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WO2020025030A1 - 一类具有免疫调节功能的芳香化合物的制备和应用 - Google Patents

一类具有免疫调节功能的芳香化合物的制备和应用 Download PDF

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WO2020025030A1
WO2020025030A1 PCT/CN2019/098925 CN2019098925W WO2020025030A1 WO 2020025030 A1 WO2020025030 A1 WO 2020025030A1 CN 2019098925 W CN2019098925 W CN 2019098925W WO 2020025030 A1 WO2020025030 A1 WO 2020025030A1
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group
substituted
unsubstituted
compound
alkyl
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PCT/CN2019/098925
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English (en)
French (fr)
Inventor
张毅
邓建稳
冯志勇
黄磊
江磊
路小丽
尚珂
寿建勇
汪兵
徐雪莉
徐圆
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上海轶诺药业有限公司
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Priority claimed from CN201810865177.6A external-priority patent/CN110790770A/zh
Priority claimed from CN201910503368.2A external-priority patent/CN112062780A/zh
Application filed by 上海轶诺药业有限公司 filed Critical 上海轶诺药业有限公司
Priority to CN201980051399.7A priority Critical patent/CN112638899B/zh
Priority to US17/264,657 priority patent/US20210347785A1/en
Priority to EP19843979.6A priority patent/EP3831823A4/en
Publication of WO2020025030A1 publication Critical patent/WO2020025030A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • A61P37/02—Immunomodulators
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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 present invention relates to the field of small molecule protein inhibitors. Specifically, the present invention provides preparation and application of a compound having an immunomodulatory function.
  • the immune system has surveillance, defense, and regulation functions.
  • Cellular immunity is mainly involved in the immune response to intracellular parasitic pathogenic microorganisms and tumor cells, in the formation of delayed allergies and autoimmune diseases, in the rejection of transplantation and in the regulation of humoral immunity.
  • Activation of T lymphocytes by antigen-presenting cells is usually regulated by two different signals.
  • the primary signal is transduced by the T cell receptor (TCR) by foreign antigen peptides presented by the major histocompatibility complex (MHC) on APC cells.
  • TCR T cell receptor
  • MHC major histocompatibility complex
  • Secondary signals also known as co-stimulation signals, are bound to T cell surface receptors by co-stimulatory molecules on APC cells, and are transmitted to T cells to regulate T cell proliferation, cytokine secretion, and effector functions.
  • Secondary signals include two ways of positive regulation and negative regulation. Positive signals promote T cell activation, and negative signals induce T cell tolerance, which is essential for the human body to adapt and
  • PD-L1 Programmed death-ligand 1
  • CD274 cluster of differentiation 274
  • B7 homolog 1 B7 homolog1, B7-H1
  • PD-L1 mRNA is expressed in almost all tissues, but PD-L1 protein is continuously expressed in only a few tissues, including liver, lungs, tonsils, and immune amnesty tissues such as the eyes and placenta.
  • PD-L1 is also expressed in activated T cells, B cells, monocytes, dendritic cells, macrophages and the like.
  • the receptor for PD-L1 is PD-1, which is mainly expressed on the surface of immune cells such as activated CD4 + T cells, CD8 + T cells, NK cells, B cells, and activated monocytes.
  • the binding of PD-L1 and PD-1 can initiate the phosphorylation of tyrosine residues in the ITIM (immunoreceptor tyrosine inhibitory module) of PD-1 cytoplasm, and promote the binding of tyrosine phospholipase to SHP2 and activate SHP2.
  • the downstream Syk and PI3K are dephosphorylated to transmit a termination signal, limiting the interaction of antigen-presenting cells or dendritic cells with T cells.
  • This combination can further inhibit the metabolism of T cells, inhibit the secretion of anti-apoptotic protein Bcl-2, reduce the secretion of effector cytokines IL-2, IFN- ⁇ , induce T cell depletion and apoptosis, thereby reducing immune T cells Participate in immune responses and exercise negative regulatory functions.
  • T cells recognize the antigen and activate it to secrete IFN- ⁇ .
  • T cell-derived IFN- ⁇ will expand and maintain T cell functions, such as up-regulating MHC molecules, enhancing antigen processing and presentation of target cells, and promoting T cell differentiation.
  • IFN- ⁇ also induces PD-L1 expression in tissues at the site of immune inflammation, preventing excessive immunity from causing damage to the tissue.
  • IFN- ⁇ can induce the expression of PD-L1 on the surface of conventional epithelial cells, vascular endothelial cells, myeloid cells, and naive T cells.
  • IFN- ⁇ -induced interferon regulatory factor 1 can also bind to interferon regulatory factor binding sites at 200bp and 320bp before the transcription start site of PD-L1 to regulate PD-L1 from the transcription level.
  • PD-L1 can combine with PD-1 on the surface of T cells to exercise negative regulatory functions, thereby protecting inflammatory sites.
  • PD-L1 The negative regulatory function of PD-L1 plays an important role in tumor immunity.
  • Konishi and others took the lead in finding PD-L1 expression in tissue samples from patients with non-small cell lung cancer, and subsequently PD-L1 was found to be expressed in the tissues of various tumor patients, including gastric cancer, lung cancer, liver cancer, and intrahepatic bile duct cancer.
  • Colon cancer pancreatic cancer, ovarian cancer, breast cancer, cervical cancer, head and neck squamous cell carcinoma, nasopharyngeal cancer, esophageal cancer, bladder cancer, renal cell carcinoma, skin cancer, oral squamous cell carcinoma, etc.
  • new protein molecules will be generated due to gene mutation, foreign gene (viral) expression or quiescent gene activation. After these proteins are degraded in the cell, certain degraded peptides can be expressed on the cell surface and become Tumor antigen.
  • the immune system can recognize tumor antigens and clear tumor cells through immune surveillance, while tumor cells use PD-L1 to escape immune attacks.
  • TIL Tumor infiltrating lymphocytes
  • IFN- ⁇ can induce tumor cells and surrounding stromal cells to express PD-L1.
  • PD-L1 of tumor cells can bind to PD-1 on TIL, inhibit the activation of TIL cells, and further cause apoptosis.
  • tumor cell-related PD-L1 can increase the apoptosis of tumor-specific T cells, and PD-L1 monoclonal antibodies can reduce this effect.
  • Tumor-associated PD-L1 can promote the expression of IL-10 by T cells and further suppress the immune response.
  • PD-L1 is not only a ligand of PD-1. It can also act as a receptor to transmit reverse signals to protect tumor cells from apoptosis induced by other anti-tumor pathways such as FAS-FASL.
  • PD-1 / PD-L1 blockers can be used in the clinical treatment of a variety of tumors.
  • antibody drugs have their own characteristics, such as high production cost, poor stability, need to be administered by injection and easy to produce immunogenicity.
  • Small molecule drugs have the advantages of good tissue permeability, convenient storage and transportation, low production cost, non-immunogenicity, and usually can be administered orally. Therefore, research and development of PD-1 / PD-L1 small molecule blockers have significant advantages. Application value and social value.
  • the object of the present invention is to provide a small molecule PD-1 / PD-L1 blocker.
  • M is selected from O or NH
  • X 1 and X 5 are each independently selected from the group consisting of N, CH, O, or S;
  • X 3 is selected from the group consisting of N, CR 3 , O, or S;
  • X 3 or X 4 is O, S or N;
  • Y 1 and Y 2 are each independently N or C;
  • Z 1 , Z 2 and Z 3 are each independently N or CR 4 ;
  • R 1 is selected from the group consisting of H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;
  • R 2 is selected from the group consisting of a substituted or unsubstituted C 6 -C 10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S, and O, or A substituted or unsubstituted 5-10 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O; and one or more hydrogen atoms on the R 2 group are replaced by R 5 ;
  • the R 3 is selected from the group consisting of H, a substituted or unsubstituted C1-C6 alkyl group, or And at least one R 3 is n1 is 1, 2, 3 or 4;
  • Ra and Rb together with adjacent N atoms form a substituted or unsubstituted 5-10 membered heterocyclic group having 1-3 heteroatoms selected from the group of N, S and O;
  • the R 4 is selected from the group consisting of H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;
  • the R 5 is selected from the group consisting of H, CN, halogen, substituted or unsubstituted (-L 1 -L 2- (CH 2 ) q- (substituted or unsubstituted 5-7 membered heteroaryl)) , Substituted or unsubstituted (-L 1 -L 2- (CH 2 ) q -N (Ra) (Rb)), -O-substituted or unsubstituted (-(CH 2 ) q -O- (CH 2 ) q -N (Ra) (Rb)), or a substituted or unsubstituted group selected from the group consisting of C 6 -C 10 aryl, having 1-3 hetero groups selected from the group N, S and O Atomic 5-10 member heteroaryl, -L 1 -L 2 -6-10 member aryl- (CH 2 ) q -N (Ra) (Rb), -L 1 -L 2 -5
  • q is selected from the group: 0, 1, 2, 3, 4, 5, 6, 7, or 8;
  • the additional condition is that the compound of formula I has a chemically stable structure.
  • said q is selected from the following group: 1, 2, 3 or 4.
  • R 2 is a group selected from the group consisting of a substituted or unsubstituted phenyl group.
  • R 2 is selected from the following group:
  • the compound has a structure represented by the following formula II:
  • the compound has a structure represented by the following formula II:
  • the R 5 ′ is selected from the group consisting of H, CN, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;
  • R 6 is (C 1 -C 8 alkylene) -N (Ra) (Rb);
  • Ring A is selected from the group consisting of: substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group N, S and O , Substituted or unsubstituted 5-10 membered heterocyclic group having 1-3 heteroatoms selected from the group of N, S and O;
  • p 1, 2, 3, or 4.
  • the compound of formula I has a structure represented by the following formula:
  • X is CH or N
  • R is a substituent selected from the group consisting of halogen, CN, C1-C6 alkyl, halogenated C1-C6 alkyl, and C1-C6 alkoxy.
  • Z 1 , Z 2 and Z 3 are each independently CR 4 .
  • Z 1 , Z 2 and Z 3 are each independently CH.
  • the compound has a structure represented by the following formula IV:
  • X 1 is selected from the group consisting of N or CH;
  • X 2 is selected from the group: N or CR 3 ;
  • X 3 is selected from the group: NR 3 , O, or S;
  • R 7 is selected from the group consisting of H, halogen.
  • the -N (Ra) Rb is selected from the following group:
  • the R 5 is selected from the group consisting of H, Me, Cl, CN, -O (CH 2 ) n- (substituted or unsubstituted 5-7 membered heteroaryl ring), -O (CH 2 ) n -N (Ra) (Rb).
  • R 5 is selected from the group consisting of H, Me, Cl, CN, or a group selected from the group consisting of:
  • n 1-2.
  • R 6 is selected from the following group:
  • the compound of formula I is selected from the following group:
  • the compound of formula I is selected from the following group:
  • a pharmaceutical composition comprising (1) the compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or Its pharmaceutically acceptable salt, hydrate or solvate; (2) a pharmaceutically acceptable carrier.
  • a compound according to the first aspect of the present invention or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or Use of the pharmaceutical composition according to the second aspect of the present invention for the preparation of a pharmaceutical composition for the prevention and / or treatment of diseases related to the activity or expression level of PD-1 / PD-L1.
  • the disease is selected from the group consisting of a tumor, a pathogen infection, and an autoimmune response-related disease.
  • the pharmaceutical composition is used for the treatment of diseases selected from the group consisting of melanoma (such as metastatic malignant melanoma), kidney cancer (such as clear cell cancer), and prostate cancer (such as Hormone refractory prostate adenocarcinoma), breast cancer, colon cancer, and lung cancer (eg, non-small cell lung cancer).
  • diseases selected from the group consisting of melanoma (such as metastatic malignant melanoma), kidney cancer (such as clear cell cancer), and prostate cancer (such as Hormone refractory prostate adenocarcinoma), breast cancer, colon cancer, and lung cancer (eg, non-small cell lung cancer).
  • Bone cancer pancreatic cancer, skin cancer, head or neck cancer, skin or eye malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastrointestinal, testicular cancer, uterine cancer, fallopian tube cancer, intrauterine Membrane cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small bowel cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft Tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), childhood solid tumor, lymphocytic lymphoma Tumor, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) neoplasm / tumor, primary CNS lymphom
  • the pharmaceutical composition is used in a combined drug regimen.
  • the combined drug regimen includes a combined tumor chemotherapy regimen and other tumor immunotherapeutics (small molecule compounds and antibodies, etc.).
  • HPV human papilloma virus
  • HBV and HCV hepatitis virus
  • KHSV Kaposi herpes sarcoma virus
  • the pharmaceutical composition is used alone or in combination for the treatment of a patient exposed to a specific toxin or pathogen.
  • viruses include but are not limited to the treatment of various viruses, pathogenic bacteria, pathogenic fungi, pathogenic parasites, and the like.
  • viruses pathogenic bacteria, pathogenic fungi, pathogenic parasites, and the like.
  • viruses pathogenic bacteria, pathogenic fungi, pathogenic parasites, and the like.
  • viruses such as HIV, hepatitis virus (A, B, C), influenza virus, herpes virus, Giardia, malaria, Leishmania, Staphylococcus aureus, Pseudomonas aeruginosa and other pathogens have established infections.
  • the pharmaceutical composition is used to induce a therapeutic autoimmune response.
  • the pharmaceutical composition is used to treat patients with inappropriate accumulation of other autoantigens, such as amyloid deposits, including A ⁇ in Alzheimer's disease, cytokines such as TNFa and IgE .
  • autoantigens such as amyloid deposits, including A ⁇ in Alzheimer's disease, cytokines such as TNFa and IgE .
  • a PD-1 / PD-L1 inhibitor comprising the compound described in the first aspect of the present invention, or a stereoisomer or tautomer thereof, or Its pharmaceutically acceptable salt, hydrate or solvate.
  • the term “about” means that the value can vary from the recited value by no more than 1%.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including (comprising)” may be open, semi-closed, and closed. In other words, the term also includes “consisting essentially of” or “consisting of”.
