CN113493469A - Compound capable of being used as immunomodulator, preparation method and application thereof - Google Patents

Compound capable of being used as immunomodulator, preparation method and application thereof Download PDF

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CN113493469A
CN113493469A CN202010191351.0A CN202010191351A CN113493469A CN 113493469 A CN113493469 A CN 113493469A CN 202010191351 A CN202010191351 A CN 202010191351A CN 113493469 A CN113493469 A CN 113493469A
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radical
alkyl
cycloalkyl
independently selected
cancer
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阳安乐
邓金根
董理进
张德伟
田林
苏忠海
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Scinnohub Pharmaceutical Co Ltd
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Chengdu Beite Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to a small molecular immunomodulator, and discloses a method for preparing the small molecular immunomodulator, the small molecular immunomodulator can be used for treating diseases such as cancers or tumors, infectious diseases, metabolic diseases and the like, and has great clinical value.

Description

Compound capable of being used as immunomodulator, preparation method and application thereof
Technical Field
The invention relates to the field of medical chemistry, in particular to a small molecular immunomodulator, a method for preparing the small molecular immunomodulator and application of the small molecular immunomodulator in medicine.
Background
The immune system plays a very important role in the control and elimination of diseases such as cancer. However, tumor cells are often able to develop strategies to escape or inhibit the monitoring of the immune system to promote their malignant growth. One of the most important mechanisms is to alter the expression of costimulatory and co-suppressive immune checkpoint molecules on immune cells. Blocking the signaling pathway of immune checkpoint molecules, such as PD1, has proven to be a highly desirable and effective therapeutic approach.
Programmed death protein-1 (PD-1) is mainly expressed in activated T cells and B cells, and after PD-1 is combined with a ligand PD-L1, activation of immune cells is inhibited, which is a normal self-stabilization mechanism of an immune system, and PD-1 is a body protector of our human body because excessive T/B cell activation can cause autoimmune diseases. However, the tumor microenvironment induces high expression of PD-1 molecules by infiltrating T cells: PD-L1 is up-regulated in various tumor cells, and the binding with PD-1 on T cells in a tumor microenvironment leads to continuous activation of a PD-1 pathway and inhibition of proliferation and activation of the T cells, so that the T cells are in an inactivated state, cannot kill the tumor cells, and finally induce immune escape.
PD-1 has two ligands, PD-L1 and PD-L2, which belong to the B7 family of proteins. PD-L1 protein is widely expressed on Antigen Presenting Cells (APCs), activated T, B cells, macrophages, placental trophoblasts, myocardial endothelium and thymic cortical epithelial cells. The expression of PD-L1 protein can be detected in a plurality of human tumor tissues, the microenvironment of the tumor part can induce the expression of PD-L1 on tumor cells, and the expressed PD-L1 is beneficial to the generation and development of tumors and induces the apoptosis of anti-tumor T cells.
PD-1/PD-L1 inhibitors are one of the most popular tumor immunotherapeutic drugs currently available. Both the PD-1 inhibitor and the PD-L1 inhibitor can effectively block the combination of PD-1 and PD-L1, thereby inhibiting a PD-1 pathway, blocking a negative regulation signal, restoring the activity of T cells and enhancing immune response.
Currently, the PD-1/PD-L1 inhibitors on the market are monoclonal drugs, such as nivolumab, palivizumab, acilizumab, dulvacizumab, avizumab and the like. Compared with the mode of intravenous injection administration or subcutaneous injection administration of the monoclonal antibody drugs, the unique oral administration mode of the small molecules can greatly improve the compliance of patients, improve the tissue permeability, reduce the irritability and the immunogenicity, is easy to administer, has fixed dosage and is suitable for oral-oral combined treatment. Therefore, the compound for targeted blocking of the interaction of PD-1/PD-L1 has good curative effect in the immunotherapy of various cancers.
Disclosure of Invention
An object of the present invention is to provide a small molecule immunomodulator which targets and blocks the interaction of PD-1/PD-L1, and in particular, the present invention provides a compound having the structure of formula I:
Figure BDA0002416027220000021
wherein, X1、X2The same or different, and each is independently selected from the group consisting of a bond, -C (O) NH-, -NHC (O) -, -CH2-、-NH-、-O-；
Y1、Y2、Y3、Y4Each independently selected from CH or N; preferably, Y1、Y2、Y3、Y4At most 2 of them are simultaneously N; preferably, Y1、Y2Not simultaneously N, Y2、Y3Not N at the same time.
R1、R2The same or different and each independently selected from hydrogen, deuterium, tritium, hydroxyl, halogenCyano, C1-4Alkoxy radical, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, C1-4Alkoxy radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; further preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, -OMe, cyclopropyl, -CF3。
R3、R4The same or different, and each is independently selected from hydrogen, deuterium, tritium, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6A cycloalkyl group; wherein R is3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
preferably, R3、R4Each independently selected from C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
more preferably, R3、R4Each independently selected from-CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4Of (C-CH)2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7And (4) substitution.
R5、R6The same or different, and each is independently selected from H, deuterium, tritium, hydroxyl, and C1-4Alkyl, halogen, cyano; preferably, R5、R6Each independently selected from C1-4Alkyl, halogen; in certain specific embodiments, R5、R6Each independently selected from CH3Or Cl.
Each R7Independently selected from hydroxy, cyano, carboxy, amino, halogen, C1-4Alkyl or-CH2OH; preferably, each R7Independently selected from hydroxy, carboxy, CH3or-CH2OH。
"- - - - - -" represents a chemical bond that may be present.
The present invention further provides a compound represented by the following formula IIa, isomers, mixtures, solvates, hydrates, prodrugs or pharmaceutically acceptable salts thereof:
Figure BDA0002416027220000031
wherein the content of the first and second substances,
X1、X2the same or different, and each is independently selected from the group consisting of a bond, -C (O) NH-, -NHC (O) -, -CH2-、-NH-、-O-；
R1、R2The same or different and each is independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, C1-4Alkoxy radical, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, C1-4Alkoxy radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; further preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, -OMe, cyclopropylRadical, -CF3。
R3、R4The same or different, and each is independently selected from hydrogen, deuterium, tritium, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6A cycloalkyl group; wherein R is3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
preferably, R3、R4Are the same as, and are selected from C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
more preferably, R3、R4Each independently selected from-CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4Of (C-CH)2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7And (4) substitution.
