WO2021148043A1 - Composé nitrophényléther, son procédé de préparation, composition pharmaceutique associée et son utilisation - Google Patents

Composé nitrophényléther, son procédé de préparation, composition pharmaceutique associée et son utilisation Download PDF

Info

Publication number
WO2021148043A1
WO2021148043A1 PCT/CN2021/074875 CN2021074875W WO2021148043A1 WO 2021148043 A1 WO2021148043 A1 WO 2021148043A1 CN 2021074875 W CN2021074875 W CN 2021074875W WO 2021148043 A1 WO2021148043 A1 WO 2021148043A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
methoxy
biphenyl
nitro
benzyl
Prior art date
Application number
PCT/CN2021/074875
Other languages
English (en)
Chinese (zh)
Inventor
赖宜生
欧阳宜强
赵磊
徐强
郭文洁
Original Assignee
中国药科大学
南京中澳转化医学研究院有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国药科大学, 南京中澳转化医学研究院有限公司 filed Critical 中国药科大学
Publication of WO2021148043A1 publication Critical patent/WO2021148043A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

Definitions

  • the invention belongs to the field of biomedicine, and specifically relates to a class of nitrophenyl ether compounds or their stereoisomers, pharmaceutically acceptable salts, crystals, and solvents as inhibitors of PD-1/PD-L1 protein-protein interaction Compounds or prodrugs, their preparation methods, pharmaceutical compositions containing these compounds, and the use of these compounds or compositions in the treatment of diseases related to PD-1/PD-L1 mediated immunosuppression, such as cancer.
  • Immune escape is a basic feature of malignant tumors. Under normal physiological conditions, the body's immune system can recognize foreign molecules and eliminate them in time. But for tumor patients, due to the low immunity of the body and the special biological characteristics of tumor cells, tumor cells can escape the recognition and killing of the immune system through various mechanisms, and ultimately survive and develop in the body. Tumor immune escape is a complex pathological process, and the escape mechanism mediated by immune checkpoints has attracted much attention.
  • Immune checkpoints are the regulators of the immune system in the human body, composed of a series of co-stimulatory molecules and co-suppressive molecules, and play an important regulatory role in the body's immune system.
  • the costimulatory molecules of immune checkpoints mainly include CD27, CD40, OX40, GITR, CD137, OX40 and ICOS, etc.
  • the co-inhibitory molecules are mainly CTLA-4, PD-1, PD-L1, PD-L2, TIM-3 , VISTA and IDO etc.
  • costimulatory molecules can enhance the immune response of the body, thereby helping immune cells to eliminate foreign molecules, while co-suppressive molecules play a negative regulatory role on the immune response, thereby maintaining the immune homeostasis of the body, and avoiding excessive immunity from causing the host Damage to normal tissues.
  • tumor cells can use immune checkpoints to achieve immune evasion.
  • the common escape mechanism is that tumor cells inhibit the activation of T lymphocytes by inducing themselves, antigen presenting cells (APC) and T lymphocytes and other surfaces to overexpress co-inhibitory molecules.
  • PD-1 programmed death receptor 1
  • PD-L1/2 programmed death receptor 1
  • PD-1/PD-L1 is currently used as a target for tumor immunotherapy The point has been fully confirmed.
  • PD-1 can also be expressed at low levels in CD4 - CD8 - T cells, B cells, dendritic cells (DC) and natural killer (NK) cells in the thymus.
  • PD-1 has two ligands, of which PD-L1 is mainly expressed in mature T cells, B cells and some non-hematopoietic cells, but PD-L1 can be expressed in inflammatory factors (such as IFN- ⁇ , TNF- ⁇ and VEGF) Under the induction of expression on a variety of cells.
  • PD-L2 expression range is relatively narrow, mainly expressed in macrophages and DC cells.
  • the negative regulation of immunity by PD-1/PD-L is mainly by inhibiting the PI3K-AKT and RAS signaling pathways, blocking the activation of transcription factors that play an important role in T cell activation, proliferation, function and survival, such as activator protein- 1 (AP-1), nuclear factor of activated T cells (NFAT) and NF- ⁇ B.
  • transcription factors that play an important role in T cell activation, proliferation, function and survival, such as activator protein- 1 (AP-1), nuclear factor of activated T cells (NFAT) and NF- ⁇ B.
  • AP-1 activator protein- 1
  • NFAT nuclear factor of activated T cells
  • NF- ⁇ B NF- ⁇ B
  • the PD-1/PD-L signaling pathway can induce and maintain the tolerance of peripheral tissues during immune responses to prevent excessive immune responses in the tissues.
  • excessive activation of the PD-1/PD-L signaling pathway will inhibit the secretion of immune stimulating factors such as IFN- ⁇ , TNF- ⁇ and IL-2 and the expression of survivin.
  • the abnormality of the PD-1/PD-L signaling pathway is closely related to the occurrence, development and poor prognosis of many human tumors.
  • tumor cells can survive through anti-apoptotic signals and inhibit the activity of antigen-specific T lymphocytes.
  • the use of PD-1 or PD-L1 antibodies to block the PD-1/PD-L signaling pathway can inhibit the growth of tumor cells.
