CN107674029A - Polycyclic compound, its pharmaceutical composition and application - Google Patents

Polycyclic compound, its pharmaceutical composition and application Download PDF

Info

Publication number
CN107674029A
CN107674029A CN201710637050.4A CN201710637050A CN107674029A CN 107674029 A CN107674029 A CN 107674029A CN 201710637050 A CN201710637050 A CN 201710637050A CN 107674029 A CN107674029 A CN 107674029A
Authority
CN
China
Prior art keywords
alkyl
substituted
unsubstituted
cycloalkyl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201710637050.4A
Other languages
Chinese (zh)
Inventor
刘胜洋
利群
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai de Novo Pharmatech Co Ltd
Original Assignee
Shanghai de Novo Pharmatech Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai de Novo Pharmatech Co Ltd filed Critical Shanghai de Novo Pharmatech Co Ltd
Publication of CN107674029A publication Critical patent/CN107674029A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a kind of polycyclic compound, its preparation method, pharmaceutical composition and application.Polycyclic compound (I), its isomers, prodrug, 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 and communicable disease etc..

Description

Polycyclic compound, its pharmaceutical composition and application
Technical field
The present invention relates to a kind of polycyclic compound, its preparation method, 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 ring or 5-6 member hetero-aromatic rings；
B1For CR5Or N；
B2For CR5, N or NR4；
B3For N or C；
X1For connecting key ,-O- ,-NR4- or-CR6R6a-；
X2For-C (O)-or-S (O)1-2-；
X3For connecting key ,-NR4- or-CR6R6a-；
Or X1And X3The X connected jointly by them2Group forms 5-8 circle heterocycles alkyl, the Heterocyclylalkyl together Further N, O, S (O) can also be selected from containing 1-20-2Hetero atom；
Y is connecting key ,-(CR6R6a)1-2-；
U and V is separately selected from N or CR3；
Z and W is separately selected from CHR3、NR3, O, C (O) or S (O)2；
L is connecting key, C2-6Alkenylene, C2-6Alkynylene or-(CR6R6a)u-；
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、-NRbS(O)2Ra、-S(O)0- 2Ra、-S(O)2N(Rb)2, aryl, cycloalkyl, the one or more in Heterocyclylalkyl and heteroaryl；
R2Or R3Separately selected from hydrogen ,-NO2、-CN、-OH、-NH2、-SH、-OR8、-OC(O)R8、-OC(O)NR7R8、- OC(O)OR8、-OP(O)(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(O)NR7R8、-NR7R8、-N(R7)C(O) OR8、-N(R7)C(O)N(R7)S(O)2R8、-N(R7)C(O)NR7R8、-N(R7)S(O)1-2R8、-N(R7)C(O)R8、-N(R7)S (O)1-2NR7R8、-N(R7)C(O)R8、-N(R7)OR8、-N(R7)C(O)NR7R8, substituted or unsubstituted alkyl, substitution or do not take The heteroaryl in generation, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl or substituted or unsubstituted aryl；
R4For H or C1-6Alkyl；
R5For H ,-OH ,-SH ,-CN ,-NO2、-NH2, halogen, alkylthio group ,-C (O) 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(O)Ra、-NRbC (O)ORa、-NRbC(O)N(Rb)2、-NRbC(O)N(Rb)2、-NRbS(O)2Ra、-NRbS(O)2N(Rb)2、-S(O)0-2Ra、-S(O)2N (Rb)2、C2-6Alkynyl, C2-6Alkenyl, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-3Alkoxy, substitution do not take The C in generation6-10Aryl, substitution or the 5-6 unit's heteroaryls not taken, substitution or the C not taken3-8Cycloalkyl or substitution do not take 3-8 first Heterocyclylalkyl；
R6For hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, or substituted or unsubstituted alkoxy；
R6aFor hydrogen, deuterium, halogen, hydroxyl, amino, alkyl ,-SRa、-ORb、-N(Rb)2、-NRbS(O)2Ra、-S(O)2N (Rb)2、-(CH2)uS(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)uC(O)OH、-(CH2)uOH、-(CH2)uN(Rb)2Or-(CH2)uC(O)N(Rb)2；
Or R6And R6a3-8 unit monocycle cycloalkyl is formed together with the C atoms connected jointly with them；
R7Or R8Separately selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substitution or Unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Alkyl, substituted or unsubstituted hetercycloalkylalkyl, substituted or unsubstituted aryl alkyl or substituted or unsubstituted heteroaryl Alkyl；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 heteroaryl alkyl, or, two RbThe N atoms one being connected jointly with them Act the monocyclic heterocycloalkyl for forming 3-8 members；
M is 1 or 2；
N is 1,2 or 3；
T is 0,1 or 2；
Q is 0,1 or 2
U is 1,2 or 3.
The A rings are preferably phenyl ring, pyridine ring, pyrimidine ring, pyrrole ring, pyrazine ring or pyrazole ring；The A rings are more preferably Phenyl ring, pyridine ring or pyrazine ring.
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 C1-3One or more in alkoxy.
The R1More preferably：H、F、Cl、Br、-CH3、-CN、-OCH3、-OCF3、-OCHF2With-NH2In one kind or more Kind.
The R4Preferably H, methyl or ethyl.
The R5In, as described C1-6Alkyl, C1-3Alkoxy, C6-10Aryl, 5-6 unit's heteroaryls, C3-8Cycloalkyl or 3-8 , can be further by 1~3 selected from halogen, hydroxyl, amino, C when circle heterocycles alkyl is substituted1-4Alkyl or halo C1-3Alkoxy Substituent substitution at an arbitrary position；
The R5Preferably H, methyl, hydroxyl, amino, methoxyl group, cyano group, phenyl or substitution phenyl in one kind or It is a variety of.
The X1、X3, in Y or L, the R6Preferably hydrogen, deuterium, halogen, substituted or unsubstituted C1-4Alkyl, substitution or not Substituted 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)uOH or-(CH2)uN(Rb)2；
The X1、X3, in Y or 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)uS(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)uC(O)OH、-(CH2)uOH、-(CH2)uN(Rb)2Or-(CH2)uC(O)N(Rb)2； Or R6aAnd R63-8 unit monocycle cycloalkyl is formed together with the C atoms connected jointly with them.
The R6Or R6aMore preferably H ,-CH3、-CF3、-CH2CH3Or F.
The X1Preferably connecting key or-NH-.
The X2Preferably X2For-C (O)-or-S (O)1-2-；
The X3Preferably connecting key or-NH-；
The X1、X2And X3Preferably following any combination：
1)X1For connecting key, X2For-C (O)-, X3For-NH-；
2)X1For connecting key, X2For-S (O)2-、X3For-NH-；
3)X1For-NH-, X2For-C (O)-, X3For connecting key；
4)X1For-NH-, X2For-S (O)2-、X3For-NH-.
Or 5) X1For-NH-, X2For-C (O)-, X3For-NH-；
The Y is preferably connecting key ,-CH2-、-CH(CH3)-、-CH(CH2CH3)-、-C(CH3)2-、-CH(CF3)-、-CH (NH2- CH)-, (OH)-,-CHF- or-CF2-；The Y is more preferably-CH2-。
The L is preferably connecting key ,-CH2-、-CH(CH3)-、-CH(CH2CH3)-、-C(CH3)2-、-CH(CF3)-、-CH (NH2- CH)-, (OH)-,-CHF- or-CF2-；The L is more preferably connecting key.
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 (O) 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(O)Ra、-NRbC(O)ORa、-NRbC(O)N(Rb)2、-NRbC(O)N(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, take Generation or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl or substituted or unsubstituted Heteroaryl.
R2Or R3In, the RAPreferably fluorine, chlorine, bromine ,-OH ,-SH ,-CN ,-NO2、-NH2, alkylthio group ,-C (O) 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(O)Ra、-NRbC(O)ORa、-NRbC(O)N(Rb)2、-NRbC(O)N(Rb)2、-NRbS(O)2Ra、-NRbS(O)2N (Rb)2、-S(O)0-2Ra、-S(O)2N(Rb)2, substituted or unsubstituted C1-4Alkyl, substituted or unsubstituted C1-4Alkoxy, C1-4 Alkylthio group, phenyl, C3-8Cycloalkyl, 5-8 circle heterocycles alkyl, 5-6 unit's heteroaryls；
