WO2021008491A1 - 一种阻断pd-1/pd-l1相互作用的联苯基衍生物及其制备方法和应用 - Google Patents

一种阻断pd-1/pd-l1相互作用的联苯基衍生物及其制备方法和应用 Download PDF

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WO2021008491A1
WO2021008491A1 PCT/CN2020/101646 CN2020101646W WO2021008491A1 WO 2021008491 A1 WO2021008491 A1 WO 2021008491A1 CN 2020101646 W CN2020101646 W CN 2020101646W WO 2021008491 A1 WO2021008491 A1 WO 2021008491A1
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cancer
substituted
compound
formula
cyclopropyl
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English (en)
French (fr)
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杨飞
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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Priority to EP20840778.3A priority Critical patent/EP4001274A4/en
Priority to CN202080036514.6A priority patent/CN113825751A/zh
Priority to US17/619,889 priority patent/US20220380342A1/en
Publication of WO2021008491A1 publication Critical patent/WO2021008491A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • 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
    • C07D405/14—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 three or more hetero rings

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to a biphenyl derivative that blocks the interaction of PD-1/PD-L1, and a preparation method and application thereof.
  • the immune system plays a very important role in controlling and eliminating diseases such as cancer.
  • tumor cells can often develop strategies to escape or suppress the surveillance of the immune system to promote their own malignant growth.
  • One of the most important mechanisms is to change 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 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 The extracellular immunoglobulin variable region is similar to the structural domain, a transmembrane region and an intracellular region. The intracellular region contains two phosphorylation sites located in the inhibitory domain and the immunoreceptor tyrosine kinase-based Based on the switch domain of immunoreceptor tyrosine kinase, it is suggested that PD1 can negatively regulate the signal pathway mediated by T cell receptor.
  • PD1 has two ligands, PD-L1 and PDL2, which differ in their expression profiles.
  • PDL1 protein is up-regulated in macrophages and dendritic cells after treatment with lipopolysaccharide (LPS) and granulocyte-macrophage colony stimulating factor (GM-CSF), and after T cells and B cells pass through T cell receptors and The B cell receptor signaling pathway will also be upregulated after stimulation. It is also highly expressed in almost all tumor cells, and the expression will be upregulated after interferon (IFN) gamma stimulation.
  • IFN interferon
  • the PD-1 expressing T cells When the PD-1 expressing T cells are in contact with the cells expressing their ligands, the functional activities after the antigen stimulation, such as cell proliferation, cytokine release and cell lysis activity are inhibited. Therefore, the interaction between PD1 and its ligand functions as an inherent negative feedback regulation mechanism that can prevent over-activation of T cells during infection, immune tolerance or tumor occurrence, thereby reducing autoimmune diseases and promoting autoimmunity Tolerance.
  • Long-term antigen stimulation such as those that occur in tumors or long-term infections, will cause T cells to express high levels of PD-1, and lack activity and no function in response to these long-term antigens, 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.
  • PD-1 deficient mice develop lupus erythematosus-like acute proliferative glomerulonephritis and dilated cardiomyopathy.
  • the use of antibodies against PDL1 to block the interaction of PD-1/PDL1 has been shown to restore and enhance T cell activation in many systems.
  • PDL1 monoclonal antibodies can also bring benefits to patients with advanced cancer.
  • Some preclinical animal tumor models show that blocking the PD-1/PD-L1 signaling pathway by monoclonal antibodies can enhance immune response and lead to immune response to a series of tumors with significantly different histology, using long-term infection
  • the interaction of PD-1/PD-L1 has been found to inhibit virus-specific CD8 T cell activation, expansion, and the 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 under long-term infections.
  • the purpose of the present invention is to provide biphenyl derivatives that block the interaction of PD-1/PD-L1, so that a new generation of PD-1/PD-L1 inhibitors is expected to be developed.
  • the first aspect of the present invention provides a compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof:
  • R 1 is selected from the following groups:
  • R 2 is selected from -NHR 6 or 4-6 membered nitrogen-containing heterocyclic group, wherein the nitrogen atom is connected to a methylene group, and the 4-6 membered nitrogen-containing heterocyclic group is optionally further selected from deuterium, Halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 Member heterocyclic group, hydroxy substituted C 3-6 cycloalkyl, carboxy substituted C 3-6 cycloalkyl, hydroxy substituted 4-6 membered heterocyclic group, carboxy substituted 4-6 membered heterocyclic group, hydroxy, C 1- 4 substituted by alkoxy, carboxy or C 1-4 alkoxy acyl substituents;
  • R 3 , R 4 , and R 5 are each independently selected from hydrogen, deuterium or C 1-4 alkyl, and the C 1-4 alkyl is optionally further selected from deuterium, halogen, cyano, ring Substituted by propyl, hydroxyl or C 1-4 alkoxy substituents;
  • R 6 is selected from C 1-4 alkyl, C 3-6 cycloalkyl or C 4-6 heterocyclic group, wherein the heterocyclic group optionally contains 1-2 heteroatoms selected from N or O, as described above
  • the group is optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group, hydroxy substituted C 3-6 cycloalkyl, carboxy substituted C 3-6 cycloalkyl, hydroxy substituted 4-6 membered heterocyclic, carboxyl Substituted by substituted 4-6 membered heterocyclic group, hydroxy group, C 1-4 alkoxy group, carboxyl group or C 1-4 alkoxy acyl group;
  • R 2 and R 1 are the same or different, provided that when R 1 is selected from When R 2 and R 1 are different, when R 1 is selected from When, R 2 and R 1 are the same or different.
  • the compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, R 3 , R 4 , and R 5 are each independently selected from hydrogen, deuterium, methyl, Ethyl or propyl, the above groups are optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, cyclopropyl, hydroxyl, methoxy or ethoxy;
  • R 6 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • the above-mentioned groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, bromine, cyano, nitro, azido, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl , Dichloromethyl, trichloromethyl, dibromomethyl, tribromomethyl, di-deuteromethyl, trideuteromethyl, hydroxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxycyclopropyl base, Substituted by substituents of hydroxyl, methoxy, ethoxy, carboxy, methoxy or ethoxy.
  • the compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, the compound of formula (I) has the following formula (IIa) compound, formula (IIb) compound or Structure of compound of formula (IIc), compound (IId) or compound (IIe):
  • R 2 is selected from -NHR 6 or 4-6 membered nitrogen-containing heterocyclic group, wherein the nitrogen atom is connected to the methylene group, provided that in the compound of formula (IIa), R 2 is not selected from In the compound of formula (IIb), R 2 is not selected from In the compound of formula (IIc), R 2 is not selected from
  • the 4-6 membered nitrogen-containing heterocyclic group is selected from the following structures: The above structure is optionally further selected by one or more selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, cyclopropyl, hydroxycyclopropyl, hydroxymethyl, hydroxyl, methoxy Substituted by substituents of ethoxy, ethoxy, carboxy, methoxy or ethoxy;
  • R 3 , R 4 , and R 5 are each independently selected from hydrogen, deuterium, methyl or ethyl;
  • R 6 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, cyclopropyl, hydroxycyclopropyl, hydroxymethyl, hydroxyl, methyl It is substituted by substituents of oxy, ethoxy, carboxy, methoxy or ethoxy.
  • the compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof are selected from the following compounds:
  • the second aspect of the present invention provides a method for preparing the aforementioned compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof, which comprises the following steps:
  • the third aspect of the present invention provides a pharmaceutical composition, which comprises the aforementioned compound of formula (I), its stereoisomer, prodrug or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.
  • the fourth aspect of the present invention provides a compound of the aforementioned formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof in the preparation, prevention and/or treatment of PD-1/PD-L1 signaling pathways.
  • the 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 bacterial infectious diseases, viral infectious diseases or fungal infectious diseases;
  • the 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, slip Meningioma, meningioma, biliary tumor,
  • the immune related diseases and disorders are selected from rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemia fibromyalgia, Alzheimer's disease, Congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis and multiple Sclerosis;
  • infectious disease or infectious disease is selected from sepsis, liver infection, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papilloma virus or influenza;
  • the metabolic disease is selected from diabetes, diabetic ketoacidosis, hyperglycemia hyperosmolar syndrome, hypoglycemia, gout, malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency, or osteoporosis .
  • the fifth aspect of the present invention provides a compound of formula (I), its stereoisomer, prodrug, or pharmaceutically acceptable salt thereof, which is used for prevention and/or treatment mediated by PD-1/PD-L1 signaling pathway 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 interaction of PD-1/PD-L1, and can be widely used in the preparation of prevention and/or treatment of cancer or tumors and immune systems mediated by PD-1/PD-L1 signaling pathway Drugs for related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases are expected to be developed into a new generation of PD-1/PD-L1 inhibitors. On this basis, the present invention has been completed.
  • Alkyl refers to a straight-chain or branched saturated aliphatic hydrocarbon group, for example, "C 1-4 alkyl” refers to a straight-chain alkyl group including 1 to 4 carbon atoms and a branch-containing alkyl group, including but It is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc.
