WO2016116061A1 - 作为hsp90抑制剂的间苯二酚类衍生物 - Google Patents
作为hsp90抑制剂的间苯二酚类衍生物 Download PDFInfo
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- WO2016116061A1 WO2016116061A1 PCT/CN2016/071697 CN2016071697W WO2016116061A1 WO 2016116061 A1 WO2016116061 A1 WO 2016116061A1 CN 2016071697 W CN2016071697 W CN 2016071697W WO 2016116061 A1 WO2016116061 A1 WO 2016116061A1
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- the present invention relates to novel resorcinol derivatives, especially compounds of formula (I), to processes for their preparation, to pharmaceutical compositions and to their use in the preparation of antitumor drugs and in the treatment of neurodegenerative diseases.
- HSP90 belongs to a small family of proteins (GHKL, derived from DNA gyrase, HSP90, histidine kinase, mutL) that normally share a very specific C-type pattern (Bergerat fold) linked to adenosine triphosphate.
- HSP90 is one of the most abundant proteins in the cell and is essential for the survival of eukaryotes.
- Human cells contain four HSP90 isoforms: constitutively expressed cytosolic ⁇ -isoforms, inducible alpha-forms, GRP94/gp96 in the endoplasmic reticulum, and mitochondrial TRAP1/HSP75. The ⁇ - and ⁇ -forms showed 85% sequence homology.
- HSP90 is a key component of the escort structure that catalyzes the folding and quality control of proteins known as HSP90 clients in normal cells and under stress conditions.
- the activity of a chaperone that is strictly dependent on adenosine triphosphatase activity is tightly regulated by the binding of other regulatory companion molecules.
- HSP90 has become crucial.
- Structurally HSP90 is a homodimer composed of three major domains: a very conserved N-terminal domain, an intermediate domain ATP domain and a C-terminal domain.
- the N and C terminal domains can bind to adenosine triphosphate.
- Most currently known inhibitors such as geldanamycin, radicicol, diarylpyrazole and anthracene derivatives, exhibit competitive binding to adenosine triphosphate at the N-terminal adenosine adenosine binding site.
- novobiocin is the prototype of an inhibitor that binds to the C-terminal pocket.
- HSP90 client is increasing (Jolly et al, J. Natl. Cancer Inst. 92; 1564-1572 (2000)), which belongs to the kinase family (Her2, B-RAF V600E, bcr-Abl, Flt3, NPM-ALK, Akt, Npm-Alk, ZAP-70), transcription factor (p53, HIF) telomerase, other chaperones, most of which are closely related to cancer development.
- the ability of HSP90 to inhibit damage folding or stabilize its client protein results in the degradation of these unfolded proteins based on proteases. Degradation of these client proteins is often used as a marker for HSP90 inhibition, typically in Her2 overexpressing cells, such as BT474 breast cancer cells, where Her2 is degraded after treatment with the compound.
- HSP70 misfolded protein-dependent chaperones
- HSP40 misfolded protein-dependent chaperones
- Heat shock proteins have been shown to provide this function in a variety of cell culture models.
- HSF1 induces HSP, and HSF1 is closely regulated by HSP90 in normal cells.
- HSP90 inhibitors such as geldanamycin and 17-AAG derivatives have been shown to disrupt this interaction and lead to HSP induction, which in turn leads to neuroprotective activity and re-solubilization and depolymerization of misfolded proteins.
- Overexpression of HSP90 significantly reduced the accumulation of misfolded proteins, and accumulation of misfolded proteins is responsible for Alzheimer's disease.
- an inverse correlation between the levels of aggregated tau and HSP70/90 has been demonstrated.
- Overexpression of HSP70, HSP27 and HSP40 reduces abnormal tau aggregation (by degradation), which is triggered by inhibition of HSP90.
- GDA 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- a pharmacologically active 4,6-disubstituted resorcinol compound is disclosed in GB 1,406,345.
- Other patent applications describe phenyl-heterocyclic compounds as HSP90 inhibitors, all of which are characterized by a specific substitution pattern with a five-membered heterocyclic ring, such as WO2006/101052 in the name of Nippon Kayaku Kabushiki Kaisha; WO2005/000300 from Vernalis, WO2004/002051 and WO2004/056782; WO2003/055860 to Ribotargets, WO2008/097640 to Synta Pharmaceuticals and WO2005/063222 to Kyowa Hakko Kogyo.
- WO2004072051 relates to a class of HSP90 inhibitors, including Luminespib:
- WO2006055760A1 reports some compounds such as
- CN1771235A discloses some compounds, such as These compounds are not ideal in terms of efficacy, pharmacokinetics, water solubility, and drug-forming properties.
- X, Y are each independently selected from N, O or S; preferably X is selected from N, O or S, and Y is selected from N or O;
- X 1 , X 2 , Y 1 , Y 2 and the carbon atoms linking X 1 and X 2 together form a 5-7 membered aromatic ring, an aliphatic saturated ring or an aliphatic unsaturated ring; preferably X 1 , X 2 , Y 1 , Y 2 and the carbon atoms connecting X 1 and X 2 together constitute a 5-6 membered aromatic ring, an aliphatic saturated ring or an aliphatic unsaturated ring;
- R 01 and R 02 are each independently selected from the group consisting of halogen, CN, OH, SH, NH 2 , CHO, COOH, C 1-10 alkyl, NC 1-10 alkylamino, N,N-di(C 1-10 alkane).
- Y 1 and Y 2 are each independently selected from C or N, preferably Y 1 and Y 2 are both C; Y 1 and two substituents on Y 2 are joined together to form a substituent R 1 , R 2 and R 3-aza-five yuan, six- or seven-membered saturated or aromatic ring;
- R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, C 1-10 alkyl, hydroxy C 1-10 alkyl, C 1-6 alkoxy-C 1-6 alkyl, halogenated C 1-10 Alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl, C 1-6 alkylamido-C 1-6 alkyl, N,N-di(C 1-6 alkyl)amino acyl -C 1-6 alkyl, N,N-di(C 1-6 alkyl)amino-C 1-6 alkanoyl, morpholinyl-C 1-6 alkanoyl, NC 1-10 alkylamino, N, N-di(C 1-10 alkyl)amino, C 1-10 alkoxy, C 1-10 alkanoyl, C 1-10 alkoxycarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkane a sulfinyl group, a
- R 1 is selected from hydrogen, C 1-6 alkane , hydroxy C 1-6 alkyl, C 3-10 cycloalkyl, C 1-4 alkoxy-C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkylsulfonyl -C 1-4 alkyl, C 1-4 alkylamido-C 1-4 alkyl, N,N-di(C 1-4 alkyl)aminoacyl-C 1-4 alkyl, N,N - bis(C 1-4 alkyl)amino-C 1-4 alkanoyl, morpholinyl-C 1-4 alkanoyl, C 3-6 cycloalkyl-C 1-4 alkyl, or R 2 and R
- the substituents of 3 are bonded to each other by a covalent bond to form a 5-, 6- or 7-membered saturated ring having a substituent R 03 or not; most preferably R 1 is selected from hydrogen, C 1-6 alkane , hydroxy C
- R 03 is selected from C 1-6 alkyl or halogen
- R 4 is selected from the group consisting of H, halogen, C 1-6 alkyl, C 3-10 cycloalkoxy, phenyl substituted C 1-6 alkyl, phenyl substituted C 2-6 alkenyl, phenyl, C 1-6 alkyl-substituted phenyl, C 3-6 cycloalkyl; preferably R 4 is selected from H, C 1-6 alkyl, phenyl substituted C 1-6 alkyl, halogen, C 3-6 ring Alkyl; more preferably R 4 is selected from C 1 -4 alkyl, Cl, Br or cyclopropyl; most preferably R 4 is selected from isopropyl.
- R 5 is selected from the group consisting of H, cyano, carboxy, C 1-6 alkoxy acyl, C 1-7 alkylaminocarbonyl, halo C 1-6 alkylaminocarbonyl, C 1-6 alkoxy-C 1 -6 alkylaminocarbonyl, N,N-di(C 1-6 alkyl)amino-C 1-6 alkylaminocarbonyl, aminocarbonyl, hydroxy C 1-6 alkylaminocarbonyl, hydroxy substituted halogen C a 1-6 alkyl, nitrile substituted indenyl group, or a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group or a 5 to 10 membered aromatic ring optionally substituted by one or more R 05 Wherein R 05 is selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl.
- R 5 is selected from the group consisting of cyano, C 1-6 alkylaminocarbonyl, halo C 1-4 alkylaminocarbonyl, C 1-4 alkoxy-C 1-4 alkylaminocarbonyl, N,N-di (C 1-4 alkyl)amino-C 1-4 alkylaminocarbonyl, aminocarbonyl, hydroxy C 1-4 alkylaminocarbonyl, hydroxy substituted halo C 1-4 alkyl, nitrile substituted fluorenyl Or a 5- to 6-membered aza-containing heteroaryl ring optionally substituted with one or more R 05 ; wherein R 05 is selected from C 1-6 alkyl.
- R 5 is selected from the group consisting of Wherein R 04 is selected from the group consisting of H, C 1-6 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, N,N-di(C 1-4 alkyl Amino-C 1-4 alkyl, hydroxy C 1-4 alkyl.
- equation (I) the above Selected from Other variables are defined by equation (I).
- R 01 and R 02 are each independently selected from the group consisting of H, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl; Defined by formula (I).
- equation (I) the above Selected from Other variables are defined by equation (I).
- n 01 , n 02 is selected from 0, 1, 2 or 3, and the sum of n 01 and n 02 is 2, 3 or 4; other variables are as defined in formula (I), and R 2 and R 3 are not joined into a ring .
- equation (I) the above Selected from Other variables are defined by equation (I).
- equation (I) the above Selected from Other variables are defined by equation (I).
- equation (I) the above Selected from Other variables are defined by equation (I).
- the above compound or a pharmaceutically acceptable salt or hydrate thereof is selected from the group consisting of a compound of the formula: or a pharmaceutically acceptable salt or hydrate thereof:
- the above compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
- Another object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate thereof, and a pharmaceutically acceptable carrier.
- Another object of the present invention is to provide the use of the above compounds for the preparation of a medicament for the treatment of a disease mediated by HSP90 protein.
- the disease mediated by the HSP90 protein of the present invention is preferably derived from cancer and neurodegenerative disorders.
- Another object of the present invention is to provide the use of the above compounds for the preparation of a medicament for the treatment of a particular type of cancer, including but not limited to cancers such as bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, including small cell lung cancer.
- a further object of the present invention is to provide for the preparation of a medicament for the treatment of a particular type of neurodegenerative disorder, including but not limited to: Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and spinal medullary muscle atrophy disease.
- Another object of the present invention is to provide an application comprising a compound of formula (I) for the simultaneous, sequential or sequential use of an anti-cancer treatment in the preparation of a treatment together with a radiation therapy or chemotherapy regimen.
- the invention provides an in vitro method for inhibiting HSP90 protein activity, the method comprising contacting the protein with an effective amount of a compound of formula (I).
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) together with known cytostatic or cytotoxic drugs, antibiotic agents, alkylating agents, antimetabolites, hormonal agents, Immunopharmaceuticals, interferon agents, cyclooxygenase inhibitors (eg COX-2 inhibitors), matrix metalloproteinase inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth Factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenic agents (eg angiogenesis inhibitors), farnesyltransferase inhibitors, ras-raf signaling pathway inhibitors, cell cycle inhibitors, other cdks Inhibitor, tubulin binding reagent, topoisomerase I inhibitor, topoisomerase II inhibitor, and the like.
- cyclooxygenase inhibitors eg COX-2 inhibitors
- matrix metalloproteinase inhibitors eg
- the present invention provides a product or kit comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and one or more chemotherapeutic agents, as defined above, for said product or reagent
- the kit is in the form of a combined preparation, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined above, and one or more chemotherapeutic agents, for simultaneous, separate or sequential use in anticancer therapy .
- the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament as defined above.
- the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament having antitumor activity.
- the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, for use in the manufacture of a treatment caused by an alteration in HSP90 activity and/or associated with a change in HSP90 activity
- a disease in particular a cancer or a neurodegenerative disorder.
- the invention encompasses all isomers, tautomers, hydrates of the compounds of the invention , solvates, complexes, N-oxides, and pharmaceutically acceptable salts.
- the pharmaceutically acceptable salt of the compound of formula (I) comprises an acid addition salt formed with an inorganic or organic acid such as nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid, three Fluoroacetic acid, propionic acid, glycolic acid, fumaric acid, lactic acid, oxalic acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, hydroxyethylsulfonate Acid and salicylic acid.
- an inorganic or organic acid such as nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid, three Fluoroacetic acid, propionic acid, glycolic acid, fumaric acid, lactic acid, oxalic acid, malonic acid, malic acid,
- the pharmaceutically acceptable salts of the compounds of the formula (I) also comprise salts with inorganic or alkaline bases, such as alkali metal or alkaline earth metals, in particular sodium, potassium, calcium, ammonium or magnesium hydroxides.
