WO2018196768A1 - Composé hétérocyclique servant d'inhibiteur de pd-l1 - Google Patents

Composé hétérocyclique servant d'inhibiteur de pd-l1 Download PDF

Info

Publication number
WO2018196768A1
WO2018196768A1 PCT/CN2018/084352 CN2018084352W WO2018196768A1 WO 2018196768 A1 WO2018196768 A1 WO 2018196768A1 CN 2018084352 W CN2018084352 W CN 2018084352W WO 2018196768 A1 WO2018196768 A1 WO 2018196768A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
tert
amino
preparation
Prior art date
Application number
PCT/CN2018/084352
Other languages
English (en)
Chinese (zh)
Inventor
王勇
赵立文
刘欣
尹伟
刘笑
于琪
Original Assignee
南京圣和药业股份有限公司
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 南京圣和药业股份有限公司 filed Critical 南京圣和药业股份有限公司
Publication of WO2018196768A1 publication Critical patent/WO2018196768A1/fr

Links

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • A61P31/10—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
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention belongs to the field of medical chemistry, and relates to a class of heterocyclic compounds as PD-L1 inhibitors and uses thereof.
  • the present invention relates to a compound represented by formula A or an isomer thereof, a pharmaceutically acceptable salt, Solvates or prodrugs, methods for their preparation, and pharmaceutical compositions containing these compounds and the use of such compounds or compositions for the treatment of cancer or infectious diseases.
  • PD-1 Programmed Cell Death-1
  • B7 ⁇ H1 ligand PD-L1
  • PD-1 is mainly expressed on the membrane surface of T cells, B cells, and natural killer cells (NK cells).
  • PD-L1 is mainly expressed on mature CD4T cells, CD8 T cells, B cells, monocytes, and dendrites.
  • Hematopoietic cells such as dendritic cells (DCs), macrophages, and some non-hematopoietic cells, such as membrane surfaces of endothelial cells, islet cells, mast cells, and the like.
  • DCs dendritic cells
  • macrophages macrophages
  • non-hematopoietic cells such as membrane surfaces of endothelial cells, islet cells, mast cells, and the like.
  • PD-L1 is highly expressed in various tumors, such as lung cancer, gastric cancer, multiple bone marrow, melanoma and breast cancer.
  • the expression of PD-L1 on the surface of tumor cells interacts with the ligand on the surface of T cells, which can induce apoptosis of T cells or reduce the reactivity of T cells, thereby inhibiting the tumor immune response and allowing tumor cells to escape immune attack. Therefore, blocking the antagonist of PD1-PDL1 signaling pathway can promote the activation of T cells, reverse the tumor immune microenvironment, and enhance the endogenous anti-tumor immune effect.
  • Targeting PD-1/PD-L1 inhibitors has broad application prospects in the field of tumor immunotherapy.
  • biomacromolecules also have some disadvantages such as immunogenicity and limitations of the route of administration. Therefore, there is still a need to develop targeted PD-1/PD-L1 inhibitors with better pharmacodynamics.
  • the inventors of the present invention have found that a class of small molecule drugs can specifically modulate and/or mediate the transduction of PD-L1 and its related protein kinases for the treatment of diseases associated with PD-1/PD-L1.
  • X and Y are each independently selected from N, O and S, and when X is N, Y is selected from O and S; when X is O or S, Y is N; when Y is N, X is selected from O and S; When Y is O or S, X is N;
  • R 1 is selected from the side chains of the amino acids Ser and Thr;
  • R 2 is selected from the group consisting of the amino acid Ser and Thr residues
  • R 3 is selected from the group consisting of H, —(CH 2 ) m C(O)OR 4 , —(CH 2 ) m C(O)N(R 5 )(R 6 ) and —(CH 2 ) m CN, wherein R 4 , R 5 , R 6 are each independently selected from H and alkyl, and m is 0, 1, 2, 3 or 4;
  • n 1, 2, 3 or 4.
  • a compound of Formula A, or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof which is represented by Formula I or II a compound or a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug:
  • Q is selected from O and S; and R 1 , R 2 and R 3 are as defined in Formula A.
  • a compound of Formula A, Formula I or II, or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, according to the invention wherein:
  • R 1 is selected from the side chains of the amino acids Ser and Thr;
  • R 2 is selected from the group consisting of the amino acid Ser and Thr residues
  • R 3 is selected from the group consisting of H, —(CH 2 ) m C(O)OR 4 , —(CH 2 ) m C(O)N(R 5 )(R 6 ) and —(CH 2 ) m CN, wherein R 4 , R 5 and R 6 are each independently selected from H and C 1-6 alkyl, and m is 1, 2, 3 or 4;
  • n 1, 2, 3 or 4.
  • a compound of Formula A, Formula I or II, or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, according to the invention wherein:
  • R 1 is selected from
  • R 2 is selected from
  • R 3 is selected from the group consisting of H, —(CH 2 ) m C(O)OR 4 , —(CH 2 ) m C(O)N(R 5 )(R 6 ) and —(CH 2 ) m CN, wherein R 4 , R 5 and R 6 are each independently selected from H and C 1-6 alkyl, and m is 1, 2, 3 or 4;
  • n 1, 2, 3 or 4.
  • a compound of Formula A, Formula I or II, or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, according to the invention wherein:
  • R 1 is selected from
  • R 2 is selected from
  • R 3 is selected from H, And n is 1, 2, 3 or 4.
  • a compound of Formula A, Formula I or II, or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, according to the invention wherein:
  • R 1 is selected from
  • R 2 is selected from with
  • a compound having the formula A or a stereoisomer thereof selected from A compound having the formula A or a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, non-limiting examples of which include:
  • Another object of the present invention is to provide a compound of the formula B or a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
  • X and Y are each independently selected from N, O and S, and when X is N, Y is selected from O and S; when X is O or S, Y is N; when Y is N, X is selected from O and S; When Y is O or S, X is N;
  • R 7 is selected from the side chain of the amino acids Asn, Gln, Asp, Glu;
  • R 8 is selected from the group consisting of the amino acid Ser and Thr residues
  • R 9 and R 10 are each independently selected from H, an alkyl group and an alkylhydroxy group, and R 9 and R 10 are not simultaneously H, and
  • R 9 or R 10 together with the amino group attached to its alpha carbon position form a nitrogen heterocycloalkyl or a nitrogen heterocycloalkyl group, optionally a one or more Substituted with a substituent selected from the group consisting of a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a halogen, and a nitro group; or
  • R 9 and R 10 together with the C atom to which they are attached form a cycloalkyl or oxacycloalkyl group, which is optionally selected from one or more selected from the group consisting of a hydroxyl group and a hydroxyalkyl group. Substituted by a substituent of a cyano group, an amino group, a halogen or a nitro group.
  • a compound of the formula B, or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof is a compound of the formula III or IV.
  • Q is selected from O and S, and R 7 , R 8 , R 9 and R 10 are as defined in Formula B.
  • the compound of Formula B or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal, or prodrug thereof, according to the present invention, wherein:
  • R 7 is selected from the side chain of the amino acids Asn, Gln, Asp, Glu;
  • R 8 is selected from the group consisting of the amino acid Ser and Thr residues
