CN109665968A - And cycle compound and its preparation method and application - Google Patents
And cycle compound and its preparation method and application Download PDFInfo
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- CN109665968A CN109665968A CN201811143915.2A CN201811143915A CN109665968A CN 109665968 A CN109665968 A CN 109665968A CN 201811143915 A CN201811143915 A CN 201811143915A CN 109665968 A CN109665968 A CN 109665968A
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Abstract
The present invention relates to a kind of and cycle compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolin or prodrugs or their mixture, comprising its pharmaceutical composition and kit product, preparation method and its preparing the purposes in the drug for preventing or treating PD-1/PD-L1 related disease.
Description
Technical field
This application involves immunotherapy fields, and in particular to can inhibit PD-1/PD-L1 interaction and cycle compound,
Pharmaceutical composition and kit product comprising the compound.The application further relates to the preparation method of the compound and its is making
Standby prevention and/or treatment and the purposes in the drug of PD-1/PD-L1 pathway dependent diseases.
Background technique
Malignant tumour greatly endangers the health of the mankind and influences the mankind as one of biggish public health problem in the whole world
Normal production and living.The mankind mainly have operation, chemotherapy, radiotherapy, endocrine therapy, targeting in the fight with malignant tumour
A variety for the treatment of means such as treatment, and immunotherapy of tumors is different from these treatment means, it is intended to human activin self immune system
To kill tumour cell and tissue.There are many therapeutic strategies, including non-specific immunostimulating agents, tumour epidemic disease for tumour immunotherapy
Seedling, adoptive immunity cell therapy, monoclonal antibody treatment and immunologic test point inhibitor, and immunologic test point inhibitor is clinically
The efficient and hypotoxicity shown, more noticeable (P.J.Medina, V.R.Adams, Pharmacotherapy 2016,
36,317-334)。
PD-1 (programmed death receptor -1, CD279) is the receptor in T cell, has shown that and works as and its ligand PD-L1
(programmed death receptor-ligand 1, CD274, B7-H1) or PD-L2 (CD273, B7-DC) combine when, inhibit from T cell by
The signal activation of body.It is living to the function of antigenic stimulus response when the cell of its ligand is expressed in the T cell contact for expressing PD-1
It moves, including proliferation, cytokine secretion and cytotoxicity are weakened.The interaction of PD-1 and its ligand PD-L1, PD-L2
Immune response (Keir Me, Butte are lowered during infection or tumor regression or during developing self tolerance
MJ,Lreeman GJ,et al.,Annu.Rev.Immunol.2008;26:677).In tumor disease or chronic infection process
In long-term antigenic stimulus, will lead to T cell PD-1 expression increase, and for long stage antigens active function lack of proper care
(Kim PS, Ahmed R, Curr.Opin.Immunol., 2010,22,223-230), this is known as " T cell exhaustion ".
In the exhaustion of the T cell as caused by the long-term antigenic stimulus in chronic infection and neoplastic disease process, PD-1/PD-
L1 approach is the crucial molecule inhibited.The interaction of PD-1/PD-L1 is blocked to have shown that reparation by target PD-1 albumen
In vitro and in vivo T cells with antigenic specificity immune function, including enhancing in tumour or chronic infection to vaccine inoculation
Response.Therefore, it is feasible for blocking the drug of the interaction of PD-L1 and PD-1.
Domestic and international well-known pharmaceutical companies numerous at present competitively put into the research and development of PD-1/PD-L1 inhibitor, but main
Want research direction still based on monoclonal antibody.It is at present biological system in the PD-1/PD-L1 inhibitor for grinding or listing
Agent, there are intrinsic preparation defects, such as monoclonal antibody class drug, and subcutaneous injection to be needed to be administered, can induce body develop drug resistance it is anti-
Body, to reduce curative effect of medication and increase side effect.Monoclonal antibody medicine prepare purification process complexity, it is expensive, it is inconvenient for use,
It has higher requirements to the compliance of patient.Therefore, medicament research and development person is easy to use it is necessary to develop, orally active small molecule
PD-1/PD-L1 inhibitor meets the clinical demand of patient.
Applicants have discovered that there is the active compound of the inhibitory activity of the interaction as PD-L1 and PD-1, tool
There is better druggability, can be used for therapeutic to enhance the immunity of cancer or chronic infection.
Summary of the invention
This application provides the inhibitor with new structural safely and effectively PD-L1 and PD-1 interaction.It is described
Inhibitor is formula (I) compound represented or itself or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polycrystalline
Type object, solvate, metabolin or prodrug or their mixture:
RespectivelyIt is each independently selected from singly-bound or double bond, and is not simultaneously double bond;
Ring G, ring J are each independently selected from C6-10Aryl and 5-14 unit's heteroaryl;
R1Selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl,
C3-10Naphthenic base, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base ,-ORa、-SRa、-C(O)Ra、-C(O)ORa、-C(O)NRaRa、-OC
(O)Ra、-NRaRaWith-NRaC(O)Ra;Work as RaWhen being multiple, each RaIt can be the same or different;Optionally, the C1-6Alkane
Base, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl, C3-10Naphthenic base, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base are by one or more Rb
Replace;Work as RbWhen being multiple, each RbIt can be the same or different;
The RaIt is each independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Halogenated alkoxy,
C6-10Aryl, C3-10Naphthenic base, 5-14 unit's heteroaryl and 4-10 circle heterocyclic ring base;
The RbIt is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, carboxyl, C1-6Alkyl, C1-6Alcoxyl
Base, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C2-6Alkenyl and C2-6Alkynyl;
A is selected from CRh、CRhRh、N、NRi, O, S, C=O, C=S, S=O andWork as RhWhen being multiple, each RhIt can phase
It is same or different;
B is selected from CRj、CRjRj、N、NRk, O, S, C=O, C=S, S=O andWork as RjWhen being multiple, each RjIt can be identical
Or it is different;
D is selected from C, CRmAnd N;
E is selected from CRnRn、NRo, O, S, C=O, C=S, S=O andWork as RnWhen being multiple, each RnIt can be identical or not
Together;
Rh、Ri、Rj、Rk、Rm、Rn、RoIt is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-6Alkyl,
C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, phenyl, 5-6 unit's heteroaryl, 4-6 circle heterocyclic ring base and C3-6Naphthenic base;
R2Selected from-(C1-6Alkyl)-NRpRp、-(C1-6Alkyl)-(5-14 unit's heteroaryl) ,-(C1-6Alkyl)-(4-10 member is miscellaneous
Ring group) ,-O- (C1-6Alkyl)-(5-14 unit's heteroaryl) ,-O- (C1-6Alkyl)-(4-10 circle heterocyclic ring base) ,-O- (C1-6Alkyl)-
NRpRp、-O-(C1-6Alkyl)-C (O) NRpRp、-O-(C1-6Alkyl)-OC (O) NRpRp、-SRp、-C(O)Rp、-C(O)ORp、-OC
(O)Rp、-OC(O)NRpRp、-NRpRp、-NRpC(O)Rp、-NRpC(O)ORp、-NRpC(O)NRpRp,-C (=NRp)NRpRp、-NRpC
(=NRp)NRpRp、-NRpS(O)Rp、-NRpS(O)2Rp、-NRpS(O)2NRpRp、-S(O)Rp、-S(O)NRpRp、-S(O)2Rp, with
And-S (O)2NRpRp;Work as RpWhen being multiple, each RpIt can be the same or different;And R2It is not carboxyl;Optionally, described-(C1-6
Alkyl)-(5-14 unit's heteroaryl) ,-(C1-6Alkyl)-(4-10 circle heterocyclic ring base) ,-O- (C1-6Alkyl)-(5-14 unit's heteroaryl) ,-
O-(C1-6Alkyl)-(4-10 circle heterocyclic ring base) by one or more RqReplace;Work as RqWhen being multiple, each RqIt can be identical or not
Together;
The Rp、RqIt is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-6Alkyl, C2-6Alkenyl, C2-6
Alkynyl, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C6-10Aryl, C3-10Naphthenic base, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base ,-
(C1-6Alkyl)-(C6-10Aryl) ,-(C1-6Alkyl)-(C3-10Naphthenic base) ,-(C1-6Alkyl)-(5-14 unit's heteroaryl) ,-(C1-6Alkane
Base)-(4-10 circle heterocyclic ring base) ,-ORr、-SRr、-C(O)Rr、-C(O)ORr、-OC(O)Rr、-OC(O)NRrRr、-NRrRr、-NRrC
(O)Rr、-NRrC(O)ORr、-NRrC(O)NRrRr,-C (=NRr)NRrRr、-NRrC (=NRr)NRrRr、-NRrS(O)Rr、-NRrS
(O)2Rr、-NRrS(O)2NRrRr、-S(O)Rr、-S(O)NRrRr、-S(O)2RrAnd-S (O)2NRrRr;Work as RrWhen being multiple, each Rr
It can be the same or different;Optionally, the C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Haloalkoxy
Base, C6-10Aryl, C3-10Naphthenic base, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base are optionally by one or more RsReplace;Work as RsFor
When multiple, each RsIt can be the same or different;
The Rr、RsIt is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-6Alkyl, C2-6Alkenyl, C2-6
Alkynyl, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C6-10Aryl, C3-10Naphthenic base, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base ,-
(C1-6Alkyl)-(C6-10Aryl) ,-(C1-6Alkyl)-(C3-10Naphthenic base) ,-(C1-6Alkyl)-(5-14 unit's heteroaryl) ,-(C1-6Alkane
Base)-(4-10 circle heterocyclic ring base) ,-ORt、-SRt、-C(O)Rt、-C(O)ORt、-OC(O)Rt、-OC(O)NRtRt、-NRtRt、-NRtC