  • alkyl includes linear or branched alkyl groups.
  • C 1 -C 8 alkyl means a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Wait.
  • alkenyl includes linear or branched alkenyl.
  • C 2 -C 6 alkenyl refers to a straight or branched chain alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 -Butenyl, or a similar group.
  • alkynyl includes straight or branched chain alkynyl.
  • C 2 -C 6 alkynyl refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or similar groups.
  • C 3 -C 8 cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms. It may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It can also be in the form of a bicyclic ring, such as a bridge ring or a spiro ring.
  • C 1 -C 8 alkoxy refers to a straight or branched chain alkoxy group having 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propoxy, butoxy, isobutoxy, tert-butoxy and the like.
  • a 3-10 membered heterocycloalkyl group having 1-3 heteroatoms selected from the group N, S and O refers to a group having 3-10 atoms and wherein 1-3 atoms are A saturated or partially saturated cyclic group of a heteroatom selected from the group N, S and O. It can be monocyclic or bicyclic, such as bridge or spiro. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.
  • C 6 -C 10 aryl refers to an aryl group having 6 to 10 carbon atoms, such as a phenyl or naphthyl group and the like.
  • the term "5- to 10-membered heteroaryl having 1-3 heteroatoms selected from the group N, S, and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from A heterocyclic ring aromatic group of the lower groups N, S and O. It can be monocyclic or fused ring.
  • pyridyl pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl, and (1,2,3) 4) -Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, and the like.
  • the groups of the present invention may be substituted with a substituent selected from the group consisting of halogen, nitrile, nitro, hydroxyl, amino, C 1 -C 6 alkyl-amine, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, halo C 2 -C 6 alkenyl, halo C 2 -C 6 alkynyl, halo C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl , C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl, C 2 -C 6 alkenyl-carbonyl, C 3 -C 6 cycl
  • halogen or halogen atom refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "Halogenated” means substituted with an atom selected from F, Cl, Br, and I.
  • the structural formulae described herein are intended to include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformers)): for example, containing asymmetry R, S configuration of the center, (Z), (E) isomers of double bonds, etc. Therefore, a single stereochemical isomer of a compound of the present invention or a mixture of enantiomers, diastereomers or geometric isomers (or conformers) thereof is within the scope of the present invention.
  • tautomers means that structural isomers with different energies can exceed low energy barriers, thereby converting each other.
  • proton tautomers ie, proton shifts
  • Valence tautomers include interconversions through the reorganization of some bonding electrons.
  • solvate refers to a complex of a compound of the present invention coordinated with a solvent molecule to form a specific ratio.
  • the present invention provides a compound represented by the following formula I, a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • M is selected from O or NH
  • X 1 and X 5 are each independently selected from the group consisting of N, CH, O, or S;
  • X 3 is selected from the group consisting of N, CR 3 , O, or S;
  • X 3 or X 4 is O, S or N;
  • Y 1 and Y 2 are each independently N or C;
  • Z 1 , Z 2 and Z 3 are each independently N or CR 4 ;
  • R 1 is selected from the group consisting of H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;
  • R 2 is selected from the group consisting of a substituted or unsubstituted C 6 -C 10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S, and O, or A substituted or unsubstituted 5-10 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O; and one or more hydrogen atoms on the R 2 group are replaced by R 5 ;
  • the R 3 is selected from the group consisting of H, a substituted or unsubstituted C1-C6 alkyl group, or And at least one R 3 is n1 is 1, 2, 3 or 4;
  • Ra and Rb together with adjacent N atoms form a substituted or unsubstituted 5-10 membered heterocyclic group having 1-3 heteroatoms selected from the group of N, S and O;
  • the R 4 is selected from the group consisting of H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;
  • the R 5 is selected from the group consisting of H, CN, halogen, substituted or unsubstituted (-L 1 -L 2- (CH 2 ) q- (substituted or unsubstituted 5-7 membered heteroaryl)) , Substituted or unsubstituted (-L 1 -L 2- (CH 2 ) q -N (Ra) (Rb)), -O-substituted or unsubstituted (-(CH 2 ) q -O- (CH 2 ) q -N (Ra) (Rb)), or a substituted or unsubstituted group selected from the group consisting of C 6 -C 10 aryl, having 1-3 hetero groups selected from the group N, S and O Atomic 5-10 member heteroaryl, -L 1 -L 2 -6-10 member aryl- (CH 2 ) q -N (Ra) (Rb), -L 1 -L 2 -5
  • q is selected from the group: 0, 1, 2, 3, 4, 5, 6, 7, or 8;
  • the additional condition is that the compound of formula I has a chemically stable structure.
  • Preferred compounds of formula I are the specific compounds shown in the examples of this application.
  • the present invention also provides a method for preparing a compound according to the first aspect of the present invention, comprising the steps of: in a suitable solvent, Compound 1 is substituted to obtain Compound 2, Compound 2 and Compound 3 are reacted with a palladium catalyst under In the presence of a base and a phosphine compound, compound 4 is obtained by reaction, compound 4 is reduced to obtain compound 5, and compound 5 is subjected to reductive amination to obtain a compound represented by formula 6.
  • the compound of the present invention has excellent PD-1 inhibitory activity
  • the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present compound are the main activities
  • the pharmaceutical composition of the ingredients can be used to prevent and / or treat a disease (eg, cancer) related to the PD-1 / PD-L1 signaling pathway.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention in a safe and effective amount and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • a pharmaceutical composition contains 1-2000 mg of a compound / agent of the invention, and more preferably 10-200 mg of a compound / agent of the invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here means that the components of the composition can be blended with the compound of the invention and with each other without significantly reducing the pharmacological effect of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • Wetting agents such as sodium lauryl sulfate
  • the administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerol; (d) disintegrating agents, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and g
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as casings and other materials known in the art. They may contain opaque agents and the release of the active compound or compounds in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound may also be microencapsulated with one or more of the aforementioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • liquid dosage forms may include inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers.
  • ethanol isopropanol
  • ethyl carbonate ethyl acetate
  • propylene glycol 1
  • 3-butanediol dimethylformamide
  • oils especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these, and the like.
  • compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous vehicles, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more other pharmaceutically acceptable compounds.
  • One or more of the other pharmaceutically acceptable compounds may be administered simultaneously, separately or sequentially with a compound of the invention.
  • a safe and effective amount of a compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dose when administered is a pharmaceutically considered effective dose.
  • a mammal such as a human
  • the dosage is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health, etc., which are all within the skill of a skilled physician.
  • the pharmaceutical composition can be used for:
  • melanoma such as metastatic malignant melanoma
  • kidney cancer such as clear cell carcinoma
  • prostate cancer such as hormone refractory prostate adenocarcinoma
  • Breast cancer colon cancer
  • lung cancer eg, non-small cell lung cancer
  • Bone cancer pancreatic cancer, skin cancer, head or neck cancer, skin or eye malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastrointestinal, testicular cancer, uterine cancer, fallopian tube cancer, intrauterine Membrane cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small bowel cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft Tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), childhood solid tumor, lymphocytic lymphoma Tumor, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) neoplasm / tumor, primary CNS lymphom
  • tumor-targeted drugs such as human papilloma virus (HPV), Hepatitis virus (HBV and HCV) and Kaposi herpes sarcoma virus (KHSV).
  • HPV human papilloma virus
  • HBV and HCV Hepatitis virus
  • KHSV Kaposi herpes sarcoma virus
  • the agents may be administered before, after or at the same time or may be co-administered with other known therapies.
  • toxins or pathogens include but are not limited to the treatment of various viruses, pathogenic bacteria, pathogenic fungi, pathogenic parasites, and the like.
  • viruses pathogenic bacteria, pathogenic fungi, pathogenic parasites, and the like.
  • viruses pathogenic bacteria, pathogenic fungi, pathogenic parasites, and the like.
  • viruses pathogenic bacteria, pathogenic fungi, pathogenic parasites, and the like.
  • viruses pathogenic bacteria, pathogenic fungi, pathogenic parasites, and the like.
  • viruses pathogenic bacteria, pathogenic fungi, pathogenic parasites, and the like.
  • viruses pathogenic bacteria, pathogenic fungi, pathogenic parasites, and the like.
  • viruses pathogenic bacteria, pathogenic fungi, pathogenic parasites, and the like.
  • viruses pathogenic bacteria, pathogenic fungi, pathogenic parasites, and the like.
  • viruses pathogenic bacteria, pathogenic fungi, pathogenic parasites, and the like.
  • viruses pathogenic bacteria, pathogenic
  • the target compound was prepared from compound 1B and (2S, 4S) -4-hydroxypyrrolidine-2-carboxylic acid under conditions similar to those of Example 5.
  • the target compound was prepared from compound 4A and 2-aminoethane-1-ol under conditions similar to those of Example 4.
  • the target compound was prepared from compound 3C and (R) -pyrrolidin-3-ol under conditions similar to those of Example 3.
  • the target compound was prepared from compound 3C and (S) -pyrrolidin-3-ol under conditions similar to those in Example 3.
  • the target compound was prepared from compound 3C and glycine under conditions similar to those of Example 3.
  • the target compound was obtained according to the method of Example 3, replacing the corresponding raw materials.
  • the target compound was obtained according to the method of Example 3, replacing the corresponding raw materials.
  • the target compound was obtained according to the method of Example 3, replacing the corresponding raw materials.
  • the target compound was obtained according to the method of Example 3, replacing the corresponding raw materials.
  • the target compound was obtained according to the method of Example 3, replacing the corresponding raw materials.
  • the target compound was obtained according to the method of Example 3, replacing the corresponding raw materials.
  • the target compound was obtained according to the method of Example 3, replacing the corresponding raw materials.
  • the target compound was obtained according to the method of Example 3, replacing the corresponding raw materials.
  • Example 17C To a solution of Example 17C (20 mg, 0.035 mmol), 2-aminoethane-1-ol (8 mg, 0.14 mmol) in dichloromethane was added a catalytic amount of acetic acid (1 drop), and the reaction solution was stirred at room temperature for 16 hours.
  • Sodium triacetoxyborohydride (63mg, 0.30mmol)
  • the reaction solution was stirred at room temperature for 4 hours, the reaction solution was quenched with water (10mL), extracted with dichloromethane three times (15mL * 3), the organic phases were combined and dried, and concentrated, and the residue
  • the title compound (4 mg, 25%) was obtained by preparative high performance liquid chromatography as a yellow solid.
  • reaction solution was quickly separated and purified by reversed phase (80% acetonitrile-10nmol / mL concentration ammonium bicarbonate aqueous solution) to obtain the target product 18D (70mg, 63%) as a pale yellow solid.
  • Example 18 To a solution of Example 18 (80 mg, 0.12 mmol), anhydrous potassium carbonate (50 mg, 0.36 mmol) in N, N-dimethylformamide (3 mL) was added 4- (chloromethyl) -5-formaldehyde -1,3-dioxazol-2-one (36 mg, 0.24 mmol), and the reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was purified by reverse phase rapid separation (65% acetonitrile-0.1% formic acid in water) to obtain the target product Example 19 (18mg, 18%) as a white solid.
  • Test Example 1 Detecting Compounds' Inhibitory Effect on PD-1 / PD-L1 Protein Binding
  • PD-1 / PD-L1 homogeneous time-resolved fluorescence (HTRF) detection technology was used to detect the binding ability of the compound to PD-L1.
  • PD1 / PD-L1 binding assay kit (Cisbio, Cat # 63ADK000CPDEC) was selected.
  • the kit contains two proteins, Tag 1-PD-L1 and Tag 2-PD-1, and Anti-Tag1-Eu 3+ and Anti- Tag2-XL 665 two antibodies.
  • Detection principle Anti-tag1-Eu 3+ as the donor of HTRF, Anti-Tag2-XL 665 as the acceptor of HTRF, when Tag 1-PD-L1 and Tag 2-PD-1 interact, the added HTRF donor The body and the acceptor are close to each other. After the donor receives the excitation energy, it transfers part of the energy to the acceptor, which will produce 665nm emission light.
  • Tag 1-PD-L1 is diluted to a working concentration of 10 nM with Diluent buffer (cat # 62DLBDDF)
  • Tag 2-PD-1 is diluted to a working concentration of 500 nM with Diluent buffer
  • Anti-Tag1-Eu 3+ is used with detection buffer (cat # 62DB1FDG) Dilute 1: 100.
  • Anti-Tag2-XL 665 is diluted 1:20 with detection buffer. Compounds to be detected are diluted with diluent buffer to a final concentration of 2X.
  • the letter A represents an IC 50 of less than 100 nM
  • the letter B stands for IC 50 from 100 nM to 1 uM;
  • the letter C represents that the IC 50 is greater than 1 uM
  • the results show that the compounds of the present invention can effectively inhibit the binding of PD-1 / PD-L1 at different concentrations. Therefore, it can be used in the treatment of diseases related to the mutual binding of PD-1 / PD-L1.
  • PD1 / PD-L1 cytology experiments require two types of cells, PD-1 effector cells and PD-L1 aAPC / CHO-K1 cells, where PD-1 effector cells express human PD-1 protein and NFAT-driven fluorescein Enzyme reporter gene, PD-L1 aAPC / CHO-K1 cells express PD-L1 protein and anti-CD3 antibody.
  • PD-1 / PD-L1 interaction can inhibit the TCR to NFAT-RE signal transmission and interrupt the NFAT-RE-mediated fluorescent signal.
  • the recovered PD-L1 aAPC / CHO-K1 cells were digested, and after centrifugation, the concentration was adjusted to 2.5 * 10 5 / mL with a medium (90% Ham's F-12 / 10% FBS). 40ul wells, 1 * 10 4 cells, were plated in 384-well plates and placed in an incubator overnight. The next day, the test compound was first diluted with a test buffer (99% RPMI1640 / 1% FBS) in a gradient to twice the required detection concentration. After the PD-1 cells were centrifuged, the detection buffer was used to adjust the concentration to 6.25 * 10 5 / mL.
