 2.92 (s, 3H), 2.47 (d, J =7.6Hz, 2H), 2.29-2.36 (m, 1H), 1.90-2.10 (m, 6H), 1.80-1.85 (m, 5H), 1.67-1.74 (m, 2H).
Embodiment 17：Compound 1-25a and 1-25b synthesis
Step 1：Compound 1-24a synthesis
Compound 1-12a (615mg, 1.53mmol) is added in dichloromethane (5mL), then adds methanolic hydrogen chloride Solution (4.0M, 8.0mL), the reaction system is stirred 4 hours at normal temperatures, be evaporated under reduced pressure removing solvent and obtain compound 1-24a (hydrochloride) (500mg, yield：97%) it is white solid.
m/z:[M+H]+303
Step 2：Compound 1-25a synthesis
Compound 1-21a (70mg, 0.21mmol) is added in dichloromethane (5mL), addition triethylamine (69mg, 0.68mmol), benzene sulfonyl chloride (44mg, 0.25mmol) is then added, the reaction system is stirred at room temperature 2 hours, is depressurized Solvent is distilled off, obtained residue silica gel column chromatography (petroleum ether：Ethyl acetate=1:1) compound 1-25a is purified to obtain (15mg, yield：17%) it is white solid.
m/z:[M+H]+443
1-25a：1H NMR(400MHz,DMSO-d6):δ9.98(s,1H),7.86-7.88(m,2H),7.55-7.61(m, 5H), 7.09-7.14 (m, 2H), 2.31 (d, J=7.2Hz, 2H), 2.02-2.06 (m, 1H), 1.89-1.92 (m, 3H), 1.77 (s,2H),1.52-1.61(m,7H),1.24-1.31(m,1H)。
Compound 1-25b 1-25a synthetic method, it is that to obtain 1-25b be white solid to initiation material with 1-12b.
1-25b：1H NMR(400MHz,DMSO-d6):δ9.92(s,1H),7.84-7.86(m,2H),7.55-7.60(m, 5H), 7.09-7.13 (m, 2H), 2.36 (d, J=8.0Hz, 2H), 2.00-2.03 (m, 1H), 1.89 (s, 1H), 1.68-1.75 (m,9H),1.24-1.31(m,3H)。
Embodiment 18：Compound 1-26a and 1-26b synthesis
It is compound 1-25a synthetic method with embodiment 17, it is former by the use of 1-12a or 1-12b and mesyl chloride as starting Material reaction obtains compound 1-26a or 1-26b.
m/z:[M+H]+381
1-26a：1H NMR(400MHz,DMSO-d6):δ10.02(s,1H),7.58-7.62(m,2H),7.09-7.14(m, 2H), 6.86 (s, 1H), 2.96 (s, 3H), 2.39 (d, J=7.2Hz, 2H), 2.08-2.12 (m, 1H), 1.99-2.05 (m, 3H),1.85(s,4H),1.64-1.70(m,3H),1.23-1.26(m,3H)。
1-26b：1H NMR(400MHz,DMSO-d6):δ9.98(s,1H),7.59-7.62(m,2H),7.10-7.15(m, 2H), 6.85 (s, 1H), 2.94 (s, 3H), 2.43 (d, J=7.6Hz, 2H), 2.13-2.17 (m, 1H), 1.92 (s, 3H), 1.81-1.86(m,6H),1.38-1.42(m,2H),1.24-1.26(m,2H)。
Embodiment 19：Compound 1-27a and 1-27b synthesis
By compound 1-24a (60mg, 0.18mmol), triethylamine (27mmol, 0.27mmol) and phenyl isocyanate (21mg, 0.18mmol) is dissolved in dichloromethane (10mL), and reaction system is stirred at room temperature 2 hours.Organic phase is divided after being washed with water Liquid, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentration, gained crude product is through silica gel column chromatography (dichloromethane： Methanol=100:1~10:1) purifying obtains compound 1-27a (35mg, yield：47%) it is white solid.
m/z:[M+H]+422
1-27a：1H NMR(400MHz,DMSO-d6):δ10.01(s,1H),8.25(s,1H),7.62-7.64(m,2H), 7.34 (d, J=7.2Hz, 2H), 7.18-7.23 (m, 2H), 7.10-7.15 (m, 2H), 6.85-6.89 (m, 1H), 5.89 (s, 1H), 2.44 (d, J=7.6Hz, 2H), 2.10-2.21 (m, 3H), 2.00-2.06 (m, 1H), 1.83-1.88 (m, 4H), 1.65- 1.74(m,6H)。
Compound 1-27b 1-25a synthetic method, it is that to obtain 1-27b be white solid to initiation material with 1-24b.
1-27b：1H NMR(400MHz,DMSO-d6):δ9.98(s,1H),8.24(s,1H),7.60-7.64(m,2H), 7.33 (d, J=8.0Hz, 2H), 7.18-7.22 (m, 2H), 7.11-7.15 (m, 2H), 6.85-6.88 (m, 1H), 5.89 (s, 1H), 2.46 (d, J=7.6Hz, 2H), 2.18-2.23 (m, 1H), 1.84-2.03 (m, 11H), 1.45 (d, J=12.4Hz, 2H)。
Embodiment 20：Compound 1-28a and 1-28b synthesis
Compound 1-24a (60mg, 0.18mmol) and triethylamine (55mmol, 0.54mmol) are dissolved in dichloromethane In (10mL), chlorobenzoyl chloride (25mg, 0.18mmol) is added dropwise at 0 DEG C.Reaction system is stirred at room temperature 2 hours, organic phase With water and brine It, separate organic phase and with anhydrous sodium sulfate drying, filtering, concentrate, gained crude product is through silica gel column chromatography (dichloromethane：Methanol=100:1~10：1) purifying obtains compound 1-28a (16mg, yield：22%) it is white solid.
m/z:[M+H]+407
1-28a：1H NMR(400MHz,CDCl3):δ8.29(s,1H),7.72-7.74(m,2H),7.51-7.59(m, 3H), 7.44-7.47 (m, 2H), 6.98-7.03 (m, 2H), 5.92 (s, 1H), 2.87 (d, J=12.0Hz, 2H), 2.60 (d, J =8.0Hz, 2H), 2.36-2.39 (m, 1H), 2.18-2.22 (m, 1H), 2.02 (s, 2H), 1.80-1.89 (m, 6H), 1.63 (d, J=12.4Hz, 2H).