R5、R6The same or different, and each is independently selected from H, deuterium, tritium, hydroxyl, and C1-4Alkyl, halogen, cyano; preferably, the first and second electrodes are formed of a metal,R5、R6each independently selected from C1-4Alkyl, halogen; in certain specific embodiments, R5、R6Each independently selected from CH3Or Cl.
Each R7Independently selected from hydroxy, cyano, carboxy, amino, halogen, C1-4Alkyl or-CH2OH; preferably, each R7Independently selected from hydroxy, carboxy, CH3or-CH2OH。
The present invention further provides a compound represented by the following formula lib, an isomer, a mixture, a solvate, a hydrate, a prodrug or a pharmaceutically acceptable salt thereof:
Figure BDA0002416027220000041
wherein the content of the first and second substances,
X1、X2the same or different, and each is independently selected from the group consisting of a bond, -C (O) NH-, -NHC (O) -, -CH2-、-NH-、-O-；
R1、R2The same or different and each is independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, C1-4Alkoxy radical, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, C1-4Alkoxy radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; further preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, -OMe, cyclopropyl, -CF3。
R3、R4The same or different, and each is independently selected from hydrogen, deuterium, tritium, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6A cycloalkyl group; wherein R is3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
preferably, R3、R4Each independently selected from C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
more preferably, R3、R4Each independently selected from-CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4Of (C-CH)2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7And (4) substitution.
R5、R6The same or different, and each is independently selected from H, deuterium, tritium, hydroxyl, and C1-4Alkyl, halogen, cyano; preferably, R5、R6Each independently selected from C1-4Alkyl, halogen; in certain specific embodiments, R5、R6Each independently selected from CH3Or Cl.
Each R7Independently selected from hydroxy, cyano, carboxy, amino, halogen, C1-4Alkyl or-CH2OH; preferably, each R7Independently selected from hydroxy, carboxy, CH3or-CH2OH。
In certain specific embodiments, the formula X of the present invention1、X2is-NH-;
in certain specific embodiments, R is as defined herein5、R6Are identical and are selected from CH3Or Cl.
The present invention also provides a compound represented by the following formula III, an isomer, a mixture, a solvate, a hydrate, a prodrug thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0002416027220000051
wherein R is1、R2The same or different and each is independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, -C1-4Alkoxy radical, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; preferably, R1、R2Same, and selected from hydrogen, deuterium, tritium, C1-4Alkoxy radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; further preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, -OMe, cyclopropyl, -CF3。
R3、R4The same or different, and each is independently selected from hydrogen, deuterium, tritium, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6A cycloalkyl group; wherein R is3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
preferably, R3、R4Each independently selected from C1-6Alkyl radical, C1-6Alkoxy radicalBase, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
more preferably, R3、R4Each independently selected from-CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4Of (C-CH)2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl optionally substituted by 1 or 2R7And (4) substitution.
Each R7Independently selected from hydroxy, cyano, carboxy, amino, halogen, C1-4Alkyl or-CH2OH; preferably, each R7Independently selected from hydroxy, carboxy, CH3or-CH2OH。
The present invention also provides a compound represented by the following formula IV, an isomer, a mixture, a solvate, a hydrate, a prodrug thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0002416027220000061
wherein R is1、R2The same or different and each is independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, -C1-4Alkoxy radical, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, C1-4Alkoxy radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; further preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, -OMe, cyclopropyl, -CF3。
R3、R4The same or different, and each is independently selected from hydrogen, deuterium, tritium, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6A cycloalkyl group; wherein R is3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
preferably, R3、R4Each independently selected from C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
more preferably, R3、R4Each independently selected from-CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4Of (C-CH)2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl optionally substituted by 1 or 2R7And (4) substitution.
Each R7Independent of each otherSelected from hydroxy, cyano, carboxy, amino, halogen, C1-4Alkyl or-CH2OH; preferably, each R7Independently selected from hydroxy, carboxy, CH3or-CH2OH。
The present invention also provides a compound represented by the following formula V, an isomer, a mixture, a solvate, a hydrate, a prodrug thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0002416027220000062
wherein R is1、R2The same or different and each is independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, -C1-4Alkoxy radical, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, C1-4Alkoxy radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; further preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, -OMe, cyclopropyl, -CF3。
R3、R4The same or different, and each is independently selected from hydrogen, deuterium, tritium, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6A cycloalkyl group; wherein R is3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
preferably, R3、R4Each independently selected from C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
more preferably, R3、R4Each independently selected from-CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4Of (C-CH)2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl optionally substituted by 1 or 2R7And (4) substitution.
Each R7Independently selected from hydroxy, cyano, carboxy, amino, halogen, C1-4Alkyl or-CH2OH; preferably, each R7Independently selected from hydroxy, carboxy, CH3or-CH2OH。
The present invention also provides a compound represented by the following formula VI, an isomer, a mixture, a solvate, a hydrate, a prodrug thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0002416027220000071
wherein R is1、R2The same or different and each is independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, -C1-4Alkoxy radical, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; preferably, R1And R is independently selected from hydrogen, deuterium, tritium and C1-4Alkoxy radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; further preferably, R1、R2Are independently selected fromFrom hydrogen, deuterium, tritium, -OMe, cyclopropyl, -CF3。
R3、R4The same or different, and each is independently selected from hydrogen, deuterium, tritium, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6A cycloalkyl group; wherein R is3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
preferably, R3、R4Each independently selected from C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
more preferably, R3、R4Each independently selected from-CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4Of (C-CH)2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl optionally substituted by 1 or 2R7And (4) substitution.
Each R7Independently selected from hydroxy, cyano, carboxy, amino, halogen, C1-4Alkyl or-CH2OH; preferably, each R7Independently selected from hydroxy, carboxy, CH3or-CH2OH。
In certain embodiments, R1、R2The same;
in certain embodiments, R3、R4The same; in certain specific embodiments, R is as described herein3、R4Are identical and are selected from the group consisting of-CH2NHCH2CH(OH)CH2COOH、-CH2NHCH2CH2OH、-CH2NHCH2COOH、-CH2NHCH(CH2OH)COOH、-CH2NHCH(CH3)CH2OH、-CH2NHCH(CH3)COOH、
Figure BDA0002416027220000081
Figure BDA0002416027220000082
In certain embodiments, the compounds of the present invention, isomers, mixtures, solvates, prodrugs or pharmaceutically acceptable salts thereof, have the structure:
Figure BDA0002416027220000083
Figure BDA0002416027220000091
in another aspect, the present invention provides a pharmaceutical composition comprising the aforementioned small molecule compound, isomer, mixture, solvate, prodrug or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention, which can be used as an immunomodulator, and a pharmaceutically acceptable carrier.