  • the alkyl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more (preferably 1, 2, 3, or 4) of the following groups, independently selected from deuterium, halogen, cyanide Group, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycle group, a hydroxy-substituted C 3- 6 cycloalkyl, carboxy substituted C 3-6 cycloalkyl, hydroxy-substituted 4-6 membered heterocyclyl, 4-6 membered heterocyclyl substituted with a carboxyl, hydroxyl, C 1-4 alkoxy Group, carboxyl or C 1-4 alkoxy acyl substituent.
  • groups independently selected from deuterium, halogen, cyanide Group, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, deuterium substituted C 1-4
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • C 3-6 cycloalkyl refers to a monocyclic cycloalkyl group containing 3 to 6 carbon atoms, including but It is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like. Cycloalkyl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, Cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered hetero Cyclic, hydroxy substituted C 3-6 cycloalkyl, carboxy substituted C 3-6 cycloalkyl, hydroxy substituted 4-6 membered heterocyclic group, carboxy substituted 4-6 membered heterocyclic group, hydroxy, C 1-4 alkane It is substituted by a substituent of an oxy group, a carboxy group or a C 1-4 alkoxy group.
  • Heterocyclyl refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent in which one or two (preferably one) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer of 0, The heteroatoms of 1, 2), but not including the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • 4-6 membered heterocyclic group refers to a monocyclic heterocyclic group containing 4 to 6 ring atoms, including but not limited to pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine Base, homopiperazinyl, etc.
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more (preferably 1, 2, 3, or 4) of the following groups, independently selected from deuterium, halogen, Cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered hetero Cyclic, hydroxy substituted C 3-6 cycloalkyl, carboxy substituted C 3-6 cycloalkyl, hydroxy substituted 4-6 membered heterocyclic group, carboxy substituted 4-6 membered heterocyclic group, hydroxy, C 1-4 alkane It is substituted by a substituent of an oxy group, a carboxy group or a C 1-4 alkoxy group.
  • Alkoxy refers to -O-(alkyl), wherein the definition of alkyl is as described above, for example, "C 1-4 alkoxy” refers to an alkyloxy group containing 1-4 carbons, including but not Limited to methoxy, ethoxy, propoxy, butoxy, etc. The alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more (preferably 1, 2, 3, or 4) of the following groups, independently selected from deuterium, halogen , cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1- 4 alkyl group substituted with deuterium, C 3-6 cycloalkyl, 4-6 membered Heterocyclic group, hydroxy substituted C 3-6 cycloalkyl, carboxy substituted C 3-6 cycloalkyl, hydroxy substituted 4-6 membered heterocyclic group, carboxy substituted 4-6 membered heterocyclic group, hydroxyl, C 1-4 Alkoxy, carboxyl or C 1-4 alkoxy acyl substituents are substituted.
  • Halogen-substituted C 1-4 alkyl refers to a 1-4 carbon alkyl group optionally substituted with fluorine, chlorine, bromine, or iodine atoms on the hydrogen on the alkyl group, including but not limited to difluoromethyl, difluoromethyl Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • C 1-4 alkoxy acyl group refers to a C 1-4 alkoxy group attached to a carbonyl group [C(O)], and is usually expressed as "C 1-4 alkyl-OC(O)-", for example, C 1 Alkoxy acyl group can be expressed as "C 1 alkyl-OC(O)-" which means methoxy acyl group; C 2 alkoxy acyl group can be expressed as "C 2 alkyl-OC(O)-” means ethoxy acyl group.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • PE means petroleum ether
  • EtOAc ethyl acetate
  • MeOH means methanol
  • DMF N,N-dimethylformamide
  • THF means tetrahydrofuran
  • DIPEA N,N-diisopropylethylamine
  • HATU 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluoro Phosphate
  • NaHCO 3 meanans sodium bicarbonate
  • KMnO 4 means potassium permanganate
  • NaBH 3 CN means sodium cyanoborohydride.
  • Optional or “optionally” means that the event or environment described later can but does not have to occur.
  • the description includes the occasion where the event or environment occurs or does not occur, that is, it includes both substituted and unsubstituted situations.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
  • Substituted means that one or more of the "hydrogen atoms" in the group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which conforms to the chemical bond theory, and those skilled in the art can determine (by experiment or theory) whether it is possible or impossible without making too much effort. Replacement. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an olefin).
  • Stepoisomer whose English name is stereoisomer, refers to the isomers produced by the different arrangements of atoms in the molecule in space. It can be divided into cis-trans isomers and enantiomers. It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers caused by the rotation of a single bond are called conformational stereo-isomers, and sometimes they are also called rotamers. Stereoisomers caused by bond lengths, bond angles, double bonds in the molecule, rings, etc. are called configuration stereo-isomers. Configuration isomers are divided into two categories.
  • isomers caused by double bonds or single bonds of ring-forming carbon atoms that cannot rotate freely become geometric isomers, also called cis-trans isomers, and are divided into Z, E two configurations.
  • cis-2-butene and trans-2-butene are a pair of geometric isomers.
  • the stereoisomers with different optical properties caused by the absence of anti-axial symmetry in the molecule are called optical isomers ( Optical isomer), divided into R and S configurations.
  • the "stereoisomers" can be understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers.
  • “Pharmaceutically acceptable salts” in the present invention refers to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, and these salts can be prepared by methods known in the art.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and 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 ingredients and thus the biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in units of parts per million (ppm).
  • NMR is measured with Bruker AVANCE-400 or AVANCE-500 nuclear magnetic instrument, and the solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD), deuterated water (D 2 O) and Deuterated chloroform (CDCl 3 ), the internal standard is tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • D 2 O deuterated water
  • CDCl 3 Deuterated chloroform
  • TMS tetramethylsilane
  • the liquid mass spectrometry LC-MS is measured with Agilent 6120 mass spectrometer.
  • HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification used for TLC is 0.15mm ⁇ 0.20mm, and the specification used for thin layer chromatography separation and purification products is 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 can be purchased on the market, or can be synthesized by using or following methods known in the art.
  • the third step Synthesis of 4-cyclopropyl-5-formylpyridine-2-carboxylic acid
  • the fourth step 4-cyclopropyl-N-(3'-(4-cyclopropyl-5-(dimethoxymethyl)pyridine-2-amido)-2,2'-dimethyl- Synthesis of [1,1'-Biphenyl]-3-yl)-5-formyl-2-pyridineamide
  • the sixth step (S)-1-((4-cyclopropyl-6-((3'-(4-cyclopropyl-5-(((2-hydroxyethyl)amino)methyl)pyridine- 2-Acylamino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)piperidine-2-carboxylic acid Synthesis
  • Examples 2-28 refer to all or part of the synthesis method in Example 1 to select corresponding raw materials for preparation.
  • Example 29 (S)-1-((4-cyclopropyl-6-((3'-(4-cyclopropyl-5-((((R)-1-ethoxy-3-hydroxy -1-oxopropan-2-yl)amino)methyl)pyridine-2-acylamino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)aminomethyl (Acyl)pyridin-3-yl)methyl)piperidine-2-carboxylic acid
  • Examples 31 to 34 were prepared by referring to all or part of the synthesis method of Example 29 or Example 30, respectively, by selecting corresponding raw materials.
  • Example 35 ((4-Cyclopropyl-6-((3'-(4-cyclopropyl-5-(((2-hydroxyethyl)amino)methyl)pyridine-2-amido)- Preparation of 2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-D-serine
  • the first step ((4-cyclopropyl-6-((3'-(4-cyclopropyl-5-(dimethoxymethyl)pyridine-2-amido)-2,2'-di Synthesis of methyl-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-D-serine ethyl ester
  • the second step ((4-cyclopropyl-6-((3'-(4-cyclopropyl-5-formylpyridine-2-amido)-2,2'-dimethyl-[1, Synthesis of 1'-Biphenyl)-3-yl)carbamoyl)pyridin-3-yl)methyl)-D-serine ethyl ester
  • the third step ((4-cyclopropyl-6-((3'-(4-cyclopropyl-5-(((2-hydroxyethyl)amino)methyl)pyridine-2-amido)- 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-D-serine ethyl ester (Example 35-1) Synthesis
  • the fourth step ((4-cyclopropyl-6-((3'-(4-cyclopropyl-5-(((2-hydroxyethyl)amino)methyl)pyridine-2-amido)- Synthesis of 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-D-serine
  • Example 36 ((4-cyclopropyl-6-((3'-(4-cyclopropyl-5-((3-hydroxy-3-methylazetidine-1-yl)methyl)pyridine -2-Acylamino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-D-serine
  • the first step ((4-cyclopropyl-6-((3'-(4-cyclopropyl-5-((3-hydroxy-3-methylazetidine-1-yl)methyl)pyridine -2-Acylamino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-D-serine ethyl ester (Example 36-1) Synthesis
  • the second step ((4-cyclopropyl-6-((3'-(4-cyclopropyl-5-((3-hydroxy-3-methylazetidine-1-yl)methyl)pyridine -2-Acylamino)-2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-D-serine
  • Examples 37-66 refer to all or part of the synthesis method of Example 35 or 36 to select corresponding raw materials for preparation.
  • the first step N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-cyclopropyl-5-( ⁇ (Methoxymethyl)-2-pyridine amide) synthesis
  • N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-cyclopropyl-5-(dimethoxymethyl) Pyridine amide) (1300 mg, 2.0 mmol) was added to THF (20 mL), and then hydrochloric acid solution (8 mL, 4M) was added thereto, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, water (8 mL) was added and stirred overnight.