Compound 1-28b 1-28a synthetic method, it is that to obtain 1-28b be white solid to initiation material with 1-24b.
1-28b：1H NMR(400MHz,CDCl3):δ7.69-7.72(m,2H),7.48-7.50(m,3H),7.39-7.43 (m, 2H), 7.36 (s, 1H), 6.98-7.04 (m, 2H), 5.83 (s, 1H), 2.51 (d, J=6.8Hz, 2H), 2.37-2.41 (m, 1H),2.20-2.27(m,2H),2.11-2.17(m,5H),2.01(s,2H),1.84-1.87(m,2H),1.58-1.61(m, 2H)。
Embodiment 21：Compound 2-1~2-3 synthesis
It is compound 1-1 synthetic method with embodiment 13, with compound 6.2, compound 7.4 or compound 8.1 and 4- Fluobenzoic acid or 4- chlorobenzoic acids are that initiation material reacts to obtain compound 2-1~2-3.
m/z:[M+H]+350
1H NMR(400MHz,CDCl3):δ7.65-7.79(m,2H),7.35-7.41(m,4H),7.04-7.24(m,3H), 5.84(s,1H),3.10(s,1H),2.72(s,2H),1.57-2.37(m,11H)。
m/z:[M+H]+380
1H NMR(400MHz,CDCl3):δ7.74-7.77(m,2H),7.44-7.47(m,2H),7.33-7.39(m,4H), 7.19-7.23 (m, 1H), 6.17 (s, 1H), 3.28 (d, J=6.4Hz, 2H), 2.97 (s, 1H), 2.60 (s, 2H), 2.24 (t, J =7.6Hz, 1H), 2.01-2.07 (m, 1H), 1.44-1.95 (m, 9H).
m/z:[M+H]+364
1H NMR(400MHz,CD3OD):δ7.89-7.93(m,2H),7.29-7.39(m,4H),7.14-7.24(m,3H), 3.19-3.21 (m, 2H), 2.95 (s, 1H), 2.58 (s, 2H), 1.79-1.89 (m, 7H), 1.64 (d, J=2.0Hz, 2H), 1.49 (d, J=12.4Hz, 2H).
Embodiment 22：Compound 3-1~3-4 synthesis
It is compound 1-1 synthetic method with embodiment 13, with compound 6.2, compound 7.4 or compound 8.1 and 3- Indolecarboxylic acid, 5- fluoro indole -3- formic acid or 6- Aminoindazoles are that initiation material reacts to obtain compound 3-1~3-4.
m/z:[M+H]+371
1H NMR(400MHz,CDCl3):δ9.22(s,1H),7.80-7.95(m,1H),7.65-7.75(m,1H),7.35- 7.48(m,5H),7.21-7.28(m,2H),5.88(s,1H),3.13(s,1H),2.73(br.s,2H),1.59-2.25(m, 11H)。
m/z:[M+H]+403
1H NMR(400MHz,CDCl3):δ8.77(s,1H),7.54-7.83(m,2H),7.33-7.41(m,4H),7.02- 7.22 (m, 2H), 5.98-6.00 (m, 1H), 3.33 (d, J=6.8Hz, 2H), 2.38 (s, 1H), 2.61 (br.s, 2H), 1.59- 2.25(m,11H)。
Compound 3-3 (cis-trans isomerism mixture) passes through prep-HPLC isolated compound 3-3a (single three-dimensional structures Type, appearance time：19.8-20.5min) and compound 3-3b (single spatial configuration, appearance time：It is 20.9-21.6min) white Color solid.
(separation method：Mobile phase A：70~95% (v/v%), Mobile phase B：30~5% (v/v%).Mobile phase A: 0.05% trifluoroacetic acid aqueous solution, Mobile phase B：Acetonitrile)
m/z:[M+H]+385
3-3a：1H NMR(400MHz,CDCl3):δ 8.60-8.69 (m, 1H), 7.91-7.93 (m, 1H), 7.81 (d, J= 2.0Hz,1H),7.44-7.46(m,1H),7.28-7.38(m,6H),7.17-7.21(m,1H),5.97-6.06(m,1H), 3.71-3.75(m,2H),1.94-2.08(m,14H)。
3-3b：1H NMR(400MHz,CDCl3):δ8.50-8.56(m,1H),7.89-7.91(m,1H),7.82(s,1H), 7.44-7.46(m,1H),7.28-7.40(m,6H),7.17-7.21(m,1H),5.98-6.04(m,1H),3.66-3.75(m, 2H),1.77-2.18(m,14H)。
Compound 3-4 (cis-trans isomerism mixture) passes through prep-HPLC isolated compound 3-4a (single three-dimensional structures Type, appearance time：17.6-18.3min) and compound 3-4b (single spatial configuration, appearance time：16.3-16.9min) it is class White solid.