(O)Rt、-NRtC(O)ORt、-NRtC(O)NRtRt,-C (=NRt)NRtRt、-NRtC (=NRt)NRtRt、-NRtS(O)Rt、-NRtS
(O)2Rt、-NRtS(O)2NRtRt、-S(O)Rt、-S(O)NRtRt、-S(O)2RtAnd-S (O)2NRtRt;Work as RtWhen being multiple, respectively
RtIt can be the same or different;Optionally, the C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Alkyl halide
Oxygroup, C6-10Aryl, C3-10Naphthenic base, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base are optionally by one or more RuReplace;Work as Ru
When being multiple, each RuIt can be the same or different;
The Rt、RuIt is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, carboxyl, C1-6Alkyl, C2-6Alkene
Base, C2-6Alkynyl, phenyl, 5-6 unit's heteroaryl, 4-6 circle heterocyclic ring base and C3-6Naphthenic base;Optionally, the C1-6Alkyl, C2-6Alkene
Base, C2-6Alkynyl, phenyl, 5-6 unit's heteroaryl, 4-6 circle heterocyclic ring base, C3-6Naphthenic base is selected from halogen, hydroxyl, cyanogen by one or more
Base, nitro, amino, carboxyl, C1-6The substituent group of alkyl replaces;
R3Selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl,
C3-10Naphthenic base, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base ,-ORv、-SRv、-C(O)Rv、-C(O)ORv、-C(O)NRvRv、-OC
(O)Rv、-NRvRvWith-NRvC(O)Rv;Work as RvWhen being multiple, each RvIt can be the same or different;Optionally, the C1-6Alkane
Base, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl, C3-10Naphthenic base, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base are by one or more Rw
Replace;Work as RwWhen being multiple, each RwIt can be the same or different;
The RvIt is each independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Halogenated alkoxy,
C6-10Aryl, C3-10Naphthenic base, 5-14 unit's heteroaryl and 4-10 circle heterocyclic ring base;
The RwIt is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, carboxyl, C1-6Alkyl, C1-6Alcoxyl
Base, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C2-6Alkenyl and C2-6Alkynyl;
R4Selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-6Alkyl, C1-6Alkoxy, phenyl, 5-6 unit's heteroaryl,
4-6 circle heterocyclic ring base, C3-6Naphthenic base ,-NRyRy、-SRy、-C(O)Ry、-C(O)ORy、-C(O)NRyRy、-OC(O)RyWith-NRyC(O)
Ry;Work as RyWhen being multiple, each RyIt can be the same or different;Optionally, the C1-6Alkyl, C1-6Alkoxy, phenyl, 5-6 member
Heteroaryl, 4-6 circle heterocyclic ring base, C3-6Naphthenic base is by one or more RzReplace;Work as RzWhen being multiple, each RzCan it is identical can also be with
It is different;
The Ry、RzIt is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, carboxyl, C1-6Alkyl, C2-6Alkene
Base, C2-6Alkynyl, phenyl, 5-6 unit's heteroaryl, 4-6 circle heterocyclic ring base and C3-6Naphthenic base;
R is selected from 1,2 and 3;When r is greater than 1, each R1It can be the same or different;
T is selected from 1,2 and 3;When t is greater than 1, each R2It can be the same or different;
I is selected from 1,2 and 3;When i is greater than 1, each R3It can be the same or different;
M is selected from 1,2 and 3;When m is greater than 1, each R4It can be the same or different;
N is selected from 1 and 2;When n is 2, each B can be the same or different.
It is found through experiments that, leading to compound shown in formula (I) has high PD-1/PD-L1 binding inhibition activity.
The application provides a kind of pharmaceutical composition, and it includes the compounds or its pharmacy of prevention or therapeutically effective amount can
Salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolin or the prodrug of receiving or
Their mixture and one or more pharmaceutically acceptable carriers.
The application provides a kind of kit product, and it includes the compound or its pharmaceutically acceptable salt, ester, alloisomerisms
Body, tautomer, polymorph, solvate, hydrate, metabolin or prodrug or their mixture or described
Pharmaceutical composition and optional package insert.
The application provides the compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polycrystalline
Type object, solvate, hydrate, metabolin or prodrug or their mixture or described pharmaceutical composition, are used for
Prevention or treatment and PD-1/PD-L1 pathway dependent diseases.
The application provides the compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polycrystalline
Type object, solvate, hydrate, metabolin or prodrug or their mixture or described pharmaceutical composition are used in preparation
Purposes in the drug of prevention or treatment and PD-1/PD-L1 pathway dependent diseases.
The application provides a kind of method prevented or treat with PD-1/PD-L1 pathway dependent diseases comprising administration prevention
Therapeutically effective amount the compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph,
Solvate, hydrate, metabolin or prodrug or their mixture or described pharmaceutical composition, and it is a kind of or more
The other therapeutic agents of kind.
Particularly, the application provide formula (II) compound represented or its pharmaceutically acceptable salt, ester, stereoisomer,
Tautomer, polymorph, solvate, metabolin or prodrug or their mixture:
Wherein:
RespectivelyIt is each independently selected from singly-bound or double bond, and is not simultaneously double bond;
X1、X2、X3It is each independently selected from C, CH or N;
Ring G, A, B, D, E, R1、R2、R3、R4, m, n, r, t, i be as defined in formula (I).
Particularly, the application provides formula (III) compound represented or its pharmaceutically acceptable salt, ester, alloisomerism
Body, tautomer, polymorph, solvate, metabolin or prodrug or their mixture:
Wherein:
RespectivelyIt is each independently selected from singly-bound or double bond, and is not simultaneously double bond;
X1、X2、X3It is each independently selected from C, CH or N;
Ring G, A, B, D, E, R1、R2、R3、R4With n such as defined in formula (I).
Particularly, the application provide formula (IV) compound represented or its pharmaceutically acceptable salt, ester, stereoisomer,
Tautomer, polymorph, solvate, metabolin or prodrug or their mixture, structure such as general formula IV institute
Show:
Wherein,
RespectivelyIt is each independently selected from singly-bound or double bond, and is not simultaneously double bond;R1、R3、R4Be each independently selected from hydrogen,
Fluorine, chlorine, C1-6Alkyl, C1-6Halogenated alkyl and C1-6Alkoxy;
R2Selected from-C1-6Alkyl-NRpRp;Each RpIt can be identical or different;
RpIt is each independently selected from hydrogen and C1-6Alkyl;Optionally, the C1-6Alkyl optionally by one or more selected from fluorine,
The substituent group substitution of chlorine, hydroxyl, alkoxy, carboxyl, ester group, amino, nitro and cyano;
X1Selected from C, CH and N;
A, B, D, E, n in any one of formula (I) to (III) as defined.
Particularly, the application offer formula (I), formula (II), formula (III) or formula (IV) compound represented or its pharmacy can
Salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolin or the prodrug of receiving or theirs is mixed
Close object, in which:
Rh、Ri、Rj、Rk、Rm、Rn、RoIt is each independently selected from hydrogen, fluorine, chlorine, hydroxyl, cyano, nitro, amino, C1-6Alkyl,
C1-6Halogenated alkyl, C1-6Alkoxy and C1-6Halogenated alkoxy.
Particularly, the application offer formula (I), formula (II), formula (III) or formula (IV) compound represented or its pharmacy can
Salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolin or the prodrug of receiving or theirs is mixed
Close object, whereinPart is selected from following structure fragment:
Particularly, the application provides formula (I) to formula (III) compound represented or its pharmaceutically acceptable salt, ester, vertical
Body isomers, tautomer, polymorph, solvate, metabolin or prodrug or their mixture, wherein R2Choosing
From-(C1-6Alkyl)-NRpRp、-(C1-6Alkyl)-(5-14 unit's heteroaryl) ,-(C1-6Alkyl)-(4-10 circle heterocyclic ring base) ,-O- (C1-6
Alkyl)-(5-14 unit's heteroaryl) ,-O- (C1-6Alkyl)-(4-10 circle heterocyclic ring base) ,-O-C1-6Alkyl-NRpRp、-O-C1-6Alkyl-C
(O)NRpRp;RpAs defined in formula (I).
In certain embodiments, R2Selected from-(C1-6Alkyl)-NRpRp, RpIt is each independently selected from hydrogen and C1-6Alkyl;Appoint
Selection of land, the C1-6Alkyl is by one or more selected from fluorine, chlorine, hydroxyl, alkoxy, carboxyl, ester group, amino, nitro and cyano
Substituent group replaces.
Particularly, the application offer formula (I), formula (II), formula (III) or formula (IV) compound represented or its pharmacy can
Salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolin or the prodrug of receiving or theirs is mixed
Close object, wherein
RespectivelyIt is each independently selected from singly-bound or double bond, and is not simultaneously double bond;
A is selected from CRh、CRhRh、N、NRi, O, S, C=O, C=S, S=O andWork as RhWhen being multiple, each RhIt can phase
It is same or different;
B is selected from CRj、CRjRj、N、NRk, C=O and C=S;Work as RjWhen being multiple, each RjIt can be identical or different;
D is selected from C, CRmAnd N;
E is selected from NRo, O, S, C=O, C=S, S=O and
Rh、Ri、Rj、Rk、Rm、RoIt is each independently selected from hydrogen, fluorine, chlorine, hydroxyl, cyano, nitro, amino, C1-6Alkyl, C1-6
Halogenated alkyl, C1-6Alkoxy and C1-6Halogenated alkoxy.
