WO2020011209A1 - Agent immunosuppresseur, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Agent immunosuppresseur, son procédé de préparation et son utilisation pharmaceutique Download PDF

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Publication number
WO2020011209A1
WO2020011209A1 PCT/CN2019/095461 CN2019095461W WO2020011209A1 WO 2020011209 A1 WO2020011209 A1 WO 2020011209A1 CN 2019095461 W CN2019095461 W CN 2019095461W WO 2020011209 A1 WO2020011209 A1 WO 2020011209A1
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alkyl
deuterium
substituted
membered
halogen
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Chinese (zh)
Inventor
张鸣鸣
张永贤
喻红平
陈椎
徐耀昌
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Abbisko Therapeutics Co Ltd
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Abbisko Therapeutics Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/40—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/40—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals
    • C07C15/42—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals monocyclic
    • C07C15/44—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals monocyclic the hydrocarbon substituent containing a carbon-to-carbon double bond
    • C07C15/46—Styrene; Ring-alkylated styrenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • 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
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, and particularly relates to an immunosuppressive agent, a preparation method thereof and pharmaceutical application.
  • the immune system plays a very important role in controlling and eliminating diseases such as cancer.
  • tumor cells often develop surveillance strategies that escape or suppress the immune system to promote their own malignant growth.
  • One of the important mechanisms is to change the expression of co-stimulation and co-suppression of immune checkpoint molecules on immune cells. Blocking the signaling pathway of immune checkpoint molecules such as PD1 has proven to be a very promising and effective treatment.
  • PD-1 Programmed cell death molecule 1
  • CD279 is a receptor molecule expressed on the surface of activated T cells, natural killer T cells, B cells, and macrophages. Its structure contains a Extracellular immunoglobulin variable domain similar domains, a transmembrane region and an intracellular region, where the intracellular region contains two phosphorylation sites, located in the immunoreceptor tyrosine kinase-based inhibitory domain and The switch domain based on immune receptor tyrosine kinases suggests that PD1 can negatively regulate T cell receptor-mediated signaling pathways.
  • PD1 has two ligands, PD-L1 and PDL2, which have different expression profiles.
  • PDL1 protein is up-regulated in macrophages and dendritic cells after lipopolysaccharide (LPS) and granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment.
  • LPS lipopolysaccharide
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • B cell receptor signaling pathways are also upregulated after stimulation. It is also highly expressed in almost all tumor cells and is upregulated after stimulation with interferon (IFN) gamma.
  • IFN interferon
  • PD-1 expressing T cells When PD-1 expressing T cells are in contact with cells expressing their ligands, functional activities such as cell proliferation, cytokine release, and cytolytic activity after stimulation of those antigens are inhibited. Therefore, the interaction of PD1 and its ligands functions as an intrinsic negative feedback regulation mechanism, which can enable people to prevent excessive activation of T cells during infection, immune tolerance or tumorigenesis, thereby reducing autoimmune diseases and promoting autoimmune Tolerance.
  • Long-term antigen stimulation such as that occurring in tumors or long-term infections, will cause T cells to express high levels of PD-1, and lack of activity in response to these long-term antigens, without function, which is what people call T-cell function Exhausted.
  • B cells also have the inhibitory effect of PD1 and its ligands and corresponding functional failure.
  • PDL1 and its ligands can negatively regulate the immune response.
  • PD-1 deficient mice develop lupus-like acute proliferative glomerulonephritis and dilated cardiomyopathy.
  • the use of PDL1 antibodies to block PD-1 / PDL1 interactions has been shown to restore and enhance T cell activation in many systems.
  • PDL1 monoclonal antibodies can also benefit patients with advanced cancer.
  • LCMV model PD-1 / PD-L1 interaction
  • PD-1 / PD-L1 interaction has been found to inhibit virus-specific CD8T cell activation, expansion, and acquisition of effector cell functions.
  • blocking the PD-1 / PDL1 pathway has also been found to enhance the response to vaccines, including the response to therapeutic vaccines in the context of long-term infection.
  • the object of the present invention is to provide a compound having a blocking effect on the PD-1 / PD-L1 interaction, so that it is expected to develop a new generation of PD-1 / PD-L1 inhibitors.
  • the first aspect of the present invention provides a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof:
  • X and Y are each independently selected from N or C (R 8 );
  • R 1 and R 2 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 Heterocyclic group, C 5-10 aryl group or 5-10 membered heteroaryl group, or R 1 and R 2 together with the nitrogen atom to which it is directly attached form a 3-10 membered heterocyclic group.
  • R 4 and R 5 are each independently selected from hydrogen or fluorine, or R 5 and R 6 and the directly connected group together form a 4-10 membered carbocyclic group or a 4-10 membered heterocyclic group, with the proviso that R 4.
  • R 5 is not selected from hydrogen at the same time;
  • Each R 7 is independently selected from the following groups:
  • Each R 10 , R 11 is independently selected from hydrogen, fluorine, cyano or methyl;
  • R 16 is selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl , -C 0-8 -S (O) r R 19 , -C 0-8 -OR 20 , -C 0-8 -C (O) OR 20 , -C 0-8 -C (O) R 20 or -C 0-8 -OC (O) R 21 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5- 10 aryl, 5-10
  • Each of R 17 and R 18 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3 A -10 membered heterocyclic group, a C 5-10 aryl group or a 5-10 membered heteroaryl group, or R 17 and R 18 together with its directly attached nitrogen atom form a 3-10 membered heterocyclic group.