  • the third step (2S,2'S)-2,2'-((((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl) two (Azaalanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(azaalkanediyl))bis(3- Hydroxy-2-methylpropionic acid) synthesis
  • N,N'-(2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-cyclopropyl-5-formyl-2-pyridine Amide) (50mg, 0.09mmol) was placed in DMF/CH 2 Cl 2 (1.8mL/0.9mL), then DIPEA (116mg, 0.90mmol) and (S)-2-amino-3-hydroxy-2-methyl were added Propionic acid (107 mg, 0.90 mmol) was stirred at room temperature for 6 hours, and NaBH(OAc) 3 (190 mg, 0.90 mmol) was added, and stirring was continued at room temperature overnight.
  • reaction solution is directly separated by reversed-phase column chromatography (eluent: water (0.1% TFA): acetonitrile), and freeze-dried to obtain (2S,2'S)-2,2'-(((((((2,2) '-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3 -Diyl))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropionic acid) TFA salt (17.2 mg, yield: 25%).
  • Examples 68 to 70 were prepared by referring to all or part of the synthesis method in Example 67 to select corresponding raw materials.
  • the IC 50 value of the compound of the embodiment of the present invention is determined by non-linear regression analysis of the inhibition percentage at different compound concentrations. The specific experimental results are shown in Table 1.
  • the effects of the compounds of the examples of the present invention on the interaction of PD-1/PD-L1 proteins expressed on the cell surface and the resulting effects on T cell function are determined by the Jurkat reporter gene cell activity test.
  • the reporter gene plasmid of NF- ⁇ B-luc and the plasmid of human PD-1 were transfected into Jurkat cells to establish a stable transfected cell line that stably expresses both PD-1 and NF- ⁇ B-Luc reporter genes.
  • Flow cytometry was used to identify the surface expression level of PD-1, and OKT-3 and Raiji cells were used to stimulate the reporter gene response to identify the reporter gene expression level.
  • the human PD-L1 expression plasmid was transfected into Raji cells to obtain a cell line stably expressing PD-L1. Then, Jurkat/NF- ⁇ B-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 reporter gene response were used to reflect the compound’s response to PD-1/PD The inhibition of -L1 interaction enhances the signal pathway of T cell activation.
  • the specific experimental methods are as follows:
  • the series of 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 T cell activity at the cellular level. activation.

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Abstract

一种式（Ⅰ）结构具有阻断PD-1/PD-L1相互作用的联苯基衍生物及其制备方法和应用。该系列化合物可广泛应用于制备预防和/或治疗由PD-1/PD-L1信号通路介导的癌症或肿瘤、免疫相关疾病及紊乱、传染性疾病、感染性疾病或代谢性疾病的药物，有望开发成新一代PD-1/PD-L1抑制剂。

Description

一种阻断PD-1/PD-L1相互作用的联苯基衍生物及其制备方法和应用 技术领域
本发明属于药物合成领域，具体涉及一种阻断PD-1/PD-L1相互作用的联苯基衍生物及其制备方法和应用。
技术背景
免疫系统在控制和清除如癌症之类的疾病中扮演着非常重要的角色。然而肿瘤细胞常常能够发展出逃逸或抑制免疫系统的监控的策略来促进自己的恶性生长。其中一个很重要的机制就是改变免疫细胞上共刺激和共抑制的免疫检查点分子的表达。阻断免疫检查点分子比如PD1的信号通路，已经被证明是非常有希望而有效的治疗手段。
程序性细胞死亡分子1(PD-1)，又被称为CD279，是表达在活化T细胞，自然杀伤T细胞，B细胞以及巨噬细胞表面的一种受体分子，它的结构包含了一个胞外的免疫球蛋白可变区类似的结构域，一个跨膜区域和一个胞内区域，其中胞内区域包含着两个磷酸化位点，位于基于免疫受体酪氨酸激酶的抑制域和基于免疫受体酪氨酸激酶的转换域，提示PD1能负向调节T细胞受体介导的信号通路。
PD1有两个配体，PD-L1和PDL2,它们在表达谱上有所不同。PDL1蛋白在巨噬细胞和树突状细胞中在脂多糖(LPS)和粒细胞－巨噬细胞集落刺激因子(GM-CSF)处理之后会上调，在T细胞和B细胞经过T细胞受体和B细胞受体信号通路的刺激之后也会有上调。它还在几乎所有的肿瘤细胞中有高表达，并且在干扰素(IFN)gamma刺激之后会有表达的上调，实际上，肿瘤PDL1的表达状态被认为在多种肿瘤种类中具有预后的相关性PD-L2的表达，相反地，是较为集中的，主要表达在树突状细胞上。
当PD-1表达的T细胞和其配体表达的细胞接触之后，那些抗原刺激之后的功能性活动，比如细胞增殖，细胞因子释放以及细胞裂解活性都被抑制了。因此，PD1和其配体的相互作用在功能上作为内在的负反馈调节机制能使人们在感染，免疫耐受或者肿瘤发生时来防止T细胞的过度活化，从而降低自身免疫疾病，促进自身免疫耐受。长期的抗原刺激，比如在肿瘤或者长期感染中发生的，会造成T细胞表达高水平的PD-1,并且在对这些长期抗原的反应中缺乏活性，没有功能，也就是人们说的T细胞功能耗竭。B细胞也有PD1及其配体带来的抑制作用以及相应的功能衰竭。
一些来自临床前动物研究的证据表明PD-1和其配体能负向调节免疫反应。PD-1缺陷的小鼠会产生红斑狼疮样的急性增生性肾小球肾炎以及扩张性心肌病。利用PDL1的抗体来阻断PD-1/PDL1的相互作用已经在很多系统中显示出恢复和增强T细胞活化的功能。PDL1的单克隆抗体也能为晚期癌症病人带来福利。一些临床前的动物肿瘤模型也显示通过单克隆抗体阻断PD-1/PD-L1的信号通路能增强免疫反应，并导致对一系列组织学上有显著不同的肿瘤的免疫反应，利用长期感染的LCMV模型，PD-1/PD-L1的相互作用已被发现能抑制病毒特异性的CD8T细胞的活化，扩增和效应细胞功能的获取。除了能增强对于长期抗原的免疫反应之外，阻断PD-1/PDL1通路还被发现能增强对于疫苗的反应，包括在长期感染环境下，对于治疗性疫苗的反应。
综上所述，除了已有的单克隆抗体之外，如果能开发阻断PD1-PDL1蛋白与蛋白相互作用的化合物,将可以作为一种可以阻断PD-1/PDL1介导的抑制信号通路的有效治疗手段来增强或者复原T细胞的功能。因此，靶向阻断PD-1/PD-L1相互作用的化合物将会在多种癌症的免疫治疗以及其他和免疫相关的疾病中具有很好的疗效。
发明内容
本发明的目的在于提供阻断PD-1/PD-L1相互作用的联苯基衍生物，从而有望开发出新一代PD-1/PD-L1抑制剂。
本发明第一方面提供一种式(I)化合物、其立体异构体、前药或其药学上可接受盐：
Figure PCTCN2020101646-appb-000001
其中，
R 1选自如下基团：
Figure PCTCN2020101646-appb-000002
R 2选自-NHR 6或4-6元含氮杂环基，其中氮原子与亚甲基连接，所述4-6元含氮杂环基任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、羟基取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、4-6元杂环基、羟基取代C 3-6环烷基、羧基取代C 3-6环烷基、羟基取代4-6元杂环基、羧基取代4-6元杂环基、羟基、C 1-4烷氧基、羧基或C 1-4烷氧酰基的取代基所取代；
R 3、R 4、R 5各自独立地选自氢、氘或C 1-4烷基，所述C 1-4烷基任选进一步被一个或多个选自氘、卤素、氰基、环丙基、羟基或C 1-4烷氧基的取代基所取代；
