WO2018041248A1 - Bcl-2 selective inhibitor and preparation and use thereof - Google Patents

Bcl-2 selective inhibitor and preparation and use thereof 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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WIPO (PCT)
Prior art keywords
methyl
group
pyridin
etoac
pyrrolo
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PCT/CN2017/100226
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French (fr)
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
Original Assignee
北京赛林泰医药技术有限公司
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Publication date
Priority claimed from CN201610800391.4A external-priority patent/CN107793412A/en
Priority claimed from CN201710604198.8A external-priority patent/CN109293656A/en
Application filed by 北京赛林泰医药技术有限公司 filed Critical 北京赛林泰医药技术有限公司
Priority to CN201780053177.XA priority Critical patent/CN109641897B/en
Publication of WO2018041248A1 publication Critical patent/WO2018041248A1/en

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    • 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

A compound represented by formula (I) is disclosed. The compound selectively inhibits an anti-apoptotic protein activity of Bcl-2, and can treat an autoimmune disease or cancer.

Description

Bcl-2选择性抑制剂及其制备和用途Bcl-2 selective inhibitor and preparation and use thereof 技术领域Technical field
本申请涉及选择性抑制Bcl-2抗凋亡蛋白活性的化合物，还涉及这些化合物的制备方法及其药物组合物和用途。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.
背景技术Background technique
细胞凋亡在保证生物体细胞增殖与消亡间的平衡中起着重要作用。这一途径的紊乱导致多种疾病。抗凋亡Bcl-2蛋白在调节细胞凋亡中发挥着重要作用，与许多疾病有关，在各种癌症和免疫系统的病症中，Bcl-2蛋白的过表达与化疗的耐受性、疾病发展和总体预后相关，因此在治疗领域需要抑制抗凋亡蛋白Bcl-2的活性化合物。专利WO2005049593和WO2005024636中描述了Bcl-2蛋白与下列癌症的关系：膀胱癌、脑癌、乳腺癌、骨髓癌、子宫颈癌、慢性淋巴细胞性白血病、结肠直肠癌、食道癌、肝细胞癌、淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑素瘤、粒细胞性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、慢性淋巴细胞性白血病、骨髓瘤、前列腺癌、小细胞肺癌或脾癌等等。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. 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.
该领域已公开报道了对靶蛋白有高度活性的抑制剂，但不具备选择性往往带来严重的副作用，例如抑制Bcl-XL导致的血小板减少症(Andrew J Souers,Joel D Leverson,Erwin R Boghaert et al.Nature Medicine,2013,19,202-210)。目前仅有Bcl-2选择性抑制剂ABT-199，被美国FDA批准用于治疗慢性淋巴细胞白血病。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). Currently, only Bcl-2 selective inhibitor ABT-199 is approved by the US FDA for the treatment of chronic lymphocytic leukemia.
发明概述Summary of invention
本申请涉及可用作一个或多个抗细胞程序死亡蛋白家族成员的抑制剂的化合物或其药学上可接受的盐、溶剂化物、多晶型物或前药，其可用于治疗与抗凋亡Bcl-2蛋白表达相关的疾病,它们对抗凋亡蛋白Bcl-2具有更高的活性，同时具备更高的选择性(相对于抗凋亡蛋白Bcl-XL)。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 ).
本申请提供了如下所述的式(I)化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药：The application provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, as described below:
Figure PCTCN2017100226-appb-000001
Figure PCTCN2017100226-appb-000001
其中，among them,
Figure PCTCN2017100226-appb-000002
为单键或双键；
Figure PCTCN2017100226-appb-000002
For single or double keys;
Ar选自芳基和杂芳基，所述芳基和杂芳基可任选的被选自卤素、氨基、羟基、(＝O)、 C1-6烷基、以及C3-8环烷基的基团取代；Ar is selected from the group consisting of aryl and heteroaryl, which may be optionally selected from the group consisting of halogen, amino, hydroxy, (=O), C 1-6 alkyl, and C 3-8 naphthenic Substituent group substitution;
X和Z各自独立地选自-O-、-S-和-NR3-；X and Z are each independently selected from -O-, -S-, and -NR 3 -;
Y选自N或CR8；Y is selected from N or CR 8 ;
R选自C1-6烷氧基、单烷基氨基、二烷基氨基、C3-8环烷基和C3-8杂环烷基，所述环烷基和杂环烷基可任选的被1-3个R9取代；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 ;
R9各自独立地选自卤素、氨基、羟基、Boc、SO2R10、C3-8环烷基、C3-8杂环烷基、Bn、(＝O)、-(CO)(CH2)mNR4R5、-(CO)(CH2)mOR6和C1-6烷基，或者两个R9可以连在一起形成3-8元杂环，并且R9可任选地被C1-6烷基或C3-8环烷基取代；R 9 is each independently selected from the group consisting of halogen, amino, hydroxy, Boc, SO 2 R 10 , C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, Bn, (=O), -(CO)(CH) 2 ) m NR 4 R 5 , -(CO)(CH 2 ) m OR 6 and C 1-6 alkyl, or two R 9 may be joined together to form a 3-8 membered heterocyclic ring, and R 9 may be optionally selected The ground is substituted by a C 1-6 alkyl group or a C 3-8 cycloalkyl group;
每个R7各自独立地选自卤素、C1-6烷基或C3-8环烷基；Each R 7 is each independently selected from halogen, C 1-6 alkyl or C 3-8 cycloalkyl;
R8选自-NO2和-SO2CF3；R 8 is selected from the group consisting of -NO 2 and -SO 2 CF 3 ;
R1、R2、R3、R4、R5、R6和R10各自独立地选自H和C1-6烷基；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;
m独立地为0、1、2、3、4、5、或6；m is independently 0, 1, 2, 3, 4, 5, or 6;
n为0、1、2、3、4、5或6n is 0, 1, 2, 3, 4, 5 or 6
p为0、1、2、或3；p is 0, 1, 2, or 3;
q为0或1。q is 0 or 1.
在一些实施方式中，
Figure PCTCN2017100226-appb-000003
为双键。In some embodiments,
Figure PCTCN2017100226-appb-000003
For double keys.
在一些实施方式中，Y为CR8，其中R8选自-NO2和-SO2CF3；In some embodiments, Y is CR 8 , wherein R 8 is selected from the group consisting of -NO 2 and -SO 2 CF 3 ;
在一些实施方式中，每个R7各自独立地选自卤素；In some embodiments, each R 7 is independently selected from halo;
在一些实施方式中，Ar选自6-10元芳基和5-10元杂芳基，所述芳基和杂芳基可任选的被选自卤素、氨基、羟基、(＝O)、C1-6烷基、以及C3-8环烷基的基团取代；优选地，所述杂芳基含有1-3个选自N、O和S的杂原子。优选地，所述芳基和杂芳基可任选的被选自卤素、氨基、羟基和C1-6烷基的基团取代。In some embodiments, Ar is selected from the group consisting of a 6-10 membered aryl group and a 5-10 membered heteroaryl group, and the aryl group and heteroaryl group are optionally selected from the group consisting of halogen, amino, hydroxy, (=O), 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. Preferably, the aryl and heteroaryl groups are optionally substituted with a group selected from the group consisting of halogen, amino, hydroxy and C1-6 alkyl.
在一些实施方式中，Ar选自5-10元杂芳基，所述芳基和杂芳基可任选的被选自卤素、氨基、羟基和C1-6烷基的基团取代；优选地，所述杂芳基含有1-3个选自N、O和S的杂原子。In some embodiments, 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.
在一些实施方式中，Ar为
Figure PCTCN2017100226-appb-000004
且Ar可任选的被选自卤素、氨基、羟基和C1-6烷基的基团取代。In some embodiments, Ar is
Figure PCTCN2017100226-appb-000004
And Ar may be optionally substituted with a group selected from the group consisting of halogen, amino, hydroxy and C1-6 alkyl.
在一些实施方式中，X和Z各自独立地选自-O-和-NR3-，其中R3选自H和C1-6烷基。In some embodiments, X and Z are each independently selected from -O- and -NR 3 -, wherein R 3 is selected from H and C 1-6 alkyl.
在一些实施方式中，X和Z各自独立地选自-O-和-NH-。In some embodiments, X and Z are each independently selected from -O- and -NH-.
在一些实施方式中，R1和R2为H。In some embodiments, R 1 and R 2 are H.
在一些实施方式中，R4、R5、R6和R10各自独立的选自C1-6烷基。In some embodiments, R 4 , R 5 , R 6 , and R 10 are each independently selected from C 1-6 alkyl.
在一些实施方式中，R9各自独立地选自卤素、Boc、SO2R10、C3-8杂环烷基、Bn、-(CO)(CH2)mNR4R5和C1-6烷基，其中R4、R5和R10各自独立的选自C1-6烷基，m为0、1、2、3、4、5或6，优选地，m为0、1、2、3、或4，更优选地，m为0、1、或2。 In some embodiments, 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.
在一些实施方式中，n为0、1、2、3或4，优选地，n为0、1、或2。In some embodiments, n is 0, 1, 2, 3 or 4, preferably n is 0, 1, or 2.
在一些实施方式中，p为0、1、或2。In some embodiments, p is 0, 1, or 2.
在一些实施方式中，q为1。In some embodiments, q is one.
在一些实施方式中，本申请提供了如下所述的式(II)化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药：In some embodiments, the application provides a compound of formula (II), or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, as described below:
Figure PCTCN2017100226-appb-000005
Figure PCTCN2017100226-appb-000005
其中，among them,
Figure PCTCN2017100226-appb-000006
为单键或双键；
Figure PCTCN2017100226-appb-000006
For single or double keys;
Ar选自芳基和杂芳基，所述芳基和杂芳基可任选的被选自卤素、氨基、羟基、(＝O)和C1-6烷基的基团取代；Ar is selected from the group consisting of an aryl group and a heteroaryl group, which may be optionally substituted with a group selected from the group consisting of halogen, amino, hydroxy, (=O) and C 1-6 alkyl;
X选自-O-、-S-和-NR3-；X is selected from the group consisting of -O-, -S-, and -NR 3 -;
R选自C1-6烷氧基、单烷基氨基、二烷基氨基、C3-8环烷基和C3-8杂环烷基，所述环烷基和杂环烷基可任选的被选自卤素、氨基、羟基、(＝O)、-(CO)(CH2)mNR4R5、-(CO)(CH2)mOR6和C1-6烷基的基团取代；R is selected from C 1-6 alkoxy, monoalkylamino, dialkylamino, C 3-8 cycloalkyl and C 3-8 heterocycloalkyl, said cycloalkyl and heterocycloalkyl Selected groups selected from the group consisting of halogen, amino, hydroxy, (=O), -(CO)(CH 2 ) m NR 4 R 5 , -(CO)(CH 2 ) m OR 6 and C 1-6 alkyl Substitute
R1、R2、R3、R4、R5和R6分别独立的选自H和C1-6烷基；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;
m独立地为0、1、2、3、4、5或6；m is independently 0, 1, 2, 3, 4, 5 or 6;
n为0、1、2、3、4、5或6。n is 0, 1, 2, 3, 4, 5 or 6.
在一些实施方式中，Ar选自6-10元芳基和5-10元杂芳基，所述芳基和杂芳基可任选的被选自卤素、氨基、羟基、(＝O)和C1-6烷基的基团取代；优选地，所述杂芳基含有1-3个选自N、O和S的杂原子；优选地，所述芳基和杂芳基可任选的被选自卤素、氨基、(＝O)和C1-6烷基的基团取代。In some embodiments, Ar is selected from the group consisting of 6-10 membered aryl and 5-10 membered heteroaryl, and the aryl and heteroaryl are optionally selected from the group consisting of halogen, amino, hydroxy, (=O), and Substituting a C 1-6 alkyl group; preferably, the heteroaryl group contains 1-3 heteroatoms selected from N, O and S; preferably, the aryl and heteroaryl groups are optional Substituted by a group selected from the group consisting of halogen, amino, (=O) and C 1-6 alkyl.
在一些实施方式中，X选自-O-和-NR3-，其中R3选自H和C1-6烷基。In some embodiments, 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.
在一些实施方式中，X选自-O-和-NH-。In some embodiments, X is selected from the group consisting of -O- and -NH-.
在一些实施方式中，R1、R2和R3为H。In some embodiments, R 1 , R 2 and R 3 are H.
在一些实施方式中，R4、R5和R6各自独立的选自C1-6烷基。 In some embodiments, R 4 , R 5 and R 6 are each independently selected from C 1-6 alkyl.
在一些实施方式中，R选自C1-6烷氧基、C3-8环烷基和C3-8杂环烷基，所述环烷基和杂环烷基可任选的被选自卤素、氨基、羟基、(＝O)、-(CO)(CH2)mNR4R5、-(CO)(CH2)mOR6和C1-6烷基的基团取代，其中R4、R5和R6分别独立的选自H和C1-6烷基，m独立地为0、1、2、3、4、5或6。In some embodiments, 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. Substituted from a group of a halogen, an amino group, a hydroxyl group, (=O), -(CO)(CH 2 ) m NR 4 R 5 , -(CO)(CH 2 ) m OR 6 and a C 1-6 alkyl group, wherein R 4 , R 5 and R 6 are each independently selected from H and C 1-6 alkyl groups, and m is independently 0, 1 , 2, 3, 4, 5 or 6.
在一些实施方式中，R选自C1-6烷氧基、C3-8环烷基和C3-8杂环烷基，所述环烷基和杂环烷基可任选的被选自卤素、氨基、羟基、(＝O)、-(CO)(CH2)mNH2、-(CO)(CH2)mOH和C1-6烷基的基团取代，m独立地为0、1、2、3、4、5或6。In some embodiments, 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. Substituted by 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.
在一些实施方式中，R选自C1-6烷氧基、C3-8环烷基和C3-8杂环烷基，所述环烷基和杂环烷基可任选的被选自卤素、氨基、羟基、(＝O)、-(CO)(CH2)mNR4R5、-(CO)(CH2)mOR6和C1-6烷基的基团取代，其中R4、R5和R6分别独立的选自H和C1-6烷基，m独立地为0、1、2、3或4。In some embodiments, 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. Substituted from a group of a halogen, an amino group, a hydroxyl group, (=O), -(CO)(CH 2 ) m NR 4 R 5 , -(CO)(CH 2 ) m OR 6 and a C 1-6 alkyl group, wherein R 4 , R 5 and R 6 are each independently selected from H and C 1-6 alkyl groups, and m is independently 0, 1, 2, 3 or 4.
在一些实施方式中，R选自C1-6烷氧基、C3-8环烷基和C3-8杂环烷基，所述环烷基和杂环烷基可任选的被选自卤素、氨基、羟基、(＝O)、-(CO)(CH2)mNH2、-(CO)(CH2)mOH和C1-6烷基的基团取代，m独立地为0、1、2、3或4。In some embodiments, 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. Substituted by 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.
在一些实施方式中，R选自C1-6烷氧基、C3-8环烷基和C3-8杂环烷基，所述环烷基和杂环烷基可任选的被卤素或C1-6烷基取代。In some embodiments, 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.
在一些实施方式中，n为0、1、2、3或4。In some embodiments, n is 0, 1, 2, 3 or 4.
在一些实施方式中，本申请化合物选自:In some embodiments, the compounds of the present application are selected from the group consisting of
Figure PCTCN2017100226-appb-000007
Figure PCTCN2017100226-appb-000007
Figure PCTCN2017100226-appb-000008
Figure PCTCN2017100226-appb-000008
Figure PCTCN2017100226-appb-000009
Figure PCTCN2017100226-appb-000009
Figure PCTCN2017100226-appb-000010
Figure PCTCN2017100226-appb-000010
或其药学上可接受的盐、溶剂化物、多晶型物或前药。 Or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.
在另一方面，本申请还涉及包含有效量的本申请的上述化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药的药物组合物。在一些实施方式中，所述药物组合物进一步包含药学上可接受的载体。所述药物组合物包括但不限于口服剂型、胃肠外给药剂型、外用剂型和直肠给药剂型。在一些实施方式中，所述药物组合物可以是口服的片剂、胶囊、丸剂、粉剂、缓释制剂、溶液和悬浮液，用于胃肠外注射的无菌溶液、悬浮液或乳液，用于外用的软膏或乳膏，或者用于直肠给药的栓剂。在其它实施方式中，所述药物组合物为适合单次施予精确剂量的单位剂型。在其它实施方式中，所述化合物的量在约0.001mg/kg体重/天-约1000mg/kg体重/天的范围内。在其它实施方式中，所述化合物的量的范围为约0.5mg/kg体重/天-约50mg/kg体重/天。在一些实施方式中，所述化合物的量为约0.001g/天-约7g/天。在其它实施方式中，所述化合物的量为约0.1g/天-约1g/天。在其它实施方式中，低于上述范围下限的剂量水平可能已经是足够的。在其它实施方式中，可能需要高于上述范围上限的剂量水平。在一些实施方式中，以单剂量施用所述化合物，每天一次。在其它实施方式中，以多剂量施用所述化合物，每天不只一次。在一些实施方式中，所述药物组合物施用于的个体为哺乳动物。在其它实施方式中，所述哺乳动物是人。In another aspect, the present application is also directed to 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. In some embodiments, 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. In some embodiments, 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. A topical ointment or cream, or a suppository for rectal administration. In other embodiments, the pharmaceutical composition is in a unit dosage form suitable for single administration of precise dosages. In other embodiments, the amount of the compound ranges from about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day. In other embodiments, the amount of the compound ranges from about 0.5 mg/kg body weight/day to about 50 mg/kg body weight/day. In some embodiments, the amount of the compound is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound is from about 0.1 g/day to about 1 g/day. In other embodiments, a dose level below the lower limit of the above range may already be sufficient. In other embodiments, dose levels above the upper limit of the above range may be required. In some embodiments, 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. In some embodiments, the individual to which the pharmaceutical composition is administered is a mammal. In other embodiments, the mammal is a human.
在另一方面，本申请提供了本申请的化合物或其药学上可接受的盐、溶剂化物、多晶型物或前药在制备治疗与抗凋亡Bcl-2蛋白表达相关的疾病的药物中的用途。In another aspect, 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.
在另一方面，本申请提供了本申请的化合物或其药学上可接受的盐、溶剂化物、多晶型物或前药，其用作治疗与抗凋亡Bcl-2蛋白表达相关的疾病的药物。In another aspect, 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.
在另一方面，本申请提供了治疗与抗凋亡Bcl-2蛋白表达相关的疾病的方法，所述方法包括向有此需要的个体施用治疗有效量的本申请的化合物、其药学上可接受的盐、溶剂化物、多晶型物或前药或其组合物。In another aspect, 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.
本申请化合物或其药学上可接受的盐、溶剂化物、多晶型物或前药可治疗的上述疾病包括自身免疫性疾病和癌症。当所述疾病为癌症时，其可选自膀胱癌、脑癌、乳腺癌、骨髓癌、子宫颈癌、慢性淋巴细胞性白血病、结肠直肠癌、食道癌、肝细胞癌、淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑素瘤、粒细胞性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、慢性淋巴细胞性白血病、骨髓瘤、前列腺癌、小细胞肺癌或脾癌。The above diseases which can be treated by the compound of the present application or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof include autoimmune diseases and cancer. When the disease is cancer, it may be selected from the group consisting of 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.
在另一方面，本申请涉及制备本申请的上述化合物或其在药学上可接受的盐、溶剂化物、多晶型物或前药的方法。In another aspect, 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.
发明详述Detailed description of the invention
在下文的详述中陈述了利用本申请原理的示例性实施方式。通过参考以下申请内容可更好地理解本申请的特征和优点。Exemplary embodiments utilizing the principles of the present application are set forth in the detailed description which follows. The features and advantages of the present application will be better understood by reference to the following claims.
应理解本申请各个方面的保护范围由权利要求书决定，并且这些权利要求范围内的方法和结构以及其等价的方法和结构均在本权利要求书涵盖的范围之内。It is to be understood that the scope of the present invention is defined by the scope of the claims and the scope of the claims
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通 过引用方式整体并入本文。Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning meaning All patents, patent applications, and publicly available materials cited throughout this document, unless otherwise indicated This is incorporated by reference in its entirety.
应理解，上述简述和下文的详述都是示例性的、解释性的，而不是对任何本申请主题的限制。除非另有具体说明，否则使用单数形式时也包括复数。除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。The above description and the following detailed description are to be considered as illustrative and not restrictive Unless otherwise specified, the use of the singular forms also includes the plural. Unless otherwise stated, the use of "or" or "or" means "and/or". In addition, the terms "comprises" and "comprising", "include", "include", and "include" are not limiting.
某些化学术语Certain chemical terms
术语“任选”、“任选的”或“任选地”是指随后描述的事件或情况可能发生也可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，“任选取代的烷基”表示“未取代的烷基”或“取代的烷基”。并且，任选取代的基团可以是未取代的(例如：-CH2CH3)、完全取代的(例如：-CF2CF3)、单取代的(例如：-CH2CH2F)或者介于单取代和完全取代之间的任意层级(例如：-CH2CHF2、-CF2CH3、-CFHCHF2等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。The term "optional,""optional," or "optionally" means that the subsequently described event or circumstance may or may not occur, the description including the occurrence of the event or condition and the occurrence of the event or condition. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". Also, 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.
可在参考文献(包括Carey和Sundberg，《高等有机化学》第四版，A卷(2000)和B卷(2001)，普莱南出版社(Plenum Press)，纽约)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、核磁、高效液相色谱、红外和紫外/可见光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和医药化学的有关术语以及实验步骤和技术是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送、以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本申请的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。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. For example, 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. In the present specification, the group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH2O-等同于-OCH2-。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. For example, -CH 2 O- is equivalent to -OCH 2 -.
本文所用术语“基团”、“化学基团”是指分子的一个特定的部分或官能团。化学基团经常被认作为嵌入或附加到一个分子中的化学实体。The term "group", "chemical group" as used herein, 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.
一些在此命名的化学基团可以用简略记号表示碳原子的总个数。例如，C1-C6烷基描述了一个烷基基团，如下定义的那样，具有总共1到6个碳原子。简略记号所示碳原子总个数不包括可能的取代基上的碳原子。Some of the chemical groups named here can indicate the total number of carbon atoms with a short mark. For example, a 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.
术语“卤素”是指溴、氯、氟或碘。术语“氨基”是指-NH2。术语“羟基”是指-OH。The term "halogen" means bromo, chloro, fluoro or iodo. The term "amino" refers to -NH 2 . The term "hydroxy" refers to -OH.
本文单独或作为其它成分的一部分使用的术语“杂原子”或“杂”是指除碳和氢之外的原子。杂原子独立地选自氧、氮、硫、磷、硅、硒和锡，但不限于这些原子。在出现两个或更多杂原子的实施方案中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的一些或全部彼此不同。The term "heteroatom" or "hetero" as used herein, alone or as part of another ingredient, 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. In embodiments where two or more heteroatoms are present, 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.
本文单独或组合使用的术语“稠”或“稠环”是指两个或更多个环共享一个或更多个键的环状结构。 The term "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.
本文单独或组合使用的术语“螺”或“螺环”是指两个或更多个环共享一个或更多个原子的环状结构。The term "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.
本文单独或作为其它组分的一部分(比如：单烷基氨基)使用的术语“烷基”是指任选取代的直链或任选取代的支链的一价饱和烃，其具有1-12个碳原子，优选1-8个碳原子，更优选1-6个碳原子，通过单键与分子的其它部分相连，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基、正庚基、2-甲基己基、3甲基己基、正辛基，正壬基、正癸基等。The term "alkyl" as used herein alone or as part of another component (eg, monoalkylamino) 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.
本文使用的术语“烷氧基”是指-ORa基团，其中Ra是以上定义的烷基，例如可以是-OC1-6烷基。烷氧基的非限定性实例包括甲氧基、乙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基等。The term "alkoxy" as used herein, refers to a -ORa group, wherein Ra is alkyl as defined above, and may, for example, be -OC 1-6 alkyl. Non-limiting examples of alkoxy groups include methoxy, ethoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
本文单独或作为其它成分的一部分使用的术语“环烷基”是指稳定的单价非芳香单环或多环碳氢基团，只包含碳原子和氢原子，可能包括稠环、螺环或桥环系统，包含3-15个，如3-10个，3-8个或3-6个成环碳原子，可饱和也可不饱和，通过单键与分子的其它部分相连。“环烷基”的非限制性实例包括环丙基、环丁基、环戊基、环己基、环己酮基、环庚基、环辛基、1H-茚基、2,3-二氢茚基、1,2,3,4-四氢萘基、5,6,7,8-四氢萘基、8,9二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-甲叉-1H-茚基、八氢-2,5-甲叉-并环戊二烯基、冰片基、十氢萘基等。本申请的杂环基包括优选3-8个碳原子、更优选环戊基、环己基、环己酮基或环庚基。The term "cycloalkyl" as used herein, alone or as part of another ingredient, 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. Non-limiting examples of "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, bicyclo[3.1.1]heptyl Bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro-4,7-methylidene-1H-indole Base, octahydro-2,5-methylene-cyclopentadienyl, borneol, decahydronaphthyl and the like. 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.
本文单独或作为其它成分的一部分使用的术语“杂环基”、“杂环烷基”、“杂环”是指稳定的3-18元单价非芳香环，包括2-12个碳原子，1-6个选自氮、氧和硫的杂原子。除非另作说明，杂环基基团可以是单环、双环、三环或四环系统，其可能包含稠环、螺环或桥环系统，杂环基上的氮、碳或硫可选择性的被氧化，氮原子可选择性的被季铵化，杂环基可以部分或完全饱和。杂环基可以通过环上的碳原子或杂原子与分子的其余部分通过一个单键连接。包含稠环的杂环基中可以包含一个或多个芳环或杂芳环，只要与分子的其余部分连接的是非芳香环上的原子。本申请杂环基优选的是一个稳定的4-11元单价非芳香单环或二环，其包含1-3个选自氮、氧和硫的杂原子，更优选的是一个稳定的4-8元单价非芳香单环，其包含1-3个选自氮、氧和硫的杂原子。杂环基的的非限制性实例包括氮杂环庚烷基、氮杂环丁基、十氢异喹啉基、二氢呋喃基、二氢吲哚基、二氧戊烷基、1,1-二氧-硫代吗啉基、咪唑烷基、咪唑啉基、异噻唑烷基、异恶唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、恶嗪基、恶唑烷基、1-氧-硫代吗啉基、2-氧哌嗪基、2-氧哌啶基、2-氧吡咯烷基、苯二酰亚氨基、哌嗪基、哌啶基、4-哌啶酮基、吡喃基、吡唑烷基、吡咯烷基、喹嗪基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢吡喃基、噻唑烷基、噻吩[1,3]二噻烷基、硫代吗啉基、三噻烷基等。The terms "heterocyclyl", "heterocycloalkyl", "heterocycle" as used herein, alone or as part of another ingredient, 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. Unless otherwise specified, 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. Oxidized, 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. Non-limiting examples of 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, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, thiazolidinyl, thiophene [1,3] Dithiaalkyl, thiomorpholinyl, trithylalkyl and the like.
本文使用的术语“芳香”、“芳香环”、“芳香的”、“芳香性的”、“芳香环的”是指平面的一个环或多个环的环部分，其具有含4n+2个电子的离域化电子共扼体系，其中n为 整数。芳环可由5、6、7、8、9或10个以上的原子形成。芳环可被任选地取代，并可为单环或稠合环的多环。本文单独或作为其它成分的一部分使用的术语“芳环”、“芳环基”、“芳香基”、“芳基”或前缀“芳”(比如在“芳烷基”中)是指碳氢环状系统，其含有氢，6-18个成环碳原子，优选6-10个成环碳原子，和至少一个芳香性的环。为本申请考虑，芳环基可以是单环、双环、三环或四环系统，其可能包含稠环或桥环系统。芳基碳原子可以通过单键跟分子的其它部分连接。芳基的非限定性实例包括苯基、奈基、蒽基、菲基、芴基、2-苯并恶唑烷酮基、2H-1,4-苯并恶唑-3(4H)-酮-7-基等。本申请中，芳基优选的为C6-C10的芳基，更优选的为苯基。The terms "aromatic", "aromatic ring", "aromatic", "aromatic", "aromatic ring" as used herein, mean 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. The terms "aromatic ring", "aryl ring group", "aryl group", "aryl group" or prefix "aryl" (such as in "aralkyl") used herein alone or as part of other ingredients mean hydrocarbon. A ring system containing hydrogen, 6-18 ring-forming carbon atoms, preferably 6-10 ring-forming carbon atoms, and at least one aromatic ring. For the purposes of this application, 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. Non-limiting examples of aryl groups include phenyl, naphthyl, anthracenyl, phenanthryl, anthracenyl, 2-benzoxazolidinone, 2H-1,4-benzoxazole-3(4H)-one -7-based and so on. In the present application, the aryl group is preferably a C 6 - C 10 aryl group, more preferably a phenyl group.
本文单独或作为其它成分的一部分使用的术语“杂芳基”是指5-16元环状系统，其包含例如1-15个碳原子，1-10个碳原子，并含有1-4个选自氮、氧和硫的杂原子，至少一个芳香环。除非另作说明，杂芳基可以是单环、双环、三环或四环系统，其可能包含稠环或桥环系统，只要与分子其它部分的连接点为芳环原子。杂芳环上的氮原子、碳原子和硫原子可以选择性的被氧化，氮原子可选择性的被季铵化。为了本申请，杂芳基优选的为稳定的4-11元单芳香环，其包含1-3个选自选自氮、氧和硫的杂原子，更优选的为稳定的5-8元单芳香环，其包含1-3个选自选自氮、氧和硫的杂原子。杂芳基的非限定性实例包括吖啶基、氮杂卓基、苯并咪唑基、苯并吲哚基、1,4-苯并二氧六环基、苯并[6][1,4]二氧杂环庚基、苯并二氧芑基、苯并二噁茂基、苯并呋喃酮基、苯并呋喃基、苯并[4,6]咪唑并[1,2-a]吡啶基、苯并萘并呋喃基、苯并吡喃酮基、苯并吡喃基、苯并吡唑基、苯并噻二唑基、苯并噻唑基、苯并噻吩基、苯并三唑基、苯并恶唑基、咔唑基、卡啉基、邻二氮萘基、二苯并呋喃基、二苯并噻吩基、呋喃酮基、呋喃基、咪唑基、吲唑基、二氢吲哚基、吲嗪基、吲哚基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异恶唑基、萘啶基、恶二唑基、恶三唑基、恶唑基、1-氧代吡嗪基、1-氧代哒嗪基、1-氧代吡啶基、1-氧代嘧啶基、环氧乙烷基、2-氧氮杂卓基、氧代吡啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩恶嗪基、1-苯基-1H-吡咯基、二氮杂萘基、喋啶基、嘌呤基、吡嗪基、吡唑基、哒嗪基、1H-吡啶-2-基、1H-吡啶-4-基、1H-吡啶-2-酮-4-基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹恶啉基、奎宁基、四氢喹啉基、4,5,6,7-四氢苯并[b]噻吩基、四唑基、噻二唑基、噻唑基、噻吩基、三嗪基、三唑基等。本申请中，杂芳基优选为5-8元杂芳基，其包含1-3个选自选自氮、氧和硫的杂原子，更优选为吡啶基、嘧啶基、噻唑基、氧代吡啶基、1H-吡啶-2-酮-4-基或噻吩基。The term "heteroaryl" as used herein, alone or as part of another ingredient, 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. For the purposes of the present application, 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. Non-limiting examples of heteroaryl groups include acridinyl, azaftyl, benzimidazolyl, benzindenyl, 1,4-benzodioxanyl, benzo[6][1,4 Dioxepane, benzodioxanyl, benzodioxanyl, benzofuranone, benzofuranyl, benzo[4,6]imidazo[1,2-a]pyridyl , benzonaphthofuranyl, benzopyranone, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, Benzooxazolyl, carbazolyl, carbolinyl, o-naphthylnaphthyl, dibenzofuranyl, dibenzothiophenyl, furanone, furyl, imidazolyl, oxazolyl, indoline Base, pyridazinyl, fluorenyl, isoxazolyl, isoindoline, isodecyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, Oxytriazolyl, oxazolyl, 1-oxopyrazinyl, 1-oxooxazinyl, 1-oxopyridinyl, 1-oxopyrimidinyl, oxiranyl, 2-oxoza Zhuoji, oxopyridinyl, phenanthryl, phenanthroline, phenazinyl, phenothiazine, phenoxazinyl, 1-phenyl-1H- Pyrrolyl, diazepine, acridinyl, fluorenyl, pyrazinyl, pyrazolyl, pyridazinyl, 1H-pyridin-2-yl, 1H-pyridin-4-yl, 1H-pyridine-2- Keto-4-yl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, quinuclyl, tetrahydroquinolyl, 4,5,6,7-tetrahydrobenzene And [b] thienyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl and the like. In the present application, 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.
本申请使用的术语“多晶型物”或“多晶型(现象)”是指本申请的化合物具有多种晶格形态。本申请的一些化合物可能有一个以上的晶体形式，本申请涵盖所有的多晶型态或其混合物。The term "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.
本申请化合物的中间体化合物及其多晶形物也在本申请的范围内。Intermediate compounds of the compounds of the present application, as well as polymorphs thereof, are also within the scope of the present application.
除非另有指定，本申请化合物所含有的烯烃双键包括E和Z异构体。Unless otherwise specified, the olefinic double bonds contained in the compounds of the present application include the E and Z isomers.
应理解，本申请化合物可能含有不对称中心。这些不对称中心可以独立的为R或S构型。一些本申请化合物也可显示出顺-反异构现象，这对于本领域技术人员而言是显而易见的。应理解，本申请化合物包括它们的单独的几何异构体和立体异构体以及它们的混合物， 包括外消旋混合物。通过实施或修改已知方法，例如层析技术和重结晶技术可以从它们的混合物中分离这些异构体，或者可以由它们的中间体的合适的异构体分别制备它们。It will be understood that 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.
本文所用术语“药学上可接受的盐”既包括加酸盐，也包括加碱盐。The term "pharmaceutically acceptable salt" as used herein includes both acid addition salts and base salts.
“药学上可接受的加酸盐”是指那些保留了化合物的游离碱的生物效力和特性、在生物学上或其它方面并非不合需要、跟无机酸或有机酸形成的盐。“药学上可接受的加碱盐”是指那些保留了化合物的游离酸的生物效力和特性、在生物学上或其它方面并非不合需要的盐。这些盐通过游离酸跟无机碱或有机碱反应制备。"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.
结晶经常产生本申请化合物的溶剂化物。本文所用术语“溶剂化物”是指由一个或多个本申请化合物分子和一个或多个溶剂分子组合而成的合体。溶剂可以是水，这种情况下，溶剂化物是水合物。另外还可以是有机溶剂。本申请化合物可在一种溶剂中反应或在一种溶剂中沉淀或结晶。本申请化合物的溶剂化物也包括在本申请的范围内。Crystallization often produces solvates of the compounds of the present application. The term "solvate" as used herein, 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.
本申请也考虑本申请化合物的前药。“前药”是指一个化合物可以在生理学状态下或溶剂化作用下被转化成具有生物活性作用的本申请化合物。因此，术语“前药”指本申请化合物药学上可接受的代谢前体，前药在给所需主体施用时可能是没有活性的，但是会在体内转化成有活性的本申请化合物。前药通常在体内，例如，通过在血液中水解，迅速转化成本申请的母化合物。前药经常在溶解性、组织兼容性、或在哺乳动物有机体内的延释方面具有优势。The present application also contemplates 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. Thus, the term "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.
本文所用术语“药物组合物”是指混合有本申请化合物和通常在本领域被接受的用来将具有生物活性的化合物传送给哺乳动物(比如人类)的介质的制剂。这种介质包含所有药学上可接受的载体。The term "pharmaceutical composition" as used herein 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.
本文所用的跟制剂、组合物或成分相关的术语“可接受的”是指对治疗主体的总体健康没有持续的有害影响。As used herein, 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.
本文所用术语“药学上可接受的”是指不影响本申请化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。The term "pharmaceutically acceptable" as used herein, 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.
“药学上可接受的载体”包括但不限于已经被相关政府行政部门批准的可以被用于人类和驯养动物的佐剂、载体、赋形剂、助剂、脱臭剂、稀释剂、保鲜剂、染料/着色剂、风味增强剂、表面活性剂和润湿剂、分散剂、悬浮剂、稳定剂、等渗剂、溶剂、或乳化剂。"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.
本文所用术语“主体”、“患者”或“个体”是指患有疾病、紊乱或病症等的个体，包括哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。The term "subject," "patient," or "individual" as used herein, refers to an individual, including a mammal, and a non-mammal, having a disease, disorder, or condition. Examples of 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. Examples of non-human mammals include, but are not limited to, birds and fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.
本文所用术语“治疗”是指对哺乳动物特别是人类的相关疾病或病症的治疗，包括The term "treating" as used herein refers to the treatment of a disease or condition associated with a mammal, particularly a human, including
(i)预防哺乳动物，特别是之前已经暴漏在某个疾病或病症下但尚未被诊断患有该疾病或病症的哺乳动物，产生相应的疾病或病症； (i) preventing a mammal, particularly a mammal that has previously been exposed to a disease or condition but has not been diagnosed with the disease or condition, producing a corresponding disease or condition;
(ii)抑制疾病或病症，即，控制其发展；(ii) inhibiting the disease or condition, ie, controlling its development;
(iii)缓解疾病或病症，即，使疾病或病症消退；(iii) alleviating the disease or condition, ie, causing the disease or condition to subside;
(iv)缓解疾病或病症引起的症状。(iv) alleviating the symptoms caused by the disease or condition.
本文所用术语“疾病”和“病症”可以互相替代，也可以是不同意思，因为某些特定疾病或病症还没有已知的致病因子(所以发病原因尚不清楚)，所以还不能被认作疾病而只能被看做不想要的状况或综合症，所述综合症或多或少有一些具体症状已经被临床研究人员证实。The terms "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.
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。The term "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. For example, 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.
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。The terms "administering," "administering," "administering," and the like, as used herein, 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.
通常，本申请的化合物，或者其药学上可接受的盐，可通过与药学上可接受的一个或多个载体形成适当的药物组合物来施用。本申请的药物组合物可以形成固体、半固体、液体或气体形态的制备物，比如片剂、胶囊、粉末、颗粒剂、软膏、溶液、栓剂、注射剂、吸入剂、凝胶、微球和气溶胶。In general, a compound of the present application, or a pharmaceutically acceptable salt thereof, 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. .
本申请的药物组合物可以通过使用在药物学上熟知的方法来制备。例如，施用方式为注射的药物组合物可以通过将本申请化合物跟无菌、蒸馏水结合来形成溶液的方式来制备。可以加入表面活性剂来帮助形成均相溶液或悬浮液。对于熟悉本领域技术的人员来说，制备这些剂型的实际方法是已知的或显而易见的。The pharmaceutical compositions of the present application can be prepared by using methods well known in the pharmacy. For example, 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.
典型的施用这些药物组合物的路径包括，但不限于，口服、外用、透皮吸收、吸入、肠外、舌下、直肠、阴道和鼻内。例如，用来口服的合适的剂量形式包括胶囊、片剂、颗粒剂和糖浆。这些剂量形式所包括的的本申请化合物可以是固体粉末或颗粒；在水溶剂或非水溶剂中的溶液或悬浊液；水中油滴型、油中滴水型乳剂等。以上提到的剂量形式可以从活性化合物和一个或多个载体通过常用药学方法制备。具体的施用路径和剂量形式要根据化合物自身的物理/化学特性以及要治疗的疾病的严重程度，并且可被本领域技术人员按常规来决定。Typical routes for administering these pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal and intranasal. For example, 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.
本申请化合物的制备Preparation of the compounds of the present application
以下反应路线图显示了制备本申请化合物的方法。The following reaction scheme shows the process for preparing the compounds of the present application.
应了解，以下描述中，只有在形成稳定化合物的情况下才允许取代基团和/或所述分子式的变量进行组合。It should be understood that in the following description, the substituent groups and/or the variables of the formula are allowed to be combined only in the case of forming a stable compound.
本领域的技术人员也应了解，在以下所述流程中，中间体化合物的官能团可能需要被 合适的保护基团保护。这些官能团包括羟基、氨基、巯基和羧基。合适的羟基保护基团包括三烷基硅基或二芳基烷基硅基(例如叔丁基甲基硅基、叔丁基二苯基硅基或三甲基硅基)、四氢吡喃基、苄基等。合适的氨基、脒基和胍保护基团包括叔丁氧羰基、苄氧羰基等。巯基的合适保护基团包括-C(O)-R"(R"表示烷基、芳基或芳基烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基团包括烷基、芳基或芳基烷基酯。保护基团可以通过本领域技术人员知道的标准技术方法加上或去掉。Those skilled in the art will also appreciate that in the processes described below, 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.
具体实施方式detailed description
以下结合实施例示例性阐述本申请的化合物及其制备方法和用途。The compounds of the present application, their preparation methods and uses are exemplified below in conjunction with the examples.
合成方法resolve resolution
流程1Process 1
Figure PCTCN2017100226-appb-000011
Figure PCTCN2017100226-appb-000011
流程2Process 2
Figure PCTCN2017100226-appb-000012
Figure PCTCN2017100226-appb-000012
可按照流程1或者流程2中所述路线制备本申请所示化合物。流程1或者流程2中反应所得的每一个产物可以通过传统分离技术来得到，这种传统技术包括但不限于过滤、蒸馏、结晶、色谱分离等。起始原料可以通过自己合成或从商业机构(例如，但不限于，Adrich或Sigma)购买获得。这些原料可以使用常规手段进行表征，比如物理常数和光谱数据。本申请所描述的化合物可以使用合成方法得到单一的异构体或者是异构体的混合物。 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.
在流程1中，使用甲磺酰氯，碱，原料1和原料2进行反应得到中间体3。中间体3水解得到中间体4。中间体4与原料5进行缩合反应得到目标化合物6。In Scheme 1, the reaction of the methanesulfonyl chloride, the base, the starting material 1 and the starting material 2 is carried out to obtain the intermediate 3. Intermediate 3 is hydrolyzed to give intermediate 4. The intermediate 4 is subjected to a condensation reaction with the starting material 5 to obtain the target compound 6.
在流程2中，使用还原剂(如三乙酰氧基硼氢化钠)，原料7和原料2进行反应得到中间体3。中间体3水解得到中间体4。中间体4与原料5进行缩合反应得到目标化合物6。In Scheme 2, a reducing agent such as sodium triacetoxyborohydride is used, and starting material 7 and starting material 2 are reacted to obtain Intermediate 3. Intermediate 3 is hydrolyzed to give intermediate 4. The intermediate 4 is subjected to a condensation reaction with the starting material 5 to obtain the target compound 6.
实施例Example
下述非限制性实施例仅仅是说明性的，不以任何方式限制本申请。The following non-limiting examples are merely illustrative and are not intended to limit the application in any way.
除非另有说明，温度是摄氏温度。试剂购自国药集团化学试剂北京有限公司，阿法埃莎(Alfa Aesar)，或北京百灵威科技有限公司等商业供应商，并且这些试剂可直接使用无需进一步纯化，除非另有说明。Unless otherwise stated, 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.
除非另有说明，下列反应在室温、无水溶剂中、氮气或氩气的正压下或使用干燥管进行；反应瓶上装有橡胶隔膜，以便通过注射器加入底物和试剂；玻璃器皿烘干和/或加热干燥。Unless otherwise stated, the following reactions were carried out at room temperature, in an anhydrous solvent, under a positive pressure of nitrogen or argon or using a drying tube; a reaction vessel was fitted with a rubber septum to add substrate and reagents via a syringe; glassware was dried and / or heat dry.
除非另有说明，柱色谱纯化使用青岛海洋化工厂的200-300目硅胶；制备薄层色谱使用烟台市化学工业研究所生产的薄层色谱硅胶预制板(HSGF254)；MS的测定用Thermo LCQ Fleet型(ESI)液相色谱-质谱联用仪；旋光测定使用SGW-3自动旋光仪,上海申光仪器仪表有限公司。Unless otherwise stated, the column chromatography was performed using 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; the thin layer chromatography was performed using a thin layer chromatography silica gel prefabricated plate (HSGF254) produced by Yantai Chemical Industry Research Institute; the measurement of MS was performed by Thermo LCQ Fleet. Type (ESI) liquid chromatography-mass spectrometer; optical rotation measurement using SGW-3 automatic polarimeter, Shanghai Shenguang Instrument Co., Ltd.
核磁数据(1H NMR)使用Varian设备于400MHz运行。核磁数据使用的溶剂有CDCl3、CD3OD、D2O、DMSO-d6等，以四甲基硅烷(0.00ppm)为基准或以残留溶剂为基准(CDCl3:7.26ppm；CD3OD:3.31ppm；D2O:4.79ppm；d6-DMSO:2.50ppm)。当标明峰形多样性时，以下简写表示不同峰形：s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(宽峰)、dd(双双重峰)、dt(双三重峰)。如果给出了耦合常数，则以Hertz(Hz)为单位。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). When the peak shape diversity is indicated, the following abbreviations indicate different peak shapes: s (single peak), d (double peak), t (triplet), q (quadruple), m (multiple peak), br (wide peak) ), dd (double doublet), dt (double triplet). If a coupling constant is given, it is in Hertz (Hz).
缩略语:Abbreviations:
Figure PCTCN2017100226-appb-000013
Figure PCTCN2017100226-appb-000013
Figure PCTCN2017100226-appb-000014
Figure PCTCN2017100226-appb-000014
实施例1Example 1
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000015
Figure PCTCN2017100226-appb-000015
步骤A：5-溴-1-(三异丙基硅基)-1H-吡咯并[2,3-b]吡啶Step A: 5-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2017100226-appb-000016
Figure PCTCN2017100226-appb-000016
5-溴-1H-吡咯并[2,3-b]吡啶(3.94g，0.02mol)溶于无水四氢呋喃(60mL)，冷却至0℃，加入LiHMDS的四氢呋喃溶液(2.2mL,0.022mol)，10分钟后，加入三异丙基氯硅烷(4.24g,0.022mol)，缓慢升至室温，搅拌40小时。将反应液倾入水中，用乙酸乙酯萃取，用饱和 食盐水洗涤有机相，无水硫酸钠干燥，除去溶剂得产品(7.0g,99％)。5-Bromo-1H-pyrrolo[2,3-b]pyridine (3.94 g, 0.02 mol) was dissolved in anhydrous tetrahydrofuran (60 mL), cooled to 0 ° C, and a solution of LiHMDS in tetrahydrofuran (2.2 mL, 0.022 mol). After 10 minutes, triisopropylchlorosilane (4.24 g, 0.022 mol) was added, and the mixture was slowly warmed to room temperature and stirred for 40 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with brine and dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl3)δ8.27(d,J＝2.4Hz,1H),7.98(d,J＝2.4Hz,1H),7.31(d,J＝3.6Hz,1H),6.49(d,J＝3.6Hz,1H),1.78～1.89(m,3H),1.12(d,J＝7.6Hz,18H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 6.49 (d) , J = 3.6 Hz, 1H), 1.78 to 1.89 (m, 3H), 1.12 (d, J = 7.6 Hz, 18H).
步骤B：(1-(三异丙基硅基)-1H-吡咯并[2,3-b]吡啶-5-基)硼酸二甲酯Step B: (1-(Triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid dimethyl ester
Figure PCTCN2017100226-appb-000017
Figure PCTCN2017100226-appb-000017
氮气保护下，5-溴-1-(三异丙基硅基)-1H-吡咯并[2,3-b]吡啶(5.37g，0.015mol)溶于无水四氢呋喃(100mL)，冷却至-78℃，加入正丁基锂的正己烷溶液(7.5mL，0.018mol)，5分钟后，加入硼酸三甲酯(2.33g,0.0225mol)，缓慢升至室温，搅拌1小时。加入饱和氯化铵水溶液淬灭反应，用乙酸乙酯萃取，用饱和食盐水洗涤有机相，无水硫酸钠干燥，除去溶剂直接投入下一步。Under a nitrogen atmosphere, 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.37 g, 0.015 mol) was dissolved in anhydrous tetrahydrofuran (100 mL) and cooled to - At 78 ° C, n-hexane solution of n-butyllithium (7.5 mL, 0.018 mol) was added. After 5 min, trimethyl borate (2.33 g, 0.0225 mol) was added, and the mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with EtOAc (EtOAc m.
步骤C：1-(三异丙基硅基)-1H-吡咯并[2,3-b]吡啶-5-酚Step C: 1-(Triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-phenol
Figure PCTCN2017100226-appb-000018
Figure PCTCN2017100226-appb-000018
室温下，将上一步得到的(1-(三异丙基硅基)-1H-吡咯并[2,3-b]吡啶-5-基)硼酸二甲酯溶于四氢呋喃(50mL)，冷却至0℃，加入氢氧化钠水溶液(15mL,0.015mol)和30％的双氧水水溶液(3mL)，保持在0℃下继续搅拌1小时。加入过量亚硫酸钠搅拌至淀粉碘化钾试纸不显色，用1N盐酸调pH为4，乙酸乙酯萃取，合并乙酸乙酯相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱进行色谱纯化残余物，以二氯甲烷洗脱，得到油状产物(3.1g,71％)。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. After adding an excess of sodium sulfite to the starch, the potassium iodide test paper was not colored, and the pH was adjusted to 4 with 1N hydrochloric acid, and the ethyl acetate was combined, and the ethyl acetate phase was combined, washed with brine, dried over anhydrous sodium sulfate, The residue was purified with EtOAcqqqqqqq
1H NMR(400MHz,CDCl3)δ7.96(d,J＝2.8Hz,1H),7.33(d,J＝2.8Hz,1H),7.29(d,J＝3.2Hz,1H),6.44(d,J＝3.6Hz,1H),4.53(br,1H),1.79～1.87(m,3H),1.12(d,J＝7.6Hz,18H)。 1 H NMR (400MHz, CDCl 3 ) δ7.96 (d, J = 2.8Hz, 1H), 7.33 (d, J = 2.8Hz, 1H), 7.29 (d, J = 3.2Hz, 1H), 6.44 (d , J = 3.6 Hz, 1H), 4.53 (br, 1H), 1.79 to 1.87 (m, 3H), 1.12 (d, J = 7.6 Hz, 18H).