  • T lymphocytes It is mainly by reversing the effect on T lymphocyte signal transduction, reactivating T lymphocytes, promoting the generation of effector T lymphocytes and memory T lymphocytes, and inhibiting the differentiation of regulatory T lymphocytes, and ultimately enhancing the tumor microenvironment
  • the immune killing ability of T lymphocytes can achieve the purpose of treating tumors.
  • PD-1/PD-L1 monoclonal antibody drugs such as Keytruda, Opdivo, Imfinzi, Tecentriq and Bavencio have been marketed worldwide, which are widely used in the clinical treatment of malignant melanoma, non-small cell lung cancer, gastric cancer, liver cancer, kidney cancer, Various solid tumors such as bladder cancer and blood cancer have significant clinical treatment effects, and the indications are still increasing.
  • clinical trials of PD-1/PD-L1 monoclonal antibody combined with other drugs to treat a variety of malignant tumors are also actively being carried out.
  • PD-1/PD-L1 monoclonal antibody drugs also have obvious shortcomings. For example, they can easily lead to excessive activation of T cells and cause immune-related side effects. In addition, they cannot be administered orally, have poor compliance, and are difficult to prepare and purify, resulting in price Expensive etc. Therefore, the development of small molecule inhibitors of PD-1/PD-L1 has important application value.
  • the present invention provides a novel nitrophenyl ether compound.
  • the nitrophenyl ether compounds of the present invention have significant inhibitory activity on the PD-1/PD-L1 protein-protein interaction, so they can be used in the preparation of inhibitors that inhibit PD-1/PD-L1 activity, and can be used as Immune checkpoint inhibitors are used in tumor immunotherapy.
  • the invention also provides a preparation method, pharmaceutical composition and application of the nitrophenyl ether compound.
  • the present invention provides a nitrophenyl ether compound with the structural characteristics of general formula (I), its stereoisomers, metabolites, metabolic precursors, prodrugs, solvates, crystals or Its pharmaceutically acceptable salt:
  • R 1 is selected from: methyl or bromine
  • R 2 is selected from: hydrogen, C 1 -C 4 alkoxy or -O(CH 2 ) n Ar; wherein, n is selected from an integer of 0-4; Ar is selected from an aryl group or an aromatic heterocyclic ring;
  • the heterocycle may optionally contain one or more heteroatoms selected from O, S or N; the aryl or aromatic heterocycle may optionally be substituted by one or more W groups;
  • W is selected from: hydrogen, Halogen, cyano, hydroxyl, mercapto, carboxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 1 -C 6 haloalkyl;
  • R 3 and R 4 are each independently selected from: hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl or the nitrogen atom to which R 3 and R 4 are connected Together to form a 5-7 membered heterocyclic ring; the alkyl, alkoxy or cycloalkyl group may be optionally substituted by one or more X groups; X is selected from: hydrogen, halogen, hydroxyl, mercapto, and methylmercapto , Carboxyl, amino, furanyl, dimethylamino, hydroxy-substituted isopropylamino, diethylamino, tetrahydropyrrolyl, morpholinyl, N-methylpiperazinyl or -NHCOR 5 ; where R 5 is selected From C 1 -C 8 alkyl; the heterocyclic ring may be substituted by carboxy or -CONR 6 R 7;
  • R 6 and R 7 are each independently selected from: hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl, or the nitrogen atom to which R 6 and R 7 are connected Together to form a 5-7 membered heterocyclic ring; the alkyl, alkoxy, cycloalkyl or heterocyclic ring may be optionally substituted by one or more Y groups; Y is selected from: hydrogen, halogen, hydroxyl, mercapto , Carboxyl, amino or acetamide group;
  • the alkyl group represents a straight chain alkyl group, a branched chain alkyl group or a cyclic alkyl group
  • the alkoxy group represents a straight chain alkoxy group, a branched chain alkoxy group or a cyclic alkoxy group
  • Amino represents linear alkylamino, branched alkylamino or cyclic alkylamino
  • the aryl group represents phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl;
  • the aromatic heterocycle represents pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridyl Monocyclic heterocyclic ring of azinyl; or quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl , Benzofuranyl, benzothienyl, 2,3-dihydrobenzo[1,4]dioxenyl, or benzo[1,3]dioxolyl bicyclic hetero ring;
  • the halogenated alkyl group is a linear or branched saturated hydrocarbon group, or a cyclic saturated hydrocarbon group, or a cyclic saturated hydrocarbon group connected to a linear or branched saturated hydrocarbon group; wherein one or more hydrogen atoms are replaced by one or more halogens. Atom substitution.
  • R 1 is selected from: methyl or bromine
  • R 2 is selected from: hydrogen or -OCH 2 Ar; wherein, Ar is selected from an aryl group or an aromatic heterocyclic ring; the aromatic heterocyclic ring may optionally contain one or more heteroatoms selected from O, S or N; The aryl or aromatic heterocycle may be optionally substituted by one or more W groups; W is selected from: hydrogen, halogen, cyano, hydroxyl, mercapto, carboxy, C 1 -C 4 alkyl or C 1- C 4 alkoxy;
