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WO2021121282A1 - Préparation et application d'une classe de composés hétérocycliques contenant n ayant une fonction immunomodulatrice - Google Patents

Préparation et application d'une classe de composés hétérocycliques contenant n ayant une fonction immunomodulatrice Download PDF

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Publication number
WO2021121282A1
WO2021121282A1 PCT/CN2020/136884 CN2020136884W WO2021121282A1 WO 2021121282 A1 WO2021121282 A1 WO 2021121282A1 CN 2020136884 W CN2020136884 W CN 2020136884W WO 2021121282 A1 WO2021121282 A1 WO 2021121282A1
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group
substituted
compound
unsubstituted
alkyl
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Chinese (zh)
Inventor
张毅
冯志勇
江磊
金贤
尚珂
寿建勇
汪兵
徐雪丽
徐圆
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Shanghai Ennovabio Pharmaceuticals Co Ltd
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Shanghai Ennovabio Pharmaceuticals Co Ltd
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Priority to CN202080074680.5A priority Critical patent/CN114641474B/zh
Publication of WO2021121282A1 publication Critical patent/WO2021121282A1/fr
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • 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
    • C07D487/10—Spiro-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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to the field of small molecule protein inhibitors. Specifically, the present invention provides the preparation and application of a heterocyclic compound with immunoregulatory function.
  • the immune system has the functions of surveillance, defense, and regulation.
  • Cellular immunity is mainly involved in the immune response to intracellular parasitic pathogenic microorganisms and the immune response to tumor cells, participates in the formation of delayed-type allergy and autoimmune diseases, participates in transplant rejection and the regulation of humoral immunity.
  • the activation of T lymphocytes by antigen presenting cells is usually regulated by two different signals.
  • the primary signal is presented by the major histocompatibility complex (MHC) on APC cells and foreign antigen peptides are transduced through the T cell receptor (TCR).
  • MHC major histocompatibility complex
  • TCR T cell receptor
  • Secondary signals also known as costimulatory signals, are transmitted to T cells through the combination of costimulatory molecules on APC cells and T cell surface receptors, which regulate T cell proliferation, cytokine secretion and effector functions. Secondary signals include 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 adjust the response of self-immune cells to different external antigens.
  • Programmed cell death protein ligand 1 (Programmed death-ligand 1, PD-L1), also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7homolog1, B7-H1), belongs to The tumor necrosis factor superfamily is a type I transmembrane glycoprotein composed of 290 amino acid residues, including an IgV-like region, an IgC-like region, a transmembrane hydrophobic region, and an intracellular tail of 30 L amino acids. The molecular weight is 40kDa.
  • PD-L1mRNA is expressed in almost all tissues, but PD-L1 protein is only continuously expressed in a small number of tissues, including liver, lung, tonsil, and immune amnesty tissues such as eyes and placenta. PD-L1 is also expressed on activated T cells, B cells, monocytes, dendritic cells, macrophages, etc.
  • the receptor of 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 combination of PD-L1 and PD-1 can initiate the phosphorylation of ITIM (immunoreceptor tyrosine inhibitory action module) tyrosine residues in the cytoplasm of PD-1, which promotes the binding of tyrosine phospholipase to SHP2 and activates SHP2,
  • ITIM immunomunoreceptor tyrosine inhibitory action module
  • the downstream Syk and PI3K are dephosphorylated to transmit the termination signal and limit the interaction between antigen-presenting cells or dendritic cells and T cells.
  • This combination can further inhibit T cell metabolism, inhibit the secretion of anti-apoptotic protein Bcl-2, reduce the secretion of effector cytokines IL-2, IFN- ⁇ , induce T cell exhaustion and apoptosis, thereby reducing immune T cells Participate in the immune response, exercise negative regulation function.
  • T cells recognize antigens and are activated to secrete IFN- ⁇ .
  • IFN- ⁇ derived from T cells can expand and maintain T cell functions, such as up-regulating MHC molecules, enhancing the antigen processing and presentation of target cells, and promoting T cell differentiation.