R 6选自C 1-4烷基、C 3-6环烷基或C 4-6杂环基，其中所述杂环基任选包含1-2个选自N或O的杂原子，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、羟基取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、4-6元杂环基、羟基取代C 3-6环烷基、羧基取代C 3-6环烷基、羟基取代4-6元杂环基、羧基取代4-6元杂环基、羟基、C 1-4烷氧基、羧基或C 1-4烷氧酰基的取代基所取代；
R 2与R 1相同或不相同，条件是，当R 1选自
Figure PCTCN2020101646-appb-000003
时，R 2与R 1不相同，当R 1选自
Figure PCTCN2020101646-appb-000004
时，R 2与R 1相同或不相同。
作为优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，R 3、R 4、R 5各自独立地选自氢、氘、甲基、乙基或丙基，上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、环丙基、羟基、甲氧基或乙氧基的取代基所取代；
R 6选自甲基、乙基、异丙基、环丙基、环丁基、环戊基、环己基、
Figure PCTCN2020101646-appb-000005
上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、硝基、叠氮基、甲基、乙 基、异丙基、二氟甲基、三氟甲基、二氯甲基、三氯甲基、二溴甲基、三溴甲基、二氘甲基、三氘甲基、羟甲基、环丙基、环丁基、环戊基、羟基环丙基、
Figure PCTCN2020101646-appb-000006
羟基、甲氧基、乙氧基、羧基、甲氧酰基或乙氧酰基的取代基所取代。
作为优选方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，所述式(I)化合物具有如下式(Ⅱa)化合物、式(Ⅱb)化合物或式(Ⅱc)化合物、式(Ⅱd)化合物或式(Ⅱe)化合物结构：
Figure PCTCN2020101646-appb-000007
其中，R 2选自-NHR 6或4-6元含氮杂环基，其中氮原子与亚甲基连接，条件是在式(Ⅱa)化合物中，R 2不选自
Figure PCTCN2020101646-appb-000008
在式(Ⅱb)化合物中，R 2不选自
Figure PCTCN2020101646-appb-000009
在式(Ⅱc)化合物中，R 2不选自
Figure PCTCN2020101646-appb-000010
所述4-6元含氮杂环基选自如下结构：
Figure PCTCN2020101646-appb-000011
上述结构任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、异丙基、环丙基、羟基环丙基、羟甲基、羟基、甲氧基、乙氧基、羧基、甲氧酰基或乙氧酰基的取代基所取代；
R 3、R 4、R 5各自独立地选自氢、氘、甲基或乙基；
R 6选自甲基、乙基、异丙基、环丙基、环丁基、环戊基、环己基、
Figure PCTCN2020101646-appb-000012
上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、异丙基、环丙基、羟基环丙基、羟甲基、羟基、甲氧基、乙氧基、羧基、甲氧酰基或乙氧酰基的取代基所取代。
作为优选方案所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，选自如下化合物：
Figure PCTCN2020101646-appb-000013
Figure PCTCN2020101646-appb-000014
Figure PCTCN2020101646-appb-000015
Figure PCTCN2020101646-appb-000016
Figure PCTCN2020101646-appb-000017
本发明第二方面提供一种前述式(I)化合物、其立体异构体、前药或其药学上可接受盐的制备方法，包括如下步骤：
Figure PCTCN2020101646-appb-000018
其中，R a、R b、R c、R d各自独立地为C 1-8烷氧基，或者R a与R b、R c与R d一起为＝O，R 1、R 2如式(I)化合物所定义。
本发明第三方面提供一种药物组合物，其包括前述的式(I)化合物、其立体异构体、前药或其药学上可接受盐及可药用的载体。
本发明第四方面提供一种前述式(I)化合物、其立体异构体、前药或其药学上可接受盐在制备预防和/或治疗由PD-1/PD-L1信号通路介导的有关疾病药物中的应用。
作为优选的方案，所述的由PD-1/PD-L1信号通路介导的有关疾病选自癌症或肿瘤、免疫相关疾病及紊乱、传染性疾病、感染性疾病或代谢性疾病。
作为进一步优选的方案，所述感染性疾病选自细菌性传染病、病毒性传染病或真菌性传染病；所述癌症或肿瘤选自淋巴瘤(包括但不限于淋巴细胞性淋巴瘤、原发性中枢神经系统淋巴瘤、T细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡中心淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤或原发性纵隔大B细胞淋巴瘤)、肉瘤(包括但不限于卡波西肉瘤、纤维肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、平滑肌肉瘤、横纹肌肉瘤、软组织肉瘤、血管肉瘤或淋巴管肉瘤)、黑色素瘤、胶质母细胞瘤、滑膜瘤、脑膜瘤、胆道肿瘤、胸腺肿瘤、神经肿瘤、精原细胞瘤、肾母细胞瘤、多形性腺瘤、肝细胞乳头状瘤、肾小管腺瘤、囊腺瘤、乳头瘤、腺瘤、平滑肌瘤、横纹肌瘤、血管瘤、淋巴管瘤、骨瘤、软骨瘤、脂肪瘤、纤维瘤、中枢神经系统肿瘤、脊柱轴瘤、脑干胶质瘤、垂体腺瘤、多发性骨髓瘤、卵巢肿瘤、骨髓增生异常综合征或间皮瘤，前列腺癌、复发或已对现有药物产生抗性的前列腺癌、甲状腺癌、甲状旁腺癌、肛门癌、睾丸癌、尿道癌、阴茎癌、膀胱癌、输尿管癌、子宫癌、卵巢癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、肾上腺癌、默克尔细胞癌、胚胎癌、慢性或急性白血病(包括但不限于急性髓系白血病、慢性髓系白血病、急性淋巴细胞白血病、慢性粒细胞白血病、慢性淋巴细胞白血病)、支气管癌、食管癌、鼻咽癌、肝细胞癌、肾细胞癌、小细胞肺癌、基底细胞癌、肺癌、乳腺癌、腺癌、乳头状癌、囊腺癌、鳞状非小细胞肺癌、非鳞状非小细胞肺癌、直肠癌、结肠癌、结直肠癌、胃癌、胰腺癌、头颈部鳞状细胞癌、头颈部癌、胃肠道、骨癌、皮肤癌、小肠癌、内分泌系统癌、肾盂癌、表皮样癌、腹壁癌、肾细胞癌、移行细胞癌或绒毛膜癌，以及转移性的肿瘤，尤其是表达PD-L1的转移性肿瘤；
所述的免疫相关疾病及紊乱选自风湿性关节炎、肾衰竭、红斑狼疮、哮喘、牛皮癣、溃疡性结肠炎、胰腺炎、过敏、纤维化、贫血纤维肌痛症、阿尔茨海默病、充血性心力衰竭、中风、主动脉瓣狭窄、动脉硬化、骨质疏松症、帕金森病、感染、克隆氏病、溃疡性结肠炎、过敏性接触性皮炎和湿疹、系统性硬化症和多发性硬化症；
所述传染性疾病或感染性疾病选自脓毒症、肝脏感染、HIV、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒、乳头瘤病毒或流感；
所述代谢性疾病选自糖尿病、糖尿病酮症酸中毒、高血糖高渗综合征、低血糖症、痛风、营养不良症、维生素A缺乏病、坏血病、维生素D缺乏病或骨质疏松症。
本发明第五方面提供一种式(I)化合物、其立体异构体、前药或其药学上可接受盐，其用作预防和/或治疗由PD-1/PD-L1信号通路介导的癌症或肿瘤、免疫相关疾病及紊乱、传染性疾病、感染性疾病或代谢性疾病的药物。
具体实施方式
本申请的发明人经过广泛而深入地研究，首次研发出一种如通式(Ⅰ)结构联苯基系列化合物。本发明系列化合物对PD-1/PD-L1的相互作用具有很强的抑制作用，可广泛应用于制备预防和/或治疗由PD-1/PD-L1信号通路介导的癌症或肿瘤、免疫相关疾病及紊乱、传染性疾病、感染性疾病或代谢性疾病的药物，有望开发成新一代PD-1/PD-L1抑制剂。在此基础上，完成了本发明。
详细说明：除非有相反陈述或特别说明，下列用在说明书和权利要求书中的术语具有下述含义。
“烷基”指直链或含支链的饱和脂族烃基团，例如，“C 1-4烷基”指包括1至4个碳原子的直链烷基和含支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基等。烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、羟基取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、4-6元杂环基、羟基取代C 3- 6环烷基、羧基取代C 3-6环烷基、羟基取代4-6元杂环基、羧基取代4-6元杂环基、羟基、C 1-4烷氧基、羧基或C 1-4烷氧酰基的取代基所取代。
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，例如，“C 3-6环烷基”指包括3至6个碳原子的单环环烷基，包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等。环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、羟基取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、4-6元杂环基、羟基取代C 3-6环烷基、羧基取代C 3-6环烷基、羟基取代4-6元杂环基、羧基取代4-6元杂环基、羟基、C 1-4烷氧基、羧基或C 1-4烷氧酰基的取代基所取代。
“杂环基”指饱和或部分不饱和单环环状烃取代基，其中1个或2个(优选1个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。例如，“4-6元杂环基”指包含4至6个环原子的单环杂环基，包括但不限于吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、羟基取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、4-6元杂环基、羟基取代C 3-6环烷基、羧基取代C 3-6环烷基、羟基取代4-6元杂环基、羧基取代4-6元杂环基、羟基、C 1-4烷氧基、羧基或C 1-4烷氧酰基的取代基所取代。
