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WO2018041248A1 - Inhibiteur sélectif de bcl -2, sa préparation et son utilisation - Google Patents

Inhibiteur sélectif de bcl -2, sa préparation et son utilisation Download PDF

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Publication number
WO2018041248A1
WO2018041248A1 PCT/CN2017/100226 CN2017100226W WO2018041248A1 WO 2018041248 A1 WO2018041248 A1 WO 2018041248A1 CN 2017100226 W CN2017100226 W CN 2017100226W WO 2018041248 A1 WO2018041248 A1 WO 2018041248A1
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WO
WIPO (PCT)
Prior art keywords
methyl
group
pyridin
etoac
pyrrolo
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2017/100226
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English (en)
Chinese (zh)
Inventor
王虎庭
朱岩
商现星
张久庆
胡远东
何伟男
张慧
张淑远
侯登
刘琦超
彭勇
韩永信
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centaurus Biopharma Co Ltd
Original Assignee
Centaurus Biopharma Co Ltd
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
Priority claimed from CN201610800391.4A external-priority patent/CN107793412A/zh
Priority claimed from CN201710604198.8A external-priority patent/CN109293656A/zh
Application filed by Centaurus Biopharma Co Ltd filed Critical Centaurus Biopharma Co Ltd
Priority to CN201780053177.XA priority Critical patent/CN109641897B/zh
Publication of WO2018041248A1 publication Critical patent/WO2018041248A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present application relates to compounds which selectively inhibit the activity of Bcl-2 anti-apoptotic proteins, as well as to processes for the preparation of these compounds, as well as pharmaceutical compositions and uses thereof.
  • Apoptosis plays an important role in ensuring the balance between cell proliferation and extinction. Disorders in this pathway lead to a variety of diseases. Anti-apoptotic Bcl-2 protein plays an important role in regulating apoptosis, and is associated with many diseases. Overexpression of Bcl-2 protein and chemotherapy tolerance, disease progression in various cancer and immune system disorders In connection with the overall prognosis, there is a need in the therapeutic field for active compounds that inhibit the anti-apoptotic protein Bcl-2.
  • Bcl-2 protein The relationship between Bcl-2 protein and the following cancers is described in the patents WO2005049593 and WO2005024636: bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, Lymphocytic leukemia, follicular lymphoma, lymphoma of T cell or B cell origin, melanoma, granulocyte leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia , myeloma, prostate cancer, small cell lung cancer or spleen cancer and so on.
  • Inhibitors that are highly active against target proteins have been publicly reported in the field, but lack of selectivity often leads to serious side effects such as inhibition of Bcl-X L- induced thrombocytopenia (Andrew J Souers, Joel D Leverson, Erwin R) Boghaert et al. Nature Medicine, 2013, 19, 202-210).
  • Bcl-2 selective inhibitor ABT-199 is approved by the US FDA for the treatment of chronic lymphocytic leukemia.
  • the present application relates to a compound useful as an inhibitor of one or more members of the anti-apoptotic protein family, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, which is useful for the treatment and anti-apoptosis Bcl-2 protein expression-related diseases, which have higher activity against the apoptotic protein Bcl-2, and have higher selectivity (relative to the anti-apoptotic protein Bcl-X L ).
  • X and Z are each independently selected from -O-, -S-, and -NR 3 -;
  • Y is selected from N or CR 8 ;
  • R is selected from C 1-6 alkoxy, monoalkylamino, dialkylamino, C 3-8 cycloalkyl and C 3-8 heterocycloalkyl, said cycloalkyl and heterocycloalkyl Selected by 1-3 R 9 ;
  • the ground is substituted by a C 1-6 alkyl group or a C 3-8 cycloalkyl group;
  • Each R 7 is each independently selected from halogen, C 1-6 alkyl or C 3-8 cycloalkyl;
  • R 8 is selected from the group consisting of -NO 2 and -SO 2 CF 3 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 10 are each independently selected from H and C 1-6 alkyl;
  • n is independently 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2, 3, 4, 5 or 6
  • p 0, 1, 2, or 3;
  • q 0 or 1.
  • Y is CR 8 , wherein R 8 is selected from the group consisting of -NO 2 and -SO 2 CF 3 ;
  • each R 7 is independently selected from halo
  • the group of C 1-6 alkyl, and C 3-8 cycloalkyl is substituted; preferably, the heteroaryl contains 1-3 heteroatoms selected from N, O and S.
  • the aryl and heteroaryl groups are optionally substituted with a group selected from the group consisting of halogen, amino, hydroxy and C1-6 alkyl.
  • Ar is selected from a 5-10 membered heteroaryl group, which may be optionally substituted with a group selected from the group consisting of halogen, amino, hydroxy, and C1-6 alkyl;
  • the heteroaryl group contains 1-3 heteroatoms selected from N, O and S.
  • Ar is And Ar may be optionally substituted with a group selected from the group consisting of halogen, amino, hydroxy and C1-6 alkyl.
  • X and Z are each independently selected from -O- and -NR 3 -, wherein R 3 is selected from H and C 1-6 alkyl.
  • X and Z are each independently selected from -O- and -NH-.
  • R 1 and R 2 are H.
  • R 4 , R 5 , R 6 , and R 10 are each independently selected from C 1-6 alkyl.
  • each R 9 is independently selected from the group consisting of halogen, Boc, SO 2 R 10 , C 3-8 heterocycloalkyl, Bn, —(CO)(CH 2 ) m NR 4 R 5 and C 1- a 6 alkyl group, wherein R 4 , R 5 and R 10 are each independently selected from C 1-6 alkyl, m is 0, 1, 2, 3, 4, 5 or 6, preferably m is 0, 1. 2, 3, or 4, more preferably, m is 0, 1, or 2.