Particularly, the application offer formula (I), formula (II), formula (III) or formula (IV) compound represented or its pharmacy can
Salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolin or the prodrug of receiving or theirs is mixed
Close object, wherein
A is selected from CRhRh, B is selected from CRjRj, D is selected from CRmAnd N, Rh、RjAnd RmIt is hydrogen, E is selected from O and C=O;N is 1;
In certain preferred aspects, R2It is selected from
In certain preferred aspects,It is singly-bound.
According to some embodiments of the application, the compound is selected from without limitation with flowering structure:
Preparation method
The further object of the application is to provide the method for preparing the compound, the described method comprises the following steps:
In above-mentioned steps, general formula (I-c) compound reacts to obtain logical formula (I) compound with alkaline reagent, whereinRing
G, ring J, A, B, D, E, R1、R2、R3、R4, m, n, r, t, i be as defined in formula (I).
In certain embodiments, the intermediate (I-c) carries out according to following reaction route 1:
Reaction route 1
Wherein,Ring G, ring J, A, B, D, E, R1、R3、R4, m, n, r, t, i such as formula (I) defined, LG is leaving group.
In certain embodiments, the first step carries out in the presence of organic base or inorganic base in proton solvent;
Second step under alkaline condition, carries out at a temperature of 10-60 DEG C (such as 20-50 DEG C, such as 25 ± 2 DEG C).
In certain embodiments, the intermediate (I-c) carries out according to following reaction route 2:
Reaction route 2
Wherein,Ring G, ring J, A, B, D, E, R1、R3、R4, m, n, r, t, i such as formula (I) defined, X is halogen.
In certain embodiments, the first step carries out in the presence of organic base or inorganic base;
Second step is carried out at a temperature of 20-100 DEG C (such as 30-80 DEG C, such as 60 ± 2 DEG C).
In preferred embodiments, above-mentioned reaction carries out under inert gas protection.
In preferred embodiments, can the protonic solvent used in the compounds process for production thereof include but unlimited
Yu Shui, methanol, ethyl alcohol, acetic acid etc..
In preferred embodiments, can the organic base used in the compounds process for production thereof include but is not limited to uncle
Sodium butoxide, triethylamine, DIPEA, pyridine or DMAP;Can the inorganic base used in the compounds process for production thereof include but unlimited
In sodium hydride, sodium hydroxide, sodium carbonate or potassium carbonate.
Definition
Unless hereinafter defined otherwise, the meaning of all technical terms and scientific terms used herein is intended to and this
Field technical staff is generally understood identical.
" alkyl " is defined as the saturated aliphatic hydrocarbons of linear chain or branched chain.The embodiment of alkyl group includes but is not limited to first
Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2-
Dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- ethyl -2- first
Base propyl, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- diformazan
Base butyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2,3- dimethylbutyl etc..If without special
It limits, alkyl can be substituted or unsubstituted.
" alkenyl " refers to the aliphatic hydrocarbon group containing a carbon-carbon double bond, can also have branch for straight chain.Alkenyl base
The embodiment of group includes, but are not limited to vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyl etc..If without special limit
Fixed, alkenyl can be substituted or unsubstituted.
" alkynyl " refers to the aliphatic hydrocarbon group containing a triple carbon-carbon bonds, can also have branch for straight chain.Alkynyl base
The embodiment of group includes, but are not limited to acetenyl, 1- propinyl, 2-propynyl, 1-, 2- or 3- butynyl etc..If without special limit
Fixed, alkynyl can be substituted or unsubstituted.
" naphthenic base " refers to comprising saturation or the unsaturated monocycle in part or multi-ring alkyl.The embodiment packet of " monocycle alkyl "
It includes: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclodecyl, cyclo-dodecyl, cyclohexenyl group.It is " polycyclic
Alkyl " includes " bridged ring base ", " and naphthenic base " and " spiro cycloalkyl group ", and " bridged ring base " refers to that monocycle alkyl any two are non-conterminous
Carbon atom is connected by alkylidene.The representative example of bicyclic bridged ring base includes but is not limited to: bornyl, bicyclic [2.2.1] heptene
It is base, bicyclic [3.1.1] heptane base, bicyclic [2.2.1] heptane base, bicyclic [2.2.2] octyl, bicyclic [3.2.2] nonyl, double
Ring [3.3.1] nonyl, bicyclic [4.2.1] nonyl etc.." and naphthenic base " is miscellaneous comprising being fused to phenyl, monocycle alkyl, monocycle
Naphthenic base in ring group or bicyclic heteroaryl, and naphthenic base includes but is not limited to: benzocyclobutene, benzocyclobutane, benzo ring
Hexane, benzo ring heptane, pyrido cyclobutane, pyridine pentalane, pyrido hexamethylene, 2,3- dihydro -1-H- indenes, 2,3- ring
Amylene and pyridine, 5,6- dihydro -4H- cyclopenta [B] thiophene, decahydronaphthalene etc.." spiro cycloalkyl group " refers to that two naphthenic base share one
The bicyclic radicals that a carbon atom is formed.The naphthenic base can be condensed on aryl, heteroaryl or heterocycle, if without special limit
Fixed, naphthenic base can be substituted or unsubstituted.
" heterocycle " refers to non-aromatic heterocyclyl groups, wherein one or more cyclization atoms be hetero atom, as oxygen, nitrogen,
Sulphur atom etc., including monocycle, condensed ring, bridged ring and loop coil include monocyclic heterocycles base, bridge heterocycle, condensed hetero ring base and spiroheterocyclic
Base.The example of " heterocycle " includes but is not limited to morpholinyl, thio-morpholinyl, THP trtrahydropyranyl, 1,1- Dioxo-thiomorpholin
Base, piperidyl, 2- oxo-pipehdinyl, pyrrolidinyl, 2- oxo-pyrrolidine, piperazine -2- ketone, 8- oxa- -3- aza-bicyclo
[3.2.1] octyl and piperazinyl.The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, and heterocycle can be with
It is substituted or unsubstituted.
" aryl " refers to the carbocyclic aromatic system containing one or two rings, wherein the ring can be in a manner of condensed
It links together.Term " aryl " includes the aromatic group of such as phenyl, naphthalene." aryl " can be with heteroaryl, heterocycle
Or it is Cycloalkylfused.If being not particularly limited, aryl can be substituted or unsubstituted.
" heteroaryl " refers to the aroma system comprising 1 to 4 atom in nitrogen, oxygen and/or sulphur.The reality of " heteroaryl "
Applying example includes but is not limited to furyl, pyridyl group, 2- oxo -1,2- dihydropyridine base, pyridazinyl, pyrimidine radicals, pyrazinyl, thiophene
Base, isoxazolyl, oxazolyl, oxadiazoles base, imidazole radicals, pyrrole radicals, pyrazolyl, triazolyl, tetrazole radical, thiazolyl, isothiazole
Base, 1,2,3- thiadiazolyl group, benzodioxole group, benzimidazolyl, indyl, isoindolyl, 1,3- dioxo-
Isoindolyl, quinolyl, indazolyl, benzisothia oxazolyl, benzoxazolyl and benzo isoxazolyl.The heteroaryl ring can be with
It condenses on aryl, heterocycle or cycloalkyl ring.If being not particularly limited, heteroaryl can be substituted or unsubstituted.
" alkoxy " refers to the group of (alkyl-O-).Wherein, alkyl is shown in related definition herein.The example includes, but unlimited
In: methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy etc..
" hydroxyl " refers to-OH group.
" halogenated " or " halogen " group refers to including F, Cl, Br or I.
" amino " refers to-NH2。
" cyano " refers to-CN.
" nitro " refers to-NO2。
" carboxyl " refers to-C (O) OH.
" ester group " refers to-C (O) O (alkyl) or-C (O) O (naphthenic base), and wherein alkyl, naphthenic base are as defined above.
" substitution " refers to one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom that
This is independently replaced by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, ability
Field technique personnel can determine in the case where not paying and excessively making great efforts and (pass through experiment or theoretical) possible or impossible substitution.
It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key
's.
" optional " refers to that group is substituted or unsubstituted.
If substituent group is described as " independently selected from ", each substituent group is selected independently of another one.Therefore, it respectively takes
Dai Jike and another (other) substituent group are identical or different.
As used herein, term " one or more " means 1 under reasonable terms or more than 1, such as 2
A, 3,4,5 or 10.
" pharmaceutically acceptable salt " refers to that above compound is able to maintain original bioactivity and is suitable for medical usage
Certain salts.The pharmaceutical salt of the compounds of this invention can be metal salt, the amine salt formed with suitable acid.
" pharmaceutical composition " indicate containing one or more compounds described herein or its physiologically pharmaceutical salt or
The mixture and the pharmaceutical carrier of other components such as physiology and excipient of pro-drug and other chemical constituents.Medicine
The purpose of compositions is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.