  • IFN- ⁇ also induces the expression of PD-L1 in the tissues of immune inflammation, preventing excessive immunity from causing damage to the tissues.
  • IFN- ⁇ can induce the expression of PD-L1 on the surface of conventional epithelial cells, vascular endothelial cells, myeloid cells, naive T cells and so on.
  • the interferon regulatory factor 1 (IRF-1) induced by IFN- ⁇ can also bind to the interferon regulatory factor binding sites 200bp and 320bp before the transcription start site of PD-L1 to regulate PD-L1 at the transcription level.
  • PD-L1 can combine with PD-1 on the surface of T cells to exercise a negative regulatory function, thereby protecting the inflammatory site.
  • PD-L1 The negative regulatory function of PD-L1 plays an important role in tumor immunity.
  • Konishi et al. were the first to find the expression of PD-L1 in tissue samples from patients with non-small cell lung cancer. Subsequently, PD-L1 was found to be expressed in the tissues of various tumor patients, including gastric cancer, lung cancer, liver cancer, and intrahepatic cholangiocarcinoma.
  • new protein molecules will be produced due to gene mutation, foreign gene (virus) 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 eliminate tumor cells through immune surveillance, while tumor cells use PD-L1 to escape immune attack.
  • TIL Tumor infiltrating lymphocytes
  • the PD-L1 of tumor cells can bind to PD-1 on TIL, inhibit the activation of TIL cells, and further lead to their apoptosis.
  • Tumor-related PD-L1 can increase tumor-specific T cell apoptosis, and PD-L1 monoclonal antibody can attenuate this effect.
  • Tumor-related 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 for PD-1, it can also act as a receptor to transmit reverse signals to protect tumor cells from apoptosis induced by FAS-FASL and other anti-tumor pathways.
  • 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, no immunogenicity, and usually oral administration. Therefore, the research and development of PD-1/PD-L1 small molecule blockers has significant advantages The application value and social value of the company.
  • the purpose of the present invention is to provide a small molecule PD-1/PD-L1 blocker.
  • the first aspect of the present invention provides a compound represented by the following formula I, its stereoisomer or its tautomer, or its pharmaceutically acceptable salt, hydrate or solvate:
  • X 1 , X 3 and X 4 are each independently selected from the following group: N, CH;
  • X 5 and X 6 are each independently selected from the following group: N, C;
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 and Z 10 are each independently N or CH;
  • R 1 , R 4 , R 6 and R 7 represent one or more substituents on the ring selected from the group consisting of H, D, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted Substituted C3-C8 cycloalkyl, substituted or untaken C1-C6 alkoxy;
  • R 2 is selected from the following group: H, D, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy; Or the R 2 group has one or more hydrogen atoms substituted by R 5 ; and the R 2 group can be located at X 1 , X 3 .
  • W 1 is a group selected from the group consisting of CR 2 and C(O);
  • W 2 is a group selected from the following group: CR 2 , C(O);
  • each R is independently selected from the following group: H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;
  • Ra and Rb together with adjacent N atoms form a substituted or unsubstituted 5-10 membered heterocyclic group with 1-3 heteroatoms selected from N, S and O;
  • R c and Rd together with adjacent N atoms form a substituted or unsubstituted 5-10 membered heterocyclic group with 1-3 heteroatoms selected from N, S and O;
  • each Each independently is a single bond or a double bond
  • the compound has the structure shown in the following formula II-1 or II-2:
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 are CH;
  • Z 7 , Z 8 , Z 9 and Z 10 are each independently N or CH; and there are 1-2 Ns in Z 7 , Z 8 , Z 9 and Z 10.
  • Z 7 is N
  • Z 8 , Z 9 and Z 10 are CH.
  • R 6 and R 7 are each independently halogen, CN, or methyl.
  • the Have a structure selected from the following group (the R 3 substituent is not included in the structure):
  • the I is a structure formed by a heterocyclic ring selected from the following group:
  • said R 3 is selected from the following group:
  • the R 5 is:
  • the compound of formula I is selected from the following group:
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (1) the compound according to the first aspect of the present invention or its stereoisomer or tautomer, or a pharmaceutically acceptable salt thereof , Hydrate or solvate; (2) pharmaceutically acceptable carrier.