  • n is 0, 1, 2, 3 or 4, preferably n is 0, 1, or 2.
  • p is 0, 1, or 2.
  • the application provides a compound of formula (II), or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, as described below:
  • X is selected from the group consisting of -O-, -S-, and -NR 3 -;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from the group consisting of H and C 1-6 alkyl;
  • n is independently 0, 1, 2, 3, 4, 5 or 6;
  • X is selected from the group consisting of -O- and -NR 3 -, wherein R 3 is selected from the group consisting of H and C 1-6 alkyl.
  • X is selected from the group consisting of -O- and -NH-.
  • R 1 , R 2 and R 3 are H.
  • R 4 , R 5 and R 6 are each independently selected from C 1-6 alkyl.
  • R is selected from the group consisting of C 1-6 alkoxy, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are optionally selected.
  • a group of a halogen, an amino group, a hydroxyl group, ( O), -(CO)(CH 2 ) m NH 2 , -(CO)(CH 2 ) m OH and a C 1-6 alkyl group, m is independently 0, 1, 2, 3, 4, 5 or 6.
  • R is selected from the group consisting of C 1-6 alkoxy, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are optionally selected.
  • a group of a halogen, an amino group, a hydroxyl group, ( O), -(CO)(CH 2 ) m NH 2 , -(CO)(CH 2 ) m OH and a C 1-6 alkyl group, m is independently 0, 1, 2, 3 or 4.
  • R is selected from C1-6 alkoxy, C3-8 cycloalkyl, and C3-8 heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are optionally halogenated Or a C 1-6 alkyl group.
  • the compounds of the present application are selected from the group consisting of
  • the present application is also directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of the present application, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, of the present application.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions include, but are not limited to, oral dosage forms, parenteral dosage forms, topical dosage forms, and rectal administration dosage forms.
  • the pharmaceutical composition may be an oral tablet, a capsule, a pill, a powder, a sustained release preparation, a solution and a suspension, a sterile solution, suspension or emulsion for parenteral injection.
  • the compound is administered in a single dose, once a day. In other embodiments, the compound is administered in multiple doses more than once a day.
  • the individual to which the pharmaceutical composition is administered is a mammal. In other embodiments, the mammal is a human.
  • the application provides a compound of the present application, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, in the manufacture of a medicament for treating a disease associated with anti-apoptotic Bcl-2 protein expression the use of.
  • the application provides a compound of the present application, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, for use in the treatment of a disease associated with anti-apoptotic Bcl-2 protein expression. drug.
  • the application provides a method of treating a disease associated with anti-apoptotic Bcl-2 protein expression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present application, which is pharmaceutically acceptable Salt, solvate, polymorph or prodrug or combination thereof.
  • the present application is directed to a method of preparing the above compounds of the present application, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.
  • optionally substituted alkyl means “unsubstituted alkyl” or "substituted alkyl”.
  • the optionally substituted group may be unsubstituted (for example: -CH 2 CH 3 ), fully substituted (for example: -CF 2 CF 3 ), monosubstituted (for example: -CH 2 CH 2 F) or Any level between single and complete substitutions (eg, -CH 2 CHF 2 , -CF 2 CH 3 , -CFHCHF 2 , etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.
  • Standard chemical terms can be found in references (including Carey and Sundberg, Advanced Organic Chemistry, Fourth Edition, Volume A (2000) and Volume B (2001), Plenum Press, New York). definition. Unless otherwise stated, conventional methods within the skill of the art, such as mass spectrometry, nuclear magnetic, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy, and pharmacological methods are employed. Unless specifically defined, the terms and experimental procedures and techniques herein for analytical chemistry, organic synthetic chemistry, and pharmaceutical and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients.
  • the manufacturer's instructions for use of the kit can be utilized, or the reaction can be carried out and purified according to methods well known in the art or as described in the present application.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification.
  • the group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • substituent -CH 2 O- is equivalent to -OCH 2 -.
  • group refers to a specific moiety or functional group of a molecule. Chemical groups are often recognized as chemical entities embedded or attached to a molecule.
  • C 1 -C 6 alkyl group describes an alkyl group, as defined below, having a total of from 1 to 6 carbon atoms.
  • the total number of carbon atoms indicated by the abbreviations does not include the carbon atoms on the possible substituents.
  • heteroatom refers to an atom other than carbon and hydrogen.
  • the heteroatoms are independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but are not limited to these atoms.
  • the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other.
  • thick or “fused ring” as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
  • spiro or "spiro” as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
  • alkyl refers to an optionally substituted straight or optionally substituted branched monovalent saturated hydrocarbon having from 1 to 12 a carbon atom, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, linked to other moieties of the molecule by a single bond, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-decyl, n-decyl and the like.
  • alkoxy refers to a -ORa group, wherein Ra is alkyl as defined above, and may, for example, be -OC 1-6 alkyl.
  • alkoxy groups include methoxy, ethoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • cycloalkyl refers to a stable, monovalent, non-aromatic monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms, and may include fused rings, spiro rings or bridges.
  • a ring system comprising 3-15, such as 3-10, 3-8 or 3-6 ring-forming carbon atoms, either saturated or unsaturated, attached to the rest of the molecule by a single bond.
  • cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexanone, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydro Mercapto, 1,2,3,4-tetrahydronaphthyl, 5,6,7,8-tetrahydronaphthyl, 8,9-dihydro-7H-benzocycloheptene-6-yl, 6,7 , 8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, indenyl, bicyclo[2.2.1]g , 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bi
  • the heterocyclic group of the present application includes preferably 3 to 8 carbon atoms, more preferably a cyclopentyl group, a cyclohexyl group, a cyclohexanone group or a cycloheptyl group.