The invention also provides application of the small molecule immunomodulatory compound in preparing medicines for treating related diseases mediated by PD-1/PD-L1 signal pathways; the related diseases mediated by the PD-1/PD-L1 signal channel are selected from cancers or tumors, infectious diseases or metabolic diseases.
The cancer or tumor of the invention is selected from the group consisting of lymphoma, sarcoma, melanoma, glioblastoma, synovioma, meningioma, biliary tract tumor, thymic tumor, neural tumor, seminoma, wilms tumor, pleomorphic adenoma, hepatocellular papilloma, tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, fibroma, central nervous system tumor, rachioma, brain stem glioma, pituitary adenoma, multiple myeloma, ovarian tumor, myelodysplastic syndrome or mesothelioma, prostate cancer, recurrent or drug-resistant prostate cancer, thyroid cancer, parathyroid cancer, anal cancer, testicular cancer, urethral cancer, penile cancer, bladder cancer, ureteral cancer, uterine cancer, ovarian cancer, fallopian tube cancer, endometrial cancer, and cancer, Cervical cancer, vaginal cancer, vulvar cancer, adrenal cancer, merkel cell carcinoma, embryonic cancer, chronic or acute leukemia, bronchial cancer, esophageal cancer, nasopharyngeal cancer, hepatocellular cancer, renal cell carcinoma, small cell lung cancer, basal cell carcinoma, lung cancer, breast cancer, adenocarcinoma, papillary cancer, cystadenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, rectal cancer, colon cancer, colorectal cancer, gastric cancer, pancreatic cancer, head and neck squamous cell cancer, head and neck cancer, gastrointestinal tract, bone cancer, skin cancer, small intestine cancer, endocrine system cancer, renal pelvis cancer, epidermoid cancer, abdominal wall cancer, renal cell carcinoma, transitional cell carcinoma, or choriocarcinoma, as well as metastatic tumors.
Infectious diseases described herein include bacterial, viral and fungal infections, particularly, but not limited to, HIV, influenza, herpes, Giardia, malaria, Leishmania, pathogenic infections caused by hepatitis viruses (A, B, & C), herpes viruses (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, EB (Epstein Barr) virus), adenovirus, influenza virus, arbovirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papilloma virus, molluscum virus, poliovirus, rabies virus, JC virus and arbovirus encephalitis virus, pathogenic infections caused by bacterial chlamydia, rickettsia bacteria, mycobacteria bacteria, and the like, Staphylococci, streptococci, pneumococci (pneumococci), meningococci and conocci, klebsiella, proteus, serratia, pseudomonas, escherichia coli, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and lyme disease bacteria, pathogenic infections caused by: candida (candida albicans, candida krusei (krusei), candida glabrata (glabrata), candida tropicalis (tropicalis), etc.), cryptococcus neoformans, aspergillus (aspergillus fumigatus), aspergillus niger (niger), etc.), mucor (mucor, humicola, rhizopus (rhizopus), trichosporon, Blastomyces dermatitidis (Blastomyces dermatitidis), Paracoccidioides brasiliensis (Paracoccidioides brasiliensis), coccidioidomycosis immitis (coccoidis capsulitis), and Histoplasma (Histoplasma capsulim), and pathogenic infections caused by: endophytic species of dysentery (Entamoeba histolytica), Baphicacanthi cubensis (Ballantidia coli), Fowler-Nordheim (Naegleriafarleri), Acanthamoeba (Acanthamoeba sp.), Giardia lamblia (Girdia lambia), Cryptosporidium (Cryptosporidium sp.), Pneumocystis carinii (Pneumocystis carinii), Plasmodium vivax (Plasmodium vivax), Babesia cubensis (Babesia microti), Trypanosoma brucei (Trypanosoma brucei), Trypanosoma cruzi (Trypanosoma cruzi), Leishmania dorsalis (Leishmania donovani), Toxoplasma gondii (Toxoa ndii), and Neosardonia bractensis (Nippostrongoides).
Detailed Description
Definition of terms
Unless otherwise indicated, the following terms appearing in the specification and claims of the present invention have the following meanings.
"alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group. For example, "C1-4Alkyl "refers to straight and branched chain alkyl groups comprising 1 to 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, and the like; "C1-6Alkyl "refers to straight chain alkyl groups and branched chain-containing alkyl groups comprising 1 to 6 carbon atoms, including but 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.
"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. For example, "C3-6Cycloalkyl "refers to a cycloalkyl group comprising 3 to 6 carbon atoms, typically C3-6Cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and the like.
"alkoxy" refers to a cyclic or acyclic alkyl group having the indicated number of carbon atoms attached through an oxygen bridge, and "alkoxy" includes the above definitions of alkyl and cycloalkyl. For example, "C1-4Alkoxy "refers to a cyclic or acyclic alkyl group having 1 to 4 carbon atoms, typically C, linked by an oxygen bridge1-4Alkoxy groups include, but are not limited to: -OMe, -OEt, -O-cycloalkyl, etc.
"halogen" means F, Cl, Br or I; "halo" means substituted by an atom selected from F, Cl, Br or I.
"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent in which one or more ring atoms are substituted with a heteroatom selected from N, O, S, the remaining ring atoms being carbon. For example: "C3-6Heterocyclyl "refers to a cyclic group comprising 3 to 6 ring atoms, including but not limited to: pyrrolidinyl, furyl, piperidinyl, piperazinyl, morpholinyl, and the like.
Unless otherwise specified, the structural formulae depicted herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)); for example, R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.
The term "solvate" as used herein refers to a complex of a compound of the present invention coordinated to a solvent molecule in a specific ratio.
The "hydrate" of the present invention refers to a complex formed by the coordination of the compound of the present invention with water.
The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound of the present invention with an acid or a base, which is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. Exemplary acid addition salts include, but are not limited to: hydrochloride, hydrobromide, sulfate, nitrate, phosphate, hydrofluoride, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, naphthenate, toluenesulfonate, benzenesulfonate, aspartate, glutamate and the like. Exemplary basic salts include, but are not limited to: alkali metal salts, alkaline earth metal salts, organic amine salts, and the like.
Abbreviations used in this disclosure are known to those skilled in the art and, unless otherwise indicated, are intended to have the meaning reported in the art; for example: pd2(dba)3Refers to tris (dibenzylideneacetone) dipalladium, Davephos refers to 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl, DMF refers to N, N-dimethylformamide, POCl3Refers to phosphorus oxychloride.