R2Or R3In, the RAIn, the alkyl, alkoxy, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl are substituted When, can be further by 1-3 selected from halogen, hydroxyl, amino, C1-3Alkyl or halo C1-3The substituent substitution of alkoxy is in office Meaning position.
R2Or R3In, R7Or R8It is preferably separately hydrogen, substituted or unsubstituted C1-6It is alkyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-8 circle heterocycles alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 members Heteroaryl, substituted or unsubstituted C3-8Cycloalkyl C1-3Alkyl, substituted or unsubstituted 3-8 circle heterocycles alkyl C1-3Alkyl, substitution Or unsubstituted phenyl C1-3Alkyl or substituted or unsubstituted 5-6 unit's heteroaryls C1-3Alkyl；Or R7And R8It is common with them The N atoms of connection form single Heterocyclylalkyl of 3-8 members together.
R7Or R8In, when the alkyl, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, aryl alkyl, heteroaryl alkyl, ring , can be further by 1~3 selected from halogen, hydroxyl, amino, C when alkyl-alkyl or substituted hetercycloalkylalkyl1-4Alkyl or Halo C1-3The substituent substitution of alkoxy is at an arbitrary position.
The R3More preferably hydrogen, fluorine, hydroxyl, cyano group, C1-4Alkyl or C1-3Alkoxy.
The RaAnd RbHydrogen, C preferably are selected from independently of one another1-4Alkyl, halo C1-3Alkyl, C3-8Cycloalkyl, 3-8 circle heterocycles alkane Base, phenyl, 5-6 unit's heteroaryls, 3-8 circle heterocycles alkyl C1-3Alkyl, C3-8Cycloalkyl C1-3Alkyl, phenylalkyl or 5-6 members are miscellaneous Aryl C1-3Alkyl, or, two RbThe monocyclic heterocycloalkyl of 3-8 members is formed together with the N atoms connected jointly with them；
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、L、X1、X2、X3、B1、B2、B3, Y, U, V, m, n and q it is defined as described above.
Following preferred embodiment is included in formula (IA) definition：
In some preferred embodiments, Y is-CH2-。
In some preferred embodiments, m 1.
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its general structure are preferably：
Wherein, B1For N or CR5, B2For NH or N (CH3)；M is N or CH；N is N or CH；
R1、R2、R5、L、X1、X2、X3, Y, U and V it is defined as described above.
Following preferred embodiment is included in formula (IA) definition：
In some preferred embodiments, R5For H.
In some preferred embodiments, R5For substituted or unsubstituted phenyl, when the phenyl is substituted, may be selected Property substituted at an arbitrary position by 1 substituent selected from fluorine, chlorine, methyl, methoxyl group, trifluoromethoxy, cyano group or amino.
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its general structure are preferably：
Wherein, D is N or CH；B2For N or CH；
R2、L、X1、X2、X3, Y, U and V it is defined as described above.
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its general structure are preferably：
Wherein, D is N or CH；E is NH or N (CH3)；
R2、L、X1、X2、X3, Y, U and V it is defined as described above.
The polycyclic compound (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or Pharmaceutically acceptable salt, its general structure are preferably：
Wherein, R1、R2、L、X1、X2、X3, Y, U and V it is defined as 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、L、X1、X2、X3、B1、B2、B3, Y, m and n it is defined as described above.
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, R1、R2、L、X1、B1、B2、 B3, U, V, n and m it is as defined above.
Method 1 comprises the following steps：Compound shown in 1a and 1b is obtained into I-a institutes by condensation reaction in the basic conditions Show 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 especially It is preferred that following reaction condition：The preferred dichloromethane of solvent, the preferred 1- of described condensing agent (3- dimethylamino-propyls) -3- ethyl carbon Diimmonium salt hydrochlorate (EDCI)；The preferred DIPEA of described alkali (DIPEA) or triethylamine (TEA), reaction temperature It is preferred that 0 DEG C~room temperature, to accelerate reaction speed, can also add the DMAP of catalytic amount into reaction system.
Method 2：
Compound shown in Formulas I b can be obtained by the reaction equation 2 shown in method 2, wherein, A rings, R1、R2、L、X1、B1、B2、 B3, U, V, n and m it is as defined above.
Method 2 comprises the following steps：Compound shown in 2a and 1b is obtained by nucleophilic substitution in the basic conditions Compound shown in I-b, the condition and step of reaction can be this area conventional condition and step, specifically preferred according to the invention following anti- Answer 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 DMAP of catalytic amount can be added in reaction system, instead Answer temperature preferably 0 DEG C~room temperature.
In the above method 1~2, other amino group or hydroxyl bases in the compound as shown in formula 1a, 1b or 2a be present During group, the amino group or oh group all should be protected by protection group, just be avoided that side reaction.If there is above-mentioned amino Blocking group or hydroxy-protective group are then needed after follow-up deprotection steps, obtain the compound as shown in Formulas I a or Ib.Appoint What suitable amido protecting group, such as：Tertbutyloxycarbonyl (Boc) group, it may be incorporated for protecting amino group.If use Boc can be in standard conditions, for example, p-methyl benzenesulfonic acid/methanol system, dichloromethane as protection group, follow-up deprotection reaction Alkane/trifluoroacetic acid system, the ether solution of hydrogen chloride of saturation or Trimethylsilyl trifluoromethanesulfonate/2,6- lutidines/bis- Carried out in chloromethanes system；Any suitable hydroxy-protective group, such as：Benzyl, it may be incorporated for protecting amino group, subsequently 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 " 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, dihydro Yin Diindyl base, 2,3- dihydrobenzos [b] thienyl, dihydrobenzo piperazine mutter base, 1,2,3,4- tetrahydric quinoline groups, Deng." spiro heterocyclic radical " refers to two Heterocyclylalkyls or a cycloalkyl and a Heterocyclylalkyl shares pair that a carbon atom is formed Cyclic group, spiro heterocyclic radical include but is not limited to：Deng.Monocyclic heterocycloalkyl and polycyclic Heterocyclylalkyl 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 and/or nitrogen original of ring skeleton Son.
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 5-7 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 " 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.
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 (MeOD-d4), deuterated dimethyl sulfoxide (DMSO-d6), tetramethylsilane is made For 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 (pre-HPLC) uses Shimadzu LC-20 preparative liquid chromatographies, and chromatographic column is：waters Xbridge Pre C18,10um, 19mm × 250mm.Isocratic condition：70% solvent orange 2 A and 30% solvent B；Mobile phase A： 0.05% trifluoroacetic acid aqueous solution (percentage is percentage by volume), Mobile phase B：Acetonitrile；Detection wavelength：214nm&254nm；Stream Speed：9.0mL/ minute.