  • heterocyclyl refers to a stable 3-18 membered monovalent non-aromatic ring, including 2-12 carbon atoms, 1 -6 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • a heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system which may contain a fused ring, spiro ring or bridged ring system, and nitrogen, carbon or sulfur on the heterocyclic group may be selective.
  • the nitrogen atom is selectively quaternized, and the heterocyclic group may be partially or fully saturated.
  • the heterocyclic group may be bonded to the remainder of the molecule through a single bond through a carbon atom or a hetero atom on the ring.
  • the heterocyclic group containing a fused ring may contain one or more aromatic or heteroaromatic rings as long as it is attached to the remainder of the molecule to an atom on the non-aromatic ring.
  • the heterocyclic group of the present application is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring comprising from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-
  • the 8-membered monovalent non-aromatic monocyclic ring contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • heterocyclic groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, indanyl, dioxopentyl, 1,1 -dioxy-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindenyl, octahydroisodecyl, oxazinyl, Oxazolidinyl, 1-oxo-thiomorpholinyl, 2-oxopyrazinyl, 2-oxopyridinyl, 2-oxopyrrolidinyl, phthalimido, piperazinyl, piperidinyl, 4-piperidinone, pyranyl, pyrazolyl, pyrrolidinyl, quinazinyl, quinuclidinyl,
  • aromatic means a ring portion of a ring or rings of a plane having 4n+2 An electronic delocalized electronic conjugate system in which n is an integer.
  • the aromatic ring may be formed of 5, 6, 7, 8, 9, or 10 or more atoms.
  • the aromatic ring may be optionally substituted and may be a monocyclic or fused ring polycyclic ring.
  • aromatic ring groups means hydrocarbon.
  • an aromatic ring group can be a monocyclic, bicyclic, tricyclic or tetracyclic system which may comprise a fused ring or bridged ring system.
  • An aryl carbon atom can be attached to the other part of the molecule by a single bond.
  • aryl groups include phenyl, naphthyl, anthracenyl, phenanthryl, anthracenyl, 2-benzoxazolidinone, 2H-1,4-benzoxazole-3(4H)-one -7-based and so on.
  • the aryl group is preferably a C 6 - C 10 aryl group, more preferably a phenyl group.
  • heteroaryl refers to a 5-16 membered ring system containing, for example, 1 to 15 carbon atoms, 1 to 10 carbon atoms, and 1 to 4 options. a hetero atom from nitrogen, oxygen and sulfur, at least one aromatic ring. Unless otherwise specified, a heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system which may contain a fused ring or bridged ring system as long as the point of attachment to the rest of the molecule is an aromatic ring atom.
  • the nitrogen, carbon and sulfur atoms on the heteroaromatic ring can be selectively oxidized, and the nitrogen atom can be selectively quaternized.
  • the heteroaryl group is preferably a stable 4-11 membered monoaromatic ring comprising from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, more preferably a stable 5-8 membered single.
  • An aromatic ring comprising from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heteroaryl group is preferably a 5-8 membered heteroaryl group containing from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, more preferably pyridyl, pyrimidinyl, thiazolyl, oxo Pyridyl, 1H-pyridin-2-one-4-yl or thienyl.
  • polymorph or "polymorph (phenomenon)" as used herein, refers to a compound of the present application having a plurality of lattice forms. Some of the compounds of the present application may have more than one crystalline form, and the present application covers all polymorphic forms or mixtures thereof.
  • the olefinic double bonds contained in the compounds of the present application include the E and Z isomers.
  • the compounds of the present application may contain asymmetric centers. These asymmetric centers can be independently R or S configurations. Some of the compounds of the present application may also exhibit cis-trans isomerism, as will be apparent to those skilled in the art. It will be understood that the compounds of the present application include their individual geometric isomers and stereoisomers, as well as mixtures thereof. Includes a racemic mixture. These isomers may be separated from their mixtures by carrying out or modifying known methods, such as chromatographic techniques and recrystallization techniques, or they may be prepared separately from the appropriate isomers of their intermediates.
  • pharmaceutically acceptable salt includes both acid addition salts and base salts.
  • “Pharmaceutically acceptable acid addition” refers to those salts which retain the biological potency and properties of the free base of the compound, are not biologically or otherwise undesirable, and are formed with inorganic or organic acids.
  • “Pharmaceutically acceptable base addition” refers to those salts which retain the biological effectiveness and properties of the free acid of the compound, which are not biologically or otherwise undesirable. These salts are prepared by reacting a free acid with an inorganic or organic base.
  • solvate refers to a combination of one or more of the molecules of the compound of the present application and one or more solvent molecules.
  • the solvent may be water, in which case the solvate is a hydrate. It may also be an organic solvent.
  • the compounds of the present application can be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the present application are also included within the scope of the present application.
  • prodrugs of the compounds of the present application.
  • Prodrug means a compound of the present application which can be converted to a biologically active compound under physiological conditions or solvation.
  • prodrug refers to a pharmaceutically acceptable metabolic precursor of a compound of the present application which may be inactive when administered to a subject in need thereof, but which will be converted in vivo to an active compound of the present application.
  • Prodrugs are usually converted in vivo, for example, by hydrolysis in the blood, to rapidly convert the parent compound for the application. Prodrugs often have advantages in solubility, tissue compatibility, or extended release in mammalian organisms.
  • composition refers to a preparation in which a compound of the present application is mixed with a medium which is generally accepted in the art for delivering a biologically active compound to a mammal such as a human.
  • This medium contains all pharmaceutically acceptable carriers.
  • the term "acceptable" in connection with a formulation, composition or ingredient means that there is no sustained deleterious effect on the overall health of the subject.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, adjuvants, carriers, excipients, auxiliaries, deodorants, diluents, preservatives, which can be used in humans and domesticated animals, which have been approved by the relevant government administration. Dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers.