- halogen we mean fluorine, chlorine, bromine or iodine.
- alkyl we mean any saturated hydrocarbon or saturated hydrocarbon substituted with 1-3 heteroatoms, wherein the hydrocarbon may be straight or branched.
- Alkyl includes alkane and heteroalkyl.
- C 1-6 alkyl means an alkane having 1 to 6 carbon atoms or an alkane having 1 to 6 carbon atoms in which 1 to 3 carbon atoms are substituted by a hetero atom.
- C 1-10 alkyl means an alkane having 1 to 10 carbon atoms or an alkane having 1 to 10 carbon atoms in which 1 to 3 carbon atoms are substituted by a hetero atom.
- alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, positive a group such as a hexyl group.
- C 2-7 alkenyl we mean an aliphatic C 2-7 hydrocarbon chain containing at least one double bond and which may be straight or branched, which may be substituted by one or two heteroatoms.
- Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1- or 2-butenyl, and the like.
- C 2-7 alkynyl we mean an aliphatic C 2-7 hydrocarbon chain containing at least one carbon-carbon triple bond and which may be straight or branched. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1- or 2-butynyl, and the like.
- cycloalkyl we mean, unless otherwise stated, a saturated cyclic hydrocarbon or a saturated cyclic hydrocarbon substituted with one or more heteroatoms.
- Cycloalkyl includes cycloalkane and heterocycloalkyl.
- Non-limiting examples of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclohexane, tetrahydrofuran, tetrahydrothiophene and the like.
- C 3-10 cycloalkyl we mean a saturated cyclic carbon containing from 3 to 10 carbon atoms saturated cyclic hydrocarbon or 3 to 10 carbon atoms substituted by one or more hetero atoms.
- Hydrogen compound Non-limiting examples of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclohexane, tetrahydrofuran, tetrahydrothiophene, pyran, pyrrolidine, imidazolidine, pyrazolidine, thiazolidine, 1,3- Dioxolane, piperidine, piperazine and morpholine, and the like.
- cycloalkenyl unless otherwise stated, we mean a cyclic hydrocarbon containing a double bond or a cyclic hydrocarbon containing a double bond substituted by one or more heteroatoms, but containing a total of Except for the ⁇ -electron system of the yoke.
- Cycloalkenyl includes cycloalkenyl and heterocycloalkenyl.
- Non-limiting examples of cycloalkenyl are cyclopentene, cyclohexene, cyclohexadiene, pyrroline, imidazoline, pyrazoline, thiazoline, dihydrofuran, and the like.
- aryl include both aromatic and heteroaryl.
- aromatic hydrocarbon group means a mono-, di- or poly-carbocyclic hydrocarbon having from 1 to 4 ring systems, which are optionally further fused to each other or by a single bond, wherein at least one carbocyclic ring is "Aromatic", wherein the term “aromatic” means a fully conjugated ⁇ -electron bond system.
- aryl groups are phenyl, alpha- or beta-naphthyl or biphenyl groups.
- heteroaryl means an aromatic heterocyclic ring, typically a 5- to 10-membered heterocyclic ring having from 1 to 3 heteroatoms selected from N, O or S; a heteroaryl ring may optionally be further Fused or attached to aromatic and non-aromatic carbocyclic and heterocyclic rings.
- Non-limiting examples of such heteroaryl groups are, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, fluorenyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, phenyl-pyrrolyl, Furanyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl, isodecyl, benzimidazolyl, quinolyl, isoquinolinyl, 1 , 2,3-triazolyl, 1-phenyl-1,2,3-triazolyl, 2,3-dihydroindenyl, 2,3-dihydrobenzofuranyl, 2,3-di Hydrobenzothiathiol; benzopyranyl, 2,3-dihydrobenzoxazinyl, 2,3-dihydroquinox
- any of the above R1 to R5 groups may be optionally substituted by one or more groups, for example, 1 to 6 groups, at any vacant position thereof, unless otherwise specified.
- Selected from: halogen, nitro, oxo ( O), cyano, C1-C6 alkyl, polyfluoroalkyl, polyfluoroalkoxy, C2-C6 alkenyl, C2-C6 alkyne , hydroxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, C3-C7 cycloalkyl, hydroxy, alkoxy, aryloxy, Heterocyclicoxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, heterocyclylcarbonyloxy, alkyleneaminooxy, carboxy, alkoxycarbonyl, aromatic Alkoxycarbonyl, cycloal
- polyfluoroalkyl or polyfluoroalkoxy we mean any of the above straight or branched C1-C8 alkyl or alkoxy groups which are substituted by more than one fluorine atom, for example, trifluoromethyl , trifluoroethyl, 1,1,1,3,3,3-hexafluoropropyl, trifluoromethoxy, and the like.
- hydroxyalkyl we mean any of the above C1-C8 alkyl groups containing a hydroxy group, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like.
- any group having the compound name will by convention mean that it consists of a moiety derived therefrom, for example, an arylamino group is an amino group further substituted with an aryl group, wherein the aryl group is as above
- the text is defined.
- any term such as an alkylthio group, an alkylamino group, a dialkylamino group, an alkoxycarbonyl group, an alkoxycarbonylamino group, a heterocyclic carbonyl group, a heterocyclic carbonylamino group, a cycloalkyloxycarbonyl group or the like is contained therein.
- Alkyl, alkoxy, aryl, C3-10 cycloalkyl and heterocyclyl moieties are as defined above.
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
- the present invention employs the following abbreviations: PG for a protecting group; DMF for N,N-dimethylformamide; PE for petroleum ether; EA for ethyl acetate; NCS for 1-chloropyrrolidine-2,5-di Ketone; NBS for 1-bromopyrrolidine-2,5-dione; NIS for 1-iodopyrrolidine-2,5-dione; eq for equivalent, equivalent; DCM for methylene chloride; DMSO for dimethyl Sulfone; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for t-butylcarbonyl is an amine protecting group; HOAc for acetic acid; NaCNBH 3 for sodium cyanoborohydride THF stands for tetrahydrofuran; Boc 2 O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; TFAA stands for
- High performance liquid chromatography was performed using a Shimadzu LC20AB system equipped with a Shimadzu SIL-20A autosampler and a Shimadzu DAD: SPD-M20A detector using Xtimate C18 (3 m packing, size 2.1 x 300 mm) column.
- 0-60AB_6 minutes Method: Apply a linear gradient, start elution with 100% A (A 0.0675% TFA in water), and end the elution with 60% B (B is 0.0625% TFA in MeCN) for a total of 4.2 minutes, then Elute at 60% B for 1 minute.
- the column was equilibrated for 0.8 minutes to reach 100:0 with a total run time of 6 minutes.
- 10-80AB_6 min method Apply a linear gradient, start elution with 90% A (A is 0.0675% TFA in water), and end the elution with 80% B (B in 0.0625% TFA in acetonitrile). 4.2 minutes, then eluted with 80% B for 1 minute.
- the column was equilibrated for 0.8 minutes to 90:10 with a total run time of 6 minutes.
- the column temperature was 50 ° C and the flow rate was 0.8 mL/min.
- the diode array detector has a scanning wavelength of 200-400 nm.
- TLC Thin layer chromatography
- a common solvent for flash column chromatography or thin layer chromatography is a mixture of dichloromethane/methanol, ethyl acetate/methanol and hexane/ethyl acetate.
- AS-H_3_40_2.35ML Chromatographic conditions Chiralpak AS-H column (specification 250x4.6mm ID, 5m packing); mobile phase 40% methanol (0.05% DEA)-CO 2 ; flow rate 2.35mL/min, detection wavelength It is 220 nm.
- OD-H_3_40_2.35M Chromatographic conditions Chiralcel OD-H column (specification 250x4.6mm ID, 5m packing), mobile phase 40% methanol (0.05% DEA)-CO 2 , flow rate 2.35mL / min, detection wavelength It is 220 nm.
- AD-H_2_50_2.35ML Chromatographic conditions Chiralpak AD-H column (specification 250x4.6mm ID, 5mm packing), mobile phase 50% methanol (0.1% MEA)-CO 2 , flow rate 2.35mL / min, detection wavelength It is 220 nm.
- Preparative SFC analysis was performed on a Waters Thar 80 Pre-SFC system using a Gilson UV detector using Chiralcel OD-H (250x4.6mm ID, 5m packing) or Chiralpak AD-H (250x4) .6mm ID, 5m filler).
- the compound is eluted with a low gradient of ethanol-carbon dioxide or methanol-carbon dioxide, with methanol or ethanol containing 0.05% NH 3 ⁇ H 2 O, 0.05% DEA or 0.1% MEA, total run The time is 20-30 minutes.
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
- the compound of the formula (I) in the present invention can be produced by the reaction scheme 1 and standard methods well known to those skilled in the art. Taking the resorcinol starting material (1-1) with a protecting group as an example, a (3+2) ring-forming reaction with a hydroxylamine-based substrate and elimination of one molecule of water to form a five-membered aromatic heterocyclic ring system (1-2) And then electrophilic halogenation on a five-membered aromatic heterocycle.
- the formed halogenate can be directly reacted with a heterocyclic aromatic boronic ester by a Suzuki reaction under palladium catalysis or a boronic acid ester is formed first, followed by a Suzuki reaction with a heterocyclic aromatic halogenated product. Both routes can introduce various aromatic and cyclic groups on the five-membered aromatic heterocyclic ring to give (1-5).
- the protecting group is removed to form a resorcinol compound (1-6), that is, an HSP90 inhibitor of the present
- the compounds of formula (I) provided herein can be prepared by Reaction Scheme 1 and standard procedures well known to those skilled in the art. Starting from a commercially available valerolactam (1-1) derivative, it can also be started from other similar derivatives having different functional groups, and R 0 is selected from H, halogen, alkyl, heteroatom-substituted alkyl, carboxylic acid, carboxylic acid.
- An acid alkyl ester, PG is a protecting group selected from the group consisting of methyl (Me), benzyl (Bn), 4-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMB), Methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), 2-tetrahydrofuranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), triisopropyl Silicon based (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl, benzoyl, pivaloyl; X' is halogen; X" is halogen Or trifluoromethanesulfonic acid and the like.
- the series of novel resorcinol compounds represented by the formula (I) of the present invention are inhibitors of the HSP90 protein and are useful for treating cancer and neurodegenerative disorders.
- the compounds of the invention have improved activity and enhanced efficacy compared to the prior art. Therefore, the compound of the formula (I) can be a therapeutic drug for cancer and neurodegenerative diseases.
- Step B To a solution of 1-(2,4-dihydroxy-5-isopropyl-phenyl)ethanone (6.00 g, 30.89 mmol, 1.00 equiv) and MeI (52.6 g, 370.7) under nitrogen at 20 °C. To a mixture of 1 mmol, 12.0 eq. of DMF (80 mL) was added EtOAc (25.2 g, 77.2 ⁇ RTIgt; The mixture was stirred at 20 ° C for 16 hours and then poured into water (80 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with EtOAc EtOAc m. The residue was purified by silica gel chromatography (EtOAc / EtOAc EtOAc EtOAc Molar, 49.5% yield) was a yellow solid.
- Step C To a solution of 1-(5-isopropyl-2,4-dimethoxy-phenyl)-ethanone (3.40 g, 15.30 mmol, 1.00 eq.) in THF under nitrogen at 20 °C. (50 ml) was added NaH (1.22 g, 30.6 mmol, 2.0 eq.) and dimethyl oxalate (5.42 g, 45.9 mmol, 3.0 eq.). The reaction mixture was further stirred at 60 ° C for 1 hour, then poured into aqueous ammonium chloride (1000 mL) and then evaporated. The combined organic phases were washed with EtOAcq EtOAc (EtOAc) Phenyl)-4-oxo-butyric acid methyl ester (4.80 g, crude) was obtained as a yellow solid.
- EtOAcq EtOAc EtOAc
- Step D Methyl 2-hydroxy-4-(5-isopropyl-2,4-dimethoxy-phenyl)-4-oxo-butanoate (4.80 g, 15.57) under nitrogen atmosphere. mmol, 1.00 equiv) in MeOH (60 mL) was added NH 2 OH ⁇ HCl (2.16 g, 31.14 mmol, 2.00 equiv). The mixture was heated to 60 degrees Celsius and stirred for 1 hour. The mixture was cooled to room temperature and poured into water (50 mL). The aqueous phase was extracted with EA (50 mL x 2). The combined organic layers were washed with EtOAc EtOAc m. The residue was purified by silica gel chromatography (EtOAc/EtOAc/EtOAc/EtOAc Ethyl acetate (4.80 g, 15.0 mmol purified, 96.5% yield).