" pharmaceutically acceptable carrier " refers to the diluent, adjuvant, excipient being administered together with therapeutic agent in the application
Or medium, and its tissue that the mankind and/or other animals are adapted for contact in the range of reasonable medical judgment without
Excessive toxicity, stimulation, allergic reaction or with reasonable benefit/risk than corresponding other problems or complication.
" effective quantity " refers to as used herein, the term be administered after can alleviate treated illness to a certain extent
The amount of the compound of one or more symptoms.
The application further includes all pharmaceutically acceptable isotopic compounds, identical as the compound, in addition to one
A or multiple atoms are by with same atoms ordinal number but atomic mass or mass number are different from atom dominant in nature
The atom of quality or mass number substitution.It is suitble to include the example of isotope in the compound to include but is not limited to hydrogen
Isotope (such as2H、3H);Carbon isotope (such as11C、13C and14C);Chlorine isotope (such as37Cl);The isotope of fluorine
(such as18F);Iodine isotope (such as123I and125I);Nitrogen isotope (such as13N and15N);Oxygen isotope (such as15O
、17O and18O);Phosphorus isotope (such as32P);And sulphur isotope (such as35S)。
" stereoisomer " indicates the isomers formed due at least one asymmetric center.There is one or more
In the compound of (such as 1,2,3 or 4) asymmetric center, racemic mixture, single enantiomerism can produce
Body, non-enantiomer mixture and individual diastereoisomer.Specific individual molecules can also with geometric isomer (it is cis-/
It is trans-) exist.Similarly, the mixing of the different form of the structure that the compound can be in Fast-Balance with two or more
Object (commonly referred to as tautomer) exists.The representative example of tautomer includes ketone-enol tautomers, phenol-
Keto tautomer, nitroso-oxime tautomer, imine-enamine tautomers etc..For example, dihydro-pyrimidin group is molten
It can be balanced and be existed with following tautomeric form in liquid.It is appreciated that scope of the present application cover it is all such with arbitrary proportion
The isomers of (such as 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or its
Mixture.
Unless otherwise specified, the compound be intended to can with stereoisomer (it includes cis- and transisomer,
Optical isomer (such as R and S enantiomter), diastereoisomer, geometric isomer, rotational isomer, conformer,
Atropisomer and its mixture) form exist.The compound can express the isomerism of more than one types, and by it
Mixture (such as racemic mixture and diastereoisomer to) composition.
The application covers all possible crystal form or polymorph of the compound, can be single polycrystalline type thing
Or the mixture of the arbitrary proportion of more than one polymorph.
It is also understood that certain compounds of the application can exist in a free form for treating, or where appropriate, with its medicine
Acceptable derivates form exists on.In the present invention, pharmaceutically acceptable derivates include but is not limited to: pharmaceutically
Acceptable salt, ester, solvate, metabolin or prodrug, by they to need its patient administration after, can directly or
It connects and the compound or its metabolin or residue is provided.Therefore, when referenced herein " compound ", it is also intended to culvert
The above-mentioned various derivative forms of lid compound.
The compound can exist in the form of solvate (preferably hydrate), wherein the compound includes to be used as institute
The polar solvent of the structural element of compound lattice is stated, especially such as water, methanol or ethyl alcohol.The amount of polar solvent especially water
Can exist with stoichiometric ratio or non-stoichiometric.
Within the scope of application further include the metabolin of the compound, i.e., is formed in body when the compound is administered
Substance.Such product can by the oxidation for the compound being for example administered, reduction, hydrolysis, amidation, desamidization, esterification,
Degreasing, enzymatic hydrolysis etc. generate.Therefore, the present invention includes the metabolin of the compound, including by making the compound and feeding
Newborn animal contact is enough to generate compound made from the method for the time of its metabolite.
The present invention further comprises the prodrug of the compound within its scope, for that itself can have smaller pharmacology living
Certain derivatives of property or the compound without pharmacological activity can be for example, by water when being administered in body or thereon
Solution cracking, which is converted to have, it is expected the active compound.Usually such prodrug can be that the functional group of the compound is derivative
Object is easy to be converted to desired therapeutical active compound in vivo.The other information used about prodrug can be found in " Pro-
Drugs as Novel Delivery Systems ", volume 14, ACS Symposium Series (T.Higuchi and
) and " Bioreversible Carriers in Drug Design, " Pergamon Press, V.Stella 1987
(E.B.Roche is edited, American Pharmaceutical Association).The prodrug can be for example by using ability
Field technique personnel are known as " preceding-part (pro-moiety) (such as " Design of Prodrugs ", H.Bundgaard
Described in (Elsevier, 1985)) " certain parts substitute appropriate functional group present in the compound to prepare.
Present invention also contemplates that the compound containing protecting group.Prepare the compound it is any during, protection
It may be necessary and/or desired in any sensitive group in relation on molecule or reactive group, the chemical combination be consequently formed
The form of the chemoproection of object.This can be realized by conventional protecting group, for example, in Protective Groups in
Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973;And T.W.Greene&P.G.M.Wuts,
Protective Groups in Organic Synthesis, John Wiley&Sons is protected those of described in 1991
Base, these bibliography are by quoting addition herein.Using methods known in the art, can be removed in follow-up phase appropriate
Protecting group.
Pharmaceutical composition and kit product
The another object of the application is to provide a kind of pharmaceutical composition, and it includes prevention or the present invention of therapeutically effective amount
Compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate,
Metabolin or prodrug or their mixture and one or more pharmaceutically acceptable carriers.
" pharmaceutically acceptable carrier " refers to the diluent, adjuvant, excipient being administered together with therapeutic agent in the application
Or medium, and its tissue that the mankind and/or other animals are adapted for contact in the range of reasonable medical judgment without
Excessive toxicity, stimulation, allergic reaction or with reasonable benefit/risk than corresponding other problems or complication.
The pharmaceutical composition of the application can be acted on systematically and/or locally be acted on.For this purpose, they can be suitble to
Approach administration, such as by injection (as in intravenous, intra-arterial, subcutaneous, peritonaeum, intramuscular injection, including instil) or it is percutaneous
Administration;Or oral, buccal, intranasal, it is transmucosal, local, in the form of eye-drops preparations or pass through inhalation.
For these administration routes, pharmaceutical composition of the invention is administered in the dosage form that can be suitble to.The dosage form include but
It is not limited to tablet, capsule, pastille, hard candy agent, powder, spray, cream, ointment, suppository, gelling agent, paste, washes
Agent, ointment, aqueous suspension, injectable solutions, elixir, syrup etc..
Content or dosage of the compound in pharmaceutical composition can be about 0.01mg to about 1000mg, be compatibly
0.1-500mg。
According to the application embodiment, described pharmaceutical composition also may include one or more other therapeutic agents,
Such as other anticancer agents, including but not limited to macromolecular (for example, protein) or small molecule are (for example, inorganic, the You Jijin of synthesis
Belong to or organic point is given).The example of the anticancer agent of macromolecular form is biological molecule, such as albumen that is natural or manually preparing
Matter.The anticancer agent of small molecule form, including but not limited to antitumor and anticancer agent, antibiotic, anti-inflammatory reagent and steroid.
The another object of the application is to provide a kind of method for preparing described pharmaceutical composition, and the method includes by institute
State compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate,
Metabolin or prodrug or their mixture are combined with one or more pharmaceutically acceptable carriers.
The another object of the application is to provide a kind of kit product, and it includes the compound or its is pharmaceutically acceptable
Salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolin or prodrug or they
Mixture or described pharmaceutical composition;And optional package insert.
Treatment method and purposes
The another object of the application is to provide the compound or its pharmaceutically acceptable salt, ester, stereoisomer, mutually
Tautomeric, polymorph, solvate, hydrate, metabolin or prodrug or their mixture or the drug
Composition, it is used to prevent or treat with PD-1/PD-L1 pathway dependent diseases.
The another object of the application is to provide the compound or its pharmaceutically acceptable salt, ester, stereoisomer, mutually
Tautomeric, polymorph, solvate, hydrate, metabolin or prodrug or their mixture or the medicine group
Object is closed in preparation for preventing or treating and the purposes in the drug of PD-1/PD-L1 pathway dependent diseases.
The another object of the application is to provide a kind of method of prevention or treatment and PD-1/PD-L1 pathway dependent diseases,
It includes the compound or its pharmaceutically acceptable salt, ester, stereoisomer, the mutually variation of administration prevention or therapeutically effective amount
Structure body, polymorph, solvate, hydrate, metabolin or prodrug or their mixture or the pharmaceutical composition
Object.
The another object of the application is to provide a kind of method of prevention or treatment and PD-1/PD-L1 pathway dependent diseases,
It includes the compound or its pharmaceutically acceptable salt, ester, stereoisomer, the mutually variation of administration prevention or therapeutically effective amount
Structure body, polymorph, solvate, hydrate, metabolin or prodrug or their mixture or the pharmaceutical composition
Object and one or more other therapeutic agents.
According to the application embodiment, described and PD-1/PD-L1 pathway dependent diseases include but is not limited to cancer
Disease, virus infection etc., and the related symptoms or disease that are caused by above-mentioned disease.As used herein, term " cancer " is
Refer to cell proliferation disorders state, including but not limited to lung cancer, cutaneum carcinoma, melanoma, the cancer of the esophagus, bladder cancer, head-neck carcinoma,
Nasopharyngeal carcinoma, bronchiolar carcinoma, breast cancer, cervical carcinoma, cancer of pancreas, liver cancer, gastric cancer, cholangiocarcinoma, prostate cancer, brain tumor, colon cancer
Or the Cancer residual after above-mentioned solid tumor excision.Term " disease of viral infection " include but is not limited to carry HIV, hepatitis A
Poison, hepatitis B, hepatitis C virus, fourth hepatovirus, herpesviral, human papilloma virus, disease caused by influenza virus.