  • Each R 19 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heterocyclic Aryloxy or -NR 22 R 23 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, carbonyl, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 Cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heterocyclic Substituted with aryl, 5-10 membered heteroaryloxy or -
  • Each R 20 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl Or 5- to 10-membered heteroaryl, the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3 -10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5-10 Substituted by heteroaryl, 5-10 membered heteroaryloxy or -NR 22 R 23 substituents;
  • Each R 21 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 Cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heterocyclic Aryl, 5-10 membered heteroaryloxy or -NR 22 R 23 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1- 10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclooxy, C 5-10 aryl, C 5-10 Substituted with aryloxy, 5-10 membered heteroaryl, 5-10 membered
  • R 22 and R 23 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkoxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino, or C 1-10 alkanoyl, the above groups are optionally further selected from one or more of deuterium , Halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C
  • R 22 and R 23 and the directly connected nitrogen atom together form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, and the above-mentioned group is optionally further selected from one or more of deuterium, halogen, and hydroxyl group.
  • Carboxyl C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy Group, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C 5-10 aryl group, C 5-10 aryloxy group , 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
  • (Z) / (E) means cis, trans isomers or a mixture of cis and trans isomers thereof;
  • n 0, 1 or 2;
  • Each p is independently 0, 1, 2 or 3;
  • n, q is independently 0, 1, 2, 3 or 4;
  • Each r is independently 0, 1, or 2.
  • R 6 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, and C.
  • R 6 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, bromine, cyano, and nitrate.
  • R 6 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, hydroxyl, bromine, cyano, Nitro, azide, methyl, cyclopropyl, phenyl, pyridyl, diazole, triazole, methoxy, or carboxyl, the above-mentioned groups are optionally further selected from one or more of deuterium, fluorine , Chloro, hydroxy, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, methanesulfonyl, methoxy, carboxyl or amino.
  • R 1 is selected from hydrogen, deuterium or methyl
  • R 1 is selected from hydrogen, deuterium or methyl
  • R 2 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group, or R 1 and R 2 together with the nitrogen atom to which it is directly attached form a 3-6 membered heterocyclic group, the above group
  • R 1 and R 2 together with the nitrogen atom to which it is directly attached form a 3-6 membered heterocyclic group, the above group
  • R 1 and R 2 together with the nitrogen atom to which it is directly attached form a 3-6 membered heterocyclic group, the above group
  • Optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxy, cyano, methyl, isopropyl, cyclopropyl, 3-oxetanyl, 3-azacyclobutyl, phenyl , Pyridyl, diazole, triazole, O, methanesulfonyl, aminosulfony
  • R 3 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, and C.
  • the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof has a compound selected from the group consisting of a compound of formula (IIa) or a compound of formula (IIb) as follows structure:
  • X and Y are each independently selected from N or C (R 8 ).
  • R 5 and R 6 and the directly connected group together form a 5-6 membered carbocyclic group or a 5-6 membered heterocyclic group.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are as described for the compound of formula (I).
  • each R 7 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is independently selected from the following groups:
  • Each R 10 , R 11 is independently selected from hydrogen, fluorine, cyano or methyl;
  • Each of R 17 and R 18 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 Heterocyclic group, C 5-8 aryl group or 5-8 membered heteroaryl group, or R 17 and R 18 together with the nitrogen atom to which it is directly attached form a 3-8 membered heterocyclic group.
  • R 22a and R 23b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkoxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3- 10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, P-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino, or C 1-10 alkanoyl, the above groups are optionally further selected from one or more of deuterium, halogen , Hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen-substit
  • R 22a and R 23b together with the directly connected nitrogen atom form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, and the above-mentioned group is optionally further selected from one or more selected from the group consisting of deuterium, halogen, and hydroxyl group.
  • R 19 , R 20 , R 21 , R 22 , R 23 , and r are as described for the compound of formula (I).
  • each R 12 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, Bromine, cyano, nitro, azido, methyl, isopropyl, vinyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, 3-azatidine, benzene Methyl, pyridyl, diazole, triazole, methanesulfonyl, aminosulfonyl, methoxy, methoxyacyl, carboxyl, acetyl, acetoxy, amino, dimethylamino, aminoacyl, or acetylamino
  • the above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, trifluoromethyl, cyclopropyl,
  • R 19 , R 20 , R 21 , R 22 , R 23 , and r are as described for the compound of formula (I).
  • each R 9 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is independently selected from -CH 2 -NR 17 R 18 .
  • R 17 is selected from hydrogen or deuterium;
  • the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof has a compound selected from the group consisting of a compound of formula (IIIa) or a compound of formula (IIIb) as follows structure:
  • X in the compound of formula (IIIa) is selected from N or CH;
  • X in the compound of formula (IIIb) is selected from N or CH;
  • R 1 is selected from hydrogen, deuterium or methyl
  • R 2 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group, or R 1 and R 2 and The directly connected nitrogen atoms together form a 3-6 membered heterocyclic group, and the above group is optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, isopropyl, and cyclopropyl.
  • 3-oxetanyl, 3-azetidinyl, phenyl, pyridyl, diazole, triazole, O, methanesulfonyl, aminosulfonyl, methoxy, methoxyacyl, Ethoxyl, carboxyl, acetyl, acetoxy, isopropoxyl, amino, dimethylamino, aminoacyl, acetylamino or
  • the aforementioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, mesyl, and methoxy , Formyloxy, acetoxy, propionyloxy, isobutyryloxy, carboxyl or amino substituents;
  • R 6 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, cyclopropyl, methoxy, or carboxyl, and the above-mentioned group is optionally further selected from one or more of deuterium, fluorine, chlorine With hydroxy, cyano, methyl, cyclopropyl, phenyl or methoxy substituents;
  • Each R 7 is independently selected from the following groups:
  • R 10 and R 11 are independently selected from hydrogen or fluorine;
  • R 17 is selected from hydrogen or deuterium;
  • Each R 12 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, methyl, cyclopropyl, methoxy, or carboxyl, and the above-mentioned groups are optionally further selected from one or more Substituted with deuterium, fluorine, chlorine, hydroxy, cyano, methyl, cyclopropyl, phenyl or methoxy;
  • Each of R 13 and R 14 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 Heteroaryl, -OR 20 , -C (O) OR 20 , -C (O) R 20 , -OC (O) R 21 or -NR 22 R 23 , the above-mentioned groups are optionally further substituted by one or more Substituted with a substituent selected from deuterium, fluorine, chlorine, hydroxy, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, methanesulfonyl, methoxy, carboxyl or amino;
  • R 22a , R 23b and the directly connected nitrogen atom together form a 4- to 10-membered heterocyclic group, and the above group is optionally further selected from one or more of deuterium, halogen, hydroxyl, carboxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 membered heteroaryl group, 5 -10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
  • R 19 , R 20 , R 21 , R 22 , R 23 , and r are as described for the compound of formula (I).