The following examples, which are intended to be illustrative only and not to be limiting as to the scope of the invention, illustrate the synthesis of the compounds and intermediates of the invention. Unless otherwise specified, all materials and reagents referred to in the present invention are commercially available.
Preparation example 1: preparation of 7-chloropyrazolo [1,5-a ] pyrimidine-3-carbaldehyde
Figure BDA0002416027220000121
7-chloropyrazolo [1,5-a ] pyrimidine (3.0g) was dissolved in N, N-dimethylformamide (20mL), and phosphorus oxychloride (6g) was added in an ice-water bath to react at room temperature for 6 hours. After the reaction was completed by LC-MS, the system was poured into ice water, added sodium carbonate solid to adjust pH to weak alkalinity, extracted with ethyl acetate (100mL 4), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 1.9g of the title compound.
MS(ESI)m/z(M+H)+＝182.0。
Preparation example 2: preparation of 7,7'- (((2,2' -dimethyl- [1,1 '-biphenyl ] -3,3' -diyl) bis (azepinyl)) bis (pyrazolo [1,5-a ] pyrimidine-3-carbaldehyde)
Figure BDA0002416027220000122
Step 1: preparation of 2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline
Figure BDA0002416027220000123
3-bromo-2-methylaniline (2.5g), potassium acetate (1.9g), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (494mg) and pinacol diboron (4.1g) were dissolved in 1, 4-dioxane (40mL), nitrogen was substituted three times, the temperature was raised to 90 ℃ for reaction for 3 hours, LCMS showed that the reaction was complete, the reaction system was cooled to room temperature, and the next reaction was carried out by a one-pot method.
Step 2: preparation of 2,2' -dimethyl- [1,1' -biphenyl ] -3,3' -diamine
Figure BDA0002416027220000124
Adding 3-bromo-2-methylaniline (2.2g), potassium carbonate (2.8g), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (494mg) and water (8mL) into the system in the last step, heating to 90 ℃ and continuing to react for 3 hours, adding water (50mL) into the system after LCMS shows that the reaction is complete, extracting ethyl acetate (50mL) for three times, combining organic phases, washing once with saturated saline (100mL), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography to obtain 2.3g of the target compound.
MS(ESI)m/z(M+H)+＝213.1.
And step 3: preparation of 7,7'- (((2,2' -dimethyl- [1,1 '-biphenyl ] -3,3' -diyl) bis (azepinyl)) bis (pyrazolo [1,5-a ] pyrimidine-3-carbaldehyde)
Figure BDA0002416027220000131
2,2' -dimethyl- [1,1' -biphenyl ] -3,3' -diamine (532mg) was dissolved in N, N-dimethylformamide (20mL), and 7-chloropyrazolo [1,5-a ] pyrimidine-3-carbaldehyde (1.0g) was added to react at 120 ℃ for 3 hours. LCMS showed the reaction was complete, concentrated under reduced pressure to remove N, N-dimethylformamide, water (50mL), ethyl acetate (50mL × 3) extracted three times, the organic phases were combined, washed once with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford the title compound 280 mg.
MS(ESI)m/z(M+H)+＝503.2.
Preparation example 3: preparation of 7,7'- ((2,2' -dichloro- [1,1 '-biphenyl ] -3,3' -diyl) bis (azadienyl) bis (pyrazolo [1,5-a ] pyrimidine-3-carbaldehyde)
Figure BDA0002416027220000132
Step 1: preparation of 2-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline
Figure BDA0002416027220000133
3-bromo-2-chloroaniline (1.5g), potassium acetate (1.08g), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (276mg) and pinacol diboron (2.23g) were dissolved in 1, 4-dioxane (30mL), replaced with nitrogen three times, heated to 90 ℃ for reaction for 3 hours, LCMS showed that the reaction was complete, the reaction system was cooled to room temperature, and the next reaction was carried out by a one-pot method.
MS(ESI)m/z(M+H)+＝254.1.
Step 2: preparation of 2,2' -dichloro- [1,1' -biphenyl ] -3,3' -diamine
Figure BDA0002416027220000141
Adding 3-bromo-2-chloroaniline (1.2g), potassium carbonate (1.51g), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (276mg) and water (5mL) into the system in the last step, heating to 90 ℃ for reaction for 3 hours, and displaying by LC-MS that the reaction is complete. The system was extracted three times with water (50mL), ethyl acetate (50mL × 3), the organic phases were combined, washed once with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 1.1 g.
MS(ESI)m/z(M+H)+＝253.0.
And step 3: preparation of 7,7'- ((2,2' -dichloro- [1,1 '-biphenyl ] -3,3' -diyl) bis (azadienyl) bis (pyrazolo [1,5-a ] pyrimidine-3-carbaldehyde)
Figure BDA0002416027220000142
2,2' -dichloro- [1,1' -biphenyl ] -3,3' -diamine (633mg) was dissolved in N, N-dimethylformamide (10mL), and 7-chloropyrazolo [1,5-a ] pyrimidine-3-carbaldehyde (1g) was added and reacted with heating at 140 ℃ for 1 hour. And after the LC-MS shows that the reaction is complete, the system is decompressed and concentrated, and the residue is purified by column chromatography to obtain 180mg of the target compound.
MS(ESI)m/z(M+H)+＝543.1.
Preparation example 4: preparation of 7,7'- (((2,2' -dimethyl- [1,1 '-biphenyl ] -3,3' -diyl) bis (azepinyl)) bis (2-methoxypyrazolo [1,5-a ] pyrimidine-3-carbaldehyde)
Figure BDA0002416027220000143
Step 1: preparation of 5-hydroxy-2-methoxypyrazoline [1,5-a ] pyrimidin-7 (4H) -one
Figure BDA0002416027220000151
3-methoxy-1H-pyrazol-5-amine (15.0g), diethyl malonate (25.5g) and sodium ethoxide (27.0g) are dissolved in ethanol (200mL), and the reaction is performed under reflux at 80 ℃ for 4 hours. After the LC-MS shows that the reaction is complete, the system is concentrated under reduced pressure, water (150mL) is added into the residue, concentrated sulfuric acid is used for adjusting the pH to be about 2, solid is separated out, the filtration is carried out, the filter cake is rinsed once by ice water (100mL), and the filter cake is dried to obtain 16.2g of the title compound.