- Step E To a solution of ethyl 5-(5-isopropyl-2,4-dimethoxyphenyl)isoxazole-3-carboxylate (4.80 g, 15.7 mmol, 1.00 eq.) in MeOH Ethylamine (3.54 g, 78.6 mmol, 5.0 eq.) was added to a solution (50 mL). The reaction mixture was stirred at 60 ° C for 2 hours. The reaction mixture was concentrated and the crude was purified eluting EtOAc EtOAc EtOAc EtOAc Oxazole-3-carboxamide (3.70 g, 11.6 mmol, 73.9% yield) as a yellow solid.
- Step F N 2 protection at room temperature, a solution of N- ethyl-5- (5-isopropyl-2,4-dimethoxyphenyl) isoxazole-3-carboxamide (3.50 g, 11 mmol) To a solution of MoCN (1.0 eq.) in MeCN (50 mL), EtOAc (EtOAc, EtOAc. The mixture was heated to 80 degrees Celsius and stirred for 16 hours. The mixture was cooled to room temperature and poured into water (30 mL). The combined organic layers were washed with EtOAc EtOAc m.
- Step G MeI (197.2 g, 1.4 mol) was added in one portion to a solution of 6-bromoisoquinoline (17.00 g, 81.7 mmol) in MeOH (170 mL). The mixture was stirred at 0 ° C for 20 minutes, then warmed to 25 ° C and stirred for 16 hours. The mixture was concentrated under reduced pressure to give 6-bromo-2-methylisoquinoline-2-indole iodide (28.8 g, crude).
- Step I 6-Bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline (16.65 g, 73.64 mmol) of dioxane (150 ml) under nitrogen at 25 ° C.
- a solution of bisphenol steryl borate (28.05 g, 110.46 mmol) and KOAc (14.45 g, 147.27 mmol) was added to the solution followed by the addition of the catalyst Pd(dppf)Cl 2 .CH 2 Cl 2 (6.01 g, 7.36 m). Moore).
- the mixture was stirred at 25 ° C for 10 minutes, then heated to 90 ° C and stirred for 14 hours.
- the mixture was cooled to 25 ° C and concentrated under reduced pressure.
- the residue was purified by chromatography EtOAcjjjjjjj MS (ESI) M/Z: 274 (MH).
- Step J to 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 under nitrogen at 25 ° C, 2,3,4-tetrahydroisoquinoline (6.15 g, 13.5 mmol) and N-ethyl-4-iodo-5-(5-isopropyl-2,4-dimethoxyphenyl)
- K 2 CO 3 (2.49 g, 18.0 mmol
- H 2 O (10.0 mL)
- Pd (PPh 3 ) 4 (1.26 g, 1.80 mmol).
- Step K N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(2-methyl-1,2, under N-protection at -78 ° C.
- 3,4-Tetrahydro-6-yl)isoxazole-3-carboxamide (1.70 g, 3.67 mmol) in DCM (16.00 mL) was slowly added BBr 3 (9.19 g, 36.67 mmol) for 2 hour.
- the reaction mixture was warmed to 0 ° C over 1 hour and then the reaction mixture was stirred at 25 ° C for additional 16 hours.
- Step A To a mixture of 7-bromoquinoline (100.00 mg, 480.65 ⁇ mol) and paraformaldehyde (433 mg, 4.8 mmol) in AcOH (3 mL) at 25 ° C, NaBH 3 CN ( 151 mg, 2.4 mmol). After the mixture was stirred at 25 ° C for 40 minutes, it was neutralized with NaOH. The whole was stirred with EtOAc EtOAc m. The crude product, 7-bromo-1-methyl-1,2,3,4-tetrahydroquinoline (155 mg) was obtained as a brown oil, which was used for the next step without further purification. MS (ESI) M/Z: 226 (MH).
- Step B a solution of 7-bromo-1-methyl-1,2,3,4-tetrahydroquinoline (250 mg, 1.11 mmol) in dioxane (7 ml) under nitrogen at 25 ° C.
- a mixture of bisphenol steryl borate (318 mg, 1.25 mmol) and KOAc (144 mg, 1.47 mmol) was added followed by the catalyst Pd(dppf)Cl 2 .CH 2 Cl 2 (272 mg, 333 ⁇ mol) ).
- the mixture was stirred at 25 ° C for 10 minutes and then heated to 90 ° C for 17 hours.
- the mixture was cooled to 25 ° C and concentrated under reduced pressure.
- Step C Dissolved in a solution of 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) under nitrogen at 25 ° C 1,2,3,4-tetrahydroquinoline (221 mg, 810.3 ⁇ mol) and N-ethyl-4-iodo-5-(5-isopropyl-2,4-dimethoxyphenyl) Addition of K 2 CO 3 (224 mg, 1.6 mmol) to a mixed solution of isoxazole-3-carboxamide (360 mg, 810 ⁇ mol) in dioxane (9.9 ml) and H 2 O (2.1 ml) Pd(dppf)Cl 2 .CH 2 Cl 2 (66 mg, 81 ⁇ mol).
- Step D N-Ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(1-methyl-1,2,3, at -78 ° C.
- 4-tetrahydro-quinolin-7-yl) isoxazole-3-carboxamide (83 mg, 184.6 [mu] mol) in DCM (5 mL) was added BBr 3 (462 mg, 1.85 mmol) over 15 min . During this time, the temperature was maintained at -78 degrees Celsius. After the addition was completed, the reaction mixture was warmed to 0 ° C and stirred for 30 minutes. The reaction mixture was then stirred at 25 ° C for an additional 16 hours.
- Step A To a mixture of 1,2,3,4-tetrahydroquinoline (2.0 g, 15.0 mmol) and paraformaldehyde (6.77 g, 75.1 mmol) in MeOH (20 mL) at 25 ° C AcOH (210 mg, 3.5 mmol) was added in one portion. The mixture was stirred at 25 ° C for 1 hour, then NaBH 3 CN (1.89 g, 30.0 mmol) was added and stirring was continued for 16 hours. The mixture was concentrated under reduced pressure. The residue was poured into water (15 ml) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with EtOAcq EtOAc (EtOAc m. ), a yellow oil. MS (ESI) M / Z: 148 (M + 1).
- Step B A solution of 1-methyl-1,2,3,4-tetrahydroquinoline (300 mg, 2.04 mmol) in DMF (5 mL) was cooled to 0 ° C then NBS (363.1 mg, 2.0 Moore). The reaction was stirred at 0 ° C for 2 hours, then warmed to 25 ° C and stirred for 16 hours. The reaction was then poured into 5 mL of water and the suspension was extracted with ethyl acetate (5 mL ⁇ 3). The combined organic phases were washed with EtOAcq EtOAc (EtOAc m. 485 mg) as a brown solid which was used in the next step without further purification. MS (ESI) M/Z: 226 (MH).
- Step C 6-bromo-1-methyl-1,2,3,4-tetrahydroquinoline (250 mg, 1.1 mmol) was dissolved in a nitrogen-protected solution at 25 ° C. Add Pd(dppf)Cl 2 .CH 2 Cl 2 (271 mg, 331.7 ⁇ mol) to the ester (318 mg, 1.2 mmol) and KOAc (325 mg, 3.3 mmol) in dioxane (7 mL). . The mixture was stirred at 25 ° C for 10 minutes, then heated to 90 ° C and stirred for 17 hours. The mixture was cooled to 25 ° C and concentrated under reduced pressure.
- Step D Dissolved in a solution of 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) under nitrogen at 25 ° C 1,2,3,4-tetrahydroquinoline (92 mg, 337.6 ⁇ mol) and N-ethyl-4-iodo-5-(5-isopropyl-2,4-dimethoxyphenyl) Addition of Pd(PPh 3 ) 2 Cl 2 (15.8 mg, 22.5) to a mixed solution of isoxazole-3-carboxamide (100 mg, 225.1 ⁇ mol) in dioxane (6.6 ml) and H 2 O (1.4 ml) Umol) and NaHCO 3 (37.8 mg, 450.2 umol).
- Step E N-Ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(1-methyl-1,2,3, at -78 ° C.
- 4-tetrahydro-quinolin-6-yl) isoxazole-3-carboxamide 50 mg, 107.9 mol, 1.00 equiv
- DCM 5 mL
- BBr 3 270 mg, 1.08 mmol, 10.00 Equivalent
- Step A Add DMAP (1.00 g, 8.2 m) to a solution of acetonitrile (200 ml) in which 4.00 g, 59 mmol, 1.00 eq. of pyrrole and (Boc) 2 O (15.60 g, 71.5 mmol, 1.20 eq.) were dissolved. Molar, 0.14 equivalents). The mixture was stirred at 25 ° C for 2 hours. The mixture was concentrated and the residue was purified EtOAcjjjjjjjjjj
- Step B Heating a mixture of tert-butyl pyrrole-1-carboxylate (4.60 g, 27.5 mmol, 1.00 equiv) and magnesium powder (720 mg, 27.5 mmol, 1.0 eq.) in THF (20 mL) in an oil bath to 66 ° C .
- 1-Bromo-2-fluoro-benzene (4.88 g, 27.89 mmol, 1.0 eq.) was slowly added over 20 minutes. After the addition was completed, the mixture was stirred at 66 ° C for 8 hours. The solvent was removed under reduced pressure and aq.
- Step C Add 1,4-dihydro-1,4-bromoimine naphthalene-9-carboxylic acid tert-butyl ester (2.43 g, 10 mmol, 1.00 eq.) and dry Pd/C under H 2 atmosphere. A solution of 200 mg of MeOH (50 ml) was stirred and stirred at 25 ° C for 2 hr.
- Step D 2.33 g of 1,2,3,4-tetrahydro-1,4-bromoimine naphthalene-9-carboxylic acid tert-butyl ester, 9.5 mmol, 1.0 eq.) was added to DCM (1.2 mL) at 0 °C. And a mixed solution of TFA (4.5 ml). The mixture was stirred at 0 ° C for 0.5 hours and then at 25 ° C for an additional 4.5 hours. After removing the solvent under reduced pressure, a 2N aqueous NaOH solution was added and the aqueous phase was extracted with DCM. The organic layer was dried with anhydrous sodium sulfate and evaporated tolulululululululululululululululululululululululu
- Step E 1,2,3,4-tetrahydro-1,4-bridgedimine naphthalene (1.38 g, 9.5 mmol, 1.00 equiv) and DIEA (1.37 g, 10.6 mmol, 1.12 eq.) anhydrous
- the DCM (20.00 mL) mixture was cooled to 0.degree. C. and TFAA (2.27 g, 10.8 mmol, 1.14 eq.). After the reaction mixture was slowly warmed to 25 ° C under a nitrogen atmosphere and stirred for 5 hours, the obtained reaction mixture was cooled to 0 ° C, and water (2 ml) was added to quench the remaining acid anhydride.
- Step F 2,2,2-Trifluoro-1-(1,2,3,4-tetrahydro-1,4-bridgedimin-9-yl)ethanone (2.24 g, 9.29 mmol, 1.00 equivalents of TFA solution (5.00 ml) was cooled to 0 ° C and fuming nitric acid (1 mL) was added dropwise. The resulting reaction mixture was stirred at 0 ° C for 1 hour and then at 25 ° C for an additional 1 hour. The mixture was poured into 300 ml of ice water and extracted three times with DCM. The combined organic phase was washed sequentially with saturated NaHCO 3 and saturated aqueous NaCl. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (EtOAc) Imidazolium-9-yl)ethanone (1.86 g, 6.50 mmol, 67.0% yield) as a yellow solid.
- EtOAc silica gel column
- Step G Dissolving 2,2,2-trifluoro-1-(6-nitro-1,2,3,4-tetrahydro-1,4-bridgedimine-naphthalen-9-yl)ethanone ( 3.5 g, 12.23 mmol, 1.00 equiv) of dioxane (20.00 ml) / ethanol (16.00 ml) / H 2 O (12.00 ml) in a mixture of NH 4 Cl (2.63 g, 49.2 mmol, 4.02) Equivalent) and iron powder (3.43 g, 61.4 mmol, 5.02 equivalents). The resulting mixture was heated to 80 ° C under a nitrogen atmosphere and stirred for 3 hours.
- Step H 2,2,2-trifluoro-1-(6-amino-1,2,3,4-tetrahydro-1,4-bridgedimin-9-yl)ethanone (2.7) ⁇ , 10.5 mmol, 1.0 eq.), bis-pinacol borate (2.68 g, 10.5 mmol, 1.0 eq.), BPO (76 mg, 316 ⁇ mol, 0.03 eq.) and tert-butyl nitrite (1.63)
- a solution of gram, 15.8 mmol, 1.5 eq. of MeCN (15.0 mL) was stirred at 25 ° C for 16 h.
- Step I N-ethyl-4-iodo-5-(5-isopropyl-2,4-dimethoxy-phenyl)-isoxazole-3-carboxamide (500 mg, 1.13) will be added. Millimol, 1.00 equivalents), 2,2,2-trifluoro-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2,3,4-tetrahydro-1,4-bridgedimine-naphthalen-9-yl)ethanone (539 mg, 1.47 mmol, 1.3 eq.), Pd(PPh 3 ) 2 Cl 2 (158 mg A solution of NaHCO 3 (283 mg, 3.38 mmol, 3.0 eq.) in THF (5.00 mL) was taken in vacuo, and then heated to 120 ° C for 30 min.