  • each R 19 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, and hydroxyl groups.
  • Each R 20 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5- 8 aryl Or 5-8 membered heteroaryl, the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3 -6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl, C 5-8 aryl, C 5-8 aryloxy, diazole , Triazole, pyridine, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkylamino substituents;
  • Each R 21 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 Cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl, C 5-8 aryl, C 5-8 aryloxy, 5-8 membered heterocyclic Aryl, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkylamino, the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxy, cyano, C 1-4 Alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclooxy, C 5-8 aromatic With C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroary
  • R 22 and R 23 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino, or C 1-4 alkanoyl, the above-mentioned groups are optionally further selected from one or more of deuterium , Halogen, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, hal
  • each R 3 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, and halogen.
  • Each R 12 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, cyclopropyl, methoxy, or carboxyl, and the methyl, cyclopropyl, methoxy is Optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, cyclopropyl, phenyl or methoxy;
  • R 13 and R 14 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 Alkoxy C 1-4 alkyl, C 3-6 cycloalkyl C 1-4 alkyl, benzyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl , Phenyl, cyano-substituted phenyl, C 1-4 alkoxyphenyl, 5-6 membered heteroaryl, C 1-4 alkoxy, halogen-substituted C 1-4 alkoxy, deuterium-substituted C 1 -4 alkoxy, carboxy, methoxy, ethoxy, isopropoxy, acetyl, acetoxy, amino, monomethylamino, dimethylamino or
  • R 22a , R 23b and its directly connected nitrogen atom together form a 4- to 6-membered heterocyclic group, and the above group is optionally further selected from one or more of deuterium, halogen, hydroxyl, carboxyl, C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl, phenyl, phenoxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, Substituted by amino, monoalkylamino, dialkylamino, or C 1-4 alkanoyl substituents.
  • the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:
  • a method for preparing the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof including the following steps:
  • R 7 ' is Alternatively, R 7 'is selected from the group:
  • R 9 ' is -C 0-3 -CHO; X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , m, n, p, q are as described for the compound of formula (I).
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned compound of formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the aforementioned compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition for the prevention and / or treatment of PD-1 / PD- Application of L1 Signaling Pathway to Related Drugs
  • the aforementioned related diseases mediated by the PD-1 / PD-L1 signaling pathway are selected from cancer or tumors, immune-related diseases and disorders, infectious diseases, infectious diseases, or metabolic diseases.
  • the infectious disease is selected from the group consisting of a bacterial infectious disease, a viral infectious disease, and a fungal infectious disease.
  • the aforementioned cancer or tumor is selected from lymphoma (including but not limited to lymphocytic lymphoma, primary central nervous system lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, follicular center Lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma or primary mediastinal large B-cell lymphoma), sarcoma (including but not limited to Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, Leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, angiosarcoma or lymphangiosarcoma), melanoma, glioblastoma, synovial tumor, meningiomas, biliary tumor, thymic tumor, neurotumor, seminoma, nephro
  • lymphoma
  • the immune-related diseases and disorders are selected from rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergies, fibrosis, anemia fibromyalgia, Alz Hemer disease, congestive heart failure, stroke, aortic valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis And multiple sclerosis.
  • the aforementioned infectious disease or infectious disease is selected from the group consisting of sepsis, liver infection, HTV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papilloma virus, or influenza.
  • the aforementioned metabolic disease is selected from the group consisting of diabetes, diabetic ketoacidosis, hyperglycemia and hypertonic syndrome, hypoglycemia, gout, malnutrition, vitamin A deficiency, scurvy, and vitamin D deficiency Or osteoporosis.
  • a fifth aspect of the present invention provides the aforementioned compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition for use in the prevention and / or treatment of PD-1 / PD-L1 signaling pathway-mediated drugs for cancer or tumors, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases.
  • the series of compounds of the present invention have a strong inhibitory effect on the PD-1 / PD-L1 interaction and can be widely used.
  • Alkyl refers to a linear or branched saturated aliphatic hydrocarbon group.
  • C 1-10 alkyl refers to a linear alkyl group containing 1 to 10 carbon atoms and a branched alkyl group, including but Not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2- Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl Group, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethyl Butyl, 2-ethylbutyl, 2-methylp
  • the alkyl group may be optionally substituted or unsubstituted.
  • Cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, for example, " C3-10 cycloalkyl” refers to a cycloalkyl group comprising 3 to 10 carbon atoms , Divided into monocyclic cycloalkyl, polycyclic cycloalkyl, of which:
  • Monocyclic cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl and others.
  • Polycyclic cycloalkyl includes spiro, fused and bridged cycloalkyl.
  • “Spirocycloalkyl” refers to polycyclic groups that share one carbon atom (called a spiro atom) between single rings. These may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has A completely conjugated ⁇ -electron system.
  • Spirocycloalkyl is divided into monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl according to the number of common spiro atoms between the rings.