  • the third aspect of the present invention provides a compound as described in the first aspect of the present invention or a stereoisomer or tautomer, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or such as
  • the pharmaceutical composition according to the second aspect of the present invention is used to prepare a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression of PD-1/PD-L1.
  • the disease is selected from the group consisting of tumors, pathogen infections, and diseases related to autoimmune response.
  • the pharmaceutical composition is used for the treatment of diseases selected from the following group: melanoma (e.g. metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma), prostate cancer (e.g. Hormone refractory prostate adenocarcinoma), breast cancer, colon cancer and lung cancer (such as non-small cell lung cancer).
  • melanoma e.g. metastatic malignant melanoma
  • renal cancer e.g. clear cell carcinoma
  • prostate cancer e.g. Hormone refractory prostate adenocarcinoma
  • breast cancer e.g. Hormone refractory prostate adenocarcinoma
  • colon cancer e.g. Hormone refractory prostate adenocarcinoma
  • lung cancer such as non-small cell lung cancer
  • the pharmaceutical composition is used in a combination regimen.
  • the combination regimen includes: a combined tumor chemotherapy regimen, other tumor immunotherapeutics (small molecule compounds, antibodies, etc.), Radiotherapy regimens, tumor-targeted drugs, tumor vaccines (such as human papillomavirus (HPV), hepatitis virus (HBV and HCV) and Kaposi herpes sarcoma virus (KHSV)).
  • HPV human papillomavirus
  • HBV and HCV hepatitis virus
  • KHSV Kaposi herpes sarcoma virus
  • the pharmaceutical composition is used alone or in combination for the treatment of patients exposed to specific toxins or pathogens.
  • toxins or pathogens include but are not limited to the treatment of various viruses, pathogenic bacteria, pathogenic fungi, pathogenic parasites, etc.
  • viruses pathogenic bacteria, pathogenic fungi, pathogenic parasites, etc.
  • viruses pathogenic bacteria, pathogenic fungi, pathogenic parasites, etc.
  • viruses pathogenic bacteria, pathogenic fungi, pathogenic parasites, etc.
  • 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 .
  • the fourth aspect of the present invention provides a PD-1/PD-L1 inhibitor, which comprises the compound as described in the first aspect of the present invention, or its stereoisomers or tautomers, Or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • 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 (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the term "containing” or “including (including)” can be open, semi-closed, and closed. In other words, the term also includes “substantially consisting of” or “consisting of”.
  • alkyl includes straight or branched chain alkyl groups.
  • C 1 -C 8 alkyl means a straight or branched alkyl group having 1-8 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 linear or branched alkenyl having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 -Butenyl, or similar groups.
  • alkynyl includes straight-chain or branched alkynyl groups.
  • C 2 -C 6 alkynyl refers to a linear or branched alkynyl group having 2-6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
  • C 3 -C 8 cycloalkyl refers to a cycloalkyl group having 3-8 carbon atoms. It may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It may also be in the form of a double ring, such as a bridged ring or a spiro ring.
  • C 1 -C 8 alkoxy refers to a linear or branched alkoxy group having 1-8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propoxy, butoxy, isobutoxy, tert-butoxy, etc.
  • a 3-10 membered heterocyclic group having 1-3 heteroatoms selected from the group consisting of N, S, and O refers to a group having 3-10 atoms and 1-3 atoms are selected Saturated or partially saturated cyclic groups of heteroatoms from the following group of N, S, and O. It can be a single ring or a double ring form, such as a bridged ring or a spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.
  • C 6 -C 10 aryl group refers to an aryl group having 6-10 carbon atoms, for example, a phenyl group or a naphthyl group and the like.
  • N, S, and O refers to those having 5-10 atoms and wherein 1-3 atoms are selected from The following group of N, S, and O heteroatoms are cyclic aromatic groups. It may be a monocyclic ring or a condensed ring form.