MS(ESI)m/z(M+H)+＝182.1.
Step 2: preparation of 5, 7-dichloro-2-methoxypyrazolo [1,5-a ] pyrimidine
Figure BDA0002416027220000152
5-hydroxy-2-methoxy pyrazoline [1,5-a ] pyrimidin-7 (4H) -one (3.0g) was dissolved in phosphorus oxychloride (10mL), and the reaction was carried out at 90 ℃ for 2 hours. After LC-MS shows that the raw material disappears, the system is slowly poured into a proper amount of ice water, sodium bicarbonate is added to adjust the pH value to be alkalescent, ethyl acetate (50mL 4) is added for extraction, organic phases are combined, anhydrous sodium sulfate is dried, reduced pressure concentration is carried out, and the residue is purified by column chromatography to obtain 1.0g of the title compound.
MS(ESI)m/z(M+H)+＝218.0.
And step 3: n is a radical of3,N3' -bis (5-chloro-2-methoxypyrazolo [1,5-a ]]Pyrimidin-7-yl) -2,2 '-dimethyl- [1,1' -biphenyl]Preparation of (E) -3,3' -diamine
Figure BDA0002416027220000153
5, 7-dichloro-2-methoxypyrazolo [1,5-a ] pyrimidine (921mg) was dissolved in N, N-dimethylformamide (10mL), 2' -dimethyl- [1,1' -biphenyl ] -3,3' -diamine (500mg) was added, and the reaction was initiated with a microwave at 120 ℃ for 2 hours, whereupon LC-MS showed completion of the reaction. The system is decompressed and concentrated, and the residue is purified by column chromatography to obtain 890mg of the target compound.
MS(ESI)m/z(M+H)+＝575.1.
And 4, step 4: n is a radical of3,N3' -bis (2-methoxypyrazolo [1,5-a ]]Pyrimidin-7-yl) -2,2 '-dimethyl- [1,1' -biphenyl]Preparation of (E) -3,3' -diamine
Figure BDA0002416027220000161
Will N3,N3' -bis (5-chloro-2-methoxypyrazolo [1,5-a ]]Pyrimidin-7-yl) -2,2 '-dimethyl- [1,1' -biphenyl]-3,3' -diamine (890mg) was dissolved in methanol (100mL), Pd/C (890mg) was added, and hydrogen was introduced after nitrogen substitution, followed by reaction at room temperature overnight. The system was filtered through celite and the filtrate was directly concentrated under reduced pressure to give 682mg of the title compound.
MS(ESI)m/z(M+H)+＝507.2.
And 5: preparation of 7,7'- (((2,2' -dimethyl- [1,1 '-biphenyl ] -3,3' -diyl) bis (azepinyl)) bis (2-methoxypyrazolo [1,5-a ] pyrimidine-3-carbaldehyde)
Figure BDA0002416027220000162
Will N3,N3' -bis (2-methoxypyrazolo [1,5-a ]]Pyrimidin-7-yl) -2,2 '-dimethyl- [1,1' -biphenyl]-3,3' -diamine (682mg) was dissolved in N, N-dimethylformamide (5mL), and phosphorus oxychloride (1.03g) was slowly added dropwise in an ice bath, and the system was naturally returned to room temperature for 4 hours. LC-MS shows that after the reaction is completed, the system is slowly poured into a proper amount of crushed ice, and the pH value is adjusted to be weak by sodium carbonateBasic, ethyl acetate (100mL 4), combined organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by column chromatography to give 410mg of the title compound.
MS(ESI)m/z(M+H)+＝563.2.
Preparation example 5: preparation of 8,8'- (((2,2' -dimethyl- [1,1 '-biphenyl ] -3,3' -diyl) bis (azepinyl)) bis (2- (trifluoromethyl) imidazo [1,2-a ] pyrazine-3-carbaldehyde)
Figure BDA0002416027220000163
Step 1: preparation of ethyl 2-bromo-4, 4, 4-trifluoro-3-oxobutyrate
Figure BDA0002416027220000171
Ethyl 4,4, 4-trifluoro-3-oxobutanoate (18.4g) was dissolved in chloroform (100mL), and a solution of bromine (16.0g) in chloroform (30mL) was added dropwise under ice-bath, followed by reaction at room temperature for 2 hours. The reaction was then quenched with saturated aqueous sodium sulfite (30mL), the layers were separated, the aqueous phase was extracted once with dichloromethane (50mL), the organic phases were combined, washed once with brine (100mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound 22.6 g.
MS(ESI)m/z(M+H)+＝263.1.
Step 2: preparation of ethyl 8-chloro-2- (trifluoromethyl) imidazo [1,2-a ] pyrazine-3-carboxylate
Figure BDA0002416027220000172
Ethyl 2-bromo-4, 4, 4-trifluoro-3-oxobutyrate (22.5g) and 3-chloropyrazin-2-amine (3.0g) were dissolved in acetonitrile (100mL) and the reaction was warmed to reflux overnight. Concentration under reduced pressure and purification of the residue by column chromatography gave the title compound 2.0 g.
MS(ESI)m/z(M+H)+＝294.1.
And step 3: diethyl 8,8'- (((2,2' -dimethyl- [1,1 '-biphenyl ] -3,3' -diyl) bis (azepindiyl)) bis (2- (trifluoromethyl) imidazole
Preparation of [1,2-a ] pyrazine-3-carboxylic acid ester)
Figure BDA0002416027220000173
Ethyl 8-chloro-2- (trifluoromethyl) imidazo [1,2-a ] pyrazine-3-carboxylate (1.45g) and 2,2' -dimethyl- [1,1' -biphenyl ] -3,3' -diamine (500mg) were dissolved in N, N-dimethylformamide (15mL), and the reaction was initiated with a microwave at 120 ℃ for 2 hours. Concentration under reduced pressure, and column chromatography purification of the residue yielded 1.5g of the objective compound.
MS(ESI)m/z(M+H)+＝727.1.
And 4, step 4: preparation of (8,8'- (((2,2' -dimethyl- [1,1 '-biphenyl ] -3,3' -diyl) bis (azepinyl)) bis (2- (trifluoromethyl) imidazo [1,2-a ] pyrazine-8, 3-diyl)) dimethanol
Figure BDA0002416027220000174
Under the condition of an ice-water bath, diethyl 8,8'- (((2,2' -dimethyl- [1,1 '-biphenyl ] -3,3' -diyl) bis (azepinyl)) bis (2- (trifluoromethyl) imidazo [1,2-a ] pyrazine-3-carboxylate) (1.0g) is dissolved in tetrahydrofuran (100mL), lithium borohydride (300mg) is added, the reaction is carried out at room temperature for 2 hours, LC-MS shows that the raw material disappears, acetone (20mL) is added to stop the reaction, the reaction is concentrated under reduced pressure, and the residue is purified by column chromatography to obtain 700mg of the target compound.