- reaction mixture was poured into water (15 mL).
- the mixture was extracted with ethyl acetate (10 mL ⁇ 2).
- the combined organic phases were washed with saturated brine (15mL), dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo to give a residue.
- Step J N-ethyl 5-(5-isopropyl-2,4-dimethoxy-phenyl)-4-(9-(2,2,2-trifluoroacetyl) at 30 °C -1,2,3,4-tetrahydro-1,4-ylidene naphthalene-6-yl)isoxazole-3-carboxamide (500 mg, 762.3 ⁇ mol, 1.0 eq.) in MeOH (4.2 K 2 CO 3 (526 mg, 3.8 mmol, 5.0 equivalent) was added to a mixed solution of hexane) and H 2 O (1.8 ml).
- Step K to N-ethyl-5-(5-isopropyl-2,4-dimethoxy-phenyl)-4-(1,2,3,4-tetrahydro) at -78 °C 1,4-imine bridge-6-yl) isoxazole-3-carboxamide (50 mg, 108.3 [mu] mol, 1.0 eq.) in anhydrous DCM (2.0mL) was slowly added dropwise BBr 3 (271 Mg, 1.08 mmol, 10.00 eq.). After the addition was completed, the solution was warmed to 30 ° C and stirred for 18 hours.
- Step A To N-ethyl-5-(5-isopropyl-2,4-dimethoxy-phenyl)-4-(1,2,3,4-tetrahydro-1,4-bridge Addition of paraformaldehyde (39 mg, 433.3) to a solution of iminonaphthalen-6-yl)isoxazole-3-carboxamide (20 mg, 43.3 ⁇ mol, 1.0 eq.) in 1,2-dichloroethane (3 mL) Micromolar, 10.00 equivalents), acetic acid (1.3 mg, 21.7 micromoles, 0.50 equivalents), tetraisopropyltitanium oxide (6.2 mg, 21.7 micromoles, 0.50 equivalents).
- Step B to N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(9-methyl-1,2,3, at -78 °C 4-tetrahydro-1,4-bridgedimine-naphthalen-6-yl)isoxazole-3-carboxamide (30 mg, 63.1 ⁇ mol, 1.0 eq.) in anhydrous DCM (2 mL) was slowly dropped into BBr 3 (158 mg, 630.8 micromoles, 10 equivalents). After the addition was completed, the solution was warmed to 30 ° C and stirred for 18 hours.
- Step A The title compound of this example was prepared according to the procedure of Steps A and B of Example 5, wherein the paraformaldehyde was replaced with acetaldehyde in step A.
- Step A The title compound of this example was prepared according to the procedure of Steps A and B of Example 5, in which the paraformaldehyde was replaced with acetone in the step A.
- Step A The title compound of this example was prepared according to the procedure of Steps A and B of Example 5, in which the paraformaldehyde was replaced with isobutyraldehyde in step A.
- Step A To a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (10.0 g, 71.8 mmol, 1.0 eq.) in DCM (120.0 mL) Molecular sieves (10.00 g), tetraisopropyltitanium oxide (1.02 g, 3.59 mmol, 0.05 equivalent) and AcOH (215.67 mg, 3.59 mmol, 0.05 eq.). The mixture was stirred at 25 ° C for 16 hours, then NaBH 3 CN (9.03 g, 143.66 mmol, 2.00 eq.) was added and stirring was continued at 25 ° C for 3 hours.
- Step B AcOH was dissolved in 5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (2.00 g, 13.05 mmol, 1.0 eq.) at 0 °C.
- Step C N-ethyl-4-iodo-5-(5-isopropyl-2,4-dimethoxy-phenyl)isoxazole-3-carboxamide (900) was dissolved under nitrogen.
- Pd(PPh 3 ) 2 Cl 2 142.5 mg, 203.0 ⁇ mol, 0.10 eq.
- TEA 616 mg, 6.1 mmol, EtOAc, EtOAc (EtOAc) 3.0 eq.
- 4,4,5,5-tetramethyl-1,3,2-dioxaborane (779 mg, 6.1 mmol, 3.0 eq.).
- the mixture was stirred at 80 ° C for 16 hours.
- Step D N-ethyl-5-(5-isopropyl-2,4-dimethoxy-phenyl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)isoxazole-3-carboxamide (500 mg, 1.13 mmol, 1.00 equiv) and 2-bromo-5-methyl-4,5 , 6,7-tetrahydrothieno[3,2-c]pyridine (268 mg, 1.13 mmol, 1.00 equivalent) in a mixed solution of dioxane (10.00 ml) and water (2.00 ml), Pd (dppf) Cl 2 .CH 2 Cl 2 (91.9 mg, 112.5 ⁇ mol, 0.10 eq.) and K 2 CO 3 (466 mg, 3.4 mmol, 3.00 eq.).
- Step E N-ethyl-5-(5-isopropyl-2,4-dimethoxy-phenyl)-4-(5-methyl-4,5) was dissolved at -78 °C. ,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)isoxazole-3-carboxamide (560 mg, 1.19 mmol, 1.00 eq.) in DCM (15 mL) BBr 3 (1.49 g, 5.96 mmol, 5.0 eq.) was added. The mixture was stirred at 25 <0>C for 16 h, MeOH (20 mL) was evaporated. The residue was purified by preparative HPLC (carboxylic acid system).
- Step A To a solution of tert-butyl 4-oxopiperidine-l-carboxylate (10.0 g, 50.2 mmol, 1.0 eq.) in DMF (100.00 mL), EtOAc (10.2 g, 100.4 mmol, 2.0 eq. ). TMSCl (6.27 g, 57.7 mmol, 1.15 eq.) was then added dropwise to the solution at 20 ° C and ventilated to a nitrogen atmosphere. After the mixture was stirred at 80 ° C for 16 hours, 300 ml of a saturated aqueous NaHCO 3 solution was added. The mixture was extracted with EtOAc (EtOAc m.
- Step B To a solution of 4-trimethylsilyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (13.9 g, 51.2 mmol, 1.0 eq. NaOAc (420 mg, 5.1 mmol, 0.1 eq.) and NBS (13.67 g, 76.8 mmol, 1.5 eq.) were added to a mixture of 150 ml) and water (150 ml). The mixture was stirred at 20 ° C for 12 hours. With 100mL saturated aqueous sodium thiosulfate solution to quench the reaction, and then washed with saturated aqueous NaHCO 3 and 200mL.
- Step C To a solution of 3-bromo-4-oxopiperidine-l-carboxylic acid tert-butyl ester (7.0 g, 25.2 mmol, 1.0 eq. 3.0 equivalents) and thiourea (2.11 g, 27.7 mmol, 1.1 equivalents). The mixture was stirred at 110 ° C for 12 hours, poured into 300 ml of water, and the solid was filtered. The solid was washed with 100 mL of water to give 4.5 g of crude red 2-amino-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester. The crude product was used directly in the next step. MS (ESI) m / z: 256.0 (M + 1).
- Step D 2-Amino-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (4.70 g, 18.4 mmol, 1.0 eq. ) in CH 3 CN (50 ml) was added CuBr 2 (4.52 g, 20.3 mmol, 1.1 eq) and tert-butyl nitrite (2.09 g, 20.3 mmol, 1.1 eq.).
- Step F To a solution of 2-bromo-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine (550.00 mg, 2.15 mmol, 1.00 eq.) in MeOH (10.00 mL) 194 mg, 6.46 mmol, 3.00 eq.) and AcOH (258 mg, 4.3 mmol, 2.0 eq.). The mixture was stirred at 20 ° C for 1 hour, then NaBH 3 CN (406 mg, 6.5 mmol, 3.0 eq.) was added and the mixture was stirred at 20 ° C for 4 hr. The reaction was 0.5 mol / L HCl solution (2mL) and quenched, then add saturated NaHCO 3 (20mL) for neutralization.
- Step G 5-(2,4-Dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-iodo-isoxazole-3-carboxamide (1.00) under nitrogen.
- TEA 510 mg, 5.04 mmol, 3.0 eq.
- Pd(PPh 3 ) 2 Cl 2 117.9 mg, 168.00 micromoles, 0.1 equivalents.
- Step H to 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)isoxazole-3-carboxamide (800 mg, 1.34 mmol, 1.0 eq.) in 1,4-dioxane (20 mL) and water (4 To a mixed solution of 2-bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine (313 mg, 1.34 mmol, 1.0 eq.) and K 2 CO 3 (371 mg, 2.7 mmol, 2.0 eq.).
- Step I to 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-N-diethyl-4-(5-methyl-4,5,6 at 0 °C
- BCl 3 to a solution of 7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)isoxazole-3-carboxamide (60 mg, 96.3 ⁇ mol, 1.0 eq.) in DCM (2 mL) (34 mg, 289 micromoles, 3.0 equivalents). After the mixture was stirred at 0 °C 1 hour, quenched with 2mL of MeOH, and the mixture was poured into 5 mL of saturated aqueous NaHCO 3.
- the mixture is then extracted with DCM (5 mL X3), and the combined organic phases were dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo to give the crude product.
- the crude product was purified by preparative HPLC (formic acid, <"&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
- Step A To N-ethyl-5-(5-isopropyl-2,4-dimethoxy-phenyl)-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)isoxazole-3-carboxamide (700 mg, 1.58 mmol, 1.0 eq.) and 6-benzyl-2-chloro-5,6,7,8-tetra Add Pd(dppf)Cl 2 (115 mg) to a mixed solution of hydrogen-1,6-diaza naphthalene (409 mg, 1.58 mmol, 1.0 equivalent) in dioxane (3 ml) and water (500 ⁇ l) , 157.5 micromoles, 0.1 equivalents) and K 2 CO 3 (435 mg, 3.2 mmol, 2.0 equivalents).
- Step B To 4-(6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-N-ethyl-5-(5- at room temperature Add 1-chloroethyl to a solution of isopropyl-2,4-dimethoxy-phenyl)-isoxazole-3-carboxamide (250 mg, 462.4 ⁇ mol, 1.00 eq.) in toluene (8 mL) Carbonyl chloride (264 mg, 1.85 mmol, 4.0 eq.) was then stirred at 110 ° C for 8 h.
- Step C To N-ethyl-5-(5-isopropyl-2,4-dimethoxy-phenyl)-4-(5,6,7,8-tetrahydro-1,6-di Addition of paraformaldehyde (200 mg, 2.2 mmol, 5.0 eq.) to a solution of azaphthalene-2-yl)isoxazole-3-carboxamide (200 mg, 443.9 ⁇ mol, 1.0 eq.) in DCM (8 mL) , tetraisopropoxytitanium (126 mg, 443.9 micromoles, 1.0 equivalents), acetic acid (27 mg, 444 micromoles, 1.0 equivalents) and Molecular sieves (300 mg, 444 micromoles, 1.0 equivalents).
- Step D N-ethyl-5-(5-isopropyl-2,4-dimethoxy-phenyl)-4-(6-methyl-5,6,7, at 0 °C BBr 3 was slowly added to a solution of 8-tetrahydro-1,6-naphthyridin-2-yl)isoxazole-3-carboxamide (60 mg, 129.2 ⁇ mol, 1.0 eq.) in DCM (8 mL) 323.6 mg, 1.3 mmol, 10.0 eq.). The mixture was stirred at 25 <0>C for 16 h, MeOH (15 mL) was slowly added and then the mixture was concentrated.
- Step A at 0 deg.] C, the POCl 3 (6.25 g, 40.8 mmol, 1.5 eq.) was added to a DMF (60 mL), and stirred at 0 °C 10 minutes. Then, 2,4-dibenzyloxy-1-isopropylbenzene (9.0 g, 27.1 mmol, 1.0 eq.) was added at 0 ° C, and stirring was continued at 0 ° C for 10 min. The temperature was raised to 15-25 ° C, stirred for 10 minutes, and then stirred at 100 ° C for 2.5 hours.
- Step B Add NH to a solution of 2,4-dibenzyl-5-isopropyl-benzaldehyde (9.5 g, 26.4 mmol, 1.0 eq.) in EtOH (100 mL) at 15-25. 2 OH ⁇ HCl (3.66 g, 52.7 mmol, 2.0 eq.), then DIEA (5.11 g, 39.5 mmol, 1.5 eq.) was added and warmed to 80 ° C and stirred for 16 hours. The reaction mixture was cooled to 15-25 ° C. The residue was dissolved in EtOAc (EtOAc) (EtOAc) The organic layer was dried, filtered and concentrated to give crude.
- EtOAc EtOAc
- Step C To a solution of (1E)-2,4-dibenzyl-5-isopropyl-benzaldehyde oxime (3.00 g, 7.99 mmol, 1.0 eq.) in DCM (3. NCS (1.28 g, 9.59 mmol, 1.2 eq.) was added, and stirred at 0 ° C - 5 ° C for 2 hours, then stirred at 15 - 25 ° C for 16 hours. The reaction mixture was concentrated to give 2,4-dibenzyloxy-N-hydroxy-5-isopropylbenzoimido chloride (4.0 g, crude). The crude product was used directly in the next step.