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 1.6
Step 1：The synthesis of compound 1.1
Phosphine acyl acetic acid three ethyl (6.2g, 27.6mmol) is dissolved in anhydrous tetrahydro furan (100mL), be cooled to- 40 DEG C, potassium tert-butoxide (3.4g, 29.9mmol) is added portionwise, reaction system stirs 10 minutes, then removes dry ice acetone bath, delays Slowly 0 DEG C is warming up to, continues stirring 10 minutes.System is cooled to -40 DEG C afterwards, add 4- phenyl cyclohexanones (4.0g, Tetrahydrofuran (5mL) solution 23.0mmol).Reaction system is warmed to room temperature and is stirred overnight naturally.Add saturated ammonium chloride water Reaction is quenched in solution, and mixture is extracted with ethyl acetate (100mL × 3), merges organic phase, anhydrous with saturated common salt water washing Sodium sulphate is dried, and solvent is distilled off in filtering, filtrate decompression, obtained residue silica gel column chromatography (petroleum ether：Ethyl acetate =5:1) compound 1.1 (5.0g, yield are purified to obtain：89%) it is colorless oil.
Step 2：The synthesis of compound 1.2
Compound 1.1 (5.0g, 20.5mmol) is dissolved in methanol (100mL), addition Pd/C (5% wet palladium carbon, 200mg).Then reaction is replaced three times with hydrogen and be stirred overnight under hydrogen system (hydrogen balloon).Filtering, filter cake methanol Washing, filtrate decompression are distilled off solvent, obtain compound 1.2 (5.0g, yield：99%) it is white solid.
Step 3：The synthesis of compound 1.3
Compound 1.2 (2.0g, 8.12mmol) is dissolved in the mixed solvent (15mL/5mL) of tetrahydrofuran and water, added Enter a hydronium(ion) lithia (1.4g, 32.5mmol).Then reaction system is stirred 3 hours at 50 DEG C.Use hydrochloric acid solution (2.0M) regulation pH is 1~2, has solid precipitation, filters, and filter cake is washed with water, dry compound 1.3 (1.4g, yield： 79%) it is white solid.
Step 4：The synthesis of compound 1.4
Compound 1.3 (1.0g, 4.59mmol) is dissolved in dichloromethane (15mL), addition oxalyl chloride (2.9g, 22.9mmol) and two drip N,N-dimethylformamides.After stirring at normal temperature 30 minutes, it is evaporated under reduced pressure and removes solvent, residue is molten Solution in acetone, and adds the aqueous sodium azide of saturation.Then reaction is stirred 1 hour at normal temperatures.Add water, use acetic acid Ethyl ester (50mL × 3) extract, merge organic phase, and use saturated common salt water washing, anhydrous sodium sulfate drying, filter, filtrate decompression Solvent is distilled off, obtained residue silica gel column chromatography (petroleum ether：Ethyl acetate=4:1) compound 1.4 is purified to obtain (0.9g, yield：81%) it is white solid.
Step 5：The synthesis of compound 1.5
Compound 1.4 (800mg, 3.29mmol) is added in toluene (20mL), then add the tert-butyl alcohol (1.2g, 16.5mmol).By reaction system return stirring 3 hours, it is evaporated under reduced pressure and removes solvent, add water, be extracted with ethyl acetate (50mL × 2) organic phase, saturated common salt water washing, are merged, anhydrous sodium sulfate drying filters, and filtrate decompression is distilled off solvent, obtained Residue silica gel column chromatography (petroleum ether：Ethyl acetate=3:1) compound 1.5 (800mg, yield are purified to obtain：84%) it is white Color solid.
Step 6：The synthesis of compound 1.6
Compound 1.5 (800mg, 2.77mmol) is added in methanol hydrochloride solution (4.0M, 20mL), is heated to 40 DEG C, Stirring 3 hours, be evaporated under reduced pressure remove solvent, obtained residue petroleum ether, obtain compound 1.6 (hydrochloride, 600mg, Yield：96%) it is white solid.
m/z:[M+H]+190
Embodiment 2：The synthesis of compound 1.7
According to compound 1.6 and synthetic method, the phosphine acyl acetic acid three ethyl in step 1 is replaced with into 2- phosphonos propionic acid three Second fat obtains compound 1.7：
m/z:[M+H]+204
Embodiment 3：The synthesis of compound 2.2
Step 1：The synthesis of compound 2.1
Under condition of ice bath, by 1- phenyl -4- piperidones (1.0g, 5.7mmol), TosMIC (1.45g, 7.4mmol) and second Alcohol (2mL) is added separately in glycol dimethyl ether (20mL), and potassium tert-butoxide (1.6g, 14.3mmol), reactant is added portionwise System is stirred overnight at room temperature.The system is poured into frozen water (70mL).Liquid separation, aqueous phase are extracted with ethyl acetate (50mL × 2).Merge Organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, crude product silica gel column layer Analyse (petroleum ether：Ethyl acetate=4:1) purifying obtains compound 2.1 (675mg, yield：62.5%) it is pale yellow oil.
m/z:[M+H]+187
Step 2：The synthesis of compound 2.2
Compound 2.1 (200mg, 1.1mmol) is added in tetrahydrofuran (30mL), instills Lithium Aluminium Hydride at room temperature The tetrahydrofuran solution of (1.3mL, 3.2mmol).After being added dropwise, reaction solution is stirred overnight at room temperature.The system is cooled to 0 DEG C Hereinafter, then it is quenched with 15% sodium hydrate aqueous solution.Filtering, filtrate are diluted with ethyl acetate (50mL), then use saturation Brine It, organic phase is separated, with anhydrous sodium sulfate drying, filtering, compound 2.2 (167mg, yield are obtained after being concentrated under reduced pressure： 82%) it is pale yellow oil.
m/z:[M+H]+191
Embodiment 4：The synthesis of compound 3.1
Divide into methanol (200mL) solution of 4- phenyl cyclohexanones (40g, 23mmol) and ammonium acetate (177g, 230mmol) After batch adding sodium cyanoborohydride (4.3g, 69mmol), by reaction system at 50 DEG C stirring reaction 16 hours.Vacuum rotary steam removes Go most of solvent (about surplus 20mL) to be diluted afterwards with water (200mL), add saturated sodium bicarbonate aqueous solution (100mL), the mixing Thing is stirred at room temperature 30 minutes.Filter, compound 3.1 (2.4g, yield are obtained after filtration cakes torrefaction：60%) it is white solid.
m/z:[M+H]+176
Embodiment 5：The synthesis of compound 4.7
Step 1：The synthesis of compound 4.1
It is -78 DEG C, double to Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal (3.0g, 19.2mmol), N- phenyl under nitrogen protection It is added dropwise in methyl tertiary butyl ether(MTBE) (75mL) solution of (trifluoromethanesulfonimide) (8.2g, 23.1mmol) double (trimethyl silicon substrates) The tetrahydrofuran solution (2.0M, 11.5mL, 23.1mmol) of Sodamide, is added dropwise, and reaction system is stirred 1 hour.Then Reaction solution is warmed to room temperature, is stirred overnight.Reaction is quenched with saturated aqueous ammonium chloride, and is extracted with ethyl acetate, organic phase With anhydrous sodium sulfate drying, to filter, be concentrated to give compound 4.1 (6.0g) be light yellow oil.
Step 2：The synthesis of compound 4.2
