CN109665968B - Fused ring compound, preparation method and application thereof - Google Patents

Fused ring compound, preparation method and application thereof Download PDF

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CN109665968B
CN109665968B CN201811143915.2A CN201811143915A CN109665968B CN 109665968 B CN109665968 B CN 109665968B CN 201811143915 A CN201811143915 A CN 201811143915A CN 109665968 B CN109665968 B CN 109665968B
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cancer
compound
pharmaceutically acceptable
stereoisomer
acceptable salt
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CN109665968A (en
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蔡家强
刘金明
王利春
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Abstract

The invention relates to a fused ring compound or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture of the compounds, a pharmaceutical composition and a kit product containing the same, a preparation method thereof and application thereof in preparing medicines for preventing or treating diseases related to PD-1/PD-L1.

Description

Fused ring compound, preparation method and application thereof
Technical Field
The application relates to the field of immunotherapy, in particular to a fused cyclic compound capable of inhibiting PD-1/PD-L1 interaction, a pharmaceutical composition containing the compound and a kit product. The application also relates to a preparation method of the compound and application of the compound in preparing a medicament for preventing and/or treating diseases related to the PD-1/PD-L1 pathway.
Background
Malignant tumors, one of the major public health problems worldwide, greatly endanger the health of human beings and affect the normal productive life of human beings. In the fight against malignant tumors, there are mainly a variety of therapeutic approaches such as surgery, chemotherapy, radiotherapy, endocrine therapy, targeted therapy, etc., and unlike these approaches, tumor immunotherapy is intended to activate the body's own immune system to kill tumor cells and tissues. There are a variety of therapeutic strategies for tumor immunotherapy, including non-specific immunostimulants, tumor vaccines, adoptive immune cell therapies, monoclonal antibody therapies, and immune checkpoint inhibitors, which have been shown clinically to be highly potent and low toxic, and are even more attractive (p.j.medina, v.r.adams, Pharmacotherapy 2016,36, 317-.
PD-1 (programmed death receptor-1, CD279) is a receptor on T cells that has been shown to inhibit signal activation from T cell receptors when bound to its ligand PD-L1 (programmed death receptor-ligand 1, CD274, B7-H1) or PD-L2(CD273, B7-DC). When a PD-1 expressing T cell is contacted with a cell expressing its ligand, the functional activities in response to antigen stimulation, including proliferation, cytokine secretion and cytotoxicity are diminished. The interaction of PD-1 and its ligands PD-L1, PD-L2 down-regulates the immune response during infection or tumor regression or during development of self-tolerance (Keir Me, button MJ, Lreeman GJ, et al, annu. rev. immunol. 2008; 26: 677). Chronic antigen stimulation during tumor diseases or chronic infections leads to increased PD-1 expression levels in T cells and dysfunction of activity against long-term antigens (kimps, Ahmed R, curr. opin. immunol.,2010,22,223-230), which is called "T cell depletion".
The PD-1/PD-L1 pathway is a key inhibitory molecule in T cell depletion caused by chronic antigen stimulation during chronic infections and neoplastic diseases. Blocking the PD-1/PD-L1 interaction by targeting PD-1 proteins has been shown to restore antigen-specific T cell immune function in vitro and in vivo, including enhancing response to vaccination in tumor or chronic infection. Therefore, drugs that block the interaction of PD-L1 with PD-1 are feasible.
At present, a plurality of famous pharmaceutical companies at home and abroad are competitively put into the development of the PD-1/PD-L1 inhibitor, but the main research direction is mainly monoclonal antibodies. The PD-1/PD-L1 inhibitors which are currently researched or marketed are biological preparations, and have inherent preparation defects, such as that monoclonal drugs need to be injected subcutaneously, and the bodies can be induced to generate drug-resistant antibodies, so that the curative effect of the drugs is reduced and side effects are increased. The preparation and purification process of the monoclonal antibody medicament is complex, the price is high, the use is inconvenient, and the compliance of patients is higher. Therefore, there is a need for drug developers to develop a convenient to use, orally effective small molecule PD-1/PD-L1 inhibitor to meet the clinical needs of patients.
Applicants have discovered effective compounds with inhibitory activity as the interaction of PD-L1 with PD-1, which are better druggable and useful for therapeutic administration to enhance immunity to cancer or chronic infections.