  • R 9 and R 10 are each independently selected from the group consisting of H, C 1-6 alkyl and C 1-6 alkyl hydroxy, and R 9 and R 10 are not H at the same time, and
  • R 9 or R 10 together with the amino group attached to its alpha carbon position form an aza C 3-6 cycloalkyl or a nitrogenoxa C 3-6 cycloalkyl group, said aza C 3-6 cycloalkyl or nitrox a hetero C 3-6 cycloalkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxyl, hydroxy C 1-6 alkyl, cyano, amino, halogen, nitro;
  • R 9 and R 10 together with the C atom to which they are attached form a C 3-6 cycloalkyl or oxa C 3-6 cycloalkyl group, said C 3-6 cycloalkyl or oxa C 3-6 cycloalkane
  • the group is optionally substituted with one or more substituents selected from the group consisting of a hydroxyl group, a hydroxy C 1-6 alkyl group, a cyano group, an amino group, a halogen, and a nitro group.
  • a compound of the formula B, or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof wherein R 9 is H, R 10 is amino group formed on the ⁇ -carbon position with C 3-6 cycloalkyl aza, aza said C 3-6 cycloalkyl optionally substituted with one or more substituents selected from hydroxy, hydroxy C 1-6 alkyl, Substituted by a substituent of a cyano group, an amino group, a halogen or a nitro group.
  • a compound of the formula B, or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof wherein R 9 is selected from C 1-3 An alkyl group, R 10 is selected from C 1-3 alkyl groups, and R 9 and R 10 together with the C atom to which they are attached form a C 3-6 cycloalkyl group, optionally a C 3-6 cycloalkyl group Or a plurality of substituents selected from the group consisting of a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a halogen, and a nitro group.
  • a compound of the formula B, or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof wherein R 9 is selected from C 1-3 An alkyl group, R 10 is selected from a C 1-3 hydroxyalkyl group, and R 9 and R 10 together with the C atom to which they are attached form an oxa C 3-6 cycloalkyl group, said oxa C 3-6 cycloalkyl group It is optionally substituted with one or more substituents selected from the group consisting of a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a halogen, and a nitro group.
  • Another object of the present invention is to provide a compound of the formula C or a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug,
  • X and Y are each independently selected from N, O and S, and when X is N, Y is selected from O and S; when X is O or S, Y is N; when Y is N, X is selected from O and S; When Y is O or S, X is N;
  • R 11 is selected from the side chains of the amino acids Ser and Thr;
  • R 12 is selected from the group consisting of amino acid Asn, Gln, Asp, Glu side chain;
  • R 15 is selected from the group consisting of H and alkyl
  • R 13 and R 14 are each independently selected from H and alkyl, and R 13 and R 14 are not H at the same time, and
  • R 13 , R 14 together with the C atom to which they are attached form a cycloalkyl group
  • R 13 or R 14 together with the imino group to which the ⁇ carbon position is bonded forms a nitrogen heterocycloalkyl group, or R 14 together with R 15 and the atom to which they are attached form an optionally substituted lactone cycloalkyl group.
  • cycloalkyl, azacycloalkyl or lactone cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, hydroxyalkyl, cyano, amino, halogen, nitro;
  • a compound of the formula C, or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof is a compound of the formula V or VI.
  • Q is selected from O and S; and R 11 , R 12 , R 13 , R 14 and R 15 are as defined in Formula C.
  • the attached imino groups together form an aza C 3-6 cycloalkyl group
  • a compound of the formula C, or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof wherein R 14 and R 15 and The attached atoms together form a lactone C 3-6 cycloalkyl group which is substituted by one or more selected from the group consisting of hydroxyl, oxo, hydroxyalkyl, cyano, amino, halogen, nitro Substituted by
  • Another object of the present invention is to provide a process for the preparation of a compound of the formula I, or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, comprising the steps of:
  • a compound of the formula ia and a compound of the formula ib are subjected to a condensation reaction to form a compound of the formula ic;
  • Pg 1 represents a protecting group of R 1
  • Pg 2 represents a protecting group of R 2
  • R 1 and R 2 are each selected from the group consisting of the amino acid Ser and Thr side chains, in order to avoid the amino acid Ser or Thr side chain
  • a conventional hydroxy protecting group may be used to protect the amino acid Ser or Thr side chain
  • Pg 1 and Pg 2 are preferably tert-butyl ( t Bu);
  • Pg 3 represents a protecting group of R 3 or is absent; as described in Formula I, R 3 is selected from H, -(CH 2 ) m C(O)OR 4 , -(CH 2 ) m C(O)N ( R 5 )(R 6 ) and —(CH 2 ) m CN; when R 3 is a group containing a hydroxyl group or an amino group which is susceptible to change in further reaction, it can be protected by a conventional protecting group; Pg 4 Pg 5 represents an amino protecting group.
  • Another object of the present invention is to provide a process for the preparation of a compound of the formula II, or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, comprising the steps of:
  • a compound of the formula ia and a compound of the formula iib are subjected to a condensation reaction to form a compound of the formula iic;
  • Pg 1 represents a protecting group for R 1
  • Pg 2 represents a protecting group for R 2
  • R 1 and R 2 are each selected from the group consisting of the amino acid Ser and Thr side chains, in order to avoid the amino acid Ser or Thr side chain Further reaction in the reaction, the conventional hydroxyl group can be used to protect the hydroxyl group
  • Pg 1 , Pg 2 is preferably tert-butyl ( t Bu);
  • Pg 3 represents the protection or absence of R 3 ; as described in Formula II, R 3 is selected from H, -(CH 2 ) m C(O)OR 4 , -(CH 2 ) m C(O)N(R 5 ) (R 6 ) and -(CH 2 ) m CN; when R 3 is a group which contains a hydroxyl group or an amino group and is susceptible to change in further reaction, it can be protected by a conventional protecting group;
  • Pg 4 and Pg 5 represent an amino protecting group.
  • Another object of the present invention is to provide a compound of Formula B, Formula C, Formula III, Formula IV, Formula V or Formula VI or a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate thereof,
  • Formula III, Formula IV, Formula V or Formula VI is a compound of Formula B, Formula C, Formula III, Formula IV, Formula V or Formula VI.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising, for example, Formula A, Formula B, Formula C, Formula I, Formula II, Formula III, Formula IV, A compound of the formula V or formula VI, or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
  • Another object of the present invention is to provide a compound of the formula A, formula B, formula C, formula I, formula II, formula III, formula IV, formula V, formula VI. Or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof or a pharmaceutical composition comprising the same for use in the manufacture of a medicament for the treatment of cancer or an infectious disease.
  • a compound of formula A, formula B, formula C, formula I, formula II, formula III, formula IV, formula V or formula VI Or a stereoisomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the treatment of a cancer or an infectious disease