By compound 4.1 (6.0g), double pinacol borates (6.87g, 27.1mmol), potassium acetate (6.13g, 62.4mmol), sodium bromide (8.6g, 8.33mmol) and Pd (dppf) Cl2Isosorbide-5-Nitrae-the dioxane of (0.76g, 1.0mmol) (65mL) mixture return stirring is stayed overnight.Then reaction system is cooled to room temperature, removal of solvent under reduced pressure, the quick post of residue Chromatographic purifying (petrol ether/ethyl acetate=50/1~10/1) obtains compound 4.2 (3.6g, two step yields：70%) it is yellow Solid.
Step 3：The synthesis of compound 4.3
Nitrogen protection under, by compound 4.2 (3.6g, 13.8mmol), 2- methyl -4- bromopyridines (2.4g, 13.8mol), Potassium carbonate (5.7g, 41.4mmol) and Pd (PPh3)4(0.32g, 0.28mmol) water/dioxane (50mL, 4:1) mixture Return stirring is stayed overnight, and then concentrates reaction solution, and is extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, filtering, dense Contracting obtains compound 4.3 (1.9g, yield：60%) it is light yellow solid.
Step 4：The synthesis of compound 4.4
Pd/C (150mg, 10%) is added into compound 4.3 (1.9g, 8.23mmol) methanol (50mL) solution, by this Reaction system is stirred overnight at room temperature under nitrogen atmosphere (hydrogen balloon).Then reaction system is filtered to remove Pd/C, filtrate is concentrated to give To compound 4.4 (1.6g, yield：84%) it is light yellow solid.
m/z:[M+H]+220
Step 5：The synthesis of compound 4.5
By compound 4.4 (1.6g, 6.87mmol) hydrochloric acid solution (4.0M, 30mL) and acetone (20mL) mixture 65 It is stirred overnight at DEG C.Then reaction system is concentrated under reduced pressure, residue adjusts pH value=9, mixture with 6N sodium hydrate aqueous solutions It is extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, filtering, concentration, residue rapid column chromatography (petroleum ether/second Acetoacetic ester=4/1~3/7) purifying obtain compound 4.5 (780mg, yield：60%) it is light yellow solid.
Step 6：The synthesis of compound 4.6
Under condition of ice bath, to compound 4.5 (780mg, 4.13mmol) and to Methyl benzenesulfonyl methyl isocyanide (784mg, In glycol dimethyl ether (20mL) and ethanol (2mL) mixture solution 4.02mmol) add potassium tert-butoxide (943mg, 7.73mmol).Reaction system is stirred overnight at room temperature, and reaction is quenched with aqueous ammonium chloride solution, then with ethyl acetate (3 × 30mL) Extraction, isolates organic phase.Organic phase saturated common salt water washing, filtering, filtrate decompression concentration.Residue rapid column chromatography (methylene chloride/methanol=19/1) purifying obtains compound 4.6 (560mg, yield：68%) it is colorless oil.
Step 7：The synthesis of compound 4.7
Pd/C (50mg, 10%) is added into compound 4.6 (560mg, 2.80mmol) methanol (20mL) solution, in hydrogen It is stirred overnight at room temperature under atmosphere (hydrogen balloon).Reacting liquid filtering removes Pd/C, and filtrate is concentrated to give compound 4.7 (418mg, production Rate：73%) it is light yellow solid.
m/z:[M+H]+205
Embodiment 6：The synthesis of compound 5.4
Step 1：The synthesis of compound 5.1
Under ice-water bath, 2- methoxy cyanophenyls (3.0g, 22.5mmol) and 2- methylpyrazines (2.2g, 23.0mmol) are dissolved In dry tetrahydrofuran (50mL), and stir 1.5 hours under nitrogen protection.Diisopropyl is slowly added on this condition Amido lithium (23mL, 45.06mmol, tetrahydrofuran solution), is added dropwise, and is warming up to 40 DEG C and continues stirring 3 hours.Reaction solution is cold But to environment temperature, it is quenched with ammonium chloride solution, ethyl acetate (50mL × 3) extraction, anhydrous sodium sulfate drying, filtering, filtrate It is concentrated under reduced pressure, residue isolates and purifies to obtain compound 5.1 with flash column chromatography (petrol ether/ethyl acetate=1/1) to be consolidated for yellow Body (2.2g, yield：39%).
m/z:[M+H]+376
Step 2：The synthesis of compound 5.2
Compound 5.1 (2.2g, 9.77mmol) is dissolved in DMF (15mL), under ice-water bath, slowly Add 60% and receive hydrogen (334mg, 8.34mmol), stir 0.5 hour at this temperature.Then 2- (trimethylsilyl) second is added Oxygen methyl chloride (SEM-Cl, 1.20g, 7.22mmol), is added dropwise, is stirred overnight at room temperature.Reaction system, acetic acid is quenched with water Ethyl ester extract (100mL × 2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, residue with flash column chromatography (petroleum ether/ Ethyl acetate=2/1) isolate and purify to obtain compound 5.2 (1.37g, yield：70%) it is brown-red solid.
m/z:[M+H]+356
Step 3：The synthesis of compound 5.3
Compound 5.2 (1.35g, 1.33mmoL) is added in dry DMF (15mL), is then dripped Add POCl3 (1.5mL), be added dropwise, be stirred overnight at room temperature.Reaction system, ethyl acetate extraction (50mL is quenched with water × 3), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, residue is with flash column chromatography (petrol ether/ethyl acetate=1/1) Isolate and purify to obtain compound 5.3 (1.05g, yield：72%) it is brownish red grease.
m/z:[M+H]+384
Step 4：The synthesis of compound 5.4
Compound 5.3 (500mg, 1.31mmol) is added in Isosorbide-5-Nitrae-dioxane (10mL) and water (2mL), ice-water bath Under, add sulfamic acid (763.1mg, 7.86mmol).Sodium chlorite (153.7mg, 1.70mmol) and potassium dihydrogen phosphate (2.14g, 15.72mmol) is dissolved in water (20mL), is then added in 5 minutes in above-mentioned reaction system, at room temperature after Continuous stirring 2 hours.Ethyl acetate extracts (20mL × 3), anhydrous sodium sulfate drying, filtering, and filtrate decompression is concentrated to give compound 5.4 (400mg, 77%) are yellow solid.
m/z:[M+H]+400
Embodiment 7：Compound 1-1 synthesis
Compound 1.6 (100mg, 0.44mmol) and indole -3-carboxylic acid (72mg, 0.44mmol) are added to dichloromethane In (20mL), EDCI (168mg, 0.88mmol) and triethylamine (222mg, 2.2mmol) are then added, by the reaction system in room The lower stirring of temperature 1 hour, add water quenching to go out reaction, be extracted with ethyl acetate (30mL × 3), merging organic phase, and use saturated aqueous common salt Solvent is distilled off in washing, anhydrous sodium sulfate drying, filtering, filtrate decompression, obtained residue silica gel column chromatography (oil Ether：Ethyl acetate=1:1) compound 5-1 (cis-trans isomerism mixture, 85mg, yield are purified to obtain：58%) it is white solid.
1H NMR(400MHz,CDCl3):δ8.69(br.s,1H),7.95-7.97(m,1H),7.82-7.84(m,1H), 7.47-7.49 (m, 4H), 7.19-7.24 (m, 3H), 6.12 (t, J=5.6Hz, 1H), 3.66 (t, J=6.8Hz, 0.33H), 3.46 (t, J=6.4Hz, 1.67H), 2.50-2.56 (m, 1H), 1.97-2.04 (m, 3H), 1.74-1.80 (m, 2H), 1.51- 1.55(m,2H),1.24-1.28(m,2H)。
m/z:[M+H]+333
Embodiment 8：Compound 1-2~1-8 synthesis
It is compound 1-1 synthetic method with embodiment 7, with compound 1.6 or 2.2 and 5- chloro-indole -3- carboxylic acids, 4- fluorine Indole -3-carboxylic acid, 1- methyl indol -3- carboxylic acids, 5- fluoro indole -3- carboxylic acids, 3- fluoro indole -3- carboxylic acids, 4- chloro-indole -3- carboxylics Acid or indole -3-carboxylic acid are that initiation material reacts to obtain compound 1-2~1-8.