Disclosure of Invention
The present application provides safe and effective inhibitors of PD-L1 interaction with PD-1 having a novel structure. The inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or a mixture of the compounds:
Figure BDA0001816389430000031
each one of
Figure BDA0001816389430000032
Each independently selected from single bonds or double bonds, and not both;
ring G and ring J are each independently selected from C6-10Aryl and 5-14 membered heteroaryl;
R1selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C6-10Aryl radical, C3-10Cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, -ORa、-SRa、-C(O)Ra、-C(O)ORa、-C(O)NRaRa、-OC(O)Ra、-NRaRaand-NRaC(O)Ra(ii) a When R isaWhen there are plural, each RaMay be the same or different; optionally, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C6-10Aryl radical, C3-10Cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl is substituted with one or more RbSubstitution; when R isbWhen there are plural, each RbMay be the same or different;
the R isaEach independently selected from hydrogen and C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, C6-10Aryl radical, C3-10Cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocyclyl;
the R isbEach independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, carboxyl, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, C2-6Alkenyl and C2-6An alkynyl group;
a is selected from CRh、CRhRh、N、NRiO, S, C-O, C-S, S-O and
Figure BDA0001816389430000033
when R ishWhen there are plural, each RhMay be the same or different;
b is selected from CRj、CRjRj、N、NRkO, S, C-O, C-S, S-O and
Figure BDA0001816389430000034
when R isjWhen there are plural, each RjMay be the same or different;
d is selected from C, CRmAnd N;
e is selected from CRnRn、NRoO, S, C-O, C-S, S-O and
Figure BDA0001816389430000035
when R isnWhen there are plural, each RnMay be the same or different;
Rh、Ri、Rj、Rk、Rm、Rn、Roeach independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and C3-6A cycloalkyl group;
R2is selected from- (C)1-6Alkyl) -NRpRp、-(C1-6Alkyl) - (5-14 membered heteroaryl), - (C)1-6Alkyl) - (4-to 10-membered heterocyclyl), -O- (C)1-6Alkyl) - (5-14 membered heteroaryl), -O- (C)1-6Alkyl) - (4-to 10-membered heterocyclyl), -O- (C)1-6Alkyl) -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)2Rpand-S (O)2NRpRp(ii) a When R ispWhen there are plural, each RpMay be the same or different; and R is2Is not a carboxyl group; optionally, the- (C)1-6Alkyl) - (5-14 membered heteroaryl), - (C)1-6Alkyl) - (4-to 10-membered heterocyclyl), -O- (C)1-6Alkyl) - (5-14 membered heteroaryl), -O- (C)1-6Alkyl) - (4-10 membered heterocyclyl) with one or more RqSubstitution; when R isqWhen there are plural, each RqMay be the same or different;
the R isp、RqEach independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Haloalkoxy, C6-10Aryl radical, C3-10Cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, - (C)1-6Alkyl group) - (C6-10Aryl), - (C)1-6Alkyl group) - (C3-10Cycloalkyl), - (C)1-6Alkyl) - (5-14 membered heteroaryl), - (C)1-6Alkyl) - (4-10 membered heterocyclyl), -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(ii) a When R isrWhen there are plural, each RrMay be the same or differentDifferent; optionally, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Haloalkoxy, C6-10Aryl radical, C3-10Cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl is optionally substituted with one or more RsSubstitution; when R issWhen there are plural, each RsMay be the same or different;
the R isr、RsEach independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Haloalkoxy, C6-10Aryl radical, C3-10Cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, - (C)1-6Alkyl group) - (C6-10Aryl), - (C)1-6Alkyl group) - (C3-10Cycloalkyl), - (C)1-6Alkyl) - (5-14 membered heteroaryl), - (C)1-6Alkyl) - (4-10 membered heterocyclyl), -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(ii) a When R istWhen there are plural, each RtMay be the same or different; optionally, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Haloalkoxy, C6-10Aryl radical, C3-10Cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl is optionally substituted with one or more RuSubstitution; when R isuWhen there are plural, each RuCan be combined withAnd may be different;
the R ist、RuEach independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, carboxyl, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and C3-6A cycloalkyl group; optionally, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6Cycloalkyl is substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amino, carboxy, C1-6Alkyl substituent substitution;
R3selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C6-10Aryl radical, C3-10Cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, -ORv、-SRv、-C(O)Rv、-C(O)ORv、-C(O)NRvRv、-OC(O)Rv、-NRvRvand-NRvC(O)Rv(ii) a When R isvWhen there are plural, each RvMay be the same or different; optionally, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C6-10Aryl radical, C3-10Cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl is substituted with one or more RwSubstitution; when R iswWhen there are plural, each RwMay be the same or different;
the R isvEach independently selected from hydrogen and C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, C6-10Aryl radical, C3-10Cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocyclyl;
the R iswEach independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, carboxyl, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, C2-6Alkenyl and C2-6An alkynyl group;
R4selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-6Alkyl radical, C1-6Alkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6Cycloalkyl, -NRyRy、-SRy、-C(O)Ry、-C(O)ORy、-C(O)NRyRy、-OC(O)Ryand-NRyC(O)Ry(ii) a When R isyWhen there are plural, each RyMay be the same or different; optionally, said C1-6Alkyl radical, C1-6Alkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6Cycloalkyl radicals substituted by one or more RzSubstitution; when R iszWhen there are plural, each RzMay be the same or different;
the R isy、RzEach independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, carboxyl, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and C3-6A cycloalkyl group;
r is selected from 1,2 and 3; when R is greater than 1, each R1May be the same or different;
t is selected from 1,2 and 3; when t is greater than 1, each R2May be the same or different;
i is selected from 1,2 and 3; when i is greater than 1, each R3May be the same or different;
m is selected from 1,2 and 3; when m is greater than 1, each R4May be the same or different;
n is selected from 1 and 2; when n is 2, each B may be the same or different.
Experiments show that the compound shown in the general formula (I) has high PD-1/PD-L1 binding inhibition activity.
The present application provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, and one or more pharmaceutically acceptable carriers.
The present application provides a kit product comprising the compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, or the pharmaceutical composition, and optionally, a package insert.
The present application provides the compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, or the pharmaceutical composition for preventing or treating a disease associated with the PD-1/PD-L1 pathway.
The application provides application of the compound or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture of the compound and the prodrug or the pharmaceutical composition in preparing medicines for preventing or treating diseases related to the PD-1/PD-L1 pathway.
The present application provides a method of preventing or treating a disease associated with the PD-1/PD-L1 pathway comprising administering a prophylactically or therapeutically effective amount of the compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, or the pharmaceutical composition, and one or more other therapeutic agents.
In particular, the present application provides a compound of formula (II), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, or prodrug thereof, or a mixture thereof:
Figure BDA0001816389430000071
wherein:
each one of
Figure BDA0001816389430000072
Each independently selected fromA bond or a double bond, and not both;
X1、X2、X3each independently selected from C, CH or N;
ring G, A, B, D, E, R1、R2、R3、R4M, n, r, t, I are as defined in formula (I).