  • R 3 and R 4 are each independently selected from: hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl or the nitrogen atom to which R 3 and R 4 are connected Together to form a 5-7 membered heterocyclic ring; the alkyl, alkoxy or cycloalkyl group may be optionally substituted by one or more X groups; X is selected from: hydrogen, halogen, hydroxyl, mercapto, and methylmercapto , Carboxyl, amino, furanyl, dimethylamino, hydroxy-substituted isopropylamino, diethylamino, tetrahydropyrrolyl, morpholinyl, N-methylpiperazinyl or -NHCOR 5 ; where R 5 is selected From C 1 -C 8 alkyl; the heterocyclic ring may be substituted by carboxy or -CONR 6 R 7;
  • R 6 and R 7 are each independently selected from: hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or the nitrogen to which R 6 and R 7 are connected Atoms together form a 5-7 membered heterocyclic ring; wherein the alkyl, alkoxy, cycloalkyl or heterocyclic ring may be optionally substituted by one or more Y groups; wherein Y is selected from: hydrogen, halogen , Hydroxyl, mercapto, carboxyl, amino or acetamide.
  • R 1 is selected from: methyl or bromine
  • R 2 is selected from: hydrogen or -OCH 2 Ar; wherein, Ar is selected from aryl or aromatic heterocycle; said aromatic heterocycle may optionally contain one or more N atoms; said aryl or aromatic heterocycle The ring may be optionally substituted with one or more W groups; W is selected from: hydrogen or cyano;
  • R 3 and R 4 are each independently selected from: hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl or the nitrogen atom to which R 3 and R 4 are connected Together to form a 5-6 membered heterocycle; the alkyl group or alkoxy group may be optionally substituted by one or more X groups; X is selected from: hydrogen, halogen, hydroxyl, carboxyl, methylmercapto, amino, and furan , Dimethylamino, hydroxy-substituted isopropylamino or -NHCOR 5 ; wherein R 5 is selected from C 1 -C 4 alkyl; the heterocyclic ring may be substituted by carboxy or -CONR 6 R 7;
  • R 6 and R 7 are each independently selected from: hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or R 6 and R 7 together with the nitrogen atom to which they are connected to form a 5-6 membered heterocyclic ring ; Wherein the alkyl group, alkoxy group or heterocyclic ring may be optionally substituted by one or more Y groups; wherein Y is selected from: hydrogen, halogen, hydroxyl, carboxyl, amino or acetamido.
  • R 1 is selected from: methyl or bromine
  • R 2 is selected from: hydrogen or -OCH 2 Ar; wherein, Ar is selected from an aryl group or a 5-6 membered aromatic heterocyclic ring; the aromatic heterocyclic ring may optionally contain one or more N atoms; the aromatic The group or aromatic heterocyclic ring may be optionally substituted by one or more W groups; W is selected from: hydrogen or cyano;
  • R 3 and R 4 are each independently selected from: hydrogen, C 1 -C 8 alkyl or R 3 and R 4 together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; the alkyl group may optionally Substituted by one or more X groups; X is selected from: hydrogen, halogen, hydroxyl, carboxyl, methylmercapto, amino, furanyl, dimethylamino, hydroxy-substituted dimethylamino or -NHCOR 5 ; wherein R 5 is selected from C 1 -C 4 alkyl; the heterocyclic ring may be substituted by carboxy or -CONR 6 R 7;
  • R 6 and R 7 are each independently selected from: hydrogen, C 1 -C 6 alkyl or R 6 and R 7 together with the nitrogen atom to which they are connected to form a 5-6 membered heterocyclic ring; wherein the alkyl or hetero The ring may be optionally substituted with one or more Y groups; wherein Y is selected from: hydrogen, halogen, hydroxyl, carboxyl, amino, or acetamido.
  • the indole compound is any one of the following compounds:
  • Another object of the present invention is to provide a preparation method of the compound represented by general formula (I), the preparation method is as follows:
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • the "method of one or more of the condensation reaction and the hydrolysis reaction” includes only condensation reaction or hydrolysis reaction; or first hydrolysis reaction, then condensation reaction; or first hydrolysis reaction, then condensation reaction, and then hydrolysis Reaction, wait.
  • the pharmaceutically acceptable salt of the compound of general formula (I) can be synthesized by general chemical methods.
  • the salt can be prepared by reacting a free base or acid with an equivalent or excess acid (inorganic acid or organic acid) or base (inorganic base or organic base) in a suitable solvent or solvent composition.
  • the present invention also provides a pharmaceutical composition, which is mainly composed of a therapeutically effective amount of active components and pharmaceutically acceptable excipients; the active components include a compound of general formula (I) or its pharmaceutically acceptable One or more of the accepted salt.
  • the adjuvant includes a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the pharmaceutical composition can be made into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc. Preference is given to tablets, capsules, liquids, suspensions and injections (solutions and suspensions).
  • any excipient known and widely used in the art can be used.