  • a test buffer 99% RPMI1640 / 1% FBS
  • the culture medium in the 384-well plate cultured overnight was blotted dry, and 20ul of the diluted compound was added to each well, and 20ul of PD-1 cells were added. After incubating in the cell incubator for 6 hours, 20ul of Bio-Glo reagent was added to each well. (Promega, cat # G7940). After 10 minutes, read the plate with a multifunctional microplate reader. Each plate should be set with a negative control (only cells and no compounds), and a blank control (only detection buffers). Based on the fluorescence value, prism5 was used to analyze the inhibitory activity of the compound.
  • the results show that the compound of the present invention can effectively block the PD-1 / PD-L1 interaction, and the half-life inhibitory concentration is equal to or better than the PD1 inhibitor in the clinical stage.
  • Human PBMC functional experiments require two types of cells, human PBMC cells and PD-L1 aAPC / CHO-K1 cells (CHO-K1 cells express full-length human PD-L1 protein and anti-hCD3 antibody).
  • the anti-hCD3 antibody expressed by aAPC cells binds to CD3 on the surface of PBMC and stimulates PBMC activation and proliferation, but the PD-1 / PD-L1 interaction can inhibit TCR signaling.
  • -L1 inhibitors block the PD-1 / PD-L1 interaction and release signals to the TCR pathway. The inhibitory effect of inhibitors was determined by detecting changes in cell surface markers CD25, PD1 and intracellular cytokines IFNr after PBMC activation.
  • the recovered PD-L1 aAPC / CHO-K1 cells and PD-L1 Negative cells were digested. After centrifugation, the cell concentration was adjusted to 2 * 10 5 / with media (90% F12 + 10% FBS) mL, 100ul per well, 2 * 10 4 cells, spread in a 96-well plate, and culture in an incubator overnight. The next day, the cells were treated with a medium containing 10 ug / ml mitomycin, left at 37 ° C for 4 h, and then the plate was washed three times with PBS. At the same time, the test compound is prepared and diluted to 2 times the required detection concentration in a gradient.
  • PBMC cells were resuscitated and adjusted to a concentration of 1 * 10 6 / mL according to the operating requirements. 50ul of the compound was added to the plate, and then 50ul of PBMC cells were added. After incubation in the cell incubator for three days, the cell supernatants were collected for ELISA to detect cytokine IFNr. Changes were collected to detect changes in CD25 and PD1 by flow cytometry.
  • the results show that the compound of the present invention can effectively block the PD-1 / PD-L1 interaction, and the half-life inhibitory concentration is equal to or better than the PD1 inhibitor in the clinical stage.
  • Test Example 4 In vivo pharmacodynamic test of small and medium molecule inhibitors for treating tumors
  • a mouse model of subcutaneously transplanted tumors was established to examine the in vivo inhibitory effects of these compounds on tumor growth.
  • the method is as follows: the specific tumor cells in culture are digested and the cells are collected by centrifugation, washed with sterile saline twice and counted, and the cell concentration is adjusted to the required concentration with physiological saline, and 0.2 ml of the cell suspension is inoculated into C57BL / 6 Or Balb / c immune healthy mice are subcutaneous. After the inoculation, the tumors were observed to grow to a specific size. Animals were randomly divided into groups of 6-7 animals each, and they were administered after weighing. The test compounds were administered once a day.
  • the results show that the compound of the present invention can effectively inhibit tumor growth in tumor-bearing mice, and its inhibitory effect is comparable to or better than that of a PD1 inhibitor in clinical stage.
  • Test Example 5 In vivo pharmacodynamic test of small and medium molecule inhibitors combined with chemotherapeutic drugs of the present invention
  • a mouse model of subcutaneously transplanted tumors was established to examine the in vivo inhibitory effects of these compounds on tumor growth.
  • the method is as follows: the specific tumor cells in culture are digested and the cells are collected by centrifugation, washed with sterile saline twice and counted, and the cell concentration is adjusted to the required concentration with physiological saline, and 0.2 ml of the cell suspension is inoculated into C57BL / 6 Or Balb / c immune healthy mice are subcutaneous. After the inoculation, the tumors were observed to grow to a specific size. The animals were randomly divided into groups of 6-7 animals. They were weighed and administered.
  • the test compound was administered in combination with bevac / carboplatin / paclitaxel / pemetrexed according to the combined administration schedule.
  • Drugs, grouping includes: carrier group, test compound combined with chemotherapeutic group, chemotherapeutic group, test compound group. Mice were tested for tumor growth every week for about 6 weeks. After the tumor volume reached the tumor end point, the mice were weighed and euthanized. Strip tumor tissue, spleen tissue, and blood samples. Calculate the tumor suppression rate, detect the immune cell composition in the tumor, spleen and blood samples, and calculate the immunomodulatory activity of the test compound and the combined drug.
  • Test Example 6 The efficacy of small molecule inhibitors combined with immune modulators in treating tumors in vivo
  • a mouse model of subcutaneously transplanted tumors was established to examine the in vivo inhibitory effects of these compounds on tumor growth.
  • the method is as follows: the specific tumor cells in culture are digested and the cells are collected by centrifugation, washed with sterile saline twice and counted, and the cell concentration is adjusted to the required concentration with physiological saline, and 0.2 ml of cell suspension is inoculated into C57BL / 6 Or Balb / c immune healthy mice are subcutaneous. After the inoculation, observe the tumor growth to a specific size. Animals are randomly divided into groups of 6-7 animals. They are weighed and administered.
  • test compound and the combined drug Nivolumab / Ipilimumab are administered according to a combined administration schedule.
  • Test Example 7 Pharmacokinetic experiment of the small molecule inhibitor of the present invention in mice
  • Test compounds were given to ICR mice intravenously (IV) and orally (PO), and blood samples were collected at different time points.
  • LC-MS / MS was used to determine the concentration of test substances in mouse plasma and calculate related parameters. The details are as follows: take the required amount of the test product, dissolve it in 5% DMSO + 10% Solutol + 85% water for injection, and prepare a solution with the required concentration for intravenous or oral administration. The animals were about 6-8 weeks old at the start of the dosing experiment.
  • Venous blood collection time 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration.
  • Oral blood collection time 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after administration.
  • Phoenix WinNonlin 7.0 software was used to calculate the pharmacokinetic parameters, such as AUC (0-t) , AUC (0- ⁇ ) , T 1/2 , C max , T max and MRT, etc. .
  • Test example 8 Pharmacokinetic experiment of small molecule inhibitor of the present invention in rats
  • Test compounds were administered to SD rats intravenously (IV) and orally (PO) separately, and blood samples were collected at different time points.
  • LC-MS / MS was used to determine the concentration of test substances in the rat plasma and calculate relevant parameters. The details are as follows: take the required amount of the test product, dissolve it in 5% DMSO + 10% Solutol + 85% water for injection, and prepare a solution with the required concentration for intravenous or oral administration. The animals were about 6-8 weeks old at the start of the dosing experiment.
  • Venous blood collection time 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration.
  • Oral blood collection time 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after administration.