In particular, the present application provides a compound of formula (III), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, or prodrug thereof, or a mixture thereof:
Figure BDA0001816389430000081
wherein:
each one of
Figure BDA0001816389430000082
Each independently selected from single bonds or double bonds, and not both;
X1、X2、X3each independently selected from C, CH or N;
ring G, A, B, D, E, R1、R2、R3、R4And n is as defined in formula (I).
In particular, the present application provides a compound of formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, or prodrug thereof, or a mixture thereof, having the structure shown in formula IV:
Figure BDA0001816389430000083
wherein the content of the first and second substances,
each one of
Figure BDA0001816389430000084
Each independently selected from single bonds or double bonds, and not both; r1、R3、R4Each independently selected from hydrogen, fluorine, chlorine, C1-6Alkyl radical, C1-6Haloalkyl and C1-6An alkoxy group;
R2is selected from-C1-6alkyl-NRpRp(ii) a Each RpMay be the same or different;
Rpeach independently selected from hydrogen and C1-6An alkyl group; optionally, said C1-6Alkyl is optionally substituted with one or more substituents selected from fluoro, chloro, hydroxy, alkoxy, carboxy, ester, amino, nitro, and cyano;
X1selected from C, CH and N;
A. b, D, E, n is as defined in any one of formulae (I) to (III).
In particular, the present application provides a compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, or prodrug thereof, or a mixture thereof, wherein:
Rh、Ri、Rj、Rk、Rm、Rn、Roeach independently selected from hydrogen, fluorine, chlorine, hydroxyl, cyano, nitro, amino, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy and C1-6A haloalkoxy group.
In particular, the present application provides compounds of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, or prodrug thereof, or a mixture thereof, wherein,
Figure BDA0001816389430000091
moieties are selected from the following structural fragments:
Figure BDA0001816389430000092
Figure BDA0001816389430000101
in particular, the present application provides compounds of formula (I) through formula (III), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, or prodrug thereof, or a mixture thereof, wherein R is2Is selected from- (C)1-6Alkyl) -NRpRp、-(C1-6Alkyl) - (5-14 membered heteroaryl), - (C)1-6Alkyl) - (4-to 10-membered heterocyclyl), -O- (C)1-6Alkyl) - (5-14 membered heteroaryl), -O- (C)1-6Alkyl) - (4-10 membered heterocyclyl), -O-C1-6alkyl-NRpRp、-O-C1-6alkyl-C (O) NRpRp；RpAs defined in formula (I).
In certain embodiments, R2Is selected from- (C)1-6Alkyl) -NRpRp，RpEach independently selected from hydrogen and C1-6An alkyl group; optionally, said C1-6The alkyl group is substituted with one or more substituents selected from the group consisting of fluorine, chlorine, hydroxyl, alkoxy, carboxyl, ester, amino, nitro and cyano.
In particular, the present application provides compounds of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, or prodrug thereof, or a mixture thereof, wherein,
each one of
Figure BDA0001816389430000102
Each independently selected from single bonds or double bonds, and not both;
a is selected from CRh、CRhRh、N、NRiO, S, C-O, C-S, S-O and
Figure BDA0001816389430000103
when R ishWhen there are plural, each RhMay be the same or different;
b is selected from CRj、CRjRj、N、NRkC ═ O and C ═ S; when R isjWhen there are plural, each RjMay be the same or different;
d is selected from C, CRmAnd N;
e is selected from NRoO, S, C-O, C-S, S-O and
Figure BDA0001816389430000111
Rh、Ri、Rj、Rk、Rm、Roeach independently selected from hydrogen, fluorine, chlorine, hydroxyl, cyano, nitro, amino, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy and C1-6A haloalkoxy group.
In particular, the present application provides compounds of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, or prodrug thereof, or a mixture thereof, wherein,
a is selected from CRhRhB is selected from CRjRjD is selected from CRmAnd N, Rh、RjAnd RmAre both hydrogen, E is selected from O and C ═ O; n is 1;
in certain preferred embodiments, R2Is selected from
Figure BDA0001816389430000112
Figure BDA0001816389430000113
In certain preferred embodiments of the present invention,
Figure BDA0001816389430000114
are all single bonds.
According to some embodiments of the present application, the compound is selected from the following structures, without limitation:
Figure BDA0001816389430000115
Figure BDA0001816389430000121
Figure BDA0001816389430000131
Figure BDA0001816389430000141
preparation method
It is a further object of the present application to provide a process for preparing said compound, said process comprising the steps of:
Figure BDA0001816389430000142
in the above step, the compound of the general formula (I-c) is reacted with an alkaline reagent to obtain a compound of the general formula (I), wherein,
Figure BDA0001816389430000143
ring G, ring J, A, B, D, E, R1、R2、R3、R4M, n, r, t, I are as defined in formula (I).
In some embodiments, the intermediates (I-c) are carried out according to the following scheme 1:
reaction scheme 1
Figure BDA0001816389430000151
Wherein the content of the first and second substances,
Figure BDA0001816389430000152
ring G, ring J, A, B, D, E, R1、R3、R4M, n, r, t, I are as defined for formula (I), LG is a leaving group.
In certain embodiments, the first step is carried out in a protic solvent in the presence of an organic or inorganic base;
the second step is carried out under alkaline conditions at a temperature of from 10 to 60 deg.C (e.g. from 20 to 50 deg.C, such as 25 + -2 deg.C).
In some embodiments, the intermediates (I-c) are carried out according to scheme 2 below:
reaction scheme 2
Figure BDA0001816389430000153
Wherein the content of the first and second substances,
Figure BDA0001816389430000154
ring G, ring J, A, B, D, E, R1、R3、R4M, n, r, t, I are as defined for formula (I), X is halogen.