  • subject refers to an individual, including a mammal, and a non-mammal, having a disease, disorder, or condition.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals For example, rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs.
  • non-human mammals include, but are not limited to, birds and fish, and the like.
  • the mammal is a human.
  • treating refers to the treatment of a disease or condition associated with a mammal, particularly a human, including
  • disease and condition as used herein may be substituted for each other or may mean different meanings, since certain specific diseases or conditions have no known causative factors (so the cause of the disease is not known), so it cannot be considered as The disease can only be seen as an undesired condition or syndrome that has more or less specific symptoms that have been confirmed by clinical researchers.
  • an "effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
  • an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.
  • a compound of the present application can be administered by forming a suitable pharmaceutical composition with one or more pharmaceutically acceptable carriers.
  • the pharmaceutical compositions of the present application can be formulated into solid, semi-solid, liquid or gaseous forms such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. .
  • compositions of the present application can be prepared by using methods well known in the pharmacy.
  • a pharmaceutical composition for administration by injection can be prepared by combining a compound of the present application with sterile, distilled water to form a solution.
  • Surfactants can be added to help form a homogeneous solution or suspension.
  • the actual methods of preparing these dosage forms are known or apparent to those skilled in the art.
  • Typical routes for administering these pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal and intranasal.
  • suitable dosage forms for oral administration include capsules, tablets, granules, and syrups.
  • the compounds of the present application included in these dosage forms may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous solvents; oil-drop type in water, drip-in-water emulsions, and the like.
  • the dosage forms mentioned above may be prepared from the active compound and one or more carriers by conventional methods of administration. The particular route of administration and dosage form will depend on the physical/chemical characteristics of the compound itself and the severity of the condition being treated, and can be conventionally determined by those skilled in the art.
  • the functional groups of the intermediate compounds may need to be Suitable protecting group protection.
  • These functional groups include a hydroxyl group, an amino group, a thiol group, and a carboxyl group.
  • Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (eg, tert-butylmethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, Benzyl and the like.
  • Suitable amino, sulfhydryl and hydrazine protecting groups include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable protecting groups for the indenyl group include -C(O)-R" (R" represents an alkyl, aryl or arylalkyl group), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or arylalkyl esters. The protecting group can be added or removed by standard techniques known to those skilled in the art.
  • the compounds described herein can be prepared following the routes described in Scheme 1 or Scheme 2.
  • Each of the products obtained by the reaction in Scheme 1 or Scheme 2 can be obtained by conventional separation techniques including, but not limited to, filtration, distillation, crystallization, chromatographic separation, and the like.
  • the starting materials can be purchased by themselves or purchased from commercial establishments such as, but not limited to, Adrich or Sigma. These materials can be characterized using conventional means such as physical constants and spectral data.
  • the compounds described herein can be synthesized using synthetic methods to obtain a single isomer or a mixture of isomers.
  • the temperature is Celsius.
  • the reagents were purchased from commercial suppliers such as Sinopharm Chemical Reagent Beijing Co., Ltd., Alfa Aesar, or Beijing Belling Technology Co., Ltd., and these reagents can be used directly without further purification unless otherwise stated.
  • reaction vessel was fitted with a rubber septum to add substrate and reagents via a syringe; glassware was dried and / or heat dry.
  • Nuclear magnetic data ( 1 H NMR) was run at 400 MHz using a Varian device.
  • the solvent used for the nuclear magnetic data is CDCl 3 , CD 3 OD, D 2 O, DMSO-d6, etc., based on tetramethylsilane (0.00 ppm) or based on residual solvent (CDCl 3 : 7.26 ppm; CD 3 OD: 3.31 ppm; D 2 O: 4.79 ppm; d6-DMSO: 2.50 ppm).
  • Step B (1-(Triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid dimethyl ester
  • the dimethyl (1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)borate obtained in the previous step was dissolved in tetrahydrofuran (50 mL) at room temperature and then cooled. At 0 ° C, aqueous sodium hydroxide (15 mL, 0.015 mol) and a 30% aqueous solution of hydrogen peroxide (3 mL) were added and stirring was continued at 0 ° C for 1 hour.
  • Step E 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine- 1(2H)-tert-butyl formate
  • Step F 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoic acid ester
  • Step G 4,4-Dimethyl-2-oxocyclohexane-1-carboxylic acid methyl ester
  • Step H Methyl 4,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-1-ene-1-carboxylate
  • Step I Methyl 4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylate
  • Methyl 4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-diphenyl]-2-carboxylate (650 mg, 2.3 mmol) was dissolved in tetrahydrofuran (20 mL), a lithium borohydride solution (3.5 mL, 14 mmol) was added, and then methanol (2.4 mL) was slowly added dropwise. After the dropwise addition was completed, the reaction solution was stirred at room temperature overnight. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) ).