MS(ESI)m/z(M+H)+＝643.1.
And 5: preparation of 8,8'- (((2,2' -dimethyl- [1,1 '-biphenyl ] -3,3' -diyl) bis (azepinyl)) bis (2- (trifluoromethyl) imidazo [1,2-a ] pyrazine-3-carbaldehyde)
Figure BDA0002416027220000181
(8,8'- (((2,2' -dimethyl- [1,1 '-biphenyl ] -3,3' -diyl) bis (azepinyl)) bis (2- (trifluoromethyl) imidazo [1,2-a ] pyrazine-8, 3-diyl)) dimethanol (700mg) was dissolved in acetonitrile (50mL), diiodoylbenzoic acid (1.6g) was added, the mixture was heated to reflux for 2 hours, LCMS showed that the starting material disappeared, and then, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 400mg of the objective compound.
MS(ESI)m/z(M+H)+＝639.1.
Preparation example 6: preparation of 8,8'- (((2,2' -dichloro- [1,1 '-biphenyl ] -3,3' -diyl) bis (azepinyl)) bis (2- (cyclopropyl) imidazo [1,2-a ] pyrazine-3-carbaldehyde)
Figure BDA0002416027220000182
Step 1: preparation of 8-chloro-2-cyclopropylimidazo [1,2-a ] pyrazine
Figure BDA0002416027220000183
3-chloropyrazin-2-amine (3.0g) was dissolved in acetonitrile (50mL), and 2-bromo-1-cyclopropylethanone (5.0g) was added thereto, followed by heating to reflux reaction for 10 hours. Concentration under reduced pressure and purification of the residue by column chromatography gave the title compound 1.4 g.
MS(ESI)m/z(M+H)+＝194.1.
Step 2: preparation of 8-chloro-2-cyclopropylimidazo [1,2-a ] pyrazine-3-carbaldehyde
Figure BDA0002416027220000191
8-chloro-2-cyclopropylimidazo [1,2-a ] pyrazine (700mg) was dissolved in N, N-dimethylformamide (10mL), and phosphorus oxychloride (2mL) was added under ice-water bath conditions, and the system was slowly warmed to room temperature for overnight reaction. After LCMS to monitor disappearance of the starting material, the reaction was quenched by pouring into crushed ice (50g), then adjusted to pH about 8 with sodium bicarbonate, extracted three times with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound 500 mg.
MS(ESI)m/z(M+H)+＝222.1.
And step 3: preparation of 8,8'- (((2,2' -dichloro- [1,1 '-biphenyl ] -3,3' -diyl) bis (azepinyl)) bis (2- (cyclopropyl) imidazo [1,2-a ] pyrazine-3-carbaldehyde)
Figure BDA0002416027220000192
8-chloro-2-cyclopropylimidazo [1,2-a ] pyrazine-3-carbaldehyde (530mg), 2 '-dichloro- [1,1' -biphenyl ] -3,3 '-diamine (252mg), tris (dibenzylideneacetone) dipalladium (180mg), 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (80mg), and cesium carbonate (980mg) were dissolved in 1, 4-dioxane (15mL) under a nitrogen atmosphere, and the reaction was initiated with a microwave at 120 ℃ for 2 hours. Concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound (150 mg).
MS(ESI)m/z(M+H)+＝623.1.
Example 1: preparation of (3S,3' S) -4,4' - (((((2, 2' -dimethyl- [1,1' -biphenyl ] -3,3' -diyl) bis (azepinyl) bis (pyrazoline [1,5-a ] pyrimidin-7, 3-diyl)) bis (methylene)) bis (azepinyl) bis (3-hydroxybutyric acid)
Figure BDA0002416027220000193
7,7'- (((2,2' -dimethyl- [1,1 '-biphenyl ] -3,3' -diyl) bis (azepindiyl)) bis (pyrazolo [1,5-a ] pyrimidine-3-carbaldehyde) (40mg) was dissolved in methanol (8mL), and (S) -4-amino-3-hydroxybutyric acid (47mg) was added thereto and reacted at room temperature for 6 hours, followed by addition of sodium cyanoborohydride (25mg) and reaction continued overnight at room temperature, LCMS showed completion of the reaction, diluted hydrochloric acid was added to adjust pH to about 5, followed by concentration under reduced pressure, and the residue was purified by reverse phase Prep-HPLC to give 8.1mg of the title compound.
MS(ESI)m/z(M+H)+＝709.3.
1H NMR(400MHz,CD3OD)δ8.28(s,2H),8.22(d,J＝5.2Hz,2H),7.46-7.44(m,4H),7.28-7.26(m,2H),5.94(d,J＝5.2Hz,2H),4.43(s,4H),4.17-4.14(m,2H),3.20(dd,J＝12.4,4.0Hz,2H),3.02(dd,J＝12.4,8.0Hz,2H),2.42(d,J＝6.4Hz,4H),2.03(s,6H).
The following exemplary compounds, structures and characterization data are shown in the following table, which can be prepared by one skilled in the art using suitable commercial reagents as starting materials and in accordance with the procedures of the above examples and preparations:
Figure BDA0002416027220000201
Figure BDA0002416027220000211
Figure BDA0002416027220000221
Figure BDA0002416027220000231
biological activity assay
1. Test reagents and materials:
Figure BDA0002416027220000232
2. test procedure
(1) The PD-1 recombinant protein and the PD-L1 recombinant protein are respectively diluted to 250nM and 25nM by Dilution Buffer;
(2) test compounds dissolved in 10mM DMSO were diluted to 1mM with Dilution Buffer, and then diluted with Dilution Buffer containing 10% DMSO at 1: diluting at 4 times ratio to obtain final reaction concentrations of 1000, 250, 62.5, 15.63, 3.91, 0.98, 0.24, 0.06, 0.015 and 0.004nM respectively, and obtaining 10 concentration gradients;
(3) adding 2 mu L of diluted compound into each reaction hole, and adding equal volume of Dilution Buffer containing 10% DMSO into the positive control hole and the negative control hole;
(4) sequentially adding 4 μ L of diluted PD-1 and 4 μ L of diluted PD-L1 (the Dilution Buffer replaces PD-L1 protein in the negative control well) into 384 wells, mixing well, and standing at room temperature for 15 min;
(5) diluting anti-Tag1-Eu3+ (1:25) and anti-Tag2-XL665(1:100) respectively by using a Detection buffer, mixing in equal volume, adding 10 mu L of antibody mixed liquor into each reaction hole, sealing a membrane, and incubating at room temperature for 2 h;
(6) fluorescence signals (excitation wavelength 320nm, emission wavelength 665nm, 615nm) were detected with a SpectraMax i3X multifunctional microplate reader instrument.