  • pyridyl pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc.
  • the groups of the present invention can be substituted by substituents selected from the group consisting of halogen, nitrile, nitro, hydroxyl, amino, C 1 -C 6 alkyl-amino, 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, halogen Substituted C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl, C 1 -C 6 alkoxy-C 1 -C 6 alkane Group, C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl, C 2 -C 6 alkenyl-carbonyl, C
  • 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” refers to substitution with an atom selected from F, Cl, Br, and I.
  • the structural formula described in the present invention is intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, containing asymmetry The R and S configuration of the center, the (Z) and (E) isomers of the double bond, etc. Therefore, a single stereochemical isomer of the compound of the present invention or a mixture of its enantiomers, diastereomers or geometric isomers (or conformational isomers) belongs to the scope of the present invention.
  • tautomers means that structural isomers with different energies can exceed the low energy barrier to convert into each other.
  • proton tautomers ie, proton transfer
  • Valence tautomers include interconversion through the recombination of some bonding electrons.
  • solvate refers to a complex in which the compound of the present invention coordinates with solvent molecules to form a specific ratio.
  • the present invention provides a compound represented by the following formula I, its stereoisomer or its tautomer, or its pharmaceutically acceptable salt, hydrate or solvate:
  • each Each independently is a single bond or a double bond
  • the preferred compound of formula I is the specific compound shown in the examples of this application.
  • the present invention also provides a method for preparing the compound according to the first aspect of the present invention.
  • the compound can be reductively amination with a compound of formula 1 to obtain a compound of formula 2, and then a metal-catalyzed reaction to obtain a compound of formula 3
  • compound 4 undergoes reductive amination reaction to obtain compound 5, and then compound 3 and compound 5 undergo a metal-catalyzed coupling reaction to obtain the compound described in the first aspect.
  • X 1 , X 3 and X 4 are each independently selected from the following group: N, CH;
  • X 5 and X 6 are each independently selected from the following group: N, C;
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 and Z 10 are each independently N or CH;
  • R 1 , R 4 , R 6 and R 7 represent one or more substituents on the ring selected from the group consisting of H, D, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted Substituted C3-C8 cycloalkyl, substituted or untaken C1-C6 alkoxy;
  • R 2 is selected from the following group: H, D, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy; Or the R 2 group has one or more hydrogen atoms substituted by R 5 ; and the R 2 group can be located at X 1 or X 3 ;
  • W 1 is a group selected from the group consisting of CR 2 and C(O);
  • W 2 is a group selected from the following group: CR 2 , C(O);
  • each R is independently selected from the following group: H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;
  • Ra and Rb together with adjacent N atoms form a substituted or unsubstituted 5-10 membered heterocyclic group with 1-3 heteroatoms selected from N, S and O;
  • the R c and R d and the adjacent N atoms together form a substituted or unsubstituted 5-10 membered heterocyclic group with 1-3 heteroatoms selected from N, S and O.
  • 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 containing the compound of the present invention are the main activities
  • the pharmaceutical composition of the components can be used to prevent and/or treat diseases related to the PD-1/PD-L1 signaling pathway (for example, cancer).
  • the pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per agent, and more preferably, contains 10-200 mg of the compound of the present invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include 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 ), wetting agents (such as sodium lauryl sulfate), coloring agents, 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 emulsifiers
  • 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 mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, 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 glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound 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 can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, 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 substances, 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 substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the present invention can 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 the compound of the present invention.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • 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 and the patient's health status, which are all within the skill range of a skilled physician.
  • the pharmaceutical composition can be used for:
  • melanoma e.g. metastatic malignant melanoma
  • kidney cancer e.g. clear cell carcinoma
  • prostate cancer e.g. hormone refractory prostate adenocarcinoma
  • breast cancer e.g. cancer, colon cancer and lung cancer (e.g. non-small cell lung cancer).