  • Step K 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3, Methyl 4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoate
  • Step L 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3, 4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid
  • Step N 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3, 4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide
  • Step B 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3, 4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl-N-((4- ((2-methoxyethyl)amino)-3-nitrophenyl)sulfonyl)benzamide
  • Step A 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester
  • Step B Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperidin-4-yl)benzoate
  • Step C 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3, Methyl 4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-piperidin-4-yl)benzoate
  • Step D 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3, 4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperidin-4-yl)benzoic acid
  • Step E 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3, 4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-piperidin-4-yl)-N-((3-nitro-4-((( Tetrahydro-2H-pyran-4-yl)methyl)amino)sulfonyl)benzamide
  • Step B 4-(3-((6-Aminopyridin-3-yl)oxy)-4-(methoxycarbonyl)phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
  • Step C Methyl 2-((6-aminopyridin-3-yl)oxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoate
  • Step D 2-((6-Aminopyridin-3-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro) -[1,1'-Diphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid methyl ester
  • Step E 2-((6-Aminopyridin-3-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro) -[1,1'-diphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid
  • Step F 2-((6-Aminopyridin-3-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro) -[1,1'-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-((3-nitro-4-(( (tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide
  • Step B 4-(3-(2-Fluorophenoxy)-4-(methoxycarbonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
  • Step D 4-(1-((4'-Chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-diphenyl]-2-yl)) Methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-fluorophenoxy)benzoate
  • Step E 4-(1-((4'-Chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-diphenyl]-2-yl)) 1,1,2,3,6-tetrahydropyridin-4-yl)-2-(2-fluorophenoxy)benzoic acid
  • Step F 4-(1-((4'-Chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-diphenyl]-2-yl)) -1,2,3,6-tetrahydropyridin-4-yl)-2-(2-fluorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-) Pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide
  • Tetrahydro-4H-pyran-4-one (20 g, 200 mmol) and chloroacetonitrile (10.56 g, 140 mmol) were dissolved in tert-butanol (20 mL) and allowed to react at room temperature for 30 min. Then, a suspension of potassium tert-butoxide (24.68 g, 220 mmol) suspended in tert-butanol (200 mL) was slowly added over a period of 30 minutes, and the reaction was continued at room temperature for 16 hours after the addition. The reaction was then diluted with water (2OmL) and EtOAc evaporated. The organic layer was extracted with EtOAc (EtOAc m.
  • Step B 2-(4-Fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile
  • Step D 4-((4-Fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide
  • Step E 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3, 4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-((4 -((4-fluorotetrahydro-2H-pyran-4-yl)methoxy-3-nitrophenyl)sulfonyl)benzamide
  • Step D 4-(((4-Fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide
  • Step E 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3, 4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-((4 -(((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)amino-3-nitrophenyl)sulfonyl)benzamide
  • Step A 4-(3-(3-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(methoxycarbonyl)phenyl)-5,6-dihydro Pyridine-1(2H)-carboxylic acid tert-butyl ester
  • Step B 2-(3-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzene Methyl formate
  • Step C 4-(1-((2-(4-Chlorophenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridine Methyl 4-(4-)-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoate
  • Step D 4-(1-((2-(4-Chlorophenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridine 4-yl)-2-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid
  • Step E 4-(1-((2-(4-Chlorophenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridine 4-yl)-2-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(3-nitro-4-((tetrahydro-2H-) Pyran-4-yl)methylamino)phenylsulfonyl)benzamide
  • Step B (1-(Triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid dimethyl ester
  • Step E 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine- 1(2H)-tert-butyl formate
  • Step F 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoic acid ester
  • Step G 4,4-Dimethyl-2-oxocyclohexane-1-carboxylic acid methyl ester
  • Step H Methyl 4,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-1-ene-1-carboxylate
  • Step I Methyl 4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylate
  • Methyl 4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-diphenyl]-2-carboxylate (650 mg) was dissolved in tetrahydrofuran (20 mL) A 4 M lithium borohydride solution (3.5 mL) was added, and then methanol (2.4 mL) was slowly added dropwise. After the addition is completed, the reaction solution Stir at room temperature overnight. The reaction was quenched with EtOAc (EtOAc) (EtOAc) .
  • Step K 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3, Methyl 4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoate
  • Step L 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3, 4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid
  • Step M bis(2-fluorophenyl)iodonium tetrafluoroborate
  • reaction mixture was directly added to a short column of 200-300 mesh silica gel (60 g), and the residue was washed with dichloromethane (600 mL) and washed with dichloromethane/methanol (20/1, 1.2 L). After the solvent was removed by concentration, the mixture was evaporated, mjjjjjj
  • Step O 4-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide
  • Step P 4-((tetrahydro-2H-pyran-4-yl)methylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide
  • Step D 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohex-1-enyl)methyl)-2,3,6-tetrahydropyridin-4-yl)-N-(4-(2-morpholinoethyl)-3-nitrophenylsulfonyl) Benzoylamide
  • Step A 6-Chloropyridyl-3-methanesulfonyl chloride
  • 6-Chloropyridin-3-amine (1.77 g) was dissolved in concentrated hydrochloric acid (14 mL) and cooled to -5.
  • thionyl chloride (4.5 mL) was slowly added dropwise, keeping the temperature below 7 ° C. After the completion of the dropwise addition, the temperature was returned to room temperature, and cuprous chloride (70 mg) was added thereto, and the mixture was cooled to -5. At ° C, the previously prepared diazonium salt solution was added, stirred for 30 minutes, and filtered. The filter cake was dissolved in ethyl acetate and dried over anhydrous sodium sulfate.
  • 6-Chloropyridinyl-3-methanesulfonyl chloride (1 g) was added to aqueous ammonia (9 mL), and stirred at room temperature for 3 hr. Then, it was poured into water, extracted with ethyl acetate, and the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the product (370 mg).