  • Spirocycloalkyl includes but is not limited to:
  • fused cycloalkyl refers to a full-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, where one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a completely conjugated ⁇ -electron system. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of constituent rings.
  • the fused cycloalkyl includes but is not limited to:
  • Bridged cycloalkyl refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more (preferably 1, 2 or 3) double bonds, but none of them The ring has a completely conjugated ⁇ -electron system. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings.
  • the bridged cycloalkyl includes but is not limited to:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl , Benzocycloheptyl and the like.
  • a cycloalkyl group may be optionally substituted or unsubstituted.
  • Heterocyclyl or “heterocyclic” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen Or S (O) r (where r is an integer of 0, 1, 2), but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon.
  • O oxygen Or S
  • Monocyclic heterocyclyls include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between single rings, where one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen and oxygen Or S (O) r (where r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2, or 3), but none of the rings have a completely conjugated pi electron system.
  • Spiro heterocyclyl is classified into monospiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl according to the number of common spiro atoms between the rings.
  • Spiro heterocyclyl includes, but is not limited to:
  • “Fused heterocyclyl” refers to a polycyclic heterocyclic group where each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more (preferably 1, 2, 3, or 4) rings may Contains one or more (preferably 1, 2, or 3) double bonds, but none of the rings have a completely conjugated ⁇ electron system, in which one or more (preferably 1, 2, 3, or 4) ring atoms are selected
  • the fused heterocyclyl includes but is not limited to:
  • Bridged heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more (preferably 1, 2, or 3) double bonds, but none of them
  • the ring has a completely conjugated ⁇ -electron system in which one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S (O) r (where r is an integer of 0, 1, 2) Heteroatoms, and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include, but are not limited to:
  • the heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, including but not limited to:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • Aryl or “aromatic ring” refers to a full-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups, polycyclic rings having a conjugated ⁇ -electron system (that For carbon atom ring) groups, for example, “C 5-10 aryl” refers to a full-carbon aryl group containing 5-10 carbons, and “5-10 member aryl” refers to a full-carbon group containing 5-10 carbons
  • Aryl includes, but is not limited to, phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:
  • the aryl group may be substituted or unsubstituted.
  • Heteroaryl or “heteroaromatic ring” refers to a heteroaromatic system containing 1 to 4 heteroatoms including nitrogen, oxygen, and S (O) r (where r is an integer of 0, 1, 2) Heteroatom, for example, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, and 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, including but It is not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:
  • Heteroaryl may be optionally substituted or unsubstituted.
  • Alkenyl refers to at least two carbon atoms and at least one carbon - carbon double bond as defined above consisting of an alkyl group, e.g., C 2- 10 alkenyl group refers to a straight chain containing 2-10 carbon atoms or branched Alkenyl. These include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.
  • Alkenyl may be substituted or unsubstituted.
  • Alkynyl refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • C 2-10 alkynyl refers to a straight or branched chain containing 2 to 10 carbons.
  • Alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
  • the alkynyl may be substituted or unsubstituted.
  • Alkoxy refers to -O- (alkyl), where alkyl is as defined above, for example, “C 1-10 alkoxy” refers to an alkyloxy group containing 1-10 carbons, including but not Limited to methoxy, ethoxy, propoxy, butoxy and the like.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • Cycloalkoxy refers to -O-cycloalkyl, where cycloalkyl is as defined above, for example, "C 3-10 cycloalkoxy” refers to a cycloalkyloxy group containing 3-10 carbons Including, but not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • the cycloalkoxy group may be optionally substituted or unsubstituted.
  • Heterocyclyloxy refers to -O-heterocyclyl, wherein the definition of heterocyclyl is as described above, for example, " C3-10 heterocyclyl” refers to heterocyclyloxy containing 3-10 carbons Including, but not limited to, azetidinyloxy, oxetanyloxy, azetyloxy, nitrogen, oxethanyloxy, and the like.
  • the heterocyclooxy group may be optionally substituted or unsubstituted.
  • C 1-10 alkanoyl refers to the monovalent atomic group remaining after the C 1-10 alkyl acid has been removed from the hydroxyl group, and is usually also expressed as "C 0-9 -C (O)-", for example, “C 1 -C (O)-"means acetyl;” C 2 -C (O)-"means propionyl;” C 3 -C (O)-"means butyryl or isobutyryl.
  • -C 0-8 -OR 20 means that the oxygen atom in -OR 20 is attached to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and the definition of C 1-8 alkyl group is as described above.
  • -C 0-8 -OC (O) R 21 refers to a -OC (O) R 21 is an oxygen atom attached to C 0-8 alkyl, wherein C 0 alkyl means a bond, C 1- 8 alkyl
  • the definition of base is as described above.
  • Halo-substituted C 1-10 alkyl refers to a 1-10 carbon alkyl group optionally substituted with hydrogen on the alkyl by fluorine, chlorine, bromine, or iodine atoms, including, but not limited to, difluoromethyl, di Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • Halo-substituted C1-10 alkoxy refers to a 1-10 carbon alkoxy group optionally substituted with hydrogen on the alkyl group by fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.
  • Deuterium-substituted C1-10 alkyl refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl is optionally substituted with a deuterium atom. Including, but not limited to, monodeuteryl, dideuteryl, trideuteryl, and the like.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • heterocyclic group optionally substituted with alkyl group means that the alkyl group may but need not exist, and this description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group are substituted independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort.
  • an amino or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom (such as an olefin) having an unsaturated bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or a physiological / pharmaceutically acceptable salt or prodrug thereof with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
  • the compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid-mass chromatography (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 or Bruker AVANCE-500 nuclear magnetic analyzer. The measurement solvents were deuterated dimethylsulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD), and deuterated water (D 2 O). And deuterated chloroform (CDCl 3 ) with an internal standard of tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethylsulfoxide
  • CD 3 OD deuterated methanol
  • D 2 O deuterated water
  • TMS deuterated chloroform
  • Liquid chromatography-mass spectrometry LC-MS was performed using an Agilent 6120 mass spectrometer.