  • the cancer comprises But not limited to melanoma, brain tumors (gliomas with malignant astroglia and oligodendroglioma), esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer (colon cancer) , rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cell carcinoma, etc.), kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, Osteochondroma, osteoma, osteosarcoma, seminoma, testicular
  • a formula of formula A, formula B, formula C, formula I, formula II, formula III, formula IV, formula V or formula VI Use of a compound, or a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment of a cancer or an infectious disease, wherein the infection Sexual diseases include, but are not limited to, bacterial, viral, and fungal infections.
  • a compound of Formula A, Formula B, Formula C, Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI It has a significant inhibitory effect on colon cancer.
  • Haldrogen and “carbon” in the compounds of the present invention include all isotopes thereof. Isotopes are understood to include those atoms having the same number of atoms but having different mass numbers, such as isotopes of hydrogen including lanthanum and cerium, and isotopes of carbon including 13 C and 14 C.
  • stereoisomer refers to a molecule having the same atomic composition and attachment in the same manner, but having a three-dimensional arrangement differently, including optical isomers, geometric isomers (also known as cis-trans isomers), "chiral” It is a molecule that has properties that cannot overlap with its mirror image; “non-chiral” refers to a molecule that can overlap with its mirror image.
  • Optical isomers are divided into enantiomers and diastereomers.
  • Enantiomer refers to two isomers of a compound that are not superimposable but are mirror images of each other.
  • Diastereomer refers to a stereoisomer that has two or more chiral neutralities and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. The mixture of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • All stereoisomeric forms of the compounds of the invention include, but are not limited to, diastereomers, enantiomers, cis and trans isomers, and mixtures thereof, such as racemic mixtures.
  • Many organic compounds exist in optically active forms, that is, they have the ability to rotate planes of plane polarized light.
  • the prefix D, L or R, S is used to indicate the absolute configuration of the molecular chiral center.
  • the prefix D, L or (+), (-) is used to designate the sign of the plane-polarized light rotation of the compound, (-) or L means that the compound is left-handed, and the prefix (+) or D means that the compound is right-handed.
  • stereoisomers are the same, but their stereostructures are different.
  • a particular stereoisomer can be an enantiomer, and a mixture of isomers is often referred to as a mixture of enantiomers.
  • the 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomers that lack optical activity.
  • the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.
  • the "pharmaceutically acceptable salt” of the present invention means an acid and/or a basic salt of a compound with an inorganic and/or organic acid and a base form, and also a zwitterionic salt (internal salt).
  • the compound of the present invention contains an amino acid side chain and an amino acid residue, so that it can form an internal salt or a salt corresponding to other inorganic inorganic and/or organic acid and base forms.
  • Crystal as used in the present invention refers to various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms.
  • the "prodrug” of the present invention refers to a compound which is converted into a compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions of a living body, that is, a compound which is converted into the invention by oxidation, reduction, hydrolysis or the like of the enzyme and/or A compound which is converted into a compound of the invention by a hydrolysis reaction such as gastric acid or the like.
  • alkyl group of the present invention means a linear or branched saturated hydrocarbon group, preferably a C 1-8 alkyl group, more preferably a C 1-6 alkyl group.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropane 1,1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic substituent comprising from 3 to 20 carbon atoms, preferably from 4 to 13 carbon atoms.
  • Non-limiting examples of monocycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the group, the cyclooctyl group and the like are preferably a cyclopentyl group or a cyclohexyl group.
  • Polycycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • the "azacycloalkylene group" of the present invention means a saturated ring comprising a nitrogen atom and a plurality of carbon atoms, and the azacycloalkylene group is preferably aza C 3-20 cycloalkyl group, more preferably aza C 4 -13 cycloalkyl. More preferably, it is an aza C 3-6 cycloalkyl group.
  • Non-limiting examples of azacycloalkyl groups include pyrrolidinyl and piperidinyl groups.
  • the "oxyheterocycloalkyl group” of the present invention means a saturated ring composed of one oxygen and a plurality of carbon atoms.
  • the oxacycloalkyl group is preferably an oxa C 3-20 cycloalkyl group, more preferably an oxa C 4-13 cycloalkyl group. More preferably, it is an oxa C 3-6 cycloalkyl group.
  • lactone cycloalkyl group of the present invention means an ester group A saturated ring composed of multiple carbon atoms.
  • the lactone cycloalkyl group is preferably a lactone C 3-20 cycloalkyl group, more preferably a lactone C 4-13 cycloalkyl group. More preferred is a lactone C 3-6 cycloalkyl group.
  • alkyl hydroxy group of the present invention means -alkyl-OH.
  • halogen of the present invention means fluorine, chlorine, bromine or iodine.
  • the "nitro group" of the present invention means -NO 2 .
  • the "cyano group" of the present invention means -CN.
  • the hydroxy "hydroxy group" of the present invention means -OH.
  • the "benzyl group” of the present invention means -CH 2 -phenyl group, abbreviated as "Bn”.
  • Tet-butoxycarbonyl group in the present invention means - (O) CO (t Bu ), abbreviated as “Boc.”
  • the "Fmoc-" of the present invention means a fluorenylmethoxycarbonyl group
  • L-amino acid of the present invention means that the ⁇ -carbon atom of the ⁇ -amino acid is left-handed; conversely, the "D-amino acid” refers to the ⁇ of the general structure CH(COOH)(NH 2 )-side chain - The carbon atom is right-handed.
  • the ⁇ -carbon atoms of other protein amino acids are asymmetric carbon atoms (ie, the four substituents bonded to the ⁇ -carbon atom are different), so the amino acids may have stereoisomers, ie, may be different Configuration (D-type and L-type two configurations).
  • Non-limiting examples of amino acids include alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gln) , glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine Acid (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), valine (Val).
  • amino acid side chain of the present invention means a component of an amino acid, and the amino acid structural formula is represented by CH(COOH)(NH 2 )-R, and R represents an amino acid side chain, for example, the structure of alanine is CH (COOH).
  • (NH 2 )-CH 3 the amino acid side chain is -CH 3 ;
  • the structure of serine is CH(COOH)(NH 2 )-CH 2 OH, the amino acid side chain is -CH 2 OH;
  • the structure of threonine is CH(COOH)(NH 2 )-CH(OH)(CH 3 ), the amino acid side chain is -CH(OH)(CH 3 ).