  • Step D 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohex-1-enyl)methyl)-2,3,6,6-tetrahydropyridin-4-yl)-N-(6-((tetrahydro-2H-pyran-4-yl)methyl) Amino)pyridin-3-ylsulfonyl)benzamide
  • Step A 4-(3-Amino-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
  • Step B 4-(4-(methoxycarbonyl)-3-((1-(triisopropylsilyl)-1H-pyrrole[2,3-b]pyridin-5-yl)amino)benzene -3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
  • Step C Methyl-2-(1H-pyrrolo[2,3-b]pyridin-5-ylamino)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoic acid ester
  • Step D Methyl-2-(1H-pyrrole[2,3-b]pyridin-5-ylamino)-4-(1-((2-(4-chlorophenyl)-4,4-di) Methylcyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoate
  • Step E 2-(1H-pyrrolid[2,3-b]pyridin-5-ylamino)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) ring Hexyl-1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid
  • Step F 2-(1H-pyrrolo[2,3-b]pyridin-5-yl)amino)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4) -yl)methylamino)benzenesulfonyl)benzamide
  • Step A 4-(2-morpholinethylamine)-3-nitrobenzenesulfonamide
  • Step B 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(2-morpholinethylamine)-3-nitrobenzenesulfonate Acyl)benzamide
  • Step A 4-(2-morpholinopropylamine)-3-nitrobenzenesulfonamide
  • Step B 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(2-morpholinylpropyl)-3-nitrobenzenesulfonate Acyl)benzamide
  • Step A (4-Chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
  • Step B Methyl 2-(4-chloro-2-fluorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate
  • Methyl 5,5-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate (5.5 g), (4-chloro-2-fluorophenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.8 g), potassium phosphate (7 g) and Pd(dppf)Cl 2 (1.2 g) were added to ethylene A mixed solvent of glyceryl ether (100 mL) and water (20 mL) was stirred at 70 ° C under N 2 overnight.
  • Methyl 2-(4-chloro-2-fluorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate (2.4 g) was dissolved in fresh dry tetrahydrofuran (100 mL) and cooled to 0 ° C A 4 M solution of lithium borohydride in tetrahydrofuran (16 mL) was added, and methanol (3.8 mL) was added dropwise, and the mixture was stirred at room temperature overnight. Then, the reaction was quenched with dilute aqueous EtOAc (EtOAc)EtOAc.
  • EtOAc dilute aqueous EtOAc
  • Step D 2-(4-Chloro-2-fluorophenyl)-4,4-dimethylcyclohex-1-enecarboxaldehyde
  • Step E 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4) -Methyl dimethylcyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoate
  • Step F 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4) -Dimethylcyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid
  • Step H 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4) -Dimethylcyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(3-nitro-4-((tetrahydro-2H-) Pyran-4-yl)methylamino)phenylsulfonyl)benzamide
  • Lithium tetrahydrogen aluminum 34 mg was dispersed in tetrahydrofuran (20 mL), and 1,4-dioxaspiro[4.5]decane-8-carbonitrile (100 mg) was added at 0 ° C, refluxed for 2 hr, and quenched with water. . The mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate.
  • Step B 4-(1,4-Dioxaspiro[4.5]decane-8-methylamine)-3-nitrobenzenesulfonamide
  • Step C N-(4-(1,4-Dioxaspiro[4.5]decane-8-ylmethylamine)-3-nitrophenylsulfonyl)-2-(1H-pyrrolo[2, 3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)-1 ,2,3,6-tetrahydropyridin-4-yl)benzamide
  • Tetrahydro-4H-pyran-4-one (20 g) and chloroacetonitrile (10.56 g) were dissolved in tert-butanol (20 mL) and allowed to react at room temperature for 30 minutes. Then, a suspension of potassium tert-butoxide (24.68 g) suspended in tert-butanol (200 mL) was slowly added over a period of 30 minutes, and the reaction was continued at room temperature for 16 hours after the addition. The reaction was then diluted with water (2OmL) and EtOAc evaporated. The mixture was extracted with EtOAc (EtOAc m.)
  • Step B 2-(4-Fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile
  • Step G 4-(((4-Fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide
  • Step H 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4) -Dimethylcyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluorotetrahydro-2H-pyran) 4-yl)methylamino)-3-nitrophenylsulfonyl)benzamide
  • Step A N-(4-(1,4-Dioxaspiro[4.5]decane-8-ylmethylamino)-3-nitrophenylsulfonyl)-2-(1H-pyrrolo[2 ,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4-dimethylcyclohex-1-enyl)) Methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide
  • Step H (R)-N-(4-((1,4-dioxan-2-yl)methylamino)-3-nitrophenylsulfonyl)-2-(1H-pyrrolo[2 ,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)- 1,2,3,6-tetrahydropyridin-4-yl)benzamide
  • Step A (R)-N-(4-((1,4-Dioxa-2-yl)methylamino)-3-nitrophenylsulfonyl)-2-(1H-pyrrolo[2 ,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4-dimethylcyclohex-1-enyl)) Methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide
  • Step H (S)-N-(4-((1,4-Diethoxyethane-2-yl)methylamine)-3-nitrobenzenesulfonyl)-2-(1H-pyrrolo[2 ,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)- 1,2,3,6-tetrahydropyridin-4-yl)benzamide
  • Step A (S)-N-(4-((1,4-Dioxa-2-yl)methylamino)-3-nitrophenylsulfonyl)-2-(1H-pyrrolo[2 ,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4-dimethylcyclohex-1-enyl)) Methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide
  • Step B 2-((1H-pyrrole[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3, 4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(3 -nitro-4-((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)phenyl)sulfonyl)benzamide
  • Step A 1-oxa-6-azaspiro[2,5]octane-6-carboxylic acid tert-butyl ester
  • Step B tert-Butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate
  • Step C 4-Fluoro-4-((2-nitro-4-sulfonylaminophenol)methyl)piperidine-1-carboxylic acid tert-butyl ester
  • Step D tert-Butyl-4-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-) 4-chlorophenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)sulfonamide)- 2-nitrophenoxy)methyl)-4-fluoropiperidine-1-carboxylate
  • Step A 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluoropiperidin-4-yl)methoxy) -3-nitrobenzenesulfonyl)benzamide hydrochloride
  • Step A 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluoro-1-(methylsulfonyl))piperidine- 4-yl)methoxy)-3-nitrobenzenesulfonyl)benzamide
  • Step A 4-Fluoro-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester
  • tert-Butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (10 g) was dissolved in dichloromethane (200 mL) and triethylamine (9 mL). The reaction solution was cooled to 0 ° C, and dichloromethane (3 mL) of methanesulfonyl chloride (3.7 mL) was slowly added dropwise. After the dropwise addition, the mixture was returned to room temperature and allowed to react overnight. Then, it was poured into water, extracted with dichloromethane, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate.