  • an Agilent 1200 DAD high-pressure liquid chromatography (Sunfire C18 150 ⁇ 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatography (Gimini C18 150 ⁇ 4.6 mm column) were used.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specifications adopted by TLC are 0.15mm ⁇ 0.20mm, and the specifications adopted by thin layer chromatography purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or they can be synthesized or synthesized according to methods known in the art.
  • Methyl 4-bromo-2,6-difluorobenzoate (7.5 g, 30 mmol) was dissolved in methanol (50 mL), and a 30% sodium methoxide methanol solution (20.16 mL, 120 mmol) was added. The reaction was stirred at 80 ° C for 16 hours. After the reaction was completed, it was poured into ice water (300 mL), and then extracted with ethyl acetate (200 mL * 2).
  • Step 2 Synthesis of methyl 2,6-dimethoxy-4-((trimethylsilyl) ethynyl) benzoate
  • Methyl 2,6-dimethoxy-4-((trimethylsilyl) ethynyl) benzoate (7.7 g, 27.26 mmol) was dissolved in methanol (150 mL) and potassium carbonate (3.76 g , 27.26 mmol), and the reaction was stirred at room temperature for 10 minutes. After completion of the reaction, filtration and concentration were performed after column chromatography [eluent: petroleum ether ⁇ petroleum ether / ethyl acetate (3/1)] to obtain methyl 4-ethynyl-2,6-dimethoxybenzoate (5.0 g, yield 83.4%).
  • Step 4 Synthesis of methyl 4- (bromoethynyl) -2,6-dimethoxybenzoate
  • Step 5 Synthesis of methyl (Z) -4- (2-bromo-1-fluorovinyl) -2,6-dimethoxybenzoate
  • Step 2 Synthesis of 3'-bromo-2,2'-dimethyl- [1,1'-biphenyl] -3-amine
  • Methyl 4-methoxymethylpicolinate (20 g, 0.12 mol) was placed in concentrated sulfuric acid (150 mL), NBS (38.3 g, 0.22 mol) was added, and the reaction was stirred at room temperature for 16 hours. After completion of the reaction, water, an aqueous sodium hydrogen carbonate solution were sequentially added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed sequentially with water, saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated. The crude product was separated by silica gel column chromatography to obtain methyl 5-bromo-4-methoxymethylpicolinate (22.5 g, yield 77%). ESI-MS 246/248 [M + H] + .
  • Methyl 5-bromo-4-methoxymethylpicolinate (22.5 g, 91.4 mmol) was dissolved in a mixed solvent of tetrahydrofuran (80 mL), methanol (80 mL) and water (32 mL), and then NaOH (9.1 g, 0.23 mol), and the reaction was stirred at room temperature for half an hour. After the reaction was completed, it was concentrated, neutralized by adding a 1M aqueous HCl solution, and then extracted by adding a dichloromethane: methanol (12: 1) solution.
  • N, N-di (2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) aniline 400 mg, 1.71 mmol
  • methyl formamide 10 mL
  • 5-formyl-4-methoxy-o-picolinic acid 373 mg, 2.06 mmol
  • 3-oxohexafluorophosphate 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridine positive ion 650 mg, 1.71 mmol
  • diisopropylethylamine 661 mg, 5.13 mmol
  • Step 4 Synthesis of (6- (3-bromo-2-chlorophenyl) -2-methoxy-4-methylpyridin-3-yl) methanol
  • the third step the synthesis of 4- (hydroxymethyl) -3-methoxybenzaldehyde
  • Step 3 Synthesis of 4-((3-bromo-2-methylbenzyl) oxo) -5-chloro-2-hydroxybenzene (m) aldehyde
  • Step 4 Synthesis of 5-((5-((3-bromo-2-methylbenzyl) oxo) -4-chloro-2-formylphenoxy) methyl) nicotinenitrile
  • the fifth step 5-((4-chloro-2-formyl-5-((2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxane Synthesis of pentyl-2-yl) benzyl) oxo) phenoxy) methyl) nicotyronitrile
  • Step 5 Synthesis of 7- (bromoethynyl) -2,2-dimethyl-4H-benzo [d] [1,3] dioxin
  • Step 8 (Z) -7- (2- (3-Bromo-2-methylphenyl) -1-fluorovinyl) -2,2-dimethyl-4H-benzo [d] [1 3) Dioxin Synthesis
  • Step 9 Synthesis of (Z) -5- (2- (3-bromo-2-methylphenyl) -1-fluorovinyl) -2- (hydroxymethyl) phenol
  • Step 10 Synthesis of (Z) -4- (2- (3-bromo-2-methylphenyl) -1-fluorovinyl) -2-hydroxybenzene (methyl) aldehyde
  • Step 11 (Z) -5-((5- (2- (3-Bromo-2-methylphenyl) -1-fluorovinyl) -2-formylphenoxy) methyl) nicotine Synthesis of nitrile
  • Step 1 Synthesis of (R) -1- (3- (3-bromo-2-methylphenoxy) propyl) pyrrolidin-3-ol
  • Step 2 Synthesis of methyl 4-chloro-5- (dibromomethyl) methylpyridine
  • Carbon tetrachloride 120 mL was added to a single-necked bottle containing methyl 4-chloro-5-methylmethylpyridine (5.3 g, 28.5 mmol), followed by N-bromosuccinimide (11.1 g, 62.8 mmol), and azobisisobutyronitrile (0.94 g, 5.7 mmol). After evacuation and nitrogen replacement, the reaction was stirred at 90 ° C for 24 hours.