  • amino acid residue of the present invention means that a part of the structure is absent compared to the structure of the parent amino acid, and is an incomplete amino acid.
  • a hydrogen atom on the amino group of the amino acid is replaced by a chemical bond to bond with another atom, or an amino acid.
  • -OH is replaced by a chemical bond to bond with other atoms.
  • Such as the structure of alanine Then its amino acid residue can be Can also be
  • the "protecting group" of the present invention is such that the nitrogen atom and the oxygen atom remain unchanged in the reaction of other parts of the molecule, and are protected by a group which is easy to remove.
  • the protecting group of the present invention includes an amino protecting group and a hydroxy protecting group, and the amino protecting group of the present invention means a group which prevents or prevents the amino group from participating in the next reaction until the protecting group is removed, and a non-limiting example includes a formyl group, an alkyl group.
  • the hydroxy protecting group of the present invention means a group which prevents or prevents the hydroxyl group from participating in the next reaction until the protecting group is removed.
  • hydroxy protecting group examples include acetyl, allyl, benzoyl, benzyl, ⁇ -methoxyethoxymethyl, methoxymethyl, dimethoxytrityl [di-( 4-methoxyphenyl)phenylmethyl], methoxytriphenyl[(4-methoxyphenyl)diphenylmethyl], p-methoxybenzyl ether, methylthiomethyl , trimethylacetyl, tetrahydropyranyl, triphenylmethyl, silicon (eg, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triiso) Propylsilyloxymethyl and triisopropylsilyl).
  • alkyl groups such as methyl and t-butyl groups, as well as other ethers such as ethoxyethyl groups.
  • NMM N-methylmorpholine
  • HATU 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • TPP triphenylphosphine
  • EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • TBDMSCl tert-butyldimethylchlorosilane
  • Fmoc-Asn(Trt)-OH N-fluorenylmethoxycarbonyl-L-asparagine.
  • Step 2 Preparation of benzyl 1-((tert-butoxycarbonyl)amino)-3-oxocyclobutane-1-carboxylate
  • Step 3 Preparation of benzyl 1-((tert-butoxycarbonyl)amino)-3-(2-ethoxy-2-oxoethylidene)cyclobutane-1-carboxylate
  • Step 4 Preparation of benzyl 1-amino-3-(2-ethoxy-2-oxoethylidene)cyclobutane-1-carboxylate
  • Step 5 1-(((9H- ⁇ -9-yl)methoxy)carbonyl)amino)-3-(2-ethoxy-2-oxoethylidene)cyclobutane-1-carboxylic acid Preparation of benzyl ester
  • Step 6 1-(((9H- ⁇ -9-yl)methoxy)carbonyl)amino)-3-(2-ethoxy-2-oxoethyl)cyclobutane-1-carboxylic acid preparation
  • Step 7 2-(3-(((9H- ⁇ -9-yl)methoxy)carbonyl)amino)-3-(2-(N-(tert-butoxy)-O-(tert-butyl) Preparation of ethyl-L-betathreonyl)nonyl-1-carbonyl)cyclobutyl)acetate
  • Step 8 2-(3-(((9H- ⁇ -9-yl)methoxy)carbonyl)amino)-3-(5-((1S,2S)-2-(tert-butoxy)- Preparation of ethyl 1-((tert-butoxycarbonyl)amino)propyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)acetate
  • Step 9 2-(3-Amino-3-(5-((1S,2S)-2-(tert-butoxy)-1-((tert-butoxycarbonyl)amino)propyl)-1,3 Of 4-(oxadiazol-2-yl)cyclobutyl)acetate
  • Step 10 Preparation of O-(tert-butyl)-N-((4-nitrophenoxy)carbonyl)-L-serine tert-butyl ester
  • Step 11 N-((1-(5-((1S,2S)-2-(tert-butoxy)-1-((tert-butoxycarbonyl)amino)propyl)-1,3,4-oxole
  • tert-butyl 2-oxazol-2-yl -3-(2-ethoxy-2-oxoethyl)cyclobutyl)carbamoyl-O-(tert-butyl)-L-serine
  • Step 12 N-((1-(5-((1S,2S)-2-(tert-butoxy)-1-((tert-butoxycarbonyl)amino)propyl)-1,3,4-oxole Preparation of oxazol-2-yl)-3-(carboxy)cyclobutyl)carbamoyl-O-(tert-butyl)-L-serine
  • Step 13 ((1-(5-((1S,2S)-1-Amino-2-hydroxypropyl)-1,3,4-oxadiazol-2-yl)-3-(carboxymethyl) Preparation of cyclobutyl)carbamoyl)-L-serine
  • Step 1 Preparation of ethyl 3-(2-amino-2-oxoethylidene)-1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate
  • Step 2 Preparation of ethyl 3-(2-amino-2-oxoethyl)-1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate
  • Step 3 Preparation of 3-(2-amino-2-oxoethyl)-1-((tert-butoxycarbonyl)amino)cyclobutanecarboxylic acid
  • Step 5 ((1-(5-((1S,2S)-1-Amino-2-hydroxypropyl)-1,3,4-oxadiazol-2-yl)-3-(2-amino-) Preparation of 2-oxoethyl)cyclobutyl)carbamoyl)-L-serine
  • the title compound was obtained according to the procedure of Steps 5, 7, 8, 9, 11, and 13 in Example 1, except that the starting material in the step 5 was 1-amino-3-(2-ethoxy-2-oxo Benzylene) benzyl cyclobutanecarboxylate (50 mg, 0.17 mmol) was dissolved in 1,4-dioxane to 3-(2-amino-2-oxoethyl)-1-carboxycyclobutylamine Hydrochloride.
  • the title compound was obtained in a similar manner to the method of the step 3 in Example 1, except that the starting material (triphenylphosphine) ethyl acetate was replaced with (triphenylphosphine) acetonitrile.
  • Step 2 Preparation of (1s,3s)-1-((tert-butoxycarbonyl)amino)-3-(cyanomethyl)cyclobutanecarboxylate
  • Step 3 Preparation of (1s,3s)-1-((tert-butoxycarbonyl)amino)-3-(cyanomethyl)cyclobutanecarboxylic acid
  • the title compound was obtained according to the procedure of Step 3 in Example 3, except that the starting material ethyl 3-(2-amino-2-oxoethyl)-1-((tert-butoxycarbonyl)amino)cyclobutane
  • the ethyl alkanoate was replaced with the ethyl ester of (1s, 3s)-1-((tert-butoxycarbonyl)amino)-3-(cyanomethyl)cyclobutanecarboxylate obtained in the above step 2.
  • Step 5 (((1s,3R)-1-(5-((1S,2S)-1-Amino-2-hydroxypropyl)-1,3,4-oxadiazol-2-yl)-3 Preparation of -(cyanomethyl)cyclobutyl)carbamoyl)-L-serine
  • the title compound was obtained according to the procedure of Steps 5, 7, 8, 9, 11, and 13 in Example 1, except that the starting material of the first step of Example 1 was 1-amino-3-(2-ethoxy-
  • the benzyl 2-oxoethylidenecyclobutanecarboxylate was replaced with the product of the above step 4 (1s, 3s)-1-cyano-3-(cyanomethyl)cyclobutylamine hydrochloride.
  • Step 1 1 - Preparation of ((benzyloxy)carbonyl)-3-oxocyclobutaneamine hydrochloride
  • Step 2 Preparation of benzyl 1-((((9H- ⁇ -9-yl)methoxy)carbonyl)amino)-3-oxocyclobutanecarboxylate
  • the title compound was obtained according to the procedure of Step 5 in Example 1, except that the starting material of the starting material of Example 1 was 1-amino-3-(2-ethoxy-2-oxoethylidene)cyclobutane.
  • the benzyl carbamate was replaced with the 1-((benzyloxy)carbonyl)-3-oxocyclobutaneamine hydrochloride obtained in the above step 1.
  • Step 3 Benzyl 1-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(tert-butoxy)-2-oxoethylidene)cyclobutane Preparation of alkacrylate
  • Step 4 1-(((9H-Indol-9-yl)methoxy)carbonyl)amino)-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid preparation
  • the title compound was obtained according to the procedure of Step 6 in Example 1, except that the starting material benzyl 1-((((9H- -9) yl)) oxy)) Ethoxy-2-oxoethylidene)cyclobutanecarboxylate is replaced by the benzyl 1-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 3-(2-(tert-Butoxy)-2-oxoethylidene)cyclobutanecarboxylate.
  • Step 5 (R,Z)-2-(3-(((9H- ⁇ -9-yl)methoxy)carbonyl)amino)-3-(4-amino-5-(tert-butoxymethyl) Of tert-butyl 9-dimethyl-7-oxo-2,8-dioxa-3,6-diazacyclo-3-ene-1-yl)cyclobutyl)acetate
  • Step 6 (R)-2-(3-((((9H- ⁇ -9-yl))methoxy)carbonyl)amino)-3-(3-(2-(tert-butoxy)-1) Preparation of tert-butyl (-(tert-butoxycarbonyl)amino)ethyl)-1,2,4-oxadiazol-5-yl)cyclobutyl)acetate
  • Step 7 ((1-(3-((R)-1-Amino-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)-3-(carboxymethyl)cyclobutane Preparation of carbamoyl)-L-pyrethine
  • Example 7 ((1-(3-((R)-1-Amino-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)-3-(2-amino-2) -Oxoethyl)cyclobutyl)carbamoyl)-L-pyrethine