  • the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin) to prepare an injection that is isotonic with blood.
  • any carriers commonly used in the art can also be used.
  • common dissolving agents and buffering agents can also be added.
  • the content of the composition of the present invention in the pharmaceutical composition is not particularly limited, and can be selected in a wide range, usually 5-95% by mass, preferably 30-85% by mass.
  • the method of administration of the pharmaceutical composition of the present invention is not particularly limited. Various dosage forms can be selected for administration according to the age, sex, and other conditions and symptoms of the patient.
  • the present invention also provides the application of the compound of general formula (I), its pharmaceutically acceptable salt or the said pharmaceutical composition in the preparation of PD-1/PD-L1 inhibitor drugs.
  • the PD-1/PD-L1 inhibitor is used to treat PD-1/PD-L1 mediated immune suppression related diseases, and the related diseases include cancer.
  • the present invention also provides the use of the compound of general formula (I), its pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of a medicine, which is used for the treatment of cancer.
  • the cancers include but are not limited to: malignant melanoma, lung cancer, breast cancer, stomach cancer, colon cancer, bladder cancer, pancreatic cancer, lymphoma, leukemia, prostate cancer, testicular cancer, kidney cancer, brain cancer, head and neck cancer, ovarian cancer
  • malignant melanoma lung cancer, breast cancer, stomach cancer, colon cancer, bladder cancer, pancreatic cancer, lymphoma, leukemia, prostate cancer, testicular cancer, kidney cancer, brain cancer, head and neck cancer, ovarian cancer
  • One or more of cancer, cervical cancer, endometrial cancer, mesothelial cancer, thyroid tumor, liver cancer, and esophageal cancer are examples of cancer, cervical cancer, endometrial cancer, mesothelial cancer, thyroid tumor, liver cancer, and esophageal cancer.
  • the present invention also provides that the compound of general formula (I), its pharmaceutically acceptable salt or the pharmaceutical composition can be combined with one or more other types of therapeutic agents and/or therapeutic methods for the treatment of PD -L/PD-L1 mediated related diseases.
  • therapeutic agents and/or treatment methods include, but are not limited to: chemotherapeutics, targeted antitumor drugs, immune checkpoint inhibitors, immune checkpoint agonists, antitumor vaccines, antiviral agents, antiviral vaccines, Cytokine therapy, adoptive cellular immunotherapy or radiation therapy.
  • chemotherapeutic agents include but are not limited to: alkylating agents, tubulin inhibitors, topozyme inhibitors, platinum drugs, antimetabolites or hormone antitumor drugs.
  • the targeted anti-tumor drugs include, but are not limited to: protein kinase inhibitors, proteasome inhibitors, isocitrate dehydrogenase inhibitors, anti-tumor drugs based on epigenetics, or cell cycle signal pathway inhibitors.
  • the immune checkpoint inhibitors include, but are not limited to: CTLA-4 inhibitors, TIM-3 inhibitors, VISTA inhibitors, LAG3 inhibitors, TIGIT inhibitors, A2AR inhibitors or VTCN1 inhibitors.
  • the immune checkpoint agonists include but are not limited to: STING agonists, 4-1BB agonists, OX40 agonists, ROR ⁇ agonists or ICOS agonists.
  • the nitrophenyl ether compound of the present invention has significant inhibitory activity on the interaction of PD-1/PD-L1, and can effectively block the immunosuppressive effect mediated by PD-1/PD-L1.
  • the in vivo pharmacodynamic evaluation results show that the compound of the present invention can significantly inhibit the growth of transplanted tumors in mice, and significantly promote the infiltration of lymphocytes in tumor tissues, increase the level of INF- ⁇ , reduce the expression of PCNA protein, and affect the immune system. Defective mice transplanted tumors have no effect, indicating that the compound of the present invention can play an anti-tumor effect by activating the host immune response.
  • Figure 1 shows that the compound of the present invention reverses the effect of PD-1/PD-L1 on inhibiting the secretion of INF- ⁇ from PBMC in a dose-dependent manner
  • Figure 2 shows the effect of the compound of the present invention on the viability of Lewis lung cancer cells at different concentrations
  • Figure 3 shows that the compound of the present invention inhibits the growth of transplanted tumors in mice with Lewis lung cancer in a dose-dependent manner
  • Figure 4 shows the effect of the compound of the present invention on the infiltration of T lymphocytes in transplanted tumors in mice, in which: A) CD45 + cells; B) CD45 + CD3 + cells; C) CD4 + CD45 + CD3 + cells; D) CD8 + CD45 + CD3 + cells.
  • Reagents and materials The reagents required for the experiment are all commercially available chemical or analytical products without special instructions.
  • Dissolve 1C (2.0g, 10.1mmol) in 30mL of anhydrous DCM, cool in an ice bath, slowly drip 1mL of phosphorus tribromide (2.7g, 10.1mmol), react for 1h, remove the ice bath, react at room temperature for 8h, spin off The solvent was cooled in an ice bath, 10 mL of water was slowly added dropwise, extracted with ethyl acetate, and concentrated to obtain 2.3 g of a white solid with a yield of 87%.