" effective quantity " refers to as used herein, the term be administered after can alleviate treated illness to a certain extent
The amount of the compound of one or more symptoms.
Dosage regimen be can adjust to provide optimal required response.For example, single bolus can be administered, can be administered at any time several
Divided dose, or dosage can be proportionally reduced or increased as indicated in the urgent need for the treatment of condition.It should be noted that dose value can be with will subtract
The type and seriousness of the light patient's condition and change, and may include single or multiple dosage.It further understands, for any specific
Individual, specific dosage regimen should be sentenced according to the profession of individual need and administration composition or the personnel for the administration for supervising composition
Break to adjust at any time.
Unless otherwise stated, otherwise as used herein, term " treatment " means to reverse, mitigates, inhibits such art
The progress of one or more symptoms of illness or the patient's condition applied by language or such illness or the patient's condition, or prevent such illness
Or one or more symptoms of the patient's condition or such illness or the patient's condition.
Unless otherwise stated, otherwise as used herein, term " prevention " means to prevent other symptom, prevention symptom
Potential metabolism inducement, inhibit the disease or illness, such as prevent the generation of disease or illness.
" individual " includes people or non-human animal as used herein.Exemplary individual human include with disease (such as this
Disease described in text) individual human (referred to as patient) or normal individual." non-human animal " includes all vertebrates in the present invention,
Such as nonmammalian (such as birds, amphibian, reptile) and mammal, such as non-human primates, domestic animal and/or
Domesticated animal (such as sheep, dog, cat, milk cow, pig etc.).
Specific embodiment
In order to keep the purpose of the present invention and technical solution clearer, this hair is further described below in conjunction with specific embodiment
It is bright.It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.Also, the following example
In unmentioned specific experiment method, according to routine experiment method carry out.
Abbreviation herein has following meanings:
Prepare embodiment:
Embodiment 1:2- ((the chloro- 4- of 3- ((4- phenyl -2,3- dihydro -1H- indenyl) oxygen) benzyl) amino) ethyl alcohol (compound
1) preparation
Step 1: the preparation of 4- phenyl -1- indone
It is stirred at room temperature down, the bromo- 1- indone of phenyl boric acid (317mg, 2.60mmol), 4- is separately added into Xiang Shui (50mL)
(500mg, 2.36mmol), tetrabutylammonium bromide (761mg, 2.36mmol), potassium carbonate (3260mg, 23.6mmol), are sufficiently stirred
It after mixing dispersion, is added palladium acetate (54mg, 0.24mmol), is stirred after nitrogen displacement in 60 DEG C of outer temperature, until TLC shows the bromo- 1- of 4-
Indone fully reacting, reaction solution are extracted with ethyl acetate (15mL × 3), are merged organic phase, are subtracted for 40 DEG C after anhydrous sodium sulfate is dry
Pressure concentration.Residue purifies to obtain title compound (420mg, the yield: 85.5%) of this step through silica gel column chromatography.
Step 2: the preparation of 4- phenyl -2,3- dihydro -1H- indenes -1- alcohol
It is stirred at room temperature down, 4- phenyl -1- indone (400mg, 1.92mmol) is dissolved completely in dehydrated alcohol (10mL), is delayed
It is slow that NaBH is added4(73mg,1.92mmol).Maintain room temperature reaction to TLC display 4- phenyl -1- indone fully reacting, Xiang Fanying
After being slowly added to ice water (50mL) quenching reaction in liquid, dilute hydrochloric acid (20mL, 1mol/L), water phase ethyl acetate are added
(15mL × 3) extraction merges organic phase, and 40 DEG C of reduced pressures, obtain the title compound of this step after anhydrous sodium sulfate is dry
(372mg, yield: 92.1%).It is directly used in next step.
Step 3: the preparation of the chloro- 4- of 3- ((4- phenyl -2,3- dihydro -1H- indenyl) oxygen) benzaldehyde
Under ice bath stirring, to 50ml flask be separately added into 4- phenyl -2,3- dihydro -1H- indenes -1- alcohol (300mg,
1.43mmol), 3- chloro-4-hydroxyl benzaldehyde (230mg, 1.43mmol) and triphenylphosphine (450mg, 1.72mmol).Nitrogen is protected
Shield is lower to be added anhydrous tetrahydro furan (15mL), and after stirring clarification, the tetrahydrofuran of DIAD (350mg, 1.72mmol) is slowly added dropwise
(2mL) solution.Room temperature reaction 6 hours is gone to after being added dropwise.After 40 DEG C of reaction solution are concentrated under reduced pressure, residue silica gel column chromatography
Chromatogram purification obtains title compound (236mg, the yield: 47.3%) of this step.
Step 4: 2- ((the chloro- 4- of 3- ((4- phenyl -2,3- dihydro -1H- indenyl) oxygen) benzyl) amino) ethyl alcohol (compound
1) preparation
It is stirred at room temperature down, the chloro- 4- of 3- ((4- phenyl -2,3- dihydro -1H- indenyl) is separately added into in anhydrous DMF (10mL)
Oxygen) benzaldehyde (210mg, 0.60mmol), ethanol amine (110mg, 1.8mmol) and appropriate molecular sieve.In outer temperature under nitrogen protection
60 DEG C are reacted 2 hours.After reaction solution is cooled to room temperature, NaBH (OAc) is added thereto3(377mg, 6.0mmol), glacial acetic acid
Reaction is stirred at room temperature to the TLC display chloro- 4- of 3- ((4- phenyl -2,3- dihydro -1H- indenyl) oxygen) in (360mg, 6.0mmol), maintenance
Benzaldehyde fully reacting.Water (60mL) is added into reaction solution, water phase merges organic phase with ethyl acetate (15mL × 3) extraction,
40 DEG C of reduced pressures after anhydrous sodium sulfate is dry, residue obtains title compound after preparing thin layer chromatography, and (82mg is received
Rate: 34.7%).
MS m/z(ESI):394.2[M+H]+
1H-NMR(400MHz,CDCl3) δ: 7.47-7.42 (m, 5H), 7.38-7.33 (m, 4H), 7.21 (d, 1H, J=
8.0Hz), 7.10 (d, 1H, J=8.0Hz), 5.78 (t, 1H, J=5.6Hz), 3.77 (s, 2H), 3.69 (t, 2H, J=
4.8Hz), 3.27-3.20 (m, 1H), 3.01-2.94 (m, 1H), 2.83 (t, 2H, J=4.8Hz), 2.58-2.51 (m, 1H),
2.29-2.21(m,1H)。
Embodiment 2:2- ((the chloro- 4- of 3- ((4- phenyl -2,3- dihydro -1H- indenyl) oxygen) benzyl) amino) propane -1,3- two
The preparation of alcohol (compound 39)
Using 1 synthetic route of embodiment, step 1 feed ethanol amine is replaced with into serinol, obtains title compound
(51mg, yield: 36.4%).
MS m/z(ESI):424.1[M+H]+。
1H-NMR(400MHz,MeOD)δ:7.59-7.57(m,1H),7.47-7.41(m,5H),7.40-7.32(m,5H),
5.94-5.92(m,1H),4.20-4.18(m,2H),3.84-3.73(m,4H),3.24-3.16(m,2H),3.01-2.94(m,
1H),2.60-2.55(m,1H),2.19-2.14(m,1H)。
Embodiment 3:2- ((the chloro- 4- of 3- ((4- phenyl -1H- indazole -1- base) methyl) benzyl) amino) ethyl alcohol (compound 3)
Preparation
Step 1: the preparation of 4- phenyl -1H- indazole
Be stirred at room temperature down, be separately added into 50mL flask the bromo- 1H- indazole of phenyl boric acid (1g, 8.2mmol), 4- (1.6g,
8.2mmol), potassium carbonate (3.4g, 24.6mmol) after addition Isosorbide-5-Nitrae-dioxane (20mL), water (5mL) are sufficiently stirred, is added
Pd(dppf)Cl2(600mg, 0.82mmol) shows the bromo- 1H- indazole of raw material 4- in 80 DEG C of outer temperature stirrings to TLC after nitrogen displacement
Water (100mL) is added into reaction solution after concentration in fully reacting, and water phase is extracted with ethyl acetate (20mL × 3), merges organic
Phase, 40 DEG C of reduced pressures after anhydrous sodium sulfate is dry.Residue is purified to obtain the title compound of this step with silica gel column chromatography
Object (920mg, yield: 58%).
MS m/z(ESI):195.1[M+H]+
1H-NMR (400MHz, DMSO-d6) δ: 13.25 (s, 1H), 8.16 (s, 1H), 7.74 (d, J=8.0Hz, 2H),
7.54 (t, J=7.6Hz, 3H), 7.44 (t, J=7.6Hz, 2H), 7.23 (d, J=7.2Hz, 1H).