In certain embodiments, the first step is carried out in the presence of an organic or inorganic base;
the second step is carried out at a temperature of from 20 to 100 deg.C (e.g., from 30 to 80 deg.C, such as 60 + -2 deg.C).
In a preferred embodiment, the above reaction is carried out under an inert gas blanket.
In preferred embodiments, protic solvents that may be used in the methods of making the compounds include, but are not limited to, water, methanol, ethanol, acetic acid, and the like.
In preferred embodiments, organic bases that may be used in the compound preparation methods include, but are not limited to, sodium tert-butoxide, triethylamine, DIPEA, pyridine or DMAP; inorganic bases that may be used in the compound preparation process include, but are not limited to, sodium hydride, sodium hydroxide, sodium carbonate, or potassium carbonate.
Definition of
Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art.
"alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, if not particularly limited.
"alkenyl" means an aliphatic hydrocarbon group containing one carbon-carbon double bond and may be straight or branched. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. Unless otherwise specified, the alkenyl group may be substituted or unsubstituted.
"alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, and can be straight or branched. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Unless otherwise specified, the alkynyl group may be substituted or unsubstituted.
"cycloalkyl" means a monocyclic or polycyclic hydrocarbon group containing saturated or partially unsaturated groups. Examples of "monocycloalkyl" include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl. "Polycycloalkyl" includes "bridged cyclic group", "fused cyclic group" and "spirocyclic group", where "bridged cyclic group" means a monocyclic group in which any two non-adjacent carbon atoms are linked by an alkylene group. Representative examples of bicyclic bridged ring groups include, but are not limited to: bornyl, bicyclo [2.2.1] heptenyl, bicyclo [3.1.1] heptenyl, bicyclo [2.2.1] heptenyl, bicyclo [2.2.2] octanyl, bicyclo [3.2.2] nonanyl, bicyclo [3.3.1] nonanyl, bicyclo [4.2.1] nonanyl, and the like. "fused cycloalkyl" includes cycloalkyl fused to phenyl, monocycloalkyl, monocyclic heterocyclyl or monocyclic heteroaryl, and cycloalkyl includes, but is not limited to: benzocyclobutene, benzocyclobutane, benzocyclohexane, benzocycloheptane, pyridocyclobutane, pyridocyclopentane, pyridocyclohexane, 2, 3-dihydro-1-H-indene, 2, 3-cyclopentenopyridine, 5, 6-dihydro-4H-cyclopentyl [ B ] thiophene, decahydronaphthalene and the like. "spirocycloalkyl" refers to a bicyclic group formed by two cycloalkyl groups sharing a common carbon atom. The cycloalkyl group may be fused to an aryl group, a heteroaryl group or a heterocyclic group, and may be substituted or unsubstituted, if not particularly limited.
"Heterocyclyl" refers to non-aromatic heterocyclic groups in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, nitrogen, sulfur, and the like, including monocyclic, fused, bridged, and spiro rings, i.e., including monocyclic heterocyclic groups, bridged heterocyclic groups, fused heterocyclic groups, and spiro heterocyclic groups. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, thiomorpholinyl, tetrahydropyranyl, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, and piperazinyl. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, and the heterocyclyl group may be substituted or unsubstituted.
"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes aromatic groups such as phenyl, naphthyl. The "aryl" may be fused with heteroaryl, heterocyclyl or cycloalkyl. The aryl group may be substituted or unsubstituted, if not particularly limited.
"heteroaryl" refers to an aromatic system comprising 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, and benzisoxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring. Unless otherwise specified, the heteroaryl group may be substituted or unsubstituted.
"alkoxy" refers to a radical of (alkyl-O-). Wherein alkyl is as defined herein. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"hydroxy" refers to an-OH group.
"halo" or "halogen" groups are meant to include F, Cl, Br or I.
"amino" means-NH2。
"cyano" means-CN.
"nitro" means-NO2。
"carboxy" refers to-C (O) OH.
"ester group" means-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"optionally" means that the group is substituted or unsubstituted.
If a substituent is described as "independently selected," each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.
As used herein, the term "one or more" means 1 or more than 1, such as 2,3, 4, 5 or 10, under reasonable conditions.
"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain their biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds of the present invention may be metal salts, amine salts with suitable acids.
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
By "pharmaceutically acceptable carrier" herein is meant a diluent, adjuvant, excipient, or vehicle that is administered with the therapeutic agent and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
The term "effective amount" as used herein refers to an amount of a compound that, when administered, will alleviate one or more symptoms of the condition being treated to some extent.
The present application also includes all pharmaceutically acceptable isotopic compounds, which are identical to the recited compounds, except that one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds include, but are not limited to, isotopes of hydrogen (e.g. hydrogen)2H、3H) (ii) a Isotopes of carbon (e.g. of11C、13C and14C) (ii) a Isotopes of chlorine (e.g. of chlorine)37Cl); isotopes of fluorine (e.g. of fluorine)18F) (ii) a Isotopes of iodine (e.g. of iodine)123I and125I) (ii) a Isotopes of nitrogen (e.g. of13N and15n); isotopes of oxygen (e.g. of15O、17O and18o); isotopes of phosphorus (e.g. of phosphorus)32P); and isotopes of sulfur (e.g. of35S)。
"stereoisomers" means isomers formed due to at least one asymmetric center. In compounds having one or more (e.g., 1,2,3, or 4) asymmetric centers, they can result in racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds may exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, dihydropyrimidine groups may exist in solution in equilibrium with the following tautomeric forms. It is understood that the scope of this application encompasses all such isomers or mixtures thereof in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
Unless otherwise indicated, the compounds are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof. The compounds may exhibit more than one type of isomerization and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
The present application encompasses all possible crystalline forms or polymorphs of the compounds, which may be single polymorphs or mixtures of more than one polymorph in any ratio.