(separation method：Mobile phase A：20%-75% (v/v%), Mobile phase B：80%-25% (v/v%), mobile phase A: 0.02% ammonium bicarbonate aqueous solution, Mobile phase B：Acetonitrile)
m/z:[M+H]+386
3-4a：1H NMR(400MHz,DMSO-d6):δ12.87(s,1H),10.05(s,1H),8.18(s,1H),7.95 (s, 1H), 7.63 (d, J=8.8Hz, 1H), 7.32-7.43 (m, 4H), 7.20 (t, J=6.8Hz, 1H), 7.06 (d, J= 8.8Hz, 1H), 2.54 (d, J=8.0Hz, 2H), 2.28-2.30 (m, 1H), 2.07-2.08 (m, 4H), 1.70-1.89 (m, 9H)。
3-4b：1H NMR(400MHz,DMSO-d6):δ12.87(s,1H),10.08(s,1H),8.19(s,1H),7.96 (s, 1H), 7.64 (d, J=8.4Hz, 1H), 7.29-7.39 (m, 4H), 7.17 (t, J=6.8Hz, 1H), 7.09 (dd, J= 8.8,1.6Hz, 1H), 2.56 (d, J=7.6Hz, 2H), 2.30-2.32 (m, 1H), 1.87-2.08 (m, 11H), 1.54 (d, J= 12.4Hz,2H)。
Embodiment 23：Compound 5-1 synthesis
Chlorophenyl isocyanate (80mg, 0.52mmol) and compound 6.2 (125mg, 0.52mmol) are added separately to two In chloromethanes (10mL), DIPEA (85mg, 0.78mmol) is then added.The system stirs 2 hours at room temperature, Reaction solution uses water and saturated common salt water washing successively.Organic phase is concentrated under reduced pressure, crude product Flash column chromatography (petroleum ethers：Acetic acid second Ester=90:10~20:80) polarity less compound 5-1a (single spatial configuration, 12mg, yield are separated to obtain：And polarity 6%) Larger compound 5-1b (single spatial configuration, 15mg, yield：6%) it is white solid
m/z:[M+H]+395
5-1a：1H NMR(400MHz,CD3OD):δ 7.15-7.39 (m, 9H), 3.43 (d, J=8.0Hz, 2H), 1.95- 2.08(m,12H),1.61-1.64(m,2H)。
5-1b：1H NMR(400MHz,CD3OD):δ 7.15-7.40 (m, 9H), 3.38 (d, J=7.6Hz, 2H), 1.75- 2.14(m,12H),1.35-1.40(m,2H)。
Embodiment 24：Compound 5-2 and 5-3 synthesis
It is compound 5-1 synthetic method with embodiment 23, with compound 8.1 and chlorophenyl isocyanate or to fluorobenzene Isocyanates is that initiation material reacts to obtain compound 5-2~5-3.
By compound 5-2 (100mg) Flash column chromatography (petroleum ethers：Ethyl acetate=90:10~20:80) separate pure Change and obtain the less compound 5-2a of polarity (66.1mg, cis-trans isomerism mixture) and the larger compound 5-2b of polarity (35.7mg, single spatial configuration) is off-white powder.
m/z:[M+H]+381
5-2a：1H NMR(400MHz,CDCl3):δ7.17-7.34(m,9H),3.80-3.99(m,1H),2.93-3.01 (m,1H),2.57-2.68(m,2H),1.73-2.22(m,10H),1.47-1.50(m,1H)。
5-2b：1H NMR(400MHz,CDCl3):δ7.18-7.39(m,9H),6.09(s,1H),4.45(s,1H),3.03 (s,1H),2.65(s,2H),1.49-2.23(m,11H)。
By compound 5-3 (160mg, cis-trans isomerism mixture) Flash column chromatography (petroleum ethers：Ethyl acetate=90:10 ~20:80) isolate and purify to obtain the less compound 5-3a of polarity (22mg, single spatial configuration) and the larger compound of polarity 5-3b (20mg, cis-trans isomerism mixture) is white solid.
m/z:[M+H]+365
5-3a：1H NMR(400MHz,CDCl3):δ7.20-7.38(m,7H),7.01-7.05(m,2H),6.16(br.s, 1H),4.48(br.s,1H),3.05(br.s,1H),2.65-2.67(m,2H),1.51-2.24(m,11H)。
5-3b：1H NMR(400MHz,CDCl3):δ7.16-7.38(m,7H),6.95-7.16(m,2H),6.17-6.30 (m,1H),4.39-4.59(m,1H),2.95-3.04(m,1H),2.66-2.70(m,2H),1.50-2.24(m,11H)。
Embodiment 25：Compound 6-1 synthesis
Compound 8.1 (50mg, 0.22mmol), triethylamine (45mg, 0.44mmol) and DMAP (5mg, 0.044mmol) it is dissolved in dichloromethane, is stirred at room temperature 2 hours after adding 3- chlorobenzoyl chlorides (56mg, 0.26mmol).Decompression Boil off solvent, compound 6-1 crude products silica gel column chromatography (petroleum ether：Ethyl acetate=10:1~2:1) isolated polarity compared with Small compound 6-1a (single spatial configuration, 1.8mg, yield：And polarity larger compound 6-1b (single three-dimensional structures 2%) Type, 14.2mg, yield：16%) it is white solid.
m/z:[M+H]+402
6-1a：1H NMR:(400MHz,CDCl3):δ 7.82 (t, J=2.0Hz, 1H), 7.66-7.70 (m, 1H), 7.47- 7.51(m,1H),7.30-7.40(m,3H),7.19-7.28(m,3H),4.36(s,1H),2.88(s,1H),2.64(s,2H), 2.16 (s, 1H), 1.79-1.87 (m, 8H), 1.70 (d, J=12.0Hz, 2H).
6-1b：1H NMR:(400MHz,CDCl3):δ 7.95 (t, J=2.0Hz, 1H), 7.81-7.87 (m, 1H), 7.53- 7.58 (m, 1H), 7.48 (t, J=8.0Hz, 1H), 7.29-7.37 (m, 4H), 7.17-7.23 (m, 1H), 4.62 (s, 1H), 2.94(s,1H),2.62(s,2H),2.02-2.08(m,4H),1.97(br.s,1H),1.84-1.89(m,2H),1.76(d,J =12.4Hz, 2H), 1.42 (d, J=12.4Hz, 2H).