  • combination medication regimens such as combined tumor chemotherapy regimens, other tumor immunotherapeutics (small molecule compounds and antibodies, etc.), radiotherapy regimens, tumor-targeted drugs, tumor vaccines, etc., such as human papillomavirus (HPV), Hepatitis viruses (HBV and HCV) and Kaposi herpes sarcoma virus (KHSV). It can be administered before, after or at the same time as the agent, or it can be co-administered with other known therapies.
  • HPV human papillomavirus
  • HBV and HCV Hepatitis viruses
  • KHSV Kaposi herpes sarcoma virus
  • the organic phase was dried with anhydrous sodium sulfate, filtered with suction, and concentrated.
  • the organic phase was dried with anhydrous sodium sulfate, filtered with suction, and concentrated.
  • Example 1-1 (S)-(2-chloro-3-(6-methoxy-5-((((5-carbonylpyrrolidin-2-yl)methyl)amino)methyl)pyridine- 2-yl)phenyl)boronic acid.
  • Example 1-2 (S)-6-(2,2'-Dichloro-3'-(6-methoxy-5-((((5-carbonylpyrrolidin-2-yl)methyl) Amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-4-methoxy-6,7-dihydro-5H-pyrrolo[3,4- d)pyrimidine-2-formaldehyde.
  • Example 1-3 Methyl (S)-1-((6-(2,2'-Dichloro-3'-(6-methoxy-5-((((5-carbonylpyrrolidine-2 -Yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-4-methoxy-6,7-dihydro-5H-pyrrole And (3,4-d)pyrimidin-2-yl)methyl)piperidine-4-carboxylate.
  • Example 1 (S)-1-((6-(2,2'-Dichloro-3'-(6-methoxy-5-((((5-carbonylpyrrolidin-2-yl)methyl (Yl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-4-methoxy-6,7-dihydro-5H-pyrrolo[3, 4-d)pyrimidin-2-yl)methyl)piperidine-4-carboxylic acid.
  • Example 1-3 To the mixed solution of Example 1-3 (30 mg, 0.039 mmol) in methanol (2 mL), tetrahydrofuran (2 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (7 mg, 0.156 mmol). Mole). The reaction solution was heated to 40°C and stirred for two hours, neutralized and concentrated.
  • Example 2-2 Methyl(S)-1-((2-(2,2'-Dichloro-3'-(6-methoxy-5-((((((S)-5-carbonyl Pyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-2H-pyrazolo[3,4-b] (Pyridin-5-yl)methyl)pyrrolidine-3-carboxylate
  • Example 5-1 (S)-5-(((((6-(2,2'-Dichloro-3'-(2-(hydroxymethyl)-4-methoxy-5,7-di Hydrogen-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl) (Amino)methyl)pyrrolidin-2-one
  • Example 5-2 (S)-5-((((6-(2,2'-Dichloro-3'-(2-(chloromethyl)-4-methoxy-5,7-di Hydrogen-6H-pyrrolo[3,4- d]pyrimidin-6-yl)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl) (Amino)methyl)pyrrolidin-2-one
  • Example 5-3 Methyl (S)-((6-(2,2'-Dichloro-3'-(6-methoxy-5-((((5-carbonylpyrrolidin-2-yl )Methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-4-methoxy-6,7-dihydro-5H-pyrrolo[ 3,4-d)pyrimidin-2-yl)methyl)glycinate
  • the mixture 5-2 (60 mg, 0.09 mmol), methyl glycinate hydrochloride (34 mg, 0.276 mmol), potassium carbonate (101 mg, 0.735 mmol), sodium iodide (3 mg, 0.02 mmol) Mol) was added to anhydrous N,N-dimethylformamide (5 mL), and the reaction was stirred at room temperature for 16 hours.
  • the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (15 mL ⁇ 3). The organic phases were combined and concentrated.
  • Test Example 1 Detecting the inhibitory effect of the compound on the mutual binding of PD-1/PD-L1 protein
  • the PD-1/PD-L1 homogeneous time-resolved fluorescence (Homogenous Time-Resolved Fluorescence, HTRF) detection technology is used to detect the binding ability of the compound with PD-L1.