Step 2: the preparation of the chloro- 4- of 3- ((4- phenyl -1H- indazole -1- base) methyl) benzaldehyde
It is stirred at room temperature down, 4- phenyl -1H- indazole (200mg, 1.03mmol), 4- (bromine is sequentially added in acetonitrile (25mL)
Methyl) -3- chlorobenzaldehyde (240mg, 1.03mmol), potassium carbonate (1.42g, 10.3mmol), 60 DEG C of reactions, TLC detection reaction
After completely, water (100mL) is added into reaction solution, water phase is extracted with ethyl acetate (20mL × 3), merges organic phase, anhydrous sulphur
40 DEG C of reduced pressures after sour sodium is dry.Residue with silica gel column chromatography purify to obtain title compound (296mg, yield:
83%).
MS m/z(ESI):347.1[M+H]+
1H-NMR (400MHz, DMSO-d6) δ: 9.96 (s, 1H), 8.27 (d, J=0.8Hz, 1H), 8.04 (d, J=
1.6Hz, 1H), 7.81-7.71 (m, 4H), 7.59-7.53 (m, 2H), 7.50 (dd, J=10.0,2.8Hz, 1H), 7.49-7.42
(m, 1H), 7.31 (d, J=6.8Hz, 1H), 6.98 (d, J=8.0Hz, 1H), 5.90 (s, 2H).
Step 3: 2- ((the chloro- 4- of 3- ((4- phenyl -1H- indazole -1- base) methyl) benzyl) amino) ethyl alcohol (compound 3)
Preparation
It is stirred at room temperature down, compound 3-chlorin -4- ((4- phenyl -1H- indazole -1- is separately added into in anhydrous DMF (10mL)
Base) methyl) benzaldehyde (100mg, 0.29mmol), ethanol amine (54mg, 0.87mmol) and appropriate molecular sieve.Under nitrogen protection in
60 DEG C of outer temperature are reacted 2 hours.After reaction solution is cooled to room temperature, NaBH (OAc) is added thereto3(610mg, 2.9mmol), ice
Reaction is stirred at room temperature to TLC display compound 3-chlorin -4- ((4- phenyl -1H- indazole -1- in acetic acid (174mg, 2.9mmol), maintenance
Base) methyl) benzaldehyde fully reacting.Water (60mL) is added into reaction solution, water phase is closed with ethyl acetate (15mL × 3) extraction
And organic phase, 40 DEG C of reduced pressures, residue obtain title compound after preparing thin layer chromatography after anhydrous sodium sulfate is dry
Object (63mg, yield: 32.4%).
MS m/z(ESI):392.1[M+H]+
1H-NMR(400MHz,MeOD)δ:8.18(s,1H),7.73–7.69(m,2H),7.55–7.50(m,2H),7.49–
7.46 (m, 3H), 7.45-7.41 (m, 1H), 7.27 (dd, J=5.6,2.4Hz, 1H), 7.15 (dd, J=8.0,1.6Hz, 1H),
6.73 (d, J=8.0Hz, 1H), 5.77 (s, 2H), 3.73 (s, 2H), 3.66-3.60 (m, 2H), 3.3-3.29 (m, 2H), 2.66
(t, J=5.6Hz, 2H);
Embodiment 4:(5- (((2- ethoxy) amino) methyl) pyridine -2- base) (4- phenyl indoline -1- base) ketone
The preparation of (compound 4)
Step 1: the preparation of 4- phenyl indoline
It is stirred at room temperature down, phenyl boric acid (350mg, 2.81mmol), 4- bromine indoline is separately added into 50mL flask
(500mg, 2.55mmol), potassium carbonate (710mg, 5.10mmol) after addition toluene (15mL), water (5mL) are sufficiently stirred, is added
Pd(dppf)Cl2(102mg, 0.14mmol) shows the reaction of 4- bromine indoline in 92 DEG C of outer temperature stirrings to TLC after nitrogen displacement
Completely, water (100mL) is added into reaction solution, water phase is extracted with ethyl acetate (20mL × 3), merges organic phase, anhydrous slufuric acid
40 DEG C of reduced pressures after sodium is dry.Residue is purified to obtain title compound (474mg, the receipts of this step with silica gel column chromatography
Rate: 86.4%).
MS m/z(ESI):196.2[M+H]+
Step 2: the preparation of 6- (4- phenyl indoline -1- carbonyl)-methyl nicotinate
Be stirred at room temperature down, sequentially added in tetrahydrofuran (30mL) 4- phenyl indoline (300mg, 1.53mmol),
5- (methoxycarbonyl group) -2-Pyridinecarboxylic Acid (280mg, 1.53mmol), HATU (1170mg, 3.06mmol) and DIPEA (1980mg,
15.3mmol), it maintains room temperature reaction to show the indoline fully reacting of 4- phenyl to TLC, water is added into reaction solution
(100mL), water phase are extracted with ethyl acetate (20mL × 3), merge organic phase, 40 DEG C of reduced pressures after anhydrous sodium sulfate is dry.
Residue is purified to obtain title compound (472mg, the yield: 86.1%) of this step with silica gel column chromatography.
MS m/z(ESI):359.2[M+H]+
Step 3: the preparation of (5- (methylol) pyridine -2- base) (4- phenyl indoline -1- base) ketone
Under 0 DEG C of stirring, 6- (4- phenyl indoline -1- carbonyl)-cigarette is sequentially added in anhydrous tetrahydro furan (10mL)
Sour methyl esters (450mg, 1.26mmol), lithium aluminium hydride reduction (24mg, 0.63mmol) maintain 0 DEG C of reaction to TLC display 6- (4- phenyl
Indoline -1- carbonyl)-methyl nicotinate fully reacting, be slowly added into reaction solution solid sal glauberi (406mg,
1.26mmol) quenching reaction.Filtrate is concentrated under reduced pressure in 40 DEG C after filtering and washing filter cake with tetrahydrofuran (10mL × 3).It is residual
Excess is purified to obtain title compound (202mg, the yield: 48.5%) of this step with silica gel column chromatography.
MS m/z(ESI):331.2[M+H]+
Step 4: the preparation of 6- (4- phenyl indoline -1- carbonyl)-nicotine formaldehyde
It is stirred at room temperature down, (5- (methylol) pyridine -2- base) (4- phenyl dihydro is sequentially added in methylene chloride (10mL)
Indoles -1- base) ketone (200mg, 0.61mmol), DMP (770mg, 1.82mmol), maintain back flow reaction to show (5- to TLC
(methylol) pyridine -2- base) (4- phenyl indoline -1- base) ketone fully reacting, unsaturated carbonate hydrogen is added into reaction solution
Sodium solution (50mL), water phase are extracted with methylene chloride (20mL × 3), merge organic phase, 40 DEG C of decompressions after anhydrous sodium sulfate is dry
Concentration.Residue is purified to obtain title compound (178mg, the yield: 88.9%) of this step with silica gel column chromatography.
MS m/z(ESI):329.2[M+H]+
Step 5: (5- (((2- ethoxy) amino) methyl) pyridine -2- base) (4- phenyl indoline -1- base) ketone
The preparation of (compound 4)
It is stirred at room temperature down, 6- (4- phenyl indoline -1- carbonyl)-nicotine first is separately added into in anhydrous DMF (10mL)
Aldehyde (170mg, 0.52mmol), ethanol amine (95mg, 1.56mmol) and appropriate molecular sieve.It is reacted under nitrogen protection in 60 DEG C of outer temperature
2 hours.After reaction solution is cooled to room temperature, NaBH (OAc) is added thereto3(327mg, 5.2mmol), glacial acetic acid (312mg,
5.2mmol), maintain to be stirred at room temperature reaction to TLC display 6- (4- phenyl indoline -1- carbonyl)-nicotine formaldehyde fully reacting.
Water (60mL) is added into reaction solution, water phase merges organic phase with ethyl acetate (15mL × 3) extraction, and anhydrous sodium sulfate is dry
40 DEG C of reduced pressures, residue obtain title compound (63mg, yield: 32.4%) after preparing thin layer chromatography afterwards.
MS m/z(ESI):374.2[M+H]+
1H-NMR(400MHz,CDCl3)δ:8.63-8.58(m,1H),8.31-8.28(m,1H),7.94-7.88(m,1H),
7.43-7.29(m,7H),7.14-7.09(m,1H),4.30-4.23(m,2H),4.08-3.92(m,2H),3.76-3.70(m,
2H),3.23-3.17(m,2H),3.00-2.87(m,2H)。
Embodiment 5:(S)-(5- (((2,3- dihydroxypropyl) amino) methyl) pyridine -2- base) (4- phenyl indoline -
1- yl) ketone (compound 36) preparation
Using 4 synthetic route of embodiment, the 5th step feed ethanol amine is replaced with into (S) -3- amino -1,2-PD, is obtained
To title compound (53mg, yield: 35.6%).
MS m/z(ESI):404.1[M+H]+。
1H-NMR(400MHz,MeOD)δ:8.63-8.61(m,1H),8.23-8.21(m,1H),8.02-8.00(m,1H),
7.80-7.78(m,1H),7.44-7.34(m,6H),7.16-7.14(m,1H),4.22-4.18(m,2H),3.94-3.92(m,
2H),3.78-3.76(m,1H),3.53-3.51(m,2H),2.79-2.75(m,2H),2.65-2.63(m,1H),2.62-2.60
(m,1H)。
Embodiment 6:2- ((the chloro- 4- of 3- ((4- (2- fluorophenyl) -2,3- dihydro -1H- indenyl) oxygen) benzyl) amino) ethyl alcohol
The preparation of (compound 37)
Using 1 synthetic route of embodiment, step 1 raw material phenyl boric acid is replaced with into 2- fluorobenzoic boric acid, obtains title compound
(47mg, yield: 34.3%).