- Step D 2,4-Dibenzyloxy-N-hydroxy-5-isopropylbenzimidoyl chloride (1.64 g, 4.00 mmol, 1.0 when 15-25 ° C)
- ethyl propan-2-ynoate 588.60 mg, 6.00 mmol, 1.50 equiv
- TEA 445.24 mg, 4.40
- the mixture was stirred at 15 to 25 ° C for 0.5 hour and then at 80 ° C for 3 hours.
- Step F 3-(2,4-Dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-isoxazole-5-carboxamide (50 mg, 106.3 ⁇ M) at -78 °C mole, 1.0 eq.) in THF (2 mL) was added n-butyl lithium (2M, 132 [mu] l, 2.5 eq) was added after stirring at -78 °C 1 hour, followed by addition of I 2 at -78 deg.] C (40.5 mg, 159.4 micromoles, 1.5 eq.) in THF (1 mL) EtOAc. The reaction solution was warmed to 15-25 ° C and stirred for 16 hours.
- Step G 3-(2,4-Dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-iodo-isoxazole-5- under nitrogen protection at 15-25 °C
- 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxos to a solution of formamide (15 mg, 25.15 ⁇ mol, 1.00 eq.) in DMF (2.5 mL) Boronocyclic-2-yl)-1,2,3,4-tetrahydroisoquinoline (13.7 mg, 50.3 micromolar, 2.00 equiv), water (500.00 UL), sodium bicarbonate (6.34 mg, 75.5) mol, 3.0 eq.), followed by addition of Pd (PPh 3) 2 Cl 2 (3.5 mg, 5.0 mol, 0.2 eq.).
- Step H to 3-(2,4-dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(2-methyl-1,2,3, at 0 °C 4-tetrahydro-isoquinolin-6-yl) isoxazole-5-carboxamide (10 mg, 16.2 mol, 1.0 eq.) in DCM (1 mL) was added BCl 3 (1M solution, 324.8 [mu] l, 20.0 The equivalent of the DCM solution was stirred at 0 ° C for 2 hours and then heated to 15-25 ° C for 1 hour. The reaction mixture was cooled to 0.degree. C., MeOH (2 mL) was evaporated and evaporated. The mixture was concentrated to give a crude material.
- Step A To a solution of 1-isopropyl-2,4-dimethoxy-benzene (2.0 g, 11.1 mmol, 1.0 eq. 12.42 mmol, 1.12 eq.). The mixture was stirred at 0 ° C for 3 hours and then at 25 ° C for 1 hour. The mixture was concentrated and the residue was purified EtOAcjjjjjjjjjj , 96.30% yield), as a yellow solid.
- Step B To a solution of 1-bromo-5-isopropyl-2,4-dimethoxy-benzene (2.77 g, 10.69 mmol, 1.0 eq.) in dry THF (100 mL) Add n-BuLi (2.5 M, 6.00 mL, 1.40 eq.). The mixture was stirred at -78 ° C for 1 hour. A solution of triisopropyl borate (6.03 g, 32.07 mmol, 3.0 eq.) in dry THF (10 mL) was then slowly added and maintained at -78. After the addition, the reaction was stirred at 25 ° C for 4 hours.
- Step C 3-Methylisoquinolin-5-amine hydrochloride (8.00 g, 53.11 mmol, 1.00 eq.) was added to EA (100 mL) and washed with 10% aqueous sodium carbonate. The organic phase was dried and concentrated to give a crystal crystal crystal crystal crystal crystal crystals The mixture was added dropwise with nitric acid (10 ml), followed by a saturated aqueous solution of sodium nitrite (4.17 g, 60.4 mmol, 1.14 eq.), and the temperature was maintained at 0 to 5 °C.
- reaction mixture was stirred at 10 ° C for 30 minutes, then added dropwise to a solution of copper bromide (9.50 g, 66.2 mmol, 1.25 eq.) in 48% aqueous H.sub.2 (100 mL). Stir for 2 hours.
- the pH of the reaction mixture was adjusted to 6-7 with a 4N aqueous NaOH solution and water (200 mL). The aqueous layer was extracted with EtOAc (EtOAc)EtOAc.
- Step D 5-Bromo-3-methylisothiazole (8.0 g, 44.9 mmol, 1.0 eq.), NBS (16.0 g, 89.9 mmol, 2.0 eq.) and AIBN (1.40 g, 8.53 mmol, 0.19 eq.
- DCE 150 ml
- the mixture of DCE (150 ml) was heated to 90 ° C and placed under a 150 W halogen lamp and stirred for 48 hours.
- the mixture was washed with a saturated NaHSO 3 solution and extracted three times with DCM.
- the combined organic layers were washed with brine w...
- the residue was purified by column chromatography (EtOAc / EtOAc /EtOAc) .
- Step E Heating a mixture of 5-bromo-3-(bromomethyl)isothiazole (4.10 g, 15.96 mmol, 1.0 eq.) and sodium carbonate (1.92 g, 18.11 mmol, 1.14 eq.) in water (90 mL) To reflux, potassium permanganate (3.28 g, 20.76 mmol, 1.3 eq.) was then added in small portions. The reaction mixture was stirred at reflux for 1 hour, cooled and filtered. The filtrate was acidified with 1N HCl and extracted three times with EA. The combined organic layers were dried with EtOAc EtOAc EtOAc EtOAc EtOAc
- Step F To a solution of 5-bromoisothiazole-3-carboxylic acid (1.26 g, 6.06 mmol, 1.0 EtOAc) The reaction mixture was refluxed at 65 ° C for 16 hours. The mixture was cooled to room temperature and quenched with saturated aqueous NaHCO 3 and the aqueous layer was extracted with EA. The organic layer was dried with EtOAc (EtOAc m.
- Step G methyl 5-bromoisothiazole-3-carboxylate (1.00 g, 4.50 mmol), (5-isopropyl-2,4-dimethoxy-phenyl)-boric acid (1.20 g, 5.36 mmol, 1.19 equiv), Pd(dppf)Cl 2 (340.00 mg, 464.67 ⁇ mol, 0.10 eq.) and K 2 CO 3 (1.29 g, 9.33 mmol, 2.07 eq.) were added to DME (30 mL) and water (0.12) ML) in a mixed solution. The reaction solution was stirred at 100 ° C for 16 hours under a nitrogen atmosphere. The mixture was filtered through celite and the filtrate was concentrated.
- Step H Methyl 5-(5-isopropyl-2,4-dimethoxy-phenyl)-isothiazole-3-carboxylate (300 mg, 933 ⁇ mol, 1.0 eq.), NIS (24) Mg (1.07 mmol, 1.14 eq.) and CAN (55 mg, 100.3 mM, 0.11 eq.) were added to MeCN (20 mL). The mixture was stirred at 82 ° C for 16 hours. The mixture was concentrated. The residue was dissolved in DCM and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated.
- Step I 4-iodo-5-(5-isopropyl-2,4-dimethoxyphenyl)isothiazole-3-carboxylic acid methyl ester (120 mg, 268.3 ⁇ mol, 1.00 equivalents), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4 - tetrahydroisoquinoline (100 mg, 366.1 micromolar, 1.36 equivalents), Pd(PPh 3 ) 2 Cl 2 (30 mg, 57 ⁇ mol, 0.21 equivalent) and NaHCO 3 (50 mg, 595.2 ⁇ mol, 2.22 equivalents) A mixed solution of dioxane (10 mL) and H 2 O (1 mL) was added.
- Step K N-ethyl-5-(5-isopropyl-2,4-dimethoxy-phenyl)-4-(2-methyl-1,2,3 at -78 °C , 4-tetrahydro-isoquinolin-6-yl) isothiazole-3-carboxamide (80 mg, 166.8 [mu] mol, 1.0 eq.) in DCM (1mL) was added a solution of BBr 3 (1 mL, 10.4 mmol, 62 equivalent). The mixture was stirred at 25 ° C for 2 hours. To the mixture were added 0.1 ml of water and 1 g of NaHCO 3 solid, and the mixture was stirred at 25 ° C for 10 minutes.
- Step A tert-Butyl 5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate (226 mg, 1.0 mM at -78 °C) To a solution of EtOAc (2 mL, EtOAc) The resulting mixture was stirred at -78.degree. C. for 1 hr then a solution of N,N-bis(trifluoromethanesulfonyl)phenylamine (467 mg, 1.2 mmol, 1.2 eq. The mixture was then warmed to room temperature and stirred for 16 hours.
- Step B 5-(Trifluoromethylsulfonyloxy)-3,3a,6,6-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid under a nitrogen atmosphere Butyl ester (350 mg, 979.43 micromoles, 1.0 equivalent), N-ethyl-5-(5-isopropyl-2,4-dimethoxy-phenyl)-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole-3-carboxamide (440 mg, 990.3 ⁇ mol, 1.01 equivalent), Pd(dppf)Cl 2 (140 mg, 191.3 ⁇ mol, 0.2 eq.) and K 2 CO 3 (280 mg, 2.03 mmol, 2.07 eq.) were added to a mixed solution of dioxane (20 mL) and water (2 mL).
- Step C To 5-[3-(ethylcarbamoyl)-5-(5-isopropyl-2,4-dimethoxy-phenyl)-isoxazol-4-yl]-3, Add a solution of 3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (290 mg, 551.7 ⁇ mol, 1.0 eq.) in EA (10 mL) Ester (4N, 1 mL). The mixture was stirred at 25 ° C for 2 hours.
- Step D To 4-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole-5-yl)-N-ethyl-5-(5-isopropyl-2,4 - Dimethoxy-phenyl)-isoxazole-3-carboxamide (234 mg, 549.9 ⁇ mol, 1.00 equivalent) in a mixture of DCE (12 mL) and MeOH (4 mL). The mixture was stirred at 25 ° C for 16 hours, then NaBH(OAc) 3 (500 mg, 2.36 mmol, 4.3 eq.) was added and the mixture was stirred at 25 ° C for 2 hours.
- NaBH(OAc) 3 500 mg, 2.36 mmol, 4.3 eq.
- Step E N-Ethyl-5-(5-isopropyl-2,4-dimethoxy-phenyl)-4-(2-methyl-1,2,3 at -78 °C , 3a, 4,6a- hexahydro-cyclopenta [c] pyrrol-5-yl) isoxazole-3-carboxamide (160 mg, 364.0 [mu] mol, 1.0 eq.) in DCM (1mL) was added BBr 3 ( 1 ml, 10.4 mmol, 28.5 equivalents). The mixture was stirred at 25 ° C for 2 hours, 0.1 ml of water and 1 g of NaHCO 3 were added to the mixture, and the resulting mixture was stirred at 25 ° C for 10 minutes.
- Step A 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 under nitrogen protection, 2,3,4-tetrahydroisoquinoline (3.66 g, 8.7 mmol, 1.3 eq.), 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-4-iodo-iso Oxazole-3-carboxylic acid ethyl ester (4.00 g, 6.7 mmol, 1.0 eq.), Pd(PPh 3 ) 2 Cl 2 (470 mg, 670.0 ⁇ mol, 0.1 eq.) and K 2 CO 3 (1.85 g, 13.4) Millimol, 2.0 eq.) was added to a mixed solution of dioxane (30 ml) and water (6 ml).
- Step B To 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-4-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6- To a solution of ethyl oxazol-3-carboxylate (2.90 g, 4.1 mmol, 1.0 eq.) in EtOAc (30 mL), EtOAc (1.20 g, 24.1 mmol, 5 eq.). The solution was heated to 90 ° C and stirred for 18 hours. . The solution was concentrated in vacuo then water (20 mL) was evaporated andEtOAc.
- Step C Addition of 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-4-(2-methyl-1,2,3,4-tetrahydroisoquinoline- 6-yl)isoxazole-3-
- carbhydrazide 1.50 g, 2.49 mmol, 1.00 eq.
- EtOAc EtOAc
- EtOAc EtOAc 1.50 equivalents
- the solution was heated to 80 ° C and stirred for 18 hours.
- the solution was cooled, concentrated and added with EtOAc (EtOAc).
- EtOAc EtOAc
- Step D 5-(2,4-Dibenzyloxy-5-isopropyl-phenyl)-4-(2-methyl-1,2,3,4-tetrahydroiso) at 0 °C Quinoline-6-yl)-3-(5-methyl-4H-1,2,4-triazol-3-yl)isoxazole (120 mg, 191.77 ⁇ mol, 1.0 eq.) in DCM (2.0 mL ) was added dropwise a solution of 3 BCl DCM (1M, 1.92 mL, 10.0 eq.), when 5 minutes. The suspension was stirred at 0 ° C for 30 minutes, then warmed to 25 ° C and stirred for 2 hours.