(7) Data processing
The ER value (Emission Ratio, Ratio of emitted fluorescence signals) was calculated as follows:
emission Ratio (ER) 665 nm/615 nm fluorescence signal
The inhibition was calculated as follows:
inhibition (Inhibition) × 100% (ER positive control-ER sample)/(ER positive control-ER negative control), wherein the positive control represents ER value in wells without compound (vehicle) and the negative control represents ER value in wells without compound (vehicle) and PD-L1 protein
(8) Fitting dose-effect curve
The log values of compound concentrations were taken as the X-axis and percent inhibition as the Y-axis, and the IC50 values were fitted with a four parameter model.
Calculating the formula:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
x: logarithmic concentration of compound; y: the inhibition rate; HillSlpoe: fitting a curve slope; top, Bottom: maximum and minimum values of the fitted curve.
The inhibitory activity of the compounds of the invention on PD-1/PD-L1 binding was determined by the above assay and the IC50 values were determined as shown in the following Table:
Figure BDA0002416027220000241
Figure BDA0002416027220000251

Claims (12)

1. a compound having the structure of formula I, isomers, mixtures, solvates, hydrates, prodrugs thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0002416027210000011
wherein, X1、X2The same or different, and each is independently selected from the group consisting of a bond, -C (O) NH-, -NHC (O) -, -CH2-、-NH-、-O-；
Y1、Y2、Y3、Y4Each independently selected from CH or N; preferably, Y1、Y2、Y3、Y4At most 2 of them are simultaneously N; preferably, Y1、Y2Not simultaneously N, Y2、Y3Not N at the same time.
R1、R2The same or different and each is independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, C1-4Alkoxy radical, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, C1-4Alkoxy radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; further preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, -OMe, cyclopropyl, -CF3。
R3、R4The same or different, and each is independently selected from hydrogen, deuterium, tritium, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6A cycloalkyl group; wherein R is3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
preferably, R3、R4Each independently selected from C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
more preferably, R3、R4Each independently selected from-CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4Of (C-CH)2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7And (4) substitution.
R5、R6The same or different, and each is independently selected from H, deuterium, tritium, hydroxyl, and C1-4Alkyl, halogen, cyano; preferably, R5、R6Are the same and are each independently selected from C1-4Alkyl, halogen; in certain specific embodiments, R5、R6Each independently selected from CH3Or Cl.
Each R7Independently selected from hydroxy, cyano, carboxy, amino, halogen, C1-4Alkyl or-CH2OH; preferably, each R7Independently selected from hydroxy, carboxy, CH3or-CH2OH。
Figure FDA0002416027210000012
Representing a possible chemical bond.
2. A compound of formula IIa or IIb, isomers, mixtures, solvates, hydrates, prodrugs or pharmaceutically acceptable salts thereof:
Figure FDA0002416027210000021
wherein the content of the first and second substances,
X1、X2the same or different, and each is independently selected from the group consisting of a bond, -C (O) NH-, -NHC (O) -, -CH2-、-NH-、-O-；
R1、R2The same or different and each is independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, C1-4Alkoxy radical, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, C1-4Alkoxy radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; further preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, -OMe, cyclopropyl, -CF3。
R3、R4The same or different, and each is independently selected from hydrogen, deuterium, tritium, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6A cycloalkyl group; wherein R is3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6A heterocyclic group,-CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
preferably, R3、R4Each independently selected from C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
more preferably, R3、R4Each independently selected from-CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4Of (C-CH)2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7And (4) substitution.
R5、R6The same or different, and each is independently selected from H, deuterium, tritium, hydroxyl, and C1-4Alkyl, halogen, cyano; preferably, R5、R6Each independently selected from C1-4Alkyl, halogen; in certain specific embodiments, R5、R6Each independently selected from CH3Or Cl.
Each R7Independently selected from hydroxy, cyano, carboxy, amino, halogen, C1-4Alkyl or-CH2OH; preferably, each R7Independently selected from hydroxy, carboxy, CH3or-CH2OH。
3. The compound of claim 1 or 2, an isomer, a mixture, a solvate, a hydrate, a prodrug thereofOr a pharmaceutically acceptable salt thereof, characterized in that said X is1、X2is-NH-; the R is5、R6Are identical and are selected from CH3Or Cl.
4. A compound of formula III, isomers, mixtures, solvates, hydrates, prodrugs thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0002416027210000031
wherein R is1、R2The same or different and each is independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, C1-4Alkoxy radical, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, C1-4Alkoxy radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; further preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, -OMe, cyclopropyl, -CF3。
R3、R4The same or different, and each is independently selected from hydrogen, deuterium, tritium, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6A cycloalkyl group; wherein R is3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
preferably, R3、R4Each independently selected from C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
more preferably, R3、R4Each independently selected from-CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4Of (C-CH)2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl optionally substituted by 1 or 2R7And (4) substitution.
Each R7Independently selected from hydroxy, cyano, carboxy, amino, halogen, C1-4Alkyl or-CH2OH; preferably, each R7Independently selected from hydroxy, carboxy, CH3or-CH2OH。
5. A compound of formula IV, isomers, mixtures, solvates, hydrates, prodrugs, or a pharmaceutically acceptable salt thereof:
Figure FDA0002416027210000041
wherein R is1、R2The same or different and each is independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, C1-4Alkoxy radical, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, C1-4Alkoxy radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; further excellenceOptionally, R1、R2Each independently selected from hydrogen, deuterium, tritium, -OMe, cyclopropyl, -CF3。
R3、R4The same or different, and each is independently selected from hydrogen, deuterium, tritium, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6A cycloalkyl group; wherein R is3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
preferably, R3、R4Each independently selected from C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
more preferably, R3、R4Each independently selected from-CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4Of (C-CH)2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl optionally substituted by 1 or 2R7And (4) substitution.