步骤D：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-溴苯甲酸甲酯Step D: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate
Figure PCTCN2017100226-appb-000019
Figure PCTCN2017100226-appb-000019
室温下，1-(三异丙基硅烷基)-1H-吡咯并[2,3-b]吡啶-5-酚(1.00g，0.0035mol)、4-溴-2-氟苯甲酸甲酯(0.885g，0.0038mol)、碳酸钾(0.967g，0.007mol)加入N,N-二甲基甲酰胺(10 mL)中，加热至80℃搅拌1小时。冷却至室温，用乙酸乙酯稀释，水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩。经硅胶柱进行色谱纯化残余物，以乙酸乙酯/二氯甲烷(5/1)洗脱，得到产品(0.48g,40％)。1-(Triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-phenol (1.00 g, 0.0035 mol), methyl 4-bromo-2-fluorobenzoate (at room temperature) 0.885 g, 0.0038 mol), potassium carbonate (0.967 g, 0.007 mol) was added to N,N-dimethylformamide (10 In mL), the mixture was heated to 80 ° C and stirred for 1 hour. After cooling to room temperature, it was diluted with EtOAc. The residue was purified by chromatography EtOAcjjjjjjj
1H NMR(400MHz,CDCl3)δ9.34(br,1H),8.11(d,J＝2.8Hz,1H),7.72(d,J＝8.4Hz,1H),7.56(d,J＝2.4Hz,1H),7.32～7.34(t,J＝2.8Hz,1H)，7.17～7.20(m,1H),6.89(d,J＝2.0Hz,1H),6.42～6.44(m,1H),3.82(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ9.34 (br, 1H), 8.11 (d, J = 2.8Hz, 1H), 7.72 (d, J = 8.4Hz, 1H), 7.56 (d, J = 2.4Hz , 1H), 7.32 to 7.34 (t, J = 2.8 Hz, 1H), 7.17 to 7.20 (m, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.42 to 6.44 (m, 1H), 3.82 ( s, 3H).
步骤E：4-(3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(甲氧羰基)苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯Step E: 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine- 1(2H)-tert-butyl formate
Figure PCTCN2017100226-appb-000020
Figure PCTCN2017100226-appb-000020
室温下，4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(493mg,1.6mmol)、2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-溴苯甲酸甲酯(460mg,1.3mmol)、磷酸钾(552mg,2.6mmol)和Pd(dppf)Cl2(106mg,0.13mmol)加入乙二醇二甲醚/水(5/1)的混合液(6mL)中，氮气保护下加热到80℃搅拌过夜。冷却至室温，加入水，用乙酸乙酯萃取，合并乙酸乙酯相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱进行色谱纯化残余物且用二氯甲烷/乙酸乙酯(4/1)洗脱，得到白色固体产物(440mg,75％)。4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid at room temperature Butyl ester (493 mg, 1.6 mmol), methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate (460 mg, 1.3 mmol), potassium phosphate (552 mg, 2.6 mmol) and Pd(dppf)Cl 2 (106 mg, 0.13 mmol) were added to a mixture of ethylene glycol dimethyl ether/water (5/1) (6 mL), and heated to 80 ° C under nitrogen overnight. . After cooling to room temperature, water was added, EtOAc was evaporated, evaporated, evaporated, evaporated, Elution with (4/1) gave a white solid product (440 mg, 75%).
1H NMR(400MHz,CDCl3)δ9.42(br,1H),8.17(d,J＝2.4Hz,1H),7.90(d,J＝8.4Hz,1H),7.56(d,J＝2.4Hz,1H),7.36(t,J＝3.2Hz,1H),7.13～7.16(m,1H),6.86(d,J＝1.6Hz,1H),6.45～6.46(m,1H),5.99～6.03(m,1H),4.00(br,2H),3.86(s,3H),3.55(t,J＝1.6Hz,2H),2.38(br,2H),1.45(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.42 (br, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 2.4 Hz) , 1H), 7.36 (t, J = 3.2 Hz, 1H), 7.13 to 7.16 (m, 1H), 6.86 (d, J = 1.6 Hz, 1H), 6.45 to 6.46 (m, 1H), 5.99 to 6.03 ( m, 1H), 4.00 (br, 2H), 3.86 (s, 3H), 3.55 (t, J = 1.6 Hz, 2H), 2.38 (br, 2H), 1.45 (s, 9H).
步骤F：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯Step F: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoic acid ester
Figure PCTCN2017100226-appb-000021
Figure PCTCN2017100226-appb-000021
将4-(3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(甲氧羰基)苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(220mg,0.49mmol)溶于二氯甲烷(2mL),冷却至0℃,加入三氟乙酸(1mL)。加毕，保持在0℃下继续搅拌3小时，加入饱和碳酸钠水溶液，用二氯甲烷萃取，有机相合并，用饱和食盐水洗涤，无水硫酸钠干燥，除去溶剂，得到目标产物(170mg,100％)。4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1 ( 2H)-tert-butyl formate (220 mg, 0.49 mmol) was dissolved in dichloromethane (2 mL), cooled to EtOAc. After the addition was completed, stirring was continued for 3 hours at 0 ° C, and a saturated aqueous solution of sodium carbonate was added, and the mixture was combined with dichloromethane. 100%).
1H NMR(400MHz,CDCl3)δ10.56(br,1H),8.06(d,J＝2.4Hz,1H),7.89(d,J＝8Hz,1H),7.64(d,J＝3.6Hz,1H),7.42(br,1H),7.10(br,1H),6.75(s,1H),6.47(d,J＝2.8Hz,1H),5.96(br,1H),3.92(br,3H),3.78(br,2H),3.35(t,J＝5.2Hz,2H),2.63(br,2H)。 1 H NMR (400MHz, CDCl 3 ) δ10.56 (br, 1H), 8.06 (d, J = 2.4Hz, 1H), 7.89 (d, J = 8Hz, 1H), 7.64 (d, J = 3.6Hz, 1H), 7.42 (br, 1H), 7.10 (br, 1H), 6.75 (s, 1H), 6.47 (d, J = 2.8 Hz, 1H), 5.96 (br, 1H), 3.92 (br, 3H), 3.78 (br, 2H), 3.35 (t, J = 5.2 Hz, 2H), 2.63 (br, 2H).
步骤G：4,4-二甲基-2-氧代环己烷-1-甲酸甲酯 Step G: 4,4-Dimethyl-2-oxocyclohexane-1-carboxylic acid methyl ester
Figure PCTCN2017100226-appb-000022
Figure PCTCN2017100226-appb-000022
将钠氢(16g,0.4mol)悬浮于新干燥四氢呋喃(500mL)中，加入碳酸二甲酯(85mL,1mol)。反应液加热至回流，滴入3,3-二甲基环己烷-1-酮(25g,0.2mol)的四氢呋喃(200mL)溶液。滴加完毕后继续回流反应2小时。冷却至0℃,倾入饱和氯化铵水溶液中，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，除去溶剂，经硅胶柱进行色谱纯化残余物且用石油醚/乙酸乙酯(40/1)洗脱，得到产品(34g,93％)。Sodium hydrogen (16 g, 0.4 mol) was suspended in fresh dry tetrahydrofuran (500 mL) and dimethyl carbonate (85 mL, 1 mol) was added. The reaction solution was heated to reflux, and a solution of 3,3-dimethylcyclohexane-1-one (25 g, 0.2 mol) in tetrahydrofuran (200 mL) was added dropwise. After the completion of the dropwise addition, the reflux reaction was continued for 2 hours. The mixture was cooled to 0 ° C, poured into aq. EtOAc EtOAc. Elution with ether / ethyl acetate (40/1) gave product (34 g, 93%).
1H NMR(400MHz,CDCl3)δ12.12(s,1H),3.76(s,3H),2.23～2.27(m,2H),2.06(s,2H),1.37～1.40(m,2H),0.96(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ12.12 (s, 1H), 3.76 (s, 3H), 2.23 ~ 2.27 (m, 2H), 2.06 (s, 2H), 1.37 ~ 1.40 (m, 2H), 0.96 (s, 6H).
步骤H：4,4-二甲基-2-(((三氟甲基)磺酰基)氧基)环己-1-烯-1-甲酸甲酯Step H: Methyl 4,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-1-ene-1-carboxylate
Figure PCTCN2017100226-appb-000023
Figure PCTCN2017100226-appb-000023
将钠氢(11.8g,0.3mol)悬浮于二氯甲烷(1L)中，冷却至0℃，加入4,4-二甲基-2-氧代环己烷-1-甲酸甲酯(27g,0.15mol)。反应液在0℃继续反应30分钟，然后冷却至-78℃，加入三氟甲磺酸酐(27mL,0.16mol)。加毕，升至室温反应40小时。然后倾入水中，用二氯甲烷萃取，萃取液用饱和食盐水洗涤，无水硫酸钠干燥，除去溶剂，得到产品(46g,99％)。Suspension of sodium hydrogen (11.8 g, 0.3 mol) in dichloromethane (1 L), cooled to 0 ° C, and added 4,4-dimethyl-2-oxocyclohexane-1-carboxylic acid methyl ester (27 g, 0.15 mol). The reaction was continued at 0 ° C for 30 minutes, then cooled to -78 ° C and trifluoromethanesulfonic acid anhydride (27 mL, 0.16 mol). After the addition, the reaction was allowed to rise to room temperature for 40 hours. Then, it was poured into water and extracted with dichloromethane. The extract was washed with brine, dried over anhydrous sodium sulfate
1H NMR(400MHz,CDCl3)δ3.80(s,3H),2.48～2.52(m,2H),2.17(s,2H),1.42～1.45(m,2H),1.00(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.80 (s, 3H), 2.48 to 2.52 (m, 2H), 2.17 (s, 2H), 1.42 to 1.45 (m, 2H), 1.00 (s, 6H).
步骤I：4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-甲酸甲酯Step I: Methyl 4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylate
Figure PCTCN2017100226-appb-000024
Figure PCTCN2017100226-appb-000024
氮气保护下，4,4-二甲基-2-(((三氟甲基)磺酰基)氧基)环己-1-烯-1-甲酸甲酯(43g,0.14mol)、对氯苯硼酸(23.4g,0.15mol)、磷酸钾(57.7g,0.27mol)，Pd(dppf)Cl2(10g,0.014mol)在乙二醇二甲醚/甲醇/水(5/1/1)的混合溶剂(700mL)中于70℃反应20小时。冷却至室温后，倾入水中，用乙酸乙酯萃取，萃取液用饱和食盐水洗涤，无水硫酸钠干燥，除去溶剂，柱层析纯化,以石油醚/二氯甲烷(3/1)洗脱，得到产品(29g,77％)。Methyl 4,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-1-ene-1-carboxylate (43 g, 0.14 mol), p-chlorobenzene under N2 Boric acid (23.4 g, 0.15 mol), potassium phosphate (57.7 g, 0.27 mol), Pd(dppf)Cl 2 (10 g, 0.014 mol) in ethylene glycol dimethyl ether/methanol/water (5/1/1) The reaction was carried out at 70 ° C for 20 hours in a mixed solvent (700 mL). After cooling to room temperature, it was poured into water and extracted with EtOAc. EtOAc was evaporated. Take off and get the product (29g, 77%).
1H NMR(400MHz,CDCl3)δ7.27(d,J＝8.0Hz,2H),7.03(d,J＝8.0Hz,2H),3.46(s,3H),2.43～2.48(m,2H),2.12～2.13(m,2H),1.47～1.50(m,2H),0.99(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.27 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 3.46 (s, 3H), 2.43 to 2.48 (m, 2H) , 2.12 to 2.13 (m, 2H), 1.47 to 1.50 (m, 2H), 0.99 (s, 6H).
步骤J：(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-二苯基]-2-基)甲醇 Step J: (4'-Chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-diphenyl]-2-yl)methanol
Figure PCTCN2017100226-appb-000025
Figure PCTCN2017100226-appb-000025
将4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-二苯基]-2-甲酸甲酯(650mg,2.3mmol)溶于四氢呋喃(20mL)中，加入硼氢化锂溶液(3.5mL,14mmol)，然后缓慢滴加甲醇(2.4mL)。滴加完毕，反应液在室温下搅拌过夜。用1N盐酸淬灭反应，然后用二氯甲烷萃取，萃取液用饱和食盐水洗涤，无水硫酸钠干燥，除去溶剂，柱层析纯化，用二氯甲烷洗脱，得到产品(330mg,57％)。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) ).
1H NMR(400MHz,CDCl3)δ7.17～7.20(m,2H),6.95～6.98(m,2H),3.84(s,2H),2.18～2.22(m,2H),1.94(s,2H),1.37～1.40(m,2H),0.88(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.17 - 7.20 (m, 2H), 6.95 - 6.98 (m, 2H), 3.84 (s, 2H), 2.18 - 2.22 (m, 2H), 1.94 (s, 2H) ), 1.37 to 1.40 (m, 2H), 0.88 (s, 6H).
步骤K：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯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
Figure PCTCN2017100226-appb-000026
Figure PCTCN2017100226-appb-000026
室温下，(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲醇(120mg,0.48mmol)溶于二氯甲烷(3mL)，冷却至0℃，加入三乙胺(98mg,0.96mmol)、甲磺酰氯(60mg,0.58mmol)，保持在0℃继续搅拌30分钟。将反应体系加入2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯(168mg,0.48mmol)的二氯甲烷(2mL)溶液中，室温搅拌过夜。加入水，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩。残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(20/1)，得到目标产物(30mg,11％)。(4'-Chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methanol (120 mg, 0.48 mmol) dissolved at room temperature Trichloromethane (3 mL) was cooled to 0.degree. C. and triethylamine (98 mg, 0.96 mmol), m. Add the reaction system to 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoic acid Methyl ester (168 mg, 0.48 mmol) in dichloromethane (2 mL) Water was added, and the mixture was combined with dichloromethane. The residue was separated by preparative EtOAc (EtOAc:MeOHMeOHMeOHMeOH
1H NMR(400MHz,CDCl3)δ10.69(br,1H),8.15(d,J＝2.0Hz,1H),7.88(d,J＝8.4Hz,1H),7.57(d,J＝2.4Hz,1H),7.39(t,J＝2.4Hz 1H),7.22(d,J＝8.0Hz,2H),7.02(d,J＝8.0Hz,1H),6.93(d,J＝8.4Hz,2H),6.78(s,1H),6.45(br,1H),5.86(br,1H),3.85(s,3H),3.22(br,4H),2.73(br,2H),2.44(s,2H),2.36(s,2H),2.01(s,2H),1.45(t,J＝5.6Hz,2H),0.94(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ10.69 (br, 1H), 8.15 (d, J = 2.0Hz, 1H), 7.88 (d, J = 8.4Hz, 1H), 7.57 (d, J = 2.4Hz , 1H), 7.39 (t, J = 2.4 Hz 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H) , 6.78 (s, 1H), 6.45 (br, 1H), 5.86 (br, 1H), 3.85 (s, 3H), 3.22 (br, 4H), 2.73 (br, 2H), 2.44 (s, 2H), 2.36 (s, 2H), 2.01 (s, 2H), 1.45 (t, J = 5.6 Hz, 2H), 0.94 (s, 6H).
步骤L：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸 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
Figure PCTCN2017100226-appb-000027
Figure PCTCN2017100226-appb-000027
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯(30mg,0.05mmol)溶于1,4-二氧六环(6mL),加入氢氧化钠水溶液(1.5mL,1.5mmol)，加热至50℃搅拌2小时。加入磷酸二氢钠饱和水溶液至pH为6，乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，除去溶剂，得到目标产物(30mg,100％)。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 methyl ester (30 mg, 0.05 mmol Dissolved in 1,4-dioxane (6 mL), added with aqueous sodium hydroxide (1.5 mL, 1.5 mmol), and then warmed to 50 ° C and stirred for 2 hr. A saturated aqueous solution of sodium dihydrogen phosphate was added to pH 6 and ethyl acetate was evaporated. EtOAc (EtOAc)
1H NMR(400MHz,CDCl3)δ10.96(br,2H),8.02(br,1H),7.77(t,J＝8.8Hz,1H),7.45(s,1H),7.16～7.22(m,3H),6.88～6.94(m,3H),6.75(d,J＝14Hz,1H),6.24(s,1H),5.77(d,J＝19.2Hz,1H),3.18(br,2H),3.09(br,2H),2.59～2.63(m,2H),2.30(br,4H),1.96(s,2H),1.35～1.43(m,2H),0.90(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ10.96 (br, 2H), 8.02 (br, 1H), 7.77 (t, J = 8.8Hz, 1H), 7.45 (s, 1H), 7.16 ~ 7.22 (m, 3H), 6.88 to 6.94 (m, 3H), 6.75 (d, J = 14 Hz, 1H), 6.24 (s, 1H), 5.77 (d, J = 19.2 Hz, 1H), 3.18 (br, 2H), 3.09 (br, 2H), 2.59 to 2.63 (m, 2H), 2.30 (br, 4H), 1.96 (s, 2H), 1.35 to 1.43 (m, 2H), 0.90 (s, 6H).
步骤M：3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯磺酰胺Step M: 3-Nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide
Figure PCTCN2017100226-appb-000028
Figure PCTCN2017100226-appb-000028
将4-氯-3-硝基苯磺酰胺(2.36g,10mmol)与(四氢-2H-吡喃-4-基)甲胺(1.61g,14mmol)溶于乙腈(30mL),然后加入二异丙基乙基胺(5.3mL,30mmol)。加热回流过夜，冷却后倾入水中，充分搅拌后过滤。用乙酸乙酯洗涤固体，干燥后得产品(3.0g,95％)。4-Chloro-3-nitrobenzenesulfonamide (2.36 g, 10 mmol) and (tetrahydro-2H-pyran-4-yl)methylamine (1.61 g, 14 mmol) were dissolved in acetonitrile (30 mL) Isopropylethylamine (5.3 mL, 30 mmol). It was heated to reflux overnight, cooled, poured into water, stirred well and filtered. The solid was washed with ethyl acetate and dried to give product (3.0 g, 95%).
1H NMR(400MHz,d6-DMSO)δ8.56(t,J＝6.0Hz,1H),8.44(d,J＝1.6Hz,1H),7.78～7.81(m,1H),7.27～7.31(m,3H),3.81～3.85(m,2H),3.31～3.35(m,2H),3.21～3.27(m,2H),1.87～1.92(m,1H),1.57～1.61(m,2H),1.23～1.29(m,2H)。 1 H NMR (400 MHz, d6-DMSO) δ 8.56 (t, J = 6.0 Hz, 1H), 8.44 (d, J = 1.6 Hz, 1H), 7.78 to 7.81 (m, 1H), 7.27 to 7.31 (m) , 3H), 3.81 to 3.85 (m, 2H), 3.31 to 3.35 (m, 2H), 3.21 to 3.27 (m, 2H), 1.87 to 1.92 (m, 1H), 1.57 to 1.61 (m, 2H), 1.23 ~1.29 (m, 2H).
步骤N：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000029
Figure PCTCN2017100226-appb-000029
将2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(30mg,0.05mmol)和三乙胺(10mg,0.1mmol) 混合后加入3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯磺酰胺(17mg,0.05mmol)、EDCI(13mg,0.07mmol)、DMAP(12mg,0.1mmol)的二氯甲烷溶液中，室温搅拌过夜。用二氯甲烷稀释，水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(20mg,44％)。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 (30 mg, 0.05 mmol) And triethylamine (10 mg, 0.1 mmol) After mixing, 3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (17 mg, 0.05 mmol), EDCI (13 mg, 0.07 mmol), DMAP ( A solution of 12 mg, 0.1 mmol) in dichloromethane was stirred at room temperature overnight. Diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate 44%).
1H NMR(400MHz,CD3OD)δ9.50(br,1H),8.93(d,J＝2.0Hz,1H),8.55(t,J＝7.2Hz,1H),8.17～8.21(m,2H),8.05(d,J＝8.4Hz,1H),7.71(d,J＝2.0Hz,2H),7.49(t,J＝2.8Hz,1H),7.24(d,J＝8.4Hz,2H),7.10(d,J＝8.4Hz,1H),6.93～6.96(m,2H),6.67(s,1H),6.56～6.57(m,1H),5.90(br,1H),4.03～4.07(m,2H),3.41～3.47(m,2H),3.27～3.30(m,2H),2.97(br,4H),2.19～2.58(m,7H),2.01(s,3H),1.74～1.78(m,2H),1.43～1.48(m,4H),0.96(s,6H)。 1 H NMR (400 MHz, CD 3 OD) δ 9.50 (br, 1H), 8.93 (d, J = 2.0 Hz, 1H), 8.55 (t, J = 7.2 Hz, 1H), 8.17 to 8.21 (m, 2H) ), 8.05 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 2.0 Hz, 2H), 7.49 (t, J = 2.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 1H), 6.93 to 6.96 (m, 2H), 6.67 (s, 1H), 6.56 to 6.57 (m, 1H), 5.90 (br, 1H), 4.03 to 4.07 (m, 2H), 3.41 to 3.47 (m, 2H), 3.27 to 3.30 (m, 2H), 2.97 (br, 4H), 2.19 to 2.58 (m, 7H), 2.01 (s, 3H), 1.74 to 1.78 (m, 2H), 1.43 to 1.48 (m, 4H), 0.96 (s, 6H).
实施例2Example 2
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基-N-((4-((2-甲氧乙基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000030
Figure PCTCN2017100226-appb-000030
步骤A：4-((2-甲氧基乙基)氨基)-3-硝基苯磺酰胺Step A: 4-((2-Methoxyethyl)amino)-3-nitrobenzenesulfonamide
Figure PCTCN2017100226-appb-000031
Figure PCTCN2017100226-appb-000031
室温下，4-氯-3-硝基苯磺酰胺(570mg,2.4mmol,)、2-甲氧基乙胺(250mg,3.3mmol)和三乙胺(900mg,7.2mmol)溶于乙腈(5mL),加热至80℃搅拌过夜。除去溶剂，加水析出固体，用水和乙醇洗涤，得到黄色固体产物(450mg,68％)。4-Chloro-3-nitrobenzenesulfonamide (570 mg, 2.4 mmol), 2-methoxyethylamine (250 mg, 3.3 mmol) and triethylamine (900 mg, 7.2 mmol) were dissolved in acetonitrile (5 mL) ), heated to 80 ° C and stirred overnight. The solvent was removed, the residue was crystallisjjjjjjjjjjjjj
1H NMR(400MHz,CDCl3)δ8.76(d,J＝2.0Hz,1H),8.57(br,1H),7.89～7.92(m,1H),6.98(d,J＝7.2Hz,1H),4.82(br,2H),3.69～3.72(m,2H),3.54～3.58(m,2H),3.44(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.76 (d, J = 2.0Hz, 1H), 8.57 (br, 1H), 7.89 ~ 7.92 (m, 1H), 6.98 (d, J = 7.2Hz, 1H) , 4.82 (br, 2H), 3.69 to 3.72 (m, 2H), 3.54 to 3.58 (m, 2H), 3.44 (s, 3H).
步骤B：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基-N-((4-((2-甲氧乙基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000032
Figure PCTCN2017100226-appb-000032
将2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(30mg,0.05mmol)和三乙胺(10mg,0.1mmol)混合后加入4-((2-甲氧基乙基)氨基)-3-硝基苯磺酰胺(15mg,0.05mmol)、EDCI(13mg,0.07mmol)、DMAP(12mg,0.1mmol)的二氯甲烷(2mL)溶液中，室温搅拌过夜，用二氯甲烷稀释，水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(20mg,46％)。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 (30 mg, 0.05 mmol) After mixing with triethylamine (10 mg, 0.1 mmol), 4-((2-methoxyethyl)amino)-3-nitrobenzenesulfonamide (15 mg, 0.05 mmol), EDCI (13 mg, 0.07 mmol), A solution of DMAP (12 mg, 0.1 mmol) in dichloromethane (2 mL) The developing solvent was dichloromethane/methanol (15/1) to give the desired product (20 mg, 46%).
1H NMR(400MHz,CD3OD)δ9.84～9.90(m,1H),8.87(d,J＝2.4Hz,1H),8.60(t,J＝5.2Hz,1H),8.12～8.15(m,1H),8.08(s,1H),7.99(d,J＝8.4Hz,1H),7.66(d,J＝2.0Hz,1H),7.46(t,J＝2.8Hz,1H),7.21～7.24(m,2H),7.01～7.05(t,J＝8.4Hz,1H),6.91～6.97(m,3H),6.62～6.64(d,J＝5.2Hz,1H),6.52(t,J＝1.6Hz,1H),5.82～5.85(m,1H),3.69(t,J＝5.6Hz,2H),3.52～3.56(m,2H),3.44(s,3H),3.01～3.29(m,4H),2.56～2.88(m,3H),2.25～2.42(m,4H),2.02～2.09(m,2H),1.42～1.47(m,2H),0.95(d,J＝3.2Hz,6H)。 1 H NMR (400 MHz, CD 3 OD) δ 9.84 - 9.90 (m, 1H), 8.87 (d, J = 2.4 Hz, 1H), 8.60 (t, J = 5.2 Hz, 1H), 8.12 to 8.15 (m) , 1H), 8.08 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.46 (t, J = 2.8 Hz, 1H), 7.21 to 7.24 (m, 2H), 7.01 to 7.05 (t, J = 8.4 Hz, 1H), 6.91 to 6.97 (m, 3H), 6.62 to 6.64 (d, J = 5.2 Hz, 1H), 6.52 (t, J = 1.6) Hz, 1H), 5.82 to 5.85 (m, 1H), 3.69 (t, J = 5.6 Hz, 2H), 3.52 to 3.56 (m, 2H), 3.44 (s, 3H), 3.01 to 3.29 (m, 4H) , 2.56 to 2.88 (m, 3H), 2.25 to 2.42 (m, 4H), 2.02 to 2.09 (m, 2H), 1.42 to 1.47 (m, 2H), 0.95 (d, J = 3.2 Hz, 6H).
实施例3Example 3
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-哌啶-4-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000033
Figure PCTCN2017100226-appb-000033
步骤A：4-(3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(甲氧羰基)苯基)哌啶-1-甲酸叔丁酯Step A: 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000034
Figure PCTCN2017100226-appb-000034
室温下，将4-(3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(甲氧羰基)苯基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯(290mg,0.64mmol)溶于甲醇(5mL)中，加入10％钯碳(100mg)，并于1atm氢气下搅拌1小时，然后加入6滴醋酸，继续在1atm氢气下搅拌过夜。硅藻土过滤，滤液浓缩，得到白色固体产物(288mg,99％)。4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(methoxycarbonyl)phenyl)-5,6-dihydropyridine at room temperature -1(2H)-tert-butyl formate (290 mg, 0.64 mmol) was dissolved in methanol (5 mL), 10% palladium carbon (100 mg) was added, and stirred under 1 atm of hydrogen for 1 hour, then 6 drops of acetic acid were added and continued. Stir under 1 atm of hydrogen overnight. The mixture was filtered through EtOAc (EtOAc)EtOAc.
1H NMR(400MHz,CDCl3)δ10.09(br,1H),8.10(d,J＝2.4Hz,1H),7.89(d,J＝8.0Hz,1H),7.61(d,J＝2.4Hz,1H),7.39(s,1H),7.00～7.02(m,1H),6.71(s,1H),6.48(d,J＝3.2Hz,1H),4.20(br,2H),3.88(s,3H),2.69-2.75(m,2H),2.54～2.60(m,1H),1.73～1.77(m,2H),1.50～1.54(m,2H),1.44(s,9H)。 1 H NMR (400MHz, CDCl 3 ) δ10.09 (br, 1H), 8.10 (d, J = 2.4Hz, 1H), 7.89 (d, J = 8.0Hz, 1H), 7.61 (d, J = 2.4Hz , 1H), 7.39 (s, 1H), 7.00 to 7.02 (m, 1H), 6.71 (s, 1H), 6.48 (d, J = 3.2 Hz, 1H), 4.20 (br, 2H), 3.88 (s, 3H), 2.69-2.75 (m, 2H), 2.54 to 2.60 (m, 1H), 1.73 to 1.77 (m, 2H), 1.50 to 1.54 (m, 2H), 1.44 (s, 9H).
步骤B：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(哌啶-4-基)苯甲酸甲酯 Step B: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperidin-4-yl)benzoate
Figure PCTCN2017100226-appb-000035
Figure PCTCN2017100226-appb-000035
4-(3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(甲氧羰基)苯基)哌啶-1-甲酸叔丁酯(288mg,0.64mmol)溶于二氯甲烷(2mL),冷却至0℃,加入三氟乙酸(1mL)，保持在0℃下继续搅拌3小时。加入饱和碳酸钠水溶液至pH为8，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，除去溶剂，得到目标产物(223mg,99％)。tert-Butyl 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (288 mg, 0.64 mmol) was dissolved in dichloromethane (2 mL), cooled to 0 <0>C, trifluoroacetic acid (1 mL) was then evaporated. A saturated aqueous solution of sodium carbonate was added to pH 8 and extracted with dichloromethane. EtOAc was evaporated.
1H NMR(400MHz,CDCl3)δ9.89(br,1H),8.17(d,J＝2.4Hz,1H),7.86(d,J＝8.0Hz,1H),7.57(d,J＝2.4Hz,1H),7.37(d,J＝3.2Hz,1H),6.99(d,J＝8.0Hz,1H),6.71(s,1H),6.46(d,J＝3.2Hz,1H),3.86(s,3H),3.11～3.15(m,2H),2.63～2.69(m,2H),2.49～2.57(m,1H),2.06(br,1H),1.72～1.75(m,2H),1.51～1.58(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.89 (br, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 2.4 Hz) , 1H), 7.37 (d, J = 3.2 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.71 (s, 1H), 6.46 (d, J = 3.2 Hz, 1H), 3.86 (s) , 3H), 3.11 to 3.15 (m, 2H), 2.63 to 2.69 (m, 2H), 2.49 to 2.57 (m, 1H), 2.06 (br, 1H), 1.72 to 1.75 (m, 2H), 1.51 to 1.58 (m, 2H).
步骤C：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-哌啶-4-基)苯甲酸甲酯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
Figure PCTCN2017100226-appb-000036
Figure PCTCN2017100226-appb-000036
将(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲醇(174mg,0.69mmol)溶于二氯甲烷(3mL)中，冷却至0℃，分别加入三乙胺(140mg,1.38mmol)和甲磺酰胺(91mg,0.79mmol)，升至室温搅拌30分钟，将该反应体系逐滴加入至2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(哌啶-4-基)苯甲酸甲酯(242mg,0.69mmol)的二氯甲烷(2mL)溶液中。滴加完毕，室温下搅拌过夜。加水淬灭反应，二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩。残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(20/1)，得到目标产物(120mg,30％)。Dissolve (4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methanol (174 mg, 0.69 mmol) In dichloromethane (3 mL), cooled to 0 ° C, and then added triethylamine (140 mg, 1.38 mmol) and methanesulfonamide (91 mg, 0.79 mmol), and the mixture was stirred at room temperature for 30 minutes, and the reaction system was added dropwise. Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperidin-4-yl)benzoate (242 mg, 0.69 mmol) 2 mL) in solution. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. The reaction was quenched with EtOAc (EtOAc)EtOAc. The residue was separated by preparative EtOAc (EtOAc:MeOHMeOHMeOHMeOH
1H NMR(400MHz,CDCl3)δ9.23(br,1H),8.13(d,J＝1.2Hz,1H),7.86(d,J＝8.0Hz,1H),7.55(d,J＝0.2Hz,1H),7.30～7.36(m,3H),7.12(br,1H),6.93(d,J＝8.0Hz,2H),6.64(s,1H),6.46(d,J＝0.5Hz,1H),3.85(s,3H),3.43(br,4H),2.44～2.67(m,5H),2.04(br,2H),1.63～1.79(m,4H),1.42(br,2H),0.96(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.23 (br, 1H), 8.13 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 0.2 Hz) , 1H), 7.30 to 7.36 (m, 3H), 7.12 (br, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.64 (s, 1H), 6.46 (d, J = 0.5 Hz, 1H) , 3.85 (s, 3H), 3.43 (br, 4H), 2.44 to 2.67 (m, 5H), 2.04 (br, 2H), 1.63 to 1.79 (m, 4H), 1.42 (br, 2H), 0.96 (s) , 6H).
步骤D：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌啶-4-基)苯甲酸 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
Figure PCTCN2017100226-appb-000037
Figure PCTCN2017100226-appb-000037
室温下，甲基-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-哌啶-4-基)苯甲酸酯(120mg,0.20mmol)溶于1,4-二氧六环(12mL),加入1N的氢氧化钠水溶液(3.0mL,3.0mmol)，加热至50℃搅拌2小时，冷却至室温后，加入磷酸二氢钠饱和水溶液调pH至6，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，除去溶剂，得到目标产物(110mg,95％)。Methyl-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl) at room temperature -3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-piperidin-4-yl)benzoate (120 mg, 0.20 mmol) was dissolved Add 1,4-dioxane (12 mL), add 1N aqueous sodium hydroxide solution (3.0 mL, 3.0 mmol), stir to 50 ° C for 2 hours, cool to room temperature, then add a saturated aqueous solution of sodium dihydrogen phosphate to adjust the pH to The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate.
1H NMR(400MHz,d6-DMSO)δ12.7(br,1H),11.68(s,1H),8.00(d,J＝2.4Hz,1H),7.73(d,J＝8.0Hz,1H),7.49～7.51(m,2H),7.34(d,J＝8.4Hz,2H),7.03～7.05(m,3H),6.70(d,J＝0.8Hz,1H),6.39～6.40(m,1H),3.21～3.28(m,2H),2.73(br,4H),2.38～2.32(m,1H),2.12～2.15(m,2H),1.95(br,2H),1.58～1.62(m,2H),1.43～1.49(br,2H),1.38(t,J＝7.2Hz,2H),0.92(s,6H)。 1 H NMR (400MHz, d6- DMSO) δ12.7 (br, 1H), 11.68 (s, 1H), 8.00 (d, J = 2.4Hz, 1H), 7.73 (d, J = 8.0Hz, 1H), 7.49 to 7.51 (m, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.03 to 7.05 (m, 3H), 6.70 (d, J = 0.8 Hz, 1H), 6.39 to 6.40 (m, 1H) , 3.21 to 3.28 (m, 2H), 2.73 (br, 4H), 2.38 to 2.32 (m, 1H), 2.12 to 2.15 (m, 2H), 1.95 (br, 2H), 1.58 to 1.62 (m, 2H) , 1.43 to 1.49 (br, 2H), 1.38 (t, J = 7.2 Hz, 2H), 0.92 (s, 6H).
步骤E：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-哌啶-4-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000038
Figure PCTCN2017100226-appb-000038
将2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌啶-4-基)苯甲酸(40mg,0.070mmol)和3-硝基-4-((四氢-2H-吡喃-4-基)甲基胺)苯甲磺酰胺(27mg,0.086mmol)溶于二氯甲烷(3mL)中，加入三乙胺(16mg,0.16mmol)、EDCI(20mg,0.10mmol)和DMAP(20mg,0.16mmol)，室温下搅拌过夜。用水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(26mg,43％)。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 (40 mg, 0.070 mmol) and 3-nitro-4-(( Tetrahydro-2H-pyran-4-yl)methylamine) Benzylsulfonamide (27 mg, 0.086 mmol) was dissolved in dichloromethane (3 mL), triethylamine (16 mg, 0.16 mmol), EDCI (20 mg) , 0.10 mmol) and DMAP (20 mg, 0.16 mmol) were stirred at room temperature overnight. The mixture was washed with water and brine, dried over NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
1H NMR(400MHz,d6-DMSO)δ12.19(br,1H),11.73(br,1H),8.74(br,1H),8.55～8.61(m,2H),8.01(s,1H),7.82(d,J＝6.4Hz,1H),7.62(br,1H),7.53(s,1H),7.47(d,J＝8.0Hz,1H),7.39(d,J＝8.2Hz,2H),7.07(d,J＝8.2Hz,2H),6.93(d,J＝8.4Hz,1H),6.51(s,1H),6.41(s,1H),3.81～3.84(m,2H),3.47(br,2H),3.21～3.28(m,6H),2.52～2.67(m,5H),2.16(br,2H),1.99(br,2H),1.84(m,1H),1.74(br,2H),1.57(d,J＝10.8Hz,2H),1.42～1.44(m,2H),1.22～1.25(m,2H),0.92(s,6H)。 1 H NMR (400MHz, d6- DMSO) δ12.19 (br, 1H), 11.73 (br, 1H), 8.74 (br, 1H), 8.55 ~ 8.61 (m, 2H), 8.01 (s, 1H), 7.82 (d, J = 6.4 Hz, 1H), 7.62 (br, 1H), 7.53 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 6.93 (d, J = 8.4 Hz, 1H), 6.51 (s, 1H), 6.41 (s, 1H), 3.81 to 3.84 (m, 2H), 3.47 (br, 2H), 3.21 to 3.28 (m, 6H), 2.52 to 2.67 (m, 5H), 2.16 (br, 2H), 1.99 (br, 2H), 1.84 (m, 1H), 1.74 (br, 2H), 1.57 (d, J = 10.8 Hz, 2H), 1.42 to 1.44 (m, 2H), 1.22 to 1.25 (m, 2H), 0.92 (s, 6H).
实施例4 Example 4
2-((6-氨基吡啶-3-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000039
Figure PCTCN2017100226-appb-000039
步骤A：2-((6-氨基吡啶-3-基)氧基)-4-溴苯甲酸甲酯Step A: Methyl 2-((6-aminopyridin-3-yl)oxy)-4-bromobenzoate
Figure PCTCN2017100226-appb-000040
Figure PCTCN2017100226-appb-000040
将4-溴-2-氟苯甲酸甲酯(3.1g，13.3mmol)与6-氨基吡啶-3-酚(1.76g，16mmol)溶于N,N-二甲基甲酰胺(30mL)，加入碳酸钾(3.67g，26.6mmol)，氮气保护下于80℃反应4小时。冷却至室温后，将反应液倾入水中，用乙酸乙酯萃取，用饱和食盐水洗涤有机相，无水硫酸钠干燥，除去溶剂。残留物经柱层析(二氯甲烷/甲醇＝20/1)纯化得到产品(0.9g,21％)。Methyl 4-bromo-2-fluorobenzoate (3.1 g, 13.3 mmol) and 6-aminopyridin-3-ol (1.76 g, 16 mmol) were dissolved in N,N-dimethylformamide (30 mL). Potassium carbonate (3.67 g, 26.6 mmol) was reacted at 80 ° C for 4 hours under nitrogen. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The residue was purified by column chromatography (dichloromethanol / methanol = 20/1).
1H NMR(400MHz,CDCl3)δ7.90(d,J＝2.8Hz,1H),7.75(d,J＝8.4Hz,1H),7.22～7.25(m,1H),7.18～7.21(m,1H),6.95(d,J＝1.6Hz,1H),6.54(d,J＝9.2Hz,1H),4.42(brs,2H),3.88(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (d, J = 2.8 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.22 to 7.25 (m, 1H), 7.18 to 7.21 (m, 1H), 6.95 (d, J = 1.6 Hz, 1H), 6.54 (d, J = 9.2 Hz, 1H), 4.42 (brs, 2H), 3.88 (s, 3H).
步骤B：4-(3-((6-氨基吡啶-3-基)氧基)-4-(甲氧羰基)苯基-3,6-二氢吡啶-1(2H)-甲酸叔丁酯Step B: 4-(3-((6-Aminopyridin-3-yl)oxy)-4-(methoxycarbonyl)phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000041
Figure PCTCN2017100226-appb-000041
氮气保护下，2-((6-氨基吡啶-3-基)氧基)-4-溴苯甲酸甲酯(850mg，2.63mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(813mg,2.63mmol)、磷酸钾(1.12g,5.26mmol)与Pd(dppf)Cl2(190mg,0.26mmol)在乙二醇二甲醚(30mL)和水(6mL)的混合溶剂中于80℃反应12小时。然后倾入水中，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，经柱层析(二氯甲烷/甲醇＝20/1)纯化得到产品(1.1g,98％)。Methyl 2-((6-aminopyridin-3-yl)oxy)-4-bromobenzoate (850 mg, 2.63 mmol), 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (813 mg, 2.63 mmol), potassium phosphate (1.12 g, 5.26 mmol) It was reacted with Pd(dppf)Cl 2 (190 mg, 0.26 mmol) in a mixed solvent of ethylene glycol dimethyl ether (30 mL) and water (6 mL) at 80 ° C for 12 hours. Then, it was poured into water, and the mixture was extracted with EtOAc. EtOAc (EtOAc m. , 98%).
1H NMR(400MHz,CDCl3)δ7.87～7.91(m,2H),7.19～7.22(m,1H),7.12～7.15(m,1H),6.85(d,J＝1.2Hz,1H),6.53～6.55(m,1H),6.04(brs,1H),4.38(s,2H),4.06(d,J＝2.8Hz,2H),3.89(s,3H),3.60(t,J＝5.6Hz,2H),2.42(brs,2H),1.49(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.87 - 7.91 (m, 2H), 7.19 - 7.22 (m, 1H), 7.12 - 7.15 (m, 1H), 6.85 (d, J = 1.2 Hz, 1H), 6.53 to 6.55 (m, 1H), 6.04 (brs, 1H), 4.38 (s, 2H), 4.06 (d, J = 2.8 Hz, 2H), 3.89 (s, 3H), 3.60 (t, J = 5.6 Hz) , 2H), 2.42 (brs, 2H), 1.49 (s, 9H).
步骤C:2-((6-氨基吡啶-3-基)氧基)-4-(1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯Step C: Methyl 2-((6-aminopyridin-3-yl)oxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoate
Figure PCTCN2017100226-appb-000042
Figure PCTCN2017100226-appb-000042
将4-(3-((6-氨基吡啶-3-基)氧基)-4-(甲氧羰基)苯基-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(1.2g,2.82mmol)溶于二氯甲烷(5mL),冷却至0℃,加入3mL三氟乙酸，保持在0℃下继续搅拌3小时。加入饱和碳酸钠水溶液至pH值为8，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，除去溶剂，得到目标产物(710mg,77％)。4-(3-((6-Aminopyridin-3-yl)oxy)-4-(methoxycarbonyl)phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.2 g, 2.82 mmol) dissolved in dichloromethane (5 mL), cooled to 0 ° C, added 3 mL of trifluoroacetic acid, and kept stirring at 0 ° C for 3 hours. Add saturated aqueous sodium carbonate solution to pH 8 with dichloromethane The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate
步骤D：2-((6-氨基吡啶-3-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-二苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯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
Figure PCTCN2017100226-appb-000043
Figure PCTCN2017100226-appb-000043
室温下，将(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-二苯基]-2-基)甲醇(231mg,0.92mmol)溶于二氯甲烷(5mL)，加入二异丙基乙基胺(232mg,1.8mmol)，冷却至0℃，加入甲磺酰氯(125mg,1.1mmol)。恢复至室温，反应10分钟后，加入2-((6-氨基吡啶-3-基)氧基)-4-(1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯(300mg,0.92mmol)，在室温下搅拌过夜，然后倾入水中，用二氯甲烷萃取。有机相经饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩后得粗产品，经薄层层析(二氯甲烷/甲醇＝40/1)纯化得产品(150mg,29％)。(4'-Chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-diphenyl]-2-yl)methanol (231 mg, 0.92 mmol) at room temperature Dichloromethane (5 mL) was added, diisopropylethylamine (232 mg, 1.8 mmol) was added, cooled to 0 ° C, and methanesulfonyl chloride (125 mg, 1.1 mmol) was added. After returning to room temperature, after reacting for 10 minutes, methyl 2-((6-aminopyridin-3-yl)oxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoate was added. (300 mg, 0.92 mmol), stirred at room temperature overnight then poured over water and extracted with dichloromethane. The organic layer was washed with EtOAc (EtOAc m.
1H NMR(400MHz,CDCl3)δ7.87(d,J＝2.8Hz,1H),7.84(d,J＝8.0Hz,1H),7.25～7.29(m,1H),7.17～7.20(m,1H),7.05～7.07(m,1H),7.02(d,J＝8.0Hz,1H),6.96～6.98(m,2H),6.78(s,1H),6.54(d,J＝8.8Hz,1H),5.92(s,1H),4.56(brs,2H),3.86(s,3H),3.20(brs,4H),2.74(brs,2H),2.27～2.48(m,4H),2.04(s,2H),1.46～1.51(m,2H),0.98(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.87 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.25 to 7.29 (m, 1H), 7.17 to 7.20 (m, 1H), 7.05 to 7.07 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.96 to 6.98 (m, 2H), 6.78 (s, 1H), 6.54 (d, J = 8.8 Hz, 1H) ), 5.92 (s, 1H), 4.56 (brs, 2H), 3.86 (s, 3H), 3.20 (brs, 4H), 2.74 (brs, 2H), 2.27 to 2.48 (m, 4H), 2.04 (s, 2H), 1.46 to 1.51 (m, 2H), 0.98 (s, 6H).
步骤E：2-((6-氨基吡啶-3-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-二苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸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
Figure PCTCN2017100226-appb-000044
Figure PCTCN2017100226-appb-000044
室温下，2-((6-氨基吡啶-3-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-二苯基]-2- 基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯(80mg,0.14mmol)溶于1,4-二氧六环(6mL),加入1N的氢氧化钠水溶液(3mL,1.5mmol)，升至50℃搅拌2小时。冷却至室温后，加入磷酸二氢钠饱和水溶液至pH值为6，乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，除去溶剂，得到产物(78mg,100％)。2-((6-Aminopyridin-3-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro) at room temperature -[1,1'-diphenyl]-2- Methyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoate (80 mg, 0.14 mmol) dissolved in 1,4-dioxane (6 mL), 1N hydrogen Aqueous sodium hydroxide (3 mL, 1.5 mmol) was stirred at 50 ° C for 2 h. After cooling to room temperature, a saturated aqueous solution of sodium dihydrogen phosphate was added to pH 6 and ethyl acetate was evaporated. ethyl acetate was evaporated. .
步骤F：2-((6-氨基吡啶-3-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000045
Figure PCTCN2017100226-appb-000045
将2-((6-氨基吡啶-3-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-二苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(78mg,0.14mmol)和三乙胺(28mg,0.28mmol)的二氯甲烷(1mL)溶液加入3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯磺酰胺(136mg,0.43mmol)、EDCI(35mg,0.18mmol)、DMAP(34mg,0.28mmol)的二氯甲烷(3mL)溶液中，室温搅拌过夜。用二氯甲烷稀释，水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(20/1)，得到目标产物(62mg,51％)。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 (78 mg, 0.14 mmol) and triethylamine (28 mg, 0.28) To a solution of dichloromethane (1 mL) was added 3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (136 mg, 0.43 mmol), EDCI ( A solution of 35 mg, 0.18 mmol), D.sub.4 (34 mg, 0.28 mmol) in dichloromethane (3 mL) Diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate 51%).
1H NMR(400MHz,d6-DMSO)δ8.60(brs,1H),8.55(s,1H),7.84～7.86(m,1H),7.69(d,J＝2.0Hz,1H),7.45(d,J＝8.0Hz,1H),7.36(d,J＝8.4Hz,2H),7.15～7.20(m,2H),7.04～7.11(m,3H),6.67(s,1H),6.47(d,J＝8.8Hz,1H),5.93～5.97(m,3H),3.82～3.86(m,2H),3.22～3.34(m,8H),2.36～2.49(m,4H),2.19(s,2H),1.96～2.02(m,2H),1.89～1.92(m,1H),1.60～1.63(m,2H),1.42～1.46(m,2H),1.26～1.30(m,2H),0.95(s,6H)。 1 H NMR (400MHz, d6- DMSO) δ8.60 (brs, 1H), 8.55 (s, 1H), 7.84 ~ 7.86 (m, 1H), 7.69 (d, J = 2.0Hz, 1H), 7.45 (d , J = 8.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.15 to 7.20 (m, 2H), 7.04 to 7.11 (m, 3H), 6.67 (s, 1H), 6.47 (d, J=8.8 Hz, 1H), 5.93 to 5.97 (m, 3H), 3.82 to 3.86 (m, 2H), 3.22 to 3.34 (m, 8H), 2.36 to 2.49 (m, 4H), 2.19 (s, 2H) , 1.96 to 2.02 (m, 2H), 1.89 to 1.92 (m, 1H), 1.60 to 1.63 (m, 2H), 1.42 to 1.46 (m, 2H), 1.26 to 1.30 (m, 2H), 0.95 (s, 6H).
实施例5Example 5
4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-二苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(2-氟苯氧基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺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)-N-((3-nitro-4-((tetrahydro-2H-pyran)- 4-yl)methyl)amino)phenyl)sulfonyl)benzamide
Figure PCTCN2017100226-appb-000046
Figure PCTCN2017100226-appb-000046
步骤A：4-溴-2-(2-氟苯氧基)苯甲酸甲酯 Step A: Methyl 4-bromo-2-(2-fluorophenoxy)benzoate
Figure PCTCN2017100226-appb-000047
Figure PCTCN2017100226-appb-000047
室温下，2-苯氟酚(3.00g,0.27mol)、4-溴-2-氟苯甲酸甲酯(6.7g,0.29mol)、碳酸钾(7.4g,0.54mol)溶于N,N-二甲基甲酰胺(100mL)，加热至80℃搅拌1h。冷却至室温，用乙酸乙酯稀释，水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经柱层析纯化(石油醚/二氯甲烷＝3/1)，得到产品(3.3g,38％)。2-Benzylfluorophenol (3.00 g, 0.27 mol), methyl 4-bromo-2-fluorobenzoate (6.7 g, 0.29 mol), potassium carbonate (7.4 g, 0.54 mol) were dissolved in N,N- at room temperature. Dimethylformamide (100 mL) was heated to 80 ° C and stirred for 1 h. The mixture was cooled to room temperature, diluted with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH %).
1H NMR(400MHz,CDCl3)δ7.81(d,J＝8.4Hz,1H),7.29～7.31(m,1H),7.11～7.24(m,3H),7.00～7.06(m,2H),3.86(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 8.4 Hz, 1H), 7.29 to 7.31 (m, 1H), 7.11 to 7.24 (m, 3H), 7.00 to 7.06 (m, 2H), 3.86 (s, 3H).
步骤B：4-(3-(2-氟苯氧基)-4-(甲氧羰基)苯基)-5,6-二氢吡啶-1(2H)–甲酸叔丁酯Step B: 4-(3-(2-Fluorophenoxy)-4-(methoxycarbonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000048
Figure PCTCN2017100226-appb-000048
室温下，4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(3.4g,11mmol)、4-溴-2-(2-氟苯氧基)苯甲酸甲酯(3g,9.2mmol)、磷酸钾(3.9g,18mmol)和Pd(dppf)Cl2(0.68g,0.93mmol)溶于乙二醇二甲醚/水(5/1)的混合溶剂(60mL)中，氮气保护下加热到80℃搅拌过夜。冷却至室温，加入水，用乙酸乙酯萃取，合并乙酸乙酯相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经柱层析纯化(石油醚/乙酸乙酯＝10/1)得到白色固体产物(3.9g,99％)。4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid at room temperature Butyl ester (3.4 g, 11 mmol), methyl 4-bromo-2-(2-fluorophenoxy)benzoate (3 g, 9.2 mmol), potassium phosphate (3.9 g, 18 mmol) and Pd(dppf)Cl 2 ( 0.68 g, 0.93 mmol) was dissolved in a mixed solvent of ethylene glycol dimethyl ether/water (5/1) (60 mL), and heated to 80 ° C under nitrogen atmosphere and stirred overnight. After cooling to room temperature, water was added, and ethyl acetate was evaporated. EtOAc was evaporated. The white solid product (3.9 g, 99%) was obtained.