It will also be appreciated that certain compounds of the present application may be present in free form for use in therapy or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to: a pharmaceutically acceptable salt, ester, solvate, metabolite or prodrug thereof, which upon administration to a patient in need thereof is capable of providing, directly or indirectly, said compound or metabolite or residue thereof. Thus, when reference is made herein to "the compound," it is also intended to encompass the various derivative forms of the compound described above.
The compounds may be present in the form of solvates, preferably hydrates, wherein the compounds comprise a polar solvent as a structural element of the crystal lattice of the compound, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.
Also included within the scope of the present application are metabolites of the compounds, i.e., substances that are formed in vivo upon administration of the compounds. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc. of the administered compound. Accordingly, the invention includes metabolites of the compounds, including compounds made by the method of contacting the compounds with a mammal for a time sufficient to produce a metabolite thereof.
The present invention further includes within its scope prodrugs of said compounds which are certain derivatives of said compounds which may themselves have little or no pharmacological activity which when administered into or onto the body may be converted into said compounds having the desired activity by e.g. hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", volume 14, ACS Symposium Series (T.Higuchi and V.Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press,1987(E.B.Roche editions, American Pharmaceutical Association). Such Prodrugs can be prepared, for example, by substituting the appropriate functional group present in the compound with certain moieties known to those skilled in the art as "pro-moieties" (e.g., "Design of Prodrugs", h.
The invention also encompasses such compounds containing protecting groups. In any process for the preparation of said compounds, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned, thereby forming a chemically protected form of said compounds. This can be achieved by conventional protecting Groups, for example, as described 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,1991, which are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.
Pharmaceutical composition and kit product
Another object of the present application is to provide a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, and one or more pharmaceutically acceptable carriers.
By "pharmaceutically acceptable carrier" herein is meant a diluent, adjuvant, excipient, or vehicle that is administered with the therapeutic agent and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
The pharmaceutical compositions of the present application may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection (e.g. intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.
For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms. Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
The amount or amount of the compound in the pharmaceutical composition may be from about 0.01mg to about 1000mg, suitably 0.1-500 mg.
According to one embodiment of the present application, the pharmaceutical composition may also comprise one or more other therapeutic agents, such as other anti-cancer agents, including but not limited to macromolecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic moieties). Examples of macromolecular forms of anticancer agents are biological molecules, such as naturally or artificially prepared proteins. Small molecule forms of anti-cancer agents, including but not limited to anti-cancer agents, antibiotics, anti-inflammatory agents, and steroids.
It is another object of the present application to provide a process for preparing the pharmaceutical composition, the process comprising combining the compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.
It is another object of the present application to provide a pharmaceutical kit product comprising said compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, or said pharmaceutical composition; and optionally, a package insert.
Methods of treatment and uses
It is another object of the present application to provide the compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, or the pharmaceutical composition for preventing or treating a disease associated with the PD-1/PD-L1 pathway.
Another object of the present application is to provide a use of the compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture of the same, or the pharmaceutical composition for the preparation of a medicament for the prevention or treatment of diseases associated with the PD-1/PD-L1 pathway.
It is another object of the present application to provide a method for preventing or treating a disease associated with the PD-1/PD-L1 pathway, which comprises administering a prophylactically or therapeutically effective amount of the compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, or the pharmaceutical composition.
It is another object of the present application to provide a method for preventing or treating a disease associated with the PD-1/PD-L1 pathway, comprising administering a prophylactically or therapeutically effective amount of the compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, or the pharmaceutical composition, and one or more other therapeutic agents.
According to one embodiment of the present application, the diseases associated with the PD-1/PD-L1 pathway include, but are not limited to, cancer, viral infections, and the like, and associated symptoms or diseases caused by the above diseases. As used herein, the term "cancer" refers to a cell proliferative disease state including, but not limited to, lung cancer, skin cancer, melanoma, esophageal cancer, bladder cancer, head and neck cancer, nasopharyngeal cancer, bronchial cancer, breast cancer, cervical cancer, pancreatic cancer, liver cancer, stomach cancer, cholangiocarcinoma, prostate cancer, brain tumor, colon cancer, or cancer residual following resection of the above-mentioned solid tumors. The term "viral infectious disease" includes, but is not limited to, diseases caused by infection with HIV virus, hepatitis a virus, hepatitis b virus, hepatitis c virus, hepatitis d virus, herpes virus, human papilloma virus, influenza virus.
The term "effective amount" as used herein refers to an amount of a compound that, when administered, will alleviate one or more symptoms of the condition being treated to some extent.
The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition being alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition.
As used herein, unless otherwise specified, the term "treating" or "treatment" means reversing, alleviating, inhibiting the progression of, or preventing such a disorder or condition, or one or more symptoms of such a disorder or condition, to which such term applies.
As used herein, unless otherwise indicated, the term "preventing" means preventing additional symptoms, preventing a potential metabolic trigger of a symptom, inhibiting the disease or disorder, e.g., arresting the occurrence of a disease or disorder.
As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) having a disease (e.g., a disease described herein) or normal individuals. "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
Detailed Description
In order to make the objects and technical solutions of the present invention clearer, the present invention is further illustrated below with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, specific experimental methods not mentioned in the following examples were carried out according to the usual experimental methods.