  • Phoenix WinNonlin 7.0 software was used to calculate the pharmacokinetic parameters, such as AUC (0-t) , AUC (0- ⁇ ) , T 1/2 , C max , T max and MRT, etc. .

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Abstract

一种具有式（I）结构的免疫调节作用的芳香化合物、制备方法和其在调节免疫，抑制PD-1/PD-L1方面的用途。

Description

一类具有免疫调节功能的芳香化合物的制备和应用 技术领域
本发明涉及小分子蛋白抑制剂领域，具体地，本发明提供了一种具有免疫调节功能的化合物的制备和应用。
背景技术
免疫系统具有监视、防御、调控等作用。细胞免疫主要参与对胞内寄生的病原微生物的免疫应答及对肿瘤细胞的免疫应答，参与迟发型变态反应和自身免疫病的形成，参与移植排斥反应及对体液免疫的调节。T淋巴细胞被抗原递呈细胞的激活通常受两种不同信号的调节。初级信号由APC细胞上的主要组织相容性复合体(MHC)呈递外来抗原肽通过T细胞受体(TCR)转导。次级信号，又称共刺激信号，通过APC细胞上的共刺激分子与T细胞表面受体结合，传递给T细胞，调节T细胞增殖，细胞因子分泌和效应功能。次级信号包括正调节和负调节两种方式，正信号促进T细胞激活，负信号诱导T细胞耐受，对人体适应和调整自身免疫细胞对外界不同抗原的反应作用至关重要。
程序性细胞死亡蛋白配体1(Programmed death-ligand 1，PD-L1)，又可称为分化簇274(cluster of differentiation 274，CD274)或者B7同源蛋白1(B7 homolog1，B7-H1)，属于肿瘤坏死因子超家族，是由290个氨基酸残基组成的I型跨膜糖蛋白，包含一个IgV样区、一个IgC样区、一个跨膜疏水区和一个30个氨基酸的胞内尾部,完整分子量为40kDa。PD-L1 mRNA在几乎所有组织中都有表达，但PD-L1蛋白只在少部分组织中持续表达，包括肝脏、肺脏、扁桃体以及免疫特赦组织如眼、胎盘等。PD-L1也表达于活化的T细胞，B细胞，单核细胞，树突状细胞，巨噬细胞等。
PD-L1的受体为PD-1，主要表达于活化的CD4+T细胞、CD8+T细胞、NK细胞、B细胞和活化的单核细胞等免疫细胞表面。PD-L1与PD-1结合可以启动PD-1胞浆区ITIM(免疫受体酪氨酸抑制作用模块)酪氨酸残基的磷酸化，促使酪氨酸磷脂酶与SHP2结合，活化SHP2，使下游Syk和PI3K发生去磷酸化从而传递终止信号，限制抗原呈递细胞或者树突状细胞与T细胞的相互作用。这种结合还可以进一步抑制T细胞的代谢，抑制抗凋亡蛋白Bcl-2的分泌，减少效应细胞因子IL-2，IFN-γ的分泌，诱导T细胞耗竭和凋亡，从而降低免疫T细胞参与的免疫应答，行使负性调节功能。
T细胞识别抗原并活化后会分泌IFN-γ。T细胞来源的IFN-γ会扩增和维持T细胞功能，比如上调MHC分子，增强目标细胞的抗原处理和呈递，促进T细胞分化。IFN-γ同时也会诱导免疫炎症部位组织的PD-L1表达，防止过度免疫对组织造成伤害。IFN-γ可以诱导常规上皮细胞，血管内皮细胞，髓样细胞，幼稚T细胞等细胞表面PD-L1的表达。IFN-γ诱导产生的干扰素调节因子1(IRF-1)也可以与PD-L1转录起始位点前200bp和320bp处的干扰素调节因子结合位点结合，从转录水平调节PD-L1。PD-L1可以与T细胞表面的PD-1结合行使负调节功能，从而保护炎性部位。
PD-L1的负性调控功能在肿瘤免疫中发挥着重要作用。2004年，Konishi等率先在非小细胞肺癌病人的组织样本中发现PD-L1的表达，随后PD-L1被发现表达于各种肿瘤病人的组织中，包括胃癌，肺癌，肝癌，肝内胆管癌，结肠癌，胰腺癌，卵巢癌，乳腺癌，子宫颈癌，头颈鳞状细胞癌，鼻咽癌，食管癌，膀胱癌，肾细胞癌，皮肤癌，口腔鳞状细胞癌等。细胞恶变过程中，由于基因突变、外源基因(病毒)表达或静止基因激活等原因会产生新的蛋白分子，这些蛋白质在细胞内降解后，某些降解的肽段可以表达于 细胞表面，成为肿瘤抗原。免疫系统可以通过免疫监察识别肿瘤抗原并清除肿瘤细胞，而肿瘤细胞则利用PD-L1逃避免疫攻击。
肿瘤部位PD-L1的表达可以通过多种途径保护肿瘤细胞免受伤害。肿瘤浸润淋巴细胞(TIL)分泌IFN-γ可诱导肿瘤细胞及周围基质细胞表达PD-L1。而肿瘤细胞的PD-L1可以与TIL上PD-1结合，抑制TIL细胞的活化，并进一步导致其凋亡。体外实验证明，肿瘤细胞相关PD-L1可以增加肿瘤特异T细胞的调亡，而PD-L1单克隆抗体可以减弱这种作用。肿瘤相关PD-L1可以促进T细胞表达IL-10，进一步抑制免疫反应。PD-L1不仅仅是PD-1的配体，他也可以作为受体传递反向的信号保护肿瘤细胞免受FAS-FASL等其他抗肿瘤途径诱导的凋亡。
目前多个已上市的靶向PD-1或者PD-L1的单克隆抗体药物证实PD-1/PD-L1的阻断剂可用于多种肿瘤的临床治疗。然而抗体药物有其自身的特点，如生产成本高，稳定性较差，需经注射给药及易产生免疫原性等。而小分子药物具有组织渗透性好，储存运输方便，生产成本较低，无免疫原性及通常可口服给药等优势，因此研究开发PD-1/PD-L1的小分子阻断剂具有显著的应用价值和社会价值。
综上所述，本领域迫切需要开发小分子的PD-1/PD-L1阻断剂。
发明内容
本发明的目的是提供一种小分子的PD-1/PD-L1阻断剂。
本发明的第一方面，提供了一种如下式I所示的化合物，其立体异构体或其互变异构体，或其药学上可接受的盐、水合物或溶剂化物：
Figure PCTCN2019098925-appb-000001
其中，
M选自O或NH；
X 2选自下组：N、NR 3、CR 3、O、S、N＝CR 3、CR 3＝N或CR 3＝CR 3；
X 4选自下组：N、CH、O、S、N＝CH、CH＝N或CH＝CH；
且X 2和X 4中有且仅有一个为选自下组的基团：CR 3＝CR 3、N＝CR 3、或CR 3＝N(在X 4中R 3为H)；
X 1和X 5各自独立地选自下组：N、CH、O或S；
X 3选自下组：N、CR 3、O或S；
且X 3或X 4中至少一个为O、S或N；
Y 1和Y 2各自独立地为N或C；
Z 1、Z 2和Z 3各自独立地为N或CR 4；
R 1选自下组：H、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基；
R 2选自下组：取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、或取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；且所述的R 2基团上有一个或多个氢原子被R 5取代；
所述的R 3选自下组：H、取代或未取代的C1-C6烷基，或
Figure PCTCN2019098925-appb-000002
且至少一个R 3为
Figure PCTCN2019098925-appb-000003
n1为1、2、3或4；
Ra和Rb各自独立地选自下组：H、-(C＝O)-取代或未取代的C 1-C 8烷基、取代或未取代的C 1-C 8烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 1-C 8烷胺基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 3-C 10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂环基；
或所述的Ra和Rb与相邻的N原子共同构成取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂环基；
所述的R 4选自下组：H、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基；
所述的R 5选自下组：H、CN、卤素、取代或未取代的(-L 1-L 2-(CH 2) q-(取代或未取代的5-7元杂芳基))、取代或未取代的(-L 1-L 2-(CH 2) q-N(Ra)(Rb))、-O-取代或未取代的(-(CH 2) q-O-(CH 2) q-N(Ra)(Rb))、或取代或未取代的选自下组的基团：C 6-C 10芳基、具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基、-L 1-L 2-6-10元芳基-(CH 2) q-N(Ra)(Rb)、-L 1-L 2-5-10元杂芳基-(CH 2) q-N(Ra)(Rb)；其中，所述的L 1和L 2各自独立地选自下组：无、取代或未取代的C 1-C 8亚烷基、-NH-C(＝O)-NH-、-C(＝O)-NH-、-O-、-S-或-NH-；或两个R 5与相连的碳原子共同构成选自下组的基团：取代或未取代的5-7元杂芳基、取代或未取代的5-7元杂环基；
q选自下组：0、1、2、3、4、5、6、7或8；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、甲基砜基、-S(＝O) 2NH 2、-S(＝O) 2NHCH 3、氧代(＝O)、-CN、羟基、-NH 2、C1-C6胺基、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、
Figure PCTCN2019098925-appb-000004
Figure PCTCN2019098925-appb-000005
或取代或未取代的选自下组的基团：C1-C6烷基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-10元杂环基(包括并环、螺环)、-(CH 2)-C6-C10芳基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)，且所述的取代为被选自下组的取代基所取代：卤素、C1-C6烷基、C1-C6烷氧基、氧代、-CN、-OH、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、-O-(CH 2) q-CN；
Figure PCTCN2019098925-appb-000006
为基团的连接位点；
各个
Figure PCTCN2019098925-appb-000007
各自独立地为单键或双键；
附加条件是式I化合物为化学上稳定的结构。
在另一优选例中，所述的q选自下组：1、2、3或4。
在另一优选例中，所述的R 2为选自下组的基团：取代或未取代的苯基。
在另一优选例中，所述的R 2选自下组：
Figure PCTCN2019098925-appb-000008
在另一优选例中，所述的化合物具有如下式II所示的结构：
Figure PCTCN2019098925-appb-000009
在另一优选例中，所述的化合物具有如下式II所示的结构：
Figure PCTCN2019098925-appb-000010
所述的R 5'选自下组：H、CN、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基；；
R 6为(C 1-C 8亚烷基)-N(Ra)(Rb)；
A环选自下组：取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂环基；
p为1、2、3或4。
在另一优选例中，所述的式I化合物具有如下式所示的结构：
Figure PCTCN2019098925-appb-000011
X为CH或N；
R为选自下组的取代基：卤素、CN、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基。
在另一优选例中，所述的
Figure PCTCN2019098925-appb-000012
为选自下组的杂环所形成的结构：
Figure PCTCN2019098925-appb-000013
Figure PCTCN2019098925-appb-000014
在另一优选例中，所述的Z 1、Z 2和Z 3各自独立地为CR 4。
在另一优选例中，所述的Z 1、Z 2和Z 3各自独立地为CH。
在另一优选例中，所述的化合物具有如下式IV所示的结构：
Figure PCTCN2019098925-appb-000015
其中，
X 1选自下组：N或CH；
X 2选自下组：N或CR 3；
X 3选自下组：NR 3、O或S；
R 7选自下组：H、卤素。
在另一优选例中，所述的-N(Ra)Rb选自下组：
Figure PCTCN2019098925-appb-000016
Figure PCTCN2019098925-appb-000017
Figure PCTCN2019098925-appb-000018
在另一优选例中，所述的R 5选自下组：H、Me、Cl、CN、-O(CH 2) n-(取代或未取代的5-7元杂芳环)、-O(CH 2) n-N(Ra)(Rb)。
在另一优选例中，所述的R 5选自下组：H、Me、Cl、CN，或选自下组的基团：
Figure PCTCN2019098925-appb-000019
Figure PCTCN2019098925-appb-000020
其中，n＝1-2。
在另一优选例中，所述的R 6选自下组：
Figure PCTCN2019098925-appb-000021
Figure PCTCN2019098925-appb-000022
在另一优选例中，所述的式I化合物选自下组：
Figure PCTCN2019098925-appb-000023
Figure PCTCN2019098925-appb-000024
Figure PCTCN2019098925-appb-000025
Figure PCTCN2019098925-appb-000026
在另一优选例中，所述的式I化合物选自下组：
Figure PCTCN2019098925-appb-000027
Figure PCTCN2019098925-appb-000028
本发明的第二方面，提供了一种药物组合物，所述的药物组合物包含(1)如本发明第一方面所述的化合物，或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物；(2)药学上可接受的载体。
本发明的第三方面，提供了一种如本发明第一方面所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物，或如本发明第二方面所述的药物组合物用于制备预防和/或治疗与PD-1/PD-L1的活性或表达量相关的疾病的药物组合物的用途。
在另一优选例中，所述的疾病选自下组：肿瘤、病原体感染、自身免疫应答相关疾病。
在另一优选例中，所述的药物组合物用于选自下组的疾病的治疗：黑素瘤(例如转移性恶性黑素瘤)、肾癌(例如透明细胞癌)、前列腺癌(例如激素不应性前列腺腺癌)、乳癌、结肠癌和肺癌(例如非小细胞肺癌)。骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内恶性黑素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃肠、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、阴户癌、何杰金氏病、非何杰金氏淋巴瘤、食道癌、小肠癌、内分泌系统的癌症、甲状腺癌、曱状旁腺癌、肾上腺癌、软組织肉瘤、尿道癌、阴茎癌、慢性或急性白血病(包括急性髓细胞样白血病、慢性髓细胞样白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病)、儿童期实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)的赘生物/肿瘤、原发性CNS淋巴瘤、肿瘤血管发生、脊髓轴(spinalaxis)肿瘤、脑干胶质瘤、垂体腺瘤、卡波西氏(Kaposi)肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、环境诱发的癌症(包括由石棉诱发的那些癌症)、及所述癌症的组合。转移性癌症，尤其是表达PD-Ll的转移性癌症
在另一优选例中，所述的药物组合物用于联合用药方案，较佳地，所述的联合用药方案包括：联合肿瘤化疗方案，其他肿瘤免疫治疗剂(小分子化合物及抗体等)，放疗方案，肿瘤靶向药，肿瘤疫苗(如人类乳头瘤病毒(HPV)、肝炎病毒(HBV和HCV)和卡波西疱疹肉瘤病毒(KHSV))。
在另一优选例中，所述的药物组合物用于单独或联合使用用于治疗暴露于特定毒素或病原体的患者的治疗。其中包括但不限于各种病毒，病原体细菌，病原体真菌，病原体寄生虫等的治疗。如HIV、肝炎病毒(甲、乙、丙)、流感病毒、疱疹病毒、贾第虫、疟疾、利什曼原虫、金黄色葡萄球菌、绿脓杆菌等病原体已建立的感染。
在另一优选例中，所述的药物组合物用于诱导治疗性自身免疫应答。
在另一优选例中，所述的药物组合物用于治疗具有不恰当的其他自身抗原积累的患 者，如淀粉状蛋白沉积物，包括阿尔茨海默病中的Αβ、细胞因子如TNFa和IgE。
本发明的第四方面，提供了一种PD-1/PD-L1抑制剂，所述抑制剂包含本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，设计并合成了一类新型PD-1小分子抑制剂。在此基础上，发明人完成了本发明。
术语
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
定义
如本文所用，术语“烷基”包括直链或支链的烷基。例如C 1-C 8烷基表示具有1-8个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用，术语“烯基”包括直链或支链的烯基。例如C 2-C 6烯基指具有2-6个碳原子的直链或支链的烯基，例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用，术语“炔基”包括直链或支链的炔基。例如C 2-C 6炔基是指具有2-6个碳原子的直链或支链的炔基，例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用，术语“C 3-C 8环烷基”指具有3-8个碳原子的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环或螺环形式。
如本文所用，术语“C 1-C 8烷氧基”是指具有1-8个碳原子的直链或支链的烷氧基；例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基”是指具有3-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环，也可以是双环形式，例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用，术语“C 6-C 10芳基”是指具有6-10个碳原子的芳基，例如，苯基或萘基等类似基团。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