- Step A A 0 °C, solution of KOH (1.41g, 25.1mmol, 150Eq) a solution of a solution of NH 2 OH ⁇ HCl (1.16g, 16.74mmol, 100Eq) in MeOH (6mL) in MeOH (3mL) solution of . After the mixture was stirred at 0 ° C for 30 minutes, the solid was filtered off, and ethyl 5-(5-isopropyl-2,4-dimethoxyphenyl)isoxazole-3-carboxylate was added to the remaining methanol solution (100.00). Mg, 333.38 umol, 1.0 Eq), and stirred at 5 ° C for 30 minutes.
- Step B N-Hydroxy-5-(5-isopropyl-2,4-dimethoxyphenyl)isoxazole-3-carboxamide (3.40 g, 11.1 mmol, mp. PBr 3 (6.01 g, 22.2 mmol, 2.0 eq) was added in one portion to a solution of 1.0 eq. The mixture was stirred at 29 ° C for 10 minutes, then warmed to 110 ° C and stirred for 8 hours. The mixture was cooled to 29 ° C then poured into saturated aqueous NaHCO 3 (60 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (EtOAc EtOAc.
- Step C MeCN (5-(isopropyl-2,4-dimethoxyphenyl)isoxazole-3-carbonitrile (1.80 g, 6.6 mmol, 1.0 eq) at ⁇ RTIgt; NIS (1.93 g, 8.59 mmol, 1.3 eq) and CAN (362 mg, 661 umol, 0.1 eq) were added to the solution. The mixture was stirred at 28 ° C for 10 minutes, then warmed to 80 ° C and stirred for 4 hours. The mixture was cooled to 28 ° C and concentrated under reduced pressure. The residue was poured into saturated aqueous NaHCO 3 (50mL) and stirred for 5 minutes.
- Step D 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydrogen under nitrogen protection 4-Iodo-5-(5-isopropyl-2,4) was added to a solution of tert-butyl isophthalate-2-carboxylate (2.30 g, 6.40 mmol, 1.0 eq.) in dioxane (30 mL).
- Step E to 6-[3-cyano-5-(5-isopropyl-2,4-dimethoxy-phenyl)-isoxazol-4-yl]-1 at 25 ° C, Sodium methoxide (2.14 g, 39.7 mmol, 10) was added to a solution of tert-butyl 2,3,4-tetrahydroisoquinoline-2-carboxylate (2.00 g, 3.97 mmol, 1.0 eq. equivalent). The mixture was stirred at 25 ° C for 2 hours, then ammonium chloride (2.12 g, 39.71 mmol, 10 eq.) was added. The reaction mixture was stirred at 25 ° C for a further 14 hours.
- Step F to 6-[3-carbamimid-5-(5-isopropyl-2,4-dimethoxy-phenyl)-isoxazol-4-yl]-1,2,3, tetrahydroisoquinoline-2-carboxylate (1.00 g, 1.92 mmol, 1.0 eq.) in EtOH (15 mL) was added K 2 CO 3 (265 mg, 1.92 mmol, 1.0 eq) was And 1-bromo-2-butanone (290 mg, 1.92 mmol, 1.0 eq.). The mixture was stirred at 80 ° C for 10 hr then EtOAc (EtOAc)EtOAc.
- Step G 6-[3-(5-Ethyl-1H-imidazol-2-yl)-5-(5-isopropyl-2,4-dimethoxy-phenyl)isoxazole-4 a mixture of -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (600 mg, 1.05 mmol, 1.00 equiv) in HCl / MeOH (4M, 15.00 mL) at 25 ° C Stir for 30 minutes.
- Step H To 3-(5-ethyl-1H-imidazol-2-yl)-5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(1,2,3 , 4-tetrahydroisoquinolin-6-yl)isoxazole (500 mg, 1.06 mmol, 1.0 eq.) in MeOH (8 mL) EtOAc (EtOAc, EtOAc. And AcOH (63.7 mg, 1.06 mmol, 1.0 eq.). The mixture was stirred at 25 °C 2 hours, then NaBH 3 CN (133 mg, 2.12 mmol, 2.0 eq). The reaction was stirred at 25 ° C for an additional 14 hours.
- Step I 3-(5-Ethyl-1H-imidazol-2-yl)-5-(5-isopropyl-2,4-dimethoxy-phenyl)-4 at -78 °C - (2-methyl-1,2,3,4-tetrahydro-isoquinolin-6-yl) isoxazole (600 mg, 1.23 mmol, 1.0 eq.) in DCM (12 mL) was added BBr 3 ( 1.54 g, 6.15 mmol, 5.0 eq.). The mixture was stirred at 25 <0>C for 16 h and slowly quenched with MeOH (20 mL).
- Step A To 3-(5-ethyl-1H-imidazol-2-yl)-5-(5-isopropyl-2,4-dimethoxy-phenyl)-4-(1,2, Add 2-bromoethanol (137.5 mg, 1.1 mmol, 4.0) to a solution of 3,4-tetrahydroisoquinolin-6-yl)isoxazole (130 mg, 275.1 ⁇ mol, 1.0 eq.) in EtOH (6 mL) Equivalent) and K 2 CO 3 (114 mg, 825.3 micromoles, 3.0 equivalents). After the mixture was stirred at 50 ° C for 16 hours, it was poured into water (30 ml) and extracted with EA (30 ml ⁇ 2).
- Step B To 2-[6-[3-(5-ethyl-1H-imidazol-2-yl)-5-(5-isopropyl-2,4-dimethoxy-) at 0 °C a solution of phenyl)-isoxazol-4-yl]-1,2,3,4-tetrahydroisoquinolin-2-yl]ethanol (80 mg, 154.9 ⁇ mol, 1.0 eq.) in DCM (EtOAc) BBr 3 (387.9 mg, 1.55 mmol, 10.0 eq.) was added. The mixture was stirred at 25 <0>C for 16 h then quenched with MeOH (15 mL).
- Step B To a solution of 7,7-dimethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (10.05 g, crude) in tetrahydrofuran under nitrogen at 20 ° C ( Boc 2 O (2.31 g, 10.57 mmol, 1 eq.) was added dropwise to the solution. After the addition was completed, the reaction mixture was stirred at 20 ° C for 20 hours. The reaction solution was poured into 20 ml of water and stirred for 5 minutes.
- the aqueous phase was extracted three times with 10 ml of ethyl acetate each time, and the organic phase was washed three times with 10 ml of brine each time, then the organic phase was dried over anhydrous sodium sulfate and filtered. Concentrate to give a crude product.
- the crude residue was purified by silica gel chromatography eluting eluting elut elut elut elut elut elut elut Hydrothieno[2,3-c]pyridine-6(7H)-carbamate (733 mg, 2.74 mmol, 25.93% yield)
- Step C Dissolving tert-butyl 7,7-dimethyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carbamate under nitrogen protection at 20 °C A solution of (733 mg, 2.74 mmol, 1 eq. The reaction solution was allowed to react at 20 ° C for one hour. The reaction solution was poured into 20 ml of water and stirred for 5 minutes. The aqueous phase was extracted three times with 10 ml of ethyl acetate each time, and the organic phase was washed three times with 10 ml of brine each time, then the organic phase was dried over anhydrous sodium sulfate and filtered.
- Step D To a tert-butyl 2-bromo-7,7-dimethyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carbamate under nitrogen at 25 ° C Acid ester (1.02 g, 2.95 mmol, 1 eq.) and 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole-3-carboxamide (1.76 g, 2.95 mmol, 1 eq.) in dioxane (20 mL) Sodium bicarbonate (743.49 mg, 8.85 mmol, 3 equivalents) and Pd(PPh 3 ) 2 Cl 2 (414.12 mg, 590.00 micromoles, 0.20 equivalents) were added to water (4 mL).
- Acid ester (1.02 g, 2.95 mmol, 1
- reaction solution was reacted at 90 ° C for 16 hours.
- the reaction mixture was cooled to room temperature and then concentrated to dryness crystals crystals crystals crystals crystals crystals crystals crystals (2,4-Dibenzyloxy-5-isopropyl-phenyl)-3-(ethylformamide)isoxazol-4-yl]-7,7-dimethyl-4,5-di Hydrothieno[2,3-c]pyridine-6(7H)-carbamate (841.00 mg, 719.95 micromoles, 24.40% yield, 63% purity).
- Step D to tert-butyl 2-[5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-3-(ethylformamide)isoxazole at 20 ° C 4-yl]-7,7-dimethyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carbamate (840 mg, 719.09 micromoles, 1 equivalent) HCl/MeOH (4 mol/L, 8 mL, 44.50 eq.) was added dropwise in methanol (8 mL). The reaction solution was stirred at 20 ° C for 15 hours. The reaction mixture was concentrated to give a crude crystals. m.j.
- Step E To 5-(2,4-dibenzyloxy-5-isopropylphenyl)-4-(7,7-dimethyl-4,5,6,7 under nitrogen at 0 °C -tetrahydrothieno[2,3-c]pyridin-2-yl)-N-ethylisoxazole-3-carboxamide (300 mg, 471.84 micromoles, 1 equivalent) in anhydrous dichloromethane (20 Boron trichloride (1 mol/L, 4.72 ml, 10 equivalents) was slowly added dropwise to the solution. The reaction solution was reacted at 0 ° C for one hour, and then heated to 20 ° C for 0.5 hour.
- Step A 1-methyl-3,5-dinitro-pyridin-2-one (2 g, 10.04 mmol, 1 eq.) and tert-butyl 4-piperidinone-1-carboxyl at room temperature
- Ammonia gas (1.37 g, 80.32 mmol, 8 eq.) was added to a solution of the acid salt in methanol (50 ml), and the mixture was stirred at 120 ° C for one hour in a sealed can.
- the reaction solution was cooled to room temperature and concentrated to give a crude material.
- Step B To a tert-butyl 3-nitro-7,8-dihydro-5H-1,6-naphthyridin-6-carboxylate (3 g, 10.74 m under hydrogen atmosphere (40 Psi) at room temperature. Pd/C (1.00 g) was added to a solution of hexane (1 ml) in methanol (100 ml), and the mixture was stirred at room temperature for 16 hr. After completion of the reaction, the reaction mixture was filtered and evaporated to ethyljjjjjjjjjjjjj % yield)
- Step C to tert-butyl 3-amino-7,8-dihydro-5H-1,6-naphthyridin-6-carboxylate (300 mg, 1.2 mmol, 1 eq.) at rt.
- CuBr 2 (402.03 mg, 1.8 mmol, 1.5 eq.) was added to a solution of acetonitrile (6 ml), then t-butyl nitrite (148.49 mg, 1.44 mmol, 1.2 eq.) was added dropwise at 0-5 ° C. After an hour, the mixture was warmed to room temperature and stirred for 15 hours.
- Step D To a tert-butyl 3-bromo-7,8-dihydro-5H-1,6-naphthyridin-6-carboxylate (160 mg, 510.87 ⁇ mol, 1) under nitrogen at 25 ° C. A solution of diammonium borohydride (194.60 mg, 766.31 ⁇ mol, 1.50 eq.) and KOAc (150.41 mg, 1.53 mmol, 3 eq.) in eq. Pd(dppf)Cl 2 .CH 2 Cl 2 (74.76 mg, 102.17 micromoles, 0.20 equivalents). The mixture was stirred at 25 ° C for 10 minutes, then heated to 100 ° C and stirred for 16 hours. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a crude material.
- Step E To a tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8- under nitrogen at 25 ° C Dihydro-5H-1,6-naphthyridin-6-carboxylate (181.20 mg, 502.98 ⁇ mol, 2.00 eq.) and N-ethyl-4-iodo-5-(5-isopropyl-2 , 4-dimethoxyphenyl) isoxazole-3-carboxamide (150.00 mg, 251.49 [mu] mol, 1.00 equiv) in dioxane (5 ml) was added NaHCO 3 (63.38 mg of the mixture solution, micro 754.46 Mole, 3.00 equivalents), H 2 O (1 mL) and Pd (PPh 3 ) 2 Cl 2 (35.30 mg, 50.30 micromoles, 0.2 eq.).
- NaHCO 3 63.38 mg of the mixture solution,
- Step F tert-butyl 3-[5-(2,4-benzyloxy-5-isopropyl-phenyl)-3-(ethylformamide)isoxazole-4 at 20 ° C
- Step G 5-(2,4-Benzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(5,6,7,8-tetrahydro) under nitrogen at 20 ° C
- a solution of -1,6-naphthyridin-3-yl)isoxazole-3-carboxylate (50.00 mg, 82.96 ⁇ mol, 1.00 eq.) in methanol (5 mL) , 829.6 [mu] mol, 10 eq) and the reaction was stirred at room temperature for 10 minutes then NaBH 3 CN at room temperature (15.64 mg, 248.88 [mu] mol, 3.00 eq.) and stirring was continued for 50 minutes.