  • Step B 4-(Aminomethyl)-4-fluoropyridine-1-carboxylic acid tert-butyl ester
  • Step C 4-Fluoro-4-(((2-nitro-4-sulfonylaminophenyl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester
  • Step D 4-((4-Fluoropiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide hydrochloride
  • Step E 4-((4-Fluoro-1-(3-epoxyheterobutane)piperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide
  • Step F 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluoro-1-(3-heopoxycyclobutane)) Piperidin-4-yl)methylamino)-3-nitrobenzenesulfonyl)benzamide
  • Step A 4-((4-Fluoro-1-methylpiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide
  • Step B 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluoro-1-methylpiperidin-4-yl) )methylamino)-3-nitrobenzenesulfonyl)benzamide
  • Step B 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluoro-1-(tetrahydro-2H-pyran)) 4-yl)piperidin-4-yl)methylamino)-3-nitrobenzenesulfonyl)benzamide
  • Step A tert-Butyl-4-((2-nitro-4-sulfonamide)methyl)piperidine-1-carboxylate
  • Step C 4-((1-Methylpiperidin-4-yl)methylamine)-3-nitrobenzenesulfonamide
  • Step D 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((1-methylpiperidin-4-yl)methylamino) )-3-nitrophenylsulfonyl)benzamide
  • Step B 2-(Hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester
  • Step C 2-(Aminomethyl)morpholine-4-carboxylic acid tert-butyl ester
  • Step D 2-(((2-Nitro-4-sulfonylaminophenyl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester
  • Step E tert-Butyl-2-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-) 4-chlorophenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)sulfonamide)- 2-nitroaniline)methyl)morpholine-4-carboxylate
  • Step A 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(morpholin-2-ylmethylamine)-3-nitro Benzenesulfonyl)benzamide
  • Step A 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-(2-(dimethylamino))acetyl)) Morpholin-2-yl)methylamine)-3-nitrobenzenesulfonyl)benzamide
  • Step A 4-Fluoro-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester
  • tert-Butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (10 g) was dissolved in dichloromethane (200 mL) and triethylamine (9 mL). The reaction solution was cooled to 0 ° C, and dichloromethane (3 mL) of methanesulfonyl chloride (3.7 mL) was slowly added dropwise. After the dropwise addition, the mixture was returned to room temperature and allowed to react overnight. Then, it was poured into water, extracted with dichloromethane, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate.
  • Step B 4-(Aminomethyl)-4-fluoropyridine-1-carboxylic acid tert-butyl ester
  • Step C 4-Fluoro-4-(((2-nitro-4-sulfonylaminophenyl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester
  • Step D 4-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorobenzene) ))-4-dimethylcyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)sulfamoyl)-2-nitrobenzene Base amino)methyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester
  • Step A 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohex-1-enyl)methyl)-1,2,3-tetrahydropyridin-4-yl)-N-(4-((4-fluoropiperidin-4-yl)methylamino)-3 -nitrophenylsulfonyl)benzamide hydrochloride
  • Step B 4-(((4-Benzylmorpholin-2-yl)methyl)amino)-3-nitrobenzenesulfonylamide
  • Step C 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-((4-benzyl-pyrimidin-2-yl)methylamino)-3 -nitrophenylsulfonyl)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)-1,2,3 ,6-tetrahydropyridin-4-yl)benzamide
  • Step A 3-Nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)benzenesulfonamide
  • Step B 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(3-nitro-4-((4-(oxetane-)- 3-yl)morpholin-2-yl)methylamino)benzenesulfonyl)benzamide
  • Step A 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluoro-1-(methylsulfonyl))piperidyl) Pyridin-4-yl)methylamino)-3-nitrophenylsulfonyl)benzamide
  • the methane is diluted, washed with water, washed with water, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated, and the residue is separated by a preparative thin layer, and the solvent is methylene chloride/methanol (15/1) to obtain the target product ( 22mg).
  • Step B 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(3-nitro-4-((4-(tetrahydro-2H-pyridyl)) Methyl-4-yl)morpholin-2-yl)methylamino)benzenesulfonyl)benzamide
  • Step A 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-2'-fluoro-5,5-di) Methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N -((3-Nitro-4-((4-(tetrahydro-2H-pyran-4-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)benzamide
  • Step A 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-2'-fluoro-5,5-di) Methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N -((3-Nitro-4-((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)benzamide
  • Step A 2-(1H-pyrrole[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4- Dimethylcyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluoro-1-(3-heterooxy)) Cyclobutane)piperidin-4-yl)methylamino)-3-nitrobenzenesulfonyl)benzamide
  • Step A 2-(1H-pyrrole[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4- Dimethylcyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluoro-1-(tetrahydro-2H) -pyran-4-yl)piperidin-4-yl)methylamino)-3-nitrobenzenesulfonyl)benzamide
  • a protein polarization screening method for Bcl-2 and Bcl-xl was established by fluorescence polarization method.
  • the basic principle is that the small molecule compound competes with the fluorophore FITC-labeled short peptide (FITC-Bim) for its binding site to Bcl2 or Bcl-xl.
  • FITC-Bim fluorophore FITC-labeled short peptide
  • the fluorescent substance FITC is irradiated by a single plane of blue-polarized light (485 nm), and the absorbed light energy jumps into the excited state, then returns to the ground state, and emits a single plane.
  • Polarized fluorescence (525 nm).