“烷氧基”指-O-(烷基)，其中烷基的定义如上所述，例如，“C 1-4烷氧基”指含1-4个碳的烷基氧基，包括但不限于甲氧基、乙氧基、丙氧基、丁氧基等。烷氧基可以是任选取代的或未取代的，当被取代时，取代基，优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、羟基取代C 1-4烷基、氘取代C 1- 4烷基、C 3-6环烷基、4-6元杂环基、羟基取代C 3-6环烷基、羧基取代C 3-6环烷基、羟基取代4-6元杂环基、羧基取代4-6元杂环基、羟基、C 1-4烷氧基、羧基或C 1-4烷氧酰基的取代基所取代。
“卤取代C 1-4烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-4个碳烷基基团，包括但不限于二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。
“C 1-4烷氧酰基”指C 1-4烷氧基连接在羰基【C(O)】上，通常也表示为“C 1-4烷基-O-C(O)-”，例如，C 1烷氧酰基可表示为“C 1烷基-O-C(O)-”是指甲氧酰基；C 2烷氧酰基可表示为“C 2烷基-O-C(O)-”是指乙氧酰基。“卤素”指氟、氯、溴或碘。“PE”是指石油醚， “EtOAc”/“EA”是指乙酸乙酯，“MeOH”是指甲醇，“DMF”是指N,N-二甲基甲酰胺，“THF”是指四氢呋喃，“DIPEA”是指N,N-二异丙基乙胺，“HATU”是指2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，“NaHCO 3”是指碳酸氢钠，“KMnO 4”是指高锰酸钾，“NaBH 3CN”是指氰基硼氢化钠。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合，也即包括取代的或未取代的两种情形。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个“氢原子”彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，符合化学上的价键理论，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯烃)结合时可能是不稳定的。
“立体异构体”，其英文名称为stereoisomer，是指由分子中原子在空间上排列方式不同所产生的异构体，它可分为顺反异构体、对映异构体两种，也可分为对映异构体和非对映异构体两大类。由于单键的旋转而引起的立体异构体称为构象异构体(conformational stereo-isomer)，有时也称为旋转异构体(rotamer)。因键长、键角、分子内有双键、有环等原因引起的立体异构体称为构型异构体(configuration stereo-isomer)，构型异构体又分为两类。其中因双键或成环碳原子的单键不能自由旋转而引起的异构体成为几何异构体(geometric isomer)，也称为顺反异构体(cis-trans isomer)，分为Z、E两种构型。例如：顺-2-丁烯和反-2-丁烯是一对几何异构体，因分子中没有反轴对称性而引起的具有不同旋光性能的立体异构体称为旋光异构体(optical isomer)，分为R、S构型。在本发明中所述“立体异构体”如未特别指明，可理解为包含上述对映异构体、构型异构体和构象异构体中的一种或几种。
“药学上可接受盐”在本发明中是指药学上可接受的酸加成盐，包括无机酸盐和有机酸盐，这些盐可通过本专业已知的方法制备。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400或AVANCE-500核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)，氘水(D 2O)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 6120质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是 0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度(℃)。
具体实施例化合物的制备
实施例1：(S)-1-((4-环丙基-6-((3'-(4-环丙基-5-(((2-羟基乙基)氨基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)哌啶-2-羧酸的制备
Figure PCTCN2020101646-appb-000019
第一步：4-环丙基-5-(二甲氧基甲基)-2-乙烯基吡啶的合成
Figure PCTCN2020101646-appb-000020
称取4-环丙基-6-乙烯基-3-烟醛(11.1g，64.0mmol)，原甲酸三甲酯(40.7g，384mmol)和对甲苯磺酸一水合物(6.08g，32.0mmol)溶于无水甲醇(115mL)。加热到55度，搅拌过夜。加入适量DIPEA中和，反应液直接浓缩旋干。粗产品经硅胶柱层析分离(PE/EA：0-5％)得到4-环丙基-5-(二甲氧基甲基)-2-乙烯基吡啶(11.1g，收率：79％)。MS m/z(ESI):220.2[M+H] +。
第二步：4-环丙基-5-(二甲氧基甲基)吡啶-2-甲酸钾的合成
Figure PCTCN2020101646-appb-000021
4-环丙基-5-(二甲氧基甲基)-2-乙烯基吡啶(4.0g，23.1mmol)溶于丙酮/水(60mL，v/v＝2:1)混合液中，再分批加入KMnO 4(8.56g，69.3mmol)。室温搅拌过夜，再加热至40度反应6小时。反应完全后过滤，MeOH/CH 3CN(50mL，v/v＝1:1)洗涤。滤液合并，加入活性碳，加热40度搅拌0.5小时，趁热过滤，再加H 2O(20mL)洗涤。滤液经减压浓缩除去大部分有机溶剂，剩余水相经冷冻干燥得到4-环丙基-5-(二甲氧基甲基)吡啶-2-甲酸钾(5.1g，粗品)。
第三步：4-环丙基-5-甲酰基吡啶-2-甲酸的合成
Figure PCTCN2020101646-appb-000022
4-环丙基-5-(二甲氧基甲基)吡啶-2-甲酸钾(2.7g，9.8mmol)溶于纯水(20mL)中，再加入盐酸溶液(10L，4.0M)，室温下搅拌约2小时。反应完全，反应液经冻干得到4-环丙基-5-甲酰基吡啶-2-甲酸(2.2g，粗品)。MS m/z(ESI):189.8[M-H] -。
第四步：4-环丙基-N-(3'-(4-环丙基-5-(二甲氧基甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)-5-甲酰基-2-吡啶酰胺的合成
Figure PCTCN2020101646-appb-000023
称取4-环丙基-5-(二甲氧基甲基)吡啶-2-甲酸钾(622mg，2.27mmol)，HATU(854mg，2.06mmol)，2,2'-二甲基-[1,1'-双苯基]-3,3'-二胺(435mg，2.05mmol)和DIPEA(1.0mL)于100mL茄形瓶中，加入THF/MTBE(12mL，1:1)，室温搅拌过夜。再加入4-环丙基-5-甲酰基吡啶-2-甲酸(452mg，2.0mmol)，HATU(598mg，1.57mmol)，以及DMF(1.0mL)，室温搅拌3小时。加入水(20mL)，EtOAc(50mL)萃取2次，饱和食盐水(10mL)洗涤有机相。无水Na 2SO 4干燥，过滤，浓缩。粗品经硅胶柱层析(PE/EA:0-12％)分离得到4-环丙基-N-(3'-(4-环丙基-5-(二甲氧基甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)-5-甲酰基-2-吡啶酰胺(344mg，收率：28％)。MS m/z(ESI):651.6[M+H] +。
第五步：(S)-1-((4-环丙基-6-((3'-(4-环丙基-5-甲酰基吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)哌啶-2-羧酸的合成
Figure PCTCN2020101646-appb-000024
4-环丙基-N-(3'-(4-环丙基-5-(二甲氧基甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)-5-甲酰基-2-吡啶酰胺(266mg，0.439mmol)和(S)-哌啶-2-羧酸(227mg，1.756mmol)加入CH 2Cl 2/DIPEA(20mL，4:1)混合溶剂，加热回流，搅拌22小时。加入NaBH(OAc) 3(372.3mg，1.756mmol)，回流下继续搅拌2小时。反应完全，反相柱层析分离，收集到的产品溶液经浓缩除去有机溶剂，再加入盐酸溶液(4.0mL，4M)，搅拌2小时。冷冻干燥得到(S)-1-((4-环丙基-6-((3'-(4-环丙基-5-甲酰基吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)哌啶-2-羧酸(153mg，收率：52％)。MS m/z(ESI):670.2[M-H] -。
第六步：(S)-1-((4-环丙基-6-((3'-(4-环丙基-5-(((2-羟基乙基)氨基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)哌啶-2-羧酸的合成
Figure PCTCN2020101646-appb-000025
(S)-1-((4-环丙基-6-((3'-(4-环丙基-5-甲酰基吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)哌啶-2-羧酸(48.0mg，0.071mmol)，乙醇胺(22.0mg，0.357mmol)和DIPEA(0.1mL，0.43mmol)溶于DMF/HOAc(3mL，5:1)，室温下搅拌2小时。再加入NaBH 3CN(22.4mg，0.355mmol)，室温搅拌1小时。反应完全，加入3滴甲醇，终止反应。粗品经反相柱层析分离得到(S)-1-((4-环丙基-6-((3'-(4-环丙基-5-(((2-羟基 乙基)氨基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)哌啶-2-羧酸(26.5mg，收率：52％)。MS m/z(ESI):715.4[M-H] -。
1H NMR(400MHz,DMSO-d 6)δ10.33(s,1H),10.31(s,1H),8.62(s,1H),8.52(s,1H),7.86(t,J＝7.9Hz,2H),7.61(s,1H),7.59(s,1H),7.32(t,J＝7.8Hz,2H),6.98(dd,J＝7.6,4.5Hz,2H),4.17(s,2H),4.03(d,J＝13.7Hz,1H),3.71(d,J＝13.6Hz,1H),3.58(t,J＝5.7Hz,2H),3.19(t,J＝5.6Hz,1H),2.90–2.79(m,2H),2.33–2.19(m,2H),2.00(s,6H),1.84–1.72(m,2H),1.55–1.36(m,4H),1.24(d,J＝6.7Hz,2H),1.20–1.06(m,4H),0.95–0.85(m,4H).