除非特别说明，否则本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C 1-C 6烷基-胺基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 2-C 6烯基、卤代C 2-C 6炔基、卤代C 1-C 6烷氧基、烯丙基、苄基、C 6-C 12芳基、C 1-C 6烷氧基-C 1-C 6烷基、C 1-C 6烷氧基-羰基、苯氧羰基、C 2-C 6炔基-羰基、C 2-C 6烯基-羰基、C 3-C 6环烷基-羰基、C 1-C 6烷基-磺酰基等。
如本文所用，“卤素”或“卤原子”指F、Cl、Br、和I。更佳地，卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用，术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用，术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
式I化合物
本发明提供了一种如下式I所示的化合物，其立体异构体或其互变异构体，或其药学上可接受的盐、水合物或溶剂化物：
Figure PCTCN2019098925-appb-000029
其中，
M选自O或NH；
X 2选自下组：N、NR 3、CR 3、O、S、N＝CR 3、CR 3＝N或CR 3＝CR 3；
X 4选自下组：N、CH、O、S、N＝CH、CH＝N或CH＝CH；
且X 2和X 4中有且仅有一个为选自下组的基团：CR 3＝CR 3、N＝CR 3、或CR 3＝N(在X 4中R 3为H)；
X 1和X 5各自独立地选自下组：N、CH、O或S；
X 3选自下组：N、CR 3、O或S；
且X 3或X 4中至少一个为O、S或N；
Y 1和Y 2各自独立地为N或C；
Z 1、Z 2和Z 3各自独立地为N或CR 4；
R 1选自下组：H、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基；
R 2选自下组：取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、或取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；且所述的R 2基团上有一个或多个氢原子被R 5取代；
所述的R 3选自下组：H、取代或未取代的C1-C6烷基，或
Figure PCTCN2019098925-appb-000030
且至少一个R 3为
Figure PCTCN2019098925-appb-000031
n1为1、2、3或4；
Ra和Rb各自独立地选自下组：H、-(C＝O)-取代或未取代的C 1-C 8烷基、取代或未取代的C 1-C 8烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 1-C 8烷胺基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 3-C 10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂环基；
或所述的Ra和Rb与相邻的N原子共同构成取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂环基；
所述的R 4选自下组：H、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基；
所述的R 5选自下组：H、CN、卤素、取代或未取代的(-L 1-L 2-(CH 2) q-(取代或未取代的5-7元杂芳基))、取代或未取代的(-L 1-L 2-(CH 2) q-N(Ra)(Rb))、-O-取代或未取代的(-(CH 2) q-O-(CH 2) q-N(Ra)(Rb))、或取代或未取代的选自下组的基团：C 6-C 10芳基、具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基、-L 1-L 2-6-10元芳基-(CH 2) q-N(Ra)(Rb)、-L 1-L 2-5-10元杂芳基-(CH 2) q-N(Ra)(Rb)；其中，所述的L 1和L 2各自独立地选自下组：无、取代或未取代的C 1-C 8亚烷基、-NH-C(＝O)-NH-、-C(＝O)-NH-、-O-、-S-或-NH-；或两个R 5与相连的碳原子共同构成选自下组的基团：取代或未取代的5-7元杂芳基、取代或未取代的5-7元杂环基；
q选自下组：0、1、2、3、4、5、6、7或8；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、甲基砜基、-S(＝O) 2NH 2、-S(＝O) 2NHCH 3、氧代(＝O)、-CN、羟基、-NH 2、C1-C6胺基、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、
Figure PCTCN2019098925-appb-000032
Figure PCTCN2019098925-appb-000033
或取代或未取代的选自下组的基团：C1-C6烷基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-10元杂环基(包括并环、螺环)、-(CH 2)-C6-C10芳基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)，且所述的取代为被选自下组的取代基所取代：卤素、C1-C6烷基、C1-C6烷氧基、氧代、-CN、-OH、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、-O-(CH 2) q-CN；
Figure PCTCN2019098925-appb-000034
为基团的连接位点；
各个
Figure PCTCN2019098925-appb-000035
各自独立地为单键或双键；
附加条件是式I化合物为化学上稳定的结构。
优选的式I化合物为本申请实施例中所示的具体化合物。
式I化合物的制备
本发明还提供了一种制备如本发明第一方面所述化合物的方法，包括步骤：在适当的溶剂中，化合物1经取代反应得到化合物2，化合物2和化合物3在钯催化剂作用下，在碱和膦化合物存在下，反应得到化合物4，化合物4经还原得到化合物5，化合物5再经过还原胺化反应得到式6所示化合物。
Figure PCTCN2019098925-appb-000036
药物组合物和施用方法
由于本发明化合物具有优异的PD-1的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗与PD-1/PD-L1信号通路相关的疾病(例如，癌症)。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2019098925-appb-000037
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并 不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
联合给药时，所述药物组合物还包括与一种或多种其他药学上可接受的化合物。该其他药学上可接受的化合物中的一种或多种可与本发明的化合物同时、分开或顺序地给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
在本发明的优选实施方式中，所述的药物组合物可以用于：
(1)用于治疗各种肿瘤，包括但不限制于黑素瘤(例如转移性恶性黑素瘤)、肾癌(例如透明细胞癌)、前列腺癌(例如激素不应性前列腺腺癌)、乳癌、结肠癌和肺癌(例如非小细胞肺癌)。骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内恶性黑素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃肠、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、阴户癌、何杰金氏病、非何杰金氏淋巴瘤、食道癌、小肠癌、内分泌系统的癌症、甲状腺癌、曱状旁腺癌、肾上腺癌、软組织肉瘤、尿道癌、阴茎癌、慢性或急性白血病 (包括急性髓细胞样白血病、慢性髓细胞样白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病)、儿童期实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)的赘生物/肿瘤、原发性CNS淋巴瘤、肿瘤血管发生、脊髓轴(spinalaxis)肿瘤、脑干胶质瘤、垂体腺瘤、卡波西氏(Kaposi)肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、环境诱发的癌症(包括由石棉诱发的那些癌症)、及所述癌症的组合。转移性癌症，尤其是表达PD-Ll的转移性癌症
(2)用于联合用药方案，例如联合肿瘤化疗方案，其他肿瘤免疫治疗剂(小分子化合物及抗体等)，放疗方案，肿瘤靶向药，肿瘤疫苗等，如人类乳头瘤病毒(HPV)、肝炎病毒(HBV和HCV)和卡波西疱疹肉瘤病毒(KHSV)。可以在所述药剂之前、之后或同时施用，或者可以与其它已知疗法共施用。
(3)用于单独或联合使用用于治疗暴露于特定毒素或病原体的患者的治疗。其中包括但不限于各种病毒，病原体细菌，病原体真菌，病原体寄生虫等的治疗。如HIV、肝炎病毒(甲、乙、丙)、流感病毒、疱疹病毒、贾第虫、疟疾、利什曼原虫、金黄色葡萄球菌、绿脓杆菌等病原体已建立的感染。
(4)用于诱导治疗性自身免疫应答，以治疗具有不恰当的其他自身抗原积累的患者，如淀粉状蛋白沉积物，包括阿尔茨海默病中的Αβ、细胞因子如TNFa和IgE。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
各实施例中：
分析方法I
LCMS仪器：Agilent 6110，UV检测器：G1315D
层析柱：Xbridge C18 3.0×50mm,2.5uM,柱温30℃
流动相：A：H 2O(0.05％TFA)，B：乙腈，梯度洗脱：0-1min 10％B，1-8min 10-95％B，9min 95％B
中间体A的合成：
3-氨基噻吩并[3,2-b]吡啶-6-甲腈
Figure PCTCN2019098925-appb-000038
(E)-2-氰基-3,3-二甲氧基丙-1-烯-1-醇酸钠
Figure PCTCN2019098925-appb-000039
在氢化钠(2.08g，52.1mmol)的乙醚(100mL)混合液中，依次加入化合物3,3-二甲氧基丙腈(5g，43.4mmol)和甲酸乙酯(6.43g，86.8mmol)，反应混合物在室温下搅拌两天，过滤，固体用乙醚洗涤三次，烘干得到目标化合物(5g，70％)。
3-氨基噻吩并[3,2-b]吡啶-6-甲腈
Figure PCTCN2019098925-appb-000040
在化合物A1(0.3g，1.8mmol)的甲醇(20mL)溶液中加入浓盐酸(0.3mL，12N),室温下搅拌10分钟后再加入噻吩-3,4-二胺(0.3g，1.8mmol)的甲醇(10mL)溶液，反应混合物在80度下搅拌2小时后，旋干，粗品用高效液相制备纯化得到白色固体目标化合物(100mg，30％)。
MS-ESI:m/z 176.0[M+H] +。
1H NMR(400MHz,CDCl 3):δ8.96(s,1H),8.78(s,1H),7.44(s,1H)。
中间体B的合成：
4-氯-2-(甲氧基甲基)噻唑并[4,5-c]吡啶
Figure PCTCN2019098925-appb-000041
N-(4-羟基吡啶-3-基)-2-甲氧基乙酰胺
Figure PCTCN2019098925-appb-000042
室温下向化合物2-甲氧基乙酸(9.8g,109.1mmol)的二氯甲烷(30mL)溶液中滴加草酰氯(218.2mmol，18.4mL)，N,N-二甲基甲酰胺(0.1mL),反应2小时后浓缩，粗品溶于二氯甲烷(10mL)中，然后将此溶液于室温下滴加入3-氨基吡啶-4-酚(8.0g,4.54mmol)，二异丙胺(38.5mL，218.1mmol)的二氯甲烷(100ml)混合液中，加热回流2小时后室温搅拌过夜，浓缩，粗品用硅胶柱纯化(二氯甲烷/甲醇＝20/1)得到白色固体目标化合物(3.1g，23％)。
1H NMR(400MHz,CDCl 3):δ11.51(brs,1H),9.18(s,1H),8.68(s,1H),7.68(dd,J＝7.2,0.8Hz,1H),6.25(d,J＝7.2Hz,1H),4.16(s,2H),3.41(s,3H)。
2-(甲氧基甲基)噻唑并[4,5-c]吡啶
Figure PCTCN2019098925-appb-000043
室温下向化合物B1(3.1g,17.0mmol)的吡啶(30ml)溶液中加入五硫化二磷(4.5g,20.4mmol)，然后加热至110℃反应3小时，浓缩，粗品溶于乙酸乙酯中，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩后粗品用硅胶柱层析纯化(石油醚/乙酸乙酯 ＝10/1-3/1洗脱)得黄色固体目标化合物(700mg,22％)。
1H NMR(400MHz,CDCl 3):δ9.30(s,1H),8.53(d,J＝5.6Hz,1H),7.87(dd,J＝7.2,0.8Hz,1H),4.89(s,2H),3.57(s,3H)。
2-(甲氧基甲基)噻唑并[4,5-c]吡啶5-氧化
Figure PCTCN2019098925-appb-000044
室温下向化合物B2(760mg,4.22mmol)的二氯甲烷(10mL)溶液中分批加入间氯过氧苯甲酸(1.14g,4.64mmol),室温反应过夜,浓缩，粗品用硅胶柱层析纯化(二氯甲烷/甲醇＝20/1洗脱)得黄色固体目标化合物(800mg,96％)。
MS(ESI):m/z＝197.1[M+H] +。
4-氯-2-(甲氧基甲基)噻唑并[4,5-c]吡啶
Figure PCTCN2019098925-appb-000045
室温下将化合物B3(800mg,4.08mmol)分批加入到三氯氧磷(10mL)中，然后升温至100℃反应1小时，浓缩旋干，粗品溶于乙酸乙酯中，依次用饱和碳酸氢钠溶液和饱和食盐水洗涤，无水硫酸钠干燥，粗品用硅胶柱层析纯化(石油醚/乙酸乙酯＝30/1-10/1洗脱)得黄色固体目标化合物(600mg,69％)。
MS(ESI):m/z＝215.2[M+H] +。
1H NMR(400MHz,CDCl 3):δ8.31(d,J＝5.6Hz,1H),7.80(d,J＝5.6Hz,1H),4.92(s,2H),3.59(s,3H)。
中间体C的合成：
6-(2-氯-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯基)-2-甲氧基尼古丁醛
Figure PCTCN2019098925-appb-000046
2-(3-溴-2-氯-苯基)-4,4,5,5-四甲基-[1,3,2]二噁硼戊环
Figure PCTCN2019098925-appb-000047
往1，3-二溴-2-氯苯(5g,18.52mmol)的1，4-二氧六环(200mL)溶液中加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)(678mg,0.93mmol),联硼酸频那醇酯(4.7g,18.52mmol),醋酸钾(5.44g,55.56mmol)。混合物在氮气球保护下90摄氏度搅拌过夜。反应液冷却后倒入水中(200mL),用乙酸乙酯(200mL*3)萃取。有机相用无水硫酸钠干燥，抽滤，浓缩。残留物通过正相硅胶层析柱(石油醚:乙酸乙酯＝100:1)纯化得到白色固体目标化合物C1(2.7g,46％)。
1HNMR(400MHz,CDCl 3):δ7.67-7.65(m,1H),7.60-7.58(m,1H),7.11-7.07(m,1H),1.36(s,12H).
6-(3-溴-2-氯苯基)-2-甲氧基尼古丁醛
Figure PCTCN2019098925-appb-000048
将C1(1.71g，5.39mmol)，6-氯-2-甲氧基吡啶-3-甲醛(1.02g，5.93mmol)，四-三苯基膦钯(312mg，0.27mmol)，1，4-二氧六环(27mL)，水(2.7mL)，碳酸钾(1.49g,10.77mmol)的混合物在氮气球保护下95摄氏度搅拌3小时。反应液冷却至室温后用二氯甲烷(100mL)稀释，然后用水(50mL)和饱和食盐水(50mL)洗涤。有机相用无水硫酸钠干燥，抽滤，浓缩。残留物通过正相硅胶层析柱(石油醚:乙酸乙酯＝100:1)纯化得到白色固体目标化合物C2(1.24g,70％)。
1HNMR(400MHz,CDCl 3):δ10.41(s,1H),8.20-8.18(m,1H),7.73-7.71(m,1H),7.52-7.50(m,1H),7.30-7.22(m,2H),4.10(s,3H).
6-(2-氯-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯基)-2-甲氧基尼古丁醛
Figure PCTCN2019098925-appb-000049
往C2(720mg,2.2mmol)的1，4-二氧六环(20mL)溶液中加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)(161mg,0.22mmol),联硼酸频那醇酯(616mg,2.43mmol),醋酸钾(606mg,6.17mmol)。混合物在氮气球保护下95摄氏度搅拌过夜。反应液冷却后倒入水中(50mL),用乙酸乙酯(50mL*3)萃取。有机相用无水硫酸钠干燥，抽滤，浓缩。残留物通过正相硅胶层析柱(石油醚:乙酸乙酯＝100:1)纯化得到白色固体目标化合物C(500mg,46％)。
1HNMR(400MHz,CDCl 3):δ10.41(s,1H),8.16(d,J＝8Hz,1H)7.72-7.70(m,1H),7.62-7.60(m,1H),7.37-7.31(m,2H),4.09(s,3H),1.37(s,12H).
实施例1：
2-(((3-((2-甲基-[1,1’-联苯基]-3-基)氨基)噻吩并[3,2-b]吡啶-6-基)甲基)氨基)乙烷-1-醇
Figure PCTCN2019098925-appb-000050
3-((2-甲基-[1,1’-联苯基]-3-基)氨基)噻吩并[3,2-b]吡啶-6-甲腈.