MS m/z(ESI):412.1[M+H]+。
1H-NMR(400MHz,MeOD)δ:7.43-7.39(m,3H),7.38-7.36(m,1H),7.34-7.24(m,4H),
7.23-7.17(m,2H),5.89-5.86(m,1H),3.74-3.71(m,2H),3.69-3.66(m,2H),3.02-2.99(m,
1H),2.83-2.80(m,1H),2.74-2.71(m,2H),2.58-2.53(m,1H),2.18-2.15(m,1H)。
Embodiment 7:2- ((the chloro- 4- of 3- ((4- phenyl -2,3- dihydro -1H- indenyl) oxygen) benzyl) amino) -2 Methylpropionic acid
The preparation of (compound 38)
Using 1 synthetic route of embodiment, step 4 feed ethanol amine is replaced with into 2- methylalanine, obtains title compound
Object (56mg, yield: 35.2%).
MS m/z(ESI):436.1[M+H]+。
1H-NMR(400MHz,MeOD)δ:7.63-7.58(m,2H),7.50-7.44(m,4H),7.40-7.35(m,2H),
7.34-7.30(m,3H),5.96-5.94(m,1H),4.11-4.08(m,2H),3.31-3.29(m,1H),3.24-3.18(m,
1H),2.60-2.54(m,1H),2.20-2.14(m,1H),1.54(s,6H)。
Biological assessment
1. compound of test case screens PD-1/PD-L1 binding inhibition activity
The inhibitory activity screening of PD-1/PD-L1 inhibitor uses the PD-1/PD-L1 Binding of Cisbio company
Assay kit carries out.
Untested compound: compound of the embodiment of the present invention;
Kit: PD-1/PD-L1 BINDING ASSAY KITS;
Producer: Cisbio;
Experimental method
Diluted chemical compound: untested compound is diluted to various concentration (nM): 10000,1000,100,10,1.
Add compound and albumen in 384 orifice plates, compound (2 μ L), Tag1-PD-L1 albumen after dilution is added in every hole
(4 μ L) and Tag2-PD-1 albumen (4 μ L).Orifice plate is closed in centrifugation, is incubated at room temperature 15 minutes.
Antibody is added: the anti-Tag1-Eu3 and anti-Tag2-XL665 (10 μ L) mixed in advance is added in every hole.Centrifugation,
Orifice plate is closed, is incubated at room temperature 2 hours.
Detection: microplate reader detects fluorescent value, SignalEx./Em.=665nm/620nm × 10000.
Data processing: data statistic analysis, IR (Inhibition Rate, %)=(SSolvent control-SCompound)/(SSolvent control-
SNegative control) * 100, IC50By 5 software of GraphPad Prism, four parametric method the Fitting Calculation.(S:SignalEx./Em)
As a result:
1 embodiment compound of table is to PD-1/PD-L1 combination inhibiting effect
Compound | IC50(μM) |
1 | 0.37 |
3 | 2.62 |
4 | 0.37 |
36 | 0.10 |
37 | 0.24 |
38 | 0.36 |
39 | 0.11 |
As can be seen from Table 1, the compound of the present invention, which combines PD-1/PD-L1, shows different inhibitory activity effects,
Wherein 1,4,36,37,38,39 inhibitory activity of compound is stronger.Therefore, the compound of the present invention can be used as effective PD-1/
PD-L1 binding inhibitors.
Claims (15)
1. a kind of formula (I) compound represented or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorphic
Object, solvate, metabolin or prodrug or their mixture:
RespectivelyIt is each independently selected from singly-bound or double bond, and is not simultaneously double bond;
Ring G, ring J are each independently selected from C6-10Aryl and 5-14 unit's heteroaryl;
R1Selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl, C3-10Ring
Alkyl, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base ,-ORa、-SRa、-C(O)Ra、-C(O)ORa、-C(O)NRaRa、-OC(O)Ra、-
NRaRaWith-NRaC(O)Ra;Work as RaWhen being multiple, each RaIt is identical or different;Optionally, the C1-6Alkyl, C2-6Alkenyl, C2-6Alkynes
Base, C6-10Aryl, C3-10Naphthenic base, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base are by one or more RbReplace;Work as RbIt is multiple
When, each RbIt is identical or different;
The RaIt is each independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C6-10Virtue
Base, C3-10Naphthenic base, 5-14 unit's heteroaryl and 4-10 circle heterocyclic ring base;
The RbIt is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, carboxyl, C1-6Alkyl, C1-6Alkoxy, C1-6
Halogenated alkyl, C1-6Halogenated alkoxy, C2-6Alkenyl, C2-6Alkynyl;
A is selected from CRh、CRhRh、N、NRi, O, S, C=O, C=S, S=O andWork as RhWhen being multiple, each RhIt can be identical or not
Together;
B is selected from CRj、CRjRj、N、NRk, O, S, C=O, C=S, S=O andWork as RjWhen being multiple, each RjIt can be identical or not
Together;
D is selected from C, CRmAnd N;
E is selected from CRnRn、NRo, O, S, C=O, C=S, S=O andWork as RnWhen being multiple, each RnIt can be identical or different;
Rh、Ri、Rj、Rk、Rm、Rn、RoIt is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-6Alkyl, C1-6Alkane
Oxygroup, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, phenyl, 5-6 unit's heteroaryl, 4-6 circle heterocyclic ring base and C3-6Naphthenic base;
R2Selected from-(C1-6Alkyl)-NRpRp、-(C1-6Alkyl)-(5-14 unit's heteroaryl) ,-(C1-6Alkyl)-(4-10 circle heterocyclic ring
Base) ,-O- (C1-6Alkyl)-(5-14 unit's heteroaryl) ,-O- (C1-6Alkyl)-(4-10 circle heterocyclic ring base) ,-O- (C1-6Alkyl)-
NRpRp、-O-(C1-6Alkyl)-C (O) NRpRp、-O-(C1-6Alkyl)-OC (O) NRpRp、-SRp、-C(O)Rp、-C(O)ORp、-OC
(O)Rp、-OC(O)NRpRp、-NRpRp、-NRpC(O)Rp、-NRpC(O)ORp、-NRpC(O)NRpRp,-C (=NRp)NRpRp、-NRpC
(=NRp)NRpRp、-NRpS(O)Rp、-NRpS(O)2Rp、-NRpS(O)2NRpRp、-S(O)Rp、-S(O)NRpRp、-S(O)2Rp, with
And-S (O)2NRpRp;Work as RpWhen being multiple, each RpIt is identical or different;And R2It is not carboxyl;Optionally, described-(C1-6Alkyl)-
(5-14 unit's heteroaryl) ,-(C1-6Alkyl)-(4-10 circle heterocyclic ring base) ,-O- (C1-6Alkyl)-(5-14 unit's heteroaryl) ,-O- (C1-6
Alkyl)-(4-10 circle heterocyclic ring base) by one or more RqReplace;Work as RqWhen being multiple, each RqIt is identical or different;
The Rp、RqIt is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynes
Base, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C6-10Aryl, C3-10Naphthenic base, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base ,-
(C1-6Alkyl)-(C6-10Aryl) ,-(C1-6Alkyl)-(C3-10Naphthenic base) ,-(C1-6Alkyl)-(5-14 unit's heteroaryl) ,-(C1-6Alkane
Base)-(4-10 circle heterocyclic ring base) ,-ORr、-SRr、-C(O)Rr、-C(O)ORr、-OC(O)Rr、-OC(O)NRrRr、-NRrRr、-NRrC
(O)Rr、-NRrC(O)ORr、-NRrC(O)NRrRr,-C (=NRr)NRrRr、-NRrC (=NRr)NRrRr、-NRrS(O)Rr、-NRrS
(O)2Rr、-NRrS(O)2NRrRr、-S(O)Rr、-S(O)NRrRr、-S(O)2RrAnd-S (O)2NRrRr;Work as RrWhen being multiple, respectively
RrIt is identical or different;Optionally, the C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C6-10
Aryl, C3-10Naphthenic base, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base are optionally by one or more RsReplace;Work as RsWhen being multiple,
Each RsIt is identical or different;
The Rr、RsIt is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynes
Base, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C6-10Aryl, C3-10Naphthenic base, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base ,-
(C1-6Alkyl)-(C6-10Aryl) ,-(C1-6Alkyl)-(C3-10Naphthenic base) ,-(C1-6Alkyl)-(5-14 unit's heteroaryl) ,-(C1-6Alkane
Base)-(4-10 circle heterocyclic ring base) ,-ORt、-SRt、-C(O)Rt、-C(O)ORt、-OC(O)Rt、-OC(O)NRtRt、-NRtRt、-NRtC
(O)Rt、-NRtC(O)ORt、-NRtC(O)NRtRt,-C (=NRt)NRtRt、-NRtC (=NRt)NRtRt、-NRtS(O)Rt、-NRtS
(O)2Rt、-NRtS(O)2NRtRt、-S(O)Rt、-S(O)NRtRt、-S(O)2RtAnd-S (O)2NRtRt;Work as RtWhen being multiple, respectively
RtIt is identical or different;Optionally, the C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C6-10
Aryl, C3-10Naphthenic base, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base are optionally by one or more RuReplace;Work as RuWhen being multiple,
Each RuIt is identical or different;
The Rt、RuIt is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, carboxyl, C1-6Alkyl, C2-6Alkenyl,
C2-6Alkynyl, phenyl, 5-6 unit's heteroaryl, 4-6 circle heterocyclic ring base and C3-6Naphthenic base;Optionally, the C1-6Alkyl, C2-6Alkenyl,
C2-6Alkynyl, phenyl, 5-6 unit's heteroaryl, 4-6 circle heterocyclic ring base, C3-6Naphthenic base by one or more selected from halogen, hydroxyl, cyano,
Nitro, amino, carboxyl, C1-6The substituent group of alkyl replaces;
R3Selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl, C3-10Ring
Alkyl, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base ,-ORv、-SRv、-C(O)Rv、-C(O)ORv、-C(O)NRvRv、-OC(O)Rv、-
NRvRvWith-NRvC(O)Rv;Work as RvWhen being multiple, each RvIt is identical or different;Optionally, the C1-6Alkyl, C2-6Alkenyl, C2-6Alkynes
Base, C6-10Aryl, C3-10Naphthenic base, 5-14 unit's heteroaryl, 4-10 circle heterocyclic ring base are by one or more RwReplace;Work as RwIt is multiple