1H NMR(400MHz,CDCl3)δ7.92(d,J＝8.4Hz,1H),7.17～7.21(m,2H),7.06～7.11(m,2H),6.90～6.93(m,2H),6.08(br,1H),4.05(d,J＝2.4Hz,2H),3.82(s,3H),3.60(t,J＝5.6Hz,2H),2.43～2.44(m,2H),1.47(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.92 (d, J = 8.4 Hz, 1H), 7.17 to 7.21 (m, 2H), 7.06 to 7.11 (m, 2H), 6.90 to 6.93 (m, 2H), 6.08(br,1H),4.05(d,J=2.4Hz,2H),3.82(s,3H), 3.60(t,J=5.6Hz,2H),2.43~2.44(m,2H),1.47(s , 9H).
步骤C：2-(2-氟苯基)-4-(1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯Step C: Methyl 2-(2-fluorophenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoate
Figure PCTCN2017100226-appb-000049
Figure PCTCN2017100226-appb-000049
将4-(3-(2-氟苯氧基)-4-(甲氧羰基)苯基)-5,6-二氢吡啶-1(2H)–甲酸叔丁酯(1g,2.3mmol)溶于二氯甲烷(4mL),加入4mL三氟乙酸后搅拌1h。加入饱和碳酸钠水溶液至pH值为8，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，除去溶剂，得到目标产物(0.7g,92％)。Dissolving 4-(3-(2-fluorophenoxy)-4-(methoxycarbonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1 g, 2.3 mmol) In dichloromethane (4 mL), 4 mL of trifluoroacetic acid was added and stirred for 1 h. A saturated aqueous solution of sodium carbonate was added to pH 8 and extracted with dichloromethane. EtOAc (EtOAc)
1H NMR(400MHz,CDCl3)δ7.91(d,J＝8.4Hz,1H),7.15～7.22(m,2H),7.04～7.08(m,2H),6.94(d,J＝1.2Hz,1H),6.87～6.91(m,1H),6.15(br,1H),3.81(s,3H),3.53～3.54(m,2H), 3.01(t,J＝5.6Hz,2H),2.40(br,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (d, J = 8.4 Hz, 1H), 7.15 - 7.22 (m, 2H), 7.04 - 7.08 (m, 2H), 6.94 (d, J = 1.2 Hz, 1H), 6.87 to 6.91 (m, 1H), 6.15 (br, 1H), 3.81 (s, 3H), 3.53 to 3.54 (m, 2H), 3.01 (t, J = 5.6 Hz, 2H), 2.40 (br) , 2H).
步骤D：4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-二苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(2-氟苯氧基)苯甲酸甲酯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
Figure PCTCN2017100226-appb-000050
Figure PCTCN2017100226-appb-000050
室温下，2-(2-氟苯基)-4-(1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯(57mg,0.17mmol)、2-(4-氯苯基)-4,4-二甲基环己-1-烯甲醛(87mg,0.35mmol)溶于二氯甲烷(5mL)，加入0.5mL醋酸，搅拌30分钟，加入三乙酰氧基硼氢化钠(144mg,0.68mmol)，室温搅拌1h，补加三乙酰氧基硼氢化钠(144mg,0.68mmol),室温继续反应1h。然后倾入水中，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩。残留物用制备薄层板分离，展开剂为(石油醚/乙酸乙酯＝4/1)，得到目标产物(20mg,21％)。Methyl 2-(2-fluorophenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoate (57 mg, 0.17 mmol), 2-(4-chlorobenzene) 4,4-Dimethylcyclohex-1-enecarboxaldehyde (87 mg, 0.35 mmol) was dissolved in dichloromethane (5 mL), 0.5 mL of acetic acid was added, stirred for 30 minutes, and sodium triacetoxyborohydride was added ( 144 mg, 0.68 mmol), stirred at room temperature for 1 h, then added sodium triacetoxyborohydride (144 mg, 0.68 mmol). Then, it was poured into water, and the mixture was extracted with methylene chloride. The residue was separated by preparative EtOAc (EtOAc:EtOAc:EtOAc)
1H NMR(400MHz,CDCl3)δ7.88(d,J＝8.4Hz,1H),7.25(d,J＝6.8Hz,2H),7.15～7.17(m,2H),7.03～7.08(m,2H),6.97(d,J＝8.8Hz 2H),6.91(d,J＝1.6Hz,1H),6.84～6.88(m,1H),6.05(br,1H),3.80(s,3H),2.92～2.95(m,4H),2.45～2.48(m,2H),2.40(br,2H),2.22～2.25(m,2H),2.00(br,2H),1.44(t,J＝6.4Hz,2H),0.97(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 6.8 Hz, 2H), 7.15 to 7.17 (m, 2H), 7.03 to 7.08 (m, 2H), 6.97 (d, J = 8.8 Hz 2H), 6.91 (d, J = 1.6 Hz, 1H), 6.84 to 6.88 (m, 1H), 6.05 (br, 1H), 3.80 (s, 3H), 2.92 ~ 2.95 (m, 4H), 2.45 to 2.48 (m, 2H), 2.40 (br, 2H), 2.22 to 2.25 (m, 2H), 2.00 (br, 2H), 1.44 (t, J = 6.4 Hz, 2H) ), 0.97 (s, 6H).
步骤E：4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-二苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(2-氟苯氧基)苯甲酸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
Figure PCTCN2017100226-appb-000051
Figure PCTCN2017100226-appb-000051
室温下，4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-二苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(2-氟苯氧基)苯甲酸甲酯(20mg,0.035mmol)溶于1,4-二氧六环(3mL),加入氢氧化钠水溶液(1.5mL,1.5mmol)，加热至50℃搅拌2h。冷却至室温后，加入磷酸二氢钠饱和水溶液至pH为6，乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，除去溶剂，得到目标产物(20mg,100％)。4-(1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-diphenyl]-2-yl)) at room temperature Methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-fluorophenoxy)benzoate (20 mg, 0.035 mmol) dissolved in 1,4-dioxane (3 mL), aqueous sodium hydroxide solution (1.5 mL, 1.5 mmol) was added, and the mixture was heated to 50 ° C and stirred for 2 h. After cooling to room temperature, a saturated aqueous solution of sodium dihydrogen phosphate was added to pH 6 and ethyl acetate was evaporated. ethyl acetate was evaporated. .
1H NMR(400MHz,CDCl3)δ7.87(d,J＝8.0Hz,1H),7.25(d,J＝8.4Hz,2H),7.00～7.18(m,4H),6.94(d,J＝8.0Hz,3H),6.70(br,1H),5.81(br,1H),3.41(br,2H),3.34(br,2H),2.89(br,2H),2.45(br,2H),2.34(br,2H),2.03(br,2H),1.41(t,J＝6.4Hz,2H),0.94(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.87 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.00 to 7.18 (m, 4H), 6.94 (d, J = 8.0 Hz, 3H), 6.70 (br, 1H), 5.81 (br, 1H), 3.41 (br, 2H), 3.34 (br, 2H), 2.89 (br, 2H), 2.45 (br, 2H), 2.34 ( Br, 2H), 2.03 (br, 2H), 1.41 (t, J = 6.4 Hz, 2H), 0.94 (s, 6H).
步骤F：4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-二苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(2-氟苯氧基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺 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
Figure PCTCN2017100226-appb-000052
Figure PCTCN2017100226-appb-000052
将4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-二苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(2-氟苯氧基)苯甲酸(20mg,0.035mmol)和TEA(10mg,0.1mmol)的二氯甲烷溶液(1mL)加入到3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯磺酰胺(11mg,0.036mmol)、EDCI(9mg,0.05mmol)、DMAP(9mg,0.07mmol)的二氯甲烷(2mL)溶液中，室温搅拌过夜，用二氯甲烷稀释，水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷：甲醇＝15：1，得到目标产物(7mg,23％)。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)benzoic acid (20 mg, 0.035 mmol) and TEA (10 mg, 0.1 mmol) in dichloromethane ( 1 mL) was added to 3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (11 mg, 0.036 mmol), EDCI (9 mg, 0.05 mmol), DMAP (9 mg, 0.07 mmol) in dichloromethane (2 mL), EtOAc. The developing solvent was dichloromethane:methanol = 15:1 to give the desired product (7 mg, 23%).
1H NMR(400MHz,CD3OD)δ8.92(d,J＝2.4Hz,1H),8.55(t,J＝5.2Hz,1H),8.17～8.19(m,1H),8.04(d,J＝8.4Hz,1H),7.28～7.33(m,2H),7.24(d,J＝8.4Hz,4H),7.01～7.03(m,1H),6.93～6.96(m,3H),6.62(br,1H),5.84(br,1H),4.01～4.05(m,2H),3.39～3.46(m,2H),3.27～3.30(m,6H),2.32～2.42(m,6H),2.04(br,3H),1.73～1.76(m,2H),1.45～1.50(m,4H),0.97(s,6H)。 1 H NMR (400 MHz, CD 3 OD) δ 8.92 (d, J = 2.4 Hz, 1H), 8.55 (t, J = 5.2 Hz, 1H), 8.17 to 8.19 (m, 1H), 8.04 (d, J) = 8.4 Hz, 1H), 7.28 to 7.33 (m, 2H), 7.24 (d, J = 8.4 Hz, 4H), 7.01 to 7.03 (m, 1H), 6.93 to 6.96 (m, 3H), 6.62 (br, 1H), 5.84 (br, 1H), 4.01 to 4.05 (m, 2H), 3.39 to 3.46 (m, 2H), 3.27 to 3.30 (m, 6H), 2.32 to 2.42 (m, 6H), 2.04 (br, 3H), 1.73 to 1.76 (m, 2H), 1.45 to 1.50 (m, 4H), 0.97 (s, 6H).
实施例6Example 6
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-((4-((4-氟四氢-2H-吡喃-4-基)甲氧基-3-硝基苯基)磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000053
Figure PCTCN2017100226-appb-000053
步骤A：3-(四氢-2H-吡喃-4-基)环氧乙烷-2-腈Step A: 3-(tetrahydro-2H-pyran-4-yl)oxirane-2-carbonitrile
Figure PCTCN2017100226-appb-000054
Figure PCTCN2017100226-appb-000054
将四氢-4H-吡喃-4-酮(20g,200mmol)与氯乙腈(10.56g,140mmol)溶于叔丁醇(20mL)，在室温下反应30分钟。然后在30分钟的时间里，将叔丁醇钾(24.68g,220mmol)悬浮于叔丁醇(200mL)的悬浊液缓慢加入，加完后继续室温反应16小时。随后将反应液用水(200mL)稀释，用3N盐酸淬灭。用乙醚萃取，用饱和食盐水洗涤有机相，无水硫酸钠干燥，除去溶剂得粗产品(18g)，直接用于下一步。 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.
步骤B：2-(4-氟四氢-2H-吡喃-4-基)-2-羟基乙腈Step B: 2-(4-Fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile
Figure PCTCN2017100226-appb-000055
Figure PCTCN2017100226-appb-000055
将实施例6步骤A所得粗产品(18g)溶于二氯甲烷(60mL)，在塑料瓶中搅拌，并冷却至0℃。加入70％的吡啶氟化氢溶液(18mL)后，恢复至室温，反应过夜。然后反应液用乙酸乙酯(200mL)稀释，用饱和碳酸氢钠溶液中和至不再放出气体。用乙酸乙酯萃取，有机相用1％的稀盐酸，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，经柱层析(二氯甲烷/甲醇＝20/1)纯化得到产品(8.2g,两步总收率37％)。The crude product obtained in Step 6 of Example 6 (18 g) was dissolved in dichloromethane (60mL), stirred in a plastic bottle and cooled to 0 °C. After adding 70% pyridine hydrogen fluoride solution (18 mL), it was returned to room temperature and allowed to react overnight. The reaction was then diluted with ethyl acetate (200 mL) and neutralized with saturated sodium bicarbonate until no gas evolved. The mixture was extracted with EtOAc. EtOAc (EtOAc)EtOAc. g, total yield of two steps of 37%).
1H NMR(400MHz,CDCl3)δ4.37(d,J＝15.6Hz,1H),3.92～3.96(m,2H),3.68～3.77(m,2H),3.37(s,1H),1.81～2.02(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 4.37 (d, J = 15.6 Hz, 1H), 3.92 to 3.96 (m, 2H), 3.68 to 3.77 (m, 2H), 3.37 (s, 1H), 1.81 2.02 (m, 4H).
步骤C:(4-氟四氢-2H-吡喃-4-基)甲醇Step C: (4-Fluorotetrahydro-2H-pyran-4-yl)methanol
Figure PCTCN2017100226-appb-000056
Figure PCTCN2017100226-appb-000056
将2-(4-氟四氢-2H-吡喃-4-基)-2-羟基乙腈(8.2g,51.5mmol)溶于异丙醇(160mL)和水(40mL)的混合溶液中,冷却至0℃,分批加入硼氢化钠(2.89g,76.4mmol)，随后升至室温反应过夜。然后加入丙酮淬灭并搅拌1小时。用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，除去溶剂，经柱层析(石油醚/乙酸乙酯＝3/1)纯化得到产品(2.8g,41％)。2-(4-Fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile (8.2 g, 51.5 mmol) was dissolved in a mixed solution of isopropyl alcohol (160 mL) and water (40 mL) and cooled To 0 ° C, sodium borohydride (2.89 g, 76.4 mmol) was added portionwise and then allowed to warm to room temperature overnight. It was then quenched with acetone and stirred for 1 hour. The mixture was extracted with EtOAc. EtOAc (EtOAc)EtOAc.
1H NMR(400MHz,CDCl3)δ3.81～3.86(m,2H),3.70～3.76(m,2H),3.58～3.65(m,2H),3.37(s,1H),1.65～1.88(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.81 to 3.86 (m, 2H), 3.70 to 3.76 (m, 2H), 3.58 to 3.65 (m, 2H), 3.37 (s, 1H), 1.65 to 1.88 (m) , 4H).
步骤D：4-((4-氟四氢-2H-吡喃-4-基)甲氧基)-3-硝基苯磺酰胺Step D: 4-((4-Fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide
Figure PCTCN2017100226-appb-000057
Figure PCTCN2017100226-appb-000057
将(4-氟四氢-2H-吡喃-4-基)甲醇(140mg,1.04mmol)，4-氯-3-硝基苯磺酰胺(225mg,0.95mmol)，60％的钠氢(114g,2.85mmol)在四氢呋喃(5mL)中室温搅拌过夜。然后加水淬灭，用乙酸乙酯萃取。有机相经饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩后得粗产品，经薄层层析(二氯甲烷/甲醇＝20/1)纯化得产品(120mg,38％)。(4-Fluorotetrahydro-2H-pyran-4-yl)methanol (140 mg, 1.04 mmol), 4-chloro-3-nitrobenzenesulfonamide (225 mg, 0.95 mmol), 60% sodium hydrogen (114 g , 2.85 mmol) was stirred at room temperature overnight in tetrahydrofuran (5 mL). It was then quenched with water and extracted with ethyl acetate. The organic phase was washed with EtOAc (EtOAc m.
1H NMR(400MHz,d6-DMSO)δ8.31(d,J＝2.4Hz,1H),8.05～8.08(m,1H),7.60(d,J＝9.2Hz,1H),7.52(s,2H),4.42(d,J＝20.0Hz,2H),3.76～3.80(m,2H),3.56～3.62(m,2H),1.80～1.90(m,4H)。 1 H NMR (400 MHz, d6-DMSO) δ 8.31 (d, J = 2.4 Hz, 1H), 8.05 - 8.08 (m, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.52 (s, 2H) ), 4.42 (d, J = 20.0 Hz, 2H), 3.76 to 3.80 (m, 2H), 3.56 to 3.62 (m, 2H), 1.80 to 1.90 (m, 4H).
步骤E：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-((4-((4-氟四氢-2H-吡喃-4-基)甲氧基-3-硝基苯基)磺酰基)苯甲酰胺 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
Figure PCTCN2017100226-appb-000058
Figure PCTCN2017100226-appb-000058
将2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(50mg,0.088mmol)和TEA(18mg,0.176mmol)的二氯甲烷溶液(1mL)加入到4-((4-氟四氢-2H-吡喃-4-基)甲氧基)-3-硝基苯磺酰胺(29mg,0.088mmol)、EDCI(22mg,0.114mmol)、DMAP(22mg,0.176mmol)的二氯甲烷(2mL)溶液中，室温搅拌过夜，用二氯甲烷稀释，水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇＝20/1，得到目标产物(30mg,39％)。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 (50 mg, 0.088 mmol) Add a solution of TEA (18 mg, 0.176 mmol) in dichloromethane (1 mL) to 4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide ( 29mg, 0.088mmol), EDCI (22mg, 0.114mmol), EtOAc (22mg, 0.176mmol) in dichloromethane (2mL) The title compound (30 mg, 39%) was obtained.
1H NMR(400MHz,d6-DMSO)δ11.59(s,1H),9.19(brs,1H),8.21(s,1H),7.88～7.95(m,2H),7.50(d,J＝8.0Hz,1H),7.44～7.46(m,1H),7.40(s,1H),7.34(d,J＝8.4Hz,2H),7.24(br,1H),7.07～7.09(m,3H),6.75(s,1H),6.33～6.34(m,1H),5.94(br,1H),4.28(d,J＝20.4Hz,2H),3.73～3.77(m,2H),3.53～3.60(m,2H),2.85～3.07(m,4H),2.32～2.43(m,4H),2.16(s,2H),2.00(s,2H),1.79～1.87(m,4H),1.41(s,2H),0.92(s,6H)。 1 H NMR (400MHz, d6- DMSO) δ11.59 (s, 1H), 9.19 (brs, 1H), 8.21 (s, 1H), 7.88 ~ 7.95 (m, 2H), 7.50 (d, J = 8.0Hz , 1H), 7.44 to 7.46 (m, 1H), 7.40 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.24 (br, 1H), 7.07 to 7.09 (m, 3H), 6.75 ( s, 1H), 6.33 to 6.34 (m, 1H), 5.94 (br, 1H), 4.28 (d, J = 20.4 Hz, 2H), 3.73 to 3.77 (m, 2H), 3.53 to 3.60 (m, 2H) , 2.85～3.07(m,4H), 2.32～2.43(m,4H), 2.16(s,2H), 2.00(s,2H), 1.79～1.87(m,4H),1.41(s,2H),0.92 (s, 6H).
实施例7Example 7
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲氧)氨基-3-硝基苯基)磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000059
Figure PCTCN2017100226-appb-000059
步骤A：(4-氟四氢-2H-吡喃-4-基)甲基甲磺酸酯Step A: (4-Fluorotetrahydro-2H-pyran-4-yl)methyl methanesulfonate
Figure PCTCN2017100226-appb-000060
Figure PCTCN2017100226-appb-000060
将(4-氟四氢-2H-吡喃-4-基)甲醇(2.8g，20.9mmol)与三乙胺(3.17g，31.3mmol)溶于二氯甲烷，冷却至0℃。滴加甲磺酰氯(3.59g，31.3mmol)，滴加完毕后恢复到室温，反应2小时。将反应液倾入水中，用二氯甲烷萃取，用饱和食盐水洗涤有机相，无水硫酸钠干燥，除去溶剂得粗产品(4.4g)，直接用于下一步。(4-Fluorotetrahydro-2H-pyran-4-yl)methanol (2.8 g, 20.9 mmol) and triethylamine (3.17 g, 31.3 mmol) were dissolved in dichloromethane and cooled to 0 °C. Methanesulfonyl chloride (3.59 g, 31.3 mmol) was added dropwise, and after completion of the dropwise addition, the mixture was returned to room temperature and reacted for 2 hours. The reaction mixture was poured into water and extracted with dichloromethane.
步骤B：4-(叠氮甲基)-4-氟四氢-2H-吡喃 Step B: 4-(azidomethyl)-4-fluorotetrahydro-2H-pyran
Figure PCTCN2017100226-appb-000061
Figure PCTCN2017100226-appb-000061
将实施例7步骤A所得粗产品(4.4g)溶于N,N-二甲基甲酰胺(60mL)，加入叠氮化钠(6.79g,104.5mmol)、碳酸氢钠(3.51g,41.8mmol)。升至120℃，反应17小时。然后冷却至室温，倾入水中，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩至约30mL，产品的乙酸乙酯溶液直接用于下一步。The crude product obtained in Step 7 of Example 7 (4.4 g) was dissolved in N,N-dimethylformamide (60 mL), sodium azide (6.79 g, 104.5 mmol), sodium hydrogencarbonate (3.51 g, 41.8 mmol) ). The temperature was raised to 120 ° C and the reaction was carried out for 17 hours. After cooling to room temperature, it was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate.
步骤C:(4-氟四氢-2H-吡喃-4-基)甲胺Step C: (4-Fluorotetrahydro-2H-pyran-4-yl)methylamine
Figure PCTCN2017100226-appb-000062
Figure PCTCN2017100226-appb-000062
向实施例7步骤B所得溶液中，加入10％的钯碳(280mg)，在氢气(1atm)下室温搅拌24小时。然后过滤，真空浓缩，经柱层析(二氯甲烷/甲醇＝10/1)纯化得到产品(1.3g,三步总收率47％)。To the solution obtained in Step B of Example 7, 10% palladium on carbon (280 mg) was added, and the mixture was stirred at room temperature under hydrogen (1 atm) for 24 hours. It was then filtered, concentrated in vacuo and purified by column chromatography (dichloromethanol / methanol = 10/1) to afford product (1.3 g, three-step total yield 47%).
1H NMR(400MHz,CDCl3)δ3.80～3.85(m,2H),3.68～3.74(m,2H),2.80(d,J＝20.8Hz,2H),1.60～1.84(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.80 to 3.85 (m, 2H), 3.68 to 3.74 (m, 2H), 2.80 (d, J = 20.8 Hz, 2H), 1.60 to 1.84 (m, 4H).
步骤D：4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯磺酰胺Step D: 4-(((4-Fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide
Figure PCTCN2017100226-appb-000063
Figure PCTCN2017100226-appb-000063
将(4-氟四氢-2H-吡喃-4-基)甲胺(1.25g,9.39mmol)，4-氯-3-硝基苯磺酰胺(2.02g,8.53mmol)，二异丙基乙基胺(3.3g,25.6mmol)溶于乙腈(30mL)，加热回流过夜。然后冷却至室温，倾入水中，用1N盐酸调至pH为6，用乙酸乙酯萃取。有机相经饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩后得粗产品。向粗产品中加入乙酸乙酯(10mL)，搅拌1小时后过滤，用乙酸乙酯洗涤，干燥得产品(1.5g,48％)。(4-Fluorotetrahydro-2H-pyran-4-yl)methanamine (1.25 g, 9.39 mmol), 4-chloro-3-nitrobenzenesulfonamide (2.02 g, 8.53 mmol), diisopropyl Ethylamine (3.3 g, 25.6 mmol) was dissolved in EtOAc (30 mL). Then it was cooled to room temperature, poured into water, adjusted to pH 6 with 1N hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate Ethyl acetate (10 mL) was added to the crude product, which was stirred for 1 hour, filtered, washed with ethyl acetate and dried to give product (1.5 g, 48%).
1H NMR(400MHz,D6-DMSO)δ8.58(t,J＝6.4Hz,1H),8.48(d,J＝2.4Hz,1H),7.82～7.84(m,1H),7.41(d,J＝9.2Hz,1H),7.33(s,1H),3.74～3.81(m,4H),3.50～3.56(m,2H),1.76～1.86(m,4H)。 1 H NMR (400 MHz, D6-DMSO) δ 8.58 (t, J = 6.4 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 7.82 to 7.84 (m, 1H), 7.41 (d, J) = 9.2 Hz, 1H), 7.33 (s, 1H), 3.74 to 3.81 (m, 4H), 3.50 to 3.56 (m, 2H), 1.76 to 1.86 (m, 4H).
步骤E：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲氧)氨基-3-硝基苯基)磺酰基)苯甲酰胺 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
Figure PCTCN2017100226-appb-000064
Figure PCTCN2017100226-appb-000064
将2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(113mg,0.20mmol)和TEA(40mg,0.40mmol)的二氯甲烷溶液(1mL)加入到4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯磺酰胺(67mg,0.20mmol)、EDCI(50mg,0.26mmol)、DMAP(49mg,0.40mmol)的二氯甲烷(2mL)溶液中，室温搅拌过夜，用二氯甲烷稀释，水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇＝20/1，得到目标产物(70mg,40％)。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 (113 mg, 0.20 mmol) And TEA (40 mg, 0.40 mmol) in dichloromethane (1 mL) was added to 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonate A solution of the amide (67 mg, 0.20 mmol), EtOAc (EtOAc, m. The organic layer was dried over anhydrous sodium sulfate (MgSO4).
1H NMR(400MHz,d6-DMSO)δ11.62(s,1H),8.48～8.54(m,2H),7.97(d,J＝2.4Hz,1H),7.76(d,J＝8.4Hz,1H),7.46～7.50(m,1H),7.33(d,J＝8.4Hz,2H),7.05～7.14(m,4H),6.74(s,1H),6.34～6.35(m,1H),5.96(br,1H),3.63～3.75(m,4H),3.47～3.53(m,2H),3.20(br,4H),2.69(br,2H),2.34(br,2H),2.15(s,2H),1.95～2.01(m,2H),1.72～1.85(m,4H),1.38～1.41(m,2H),0.92(s,6H)。 1 H NMR (400MHz, d6- DMSO) δ11.62 (s, 1H), 8.48 ~ 8.54 (m, 2H), 7.97 (d, J = 2.4Hz, 1H), 7.76 (d, J = 8.4Hz, 1H ), 7.46 to 7.50 (m, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.05 to 7.14 (m, 4H), 6.74 (s, 1H), 6.34 to 6.35 (m, 1H), 5.96 ( Br, 1H), 3.63 to 3.75 (m, 4H), 3.47 to 3.53 (m, 2H), 3.20 (br, 4H), 2.69 (br, 2H), 2.34 (br, 2H), 2.15 (s, 2H) , 1.95 to 2.01 (m, 2H), 1.72 to 1.85 (m, 4H), 1.38 to 1.41 (m, 2H), 0.92 (s, 6H).
实施例8Example 8
4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(3-氟-1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-(3-硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯基磺酰基)苯甲酰胺4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridine-4- 2-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(3-nitro-4-((tetrahydro-2H-pyran)- 4-yl)methylamino)phenylsulfonyl)benzamide
Figure PCTCN2017100226-appb-000065
Figure PCTCN2017100226-appb-000065
步骤A：4-(3-(3-氟-1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(甲氧羰基)苯基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯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
Figure PCTCN2017100226-appb-000066
Figure PCTCN2017100226-appb-000066
将4-(3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(甲氧羰基)苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1.08g,2.4mmol)与选择性氟试剂(1.02g,2.9mmol)溶于乙腈(30mL)/水(6mL)中,加 热至40℃搅拌4小时。然后冷却至室温，加水，用乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析，用二氯甲烷/乙酸乙酯＝4/1洗脱，得到目标产物(165mg,15％)。4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1 ( 2H)-tert-butyl carboxylic acid (1.08 g, 2.4 mmol) and a selective fluoro reagent (1.02 g, 2.9 mmol) in acetonitrile (30 mL) / water (6 mL) Heat to 40 ° C for 4 hours. It was then cooled to room temperature, added with water and extracted with EtOAc. The organic layer was washed with EtOAc EtOAc m.
1H NMR(400MHz,CDCl3)δ8.88(s,1H),8.20(d,J＝2.8Hz,1H),7.94(d,J＝8Hz,1H),7.52(d,J＝2.4Hz,1H),7.19～7.22(m,1H),7.12(t,J＝1.6Hz,1H),6.91(d,J＝1.6Hz,1H),6.05(br,1H),4.03～4.04(br,2H),3.85(s,3H),3.59(t,J＝6.0Hz,2H),2.42(br,2H),1.47(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.88 (s, 1H), 8.20 (d, J = 2.8 Hz, 1H), 7.94 (d, J = 8 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.19 to 7.22 (m, 1H), 7.12 (t, J = 1.6 Hz, 1H), 6.91 (d, J = 1.6 Hz, 1H), 6.05 (br, 1H), 4.03 to 4.04 (br, 2H) ), 3.85 (s, 3H), 3.59 (t, J = 6.0 Hz, 2H), 2.42 (br, 2H), 1.47 (s, 9H).
步骤B：2-(3-氟-1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯Step B: 2-(3-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzene Methyl formate
Figure PCTCN2017100226-appb-000067
Figure PCTCN2017100226-appb-000067
将4-(3-(3-氟-1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(甲氧羰基)苯基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯(165mg,0.35mmol)溶于二氯甲烷(3mL),冷却至0℃,加入三氟乙酸(3mL)，保持在0℃下继续搅拌3h。然后加入饱和碳酸钠溶液调至pH值为9，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，除去溶剂，得到目标产物(130mg,100％)。4-(3-(3-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(methoxycarbonyl)phenyl)-5,6-dihydropyridine- 1(2H)-tert-Butyl carboxylic acid (165 mg, 0.35 mmol) was dissolved in dichloromethane (3 mL), cooled to EtOAc. Then, a saturated sodium carbonate solution was added to adjust to a pH of 9 and extracted with methylene chloride. The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate and evaporated to give the desired product (130 mg, 100%).
1H NMR(400MHz,CDCl3)δ8.98(br,1H),8.20(d,J＝2.8Hz,1H),7.92(d,J＝8.4Hz,1H),7.50(d,J＝2.4Hz,1H),7.20～7.22(m,1H),7.10(d,J＝2.4Hz,1H),6.92(d,J＝1.6Hz,1H),6.14～6.15(m,1H),3.84(s,3H),3.50(d,J＝2.8Hz,2H),3.06(t,J＝5.6Hz,2H),2.36(br,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.98 (br, 1H), 8.20 (d, J = 2.8 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 2.4 Hz) , 1H), 7.20 to 7.22 (m, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.92 (d, J = 1.6 Hz, 1H), 6.14 to 6.15 (m, 1H), 3.84 (s, 3H), 3.50 (d, J = 2.8 Hz, 2H), 3.06 (t, J = 5.6 Hz, 2H), 2.36 (br, 2H).
步骤C：4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(3-氟-1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酸甲酯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
Figure PCTCN2017100226-appb-000068
Figure PCTCN2017100226-appb-000068
将2-(3-氟-1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯(120mg,0.33mmol)和2-(4-氯苯基)-4,4-二甲基环己-1-烯甲醛(162mg,0.65mmol)溶于二氯甲烷(5mL)，室温下加入醋酸(0.5mL)，保持室温搅拌30分钟后,加入三乙酰氧基硼氢化钠(276mg,1.30mmol)，室温搅拌过夜。然后加碳酸钠溶液调至pH为9，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩。残留物用制备薄层板分离，展开剂为二氯甲烷/乙酸乙酯＝1/1，得产物(70mg,36％)。2-(3-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoic acid Ester (120 mg, 0.33 mmol) and 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxaldehyde (162 mg, 0.65 mmol) dissolved in dichloromethane (5 mL) Acetic acid (0.5 mL) was stirred at room temperature for 30 min, then sodium triacetoxyborohydride (276 mg, 1.30 mmol). The sodium carbonate solution was then added to pH 9 and extracted with dichloromethane. The residue was isolated with a EtOAc EtOAc (EtOAc:EtOAc)
1H NMR(400MHz,CDCl3)δ10.09(br,1H),8.17(d,J＝2.8Hz,1H),7.89(d,J＝8.0Hz,1H),7.51(d,J＝2.4Hz,1H),7.24(d,J＝8.4Hz,2H),7.09～7.12(m,2H),6.95(d,J＝8.4Hz, 2H),6.84(d,J＝1.6Hz,1H),5.95(br,1H),3.83(s,3H),3.11(br,4H),2.66(br,2H),2.43(br,2H),2.30(br,2H),2.01(br,2H),1.44(t,J＝6.4Hz,2H),0.95(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 10.09 (br, 1H), 8.17 (d, J = 2.8 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 2.4 Hz) , 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.09 to 7.12 (m, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 1.6 Hz, 1H), 5.95 (br, 1H), 3.83 (s, 3H), 3.11 (br, 4H), 2.66 (br, 2H), 2.43 (br, 2H), 2.30 (br, 2H), 2.01 (br, 2H), 1.44 ( t, J = 6.4 Hz, 2H), 0.95 (s, 6H).
步骤D：4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(3-氟-1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酸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
Figure PCTCN2017100226-appb-000069
Figure PCTCN2017100226-appb-000069
将4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(3-氟-1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酸甲酯(70mg,0.12mmol)溶于1,4-二氧六环(3mL)，加入1N的氢氧化钠水溶液(1.5mL,1.5mmol)，在50℃下搅拌2小时。加磷酸二氢钠饱和水溶液至pH为6，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，除去溶剂，得到目标产物(70mg,100％)。4-(1-((2-(4-Chlorophenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridine-4 Methyl 2-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoate (70 mg, 0.12 mmol) was dissolved in 1,4-dioxane (3 mL), a 1N aqueous sodium hydroxide solution (1.5 mL, 1.5 mmol) was added, and the mixture was stirred at 50 ° C for 2 hours. A saturated aqueous solution of sodium dihydrogen phosphate was added to pH 6 and extracted with ethyl acetate. EtOAc (EtOAc)
1H NMR(400MHz,DMSO)δ12.87(br,1H),11.52(br,1H),8.08(d,J＝2.8Hz,1H),7.79(d,J＝8.4Hz,1H),7.50(t,J＝2.4Hz,1H),7.49(d,J＝2.4Hz,1H),7.47(d,J＝8.4Hz,2H),7.27～7.29(m,1H),7.07(d,J＝8.4Hz,2H),6.97(d,J＝1.6Hz,1H),6.16(br,1H),2.83(br,4H),2.31～2.36(m,4H),2.15～2.18(m,2H),1.97(br,2H),1.39(t,J＝6.4Hz,2H),0.94(s,6H)。 1 H NMR (400 MHz, DMSO) δ 12.87 (br, 1H), 11.52 (br, 1H), 8.08 (d, J = 2.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.50 ( t, J = 2.4 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.27 to 7.29 (m, 1H), 7.07 (d, J = 8.4) Hz, 2H), 6.97 (d, J = 1.6 Hz, 1H), 6.16 (br, 1H), 2.83 (br, 4H), 2.31 to 2.36 (m, 4H), 2.15 to 2.18 (m, 2H), 1.97 (br, 2H), 1.39 (t, J = 6.4 Hz, 2H), 0.94 (s, 6H).
步骤E：4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(3-氟-1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-(3-硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯基磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000070
Figure PCTCN2017100226-appb-000070
将4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(3-氟-1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酸(70mg,0.12mmol)和三乙胺(30mg,0.24mmol)的二氯甲烷(1mL)溶液加入3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯磺酰胺(38mg,0.12mmol)、EDCI(30mg,0.15mmol)、DMAP(29mg,0.24mmol)的二氯甲烷(2mL)溶液中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇＝15/1，得到产物(20mg,19％)。4-(1-((2-(4-Chlorophenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridine-4 2-yl-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid (70 mg, 0.12 mmol) and triethylamine (30 mg, 0.24 mmol) Methyl chloride (1 mL) solution was added 3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (38 mg, 0.12 mmol), EDCI (30 mg, 0.15 mmol) And a solution of DMAP (29 mg, 0.24 mmol) in dichloromethane (2 mL), EtOAc. The thin layer was separated and the developing solvent was methylene chloride / methanol = 15 / 1 to give product (20 mg, 19%).
1H NMR(400MHz,DMSO)δ11.48(br,1H),9.53(br,1H),8.47(br,2H),8.02～8.03(m,1H),7.73～7.76(m,1H),7.47～7.52(m,3H),7.33(d,J＝8.4Hz,2H),7.07～7.15(m,4H),6.80(s,1H),5.99(br,1H),3.81～3.85(m,2H),3.22～3.25(m,4H),2.69～3.08(m,4H),2.31～2.43(m,4H),2.18(br,2H),1.97～2.00(m,2H),1.85(br,1H),1.57～1.60(m,2H),1.38～1.43(m,2H),1.24～1.28(m,2H), 0.93(s,6H)。 1 H NMR (400MHz, DMSO) δ11.48 (br, 1H), 9.53 (br, 1H), 8.47 (br, 2H), 8.02 ~ 8.03 (m, 1H), 7.73 ~ 7.76 (m, 1H), 7.47 ～7.52 (m, 3H), 7.33 (d, J=8.4 Hz, 2H), 7.07 to 7.15 (m, 4H), 6.80 (s, 1H), 5.99 (br, 1H), 3.81 to 3.85 (m, 2H) ), 3.22 to 3.25 (m, 4H), 2.69 to 3.08 (m, 4H), 2.31 to 2.43 (m, 4H), 2.18 (br, 2H), 1.97 to 2.00 (m, 2H), 1.85 (br, 1H) ), 1.57 to 1.60 (m, 2H), 1.38 to 1.43 (m, 2H), 1.24 to 1.28 (m, 2H), 0.93 (s, 6H).
实施例9Example 9
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((四氢-2H-吡喃-4-基)甲基氨基)-3-(三氟甲基磺酰基)苯基磺酰基)苯甲酰胺2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane- 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((tetrahydro-2H-pyran-4-yl)methylamino)- 3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide
Figure PCTCN2017100226-appb-000071
Figure PCTCN2017100226-appb-000071
步骤A：5-溴-1-(三异丙基硅基)-1H-吡咯并[2,3-b]吡啶Step A: 5-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2017100226-appb-000072
Figure PCTCN2017100226-appb-000072
5-溴-1H-吡咯并[2,3-b]吡啶(3.94g)溶于无水四氢呋喃(60mL)，冷却至0℃，加入1N的LiHMDS的四氢呋喃溶液(2.2mL)，10分钟后，加入三异丙基氯硅烷(4.24g)，缓慢升至室温，搅拌40小时。将反应液倾入水中，用乙酸乙酯萃取，用饱和氯化钠水溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得产品(7.0g)。5-Bromo-1H-pyrrolo[2,3-b]pyridine (3.94 g) was dissolved in anhydrous tetrahydrofuran (60 mL), cooled to 0 ° C, and 1N a solution of LiHMDS in tetrahydrofuran (2.2 mL). Triisopropylchlorosilane (4.24 g) was added, and the mixture was slowly warmed to room temperature and stirred for 40 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
1H NMR(400MHz,CDCl3)δ8.27(d,J＝2.4Hz,1H),7.98(d,J＝2.4Hz,1H),7.31(d,J＝3.6Hz,1H),6.49(d,J＝3.6Hz,1H),1.78～1.89(m,3H),1.12(d,J＝7.6Hz,18H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 6.49 (d) , J = 3.6 Hz, 1H), 1.78 to 1.89 (m, 3H), 1.12 (d, J = 7.6 Hz, 18H).
步骤B：(1-(三异丙基硅基)-1H-吡咯并[2,3-b]吡啶-5-基)硼酸二甲酯Step B: (1-(Triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid dimethyl ester
Figure PCTCN2017100226-appb-000073
Figure PCTCN2017100226-appb-000073
氮气保护下，5-溴-1-(三异丙基硅基)-1H-吡咯并[2,3-b]吡啶(5.37g)溶于无水四氢呋喃(100mL)，冷却至-78℃，加入2.4M的正丁基锂的正己烷溶液(7.5mL)，5分钟后，加入硼酸三甲酯(2.33g)，缓慢升至室温，搅拌1小时。加入饱和氯化铵水溶液淬灭反应，用乙酸乙酯萃取，用饱和氯化钠水溶液洗涤有机相，无水硫酸钠干燥，除去溶剂直接投入下一步。5-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.37 g) was dissolved in anhydrous tetrahydrofuran (100 mL) and cooled to -78 ° C under nitrogen. A 2.4 M solution of n-butyllithium in n-hexane (7.5 mL) was added, and after 5 minutes, trimethyl borate (2.33 g) was added, and the mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with EtOAc (EtOAc m.
步骤C：1-(三异丙基硅基)-1H-吡咯并[2,3-b]吡啶-5-酚Step C: 1-(Triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-phenol
Figure PCTCN2017100226-appb-000074
Figure PCTCN2017100226-appb-000074
室温下，将实施例9步骤B得到的(1-(三异丙基硅基)-1H-吡咯并[2,3-b]吡啶-5-基)硼酸二甲酯溶于四氢呋喃(50mL)，冷却至0℃，加入1M的氢氧化钠水溶液(15mL)和30％的双氧水水溶液(3mL)，保持在0℃下继续搅拌1小时。加入过量亚硫酸钠搅拌至淀粉碘化钾试纸不显色，用1M盐酸调pH为4，乙酸乙酯萃取，合并乙酸乙酯相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩，经硅胶柱进行色谱纯化残余物，以二氯甲烷洗脱，得到油状产物(3.1g)。 The (1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid dimethyl ester obtained in Step 9 of Example 9 was dissolved in tetrahydrofuran (50 mL) at room temperature. After cooling to 0 ° C, a 1 M aqueous solution of sodium hydroxide (15 mL) and a 30% aqueous solution of hydrogen peroxide (3 mL) were added, and stirring was continued at 0 ° C for 1 hour. After adding excess sodium sulfite, the mixture was stirred until the starch potassium iodide test paper was not colored. The pH was adjusted to 4 with 1M hydrochloric acid, and the ethyl acetate was combined. The ethyl acetate phase was combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated. The residue was purified with EtOAcqqqqqq
1H NMR(400MHz,CDCl3)δ7.96(d,J＝2.8Hz,1H),7.33(d,J＝2.8Hz,1H),7.29(d,J＝3.2Hz,1H),6.44(d,J＝3.6Hz,1H),4.53(br,1H),1.79～1.87(m,3H),1.12(d,J＝7.6Hz,18H)。 1 H NMR (400MHz, CDCl 3 ) δ7.96 (d, J = 2.8Hz, 1H), 7.33 (d, J = 2.8Hz, 1H), 7.29 (d, J = 3.2Hz, 1H), 6.44 (d , J = 3.6 Hz, 1H), 4.53 (br, 1H), 1.79 to 1.87 (m, 3H), 1.12 (d, J = 7.6 Hz, 18H).
步骤D：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-溴苯甲酸甲酯Step D: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate
Figure PCTCN2017100226-appb-000075
Figure PCTCN2017100226-appb-000075
室温下，1-(三异丙基硅烷基)-1H-吡咯并[2,3-b]吡啶-5-酚(1.00g)、4-溴-2-氟苯甲酸甲酯(0.885g)、碳酸钾(0.967g)加入N,N-二甲基甲酰胺(10mL)中，加热至80℃搅拌1小时。冷却至室温，用乙酸乙酯稀释，水和饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩。经硅胶柱进行色谱纯化残余物，以乙酸乙酯/二氯甲烷(5/1)洗脱，得到产品(0.48g)。1-(Triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-phenol (1.00 g), methyl 4-bromo-2-fluorobenzoate (0.885 g) at room temperature Potassium carbonate (0.967 g) was added to N,N-dimethylformamide (10 mL), and the mixture was stirred at 80 ° C for 1 hour. After cooling to room temperature, it was diluted with EtOAc EtOAc. The residue was purified by chromatography EtOAcjjjjjjj
1H NMR(400MHz,CDCl3)δ9.34(br,1H),8.11(d,J＝2.8Hz,1H),7.72(d,J＝8.4Hz,1H),7.56(d,J＝2.4Hz,1H),7.32～7.34(t,J＝2.8Hz,1H)，7.17～7.20(m,1H),6.89(d,J＝2.0Hz,1H),6.42～6.44(m,1H),3.82(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ9.34 (br, 1H), 8.11 (d, J = 2.8Hz, 1H), 7.72 (d, J = 8.4Hz, 1H), 7.56 (d, J = 2.4Hz , 1H), 7.32 to 7.34 (t, J = 2.8 Hz, 1H), 7.17 to 7.20 (m, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.42 to 6.44 (m, 1H), 3.82 ( s, 3H).
步骤E：4-(3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(甲氧羰基)苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯Step E: 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine- 1(2H)-tert-butyl formate
Figure PCTCN2017100226-appb-000076
Figure PCTCN2017100226-appb-000076
室温下，4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(493mg)、2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-溴苯甲酸甲酯(460mg)、磷酸钾(552mg)和Pd(dppf)Cl2(106mg)加入乙二醇二甲醚/水(5/1)的混合液(6mL)中，氮气保护下加热到80℃搅拌过夜。冷却至室温，加入水，用乙酸乙酯萃取，合并乙酸乙酯相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩，经硅胶柱进行色谱纯化残余物且用二氯甲烷/乙酸乙酯(4/1)洗脱，得到产品(440mg)。4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid at room temperature Butyl ester (493 mg), methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate (460 mg), potassium phosphate (552 mg) and Pd ( Dppf)Cl 2 (106 mg) was added to a mixture of ethylene glycol dimethyl ether/water (5/1) (6 mL), and heated to 80 ° C under nitrogen atmosphere and stirred overnight. After cooling to room temperature, water was added, and ethyl acetate was evaporated. EtOAc was evaporated. The ethyl ester (4/1) was eluted to give the product (440 mg).
1H NMR(400MHz,CDCl3)δ9.42(br,1H),8.17(d,J＝2.4Hz,1H),7.90(d,J＝8.4Hz,1H),7.56(d,J＝2.4Hz,1H),7.36(t,J＝3.2Hz,1H),7.13～7.16(m,1H),6.86(d,J＝1.6Hz,1H),6.45～6.46(m,1H),5.99～6.03(m,1H),4.00(br,2H),3.86(s,3H),3.55(t,J＝1.6Hz,2H),2.38(br,2H),1.45(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.42 (br, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 2.4 Hz) , 1H), 7.36 (t, J = 3.2 Hz, 1H), 7.13 to 7.16 (m, 1H), 6.86 (d, J = 1.6 Hz, 1H), 6.45 to 6.46 (m, 1H), 5.99 to 6.03 ( m, 1H), 4.00 (br, 2H), 3.86 (s, 3H), 3.55 (t, J = 1.6 Hz, 2H), 2.38 (br, 2H), 1.45 (s, 9H).
步骤F：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯Step F: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoic acid ester
Figure PCTCN2017100226-appb-000077
Figure PCTCN2017100226-appb-000077
将4-(3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(甲氧羰基)苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(220mg)溶于二氯甲烷(2mL),冷却至0℃,加入三氟乙酸(1mL)。加毕，保持在0℃下继续搅拌3小时，加入饱和碳酸钠水溶液，用二氯甲烷萃取，有机相合并，用饱和氯化 钠水溶液洗涤，无水硫酸钠干燥，除去溶剂，得到产品(170mg)。4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1 ( 2H)-tert-butyl formate (220 mg) was dissolved in dichloromethane (2 mL). After the addition, stirring was continued at 0 ° C for 3 hours, saturated aqueous sodium carbonate solution was added, extracted with dichloromethane, and the organic phases were combined and chlorinated with saturated. The aqueous solution was washed with sodium sulfate and dried over anhydrous sodium sulfate
1H NMR(400MHz,CDCl3)δ10.56(br,1H),8.06(d,J＝2.4Hz,1H),7.89(d,J＝8Hz,1H),7.64(d,J＝3.6Hz,1H),7.42(br,1H),7.10(br,1H),6.75(s,1H),6.47(d,J＝2.8Hz,1H),5.96(br,1H),3.92(br,3H),3.78(br,2H),3.35(t,J＝5.2Hz,2H),2.63(br,2H)。 1 H NMR (400MHz, CDCl 3 ) δ10.56 (br, 1H), 8.06 (d, J = 2.4Hz, 1H), 7.89 (d, J = 8Hz, 1H), 7.64 (d, J = 3.6Hz, 1H), 7.42 (br, 1H), 7.10 (br, 1H), 6.75 (s, 1H), 6.47 (d, J = 2.8 Hz, 1H), 5.96 (br, 1H), 3.92 (br, 3H), 3.78 (br, 2H), 3.35 (t, J = 5.2 Hz, 2H), 2.63 (br, 2H).
步骤G：4,4-二甲基-2-氧代环己烷-1-甲酸甲酯Step G: 4,4-Dimethyl-2-oxocyclohexane-1-carboxylic acid methyl ester
Figure PCTCN2017100226-appb-000078
Figure PCTCN2017100226-appb-000078
将钠氢(16g)悬浮于新干燥四氢呋喃(500mL)中，加入碳酸二甲酯(85mL)。反应液加热至回流，滴入3,3-二甲基环己烷-1-酮(25g)的四氢呋喃(200mL)溶液。滴加完毕后继续回流反应2小时。冷却至0℃,倾入饱和氯化铵水溶液中，用乙酸乙酯萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，除去溶剂，经硅胶柱进行色谱纯化残余物且用石油醚/乙酸乙酯(40/1)洗脱，得到产品(34g)Sodium hydrogen (16 g) was suspended in fresh dry tetrahydrofuran (500 mL) and dimethyl carbonate (85 mL) was added. The reaction solution was heated to reflux, and a solution of 3,3-dimethylcyclohexane-1-one (25 g) in tetrahydrofuran (200 mL). After the completion of the dropwise addition, the reflux reaction was continued for 2 hours. The mixture was cooled to 0 ° C, poured into aq. EtOAc EtOAc. Elution with petroleum ether / ethyl acetate (40/1) gave product (34 g)
1H NMR(400MHz,CDCl3)δ12.12(s,1H),3.76(s,3H),2.23～2.27(m,2H),2.06(s,2H),1.37～1.40(m,2H),0.96(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ12.12 (s, 1H), 3.76 (s, 3H), 2.23 ~ 2.27 (m, 2H), 2.06 (s, 2H), 1.37 ~ 1.40 (m, 2H), 0.96 (s, 6H).
步骤H：4,4-二甲基-2-(((三氟甲基)磺酰基)氧基)环己-1-烯-1-甲酸甲酯Step H: Methyl 4,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-1-ene-1-carboxylate
Figure PCTCN2017100226-appb-000079
Figure PCTCN2017100226-appb-000079
将钠氢(11.8g)悬浮于二氯甲烷(1L)中，冷却至0℃，加入4,4-二甲基-2-氧代环己烷-1-甲酸甲酯(27g)。反应液在0℃继续反应30分钟，然后冷却至-78℃，加入三氟甲磺酸酐(27mL)。加毕，升至室温反应40小时。然后倾入水中，用二氯甲烷萃取，萃取液用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，除去溶剂，得到产品(46g)Sodium hydrogen (11.8 g) was suspended in dichloromethane (1 L), cooled to 0.degree. C., and 4,4-dimethyl-2-oxocyclohexane-1-carboxylic acid methyl ester (27 g). The reaction solution was continued at 0 ° C for 30 minutes, then cooled to -78 ° C, and trifluoromethanesulfonic acid anhydride (27 mL). After the addition, the reaction was allowed to rise to room temperature for 40 hours. Then, it was poured into water, and extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl3)δ3.80(s,3H),2.48～2.52(m,2H),2.17(s,2H),1.42～1.45(m,2H),1.00(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.80 (s, 3H), 2.48 to 2.52 (m, 2H), 2.17 (s, 2H), 1.42 to 1.45 (m, 2H), 1.00 (s, 6H).