  • Dissolve 1F in 5mL methanol add LiOH (50mg), react for 5h, spin off the solvent, add 10mL saturated brine, cool in an ice bath, adjust pH to 2 with 6M hydrochloric acid, filter with suction, and dry to obtain a white solid of 65mg, yield 54%.
  • Dissolve 33B (0.8g, 2.2mmol), m-cyanobenzyl bromide (0.5g, 2.4mmol) and K 2 CO 3 (0.6g, 4.4mmol) in 10mL DMF, react at room temperature for 1 hour, add 50mL saturated brine , Suction filtration, drying, to obtain 0.7 g of white solid, with a yield of 67%.
  • Dissolve 33C (0.22g, 0.46mmol) in 5mL DMF, add L-threonine methyl ester hydrochloride (0.14g, 0.92mmol), TEA (0.12g, 1.38mmol), glacial acetic acid (0.14g, 2.3mmol) and sodium cyanoborohydride (0.14g, 2.3mmol), react at room temperature for 24h, add 10mL water, extract with ethyl acetate, concentrate under reduced pressure, and directly put into the next reaction.
  • the purchased kit contains the reagents needed for experiments such as PD-1, PD-L1, Anti-tag1-Eu, Anti-tag2-XL665, Dilute Buffer and Detection Buffer ; Positive drug BMS-1018; M1000 Multifunctional Microplate Reader; Echo520 Ultrasonic Micro Liquid Transfer System (Labcyte).
  • the inhibitory activity of the compounds of the examples on the PD-1/PD-L1 protein-protein interaction is shown in Table 1. The results show that the compound of the present invention can significantly inhibit the interaction of PD-1/PD-L1.
  • BMS-1018 is the No. 1018 compound in patent WO 2015160641 A2.
  • Cytokines are a class of unique proteins with dual effects and regulation. They play an important role in immune regulation in the response of lymphocytes. Activated human peripheral blood mononuclear cells (PBMC) can release cytokines such as IFN- ⁇ , IL-2 and TNF- ⁇ , and when PD-1 expressed on the PBMC membrane binds to its ligand PD-L1, it will inhibit the cell Factor release.
  • PBMC peripheral blood mononuclear cells
  • the purpose of this experiment is to test the ability of the compound of the present invention to reverse PD-1/PD-L1's inhibition of PBMC secretion of INF- ⁇ .
  • the level of INF- ⁇ can be significantly increased at a concentration of 100 nM, which indicates that the compound of the present invention can block the inhibitory effect of PD-1/PD-L1 on PBMC, thereby promoting the secretion of INF- ⁇ .
  • the MTT method is used to detect the effect of the compound of the present invention on the activity of Lewis lung cancer cells, and the purpose is to investigate whether the compound of the present invention has cytotoxicity.
  • PCNA Proliferating cell nuclear antigen
  • mice select female mice aged 7-8 weeks and raise them in an SPF-class animal breeding room for one week. Each mouse weighs about 18-20g.
  • Treatment of tumor cells Collect tumor cells in logarithmic growth phase, centrifuge at 180g for 5 min (4°C), wash twice with pre-cooled PBS, pipette evenly, and make a final cell concentration of 1 ⁇ 10 7 /mL, ice bath for later use.
  • Tumor cell transplantation The tumor cell suspension was inoculated subcutaneously into the right axilla of the mouse, and the number of tumor cells inoculated was 1 ⁇ 10 6 per mouse. The tumor size of the mouse was measured with a vernier caliper every two days, and the mouse weight was weighed once. When the average tumor volume reaches about 40mm 3 , the drug is started.
  • mice When the tumor volume reached a certain size, the animal experiment was ended. Weigh the weight of the mice, take blood from their eyeballs, and euthanize the mice, strip the tumor tissues, weigh the tumor tissues and take pictures. At the same time, some tissues were placed in 10% neutral fixative, samples were sent for paraffin-embedded tissues, paraffin tissue sections were made, and H&E staining, TUNEL and immunohistochemical analysis were performed. Refer to the test kit instructions for experimental operations.
  • mice transplanted with Lewis lung cancer were divided into 4 groups with 6 mice in each group.
  • Model group (solvent: PBS+2% Tween 20+2% DMSO, intragastric administration, once a day), positive control group (BMS-1018, intragastric administration, once a day, dose: 5mg/kg),
  • Drug treatment group 1 compound 33, intragastric administration, once a day, dose: 2 mg/kg
  • drug treatment group 2 compound 33, intragastric administration, once a day, dose: 5 mg/kg.
  • Model group (solvent: PBS+2% Tween 20+2% DMSO, intragastric administration, once a day), positive control group (BMS-1018, intragastric administration, once a day, dose: 5mg/kg), Drug treatment group 1 (compound 33, intragastric administration, once a day, dose: 2 mg/kg), drug treatment group 2 (compound 33, intragastric administration, once a day, dose: 5 mg/kg).
  • mice transplanted with CT26 colorectal tumors were divided into 5 groups with 6 mice in each group.
  • Model group (solvent: PBS+2% Tween 20+2% DMSO, intragastric administration, once a day), positive control group-1 (5-FU, dose: 25mg/kg, intraperitoneal injection, once every two days ), positive control group-2 (BMS-1018, intragastric administration, once a day, dose: 5mg/kg), drug treatment group (compound 33, intragastric administration, once a day, dose: 5mg/kg), combined Administration group (5-FU, dose: 25 mg/kg, intraperitoneal injection, once every two days; compound 33, intragastric administration, once a day, dose: 5 mg/kg).