  • HTRF Hemogenous Time-Resolved Fluorescence
  • PD1/PD-L1 binding assay kit (Cisbio, Cat#63ADK000CPDEC), which contains two proteins Tag 1-PD-L1 and Tag 2-PD-1, and Anti-Tag1-Eu 3+ and Anti- Tag2-XL 665 two antibodies.
  • Tag 1-PD-L1 interacts with Tag 2-PD-1
  • the added HTRF donor The body and the acceptor are close to each other. After the donor receives the excitation energy, part of the energy is transferred to the acceptor, which will generate 665nm emission light.
  • Tag 1-PD-L1 is diluted with Diluent buffer (cat#62DLBDDF) to a working concentration of 10nM
  • Tag 2-PD-1 is diluted with Diluent buffer to a working concentration of 500nM
  • 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
  • the compound to be detected is diluted with diluent buffer to a final concentration of 2X.
  • the letter A represents IC 50 is less than 10nM
  • the letter B represents an IC 50 of 10nM to 100nM
  • the letter C represents IC 50 is greater than 100nM
  • the compound 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 combination of PD-1/PD-L1.
  • the cytology experiment of PD1/PD-L1 requires two kinds of cells, PD-1 effector cells and PD-L1 aAPC/CHO-K1 cells, among which PD-1 effector cells express human PD-1 protein and fluorescein driven by NFAT Enzyme reporter gene, PD-L1 aAPC/CHO-K1 cells express PD-L1 protein and anti-CD3 antibody.
  • PD-1 effector cells express human PD-1 protein and fluorescein driven by NFAT Enzyme reporter gene
  • PD-L1 aAPC/CHO-K1 cells express PD-L1 protein and anti-CD3 antibody.
  • the inhibitor of PD-1 or PD-L1 When the inhibitor of PD-1 or PD-L1 is added, the interaction of PD-1/PD-L1 is blocked, the signal inhibition of the TCR to NFAT-RE pathway is lifted, and the fluorescence signal is enhanced, and the fluorescence signal is enhanced.
  • the strength is used to judge the blocking effect of the inhibitor.
  • the recovered PD-L1 aAPC/CHO-K1 cells were digested, centrifuged, and the concentration was adjusted to 2.5*10 5 /mL with the culture medium (90% Ham's F-12/10% FBS). 40ul wells, 1*10 4 cells were spread in a 384-well plate and placed in an incubator for overnight culture.
  • the detection buffer 99% RPMI1640/1% FBS
  • the detection buffer uses the detection buffer to adjust the concentration to 6.25*10 5 /mL.
  • the letter A represents IC 50 is less than 100nM
  • the letter B represents an IC 50 of 100nM to 500nM
  • the letter C represents IC 50 is greater than 500nM
  • Test Example 3 The pharmacokinetic experiment of the small and medium molecule inhibitor of the present invention in mice
  • test compound was administered to ICR mice intravenously (IV) and orally (PO) separately, blood samples were collected at different time points, and the concentration of the test substance in the mouse plasma was determined by LC-MS/MS and related parameters were calculated. 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 make a solution of the required concentration for intravenous or oral administration. The age of the animals was about 6-8 weeks at the beginning of the dosing experiment. Intravenous 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.
  • Test Example 4 Rat pharmacokinetic experiment of small and medium molecule inhibitors of the present invention
  • SD rats were administered the test compound intravenously (IV) or orally (PO) once, and blood samples were collected at different time points.
  • concentration of the test substance in the rat plasma was determined by LC-MS/MS and related parameters were calculated. 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 make a solution of the required concentration for intravenous or oral administration. The age of the animals was about 6-8 weeks at the beginning of the dosing experiment.
  • Intravenous 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.

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Abstract

Un composé représenté par La formule I a une application dans la régulation de l'immunité et l'inhibition de PD-1/PD-L1.
PCT/CN2020/136884 2019-12-17 2020-12-16 Préparation et application d'une classe de composés hétérocycliques contenant n ayant une fonction immunomodulatrice Ceased WO2021121282A1 (fr)

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