Embodiment 26：Compound 6-2~6-3 synthesis
It is compound 6-1 synthetic method with embodiment 25, is starting with compound 6.2 or 7.4 and 3- chlorobenzoyl chlorides Raw material reacts to obtain compound 6-2~6-3.
m/z:[M+H]+416
1H NMR(400MHz,CDCl3):δ7.90-7.91(m,1H),7.76-7.82(m,1H),7.50-7.61(m,1H), 7.49 (t, J=8.0Hz, 1H), 7.29-7.37 (m, 4H), 7.18-7.24 (m, 1H), 4.45-4.52 (m, 1H), 3.11-3.18 (m,2H),1.95-2.15(m,4H),1.69-1.93(m,9H),1.51-1.58(m,1H)。
m/z:[M+H2O]+433
1H NMR(400MHz,CDCl3):δ7.69-7.92(m,2H),7.55-7.60(m,1H),7.42-7.53(m,1H), 7.28-7.37(m,4H),7.18-7.24(m,1H),4.69-4.95(m,1H),2.91-2.97(m,1H),2.52-2.74(m, 4H),1.82-1.91(m,3H),1.67-1.75(m,3H),1.32-1.52(m,5H)。
Embodiment 27：Compound 7-1 synthesis
Step 1：The synthesis of compound 9.1
Under nitrogen protection, methyl cinnamate (1g, 6.1mmol) and TosMIC (1.31g, 6.71mmol) are dissolved in tetrahydrochysene furan Mutter (20mL) and the mixed solution of dimethyl sulfoxide (5mL) in, into reaction system add sodium hydrogen (60%, 370mg, 9.15mmol) Tetrahydrofuran (10mL) suspension in.After being added dropwise, 80 DEG C of 2 hours of stirring are heated to.Reaction solution is cooled to room temperature, adds Reaction, ethyl acetate (50mL × 2) extraction is quenched in water (100mL).Merge organic phase, washed with saturated common salt, anhydrous sodium sulfate It is concentrated under reduced pressure after drying.Crude product silica gel column chromatography (petroleum ether：Ethyl acetate=4:1~>1:1) isolated compound 9.1 (1.1g, yield：90%) it is white solid.
Step 2：The synthesis of compound 9.2
Compound 9.1 (1.1g, 5.5mmol) and a hydronium(ion) lithia (1.84g, 44mmol) are dissolved in methanol (20mL), The in the mixed solvent of tetrahydrofuran (20mL) and water (10mL), reaction system stir 16 hours at 80 DEG C.After being cooled to room temperature Water (40mL) is added into reaction system, decompression boils off organic solvent.Filter off the precipitation in aqueous phase.Filtrate is adjusted with hydrochloric acid (1.0M) PH to 5~6, after stirring 30 minutes, filter, compound 9.2 (450mg, yield are obtained after filtration cakes torrefaction：49%) consolidate for grey Body.
Step 3：Compound 7-1 synthesis
Compound 7-1 presses the compound 1-1 of embodiment 10 synthetic method, is obtained with the reaction of compound 9.2 and 6.2.Chemical combination Thing 7-1 silica gel column chromatography (petroleum ethers：Ethyl acetate=4:1~1:1) the less compound 7-1a of isolated polarity The larger compound 7-1b (8.3mg, single spatial configuration) of (8.8mg, single spatial configuration) and polarity is white solid.
m/z:[M+H]+411
7-1a：1H NMR(400MHz,CDCl3):δ 8.53 (s, 1H), 7.52 (t, J=6.4Hz, 1H), 7.29-7.48 (m, 9H), 7.16-7.22 (m, 1H), 6.76 (t, J=6.4Hz, 1H), 5.49 (br.s, 1H), 3.39 (dd, J=8.0,6.0Hz, 2H),2.05-2.12(m,1H),1.93-2.01(m,2H),1.88(s,2H),1.61-1.83(m,9H)。
7-1b：1H NMR(400MHz,CDCl3):δ 8.66 (s, 1H), 7.52 (t, J=6.8Hz, 1H), 7.32-7.48 (m, 9H), 7.18-7.24 (m, 1H), 6.76 (t, J=6.8Hz, 1H), 5.50 (br.s, 1H), 3.44 (dd, J=7.6,6.0Hz, 2H),2.00-2.24(m,1H),1.93-1.99(m,2H),1.78-1.91(m,6H),1.63(s,2H),1.56-1.61(m, 1H),1.44-1.52(m,2H)。
Embodiment 28：Compound 7-2 synthesis
It is compound 7-1 synthetic method with embodiment 27, the compound 6.2 in step 3 is replaced with 7.4 and obtains chemical combination Thing 7-2.
Compound 7-2 (126mg, cis-trans isomerism mixture) separates (petroleum ether with silica gel column chromatography：Ethyl acetate=4:1 ~1:1) the less compound 7-2a of polarity (2.0mg, cis-trans-isomer mixture) and the larger compound 7-2b of polarity are obtained (22.7mg, single spatial configuration) is white solid.
m/z:[M+H]+411
7-2a：1H NMR(400MHz,CDCl3):δ 8.47 (s, 1H), 7.48 (t, J=6.4Hz, 1H), 7.29-7.39 (m, 9H), 7.16-7.22 (m, 1H), 6.71 (t, J=6.4Hz, 1H), 5.47 (br.s, 1H), 2.92,2.95 (two s, 1H), 2.85,3.07 (two d, J=6.0Hz, 2H), 2.49,2.58 (two s, 2H), 1.96-2.02 (m, 1H), 1.76-1.87 (m, 3H),1.37-1.47(m,3H),1.26(br.s,2H),1.04-1.12(m,2H)。
7-2b：1H NMR(400MHz,CDCl3):δ 8.66 (s, 1H), 7.54 (t, J=6.4Hz, 1H), 7.43-7.51 (m, 4H), 7.33-7.41 (m, 5H), 7.17-7.24 (m, 1H), 6.76 (t, J=6.4Hz, 1H), 5.60 (br.s, 1H), 3.04 (d, J=5.6Hz, 2H), 2.82 (s, 1H), 2.46 (s, 2H), 1.73-1.83 (m, 3H), 1.28-1.51 (m, 8H).