  • FITC-Bim fails to bind to the macromolecular substance Bcl-2 or Bcl-xl, the small molecule rotates or flips faster, and the emitted light will be depolarized relative to the plane of the excitation light. That is to say, when the compound is competitively bound to Bcl-2 or Bcl-xl, FITC-Bim will exist in a free state and its polarization value will decrease. Therefore, the ability of the compound to bind to Bcl-2 or Bcl-xl can be reflected by the change in the polarization value.
  • test mixture was then incubated at 23 ° C for 30 minutes with shaking, after which 4 ⁇ L of reaction buffer containing 8 nM FITC-Bim was added and incubation was continued for 60 minutes at room temperature.
  • the polarization value was measured by EnVision under Ex485/Em530. Prism data analysis software by processing the data obtained and the IC 50 value of the compound.
  • the detection reagent establishes a screening method for suspension cell proliferation inhibition.
  • the culture medium is cultured at 37 ° C, 95% air and 5% CO 2 , and cultured in a 25 cm 2 or 75 cm 2 plastic tissue culture flask. In the middle, subculture is carried out 2 to 3 times a week.
  • the cells were seeded at a density of 8 ⁇ 10 3 cells/well (DOHH2) and 6 ⁇ 10 3 cells/well (Molt-4) in a 96-well cell culture plate. Medium, 195 ⁇ L/well, and cultured at 37 ° C, 95% air and 5% CO 2 .
  • the compound is added to the culture plate inoculated with the cells.
  • the final concentration of DMSO in the cell culture medium was 0.1%, and the final concentration of the test compound was 0.3 nM to 10 ⁇ M.
  • the above cells were incubated at 37 ° C for 3 days.
  • Example 7 0.64 212.4 Example 8 1.90 329.5 Example 16 0.62 109.1 Example 18 0.78 140.9 Example 20 0.83 64.2 Example 21 0.60 97.2 Example 22 1.35 80.7 Example 23 1.76 49.4 Example 28 0.51 69.9 Example 29 1.59 32.2 Example 30 0.76 27.4 Example 34 0.36 50.2 Example 38 0.67 40.9 Example 40 1.34 97.0 Example 41 1.21 65.2 Example 42 0.92 48.6 Example 43 0.65 149.7 Example 44 1.57 63.1
  • Example 38 98.8 >1000 Not tested
  • Example 40 97.0 >1000 Not tested

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Abstract

L'invention concerne un composé représenté par la formule (I). Le composé inhibe sélectivement une activité de protéine anti-apoptotique de Bcl -2, et peut traiter une maladie auto-immune ou un cancer.
PCT/CN2017/100226 2016-09-01 2017-09-01 Inhibiteur sélectif de bcl -2, sa préparation et son utilisation Ceased WO2018041248A1 (fr)

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WO2019210828A1 (fr) 2018-04-29 2019-11-07 Beigene, Ltd. Inhibiteurs de bcl-2
CN111747949A (zh) * 2019-03-29 2020-10-09 首药控股(北京)股份有限公司 Bcl-2选择性抑制剂的制备方法
EP3565815A4 (fr) * 2017-01-07 2020-10-28 Shanghai Fochon Pharmaceutical Co., Ltd. Composés en tant qu'agents induisant l'apoptose sélective de bcl-2
US11091478B2 (en) 2017-04-18 2021-08-17 Fochon Pharmaceutical Co., Ltd. Apoptosis-inducing agents
JP2022506442A (ja) * 2018-10-29 2022-01-17 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド トリフルオロメチル置換スルファミド系選択的ｂｃｌ－２阻害剤
CN114008035A (zh) * 2019-06-14 2022-02-01 北京盛诺基医药科技股份有限公司 一种shp2磷酸酶变构抑制剂
WO2022028353A1 (fr) 2020-08-06 2022-02-10 北京诺诚健华医药科技有限公司 Composé hétérocyclique en tant qu'inhibiteur de bcl-2
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3565815A4 (fr) * 2017-01-07 2020-10-28 Shanghai Fochon Pharmaceutical Co., Ltd. Composés en tant qu'agents induisant l'apoptose sélective de bcl-2
US11053239B2 (en) 2017-01-07 2021-07-06 Fochon Pharmaceuticals, Ltd. Compounds as BLC-2-selective apoptosis-inducing agents
US11091478B2 (en) 2017-04-18 2021-08-17 Fochon Pharmaceutical Co., Ltd. Apoptosis-inducing agents
US12312349B2 (en) 2017-04-18 2025-05-27 Fochon Pharmaceuticals, Ltd. Apoptosis-inducing agents
WO2019210828A1 (fr) 2018-04-29 2019-11-07 Beigene, Ltd. Inhibiteurs de bcl-2
JP2022506442A (ja) * 2018-10-29 2022-01-17 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド トリフルオロメチル置換スルファミド系選択的ｂｃｌ－２阻害剤
JP7473545B2 (ja) 2018-10-29 2024-04-23 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド トリフルオロメチル置換スルファミド系選択的ｂｃｌ－２阻害剤
CN111747949A (zh) * 2019-03-29 2020-10-09 首药控股(北京)股份有限公司 Bcl-2选择性抑制剂的制备方法
CN111747949B (zh) * 2019-03-29 2022-07-01 首药控股(北京)股份有限公司 Bcl-2选择性抑制剂的制备方法
CN114008035A (zh) * 2019-06-14 2022-02-01 北京盛诺基医药科技股份有限公司 一种shp2磷酸酶变构抑制剂
US12286430B2 (en) 2020-04-15 2025-04-29 Beigene, Ltd. Bcl-2 inhibitor
WO2022028353A1 (fr) 2020-08-06 2022-02-10 北京诺诚健华医药科技有限公司 Composé hétérocyclique en tant qu'inhibiteur de bcl-2

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