Figure PCTCN2019098925-appb-000051
向中间体A(65mg,0.37mmol),(2-甲基-[1,1’-联苯基]-3-基)硼酸(157mg,0.74mmol)的二氯甲烷(5mL)溶液中加入醋酸铜(67mg,0.37mmol)和三乙胺(75mg,0.74mmol)，反应液在室温下敞口搅拌16小时；反应液浓缩，残渣通过正相快速分离纯化(石油醚/乙酸 乙酯＝1.5/1)得到目标化合物1A(28mg,22％)，为黄色固体。
MS(ESI):m/z＝342.1[M+H] +。
3-((2-甲基-[1,1’-联苯基]-3-基)氨基)噻吩并[3,2-b]吡啶-6-甲醛
Figure PCTCN2019098925-appb-000052
在冰浴下向化合物1A(28mg,0.08mmol)的无水二氯甲烷(4mL)溶液中滴入二异丁基氢化铝(0.1mL,0.10mmol，1M的甲苯溶液)。反应液自然升至室温共搅拌1小时；TLC显示原料完全消失，反应液在冰浴下加水淬灭，粗品通过正相快速分离纯化(石油醚/乙酸乙酯＝1/1)得到目标化合物1B(20mg,74％)，为黄色固体。
MS(ESI):m/z＝345.1[M+H] +。
2-(((3-((2-甲基-[1,1’-联苯基]-3-基)氨基)噻吩并[3,2-b]吡啶-6-基)甲基)氨基)乙烷-1-醇
Figure PCTCN2019098925-appb-000053
向化合物1B(20mg,0.060mmol),2-氨基乙烷-1-醇(11mg,0.18mmol)的二氯甲烷(3mL)溶液中加入催化量的醋酸(1滴)，反应液室温搅拌2小时后加入三乙酰氧基硼氢化钠(64mg,0.30mmol)，反应液继续搅拌过夜；反应液浓缩，粗品通过制备型高效液相色谱纯化获得目标化合物(6.8mg，30％)，为白色固体。
MS(ESI):m/z＝390.3[M+H] +。
1H NMR(400MHz,MeOH-d 4)δ8.63(s,1H),8.30(s,1H),7.47-7.28(m,6H),7.22-7.20(m,1H),7.00(s,1H),6.86(d,J＝7.4Hz,1H),3.98(s,2H),3.68(t,J＝5.6Hz,2H),2.77(t,J＝5.6Hz,2H),2.21(s,3H)。
实施例2
(2S,4S)-4-羟基-1-((3-((2-甲基-[1,1’-联苯基]-3-基)氨基)噻吩并[3,2-b]吡啶-6-基)甲基)吡咯烷-2-羧酸
Figure PCTCN2019098925-appb-000054
目标化合物在类似于实施例5的条件下制备自化合物1B和(2S,4S)-4-羟基吡咯烷-2-羧酸。
MS(ESI):m/z＝460.2[M+H] +。
1H NMR(400MHz,MeOH-d 4)δ8.75(s,1H),8.47(s,1H),8.42(s,1H),7.45-7.37(m,3H),7.35-7.28(m,3H),7.22-7.20(m,1H),7.07(s,1H),6.87(dd,J＝7.7,1.2Hz,1H),4.51-4.36(m,3H),3.88-3.80(m,1H),3.47-3.39(m,1H),3.23-3.16(m,1H),2.68-2.57(m,1H),2.19(s,3H),2.16-2.06(m,1H)。
实施例3
2-(((4-((2-氯-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)氨基)乙酰胺
Figure PCTCN2019098925-appb-000055
N-(2-氯-[1,1’-联苯基]-3-基)-2-(甲氧基甲基)噻唑并[4,5-c]吡啶-4-胺
Figure PCTCN2019098925-appb-000056
将中间体B(500mg,2.33mmol)，2-氯-[1,1’-联苯基]-3-胺(312mg,1.55mmol)和对甲苯磺酸一水合物(444mg,2.33mmol)的异丙醇(8mL)的溶液,在微波反应器中，加热到170℃并搅拌一个小时；反应液用乙酸乙酯稀释，饱和的碳酸氢钠水溶液洗涤两次，有机相浓缩，残渣通过正相快速分离纯化(石油醚/乙酸乙酯＝10/1)到得标题化合物(300mg,51％)，为白色固体。
MS(ESI):m/z＝382.1[M+H] +。
(4-((2-氯-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲醇
Figure PCTCN2019098925-appb-000057
在冰水浴条件下，向化合物3A(87mg,0.23mmol)的二氯甲烷(4mL)的溶液中缓慢加入三溴化硼(0.46mL,0.46mmol)的二氯甲烷溶液，反应液在零度搅拌一小时；反应液通过二氯甲烷稀释，饱和的碳酸氢钠水溶液洗涤两次，有机相浓缩，残渣通过正相快速分离纯化(石油醚/乙酸乙酯＝4/1)到得标题化合物(45mg,52％)，为白色固体。
MS(ESI):m/z＝368.0[M+H] +。
2-(溴甲基)-N-(2-氯-[1,1’-联苯基]-3-基)噻唑并[4,5-c]吡啶-4-胺
Figure PCTCN2019098925-appb-000058
在冰水浴条件下，向化合物3B(45mg,0.12mmol)的二氯甲烷(4mL)的溶液,缓慢加入三溴化磷(65mg,0.24mmol)，反应液在零度搅拌一小时；反应液通过二氯甲烷稀释，饱和的碳酸氢钠水溶液洗涤两次，有机相浓缩，残渣通过正相快速分离纯化(石油醚/乙酸乙酯＝8/1)到得标题化合物(35mg,68％)，为白色固体。
MS(ESI):m/z＝430.0[M+H] +。
2-(((4-((2-氯-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)氨基)乙酰胺
Figure PCTCN2019098925-appb-000059
向化合物3C(10mg,0.023mmol),2-氨基乙酰胺盐酸(8mg,0.069mmol)的乙腈溶液(3mL)中加入无水碳酸钾(19mg,0.138mmol)，反应液继续搅拌过夜，过滤，浓缩，残渣通过制备型高效液相色谱纯化获得目标产物(4mg,41％)，为白色固体。
MS(ESI):m/z＝424.1[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.71(dd,J＝8.3,1.5Hz,1H),8.04(d,J＝5.7Hz,1H),7.45-7.39(m,5H),7.39-7.34(m,2H),7.01(dd,J＝7.6,1.5Hz,1H),4.25(s,2H),3.40(s,2H)。
实施例4
(2S,4S)-1-((4-((2-氯-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)-4-羟基吡咯烷-2-羧酸
Figure PCTCN2019098925-appb-000060
4-((2-氯-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-甲醛
Figure PCTCN2019098925-appb-000061
在冰水浴的条件下，向化合物3B(100mg,0.27mmol)的二氯甲烷溶液(5mL)中分批加入戴斯-马丁氧化剂(229mg,0.54mmol)，反应液继续搅拌一小时，反应用水淬灭，萃取，干燥，浓缩，残渣通过正相快速分离纯化(石油醚/乙酸乙酯＝10/1)到得标题化合物(70mg,71％)，为黄色固体。
MS(ESI):m/z＝366.1[M+H] +。
甲基(2S,4S)-1-((4-((2-氯-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)-4-羟基吡咯烷-2-羧酸酯
Figure PCTCN2019098925-appb-000062
向化合物4A(40mg,0.11mmol),甲基(2S,4S)-4-羟基吡咯烷-2-羧酸酯盐酸(40mg,0.22mmol)的二氯甲烷(5mL)溶液中加入催化量的醋酸(1滴)，反应液常温搅拌三个小时，加入氰基硼氢化钠(14mg,0.22mmol),继续搅拌过夜，反应完全后加水淬灭，萃取，过滤，浓缩，残渣通过正相快速分离纯化(石油醚/乙酸乙酯＝2/1)到得标题化合物(15mg,28％)，为白色固体。
MS(ESI):m/z＝495.1[M+H] +。
(2S,4S)-1-((4-((2-氯-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)-4-羟基吡咯烷-2-羧酸
Figure PCTCN2019098925-appb-000063
向化合物4B(15mg,0.030mmol)的甲醇(3mL)和水(0.5mL)溶液中加入氢氧化锂一水合物(3mg,0.060mmol)，反应液继续常温搅拌一小时，浓缩，残渣通过制备型高效液相色谱纯化获得目标产物(7mg,50％)，为白色固体。
MS(ESI):m/z＝481.1[M+H] +。
1H NMR(400MHz,CD 3OD)δ8.68(dd,J＝8.2,1.5Hz,1H),8.02(d,J＝5.7Hz,1H),7.45-7.31(m,7H),7.00(dd,J＝7.5,1.6Hz,1H),4.58(s,1H),4.48(d,J＝15.6Hz,1H),4.29(s,1H),4.18(d,J＝15.3Hz,1H),3.54-3.45(m,1H),3.21-3.19(m,1H),2.91-2.84(m,1H),2.55-2.46(m,1H),1.99-1.90(m,1H)。
实施例5
2-(((4-((2-氯-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)氨基)乙烷-1-醇
Figure PCTCN2019098925-appb-000064
目标化合物在类似于实施例4的条件下制备自化合物4A和2-氨基乙烷-1-醇。
MS(ESI):m/z＝411.1[M+H] +。
1H NMR(400MHz,MeOD-d 4)δ8.72(dd,J＝8.3,1.5Hz,1H),8.04(d,J＝5.7Hz,1H),7.48-7.32(m,7H),7.01(dd,J＝7.6,1.5Hz,1H),4.27(s,2H),3.69(t,J＝5.5Hz,2H),2.86(t,J＝5.5Hz,2H)。
实施例6
(R)-1-((4-((2-氯-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)吡咯烷-3-醇
Figure PCTCN2019098925-appb-000065
目标化合物在类似于实施例3的条件下制备自化合物3C和(R)-吡咯烷-3-醇。
MS(ESI):m/z＝437.1[M+H] +。
1H NMR(400MHz,CD3OD)δ8.72(dd,J＝8.3,1.6Hz,1H),8.03(d,J＝5.7Hz,1H),7.44-7.32(m,7H),7.00(dd,J＝7.6,1.6Hz,1H),4.58(s,1H),4.40-4.34(m,1H),4.13(d,J＝3.2Hz,2H),3.01-2.89(m,2H),2.75-2.67(m,2H),2.20-2.10(m,1H),1.80-1.72(m,1H)。
实施例7
(S)-1-((4-((2-氯-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)吡咯烷-3-醇
Figure PCTCN2019098925-appb-000066
目标化合物在类似于实施例3的条件下制备自化合物3C和(S)-吡咯烷-3-醇。
MS(ESI):m/z＝437.1[M+H] +。
1H NMR(400MHz,CD3OD)δ8.72(dd,J＝8.3,1.6Hz,1H),8.04(d,J＝5.7Hz,1H),7.44-7.33(m,7H),7.01(dd,J＝7.6,1.6Hz,1H),4.58(s,1H),4.41-4.35(m,1H),4.14(d,J＝3.2Hz,2H),3.00-2.89(m,2H),2.76-2.67(m,2H),2.22-2.12(m,1H),1.81-1.72(m,1H)。
实施例8
((4-((2-氯-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)甘氨酸
Figure PCTCN2019098925-appb-000067
目标化合物在类似于实施例3的条件下制备自化合物3C和甘氨酸。
MS(ESI):m/z＝425.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ8.77(d,J＝8.8Hz,1H),8.67(s,1H),8.06(d,J＝5.4Hz,1H),7.53(d,J＝5.4Hz,1H),7.48-7.38(m,6H),7.02(dd,J＝7.7,1.5Hz,1H),4.17(s,2H),3.09(s,2H)。
实施例9
2-(((4-((2-氯-3’-(3-氯丙氧基)-2’-甲基-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)氨基)乙烷-1-醇
Figure PCTCN2019098925-appb-000068
目标化合物根据实施例3方法，替换相应原料获得。
MS(ESI):m/z＝517.1[M+H] +。
1H NMR(400MHz,CD 3OD)δ8.75(d,J＝6.9Hz,1H),8.05(d,J＝5.7Hz,1H),7.41(d,J＝5.7Hz,1H),7.38-7.31(m,1H),7.19(t,J＝7.9Hz,1H),6.95(d,J＝7.7Hz,1H),6.88(dd,J＝7.5,1.5Hz,1H),6.74(d,J＝7.6Hz,1H),4.25(s,2H),4.17(m,2H),3.79(t,J＝6.4Hz,2H),3.68(t,J＝5.5Hz,2H),2.84(t,J＝5.5Hz,2H),2.30-2.22(m,2H),1.96(s,3H)。
实施例10
2-(((4-((2-氯-3-(2,3-二氢苯并[b][1,4]二噁英-6-基)苯基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)氨基)乙烷-1-醇
Figure PCTCN2019098925-appb-000069
目标化合物根据实施例3方法，替换相应原料获得。
MS(ESI):m/z＝469.1[M+H] +。
1H NMR(400MHz,CD 3OD)δ8.65(dd,J＝8.3,1.5Hz,1H),8.04(d,J＝5.7Hz,1H),7.40(d,J＝5.7Hz,1H),7.35-7.29(m,1H),6.99(dd,J＝7.6,1.6Hz,1H),6.90-6.85(m,3H),4.35(s,2H),4.27(s,4H),3.75-3.69(m,2H),2.97-2.91(m,2H)。
实施例11
2-(((4-((2-氯-3’-(2-吗啉代乙氧基)-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)氨基)乙烷-1-醇
Figure PCTCN2019098925-appb-000070
目标化合物根据实施例3方法，替换相应原料获得。
MS(ESI):m/z＝540.1[M+H] +。
1H NMR(400MHz,CD 3OD)δ8.70(dd,J＝8.3,1.5Hz,1H),8.01(d,J＝5.7Hz,1H),7.36(d,J＝5.7Hz,1H),7.32(m,2H),7.00-6.93(m,4H),4.23(s,2H),4.15(t,J＝5.5Hz,2H),3.72-3.65(m,6H),2.84(t,J＝5.5Hz,2H),2.79(t,J＝5.5Hz,2H),2.61-2.54(m,4H)。
实施例12
1-(4-((2’-氯-3’-((2-(((2-羟基乙基)氨基)甲基)噻唑并[4,5-c]吡啶-4-基)氨基)-[1,1’-联苯基]-3-基)氧代)丁基)吡咯烷-3-醇
Figure PCTCN2019098925-appb-000071
目标化合物根据实施例3方法，替换相应原料获得。
MS(ESI):m/z＝568.6[M+H] +。
1H NMR(400MHz,CD 3OD)δ8.70(dd,J＝8.3,1.6Hz,1H),8.03(d,J＝5.7Hz,1H),7.40(d,J＝5.7Hz,1H),7.38-7.29(m,2H),7.03-6.90(m,4H),4.34(ddd,J＝9.5,6.3,3.2Hz,1H),4.25(s,2H),4.03(t,J＝6.1Hz,2H),3.68(t,J＝5.4Hz,2H),2.93-2.73(m,4H),2.70-2.50(m,4H),2.17-2.06(m,1H),1.86-1.68(m,5H)。
实施例13
((4-((2-氯-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)甘氨酸甲酯
Figure PCTCN2019098925-appb-000072
目标化合物根据实施例3方法，替换相应原料获得。
MS(ESI):m/z＝438.9[M+H] +。