Embodiment 29：Compound 7-3 synthesis
It is compound 7-1 synthetic method with embodiment 27, is with 2- trifluoromethoxies methyl cinnamate and compound 9.5 Initiation material reacts to obtain compound 7-3.
m/z:[M+H]+498
1H NMR(400MHz,DMSO-d6):δ 11.08 (s, 1H), 8.28 (d, J=5.2Hz, 1H), 7.48-7.34 (m, 4H), 7.15-7.08 (m, 3H), 6.25 (d, J=1.6Hz, 1H), 2.90 (d, J=6.0Hz, 2H), 2.42 (s, 3H), 2.20 (s,3H),1.70-1.66(m,6H),1.41-1.38(m,6H)。
Biological test embodiment：The measure of IDO bioactivity
Embodiment 1：IDO inhibitory activity test (IC based on HeLa cells50)
HeLa cell lines source：ATCC, with MEM/EBSS fluid nutrient medium cultures, it is possible to additionally incorporate fetal bovine serum (10% FBS), Pen .- Strep (100,000U/L), nonessential amino acid (0.1mM), Sodium Pyruvate (Na-pyruvate) (1.0mM).Cell keeps 37 DEG C, 95% humidity and 5% carbon dioxide in incubator.With gamma interferon (IFN γ) altogether Incubation makes it express IDO, and it can be in the medium N- formylkynurenines by tryptophan metabolism to make it.Specific experiment method is such as Under：
HeLa cells are planted in 96 orifice plates with the amount of 25,000 cells/wells, 100 μ l culture medium is contained per hole, Next with the test compound of IFN γ and certain concentration (10 μM of concentration range arrives 1nM, be its in conventional medium most Volume is 200 μ L afterwards) inducing cell is overnight, and it is expressed people and recombinate IDO.Followed by incubation, by supernatant liquor (140 μ L) It is transferred in 96 orifice plates, adds 6.1N TCA (10 μ L) and continue to be incubated 30 minutes at 50 DEG C afterwards, make N- formyls dog caused by IDO Urinary ammonia acid is fully hydrolyzed as kynurenin.Reaction solution is centrifuged 10 minutes under 2500rpm rotating speeds afterwards, removes solid precipitation Thing, supernatant is transferred in another 96 orifice plate with 100 μ L/ holes afterwards, and adds 100 μ L 2% (w/v) 4- (N, N- bis- Methylamino) benzaldehyde acetum.It is incubated 10 minutes at room temperature, the solution that kynurenin produces yellow can be with using enzyme Mark instrument (TECAN Infinite M1000Pro) records its absorbance having at 480nm.
The suppression percentage of each concentration of testing compound is made to be measured with reference to comparative evaluation with 0.1% DMSO blank solutions The decrement of kynurenin determines in chemical combination objects system, data Graph Pad4 are obtained by nonlinear regression IC50Value.
Polycyclic compound active testing result of the present invention, IC50Value report scope be：+ 10-1 μM is represented, ++ represent 1-0.5 μM, +++ 0.5-0.05 μM is represented, ++++represent<0.05μM.

Claims (21)

1. a kind of polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or medicine Acceptable salt on；
Wherein, A rings are phenyl, naphthyl, 5-6 unit monocycles heteroaryl, 8-12 members and ring heteroaryl；
B rings are C6-12Bridged ring base or 6-12 member bridge heterocyclic radicals；
Y is connecting key ,-O- ,-NR4- or-CR5R5a-；
Z be-C (O)-,-S (O)1-2- or-S (O) (NCN)-；
X is connecting key ,-NR4- or-CR5R5a-；Also, it is connecting key during X with Y differences；
Or the Z groups that are connected jointly by them of X and Y form 5-8 circle heterocycles alkyl together, the Heterocyclylalkyl can be with Further N, O, S (O) are selected from containing 1-20-2Hetero atom；
L1For connecting key or-(L)t-；
L2For connecting key, C2-6Alkenylene, C2-6Alkynylene or-(L)t-；
L is CR6R6a；
R1Selected from hydrogen, halogen, hydroxyl, alkyl, alkoxy, alkylthio group, haloalkyl, halogenated alkoxy, amino, C2-6Alkynyl, C2-6 Alkenyl ,-SH ,-CN ,-NO2、-ORb、-OC(O)Ra、-OC(O)ORb、-OC(O)N(Rb)2、-C(O)ORb、-C(O)Ra、-C(O)N (Rb)2、-N(Rb)2、-NRbC(O)Ra、-N(Rb)C(O)ORb、-N(Rb)C(O)N(Rb)2、-(CH2)tN(Rb)2、-NRbS(O)2Ra、- S(O)0-2Ra、-S(O)2N(Rb)2, cycloalkyl, Heterocyclylalkyl, substitution or be substitution aryl and substitution or be substitution heteroaryl One or more in base；When the aryl or heteroaryl are substituted, optionally by 1~3 selected from halogen, amino, Cyano group, hydroxyl, C1-3Alkyl, C1-3Alkoxy, halo C1-3Alkoxy or halo C1-3The substituent of alkyl substitutes optional position again；