- Step H to 5-(2,4-benzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(6-methyl-5,6, under a nitrogen atmosphere at 0 ° C. 7,8-Tetrahydro-1,6-naphthyridin-3-yl)isoxazole-3-carboxylate (40 mg, 64.86 micromoles, 1 eq.) in anhydrous dichloromethane (2.5 mL) Boron trichloride (1 mol/liter, 0.648 ml, 10 equivalents) was slowly added dropwise to the solution. The reaction solution was reacted at 0 ° C for one hour, and then heated to 20 ° C for 14 hours.
- Step A 6-Bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline (1.00 g, 4.42 mmol, 1.0 eq.) of dioxane under nitrogen at 25 ° C
- bisphenol steryl borate (1.68 g, 6.63 mmol, 1.5 eq.
- KOAc (1.30 g, 13.26 mmol, 3.0 eq.)
- Mg, 442.00 micromolar The mixture was heated to 90 ° C and stirred for 2 hours. The mixture was filtered through celite and concentrated under reduced pressure.
- Step B N 2 protection at room temperature, a solution of 5- (2,4-bis-benzyloxy-5-isopropyl - phenyl) - isoxazole-3-carboxylate (2.00 g, 4.24 mmol
- Step C to 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 under nitrogen at 25 ° C, 2,3,4-tetrahydroisoquinoline (6.15 g, 13.5 mmol) and 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-4-iodo-isoxazole- 3- carboxylate (1.50 g, 2.51 mmol, 1.0 eq.) in dioxane (15 mL) was added the mixture solution of NaHCO 3 (632.60 mg, 7.53 mmol, 3.0 eq.), H 2 O (3.00 mL And Pd(PPh 3 ) 2 Cl 2 (176.18 mg, 251.00 mmol, 0.10 equivalent).
- Step D 5-(2,4-Dibenzyloxy-5-isopropylbenzene-4-(2-methyl-1,2,3,4-tetrahydroiso) at -20 ° C under nitrogen.
- the mixture was cooled to -20 ° C and stirred for 0.5 hours.
- Step E (5-(2,4-Dibenzyloxy)-5-isopropylbenzene)-4-(2-methyl-1,2,3,4- under 5°CN 2 protection
- dichloromethane 5 mL, EtOAc
- the mixture was stirred at 5 ° C for 1 hour.
- a saturated NaHCO 3 solution (1.0 ml) and a saturated aqueous Na 2 SO 3 (l. It was diluted with 15 ml of water and the aqueous phase was extracted with dichloromethane (15 ml x 2).
- Step F (5-(2,4-Dibenzyloxy)-5-isopropylbenzene)-4-(2-methyl-1,2,3,4- under protection of 5 ° C under N 2
- tetrahydroisoquinolin-6-yl)isoxazole-3-carbaldehyde (200.00 mg, 349.23 ⁇ mol, 1.0 eq.)
- EtOAc 5.69 mg, 17.465.
- trimethyl(trifluoromethyl)silyl 60 mg, 419 micromoles, 1.2 equivalents. The mixture was stirred at 5 degrees Celsius for 4 hours.
- Tetrabutylammonium fluoride (136.96 mg, 523.85 micromoles, 1.50 equivalents) was added to the mixture at 5 ° C and stirred for 12 hours. The mixture was poured into water (15 mL). The combined organic layers were dried with anhydrous sodium s The residue was purified by EtOAc (EtOAc/MeOH) 1,2,3,4-tetrahydroisoquinolin-6-yl)isoxazol-3-yl)-2,2,2-trifluoroethanol (100.0 mg, 155.59 mmol, 44.55% yield) It is a yellow solid. MS (ESI) M / Z: 643.2 (M + 1).
- Step G To 1-(5-(2,4-dibenzyloxy)-5-isopropylbenzene)-4-(2-methyl-1,2,3,4- at -20 °C Add 1 mol/ of tetrahydroisoquinolin-6-yl)isoxazol-3-yl)-2,2,2-trifluoroethanol (100.00 mg, 155.59 ⁇ mol, 1.0 eq.) in DCM (8 mL) L's BCl 3 . DCM (2 ml).
- Step A 5-(2,4-Dihydroxy-5-isopropylphenyl)-4-iodo-isoxazole-3-carbonitrile (300 mg, 545 ⁇ M) under nitrogen at 15-25 ° C.
- 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane to a solution of 1.00 equivalents) in dioxane (4.5 ml) -2-yl)-1,2,3,4-tetrahydroisoquinoline (372 mg, 818 ⁇ mol, 1.5 eq.), water (900.00 ⁇ L), sodium bicarbonate (224 mg, 2.7 mmol, 4.9 equiv.), followed by addition of Pd (PPh 3) 2 Cl 2 (77 mg, 109 mol, 0.2 eq.).
- Step B to 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) oxazole-3-carbonitrile (150 mg, 263 mol, 1.0 eq.) in MeOH (4 mL) was added NaHCO 3 (221 mg, 2.6 mmol, 10.0 equiv) was added. The mixture was stirred at 40 ° C for 6.5 hours. Aminonitrile (221 mg, 5 mmol, 20.0 eq.) was then added and stirred at 40 <0>C for 4 h.
- Step C N-cyano-5-(2,4-dibenzyloxy-5-isopropylphenyl)-4-(2-methyl-1,2,3,4 at 0 °C - tetrahydro-isoquinolin-6-yl) isoxazole-3-carboxamidine (78 mg, 127 mol, 1.0 eq.) in DCM (6 mL) was added a solution of BCl 3 (1M, 1.3 mL, 10.0 equiv) The DCM solution was stirred at 0 ° C for 2 hours and then heated to 15-25 ° C for 1 hour. The reaction mixture was cooled to 0.degree. C., MeOH (3 mL) was evaporated and evaporated. The mixture was concentrated to give a crude material.
- Step A To 2-(thien-2-yl)ethylamine (3.0 g, 23.6 mmol, 1.00 eq.) and ethyl 2-carbaldehydecarboxylate (4.8 g, 23.6 mmol, 1.00 at 15-25 ° C) Ethyl acetate (1.4 g, 23.6 mmol, 1.0 eq.), NaBH (OAc) 3 (10.0 g, 47.2 mmol, 2.0 eq.). The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was poured into water (60 ml) The combined organic layers were dried, filtered and evaporated tolulululululululululululululululululu Used directly in the next step.
- Step B at 0 deg.] C, a solution of ethyl 2 - ((2- (thiophen-2-yl) ethyl) amino) acetate (3.2 g, 15.0 mmol, 1.00 equiv) and NaHCO 3 (3.8 g, Ethyl chloroformate (1.6 g, 15.0 mmol, 1.00 eq.) was added dropwise to a solution of THF (40.0 mL). The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was poured into saturated aqueous NaHCO 3 (80 ml), and extracted with EA (, l ⁇ 60 ml). . The combined organic layers were dried, filtered and concentrated to give crude.
- Step C To a solution of ethyl 2-((ethoxycarbonyl)(2-(thien-2-yl)ethyl)amino)acetate (2.9 g, 10.2 mmol, 1.00 eq.) at 0 °. NaOH/H2O (20.3 mL, 20.4 mmol, 2.00 eq, 1 M) was added dropwise to a solution of EtOH (20.0 mL). The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was poured into water (EtOAc) (EtOAc)EtOAc. The combined organic layers were dried, filtered and evaporated tolulululululululululululululululululululu
- Step E To ethyl (2-chloro-2-ethoxy)(2-(thien-2-yl)ethyl)carbamate (4.8 g, 17 mmol, 1.00 eq.) at 0 °C AlCl 3 (5.8 g, 43 mmol, 2.5 eq.) was added to a solution of DCM (50.0 mL). The mixture was stirred at 25 ° C for 1 hour. To the reaction mixture was added EtOH (5.0 ml), and the mixture was poured on ice and stirred for 1 hour. The mixture was extracted with DCM (60 mL x liter). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered, and concentrated to give the crude product.
- Step F To a solution of AlCl 3 (2.0 g, 15 mmol, 3.0 eq.) in DCM (20.0 mL) , 6.0 equivalents). The mixture was stirred at 0 ° C for 5 minutes. Subsequent addition of ethyl 4-oxo-7,8-dihydro-4H-thiophene[2,3-d]azepine-6(5H)-formate (1.2 g, 5.0 mmol, 1.0 eq) DCM (10.0 mL) solution. The reaction mixture was stirred at 25 ° C for 12 hours. The reaction mixture was poured into aq. EtOAc (EtOAc m.
- Step G To a solution of ethyl 7,8-dihydro-4H-thiophene [2,3-d]azepine-6(5H)-formate (700 mg, 3.1 mmol, 1.00 eq. at 25 ° C) ) in CHCl 3 (15.0 mL) was added TMSI (12.4 g, 62 mmol, 20.0 eq.) .. The mixture was stirred at 80 ° C for 12 hours. To the reaction mixture was added NaOH (10.0 mL, 2M) and poured into saturated aqueous NaHCO 3 (100 mL), the mixture was extracted with DCM (60 mL ⁇ L).
- Step H to 5,6,7,8-tetrahydro-4H-thiophene [2,3-d]azepine (550 mg, 3.6 mmol, 1.00 eq.) in DCM (10.0 mL) Et3N (1.1 g, 11. mmol, 3.0 eq.) and Boc 2 O (1.2 g, 5.4 mmol, 1.5 eq.) were added to the solution. The mixture was stirred at 25 ° C for 12 hours. The reaction mixture was poured into water (60 mL) The combined organic layers were dried over anhydrous Na 2 SO 4, filtered, and concentrated to give the crude product.
- Step I To a tert-butyl 7,8-dihydro-4H-thiophene [2,3-d]azepine-6(5H)-formate at 25 ° C (500 mg, 2.0 mmol, 1.00 NBS (245 mg, 1.4 mmol, 0.7 eq.) was added to a solution of EtOAc. The mixture was stirred at 25 ° C for 2 hours. To the reaction mixture was poured into saturated aqueous NaHSO 3 (30 mL), the mixture was extracted with DCM (30 mL ⁇ L). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered, and concentrated to give the crude product.
- Step J N-ethyl-5-(5-isopropyl-2,4-dibenzyloxy-phenyl)-4-(4,4,5,5-tetramethyl- under N-protection with nitrogen 1,3,2-dioxaborolan-2-yl)isoxazole-3-carboxamide (1.1 g, 1.8 mmol, 1.40 equiv), tert-butyl 2-bromo-7,8-di Hydrogen-4H-thiophene [2,3-d] azepine-6(5H)-formate (420 mg, 1.3 mmol) in dioxane (20.00 mL) and water (4.00 mL) Pd(PPh 3 ) 2 Cl 2 (88 mg, 126 ⁇ mol, 0.10 eq.) and NaHCO 3 (212 mg, 2.5 mmol, 2.00 eq.).
- Step K Add HCl/MeOH (4M, 10.00 mL) to tert-butyl 2-(5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-3-(ethylaminomethyl) Acyl)isoxazol-4-yl)-4,5,7,8-tetrahydrothiophene [2,3-d]azepine-formate (880 mg, 1.2 mmol, 1.00 equiv) in MeOH ( 10.00 ml) in solution and stirred at 25 ° C for 1 hour.
- Step L to 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(5,6,7,8-tetrahydro-4H-thiophene [2 , 3-d]azepine-2-yl)isoxazole-3-carboxamide (730 mg, 1.2 mmol, 1.0 eq.) in MeOH (15 mL). Mole, 83.5 equivalents) and AcOH (70 mg, 1.2 mmol, 1.0 eq.). The mixture was stirred at 25 ° C for 2 hours then NaBH 3 CN (147 mg, 2.3 mmol, 2.0 eq.). The reaction was stirred for a further 12 hours at 25 ° C.
- EtOAc EtOAc
- EtOAc EtOAc
- EtOAc EtOAc
- Step M to 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(6-methyl-4,5,7, at 0 °C
- BCl 3 to a solution of 8-tetrahydrothiophene [2,3-d]azerazin-2-yl)isoxazole-3-carboxamide (100 mg, 157 ⁇ mol, 1.0 eq.) in DCM (8 mL)
- the (1 M, 0.8 mL, 5.0 eq.) DCM solution was stirred at 0 ° C for 2 hr and then warmed to 15-25 ° C for 1 hour.
- the reaction mixture was cooled to 0.degree.
- Step A Slowly add a solution of pyrrole (6.00 g, to a solution of 2,2,2-trichloroacetyl chloride (19.51 g, 107.32 mmol, 1.20 equivalent) in tetrahydrofuran (36 ml) under a nitrogen atmosphere at 25 ° C. 89.43 mmol, 1.00 equiv) of tetrahydrofuran (120 mL).
- the reaction solution was stirred at 25 ° C for 5 minutes, then warmed to 67 ° C and stirred for 2 hours.
- the reaction solution was cooled to room temperature, and a solution of sodium hydrogen carbonate (10 g) in water (50 ml) was slowly added dropwise to the mixture.