实施例2～28参照实施例1全部或部分合成方法选择相应的原料进行制备。
Figure PCTCN2020101646-appb-000026
Figure PCTCN2020101646-appb-000027
Figure PCTCN2020101646-appb-000028
Figure PCTCN2020101646-appb-000029
实施例29：(S)-1-((4-环丙基-6-((3'-(4-环丙基-5-((((R)-1-乙氧基-3-羟基-1-氧代丙烷-2-基)氨基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)哌啶-2-羧酸的制备
Figure PCTCN2020101646-appb-000030
(S)-1-((4-环丙基-6-((3'-(4-环丙基-5-甲酰基吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)哌啶-2-羧酸(50.0mg，0.074mmol)，D-丝氨酸乙酯盐酸盐(63.0mg，0.372mmol)和DIPEA(0.07mL，0.372mmol)溶于DMF/HOAc(3mL/1mL)，室温下搅拌2小时。再加入NaBH 3CN(23.0mg，0.372mmol)，室温搅拌16小时。反应完全，加入3滴甲醇，终止反应。粗品经反相柱层析分离得到(S)-1-((4-环丙基-6-((3'-(4-环丙基-5-((((R)-1-乙氧基-3-羟基-1-氧代丙烷-2-基)氨基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)哌啶-2-羧酸(32mg，收率：55％)。MS m/z(ESI):789.4[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ10.36(s,1H),10.33(s,1H),8.71(s,1H),8.57(s,1H),7.82(dd,J＝15.3,8.0Hz,2H),7.64(s,1H),7.60(s,1H),7.33(t,J＝7.9Hz,2H),7.00(t,J＝6.9Hz,2H),4.45(brs,2H),4.22(q,J＝7.1,6.6Hz,2H),3.92(brs,2H),3.00–2.85(m,2H),2.45–2.40(m,2H),2.36–2.28(m,2H),2.00(d,J＝3.3Hz,6H),1.80–1.70(m,2H),1.65–1.40(m,4H),1.25(t,J＝7.1Hz,3H),1.21–1.08(m,4H),1.00–0.75(m,4H).
实施例30：(S)-1-((6-((3'-(5-((((R)-1-羧基-2-羟基乙基)氨基)甲基)-4-环丙基吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)-4-环丙基吡啶-3-基)甲基)哌啶-2-羧酸的制备
Figure PCTCN2020101646-appb-000031
(S)-1-((4-环丙基-6-((3'-(4-环丙基-5-((((R)-1-乙氧基-3-羟基-1-氧代丙烷-2-基)氨基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)哌啶-2-羧酸(17.0mg，0.022mmol)溶于甲醇/四氢呋喃/水(1mL/1mL/1mL)，再加入LiOH·H 2O(9mg，0.22mmol)，室温下反应1小时。反应完后浓缩，用1N HCl调至弱酸性，粗品经反相柱层析分离得到(S)-1-((6-((3'-(5-((((R)-1-羧基-2-羟基乙基)氨基)甲基)-4-环丙基吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)-4-环丙基吡啶-3-基)甲基)哌啶-2-羧酸(12mg，收率：73％)。MS m/z(ESI):761.4[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ10.32(s,1H),10.30(s,1H),8.59(s,1H),8.52(s,1H),7.87(dd,J＝8.0,4.2Hz,2H),7.60(s,1H),7.59(s,1H),7.32(t,J＝7.8Hz,2H),6.98(d,J＝7.7Hz,2H),4.16(d,J＝13.8Hz,1H),4.02(dd,J＝13.7,5.9Hz,2H),3.76–3.63(m,2H),3.24–3.16(m,2H),2.90–2.79(m,1H),2.48–2.40(m,1H),2.37–2.20(m,3H),2.01(s,6H),1.83–1.71(m,2H),1.53–1.38(m,4H),1.18–1.05(m,4H),0.94–0.73(m,4H).
实施例31～34分别参照实施例29或实施例30全部或部分合成方法选择相应的原料制备。
Figure PCTCN2020101646-appb-000032
实施例35：((4-环丙基-6-((3'-(4-环丙基-5-(((2-羟基乙基)氨基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸的制备
Figure PCTCN2020101646-appb-000033
第一步：((4-环丙基-6-((3'-(4-环丙基-5-(二甲氧基甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸酸乙酯的合成
Figure PCTCN2020101646-appb-000034
4-环丙基-N-(3'-(4-环丙基-5-(二甲氧基甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)-5-甲酰基-2-吡啶酰胺(300mg，0.497mmol)溶于DMF(3mL)，然后加入D-丝氨酸乙酯盐酸盐(420mg，2.48mmol)，三乙胺(250mg，2.48mmol)和乙酸(1mL)。混合物在室温下搅拌2小时，然后加入NaBH 3CN(94mg，1.49mmol)，室温搅拌过夜。LCMS检测反应完全，该反应液直接使用反相柱层析分离得到((4-环丙基-6-((3'-(4-环丙基-5-(二甲氧基甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸酸乙酯(300mg,收率：84％)。MS m/z(ESI):722.4[M+H] +。
第二步：((4-环丙基-6-((3'-(4-环丙基-5-甲酰基吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸酸乙酯的合成
Figure PCTCN2020101646-appb-000035
((4-环丙基-6-((3'-(4-环丙基-5-(二甲氧基甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸酸乙酯(300mg，0.416mmol)溶于THF(10mL)，搅拌下加入盐酸溶液(10mL，4M)，室温搅拌1小时。LCMS检测反应完全，将反应体系置于冰浴冷却，加入饱和NaHCO 3水溶液中和。用乙酸乙酯萃取3次(20mL)，合并有机相，再用饱和食盐水洗，无水Na 2SO 4干燥，过滤，浓缩，得到粗品(260mg，收率：93％)，直接用于下步反应。MS m/z(ESI):676.6[M+H] +。
第三步：((4-环丙基-6-((3'-(4-环丙基-5-(((2-羟基乙基)氨基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸乙酯(实施例35-1)的合成
Figure PCTCN2020101646-appb-000036
((4-环丙基-6-((3'-(4-环丙基-5-甲酰基吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸酸乙酯(60mg，0.089mmol)溶于DMF(3mL)，再加入2-氨基乙醇(54mg，0.89mmol)和乙酸(1mL)。混合物在室温下搅拌2小时，然后加入NaBH 3CN(17mg，0.267mmol)，搅拌过夜。LCMS检测反应完全，反应液直接使用反相柱层析分离得到((4-环丙基-6-((3'-(4-环丙基-5-(((2-羟基乙基)氨基)甲基)吡啶-2-酰氨 基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸乙酯(45mg，收率：70％)。MS m/z(ESI):721.4[M+H] +；361.2[1/2M+H] +。
1H NMR(400MHz,DMSO-d 6)δ10.31(s,2H),8.59(s,1H),8.54(s,1H),7.87(d,J＝8.2Hz,2H),7.60(s,1H),7.59(s,1H),7.32(t,J＝7.8Hz,2H),6.98(d,J＝7.6Hz,2H),4.85(t,J＝5.8Hz,1H),4.15–4.00(m,5H),3.90(d,J＝13.7Hz,1H),3.61(t,J＝5.2Hz,2H),3.56–3.48(m,2H),2.74(brs,2H),2.37–2.22(m,2H),2.00(s,6H),1.20(t,J＝7.1Hz,3H),1.19–1.06(m,4H),0.92–0.79(m,4H).
第四步：((4-环丙基-6-((3'-(4-环丙基-5-(((2-羟基乙基)氨基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸的合成
Figure PCTCN2020101646-appb-000037
((4-环丙基-6-((3'-(4-环丙基-5-(((2-羟基乙基)氨基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸乙酯(20mg，0.028mmol)溶于THF(3mL)和水(3mL)，再加入LiOH·H 2O(6mg，0.14mmol)，室温下搅拌1小时。LCMS检测反应完全，使用乙酸调节成酸性，直接反相柱层析分离得到((4-环丙基-6-((3'-(4-环丙基-5-(((2-羟基乙基)氨基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸(15mg，收率：78％)。MS m/z(ESI):693.4[M+H] +；347.2[1/2M+H] +。
1H NMR(400MHz,DMSO-d 6)δ10.32(s,2H),8.61(s,1H),8.59(s,1H),7.87(d,J＝8.1Hz,2H),7.61(s,1H),7.60(s,1H),7.32(t,J＝7.8Hz,2H),6.98(d,J＝7.7Hz,1H),4.20–4.10(m,3H),3.99(d,J＝13.7Hz,1H),3.65(t,J＝5.7Hz,2H),3.57(t,J＝5.6Hz,2H),3.28(t,J＝5.0Hz,1H),2.80(t,J＝5.6Hz,2H),2.40–2.22(m,2H),2.00(s,6H),1.20–1.08(m,4H),0.95–0.80(m,4H).
实施例36：((4-环丙基-6-((3'-(4-环丙基-5-((3-羟基-3-甲基吖丁啶-1-基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸的制备
Figure PCTCN2020101646-appb-000038
第一步：((4-环丙基-6-((3'-(4-环丙基-5-((3-羟基-3-甲基吖丁啶-1-基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸乙酯(实施例36-1)的合成
Figure PCTCN2020101646-appb-000039
((4-环丙基-6-((3'-(4-环丙基-5-甲酰基吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸酸乙酯(60mg，0.089mmol)溶于DMF(3mL)，再依次加入3-甲基吖丁啶-3-醇盐酸盐(33mg，0.267mmol)，三乙胺(27mg，0.267mmol)和乙酸(1mL)。混合物在室温下搅拌2小时，然后加入NaBH 3CN(17mg，0.267mmol)， 搅拌过夜。LCMS检测反应完全，反应液直接反相柱层析分离得到((4-环丙基-6-((3'-(4-环丙基-5-((3-羟基-3-甲基吖丁啶-1-基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸乙酯(40mg，收率：60％)。MS m/z(ESI):747.4[M+H] +；374.2[1/2M+H] +。
1H NMR(400MHz,DMSO-d 6)δ10.31(s,1H),10.29(s,1H),8.54(s,1H),8.48(s,1H),7.88(d,J＝8.1Hz,2H),7.59(s,2H),7.31(t,J＝7.8Hz,2H),6.98(d,J＝7.5Hz,2H),5.19(s,1H),4.85(s,1H),4.15–4.01(m,3H),3.90(dd,J＝13.5,5.7Hz,1H),3.85(s,2H),3.61(brs,2H),3.23(d,J＝6.8Hz,2H),2.99(d,J＝6.4Hz,2H),2.35–2.19(m,2H),2.00(s,6H),1.38(s,3H),1.20(t,J＝7.1Hz,3H),1.12(d,J＝8.1Hz,4H),0.90–0.80(m,4H).