R2Or R3Independently selected from hydrogen ,-NO2、-CN、-OH、-NH2、-SH、-OR8、-OC(O)R8、-OC(O)NR7R8、-OC(O) OR8、-OP(O)(O-R7)2、-B(O-R7)2、-OS(O)2(OH)、-OS(O)1-2R8、-S(O)1-2OR8、-S(O)2NR7R8、-S(O)0- 2R8、-S(O)2N(R7)C(O)NR7R8、-C(O)OR8、-C(O)R8、-C(O)N(OH)R8,-C (=Rc)NR7R8、-NR7R8、-N(R7) C(O)OR8、-N(R7)C(O)N(R7)S(O)2R8、-N(R7) C (=Rc)NR7R8、-N(R7)S(O)1-2R8、-N(R7)C(O)R8、-N (R7)S(O)1-2NR7R8、-N(R7) C (=Rc)R8、-N(R7)OR8、-N(R7)C(O)NR7R8, oxo base, halogen, C2-6Alkynyl, C2-6 Alkenyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substitution do not take The Heterocyclylalkyl in generation or substituted or unsubstituted aryl；As described R2Or R3For substituted alkyl, the cycloalkyl of substitution, substitution Heterocyclylalkyl, substitution aryl or substitution heteroaryl when can be by following 1~3 RAGroup substitutes at an arbitrary position：- OH、-SH、-CN、-NO2、-NH2, halogen, alkylthio group ,-C (=Rc)N(Rb)2、-OC(O)Ra、-OC(O)ORb、-OC(O)N (Rb)2、-C(O)ORb、-C(O)Ra、-C(O)N(Rb)2、-N(Rb)2、-NRbC(O)Ra、-NRbC (=Rc)Ra、-NRbC(O)ORa、- NRbC(O)N(Rb)2、-NRbC (=Rc)N(Rb)2、-(CH2)tN(Rb)2、-NRbS(O)2Ra、-NRbS(O)2N(Rb)2、-S(O)0- 2Ra、-S(O)2N(Rb)2, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted C2-6Alkynyl, Substituted or unsubstituted C2-6It is alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl or substituted or unsubstituted heteroaryl；RAIn, the alkyl, alkoxy, C2-6Alkynyl, C2-6It is alkenyl, aryl, miscellaneous , can be further by 1~3 selected from halogen, hydroxyl, amino, C when aryl, cycloalkyl or Heterocyclylalkyl are substituted1-4Alkyl or Halo C1-3The substituent substitution of alkoxy is at an arbitrary position；
R4For hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted Heterocyclylalkyl；Institute The Heterocyclylalkyl for stating substituted alkyl, the cycloalkyl of substitution or substitution is substituted at an arbitrary position by following one or more groups： Halogen, hydroxyl, alkyl, Heterocyclylalkyl, cycloalkyl, alkoxy, amino, aryl, heteroaryl ,-SRa、-N(Rb)2、-S(O)2N (Rb)2、-NRbC(O)N(Rb)2、-NRbC(O)Ra、-C(O)Ra、-S(O)0-2Ra、-C(O)ORb、-(CH2)tOH or-(CH2)tN (Rb)2；
R5And R6Separately selected from hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, take Generation or unsubstituted Heterocyclylalkyl, or substituted or unsubstituted alkoxy；The substituted alkyl, the cycloalkyl of substitution, substitution Heterocyclylalkyl, or the alkoxy of substitution substituted at an arbitrary position by following one or more groups：It is halogen, hydroxyl, alkyl, miscellaneous Cycloalkyl, cycloalkyl, alkoxy, amino, aryl, heteroaryl ,-SRa、-N(Rb)2、-S(O)2N(Rb)2、-NRbC(O)N(Rb)2、- NRbC(O)Ra、-C(O)Ra、-S(O)0-2Ra、-C(O)ORb、-(CH2)tOH or-(CH2)tN(Rb)2；
R5aAnd R6aSeparately selected from hydrogen, deuterium, halogen, hydroxyl, amino, alkyl ,-SRa、-ORb、-N(Rb)2、-NRbS(O)2Ra、-S(O)2N(Rb)2、-(CH2)tS(O)0-2CH3、-OS(O)3H、-OP(O)(O-Rb)2、-OC(O)Ra、-OC(O)N(Rb)2、-C (O)N(Rb)2、-(CH2)tC(O)OH、-(CH2)tOH、-(CH2)tN(Rb)2Or-(CH2)tC(O)N(Rb)2；
Or R5And R5a3-8 unit monocycle cycloalkyl is formed together with the C atoms connected jointly with them；
Or R6And R6a3-8 unit monocycle cycloalkyl is formed together with the C atoms connected jointly with them；
R7Selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substitution Or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkanes Base alkyl, substituted or unsubstituted hetercycloalkylalkyl, substituted or unsubstituted aryl alkyl or substituted or unsubstituted heteroaryl Base alkyl；
R8Selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substitution Or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkanes Base alkyl, substituted or unsubstituted hetercycloalkylalkyl, substituted or unsubstituted aryl alkyl or substituted or unsubstituted heteroaryl Base alkyl ,-(L)t-R7、-(L)u-OR7、-(L)u-N(R7)2、-(L)t-C(O)OR7、-(L)u-OC(O)R7、-(L)t-C(O)N (R7)2、-(L)u-N(R7)C(O)Rd、-(L)u-N(R7)C(O)N(R7)2、-(L)u-N(R7)C(S)N(R7)2、-(L)u-OS(O)1- 2R7、-(L)u-S(O)1-2OR7、-(L)u-S(O)0-2R7、-(L)u-N(Rd)S(O)2N(R7)2、-(L)u-S(O)2N(R7)2、-(L)u- N(Rd)S(O)2R7Or-(L)u-OP(O)(O-R7)2；
Or R7And R8Single Heterocyclylalkyl of 3-8 members is formed together with the N atoms connected jointly with them；