  • Step 1 (R)-(1-(5-(1-(((9H- ⁇ -9-yl))methoxy)carbonyl)amino)-3-(3-(2-amino-2-oxo) Preparation of tert-butyl ester of ethyl)cyclobutyl)-1,2,4-oxadiazol-3-yl)-2-(tert-butoxy)ethyl)carbamate
  • the title compound was obtained according to the procedure of Steps 5 and 6 in Example 6 except that the starting material was 1-((((9H-in-9-yl)methoxy)carbonyl)amino)-3-(2-) Replacement of (tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid with 3-(2-amino-2-oxoethyl)-1-((tert-butoxycarbonyl)amino)cyclobutane Formic acid.
  • Step 2 ((1-(3-((R)-1-Amino-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)-3-(2-amino-2-) Preparation of oxoethyl)cyclobutyl)carbamoyl)-L-pyrethine
  • Step 1 Preparation of (9H-fluoren-9-yl)methyl-((1r,3r)-3-(cyanomethyl)-1-(fluorocarbonyl)cyclobutyl)carbamate
  • Step 2 ((R)-1-(5-((1r,3R)-1-(((9H- ⁇ -9-yl)methoxy)carbonyl)amino)-3-(cyanomethyl) Of tert-butyl)-1,2,4-oxadiazol-3-yl)2-(tert-butoxy)ethyl)carbamic acid tert-butyl ester
  • the title compound was obtained according to the procedure of Steps 5 and 6 in Example 6 except that the starting material was 1-((((9H-in-9-yl)methoxy)carbonyl)amino)-3-(2-) Replacement of (tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid with (9H-fluoren-9-yl)methyl(3-(cyanomethyl)-1-(fluorocarbonyl)cyclobutane Carbamate.
  • Step 3 (((1R,3S)-1-(3-((R)-1-Amino-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)-3-( Preparation of cyanomethyl)cyclobutyl)carbamoyl)-L-pyrethine
  • the title compound was obtained by the procedure of Steps 9, 11, and 13 in Example 1. The difference is that the starting material is 2-(3-(((9H- ⁇ -9-yl)methoxy)carbonyl)amino)-3-(5-((1S,2S)-2-(tert-butoxy) ) ethyl-1-((tert-butoxycarbonyl)amino)propyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)acetate was replaced by ((R)-1-(5) -((1r,3R)-1-(((9H- ⁇ -9-yl)methoxy)carbonyl)amino)-3-(cyanomethyl)cyclobutyl)-1,2,4- Tert-butyl ester of oxadiazol-3-yl)2-(tert-butoxy)ethyl)carbamate.
  • Step 7 (2S,4R)-2-(5-((6S,10S)-10-(tert-butoxymethyl)-13,13-dimethyl-3,8,11-trioxo-1, 1,1-triphenyl-12-oxy-2,7,9-azatetradecane-6-yl)-1,3,4-oxadiazol-2-yl)-4-((uncle Preparation of tert-butyl butyl dimethylsilyl)oxy)tetrahydropyrrole-1-carboxylate
  • Step 8 (((S)-4-Amino-1-(5-((2S,4R)-4-hydroxytetrahydropyrrole-2-yl)-1,3,4-oxadiazol-2-yl) Preparation of -4-oxobutyl)carbamoyl)-L-serine
  • Methyl (2S,3S)-3-hydroxytetrahydropyrrole-2-carboxylate (4.4 g, 30.3 mmol, 1 eq) was dissolved in tetrahydrofuran (40 mL), and aqueous sodium hydrogencarbonate (8.9 g, 106.1 Methyl acetate (3.5 eq, dissolved in 40 mL of water) and di-tert-butyl dicarbonate (6.28 g, 28.8 mmol, 0.95 eq) was added dropwise at 0 ° C, and then stirred at room temperature for 24 h. Water and ethyl acetate were added to the mixture, and the mixture was evaporated.
  • Step 3 (((S)-4-Amino-1-(5-((2S,3S)-3-hydroxytetrahydropyrrole-2-yl)-1,3,4-oxadiazol-2-yl) Preparation of -4-oxobutyl)carbamoyl)-L-serine
  • the preparation method is the same as the preparation method of Step 1 to Step 8 in Example 11, except that the starting material (2S, 4R)-N-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolecarboxylic acid A in Example 11 is prepared.
  • the ester was replaced with the product of the above step 2 (2S,3S)-N-(tert-butoxycarbonyl)-3-hydroxy-2-pyrrolecarboxylic acid methyl ester.
  • N-(tert-Butoxycarbonyl)-O-(tert-butyl)-L-threonine (5 g, 18.2 mmol, 1 eq) was dissolved in N,N-dimethylformamide (35 mL).
  • Methyl iodide (2.8 g, 20.0 mmol, 1.1 eq)
  • potassium carbonate (7.9 g, 54.5 mmol, 3 eq) was added and stirred at room temperature for about 3 h. After the reaction was completed, water and ethyl acetate were added to the mixture, and the mixture was evaporated. 99.0%.
  • N-(tert-Butoxycarbonyl)-O-(tert-butyl)-L-threonine methyl ester (5.2 g, 18.0 mmol) was dissolved in methanol, and hydrazine hydrate (15 mL) was added to the solution and stirred at room temperature. 24h. After the reaction was completed, the methanol was evaporated to dryness. EtOAc was evaporated. The yield was 100.0%.
  • Step 3 ((5S,10S,11R)-1-(9H- ⁇ -9-yl)-11,13,13-trimethyl-3,6,9-trioxo-5-(3-oxo Preparation of tert-butyl 3-(tritylmethylamino)propyl)-2,12-dioxa-4,7,8-triazatetradecane-10-yl)carbamate
  • Step 4 ((1S,2R)-1-(5-((S)-1-(((9H- ⁇ -9-yl)methoxy)carbonyl)amino)-4-oxo-4-()
  • Step 5 ((1S,2R)-1-(5-((S)-1-Amino-4-oxo-4-(tritylamino)butyl)-1,3,4-oxadiazole Preparation of tert-butyl 2-yl)-2-(tert-butoxy)propyl)carbamate
  • the preparation method is the same as the preparation method of the first step in the embodiment 12 except that (2S,3S)-3-hydroxytetrahydropyrrole-2-carboxylic acid is replaced by (2S,4R)-4-hydroxytetrahydropyrrole-2. - Formic acid.
  • the preparation method is the same as the preparation method of the first step in the embodiment 11, except that the methyl (2S,4R)-N-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolecarboxylate is replaced with (2S, 4R). Methyl 4-hydroxytetrahydropyrrole-2-carboxylate.
  • the preparation method is the same as the preparation method of the step 8 in the embodiment 11, except that (2S,4R)-2-(5-((6S,10S)-10-(tert-butoxymethyl)-13,13-di Methyl-3,8,11-trioxo-1,1,1-triphenyl-12-oxy-2,7,9-azatetradecane-6-yl)-1,3,4 - Oxadiazol-2-yl)-4-((tert-butyldimethylsilyl)oxy)tetrahydropyrrole-1-carboxylic acid tert-butyl ester was replaced by (1R,4S)-2-((( S)-1-(5-((1S,2R)-2-tert-butoxy-1-(tert-butoxycarbonyl)amino)propyl)-1,3,4-oxadiazol-2-yl) -4-Oxo-4-(tritylamino)butyl)carbamoyl)-4-(
  • the preparation method is the same as the production method of Example 13, except that the 4-hydroxyproline in Step 7 is replaced with 3-hydroxyproline to prepare the target compound.
  • 1 H NMR 400 MHz, D 2 O: ⁇ 4.67-4.65 (d, 1H), 4.43-4.42 (d, 1H), 4.39-4.35 (m, 1H), 4.23-4.19 (m, 1H), 4.15 -4.13(t,1H),3.57-3.45(t,2H),3.05-3.02(m,2H),2.90-2.89(d,2H),2.46-2.43(m,1H),2.34-2.29(m, 1H), 1.35-1.33 (d, 3H).
  • ESI-MS m/z: 401.3 [M+H] + .
  • the preparation method was the same as the preparation method of Example 12 except that the (2S,3S)-3-hydroxytetrahydropyrrole-2-carboxylic acid in the step 1 of Example 12 was replaced with 1-amino-3-(hydroxymethyl group).
  • the target compound can be obtained by replacing cyclobutane-1-carboxylic acid with O-(tert-butyl)-L-serine tert-butyl ester with O-(tert-butyl)-L-threonine tert-butyl ester.
  • the preparation method was the same as that of the production method of Example 12 except that (2S,3S)-3-hydroxytetrahydropyrrole-2-carboxylic acid was replaced with 1-aminocyclopropane-1-carboxylic acid to obtain the target compound.
  • 1 H NMR 400 MHz, D 2 O
  • ESI-MS m/z: 357.2 [M+H] + .
  • the preparation method was the same as the preparation method of Example 12 except that (2S,3S)-3-hydroxytetrahydropyrrole-2-carboxylic acid was replaced by 1-amino-3-(hydroxymethyl)cyclobutane-1- Formic acid can be used to prepare the target compound.
  • the preparation methods of steps 1 to 5 are the same as the preparation methods of steps 1 to 5 in Example 13, and the preparation methods of steps 6 to 8 are the same as the preparation methods of steps 6 to 8 in Example 11, except that O-(tert-butyl group) is used.
  • the L-serine tert-butyl ester is replaced with methyl 1-aminocyclopropane-1-carboxylate to obtain the target compound.
  • the preparation method is the same as the preparation method of Example 12, except that (2S,3S)-3-hydroxytetrahydropyrrole-2-carboxylic acid is replaced by 1-amino-3-hydroxycyclobutane-1-carboxylic acid.
  • the target compound is obtained.