  • Step 4 Synthesis of methyl 4-chloro-5- (dimethoxymethyl) methylpicolinate
  • Step 5 Synthesis of 4-chloro-5- (dimethoxymethyl) o-picolinic acid
  • Step 2 Synthesis of methyl 4-chloro-5- (dibromomethyl) methylpyridine
  • Carbon tetrachloride 120 mL was added to a single-necked bottle containing methyl 4-chloro-5-methylmethylpyridine (5.3 g, 28.5 mmol), followed by N-bromosuccinimide (11.1 g, 62.8 mmol), and azobisisobutyronitrile (0.94 g, 5.7 mmol). After evacuation, the reaction solution was stirred at 90 ° C for 24 hours.
  • Step 4 Synthesis of methyl 4-cyclopropyl-5-formylmethylpyridate
  • Methyl (Z) -4- (2- (3'-amino-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -1-fluorovinyl)- 2,6-Dimethoxybenzoate (1.4 g, 3.2 mmol) was dissolved in dichloromethane (10 mL), diisobutylaluminum hydride (32 mL, 32 mmol) was added, and the reaction was stirred at room temperature for 2 hours.
  • Step 3 (Z) -5- (Dimethoxymethyl) -N- (3 '-(2-fluoro-2- (4- (hydroxymethyl) -3,5-dimethoxyphenyl) ) Vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -4-methoxymethylpyridinamide
  • Step 4 (Z) -N- (3 '-(2-fluoro-2- (4- (hydroxymethyl) -3,5-dimethoxyphenyl) vinyl) -2,2'-di Synthesis of methyl- [1,1'-biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide
  • Step 5 (Z) -N- (3 '-(2-fluoro-2- (4-formyl-3,5-dimethoxyphenyl) vinyl) -2,2'-dimethyl- Synthesis of [1,1'-Biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide
  • Step 6 (Z) -N- (3 '-(2-fluoro-2- (4-(((2-hydroxyethyl) amino) methyl) -3,5-dimethoxyphenyl) ethylene Phenyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -5-(((2-hydroxyethyl) amino) methyl) -4-methoxy Synthesis of Pyridylamide
  • the first step Synthesis of 2-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) aniline
  • Step 4 (Z) -N- (2-chloro-3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2'-methyl- [1 , 1'-Biphenyl] -3-yl) -5- (dimethoxymethyl) -4-methoxymethylpyridinamide
  • Step 5 (Z) -N- (2-chloro-3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2'-methyl- [1 , 1'-Biphenyl] -3-yl) -5-Formyl-4-methoxymethylpyridinamide
  • Examples 18 to 20 are prepared by the synthetic method of reference example 17:
  • Step 3 (Z) -2-((((6- (2-chloro-3 '-(2-fluoro-2- (4-(((2-hydroxyethyl) amino) methyl) -3- Methoxyphenyl) vinyl) -2'-methyl- [1,1'-biphenyl] -3-yl) -2-methoxy-4-methylpyridin-3-yl) methyl) Synthesis of Amino) ethane-1-ol
  • the second step (((1Z, 1'Z)-(2,2'-dimethyl- [1,1'-biphenyl] -3,3'-diyl) bis (1-fluoroethylene- Synthesis of 2,1-diyl)) bis (2,6-dimethoxy-4,1-phenylene)) dimethanol
  • Step 4 2,2 '-(((((((1Z, 1'Z)-(2,2'-dimethyl- [1,1'-biphenyl] -3,3'-diyl) Bis (1-fluoroethylene-2,1-diyl)) bis (2,6-dimethoxy-4,1-phenylene)) bis (methylene)) bis (azetanediyl)) Synthesis of bis (ethane-1-ol)
  • the first step Synthesis of methyl (Z) -6- (2- (3-chloro-2-methylphenyl) -1-fluorovinyl) -4-methoxynicotanoate
  • Step 2 Synthesis of (Z)-(6- (2- (3-chloro-2-methylphenyl) -1-fluorovinyl) -4-methoxypyridin-3-yl) methanol
  • Step 4 (Z) -N- (3 '-(2-fluoro-2- (5-formyl-4-methoxypyridin-2-yl) vinyl) -2,2'-dimethyl -[1,1'-Biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide
  • Step 5 (Z) -N- (3 '-(2-fluoro-2- (5-(((2-hydroxyethyl) amino) methyl) -4-methoxypyridin-2-yl) Vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -5-(((2-hydroxyethyl) amino) methyl) -4-methoxy Of methylpyridylamide
  • Examples 39 to 58 are prepared by the synthetic method of reference example 38:
  • Step 5 (Z)-(7-chloro-2- (3 '-(2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2,2' Of dimethyl- [1,1'-biphenyl] -3-yl) benzo [d] oxazol-5-yl) methanol
  • Step 6 (Z) -7-chloro-2- (3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2'-dimethyl Synthesis of-[1,1'-biphenyl] -3-yl) benzo [d] oxazole-5-carboxaldehyde
  • Examples 60 to 61 are prepared by the synthetic method of reference example 59:
  • Example 62 (Z) -2-((4- (1-fluoro-2- (3 '-((3-(((2-hydroxyethyl) amino) methyl) -1,7-diaza Naphthalene-8-yl) amino) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxybenzyl) amino) ethane-1 -Alcohol preparation
  • Trifluoro (vinyl) was added to a suspension of 3-bromo-8-chloro-1,7-diazanaphthalene (1.96 g, 8 mmol) in 1,4-dioxane / water (50 mL / 20 mL).
  • Potassium borate (1.25 g, 9.6 mmol
  • sodium carbonate 2.5 g, 24 mmol
  • [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (584 mg, 0.8 mmol).