m/z:[M+H]+367
1H NMR(400MHz,CDCl3):δ8.61-8.67(m,1H),7.99-8.04(m,1H),7.77-7.79(m,1H), 7.38 (d, J=12.8Hz, 1H), 7.29-7.35 (m, 3H), 7.19-7.27 (m, 3H), 5.87-6.02 (m, 1H), 3.42- 3.66(m,2H),2.49-2.69(m,1H),1.97-2.10(m,3H),1.71-1.86(m,3H),1.50-1.58(m,2H), 1.26-1.30(m,1H)。
Compound 1-3 (cis-trans-isomer mixture) silica gel column chromatography (petroleum ethers:Ethyl acetate=9:1~1:4) divide It is white solid from the less 1-3a of polarity (single spatial configuration) and the larger 1-3b (single spatial configuration) of polarity is obtained.
m/z:[M+H]+351
1-3a,1H NMR(400MHz,CDCl3+CD3OD):δ7.93-7.97(m,1H),7.76(s,1H),7.08-7.30 (m, 6H), 6.91-6.97 (m, 1H), 3.52 (d, J=7.6Hz, 2H), 2.57-2.63 (m, 1H), 1.65-2.08 (m, 9H).
1-3b,1H NMR(400MHz,CDCl3+CD3OD):δ7.76-7.80(m,1H),7.57(s,1H),6.88-7.05 (m, 6H), 6.70-6.75 (m, 1H), 3.08 (d, J=7.2Hz, 2H), 2.24-2.30 (m, 1H), 0.93-1.81 (m, 9H).
Compound 1-4 (cis-trans-isomer mixture) silica gel column chromatography (petroleum ethers:Ethyl acetate=9:1~1:4) divide It is white solid from the less 1-4a of polarity (single spatial configuration) and the larger 1-4b (single spatial configuration) of polarity is obtained.
m/z:[M+H]+347
1-4a,1H NMR(400MHz,CDCl3):δ7.91-7.93(m,1H),7.71(s,1H),7.21-7.41(m,8H), 5.96-6.09(m,1H),3.85(s,3H),3.63-3.66(m,2H),2.62-2.69(m,1H),1.73-2.10(m,9H)。
1-4b,1H NMR(400MHz,CDCl3):δ7.93-7.95(m,1H),7.71(s,1H),7.18-7.42(m,8H), 6.05-6.08 (m, 1H), 3.86 (s, 3H), 3.44 (d, J=6.4Hz, 2H), 2.49-2.57 (m, 1H), 1.18-2.04 (m, 9H)。
Compound 1-5 (cis-trans-isomer mixture) silica gel column chromatography (petroleum ethers:Ethyl acetate=1:1) it is isolated The less 1-5a of polarity (single spatial configuration) and the larger 1-5b (single spatial configuration) of polarity is white solid.
m/z:[M+H]+351
1-5a,1H NMR(400MHz,DMSO-d6):δ 11.63 (s, 1H), 8.10 (d, J=2.8Hz, 1H), 7.94 (t, J =5.6Hz, 1H), 7.81 (dd, J=3.2,10.4Hz, 1H), 7.42 (dd, J=4.4,8.8Hz, 1H), 7.26-7.32 (m, 4H), 7.16-7.20 (m, 1H), 6.96-7.01 (m, 1H), 3.38 (t, J=7.2Hz, 2H), 2.50-2.56 (m, 1H), 1.97 (s,1H),1.68-1.77(m,4H),1.58-1.62(m,4H)。
1-5b,1H NMR(400MHz,DMSO-d6):δ 11.64 (s, 1H), 8.12 (d, J=3.2Hz, 1H), 7.96 (t, J =6.0Hz, 1H), 7.82 (dd, J=2.4,10.4Hz, 1H), 7.42 (dd, J=4.8,8.8Hz, 1H), 7.21-7.29 (m, 4H), 7.14-7.17 (m, 1H), 6.96-7.02 (m, 1H), 3.15 (t, J=6.4Hz, 2H), 2.47-2.50 (m, 1H), 1.81- 1.90(m,4H),1.61(s,1H),1.41-1.45(m,2H),1.09-1.13(m,2H)。
Compound 1-6 (cis-trans-isomer mixture) silica gel column chromatography (petroleum ethers:Ethyl acetate=10:1~1:1) divide It is white from the less 1-6a of polarity (single spatial configuration) and the larger 1-6b (cis-trans-isomer mixture) of polarity is obtained Solid.
m/z:[M+H]+351
1-6a,1H NMR(400MHz,CDCl3):δ 8.79 (s, 1H), 7.83 (d, J=2.8Hz, 1H), 7.71 (d, J= 8.0Hz, 1H), 7.26-7.36 (m, 4H), 7.16-7.24 (m, 2H), 7.01 (dd, J=10.8,8.0Hz, 1H), 5.99 (s, 1H), 3.65 (dd, J=7.6,6.4Hz, 2H), 2.62-2.71 (m, 1H), 2.04-2.12 (m, 1H), 1.70-1.90 (m, 8H).
1-6b,1H NMR(400MHz,CDCl3):δ 8.75 (s, 1H), 7.84 (two d, J=2.8Hz, 1H), 7.74 (two D, J=7.6Hz, 1H), 7.29-7.35 (m, 3H), 7.18-7.25 (m, 3H), 6.97-7.05 (m, 1H), 6.09,5.99 (two Br.s, 1H), 3.65,3.45 (two dd, J=7.6,6.4Hz, 2H), 2.48-2.59 (m, 1H), 1.94-2.06 (m, 3H), 1.70-1.89(m,2H),1.47-1.56(m,2H),1.25-1.32(m,2H)。
m/z:[M+H]+367
1H NMR(400MHz,DMSO-d6):δ 11.64 (s, 1H), 8.15 (dd, J=8.4Hz, J=3.2Hz, 1H), 8.09 (dd, J=8.4,2.4Hz, 1H), 7.97-8.01 (m, 1H), 7.48 (d, J=2.0Hz, 1H), 7.10-7.31 (m, 6H), 4.10-4.13(m,1H),3.37-3.40(m,1H),3.13-3.18(m,2H),1.10-2.03(m,8H)。
m/z:[M+H]+334
1H NMR(400MHz,DMSO-d6):δ 11.5 (s, 1H), 8.15 (d, J=7.6Hz, 1H), 8.03 (d, J= 2.8Hz, 1H), 7.93 (t, J=5.6Hz, 1H), 7.43 (d, J=7.6Hz, 1H), 7.17-7.21 (m, 2H), 7.07-7.16 (m, 2H), 6.95 (d, J=8.0Hz, 2H), 6.74 (t, J=7.2Hz, 1H), 3.72 (d, J=12.8Hz, 2H), 3.19 (t, J =6.4Hz, 2H), 2.60-2.66 (m, 2H), 1.98-2.03 (m, 1H), 1.78-1.81 (m, 2H), 1.44-1.75 (m, 2H).
Embodiment 9：Compound 2-1 synthesis
It is compound 1-1 synthetic method with embodiment 7, is that initiation material reacts with compound 1.6 and indazole -3- carboxylic acids Obtain compound 2-1.
m/z:[M+H]+334
1H NMR(400MHz,CDCl3):δ 10.51 (br.s, 1H), 8.46 (d, J=8.4Hz, 1H), 7.53-7.55 (m, 1H),7.44-7.48(m,1H),7.29-7.34(m,3H),7.20-7.23(m,3H),3.63-3.67(m,0.65H),3.45 (t, J=6.4Hz, 1.35H), 2.52-2.57 (m, 1H), 1.95-2.04 (m, 3H), 1.70-1.82 (m, 2H), 1.49-1.53 (m,2H),1.22-1.47(m,2H)。
Embodiment 10：Compound 3-1 synthesis
It is compound 1-1 synthetic method with embodiment 7, with compound 1.6 and pyrazolo [1,5-a] pyridine-3-carboxylic acid React to obtain compound 3-1 for initiation material.
m/z:[M+H]+334
1H NMR:(400MHz,CDCl3):δ8.49-8.54(m,1H),8.32-8.38(m,1H),8.18,8.17(two s,1H),7.9-7.41(m,4H),7.18-7.25(m,2H),6.92-6.98(m,1H),6.01,5.92(two br.s,1H), 3.61,3.41 (two dd, J=6.0Hz (6.4Hz), 7.6Hz (6.4Hz), 2H), 2.48-2.70 (two m, 1H), 1.94- 2.05(m,3H),1.72-1.84(m,3H),1.46-1.58,1.16-1.26(two m,3H)。
Embodiment 11：Compound 4-1~4-2 synthesis
It is compound 1-1 synthetic method with embodiment 7, with compound 1.6 and indole -4-carboxylic acid or indazole -4- carboxylic acids React to obtain compound 4-1~4-2 for initiation material.
m/z:[M+H]+333
1H NMR(400MHz,CDCl3):δ8.51(br.s,1H),7.51-7.54(m,2H),7.28-7.35(m,4H), 7.17-7.24(m,3H),6.95-6.96(m,0.67H),6.92-6.93(m,0.34H),6.33-6.36(m,0.67H), 6.24-6.27 (m, 0.33H), 3.64-3.67 (m, 0.67H), 3.46 (t, J=6.4Hz, 1.33H), 2.63-2.66 (m, 0.33H),2.43-2.54(m,0.67H),1.94-2.02(m,2H),1.71-1.85(m,3H),1.46-1.53(m,2H), 1.22-1.29(m,2H)。
m/z:[M+H]+334
1H NMR(400MHz,CDCl3):δ10.32(br.s,1H),8.52-8.58(m,1H),7.66-7.69(m,1H), 7.51-7.54(m,1H),7.44-7.48(m,1H),7.30-7.33(m,3H),7.19–7.24(m,2H),6.36(br.s, 0.5H), 6.26 (br.s, 0.5H), 3.68 (t, J=6.4Hz, 1H), 3.48 (t, J=6.4Hz, 1H), 2.66-2.69 (m, 0.5H),2.58-2.61(m,0.5H),1.98-2.11(m,2H),1.75-1.85(m,3H),1.49-1.56(m,2H),1.22- 1.32(m,2H)。
Embodiment 12：Compound 5-1~5-4 synthesis
It is compound 1-1 synthetic method with embodiment 7, with compound 1.6 and isoquinolin -5- carboxylic acids, quinoline -4- carboxylics Acid, isoquinolin -3- carboxylic acids or quinoline-3-carboxylic acid are that initiation material reacts to obtain compound 5-1~5-4.
m/z:[M+H]+345
1H NMR:(400MHz,CDCl3):δ 9.32 (s, 1H), 8.70,8.69 (two s, 1H), 8.41 (t, J=8.0Hz, 1H),8.06,8.04(two s,1H),7.79-7.85(m,1H),7.67-7.74(m,1H),7.27-7.37(m,3H),7.18- 7.26 (m, 2H), 6.22,6.15 (two br.s, 1H), 3.70,3.51 (two br.t, J=6.4Hz, 2H), 2.63-2.72, 2.50-2.60(two m,1H),1.96-2.14(m,2H),1.71-1.90(m,3H),1.50-1.60(m,2H),1.21-1.38 (m,2H)。
m/z:[M+H]+345
1H NMR(400MHz,CDCl3):δ8.95-8.97(m,1H),8.23-8.27(m,1H),8.16-8.18(m,1H), 7.77-7.82(m,1H),7.62-7.67(m,1H),7.44-7.47(m,1H),7.29-7.34(m,3H),7.20-7.23(m, 2H), 6.21 (t, J=5.6Hz, 0.6H), 6.14 (t, J=5.6Hz, 0.4H), 3.67-3.72 (m, 0.8H), 3.50 (t, J= 6.4Hz,1.2H),2.66-2.70(m,0.4H),2.51-2.58(m,0.6H),2.00-2.03(m,2H),1.76-1.84(m, 4H),1.49-1.59(m,1H),1.23-1.32(m,2H)。
m/z:[M+H]+345
1H NMR(400MHz,CDCl3):δ9.19-9.20(m,1H),8.66(s,1H),8.32-8.43(m,1H),8.01- 8.08(m,2H),7.71-7.82(m,2H),7.29-7.35(m,3H),7.19-7.24(m,2H),3.67-3.70(m,0.7H), 3.49 (t, J=6.4Hz, 1.3H), 2.63-2.68 (m, 0.35H), 2.51-2.57 (m, 0.65H), 1.97-2.14 (m, 2H), 1.73-1.88(m,4H),1.49-1.58(m,1H),1.23-1.33(m,2H)。