1H NMR(400MHz,CD 3OD)δ8.72(dd,J＝8.3,1.6Hz,1H),8.04(d,J＝5.7Hz,1H),7.46-7.33(m,7H),7.01(dd,J＝7.6,1.6Hz,1H),4.27(s,2H),3.71(s,3H),3.56(s,2H)。
实施例14
((4-((2-氯-3’-(3-((3-羟基丙基)(甲基)氨基)丙氧基)-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)甘氨酸
Figure PCTCN2019098925-appb-000073
目标化合物根据实施例3方法，替换相应原料获得。
MS(ESI):m/z＝570.5[M+H] +。
1H NMR(400MHz,CD 3OD)δ8.70(d,J＝7.0Hz,1H),8.04(d,J＝5.7Hz,1H),7.40(d,J＝5.6Hz,1H),7.34(m,2H),7.04-6.94(m,4H),4.38(s,2H),4.15(t,J＝5.7Hz,2H),3.67(t,J＝5.7Hz,2H),3.44(s,2H),3.29-3.23(m,2H),3.18(t,J＝7.4Hz,2H),2.82(s,3H),2.27-2.15(m,2H),1.95-1.85(m,2H)。
实施例15
((4-((2-氯-3’-(3-(3-羟基吡咯烷-1-基)丙氧基)-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)甘氨酸
Figure PCTCN2019098925-appb-000074
目标化合物根据实施例3方法，替换相应原料获得。
MS(ESI):m/z＝568.5[M+H] +。
1H NMR(400MHz,CD3OD-d4)δ8.71(d,J＝7.0Hz,1H),8.06(d,J＝5.7Hz,1H),7.41(d,J＝5.7Hz,1H),7.35(td,J＝8.1,1.5Hz,2H),7.04–6.94(m,4H),4.53(s,1H),4.43(s,2H),4.15(t,J＝5.7Hz,2H),3.64–3.53(m,2H),3.49(s,2H),3.42–3.32(m,4H),2.26–2.18(m,3H),2.07-1.95(m,1H)。
实施例16
((4-((2-氯-3’-(3-(3-羟基吡咯烷-1-基)丙氧基)-2’-甲基-[1,1’-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)甘氨酸
Figure PCTCN2019098925-appb-000075
目标化合物根据实施例3方法，替换相应原料获得。
MS(ESI):m/z＝582.5[M+H] +。
1H NMR(400MHz,CD3OD)δ8.74(dd,J＝8.3,1.5Hz,1H),8.07(d,J＝5.7Hz,1H),7.42(d,J＝5.7Hz,1H),7.35(m,1H),7.19(m,1H),6.95(d,J＝8.3Hz,1H),6.87(dd,J＝7.5,1.5Hz,1H),6.76(d,J＝7.0Hz,1H),4.54-4.47(m,1H),4.37(s,2H),4.18-4.11(m,2H),3.57-3.44(m,2H),3.42(s,2H),3.40-3.27(m,4H),2.27-2.17(m,3H),2.14-1.94(m,4H)。
实施例17
2-(((4-((2-氯-[1,1’-联苯基]-3-基)氨基)噻唑并[5,4-c]吡啶-2-基)甲基)氨基)乙烷-1-醇
Figure PCTCN2019098925-appb-000076
N-(2-氯-[1,1’-联苯基]-3-基)-2-甲硫基唑并[5,4-c]吡啶-4-胺
Figure PCTCN2019098925-appb-000077
向4-氯-2-甲硫基唑并[5,4-c]吡啶(75mg,0.41mmol),2-氯-[1,1’-联苯基]-3-胺(116mg,0.57mmol)的甲苯(4mL)溶液中加入三(二苯亚甲基丙酮)二钯(36mg,0.04mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(46mg,0.08mmol)和碳酸铯(267mg,0.82mmol)，在氮气的保护下，反应液加热到90℃并搅拌8小时，反应液冷却后用硅藻土过滤，二氯甲烷洗脱，滤液浓缩，残渣通过正相快速分离纯化(石油醚/乙酸乙酯＝9/1)得到目标化合物17B(120mg,83％)，为浅黄色固体。
MS(ESI):m/z＝351.9[M+H] +。
4-((2-氯-[1,1’-联苯基]-3-基)氨基)噻唑并[5,4-c]吡啶-2-甲醛
Figure PCTCN2019098925-appb-000078
室温下向化合物17B(40mg,0.11mmol)的1-甲基-2-吡咯烷酮(4mL)的溶液中加入二氧化锡(61mg,0.55mmol)，混合物在微波下加热到120℃搅拌两小时，冷却后反应粗品经制备型高效液相色谱纯化得到标题化合物17C(20mg粗品,35％)，为黄色固体。
MS(ESI):m/z＝383.9[M+18+H] +。
2-(((4-((2-氯-[1,1’-联苯基]-3-基)氨基)噻唑并[5,4-c]吡啶-2-基)甲基)氨基)乙烷-1-醇
Figure PCTCN2019098925-appb-000079
向实施例17C(20mg,0.035mmol),2-氨基乙烷-1-醇(8mg,0.14mmol)的二氯甲烷溶液中加入催化量的醋酸(1滴)，反应液室温搅拌16小时后加入三乙酰氧基硼氢化钠(63mg,0.30mmol),反应液继续室温搅拌4小时，反应液用水(10mL)淬灭，二氯甲烷萃取三次(15mL*3)，有机相合并干燥后浓缩，残渣通过制备型高效液相色谱纯化获得目标化合物(4mg，25％)，为黄色固体。
MS(ESI):m/z＝410.9[M+H] +。
1H NMR(400MHz,MeOD-d 4)δ8.08(d,J＝5.8Hz,1H),7.65(dd,J＝8.1,1.6Hz,1H),7.45-7.33(m,7H),7.21(dd,J＝7.7,1.6Hz,1H),4.33(s,2H),3.71(t,J＝5.4Hz,2H),2.92(t,J＝5.4Hz,2H)。
实施例18:
(S)-((4-((2,2'-二氯-3'-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1'-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)甘氨酸
Figure PCTCN2019098925-appb-000080
甲基((4-((3-溴-2-氯苯基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)甘氨酸酸酯
Figure PCTCN2019098925-appb-000081
向化合物18A(100mg,0.23mmol),甘氨酸甲酯盐酸盐(58mg,0.46mmol)的乙腈溶液(3mL)中加入无水碳酸钾(191mg,1.38mmol),反应液常温搅拌过夜，待反应完成后，萃取，浓缩，粗品通过正相快速分离纯化(乙酸乙酯:石油醚＝7:1)获得目标产物18B(80mg,79％)，为淡黄色固体。
MS(ESI):m/z＝440.7[M+H] +.
甲基((4-((2,2'-二氯-3'-(5-甲酰基-6-甲氧基吡啶-2-基)-[1,1'-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)甘氨酸酸酯
Figure PCTCN2019098925-appb-000082
向化合物18B(80mg,0.18mmol),6-(2-氯-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯基)-2-甲氧基尼古丁醛(101mg,0.27mmol),碳酸钾(75mg,0.54mmol)的二氧六环(3mL)和水(0.5mL)的混合物中，加入1,1'-双二苯基膦基二茂铁二氯化钯二氯甲烷络合物(15mg,0.018mmol)，反应液在氮气保护下，加热到95℃搅拌两个小时。过滤，浓缩，残渣通过正相快速分离纯化(乙酸乙酯:石油醚＝8:1)获得目标产物18C(100mg,89％)，为淡黄色固体。MS(ESI):m/z＝607.9[M+H] +.
甲基(S)-((4-((2,2'-二氯-3'-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1'-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)甘氨酸酸酯
Figure PCTCN2019098925-appb-000083
向化合物18C(100mg,0.16mmol),(S)-5-(氨基甲基)吡咯烷-2-酮盐酸(121mg,0.80mmol)的N，N-二甲基甲酰胺混合溶液中,加入N，N-二异丙基乙胺(104mg,0.80mmol)，反应液加热到50℃并在该温度下搅拌两个小时后。分批加入三乙酰氧基硼氢化钠(170mg,0.80mmol)，反应液继续搅拌一小时。待反应完成后，用少量的甲醇淬灭，反应液通过反相快速分离纯化(80％乙腈-10nmol/mL浓度碳酸氢铵水溶液)获得目标产物18D(70mg，63％)，为淡黄色固体。
MS(ESI):m/z＝706.0[M+H] +.
(S)-((4-((2,2'-二氯-3'-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1'-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)甘氨酸
Figure PCTCN2019098925-appb-000084
向化合物18D(70mg,0.10mmol)的甲醇(3mL)和水(0.5mL)的混合物中,加入氢氧化锂一水合物(17mg,0.40mmol)，反应液常温下搅拌两个小时。待反应完成后，反应液通过反相快速分离纯化(35％的乙腈-0.1％的甲酸水溶液洗脱)获得目标产物实施例18(30mg,43％)，为淡黄色固体。
MS(ESI):m/z＝692.0[M+H] +.
NMR: 1H NMR(400MHz,DMSO-d 6)δ8.84(d,J＝8.7Hz,1H),8.63(s,1H),8.08(d,J＝5.6Hz,1H),7.79(d,J＝7.4Hz,1H),7.68(s,1H),7.64(dd,J＝7.8,1.4Hz,1H),7.55(d,J＝5.6Hz,1H),7.51(m,1H),7.44(m,1H),7.39(dd,J＝7.7,1.7Hz,1H),7.25(d,J＝7.7Hz,1H),7.02(d,J＝7.8Hz,1H),4.18(s,2H),3.89(s,3H),3.68(s,2H),3.60(m,1H),3.22(s,2H),2.52(d,J＝5.8Hz,2H),2.10-2.00(m,3H),1.72-1.60(m,1H).
实施例19:
(5-甲基-2-羰基-1,3-二噁唑-4-基)甲基(S)-((4-((2,2'-二氯-3'-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1'-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)甘氨酸酸酯
Figure PCTCN2019098925-appb-000085
(5-甲基-2-羰基-1,3-二噁唑-4-基)甲基(S)-((4-((2,2'-二氯-3'-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1'-联苯基]-3-基)氨基)噻唑并[4,5-c]吡啶-2-基)甲基)甘氨酸酸酯
Figure PCTCN2019098925-appb-000086
向实施例18(80mg,0.12mmol),无水碳酸钾(50mg,0.36mmol)的N,N-二甲基甲酰胺(3mL)的溶液中,加入4-(氯甲基)-5-甲基-1,3-二噁唑-2-酮(36mg,0.24mmol)，反应液常温下搅拌过夜。待反应完成后，反应液通过反相快速分离纯化(65％的乙腈-0.1％的甲酸水溶液洗脱)获得目标产物实施例19(18mg,18％)，为白色固体。
MS(ESI):m/z＝804.2[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ8.84(dd,J＝8.3,1.4Hz,1H),8.62(s,1H),8.09(d,J＝5.6Hz,1H),7.79(d,J＝7.6Hz,1H),7.67(s,1H),7.64(dd,J＝7.7,1.7Hz,1H),7.56(d,J＝5.6Hz,1H),7.51(m,1H),7.45(m,1H),7.39(dd,J＝7.5,1.7Hz,1H),7.25(d,J＝7.6Hz,1H),7.02(dd,J＝7.5,1.4Hz,1H),4.97(s,2H),4.21(d,J＝5.6Hz,2H),3.89(s,3H),3.68(s,2H),3.65-3.58(m,1H),3.55(d,J＝6.6Hz,2H),3.51-3.41(m,1H),2.52(d,J＝5.9Hz,2H),2.11(s,3H),2.10-2.01(m,3H),1.72-1.60(m,1H).
以下各个化合物采用与实施例18-19类似的方法，替换相应原料获得。
Figure PCTCN2019098925-appb-000087
Figure PCTCN2019098925-appb-000088
Figure PCTCN2019098925-appb-000089
Figure PCTCN2019098925-appb-000090
Figure PCTCN2019098925-appb-000091
Figure PCTCN2019098925-appb-000092
Figure PCTCN2019098925-appb-000093
Figure PCTCN2019098925-appb-000094
测试例1:检测化合物对PD-1/PD-L1蛋白相互结合的抑制效应
采用PD-1/PD-L1均相时间分辨荧光(Homogenous Time-Resolved Fluorescence,HTRF)检测技术来检测化合物跟PD-L1的结合能力。
选用PD1/PD-L1 binding assay试剂盒(Cisbio,Cat#63ADK000CPDEC)，该试剂盒包含Tag 1-PD-L1和Tag 2-PD-1两个蛋白，及Anti-Tag1-Eu 3+和Anti-Tag2-XL 665两个抗体。检测原理：Anti-tag1-Eu 3+作为HTRF的供体，Anti-Tag2-XL 665作为HTRF的受体，当Tag 1-PD-L1和Tag 2-PD-1相互作用时，加入的HTRF供体和受体相互靠近，供体接受到激发能量后，将部分能量转移到受体，会产生665nm发射光。当加入化合物阻断了PD1/PD-L1相互作用时，只产生620nm发射光。通过比较665nm/620nm的比值，来确定化合物的抑制效果。Tag 1-PD-L1用Diluent buffer(cat#62DLBDDF)稀释成工作浓度10nM，Tag 2-PD-1用Diluent buffer稀释成工作浓度500nM，Anti-Tag1-Eu 3+用detection buffer(cat#62DB1FDG)按1:100稀释，Anti-Tag2-XL 665用detection buffer按1:20稀释，待检测化合物用diluent buffer梯度稀释成2X的终浓度。在384孔板中每孔先加入2μL化合物，再分别先后加入4μL Tag 1-PD-L1，4μL Tag 2-PD-1，室温孵育15分钟。加入5μL Anti-Tag1-Eu 3+和5μL Anti-Tag2-XL 665，室温孵育过夜，用BioTek Synergy TMNeo2多功能酶标仪检测，获得665nm/620nm比值。用PrismGraphd 5.02拟合IC50曲线。
表1本发明部分化合物的IC 50值
化合物编号 PD-L1 IC 50
1 A
2 A
3 A
4 A
5 A
6 B
7 B
8 A
9 N/T
10 A
11 N/T
12 A
13 N/T
14 A
15 A
16 A
17 B
18 A
19 A
20 A
21 A
22 A
23 A
24 A
25 A
26 B
27 A
28 A
29 A
30 A
31 A
32 A
33 A
34 A
35 N/T
36 N/T
37 N/T
38 N/T
39 A
40 A
41 A
42 A
43 A
44 A
45 A
46 A
47 A
48 A
49 A
50 A
51 A
52 A
53 A
54 A
55 A
56 A
57 NT
58 NT
字母A代表IC 50小于100nM；
字母B代表IC 50为100nM至1uM；
字母C代表IC 50为大于1uM；
结果显示，本发明中化合物可在不同浓度下有效抑制PD-1/PD-L1的结合。因此可用于与PD-1/PD-L1互相结合相关的疾病治疗中。
测试例2：细胞学NFAT报告基因实验