The abbreviations herein have the following meanings:
Figure BDA0001816389430000241
Figure BDA0001816389430000251
preparation examples:
example 1: preparation of 2- ((3-chloro-4- ((4-phenyl-2, 3-dihydro-1H-indenyl) oxy) benzyl) amino) ethanol (Compound 1)
Figure BDA0001816389430000252
The first step is as follows: preparation of 4-phenyl-1-indanone
Under stirring at room temperature, phenylboronic acid (317mg,2.60mmol), 4-bromo-1-indanone (500mg,2.36mmol), tetrabutylammonium bromide (761mg,2.36mmol) and potassium carbonate (3260mg,23.6mmol) are added to water (50mL), after stirring and dispersing, palladium acetate (54mg,0.24mmol) is added, after nitrogen substitution, stirring is carried out at an external temperature of 60 ℃ until TLC shows that the 4-bromo-1-indanone is completely reacted, the reaction solution is extracted with ethyl acetate (15 mL. times.3), the organic phases are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40 ℃. The residue was purified by silica gel column chromatography to give the title compound of this step (420mg, yield: 85.5%).
The second step is that: preparation of 4-phenyl-2, 3-dihydro-1H-inden-1-ol
4-phenyl-1-indanone (400mg,1.92mmol) was completely dissolved in absolute ethanol (10mL) with stirring at room temperature, and NaBH was slowly added4(73mg,1.92 mmol). The reaction was maintained at room temperature until TLC showed completion of the 4-phenyl-1-indanone reaction, ice water (50mL) was slowly added to the reaction solution to quench the reaction, then dilute hydrochloric acid (20mL,1mol/L) was added, the aqueous phase was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40 ℃ to give the title compound of this step (372mg, yield: 92.1%). Used directly in the next step.
The third step: preparation of 3-chloro-4- ((4-phenyl-2, 3-dihydro-1H-indenyl) oxy) benzaldehyde
To a 50ml flask were added 4-phenyl-2, 3-dihydro-1H-inden-1-ol (300mg,1.43mmol), 3-chloro-4-hydroxybenzaldehyde (230mg,1.43mmol), and triphenylphosphine (450mg,1.72mmol), respectively, with stirring in an ice bath. Anhydrous tetrahydrofuran (15mL) was added under nitrogen and after clarification with stirring, a solution of DIAD (350mg,1.72mmol) in tetrahydrofuran (2mL) was added slowly dropwise. After the dropwise addition, the reaction mixture is turned to room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure at 40 ℃ and the residue was purified by silica gel column chromatography to give the title compound of this step (236mg, yield: 47.3%).
The fourth step: preparation of 2- ((3-chloro-4- ((4-phenyl-2, 3-dihydro-1H-indenyl) oxy) benzyl) amino) ethanol (Compound 1)
To dry DMF (10mL) was added, with stirring at room temperature, 3-chloro-4- ((4-phenyl-2, 3-dihydro-1H-indenyl) oxy) benzaldehyde (210mg,0.60mmol), ethanolamine (110mg,1.8mmol) and the appropriate amount of molecular sieves, respectively. Reacting for 2 hours at the external temperature of 60 ℃ under the protection of nitrogen. After the reaction mixture was cooled to room temperature, NaBH (OAc) was added thereto3(377mg,6.0mmol), glacial acetic acid (360mg,6.0mmol), and the reaction was stirred at room temperature until TLC showed completion of the reaction for 3-chloro-4- ((4-phenyl-2, 3-dihydro-1H-indenyl) oxy) benzaldehyde. Water (60mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40 ℃ to obtain the title compound (82mg, yield: 34.7%) after purification of the residue by preparative thin layer chromatography.
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)。
Example 2: preparation of 2- ((3-chloro-4- ((4-phenyl-2, 3-dihydro-1H-indenyl) oxy) benzyl) amino) propane-1, 3-diol (Compound 39)
Figure BDA0001816389430000271
Using the synthetic route of example 1, the starting material ethanolamine of step 1 was replaced with serinol to give the 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)。
Example 3: preparation of 2- ((3-chloro-4- ((4-phenyl-1H-indazol-1-yl) methyl) benzyl) amino) ethanol (Compound 3)
Figure BDA0001816389430000272
The first step is as follows: preparation of 4-phenyl-1H-indazole
To a 50mL flask were added phenylboronic acid (1g,8.2mmol), 4-bromo-1H-indazole (1.6g,8.2mmol), and potassium carbonate (3.4g,24.6mmol) with stirring at room temperature, followed by addition of 1, 4-dioxane (20mL) and water (5mL), followed by stirring thoroughly, followed by addition of Pd (dppf) Cl2(600mg,0.82mmol), after displacement with nitrogen, stirring at 80 ℃ until TLC showed complete reaction of the starting 4-bromo-1H-indazole, concentrating, adding water (100mL) to the reaction mixture, extracting the aqueous phase with ethyl acetate (20 mL. times.3), combining the organic phases, drying over anhydrous sodium sulfate, and concentrating under reduced pressure at 40 ℃. The residue was purified by silica gel column chromatography to give the title compound of this step (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)。
The second step is that: preparation of 3-chloro-4- ((4-phenyl-1H-indazol-1-yl) methyl) benzaldehyde
After completion of the reaction by TLC, 4-phenyl-1H-indazole (200mg,1.03mmol), 4- (bromomethyl) -3-chlorobenzaldehyde (240mg,1.03mmol), and potassium carbonate (1.42g,10.3mmol) were added to acetonitrile (25mL) in this order under stirring at room temperature, water (100mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 40 ℃. The residue was purified by silica gel column chromatography to give the 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)。
The third step: preparation of 2- ((3-chloro-4- ((4-phenyl-1H-indazol-1-yl) methyl) benzyl) amino) ethanol (Compound 3)
To anhydrous DMF (10mL) was added the compound 3-chloro-4- ((4-phenyl-1H-indazol-1-yl) methyl) benzaldehyde (100mg,0.29mmol), ethanolamine (54mg,0.87mmol) and appropriate amount of molecular sieve, respectively, with stirring at room temperature. Reacting for 2 hours at the external temperature of 60 ℃ under the protection of nitrogen. After the reaction mixture was cooled to room temperature, NaBH (OAc) was added thereto3(610mg,2.9mmol), glacial acetic acid (174mg,2.9mmol), and the reaction was stirred at room temperature until TLC showed complete reaction of the compound 3-chloro-4- ((4-phenyl-1H-indazol-1-yl) methyl) benzaldehyde. Water (60mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40 ℃ to obtain the title compound (63mg, yield: 32.4%) after purification of the residue by preparative thin layer chromatography.