m/z:[M+H]+345
1H NMR(400MHz,CD3OD):δ 9.27 (d, J=2.0Hz, 1H), 8.81-8.83 (m, 1H), 8.07-8.13 (m, 2H), 7.88-7.93 (m, 1H), 7.71-7.74 (m, 1H), 7.13-7.30 (m, 5H), 3.63 (d, J=8.0Hz, 1H), 3.38 (d, J=7.2Hz, 1H), 2.49-2.67 (m, 1H), 1.49-2.16 (m, 8H), 1.20-1.31 (m, 1H).
Embodiment 13：Compound 6-1 synthesis
It is compound 1-1 synthetic method with embodiment 7, is initiation material with compound 1.7 and 5- fluoro indole -3- carboxylic acids Reaction obtains compound 6-1.
m/z:[M+H]+365
1H NMR(400MHz,CDCl3):δ 8.87 (br.s, 1H), 7.78 (d, J=2.8Hz, 1H), 7.63-7.66 (m, 1H),7.34-7.38(m,1H),7.27-7.31(m,2H),7.18-7.21(m,3H),6.99-7.05(m,1H),5.73(d,J =8.8Hz, 1H), 4.20-4.26 (m, 1H), 2.46-2.52 (m, 1H), 1.93-2.00 (m, 4H), 1.47-1.55 (m, 2H), 1.26-1.34(m,6H)。
Embodiment 14：Compound 7-1~7-2 synthesis
It is compound 1-1 synthetic method with embodiment 7, with compound 1.6 or 2.2 and indole-3-acetic acid or indoles -3- Carboxylic acid is that initiation material reacts to obtain compound 7-1~7-2.
Compound 7-1 (cis-trans-isomer mixture) silica gel column chromatography (petroleum ethers:Ethyl acetate=9:1~1:4) divide It is white solid from the less 7-1a of polarity (single spatial configuration) and the larger 7-1b (single spatial configuration) of polarity is obtained.
m/z:[M+H]+347
7-1a,1H NMR(400MHz,CDCl3):δ8.26(br.s,1H),7.43-7.62(m,2H),7.16-7.31(m, 7H), 5.76-5.80 (m, 1H), 3.79 (s, 2H), 3.10 (t, J=6.4Hz, 2H), 2.34-2.42 (m, 1H), 0.92-1.87 (m,9H)。
7-1b,1H NMR(400MHz,CDCl3):δ8.20-8.24(m,1H),7.42-7.62(m,2H),7.17-7.31 (m, 7H), 5.66-5.78 (m, 1H), 3.78 (d, J=2.4Hz, 2H), 3.08-3.32 (m, 2H), 2.34-2.58 (m, 1H), 0.92-1.87(m,9H)。
m/z:[M+H]+348
1H NMR(400MHz,DMSO-d6):δ 10.85 (s, 1H), 7.94 (t, J=5.2Hz, 1H), 7.56 (d, J= 8.0Hz, 1H), 7.35 (d, J=8.0Hz, 1H), 7.17-7.21 (m, 3H), 7.04-7.09 (m, 1H), 6.95-6.99 (m, 1H), 6.92 (d, J=8.0Hz, 2H), 6.73 (t, J=7.6Hz, 1H), 3.67 (d, J=12.4Hz, 2H), 3.52 (s, 2H), 2.99 (t, J=6.4Hz, 2H), 2.54-2.60 (m, 2H), 1.98-2.03 (m, 1H), 1.71 (d, J=12.0Hz, 2H), 1.45-1.58(m,2H)。
Embodiment 15：Compound 8-1 synthesis
It is compound 1-1 synthetic method with embodiment 7, is initiation material with compound 3.1 and 5- fluoro indole -3- carboxylic acids Reaction obtains compound 8-1.
m/z:[M+H]+337
1H NMR(400MHz,CDCl3):δ 8.86 (br.s, 1H), 7.78 (d, J=2.8Hz, 1H), 7.67 (dd, J= 10.0,2.4Hz, 1H), 7.31-7.40 (m, 3H), 7.20-7.29 (m, 3H), 7.04 (dt, J=8.8,2.4Hz, 1H), 5.76 (d, J=8.0Hz, 1H), 4.08-4.20 (m, 1H), 2.52-2.62 (m, 1H), 2.27-2.35 (m, 2H), 1.98-2.07 (m, 2H),1.66-1.78(m,2H),1.40-1.52(m,2H)。
Embodiment 16：Compound 9-1 synthesis
Step 1：The synthesis of compound 4.1
5- fluoro indoles (1g, 7.48mmol) and sulfur trioxide pyridine (1.3g, 8.1mmol) are added to pyridine (20mL) In, reaction system is heated to 105 DEG C and stirred 4 hours.Water (200mL) is added into reaction system and uses ethyl acetate (100mL afterwards × 2) extract.Aqueous phase is separated, compound 4.1 (1.5g, yield are obtained after aqueous phase is freezed：99%) it is yellow oil.
Step 2：The synthesis of compound 4.2
Compound 4.1 (1.5g, 5.1mmol) is dissolved in the in the mixed solvent of sulfolane (10mL) and acetonitrile (20mL), to 80 DEG C are heated to after addition POCl3 (1.56g, 10.2mmol) in mixture to stir 16 hours.It is residual after decompression boils off acetonitrile Stay thing to be dissolved in ethyl acetate (200mL), washed respectively with water and saturated common salt, separate organic phase, and done with anhydrous sodium sulfate It is concentrated under reduced pressure after dry.Crude product silica gel column chromatography (petroleum ether：Ethyl acetate=5:1~3:1) purifying obtains compound 4.2 (400mg, yield：34%) it is colorless oil.
Step 3：Compound 9-1 synthesis
By compound 4.2 (100mg, 0.43mmol), compound 3.1 (75mg, 0.43mmol), triethylamine (130mg, 1.29mmol) it is dissolved in DMAP (6.0mg, 0.043mmol) in dichloromethane (10mL), by reaction system in room The lower stirring of temperature 3 hours.Decompression boils off solvent, crude product silica gel column chromatography (petroleum ether：Ethyl acetate=5:1-1:1) it is isolated Compound 9-1 (12.5mg, yield：8%) it is white solid.
m/z:[M+H]+373
1H NMR(400MHz,CDCl3):δ 8.74 (s, 1H), 7.87 (d, J=2.8Hz, 1H), 7.60 (dd, J=9.2, 2.4Hz, 1H), 7.42 (dd, J=9.2,4.0Hz, 1H), 7.30 (br.s, 1H), 7.26 (br.s, 1H), 7.08-7.22 (m, 4H), 4.48 (d, J=7.2Hz, 1H), 3.18-3.29 (m, 1H), 2.38-2.48 (m, 1H), 1.95-2.04 (m, 2H), 1.82- 1.90(m,2H),1.40-1.52(m,2H),1.31-1.39(m,2H)。
Embodiment 17：Compound 9-2 synthesis
It is compound 9-1 synthetic method with embodiment 16, is initiation material reaction with compound 1.6 and 4.2 Compound 9-2.
m/z:[M+H]+387
1H NMR(400MHz,CDCl3):δ 8.74 (s, 1H), 7.87,7.85 (two d, J=2.8Hz, 1H), 7.58- 7.64(m,1H),7.39-7.45(m,1H),7.28-7.33(m,2H),7.16-7.24(m,2H),7.07-7.15(m,2H), 4.53,4.46 (two d, J=6.4Hz, 1H), 3.06,2.87 (two dd, J=6.4,7.6Hz (6.4Hz), 2H), 2.38- 2.59(m,1H),1.80-1.95(m,3H),1.39-1.58(m,4H),0.97-1.11(m,2H)。
Embodiment 18：Compound 10-2 synthesis
Step 5：Compound 10-1 synthesis
Compound 5.4 (400mg, 1.00mmol), compound 4.7 (224.4mg, 1.10mmol), EDCI (287.6mg, 1.50mmol), DIPEA (387.3mg, 3.00mmol) and DMAP (6.1mg, 0.05mmol) It is dissolved in dichloromethane (20mL), reactant mixture is concentrated under reduced pressure after being stirred overnight at room temperature, residue flash column chromatography (oil Ether/ethyl acetate=1/2) isolate and purify to obtain compound 10-1 (450mg, yield：77%) it is yellow solid.
Step 6：Compound 10-2 synthesis
Compound 10-1 (320.0mg, 0.55mmol) and trifluoracetic acid (1mL) are added in dichloromethane (20mL), instead Answer mixture be heated to 50 DEG C be stirred overnight after be concentrated under reduced pressure.Residue high performance liquid chromatography (X BridgeTM prep C18, 10um, 19*250mm column S/N, mobile phase A:0.1% trifluoroacetic acid aqueous solution, Mobile phase B：Acetonitrile, Detection wavelength： 214,254nm) isolate and purify to obtain compound 10-1a (63mg, yield：And compound 10-1b (22.2mg, yield 20%)： 7%), it is yellow solid.
m/z:[M+H]+456
10-1a,1H NMR(400MHz,DMSO-d6):δ 12.70 (s, 1H), 8.65 (t, J=6.0Hz, 1H), 8.62 (d, J =6.0Hz, 1H), 8.54 (d, J=2.8Hz, 1H), 8.38 (d, J=2.8Hz, 1H), 7.78 (s, 1H), 7.72 (d, J= 6.0Hz, 1H), 7.50-7.43 (m, 2H), 7.06 (d, J=8.0Hz, 1H), 7.04 (t, J=8.0Hz, 1H), 3.75 (s, 3H), 3.26 (t, J=6.0Hz, 2H), 2.75-2.73 (m, 1H), 2.64 (s, 3H), 1.91 (t, J=12.8Hz, 4H), 1.52-1.50 (m,1H),1.50-1.48(m,2H),1.23-1.15(m,2H)。
10-1b,1H NMR(400MHz,DMSO-d6):δ 12.70 (s, 1H), 8.67 (t, J=6.0Hz, 1H), 8.54 (d, J =6.0Hz, 1H), 8.51 (d, J=2.8Hz, 1H), 8.37 (d, J=2.8Hz, 1H), 7.78 (s, 1H), 7.77 (d, J= 6.0Hz, 1H), 7.46-7.42 (m, 2H), 7.05 (d, J=8.0Hz, 1H), 7.03 (t, J=8.0Hz, 1H), 3.73 (s, 3H), 3.46 (t, J=6.0Hz, 2H), 2.66-2.64 (m, 2H), 1.80-1.65 (m, 11H).
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.
Compound number Hela cells IC50 Compound number Hela cells IC50
1-1 ++++ 1-2 ++++
1-3a ++++ 1-3b ++++
1-4a ++++ 1-4b ++++
1-5 ++++ 1-5a ++++
1-5b ++++ 1-6a ++++
1-6b ++++ 1-7 ++++
2-1 ++ 3-1 +++
4-1 ++++ 4-2 +++
5-1 ++++ 5-2 +++
5-4 +++ 6-1 ++++
7-1a + 7-1b ++
8-1 + 9-1 +
9-2 ++ 10-1b +++