  • mice transplanted with CT26 colorectal tumors were divided into 4 groups with 6 mice in each group.
  • Model group (solvent: PBS+2% Tween 20+2% DMSO, intragastric administration, once a day), positive control group-1 (5-FU, dose: 25mg/kg, intraperitoneal injection, once every two days ), positive control group-2 (BMS-1018, intragastric administration, once a day, dose: 5mg/kg), drug treatment group (compound 33, intragastric administration, once a day, dose: 5mg/kg).
  • Model group (solvent: PBS+2% Tween 20+2% DMSO, intragastric administration, once a day), positive control group (BMS-1018, intragastric administration, once a day, dose: 5mg/kg), Drug treatment group (Compound 33, intragastric administration, once a day, dose: 5mg/kg).
  • Example Compound 33 can significantly inhibit the growth of Lewis lung cancer transplanted tumors in mice at 2 mg/kg and 5 mg/kg, showing a dose-dependent, and no Affect the weight of mice.
  • the inhibitory activity of compound 33 on transplanted tumors was significantly better than that of the control group BMS-1018 (tumor inhibition rate 19.6%).
  • Example Compound 33 can significantly promote the infiltration of T lymphocytes in tumor tissues at the doses of 2 mg/kg and 5 mg/kg, and increase the level of IFN- ⁇ , Reduce the expression of PCNA protein, and at a dose of 5 mg/kg, compound 33 reverses PD-1/PD-L1 mediated immunosuppression stronger than the BMS-1018 control group.
  • Example Compound 33 showed a dose-dependent inhibition of the growth of B16F1 melanoma transplanted tumors in mice at the doses of 2 mg/kg and 5 mg/kg, and had no effect on the body weight of the mice. At the dose (5 mg/kg), the inhibitory activity of compound 33 on transplanted tumors was better than that of the BMS-1018 control group.
  • the results of immunohistochemistry and TUNEL experiments show that the compound 33 administration group of Example can also significantly promote the infiltration of T lymphocytes in tumor tissues, increase the level of IFN- ⁇ , reduce the expression of PCNA protein, and the effect is stronger than that at the same dose. BMS-1018.
  • Example Compound 33 can inhibit the growth of CT26 colorectal cancer BALB/c mice transplanted tumors, and the combination with 5-FU can increase the tumor inhibition rate of the latter.
  • Example Compound 33 can effectively inhibit the growth of PAN02 pancreatic cancer transplanted tumors in mice at a dose of 5 mg/kg.
  • Immunohistochemistry and TUNEL experiments show that compound 33 can block the immunosuppressive effect mediated by PD-1/PD-L1.
  • T lymphocytes are the core executors of the human immune system and play an important role in tumor immune response.
  • Tumor infiltrating lymphocytes are those white blood cells that leave the bloodstream and enter the tumor. When there are a large number of tumor-infiltrating lymphocytes in the tumor microenvironment, it indicates that the body has initiated an immune response against tumors.
  • the activation of the PD-1/PD-L1 signaling pathway will inhibit the anti-tumor immune microenvironment, resulting in a decrease in lymphocyte infiltration.
  • the purpose of this experiment is to analyze the effect of the compound of the present invention on the infiltration of T lymphocytes in the tumor microenvironment.
  • Example Compound 33 can significantly promote CD45 + white blood cells, CD45 + CD3 + T lymphocytes, CD8 + CD45 + CD3 + cells at the doses of 2 mg/kg and 5 mg/kg.
  • the infiltration of toxic T cells is dose-dependent, while the effect on CD4 + CD45 + CD3 + regulatory T lymphocytes is weak.
  • the ability of Example Compound 33 to promote lymphocyte infiltration is stronger than that of BMS-1018, especially the increase in CD45 + CD3 + CD8 + cytotoxic T lymphocyte infiltration.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne le domaine des médicaments, et en particulier un composé nitrophényléther ayant des caractéristiques structurales d'une formule générale (I), un stéréoisomère, un métabolite, un précurseur métabolique, un promédicament, un solvate, un cristal ou un sel pharmaceutiquement acceptable de celui-ci, leur procédé de préparation et leur utilisation en tant qu'inhibiteurs de PD-1/PD-L1. Les résultats d'expériences pharmacologiques montrent que le composé selon la présente invention présente une activité d'inhibition remarquable sur l'interaction protéine-protéine PD-1/PD-L1 et peut inhiber efficacement l'évasion immunitaire de la tumeur médiée par PD-1/PD-L1, de sorte que le composé peut être utilisé pour préparer un médicament inhibiteur présentant l'activité d'inhibition de PD-1/PD-L1 et peut être utilisé en tant que médicament inhibiteur de point de contrôle immunitaire pour l'immunothérapie de tumeurs.
PCT/CN2021/074875 2020-01-20 2021-02-02 Composé nitrophényléther, son procédé de préparation, composition pharmaceutique associée et son utilisation WO2021148043A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010064241.8A CN111187172B (zh) 2020-01-20 2020-01-20 硝基苯醚类化合物、其制备方法和药物组合物与用途
CN202010064241.8 2020-01-20