步骤I：4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-甲酸甲酯Step I: Methyl 4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylate
Figure PCTCN2017100226-appb-000080
Figure PCTCN2017100226-appb-000080
氮气保护下，4,4-二甲基-2-(((三氟甲基)磺酰基)氧基)环己-1-烯-1-甲酸甲酯(43g)、对氯苯硼酸(23.4g)、磷酸钾(57.7g)，Pd(dppf)Cl2(10g)在乙二醇二甲醚/甲醇/水(5/1/1)的混合溶剂(700mL)中于70℃反应20小时。冷却至室温后，倾入水中，用乙酸乙酯萃取，萃取液用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，除去溶剂，柱层析纯化,以石油醚/二氯甲烷(3/1)洗脱，得到产品(29g)Methyl 4,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-1-ene-1-carboxylate (43 g), p-chlorophenylboronic acid (23.4) g), potassium phosphate (57.7 g), Pd(dppf)Cl 2 (10 g) in a mixed solvent of ethylene glycol dimethyl ether / methanol / water (5 / 1 / 1) (700 mL) at 70 ° C for 20 hours . After cooling to room temperature, it was poured into water, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated. ) elution, get product (29g)
1H NMR(400MHz,CDCl3)δ7.27(d,J＝8.0Hz,2H),7.03(d,J＝8.0Hz,2H),3.46(s,3H),2.43～2.48(m,2H),2.12～2.13(m,2H),1.47～1.50(m,2H),0.99(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.27 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 3.46 (s, 3H), 2.43 to 2.48 (m, 2H) , 2.12 to 2.13 (m, 2H), 1.47 to 1.50 (m, 2H), 0.99 (s, 6H).
步骤J：(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-二苯基]-2-基)甲醇Step J: (4'-Chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-diphenyl]-2-yl)methanol
Figure PCTCN2017100226-appb-000081
Figure PCTCN2017100226-appb-000081
将4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-二苯基]-2-甲酸甲酯(650mg)溶于四氢呋喃(20mL)中，加入4M的硼氢化锂溶液(3.5mL)，然后缓慢滴加甲醇(2.4mL)。滴加完毕，反应液 在室温下搅拌过夜。用1M盐酸淬灭反应，然后用二氯甲烷萃取，萃取液用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，除去溶剂，柱层析纯化，用二氯甲烷洗脱，得到产品(330mg)。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) .
1H NMR(400MHz,CDCl3)δ7.17～7.20(m,2H),6.95～6.98(m,2H),3.84(s,2H),2.18～2.22(m,2H),1.94(s,2H),1.37～1.40(m,2H),0.88(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.17 - 7.20 (m, 2H), 6.95 - 6.98 (m, 2H), 3.84 (s, 2H), 2.18 - 2.22 (m, 2H), 1.94 (s, 2H) ), 1.37 to 1.40 (m, 2H), 0.88 (s, 6H).
步骤K：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯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
Figure PCTCN2017100226-appb-000082
Figure PCTCN2017100226-appb-000082
室温下，(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲醇(120mg)溶于二氯甲烷(3mL)，冷却至0℃，加入三乙胺(98mg)、甲磺酰氯(60mg)，保持在0℃继续搅拌30分钟。将反应体系加入2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯(168mg)的二氯甲烷(2mL)溶液中，室温搅拌过夜。加入水，用二氯甲烷萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩。残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(20/1)，得到目标产物(30mg)。(4'-Chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methanol (120 mg) was dissolved in dichloromethane at room temperature Methane (3 mL) was cooled to 0 ° C. triethylamine (98 mg) and methanesulfonyl chloride (60 mg) were then weighed and kept stirring at 0 ° C for 30 minutes. Add the reaction system to 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoic acid Methyl ester (168 mg) in dichloromethane (2 mL) Water was added, and the mixture was extracted with methylene chloride. The residue was separated by preparative EtOAc (EtOAc) elute
1H NMR(400MHz,CDCl3)δ10.69(br,1H),8.15(d,J＝2.0Hz,1H),7.88(d,J＝8.4Hz,1H),7.57(d,J＝2.4Hz,1H),7.39(t,J＝2.4Hz 1H),7.22(d,J＝8.0Hz,2H),7.02(d,J＝8.0Hz,1H),6.93(d,J＝8.4Hz,2H),6.78(s,1H),6.45(br,1H),5.86(br,1H),3.85(s,3H),3.22(br,4H),2.73(br,2H),2.44(s,2H),2.36(s,2H),2.01(s,2H),1.45(t,J＝5.6Hz,2H),0.94(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ10.69 (br, 1H), 8.15 (d, J = 2.0Hz, 1H), 7.88 (d, J = 8.4Hz, 1H), 7.57 (d, J = 2.4Hz , 1H), 7.39 (t, J = 2.4 Hz 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H) , 6.78 (s, 1H), 6.45 (br, 1H), 5.86 (br, 1H), 3.85 (s, 3H), 3.22 (br, 4H), 2.73 (br, 2H), 2.44 (s, 2H), 2.36 (s, 2H), 2.01 (s, 2H), 1.45 (t, J = 5.6 Hz, 2H), 0.94 (s, 6H).
步骤L：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸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
Figure PCTCN2017100226-appb-000083
Figure PCTCN2017100226-appb-000083
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯(30mg)溶于1,4-二氧六环(6mL),加入1M的氢氧化钠水溶液(1.5mL)，加热至50℃搅拌2小时。加入磷酸二氢钠饱和水溶液至pH为6，乙酸乙酯萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，除去溶剂，得到目标产物(30mg)。2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-5,5-dimethyl-3,4,5) Methyl 6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoate (30 mg) 1,4-Dioxane (6 mL) was added to a 1M aqueous solution of sodium hydroxide (1.5 mL), and the mixture was warmed to 50 ° C and stirred for 2 hours. A saturated aqueous solution of sodium dihydrogen phosphate was added to pH 6 and ethyl acetate was evaporated. EtOAc was evaporated.
1H NMR(400MHz,CDCl3)δ10.96(br,2H),8.02(br,1H),7.77(t,J＝8.8Hz,1H),7.45(s,1H),7.16～7.22(m,3H),6.88～6.94(m,3H),6.75(d,J＝14Hz,1H),6.24(s,1H),5.77(d,J＝19.2Hz,1H),3.18(br,2H),3.09(br,2H),2.59～2.63(m,2H),2.30(br,4H),1.96(s,2H),1.35～1.43(m,2H),0.90(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ10.96 (br, 2H), 8.02 (br, 1H), 7.77 (t, J = 8.8Hz, 1H), 7.45 (s, 1H), 7.16 ~ 7.22 (m, 3H), 6.88 to 6.94 (m, 3H), 6.75 (d, J = 14 Hz, 1H), 6.24 (s, 1H), 5.77 (d, J = 19.2 Hz, 1H), 3.18 (br, 2H), 3.09 (br, 2H), 2.59 to 2.63 (m, 2H), 2.30 (br, 4H), 1.96 (s, 2H), 1.35 to 1.43 (m, 2H), 0.90 (s, 6H).
步骤M：二(2-氟苯基)碘鎓四氟硼酸盐Step M: bis(2-fluorophenyl)iodonium tetrafluoroborate
Figure PCTCN2017100226-appb-000084
Figure PCTCN2017100226-appb-000084
在室温下，将85％的间氯过氧苯甲酸(6.1g)加入到二氯甲烷(100mL)中，加入1-氟-2-碘苯(6g)，然后缓慢滴加三氟化硼乙醚(8.5mL)。所得反应液继续在室温下搅拌1.5小时后，冷却至0℃，加入2-氟苯硼酸(4.2g)，恢复至室温搅拌1小时。所得反应液直接加入装有200～300目硅胶(60g)的短柱中纯化，以二氯甲烷(600mL)洗去杂质，二氯甲烷/甲醇(20/1,1.2L)洗得粗产品。浓缩除去溶剂后，用二氯甲烷(30mL)、乙醚(100mL)的混合液打浆，过滤干燥得产品(8.8g)。85% m-chloroperoxybenzoic acid (6.1 g) was added to dichloromethane (100 mL) at room temperature, 1-fluoro-2-iodobenzene (6 g) was added, and then boron trifluoride etherate was slowly added dropwise. (8.5 mL). The obtained reaction liquid was further stirred at room temperature for 1.5 hours, and then cooled to 0 ° C, 2-fluorophenylboronic acid (4.2 g) was added, and the mixture was stirred at room temperature for 1 hour. The obtained 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, mjjjjjjj
1H NMR(400MHz,CDCl3)δ8.19～8.22(m,2H),7.66～7.72(m,2H),7.29～7.38(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.19 - 8.22 (m, 2H), 7.66 - 7.72 (m, 2H), 7.29 - 7.38 (m, 4H).
步骤N：1-氟-2-((三氟甲基)磺酰基)苯Step N: 1-fluoro-2-((trifluoromethyl)sulfonyl)benzene
Figure PCTCN2017100226-appb-000085
Figure PCTCN2017100226-appb-000085
将二(2-氟苯基)碘鎓四氟硼酸盐(1.0g)、三氟亚甲磺酸钠(507mg)、氧化亚铜(36mg)加入N,N-二甲基甲酰胺(10mL)中，反应液在氮气保护下50℃搅拌过夜。然后将反应液冷却至室温，倾入水中，用乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产品。经柱层析纯化，以石油醚/二氯甲烷(3/1)洗脱，得产品(1g)。Add bis(2-fluorophenyl)iodonium tetrafluoroborate (1.0 g), sodium trifluoromethanesulfonate (507 mg), cuprous oxide (36 mg) to N,N-dimethylformamide (10 mL) The reaction solution was stirred at 50 ° C overnight under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate Purification by column chromatography eluting with petroleum ether / dichloromethane (3/1) to afford product (1 g).
1H NMR(400MHz,CDCl3)δ8.00～8.04(m,1H),7.82～7.88(m,1H),7.43～7.48(m,1H),7.33～7.38(m,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 to 8.04 (m, 1H), 7.82 to 7.88 (m, 1H), 7.43 to 7.48 (m, 1H), 7.33 to 7.38 (m, 1H).
步骤O：4-氟-3-(三氟甲基磺酰基)苯磺酰胺Step O: 4-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide
Figure PCTCN2017100226-appb-000086
Figure PCTCN2017100226-appb-000086
0℃下，1-氟-2-(三氟甲基磺酰基)苯(1g)，溶于氯磺酸(3mL)中，在氮气保护下于120℃搅拌22小时。冷至室温，加入二氯亚砜(1mL)，氮气保护下于室温反应24小时。然后将体系倾入-50℃的乙酸异丙酯与水的混合液中淬灭，升至室温，分出有机相，重新冷却至-50℃，在氮气保护下加入氨水(6mL)反应1小时。加入6M的盐酸(10mL)淬灭反应，升至室温，分出有机相，用4M的盐酸溶液洗涤2次，无水硫酸钠干燥，浓缩得粗产品。经柱层析纯化，以石油醚/乙酸乙酯(2/1)洗脱，得产品(1g)。1-Fluoro-2-(trifluoromethylsulfonyl)benzene (1 g) was dissolved in chlorosulfonic acid (3 mL) and stirred at 120 ° C for 22 hours under nitrogen. After cooling to room temperature, thionyl chloride (1 mL) was added and the mixture was reacted at room temperature for 24 hours under nitrogen atmosphere. Then, the system was poured into a mixture of isopropyl acetate and water at -50 ° C, quenched, raised to room temperature, the organic phase was separated, re-cooled to -50 ° C, and ammonia (6 mL) was added under nitrogen for 1 hour. . The reaction was quenched by the addition of EtOAc EtOAc (EtOAc)EtOAc. Purification by column chromatography eluting with petroleum ether / ethyl acetate (2/1) to afford product (1 g).
1H NMR(400MHz,D6-DMSO)δ8.45～8.49(m,1H),8.42～8.44(m,1H),7.98(t,J＝9.2Hz,1H),7.81(s,2H)。 1 H NMR (400 MHz, D6-DMSO) δ 8.45 - 8.49 (m, 1H), 8.42 - 8.44 (m, 1H), 7.78 (t, J = 9.2 Hz, 1H), 7.81 (s, 2H).
步骤P：4-((四氢-2H-吡喃-4-基)甲基氨基)-3-(三氟甲基磺酰基)苯磺酰胺Step P: 4-((tetrahydro-2H-pyran-4-yl)methylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide
Figure PCTCN2017100226-appb-000087
Figure PCTCN2017100226-appb-000087
4-氟-3-(三氟甲基磺酰基)苯磺酰胺(100mg)，(四氢-2H-吡喃-4-基)甲胺(45mg)溶于乙腈(10mL)，80℃搅拌3小时，反应完全，加水，用乙酸乙酯萃取，用饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，浓缩，薄层层析，石油醚/乙酸乙酯＝1/1，得产品(140mg)。4-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (100 mg), (tetrahydro-2H-pyran-4-yl)methanamine (45 mg) dissolved in acetonitrile (10 mL). After the reaction was completed, the mixture was extracted with EtOAc. EtOAc (EtOAc)EtOAc. 140mg).
1H NMR(400MHz,DMSO)δ8.00(d,J＝2.0Hz,1H),7.91～7.94(m,1H),7.36(s,2H),7.24(d,J＝7.24Hz,1H),7.17(t,J＝5.6Hz,1H),3.82～3.85(m,2H),3.22～3.30(m,4H),1.81～1.87(m,1H),1.42(d,J＝12.4Hz,2H),1.18～1.27(m,2H)。 1 H NMR (400MHz, DMSO) δ8.00 (d, J = 2.0Hz, 1H), 7.91 ~ 7.94 (m, 1H), 7.36 (s, 2H), 7.24 (d, J = 7.24Hz, 1H), 7.17 (t, J = 5.6 Hz, 1H), 3.82 to 3.85 (m, 2H), 3.22 to 3.30 (m, 4H), 1.81 to 1.87 (m, 1H), 1.42 (d, J = 12.4 Hz, 2H) , 1.18 ~ 1.27 (m, 2H).
步骤Q：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基) 甲基)2,3-四氢吡啶-4-基)-N-(4-((四氢-2H-吡喃-4-基)甲基氨基)-3-(三氟甲基磺酰基)苯基磺酰基)苯甲酰胺Step Q: 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohex-1-enyl) Methyl) 2,3-tetrahydropyridin-4-yl)-N-(4-((tetrahydro-2H-pyran-4-yl)methylamino)-3-(trifluoromethylsulfonyl) Phenylsulfonyl)benzamide
Figure PCTCN2017100226-appb-000088
Figure PCTCN2017100226-appb-000088
将2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(50mg)和三乙胺(18mg)混合后加入4-((四氢-2H-吡喃-4-基)甲基氨基)-3-(三氟甲基磺酰基)苯磺酰胺(36mg)、EDCI(22mg)、DMAP(22mg)的二氯甲烷溶液中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(28mg)。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 (50 mg) and triethylamine (18 mg), after mixing, 4-((tetrahydro-2H-pyran-4-yl)methylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (36 mg), EDCI (22 mg), DMAP (22 mg) in methylene chloride solution, stirred at room temperature overnight, diluted with dichloromethane, washed with water, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The solvent was dichloromethane/methanol (15/1) to give the desired product (28mg).
1H NMR(400MHz,CDCl3)δ9.48～9.58(m,1H),8.47(d,J＝2.4Hz,1H),8.29～8.32(m,1H),8.13(d,J＝2.4Hz,1H),8.04(d,J＝8.4Hz,1H),7.74(d,J＝2.0Hz,1H),7.48(t,J＝2.8Hz,1H),7.24(d,J＝8.4Hz,2H),7.09(t,J＝5.2Hz,1H),7.00～7.03(m,1H),6.93～6.95(m,2H),6.85(d,J＝9.2Hz,1H),6.62(br,1H),6.57～6.58(m,1H),5.80(br,1H),4.02～4.05(m,2H),3.40～3.46(m,4H),3.18(t,J＝5.6Hz,2H),2.77～2.86(m,2H),2.39～2.44(m,4H),2.05(br,2H),1.89～1.95(m,1H),1.60～1.75(m,8H),0.97(S,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.48 to 9.58 (m, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.29 to 8.32 (m, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.48 (t, J = 2.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H) , 7.09 (t, J = 5.2 Hz, 1H), 7.00 to 7.03 (m, 1H), 6.93 to 6.95 (m, 2H), 6.85 (d, J = 9.2 Hz, 1H), 6.62 (br, 1H), 6.57 to 6.58 (m, 1H), 5.80 (br, 1H), 4.02 to 4.05 (m, 2H), 3.40 to 3.46 (m, 4H), 3.18 (t, J = 5.6 Hz, 2H), 2.77 to 2.86 ( m, 2H), 2.39 to 2.44 (m, 4H), 2.05 (br, 2H), 1.89 to 1.95 (m, 1H), 1.60 to 1.75 (m, 8H), 0.97 (S, 6H).
实施例10Example 10
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-2,3,6-四氢吡啶-4-基)-N-(4-(2-吗啉乙基)-3-硝基苯基磺酰基)苯甲酰胺2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane- 1-alkenyl)methyl)-2,3,6-tetrahydropyridin-4-yl)-N-(4-(2-morpholinoethyl)-3-nitrophenylsulfonyl)benzamide
Figure PCTCN2017100226-appb-000089
Figure PCTCN2017100226-appb-000089
步骤A：1-吗啉基-2-(2-硝基苯基)乙基-1-酮Step A: 1-morpholinyl-2-(2-nitrophenyl)ethyl-1-one
Figure PCTCN2017100226-appb-000090
Figure PCTCN2017100226-appb-000090
2-(2-硝基苯基)乙酸(9g)悬浮于二氯甲烷(100mL)中，冷却至0℃。加入N,N-二甲基甲酰胺(0.5mL)，缓慢滴加草酰氯(6.35mL)。滴加完毕后，恢复至室温搅拌2小时。然后真空浓缩得到油状物，将该油状物溶于二氯甲烷(20mL)中，滴入含吗啉(5.2mL)、三乙胺(17mL)的0℃的二氯甲烷溶液(100mL)中。滴加完毕后恢复至室温，反应过夜。反应液倾入水中，用乙酸乙酯萃取，用饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得粗产品。用石油醚/二氯甲烷洗涤后得产品(10.7g)。2-(2-Nitrophenyl)acetic acid (9 g) was suspended in dichloromethane (100 mL) and cooled to EtOAc. N,N-Dimethylformamide (0.5 mL) was added, and oxalyl chloride (6.35 mL) was slowly added dropwise. After the completion of the dropwise addition, the mixture was returned to room temperature and stirred for 2 hours. The oil was then concentrated in vacuo to give crystals crystals crystals crystals crystalsssssssssssssssssssssssssssss After the completion of the dropwise addition, the mixture was returned to room temperature and allowed to react overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The product (10.7 g) was obtained after washing with petroleum ether / dichloromethane.
1H NMR(400MHz,CDCl3)δ8.10～8.12(m,1H),7.57～7.61(m,1H),7.43～7.48(m,1H),7.33～7.35(m,1H),4.05(s,2H),3.69～3.78(m,4H),3.59～3.65(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 to 8.12 (m, 1H), 7.57 to 7.61 (m, 1H), 7.43 to 7.48 (m, 1H), 7.33 to 7.35 (m, 1H), 4.05 (s) , 2H), 3.69 to 3.78 (m, 4H), 3.59 to 3.65 (m, 4H).
步骤B：4-(2-硝基苯乙基)吗啉 Step B: 4-(2-Nitrophenylethyl)morpholine
Figure PCTCN2017100226-appb-000091
Figure PCTCN2017100226-appb-000091
1-吗啉基-2-(2-硝基苯基)乙基-1-酮(2g)溶于四氢呋喃(50mL)中，氮气保护，冷却至0℃。加入1M的硼烷四氢呋喃溶液(24mL)，恢复至室温反应12小时。然后加入甲醇和盐酸猝灭，并在80℃下搅拌3小时，冷却后倾入水中，用乙酸乙酯萃取，用饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得粗产品。经柱层析纯化，以二氯甲烷/乙酸乙酯(5/1)洗脱得产品(1.8g)。1-Morolinyl-2-(2-nitrophenyl)ethyl-1-one (2 g) was dissolved in tetrahydrofuran (50 mL). A 1 M solution of borane in tetrahydrofuran (24 mL) was added and the mixture was returned to room temperature for 12 hours. Then, methanol and hydrochloric acid were added and quenched, and the mixture was stirred at 80 ° C for 3 hours. After cooling, the mixture was poured into water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. . Purification by column chromatography eluting with dichloromethane /EtOAc (EtOAc)
1H NMR(400MHz,CDCl3)δ7.91(d,J＝8.4Hz,1H),7.52～7.56(m,1H),7.35～7.40(m,2H),3.73(t,J＝4.8Hz,4H),3.11(t,J＝8.0Hz,2H),2.65(t,J＝8.0Hz,2H),2.54(t,J＝4.8Hz,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (d, J = 8.4 Hz, 1H), 7.52 to 7.56 (m, 1H), 7.35 to 7.40 (m, 2H), 3.73 (t, J = 4.8 Hz, 4H), 3.11 (t, J = 8.0 Hz, 2H), 2.65 (t, J = 8.0 Hz, 2H), 2.54 (t, J = 4.8 Hz, 4H).
步骤C：4-(2-吗啉乙基)-3-硝基苯磺酰胺Step C: 4-(2-morpholinethyl)-3-nitrobenzenesulfonamide
Figure PCTCN2017100226-appb-000092
Figure PCTCN2017100226-appb-000092
将4-(2-硝基苯乙基)吗啉(3.5g)加入氯磺酸(6mL)中，在氮气保护下于120℃搅拌2小时。缓慢滴入冷却至0℃的氨水中，滴加完毕后继续反应1小时。反应液倾入水中，用乙酸乙酯萃取，用饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得粗产品。经柱层析纯化，以二氯甲烷/甲醇(25/1)洗脱得产品(500mg)。4-(2-Nitrophenylethyl)morpholine (3.5 g) was added to chlorosulfonic acid (6 mL) and stirred at 120 ° C for 2 hr under nitrogen. The ammonia water cooled to 0 ° C was slowly dropped, and the reaction was continued for 1 hour after the completion of the dropwise addition. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Purification by column chromatography eluting with dichloromethane / methanol (25 / 1)
1H NMR(400MHz,CDCl3)δ8.42(d,J＝2.0Hz,1H),8.04～8.06(m,1H),7.57(d,J＝8.0Hz,1H),5.18(br,2H),3.68(t,J＝4.8Hz,4H),3.15(t,J＝7.2Hz,2H),2.64(t,J＝7.2Hz,2H),2.49(t,J＝4.8Hz,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.42 (d, J = 2.0 Hz, 1H), 8.04 to 8.06 (m, 1H), 7.57 (d, J = 8.0 Hz, 1H), 5.18 (br, 2H) , 3.68 (t, J = 4.8 Hz, 4H), 3.15 (t, J = 7.2 Hz, 2H), 2.64 (t, J = 7.2 Hz, 2H), 2.49 (t, J = 4.8 Hz, 4H).
步骤D：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-2,3,6-四氢吡啶-4-基)-N-(4-(2-吗啉乙基)-3-硝基苯基磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000093
Figure PCTCN2017100226-appb-000093
将2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(33mg)和三乙胺(12mg)混合后加入4-(2-吗啉乙基)-3-硝基苯磺酰胺(18mg)、EDCI(14mg)、DMAP(14mg)的二氯甲烷溶液中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(27mg)。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 (33 mg) and triethylamine (12 mg), after mixing, a solution of 4-(2-morpholinethyl)-3-nitrobenzenesulfonamide (18 mg), EDCI (14 mg), DMAP (14 mg) in dichloromethane Diluted with chloromethane, washed with water several times, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue was separated by preparative thin layer, and the solvent was methylene chloride/methanol (15/1) to give the desired product. (27mg).
1H NMR(400MHz,CDCl3)δ10.30～10.34(m,1H),8.50(s,1H),8.07(d,J＝6.8Hz,1H),7.90～7.95(m,2H),7.81(d,J＝8.0Hz,1H),7.38(s,2H),7.23～7.26(m,2H),6.94～6.96(m,3H),6.67～6.71(m,2H),6.33(s,1H),5.85(s,1H),3.83(br,4H),3.34～3.41(m,4H),3.19(br,4H),2.80～2.88(m,6H),2.53(br,2H),2.35(br,2H),2.03(s,2H),1.42～1.44(m,2H),0.95(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 10.30 - 10.34 (m, 1H), 8.50 (s, 1H), 8.07 (d, J = 6.8 Hz, 1H), 7.90 - 7.95 (m, 2H), 7.81 (d) , J=8.0 Hz, 1H), 7.38 (s, 2H), 7.23 to 7.26 (m, 2H), 6.94 to 6.96 (m, 3H), 6.67 to 6.71 (m, 2H), 6.33 (s, 1H), 5.85 (s, 1H), 3.83 (br, 4H), 3.34 to 3.41 (m, 4H), 3.19 (br, 4H), 2.80 to 2.88 (m, 6H), 2.53 (br, 2H), 2.35 (br, 2H), 2.03 (s, 2H), 1.42 to 1.44 (m, 2H), 0.95 (s, 6H).
实施例11Example 11
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲 基)-2,3,6,6-四氢吡啶-4-基)-N-(6-((四氢-2H-吡喃-4-基)甲基氨基)吡啶-3-基磺酰基)苯甲酰胺2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane- 1-alkenyl) -2,3,6,6-tetrahydropyridin-4-yl)-N-(6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridin-3-ylsulfonyl Benzoylamide
Figure PCTCN2017100226-appb-000094
Figure PCTCN2017100226-appb-000094
步骤A：6-氯吡啶基-3-甲磺酰氯Step A: 6-Chloropyridyl-3-methanesulfonyl chloride
Figure PCTCN2017100226-appb-000095
Figure PCTCN2017100226-appb-000095
将6-氯吡啶基-3-胺(1.77g)溶于浓盐酸(14mL)中，冷却至-5℃。缓慢滴加亚硝酸钠(1.04g)的水溶液(12mL)，滴加过程中，保持温度在-5℃至0℃之间，滴加完毕后保持下0℃以下备用。6-Chloropyridin-3-amine (1.77 g) was dissolved in concentrated hydrochloric acid (14 mL) and cooled to -5. An aqueous solution (12 mL) of sodium nitrite (1.04 g) was slowly added dropwise, and the temperature was maintained between -5 ° C and 0 ° C during the dropwise addition. After the completion of the dropwise addition, the mixture was kept below 0 ° C for use.
向冷却至-3℃的水中，缓慢滴加二氯亚砜(4.5mL)，保持温度低于7℃，滴加完毕后，恢复至室温，加入氯化亚铜(70mg)，冷却至-5℃，加入前面制备的重氮盐溶液，搅拌30分钟后过滤。滤饼溶于乙酸乙酯，用无水硫酸钠干燥，除去溶剂得产品(1.1g)。To the water cooled to -3 ° C, 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.
1H NMR(400MHz,CDCl3)δ9.04(d,J＝2.4Hz,1H),8.25～8.28(m,1H),7.61(d,J＝8.4Hz,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.04 (d, J = 2.4 Hz, 1H), 8.25 - 8.28 (m, 1H), 7.61 (d, J = 8.4 Hz, 1H).
步骤B：6-氯吡啶基-3-甲磺酰胺Step B: 6-Chloropyridyl-3-methanesulfonamide
Figure PCTCN2017100226-appb-000096
Figure PCTCN2017100226-appb-000096
将6-氯吡啶基-3-甲磺酰氯(1g)加入氨水(9mL)中，在室温下搅拌3小时。然后倾入水中，用乙酸乙酯萃取，用饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得产品(370mg)。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).
1H NMR(400MHz,d6-DMSO)δ8.78(d,J＝2.4Hz,1H),8.19～8.22(m,1H),7.76(d,J＝8.8Hz,1H),7.70(br,2H)。 1 H NMR (400MHz, d6- DMSO) δ8.78 (d, J = 2.4Hz, 1H), 8.19 ~ 8.22 (m, 1H), 7.76 (d, J = 8.8Hz, 1H), 7.70 (br, 2H ).
步骤C：6-(((四氢-2H-吡喃-4-基)甲基)氨基)吡啶-3-磺酰胺Step C: 6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyridine-3-sulfonamide
Figure PCTCN2017100226-appb-000097
Figure PCTCN2017100226-appb-000097
将6-氯吡啶基-3-甲磺酰胺(193mg)、(四氢-2H-吡喃-4-基)甲基胺(138mg)溶于N,N-二甲基甲酰胺(5mL)中，反应液在105℃下搅拌24小时。然后将反应液冷却至室温，倾入水中，用乙酸乙酯萃取，用饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得粗产品。经柱层析纯化，以乙酸乙酯洗脱得产品(110mg)。6-Chloropyridyl-3-methanesulfonamide (193 mg), (tetrahydro-2H-pyran-4-yl)methylamine (138 mg) was dissolved in N,N-dimethylformamide (5 mL) The reaction solution was stirred at 105 ° C for 24 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Purification by column chromatography eluting EtOAc (EtOAc)
1H NMR(400MHz,d6-DMSO)δ8.32(d,J＝2.4Hz,1H),7.64～7.67(m,1H),7.38(t,J＝5.6Hz,1H),7.08(s,2H),6.55(d,J＝8.8Hz,1H),3.82～3.86(m,2H),3.18～3.40(m,4H),1.74～1.82(m,1H),1.58～1.62(m,2H),1.14～1.23(m,2H)。 1 H NMR (400MHz, d6- DMSO) δ8.32 (d, J = 2.4Hz, 1H), 7.64 ~ 7.67 (m, 1H), 7.38 (t, J = 5.6Hz, 1H), 7.08 (s, 2H ), 6.55 (d, J = 8.8 Hz, 1H), 3.82 to 3.86 (m, 2H), 3.18 to 3.40 (m, 4H), 1.74 to 1.82 (m, 1H), 1.58 to 1.62 (m, 2H), 1.14 to 1.23 (m, 2H).
步骤D：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-2,3,6,6-四氢吡啶-4-基)-N-(6-((四氢-2H-吡喃-4-基)甲基氨基)吡啶-3-基磺酰基)苯甲酰胺 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
Figure PCTCN2017100226-appb-000098
Figure PCTCN2017100226-appb-000098
将2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(30mg)和三乙胺(10mg)混合后加入6-((四氢-2H-吡喃-4-基)甲基氨基)吡啶-3-磺酰胺(14mg)、EDCI(13mg)、DMAP(13mg)的二氯甲烷溶液中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(10mg)。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 (30 mg) and triethylamine (10 mg), after mixing, a solution of 6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide (14 mg), EDCI (13 mg), DMAP (13 mg) in dichloromethane The mixture was stirred at room temperature overnight, diluted with methylene chloride, washed with water, washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and evaporated. 15/1), the target product (10 mg) was obtained.
1H NMR(400MHz,CDCl3)δ9.50(br,1H),8.73(d,J＝2.4Hz,1H),8.15(d,J＝2.4Hz,1H),8.07(d,J＝8.0Hz,2H),7.67(d,J＝2.4Hz,1H),7.46(t,J＝2.8Hz,1H),7.23(d,J＝8.4Hz,2H),7.06～7.08(m,1H),6.93(d,J＝8.4Hz,2H),6.64(s,1H),6.54～6.55(m,1H),6.38(d,J＝9.2Hz,1H),5.87(br,1H),5.34～5.38(m,1H),3.97～4.01(m,2H),3.35～3.41(m,2H),3.25～3.28(m,2H),2.96～3.05(m,4H),2.22～2.56(m,6H),2.00(s,2H),1.85～1.89(m,1H),1.66～1.70(m,2H),1.34～1.45(m,4H),0.94(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.50 (br, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 8.0 Hz) , 2H), 7.67 (d, J = 2.4 Hz, 1H), 7.46 (t, J = 2.8 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.06 to 7.08 (m, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.64 (s, 1H), 6.54 to 6.55 (m, 1H), 6.38 (d, J = 9.2 Hz, 1H), 5.87 (br, 1H), 5.34 to 5.38 ( m,1H), 3.97 to 4.01 (m, 2H), 3.35 to 3.41 (m, 2H), 3.25 to 3.28 (m, 2H), 2.96 to 3.05 (m, 4H), 2.22 to 2.56 (m, 6H), 2.00 (s, 2H), 1.85 to 1.89 (m, 1H), 1.66 to 1.70 (m, 2H), 1.34 to 1.45 (m, 4H), 0.94 (s, 6H).
实施例12Example 12
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-(1-甲基哌啶-4-基氨基)-3-(三氟甲基磺酰基)苯基磺酰基)苯甲酰胺2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane- 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-methylpiperidin-4-ylamino)-3-(trifluoro Methylsulfonyl)phenylsulfonyl)benzamide
Figure PCTCN2017100226-appb-000099
步骤A：4-(1-甲基哌啶-4-基氨基)-3-(三氟甲磺酰基)苯磺酰胺
Figure PCTCN2017100226-appb-000099
Step A: 4-(1-Methylpiperidin-4-ylamino)-3-(trifluoromethanesulfonyl)benzenesulfonamide
Figure PCTCN2017100226-appb-000100
Figure PCTCN2017100226-appb-000100
4-氟-3-(三氟甲基磺酰基)苯磺酰胺(60mg)、1-甲基哌啶-4-胺(26mg)溶于乙腈，80℃搅拌3小时后，倾入水中，用乙酸乙酯萃取，用饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，浓缩得粗产品。经二氯甲烷打浆，将过滤所得滤液真空除去溶剂，得固体产品(60mg)。4-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (60 mg), 1-methylpiperidin-4-amine (26 mg) dissolved in acetonitrile, stirred at 80 ° C for 3 hours, then poured into water The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The mixture was filtered with methylene chloride.
1H NMR(400MHz,CDCl3)δ8.29(d,J＝2.0Hz,1H),7.96～7.99(m,1H),6.96(d,J＝6.4Hz,1H),6.86(d,J＝8.4Hz,1H),4.93(br,2H),3.52(br,1H),2.74(br,2H),2.23～2.32(m,5H),2.03～2.07(m,2H),1.63～1.72(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.29 (d, J = 2.0 Hz, 1H), 7.96 - 7.99 (m, 1H), 6.96 (d, J = 6.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.93 (br, 2H), 3.52 (br, 1H), 2.74 (br, 2H), 2.23 to 2.32 (m, 5H), 2.03 to 2.07 (m, 2H), 1.63 to 1.72 (m) , 2H).
步骤B：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基) 甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-(1-甲基哌啶-4-基氨基)-3-(三氟甲基磺酰基)苯基磺酰基)苯甲酰胺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-(4-(1-methylpiperidin-4-ylamino)-3-(trifluoromethylsulfonyl) Phenylsulfonyl)benzamide
Figure PCTCN2017100226-appb-000101
Figure PCTCN2017100226-appb-000101
将2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(40mg)和三乙胺(14mg)混合后加入4-(1-甲基哌啶-4-基氨基)-3-(三氟甲磺酰基)苯磺酰胺(28mg)、EDCI(17mg)、DMAP(17mg)的二氯甲烷溶液中，室温搅拌过夜。用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，真空浓缩得粗产品。经制备薄层板分离，展开剂为二氯甲烷/甲醇/氨水(400/40/1)，得到产品(40mg)。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 (40 mg) and triethylamine (14 mg), after mixing, 4-(1-methylpiperidin-4-ylamino)-3-(trifluoromethanesulfonyl)benzenesulfonamide (28 mg), EDCI (17 mg), DMAP (17 mg) The mixture was stirred at room temperature overnight in a methane solution. Diluted with dichloromethane, washed with water several times, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate The resulting thin layer was separated, and the developing solvent was dichloromethane/methanol/aqueous ammonia (400/40/1) to give the product (40 mg).
1H NMR(400MHz,CDCl3)δ9.16(br,1H),8.47(s,1H),8.25～8.28(m,1H),8.17(s,1H),8.03～8.06(m,1H),7.69(s,1H),7.47(s,1H),7.25(s,2H),7.02～7.12(m,2H),6.96(d,J＝8.0Hz,2H),6.81～6.83(m,1H),6.68(s,1H),6.56(s,1H),5.91(br,1H),3.64(br,1H),2.82～3.02(m,6H),2.22～2.53(m,11H),2.02(br,4H),1.56～1.71(m,2H),1.45(br,2H),0.97(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ9.16 (br, 1H), 8.47 (s, 1H), 8.25 ~ 8.28 (m, 1H), 8.17 (s, 1H), 8.03 ~ 8.06 (m, 1H), 7.69 (s, 1H), 7.47 (s, 1H), 7.25 (s, 2H), 7.02 to 7.12 (m, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.81 to 6.83 (m, 1H) , 6.68 (s, 1H), 6.56 (s, 1H), 5.91 (br, 1H), 3.64 (br, 1H), 2.82 to 3.02 (m, 6H), 2.22 to 2.53 (m, 11H), 2.02 (br) , 4H), 1.56 to 1.71 (m, 2H), 1.45 (br, 2H), 0.97 (s, 6H).
实施例13Example 13
2-(1H-吡咯并[2,3-b]吡啶-5-基)氨基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(3-硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯磺酰基)苯甲酰胺2-(1H-pyrrolo[2,3-b]pyridin-5-yl)amino)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-) 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)) Methylamino)benzenesulfonyl)benzamide
Figure PCTCN2017100226-appb-000102
Figure PCTCN2017100226-appb-000102
步骤A：4-(3-氨基-4-(甲氧羰基)苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯Step A: 4-(3-Amino-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000103
Figure PCTCN2017100226-appb-000103
2-氨基-4-氯苯甲酸甲酯(186mg)、4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯甲酸乙酯(364mg)、Pd(dppf)Cl2(73mg)、磷酸钾(424mg)在1,4-二氧六环(9mL)和水(3mL)的混合溶剂中，在氮气保护下于100℃搅拌过夜。反应液冷却至室温后，倾入水中，用乙酸乙酯萃取，用饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得粗产品。经柱层析纯化用石油醚/乙酸乙酯(5/1)洗脱得产品(280mg)。Methyl 2-amino-4-chlorobenzoate (186 mg), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (364 mg), Pd(dppf)Cl 2 (73 mg), potassium phosphate (424 mg) in a mixed solvent of 1,4-dioxane (9 mL) and water (3 mL), and stirred at 100 ° C overnight under nitrogen atmosphere. . After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Purification by column chromatography eluting with petroleum ether / ethyl acetate (5/1)
1H NMR(400MHz,CDCl3)δ7.81(d,J＝8.4Hz,1H),6.67～6.70(m,1H),6.62(d,J＝1.6Hz,1H),6.10(br,1H),5.72(br,1H),4.07(d,J＝2.4Hz,2H),3.86(s,3H),3.62(t,J＝5.6Hz,2H),2.48(br,2H),1.49(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 8.4 Hz, 1H), 6.67 to 6.70 (m, 1H), 6.62 (d, J = 1.6 Hz, 1H), 6.10 (br, 1H) , 5.72 (br, 1H), 4.07 (d, J = 2.4 Hz, 2H), 3.86 (s, 3H), 3.62 (t, J = 5.6 Hz, 2H), 2.48 (br, 2H), 1.49 (s, 9H).
步骤B：4-(4-(甲氧羰基)-3-((1-(三异丙基硅基)-1H-吡咯[2,3-b]并吡啶-5-基)氨基)苯 基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯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
Figure PCTCN2017100226-appb-000104
Figure PCTCN2017100226-appb-000104
4-(3-氨基-4-(甲氧羰基)苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(1.1g)、5-溴-1-(三异丙基硅基)-1H-吡咯[2,3-b]并吡啶(1.57g)、Pd2(dba)3(302mg)、xant-Phos(315mg)、碳酸铯(2.15g)在甲苯(40mL)中于氮气保护下90℃搅拌过夜。反应液冷却至室温后，倾入水中，用乙酸乙酯萃取，用饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得粗产品。经薄层层析纯化，以石油醚/乙酸乙酯(10/1)为展开剂得产品(390mg)。4-(3-Amino-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.1 g), 5-bromo-1-(triisopropyl) -Silyl)-1H-pyrrole[2,3-b]pyridine (1.57g), Pd 2 (dba) 3 (302mg), xant-Phos (315mg), cesium carbonate (2.15g) in toluene (40mL) The mixture was stirred at 90 ° C under nitrogen for overnight. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Purification by thin layer chromatography gave EtOAc (EtOAc)
1H NMR(400MHz,CDCl3)δ9.37(s,1H),8.20(d,J＝2.4Hz,1H),7.93(d,J＝8.4Hz,1H),7.78(d,J＝2.4Hz,1H),7.36(d,J＝3.6Hz,1H),6.92(s,1H),6.71～6.73(m,1H),6.55(d,J＝3.6Hz,1H),6.00(br,1H),4.02(br,2H),3.93(s,3H),3.55(t,J＝5.2Hz,2H),2.36(br,2H),1.85～1.92(m,3H),1.47(s,9H),1.16(d,J＝7.6Hz,18H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.37 (s, 1H), 8.20 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 2.4 Hz) , 1H), 7.36 (d, J = 3.6 Hz, 1H), 6.92 (s, 1H), 6.71 to 6.73 (m, 1H), 6.55 (d, J = 3.6 Hz, 1H), 6.00 (br, 1H) , 4.02 (br, 2H), 3.93 (s, 3H), 3.55 (t, J = 5.2 Hz, 2H), 2.36 (br, 2H), 1.85 to 1.92 (m, 3H), 1.47 (s, 9H), 1.16 (d, J = 7.6 Hz, 18H).
步骤C：甲基-2-(1H-吡咯并[2,3-b]吡啶-5-基氨基)-4-(1,2,3,6-四氢吡啶-4-基)苯甲酸酯Step C: Methyl-2-(1H-pyrrolo[2,3-b]pyridin-5-ylamino)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoic acid ester
Figure PCTCN2017100226-appb-000105
Figure PCTCN2017100226-appb-000105
将4-(4-(甲氧羰基)-3-((1-(三异丙基硅基)-1H-吡咯[2,3-b]并吡啶-5-基)氨基)苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(200mg)溶于(5mL)二氯甲烷中，0℃下加入三氟乙酸(5mL)，并搅拌2小时，饱和碳酸钠溶液调节pH至9，二氯甲烷萃取，无水硫酸钠干燥，除去溶剂得到产品(110mg)。4-(4-(Methoxycarbonyl)-3-((1-(triisopropylsilyl)-1H-pyrrole[2,3-b]pyridin-5-yl)amino)phenyl)- 3,6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (200 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added at 0 ° C, and stirred for 2 hours, saturated sodium carbonate solution The pH was adjusted to 9, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and solvent was evaporated to afford product (110 mg).
1H NMR(400MHz,CDCl3)δ9.37(s,1H),8.95(br,1H),8.27(d,J＝2.4Hz,1H),7.91(d,J＝8.0Hz,1H),7.84(d,J＝2.0Hz,1H),7.34～7.36(m,1H),6.87(s,1H),6.72～6.75(m,1H),6.49～6.51(m,1H),6.07(s,1H),3.92(s,3H),3.44～3.46(m,2H),2.99～3.02(m,2H),2.26～2.29(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.37 (s, 1H), 8.95 (br, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.34 to 7.36 (m, 1H), 6.87 (s, 1H), 6.72 to 6.75 (m, 1H), 6.49 to 6.51 (m, 1H), 6.07 (s, 1H) ), 3.92 (s, 3H), 3.44 to 3.46 (m, 2H), 2.99 to 3.02 (m, 2H), 2.26 to 2.29 (m, 2H).
步骤D：甲基-2-(1H-并吡咯[2,3-b]吡啶-5-基氨基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸酯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
Figure PCTCN2017100226-appb-000106
Figure PCTCN2017100226-appb-000106
将甲基-2-(1H-吡咯并[2,3-b]吡啶-5-基氨基)-4-(1,2,3,6-四氢吡啶-4-基)苯甲酸酯(110mg)，2-(4-氯苯基)-4,4-二甲基环己基-1-烯基苯甲醛(460mg)溶于(30mL)二氯甲烷中，加入醋酸(0.5mL)，搅拌30分钟后，加入三乙酰氧基硼氢化钠(235mg)，室温下搅拌过夜，加入饱和碳酸钠溶液调节pH至9，二氯甲烷萃取，除去溶剂。混合物经薄层层析纯化，展开剂为二氯甲烷/甲醇/氨水(40/1/3)，得到目标产物(50mg)。 Methyl-2-(1H-pyrrolo[2,3-b]pyridin-5-ylamino)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoate ( 110 mg), 2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-enylbenzaldehyde (460 mg) was dissolved in dichloromethane (30 mL). After 30 minutes, sodium triacetoxyborohydride (235 mg) was added, and the mixture was stirred at room temperature overnight, and a saturated sodium carbonate solution was added to adjust pH to 9, and dichloromethane was evaporated to remove solvent. The mixture was purified by EtOAc (EtOAc) elute
1H NMR(400MHz,CDCl3)δ9.38(s,1H),9.29(s,1H),8.25(s,1H),7.90(d,J＝8.4Hz,1H),7.83(s,1H),7.37～7.39(m,1H),7.21(d,J＝8.4Hz,2H),6.92(d,J＝8.0Hz,2H),6.73(s,1H),6.52～6.57(m,2H),5.78(s,1H),3.92(s,3H),2.88～3.48(m,4H),2.29～2.51(m,4H),1.98～2.06(m,4H),1.45～1.53(m,2H),0.96(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ9.38 (s, 1H), 9.29 (s, 1H), 8.25 (s, 1H), 7.90 (d, J = 8.4Hz, 1H), 7.83 (s, 1H) , 7.37 to 7.39 (m, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 6.73 (s, 1H), 6.52 to 6.57 (m, 2H), 5.78 (s, 1H), 3.92 (s, 3H), 2.88 to 3.48 (m, 4H), 2.29 to 2.51 (m, 4H), 1.98 to 2.06 (m, 4H), 1.45 to 1.53 (m, 2H), 0.96 (s, 6H).
步骤E：2-(1H-并吡咯[2,3-b]吡啶-5-基氨基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸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
Figure PCTCN2017100226-appb-000107
Figure PCTCN2017100226-appb-000107
将甲基-2-(1H-并吡咯[2,3-b]吡啶-5-基氨基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸酯Methyl-2-(1H-pyrrole[2,3-b]pyridin-5-ylamino)-4-(1-((2-(4-chlorophenyl)-4,4-dimethyl) Cyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoate
分散于1N氢氧化钠溶液(5mL)与二氧六环(5mL)的混合溶液中，50℃下搅拌6小时，反应冷却至室温后，加入过量饱和磷酸二氢钠溶液调节pH至6，乙酸乙酯萃取，无水硫酸钠干燥，除去溶剂得到产品(45mg)。Disperse in a mixed solution of 1N sodium hydroxide solution (5mL) and dioxane (5mL), stir at 50 ° C for 6 hours, after the reaction was cooled to room temperature, add excess saturated sodium dihydrogen phosphate solution to adjust the pH to 6, acetic acid The ethyl ester was extracted, dried over anhydrous sodium sulfate and evaporated to ethylamine.
1H NMR(400MHz,d6-DMSO)δ12.83(br,1H),11.65(s,1H),9.48(s,1H),8.10(s,1H),7.84(d,J＝2.4Hz,1H),7.79(d,J＝8.0Hz,1H),7.47～7.49(m,1H),7.31(d,J＝8.0Hz,2H),7.04(d,J＝8.0Hz,2H),6.72～6.74(m,2H),6.43(s,1H),5.98(s,1H),2.81(s,4H),2.30～2.35(m,2H),2.10～2.20(m,4H),1.94～1.96(m,2H),1.35～1.39(m,2H),0.91(s,6H)。 1 H NMR (400MHz, d6- DMSO) δ12.83 (br, 1H), 11.65 (s, 1H), 9.48 (s, 1H), 8.10 (s, 1H), 7.84 (d, J = 2.4Hz, 1H ), 7.79 (d, J = 8.0 Hz, 1H), 7.47 to 7.49 (m, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.72 to 6.74 (m, 2H), 6.43 (s, 1H), 5.98 (s, 1H), 2.81 (s, 4H), 2.30 to 2.35 (m, 2H), 2.10 to 2.20 (m, 4H), 1.94 to 1.96 (m) , 2H), 1.35 to 1.39 (m, 2H), 0.91 (s, 6H).
步骤F：2-(1H-吡咯并[2,3-b]吡啶-5-基)氨基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(3-硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000108
Figure PCTCN2017100226-appb-000108
将2-(1H-并吡咯[2,3-b]吡啶-5-基氨基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(45mg)和3-硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯磺酰胺(32mg)溶于二氯甲烷(5mL)中，加入三乙胺(18mg)、EDCI(22mg)、DMAP(17mg)，室温下搅拌过夜，加入水淬灭反应，二氯甲烷萃取，1M盐酸洗有机相，随后用饱和氯化钠溶液洗有机相，无水硫酸钠干燥，除去溶剂得混合物，混合物用制备薄层板分离，展开剂为二氯甲烷/甲醇/氨水(400/40/3)，得到目标产物(26mg)。2-(1H-Pyropyr[2,3-b]pyridin-5-ylamino)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-) 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (45 mg) and 3-nitro-4-((tetrahydro-2H-pyran-4-) Methylamino)benzenesulfonamide (32 mg) was dissolved in dichloromethane (5 mL), triethylamine (18 mg), EDCI (22 mg), DMAP (17 mg). Extraction with methylene chloride, washing the organic phase with 1M hydrochloric acid, then washing the organic phase with saturated sodium chloride solution, drying over anhydrous sodium sulfate, removing the solvent to obtain a mixture, and the mixture was separated by preparative thin layer, and the developing solvent was dichloromethane/methanol. /Ammonia (400/40/3) gave the desired product (26 mg).
1H NMR(400MHz,CDCl3)δ10.41(br,1H),9.81(br,1H),8.86(s,1H),8.40(s,1H),8.01～8.06(m,2H),7.63～7.73(m,2H),7.31(d,J＝8.0Hz,2H),6.97～6.99(m,2H),6.85(d,J＝8.0Hz,1H),6.71(s,1H),6.44(s,1H),6.33(s,1H),5.82(s,1H),3.98～4.02(m,2H),3.62～3.71(m,2H),3.36～3.43(m,2H),3.22～3.24(m,2H),2.87～3.07(m,4H),2.43～2.66(m,4H),2.04～2.09(m,2H),1.92～1.98(m,1H),1.70～1.76(m,2H),1.39～1.52(m,4H),0.97(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ10.41 (br, 1H), 9.81 (br, 1H), 8.86 (s, 1H), 8.40 (s, 1H), 8.01 ~ 8.06 (m, 2H), 7.63 ~ 7.73 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.97 to 6.99 (m, 2H), 6.85 (d, J = 8.0 Hz, 1H), 6.71 (s, 1H), 6.44 (s) , 1H), 6.33 (s, 1H), 5.82 (s, 1H), 3.98 to 4.02 (m, 2H), 3.62 to 3.71 (m, 2H), 3.36 to 3.43 (m, 2H), 3.22 to 3.24 (m) , 2H), 2.87 to 3.07 (m, 4H), 2.43 to 2.66 (m, 4H), 2.04 to 2.09 (m, 2H), 1.92 to 1.98 (m, 1H), 1.70 to 1.76 (m, 2H), 1.39 ~ 1.52 (m, 4H), 0.97 (s, 6H).