  • the reaction was stirred at 95 ° C for 2 hours. Then use dichloromethane and a water layer.
  • Step 4 8-((3'-bromo-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphthalene-3 -Synthesis of formaldehyde
  • Step 5 (8-((3'-bromo-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphthalene- Synthesis of 3-yl) methanol
  • Step 8 (Z) -8-((3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1 , 1'-Biphenyl] -3-yl) amino) -1,7-Diazanaphthalene-3-carbaldehyde
  • Examples 63 to 71 are prepared by the synthesis method of reference example 62:
  • Step 4 Synthesis of (E)-(4-((4-bromo-2,3-dihydro-1H-inden-1-ylidene) methyl) -2-methoxyphenyl) methanol
  • Step 5 (E) -5-formyl-N- (3- (1- (4- (hydroxymethyl) -3-methoxybenzylidene) -2,3-dihydro-1H-indene Synthesis of 4--4-yl) -2-methylphenyl) -4-methoxymethylpyridinamide
  • Step 6 (E) -5-formyl-N- (3- (1- (4-formyl-3-methoxybenzylidene) -2,3-dihydro-1H-indene-4- Of methyl) -2-methylphenyl) -4-methoxymethylpyridamide
  • Examples 73 to 79 are prepared by the synthetic method of reference example 72:
  • Example 80 Dimethyl 2,2 '-(((((((((((((((((((((1E, 1'E) -2,2', 3,3'-tetrahydro-1H, 1'H- [4,4'-linked Indene] -1,1'-diylidene) bis (methylidene)) bis (2-methoxy-4,1-phenylene)) bis (methylene)) bis (azepinediyl )) (2R, 2'R) -bis (3-hydroxypropionate)
  • Step 2 (((((((1E, 1'E) -2,2 ', 3,3'-tetrahydro-1H, 1'H- [4,4'-biindene] -1,1'-di Synthesis of subunits) bis (methylidene)) bis (2-methoxy-4,1-phenylene)) dimethanol
  • Second step (R, Z) -5-((5- (1-fluoro-2- (3 '-(3-hydroxypyrrolidin-1-yl) propoxy) -2,2' -Dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-(((2-hydroxyethyl) amino) methyl) phenoxy) methyl) synthesis
  • Examples 96 to 97 are prepared by the synthetic method of reference example 95:
  • Second step (Z) -5-((4-chloro-5-((3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2 Synthesis of '-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) -2-formylphenoxy) methyl) nicotinenitrile
  • the third step (Z) -5-((4-chloro-5-((3 '-(2-fluoro-2- (4-(((2-hydroxyethyl) amino) methyl) -3- Methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) -2-(((2-hydroxyethyl) amino ) Methyl) phenoxy) methyl) nicotine nitrile
  • Examples 99 to 100 are prepared by the synthetic method of reference example 98:
  • Step 3 5-((5-((Z) -1-fluoro-2- (3 '-((Z) -2-fluoro-2- (4-(((2-hydroxyethyl) amino)) (Methyl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-(((2- Synthesis of hydroxyethyl) amino) methyl) phenoxy) methyl) nicotinenitrile
  • Examples 102 to 103 are prepared by the synthetic method of reference example 101:
  • Examples 104 to 124 were prepared by referring to the synthetic method of Example 1:
  • Example 125 (4-((Z) -1-Fluoro-2- (3 '-(5-(((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methoxymethyl Of pyridylamino) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxybenzyl) -D-serine
  • Second step methyl (Z)-(4- (1-fluoro-2- (3 '-(5-formyl-4-methoxymethylpyridylamino) -2,2'-dimethyl -[1,1'-Biphenyl] -3-yl) vinyl) -2-methoxybenzyl) -D-serine
  • the third step methyl (4-((Z) -1-fluoro-2- (3 '-(5-(((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methyl Oxymethylpyridinylamino) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxybenzyl) -D-serine Synthesis
  • the fourth step (4-((Z) -1-fluoro-2- (3 '-(5-(((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methoxy Synthesis of methylpyridylamino) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxybenzyl) -D-serine
  • Examples 126 to 188 were prepared by the synthesis method of reference example 125:
  • Examples 199 to 201 are prepared by the synthetic method of reference example 62:
  • Example 202 (S) -1-((8-((3 '-((Z) -2-fluoro-2- (4-(((R) -3-hydroxypyrrolidin-1-yl) methyl Yl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphthalene- Preparation of 3-yl) methyl) piperidine-2-carboxylic acid
  • the fourth step (S) -1-((8-((3 '-((Z) -2-fluoro-2- (4-(((R) -3-hydroxypyrrolidin-1-yl) methyl Yl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphthalene- Synthesis of 3-yl) methyl) piperidine-2-carboxylic acid
  • Examples 203 to 212 are prepared by the synthetic method of reference example 202:
  • Examples 226 to 230 are prepared by the synthetic method of Reference Example 62:
  • the effect of the compound of the embodiment of the present invention and the positive compound on the PD-1 / PD-L1 protein interaction expressed on the cell surface and the effect of the T cell function brought about by it are determined by the Jurkat reporter gene cell activity test.
  • the NF-kB-luc reporter gene plasmid and human PD-1 plasmid were transfected into Jurkat cells to establish a stable transgenic cell line that stably expresses both PD-1 and NF-kB-Luc reporter genes.
  • Flow cytometry was used to identify the surface expression level of PD-1, and reporter gene response after stimulation with OKT-3 and Raiji cells was used to identify the expression level of the reporter gene.
  • human PD-L1 expression plasmid was transfected into Raji cells to obtain a cell line stably expressing PD-L1. Then Jurkat / NF-kB-luc / PD1 cells and Raji-PD-L1 cells were co-cultured and stimulated with OKT-3. Compounds were added on this basis, and the readings of the gene response were reported to reflect the compounds' response to PD-1 / PD. Inhibition of -L1 interaction enhances T cell activation signaling pathway.