Publications (1)

Publication Number Publication Date
WO2021148043A1 true WO2021148043A1 (fr) 2021-07-29

Family

ID=70704226

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/074875 WO2021148043A1 (fr) 2020-01-20 2021-02-02 Composé nitrophényléther, son procédé de préparation, composition pharmaceutique associée et son utilisation

Country Status (2)

Country Link
CN (1) CN111187172B (fr)
WO (1) WO2021148043A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024088036A1 (fr) * 2022-10-26 2024-05-02 西安新通药物研究股份有限公司 Dérivé de biphényle asymétrique, son procédé de préparation et son utilisation médicale

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111187172B (zh) * 2020-01-20 2021-10-29 中国药科大学 硝基苯醚类化合物、其制备方法和药物组合物与用途
CN113943330A (zh) * 2020-07-17 2022-01-18 中国科学院上海药物研究所 一类含糖结构化合物、其制备方法、药物组合物和用途
CN113214041A (zh) * 2021-04-29 2021-08-06 河北唯达生物医药产业技术研究有限公司 一种新型的制备3-碘-2溴甲苯的方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105705489A (zh) * 2013-09-04 2016-06-22 百时美施贵宝公司 用作免疫调节剂的化合物
CN106536515A (zh) * 2014-04-14 2017-03-22 百时美施贵宝公司 用作免疫调节剂的化合物
CN107417564A (zh) * 2016-05-23 2017-12-01 中国医学科学院药物研究所 苯醚类衍生物、及其制法和药物组合物与用途
CN108368090A (zh) * 2015-10-15 2018-08-03 百时美施贵宝公司 作为免疫调节剂的化合物
CN109305934A (zh) * 2018-08-07 2019-02-05 成都海博锐药业有限公司 苯醚类衍生物及可药用盐、医药上的用途
CN111187172A (zh) * 2020-01-20 2020-05-22 中国药科大学 硝基苯醚类化合物、其制备方法和药物组合物与用途
CN111909108A (zh) * 2019-09-02 2020-11-10 中国药科大学 联苯类化合物及其制备方法和医药用途