实施例14Example 14
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲 基)-1,2,3,6-四氢吡啶-4-基)-N-(4-(2-吗啉乙基胺)-3-硝基苯磺酰基)苯甲酰胺2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-) 1-alkenyl) -1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(2-morpholinethylamine)-3-nitrobenzenesulfonyl)benzamide
Figure PCTCN2017100226-appb-000109
Figure PCTCN2017100226-appb-000109
步骤A：4-(2-吗啉乙基胺)-3-硝基苯磺酰胺Step A: 4-(2-morpholinethylamine)-3-nitrobenzenesulfonamide
Figure PCTCN2017100226-appb-000110
Figure PCTCN2017100226-appb-000110
将4-氯-3-硝基苯磺酰胺(1.0g)，2-吗啉乙基胺(605mg)，DIEA(1.6g)溶于乙腈(30mL)中，回流过夜，反应冷却至室温后，加水淬灭反应，二氯甲烷/甲醇混合液萃取，除去溶剂得到粗品，石油醚打浆，抽滤得到黄色产品(1.2g)。4-Chloro-3-nitrobenzenesulfonamide (1.0 g), 2-morpholinylethylamine (605 mg), DIEA (1.6 g) was dissolved in acetonitrile (30 mL) and refluxed overnight. The reaction was quenched with water and extracted with a methylene chloride/methanol mixture. The solvent was evaporated to afford crude oil, petroleum ether, and filtered to give a yellow product (1.2 g).
1H NMR(400MHz,d6-DMSO)δ8.72～8.75(m,1H),8.46(d,J＝2.4Hz,1H),7.83(d,J＝9.6Hz,1H),7.31(s,2H),7.20(d,J＝9.2Hz,1H),3.58(s,4H),3.46～3.49(m,2H),2.60～2.65(m,2H),2.41～2.44(m,4H)。 1 H NMR (400 MHz, d6-DMSO) δ 8.72 - 8.75 (m, 1H), 8.46 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 9.6 Hz, 1H), 7.31 (s, 2H) ), 7.20 (d, J = 9.2 Hz, 1H), 3.58 (s, 4H), 3.46 to 3.49 (m, 2H), 2.60 to 2.65 (m, 2H), 2.41 to 2.44 (m, 4H).
步骤B：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-(2-吗啉乙基胺)-3-硝基苯磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000111
Figure PCTCN2017100226-appb-000111
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(60mg)、4-(2-吗啉乙基胺)-3-硝基苯磺酰胺(35mg)、EDCI(26mg)、DMAP(20mg)、TEA(22mg)溶于二氯甲烷(10mL)中，室温下搅拌过夜，加水淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，除去溶剂，粗品用薄层析制备板分离，展开剂为二氯甲烷/甲醇(20/1)，得到产品(30mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl) -1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (60 mg), 4-(2-morpholinethylamine)-3-nitrobenzenesulfonate The amide (35 mg), EDCI (26 mg), DMA (20 mg), EtOAc (20 mg), EtOAc (EtOAc) elute The solvent was removed, and the crude material was crystallised eluted elution elution elution
1H NMR(400MHz,d6-DMSO)δ11.68(s,1H),8.69(s,1H),8.50(s,1H),7.98(s,1H),7.79(d,J＝9.6Hz,1H),7.49～7.51(m,3H),7.34(d,J＝8.4Hz,2H),7.07～7.13(m,3H),6.95～6.98(m,1H),6.72(s,1H),6.36(s,1H),5.97(s,1H),3.61(s,4H),3.39～3.50(m,2H),2.62～2.66(m,6H),2.52～2.59(m,4H),2.31～2.43(m,4H),2.14～2.17(m,2H),1.95～2.02(m,2H),1.39～1.44(m,2H),0.93(s,6H)。 1 H NMR (400MHz, d6- DMSO) δ11.68 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 7.98 (s, 1H), 7.79 (d, J = 9.6Hz, 1H ), 7.49 to 7.51 (m, 3H), 7.34 (d, J = 8.4 Hz, 2H), 7.07 to 7.13 (m, 3H), 6.95 to 6.98 (m, 1H), 6.72 (s, 1H), 6.36 ( s, 1H), 5.97 (s, 1H), 3.61 (s, 4H), 3.39 to 3.50 (m, 2H), 2.62 to 2.66 (m, 6H), 2.52 to 2.59 (m, 4H), 2.31 to 2.43 ( m, 4H), 2.14 to 2.17 (m, 2H), 1.95 to 2.02 (m, 2H), 1.39 to 1.44 (m, 2H), 0.93 (s, 6H).
实施例15Example 15
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-(3-吗啉丙基胺)-3-硝基苯磺酰基)苯甲酰胺 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-) 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(3-morpholinylpropyl)-3-nitrobenzenesulfonyl)benzene Formamide
Figure PCTCN2017100226-appb-000112
Figure PCTCN2017100226-appb-000112
步骤A：4-(2-吗啉丙基胺)-3-硝基苯磺酰胺Step A: 4-(2-morpholinopropylamine)-3-nitrobenzenesulfonamide
Figure PCTCN2017100226-appb-000113
Figure PCTCN2017100226-appb-000113
将4-氯-3-硝基苯磺酰胺(1.0g)、2-吗啉丙基胺(670mg)、DIEA(1.6g)溶于乙腈(30mL)中，回流过夜，反应冷却至室温后，倒入水中，二氯甲烷/甲醇萃取，除去溶剂的粗品，石油醚打浆，抽滤得到黄色产品(1.1g)。4-Chloro-3-nitrobenzenesulfonamide (1.0 g), 2-morpholinylpropylamine (670 mg), DIEA (1.6 g) was dissolved in acetonitrile (30 mL) and refluxed overnight. It was poured into water, extracted with dichloromethane/methanol, and the crude solvent was removed, and petroleum ether was beaten and filtered to give a yellow product (1.1 g).
1H NMR(400MHz,d6-DMSO)δ8.73～8.76(m,1H),8.47(d,J＝2.4Hz,1H),7.82～7.85(m,1H),7.32(s,2H),7.26(d,J＝9.6Hz,1H),3.60(s,4H),3.45～3.48(m,2H),2.37～2.39(m,6H),1.79～1.81(m,2H)。 1 H NMR (400 MHz, d6-DMSO) δ 8.73 - 8.76 (m, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.82 - 7.85 (m, 1H), 7.32 (s, 2H), 7.26 (d, J = 9.6 Hz, 1H), 3.60 (s, 4H), 3.45 to 3.48 (m, 2H), 2.37 to 2.39 (m, 6H), 1.79 to 1.81 (m, 2H).
步骤B：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-(2-吗啉丙基胺)-3-硝基苯磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000114
Figure PCTCN2017100226-appb-000114
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(60mg)，4-(2-吗啉丙基胺)-3-硝基苯磺酰胺(36mg)，EDCI(26mg)，DMAP(20mg)，TEA(22mg)溶于二氯甲烷(20mL)中，室温下搅拌过夜，加水淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，除去溶剂，粗品用薄层析制备板分离，展开剂为二氯甲烷/甲醇(15/1)，得到产品(30mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl) -1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (60 mg), 4-(2-morpholinylpropylamine)-3-nitrobenzenesulfonate The amide (36 mg), EDCI (26 mg), EtOAc (20 mg), EtOAc (EtOAc) (EtOAc) The solvent was removed, and the crude material was crystallised eluted elution elution elution
1H NMR(400MHz,d6-DMSO)δ11.65(s,1H),8.62(s,1H),8.49(s,1H),7.98(d,J＝2.4Hz,1H),7.77(d,J＝8.0Hz,1H),7.46～7.51(m,3H),7.35(d,J＝8.0Hz,2H),7.07～7.13(m,3H),6.97～7.00(m,1H),6.77(s,1H),6.37(s,1H),5.98(s,1H),3.68(s,4H),3.38～3.44(m,2H),2.55～2.86(m,6H),2.44～2.47(m,4H),2.34～2.39(m,4H),2.14～2.21(m,2H),1.97～2.02(m,2H),1.79～1.89(m,2H),1.38～1.45(m,2H),0.94(s,6H)。 1 H NMR (400MHz, d6- DMSO) δ11.65 (s, 1H), 8.62 (s, 1H), 8.49 (s, 1H), 7.98 (d, J = 2.4Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.46 to 7.51 (m, 3H), 7.35 (d, J = 8.0 Hz, 2H), 7.07 to 7.13 (m, 3H), 6.97 to 7.00 (m, 1H), 6.77 (s, 1H), 6.37 (s, 1H), 5.98 (s, 1H), 3.68 (s, 4H), 3.38 to 3.44 (m, 2H), 2.55 to 2.86 (m, 6H), 2.44 to 2.47 (m, 4H) , 2.34 to 2.39 (m, 4H), 2.14 to 2.21 (m, 2H), 1.97 to 2.02 (m, 2H), 1.79 to 1.89 (m, 2H), 1.38 to 1.45 (m, 2H), 0.94 (s, 6H).
实施例16Example 16
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(3-硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯基磺酰基)苯甲酰胺 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4-dimethyl) Cyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran)- 4-yl)methylamino)phenylsulfonyl)benzamide
Figure PCTCN2017100226-appb-000115
Figure PCTCN2017100226-appb-000115
步骤A：(4-氯-2-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷Step A: (4-Chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Figure PCTCN2017100226-appb-000116
Figure PCTCN2017100226-appb-000116
室温下，将1-溴-4-氯-2-氟苯(2g)、联硼酸频那醇酯(4.8g)、四(三苯基膦)钯(1g)和醋酸钾(2.8g)加入甲苯(30mL)中，在N2保护下80℃搅拌过夜。反应完全，冷却至室温，倾入水中，用乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，真空浓缩得粗产品。经柱层析纯化，以石油醚/二氯甲烷(4/1)洗脱，得到产品(700mg)。1-Bromo-4-chloro-2-fluorobenzene (2g), boranoic acid pinacol ester (4.8g), tetrakis(triphenylphosphine)palladium (1g) and potassium acetate (2.8g) were added at room temperature. Intoluene (30 mL) was stirred at 80 ° C under N 2 overnight. The reaction was completed, cooled to room temperature, poured into water, EtOAc (EtOAc)EtOAc. Purification by column chromatography eluting with EtOAc (EtOAc)
1H NMR(400MHz,CDCl3)δ7.65～7.69(m,1H),7.12～7.15(m,1H),7.05～7.08(m,1H),1.36(s,12H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 - 7.69 (m, 1H), 7.12 - 7.15 (m, 1H), 7.05 - 7.08 (m, 1H), 1.36 (s, 12H).
步骤B：2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯甲酸甲酯Step B: Methyl 2-(4-chloro-2-fluorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate
Figure PCTCN2017100226-appb-000117
Figure PCTCN2017100226-appb-000117
室温下，将5,5-二甲基-2-(三氟甲基磺酰氧基)环己-1-烯甲酸甲酯(5.5g)、(4-氯-2-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(4.8g)、磷酸钾(7g)和Pd(dppf)Cl2(1.2g)加入乙二醇二甲醚(100mL)和水(20mL)的混合溶剂中，在N2保护下70℃搅拌过夜。然后冷却至室温，倾入水中,用乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，真空浓缩得粗产品。经柱层析纯化，用石油醚/二氯甲烷(4/1)洗脱，得到产品(2.4g)。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. After cooling to room temperature, it was poured into water, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate Purification by column chromatography eluting with EtOAc (EtOAc)
1H NMR(400MHz,CDCl3)δ7.04～7.10(m,2H),6.97(t,J＝8.0Hz,1H),3.50(s,3H),2.47～2.51(m,2H),2.10(t,J＝2.4Hz,2H),1.50(t,J＝6.4Hz,2H),1.00(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.04 to 7.10 (m, 2H), 6.97 (t, J = 8.0 Hz, 1H), 3.50 (s, 3H), 2.47 to 2.51 (m, 2H), 2.10 ( t, J = 2.4 Hz, 2H), 1.50 (t, J = 6.4 Hz, 2H), 1.00 (s, 6H).
步骤C：(2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲醇Step C: (2-(4-Chloro-2-fluorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol
Figure PCTCN2017100226-appb-000118
Figure PCTCN2017100226-appb-000118
将2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯甲酸甲酯(2.4g)溶于新干燥的四氢呋喃(100mL)中，冷却至0℃，加入4M的硼氢化锂的四氢呋喃溶液(16mL)，滴加甲醇(3.8mL)后恢复至室温搅拌过夜。然后加入稀盐酸淬灭反应，用乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，除去溶剂，得到产品(1.2g)。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.
1H NMR(400MHz,CDCl3)δ7.00～7.11(m,3H),3.87(s,2H),2.32(br,2H),1.99(s,2H),1.50(t,J＝6.4Hz,2H),0.99(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.00 - 7.11 (m, 3H), 3.87 (s, 2H), 2.32 (br, 2H), 1.99 (s, 2H), 1.50 (t, J = 6.4 Hz, 2H), 0.99 (s, 6H).
步骤D：2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯甲醛 Step D: 2-(4-Chloro-2-fluorophenyl)-4,4-dimethylcyclohex-1-enecarboxaldehyde
Figure PCTCN2017100226-appb-000119
Figure PCTCN2017100226-appb-000119
在室温下，将氯铬酸吡啶(1.9g)溶于二氯甲烷(20mL)，加入(2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲醇(1.2g)，室温搅拌30分钟，然后浓缩，柱层析分离，展开剂为二氯甲烷，得到产品(1g)。Pyridine chlorochromate (1.9 g) was dissolved in dichloromethane (20 mL) at room temperature and (2-(4-chloro-2-fluorophenyl)-4,4-dimethylcyclohexan-1- Alkenyl)methanol (1.2 g) was stirred at room temperature for 30 minutes, then concentrated and purified by column chromatography eluting with dichloromethane.
1H NMR(400MHz,CDCl3)δ9.46(d,J＝1.6Hz,1H),7.14～7.18(m,2H),7.09(t,J＝8Hz,1H),2.39(t,J＝6.4Hz,2H),2.20～2.29(m,2H),7.10(br,1H),1.51(t,J＝5.6Hz,2H),1.01(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.46 (d, J = 1.6 Hz, 1H), 7.14 - 7.18 (m, 2H), 7.09 (t, J = 8 Hz, 1H), 2.39 (t, J = 6.4 Hz, 2H), 2.20 to 2.29 (m, 2H), 7.10 (br, 1H), 1.51 (t, J = 5.6 Hz, 2H), 1.01 (s, 6H).
步骤E：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯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
Figure PCTCN2017100226-appb-000120
Figure PCTCN2017100226-appb-000120
在室温下，将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯(660mg)、2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯甲醛(1g)溶于二氯甲烷(10mL)，加入醋酸(2mL)，搅拌30分钟后,加入三乙酰氧基硼氢化钠(1.6g)，室温搅拌过夜。加碳酸钠水溶液调pH为8，用二氯甲烷萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，真空浓缩得粗产品。经薄层层析纯化，展开剂为石油醚/乙酸乙酯(1/1)，得到产品(486mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoic acid A at room temperature Ester (660 mg), 2-(4-chloro-2-fluorophenyl)-4,4-dimethylcyclohex-1-enecarboxaldehyde (1 g) was dissolved in dichloromethane (10 mL), and acetic acid (2 mL) After stirring for 30 minutes, sodium triacetoxyborohydride (1.6 g) was added and stirred at room temperature overnight. The aqueous sodium carbonate solution was adjusted to pH 8 and extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated Purification by thin layer chromatography, EtOAc (EtOAc) (EtOAc)
1H NMR(400MHz,CDCl3)δ9.56(br,1H),8.19(d,J＝2.4Hz,1H),7.88(d,J＝8.0Hz,1H),7.54(d,J＝2.4Hz,1H),7.37(t,J＝7.2Hz 1H),7.13～7.15(m,1H),7.02～7.07(m,2H),6.94(t,J＝8.0Hz,1H),6.88(s,1H),6.45～6.47(m,1H),6.01(br,1H),3.86(s,3H),2.88(br,2H),2.80(br,2H),2.37～2.40(m,4H),2.23(br,2H),1.93～1.98(m,2H),1.43～1.46(m,2H),0.96(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.56 (br, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 2.4 Hz) , 1H), 7.37 (t, J = 7.2 Hz 1H), 7.13 to 7.15 (m, 1H), 7.02 to 7.07 (m, 2H), 6.94 (t, J = 8.0 Hz, 1H), 6.88 (s, 1H) ), 6.45 to 6.47 (m, 1H), 6.01 (br, 1H), 3.86 (s, 3H), 2.88 (br, 2H), 2.80 (br, 2H), 2.37 to 2.40 (m, 4H), 2.23 ( Br, 2H), 1.93 to 1.98 (m, 2H), 1.43 to 1.46 (m, 2H), 0.96 (s, 6H).
步骤F：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸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
Figure PCTCN2017100226-appb-000121
Figure PCTCN2017100226-appb-000121
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸甲酯(486mg)溶于1,4-二氧六环(20mL)，加入1M的氢氧化钠水溶液(10mL)，在50℃下搅拌2小时，加磷酸二氢钠饱和水溶液至pH为6，用乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，除去溶剂，得到产品(400mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4-dimethyl) Methyl cyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoate (486 mg) was dissolved in 1,4-dioxane (20 mL). After adding 1 M aqueous sodium hydroxide solution (10 mL), and stirring at 50 ° C for 2 hours, a saturated aqueous solution of sodium dihydrogen phosphate was added to pH 6 and extracted with ethyl acetate. The solvent was removed to give the product (400 mg).
1H NMR(400MHz,D6-DMSO)δ11.63(s,1H),7.99(d,J＝2.4Hz,1H),7.68(d,J＝8.0Hz,1H),7.45(s,2H),7.33～7.35(m,1H),7.17～7.22(m,2H),7.10(t,J＝8.0Hz,1H),6.86(br, 1H),6.36(br,1H),6.06(br,1H),2.78(br,2H),2.71(br,2H),2.25～2.31(m,4H),2.15(br,2H),1.90(br,2H),1.37～1.40(m,2H),0.92(s,6H)。 1 H NMR (400MHz, D6- DMSO) δ11.63 (s, 1H), 7.99 (d, J = 2.4Hz, 1H), 7.68 (d, J = 8.0Hz, 1H), 7.45 (s, 2H), 7.33 to 7.35 (m, 1H), 7.17 to 7.22 (m, 2H), 7.10 (t, J = 8.0 Hz, 1H), 6.86 (br, 1H), 6.36 (br, 1H), 6.06 (br, 1H) , 2.78 (br, 2H), 2.71 (br, 2H), 2.25 to 2.31 (m, 4H), 2.15 (br, 2H), 1.90 (br, 2H), 1.37 to 1.40 (m, 2H), 0.92 (s) , 6H).
步骤G：3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯磺酰胺Step G: 3-Nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide
Figure PCTCN2017100226-appb-000122
Figure PCTCN2017100226-appb-000122
将4-氯-3-硝基苯磺酰胺(2.36g)与(四氢-2H-吡喃-4-基)甲胺(1.61g)溶于乙腈(30mL),然后加入DIEA(5.3mL)，加热回流过夜。冷却后倾入水中，充分搅拌后过滤。用乙酸乙酯洗涤固体，干燥后得产品(3.0g)。4-Chloro-3-nitrobenzenesulfonamide (2.36 g) and (tetrahydro-2H-pyran-4-yl)methylamine (1.61 g) were dissolved in acetonitrile (30 mL) then DIEA (5.3 mL) Heated to reflux overnight. After cooling, pour into water, stir well, and filter. The solid was washed with ethyl acetate and dried to give product (3.0 g).
1H NMR(400MHz,d6-DMSO)δ8.56(t,J＝6.0Hz,1H),8.44(d,J＝1.6Hz,1H),7.78～7.81(m,1H),7.27～7.31(m,3H),3.81～3.85(m,2H),3.31～3.35(m,2H),3.21～3.27(m,2H),1.87～1.92(m,1H),1.57～1.61(m,2H),1.23～1.29(m,2H)。 1 H NMR (400 MHz, d6-DMSO) δ 8.56 (t, J = 6.0 Hz, 1H), 8.44 (d, J = 1.6 Hz, 1H), 7.78 to 7.81 (m, 1H), 7.27 to 7.31 (m) , 3H), 3.81 to 3.85 (m, 2H), 3.31 to 3.35 (m, 2H), 3.21 to 3.27 (m, 2H), 1.87 to 1.92 (m, 1H), 1.57 to 1.61 (m, 2H), 1.23 ~1.29 (m, 2H).
步骤H：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(3-硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯基磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000123
Figure PCTCN2017100226-appb-000123
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(30mg)和三乙胺(10mg)混合后加入3-(硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯磺酰胺(17mg)、EDCI(13mg)、DMAP(13mg)的二氯甲烷(3mL)溶液中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到产品(20mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4-di) Methylcyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (30 mg) and triethylamine (10 mg) were mixed and added to 3-(nitro 4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide (17 mg), EDCI (13 mg), EtOAc (EtOAc) Diluted with dichloromethane, washed with water several times, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue was separated by preparative thin-layer, and the solvent was methylene chloride/methanol (15/1). The product (20 mg) was obtained.
1H NMR(400MHz,CDCl3)δ10.31(br,1H),8.92(d,J＝2.0Hz,2H),8.52～8.55(m,1H),8.17～8.20(m,2H),8.06(d,J＝8.4Hz,1H),7.69(d,J＝2.4Hz,1H),7.45(t,J＝3.2Hz,1H),7.11～7.13(m,1H),7.00～7.06(m,2H),6.91～6.94(m,2H),6.68(br,1H),6.55～6.57(m,1H),5.94(br,1H),4.01～4.05(m,2H),3.39～3.46(m,2H),3.27(t,J＝6.4Hz,2H),2.76～2.85(m,4H),2.17～2.37(m,6H),1.93～2.02(m,4H),1.72～1.76(m,2H),1.54～1.59(m,1H),1.25(br,2H),0.95(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 10.31 (br, 1H), 8.92 (d, J = 2.0 Hz, 2H), 8.52 to 8.55 (m, 1H), 8.17 to 8.20 (m, 2H), 8.06 ( d, J = 8.4 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.45 (t, J = 3.2 Hz, 1H), 7.11 to 7.13 (m, 1H), 7.00 to 7.06 (m, 2H) ), 6.91 to 6.94 (m, 2H), 6.68 (br, 1H), 6.55 to 6.57 (m, 1H), 5.94 (br, 1H), 4.01 to 4.05 (m, 2H), 3.39 to 3.46 (m, 2H) ), 3.27 (t, J = 6.4 Hz, 2H), 2.76 to 2.85 (m, 4H), 2.17 to 2.37 (m, 6H), 1.93 to 2.02 (m, 4H), 1.72 to 1.76 (m, 2H), 1.54 to 1.59 (m, 1H), 1.25 (br, 2H), 0.95 (s, 6H).
实施例17Example 17
N-(4-(1,4-二氧杂螺[4.5]癸烷-8-基甲基胺)-3-硝基苯磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰胺 N-(4-(1,4-Dioxaspiro[4.5]decane-8-ylmethylamine)-3-nitrobenzenesulfonyl)-2-(1H-pyrrolo[2,3-b Pyridine-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)-1,2, 3,6-tetrahydropyridin-4-yl)benzamide
Figure PCTCN2017100226-appb-000124
Figure PCTCN2017100226-appb-000124
步骤A：1,4-二氧杂螺[4.5]癸烷-8-甲胺Step A: 1,4-Dioxaspiro[4.5]decane-8-methylamine
Figure PCTCN2017100226-appb-000125
Figure PCTCN2017100226-appb-000125
将四氢铝锂(34mg)分散于四氢呋喃(20mL)中，0℃下加入1,4-二氧杂螺[4.5]癸烷-8-甲腈(100mg)，回流2小时，加水淬灭反应。二氯甲烷萃取，无水硫酸钠干燥，除去溶剂得到产品(40mg)。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.
1H NMR(400MHz,CDCl3)δ3.94～3.90(m,4H),2.55(d,J＝6.0Hz,2H),1.75(d,J＝10.0Hz,4H),1.49～1.55(m,2H),1.16～1.32(m,5H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.94 to 3.90 (m, 4H), 2.55 (d, J = 6.0 Hz, 2H), 1.75 (d, J = 10.0 Hz, 4H), 1.49 to 1.55 (m, 2H), 1.16 to 1.32 (m, 5H).
步骤B：4-(1,4-二氧杂螺[4.5]癸烷-8-甲基胺)-3-硝基苯磺酰胺Step B: 4-(1,4-Dioxaspiro[4.5]decane-8-methylamine)-3-nitrobenzenesulfonamide
Figure PCTCN2017100226-appb-000126
Figure PCTCN2017100226-appb-000126
将4-氯-3-硝基苯磺酰胺(50mg)，1,4-二氧杂螺[4.5]癸烷-8-甲胺(50mg)，DIEA(81mg)溶于乙腈(20mL)中，回流过夜。加入水淬灭反应，二氯甲烷/甲醇萃取，除去溶剂得到粗品，粗品用薄层析制备板分离，展开剂为二氯甲烷/甲醇(30/1)，得到纯品(45mg)。4-Chloro-3-nitrobenzenesulfonamide (50 mg), 1,4-dioxaspiro[4.5]decane-8-methylamine (50 mg), EtOAc (EtOAc) Reflux overnight. The reaction was quenched by EtOAc EtOAc (EtOAc)EtOAc.
1H NMR(400MHz,d6-DMSO)δ8.55(t,J＝7.6Hz,1H),8.45(d,J＝2.4Hz,1H),7.79～7.82(m,1H),7.31(s,2H),7.26(d,J＝9.6Hz,1H),3.83(s,4H),3.30(br,2H),1.65～1.75(m,5H),1.39～1.45(m,2H),1.22～1.29(m,2H)。 1 H NMR (400MHz, d6- DMSO) δ8.55 (t, J = 7.6Hz, 1H), 8.45 (d, J = 2.4Hz, 1H), 7.79 ~ 7.82 (m, 1H), 7.31 (s, 2H ), 7.26 (d, J = 9.6 Hz, 1H), 3.83 (s, 4H), 3.30 (br, 2H), 1.65 to 1.75 (m, 5H), 1.39 to 1.45 (m, 2H), 1.22 to 1.29 ( m, 2H).
步骤C：N-(4-(1,4-二氧杂螺[4.5]癸烷-8-基甲基胺)-3-硝基苯磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰胺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
Figure PCTCN2017100226-appb-000127
Figure PCTCN2017100226-appb-000127
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(50mg)，4-(1,4-二氧杂螺[4.5]癸烷-8-甲基胺)-3-硝基苯磺酰胺(29mg)，EDCI(32mg)，DMAP(17mg)，TEA(18mg)溶于二氯甲烷(20mL)中，室温下搅拌过夜。加水淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，除去溶剂，粗品用薄层析制备板分离，展开剂为二氯甲烷/甲醇(20/1)，得到纯品(35mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl) 1-(Alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (50 mg), 4-(1,4-dioxaspiro[4.5]decane-8 Methylamine)-3-nitrobenzenesulfonamide (29 mg), EDCI (32 mg), EtOAc (EtOAc) (EtOAc) The reaction was quenched with EtOAc (EtOAc)EtOAc.
1H NMR(400MHz,CDCl3)δ9.16(br,1H),8.92(s,1H),8.54(s,1H),8.15～8.17(m,2H),8.04(d,J＝8.4Hz,1H),7.71(s,1H),7.46(s,1H),7.22～7.24(m,2H),7.07(s,1H),6.90～6.95(m,3H),6.66(s,1H),6.56(s,1H),5.88(s,1H),3.96(s,4H),3.24～3.27(m,2H),2.82～3.08(m,4H),2.18～2.48(m,6H),2.01(s,2H),1.76～1.89(m,5H),1.55～1.63(m,2H),1.38～1.47(m,4H),0.95(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ9.16 (br, 1H), 8.92 (s, 1H), 8.54 (s, 1H), 8.15 ~ 8.17 (m, 2H), 8.04 (d, J = 8.4Hz, 1H), 7.71 (s, 1H), 7.46 (s, 1H), 7.22 to 7.24 (m, 2H), 7.07 (s, 1H), 6.90 to 6.95 (m, 3H), 6.66 (s, 1H), 6.56 (s, 1H), 5.88 (s, 1H), 3.96 (s, 4H), 3.24 to 3.27 (m, 2H), 2.82 to 3.08 (m, 4H), 2.18 to 2.48 (m, 6H), 2.01 (s) , 2H), 1.76 to 1.89 (m, 5H), 1.55 to 1.63 (m, 2H), 1.38 to 1.47 (m, 4H), 0.95 (s, 6H).
实施例18Example 18
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟四氢-2H-吡喃-4-基)甲基氨基)-3-硝基苯基磺酰基)苯甲酰胺2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4-dimethyl) Cyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluorotetrahydro-2H-pyran-4-) Methylamino)-3-nitrophenylsulfonyl)benzamide
Figure PCTCN2017100226-appb-000128
Figure PCTCN2017100226-appb-000128
步骤A：3-(四氢-2H-吡喃-4-基)环氧乙烷-2-腈Step A: 3-(tetrahydro-2H-pyran-4-yl)oxirane-2-carbonitrile
Figure PCTCN2017100226-appb-000129
Figure PCTCN2017100226-appb-000129
将四氢-4H-吡喃-4-酮(20g)与氯乙腈(10.56g)溶于叔丁醇(20mL)，在室温下反应30分钟。然后在30分钟的时间里，将叔丁醇钾(24.68g)悬浮于叔丁醇(200mL)的悬浊液缓慢加入，加完后继续室温反应16小时。随后将反应液用水(200mL)稀释，用3M盐酸淬灭。用乙醚萃取，用饱和氯化钠水溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得粗产品(18g)，直接用于下一步。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.)
步骤B：2-(4-氟四氢-2H-吡喃-4-基)-2-羟基乙腈Step B: 2-(4-Fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile
Figure PCTCN2017100226-appb-000130
Figure PCTCN2017100226-appb-000130
将实施例18步骤A所得粗产品(18g)溶于二氯甲烷(60mL)，在塑料瓶中搅拌，并冷却至0℃。加入70％的氟化氢吡啶溶液(18mL)后，恢复至室温，反应过夜。然后反应液用乙酸乙酯(200mL)稀释，用饱和碳酸氢钠溶液中和至不再放出气体。用乙酸乙酯萃取，有机相用1％的稀盐酸，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，经柱层析(二氯甲烷/甲醇＝20/1)纯化得到产品(8.2g)。The crude product from Example 18 Step A (18 g) was dissolved in dichloromethane (60 mL). After adding a 70% solution of hydrogen fluoride in pyridine (18 mL), it was returned to room temperature and allowed to react overnight. The reaction was then diluted with ethyl acetate (200 mL) and neutralized with saturated sodium bicarbonate until no gas evolved. The mixture was extracted with EtOAc. EtOAc (EtOAc)EtOAc. g).
1H NMR(400MHz,CDCl3)δ4.37(d,J＝15.6Hz,1H),3.92～3.96(m,2H),3.68～3.77(m,2H),3.37(s,1H),1.81～2.02(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 4.37 (d, J = 15.6 Hz, 1H), 3.92 to 3.96 (m, 2H), 3.68 to 3.77 (m, 2H), 3.37 (s, 1H), 1.81 2.02 (m, 4H).
步骤C：(4-氟四氢-2H-吡喃-4-基)甲醇Step C: (4-Fluorotetrahydro-2H-pyran-4-yl)methanol
Figure PCTCN2017100226-appb-000131
Figure PCTCN2017100226-appb-000131
将2-(4-氟四氢-2H-吡喃-4-基)-2-羟基乙腈(8.2g)溶于异丙醇(160mL)和水(40mL)的混合溶液中,冷却至0℃，分批加入硼氢化钠(2.89g)，随后升至室温反应过夜。然后加入丙酮淬灭并搅拌1小时。用乙酸乙酯萃取，有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，除去溶剂，经柱层析(石油醚/乙酸乙酯＝3/1)纯化得到产品(2.8g)。2-(4-Fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile (8.2 g) was dissolved in a mixed solution of isopropyl alcohol (160 mL) and water (40 mL) and cooled to 0 ° C Sodium borohydride (2.89 g) was added in portions and then allowed to warm to room temperature overnight. It was then quenched with acetone and stirred for 1 hour. The mixture was extracted with EtOAc. EtOAc (EtOAc)EtOAc.
1H NMR(400MHz,CDCl3)δ3.81～3.86(m,2H),3.70～3.76(m,2H),3.58～3.65(m,2H),3.37(s,1H),1.65～1.88(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.81 to 3.86 (m, 2H), 3.70 to 3.76 (m, 2H), 3.58 to 3.65 (m, 2H), 3.37 (s, 1H), 1.65 to 1.88 (m) , 4H).
步骤D：(4-氟四氢-2H-吡喃-4-基)甲基甲磺酸酯Step D: (4-Fluorotetrahydro-2H-pyran-4-yl)methylmethanesulfonate
Figure PCTCN2017100226-appb-000132
Figure PCTCN2017100226-appb-000132
将(4-氟四氢-2H-吡喃-4-基)甲醇(2.8g)与三乙胺(3.17g)溶于二氯甲烷(30mL)，冷却至0℃。滴加甲磺酰氯(3.59g)，滴加完毕后恢复到室温，反应2小时。将反应液倾入水中，用二氯甲烷萃取，用饱和氯化钠水溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得粗产品(4.4g)，直接用于下一步(4-Fluorotetrahydro-2H-pyran-4-yl)methanol (2.8 g) and triethylamine (3.17 g) were dissolved in dichloromethane (30 mL) and cooled to 0. Methanesulfonyl chloride (3.59 g) was added dropwise, and after completion of the dropwise addition, it was returned to room temperature and reacted for 2 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate.
步骤E：4-(叠氮甲基)-4-氟四氢-2H-吡喃Step E: 4-(azidomethyl)-4-fluorotetrahydro-2H-pyran
Figure PCTCN2017100226-appb-000133
Figure PCTCN2017100226-appb-000133
将实施例18步骤D所得粗产品(4.4g)溶于N,N-二甲基甲酰胺(60mL)，加入叠氮化钠(6.79g)、碳酸氢钠(3.51g)。升至120℃，反应17小时。然后冷却至室温，倾入水中，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩至约30mL，产品的乙酸乙酯溶液直接用于下一步。The crude product (4.4 g) obtained in Step D of Example 18 was dissolved in N,N-dimethylformamide (60mL), and sodium azide (6.79 g) and sodium hydrogencarbonate (3.51 g). The temperature was raised to 120 ° C and the reaction was carried out for 17 hours. After cooling to room temperature, it was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate.
步骤F：(4-氟四氢-2H-吡喃-4-基)甲胺Step F: (4-Fluorotetrahydro-2H-pyran-4-yl)methylamine
Figure PCTCN2017100226-appb-000134
Figure PCTCN2017100226-appb-000134
向实施例18步骤E所得溶液中，加入10％的钯碳(280mg)，在氢气(1atm)下室温搅拌24小时。然后过滤，真空浓缩，经柱层析纯化，以二氯甲烷/甲醇(10/1)洗脱，得到产品(1.3g)。To the solution obtained in the step E of Example 18, 10% palladium carbon (280 mg) was added, and the mixture was stirred at room temperature under hydrogen (1 atm) for 24 hours. It was then filtered, concentrated in vacuo and purified eluting elut elut elut elut elut elut elut
1H NMR(400MHz,CDCl3)δ3.80～3.85(m,2H),3.68～3.74(m,2H),2.80(d,J＝20.8Hz,2H),1.60～1.84(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.80 to 3.85 (m, 2H), 3.68 to 3.74 (m, 2H), 2.80 (d, J = 20.8 Hz, 2H), 1.60 to 1.84 (m, 4H).
步骤G：4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯磺酰胺Step G: 4-(((4-Fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide
Figure PCTCN2017100226-appb-000135
Figure PCTCN2017100226-appb-000135
将(4-氟四氢-2H-吡喃-4-基)甲胺(1.25g)，4-氯-3-硝基苯磺酰胺(2.02g)，DIEA(3.3g)溶于乙腈(30mL)，加热回流过夜。然后冷却至室温，倾入水中，用1M盐酸调至pH为6，用乙酸乙酯萃取。有机相经饱和氯化钠水溶液洗涤，无水硫酸钠干燥，真空浓缩后得粗产品。向粗产品中加入乙酸乙酯(10mL)，搅拌1小时后过滤，用乙酸乙酯洗涤，干燥得产品(1.5g)。(4-Fluorotetrahydro-2H-pyran-4-yl)methanamine (1.25 g), 4-chloro-3-nitrobenzenesulfonamide (2.02 g), DIEA (3.3 g) dissolved in acetonitrile (30 mL) ), heated to reflux overnight. Then it was cooled to room temperature, poured into water, adjusted to pH 6 with 1M hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate (10 mL) was added to the crude product, which was stirred for 1 hour, filtered, washed with ethyl acetate and evaporated
1H NMR(400MHz,D6-DMSO)δ8.58(t,J＝6.4Hz,1H),8.48(d,J＝2.4Hz,1H),7.82～7.84(m,1H),7.41(d,J＝9.2Hz,1H),7.33(s,1H),3.74～3.81(m,4H),3.50～3.56(m,2H),1.76～1.86(m,4H)。 1 H NMR (400 MHz, D6-DMSO) δ 8.58 (t, J = 6.4 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 7.82 to 7.84 (m, 1H), 7.41 (d, J) = 9.2 Hz, 1H), 7.33 (s, 1H), 3.74 to 3.81 (m, 4H), 3.50 to 3.56 (m, 2H), 1.76 to 1.86 (m, 4H).
步骤H：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟四氢-2H-吡喃-4-基)甲基氨基)-3-硝基苯基磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000136
Figure PCTCN2017100226-appb-000136
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基) 甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(30mg)和三乙胺(10mg)混合后加入4-((4-氟四氢-2H-吡喃-4-基)甲基氨基)-3-硝基苯磺酰胺(17mg)、EDCI(13mg)、DMAP(13mg)的二氯甲烷(3mL)溶液中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到产品(16mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4-di) Methylcyclohex-1-enyl) Methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (30 mg) and triethylamine (10 mg) were combined and then added 4-((4-fluorotetrahydro-2H-pyran)- A solution of 4-yl)methylamino)-3-nitrobenzenesulfonamide (17 mg), EDCI (13 mg), D.sub.3 (13 mg) in dichloromethane (3 mL) After several times, it was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated.
1H NMR(400MHz,CDCl3)δ9.77(br,1H),8.91(d,J＝2.4Hz,1H),8.67(t,J＝6.0Hz,1H),8.14～8.17(m,2H),8.01(d,J＝8.4Hz,1H),7.67(d,J＝2.4Hz,1H),7.47(t,J＝2.8Hz,1H),6.97～7.09(m,4H),6.90(m,1H),6.66(br,1H),6.53～6.54(m,1H),5.89(br,1H),3.86～3.90(m,2H),3.71～3.77(m,2H),3.51～3.57(m,2H),2.88～2.97(m,4H),2.21～2.55(m,6H),1.71～2.01(m,6H),1.44(br,2H),0.94(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.77 (br, 1H), 8.91 (d, J = 2.4 Hz, 1H), 8.67 (t, J = 6.0 Hz, 1H), 8.14 to 8.17 (m, 2H) , 8.01 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.47 (t, J = 2.8 Hz, 1H), 6.97 - 7.09 (m, 4H), 6.90 (m, 1H), 6.66 (br, 1H), 6.53 to 6.54 (m, 1H), 5.89 (br, 1H), 3.86 to 3.90 (m, 2H), 3.71 to 3.77 (m, 2H), 3.51 to 3.57 (m, 2H), 2.88 to 2.97 (m, 4H), 2.21 to 2.55 (m, 6H), 1.71 to 2.01 (m, 6H), 1.44 (br, 2H), 0.94 (s, 6H).
实施例19Example 19
N-(4-(1,4-二氧杂螺[4.5]癸烷-8-基甲基氨基)-3-硝基苯基磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰胺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
Figure PCTCN2017100226-appb-000137
Figure PCTCN2017100226-appb-000137
步骤A：N-(4-(1,4-二氧杂螺[4.5]癸烷-8-基甲基氨基)-3-硝基苯基磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰胺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
Figure PCTCN2017100226-appb-000138
Figure PCTCN2017100226-appb-000138
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(30mg)和三乙胺(10mg)混合后加入4-(1,4-二氧杂螺[4.5]癸烷-8-基甲基氨基)-3-硝基苯磺酰胺(17mg)、EDCI(13mg)、DMAP(13mg)的二氯甲烷(3mL)溶液中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到产品(14mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4-di) Methylcyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (30 mg) and triethylamine (10 mg) were mixed and then added 4-(1, 4-Dioxaspiro[4.5]decane-8-ylmethylamino)-3-nitrobenzenesulfonamide (17 mg), EDCI (13 mg), DMAP (13 mg) in dichloromethane (3 mL) Stir at room temperature overnight, dilute with dichloromethane, wash with water several times, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate, and the residue is separated by preparative thin layer, and the solvent is dichloromethane/methanol (15/ 1), the product (14 mg) was obtained.
1H NMR(400MHz,CDCl3)δ9.75(br,1H),8.90(d,J＝2.0Hz,1H),8.55(t,J＝5.2Hz,1H),8.13～8.16(m,1H),8.04(d,J＝8.4Hz,1H),7.69(d,J＝2.8Hz,1H),7.48(t,J＝2.8Hz,1H),6.99～7.10(m,3H),6.89～6.93(m,2H),6.66(br,1H),6.54～6.55(m,1H),5.90(br,1H),3.96(t,J＝2.8Hz,4H),3.25(t,J＝6.4Hz,2H),2.85～3.07(m,4H),2.18～2.62(m,6H),1.73～2.02(m,7H),1.55～1.62(m,2H),1.38～1.45(m,4H),0.95(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ9.75 (br, 1H), 8.90 (d, J = 2.0Hz, 1H), 8.55 (t, J = 5.2Hz, 1H), 8.13 ~ 8.16 (m, 1H) , 8.04 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 2.8 Hz, 1H), 7.48 (t, J = 2.8 Hz, 1H), 6.99 - 7.10 (m, 3H), 6.89 - 6.93 ( m, 2H), 6.66 (br, 1H), 6.54 to 6.55 (m, 1H), 5.90 (br, 1H), 3.96 (t, J = 2.8 Hz, 4H), 3.25 (t, J = 6.4 Hz, 2H) ), 2.85 to 3.07 (m, 4H), 2.18 to 2.62 (m, 6H), 1.73 to 2.02 (m, 7H), 1.55 to 1.62 (m, 2H), 1.38 to 1.45 (m, 4H), 0.95 (s) , 6H).
实施例20 Example 20
(R)-N-(4-((1,4-二恶烷-2-基)甲基氨基)-3-硝基苯基磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰胺(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
Figure PCTCN2017100226-appb-000139
Figure PCTCN2017100226-appb-000139
步骤A：(R)-4-((苄氧基)甲基)-2,2-二甲基-1,3-二氧戊环Step A: (R)-4-((Benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolane
Figure PCTCN2017100226-appb-000140
Figure PCTCN2017100226-appb-000140
将(R)-(2,2-二甲基-1,3-二氧戊环-4-基)甲醇(5g)溶于N,N-二甲基甲酰胺(50mL)，冷却至0℃。分批加入钠氢(1.6g)，加完后继续保持在0℃搅拌30分钟后，加入苄溴(4.5mL)。恢复至室温，搅拌5小时。将反应液倾入水中，用乙酸乙酯萃取，用饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得粗产品。经柱层析纯化，以石油醚/乙酸乙酯(15/1)洗脱得产品(4.7g)。(R)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methanol (5 g) was dissolved in N,N-dimethylformamide (50 mL), cooled to 0 ° C . Sodium hydrogen (1.6 g) was added portionwise, and after stirring, the mixture was stirred at 0 ° C for 30 minutes, then benzyl bromide (4.5 mL) was added. Return to room temperature and stir for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Purification by column chromatography eluting with EtOAc (EtOAc)
1H NMR(400MHz,CDCl3)δ7.24～7.30(m,5H),4.49～4.57(m,2H),4.23～4.29(m,1H),3.99～4.03(m,1H),3.68～3.72(m,1H),3.49～3.53(m,1H),3.41～3.45(m,1H),1.38(s,3H),1.32(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.24 - 7.30 (m, 5H), 4.49 - 4.57 (m, 2H), 4.23 - 4.29 (m, 1H), 3.99 - 4.03 (m, 1H), 3.68 - 3.72 (m, 1H), 3.49 to 3.53 (m, 1H), 3.41 to 3.45 (m, 1H), 1.38 (s, 3H), 1.32 (s, 3H).
步骤B：(S)-3-(苄氧基)丙烷-1,2-二醇Step B: (S)-3-(Benzyloxy)propane-1,2-diol
Figure PCTCN2017100226-appb-000141
Figure PCTCN2017100226-appb-000141
将(R)-4-((苄氧基)甲基)-2,2-二甲基-1,3-二氧戊环(4.7g)溶于乙酸(30mL)中，加入水(30mL)，反应液在60℃下搅拌1小时。冷却至室温，然后倾入水中，用乙酸乙酯萃取，依次用饱和碳酸氢钠溶液，饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得产品(2.6g)。(R)-4-((Benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolane (4.7 g) was dissolved in acetic acid (30 mL), water (30 mL) The reaction solution was stirred at 60 ° C for 1 hour. After cooling to room temperature, it was poured into water, and extracted with ethyl acetate. The organic phase was washed successively with saturated sodium hydrogen carbonate and saturated sodium chloride solution and dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl3)δ7.31～7.40(m,5H),4.58(s,2H),3.90～3.94(m,1H),3.55～3.76(m,4H),2.61(br,1H),2.18(br,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.31 to 7.40 (m, 5H), 4.58 (s, 2H), 3.90 to 3.94 (m, 1H), 3.55 to 3.76 (m, 4H), 2.61 (br, 1H) ), 2.18 (br, 1H).
步骤C：(R)-2-((苄氧基)甲基)-1,4-二氧六环Step C: (R)-2-((Benzyloxy)methyl)-1,4-dioxane
Figure PCTCN2017100226-appb-000142
Figure PCTCN2017100226-appb-000142
将(S)-3-(苄氧基)丙烷-1,2-二醇(2.6g)溶于1,2-二氯乙烷(52mL)中，加入四丁基溴化铵(2.4g)。缓慢加入50％的氢氧化钠溶液(50mL)，在50℃下搅拌过夜。然后加入1,2-二氯乙烷(52mL)，缓慢加入50％的氢氧化钠溶液(50mL)，继续在50℃下搅拌48小时。然后将反应液冷却至室温，倾入水中，用二氯甲烷萃取，用饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得粗产品。经柱层析纯化，以石油醚/乙酸乙酯(5/1)洗脱得产品(1g)。(S)-3-(Benzyloxy)propane-1,2-diol (2.6 g) was dissolved in 1,2-dichloroethane (52 mL), and tetrabutylammonium bromide (2.4 g) was added. . A 50% sodium hydroxide solution (50 mL) was slowly added and stirred at 50 ° C overnight. Then 1,2-dichloroethane (52 mL) was added, 50% sodium hydroxide solution (50 mL) was slowly added, and stirring was continued at 50 ° C for 48 hours. The reaction solution was then cooled to room temperature, poured into water, extracted with dichloromethane, and the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Purification by column chromatography eluting with EtOAc (EtOAc)
1H NMR(400MHz,CDCl3)δ7.27～7.37(m,5H),4.55(s,2H),3.59～3.85(m,6H),3.40～3.50(m,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.27 - 7.37 (m, 5H), 4.55 (s, 2H), 3.59 - 3.85 (m, 6H), 3.40 - 3.50 (m, 3H).
步骤D：(R)-(1,4-二氧六环-2-基)甲醇Step D: (R)-(1,4-dioxan-2-yl)methanol
Figure PCTCN2017100226-appb-000143
Figure PCTCN2017100226-appb-000143
将(R)-2-((苄氧基)甲基)-1,4-二氧六环溶于乙醇(20mL)，加入10％的钯碳(150mg)，反应液在氢气(1atm)下室温反应过夜。然后将反应液过滤，滤液真空除去溶剂得产品(510 mg)。(R)-2-((Benzyloxy)methyl)-1,4-dioxane was dissolved in ethanol (20 mL), 10% palladium on carbon (150 mg) was added, and the reaction mixture was hydrogen (1 atm) The reaction was carried out at room temperature overnight. The reaction solution is then filtered, and the filtrate is vacuum removed to obtain the product (510). Mg).
1H NMR(400MHz,CDCl3)δ3.68～3.84(m,5H),3.53～3.64(m,3H),3.44～3.49(m,1H),2.21(br,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.68 - 3.84 (m, 5H), 3.53 - 3.64 (m, 3H), 3.44 - 3.49 (m, 1H), 2.21 (br, 1H).
步骤E：(S)-(1,4-二氧六环-2-基)甲基甲磺酸酯Step E: (S)-(1,4-dioxan-2-yl)methyl methanesulfonate
Figure PCTCN2017100226-appb-000144
Figure PCTCN2017100226-appb-000144
将(R)-(1,4-二氧六环-2-基)甲醇(510mg)溶于二氯甲烷(10mL)，加入三乙胺(1.2mL)，冷却至0℃。向混合液中缓慢滴加甲磺酰氯(593mg)的二氯甲烷(2mL)溶液，滴加完毕后，恢复到室温搅拌2小时。然后将反应液倾入水中，用二氯甲烷萃取，用饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得产品(800mg)。(R)-(1,4-Dioxocyclo-2-yl)methanol (510 mg) was dissolved in dichloromethane (10 mL), triethylamine (1. A solution of methanesulfonyl chloride (593 mg) in dichloromethane (2 mL) was slowly added dropwise to the mixture, and after the dropwise addition was completed, the mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was poured into water, extracted with dichloromethane, and the organic phase was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl3)δ4.19～4.21(m,2H),3.71～3.91(m,5H),3.58～3.65(m,1H),3.43～3.48(m,1H),3.06(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 4.19 to 4.21 (m, 2H), 3.71 to 3.91 (m, 5H), 3.58 to 3.65 (m, 1H), 3.43 to 3.48 (m, 1H), 3.06 (s) , 3H).
步骤F：(R)-(1,4-二氧六环-2-基)甲基胺Step F: (R)-(1,4-dioxan-2-yl)methylamine
Figure PCTCN2017100226-appb-000145
Figure PCTCN2017100226-appb-000145
将(S)-(1,4-二氧六环-2-基)甲基甲磺酸酯(800mg)溶于N,N-二甲基甲酰胺(10mL)，加入叠氮化钠(1.4g)、碳酸氢钠(726mg)，反应液在120℃下搅拌过夜。将反应液冷却至室温后，倾入水中，用乙酸乙酯萃取，用饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，浓缩后加入10％的钯碳(100mg)，在氢气(1atm)下室温搅拌48小时。然后过滤，真空除去溶剂得产品(330mg)。(S)-(1,4-Dioxocyclo-2-yl)methyl methanesulfonate (800 mg) was dissolved in N,N-dimethylformamide (10 mL) and sodium azide (1.4) was added. g), sodium hydrogencarbonate (726 mg), and the reaction mixture was stirred at 120 ° C overnight. After cooling the reaction mixture to room temperature, it was poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated, then, then, then,,,,,,,,,,,,,,, ) Stir at room temperature for 48 hours. It was then filtered and the solvent was removed in vacuo to give (330 mg).