第二步：((4-环丙基-6-((3'-(4-环丙基-5-((3-羟基-3-甲基吖丁啶-1-基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸的合成
Figure PCTCN2020101646-appb-000040
((4-环丙基-6-((3'-(4-环丙基-5-((3-羟基-3-甲基吖丁啶-1-基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸乙酯(15mg，0.02mmol)溶于THF(3mL)和水(3mL)，再加入LiOH·H 2O(4mg，0.10mmol)，室温搅拌1小时。LCMS检测反应完全，使用乙酸调成酸性后反相柱层析分离得到((4-环丙基-6-((3'-(4-环丙基-5-((3-羟基-3-甲基吖丁啶-1-基)甲基)吡啶-2-酰氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)氨基甲酰)吡啶-3-基)甲基)-D-丝氨酸(10mg,收率：69％)。MS m/z(ESI):719.4[M+H] +；360.2[1/2M+H] +。
1H NMR(400MHz,DMSO-d 6)δ10.33(s,1H),10.30(s,1H),8.59(s,1H),8.48(s,1H),7.88(d,J＝8.0Hz,1H),7.87(d,J＝8.0Hz,1H),7.60(s,1H),7.59(s,1H),7.32(t,J＝7.8Hz,2H),6.98(d,J＝7.6Hz,2H),5.21(s,1H),4.13(d,J＝13.8Hz,1H),3.98(d,J＝13.5Hz,1H),3.86(s,2H),3.60(d,J＝5.4Hz,2H),3.24(d,J＝6.8Hz,2H),3.25–3.15(m,1H),3.00(d,J＝6.7Hz,2H),2.36–2.24(m,2H),2.01(s,6H),1.38(s,3H),1.19–1.08(m,4H),0.90–0.82(m,4H).
实施例37～66参照实施例35或36全部或部分合成方法选择相应的原料制备。
Figure PCTCN2020101646-appb-000041
Figure PCTCN2020101646-appb-000042
Figure PCTCN2020101646-appb-000043
Figure PCTCN2020101646-appb-000044
Figure PCTCN2020101646-appb-000045
实施例67：(2S,2'S)-2,2'-((((((2,2'-二甲基-[1,1'-联苯基]-3,3'-二基)二(氮杂烷二基))二(羰基))二(4-环丙基吡啶-6,3-二基))二(亚甲基))二(氮杂烷二基))二(3-羟基-2-甲基丙酸)的制备
Figure PCTCN2020101646-appb-000046
第一步：N,N'-(2,2'-二甲基-[1,1'-联苯基]-3,3'-二基)二(4-环丙基-5-(二甲氧基甲基)-2-吡啶酰胺)的合成
Figure PCTCN2020101646-appb-000047
称取4-环丙基-5-(二甲氧基甲基)吡啶-2-甲酸钾(2.80g，10.1mmol)，HATU(3.54g，9.24mmol)，2,2'-二甲基-[1,1'-双苯基]-3,3'-二胺(700mg，3.3mmol)和DIPEA(2.5mL)于100mL茄形瓶中，再加入DMF/THF(20mL，v/v＝4/1)，室温搅拌6小时。反应过滤，洗涤。滤液浓缩，硅胶柱层析分离得到N,N'-(2,2'-二甲基-[1,1'-联苯基]-3,3'-二基)二(4-环丙基-5-(二甲氧基甲基)-2-吡啶酰胺)(1.30g，收率：61％)。MS m/z(ESI):651.6[M+H] +。
第二步：N,N'-(2,2'-二甲基-[1,1'-联苯基]-3,3'-二基)二(4-环丙基-5-甲酰基-2-吡啶酰胺)的合成
Figure PCTCN2020101646-appb-000048
N,N'-(2,2'-二甲基-[1,1'-联苯基]-3,3'-二基)二(4-环丙基-5-(二甲氧基甲基)-2-吡啶酰胺)(1300mg，2.0mmol)加入THF(20mL)，再向其中加入盐酸溶液(8mL，4M)，室温搅拌4小时。反应完全，加入水(8mL)，搅拌过夜。过滤，真空干燥得到N,N'-(2,2'-二甲基-[1,1'-联苯基]-3,3'-二基)二(4-环丙基-5-甲酰基-2-吡啶酰胺)(995mg，收率：90％)。MS m/z(ESI):559.2[M+H] +。
第三步：(2S,2'S)-2,2'-((((((2,2'-二甲基-[1,1'-联苯基]-3,3'-二基)二(氮杂烷二基))二(羰基))二(4-环丙基吡啶-6,3-二基))二(亚甲基))二(氮杂烷二基))二(3-羟基-2-甲基丙酸)的合成
Figure PCTCN2020101646-appb-000049
N,N'-(2,2'-二甲基-[1,1'-联苯基]-3,3'-二基)二(4-环丙基-5-甲酰基-2-吡啶酰胺)(50mg，0.09mmol)置于DMF/CH 2Cl 2(1.8mL/0.9mL)，然后加入DIPEA(116mg，0.90mmol)和(S)-2-氨基-3-羟基-2-甲基丙酸(107mg，0.90mmol)，室温搅拌6小时，再加入NaBH(OAc) 3(190mg，0.90mmol)，室温下继续搅拌过夜。反应完后反应液直接反相柱层析分离(洗脱剂：水(0.1％TFA)：乙腈)，冷冻干燥得到(2S,2'S)-2,2'-((((((2,2'-二甲基-[1,1'-联苯基]-3,3'-二基)二(氮烷二基))二(羰基))二(4-环丙基吡啶-6,3-二基))二(亚甲基))二(氮烷二基))二(3-羟基-2-甲基丙酸)的TFA盐(17.2mg，收率：25％)。MS m/z(ESI):382.8[1/2M+H] +；765.7[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ10.38(s,2H),8.74(s,2H),7.80(d,J＝8.0Hz,2H),7.67(s,2H),7.34(t,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),4.54-4.46(m,4H),3.97(d,J＝12.0 Hz,2H),3.84(d,J＝12.0Hz,2H),2.43-2.36(m,4H),2.00(s,6H),1.56(s,6H),1.24-1.16(m,4H),0.96-0.91(m,4H).