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)；
Example 4: preparation of (5- (((2-hydroxyethyl) amino) methyl) pyridin-2-yl) (4-phenylindolin-1-yl) methanone (Compound 4)
Figure BDA0001816389430000291
The first step is as follows: preparation of 4-phenylindolines
To a 50mL flask, phenylboronic acid (350mg,2.81 m) was added, respectively, with stirring at room temperaturemol), 4-bromoindoline (500mg,2.55mmol), potassium carbonate (710mg,5.10mmol), toluene (15mL) and water (5mL) were added, and after stirring thoroughly, Pd (dppf) Cl was added2(102mg,0.14mmol), after replacement with nitrogen, stirred at 92 ℃ until TLC showed completion of the 4-bromoindoline reaction, water (100mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40 ℃. The residue was purified by silica gel column chromatography to give the title compound of this step (474mg, yield: 86.4%).
MS m/z(ESI):196.2[M+H]+
The second step is that: preparation of 6- (4-phenylindoline-1-carbonyl) -nicotinic acid methyl ester
4-Phenylindoline (300mg,1.53mmol), 5- (methoxycarbonyl) -2-pyridinecarboxylic acid (280mg,1.53mmol), HATU (1170mg,3.06mmol) and DIPEA (1980mg,15.3mmol) were added to tetrahydrofuran (30mL) in this order with stirring at room temperature, the reaction was maintained at room temperature until TLC showed completion of the reaction of 4-phenylindoline, water (100mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40 ℃. The residue was purified by silica gel column chromatography to give the title compound of this step (472mg, yield: 86.1%).
MS m/z(ESI):359.2[M+H]+
The third step: preparation of (5- (hydroxymethyl) pyridin-2-yl) (4-phenylindolin-1-yl) methanone
6- (4-Phenylindoline-1-carbonyl) -nicotinic acid methyl ester (450mg,1.26mmol) and lithium aluminum hydride (24mg,0.63mmol) were added to anhydrous tetrahydrofuran (10mL) in this order with stirring at 0 ℃ and the reaction was maintained at 0 ℃ until TLC showed completion of the reaction of 6- (4-phenylindoline-1-carbonyl) -nicotinic acid methyl ester, and solid sodium sulfate decahydrate (406mg,1.26mmol) was slowly added to the reaction mixture to quench the reaction. After filtration and washing of the filter cake with tetrahydrofuran (10 mL. times.3), the filtrate was concentrated at 40 ℃ under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound of this step (202mg, yield: 48.5%).
MS m/z(ESI):331.2[M+H]+
The fourth step: preparation of 6- (4-phenylindoline-1-carbonyl) -nicotinecarboxaldehyde
(5- (hydroxymethyl) pyridin-2-yl) (4-phenylindolin-1-yl) methanone (200mg,0.61mmol) and DMP (770mg,1.82mmol) were added to dichloromethane (10mL) in this order with stirring at room temperature, and the reaction was maintained under reflux until TLC showed that (5- (hydroxymethyl) pyridin-2-yl) (4-phenylindolin-1-yl) methanone had reacted completely, a saturated sodium bicarbonate solution (50mL) was added to the reaction mixture, the aqueous phase was extracted with dichloromethane (20 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40 ℃. The residue was purified by silica gel column chromatography to give the title compound of this step (178mg, yield: 88.9%).
MS m/z(ESI):329.2[M+H]+
The fifth step: preparation of (5- (((2-hydroxyethyl) amino) methyl) pyridin-2-yl) (4-phenylindolin-1-yl) methanone (Compound 4)
6- (4-Phenylindoline-1-carbonyl) -nicotinecarboxaldehyde (170mg,0.52mmol), ethanolamine (95mg,1.56mmol) and an appropriate amount of molecular sieves were added to anhydrous DMF (10mL) with stirring at room temperature, respectively. Reacting for 2 hours at the external temperature of 60 ℃ under the protection of nitrogen. After the reaction mixture was cooled to room temperature, NaBH (OAc) was added thereto3(327mg,5.2mmol), glacial acetic acid (312mg,5.2mmol), and stirred at room temperature until TLC indicated completion of the 6- (4-phenylindoline-1-carbonyl) -nicotinecarboxaldehyde reaction. Water (60mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40 ℃ to obtain the title compound (63mg, yield: 32.4%) after purification of the residue by preparative thin layer chromatography.
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)。
Example 5: preparation of (S) - (5- (((2, 3-dihydroxypropyl) amino) methyl) pyridin-2-yl) (4-phenylindolin-1-yl) methanone (Compound 36)
Figure BDA0001816389430000311
Using the synthetic route of example 4, the starting ethanolamine for the fifth step was replaced with (S) -3-amino-1, 2-propanediol to give the 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)。
EXAMPLE 6 preparation of 2- ((3-chloro-4- ((4- (2-fluorophenyl) -2, 3-dihydro-1H-indenyl) oxy) benzyl) amino) ethanol (Compound 37)
Figure BDA0001816389430000312
Using the synthetic route of example 1, the starting phenylboronic acid of step 1 was replaced with 2-fluorophenylboronic acid to give the 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)。
EXAMPLE 7 preparation of 2- ((3-chloro-4- ((4-phenyl-2, 3-dihydro-1H-indenyl) oxy) benzyl) amino) -2-methylpropanoic acid (Compound 38)
Figure BDA0001816389430000321
Using the synthetic route of example 1, substituting the starting ethanolamine from step 4 with 2-methylalanine, the title compound was obtained (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 evaluation
Test example 1 Compound binding inhibition Activity screening for PD-1/PD-L1
The screening of the inhibitory activity of the PD-1/PD-L1 inhibitor is carried out by adopting a PD-1/PD-L1 Binding Assay kit of Cisbio company.