1H NMR(400MHz,CDCl3)δ3.68～3.81(m,4H),3.52～3.62(m,2H),3.31～3.36(m,1H),2.68～2.69(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.68 to 3.81 (m, 4H), 3.52 to 3.62 (m, 2H), 3.31 to 3.36 (m, 1H), 2.68 to 2.69 (m, 2H).
步骤G：(R)-4-(((1,4-二氧六环-2-基)甲基)氨基)-3-硝基苯基磺酰胺Step G: (R)-4-(((1,4-Dioxacyclo-2-yl)methyl)amino)-3-nitrophenylsulfonamide
Figure PCTCN2017100226-appb-000146
Figure PCTCN2017100226-appb-000146
将(R)-(1,4-二氧六环-2-基)甲基胺(330mg)、4-氯-3-硝基苯磺酰胺(679mg)、三乙胺(1mL)加入乙腈(10mL)中，反应液回流过夜。然后将反应液冷却至室温后，倾入水中，用二氯甲烷、甲醇混合液萃取，饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得粗产品。经柱层析纯化，以二氯甲烷/甲醇(40/1到5/1)洗脱得产品(300mg)。Add (R)-(1,4-dioxan-2-yl)methylamine (330 mg), 4-chloro-3-nitrobenzenesulfonamide (679 mg), triethylamine (1 mL) to acetonitrile ( In 10 mL), the reaction solution was refluxed overnight. After the reaction mixture was cooled to room temperature, it was poured into water, extracted with a mixture of dichloromethane and methanol, and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Purification by column chromatography eluting with dichloromethane / methanol (40/1 to 5/1).
1H NMR(400MHz,d6-DMSO)δ8.50(t,J＝5.6Hz,1H),8.45(d,J＝1.6Hz,1H),7.81～7.84(m,1H),7.32(s,2H),7.26(d,J＝9.2Hz,1H),3.75～3.80(m,3H),3.37～3.65(m,5H),3.28～3.33(m,1H)。 1 H NMR (400MHz, d6- DMSO) δ8.50 (t, J = 5.6Hz, 1H), 8.45 (d, J = 1.6Hz, 1H), 7.81 ~ 7.84 (m, 1H), 7.32 (s, 2H ), 7.26 (d, J = 9.2 Hz, 1H), 3.75 to 3.80 (m, 3H), 3.37 to 3.65 (m, 5H), 3.28 to 3.33 (m, 1H).
步骤H：(R)-N-(4-((1,4-二恶烷-2-基)甲基氨基)-3-硝基苯基磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰胺 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
Figure PCTCN2017100226-appb-000147
Figure PCTCN2017100226-appb-000147
将2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(30mg)和三乙胺(10mg)混合后加入(R)-4-((1,4-二恶烷-2-基)甲基氨基)-3-硝基苯磺酰胺(18mg)、EDCI(13mg)、DMAP(13mg)的二氯甲烷(3mL)溶液中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到产品(16mg)。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 (30 mg) and triethylamine (10 mg), after mixing, (R)-4-((1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamide (18 mg), EDCI (13 mg), DMAP (13 mg) The mixture was stirred at room temperature overnight, diluted with methylene chloride, washed with water, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The developing solvent was dichloromethane/methanol (15/1) to give the product (16 mg).
1H NMR(400MHz,CDCl3)δ9.79(br,1H),8.88(d,J＝2.0Hz,1H),8.61(t,J＝4.8Hz,1H),8.12～8.15(m,1H),8.07(s,1H),7.98(d,J＝8.4Hz,1H),7.66(d,J＝2.0Hz,1H),7.45(t,J＝2.8Hz,1H),7.22(d,J＝8.4Hz,2H),6.88～7.01(m,4H),6.61(s,1H),6.52(br,1H),5.80(br,1H),3.61～3.96(m,6H),3.07～3.53(m,7H),2.65～2.91(m,2H),2.39(br,4H),2.02(s,2H),1.42(s,2H),0.95(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ9.79 (br, 1H), 8.88 (d, J = 2.0Hz, 1H), 8.61 (t, J = 4.8Hz, 1H), 8.12 ~ 8.15 (m, 1H) , 8.07 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.45 (t, J = 2.8 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.88 to 7.01 (m, 4H), 6.61 (s, 1H), 6.52 (br, 1H), 5.80 (br, 1H), 3.61 to 3.96 (m, 6H), 3.07 to 3.53 (m) , 7H), 2.65 to 2.91 (m, 2H), 2.39 (br, 4H), 2.02 (s, 2H), 1.42 (s, 2H), 0.95 (s, 6H).
实施例21Example 21
(R)-N-(4-((1,4-二恶烷-2-基)甲基氨基)-3-硝基苯基磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰胺(R)-N-(4-((1,4-dioxan-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
Figure PCTCN2017100226-appb-000148
Figure PCTCN2017100226-appb-000148
步骤A：(R)-N-(4-((1,4-二恶烷-2-基)甲基氨基)-3-硝基苯基磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰胺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
Figure PCTCN2017100226-appb-000149
Figure PCTCN2017100226-appb-000149
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(30mg)和三乙胺(10mg)混合后加入(R)-4-((1,4-二恶烷-2-基)甲基氨基)-3-硝基苯磺酰胺(17mg)、EDCI(13mg)、DMAP(13mg)的二氯甲烷(3mL) 溶液中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到产品(16mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4-di) (R)-4 was added after mixing methylcyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (30 mg) and triethylamine (10 mg). -((1,4-Dioxa-2-yl)methylamino)-3-nitrobenzenesulfonamide (17 mg), EDCI (13 mg), DMAP (13 mg) in dichloromethane (3 mL) The solution was stirred at room temperature overnight, diluted with methylene chloride, washed with water, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. (15/1), the product (16 mg) was obtained.
1H NMR(400MHz,CDCl3)δ9.62(br,1H),8.90(d,J＝2.0Hz,1H),8.62(t,J＝5.2Hz,1H),8.13～8.16(m,2H),8.01(d,J＝8.4Hz,1H),7.69(d,J＝1.6Hz,1H),7.46(t,J＝2.8Hz,1H),6.99～7.06(m,3H),3.90～6.94(m,2H),6.64(br,1H),6.54(br,1H),5.87(br,1H),3.72～3.97(m,5H),3.58～3.70(m,1H),3.30～3.54(m,3H),2.82～3.28(m,4H),2.20～2.80(m,6H),1.94～2.02(m,2H),1.43(s,2H),0.95(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ9.62 (br, 1H), 8.90 (d, J = 2.0Hz, 1H), 8.62 (t, J = 5.2Hz, 1H), 8.13 ~ 8.16 (m, 2H) , 8.01 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.46 (t, J = 2.8 Hz, 1H), 6.99 - 7.06 (m, 3H), 3.90 - 6.94 ( m, 2H), 6.64 (br, 1H), 6.54 (br, 1H), 5.87 (br, 1H), 3.72 to 3.97 (m, 5H), 3.58 to 3.70 (m, 1H), 3.30 to 3.54 (m, 3H), 2.82 to 3.28 (m, 4H), 2.20 to 2.80 (m, 6H), 1.94 to 2.02 (m, 2H), 1.43 (s, 2H), 0.95 (s, 6H).
实施例22Example 22
(S)-N-(4-((1,4-二氧乙烷-2-基)甲基胺)-3-硝基苯磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰胺(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
Figure PCTCN2017100226-appb-000150
Figure PCTCN2017100226-appb-000150
步骤A：(S)-4-(苄基氧甲基)-2,2-二甲基-1,3-二氧戊环Step A: (S)-4-(Benzyloxymethyl)-2,2-dimethyl-1,3-dioxolane
Figure PCTCN2017100226-appb-000151
Figure PCTCN2017100226-appb-000151
将(S)-(2,2-二甲基-1,3-二氧戊环-4-基)甲基醇(10.0g)溶于N,N-二甲基甲酰胺(50mL)中，0℃下加入氢化钠(1.8g)，搅拌1小时后，加入苄溴(12.9g)，室温下搅拌过夜，加水淬灭反应，乙酸乙酯萃取，除去溶剂得粗品，粗品用柱层析纯化，以石油醚/乙酸乙酯(15/1)洗脱，得到产品(3.8g)。(S)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl alcohol (10.0 g) was dissolved in N,N-dimethylformamide (50 mL). Sodium hydride (1.8 g) was added at 0 ° C. After stirring for 1 hour, benzyl bromide (12.9 g) was added, and the mixture was stirred at room temperature overnight. Elution with petroleum ether/ethyl acetate (15/1) gave product (3.8 g).
1H NMR(400MHz,CDCl3)δ7.25～7.35(m,5H),4.54～4.61(m,2H),4.27～4.33(m,1H),4.04～4.07(m,1H),3.73～3.76(m,1H),3.54～3.58(m,1H),3.45～3.49(m,1H),1.43(s,3H),1.37(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.25 to 7.35 (m, 5H), 4.54 to 4.61 (m, 2H), 4.27 to 4.33 (m, 1H), 4.04 to 4.07 (m, 1H), 3.73 to 3.76 (m, 1H), 3.54 to 3.58 (m, 1H), 3.45 to 3.49 (m, 1H), 1.43 (s, 3H), 1.37 (s, 3H).
步骤B：(R)-3-(苄氧基)丙烷-1,2-二醇Step B: (R)-3-(Benzyloxy)propane-1,2-diol
Figure PCTCN2017100226-appb-000152
Figure PCTCN2017100226-appb-000152
将(S)-4-(苄基氧甲基)-2,2-二甲基-1,3-二氧戊环(3.8g)溶于醋酸(30mL)和水(30mL)的混合溶液中，在60℃下搅拌2小时。用二氯甲烷/甲醇萃取水相3次，所得有机相用饱和碳酸氢钠溶液和饱和氯化钠各洗一次，无水硫酸钠干燥，除去溶剂得到产品(1.8g)。(S)-4-(Benzyloxymethyl)-2,2-dimethyl-1,3-dioxolane (3.8 g) was dissolved in a mixed solution of acetic acid (30 mL) and water (30 mL) Stir at 60 ° C for 2 hours. The aqueous phase was extracted three times with dichloromethane/methanol, and the obtained organic phase was washed with saturated sodium hydrogen carbonate and saturated sodium chloride and dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl3)δ7.25～7.35(m,5H),4.55(s,2H),3.88～3.92(m,1H),3.52～3.72(m,4H),2.70(br,1H),2.22(br,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.25 - 7.35 (m, 5H), 4.55 (s, 2H), 3.88 - 3.92 (m, 1H), 3.52 - 3.72 (m, 4H), 2.70 (br, 1H) ), 2.22 (br, 1H).
步骤C：(S)-2-(苄氧基甲基)-1,4-二氧六环Step C: (S)-2-(Benzyloxymethyl)-1,4-dioxane
Figure PCTCN2017100226-appb-000153
Figure PCTCN2017100226-appb-000153
将(R)-3-(苄氧基)丙烷-1,2-二醇(1.8g)溶于1,2-二氯乙烷(50mL)中，加入四丁基溴化铵(1.8g)，随后加入50％的NaOH溶液(25mL)，在50℃下搅拌过夜。再次补加1,2-二氯乙烷(50mL)和50％的NaOH溶液(25mL)，在50℃下继续搅拌48小时。然后用二氯甲烷萃取，饱和氯化钠溶液洗有机相，有机相用无水硫酸钠干燥，除去溶剂得粗品，粗品用柱层析分离，淋洗剂为石油醚/乙酸乙酯(5/1)，得到产品(750mg)。(R)-3-(Benzyloxy)propane-1,2-diol (1.8 g) was dissolved in 1,2-dichloroethane (50 mL), and tetrabutylammonium bromide (1.8 g) was added. Then, a 50% NaOH solution (25 mL) was added and stirred at 50 ° C overnight. Further, 1,2-dichloroethane (50 mL) and 50% NaOH solution (25 mL) were added, and stirring was continued at 50 ° C for 48 hours. Then, it is extracted with dichloromethane, and the organic phase is washed with a saturated sodium chloride solution. The organic phase is dried over anhydrous sodium sulfate and the solvent is evaporated to give a crude product. The crude product is separated by column chromatography. 1), the product (750 mg) was obtained.
1H NMR(400MHz,CDCl3)δ7.28～7.38(m,5H),4.55(s,2H),3.62～3.82(m,6H), 3.41～3.47(m,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.28 - 7.38 (m, 5H), 4.55 (s, 2H), 3.62 - 3.82 (m, 6H), 3.41 - 3.47 (m, 3H).
步骤D：(S)-(1,4-二氧乙烷-2-基)甲醇Step D: (S)-(1,4-Diethoxyethane-2-yl)methanol
Figure PCTCN2017100226-appb-000154
Figure PCTCN2017100226-appb-000154
将(S)-2-(苄氧基甲基)-1,4-二氧六环(750mg)溶于甲醇(20mL)中，加入10％的钯炭(200mg)，在氢气(1atm)下室温搅拌过夜，过滤，浓缩，得到产品(365mg)。(S)-2-(Benzyloxymethyl)-1,4-dioxane (750 mg) was dissolved in methanol (20 mL) and 10% palladium charcoal (200 mg) was added under hydrogen (1 atm) Stir at room temperature overnight, filter and concentrate to give product (365 mg).
1H NMR(400MHz,CDCl3)δ3.68～3.84(m,5H),3.60～3.66(m,2H),3.52～3.58(m,1H),3.44～3.49(m,1H),1.95(t,J＝6.0Hz,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.68 to 3.84 (m, 5H), 3.60 to 3.66 (m, 2H), 3.52 to 3.58 (m, 1H), 3.44 to 3.49 (m, 1H), 1.95 (t) , J = 6.0 Hz, 1H).
步骤E：(R)-(1,4-二氧乙烷-2-基)甲基甲磺酸酯Step E: (R)-(1,4-Diethoxyethane-2-yl)methyl methanesulfonate
Figure PCTCN2017100226-appb-000155
Figure PCTCN2017100226-appb-000155
(S)-(1,4-二氧乙烷-2-基)甲醇(365mg)溶于二氯甲烷(20mL)中，加入三乙胺(616mg)，冷却至0℃，加入甲磺酰氯(419mg)，随后于室温下搅拌4小时。然后倾入水中，用二氯甲烷萃取，饱和氯化钠洗有机相，无水硫酸钠干燥，除去溶剂得到产品(590mg)。(S)-(1,4-Diethoxyethane-2-yl)methanol (365 mg) was dissolved in dichloromethane (20 mL), triethylamine (616 mg) was added, cooled to 0 ° C, and methanesulfonyl chloride was added. 419 mg), followed by stirring at room temperature for 4 hours. Then, it was poured into water, extracted with dichloromethane, and the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl3)δ4.19～4.21(m,2H),3.71～3.91(m,5H),3.58～3.64(m,1H),3.43～3.48(m,1H),3.07(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 4.19 to 4.21 (m, 2H), 3.71 to 3.91 (m, 5H), 3.58 to 3.64 (m, 1H), 3.43 to 3.48 (m, 1H), 3.07 (s) , 3H).
步骤F：(S)-2-(叠氮甲基)-1,4-二氧六环Step F: (S)-2-(azidomethyl)-1,4-dioxane
Figure PCTCN2017100226-appb-000156
Figure PCTCN2017100226-appb-000156
将(R)-(1,4-二氧乙烷-2-基)甲基甲磺酸酯(590mg)溶于N,N-二甲基甲酰胺(20mL)中，加入叠氮化钠(990mg)，碳酸氢钠(512mg)，于120℃下搅拌过夜。然后将混合体系倒入水中，二氯甲烷/甲醇萃取水相2次，减压除去大部分溶剂直至剩余混合液约为30mL，所得混合物直接用于下一步反应。(R)-(1,4-Diethoxyethane-2-yl)methyl methanesulfonate (590 mg) was dissolved in N,N-dimethylformamide (20 mL), and sodium azide was added. 990 mg), sodium hydrogencarbonate (512 mg), stirred at 120 ° C overnight. The mixed system was then poured into water, and the aqueous phase was extracted twice with dichloromethane/methanol, and most of the solvent was removed under reduced pressure until the remaining mixture was about 30 mL, and the mixture was directly used for the next reaction.
步骤F：(S)-(1,4-二氧六环-2-基)甲基胺Step F: (S)-(1,4-dioxan-2-yl)methylamine
Figure PCTCN2017100226-appb-000157
Figure PCTCN2017100226-appb-000157
向(S)-2-(叠氮甲基)-1,4-二氧六环的混合液中加入甲醇(30mL)，加入10％的钯炭(100mg)，在氢气(1atm)气氛中室温下搅拌24小时。然后过滤，浓缩，得产品(280mg)。To a mixture of (S)-2-(azidomethyl)-1,4-dioxane, methanol (30 mL) was added, 10% palladium on carbon (100 mg) was added, and the atmosphere was placed in a hydrogen (1 atm) atmosphere. Stir under 24 hours. It was then filtered and concentrated to give the product (280 mg).
1H NMR(400MHz,CDCl3)δ3.68～3.81(m,4H),3.52～3.62(m,2H),3.31～3.36(m,1H),2.68～2.69(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.68 to 3.81 (m, 4H), 3.52 to 3.62 (m, 2H), 3.31 to 3.36 (m, 1H), 2.68 to 2.69 (m, 2H).
步骤G：(S)-4-((1,4-二氧乙烷-2-基)甲基胺)-3-硝基苯磺酰胺Step G: (S)-4-((1,4-Diethoxyethane-2-yl)methylamine)-3-nitrobenzenesulfonamide
Figure PCTCN2017100226-appb-000158
Figure PCTCN2017100226-appb-000158
将4-氯-3-硝基苯磺酰胺(399mg)，(S)-(1,4-二氧乙烷-2-基)甲基胺(280mg)，DIEA(1.0g)溶于乙腈(10mL)中，回流过夜，冷却至室温后有黄色固体析出，抽滤并用少量乙腈淋洗得到产品(300mg)。4-Chloro-3-nitrobenzenesulfonamide (399 mg), (S)-(1,4-dioxoethane-2-yl)methylamine (280 mg), DIEA (1.0 g) dissolved in acetonitrile In 10 mL), it was refluxed overnight. After cooling to room temperature, a yellow solid was precipitated, filtered, and rinsed with a small amount of acetonitrile to afford product (300 mg).
1H NMR(400MHz,d6-DMSO)δ8.51(t,J＝6.0Hz,1H),8.46(d,J＝2.0Hz,1H),7.81～7.84(m,1H),7.32(s,2H),7.26(d,J＝9.2Hz,1H),3.75～3.82(m,3H),3.37～3.66(m,5H),3.28～3.34(m,1H)。 1 H NMR (400MHz, d6- DMSO) δ8.51 (t, J = 6.0Hz, 1H), 8.46 (d, J = 2.0Hz, 1H), 7.81 ~ 7.84 (m, 1H), 7.32 (s, 2H ), 7.26 (d, J = 9.2 Hz, 1H), 3.75 to 3.82 (m, 3H), 3.37 to 3.66 (m, 5H), 3.28 to 3.34 (m, 1H).
步骤H：(S)-N-(4-((1,4-二氧乙烷-2-基)甲基胺)-3-硝基苯磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰胺 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
Figure PCTCN2017100226-appb-000159
Figure PCTCN2017100226-appb-000159
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(50mg)，(S)-4-((1,4-二氧乙烷-2-基)甲基胺)-3-硝基苯磺酰胺(28mg)，EDCI(32mg)，DMAP(17mg)，TEA(27mg)溶于二氯甲烷(20mL)中，室温下搅拌过夜，反应完全，加水淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，除去溶剂，粗品用薄层析制备板分离，展开剂为二氯甲烷/甲醇(15/1)，得到产品(30mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl) -1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (50 mg), (S)-4-((1,4-dimethoxyethane-2) -Methylamine)-3-nitrobenzenesulfonamide (28 mg), EDCI (32 mg), DMAP (17 mg), TEA (27 mg) dissolved in dichloromethane (20 mL) The reaction was quenched with water, EtOAc (EtOAc)EtOAc.
1H NMR(400MHz,CDCl3)δ9.81(br,1H),8.90(d,J＝2.4Hz,1H),8.61～8.64(m,1H),8.14～8.17(m,1H),8.10(s,1H),7.99(d,J＝8.0Hz,1H),7.74(s,1H),7.45～7.47(m,1H),7.21(d,J＝8.0Hz,2H),6.91～6.93(m,4H),6.55～6.57(m,2H),5.76(s,1H),3.74～3.93(m,5H),3.63～3.69(m,1H),3.31～3.50(m,5H),3.06～3.23(m,2H),2.71～2.91(m,2H),2.39～2.53(m,4H),2.09(s,2H),1.46～1.51(m,2H),0.95(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.81 (br, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.61 to 8.64 (m, 1H), 8.14 to 8.17 (m, 1H), 8.10 ( s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.45 to 7.47 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 6.91 to 6.93 (m) , 4H), 6.55 to 6.57 (m, 2H), 5.76 (s, 1H), 3.74 to 3.93 (m, 5H), 3.63 to 3.69 (m, 1H), 3.31 to 3.50 (m, 5H), 3.06 to 3.23 (m, 2H), 2.71 to 2.91 (m, 2H), 2.39 to 2.53 (m, 4H), 2.09 (s, 2H), 1.46 to 1.51 (m, 2H), 0.95 (s, 6H).
实施例23Example 23
(S)-N-(4-((1,4-二恶烷-2-基)甲基氨基)-3-硝基苯基磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰胺(S)-N-(4-((1,4-dioxan-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
Figure PCTCN2017100226-appb-000160
Figure PCTCN2017100226-appb-000160
步骤A：(S)-N-(4-((1,4-二恶烷-2-基)甲基氨基)-3-硝基苯基磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰胺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
Figure PCTCN2017100226-appb-000161
Figure PCTCN2017100226-appb-000161
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(30mg)和三乙胺(10mg)混合后加入(S)-4-((1,4-二恶烷-2-基)甲基氨基)-3-硝基苯磺酰胺(17mg)、EDCI(13mg)、DMAP(13mg)的二氯甲烷(5mL)溶液中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(6mg)。 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4-di) Methylcyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (30 mg) and triethylamine (10 mg) were mixed and added to (S)-4 a solution of ((1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamide (17 mg), EDCI (13 mg), DMAP (13 mg) in dichloromethane (5 mL) Stir at room temperature overnight, dilute with dichloromethane, wash with water several times, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate, and the residue is separated by preparative thin layer, and the solvent is dichloromethane/methanol (15/ 1) The target product (6 mg) was obtained.
1H NMR(400MHz,CDCl3)δ9.70(br,1H),8.90(d,J＝2.0Hz,1H),8.62(t,J＝5.2Hz,1H),8.13～8.16(m,2H),8.02(d,J＝8.4Hz,1H),7.69(d,J＝1.6Hz,1H),7.46(s,1H),6.99～7.06(m,3H),6.92(t,J＝8.0Hz,2H),6.64(s,1H),6.53(d,J＝1.6Hz,1H),5.86(br,1H),3.74～3.97(m,5H),3.60～3.73(m,1H),3.28～3.54(m,3H),2.86～3.28(m,4H),2.54～5.85(m,2H),2.18～2.54(m,4H),1.95～2.02(m,2H),1.43(d,J＝2.4Hz,2H),0.95(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ9.70 (br, 1H), 8.90 (d, J = 2.0Hz, 1H), 8.62 (t, J = 5.2Hz, 1H), 8.13 ~ 8.16 (m, 2H) , 8.02 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.46 (s, 1H), 6.99 - 7.06 (m, 3H), 6.92 (t, J = 8.0 Hz, 2H), 6.64 (s, 1H), 6.53 (d, J = 1.6 Hz, 1H), 5.86 (br, 1H), 3.74 to 3.97 (m, 5H), 3.60 to 3.73 (m, 1H), 3.28 to 3.54 (m, 3H), 2.86 to 3.28 (m, 4H), 2.54 to 5.85 (m, 2H), 2.18 to 2.54 (m, 4H), 1.95 to 2.02 (m, 2H), 1.43 (d, J = 2.4 Hz) , 2H), 0.95 (s, 6H).
实施例24Example 24
2-((1H-吡咯[2,3-b]并吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-((3-硝基-4-((2-(四氢-2H-吡喃-4-基)乙基)氨基)苯基)磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000162
Figure PCTCN2017100226-appb-000162
步骤A：3-硝基-4-((2-(四氢-2H-吡喃-4-基)乙基)氨基)苯磺酰胺Step A: 3-Nitro-4-((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)benzenesulfonamide
Figure PCTCN2017100226-appb-000163
Figure PCTCN2017100226-appb-000163
将4-氯-3-硝基苯磺酰胺(714mg)，2-(四氢-2H-吡喃-4-基)乙烷-1-胺盐酸盐(500mg)，DIEA(1.5mL)在乙腈(20mL)中回流48小时。冷却至室温后倾入水中，用乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥。真空浓缩除去溶剂得产品(900mg)。4-Chloro-3-nitrobenzenesulfonamide (714 mg), 2-(tetrahydro-2H-pyran-4-yl)ethane-1-amine hydrochloride (500 mg), DIEA (1.5 mL) It was refluxed for 48 hours in acetonitrile (20 mL). After cooling to room temperature, it was poured into water, extracted with ethyl acetate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give the product (900 mg).
1H NMR(400MHz,d6-DMSO)δ8.45～8.48(m,2H),7.80～7.83(m,1H),7.30(s,2H),7.23(d,J＝9.2Hz,1H),3.79～3.83(m,2H),3.42～3.46(m,2H),3.22～3.29(m,2H),1.53～1.63(m,5H),1.14～1.23(m,2H)。 1 H NMR (400 MHz, d6-DMSO) δ 8.45 to 8.48 (m, 2H), 7.80 to 7.83 (m, 1H), 7.30 (s, 2H), 7.23 (d, J = 9.2 Hz, 1H), 3.79 ～3.83 (m, 2H), 3.42 to 3.46 (m, 2H), 3.22 to 3.29 (m, 2H), 1.53 to 1.63 (m, 5H), 1.14 to 1.23 (m, 2H).
步骤B：2-((1H-吡咯[2,3-b]并吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-((3-硝基-4-((2-(四氢-2H-吡喃-4-基)乙基)氨基)苯基)磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000164
Figure PCTCN2017100226-appb-000164
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(57mg)，3-硝基-4-((2-(四氢-2H-吡喃-4-基)乙基)氨基)苯磺酰胺(33mg)，EDCI(29mg)，DMAP(18mg)，TEA(20mg)加入二氯甲烷(5mL)中，室温下搅拌过夜。然后倾入水中，用二氯甲烷萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，除去溶剂得粗产品。经薄层层析纯化，展开剂为二氯甲烷/甲醇(15/1)，得到产品(30mg)。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)benzoic acid (57 mg), 3-nitro-4-((2-(tetrahydro-2H-py) Methyl-4-yl)ethyl)amino)benzenesulfonamide (33 mg), EDCI (29 mg), EtOAc (EtOAc) (EtOAc) Then, it was poured into water, extracted with dichloromethane, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to give a crude product. Purification by thin layer chromatography, methylene chloride / methanol (15 /1)
1H NMR(400MHz,CDCl3)δ10.27(br,1H),8.89(d,J＝2.0Hz,1H),8.39(t,J＝4.8Hz, 1H),8.13～8.16(m,1H),8.09(br,1H),7.93(d,J＝8.4Hz,1H),7.78(s,1H),7.45～7.47(m,1H),7.20(d,J＝8.0Hz,2H),6.91～6.94(m,4H),6.55～6.58(m,2H),5.78(s,1H),3,96～3.99(m,2H),3.54(br,2H),3.37～3.43(m,4H),3.00(br,2H),2.42(br,4H),1.98～2.04(m,3H),1.64～1.73(m,6H),1.26～1.40(m,4H),0.95(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ10.27 (br, 1H), 8.89 (d, J = 2.0Hz, 1H), 8.39 (t, J = 4.8Hz, 1H), 8.13 ~ 8.16 (m, 1H) , 8.09 (br, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.45 to 7.47 (m, 1H), 7.20 (d, J = 8.0 Hz, 2H), 6.91 - 6.94 (m, 4H), 6.55 to 6.58 (m, 2H), 5.78 (s, 1H), 3, 96 to 3.99 (m, 2H), 3.54 (br, 2H), 3.37 to 3.43 (m, 4H), 3.00 (br, 2H), 2.42 (br, 4H), 1.98 to 2.04 (m, 3H), 1.64 to 1.73 (m, 6H), 1.26 to 1.40 (m, 4H), 0.95 (s, 6H).
实施例25Example 25
叔丁基-4-((4-(N-(2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰基)磺酰胺)-2-硝基苯氧基)甲基)-4-氟哌啶-1-羧酸酯tert-Butyl-4-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-)) Phenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)sulfonamide)-2-nitrate Phenoxy)methyl)-4-fluoropiperidine-1-carboxylate
Figure PCTCN2017100226-appb-000165
Figure PCTCN2017100226-appb-000165
步骤A：1-氧杂-6-氮杂螺[2,5]辛烷-6-甲酸叔丁酯Step A: 1-oxa-6-azaspiro[2,5]octane-6-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000166
Figure PCTCN2017100226-appb-000166
将60％的钠氢(5.28g)加入二甲亚枫(250mL)中，并在0℃下冷却。加入三甲基碘化硫(29g)，恢复至室温搅拌40分钟后，加入4-哌啶酮-1-甲酸叔丁酯(25g)。继续在室温下搅拌1小时后，升温至55℃搅拌1.5小时。然后将反应液倾入冰水中，用乙酸乙酯萃取，饱和氯化钠水溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得产品(26g)。60% sodium hydrogen (5.28 g) was added to dimethyl sulfoxide (250 mL) and cooled at 0 °C. Trimethyl sulfonium iodide (29 g) was added, and the mixture was returned to room temperature and stirred for 40 minutes, then tert-butyl 4-piperidone-1-carboxylate (25 g). After stirring at room temperature for 1 hour, the temperature was raised to 55 ° C and stirred for 1.5 hours. Then, the reaction mixture was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl3)δ3.69～3.72(m,2H),3.38～3.45(m,2H),2.68(s,2H),1.75～1.82(m,2H),1.42～1.48(m,11H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.69 to 3.72 (m, 2H), 3.38 to 3.45 (m, 2H), 2.68 (s, 2H), 1.75 to 1.82 (m, 2H), 1.42 to 1.48 (m) , 11H).
步骤B：4-氟-4-(羟甲基)哌啶-1-甲酸叔丁酯Step B: tert-Butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate
Figure PCTCN2017100226-appb-000167
Figure PCTCN2017100226-appb-000167
将70％的氟化氢吡啶(7.8mL)加入二氯甲烷(150mL)中，在0℃下冷却。将1-氧杂-6-氮杂螺[2,5]辛烷-6-甲酸叔丁酯(26g)的二氯甲烷(150mL)溶液缓慢滴入。滴加完毕后，反应液在室温下反应过夜，然后用碳酸钠溶液中和，用二氯甲烷萃取，依次用1M的盐酸及饱和氯化钠水溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得粗产品。经柱层析纯化，以石油醚/乙酸乙酯(3/1)洗脱，得产品(14g)。70% hydrogen fluoride pyridine (7.8 mL) was added to dichloromethane (150 mL) and cooled at 0 °C. A solution of 1-oxa-6-azaspiro[2,5]octane-6-carboxylic acid tert-butyl ester (26 g) in dichloromethane (150 mL) was slowly added dropwise. After the completion of the dropwise addition, the reaction mixture was reacted at room temperature overnight, then neutralized with a sodium carbonate solution, extracted with dichloromethane, and the organic phase was washed successively with 1M hydrochloric acid and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Get a rough product. Purification by column chromatography eluting with EtOAc /EtOAc (EtOAc)
1H NMR(400MHz,CDCl3)δ3.93(br,2H),3.56～3.62(m,2H),3.09(t,J＝12.0Hz,2H),2.04(t,J＝6.8Hz,1H),1.84～1.91(m,2H),1.45～1.64(m,11H)。 1 H NMR (400MHz, CDCl 3 ) δ3.93 (br, 2H), 3.56 ~ 3.62 (m, 2H), 3.09 (t, J = 12.0Hz, 2H), 2.04 (t, J = 6.8Hz, 1H) , 1.84 to 1.91 (m, 2H), 1.45 to 1.64 (m, 11H).
步骤C：4-氟-4-((2-硝基-4-磺酰氨基苯酚)甲基)哌啶-1-甲酸叔丁酯Step C: 4-Fluoro-4-((2-nitro-4-sulfonylaminophenol)methyl)piperidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000168
Figure PCTCN2017100226-appb-000168
将4-氟-4-(羟甲基)哌啶-1-甲酸叔丁酯(1.0g)、4-氯-3-硝基苯磺酰氨(1.0g)溶于四氢呋喃(30mL)。将溶液冷却至0℃，加入60％的钠氢(344mg)，恢复至室温搅拌过夜。然后将反应液倾入水中，用二氯甲烷萃取，饱和氯化钠水溶液洗涤有机相，无水硫酸钠干燥，除去溶剂得粗产品，经柱层析纯化，以二氯甲烷/乙酸乙酯(3/1)洗脱得产品(800g)。 4-Fluoro-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (1.0 g), 4-chloro-3-nitrobenzenesulfonylamide (1.0 g) was dissolved in tetrahydrofuran (30 mL). The solution was cooled to 0 ° C, 60% sodium hydrogen (344 mg) was added and the mixture was stirred at room temperature overnight. The reaction mixture is poured into water, extracted with dichloromethane, and the organic layer is washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. 3/1) Product eluted (800 g).
1H NMR(400MHz,CDCl3)δ8.44(d,J＝2.4Hz,1H),8.08～8.11(m,1H),7.21(d,J＝8.8Hz,1H),4.87(s,2H),4.19(d,J＝17.6Hz,1H),3.94～4.09(m,2H),3.58～3.64(m,1H),3.08～3.16(m,2H),1.64～2.04(m,4H),1.48(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.44 (d, J = 2.4 Hz, 1H), 8.08 - 8.11 (m, 1H), 7.21. (d, J = 8.8 Hz, 1H), 4.87 (s, 2H) , 4.19 (d, J = 17.6 Hz, 1H), 3.94 to 4.09 (m, 2H), 3.58 to 3.64 (m, 1H), 3.08 to 3.16 (m, 2H), 1.64 to 2.04 (m, 4H), 1.48 (s, 9H).
步骤D：叔丁基-4-((4-(N-(2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰基)磺酰胺)-2-硝基苯氧基)甲基)-4-氟哌啶-1-羧酸酯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
Figure PCTCN2017100226-appb-000169
Figure PCTCN2017100226-appb-000169
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(100mg)，4-氟-4-((2-硝基-4-磺酰氨基苯酚)甲基)哌啶-1-甲酸叔丁酯(76mg)溶于(20mL)二氯甲烷中，分别加入EDCI(65mg)，DMAP(33mg)，TEA(53mg)，室温下搅拌过夜，加水淬灭反应，二氯甲烷萃取，除去溶剂得粗品，粗品用薄层析制备板分离，展开剂为二氯甲烷/甲醇(12/1)，得到纯品(100mg)。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)benzoic acid (100 mg), 4-fluoro-4-((2-nitro-4-sulfonylamino) Phenyl)methyl)piperidine-1-carboxylic acid tert-butyl ester (76 mg) was dissolved in dichloromethane (20 mL), EtOAc (EtOAc) (EtOAc) The reaction was quenched, extracted with methylene chloride, and then evaporated to ethylamine.
1H NMR(400MHz,CDCl3)δ9.44(br,1H),8.57(s,1H),8.33(d,J＝10.8Hz,1H),8.03(br,1H),7.94(d,J＝8.4Hz,1H),7.63(d,J＝2.4Hz,1H),7.45(t,J＝3.6Hz,1H),7.23(d,J＝8.4Hz,2H),7.14(d,J＝8.8Hz,1H),7.04(d,J＝8.0Hz,1H),6.93(d,J＝8.4Hz,2H),6.63(s,1H),6.52～6.51(m,1H),5.85(s,1H),4.16(d,J＝16Hz,2H),4.03(br,2H),3.15～3.09(m,6H),2.67～2.53(m,2H),2.39～2.29(m,4H),2.03～1.97(m,4H),1.83～1.63(m,2H),1.48(s,9H),0.95(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.44 (br, 1H), 8.57 (s, 1H), 8.33 (d, J = 10.8 Hz, 1H), 8.03 (br, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.45 (t, J = 3.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.8 Hz) , 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.63 (s, 1H), 6.52 to 6.51 (m, 1H), 5.85 (s, 1H) , 4.16 (d, J = 16 Hz, 2H), 4.03 (br, 2H), 3.15 to 3.09 (m, 6H), 2.67 to 2.53 (m, 2H), 2.39 to 2.29 (m, 4H), 2.03 to 1.97 ( m, 4H), 1.83 to 1.63 (m, 2H), 1.48 (s, 9H), 0.95 (s, 6H).
实施例26Example 26
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟哌啶-4-基)甲氧基)-3-硝基苯磺酰基)苯甲酰胺盐酸盐2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-) 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluoropiperidin-4-yl)methoxy)-3- Nitrobenzenesulfonyl)benzamide hydrochloride
Figure PCTCN2017100226-appb-000170
Figure PCTCN2017100226-appb-000170
步骤A：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟哌啶-4-基)甲氧基)-3-硝基苯磺酰基)苯甲酰胺盐酸盐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
Figure PCTCN2017100226-appb-000171
Figure PCTCN2017100226-appb-000171
将叔丁基-4-((4-(N-(2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基 环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰基)磺酰胺)-2-硝基苯氧基)甲基)-4-氟哌啶-1-羧酸酯(90mg)溶于氯化氢的甲醇溶液(30mL)中，室温下搅拌过夜，减压下除去溶剂得到产品(70mg)。tert-Butyl-4-((4-(N-(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)benzoyl)sulfonamide)-2-nitrophenoxy)methyl)-4- The fluoropiperidine-l-carboxylate (90 mg) was dissolved in a methanolic solution of hydrogen chloride (30 mL), and stirred at room temperature overnight.
1H NMR(400MHz,d6-DMSO)δ11.81(s,1H),10.24(s,1H),9.08(s,2H),8.41(d,J＝2.4Hz,1H),8.15～8.13(m,1H),8.04(d,J＝2.4Hz,1H),7.62(d,J＝3.2Hz,1H),7.55～7.47(m,3H),7.31(d,J＝8.4Hz,2H),7.08(d,J＝8.4Hz,3H),6.71(s,1H),6.43～6.42(m,1H),5.91(s,1H),4.40(d,J＝21Hz,2H),3.72～3.68(m,2H),3.56～3.54(m,2H),3.34～3.28(m,4H),3.07～2.99(m,2H),2.91～2.86(m,1H),2.66～2.58(m,1H),2.30～2.26(m,2H),2.10～1.93(m,6H),1.43～1.40(m,2H),0.92(s,6H)。 1 H NMR (400 MHz, d6-DMSO) δ 11.81 (s, 1H), 10.24 (s, 1H), 9.08 (s, 2H), 8.41 (d, J = 2.4 Hz, 1H), 8.15 to 8.13 (m) , 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 3.2 Hz, 1H), 7.55 to 7.47 (m, 3H), 7.31 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 3H), 6.71 (s, 1H), 6.43 to 6.42 (m, 1H), 5.91 (s, 1H), 4.40 (d, J = 21 Hz, 2H), 3.72 to 3.68 (m) , 2H), 3.56 to 3.54 (m, 2H), 3.34 to 3.28 (m, 4H), 3.07 to 2.99 (m, 2H), 2.91 to 2.86 (m, 1H), 2.66 to 2.58 (m, 1H), 2.30 ～2.26 (m, 2H), 2.10 to 1.93 (m, 6H), 1.43 to 1.40 (m, 2H), 0.92 (s, 6H).
实施例27Example 27
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟-1-(甲磺酰基)哌啶-4-基)甲氧基)-3-硝基苯磺酰基)苯甲酰胺2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-) 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluoro-1-(methylsulfonyl)piperidin-4-yl) )methoxy)-3-nitrobenzenesulfonyl)benzamide
Figure PCTCN2017100226-appb-000172
Figure PCTCN2017100226-appb-000172
步骤A：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟-1-(甲磺酰基)哌啶-4-基)甲氧基)-3-硝基苯磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000173
Figure PCTCN2017100226-appb-000173
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟哌啶-4-基)甲氧基)-3-硝基苯磺酰基)苯甲酰胺盐酸盐(60mg)分散于二氯甲烷(20mL)中，加入吡啶(0.5mL)，室温下加入甲磺酰氯(7.5mg)并搅拌过夜，加水淬灭反应，二氯甲烷萃取，1N盐酸洗有机相，饱和氯化钠水溶液洗，无水硫酸钠干燥，除去溶剂得粗品，粗品用薄层析制备板分离，展开剂为二氯甲烷/甲醇(8/1)，得到纯品(20mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl) -1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluoropiperidin-4-yl)methoxy)-3 -Nitrophenylsulfonyl)benzamide hydrochloride (60 mg) was dissolved in dichloromethane (20 mL), pyridine (0.5 mL) was added, methanesulfonyl chloride (7.5 mg) was added at room temperature and stirred overnight, quenched with water The reaction mixture is extracted with dichloromethane, and the organic phase is washed with 1N hydrochloric acid, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. /1), obtained pure product (20 mg).
1H NMR(400MHz,d6-DMSO)δ11.59(s,1H),9.20(s,1H),8.20(s,1H),7.95～7.88(m,2H),7.52～7.46(m,2H),7.35(d,J＝8.0Hz,2H),7.18(s,1H),7.10～7.08(m,3H),6.76(s,1H),6.64(s,1H),6.33(s,1H),5.95(s,1H),4.30(d,J＝16Hz,2H),3.51～3.46(m,2H),3.27～3.20(m,4H),2.99～2.90(m,5H),2.42～2.35(m,2H),2.21～2.13(m,2H),1.93～1.79(m,8H),1.46～1.39(m,2H),0.93(s,6H)。 1 H NMR (400MHz, d6- DMSO) δ11.59 (s, 1H), 9.20 (s, 1H), 8.20 (s, 1H), 7.95 ~ 7.88 (m, 2H), 7.52 ~ 7.46 (m, 2H) , 7.35 (d, J = 8.0 Hz, 2H), 7.18 (s, 1H), 7.10 to 7.08 (m, 3H), 6.76 (s, 1H), 6.64 (s, 1H), 6.33 (s, 1H), 5.95 (s, 1H), 4.30 (d, J = 16 Hz, 2H), 3.51 to 3.46 (m, 2H), 3.27 to 3.20 (m, 4H), 2.99 to 2.90 (m, 5H), 2.42 to 2.35 (m) , 2H), 2.21 to 2.13 (m, 2H), 1.93 to 1.79 (m, 8H), 1.46 to 1.39 (m, 2H), 0.93 (s, 6H).
实施例28Example 28
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟-1-(3-杂氧环丁烷)哌啶-4-基)甲基氨基)-3-硝基苯磺酰基)苯甲酰胺 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-) 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluoro-1-(3-heopoxycyclobutane))piperidine 4-yl)methylamino)-3-nitrobenzenesulfonyl)benzamide
Figure PCTCN2017100226-appb-000174
Figure PCTCN2017100226-appb-000174
步骤A：4-氟-4-(((甲基磺酰基)氧基)甲基)哌啶-1-甲酸叔丁酯Step A: 4-Fluoro-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000175
Figure PCTCN2017100226-appb-000175
将4-氟-4-(羟甲基)哌啶-1-甲酸叔丁酯(10g)溶于二氯甲烷(200mL)中，加入三乙胺(9mL)。将反应液冷却至0℃，缓慢滴加甲磺酰氯(3.7mL)的二氯甲烷溶液(10mL)，滴加完毕后恢复至室温，反应过夜。然后倾入水中，用二氯甲烷萃取，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，真空除去溶剂得到产品(12g)。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.
1H NMR(400MHz,CDCl3)δ4.20(d,J＝20.0Hz,2H),3.99(br,2H),3.07～3.11(m,5H),1.86～1.92(m,2H),1.52～1.69(m,2H),1.45(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 4.20 (d, J = 20.0 Hz, 2H), 3.99 (br, 2H), 3.07 to 3.11 (m, 5H), 1.86 to 1.92 (m, 2H), 1.52 1.69 (m, 2H), 1.45 (s, 9H).
步骤B：4-(氨甲基)-4-氟吡啶-1-甲酸叔丁酯Step B: 4-(Aminomethyl)-4-fluoropyridine-1-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000176
Figure PCTCN2017100226-appb-000176
将4-氟-4-(((甲基磺酰基)氧基)甲基)哌啶-1-甲酸叔丁酯(12g)、叠氮化钠(12g)、碳酸氢钠(7.5g)加入N,N-二甲基甲酰胺中，在120℃下反应16小时。然后倾入水中，用乙酸乙酯萃取，饱和食盐水洗涤三次，无水硫酸钠干燥，真空浓缩至约200mL。加入10％的钯碳(1.2g)，在氢气(1atm)下室温搅拌过夜。然后过滤除去钯碳，浓缩得到粗产品。经柱层析纯化，以二氯甲烷/甲醇(20/1)洗脱得产品(5.5g)。Add 4-fluoro-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (12g), sodium azide (12g), sodium bicarbonate (7.5g) The reaction was carried out at 120 ° C for 16 hours in N,N-dimethylformamide. Then, it was poured into water, extracted with ethyl acetate, and washed with saturated brine over Celite. 10% palladium on carbon (1.2 g) was added and stirred at room temperature under hydrogen (1 atm) overnight. The palladium on carbon was then removed by filtration and concentrated to give a crude product. Purification by column chromatography eluting with dichloromethane /MeOH (20/1)
1H NMR(400MHz,CDCl3)δ3.96(br,1H),3.04～3.11(m,2H),2.72(d,J＝20.4Hz,2H),1.82～1.92(m,2H),1.41～1.69(m,11H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.96 (br, 1H), 3.04 to 3.11 (m, 2H), 2.72 (d, J = 20.4 Hz, 2H), 1.82 to 1.92 (m, 2H), 1.41 1.69 (m, 11H).
步骤C：4-氟-4-(((2-硝基-4-磺酰氨苯基)氨基)甲基)哌啶-1-甲酸叔丁酯Step C: 4-Fluoro-4-(((2-nitro-4-sulfonylaminophenyl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000177
Figure PCTCN2017100226-appb-000177
将4-(氨甲基)-4-氟吡啶-1-甲酸叔丁酯(5.5g)、4-氯-3-硝基苯磺酰氨(4.0g)、三乙胺(6.5mL)加入乙腈(150mL)中，加热回流过夜。然后倾入水中，用二氯甲烷/甲醇混合液萃取，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，除去溶剂，经柱层析纯化，以二氯甲烷/甲醇(30/1)洗脱得粗产品。将粗产品加入乙酸乙酯(10mL)中，室温搅拌1小时后过滤，以乙酸乙酯洗涤固体并干燥得产品(3.4g)。Add 4-(aminomethyl)-4-fluoropyridine-1-carboxylic acid tert-butyl ester (5.5 g), 4-chloro-3-nitrobenzenesulfonylamide (4.0 g), triethylamine (6.5 mL) It was heated to reflux overnight in acetonitrile (150 mL). Then, it is poured into water, extracted with a dichloromethane/methanol mixture, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated. Get a rough product. The crude product was added to ethyl acetate (10 mL).
1H NMR(400MHz,d-DMSO)δ8.56(t,J＝6.4Hz,1H),8.46(d,J＝2.4Hz,1H),7.79～7.82(m,1H),7.39(d,J＝9.6Hz,1H),7.32(s,2H),3.72～3.83(m,4H),2.95(br,2H),1.78～1.84(m,2H),1.54～1.73(m,2H),1.38(s,9H)。 1 H NMR (400 MHz, d-DMSO) δ 8.56 (t, J = 6.4 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 7.79 to 7.82 (m, 1H), 7.39 (d, J) = 9.6 Hz, 1H), 7.32 (s, 2H), 3.72 to 3.83 (m, 4H), 2.95 (br, 2H), 1.78 to 1.84 (m, 2H), 1.54 to 1.73 (m, 2H), 1.38 ( s, 9H).
步骤D：4-((4-氟哌啶-4-基)甲基氨基)-3-硝基苯磺酰胺盐酸盐Step D: 4-((4-Fluoropiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide hydrochloride
Figure PCTCN2017100226-appb-000178
Figure PCTCN2017100226-appb-000178
将4-氟-4-(((2-硝基-4-磺酰氨苯基)氨基)甲基)哌啶-1-甲酸叔丁酯(1.0g)溶于氯化氢的甲醇溶液(30mL)中，室温下搅拌过夜，除去溶剂得到产品(700mg)。4-Fluoro-4-(((2-nitro-4-sulfonylaminophenyl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (1.0 g) was dissolved in hydrogen chloride in methanol (30 mL) The mixture was stirred at room temperature overnight, and the solvent was evaporated to give the product (700 mg).
1H NMR(400MHz,d6-DMSO)8.93(br,1H),8.83(br,1H),8.62(t,J＝10.0Hz,1H),8.45(d,J＝2.0Hz,1H),7.83～7.79(m,1H),7.40(d,J＝8.0Hz,1H),7.34(s,2H),3.84～3.78(m,2H),3.26～3.23(m,2H),2.99～2.90(m,2H),2.07～1.85(m,4H)。 1 H NMR (400MHz, d6- DMSO) 8.93 (br, 1H), 8.83 (br, 1H), 8.62 (t, J = 10.0Hz, 1H), 8.45 (d, J = 2.0Hz, 1H), 7.83 ~ 7.79 (m, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.34 (s, 2H), 3.84 to 3.78 (m, 2H), 3.26 to 3.23 (m, 2H), 2.99 to 2.90 (m, 2H), 2.07 to 1.85 (m, 4H).
步骤E：4-((4-氟-1-(3-环氧杂丁烷)哌啶-4-基)甲基氨基)-3-硝基苯磺酰胺Step E: 4-((4-Fluoro-1-(3-epoxyheterobutane)piperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide
Figure PCTCN2017100226-appb-000179
Figure PCTCN2017100226-appb-000179
将4-((4-氟哌啶-4-基)甲基氨基)-3-硝基苯磺酰胺盐酸盐(50mg)分散于二氯甲烷(20mL)中,加入三乙胺(34mg)并于室温下搅拌20分钟后，加入3-氧杂环丁酮(20mg)，醋酸硼氢化钠(57mg)，于室温下搅拌过夜，加入饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，除去溶剂，得到粗品，粗品用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(32mg)。4-((4-Fluoropiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide hydrochloride (50 mg) was dissolved in dichloromethane (20 mL) and triethylamine (34 mg) After stirring at room temperature for 20 minutes, 3-oxetanone (20 mg), sodium borohydride (57 mg) was added and stirred at room temperature overnight. The mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then evaporated to give the crude product, and the crude product was separated from methylene chloride/methanol (15/1).