实施例68～70参照实施例67全部或部分合成方法选择相应的原料制备。
Figure PCTCN2020101646-appb-000050
上述实施例制备得到的部分化合物核磁数据如下：
Figure PCTCN2020101646-appb-000051
Figure PCTCN2020101646-appb-000052
Figure PCTCN2020101646-appb-000053
Figure PCTCN2020101646-appb-000054
Figure PCTCN2020101646-appb-000055
生物学测试评价
一、PD1-PDL1HTRF结合活性测试
本发明实施例化合物对于PD-1/PD-L1蛋白相互作用的影响通过Cisbio的PD-1/PD-L1 binding assay kit来测定(#64ICP01PEG或者64ICP01PEH)，具体实验方法如下：
1)在384孔板中加入稀释好的化合物以及4μL的Tag1-PD-L1蛋白和4μL的Tag2-PD1蛋白；
2)在室温孵育15分钟，再加入5μL的抗Tag1-Eu3+的抗体和5μL抗Tag2-XL665的抗体；
3)室温孵育2小时或4度孵育过夜之后，Pelkin Elmer的Envision上读数。分别读取665nm下的读数和620nm下的读数，将二者的比值作为每个孔的读数；
4)将化合物处理之后得到每个孔的读数和DMSO处理的孔的读数进行比较，得到化合物抑制百分比；
5)通过非线性回归分析不同化合物浓度下的抑制百分比来测定本发明实施例化合物的IC 50值。具体实验结果见表1。
二、Jurkat报告基因细胞活性测试
本发明实施例化合物对于表达在细胞表面的PD-1/PD-L1蛋白相互作用的影响以及带来的T细胞功能的影响通过Jurkat报告基因细胞活性测试来测定。
简言之，就是将NF-κB-luc的报告基因质粒和人体PD-1的质粒转染到Jurkat细胞中，建立同时稳定表达PD-1和NF-κB-Luc报告基因的稳转细胞株，采用流式细胞术鉴 定PD-1的表面表达水平，用OKT-3以及Raiji细胞刺激之后报告基因的反应来鉴定报告基因的表达水平。
另外，将人体PD-L1的表达质粒转染到Raji细胞中得到稳定表达PD-L1的细胞株。然后通过Jurkat/NF-κB-luc/PD1细胞和Raji-PD-L1细胞共培养，并用OKT-3刺激，在此基础上加入化合物，通过报告基因反应的读数来反映化合物对PD-1/PD-L1相互作用的抑制作用对于T细胞活化信号通路的增强。具体实验方法如下：
1)在白色96孔板中(corning,3610)加入30μL的不同稀释浓度的化合物或者抗体，再加入10μL的OKT3(Biolegend,317326)(OKT3终浓度为1μg/mL)；
2)每孔加入20μL Raji-PD-L1细胞悬液，每孔5×10 4cells，培养箱中孵育20分钟；
3)每孔加入20μL Jurkat/NF-κb-luc/PD-1细胞悬液，每孔5×10 4cells，混匀，6h后检测Bright-glo(Promega,E2620)；
4)将化合物处理之后得到每个孔的读数和DMSO处理的孔的读数进行比较，得到化合物作用的活化倍数；
5)通过非线性回归分析不同化合物浓度下的活化倍数来测定本发明实施例化合物的EC 50值。具体实验结果见表1：
表1：生物学测试结果
Figure PCTCN2020101646-appb-000056
Figure PCTCN2020101646-appb-000057
从具体实施例化合物生物活性数据来看，本发明系列化合物对PD-1/PD-L1的蛋白相互作用具有很强的抑制作用，而且这种抑制作用在细胞水平上能增强或恢复T细胞的活化。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 式(I)化合物、其立体异构体、前药或其药学上可接受盐：
    Figure PCTCN2020101646-appb-100001
    其中，
    R 1选自如下基团：
    Figure PCTCN2020101646-appb-100002
    R 2选自-NHR 6或4-6元含氮杂环基，其中氮原子与亚甲基连接，所述4-6元含氮杂环基任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、羟基取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、4-6元杂环基、羟基取代C 3-6环烷基、羧基取代C 3-6环烷基、羟基取代4-6元杂环基、羧基取代4-6元杂环基、羟基、C 1-4烷氧基、羧基或C 1-4烷氧酰基的取代基所取代；
    R 3、R 4、R 5各自独立地选自氢、氘或C 1-4烷基，所述C 1-4烷基任选进一步被一个或多个选自氘、卤素、氰基、环丙基、羟基或C 1-4烷氧基的取代基所取代；
    R 6选自C 1-4烷基、C 3-6环烷基或C 4-6杂环基，其中所述杂环基任选包含1-2个选自N或O的杂原子，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、羟基取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、4-6元杂环基、羟基取代C 3-6环烷基、羧基取代C 3-6环烷基、羟基取代4-6元杂环基、羧基取代4-6元杂环基、羟基、C 1-4烷氧基、羧基或C 1-4烷氧酰基的取代基所取代；
    条件是，当R 1为
    Figure PCTCN2020101646-appb-100003
    时，R 2与R 1不相同。
  2. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，
    R 3、R 4、R 5各自独立地选自氢、氘、甲基、乙基或丙基，上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、环丙基、羟基、甲氧基或乙氧基的取代基所取代；
    R 6选自甲基、乙基、异丙基、环丙基、环丁基、环戊基、环己基、
    Figure PCTCN2020101646-appb-100004
    上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、硝基、叠氮基、甲基、乙基、异丙基、二氟甲基、三氟甲基、二氯甲基、三氯甲基、二溴甲基、三溴甲基、二氘甲基、三氘甲基、羟甲基、环丙基、环丁基、环戊基、羟基环丙基、
    Figure PCTCN2020101646-appb-100005
    羟基、甲氧基、乙氧基、羧基、甲氧酰基或乙氧酰基的取代基所取代。
  3. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其 特征在于，所述式(I)化合物具有如下式(Ⅱa)化合物、式(Ⅱb)化合物或式(Ⅱc)化合物、式(Ⅱd)化合物或式(Ⅱe)化合物结构：
    Figure PCTCN2020101646-appb-100006
    其中，R 2选自-NHR 6或4-6元含氮杂环基，其中氮原子与亚甲基连接，
    条件是在式(Ⅱa)化合物中，R 2不选自
    Figure PCTCN2020101646-appb-100007
    在式(Ⅱb)化合物中，R 2不选自
    Figure PCTCN2020101646-appb-100008
    在式(Ⅱc)化合物中，R 2不选自
    Figure PCTCN2020101646-appb-100009
    所述4-6元含氮杂环基选自如下结构：
    Figure PCTCN2020101646-appb-100010
    上述结构任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、异丙基、环丙基、羟基环丙基、羟甲基、羟基、甲氧基、乙氧基、羧基、甲氧酰基或乙氧酰基的取代基所取代；
    R 3、R 4、R 5各自独立地选自氢、氘、甲基或乙基；
    R 6选自甲基、乙基、异丙基、环丙基、环丁基、环戊基、环己基、
    Figure PCTCN2020101646-appb-100011
    上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、异丙基、环丙基、羟基环丙基、羟甲基、羟基、甲氧基、乙氧基、羧基、甲氧酰基或乙氧酰基的取代基所取代。
  4. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，选自如下化合物：
    Figure PCTCN2020101646-appb-100012
    Figure PCTCN2020101646-appb-100013
    Figure PCTCN2020101646-appb-100014
    Figure PCTCN2020101646-appb-100015
  5. 一种权利要求1-4任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐的制备方法，其特征在于，包括如下步骤：
    Figure PCTCN2020101646-appb-100016
    其中，R a、R b、R c、R d各自独立地为C 1-8烷氧基，或者R a与R b、R c与R d一起为＝O，R 1、R 2如权利要求1所述。
  6. 一种药物组合物，其包括权利要求1-4任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐及可药用的载体。
  7. 一种权利要求1-4任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐在制备预防和/或治疗由PD-1/PD-L1信号通路介导的有关疾病药物中的应用。
  8. 根据权利要求7所述的应用，其特征在于，所述的由PD-1/PD-L1信号通路介导的有关疾病选自癌症或肿瘤、免疫相关疾病及紊乱、传染性疾病、感染性疾病或代谢性疾病。
  9. 根据权利要求8所述的应用，其特征在于，所述感染性疾病选自细菌性传染病、病毒性传染病或真菌性传染病；所述癌症或肿瘤选自淋巴瘤(包括但不限于淋巴细胞性淋巴瘤、原发性中枢神经系统淋巴瘤、T细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡中心淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤或原发性纵隔大B细胞淋巴瘤)、肉瘤(包括但不限于卡波西肉瘤、纤维肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、平滑肌肉瘤、横纹肌肉瘤、软组织肉瘤、血管肉瘤或淋巴管肉瘤)、黑色素瘤、胶质母细胞瘤、滑膜瘤、脑膜瘤、胆道肿瘤、胸腺肿瘤、神经肿瘤、精原细胞瘤、肾母细胞瘤、多形性腺瘤、肝细胞乳头状瘤、肾小管腺瘤、囊腺瘤、乳头瘤、腺瘤、平滑肌瘤、横纹肌瘤、血管瘤、淋巴管瘤、骨瘤、软骨瘤、脂肪瘤、纤维瘤、中枢神经系统肿瘤、脊柱轴瘤、脑干胶质瘤、垂体腺瘤、多发性骨髓瘤、卵巢肿瘤、骨髓增生异常综合征或间皮瘤，前列腺癌、复发或已对现有药物产生抗性的前列腺癌、甲状腺癌、甲状旁腺癌、肛门癌、睾丸癌、尿道癌、阴茎癌、膀胱癌、输尿管癌、子宫癌、卵巢癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、肾上腺癌、默克尔细胞癌、胚胎癌、慢性或急性白血病(包括但不限于急性髓系白血病、慢性髓系白血病、急性淋巴细胞白血病、慢性粒细胞白血病、慢性淋巴细胞白血病)、支气管癌、食管癌、鼻咽癌、肝细胞癌、肾细胞癌、小细胞肺癌、基 底细胞癌、肺癌、乳腺癌、腺癌、乳头状癌、囊腺癌、鳞状非小细胞肺癌、非鳞状非小细胞肺癌、直肠癌、结肠癌、结直肠癌、胃癌、胰腺癌、头颈部鳞状细胞癌、头颈部癌、胃肠道、骨癌、皮肤癌、小肠癌、内分泌系统癌、肾盂癌、表皮样癌、腹壁癌、肾细胞癌、移行细胞癌或绒毛膜癌，以及转移性的肿瘤，尤其是表达PD-L1的转移性肿瘤；
    所述的免疫相关疾病及紊乱选自风湿性关节炎、肾衰竭、红斑狼疮、哮喘、牛皮癣、溃疡性结肠炎、胰腺炎、过敏、纤维化、贫血纤维肌痛症、阿尔茨海默病、充血性心力衰竭、中风、主动脉瓣狭窄、动脉硬化、骨质疏松症、帕金森病、感染、克隆氏病、溃疡性结肠炎、过敏性接触性皮炎和湿疹、系统性硬化症和多发性硬化症；
    所述传染性疾病或感染性疾病选自脓毒症、肝脏感染、HIV、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒、乳头瘤病毒或流感；
    所述代谢性疾病选自糖尿病、糖尿病酮症酸中毒、高血糖高渗综合征、低血糖症、痛风、营养不良症、维生素A缺乏病、坏血病、维生素D缺乏病或骨质疏松症。
  10. 根据权利要求1-4任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其用作预防和/或治疗由PD-1/PD-L1信号通路介导的癌症或肿瘤、免疫相关疾病及紊乱、传染性疾病、感染性疾病或代谢性疾病的药物。
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