Test compounds: compounds of the examples of the present invention;
the kit comprises: PD-1/PD-L1 BINDING ASSAY KITS;
the manufacturer: cisbio;
experimental methods
Compound dilution: test compounds were diluted to different concentrations (nM): 10000, 1000, 100, 10,1.
Compounds and proteins were added to 384 well plates, and diluted compounds (2. mu.L), Tag1-PD-L1 protein (4. mu.L) and Tag2-PD-1 protein (4. mu.L) were added to each well. Centrifuge, seal the well plate, incubate for 15 minutes at room temperature.
Adding an antibody: each well was charged with anti-Tag1-Eu3 and anti-Tag2-XL665 mixed in advance (10. mu.L). Centrifuge, seal the well plate, incubate for 2 hours at room temperature.
And (3) detection: fluorescence, Signal, detected by microplate readerEx./Em.＝665nm/620nm×10000。
Data processing: statistical analysis of data, IR (Inhibition Rate,%) (S)Solvent control-SCompound (I))/(SSolvent control-SNegative control)*100，IC50Calculated by GraphPad Prism 5 software four parameter fit. (S: Signal)Ex./Em)
As a result:
TABLE 1 inhibition of PD-1/PD-L1 binding by the compounds of the examples
Compound (I) 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 compounds of the present invention showed different inhibitory activities on PD-1/PD-L1 combination, wherein the inhibitory activities of compounds 1,4, 36, 37, 38 and 39 were stronger. Therefore, the compound of the invention can be used as a potent PD-1/PD-L1 binding inhibitor.

Claims (13)

1. A compound of formula IV, or a pharmaceutically acceptable salt or stereoisomer thereof:
Figure FDA0003353927440000011
wherein each one
Figure FDA0003353927440000012
Each independently selected from single bonds or double bonds, and not both;
R1、R3and R4Each independently selected from hydrogen, fluorine, chlorine and C1-6An alkyl group;
R2is selected from-C1-6alkyl-NRpRp(ii) a Each RpMay be the same or different;
Rpeach independently selected from hydrogen and C1-6An alkyl group; optionally, said C1-6Alkyl is substituted with one or more substituents selected from the group consisting of hydroxy and carboxy;
X1selected from C, CH and N;
a is selected from CRhAnd CRhRh；
B is selected from CRj、CRjRjN and NRk；
D is selected from C, CRmAnd N;
e is selected from CRnRn、NRoO and C ═ O;
Rh、Rj、Rk、Rm、Rnand RoAre all hydrogen;
n is selected from 1 and 2; when n is 2, each B is the same or different.
2. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof,
each one of
Figure FDA0003353927440000013
Each independently selected from single bonds or double bonds, and not both;
a is selected from CRhAnd CRhRh；
B is selected from CRj、CRjRjAnd N;
d is selected from CRmAnd N;
e is selected from O and C ═ O;
Rh、Rjand RmAre all hydrogen;
R1、R3、R4each independently selected from hydrogen, fluorine and chlorine;
R2is selected from
Figure FDA0003353927440000021
3. A compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, when R is2Is composed of
Figure FDA0003353927440000022
When R is2Is selected from
Figure FDA0003353927440000023
4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof,
Figure FDA0003353927440000024
are all single bonds;
a is selected from CRhRhB is selected from CRjRjD is selected from CRmAnd N, Rh、RjAnd RmAre both hydrogen, E is selected from O and C ═ O; n is 1.
5. The following compound, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from:
Figure FDA0003353927440000025
Figure FDA0003353927440000031
6. a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-5, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
7. A process for the preparation of a compound according to claim 1, comprising the steps of:
Figure FDA0003353927440000041
in the step, the compound of the general formula (I-c) reacts with an alkaline reagent to obtain a compound of the general formula (I), wherein ring G is a benzene ring; ring J is
Figure FDA0003353927440000042
m, r, t and i are respectively 1;
Figure FDA0003353927440000043
X1、A、B、D、E、R1、R2、R3、R4and n is as defined in claim 1.
8. A kit product comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 6, and optionally a package insert.
9. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof, a pharmaceutical composition according to claim 6 or a kit of parts according to claim 8 for the manufacture of a medicament for the treatment and/or prevention of a disease associated with the PD-1/PD-L1 pathway.
10. The use of claim 9, wherein the disease is cancer or a viral infectious disease.
11. The use according to claim 10, wherein the cancer is selected from lung cancer, skin cancer, esophageal cancer, bladder cancer, head and neck cancer, nasopharyngeal cancer, bronchial cancer, breast cancer, cervical cancer, pancreatic cancer, liver cancer, stomach cancer, bile duct cancer, prostate cancer, brain tumor, colon cancer or cancer residues after resection of the above solid tumors.
12. The use according to claim 10, wherein the virus is selected from the group consisting of HIV virus, hepatitis a virus, hepatitis b virus, hepatitis c virus, hepatitis d virus, herpes virus, human papilloma virus and influenza virus.
13. The use of claim 11, wherein the skin cancer is melanoma.
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