As described R7Or R8For substituted alkyl, substituted or unsubstituted alkoxy, the cycloalkyl substituted, the heterocycle alkane substituted Base, the aryl of substitution, the heteroaryl of substitution, the cycloalkyl-alkyl of substitution, the hetercycloalkylalkyl of substitution, the aryl alkane of substitution Can be by following 1~3 R when base or the heteroaryl alkyl of substitutionBGroup substitutes at an arbitrary position：-OH、-SH、-CN、-NO2、- NH2, halogen, alkylthio group ,-C (=Rc)N(Rf)2、-OC(O)Rf、-OC(O)ORf、-OC(O)N(Rf)2、-C(O)ORf、-C(O) Rf、-C(O)N(Rf)2、-N(Rf)2、-NRfC(O)Rg、-NRfC (=Rc)Rg、-NRfC(O)ORf、-NRfC(O)N(Rf)2、-NRfC (=Rc)N(Rf)2、-(CH2)tN(Rf)2、-NRfS(O)2Rg、-NRfS(O)2N(Rf)2、-S(O)0-2Rg、-S(O)2N(Rf)2, substitution Or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C2-6Alkene Base, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl or substitution or not Substituted heteroaryl；RBIn, the alkyl, alkoxy, C2-6Alkenyl, C2-6Alkynyl, aryl, heteroaryl, cycloalkyl or heterocycle alkane , can be further by 1~3 selected from hydroxyl, halogen, amino, C when base is substituted1-4Alkyl or halo C1-3The substituent of alkyl takes In generation, is at an arbitrary position；
RaAnd RbIt is each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, Heterocyclylalkyl Alkyl, cycloalkyl-alkyl, aryl alkyl or aryl alkyl, or, two RbFormed together with the N atoms connected jointly with them The monocyclic heterocycloalkyl of 3-8 members；
=RcSelected from=O ,=S ,=NH or=N (OH)；
RgAnd RfIt is each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, Heterocyclylalkyl Alkyl, cycloalkyl-alkyl, aryl alkyl or aryl alkyl, or, two RfFormed together with the N atoms connected jointly with them The monocyclic heterocycloalkyl of 3-8 members；
N is 1,2 or 3；
M is 1 or 2；
T is 1,2,3,4,5 or 6；
U is 2,3,4,5 or 6.
2. polycyclic compound (I) as claimed in claim 1, its isomers, prodrug, solvate, hydrate, stable same position Plain derivative or pharmaceutically acceptable salt, it is characterised in that：A rings are phenyl, pyridine radicals, pyrimidine radicals, naphthyl, indyl, different Indyl, indazolyl, pyrrole radicals, pyrazolyl, benzo isoxazolyl, benzofuranyl or benzothienyl；
And/or B rings are C8-12Three ring bridged ring bases or 8-12 membered tricyclic bridge heterocyclic radicals.
3. polycyclic compound (I) as claimed in claim 2, its isomers, prodrug, solvate, hydrate, stable same position Plain derivative or pharmaceutically acceptable salt, it is characterised in that：Described B rings be adamantyl, bicyclic [2.2.2] octyl, Or 2-aza-adamantane base.
4. polycyclic compound (I) as claimed in claim 1, its isomers, prodrug, solvate, hydrate, stable same position Plain derivative or pharmaceutically acceptable salt, it is characterised in that：The R1For hydrogen, halogen, hydroxyl, sulfydryl, cyano group, amino, C1-3 Alkoxy, C1-3Alkylthio group, C1-3Alkyl, halo C1-3Alkyl and halo C1-3Alkoxy, substitution are one in the phenyl of substitution Kind is a variety of；N is 1 or 2.
5. polycyclic compound (I) as claimed in claim 1, its isomers, prodrug, solvate, hydrate, stable same position Plain derivative or pharmaceutically acceptable salt, it is characterised in that：Described X, Y, Z are preferably following any combination：
1) X is-NR4-, Y be connecting key, Z be-C (O)-；
2) X be connecting key, Y be-NR4-, Z be-C (O)-；
3) X is-NR4-, Y be-NR4-, Z be-C (O)-；
4) X is-NR4-, Y be connecting key, Z be-S (O)2-；
Or 5) X be connecting key, Y be-NR4-, Z be-S (O)2-。
6. polycyclic compound (I) as claimed in claim 5, its isomers, prodrug, solvate, hydrate, stable same position Plain derivative or pharmaceutically acceptable salt, it is characterised in that：Described X, Y, Z are preferably following any combination：
1) X be-NH-, Y be connecting key, Z be-C (O)-；
2) X be connecting key, Y be-NH-, Z be-C (O)-；
3) X be-NH-, Y be-NH-, Z be-C (O)-；
4) X be-NH-, Y be connecting key, Z be-S (O)2-；
Or 5) X be connecting key, Y be that-NH-, Z are-S (O)2-。
7. polycyclic compound (I) as claimed in claim 1, its isomers, prodrug, solvate, hydrate, stable same position Plain derivative or pharmaceutically acceptable salt, it is characterised in that：The L is-CH2-、-CH(CH3)-、-CH(CH2CH3)-、-C (CH3)2-、-CH(CF3)-、-CH(NH2- CH)-, (OH)-,-CHF- or-CF2-；
And/or L2For connecting key；
And/or R5For H ,-CH3、-CF3、-CH2CH3Or F；
And/or the R3For hydrogen, hydroxyl or methyl；M is 0 or 1.