Claims (19)

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 ring or 5-6 member hetero-aromatic rings；
B1For CR5Or N；
B2For CR5, N or NR4；
B3For N or C；
X1For connecting key ,-O- ,-NR4- or-CR6R6a-；
X2For-C (O)-or-S (O)1-2-；
X3For connecting key ,-NR4- or-CR6R6a-；
Y is connecting key or-(CR6R6a)1-2-；
U and V is separately selected from N or CR3；
Z and W is separately selected from CHR3、NR3, O, C (O) or S (O)2；
L is connecting key, C2-6Alkenylene, C2-6Alkynylene or-(CR6R6a)u-；
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, aryl, cycloalkyl, the one or more in Heterocyclylalkyl and heteroaryl；
R2Or R3Separately selected from hydrogen ,-NO2、-CN、-OH、-NH2、-SH、-OR8、-OC(O)R8、-OC(O)NR7R8、-OC (O)OR8、-OP(O)(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(O)NR7R8、-NR7R8、-N(R7)C(O) OR8、-N(R7)C(O)N(R7)S(O)2R8、-N(R7)C(O)NR7R8、-N(R7)S(O)1-2R8、-N(R7)C(O)R8、-N(R7)S (O)1-2NR7R8、-N(R7)C(O)R8、-N(R7)OR8、-N(R7)C(O)NR7R8, substituted or unsubstituted alkyl, substitution or do not take The heteroaryl in generation, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl or substituted or unsubstituted aryl；When Described R2Or R3For substituted alkyl, the cycloalkyl of substitution, the Heterocyclylalkyl of substitution, the aryl of substitution or the heteroaryl of substitution When can be by following 1~3 RAGroup substitutes at an arbitrary position：-OH、-SH、-CN、-NO2、-NH2, halogen, alkylthio group ,-C (O) 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(O)Ra、-NRbC(O)ORa、-NRbC(O)N(Rb)2、-NRbC(O)N(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, substitution or do not take The aryl in generation, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl or substituted or unsubstituted heteroaryl； RAIn, can be further by 1~3 choosing when the alkyl, alkoxy, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl are substituted From halogen, hydroxyl, amino, C1-4Alkyl or halo C1-3The substituent substitution of alkoxy is at an arbitrary position；
R4For hydrogen or C1-6Alkyl；
R5For hydrogen ,-OH ,-SH ,-CN ,-NO2、-NH2, halogen, alkylthio group ,-C (O) 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(O)Ra、-NRbC(O)ORa、- NRbC(O)N(Rb)2、-NRbC(O)N(Rb)2、-NRbS(O)2Ra、-NRbS(O)2N(Rb)2、-S(O)0-2Ra、-S(O)2N(Rb)2、C2-6 Alkynyl, C2-6Alkenyl, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-3Alkoxy, substituted or unsubstituted C6-10 Aryl, substitution or the 5-6 unit's heteroaryls not taken, substitution or the C not taken3-8Cycloalkyl or substitution do not take 3-8 circle heterocycles alkyl； As described C1-6Alkyl, C1-3Alkoxy, C6-10Aryl, 5-6 unit's heteroaryls, C3-8Cycloalkyl or 3-8 circle heterocycles alkyl are substituted When, can be further by 1~3 selected from halogen, hydroxyl, amino, C1-4Alkyl or halo C1-3The substituent substitution of alkoxy is in office Meaning position；
R6For hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle Alkyl, or substituted or unsubstituted alkoxy；The substituted alkyl, the cycloalkyl of substitution, the Heterocyclylalkyl of substitution, or substitution Alkoxy substituted at an arbitrary position by following one or more groups：Halogen, hydroxyl, alkyl, Heterocyclylalkyl, cycloalkyl, alkane Epoxide, 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)uOH or-(CH2)uN(Rb)2；
R6aFor hydrogen, deuterium, halogen, hydroxyl, amino, alkyl ,-SRa、-ORb、-N(Rb)2、-NRbS(O)2Ra、-S(O)2N(Rb)2、- (CH2)uS(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)uC (O)OH、-(CH2)uOH、-(CH2)uN(Rb)2Or-(CH2)uC(O)N(Rb)2；
Or R6And R6a3-8 unit monocycle cycloalkyl is formed together with the C atoms connected jointly with them；
R7Or R8Separately it is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substitution or does not take The Heterocyclylalkyl in generation, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl alkane Base, substituted or unsubstituted hetercycloalkylalkyl, substituted or unsubstituted aryl alkyl or substituted or unsubstituted heteroaryl alkane Base；When the alkyl, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, aryl alkyl, heteroaryl alkyl, cycloalkyl-alkyl or miscellaneous , can be further by 1~3 selected from halogen, hydroxyl, amino, C when cycloalkyl-alkyl is substituted1-4Alkyl or halo C1-3Alkoxy Substituent substitution at an arbitrary position；Or R7And R8Single heterocycle alkane of 3-8 members is formed together with the N atoms connected jointly with them Base；
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；
M is 1 or 2；N is 1,2 or 3；T is 0,1 or 2；Q is 0,1 or 2；U is 1,2 or 3.
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 be phenyl ring, pyridine ring, pyrazine ring, pyrimidine ring, pyrrole ring, Or pyrazole ring.
3. 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：R1For hydrogen, halogen, hydroxyl, sulfydryl, cyano group, amino, C1-3Alcoxyl Base, C1-3Alkylthio group, C1-4Alkyl, halo C1-3Alkyl or halo C1-3Alkoxy；N is 1 or 2.
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 Y is-CH2-、-CH(CH3)-、-CH(CH2CH3)-、-C (CH3)2-、-CH(CF3)-,-CHF- or-CF2-。
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：L is connecting key；R2For substituted or unsubstituted C1-3Alkyl, take Generation or unsubstituted C6-10Aryl, substituted or unsubstituted 6-10 unit's heteroaryls, substituted or unsubstituted C3-8Cycloalkyl or substitution Or unsubstituted 3-8 circle heterocycles alkyl；As the C1-3Alkyl, C6-10Aryl, 6-10 unit's heteroaryls, C3-8Cycloalkyl or 3-8 members Heterocyclylalkyl can be by following 1~3 R when substitutedAGroup substitutes at an arbitrary position；RAThe definition of group such as claim 1 institute State.
6. the polycyclic compound (I), its isomers, prodrug, stable isotope as described in any one of Claims 1 to 5 derive Thing or pharmaceutically acceptable salt, it is characterised in that：Its general structure is：
Wherein, A rings, R1、R2、L、X1、X2、X3、B1、B2、B3, Y, U, V, m, n and q definition such as any one of Claims 1 to 5 institute State.
7. the polycyclic compound (I), its isomers, prodrug, stable isotope as described in any one of Claims 1 to 5 derive Thing or pharmaceutically acceptable salt, it is characterised in that：Its general structure is：
Wherein, B1For N or CR5, B2For NH or N (CH3)；
R1、R2、R5、L、X1、X2、X3, Y, U and V definition as described in any one of Claims 1 to 5.
8. the polycyclic compound (I), its isomers, prodrug, stable isotope as described in any one of Claims 1 to 5 derive Thing or pharmaceutically acceptable salt, it is characterised in that：Its general structure is：
Wherein, D is N or CH；B2For N or CH；
R2、L、X1、X2、X3, Y, U and V definition as described in any one of Claims 1 to 5.
9. the polycyclic compound (I), its isomers, prodrug, stable isotope as described in any one of Claims 1 to 5 derive Thing or pharmaceutically acceptable salt, it is characterised in that：Its general structure is：
Wherein, D is N or CH；E is NH or N (CH3)；
R2、L、X1、X2、X3, Y, U and V definition as described in any one of Claims 1 to 5.
10. the polycyclic compound (I), its isomers, prodrug, stable isotope as described in any one of Claims 1 to 5 derive Thing or pharmaceutically acceptable salt, it is characterised in that：Its general structure is：
Wherein, R1、R2、L、X1、X2、X3, Y, U and V definition as described in any one of Claims 1 to 5.
11. the polycyclic compound (I), its isomers, prodrug, stable isotope as described in any one of Claims 1 to 5 derive Thing or pharmaceutically acceptable salt, it is characterised in that：Its general structure is following any：
Wherein, A rings, R1、R2、L、X1、X2、X3、B1、B2、B3, Y, m and n definition as described in any one of Claims 1 to 5.
12. 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：
13. 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 1~12, its isomers, prodrug, isotope stably Derivative or pharmaceutically acceptable salt.
14. pharmaceutical composition as claimed in claim 13, 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.
15. polycyclic compound (I), its isomers, prodrug, stable isotope derive as described in any one of claim 1~12 Thing or pharmaceutically acceptable salt, or as the described pharmaceutical composition of claim 13 or 14 is preparing IDO Application in inhibitor.
16. polycyclic compound (I), its isomers, prodrug, stable isotope derive as described in any one of claim 1~12 Thing or pharmaceutically acceptable salt, or as the described pharmaceutical composition of claim 13 or 14 is preparing stimulation T cell hyperproliferation agent In application.
17. polycyclic compound (I), its isomers, prodrug, stable isotope derive as described in any one of claim 1~12 Thing or pharmaceutically acceptable salt, or as the described pharmaceutical composition of claim 13 or 14 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.
18. application as claimed in claim 17, 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.
19. application as claimed in claim 17, 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.
CN201710637050.4A 2016-08-02 2017-07-31 Polycyclic compound, its pharmaceutical composition and application Pending CN107674029A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610624283 2016-08-02
CN2016106242836 2016-08-02