  • the specific experimental methods are as follows:
  • the compounds of the present invention have a strong inhibitory effect on the protein interaction of PD-1 / PD-L1, and this inhibitory effect can enhance or restore the T cell at the cellular level. activation.

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Abstract

L'invention concerne un agent immunosuppresseur ayant la structure de formule (I), son procédé de préparation et son utilisation pharmaceutique. La présente invention concerne une série de composés ayant une forte activité inhibitrice sur l'interaction PD-1/PD-L1, qui peuvent être largement utilisés dans la préparation de médicaments pour prévenir et/ou traiter des cancers ou des tumeurs, des maladies et des troubles liés à l'immunité, des maladies transmissibles, des maladies infectieuses ou des maladies métaboliques à médiation par la voie de signalisation PD-1/PD-L1, et sont supposés être développés en une nouvelle génération d'inhibiteurs PD-1/PD-L1.
PCT/CN2019/095461 2018-07-11 2019-07-10 Agent immunosuppresseur, son procédé de préparation et son utilisation pharmaceutique Ceased WO2020011209A1 (fr)

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WO2021139647A1 (fr) 2020-01-07 2021-07-15 上海和誉生物医药科技有限公司 Dérivé de biphényle fluor à double liaison, son procédé de préparation et son utilisation pharmaceutique
US11130740B2 (en) 2017-04-25 2021-09-28 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1H-indene analogs and methods using same
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WO2022033303A1 (fr) * 2020-08-11 2022-02-17 中国人民解放军军事科学院军事医学研究院 Dérivé de benzylamine, son procédé de préparation et son utilisation
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CN114315787A (zh) * 2021-12-30 2022-04-12 广州佳途科技股份有限公司 一种维兰特罗ep杂质2的制备方法及应用
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WO2022257833A1 (fr) * 2021-06-07 2022-12-15 上海海雁医药科技有限公司 Intermédiaire de dérivé de phénylpropyl pyridine substitué et procédé de préparation dudit intermédiaire
CN115605475A (zh) * 2020-06-17 2023-01-13 上海和誉生物医药科技有限公司（Cn） 一种免疫抑制剂、其制备方法和应用
WO2023114365A1 (fr) * 2021-12-16 2023-06-22 Aligos Therapeutics, Inc. Méthodes et compositions pour le ciblage de pd-l1
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US11426364B2 (en) 2016-06-27 2022-08-30 Chemocentryx, Inc. Immunomodulator compounds
US11793771B2 (en) 2016-06-27 2023-10-24 Chemocentryx, Inc. Immunomodulator compounds
US11130740B2 (en) 2017-04-25 2021-09-28 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1H-indene analogs and methods using same
US11708326B2 (en) 2017-07-28 2023-07-25 Chemocentryx, Inc. Immunomodulator compounds
US11691985B2 (en) 2017-08-08 2023-07-04 Chemocentryx, Inc. Macrocyclic immunomodulators
US11059834B2 (en) 2017-08-08 2021-07-13 Chemocentryx, Inc. Macrocyclic immunomodulators
US11135210B2 (en) 2018-02-22 2021-10-05 Chemocentryx, Inc. Indane-amines as PD-L1 antagonists
US11759458B2 (en) 2018-02-22 2023-09-19 Chemocentryx, Inc. Indane-amines as PD-L1 antagonists
US12083118B2 (en) 2018-03-29 2024-09-10 Arbutus Biopharma Corporation Substituted 1,1′-biphenyl compounds, analogues thereof, and methods using same
US12533354B2 (en) 2019-05-15 2026-01-27 Chemocentryx, Inc. Triaryl compounds for treatment of PD-L1 diseases
US11266643B2 (en) 2019-05-15 2022-03-08 Chemocentryx, Inc. Triaryl compounds for treatment of PD-L1 diseases
US11485708B2 (en) 2019-06-20 2022-11-01 Chemocentryx, Inc. Compounds for treatment of PD-L1 diseases
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US11866429B2 (en) 2019-10-16 2024-01-09 Chemocentryx, Inc. Heteroaryl-biphenyl amines for the treatment of PD-L1 diseases
US12497383B2 (en) 2019-10-16 2025-12-16 Chemocentryx, Inc. Heteroaryl-biphenyl amides for the treatment of PD-L1 diseases
WO2021139647A1 (fr) 2020-01-07 2021-07-15 上海和誉生物医药科技有限公司 Dérivé de biphényle fluor à double liaison, son procédé de préparation et son utilisation pharmaceutique
US12473282B2 (en) 2020-01-07 2025-11-18 Abbisko Therapeutics Co., Ltd. Biphenyl fluorine double bond derivative, preparation method therefor, and pharmaceutical application thereof
CN115605475A (zh) * 2020-06-17 2023-01-13 上海和誉生物医药科技有限公司（Cn） 一种免疫抑制剂、其制备方法和应用
WO2022033303A1 (fr) * 2020-08-11 2022-02-17 中国人民解放军军事科学院军事医学研究院 Dérivé de benzylamine, son procédé de préparation et son utilisation
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WO2022257833A1 (fr) * 2021-06-07 2022-12-15 上海海雁医药科技有限公司 Intermédiaire de dérivé de phénylpropyl pyridine substitué et procédé de préparation dudit intermédiaire
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WO2023114365A1 (fr) * 2021-12-16 2023-06-22 Aligos Therapeutics, Inc. Méthodes et compositions pour le ciblage de pd-l1
CN114315787A (zh) * 2021-12-30 2022-04-12 广州佳途科技股份有限公司 一种维兰特罗ep杂质2的制备方法及应用

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