  • the preparation method is the same as the preparation method of Example 15, except that N 2 -(((9H-fluoren-9-yl)methoxy)carbonyl)-N 5 -trityl-L-glutamine is replaced with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid can be obtained to obtain the target compound.
  • the preparation method is the same as the preparation method of Example 17, except that N 2 -(((9H-fluoren-9-yl)methoxy)carbonyl)-N 5 -trityl-L-glutamine is replaced with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid can be obtained to obtain the target compound.
  • the preparation method of the steps 1 to 5 is the same as the preparation method of the steps 1 to 5 in the embodiment 13, except that N 2 -(((9H-fluoren-9-yl)methoxy)carbonyl)-N 5 -3 Benzyl-L-glutamine is replaced by 1-(((9H- ⁇ -9-yl)methoxy)carbonyl))amino)cyclopropane-1-carboxylic acid, and the preparation methods of steps 6-8 are the same In the preparation method of 6 to 8 in Example 11, the target compound can be obtained.
  • Methyl 4-aminotetrahydro-2H-pyran-4-carboxylate (6.50 g, 0.04 mol) was dissolved in 65 mL of tetrahydrofuran and 65 mL of water, sodium bicarbonate (12.10 g, 0.14 mol) was added, and the mixture was stirred and cooled to 0 ° C.
  • Di-tert-butyl dicarbonate (8.50 g, 0.038 mol) was added, and the reaction was allowed to warm up to room temperature for about 24 h. The reaction mixture was concentrated with EtOAc (EtOAc)EtOAc.
  • Step 4 (4-(2-(N 2 -((9H-indol-9-yl)methoxy)carbonyl)-N 5 -trityl-L-glutamyl)indole-1-carbonyl)
  • Step 4 (4-(2-(N 2 -((9H-indol-9-yl)methoxy)carbonyl)-N 5 -trityl-L-glutamyl)indole-1-carbonyl)
  • Step 7 N-(((S)-1-(5-(4-(di-tert-Butyl)-)-tetrahydro-2H-pyran-4-yl)-1,3,4-Ethyl Preparation of oxazol-2-yl)-4-carbonyl-4-(tritylamino)butyl)carbamoyl)-O-(tert-butyl)-L-threonine tert-butyl ester
  • Methyl 4-aminotetrahydro-2H-pyran-4-carboxylate (6.50 g, 0.04 mol) was dissolved in 65 mL of tetrahydrofuran and 65 mL of water, sodium bicarbonate (12.10 g, 0.14 mol) was added, and the mixture was stirred and cooled to 0 ° C. Add di-tert-butyl dicarbonate (8.50 g, 0.038 mol) and add to room temperature for about 24 h. The reaction mixture was concentrated with EtOAc (EtOAc)EtOAc.
  • Methyl 4-(tert-butoxycarbonyl)aminotetrahydro-2H-pyran-4-carboxylate (7.00 g, 27.02 mmol) was dissolved in 70 mL of methanol, then 40 mL water was added, then (1.63 g, 40. After reacting for 4 h, the reaction mixture was adjusted to pH 4-5 with 1N hydrochloric acid, and then extracted with ethyl acetate, washed with water and dried to give a white solid, 5.0 g, yield 75.7%.
  • Step 7 Tert-Butyl (S,Z)-4-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((
  • Step 8 Tert-Butyl (S)-4-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-(4-((tert-butoxycarbonyl)amino) Preparation of ethyl tetrahydro-2H-pyrano-pyridin-4-yl)-1,2,4-oxadiazol-5-yl)butanoate
  • Step 11 (S)-4-(3-(4-Aminotetrahydro-2H-pyran-4-yl)-1,2,4-oxadiazol-5-yl)-4-(3-(( S)-1-carboxy-2-hydroxyethyl)ureido)butyric acid
  • Step 1 Preparation of (2S,4R)-1-tert-butoxycarbonyl-2-cyano-4-(tert-butyldimethylsilyl)oxytetrahydropyrrole
  • the crude compound was purified by silica gel column chromatography (eluent: 0-5% ethyl acetate in petroleum ether). The mixture was cooled to 44.61 g of a white solid compound 1b (yield: 91.7%).
  • Tetrahydrofuran was distilled off under reduced pressure, and ethanol (200 mL) and sodium acetate (3.29 g, 40.05 mmol) were directly added thereto, and the mixture was stirred and refluxed for 2.5 hours. The reaction mixture was evaporated under reduced pressure. EtOAc was evaporated, evaporated, evaporated, evaporated, evaporated. Agent: 0-25% ethyl acetate in petroleum ether) gave 7.18 g of pale yellow solid 1d (yield: 29.2%).
  • Step 4 (2S,4R)-1-tert-Butoxycarbonyl-2-(5-((S)-1-amino-3-keto-3-(tritylamino)propyl)-1, Preparation of 2,4-oxadiazol-3-yl)-4-((tert-butyldimethylsilyl)oxy)tetrahydropyrrole
  • Step 1 (2S,4R)-1-tert-Butoxycarbonyl-2-(5-((5S,9S)-9-((R)-1-(tert-butyl)ethyl)-12,12- Dimethyl-3,7,10-trione-1,1,1-triphenyl-11-oxa-2,6,8-triaza-5-yl)-1,2,4- Preparation of Oxadiazol-3-yl)-4-((tert-butyldimethylsilyl)oxy)tetrahydropyrrole
  • Step 2 (2S,3R)-2-(3-((S)-3-Amino-1-(3-((2S,4R)-4-hydroxytetrahydropyrrole-2-yl)-1,2 Of 4-oxaoxazol-5-yl)-3-oxopropyl)ureido)-3-hydroxybutyric acid
  • Step 3 Preparation of O-(tert-butyl)-N-((4-nitrophenoxy)carbonyl)-L-threonine tert-butyl ester
  • Step 2 Preparation of (R)-(2-(tert-butoxy)-1-cyanoethyl)carbamic acid tert-butyl ester
  • the compound 4a (39 g, 149.81 mmol) was dissolved in pyridine (118.5 g, 1498.1 mmol), and the mixture was cooled in an ice bath, and trifluoroacetic anhydride (47.2 g, 224.72 mmol) was added dropwise at -5 ° C for 40 min, and the ice bath was removed.
  • the reaction mixture was stirred at room temperature for 3.5 hr, and the mixture was evaporated, evaporated, evaporated, evaporated Yield: 102.9%).
  • Step 3 Preparation of (R,Z)-(1-amino-3-(tert-butoxy)-1-(indolyl)propan-2-yl)carbamic acid tert-butyl ester
  • Step 4 tert-Butyl-((5S,Z)-9-amino-13,13-dimethyl-3,6-dione-1,1,1-triphenyl-7,12-dioxo
  • Step 5 ((R)-1-(5-((S)-1-(((9H- ⁇ -9-yl)methoxy)carbonyl)))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))
  • the compound 4d (28.0 g, 32.79 mmol) was dissolved in ethanol (420 mL), and a solution of sodium acetate (4.04 g, 49.19 mmol) in water (60 mL) was added, and the mixture was stirred and refluxed for 2 hr. It was washed several times with saturated brine, distilled under reduced pressure, and purified by silica gel column chromatography (eluent: 0-30% ethyl acetate in petroleum ether). 6.6 g of milky white solid 4e was obtained (yield: 24.1%).
  • Step 6 ((R)-1-(5-((S)-1-Amino-3-keto-3-(tritylamino)propyl)-1,2,4-oxadiazole- Preparation of tert-butyl 3-yl)-2-(tert-butoxy)ethyl)carbamate
  • Example 29 The title compound was synthesized in a similar manner to the preparation of the compound 2b in Example 29, in which the H-Thr(O t Bu)-O t Bu in Example 29 was replaced with (S)-2-keto-3-aminotetrahydrofuran. .
  • Step 8 ((R)-2-(tert-Butoxy)-1-(5-((S)-3-keto-1-(3-((S)-2-ketotetrahydrofuran-3- Preparation of tert-butyl ester of ureido)-3-(tritylamino)propyl)-1,2,4-oxadiazol-3-yl)ethyl)carbamate
  • Step 9 (S)-3-(3-((R)-1-Amino-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)-3-(3-(( Preparation of S)-2-ketotetrahydrofuran-3-yl)ureido)propanamide
  • Step 5a 1-(3-((S)-1-(3-((R))-2-(tert-butoxy)-1-((tert-butoxycarbonyl)amino)ethyl)-1,2, Preparation of methyl 4-oxadiazol-5-yl)-3-keto-3-(tritylamino)propyl)ureido)cyclopropane-1-carboxylate
  • Step 5b 1-(3-((S)-1-(3-((R))-2-(tert-butoxy)-1-((tert-butoxycarbonyl)amino)ethyl)-1,2 Of 4-oxaoxazol-5-yl)-3-keto-3-(tritylamino)propyl)ureido)cyclopropane-1-carboxylic acid
  • the compound 5a (770 mg, 1.02 mmol) was dissolved in tetrahydrofuran (6 mL), and a solution of lithium hydroxide (85 mg, 2.04 mmol) in water (1.1 mL) was added at room temperature, and the mixture was stirred and refluxed for 3 hr.
  • Step 5c 1-(3-((S)-3-Amino-1-(3-((R)-1-amino-2-hydroxyethyl)-1,2,4-oxadiazole-5- Preparation of benzyl-3-propyloxy)ureido)cyclopropane-1-carboxylic acid
  • Example 32 The title compound was synthesized in a similar manner to the preparation of compound 5 in Example 32, in which Boc-L-Ser(tBu)-OH in Example 32 was replaced with Boc-D-Ser(tBu)-OH, using Fmoc-D -Asn(Trt)-OH replaces Fmoc-L-Asn(Trt)-OH in Example 5.
  • the crude product was purified by preparative liquid to give the title compound.
  • Step 2 Preparation of methyl 1-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate
  • the compound 8a (4 g, 27.56 mmol) was dissolved in methanol (40 mL), and the mixture was cooled in an ice bath, and thionyl chloride (6.5 g, 55.13 mmol) was slowly added dropwise at 0 ° C. After the addition was completed, the mixture was heated to reflux for 4 h. The solvent was distilled off under reduced pressure to give a pale yellow oily liquid, which was taken directly to the next step.
  • Step 3 Preparation of methyl 1-((tert-butoxycarbonyl)amino)-3-(hydroxymethyl)cyclobutane-1-carboxylate
  • Step 4 Preparation of methyl 1-((tert-butoxycarbonyl)amino)-3-(tert-butyldimethylsilyloxy)cyclobutane-1-carboxylate
  • Step 5 Preparation of 1-((tert-Butoxycarbonyl)amino)-3-(tert-butyldimethylsilyloxy)cyclobutane-1-carboxylic acid
  • the compound 8d (1.6 g, 4.283 mmol) was dissolved in methanol (16 mL), and a solution of lithium hydroxide monohydrate (270 mg, 6.425 mmol) in water (3.2 mL) was added, and the mixture was stirred at room temperature for 3 h, and the solvent was evaporated under reduced pressure.
  • the ethyl ester and water were dissolved and separated, and the organic phase was extracted with water several times.
  • the aqueous phase was combined, the acid was combined with 1M citric acid solution, and then extracted with ethyl acetate.
  • the organic phase was combined, dried over anhydrous Na 2 SO 4 and evaporated. There was obtained 1.42 g of a colorless oily liquid 8e (yield: 92.2%).
  • Step 7 Preparation of tert-butyl (3-tert-butyldimethylsilylmethyl-1-cyanocyclobutyl)carbamate
  • Step 8 Preparation of (Z)-(3-tert-butyldimethylsilylmethyl-1-(N'-hydroxymethylindenyl)cyclobutyl)carbamic acid tert-butyl ester
  • Step 9 (Z)-(1-(N'-((N 2 -((9H- ⁇ -9-yl)methoxy)carbonyl)-N 4 -trityl-L-asparagine Preparation of tert-butyl ester of hydroxy)hydroxymethylindenyl)-3-(tert-butyldimethylsilylmethyl)cyclobutylcarbamate
  • Step 10 (S)-(1-(5-(1-(((9H- ⁇ -9-yl))methoxy)carbonyl)amino)-3-yl-3-yl-3-triphenylmethylamino Of propyl)-1,2,4-oxadiazol-3-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)carbamic acid tert-butyl ester preparation
  • Step 11 (S)-(1-(5-(1-Amino-3-keto-3-(tritylamino)propyl)-1,2,4-oxadiazol-3-yl) Preparation of tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)carbamate
  • Step 12 N-(((S)-1-(3-(1-((tert-Butyloxycarbonyl))amino)-3-(((tert-butyldimethylsilyl)oxy)methyl)) Butyl)-1,2,4-oxadiazol-5-yl)-3-keto-3-(tritylamino)propyl)carbamoyl)-O-(tert-butyl)-L -Preparation of threonine tert-butyl ester
  • Step 13 (2S,3R)-2-(3-((S)-3-Amino-1-(3-(1-amino-3-(hydroxymethyl)cyclobutyl)-1,2,4 -Oxadiazole-5-yl)-3-oxopropyl)ureido)-3-hydroxybutyric acid
  • Example 35 The title compound was synthesized in a similar manner to the preparation of the compound in Example 35. Wherein Fmoc-Asn(Trt)-OH in Example 8 was replaced with Fmoc-Asp(OtBu)-OH, and H-Thr (OtBu) in Example 35 was replaced with H-Ser(O t Bu)-O t Bu -OtBu.
  • Compound A The compound represented by the following formula (Compound A) was prepared according to the method disclosed in Example 2 of WO2015/033301 (PCT/IB2014/064281), and identified by hydrogen spectrum and mass spectrometry,
  • the pharmacokinetic characteristics of Compound A and the antitumor effect on the subcutaneous xenograft model of colon cancer CT26 cells were tested using the following Experimental Examples 1 and 2, and the results showed that the bioavailability (F) and inhibition of Compound A were observed.
  • the tumor rate is weaker than some of the compounds of the invention.
  • the experiment was carried out using the compound of the present invention prepared in the above examples and the compound of Example 2 ("Compound A") in WO2015/033301.
  • the oral drug was dissolved in physiological saline to prepare a clear solution of 0.5 mg/mL, and the intravenous drug was dissolved in physiological saline to prepare a 0.1 mg/mL clear solution.
  • mice Male BALB/c mice, 3 in each group, weighing 18-22 g, were provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd.
  • test mice were given an environmental adaptation period of 2 to 4 days before the experiment, and were fasted for 8-12 hours before administration, and given water for 2 hours after administration, and fed after 4 hours.
  • Acetonitrile (chromatographically pure): produced by Spectrum;
  • mice were fasted but allowed to drink water for 12 hours, and the blank plasma was taken at 0 o'clock;
  • step 2) taking the mouse in step 1), administering intragastric administration (IG) to the test compound 10 mg/kg; intravenous (IV) administering the test compound 1 mg/kg;
  • Example 1 The pharmacokinetic experimental data are shown in Table 1. The results indicate that after oral administration of the compound of the above examples, there is a certain amount of exposure and a suitable half-life in the plasma of the animal, especially Example 4, Example 5
  • Example 8 The compounds of Example 8, Example 6 and Example 22 have very good half-life, area under the curve and bioavailability, have good drug-forming properties, and have good clinical application prospects.
  • mice Female BALB/c mice, 3 in each group, weighing 18-22 g, were provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. The test mice were given an environmental adaptation period of 2 to 4 days before the experiment, and were fasted for 8-12 hours before administration, and given water for 2 hours after administration, and fed after 4 hours.
  • Compound A was prepared according to the method disclosed in Example 2 of WO 2015/033301.
  • the animals were randomly divided into groups of 6 each, and each test group was orally administered with 20 mg/kg, one day. Once, continuous administration for 14 days. The changes in body weight of the experimental animals and whether the tumor growth was inhibited or delayed were examined. Tumor diameters were measured with vernier calipers three times a week.
  • T/C T RTV / C RTV X 100% (T RTV : treatment group RTV; C RTV : solvent control group RTV).
  • TGI [1 - (the average tumor volume at the end of a treatment group - the average tumor volume at the start of administration of the treatment group) / (the average of the solvent control group at the end of treatment) Tumor volume - mean tumor volume at the start of treatment in the solvent control group)] X 100%.
  • the compound of the present invention has no effect on the body weight of the mouse colon cancer CT26 cell subcutaneous homologous tumor in the BALB/C mouse model.
  • Table 2 shows the administration of Example 4, Example 5, Example 35 and Compound A.
  • the effect of body weight indicated that the body weight of the control group and each drug-administered group gradually increased during the administration period and was well tolerated.
  • the evaluation index of drug efficacy is shown in Table 3.
  • the average tumor volume of the tumor-bearing mice in the solvent control group reached 3672 mm 3 , and the average tumor volume of the tumor-bearing mice in the other drug-administered groups was average. It is smaller than the average tumor volume of the control group, wherein the compound of Example 4 has a T/C value of 41.5% on the 15th day and a TGI value of 52.4%, indicating that it has a significant inhibitory effect on CT26 colon cancer xenografts, and the effect is obvious.
  • the average tumor volume of the tumor-bearing mice in the solvent control group reached 1524 mm 3 , and the average tumor volume of the tumor-bearing mice in each of the other test groups was smaller than the average tumor volume of the control group.
  • the compound of Example 5 had a T/C value of 39.0% at day 14 and a TGI value of 63.7%, indicating that it had a significant inhibitory effect on CT26 colon cancer xenografts.