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105705489A (zh) * 2013-09-04 2016-06-22 百时美施贵宝公司 用作免疫调节剂的化合物
CN106536515A (zh) * 2014-04-14 2017-03-22 百时美施贵宝公司 用作免疫调节剂的化合物
CN108368090A (zh) * 2015-10-15 2018-08-03 百时美施贵宝公司 作为免疫调节剂的化合物
CN107417564A (zh) * 2016-05-23 2017-12-01 中国医学科学院药物研究所 苯醚类衍生物、及其制法和药物组合物与用途
CN109219592A (zh) * 2016-05-23 2019-01-15 中国医学科学院药物研究所 苄苯醚类衍生物、 及其制法和药物组合物与用途
CN109311792A (zh) * 2016-05-23 2019-02-05 中国医学科学院药物研究所 苯醚类衍生物、及其制法和药物组合物与用途
CN109305934A (zh) * 2018-08-07 2019-02-05 成都海博锐药业有限公司 苯醚类衍生物及可药用盐、医药上的用途
CN111909108A (zh) * 2019-09-02 2020-11-10 中国药科大学 联苯类化合物及其制备方法和医药用途
CN111187172A (zh) * 2020-01-20 2020-05-22 中国药科大学 硝基苯醚类化合物、其制备方法和药物组合物与用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YUE LU, JIN SHUANG-LONG;GAO JIAN;GUO WEN-JIE;XU QIANG;LAI YI-SHENG: "Design, Synthesis and Biological Evaluation of Diphenyl-based PD-L1 Inhibitors", CHINESE JOURNAL OF MEDICINAL CHEMISTRY, GAI-KAI BIANJIBU, CN, vol. 29, no. 6, 1 December 2019 (2019-12-01), CN, pages 417 - 425, XP055831581, ISSN: 1005-0108, DOI: 10.14142/j.cnki.cn21-1313/r.2019.06.001 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024088036A1 (fr) * 2022-10-26 2024-05-02 西安新通药物研究股份有限公司 Dérivé de biphényle asymétrique, son procédé de préparation et son utilisation médicale

Also Published As

Publication number Publication date
CN111187172A (zh) 2020-05-22
CN111187172B (zh) 2021-10-29

Similar Documents

Publication Publication Date Title
WO2021148043A1 (fr) Composé nitrophényléther, son procédé de préparation, composition pharmaceutique associée et son utilisation
RU2744975C2 (ru) Фенилатное производное, получение и фармацевтическая композиция и применение
KR20170070140A (ko) 암을 치료하기 위한 방법
EA018152B1 (ru) Кристаллическая форма дигидрохлорида метил ((1s)-1-(((2s)-2-(5-(4'-(2-((2s)-1-((2s)-2-((метоксикарбонил)амино)-3-метилбутаноил)-2-пирролидинил)-1н-имидазол-5-ил)-4-бифенилил)-1н-имидазол-2-ил)-1-пирролидинил)карбонил)-2-метилпропил)карбамата
US11236049B2 (en) Amorphous and crystalline forms of IDO inhibitors
CN111153846B (zh) 吡咯类化合物、其制备方法和药物组合物与用途
WO2021143936A1 (fr) Composés d'indole, procédé de préparation correspondant, composition pharmaceutique et utilisation associée
CN116041277A (zh) 苯基和联苯基取代的五元杂环类化合物及其制备方法、药物组合物和应用
CN113444075A (zh) 二氢吲哚衍生物、及其制法和药物组合物与用途
TW201922690A (zh) 環－amp反應元素結合蛋白的抑制劑
WO2021175317A1 (fr) Cristal de composé tricyclique agissant sur la protéine crbn et son procédé de préparation
CN107434789B (zh) 苯并三氮唑类衍生物、及其制法和药物组合物与用途
CN115974807B (zh) 2-苯基-5-联苯基-1,3,4-噁二唑类化合物及其制备方法、药物组合物和应用
WO2023050104A1 (fr) Dérivé d'indoline, son procédé de préparation, composition pharmaceutique et utilisation
WO2022105782A1 (fr) Composé de benzisothiazole, son procédé de préparation, composition pharmaceutique et utilisation associées
WO2024074538A1 (fr) Formes de dérivés de carbamate et utilisations associées
EA041037B1 (ru) Аморфные и кристаллические формы ido-ингибиторов

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21744892

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21744892

Country of ref document: EP

Kind code of ref document: A1