PD1/PD-L1的细胞学实验需要有两种细胞，PD-1效应细胞和PD-L1 aAPC/CHO-K1细胞，其中PD-1效应细胞表达人PD-1蛋白和由NFAT驱动的荧光素酶报告基因，PD-L1 aAPC/CHO-K1细胞表达PD-L1蛋白和anti-CD3 antibody。当这两种细胞共培养时，PD-1/PD-L1的相互作用会抑制TCR至NFAT-RE的信号传递，中断NFAT-RE介导的荧光信号。当加入PD-1或PD-L1的抑制剂时，阻断了PD-1/PD-L1的相互作用，解除了对TCR至NFAT-RE通路的信号抑制，使荧光信号增强，通过荧光信号的强弱来判断抑制剂的阻断效果。
实验第一天，将复苏的PD-L1 aAPC/CHO-K1细胞消化处理，离心后用培养基(90％Ham’s F-12/10％FBS)将浓度调为2.5*10 5/mL，按每孔40ul，1*10 4细胞的量铺在384孔板中，置于培养箱中过夜培养。第二天，先将待测化合物用检测buffer(99％RPMI1640/1％FBS)按梯度稀释到所需检测浓度的2倍，PD-1细胞离心后用检测buffer调成浓度为6.25*10 5/mL。将过夜培养的384孔板中的培养基吸干，每孔加入20ul稀释好的化合物，再加入20ul PD-1细胞，在细胞培养箱中孵育6小时后，每孔再加入20ul Bio-Glo试剂(Promega,cat#G7940)，10分钟后，用多功能酶标仪读板。每块板需设置阴性对照(只加细胞，不加化合物)，和空白对照(只加检测buffer)。根据荧光值，用prism5来分析化合物的抑制活性。
结果显示，本发明化合物能够有效阻断PD-1/PD-L1的相互作用，半活抑制浓度与临床阶段的PD1抑制剂相当或更佳。
测试例3：Human PBMC功能学实验
Human PBMC功能学实验需要两种细胞，human PBMC细胞和PD-L1 aAPC/CHO-K1 细胞(CHO-K1细胞表达全长的human PD-L1蛋白及anti-hCD3抗体)。当这两种细胞共培养时，aAPC细胞表达的anti-hCD3抗体与PBMC表面CD3结合，刺激PBMC活化增殖，但PD-1/PD-L1的相互作用会抑制TCR信号传递，当加入PD1或PD-L1抑制剂时，阻断了PD-1/PD-L1的相互作用，解除了对TCR通路的信号。通过检测PBMC活化后细胞表面标志CD25,PD1以及胞内细胞因子IFNr变化判断抑制剂的阻断效果。
实验第一天，将复苏的PD-L1 aAPC/CHO-K1细胞和PD-L1 Negative细胞消化处理，离心后用培养基(90％F12+10％FBS)将细胞浓度调整为2*10 5/mL，按每孔100ul，2*10 4细胞的量铺在96孔板中，置于培养箱中过夜培养。第二天，用含10ug/ml mitomycin的培养基处理细胞，37℃放置4h，然后用PBS洗板三次。同时配制待测化合物，按梯度稀释到所需检测浓度的2倍。PBMC细胞按操作要求复苏并调整浓度到1*10 6/mL，板中先加入50ul化合物，然后加入50ul PBMC细胞，细胞培养箱中孵育三天后分别收集细胞上清用于ELISA检测细胞因子IFNr的变化，收集细胞流式检测CD25,PD1的变化。
结果显示，本发明化合物能够有效阻断PD-1/PD-L1的相互作用，半活抑制浓度与临床阶段的PD1抑制剂相当或更佳。
测试例4：本发明中小分子抑制剂治疗肿瘤体内药效实验
建立皮下移植肿瘤的小鼠模型，以检查这些化合物对肿瘤生长的体内抑制效果。方法如下：将培养的特定肿瘤细胞消化后离心收集细胞，用无菌生理盐水清洗两遍后计数，用生理盐水调整细胞浓度至所需的浓度，取0.2ml细胞混悬液接种到C57BL/6或者Balb/c免疫健全小鼠皮下。接种后观察肿瘤生长至特定大小，动物随机分组，每组6-7只，称重后给药，待测化合物每天给药一次，分组包括：载体组，对照抗PD-L1抗体组，待测化合物组。小鼠每周检测肿瘤生长，共大约6周，待肿瘤体积达到肿瘤终点后，称量小鼠体重，并进行安乐死。剥取肿瘤组织，脾脏组织及血液样本。计算肿瘤抑制率，检测肿瘤、脾脏及血液样本中免疫细胞组成，计算待测化合物免疫调节活性。
结果显示，本发明化合物能够在荷瘤小鼠中有效抑制肿瘤生长，其抑制效果与临床阶段的PD1抑制剂相当或更佳。
测试例5：本发明中小分子抑制剂联合化疗药治疗肿瘤体内药效实验
建立皮下移植肿瘤的小鼠模型，以检查这些化合物对肿瘤生长的体内抑制效果。方法如下：将培养的特定肿瘤细胞消化后离心收集细胞，用无菌生理盐水清洗两遍后计数，用生理盐水调整细胞浓度至所需的浓度，取0.2ml细胞混悬液接种到C57BL/6或者Balb/c免疫健全小鼠皮下。接种后观察肿瘤生长至特定大小，动物随机分组，每组6-7只，称重后给药，待测化合物与联用药贝伐/卡铂/紫杉醇/培美曲塞按照联合给药方案给药，分组包括：载体组，测试化合物联合化疗药组，化疗药组，测试化合物组。小鼠每周检测肿瘤生长，共大约6周，待肿瘤体积达到肿瘤终点后，称量小鼠体重，并进行安乐死。剥取肿瘤组织，脾脏组织及血液样本。计算肿瘤抑制率，检测肿瘤、脾脏及血液样本中免疫细胞组成，计算待测化合物及联合用药的免疫调节活性。
结果显示，本发明化合物联合化疗药物能够在荷瘤小鼠中更有效抑制肿瘤生长，其抑制效果优于单用化疗药。
测试例6：本发明中小分子抑制剂联合免疫调节剂治疗肿瘤体内药效实验
建立皮下移植肿瘤的小鼠模型，以检查这些化合物对肿瘤生长的体内抑制效果。方 法如下：将培养的特定肿瘤细胞消化后离心收集细胞，用无菌生理盐水清洗两遍后计数，用生理盐水调整细胞浓度至所需的浓度，取0.2ml细胞混悬液接种到C57BL/6或者Balb/c免疫健全小鼠皮下。接种后观察肿瘤生长至特定大小，动物随机分组，每组6-7只，称重后给药，待测化合物与联用药Nivolumab/Ipilimumab按照联合给药方案给药，分组包括：载体组，测试化合物联合免疫调节药组，免疫调节药组，测试化合物组。小鼠每周检测肿瘤生长，共大约6周，待肿瘤体积达到肿瘤终点后，称量小鼠体重，并进行安乐死。剥取肿瘤组织，脾脏组织及血液样本。计算肿瘤抑制率，检测肿瘤、脾脏及血液样本中免疫细胞组成，计算待测化合物及联合用药的免疫调节活性。
结果显示，本发明化合物联合免疫调节剂药物能够在荷瘤小鼠中更有效抑制肿瘤生长，其抑制效果优于单用免疫调节剂。
测试例7：本发明中小分子抑制剂小鼠药代动力学实验
分别单次静脉(IV)和口服(PO)给予ICR小鼠测试化合物，于不同时间点采集血样，LC-MS/MS测定小鼠血浆中受试物的浓度并计算相关参数。具体如下：取所需量供试品，溶于5％DMSO+10％Solutol+85％注射用水中，配成所需浓度的溶液，用于静脉或口服。给药实验开始时动物年龄约6-8周。静脉采血时间：给药后0.083h，0.25h，0.5h，1h，2h，4h，8h和24h。口服采血时间：给药后0.25h，0.5h，1h，2h，4h，6h，8h和24h。建立生物样品分析方法及样品检测方法。过不同时间点的血药浓度数据，运用Phoenix WinNonlin 7.0软件计算药代动力学参数，如AUC (0-t)，AUC (0-∞)，T 1/2，C max，T max和MRT等。
结果显示，本发明化合物具有优异的药代动力学性质。
测试例8：本发明中小分子抑制剂大鼠药代动力学实验
分别单次静脉(IV)和口服(PO)给予SD大鼠测试化合物，于不同时间点采集血样，LC-MS/MS测定大鼠血浆中受试物的浓度并计算相关参数。具体如下：取所需量供试品，溶于5％DMSO+10％Solutol+85％注射用水中，配成所需浓度的溶液，用于静脉或口服。给药实验开始时动物年龄约6-8周。静脉采血时间：给药后0.083h，0.25h，0.5h，1h，2h，4h，8h和24h。口服采血时间：给药后0.25h，0.5h，1h，2h，4h，6h，8h和24h。建立生物样品分析方法及样品检测方法。过不同时间点的血药浓度数据，运用Phoenix WinNonlin 7.0软件计算药代动力学参数，如AUC (0-t)，AUC (0-∞)，T 1/2，C max，T max和MRT等。
结果显示，本发明化合物具有优异的药代动力学性质。
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. 一种如下式I所示的化合物，其立体异构体或其互变异构体，或其药学上可接受的盐、水合物或溶剂化物：
    Figure PCTCN2019098925-appb-100001
    其中，
    M选自O或NH；
    X 2选自下组：N、NR 3、CR 3、O、S、N＝CR 3、CR 3＝N或CR 3＝CR 3；
    X 4选自下组：N、CH、O、S、N＝CH、CH＝N或CH＝CH；
    且X 2和X 4中有且仅有一个为选自下组的基团：CR 3＝CR 3、N＝CR 3、或CR 3＝N(在X 4中R 3为H)；
    X 1和X 5各自独立地选自下组：N、CH、O或S；
    X 3选自下组：N、CR 3、O或S；
    且X 3或X 4中至少一个为O、S或N；
    Y 1和Y 2各自独立地为N或C；
    Z 1、Z 2和Z 3各自独立地为N或CR 4；
    R 1选自下组：H、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基；
    R 2选自下组：取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、或取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；且所述的R 2基团上有一个或多个氢原子被R 5取代；
    所述的R 3选自下组：H、取代或未取代的C1-C6烷基，或
    Figure PCTCN2019098925-appb-100002
    且至少一个R 3为
    Figure PCTCN2019098925-appb-100003
    n1为1、2、3或4；
    Ra和Rb各自独立地选自下组：H、-(C＝O)-取代或未取代的C 1-C 8烷基、取代或未取代的C 1-C 8烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 1-C 8烷胺基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 3-C 10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂环基；
    或所述的Ra和Rb与相邻的N原子共同构成取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂环基；
    所述的R 4选自下组：H、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基；
    所述的R 5选自下组：H、CN、卤素、取代或未取代的(-L 1-L 2-(CH 2) q-(取代或未取代的5-7元杂芳基))、取代或未取代的(-L 1-L 2-(CH 2) q-N(Ra)(Rb))、-O-取代或未取代的 (-(CH 2) q-O-(CH 2) q-N(Ra)(Rb))、或取代或未取代的选自下组的基团：C 6-C 10芳基、具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基、-L 1-L 2-6-10元芳基
    -(CH 2) q-N(Ra)(Rb)、-L 1-L 2-5-10元杂芳基-(CH 2) q-N(Ra)(Rb)；其中，所述的L 1和L 2各自独立地选自下组：无、取代或未取代的C 1-C 8亚烷基、-NH-C(＝O)-NH-、-C(＝O)-NH-、-NH-C(＝O)-、-C(＝O)-、-O-、-S-或-NH-；或两个R 5与相连的碳原子共同构成选自下组的基团：取代或未取代的5-7元杂芳基、取代或未取代的5-7元杂环基；
    q选自下组：0、1、2、3、4、5、6、7或8；
    除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、甲基砜基、-S(＝O) 2NH 2、-S(＝O) 2NHCH 3、氧代(＝O)、-CN、羟基、-NH 2、C1-C6胺基、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、
    Figure PCTCN2019098925-appb-100004
    Figure PCTCN2019098925-appb-100005
    或取代或未取代的选自下组的基团：C1-C6烷基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-10元杂环基(包括并环、螺环)、-(CH 2)-C6-C10芳基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)，且所述的取代为被选自下组的取代基所取代：卤素、C1-C6烷基、C1-C6烷氧基、氧代、-CN、-OH、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、-O-(CH 2) q-CN；
    Figure PCTCN2019098925-appb-100006
    为基团的连接位点；
    各个
    Figure PCTCN2019098925-appb-100007
    各自独立地为单键或双键；
    附加条件是式I化合物为化学上稳定的结构。
  2. 如权利要求1所述的化合物，其立体异构体或其互变异构体，或其药学上可接受的盐、水合物或溶剂化物，其特征在于，所述的化合物具有如下式II所示的结构：
    Figure PCTCN2019098925-appb-100008
  3. 如权利要求1所述的化合物，其立体异构体或其互变异构体，或其药学上可接受的盐、水合物或溶剂化物，其特征在于，所述的化合物具有如下式III所示的结构：
    Figure PCTCN2019098925-appb-100009
    所述的R 5'选自下组：H、CN、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基；
    R 6为(C 1-C 8亚烷基)-N(Ra)(Rb)；
    A环选自下组：取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂环基；
    p为1、2、3或4。
  4. 如权利要求1所述的化合物，其特征在于，所述的
    Figure PCTCN2019098925-appb-100010
    为选自下组的杂环所形成的结构：
    Figure PCTCN2019098925-appb-100011
    Figure PCTCN2019098925-appb-100012
  5. 如权利要求1所述的化合物，其特征在于，所述的化合物具有如下式IV所示的结构：
    Figure PCTCN2019098925-appb-100013
    其中，
    X 1选自下组：N或CH；
    X 2选自下组：N或CR 3；
    X 3选自下组：NR 3、O或S；
    R 7选自下组：H、卤素、取代或未取代的C1-C6烷基。
  6. 如权利要求1所述的化合物，其特征在于，所述的式I化合物选自下组：
    Figure PCTCN2019098925-appb-100014
    Figure PCTCN2019098925-appb-100015
    Figure PCTCN2019098925-appb-100016
    Figure PCTCN2019098925-appb-100017
    Figure PCTCN2019098925-appb-100018
    Figure PCTCN2019098925-appb-100019
  7. 一种药物组合物，其特征在于，包含(1)如权利要求1所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物；(2)药学上可接受的载体。
  8. 如权利要求1所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物或如权利要求7所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗与PD-1/PD-L1的活性或表达量相关的疾病的药物组合物。
  9. 如权利要求8所述的用途，其特征在于，所述的疾病选自下组：肿瘤、病原体感染、自身免疫应答相关疾病。
  10. 一种PD-1/PD-L1抑制剂，其特征在于，所述抑制剂包含权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
PCT/CN2019/098925 2018-08-01 2019-08-01 一类具有免疫调节功能的芳香化合物的制备和应用 WO2020025030A1 (zh)

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US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
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