Abstract

La présente invention se rapporte au domaine de la chimie médicale, et concerne un composé hétérocyclique faisant office d'inhibiteur de PD-L1. La présente invention concerne particulièrement un composé représenté par la formule A, ou un isomère, un sel pharmaceutiquement acceptable, un solvate ou un promédicament de celui-ci, des procédés de préparation correspondants, une composition pharmaceutique contenant ces composés, et une utilisation de ces composés ou composition dans le traitement de cancers ou de maladies infectieuses.
PCT/CN2018/084352 2017-04-26 2018-04-25 Composé hétérocyclique servant d'inhibiteur de pd-l1 WO2018196768A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710280707 2017-04-26
CN201710280707.6 2017-04-26

Publications (1)

Publication Number Publication Date
WO2018196768A1 true WO2018196768A1 (fr) 2018-11-01

Family

ID=63920214

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/084352 WO2018196768A1 (fr) 2017-04-26 2018-04-25 Composé hétérocyclique servant d'inhibiteur de pd-l1

Country Status (3)

Country Link
CN (1) CN108794422B (fr)
TW (1) TW201841896A (fr)
WO (1) WO2018196768A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020083336A1 (fr) * 2018-10-25 2020-04-30 南京圣和药业股份有限公司 Composés de 1,3,4-oxadiazole-2-cyclobutyl, procédé de préparation correspondant et utilisation associée
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11059834B2 (en) 2017-08-08 2021-07-13 Chemocentryx, Inc. Macrocyclic immunomodulators
US11130740B2 (en) 2017-04-25 2021-09-28 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1H-indene analogs and methods using same
US11135210B2 (en) 2018-02-22 2021-10-05 Chemocentryx, Inc. Indane-amines as PD-L1 antagonists
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11266643B2 (en) 2019-05-15 2022-03-08 Chemocentryx, Inc. Triaryl compounds for treatment of PD-L1 diseases
US11426364B2 (en) 2016-06-27 2022-08-30 Chemocentryx, Inc. Immunomodulator compounds
US11485708B2 (en) 2019-06-20 2022-11-01 Chemocentryx, Inc. Compounds for treatment of PD-L1 diseases
US11708326B2 (en) 2017-07-28 2023-07-25 Chemocentryx, Inc. Immunomodulator compounds
US11713307B2 (en) 2019-10-16 2023-08-01 Chemocentryx, Inc. Heteroaryl-biphenyl amides for the treatment of PD-L1 diseases
US11866429B2 (en) 2019-10-16 2024-01-09 Chemocentryx, Inc. Heteroaryl-biphenyl amines for the treatment of PD-L1 diseases
US11872217B2 (en) 2019-07-10 2024-01-16 Chemocentryx, Inc. Indanes as PD-L1 inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015033301A1 (fr) * 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited Dérivés 1,3,4-oxadiazole et 1,3,4-thiadiazole servant d'immunomodulateurs
CN105814028A (zh) * 2013-09-06 2016-07-27 奥瑞基尼探索技术有限公司 作为免疫调节剂的1，2，4-*二唑衍生物
WO2016142833A1 (fr) * 2015-03-10 2016-09-15 Aurigene Discovery Technologies Limited Composés 1,2,4-oxadiazoles et thiadiazoles utilisés comme immunomodulateurs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015033301A1 (fr) * 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited Dérivés 1,3,4-oxadiazole et 1,3,4-thiadiazole servant d'immunomodulateurs
CN105814028A (zh) * 2013-09-06 2016-07-27 奥瑞基尼探索技术有限公司 作为免疫调节剂的1，2，4-*二唑衍生物
WO2016142833A1 (fr) * 2015-03-10 2016-09-15 Aurigene Discovery Technologies Limited Composés 1,2,4-oxadiazoles et thiadiazoles utilisés comme immunomodulateurs

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11793771B2 (en) 2016-06-27 2023-10-24 Chemocentryx, Inc. Immunomodulator compounds
US11426364B2 (en) 2016-06-27 2022-08-30 Chemocentryx, Inc. Immunomodulator compounds
US11130740B2 (en) 2017-04-25 2021-09-28 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1H-indene analogs and methods using same
US11708326B2 (en) 2017-07-28 2023-07-25 Chemocentryx, Inc. Immunomodulator compounds
US11691985B2 (en) 2017-08-08 2023-07-04 Chemocentryx, Inc. Macrocyclic immunomodulators
US11059834B2 (en) 2017-08-08 2021-07-13 Chemocentryx, Inc. Macrocyclic immunomodulators
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11759458B2 (en) 2018-02-22 2023-09-19 Chemocentryx, Inc. Indane-amines as PD-L1 antagonists
US11135210B2 (en) 2018-02-22 2021-10-05 Chemocentryx, Inc. Indane-amines as PD-L1 antagonists
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
WO2020083336A1 (fr) * 2018-10-25 2020-04-30 南京圣和药业股份有限公司 Composés de 1,3,4-oxadiazole-2-cyclobutyl, procédé de préparation correspondant et utilisation associée
US11266643B2 (en) 2019-05-15 2022-03-08 Chemocentryx, Inc. Triaryl compounds for treatment of PD-L1 diseases
US11485708B2 (en) 2019-06-20 2022-11-01 Chemocentryx, Inc. Compounds for treatment of PD-L1 diseases
US11872217B2 (en) 2019-07-10 2024-01-16 Chemocentryx, Inc. Indanes as PD-L1 inhibitors
US11713307B2 (en) 2019-10-16 2023-08-01 Chemocentryx, Inc. Heteroaryl-biphenyl amides for the treatment of PD-L1 diseases
US11866429B2 (en) 2019-10-16 2024-01-09 Chemocentryx, Inc. Heteroaryl-biphenyl amines for the treatment of PD-L1 diseases

Also Published As

Publication number Publication date
CN108794422B (zh) 2022-07-01
CN108794422A (zh) 2018-11-13
TW201841896A (zh) 2018-12-01

Similar Documents

Publication Publication Date Title
WO2018196768A1 (fr) Composé hétérocyclique servant d'inhibiteur de pd-l1
CN108863963B (zh) 作为pd-l1抑制剂的杂环类化合物
JP7032583B2 (ja) アルギナーゼ活性を阻害する組成物及び方法
TWI820044B (zh) 抗體－吡咯并苯二氮呯衍生物複合體
ES2758506T3 (es) Péptidos citotóxicos y conjugados de estos
ES2657014T3 (es) Péptidos citotóxicos y conjugados de fármaco anticuerpo de los mismos
BR112016017261B1 (pt) Composto, composição farmacêutica, uso de um composto e processo para a fabricação de um composto
JP2022545542A (ja) ピラゾール化合物、その製剤並びに化合物及び／又は製剤を使用する方法
JP4927566B2 (ja) Ｐａｒ−２アゴニスト
JP4728248B2 (ja) Ｐａｒ−２アンタゴニスト
JPH05505820A (ja) 新規化合物
JP6953435B2 (ja) 二量体化合物
WO2023022231A1 (fr) Inhibiteur de liaison covalente réversible pour le traitement ou la prévention d'une infection virale
JP2017528514A (ja) 新規化合物
JP2017528514A5 (fr)
US20230382886A1 (en) Conjugated tlr7 and nod2 agonists
JP7339285B2 (ja) Ｔｌｒ７ペプチドコンジュゲート
WO2006104190A1 (fr) Agoniste de par-2
JPH08507552A (ja) 抗腫瘍剤として有用な新規な３−（置換メチル）−４−オキサ−１−アザビシクロ［３．２．０］ヘプタン−７−オン誘導体
JP2019532021A (ja) Ｃ５ａ受容体アンタゴニストとしての環状ペプチド

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: 18791829

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: 18791829

Country of ref document: EP

Kind code of ref document: A1