Each R7Independently selected from hydroxy, cyano, carboxy,Amino, halogen, C1-4Alkyl or-CH2OH; preferably, each R7Independently selected from hydroxy, carboxy, CH3or-CH2OH。
6. A compound of formula V, an isomer, a mixture, a solvate, a hydrate, a prodrug, or a pharmaceutically acceptable salt thereof:
Figure FDA0002416027210000042
wherein R is1、R2The same or different and each is independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, -C1-4Alkoxy radical, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, C1-4Alkoxy radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; further preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, -OMe, cyclopropyl, -CF3。
R3、R4The same or different, and each is independently selected from hydrogen, deuterium, tritium, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6A cycloalkyl group; wherein R is3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
preferably, R3、R4Each independently selected from C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
more preferably, R3、R4Each independently selected from-CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4Of (C-CH)2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl optionally substituted by 1 or 2R7And (4) substitution.
Each R7Independently selected from hydroxy, cyano, carboxy, amino, halogen, C1-4Alkyl or-CH2OH; preferably, each R7Independently selected from hydroxy, carboxy, CH3or-CH2OH。
7. A compound of formula VI, an isomer, a mixture, a solvate, a hydrate, a prodrug, or a pharmaceutically acceptable salt thereof:
Figure FDA0002416027210000051
wherein R is1、R2The same or different and each is independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, C1-4Alkoxy radical, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; preferably, R1、R2Each independently selected from hydrogen, deuterium, tritium, C1-4Alkoxy radical, C3-6Cycloalkyl radical, C1-6A haloalkyl group; further preferred isEarth, R1、R2Each independently selected from hydrogen, deuterium, tritium, -OMe, cyclopropyl, -CF3。
R3、R4The same or different, and each is independently selected from hydrogen, deuterium, tritium, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6A cycloalkyl group; wherein R is3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
preferably, R3、R4Each independently selected from C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4C of (A)1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl radical, -CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl is optionally substituted by 1, 2R7Substitution;
more preferably, R3、R4Each independently selected from-CH2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl radical, said R3Or R4Of (C-CH)2NHC1-6Alkyl, -CH2C3-6Heterocyclyl radical, -CH2NHCH2C3-6Cycloalkyl optionally substituted by 1 or 2R7And (4) substitution.
Each R7Independently selected from hydroxy, cyano, carboxy, ammoniaRadical, halogen, C1-4Alkyl or-CH2OH; preferably, each R7Independently selected from hydroxy, carboxy, CH3or-CH2OH。
8. The compound of any one of claims 1-7, wherein R is1、R2The same; the R is3、R4Also, preferably, said R3、R4Are identical and are selected from the group consisting of-CH2NHCH2CH(OH)CH2COOH、-CH2NHCH2CH2OH、-CH2NHCH2COOH、-CH2NHCH(CH2OH)COOH、-CH2NHCH(CH3)CH2OH、-CH2NHCH(CH3)COOH、
Figure FDA0002416027210000061
9. The compound of claim 8, an isomer, mixture, solvate, prodrug or a pharmaceutically acceptable salt thereof, having the structure:
Figure FDA0002416027210000062
Figure FDA0002416027210000071
10. a pharmaceutical composition comprising a compound of any one of claims 1-9, an isomer, a mixture, a solvate, a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. Use of a compound or pharmaceutical composition of any one of claims 1-10 for the manufacture of a medicament for the treatment of a disease associated with a PD-1/PD-L1 mediated signaling pathway; the related diseases mediated by the PD-1/PD-L1 signal channel are selected from cancers or tumors, infectious diseases or metabolic diseases.
12. The use according to claim 11, wherein the cancer or tumor is selected from the group consisting of lymphoma, sarcoma, melanoma, glioblastoma, synovioma, meningioma, biliary tract tumor, thymus tumor, neural tumor, seminoma, wilms' tumor, pleomorphic adenoma, hepatocellular papilloma, tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, fibroma, central nervous system tumor, rachioma, brain stem glioma, pituitary adenoma, multiple myeloma, ovarian tumor, myelodysplastic syndrome or mesothelioma, prostate cancer, recurrent or prostate cancer that has become resistant to existing drugs, thyroid cancer, parathyroid cancer, anal cancer, testicular cancer, urethral cancer, penile cancer, bladder cancer, ureter cancer, and combinations thereof, Uterine cancer, ovarian cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, adrenal cancer, merkel cell cancer, embryonic cancer, chronic or acute leukemia, bronchial cancer, esophageal cancer, nasopharyngeal cancer, hepatocellular cancer, renal cell cancer, small-cell lung cancer, basal cell cancer, lung cancer, breast cancer, adenocarcinoma, papillary cancer, cystadenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, rectal cancer, colon cancer, colorectal cancer, gastric cancer, pancreatic cancer, head and neck squamous cell cancer, head and neck cancer, gastrointestinal tract, bone cancer, skin cancer, small-intestine cancer, cancer of the endocrine system, renal pelvis cancer, epidermoid carcinoma, abdominal wall cancer, renal cell carcinoma, transitional cell carcinoma, or choriocarcinoma, as well as metastatic tumors; the infectious diseases include bacterial, viral and fungal infections, particularly, but not limited to, HIV, influenza, herpes, Giardia, malaria, Leishmania, pathogenic infections caused by hepatitis virus, herpes virus, adenovirus, influenza virus, arbovirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papilloma virus, molluscum virus, poliovirus, rabies virus, JC virus and arbovirus encephalitis virus, pathogenic infections caused by bacterial chlamydia, rickettsia bacteria, mycobacteria, staphylococci, streptococcus, pneumococcus, meningococci and conococci, Klebsiella, proteus, Serratia, Pseudomonas, HIV, and other strains, HIV, and its derivatives, HIV, and other strains, and strains, escherichia coli, legionella, diphtheria, salmonella, bacillus, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and lyme disease bacteria, pathogenic infections caused by the following fungi: candida, cryptococcus neoformans, aspergillus niger, mucor, trichosporon, blastomyces dermatitidis, paracoccidioides brasiliensis, coccidioidomycosis immitis, and histoplasma capsulatum, and pathogenic infections caused by: proteus dysenteriae, Gliocladium colophonium, Fonax, Proteus spinosus, Giardia haumela, Cryptosporidium, Pneumocystis carinii, Plasmodium vivax, Babesia gordonii, Trypanosoma brucei, Trypanosoma cruzi, Leishmania dorsalis, Toxoplasma gondii, and Glynodera sessiliensis.
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