8. polycyclic compound (I) as claimed in claim 1, its isomers, prodrug, solvate, hydrate, stable same position Plain derivative or pharmaceutically acceptable salt, it is characterised in that：The R2For：It is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl group, different Propyl group, the tert-butyl group, methoxyl group, ethyoxyl, isopropoxy, cyclohexyl epoxide, phenyl epoxide, benzyl epoxide, difluoromethyl, benzene Base, pyridine radicals, pyrimidine radicals, pyrazinyl, quinolyl, isoquinolyl, tetrazole ,-C (O) OH ,-OH ,-NO2、-NH2、-NHC(O) CH3、-CN、-OCF3、-CF3、-CH2OH、-CH2NH2、-OP(O)(OH)2、
9. the polycyclic compound (I), its isomers, prodrug, stable isotope as described in any one of claim 1~8 derive Thing or pharmaceutically acceptable salt, it is characterised in that：Its general structure is：
Wherein, U is NH or CH2；
A rings, R1、R2、R3、L1、L2, X, Y, Z and n definition as described in any one of claim 1~8.
10. the polycyclic compound (I), its isomers, prodrug, stable isotope as described in any one of claim 1~8 derive Thing or pharmaceutically acceptable salt, it is characterised in that：Its general structure is following any：
Wherein, A rings, R1、R2、R3、L1、L2, X, Y, Z and n definition as described in any one of claim 1~8.
11. the polycyclic compound (I), its isomers, prodrug, stable isotope as described in any one of claim 1~8 derive Thing or pharmaceutically acceptable salt, it is characterised in that：Its general structure is following any：
Wherein,The stereoisomeric configurations of the singly-bound of mark are respectively cis, trans, or the mixing of cis and trans；A rings, R1、 R2、R3、L1、L2, X, Y, Z and n definition as described in any one of claim 1~8.
12. the polycyclic compound (I), its isomers, prodrug, stable isotope as described in any one of claim 1~8 derive Thing or pharmaceutically acceptable salt, it is characterised in that：Its general structure is following any：
Wherein, U is N or CH；
R1、R2、R3、L1、L2, X, Y, Z and n definition as described in any one of claim 1~8.
13. the polycyclic compound (I), its isomers, prodrug, stable isotope as described in any one of claim 1~8 derive Thing or pharmaceutically acceptable salt, it is characterised in that：Its general structure is following any：
Wherein, V is N or CH；
R1、R2、R3、L1、L2, X, Y, Z and n definition as described in any one of claim 1~8.
14. the polycyclic compound (I), its isomers, prodrug, stable isotope as described in any one of claim 1~8 derive Thing or pharmaceutically acceptable salt, it is characterised in that：Its general structure is following any：
Wherein, M O or NH；V is N or CH；
R1、R2、R3、L1、L2, X, Y, Z and n definition as described in any one of claim 1~8.
15. polycyclic compound (I) as claimed in claim 1, its isomers, prodrug, stable isotope derivatives or pharmacy Upper acceptable salt, it is characterised in that：Compound as shown in formula (I) is following any structure：
16. a kind of pharmaceutical composition, it includes the active component of therapeutically effective amount and pharmaceutically acceptable auxiliary material；The work Property component include polycyclic compound (I) as described in any one of claim 1~15, its isomers, prodrug, isotope stably Derivative or pharmaceutically acceptable salt.
17. pharmaceutical composition as claimed in claim 16, it is characterised in that：In described pharmaceutical composition, the active component Also include other therapeutic agents of cancer, virus infection or autoimmune disease；
And/or in described pharmaceutical composition, the pharmaceutically acceptable auxiliary material includes pharmaceutically acceptable carrier, dilution Agent and/or excipient.
18. polycyclic compound (I), its isomers, prodrug, stable isotope derive as described in any one of claim 1~15 Thing or pharmaceutically acceptable salt, or as the described pharmaceutical composition of claim 16 or 17 is preparing IDO Application in inhibitor.
19. polycyclic compound (I), its isomers, prodrug, stable isotope derive as described in any one of claim 1~15 Thing or pharmaceutically acceptable salt, or as the described pharmaceutical composition of claim 16 or 17 is preparing treatment, alleviation and/or prevention By the application in the medicine of the relevant disease of IDO mediation；The correlation of described 2,3- dioxygenases mediation Disease includes：Viral or other infection, cancer or autoimmune diseases.
20. application as claimed in claim 19, it is characterised in that：The polycyclic compound (I), its isomers, prodrug, stably Isotope derivatives or pharmaceutically acceptable salt, or described pharmaceutical composition and one or more other species are used to control The therapeutic agent and/or treatment method for treating cancer are used in combination；Other species for treating cancer therapeutic agent and/or control Treatment method be Antitubulin, alkylating agent, topological enzyme I/II inhibitor, platinum-like compounds, antimetabolitas, hormone and Hormone analogs, signal transduction pathway inhibitor, angiogenesis inhibitors, targeted therapy, immunotherapeutic agent, promote apoptosis agent, be thin One or more in born of the same parents' cycle signalling pathways inhibitor and radiotherapy.
21. application as claimed in claim 19, it is characterised in that：Described viral or other infection is skin infection, stomach and intestine Road infection, urogenital infections and/or systemic infection；Described cancer is osteocarcinoma, lung cancer, stomach cancer, colon cancer, pancreas Cancer, breast cancer, prostate cancer, lung cancer, the cancer of the brain, oophoroma, carcinoma of urinary bladder, cervix cancer, carcinoma of testis, kidney, head and neck cancer, lymph One or more in cancer, leukaemia and cutaneum carcinoma；Described autoimmune disease is rheumatoid arthritis, systemic red Yabbi sore, MCTD, system chorionitis, dermatomyositis, nodular vasculitis, nephrosis, endocrine relevant disease, liver Disease, psoriasis and due to the one or more in autoimmune response caused by infection；The virus infection is by influenza, the third type Hepatitis viruse, HPV, cytomegalovirus, epstein-Barr virus, poliovirus, varicella-band Infected caused by one or more in shape herpesviral, Coxsackie virus and human immunodeficiency virus.
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WO2023236752A1 (en) * 2022-06-08 2023-12-14 苏州远智医药科技有限公司 Heterocyclic derivative, and pharmaceutical composition and application thereof

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