1H NMR(400MHz,CDCl3)δ8.78(d,J＝2.4Hz,1H),8.65～8.62(m,1H),7.93～7.89(m,1H),7.03(d,J＝8.0Hz,1H),4.88(s,2H),4.71～4.68(m,2H),4.61～4.58(m,2H),3.59～3.53(m,3H),2.65～2.62(m,2H),2.24～2.18(m,2H),2.07～2.01(m,2H),1.89～1.72(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (d, J = 2.4 Hz, 1H), 8.65 - 8.62 (m, 1H), 7.93 - 7.89 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H), 4.88 (s, 2H), 4.71 to 4.68 (m, 2H), 4.61 to 4.58 (m, 2H), 3.59 to 3.53 (m, 3H), 2.65 to 2.62 (m, 2H), 2.24 to 2.18 ( m, 2H), 2.07 to 2.01 (m, 2H), 1.89 to 1.72 (m, 2H).
步骤F：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟-1-(3-杂氧环丁烷)哌啶-4-基)甲基氨基)-3-硝基苯磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000180
Figure PCTCN2017100226-appb-000180
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(47mg)，4-((4-氟-1-(3-环氧杂丁烷)-哌啶-4-基)甲基氨基)-3-硝基苯磺酰胺(32mg)，EDCI(29mg)，DMAP(15mg)，TEA(24mg)溶于二氯甲烷(30mL)中，室温下搅拌过夜，加入水淬灭反应，二氯甲烷萃取，除去溶剂得粗品，粗品用制备薄层板分离，展开剂为二氯甲烷/甲醇/氨水(60/6/1)，得到产物(28mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl) 1-(Alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (47 mg), 4-((4-fluoro-1-(3-epoxyheterobutane) -piperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide (32 mg), EDCI (29 mg), DMAP (15 mg), TEA (24 mg) Stir overnight, add water to quench the reaction, extract with methylene chloride, remove the solvent to obtain a crude product, and the crude product is separated by preparative thin layer, and the developing solvent is dichloromethane/methanol/aqueous ammonia (60/6/1) to obtain product (28 mg). ).
1H NMR(400MHz,CDCl3)δ9.04(s,1H),8.94(d,J＝2.0Hz,1H),8.72～8.69(m,1H),8.19～8.16(m,2H),8.06(d,J＝8.2Hz,1H),7.71(d,J＝2.0Hz,1H),7.49～7.47(m,1H),7.26(d,J＝8.0Hz,2H),7.15～7.13(m,1H),7.00～6.95(m,3H),6.71(s,1H),6.59～6.57(m,1H),5.95(s,1H),4.73～4.70(m,2H),4.65～4.62(m,2H),3.59～3.53(m,3H),2.94～2.87(m,4H),2.67～2.64(m,2H),2.43～2.20(m,8H),2.02～2.01(m,4H),1.90～1.73(m,2H),1.47～1.42(m,2H),0.97(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ9.04 (s, 1H), 8.94 (d, J = 2.0Hz, 1H), 8.72 ~ 8.69 (m, 1H), 8.19 ~ 8.16 (m, 2H), 8.06 ( d, J = 8.2 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.49 to 7.47 (m, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.15 to 7.13 (m, 1H) ), 7.00 to 6.95 (m, 3H), 6.71 (s, 1H), 6.59 to 6.57 (m, 1H), 5.95 (s, 1H), 4.73 to 4.70 (m, 2H), 4.65 to 4.62 (m, 2H) ), 3.59 to 3.53 (m, 3H), 2.94 to 2.87 (m, 4H), 2.67 to 2.64 (m, 2H), 2.43 to 2.20 (m, 8H), 2.02 to 2.01 (m, 4H), 1.90 to 1.73 (m, 2H), 1.47 to 1.42 (m, 2H), 0.97 (s, 6H).
实施例29Example 29
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟-1-甲基哌啶-4-基)甲基氨基)-3-硝基苯磺酰基)苯甲酰胺 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-) 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluoro-1-methylpiperidin-4-yl)methyl) Amino)-3-nitrobenzenesulfonyl)benzamide
Figure PCTCN2017100226-appb-000181
Figure PCTCN2017100226-appb-000181
步骤A：4-((4-氟-1-甲基哌啶-4-基)甲基氨基)-3-硝基苯磺酰胺Step A: 4-((4-Fluoro-1-methylpiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide
Figure PCTCN2017100226-appb-000182
Figure PCTCN2017100226-appb-000182
将4-((4-氟哌啶-4-基)甲基氨基)-3-硝基苯磺酰胺盐酸盐(50mg)溶于乙腈(6mL)和甲醇(3mL)的混合溶液中，加入三乙胺(0.3mL)，室温下搅拌20分钟后，加入醋酸(1mL)和30％甲醛水溶液(1mL)，室温下继续搅拌20分钟后，加入醋酸硼氢化钠(90mg)，室温下搅拌过夜，加入饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取，除去溶剂得粗品，粗品用制备薄层板分离，展开剂为二氯甲烷/甲醇/氨水(60/6/1)，得到目标产物(46mg)。4-((4-Fluoropiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide hydrochloride (50 mg) was dissolved in a mixture of acetonitrile (6 mL) and methanol (3 mL) After stirring for 20 minutes at room temperature, acetic acid (1 mL) and 30% aqueous formaldehyde (1 mL) were added, and the mixture was stirred at room temperature for 20 minutes, then sodium borohydride (90 mg) was added and stirred at room temperature overnight. The reaction was quenched by the addition of a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane. The solvent was evaporated to give a crude product. The crude material was separated from the crude material. The solvent was methylene chloride/methanol/methanol (60/6/1) to give the desired product. (46 mg).
1H NMR(400MHz,d6-DMSO)δ8.58～8.55(m,1H),8.45(d,J＝2.4Hz,1H),7.82～7.79(m,1H),7.37(d,J＝8.0Hz,1H),7.32(br,2H),3.76～3.69(m,2H),2.76～2.68(m,2H),2.30～2.21(m,5H),1.89～1.68(m,4H)。 1 H NMR (400 MHz, d6-DMSO) δ 8.58 to 8.55 (m, 1H), 8.45 (d, J = 2.4 Hz, 1H), 7.82 to 7.79 (m, 1H), 7.37 (d, J = 8.0 Hz) , 1H), 7.32 (br, 2H), 3.76 to 3.69 (m, 2H), 2.76 to 2.68 (m, 2H), 2.30 to 2.21 (m, 5H), 1.89 to 1.68 (m, 4H).
步骤B：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟-1-甲基哌啶-4-基)甲基氨基)-3-硝基苯磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000183
Figure PCTCN2017100226-appb-000183
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(75mg)，4-((4-氟-1-甲基哌啶-4-基)甲基氨基)-3-硝基苯磺酰胺(46mg)，EDCI(48mg)，DMAP(25mg)，TEA(39mg)溶于二氯甲烷(30mL)中，室温下搅拌过夜，加入水淬灭反应，二氯甲烷萃取，除去溶剂得粗品，粗品用制备薄层板分离，展开剂为二氯甲烷/甲醇/氨水(60/6/1)，得到产物(8mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl) 1-(Alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (75 mg), 4-((4-fluoro-1-methylpiperidin-4-yl) Methylamino)-3-nitrobenzenesulfonamide (46 mg), EDCI (48 mg), DMAP (25 mg), EtOAc (30 mg) The reaction was extracted with methylene chloride. The solvent was evaporated to give crude crystals. m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
1H NMR(400MHz,CDCl3)δ10.37(br,1H),8.79(s,1H),8.48(s,1H),7.99～7.82(m,3H),7.49～7.40(m,2H),7.23(d,J＝8.0Hz,2H),7.08～7.07(m,1H),6.94(d,J＝8.0Hz,2H),6.75～6.69(m,2H),6.39(s,1H),5.91(s,1H),5.48(s,1H),3.54～3.48(m,2H),3.22～3.16(m,2H),3.04～2.95(m,4H),2.83～2.66(m,5H),2.59～2.50(m,2H),2.35～2.24(m,6H),2.01～1.94(m,4H),1.45～1.39(m,2H),0.94(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ10.37 (br, 1H), 8.79 (s, 1H), 8.48 (s, 1H), 7.99 ~ 7.82 (m, 3H), 7.49 ~ 7.40 (m, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.08 to 7.07 (m, 1H), 6.94 (d, J = 8.0 Hz, 2H), 6.75 to 6.69 (m, 2H), 6.39 (s, 1H), 5.91 (s, 1H), 5.48 (s, 1H), 3.54 to 3.48 (m, 2H), 3.22 to 3.16 (m, 2H), 3.04 to 2.95 (m, 4H), 2.83 to 2.66 (m, 5H), 2.59 ～ 2.50 (m, 2H), 2.35 to 2.24 (m, 6H), 2.01 to 1.94 (m, 4H), 1.45 to 1.39 (m, 2H), 0.94 (s, 6H).
实施例30Example 30
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟-1-(四氢-2H-吡喃-4-基)哌啶-4-基)甲基氨基)-3-硝基苯磺酰基)苯甲酰胺 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-) 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluoro-1-(tetrahydro-2H-pyran-4-) (piperidin-4-yl)methylamino)-3-nitrobenzenesulfonyl)benzamide
Figure PCTCN2017100226-appb-000184
步骤A：4-((4-氟-1-(四氢-2H-吡喃-4-基)哌啶-4-基)甲基氨基)-3-硝基苯磺酰胺
Figure PCTCN2017100226-appb-000184
Step A: 4-((4-Fluoro-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide
Figure PCTCN2017100226-appb-000185
Figure PCTCN2017100226-appb-000185
将4-((4-氟哌啶-4-基)甲基氨基)-3-硝基苯磺酰胺盐酸盐(50mg)分散于二氯甲烷(20mL)中,加入三乙胺(34mg)并于室温下搅拌20分钟后，加入3-氧杂环丁酮(20mg)，醋酸硼氢化钠(57mg)，与室温下搅拌过夜，加入饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，除去溶剂，得到粗品，粗品用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(32mg)。4-((4-Fluoropiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide hydrochloride (50 mg) was dissolved in dichloromethane (20 mL) and triethylamine (34 mg) After stirring at room temperature for 20 minutes, 3-oxetanone (20 mg), sodium borohydride (57 mg) was added, and the mixture was stirred at room temperature overnight. The mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then evaporated to give the crude product, and the crude product was separated from methylene chloride/methanol (15/1).
1H NMR(400MHz,d6-DMSO)δ8.57(br,1H),8.45(s,1H),7.82～7.79(m,1H),7.38(d,J＝8.0Hz,1H),7.33(s,2H),3.89～3.73(m,4H),3.07～2.93(m,2H),2.76～2.67(m,2H),2.24～2.10(m,2H),2.00～1.92(m,2H),1.85～1.59(m,5H),1.47～1.35(m,2H)。 1 H NMR (400MHz, d6- DMSO) δ8.57 (br, 1H), 8.45 (s, 1H), 7.82 ~ 7.79 (m, 1H), 7.38 (d, J = 8.0Hz, 1H), 7.33 (s , 2H), 3.89 to 3.73 (m, 4H), 3.07 to 2.93 (m, 2H), 2.76 to 2.67 (m, 2H), 2.24 to 2.10 (m, 2H), 2.00 to 1.92 (m, 2H), 1.85 ~1.59 (m, 5H), 1.47 to 1.35 (m, 2H).
步骤B：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟-1-(四氢-2H-吡喃-4-基)哌啶-4-基)甲基氨基)-3-硝基苯磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000186
Figure PCTCN2017100226-appb-000186
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(68mg)，4-((4-氟-1-(四氢-2H-吡喃-4-基)哌啶-4-基)甲基氨基)-3-硝基苯磺酰胺(50mg)，EDCI(44mg)，DMAP(15mg)，TEA(36mg)溶于二氯甲烷(30mL)中，室温下搅拌过夜，加入水淬灭反应，二氯甲烷萃取，除去溶剂得粗品，粗品用制备薄层板分离，展开剂为二氯甲烷/甲醇/氨水(60/6/1)，得到产物(30mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl) 1-(Alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (68 mg), 4-((4-fluoro-1-(tetrahydro-2H-pyran) -4-yl)piperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide (50 mg), EDCI (44 mg), DMAP (15 mg), TEA (36 mg) dissolved in dichloromethane (30mL) The mixture was stirred at room temperature overnight, quenched with water, extracted with dichloromethane, and the solvent was evaporated to give a crude material. The crude material was separated by preparative thin layer, and the solvent was methylene chloride / methanol / ammonia (60 / 6 / 1 ) Product (30 mg).
1H NMR(400MHz,CDCl3)δ9.78(br,1H),8.89(s,1H),8.63～8.61(m,1H),8.09(s,1H),8.00(d,J＝8.0Hz,2H),7.64(d,J＝2.4Hz,1H),7.46～7.45(m,1H),7.25(d,J＝8.0Hz,2H),7.14(d,J＝8.0Hz,1H),6.95(d,J＝8.0Hz,2H),6.84(d,J＝8.0Hz,1H),6.74(s,1H),6.52～6.51(m,1H),5.96(s,1H),4.08～4.05(m,2H),3.55～3.49(m,2H),3.43～3.37(m,2H),3.02～2.91(m,6H),2.77～2.67(m,3H),2.44～2.42(m,2H),2.35～2.30(m,2H),2.23～2.20(m,2H),2.04～1.99(m,6H),1.87～1.85(m,2H),1.75～1.66(m,2H),1.44～1.42(m,2H),0.96(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ9.78 (br, 1H), 8.89 (s, 1H), 8.63 ~ 8.61 (m, 1H), 8.09 (s, 1H), 8.00 (d, J = 8.0Hz, 2H), 7.64 (d, J = 2.4 Hz, 1H), 7.46 to 7.45 (m, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 1H), 6.95 ( d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 1H), 6.74 (s, 1H), 6.52 to 6.51 (m, 1H), 5.96 (s, 1H), 4.08 to 4.05 (m) , 2H), 3.55 to 3.49 (m, 2H), 3.43 to 3.37 (m, 2H), 3.02 to 2.91 (m, 6H), 2.77 to 2.67 (m, 3H), 2.44 to 2.42 (m, 2H), 2.35 ～2.30 (m, 2H), 2.23 to 2.20 (m, 2H), 2.04 to 1.99 (m, 6H), 1.87 to 1.85 (m, 2H), 1.75 to 1.66 (m, 2H), 1.44 to 1.42 (m, 2H), 0.96 (s, 6H).
实施例31Example 31
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((1-甲基哌啶-4-基)甲基氨基)-3-硝基苯磺酰基)苯甲酰胺 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-) 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((1-methylpiperidin-4-yl)methylamino)-3 -nitrophenylsulfonyl)benzamide
Figure PCTCN2017100226-appb-000187
Figure PCTCN2017100226-appb-000187
步骤A：叔丁基-4-((2-硝基-4-磺酰胺苯胺)甲基)哌啶-1-羧酸酯Step A: tert-Butyl-4-((2-nitro-4-sulfonamide)methyl)piperidine-1-carboxylate
Figure PCTCN2017100226-appb-000188
Figure PCTCN2017100226-appb-000188
将4-氯-3-硝基苯磺酰胺(200mg)，叔丁基-4-(胺甲基)哌啶-1-羧酸酯(200mg)，DIEA(1.0g)溶于乙腈(20mL)中，70℃下回流过夜，冷却至室温后加水淬灭反应，二氯甲烷萃取，1N盐酸洗，饱和氯化钠洗，减压除去溶剂，二氯甲烷打浆，抽滤得到黄色产品(140mg)。4-Chloro-3-nitrobenzenesulfonamide (200 mg), tert-butyl-4-(aminomethyl)piperidine-1-carboxylate (200 mg), DIEA (1.0 g) dissolved in acetonitrile (20 mL) The mixture was refluxed at 70 ° C overnight, cooled to room temperature, then quenched with water, EtOAc (EtOAc)EtOAc. .
1H NMR(400MHz,d6-DMSO)δ8.57～8.54(m,1H),8.45(s,1H),7.80(d,J＝7.2Hz,1H),7.30～7.26(m,3H),3.93(d,J＝10.0Hz,2H),3.35～3.30(m,2H),2.71～2.60(m,2H),1.85～1.78(m,1H),1.66(d,J＝10.0Hz,2H),1.11～1.01(m,2H)。 1 H NMR (400 MHz, d6-DMSO) δ 8.57 to 8.54 (m, 1H), 8.45 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.30 to 7.26 (m, 3H), 3.93 (d, J = 10.0 Hz, 2H), 3.35 to 3.30 (m, 2H), 2.71 to 2.60 (m, 2H), 1.85 to 1.78 (m, 1H), 1.66 (d, J = 10.0 Hz, 2H), 1.11 to 1.01 (m, 2H).
步骤B：3-硝基-4-(哌啶-4-基甲基胺)苯磺酰胺盐酸盐Step B: 3-Nitro-4-(piperidin-4-ylmethylamine)benzenesulfonamide hydrochloride
Figure PCTCN2017100226-appb-000189
Figure PCTCN2017100226-appb-000189
将叔丁基-4-((2-硝基-4-磺酰胺苯胺)甲基)哌啶-1-羧酸酯(140mg)溶于氯化氢的甲醇溶液(30mL)中,室温下搅拌过夜，除去溶剂，得到目标产物(110mg)。tert-Butyl-4-((2-nitro-4-sulfonamidobenzyl)methyl)piperidine-1-carboxylate (140 mg) was dissolved in MeOH MeOH (30 mL) The solvent was removed to give the aimed product (110 mg).
1H NMR(400MHz,d6-DMSO)δ8.75(br,1H),8.69～8.68(m,1H),8.53(d,J＝2.4Hz,1H),8.45(br,1H),7.89～7.87(m,1H),7.41(s,2H),7.35(d,J＝9.2Hz,1H),3.46～3.42(m,2H),3.35～3.27(m,2H),2.92～2.83(m,2H),2.07～1.98(m,1H),1.93～1.89(m,2H),1.48～1.39(m,2H)。 1 H NMR (400 MHz, d6-DMSO) δ 8.75 (br, 1H), 8.69 - 8.68 (m, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.45 (br, 1H), 7.89 - 7.87 (m, 1H), 7.41 (s, 2H), 7.35 (d, J = 9.2 Hz, 1H), 3.46 to 3.42 (m, 2H), 3.35 to 3.27 (m, 2H), 2.92 to 2.83 (m, 2H) ), 2.07 to 1.98 (m, 1H), 1.93 to 1.89 (m, 2H), 1.48 to 1.39 (m, 2H).
步骤C：4-((1-甲基哌啶-4-基)甲基胺)-3-硝基苯磺酰胺Step C: 4-((1-Methylpiperidin-4-yl)methylamine)-3-nitrobenzenesulfonamide
Figure PCTCN2017100226-appb-000190
Figure PCTCN2017100226-appb-000190
将3-硝基-4-(哌啶-4-基甲基胺)苯磺酰胺盐酸盐(50mg)溶于乙腈(6mL)和甲醇(3mL)的混合溶液中，加入三乙胺(0.3mL)，室温下搅拌20分钟后，加入醋酸(1mL)和30％甲醛水溶液(1mL)，室温下继续搅拌20分钟后，加入醋酸硼氢化钠(100mg)，室温下搅拌过夜，加入饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取，除去溶剂得粗品，粗品用制备薄层板分离，展开剂为二氯甲烷/甲醇/氨水(60/6/1)，得到目标产物(50mg)。3-Nitro-4-(piperidin-4-ylmethylamine)benzenesulfonamide hydrochloride (50 mg) was dissolved in a mixture of acetonitrile (6 mL) and methanol (3 mL). After stirring for 20 minutes at room temperature, acetic acid (1 mL) and 30% aqueous formaldehyde (1 mL) were added. After stirring at room temperature for 20 minutes, sodium borohydride (100 mg) was added, stirred at room temperature overnight, and saturated hydrogen carbonate was added. The sodium solution was quenched, extracted with methylene chloride, and the solvent was evaporated to give a crude material. The crude material was separated from methylene chloride/methanol/methanol (60/6/1)
1H NMR(400MHz,d6-DMSO)δ8.59～8.56(m,1H),8.46(d,J＝5.6Hz,1H),7.83～7.80(m,1H),7.33(s,2H),7.28(d,J＝9.2Hz,1H),3.39～3.34(m,2H),2.97～2.93(m,2H),2.32(s,3H),2.19～2.10(m,2H),1.75～1.72(m,3H),1.36～1.27(m,2H)。 1 H NMR (400 MHz, d6-DMSO) δ 8.59 to 8.56 (m, 1H), 8.46 (d, J = 5.6 Hz, 1H), 7.83 to 7.80 (m, 1H), 7.33 (s, 2H), 7.28 (d, J=9.2 Hz, 1H), 3.39 to 3.34 (m, 2H), 2.97 to 2.93 (m, 2H), 2.32 (s, 3H), 2.19 to 2.10 (m, 2H), 1.75 to 1.72 (m) , 3H), 1.36 to 1.27 (m, 2H).
步骤D：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((1-甲基哌啶-4-基)甲基氨基)-3-硝基苯磺酰基)苯甲酰胺 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
Figure PCTCN2017100226-appb-000191
Figure PCTCN2017100226-appb-000191
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(86mg)，4-((1-甲基哌啶-4-基)甲基胺)-3-硝基苯磺酰胺(50mg)，EDCI(55mg)，DMAP(29mg)，TEA(45mg)溶于二氯甲烷(30mL)中，室温下搅拌过夜，加入水淬灭反应，二氯甲烷萃取，除去溶剂得粗品，粗品用制备薄层板分离，展开剂为二氯甲烷/甲醇(4/1)，得到产物(17mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl) 1-(Alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (86 mg), 4-((1-methylpiperidin-4-yl)methylamine -3-nitrobenzenesulfonamide (50 mg), EDCI (55 mg), DMAP (29 mg), TEA (45 mg) dissolved in dichloromethane (30 mL), stirred at room temperature overnight, quenched with water, dichloro The methane was extracted, the solvent was evaporated to give a crude material, and the crude material was purified from methylene chloride/methanol (4/1) to afford product (17 mg).
1H NMR(400MHz,d6-DMSO)δ11.55(s,1H),8.41(s,2H),7.95(s,1H),7.69(d,J＝7.2Hz,1H),7.50(d,J＝8.0Hz,1H),7.45(s,1H),7.35(d,J＝8.0Hz,3H),7.07(d,J＝8.0Hz,3H),6.91～6.89(m,1H),6.78(s,1H),6.33(s,1H),5.99(s,1H),3.40～3.35(m,4H),2.86～2.78(m,4H),2.71～2.67(m,5H),2.35～2.28(m,4H),2.14(s,2H),2.02～1.99(m,2H),1.90～1.85(m,3H),1.41～1.37(m,4H),0.94(s,6H)。 1 H NMR (400MHz, d6- DMSO) δ11.55 (s, 1H), 8.41 (s, 2H), 7.95 (s, 1H), 7.69 (d, J = 7.2Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.35 (d, J = 8.0 Hz, 3H), 7.07 (d, J = 8.0 Hz, 3H), 6.91 to 6.89 (m, 1H), 6.78 (s) , 1H), 6.33 (s, 1H), 5.99 (s, 1H), 3.40 to 3.35 (m, 4H), 2.86 to 2.78 (m, 4H), 2.71 to 2.67 (m, 5H), 2.35 to 2.28 (m) , 4H), 2.14 (s, 2H), 2.02 to 1.99 (m, 2H), 1.90 to 1.85 (m, 3H), 1.41 to 1.37 (m, 4H), 0.94 (s, 6H).
实施例32Example 32
叔丁基-2-((4-(N-(2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰)磺酰胺)-2-硝基苯胺)甲基)吗啉-4-羧酸酯tert-Butyl-2-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-)-chloride Phenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)sulfonamide)-2-nitrate Benzoamine)methyl)morpholine-4-carboxylate
Figure PCTCN2017100226-appb-000192
Figure PCTCN2017100226-appb-000192
步骤A：2-((苄氧基)甲基)吗啉Step A: 2-((Benzyloxy)methyl)morpholine
Figure PCTCN2017100226-appb-000193
Figure PCTCN2017100226-appb-000193
将2-氨基乙基硫酸酯(25.6g)加入40％的氢氧化钠水溶液(60mL)中，再加入2-((苄氧基)甲基)环氧乙烷(9mL)、甲醇(20mL)。反应液在50℃下搅拌1小时。然后补加40％的氢氧化钠水溶液(60mL)，反应液在50℃下搅拌过夜。用盐酸中和，乙酸乙酯萃取，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，除去溶剂，经柱层析纯化，用二氯甲烷/甲醇(30/1～3/1)洗脱，得到产品(5g)。Add 2-aminoethyl sulfate (25.6 g) to 40% aqueous sodium hydroxide (60 mL), then add 2-((benzyloxy)methyl)oxirane (9 mL), methanol (20 mL) . The reaction solution was stirred at 50 ° C for 1 hour. Then, a 40% aqueous sodium hydroxide solution (60 mL) was added, and the reaction solution was stirred at 50 ° C overnight. It is neutralized with hydrochloric acid, extracted with ethyl acetate, washed with EtOAc EtOAc The product (5g) was obtained.
1H NMR(400MHz,CDCl3)δ7.25～7.36(m,5H),3.89～3.94(m,1H),3.69～3.81(m,2H),3.46～3.56(m,4H),2.83～2.87(m,1H),2.65～2.68(m,1H),2.19～2.25(m,1H),2.00～2.05(m,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.25 to 7.36 (m, 5H), 3.89 to 3.94 (m, 1H), 3.69 to 3.81 (m, 2H), 3.46 to 3.56 (m, 4H), 2.83 to 2.87 (m, 1H), 2.65 to 2.68 (m, 1H), 2.19 to 2.25 (m, 1H), 2.00 to 2.05 (m, 1H).
步骤B：2-(羟甲基)吗啉-4-甲酸叔丁酯Step B: 2-(Hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000194
Figure PCTCN2017100226-appb-000194
将2-((苄氧基)甲基)吗啉(1.0g)、碳酸钾(667mg)、二碳酸二叔丁酯(1.58g)加入二氯甲烷(10mL)中，在室温下搅拌过夜。将反应液倾入水中，用二氯甲烷萃取，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩。残留物溶于甲醇(10mL)，加入10％的钯碳(300mg)，氢气(1atm)气氛下于40℃反应过夜。过滤后，真空除去溶剂，经柱层析纯化，以二氯甲烷/ 甲醇(60/1)洗脱，得产品(0.7g)。2-((Benzyloxy)methyl)morpholine (1.0 g), potassium carbonate (667 mg), di-tert-butyl dicarbonate (1.58 g) was added to dichloromethane (10 mL) and stirred at room temperature overnight. The reaction mixture was poured into water, extracted with dichloromethane, washed with saturated aqueous The residue was dissolved in methanol (10 mL), and 10% palladium carbon (300 mg) was added, and the mixture was reacted at 40 ° C overnight under a hydrogen (1 atm) atmosphere. After filtration, the solvent is removed in vacuo and purified by flash chromatography eluting with dichloromethane The product was eluted with methanol (60/1) to give the product (0.7 g).
1H NMR(400MHz,CDCl3)δ3.86～3.92(m,3H),3.66～3.69(m,1H),3.48～3.60(m,2H),2.73～2.97(m,2H),1.97(br,1H),1.46(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.86 to 3.92 (m, 3H), 3.66 to 3.69 (m, 1H), 3.48 to 3.60 (m, 2H), 2.73 to 2.97 (m, 2H), 1.97 (br) , 1H), 1.46 (s, 9H).
步骤C：2-(氨基甲基)吗啉-4-甲酸叔丁酯Step C: 2-(Aminomethyl)morpholine-4-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000195
Figure PCTCN2017100226-appb-000195
将2-(羟甲基)吗啉-4-甲酸叔丁酯(0.7g)、三乙胺(648mg)加入二氯甲烷(10mL)中，冷却至0℃，滴加甲磺酰氯(515mg)的二氯甲烷(2mL)溶液。滴加完毕后，恢复到室温，反应2小时，然后倾入水中，用二氯甲烷萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥。真空除去溶剂后，加入叠氮化钠(624mg)、碳酸氢钠(538mg)、N,N-二甲基甲酰胺(10mL)，在120℃下反应过夜。倾入水中，用乙酸乙酯萃取，饱和氯化钠溶液洗涤多次，无水硫酸钠干燥，浓缩至约20mL后，加入10％的钯碳(130mg)，在氢气(1atm)气氛下室温反应过夜。过滤后，真空除去溶剂，经柱层析纯化，以二氯甲烷/甲醇(30/1)洗脱，得产品(0.7g)。2-(Hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester (0.7 g), triethylamine (648 mg) was added to dichloromethane (10 mL), cooled to 0 ° C, and methanesulfonyl chloride (515 mg) was added dropwise. A solution of dichloromethane (2 mL). After completion of the dropwise addition, the mixture was returned to room temperature, and reacted for 2 hours, then poured into water, extracted with dichloromethane, washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After removing the solvent in vacuo, sodium azide (624 mg), sodium hydrogencarbonate (538 mg), and N,N-dimethylformamide (10 mL) were added and allowed to react at 120 ° C overnight. Pour into water, extract with ethyl acetate, wash several times with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate to about 20 mL, add 10% palladium carbon (130 mg), react at room temperature under hydrogen (1 atm) atmosphere. overnight. After filtration, the solvent was evaporated in vacuo tolululululululululululululu
1H NMR(400MHz,CDCl3)δ3.83～3.90(m,3H),3.49～3.55(m,1H),3.32～3.38(m,1H),2.92(br,1H),2.73～2.75(m,2H),2.63(br,1H),1.49(br,2H),1.46(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.83 to 3.90 (m, 3H), 3.49 to 3.55 (m, 1H), 3.32 to 3.38 (m, 1H), 2.92 (br, 1H), 2.73 to 2.75 (m) , 2H), 2.63 (br, 1H), 1.49 (br, 2H), 1.46 (s, 9H).
步骤D：2-(((2-硝基-4-磺酰氨基苯基)氨基)甲基)吗啉-4-甲酸叔丁酯Step D: 2-(((2-Nitro-4-sulfonylaminophenyl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000196
Figure PCTCN2017100226-appb-000196
将2-(氨基甲基)吗啉-4-甲酸叔丁酯(0.7g)、4-氯-3-硝基苯磺酰氨(0.76g)、三乙胺(0.83g)加入乙腈(20mL)中，反应液加热回流过夜。然后倾入水中，用乙酸乙酯萃取，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，除去溶剂，所得残余物。加入乙酸乙酯(5mL)，室温搅拌1小时后过滤，以乙酸乙酯洗涤，干燥得产品(0.5g)。2-(Aminomethyl)morpholine-4-carboxylic acid tert-butyl ester (0.7 g), 4-chloro-3-nitrobenzenesulfonylamide (0.76 g), triethylamine (0.83 g) was added to acetonitrile (20 mL) In the reaction, the reaction solution was heated to reflux overnight. Then, it was poured into water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated. Ethyl acetate (5 mL) was added, and the mixture was stirred at room temperature for 1 hour, then filtered, washed with ethyl acetate
1H NMR(400MHz,D6-DMSO)δ8.56(t,J＝5.6Hz,1H),8.48(d,J＝2.4Hz,1H),7.83～7.86(m,1H),7.30～7.34(m,3H),3.86～3.91(m,2H),3.60～3.72(m,3H),3.40～3.51(m,2H),2.67～2.91(m,1H),1.40(s,9H)。 1 H NMR (400MHz, D6- DMSO) δ8.56 (t, J = 5.6Hz, 1H), 8.48 (d, J = 2.4Hz, 1H), 7.83 ~ 7.86 (m, 1H), 7.30 ~ 7.34 (m , 3H), 3.86 to 3.91 (m, 2H), 3.60 to 3.72 (m, 3H), 3.40 to 3.51 (m, 2H), 2.67 to 2.91 (m, 1H), 1.40 (s, 9H).
步骤E：叔丁基-2-((4-(N-(2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰)磺酰胺)-2-硝基苯胺)甲基)吗啉-4-羧酸酯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
Figure PCTCN2017100226-appb-000197
Figure PCTCN2017100226-appb-000197
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(80mg)，2-(((2-硝基-4-磺酰氨基苯基)氨基)甲基)吗啉-4-甲酸叔丁酯(58mg)，EDCI(80mg)，DMAP(17mg)，TEA(43mg)溶于二氯甲烷(30mL)中，室温下搅拌过夜，加入水淬灭反应，二氯甲烷萃取，除去溶剂得粗品，粗品用制备薄层板分离，展开剂为二氯甲烷/甲醇(20/1)，得到产物(90mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl) 1-(Alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (80 mg), 2-(((2-nitro-4-sulfonylaminophenyl)) Amino)methyl)morpholine-4-carboxylic acid tert-butyl ester (58 mg), EDCI (80 mg), DMAP (17 mg), TEA (43 mg) dissolved in dichloromethane (30 mL) The reaction was quenched, extracted with EtOAc (EtOAc m.
1H NMR(400MHz,CDCl3)δ9.02(br,1H),8.91(d,J＝2.4Hz,1H).8.67～8.64(m,1H),8.17～8.14(m,2H),8.05(d,J＝8.0Hz,1H),7.69(d,J＝5.6Hz,1H),7.47～7.45(m,1H),7.24(d,J＝8.0Hz,2H),7.08(s,1H),6.95～6.91(m,3H),6.67(s,1H),6.57～6.55(m,1H),5.91(s,1H), 4.04～3.87(m,3H),3.76～3.69(m,1H),3.62～3.56(m,1H),3.52～3.47(m,1H),3.42～3.36(m,1H),3.03～2.82(m,6H),2.38～2.23(m,6H),2.00(s,2H),1.51～1.46(m,11H),0,96(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.02 (br, 1H), 8.91 (d, J = 2.4 Hz, 1H). 8.67 to 8.64 (m, 1H), 8.17 to 8.14 (m, 2H), 8.05 ( d, J = 8.0 Hz, 1H), 7.69 (d, J = 5.6 Hz, 1H), 7.47 to 7.45 (m, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.08 (s, 1H), 6.95 to 6.91 (m, 3H), 6.67 (s, 1H), 6.57 to 6.55 (m, 1H), 5.91 (s, 1H), 4.04 to 3.87 (m, 3H), 3.76 to 3.69 (m, 1H), 3.62 to 3.56 (m, 1H), 3.52 to 3.47 (m, 1H), 3.42 to 3.36 (m, 1H), 3.03 to 2.82 (m, 6H), 2.38 to 2.23 (m, 6H), 2.00 (s, 2H) ), 1.51 to 1.46 (m, 11H), 0, 96 (s, 6H).
实施例33Example 33
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-(吗啉-2-基甲基胺)-3-硝基苯磺酰基)苯甲酰胺2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-) 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(morpholin-2-ylmethylamine)-3-nitrobenzenesulfonyl Benzoylamide
Figure PCTCN2017100226-appb-000198
Figure PCTCN2017100226-appb-000198
步骤A：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-(吗啉-2-基甲基胺)-3-硝基苯磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000199
Figure PCTCN2017100226-appb-000199
将叔丁基-2-((4-(N-(2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰)磺酰胺)-2-硝基苯胺)甲基)吗啉-4-羧酸酯(80mg)溶于二氯甲烷(4mL)中，0℃下加入三氟乙酸(4mL)，0℃下继续搅拌2小时，加入过量饱和碳酸氢钠溶液，二氯甲烷萃取，饱和氯化钠洗有机相，无水硫酸钠干燥，除去溶剂得产物(70mg)。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 (80 mg) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (4 mL) was added at 0 ° C, and stirring was continued at 0 ° C for 2 s. The sodium hydrogencarbonate solution was extracted with dichloromethane, and the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate.
1H NMR(400MHz,d-DMSO)δ11.55(s,1H),9.00(br,2H),8.37～8.31(m,2H),7.90(d,J＝2.4Hz,1H),7.66～7.33(m,1H),7.49(d,J＝8.0Hz,1H),7.42～7.40(m,1H),7.34～7.29(m,3H),7.09～7.04(m,3H),6.84(d,J＝8.0Hz,1H),6.77(s,1H),6.29～6.28(m,1H),5.98(s,1H),3.95～3.89(m,2H),3.73～3.68(m,1H),3.54～3.50(m,1H),3.44～3.39(m,1H),3.22～3.15(m,1H),3.06～3.03(m,1H),2.91～2.72(m,6H),2.34～2.31(m,2H),2.28～2.23(m,2H),2.16～2.11(m,2H),1.38～1.35(m,2H),1.96～1.93(m,2H),0.91(s,6H)。 1 H NMR (400MHz, d- DMSO) δ11.55 (s, 1H), 9.00 (br, 2H), 8.37 ~ 8.31 (m, 2H), 7.90 (d, J = 2.4Hz, 1H), 7.66 ~ 7.33 (m, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.42 to 7.40 (m, 1H), 7.34 to 7.29 (m, 3H), 7.09 to 7.04 (m, 3H), 6.84 (d, J) = 8.0 Hz, 1H), 6.77 (s, 1H), 6.29 to 6.28 (m, 1H), 5.98 (s, 1H), 3.95 to 3.89 (m, 2H), 3.73 to 3.68 (m, 1H), 3.54 3.50 (m, 1H), 3.44 to 3.39 (m, 1H), 3.22 to 3.15 (m, 1H), 3.06 to 3.03 (m, 1H), 2.91 to 2.72 (m, 6H), 2.34 to 2.31 (m, 2H) ), 2.28 to 2.23 (m, 2H), 2.16 to 2.11 (m, 2H), 1.38 to 1.35 (m, 2H), 1.96 to 1.93 (m, 2H), 0.91 (s, 6H).
实施例34Example 34
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-(2-(二甲基胺)乙酰基)吗啉-2-基)甲基胺)-3-硝基苯磺酰基)苯甲酰胺2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-) 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-(2-(dimethylamino))acetyl)morpholine- 2-yl)methylamine)-3-nitrobenzenesulfonyl)benzamide
Figure PCTCN2017100226-appb-000200
Figure PCTCN2017100226-appb-000200
步骤A：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-(2-(二甲基胺)乙酰基)吗啉-2-基)甲基胺)-3-硝基苯磺酰基)苯甲酰胺 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
Figure PCTCN2017100226-appb-000201
Figure PCTCN2017100226-appb-000201
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-(吗啉-2-基甲基胺)-3-硝基苯磺酰基)苯甲酰胺(50mg)，N,N-二甲基甘氨酸(12mg)，EDCI(33mg)，DMAP(7mg)，TEA(17mg)溶于二氯甲烷(20mL)中，室温下搅拌过夜，加入水淬灭反应，二氯甲烷萃取，除去溶剂得粗品，粗品用制备薄层板分离，展开剂为二氯甲烷/甲醇/氨水(60/5/1)，得到产物(13mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl) -1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(morpholin-2-ylmethylamine)-3-nitrobenzenesulfonate Acyl)benzamide (50 mg), N,N-dimethylglycine (12 mg), EDCI (33 mg), DMAP (7 mg), TEA (17 mg) The reaction was quenched by the addition of EtOAc (EtOAc)EtOAc.
1H NMR(400MHz,d6-DMSO)δ11.68(s,1H),10.55(br,1H),8.53～8.47(m,2H),7.97(s,1H),7.78～7.74(m,1H),7.50～7.46(m,3H),7.30(d,J＝8.0Hz,2H),7.08～7.03(m,4H),6.71(s,1H),6.34(s,1H),5.89(s,1H),4.47～4.26(m,2H),4.20～4.10(m,2H),3.93～3.88(m,1H),3.75～3.70(m,1H),3.64～3.56(m,4H),3.20～3.14(m,2H),3.03～2.96(m,1H),2.81～2.74(m,7H),2.70～2.64(m,1H),2.32～2.26(m,4H),1.98～1.94(m,2H),1.41～1.37(m,2H),0.91(s,6H)。 1 H NMR (400MHz, d6- DMSO) δ11.68 (s, 1H), 10.55 (br, 1H), 8.53 ~ 8.47 (m, 2H), 7.97 (s, 1H), 7.78 ~ 7.74 (m, 1H) , 7.50 to 7.46 (m, 3H), 7.30 (d, J = 8.0 Hz, 2H), 7.08 to 7.03 (m, 4H), 6.71 (s, 1H), 6.34 (s, 1H), 5.89 (s, 1H) ), 4.47 to 4.26 (m, 2H), 4.20 to 4.10 (m, 2H), 3.93 to 3.88 (m, 1H), 3.75 to 3.70 (m, 1H), 3.64 to 3.56 (m, 4H), 3.20 to 3.14 (m, 2H), 3.03 to 2.96 (m, 1H), 2.81 to 2.74 (m, 7H), 2.70 to 2.64 (m, 1H), 2.32 to 2.26 (m, 4H), 1.98 to 1.94 (m, 2H) , 1.41 to 1.37 (m, 2H), 0.91 (s, 6H).
实施例35Example 35
4-((4-(N-(2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰基)氨磺酰基)-2-硝基苯基氨基)甲基)-4-氟哌啶-1-羧酸叔丁酯4-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl))-) 4-Dimethylcyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)sulfamoyl)-2-nitrophenylamino) Methyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000202
Figure PCTCN2017100226-appb-000202
步骤A：4-氟-4-(((甲基磺酰基)氧基)甲基)哌啶-1-甲酸叔丁酯Step A: 4-Fluoro-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000203
Figure PCTCN2017100226-appb-000203
将4-氟-4-(羟甲基)哌啶-1-甲酸叔丁酯(10g)溶于二氯甲烷(200mL)中，加入三乙胺(9mL)。将反应液冷却至0℃，缓慢滴加甲磺酰氯(3.7mL)的二氯甲烷溶液(10mL)，滴加完毕后恢复至室温，反应过夜。然后倾入水中，用二氯甲烷萃取，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，真空除去溶剂得到产品(12g)。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.
1H NMR(400MHz,CDCl3)δ4.20(d,J＝20.0Hz,2H),3.99(br,2H),3.07～3.11(m,5H),1.86～1.92(m,2H),1.52～1.69(m,2H),1.45(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 4.20 (d, J = 20.0 Hz, 2H), 3.99 (br, 2H), 3.07 to 3.11 (m, 5H), 1.86 to 1.92 (m, 2H), 1.52 1.69 (m, 2H), 1.45 (s, 9H).
步骤B：4-(氨甲基)-4-氟吡啶-1-甲酸叔丁酯Step B: 4-(Aminomethyl)-4-fluoropyridine-1-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000204
Figure PCTCN2017100226-appb-000204
将4-氟-4-(((甲基磺酰基)氧基)甲基)哌啶-1-甲酸叔丁酯(12g)、叠氮化钠(12g)、碳酸氢钠(7.5g)加入N,N-二甲基甲酰胺中，在120℃下反应16小时。然后倾入水中，用乙酸乙酯萃取，饱和食盐水洗涤三次，无水硫酸钠干燥，真空浓缩至约200mL。加入10％的钯碳(1.2g)，在氢气(1atm)下室温搅拌过夜。然后过滤除去钯碳，浓缩得到粗产品。经柱层析纯化， 以二氯甲烷/甲醇(20/1)洗脱得产品(5.5g)。Add 4-fluoro-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (12g), sodium azide (12g), sodium bicarbonate (7.5g) The reaction was carried out at 120 ° C for 16 hours in N,N-dimethylformamide. Then, it was poured into water, extracted with ethyl acetate, and washed with saturated brine over Celite. 10% palladium on carbon (1.2 g) was added and stirred at room temperature under hydrogen (1 atm) overnight. The palladium on carbon was then removed by filtration and concentrated to give a crude product. Purified by column chromatography, The product (5.5 g) was eluted with dichloromethane / methanol (20/1).
1H NMR(400MHz,CDCl3)δ3.96(br,1H),3.04～3.11(m,2H),2.72(d,J＝20.4Hz,2H),1.82～1.92(m,2H),1.41～1.69(m,11H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.96 (br, 1H), 3.04 to 3.11 (m, 2H), 2.72 (d, J = 20.4 Hz, 2H), 1.82 to 1.92 (m, 2H), 1.41 1.69 (m, 11H).
步骤C：4-氟-4-(((2-硝基-4-磺酰氨苯基)氨基)甲基)哌啶-1-甲酸叔丁酯Step C: 4-Fluoro-4-(((2-nitro-4-sulfonylaminophenyl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2017100226-appb-000205
Figure PCTCN2017100226-appb-000205
将4-(氨甲基)-4-氟吡啶-1-甲酸叔丁酯(5.5g)、4-氯-3-硝基苯磺酰氨(4.0g)、三乙胺(6.5mL)加入乙腈(150mL)中，加热回流过夜。然后倾入水中，用二氯甲烷/甲醇混合液萃取，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，除去溶剂，经柱层析纯化，以二氯甲烷/甲醇(30/1)洗脱得粗产品。将粗产品加入乙酸乙酯(10mL)中，室温搅拌1小时后过滤，以乙酸乙酯洗涤固体并干燥得产品(3.4g)。Add 4-(aminomethyl)-4-fluoropyridine-1-carboxylic acid tert-butyl ester (5.5 g), 4-chloro-3-nitrobenzenesulfonylamide (4.0 g), triethylamine (6.5 mL) It was heated to reflux overnight in acetonitrile (150 mL). Then, it is poured into water, extracted with a dichloromethane/methanol mixture, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated. Get a rough product. The crude product was added to ethyl acetate (10 mL).
1H NMR(400MHz,d6-DMSO)δ8.56(t,J＝6.4Hz,1H),8.46(d,J＝2.4Hz,1H),7.79～7.82(m,1H),7.39(d,J＝9.6Hz,1H),7.32(s,2H),3.72～3.83(m,4H),2.95(br,2H),1.78～1.84(m,2H),1.54～1.73(m,2H),1.38(s,9H)。 1 H NMR (400 MHz, d6-DMSO) δ 8.56 (t, J = 6.4 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 7.79 to 7.82 (m, 1H), 7.39 (d, J) = 9.6 Hz, 1H), 7.32 (s, 2H), 3.72 to 3.83 (m, 4H), 2.95 (br, 2H), 1.78 to 1.84 (m, 2H), 1.54 to 1.73 (m, 2H), 1.38 ( s, 9H).
步骤D：4-((4-(N-(2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰基)氨磺酰基)-2-硝基苯基氨基)甲基)-4-氟哌啶-1-羧酸叔丁酯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
Figure PCTCN2017100226-appb-000206
Figure PCTCN2017100226-appb-000206
将2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(100mg)和三乙胺(36mg)混合后加入4-氟-4-(((2-硝基-4-磺酰氨苯基)氨基)甲基)哌啶-1-甲酸叔丁酯(73mg)、EDCI(69mg)、DMAP(44mg)的二氯甲烷溶液(3mL)中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(100mg)。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 (100 mg) and triethylamine (36 mg), after mixing, 4-fluoro-4-((2-nitro-4-sulfonylaminophenyl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (73 mg), EDCI (69 mg) , DMAP (44 mg) in dichloromethane (3 mL), EtOAc. The layers were separated, and the developing solvent was dichloromethane/methanol (15/1) to give the desired product (100 mg).
1H NMR(400MHz,CD3Cl)δ9.14(br,1H),8.94(d,J＝2.4Hz,1H),8.69(t,J＝6.0Hz,1H),8.16～8.19(m,2H),8.05(d,J＝8.4Hz,1H),7.69(d,J＝2.4Hz,1H),7.46(t,J＝2.8Hz,1H),7.40(d,J＝8.4Hz,2H),7.10～7.12(m,1H),6.93～6.99(m,3H),6.67(br,1H),6.55～6.57(m,1H),5.92(br,1H),4.05(br,2H),3.51～3.58(m,2H),3.06～3.13(m,2H),2.87(br,4H),2.14～2.45(m,6H),1.99(br,4H),1.53～1.74(m,2H),1.48(s,9H),1.43(br,2H),0.95(s,6H)。 1 H NMR (400 MHz, CD 3 Cl) δ 9.14 (br, 1H), 8.94 (d, J = 2.4 Hz, 1H), 8.69 (t, J = 6.0 Hz, 1H), 8.16 to 8.19 (m, 2H) ), 8.05 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.46 (t, J = 2.8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.10 to 7.12 (m, 1H), 6.93 to 6.99 (m, 3H), 6.67 (br, 1H), 6.55 to 6.57 (m, 1H), 5.92 (br, 1H), 4.05 (br, 2H), 3.51 - 3.58 (m, 2H), 3.06 to 3.13 (m, 2H), 2.87 (br, 4H), 2.14 to 2.45 (m, 6H), 1.99 (br, 4H), 1.53 to 1.74 (m, 2H), 1.48 ( s, 9H), 1.43 (br, 2H), 0.95 (s, 6H).
实施例36Example 36
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3-四氢吡啶-4-基)-N-(4-((4-氟哌啶-4-基)甲基氨基)-3-硝基苯基磺酰基)苯甲酰胺盐酸盐 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane- 1-alkenyl)methyl)-1,2,3-tetrahydropyridin-4-yl)-N-(4-((4-fluoropiperidin-4-yl)methylamino)-3-nitro Phenylsulfonyl)benzamide hydrochloride
Figure PCTCN2017100226-appb-000207
Figure PCTCN2017100226-appb-000207
步骤A：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3-四氢吡啶-4-基)-N-(4-((4-氟哌啶-4-基)甲基氨基)-3-硝基苯基磺酰基)苯甲酰胺盐酸盐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
Figure PCTCN2017100226-appb-000208
Figure PCTCN2017100226-appb-000208
将4-((4-(N-(2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)4二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰基)氨磺酰基)-2-硝基苯基氨基)甲基)-4-氟哌啶-1-羧酸叔丁酯(100mg)溶于氯化氢的甲醇溶液(3mL)，室温搅拌过夜，除去溶剂，薄层层析，展开剂为二氯甲烷/甲醇/氨水(40/10/1)，得到目标产物(50mg)。4-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl))) 4 dimethylcyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)sulfamoyl)-2-nitrophenylamino) Tert-butyl 4-fluoropiperidine-1-carboxylate (100 mg) was dissolved in a solution of hydrogen chloride in methanol (3 mL), stirred at room temperature overnight, solvent was removed, and the solvent was evaporated. Ammonia water (40/10/1) gave the target product (50 mg).