Publications (1)

Publication Number Publication Date
CN107674029A true CN107674029A (en) 2018-02-09

Family

ID=61133126

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710637050.4A Pending CN107674029A (en) 2016-08-02 2017-07-31 Polycyclic compound, its pharmaceutical composition and application

Country Status (1)

Country Link
CN (1) CN107674029A (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3556362A1 (en) * 2018-04-16 2019-10-23 Ecole Polytechnique Federale De Lausanne (Epfl) Sting inhibitors
WO2020092183A1 (en) 2018-11-01 2020-05-07 Merck Sharp & Dohme Corp. Novel substituted pyrazole compounds as indoleamine 2,3-dioxygenase inhibitors
CN112375027A (en) * 2020-12-07 2021-02-19 中国药科大学 Indolesulfonamide derivative and medical application thereof
CN113072497A (en) * 2021-01-12 2021-07-06 西湖大学 Protease inhibitors, their preparation and use
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5
CN114213310A (en) * 2021-12-31 2022-03-22 中国药科大学 Indoline compound and derivative, preparation method, pharmaceutical composition and application thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101384544A (en) * 2005-12-22 2009-03-11 格吕伦塔尔有限公司 Substituted cyclohexylmethyl derivatives
CN103635458A (en) * 2011-03-25 2014-03-12 艾伯维公司 Trpv1 antagonists
WO2015150097A1 (en) * 2014-04-04 2015-10-08 Iomet Pharma Ltd Indole derivatives for use in medicine
WO2015188085A1 (en) * 2014-06-06 2015-12-10 Flexus Biosciences, Inc. Immunoregulatory agents
WO2016073774A2 (en) * 2014-11-05 2016-05-12 Flexus Biosciences, Inc. Immunoregulatory agents
WO2016073770A1 (en) * 2014-11-05 2016-05-12 Flexus Biosciences, Inc. Immunoregulatory agents
WO2016071293A2 (en) * 2014-11-03 2016-05-12 Iomet Pharma Ltd Pharmaceutical compound

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101384544A (en) * 2005-12-22 2009-03-11 格吕伦塔尔有限公司 Substituted cyclohexylmethyl derivatives
CN103635458A (en) * 2011-03-25 2014-03-12 艾伯维公司 Trpv1 antagonists
WO2015150097A1 (en) * 2014-04-04 2015-10-08 Iomet Pharma Ltd Indole derivatives for use in medicine
WO2015188085A1 (en) * 2014-06-06 2015-12-10 Flexus Biosciences, Inc. Immunoregulatory agents
WO2016071293A2 (en) * 2014-11-03 2016-05-12 Iomet Pharma Ltd Pharmaceutical compound
WO2016073774A2 (en) * 2014-11-05 2016-05-12 Flexus Biosciences, Inc. Immunoregulatory agents
WO2016073770A1 (en) * 2014-11-05 2016-05-12 Flexus Biosciences, Inc. Immunoregulatory agents

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
COLUMBUS，OHIO: "US REGISTRY[Online]", 《REGISTRY》 *
HEINRICH RUEEGER ET AL.: "Design, Synthesis and SAR of a Series of 2-Substituted 4-Amino-quinazoline Neuropeptide Y Y5 Receptor Antagonists", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
ISMAIL SALAMA ET AL.: "Structure-Selectivity Investigations of D2-Like Receptor Ligands by CoMFA and CoMSIA Guiding the Discovery of D3 Selective PET Radioligands", 《JOURNAL OF MEDICINAL CHEMISTRY》 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3556362A1 (en) * 2018-04-16 2019-10-23 Ecole Polytechnique Federale De Lausanne (Epfl) Sting inhibitors
WO2019201939A1 (en) * 2018-04-16 2019-10-24 Ecole Polytechnique Federale De Lausanne (Epfl) Sting inhibitors
WO2020092183A1 (en) 2018-11-01 2020-05-07 Merck Sharp & Dohme Corp. Novel substituted pyrazole compounds as indoleamine 2,3-dioxygenase inhibitors
EP3873464A4 (en) * 2018-11-01 2022-06-08 Merck Sharp & Dohme Corp. Novel substituted pyrazole compounds as indoleamine 2,3-dioxygenase inhibitors
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5
CN112375027A (en) * 2020-12-07 2021-02-19 中国药科大学 Indolesulfonamide derivative and medical application thereof
CN112375027B (en) * 2020-12-07 2023-03-31 中国药科大学 Indolesulfonamide derivative and medical application thereof
CN113072497A (en) * 2021-01-12 2021-07-06 西湖大学 Protease inhibitors, their preparation and use
US11958830B2 (en) 2021-01-12 2024-04-16 Westlake Pharmaceuticals (Hangzhou) Co., Ltd. Protease inhibitors, preparation, and uses thereof
CN114213310A (en) * 2021-12-31 2022-03-22 中国药科大学 Indoline compound and derivative, preparation method, pharmaceutical composition and application thereof
CN114213310B (en) * 2021-12-31 2024-02-23 中国药科大学 Indoline compound and derivative thereof, preparation method, pharmaceutical composition and application

Similar Documents

Publication Publication Date Title
CN105884780B (en) Polycyclic compound, its pharmaceutical composition and application
CN107674029A (en) Polycyclic compound, its pharmaceutical composition and application
JP6911031B2 (en) Heterocyclic compounds as immunomodulators
EP3517112B1 (en) Heteroaryl compounds useful as inhibitors of sumo activating enzyme
CN106977495B (en) DNA-PK inhibitors
CN107344931A (en) Benzazepine derivative, its preparation method, pharmaceutical composition and application
US10851092B2 (en) Pyridine compound
CN107663159A (en) Polycyclic compound, its pharmaceutical composition and application
CN107674013A (en) Polycyclic compound, its preparation method, pharmaceutical composition and application
JP2021501807A (en) Pyrimidine derivative as an inhibitor of PD1 / PD-L1 activation
TW201718581A (en) Heterocyclic compounds as immunomodulators
CN107556244A (en) And cycle compound, its pharmaceutical composition and application
CN102209714A (en) Triazine, pyrimidine and pyridine analogs and their use as therapeutic agents and diagnostic probes
CN102119162A (en) Diazacarbazoles and methods of use
WO2017028798A1 (en) Pyridazinone compound, preparation method, pharmaceutical composition and use thereof
CN104557871B (en) Arylmorpholine compounds with spiro substituents as well as preparation method and use thereof
CN106478634A (en) Condensed imidazole compound, its preparation method, pharmaceutical composition and purposes
CN110156656A (en) Five yuan of heteroaromatic ring derivatives, preparation method, pharmaceutical composition and application
CN106336413A (en) Compounds used as JAK inhibitor, and use of compounds
TWI826535B (en) Cyclic dinucleotide analogs, pharmaceutical compositions and applications thereof
CN110372703A (en) Five-ring heterocycles miazines compound and application thereof
WO2020224626A1 (en) Compound used as kinase inhibitor and application thereof
CN104557913B (en) Pyridopyrimidine compounds as well as preparation method and application thereof
CN109721597A (en) Pyrido azepine derivate, its pharmaceutical composition and application
CN113366008A (en) CD73 inhibitor, preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20180209

WD01 Invention patent application deemed withdrawn after publication