When, each RwIt is identical or different;
The RvIt is each independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C6-10Virtue
Base, C3-10Naphthenic base, 5-14 unit's heteroaryl and 4-10 circle heterocyclic ring base;
The RwIt is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, carboxyl, C1-6Alkyl, C1-6Alkoxy, C1-6
Halogenated alkyl, C1-6Halogenated alkoxy, C2-6Alkenyl and C2-6Alkynyl;
R4Selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-6Alkyl, C1-6Alkoxy, phenyl, 5-6 unit's heteroaryl, 4-6 member
Heterocycle, C3-6Naphthenic base ,-NRyRy、-SRy、-C(O)Ry、-C(O)ORy、-C(O)NRyRy、-OC(O)RyWith-NRyC(O)Ry;When
RyWhen being multiple, each RyIt is identical or different;Optionally, the C1-6Alkyl, C1-6Alkoxy, phenyl, 5-6 unit's heteroaryl, 4-6 member
Heterocycle, C3-6Naphthenic base is by one or more RzReplace;Work as RzWhen being multiple, each RzIt is identical or different;
The Ry、RzIt is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, carboxyl, C1-6Alkyl, C2-6Alkenyl,
C2-6Alkynyl, phenyl, 5-6 unit's heteroaryl, 4-6 circle heterocyclic ring base and C3-6Naphthenic base;
R is selected from 1,2 and 3;When r is greater than 1, each R1It is identical or different;
T is selected from 1,2 and 3;When t is greater than 1, each R2It is identical or different;
I is selected from 1,2 and 3;When i is greater than 1, each R3It is identical or different;
M is selected from 1,2 and 3;When m is greater than 1, each R4It is identical or different;
N is selected from 1 and 2;When n is 2, each B is identical or different.
2. compound according to claim 1 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, more
Crystal form object, solvate, metabolin or prodrug or their mixture, structure is as shown in logical formula (II):
Wherein:
RespectivelyIt is each independently selected from singly-bound or double bond, and is not simultaneously double bond;
X1、X2、X3It is each independently selected from C, CH or N;
Ring G, A, B, D, E, R1、R2、R3、R4, m, n, r, t, i it is as defined in claim 1.
3. compound according to claim 1 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, more
Crystal form object, solvate, metabolin or prodrug or their mixture, structure is as shown in logical formula (III):
Wherein:
RespectivelyIt is each independently selected from singly-bound or double bond, and is not simultaneously double bond;
X1、X2、X3It is each independently selected from C, CH or N;
Ring G, A, B, D, E, R1、R2、R3、R4It is defined with any one of n such as claim 1-2.
4. according to claim 1 compound described in any one of -3 or its pharmaceutically acceptable salt, ester, stereoisomer,
Tautomer, polymorph, solvate, metabolin or prodrug or their mixture, in which:
Rh、Ri、Rj、Rk、Rm、Rn、RoIt is each independently selected from hydrogen, fluorine, chlorine, hydroxyl, cyano, nitro, amino, C1-6Alkyl, C1-6Halogen
Substituted alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy.
5. according to claim 1 compound described in any one of -4 or its pharmaceutically acceptable salt, ester, stereoisomer,
Tautomer, polymorph, solvate, metabolin or prodrug or their mixture, whereinPortion
It is selected from following structure fragment:
6. according to claim 1 compound described in any one of -5 or its pharmaceutically acceptable salt, ester, stereoisomer,
Tautomer, polymorph, solvate, metabolin or prodrug or their mixture, wherein R2Selected from-(C1-6Alkane
Base)-NRpRp、-(C1-6Alkyl)-(5-14 unit's heteroaryl) ,-(C1-6Alkyl)-(4-10 circle heterocyclic ring base) ,-O- (C1-6Alkyl)-(5-
14 unit's heteroaryls) ,-O- (C1-6Alkyl)-(4-10 circle heterocyclic ring base) ,-O-C1-6Alkyl-NRpRp、-O-C1-6Alkyl-C (O) NRpRp;
RpAs defined in claim 1.
7. compound according to claim 1 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, more
Crystal form object, solvate, metabolin or prodrug or their mixture, structure is as shown in general formula IV:
Wherein, respectivelyIt is each independently selected from singly-bound or double bond, and is not simultaneously double bond;
R1、R3、R4It is each independently selected from hydrogen, fluorine, chlorine, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alkoxy;
R2Selected from-C1-6Alkyl-NRpRp;Each RpIt can be identical or different;
RpIt is each independently selected from hydrogen and C1-6Alkyl;Optionally, the C1-6Alkyl by one or more selected from fluorine, chlorine, hydroxyl,
The substituent group substitution of alkoxy, carboxyl, ester group, amino, nitro and cyano;
X1Selected from C, CH and N;
A, any one of B, D, E, n such as claim 1-6 are defined.
8. compound according to claim 1-7 or its pharmaceutically acceptable salt, ester, stereoisomer, interconversion
Isomers, polymorph, solvate, metabolin or prodrug or their mixture, wherein
RespectivelyIt is each independently selected from singly-bound or double bond, and is not simultaneously double bond;
A is selected from CRh、CRhRh、N、NRi, O, S, C=O, C=S, S=O andWork as RhWhen being multiple, each RhIt can be identical or not
Together;
B is selected from CRj、CRjRj、N、NRk, C=O and C=S;Work as RjWhen being multiple, each RjIt can be identical or different;
D is selected from C, CRmAnd N;
E is selected from NRo, O, S, C=O, C=S, S=O and
Rh、Ri、Rj、Rk、Rm、RoIt is each independently selected from hydrogen, fluorine, chlorine, hydroxyl, cyano, nitro, amino, C1-6Alkyl, C1-6It is halogenated
Alkyl, C1-6Alkoxy and C1-6Halogenated alkoxy.
R1、R3、R4It is each independently selected from hydrogen, fluorine, chlorine, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alkoxy;
R2It is selected from
9. compound according to claim 1-8 or its pharmaceutically acceptable salt, ester, stereoisomer, interconversion
Isomers, polymorph, solvate, metabolin or prodrug or their mixture, wherein
It is singly-bound;
A is selected from CRhRh, B is selected from CRjRj, D is selected from CRmAnd N, Rh、RjAnd RmIt is hydrogen, E is selected from O and C=O;N is 1.
10. compound according to claim 1 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer,
Polymorph, solvate, metabolin or prodrug or their mixture, wherein the compound is selected from:
11. a kind of pharmaceutical composition, described pharmaceutical composition contains -10 any one according to claim 1 of therapeutically effective amount
The compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, generation
Thank object or prodrug or their mixture and pharmaceutically acceptable carrier.
The preparation method of formula described in a kind of claim 1 12. (I) compound represented, which comprises the following steps:
In the step, general formula (I-c) compound reacts to obtain logical formula (I) compound with alkaline reagent, whereinRing G, ring
J、A、B、D、E、R1、R2、R3、R4, m, n, r, t, i it is as defined in claim 1.
13. kit product, it includes compound of any of claims 1-10 or its pharmaceutically acceptable salt, ester,
Stereoisomer, tautomer, polymorph, solvate, metabolin or prodrug or their mixture, Huo Zhequan
Benefit require 10 pharmaceutical composition and optional package insert.
14. compound of any of claims 1-10 or its pharmaceutically acceptable salt, ester, stereoisomer, interconversion
Medicine group described in isomers, polymorph, solvate, metabolin or prodrug or their mixture, claim 11
Kit product described in object or claim 13 is closed to use in preparation treatment and/or prevention with PD-1/PD-L1 pathway dependent diseases
On the way.
15. purposes according to claim 14, wherein the disease is cancer or disease of viral infection;
The cancer is preferably lung cancer, cutaneum carcinoma, melanoma, the cancer of the esophagus, bladder cancer, head-neck carcinoma, nasopharyngeal carcinoma, bronchus
Cancer, breast cancer, cervical carcinoma, cancer of pancreas, liver cancer, gastric cancer, cholangiocarcinoma, prostate cancer, brain tumor, colon cancer or above-mentioned solid tumor are cut
Cancer residual after removing;
The virus is preferably inhibition of HIV, hepatitis A virus, hepatitis B, hepatitis C virus, fourth hepatovirus, herpesviral, human milk head
Tumor virus and influenza virus.
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