1H NMR(400MHz,d6-DMSO)δ11.52(br,1H),8.49～8.71(m,2H),8.35～8.44(m,2H),7.1(d,J＝2.4Hz,1H),7.65～7.68(m,1H),7.48(d,J＝8.4Hz,1H),7.41～7.42(m,1H),7.31～7.33(m,3H),6.98～7.09(m,4H),6.76(br,1H),6.28～6.30(br,1H),5.98(br,1H),3.67～3.73(m,2H),3.21～3.24(m,2H),2.91～2.98(m,2H),2.79(br,4H),2.24～2.32(m,4H),2.13(br,2H),1.77～2.07(m,6H),1.35～1.38(m,2H),0.91(s,6H)。 1 H NMR (400 MHz, d6-DMSO) δ 11.52 (br, 1 H), 8.49 - 8.71 (m, 2H), 8.35 - 8.44 (m, 2H), 7.1 (d, J = 2.4 Hz, 1H), 7.65 ~ 7.68 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.41 to 7.42 (m, 1H), 7.31 to 7.33 (m, 3H), 6.98 to 7.09 (m, 4H), 6.76 (br , 1H), 6.28 to 6.30 (br, 1H), 5.98 (br, 1H), 3.67 to 3.73 (m, 2H), 3.21 to 3.24 (m, 2H), 2.91 to 2.98 (m, 2H), 2.79 (br) , 4H), 2.24 to 2.32 (m, 4H), 2.13 (br, 2H), 1.77 to 2.07 (m, 6H), 1.35 to 1.38 (m, 2H), 0.91 (s, 6H).
实施例37Example 37
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-(4-((4-苄基-嘧啶-2-基)甲基氨基)-3-硝基苯基磺酰基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰胺2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-((4-benzyl-pyrimidin-2-yl)methylamino)-3-nitro Phenylsulfonyl)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)-1,2,3,6- Tetrahydropyridin-4-yl)benzamide
Figure PCTCN2017100226-appb-000209
Figure PCTCN2017100226-appb-000209
步骤A：(4-苄基吗啉-2-基)甲基胺Step A: (4-Benzylmorpholin-2-yl)methylamine
Figure PCTCN2017100226-appb-000210
Figure PCTCN2017100226-appb-000210
将4-苄基-2-(氯甲基)吗啉(1.4g)、叠氮化钠(1.21g)、碘化钾(315mg)、碳酸氢钠(1.04g)加入到N,N-二甲基甲酰胺(20mL)中，在100℃下反应48小时。然后倾入水中，用乙酸乙酯萃取，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩至约20mL后，加入10％的钯碳(150mg)，在氢气(1atm)气氛下室温搅拌过夜。过滤后，除去溶剂得产品(1.2g)Add 4-benzyl-2-(chloromethyl)morpholine (1.4g), sodium azide (1.21g), potassium iodide (315mg), sodium bicarbonate (1.04g) to N,N-dimethyl The reaction was carried out at 100 ° C for 48 hours in formamide (20 mL). Then, it was poured into water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then evaporated to dryness to toluene (20 mL), and then added 10% palladium carbon (150 mg), and stirred at room temperature under a hydrogen atmosphere (1 atm) overnight. . After filtration, the solvent was removed to obtain a product (1.2 g)
1H NMR(400MHz,CDCl3)δ7.23～7.31(m,5H),3.83～3.88(m,1H),3.64～3.70(m,1H),3.44～3.52(m,3H),2.64～2.70(m,4H),2.12～2.18(m,1H),1.87(t,J＝10.4Hz,2H),1.52(br, 2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.23 to 7.31 (m, 5H), 3.83 to 3.88 (m, 1H), 3.64 to 3.70 (m, 1H), 3.44 to 3.52 (m, 3H), 2.64 to 2.70 (m, 4H), 2.12 to 2.18 (m, 1H), 1.87 (t, J = 10.4 Hz, 2H), 1.52 (br, 2H).
步骤B：4-(((4-苄基吗啉-2-基)甲基)氨基)-3-硝基苯磺酰氨Step B: 4-(((4-Benzylmorpholin-2-yl)methyl)amino)-3-nitrobenzenesulfonylamide
Figure PCTCN2017100226-appb-000211
Figure PCTCN2017100226-appb-000211
将(4-苄基吗啉-2-基)甲基胺(1.2g)、4-氯-3-硝基苯磺酰氨(1.55g)、三乙胺(2mL)加入乙腈(30mL)中，反应液加热回流过夜。然后倾入水中，用乙酸乙酯萃取，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，除去溶剂，所得残余物，经柱层析纯化，以洗脱液二氯甲烷/甲醇(30/1)洗脱得粗产品。加入乙酸乙酯(10mL)，室温搅拌1小时后过滤，以乙酸乙酯洗涤，干燥得产品(1.1g)。(4-Benzylmorpholin-2-yl)methylamine (1.2g), 4-chloro-3-nitrobenzenesulfonylamide (1.55g), triethylamine (2mL) was added to acetonitrile (30mL) The reaction solution was heated to reflux overnight. Then, it is poured into water, extracted with ethyl acetate, washed with aq. The crude product eluted. Ethyl acetate (10 mL) was added, and the mixture was stirred at room temperature for 1 hr then filtered and washed with ethyl acetate
1H NMR(400MHz,D6-DMSO)δ8.52(t,J＝5.6Hz,1H),8.44(d,J＝2.4Hz,1H),7.79～7.82(m,1H),7.21～7.33(m,7H),3.81～3.83(m,1H),3.70～3.75(m,1H),3.38～3.57(m,5H),2.75～2.78(m,1H),2.59～2.62(m,1H),2.05～2.11(m,1H),1.89～1.97(m,1H)。 1 H NMR (400MHz, D6- DMSO) δ8.52 (t, J = 5.6Hz, 1H), 8.44 (d, J = 2.4Hz, 1H), 7.79 ~ 7.82 (m, 1H), 7.21 ~ 7.33 (m , 7H), 3.81 to 3.83 (m, 1H), 3.70 to 3.75 (m, 1H), 3.38 to 3.57 (m, 5H), 2.75 to 2.78 (m, 1H), 2.59 to 2.62 (m, 1H), 2.05 ～2.11 (m, 1H), 1.89 to 1.97 (m, 1H).
步骤C：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-(4-((4-苄基-嘧啶-2-基)甲基氨基)-3-硝基苯基磺酰基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酰胺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
Figure PCTCN2017100226-appb-000212
Figure PCTCN2017100226-appb-000212
将2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(30mg)和三乙胺(36mg)混合后加入4-(((4-苄基吗啉-2-基)甲基)氨基)-3-硝基苯磺酰氨(20mg)、EDCI(19mg)、DMAP(12mg)的二氯甲烷溶液(3mL)中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(20mg)。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 (30 mg) and triethylamine (36 mg), after mixing, 4-(((4-benzylmorpholin-2-yl)methyl)amino)-3-nitrobenzenesulfonylamide (20 mg), EDCI (19 mg), DMAP (12 mg) Methylene chloride solution (3 mL), stirred at room temperature overnight, diluted with dichloromethane, washed twice with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue The title product (20 mg) was obtained from methylene chloride/methanol (15/1).
1H NMR(400MHz,CD3Cl)δ9.20(br,1H),8.88(d,J＝2.0Hz,1H),8.64(t,J＝4.8Hz,1H),8.09～8.12(m,2H),8.02(d,J＝8.4Hz,1H),7.67(d,,J＝2.0Hz,1H),7.21～7.34(m,9H),7.06(br,1H),6.93(d,J＝8.4Hz,2H),6.86(d,J＝9.2Hz,1H),6.65(br,1H),6.53～6.54(m,1H),5.87(br,1H),3.83～3.96(m,2H),3.68～3.79(m,1H),3.51～3.61(m,2H),3.30～3.45(m,3H),2.67～3.19(m,6H),2.14～2.60(m,5H),1.89～2.14(m,4H),1.42～1.46(m,2H),0.94(s,6H)。 1 H NMR (400 MHz, CD 3 Cl) δ 9.20 (br, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.64 (t, J = 4.8 Hz, 1H), 8.09 to 8.12 (m, 2H) ), 8.02 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.21 to 7.34 (m, 9H), 7.06 (br, 1H), 6.93 (d, J = 8.4) Hz, 2H), 6.86 (d, J = 9.2 Hz, 1H), 6.65 (br, 1H), 6.53 to 6.54 (m, 1H), 5.87 (br, 1H), 3.83 to 3.96 (m, 2H), 3.68 ～3.79 (m, 1H), 3.51 to 3.61 (m, 2H), 3.30 to 3.45 (m, 3H), 2.67 to 3.19 (m, 6H), 2.14 to 2.60 (m, 5H), 1.89 to 2.14 (m, 4H), 1.42~1.46 (m, 2H), 0.94 (s, 6H).
实施例38Example 38
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(3-硝基-4-((4-(氧杂环丁烷-3-基)吗啉-2-基)甲基氨基)苯磺酰基)苯甲酰胺 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane- 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(3-nitro-4-((4-(oxetan-3-yl)) )morpholin-2-yl)methylamino)benzenesulfonyl)benzamide
Figure PCTCN2017100226-appb-000213
Figure PCTCN2017100226-appb-000213
步骤A：3-硝基-4-(((4-(氧杂环丁-3-基)吗啉-2-基)甲基)氨基)苯磺酰氨Step A: 3-Nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)benzenesulfonamide
Figure PCTCN2017100226-appb-000214
Figure PCTCN2017100226-appb-000214
将4-((吗啉-2-基甲基)氨基)-3-硝基苯基甲磺酰氨盐酸盐(70mg)、3-氧杂环丁酮(3滴)、三乙胺(3滴)加入二氯甲烷(5mL)/N,N-二甲基甲酰胺(1mL)的混合溶液中，室温搅拌30分钟。加入三乙酰氧基硼氢化钠(100mg)，室温反应过夜。然后将反应液倾入水中，用二氯甲烷萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产品。经薄层层析纯化，以二氯甲烷/甲醇(20/1)为展开剂，得产品(24mg)。4-((morpholin-2-ylmethyl)amino)-3-nitrophenylmethanesulfonylamino hydrochloride (70 mg), 3-oxetanone (3 drops), triethylamine ( 3 drops) was added to a mixed solution of dichloromethane (5 mL) / N, N-dimethylformamide (1 mL), and stirred at room temperature for 30 min. Sodium triacetoxyborohydride (100 mg) was added and allowed to react at room temperature overnight. Then, the reaction mixture was poured into water, extracted with dichloromethane, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Purification by thin layer chromatography, methylene chloride / methanol (20/1)
1H NMR(400MHz,CDCl3)δ8.77(d,J＝2.0Hz,1H),8.61(t,J＝5.2Hz,1H),7.88～7.91(m,1H),6.95(d,J＝9.2Hz,1H),4.79(s,2H),4.66～4.70(m,2H),4.62(t,J＝6.0Hz,2H),3.96～4.00(m,1H),3.88～3.93(m,1H),3.72～3.79(m,1H),3.38～3.56(m,3H),2.69～2.72(m,1H),2.59～2.63(m,1H),2.10～2.17(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ8.77 (d, J = 2.0Hz, 1H), 8.61 (t, J = 5.2Hz, 1H), 7.88 ~ 7.91 (m, 1H), 6.95 (d, J = 9.2 Hz, 1H), 4.79 (s, 2H), 4.66 to 4.70 (m, 2H), 4.62 (t, J = 6.0 Hz, 2H), 3.96 to 4.00 (m, 1H), 3.88 to 3.93 (m, 1H) ), 3.72 to 3.79 (m, 1H), 3.38 to 3.56 (m, 3H), 2.69 to 2.72 (m, 1H), 2.59 to 2.63 (m, 1H), 2.10 to 2.17 (m, 1H).
步骤B：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(3-硝基-4-((4-(氧杂环丁烷-3-基)吗啉-2-基)甲基氨基)苯磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000215
Figure PCTCN2017100226-appb-000215
将2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(40mg)和三乙胺(12mg)混合后加入3-硝基-4-(((4-(氧杂环丁-3-基)吗啉-2-基)甲基)氨基)苯磺酰氨(24mg)、EDCI(23mg)、DMAP(15mg)的二氯甲烷溶液(3mL)中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(20mg)。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 (40 mg) and triethylamine (12 mg) was added, followed by the addition of 3-nitro-4-((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)benzenesulfonamide (24 mg), EDCI ( 23 mg), DMAP (15 mg) in dichloromethane (3 mL), EtOAc. The thin layer was separated and the developing solvent was dichloromethane/methanol (15/1) to give the desired product (20 mg).
1H NMR(400MHz,CD3Cl)δ9.03(br,1H),8.91(d,J＝2.4Hz,1H),8.67(t,J＝4.8Hz,1H),8.14～8.17(m,2H),8.05(d,J＝8.4Hz,1H),7.68(d,J＝2.4Hz,1H),7.45(t,J＝2.8Hz,1H),7.24(d,J＝8.0Hz,2H),7.12～7.14(m,1H),6.89～6.95(m,3H),6.69(s,1H),6.55～6.56(m,1H),5.95(br,1H),4.61～4.71(m,4H),3.88～4.01(m,2H),3.72～3.81(m,1H),3.35～3.57(m,3H),2.84(br,3H),2.70(d,J＝10.8Hz,1H),2.61(d,J＝10.8Hz,1H),2.35～2.38(m,2H),2.09～2.30(m,5H),1.93～2.04(m,4H),1.40～1.43(m,2H),0.95(s,6H)。 1 H NMR (400 MHz, CD 3 Cl) δ 9.03 (br, 1H), 8.91 (d, J = 2.4 Hz, 1H), 8.67 (t, J = 4.8 Hz, 1H), 8.14 to 8.17 (m, 2H) ), 8.05 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.45 (t, J = 2.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.12 to 7.14 (m, 1H), 6.89 to 6.95 (m, 3H), 6.69 (s, 1H), 6.55 to 6.56 (m, 1H), 5.95 (br, 1H), 4.61 to 4.71 (m, 4H), 3.88 to 4.01 (m, 2H), 3.72 to 3.81 (m, 1H), 3.35 to 3.57 (m, 3H), 2.84 (br, 3H), 2.70 (d, J = 10.8 Hz, 1H), 2.61 (d, J = 10.8 Hz, 1H), 2.35 to 2.38 (m, 2H), 2.09 to 2.30 (m, 5H), 1.93 to 2.04 (m, 4H), 1.40 to 1.43 (m, 2H), 0.95 (s, 6H) .
实施例39 Example 39
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟基-1-(甲基磺酰基)哌啶-4-基)甲基氨基)-3-硝基苯基磺酰基)苯甲酰胺2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane- 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((4-fluoro-1-(methylsulfonyl)piperidin-4) -yl)methylamino)-3-nitrophenylsulfonyl)benzamide
Figure PCTCN2017100226-appb-000216
Figure PCTCN2017100226-appb-000216
步骤A：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟基-1-(甲基磺酰基)哌啶-4-基)甲基氨基)-3-硝基苯基磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000217
Figure PCTCN2017100226-appb-000217
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3-四氢吡啶-4-基)-N-(4-((4-氟哌啶-4-基)甲基氨基)-3-硝基苯基磺酰基)苯甲酰胺盐酸盐(40mg),甲基磺酰氯(5mg)和三乙胺(20mg)溶于二氯甲烷溶液(3mL)中，0℃搅拌2小时，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(22mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane) -1-alkenyl)methyl)-1,2,3-tetrahydropyridin-4-yl)-N-(4-((4-fluoropiperidin-4-yl)methylamino)-3-nitrate Methyl phenylsulfonyl) benzamide hydrochloride (40 mg), methanesulfonyl chloride (5 mg) and triethylamine (20 mg) were dissolved in dichloromethane (3 mL) and stirred at 0 ° C for 2 hr. 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).
1H NMR(400MHz,CD3Cl)δ9.17(br,1H),8.94(d,J＝2.4Hz,1H),8.67(t,J＝6.4Hz,1H),8.13～8.17(m,2H),8.03(d,J＝8.4Hz,1H),7.68(d,J＝2.4Hz,1H),7.46(t,J＝2.8Hz,1H),7.23(d,J＝8.4Hz,2H),7.09(br,1H),6.93～6.98(m,3H),6.66(s,1H),6.55～6.56(m,1H),5.90(br,1H),3.78～3.82(m,2H),3.55～3.61(m,2H),2.87～3.06(m,6H),2.83(s,3H),2.18～2.50(m,6H),2.07～2.17(m,2H),1.99～2.06(m,2H),1.73～1.95(m,2H),1.40～1.46(m,2H),0.95(s,6H)。 1 H NMR (400 MHz, CD 3 Cl) δ 9.17 (br, 1H), 8.94 (d, J = 2.4 Hz, 1H), 8.67 (t, J = 6.4 Hz, 1H), 8.13 to 8.17 (m, 2H) ), 8.03 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.46 (t, J = 2.8 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.09 (br, 1H), 6.93 to 6.98 (m, 3H), 6.66 (s, 1H), 6.55 to 6.56 (m, 1H), 5.90 (br, 1H), 3.78 to 3.82 (m, 2H), 3.55 - 3.61 (m, 2H), 2.87 to 3.06 (m, 6H), 2.83 (s, 3H), 2.18 to 2.50 (m, 6H), 2.07 to 2.17 (m, 2H), 1.99 to 2.06 (m, 2H), 1.73 to 1.95 (m, 2H), 1.40 to 1.46 (m, 2H), 0.95 (s, 6H).
实施例40Example 40
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(3-硝基-4-((4-(四氢-2H-吡喃-4-基)吗啉-2-基)甲基氨基)苯磺酰基)苯甲酰胺2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane- 1-alkenyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(3-nitro-4-((4-(tetrahydro-2H-pyran-4) -yl)morpholin-2-yl)methylamino)benzenesulfonyl)benzamide
Figure PCTCN2017100226-appb-000218
Figure PCTCN2017100226-appb-000218
步骤A：3-硝基-4-(((4-(四氢-2H-吡喃-4-基)吗啉-2-基)甲基)氨基)苯磺酰氨 Step A: 3-Nitro-4-((4-(tetrahydro-2H-pyran-4-yl)morpholin-2-yl)methyl)amino)benzenesulfonamide
Figure PCTCN2017100226-appb-000219
Figure PCTCN2017100226-appb-000219
将4-((吗啉-2-基甲基)氨基)-3-硝基苯基甲磺酰氨盐酸盐(70mg)、四氢-4H-吡喃-4-酮(3滴)、三乙胺(3滴)加入二氯甲烷(5mL)/N,N-二甲基甲酰胺(1mL)的混合溶液中，室温搅拌30分钟。加入三乙酰氧基硼氢化钠(100mg)，室温反应过夜。然后将反应液倾入水中，用二氯甲烷萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产品。经薄层层析纯化，以二氯甲烷/甲醇(20/1)为展开剂，得产品(30mg)。4-((morpholin-2-ylmethyl)amino)-3-nitrophenylmethanesulfonylamino hydrochloride (70 mg), tetrahydro-4H-pyran-4-one (3 drops), Triethylamine (3 drops) was added to a mixed solution of dichloromethane (5 mL) / N, N-dimethylformamide (1 mL), and stirred at room temperature for 30 min. Sodium triacetoxyborohydride (100 mg) was added and allowed to react at room temperature overnight. Then, the reaction mixture was poured into water, extracted with dichloromethane, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Purification by thin layer chromatography, methylene chloride / methanol (20/1).
1H NMR(400MHz,d6-DMSO)δ8.54(t,J＝5.6Hz,1H),8.46(d,J＝2.0Hz,1H),7.81～7.84(m,1H),7.32(s,2H),7.25(d,J＝8.8Hz,1H),3.82～3.88(m,3H),3.66～3.71(m,1H),3.40～3.59(m,3H),3.22～3.28(m,2H),2.88(d,J＝10.4Hz,1H),2.71(d,J＝10.4Hz,1H),2.31～2.36(m,1H),2.14～2.20(m,1H),1.99～2.04(m,1H),1.68～1.71(m,2H),1.31～1.41(m,2H)。 1 H NMR (400MHz, d6- DMSO) δ8.54 (t, J = 5.6Hz, 1H), 8.46 (d, J = 2.0Hz, 1H), 7.81 ~ 7.84 (m, 1H), 7.32 (s, 2H ), 7.25 (d, J = 8.8 Hz, 1H), 3.82 to 3.88 (m, 3H), 3.66 to 3.71 (m, 1H), 3.40 to 3.59 (m, 3H), 3.22 to 3.28 (m, 2H), 2.88 (d, J = 10.4 Hz, 1H), 2.71 (d, J = 10.4 Hz, 1H), 2.31 to 2.36 (m, 1H), 2.14 to 2.20 (m, 1H), 1.99 to 2.04 (m, 1H) , 1.68 to 1.71 (m, 2H), 1.31 to 1.41 (m, 2H).
步骤B：2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(3-硝基-4-((4-(四氢-2H-吡喃-4-基)吗啉-2-基)甲基氨基)苯磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000220
Figure PCTCN2017100226-appb-000220
将2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(42mg)和三乙胺(15mg)混合后加入3-硝基-4-(((4-(四氢-2H-吡喃-4-基)吗啉-2-基)甲基)氨基)苯磺酰氨(30mg)、EDCI(29mg)、DMAP(18mg)的二氯甲烷溶液(3mL)中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(43mg)。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 (42 mg) and triethylamine (15 mg), after mixing, 3-nitro-4-((4-(tetrahydro-2H-pyran-4-yl)morpholin-2-yl)methyl)amino)benzenesulfonamide (30 mg) , EDCI (29 mg), DMAP (18 mg) in dichloromethane (3 mL), EtOAc. The residue was separated by preparative EtOAc (EtOAc) (EtOAc)
1H NMR(400MHz,D6-DMSO)δ11.58(br,1H),8.42(s,2H),7.94(d,J＝2.4Hz,1H),7.68～7.71(m,1H),7.43～7.49(m,2H),7.32～7.37(m,3H),7.05～7.11(m,3H),6.85～6.93(m,1H),6.76(s,1H),6.31～6.92(m,1H),5.98(br,1H),3.85～3.89(m,3H),3.70(br,1H),3.43～3.57.(m,2H),3.34～3.39(m,2H),3.19～3.28(m,3H),2.74～3.05(m,6H),2.30(br,3H),2.15(br,3H),1.97(br,3H),1.69～1.74(m,2H),1.37～1.39(m,4H),0.92(s,6H)。 1 H NMR (400MHz, D6- DMSO) δ11.58 (br, 1H), 8.42 (s, 2H), 7.94 (d, J = 2.4Hz, 1H), 7.68 ~ 7.71 (m, 1H), 7.43 ~ 7.49 (m, 2H), 7.32 to 7.37 (m, 3H), 7.05 to 7.11 (m, 3H), 6.85 to 6.93 (m, 1H), 6.76 (s, 1H), 6.31 to 6.92 (m, 1H), 5.98 (br, 1H), 3.85 to 3.89 (m, 3H), 3.70 (br, 1H), 3.43 to 3.57. (m, 2H), 3.34 to 3.39 (m, 2H), 3.19 to 3.28 (m, 3H), 2.74 to 3.05 (m, 6H), 2.30 (br, 3H), 2.15 (br, 3H), 1.97 (br, 3H), 1.69 to 1.74 (m, 2H), 1.37 to 1.39 (m, 4H), 0.92 ( s, 6H).
实施例41Example 41
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-2'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-((3-硝基-4-(((4-(四氢-2H-吡喃-4-基)吗啉-2-基)甲基)氨基)苯基)磺酰基)苯甲酰胺 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-2'-fluoro-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-(((4-(tetrahydro-2H-pyran-4-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)benzamide
Figure PCTCN2017100226-appb-000221
Figure PCTCN2017100226-appb-000221
步骤A：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-2'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-((3-硝基-4-(((4-(四氢-2H-吡喃-4-基)吗啉-2-基)甲基)氨基)苯基)磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000222
Figure PCTCN2017100226-appb-000222
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(50mg)和三乙胺(20mg)加入3-硝基-4-(((4-(四氢-2H-吡喃-4-基)吗啉-2-基)甲基)氨基)苯磺酰氨(34mg)、EDCI(32mg)、4-ppy(25mg)的二氯甲烷(3mL)溶液中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(30mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4-di) Methylcyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (50 mg) and triethylamine (20 mg) were added to 3-nitro-4- (((4-(tetrahydro-2H-pyran-4-yl)morpholin-2-yl)methyl)amino)benzenesulfonylamide (34 mg), EDCI (32 mg), 4-ppy (25 mg) In a dichloromethane (3 mL) solution, stirred at room temperature overnight, diluted with methylene chloride, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue The title product (30 mg) was obtained from methylene chloride/methanol (15/1).
1H NMR(400MHz,CDCl3)δ8.90～8.94(m,2H),8.67(t,J＝5.2Hz,1H),8.13～8.17(m,2H),8.05(d,J＝8.4Hz,1H),7.68(d,J＝2.4Hz,1H),7.40(t,J＝3.2Hz,1H),7.12(d,J＝8.0Hz,1H),7.00～7.06(m,2H),6.89～6.93(m,2H),6.69(s,1H),6.54～6.55(m,1H),5.94(br,1H),3.94～4.06(m,3H),3.79～3.90(m,1H),3.67～3.76(m,1H),3.33～3.49(m,4H),2.74～2.92(m,5H),2.14～2.49(m,9H),1.90～2.06(m,3H),1.73～1.83(m,2H),1.56～1.59(m,2H),1.43(br,2H),0.95(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.90 to 8.94 (m, 2H), 8.67 (t, J = 5.2 Hz, 1H), 8.13 to 8.17 (m, 2H), 8.05 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.40 (t, J = 3.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.00 to 7.06 (m, 2H), 6.89 - 6.93 (m, 2H), 6.69 (s, 1H), 6.54 to 6.55 (m, 1H), 5.94 (br, 1H), 3.94 to 4.06 (m, 3H), 3.79 to 3.90 (m, 1H), 3.67 3.76 (m, 1H), 3.33 to 3.49 (m, 4H), 2.74 to 2.92 (m, 5H), 2.14 to 2.49 (m, 9H), 1.90 to 2.06 (m, 3H), 1.73 to 1.83 (m, 2H) ), 1.56 to 1.59 (m, 2H), 1.43 (br, 2H), 0.95 (s, 6H).
实施例42Example 42
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-2'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-((3-硝基-4-(((4-(氧杂环丁烷-3-基)吗啉-2-基)甲基)氨基)苯基)磺酰基)苯甲酰胺2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((4'-chloro-2'-fluoro-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-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)benzamide
Figure PCTCN2017100226-appb-000223
Figure PCTCN2017100226-appb-000223
步骤A：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(1-((4'-氯-2'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-((3-硝基-4-(((4-(氧杂环丁烷-3-基)吗啉-2-基)甲基)氨基)苯基)磺酰基)苯甲酰胺 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
Figure PCTCN2017100226-appb-000224
Figure PCTCN2017100226-appb-000224
将2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(47mg)和三乙胺(16mg)加入3-硝基-4-(((4-(氧杂环丁-3-基)吗啉-2-基)甲基)氨基)苯磺酰氨(30mg)、EDCI(15mg)、4-ppy(24mg)的二氯甲烷(3mL)溶液中，室温搅拌过夜，用二氯甲烷稀释，水洗多次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，残留物用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(20mg)。2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-4,4-di) Methylcyclohex-1-enyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (47 mg) and triethylamine (16 mg) were added to 3-nitro-4- (((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)benzenesulfonylamide (30 mg), EDCI (15 mg), 4-ppy (24 mg) in dichloromethane (3mL) solution, stirred at room temperature overnight, diluted with dichloromethane, washed several times with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, the residue was separated by preparative thin layer, the developing agent was dichloro Methane/methanol (15/1) gave the desired product (20 mg).
1H NMR(400MHz,CDCl3)δ9.10(br,1H),8.92(d,J＝2.4Hz,1H),8.68(t,J＝5.2Hz,1H),8.15～8.19(m,2H),8.06(d,J＝8.4Hz,1H),7.70(d,J＝2.4Hz,1H),7.47(t,J＝3.2Hz,1H),7.14(d,J＝8.0Hz,1H),7.02～7.08(m,2H),6.91～6.95(m,2H),6.71(s,1H),6.56～6.58(m,1H),5.97(br,1H),4.62～4.72(m,4H),3.89～4.03(m,2H),3.75～3.81(m,1H),3.37～3.58(m,3H),2.71～2.86(m,5H),2.61～2.64(m,1H),2.10～2.43(m,7H),1.93～2.20(m,3H),1.45(br,2H),0.96(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.10 (br, 1H), 8.92 (d, J = 2.4 Hz, 1H), 8.68 (t, J = 5.2 Hz, 1H), 8.15 to 8.19 (m, 2H) , 8.06 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.47 (t, J = 3.2 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.02 ～7.08 (m, 2H), 6.91 to 6.95 (m, 2H), 6.71 (s, 1H), 6.56 to 6.58 (m, 1H), 5.97 (br, 1H), 4.62 to 4.72 (m, 4H), 3.89 ～4.03 (m, 2H), 3.75 to 3.81 (m, 1H), 3.37 to 3.58 (m, 3H), 2.71 to 2.86 (m, 5H), 2.61 to 2.64 (m, 1H), 2.10 to 2.43 (m, 7H), 1.93 to 2.20 (m, 3H), 1.45 (br, 2H), 0.96 (s, 6H).
实施例43Example 43
2-(1H-吡咯[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟-1-(3-杂氧环丁烷)哌啶-4-基)甲基氨基)-3-硝基苯磺酰基)苯甲酰胺2-(1H-pyrrole[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-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
Figure PCTCN2017100226-appb-000225
Figure PCTCN2017100226-appb-000225
步骤A：2-(1H-吡咯[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟-1-(3-杂氧环丁烷)哌啶-4-基)甲基氨基)-3-硝基苯磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000226
Figure PCTCN2017100226-appb-000226
将4-((4-氟-1-(3-环氧杂丁烷)-哌啶-4-基)甲基氨基)-3-硝基苯磺酰胺(50mg)溶于二氯甲烷(50mL)中，加入DIEA(50mg)，4-ppy(58mg)，2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(98 mg)，5分钟后加入EDCI(48mg)，室温搅拌过夜，用二氯甲烷稀释，1N盐酸洗有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，粗品用制备薄层板分离，展开剂为二氯甲烷/甲醇(15/1)，得到目标产物(40mg)。4-((4-Fluoro-1-(3-epoxyheterobutane)-piperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide (50 mg) was dissolved in dichloromethane (50 mL) , adding DIEA (50 mg), 4-ppy (58 mg), 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 (98 After 5 minutes, EDCI (48 mg) was added, and the mixture was stirred at room temperature overnight, diluted with methylene chloride, washed with 1N hydrochloric acid, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. The title compound (40 mg) was obtained.
1H NMR(400MHz,CDCl3)δ9.83(br,1H),8.89(d,J＝2.0Hz,1H),8.65(t,J＝5.6Hz,1H),8.12～8.08(m,2H),7.99(d,J＝8.0Hz,1H),7.66(d,J＝2.4Hz,1H),7.47～7.45(m,1H),7.08～6.88(m,5H),6.65(s,1H),6.53～6.51(m,1H),5.88(s,1H),4.69(t,J＝6.4Hz,2H),4.61(t,J＝6.4Hz,2H),3.56～3.50(m,3H),3.07～2.99(m,4H),2.66～2.59(m,4H),2.37～2.18(m,6H),2.05～1.72(m,6H),1.46～1.43(m,2H),0.94(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.83 (br, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.65 (t, J = 5.6 Hz, 1H), 8.12 to 8.08 (m, 2H) , 7.99 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.47 to 7.45 (m, 1H), 7.08 to 6.88 (m, 5H), 6.65 (s, 1H), 6.53 to 6.51 (m, 1H), 5.88 (s, 1H), 4.69 (t, J = 6.4 Hz, 2H), 4.61 (t, J = 6.4 Hz, 2H), 3.56 to 3.50 (m, 3H), 3.07 ～2.99 (m, 4H), 2.66 to 2.59 (m, 4H), 2.37 to 2.18 (m, 6H), 2.05 to 1.72 (m, 6H), 1.46 to 1.43 (m, 2H), 0.94 (s, 6H) .
实施例44Example 44
2-(1H-吡咯[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟-1-(四氢-2H-吡喃-4-基)哌啶-4-基)甲基氨基)-3-硝基苯磺酰基)苯甲酰胺2-(1H-pyrrole[2,3-b]pyridin-5-yloxy)-4-(1-((2-(4-chloro-2-fluorophenyl)-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
Figure PCTCN2017100226-appb-000227
Figure PCTCN2017100226-appb-000227
步骤A：2-(1H-吡咯[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己基-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)-N-(4-((4-氟-1-(四氢-2H-吡喃-4-基)哌啶-4-基)甲基氨基)-3-硝基苯磺酰基)苯甲酰胺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
Figure PCTCN2017100226-appb-000228
Figure PCTCN2017100226-appb-000228
将-((4-氟-1-(四氢-2H-吡喃-4-基)哌啶-4-基)甲基氨基)-3-硝基苯磺酰胺(50mg)溶于二氯甲烷(50mL)中，加入DIEA(47mg)，4-ppy(53mg)，2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(1-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)-1,2,3,6-四氢吡啶-4-基)苯甲酸(91mg)，5分钟后加入EDCI(44mg)，室温搅拌过夜，用二氯甲烷稀释，1N盐酸洗有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，粗品用制备薄层板分离，展开剂为二氯甲烷/甲醇(10/1)，得到目标产物(38mg)。-((4-Fluoro-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide (50 mg) was dissolved in dichloromethane (50 mL), DIEA (47 mg), 4-ppy (53 mg), 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 ( After 5 minutes, EDCI (44 mg) was added, and the mixture was stirred at room temperature overnight, diluted with methylene chloride, washed with 1N hydrochloric acid, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate The title compound (38 mg) was obtained from methylene chloride/methanol (10/1).
1H NMR(400MHz,CDCl3)δ10.27(br,1H),8.79(s,1H),8.52～8.49(m,1H),8.07～8.02(m,2H),7.90(d,J＝8.0Hz,1H),7.51(s,1H),7.41(s,1H),7.12～7.00(m,3H),6.94～6.90(m,1H),6.76～6.74(m,2H),6.38(s,1H),5.95(s,1H),4.05～4.03(m,2H),3.57～3.35(m,6H),3.22～3.19(m,2H),3.07～2.82(m,7H),2.53～2.49(m,2H),2.36～2.24(m,6H),2.11～2.05(m,2H),1.97～1.95(m,4H),1.80～1.72(m,2H),0.94(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ10.27 (br, 1H), 8.79 (s, 1H), 8.52 ~ 8.49 (m, 1H), 8.07 ~ 8.02 (m, 2H), 7.90 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.41 (s, 1H), 7.12 to 7.00 (m, 3H), 6.94 to 6.90 (m, 1H), 6.76 to 6.74 (m, 2H), 6.38 (s, 1H), 5.95 (s, 1H), 4.05 to 4.03 (m, 2H), 3.57 to 3.35 (m, 6H), 3.22 to 3.19 (m, 2H), 3.07 to 2.82 (m, 7H), 2.53 to 2.49 ( m, 2H), 2.36 to 2.24 (m, 6H), 2.11 to 2.05 (m, 2H), 1.97 to 1.95 (m, 4H), 1.80 to 1.72 (m, 2H), 0.94 (s, 6H).
生物活性实验Biological activity experiment
1.化合物的体外蛋白活性测定： 1. Determination of in vitro protein activity of compounds:
采用荧光偏振方法建立了Bcl-2以及Bcl-xl的蛋白活性筛选方法。其基本原理是：小分子化合物与荧光基团FITC标记的短肽(FITC-Bim)竞争其与Bcl2或者Bcl-xl的结合位点。当FITC-Bim与大分子物质Bcl2或者Bcl-xl结合之后，荧光物质FITC经单一平面的蓝偏振光(485nm)照射后，吸收光能跃入激发态，随后回复至基态，并发出单一平面的偏振荧光(525nm)。相反，如果FITC-Bim未能与大分子物质Bcl-2或者Bcl-xl结合，小分子旋转或翻转速度快，发射光相对于激发光平面将去偏振化。也就是说当化合物竞争性的与Bcl-2或者Bcl-xl结合之后，FITC-Bim便会以游离状态存在，其偏振值降低。因此，通过偏振值的变化可以反映化合物与Bcl-2或者Bcl-xl的结合能力。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. When FITC-Bim is combined with the macromolecular substance Bcl2 or Bcl-xl, 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). Conversely, if 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.
具体操作如下：首先将10mM的化合物储存液用DMSO稀释至1mM或0.1mM，之后用DMSO进行3倍梯度稀释。取4μL梯度稀释的化合物转移到96μL反应缓冲液中(PBS,pH7.4；50mM NaCl；0.01％NP40和2mM二硫代苏糖醇(DTT))，而后将这种进一步稀释的化合物加入到384-孔黑色圆底板
Figure PCTCN2017100226-appb-000229
中，接着添加8μL反应缓冲液配制的含有2nM Bcl-2或者Bcl-xl的蛋白溶液。然后将上述测试混合物在23℃摇晃孵育30分钟，之后添加4μL含有8nM FITC-Bim的反应缓冲液并继续室温孵育60分钟。通过EnVision在Ex485/Em530下进行偏振光值测定。通过数据分析软件Prism处理数据并得到该化合物的IC50值。The specific procedure was as follows: First, 10 mM of the compound stock solution was diluted to 1 mM or 0.1 mM with DMSO, followed by 3-fold gradient dilution with DMSO. 4 μL of the serially diluted compound was transferred to 96 μL of reaction buffer (PBS, pH 7.4; 50 mM NaCl; 0.01% NP40 and 2 mM dithiothreitol (DTT)), and then this further diluted compound was added to 384. - hole black round bottom plate
Figure PCTCN2017100226-appb-000229
Then, a protein solution containing 2 nM Bcl-2 or Bcl-xl prepared by adding 8 μL of the reaction buffer was added. The test mixture was then incubated at 23 ° C for 30 minutes with shaking, after which 4 μL 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.
2.化合物的细胞增殖活性测定：2. Determination of cell proliferation activity of the compound:
采用Promega公司的
Figure PCTCN2017100226-appb-000230
检测试剂建立了悬浮细胞增殖抑制筛选方法。Using Promega
Figure PCTCN2017100226-appb-000230
The detection reagent establishes a screening method for suspension cell proliferation inhibition.
人滤泡B淋巴瘤细胞DOHH2以及人急性成淋巴细胞性白血病细胞Molt-4用补充有10％胎牛血清
Figure PCTCN2017100226-appb-000231
的RPMI-1640
Figure PCTCN2017100226-appb-000232
培养基进行培养，培养条件是37℃，95％空气和5％的CO2，培养于25cm2或75cm2塑料组织培养瓶
Figure PCTCN2017100226-appb-000233
中，一周传代培养2～3次。Human follicular B lymphoma cell DOHH2 and human acute lymphoblastic leukemia cell Molt-4 supplemented with 10% fetal bovine serum
Figure PCTCN2017100226-appb-000231
RPMI-1640
Figure PCTCN2017100226-appb-000232
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.
Figure PCTCN2017100226-appb-000233
In the middle, subculture is carried out 2 to 3 times a week.
将细胞分别以8×103细胞/孔(DOHH2)和6×103细胞/孔(Molt-4)的密度接种在96-孔细胞培养板
Figure PCTCN2017100226-appb-000234
中，195μL/孔，并在37℃，95％空气和5％的CO2中进行培养。24小时后加入待测化合物：将化合物从10mM(溶于DMSO中)开始用DMSO进行3倍梯度稀释，每个浓度取4μL加入到96μL的无血清培养基中，最后取5μL培养基稀释后的化合物加入到接种有细胞的培养版中。细胞培养液中DMSO的终浓度为0.1％，所试化合物的终浓度是0.3nM～10μM。将上述细胞37℃温育3天。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.
Figure PCTCN2017100226-appb-000234
Medium, 195 μL/well, and cultured at 37 ° C, 95% air and 5% CO 2 . Add the test compound after 24 hours: start the compound from 10 mM (dissolved in DMSO) with 3-fold gradient dilution with DMSO, add 4 μL of each concentration to 96 μL of serum-free medium, and finally dilute with 5 μL of medium. 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 μM. The above cells were incubated at 37 ° C for 3 days.
3天后，通过CellTiter-Blue(Promega)试剂盒进行细胞活力测定，最后通过Prism程序计算化合物对细胞增殖的半抑制浓度，即IC50值。3 days later, performed by CellTiter-Blue (Promega) to determine cell viability kit, Compound% inhibition of cell proliferation is calculated by the Prism program last, i.e., IC 50 values.
根据本文所述的生物学方法对上述实施例制备的化合物进行分析。其结果显示于下表：The compounds prepared in the above examples were analyzed according to the biological methods described herein. The results are shown in the table below:
体外蛋白活性：In vitro protein activity:
化合物Compound Bcl-2IC50(nM)Bcl-2IC 50 (nM) Bcl-xl IC50(nM)Bcl-xl IC 50 (nM)
ABT-199ABT-199 2.752.75 45.145.1
实施例1Example 1 0.910.91 208.5208.5
实施例2Example 2 1.131.13 312.9312.9
实施例6Example 6 0.730.73 166.3166.3
实施例7Example 7 0.640.64 212.4212.4
实施例8Example 8 1.901.90 329.5329.5
实施例16Example 16 0.620.62 109.1109.1
实施例18Example 18 0.780.78 140.9140.9
实施例20Example 20 0.830.83 64.264.2
实施例21Example 21 0.600.60 97.297.2
实施例22Example 22 1.351.35 80.780.7
实施例23Example 23 1.761.76 49.449.4
实施例28Example 28 0.510.51 69.969.9
实施例29Example 29 1.591.59 32.232.2
实施例30Example 30 0.760.76 27.427.4
实施例34Example 34 0.360.36 50.250.2
实施例38Example 38 0.670.67 40.940.9
实施例40Example 40 1.341.34 97.097.0
实施例41Example 41 1.211.21 65.265.2
实施例42Example 42 0.920.92 48.648.6
实施例43Example 43 0.650.65 149.7149.7
实施例44Example 44 1.571.57 63.163.1
细胞增殖活性：Cell proliferation activity:
化合物Compound DOHH2IC50(nM)DOHH2IC 50 (nM) Molt4IC50(nM)Molt4IC 50 (nM) MV-411MV-411
ABT-199ABT-199 147.9147.9 >1000>1000 255.4255.4
实施例1Example 1 31.731.7 >1000>1000 46.946.9
实施例2Example 2 64.664.6 >1000>1000 未测试Not tested
实施例6Example 6 87.087.0 >1000>1000 49.549.5
实施例7Example 7 54.154.1 >1000>1000 38.638.6
实施例8Example 8 90.290.2 >1000>1000 135.2135.2
实施例16Example 16 71.571.5 >1000>1000 未测试Not tested
实施例18Example 18 19.819.8 >1000>1000 30.630.6
实施例20Example 20 17.817.8 >1000>1000 22.022.0
实施例21Example 21 14.214.2 >1000>1000 20.920.9
实施例22Example 22 11.811.8 >1000>1000 12.812.8
实施例23Example 23 9.39.3 >1000>1000 14.014.0
实施例28Example 28 14.314.3 >1000>1000 未测试Not tested
实施例29Example 29 94.794.7 >1000>1000 未测试Not tested
实施例30Example 30 42.042.0 >1000>1000 未测试Not tested
实施例34Example 34 14.014.0 >1000>1000 未测试Not tested
实施例38Example 38 98.898.8 >1000>1000 未测试Not tested
实施例40Example 40 97.097.0 >1000>1000 未测试Not tested
Figure PCTCN2017100226-appb-000235
Figure PCTCN2017100226-appb-000235

Claims (16)

  1. 式(I)化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药：a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof:
    Figure PCTCN2017100226-appb-100001
    Figure PCTCN2017100226-appb-100001
    其中，among them,
    Figure PCTCN2017100226-appb-100002
    为单键或双键；
    Figure PCTCN2017100226-appb-100002
    For single or double keys;
    Ar选自6-10元芳基和5-10元杂芳基，所述芳基和杂芳基任选地被选自卤素、氨基、羟基、(＝O)、C1-6烷基、以及C3-8环烷基的基团取代，所述杂芳基含有1-3个选自N、O和S的杂原子；Ar is selected from the group consisting of a 6-10 membered aryl group and a 5-10 membered heteroaryl group, which are optionally selected from the group consisting of halogen, amino, hydroxy, (=O), C1-6 alkyl, And a group substituted by a C 3-8 cycloalkyl group containing from 1 to 3 heteroatoms selected from N, O and S;
    X和Z各自独立地选自-O-、-CR3、-S-和-NR3-；X and Z are each independently selected from -O-, -CR 3 , -S- and -NR 3 -;
    Y选自N或CR8；Y is selected from N or CR 8 ;
    R选自C1-6烷氧基、-NR4R5、C3-8环烷基和C3-8杂环烷基，所述环烷基和杂环烷基可任选地被1-3个R9取代，所述杂环烷基含有1-3个N、O、S为杂原子；R is selected from C 1-6 alkoxy, -NR 4 R 5 , C 3-8 cycloalkyl and C 3-8 heterocycloalkyl, and the cycloalkyl and heterocycloalkyl may be optionally 1 - 3 R 9 substituted groups, the heterocycloalkyl group containing 1-3 N, O, S are heteroatoms;
    R9各自独立地选自卤素、氨基、羟基、Boc、SO2R10、C3-8环烷基、C3-8杂环烷基、Bn、(＝O)、-(CO)(CH2)mNR4R5、-(CO)(CH2)mOR6和C1-6烷基，或者两个R9可以连在一起形成3-8元杂环，并且R9可任选地被C1-6烷基或C3-8环烷基取代；所述杂环含有1-3个选自N、O和S的杂原子；R 9 is each independently selected from the group consisting of halogen, amino, hydroxy, Boc, SO 2 R 10 , C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, Bn, (=O), -(CO)(CH) 2 ) m NR 4 R 5 , -(CO)(CH 2 ) m OR 6 and C 1-6 alkyl, or two R 9 may be joined together to form a 3-8 membered heterocyclic ring, and R 9 may be optionally selected The ground is substituted with a C 1-6 alkyl group or a C 3-8 cycloalkyl group; the heterocyclic ring contains 1-3 hetero atoms selected from N, O and S;
    每个R7各自独立地选自卤素、C1-6烷基或C3-8环烷基；Each R 7 is each independently selected from halogen, C 1-6 alkyl or C 3-8 cycloalkyl;
    R8选自-NO2和-SO2CF3；R 8 is selected from the group consisting of -NO 2 and -SO 2 CF 3 ;
    R1、R2、R3、R4、R5、R6和R10各自独立地选自H和C1-6烷基；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;
    m独立地为0、1、2、3、4、5、或6；m is independently 0, 1, 2, 3, 4, 5, or 6;
    n为0、1、2、3、4、5或6；n is 0, 1, 2, 3, 4, 5 or 6;
    p为0、1、2、或3；和p is 0, 1, 2, or 3; and
    q为0或1。q is 0 or 1.
  2. 根据权利要求1所述的化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药，其中，
    Figure PCTCN2017100226-appb-100003
    为双键。    The compound of claim 1 or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein
    Figure PCTCN2017100226-appb-100003
    For double keys.
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药，其中，Y为CR8，且R8选自-NO2和-SO2CF3。The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein Y is CR 8 and R 8 is selected from the group consisting of -NO 2 and -SO 2 CF 3 .
  4. 根据权利要求1-3中任意一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药，其中，R7选自卤素。A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein R 7 is selected from halogen.
  5. 根据权利要求1-4所述的化合物或其药学上可接受的盐、溶剂化物、多晶形物或前 药，其中，Ar选自苯基、吡啶基或
    Figure PCTCN2017100226-appb-100004
    且Ar任选地被选自卤素、氨基、羟基和C1-6烷基的基团取代。    The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein Ar is selected from phenyl, pyridyl or
    Figure PCTCN2017100226-appb-100004
    And Ar is optionally substituted with a group selected from the group consisting of a halogen, an amino group, a hydroxyl group, and a C 1-6 alkyl group.
  6. 根据权利要求1-5中任意一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药，其中，X和Z各自独立地选自-O-和-NR3-，且R3选自H和C1-6烷基。The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein X and Z are each independently selected from -O- and -NR 3 -, and R 3 is selected from the group consisting of H and C 1-6 alkyl.
  7. 根据权利要求1-6中任意一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药，其中，R1和R2为H。The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein R 1 and R 2 are H.
  8. 根据权利要求1-7中任意一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药，其中，R4、R5、R6和R10各自独立地选自C1-6烷基。The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein R 4 , R 5 , R 6 and R 10 are each independently selected From C 1-6 alkyl.
  9. 根据权利要求1-8中任意一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药，其中，R选自C1-6烷氧基、C5-6环烷基和6元杂环烷基，所述环烷基任选地与5元或6元杂环烷基形成双螺环，上述各杂环烷基独立地含有1-2个选自N和O的杂原子。The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein R is selected from C 1-6 alkoxy, C 5-6 a cycloalkyl group and a 6-membered heterocycloalkyl group, the cycloalkyl group optionally forming a double spiro ring with a 5- or 6-membered heterocycloalkyl group, each of the above heterocycloalkyl groups independently containing 1-2 selected from N And O's hetero atom.
  10. 根据权利要求1-9中任意一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药，其中，R9选自卤素、Boc、SO2R10、C3-8杂环烷基、Bn、-(CO)(CH2)mNR4R5、C1-6烷基苯基和C1-6烷基，其中R4、R5和R10各自独立地选自C1-6烷基；m为1或2。The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein R 9 is 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 , C 1-6 alkylphenyl and C 1-6 alkyl, wherein R 4 , R 5 and R 10 are each independently Is selected from C 1-6 alkyl; m is 1 or 2.
  11. 根据权利要求1-10中任意一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药，其中，n为0、1、2或3。A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein n is 0, 1, 2 or 3.
  12. 根据权利要求1-11中任意一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药，其中，p为1和/或q为1。A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein p is 1 and/or q is 1.
  13. 根据权利要求1-12中任意一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药，其中所述化合物选自以下化合物：A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein the compound is selected from the group consisting of:
    Figure PCTCN2017100226-appb-100005
    Figure PCTCN2017100226-appb-100005
    Figure PCTCN2017100226-appb-100006
    Figure PCTCN2017100226-appb-100006
    Figure PCTCN2017100226-appb-100007
    Figure PCTCN2017100226-appb-100007
    Figure PCTCN2017100226-appb-100008
    Figure PCTCN2017100226-appb-100008
    Figure PCTCN2017100226-appb-100009
    Figure PCTCN2017100226-appb-100009
  14. 权利要求1-13中任意一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药在制备抑制Bcl-2蛋白表达的药物中的应用。Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, for the manufacture of a medicament for inhibiting the expression of a Bcl-2 protein.
  15. 权利要求1-13中任意一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药在制备治疗自身免疫性疾病或癌症的药物中的应用。Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, for the manufacture of a medicament for the treatment of an autoimmune disease or cancer.
  16. 根据权利要求15所述的应用，其中所述癌症选自膀胱癌、脑癌、乳腺癌、骨髓癌、子宫颈癌、慢性淋巴细胞性白血病、结肠直肠癌、食道癌、肝细胞癌、淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑素瘤、粒细胞性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、慢性淋巴细胞性白血病、骨髓瘤、前列腺癌、小细胞肺癌或脾癌。 The use according to claim 15, wherein the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphocytes 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, bone marrow Tumor, prostate cancer, small cell lung cancer or spleen cancer.
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