- Step B To a solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone (22.00 g, 103.55 mmol, 1.00 eq.) in dichloromethane (250). Iodine chloride (16.81 g, 103.55 mmol, 1.00 equivalent) was added dropwise to the solution, and the reaction mixture was stirred at 20 ° C for 5 hours. The reaction solution was washed with aq. EtOAc (EtOAc) The organic phase was combined with water (50 ml), 1 mol/l of sodium thiosulfate (100 ml) and brine (100 ml) and dried over anhydrous sodium sulfate. Chloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone (33.00 g, 97.53 mmol, 94.19% yield)
- Step C 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone (34.60 g, 102.26 mmol, 1.0 eq.) of methanol under nitrogen at 25 ° C.
- a solution of sodium methoxide (6.63 g) in methanol (50 ml) was added dropwise (200 ml).
- the reaction solution was reacted at 25 ° C for 2 hours.
- the reaction mixture was poured into water (150 ml)
- the organic phases were combined and washed twice with brine (200 mL). Drying over anhydrous sodium sulfate, EtOAc ⁇
- Step D a solution of methyl 4-iodo-1H-pyrrole-2-carboxylic acid methyl ester (9.00 g, 35.85 mmol, 1.00 eq.) in dimethyl sulphoxide (80 ml) at 20 ° C under nitrogen. Potassium hydroxide (14.08 g, 250.95 mmol, 7.00 equivalent) was added. The reaction solution was reacted at 20 ° C for 3 hours, and then dibromoethane (53.88 g, 286.80 mmol, 8.00 equivalent) was added dropwise to the reaction mixture. The reaction solution was reacted at 20 ° C for 10 hours.
- Step E To a solution of methyl 1-(2-bromoethyl)-4-iodo-1H-pyrrole-2-carboxylate (4.00 g, 11.17 mmol, 1.00 eq. Aqueous ammonia (14.56 g, 124.55 mmol, 11.15 equivalent) was added dropwise to the solution, and the reaction mixture was stirred at 20 ° C for 1 hour, and then the mixture was warmed to 78 ° C and stirred for 12 hours. After the reaction was completed, the reaction mixture was evaporated.
- Step F 7-iodo-3,4-dihydropyrrolo[1,2-a]pyrazine-1(2H)-one (1.90 g, 7.25 mmol, 1.00 equivalent) under nitrogen at 0 °C.
- BH 3 -Me 2 S (10 M, 7.25 ml, 10.00 eq.) was added dropwise in THF (40 mL).
- the reaction solution was stirred at 0 ° C for 30 minutes, then heated to 20 ° C for 1 hour, and finally heated to 67 ° C for 12 hours. After completion of the reaction, the reaction solution was cooled to 0 ° C and then quenched with methanol (5 ml) and then refluxed at 67 ° C for 4 hours.
- the reaction mixture was concentrated under reduced pressure to dryness crystals crystals crystalsssssssssssssssssssssssssssssssssssssssssssssss
- Step G To a solution of 7-iodo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (1.80 g, 7.26 mmol, 1.00 eq) in tetrahydrofuran under 20 ° C under nitrogen. Triethylamine (3.67 g, 36.30 mmol, 5.0 eq.) and (Boc) 2 O (3.17 g, 14.52 mmol, 2.00 eq.) were added to the solution, and the mixture was stirred at 20 ° C for 2 hr.
- Step H Preparation of the title compound of this example according to the procedure of Steps J, K, L and M of Example 22 Wherein t-butyl 2-bromo-7,8-dihydro-4H-thiophene[2,3-d]azepine-6(5H)-formate is replaced with t-butyl 7- in step J Iodo-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-formate.
- Step A 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (4.5 g, 22.95 mmol, 1.00 equivalent) in methanol (50.00) under nitrogen at 25 °C. DIPEA (7.42 g, 57.37 mmol, 2.50 equiv) and (Boc) 2 O (12.52 g, 57.37 mmol, 2.50 eq.). After the addition was completed, the reaction mixture was stirred at 25 ° C for 18 hours.
- Step B Dissolving bis-tert-butyl 6,7-dihydro-1H-imidazo[4,5-c]pyridine-1,5(4H)-dicarboxylate (5.40 g) under nitrogen protection at 25 °C To a solution of 16.70 mmol, 1.00 eq. of methanol (40.00 mL) was added 1 mol/L NaOH (20 mL). After the addition was completed, the reaction mixture was stirred at 25 ° C for 1 hour.
- Step C 1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylate (3.30 g, 14.78 mmol, 1.00 equivalent) was dissolved in nitrogen at 10 ° C. To a solution of tetrahydrofuran (30.00 mL) was added NIS (4.99 g, 22.17 mmol, 1.50 eq.). After the addition was completed, the reaction mixture was stirred at 10 ° C for 1 hour. The reaction mixture was diluted with EtOAc EtOAc (EtOAc) The combined organic layers were washed with EtOAcq.
- EtOAc EtOAc
- Step D Dissolved with tert-butyl 2-iodo-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylate (150 mg, under nitrogen protection at 10 ° C, Sodium hydride (34.37 mg, 859.18 micromoles, 2.00 equiv) and methyl iodide (630.00 mg, 4.44 mmol, 10.33 equivalent) were added to a solution of 429.59 mmol, 1.00 eq. After the addition was completed, the reaction mixture was stirred at 10 ° C for 16 hours.
- Step E The title compound of this example was prepared according to the sequence of Steps J, K, L and M of Example 22, wherein in step J, tert-butyl 2-bromo-7,8-dihydro-4H-thiophene [2, 3-d]azepine-6(5H)-formate was replaced with tert-butyl 2-iodo-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-5 - formate.
- Step A Slowly add NaN to a solution of 6-bromo-3,4-dihydronaphthalene-2(1H)-one (2.25 g, 10 mmol) in methanesulfonic acid (20.00 mL) at 0 °C. 3 (1.06 g, 16 mmol), which lasted 0.5 hours.
- the reaction mixture was stirred at 0 <0>C for 3.5 h then the reaction mixture was stirred at 25 <0>C for a further 16 h.
- the mixture was then slowly added dropwise with saturated aqueous NaHCO 3 (100 mL) and extracted with ethyl acetate (100 mL x3).
- Step B To a solution of 7-bromo-4,5-dihydro-1H-3-benzo[d]azepine-2(3H)-one (800 mg, 3.3 mmol) in THF at 0 °C BH 3 -Me 2 S (3.3 ml, 10 M) was added dropwise (8.00 ml). The reaction mixture was stirred at 0 ° C for 1 hour and at 25 ° C for 3 hours, then the reaction mixture was stirred at 70 ° C for a further 16 hours. Then, the mixture was cooled to 0 ° C, and MeOH (4 ml) was slowly added dropwise to the reaction mixture at 0 ° C, and stirred at 25 ° C for 0.5 hour. The reaction mixture was concentrated in vacuo to give crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal
- Step C To a solution of 7-bromo-2,3,4,5-tetrahydro-1H-3-benzo[d]azepine (800 mg, 3.54 mmol) in THF (16.00 ml) at 25 °C TEA (1.07 g, 10.6 mmol) was added followed by Boc 2 O (1.16 g, 10.6 mmol). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated in vacuo to give a crude material.
- Step D The title compound of this example was prepared according to the sequence of Steps J, K, L and M of Example 22, wherein in step J, tert-butyl 2-bromo-7,8-dihydro-4H-thiophene [2, 3-d] caprolactam-6(5H)-formate was replaced with tert-butyl 7-bromo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-formic acid Ester, the product was a white solid.
- Step A Slowly add NaN to a solution of 6-bromo-3,4-dihydronaphthalene-2(1H)-one (2.25 g, 10 mmol) in methanesulfonic acid (20.00 mL) at 0 °C. 3 (1.06 g, 16 mmol), which lasted 0.5 hours.
- the reaction mixture was stirred at 0 <0>C for 3.5 h then the reaction mixture was stirred at 25 <0>C for a further 16 h.
- the mixture was then slowly added dropwise with saturated aqueous NaHCO 3 (100 mL) and extracted with ethyl acetate (100 mL x3).
- Step B To a solution of 7-bromo-4,5-dihydro-1H-benzo[c]azepine-3(2H)-one (400 mg, 1.7 mmol) in THF (4.00). BH 3 -Me 2 S (1.7 ml, 10 M) was added dropwise in ML. The reaction mixture was stirred at 0 ° C for 1 hour and at 25 ° C for 3 hours, then the reaction mixture was stirred at 70 ° C for a further 16 hours. Then, the mixture was cooled to 0 ° C, and MeOH (2 ml) was slowly added dropwise to the reaction mixture at 0 ° C, and stirred at 25 ° C for 0.5 hour. The reaction mixture was concentrated in vacuo to give crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal
- Step C To a solution of 7-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine (400 mg, 1.7 mmol) in THF (8.00 mL) at 25 °C TEA (537 mg, 5.3 mmol) was added followed by Boc 2 O (579 mg, 5.3 mmol). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated in vacuo to give a crude material.
- Step D The title compound of this example was prepared according to the sequence of Steps J, K, L and M of Example 22, wherein in step J, tert-butyl 2-bromo-7,8-dihydro-4H-thiophene [2, 3-d]azepine-6(5H)-formate was replaced with tert-butyl 7-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-formic acid ester.
- Step A 3-(2,4-Dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-iodo-isoxazole-5- under nitrogen protection at 15-25 °C
- Toluene 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane was added to a solution of formamide (300 mg, 503 ⁇ mol, 1.00 eq.) in DMF (7.5 mL).
- Step B Add HCl/MeOH (4M, 2.00 mL) to t-butyl-7(3-(2,4-dibenzyloxy-5-isopropylphenyl)-5- Ethylcarbamoyl)isoxazol-4-yl)-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylate (200 mg, 279 ⁇ mol, 1.0 eq.) In MeOH (2.00 mL) solution. The mixture was stirred at 25 ° C for 1 hour. The mixture was concentrated at 40 ° C to give a crude material. The crude product was dissolved in DCM (10 ml), the solution was added NaHCO 3 (1g), stirred for 1 hour.
- Step C To 3-(2,4-dibenzyloxy-5-isopropylphenyl)-N-ethyl-4-(2,3,4,5-tetrahydro-1H-3-benzo Add a solution of formaldehyde (211 mg, 162 ⁇ mol, 1.0 eq, 40) to a solution of oxazol-7-yl)isoxazole-5-carboxamide (100 mg, 162 ⁇ mol, 1.0 eq.) in MeOH (5 mL) % content) and AcOH (10 mg, 16 ⁇ mmol, 1.0 equivalent). The mixture was stirred at 25 ° C for 10 minutes and then NaBH 3 CN (31 mg, 487.
- Step D To 3-(2,4-dibenzyloxy-5-isopropylphenyl)-N-ethyl-4-(3-methyl-2,3,4,5 at 0 °C - tetrahydro -1H- benzo [d] azepin-7-yl) isoxazol-5-carboxamide (60 mg, 95 mol, 1.0 eq.) in DCM (5 mL) was added BCl 3 ( 1 M, 952 ⁇ L, 10.0 eq. of DCM solution was stirred at 0 ° C for 2 hr and then warmed to 15-25 ° C for 1 hour. The reaction mixture was cooled to 0.degree. C., MeOH (2 mL) was evaporated and evaporated.
- Step A To 3-(2,4-dibenzyloxy-5-isopropylphenyl)-N-ethyl-4-(2,3,4,5-tetrahydro-1H at 0 °C -3-azepin-7-yl) isoxazol-5-carboxamide (130 mg, 211 mol, 1.0 eq.) in DCM (10 mL) was added a solution of BCl 3 (1M, 2.1 mL, 10.0 The equivalent of the DCM solution was stirred at 0 ° C for 2 hours and then heated to 15-25 ° C for 1 hour. The reaction mixture was cooled to 0.degree. C., MeOH (4 mL) was evaporated and evaporated. The mixture was concentrated to give a crude material.
- Step A To a solution of 6-bromoisoquinoline (250 mg, 1.2 mmol) in dioxane (150 ml) was added a bis- benzoate boronate (366 mg, 1.4). mmol) and KOAc (354 mg, 3.6 mmol), followed by addition of the catalyst Pd (dppf) Cl 2 .CH 2 Cl 2 (294 mg, 360 mol). The mixture was stirred at 25 ° C for 10 minutes, then heated to 90 ° C and stirred for 17 hours.
- a bis- benzoate boronate 366 mg, 1.4
- KOAc 354 mg, 3.6 mmol
- Step B 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (128 mg, 503) under nitrogen at 25 ° C. Micromolar) and 3-(2,4-dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-iodo-isoxazol-5-carboxamide (200 mg, 335 ⁇ mol) K 2 CO 3 (231 mg, 1.7 mmol), H 2 O (5.0 ml) and Pd(PPh 3 ) 2 Cl 2 (71 mg, 101 ⁇ mol) were added to a mixture of DMF (20 mL).
- Step C To 3-(2,4-dibenzyloxy-5-isopropylphenyl)-N-ethyl-4-(isoquinolin-6-yl)isoxazole at 0 °C 5-carboxamide (180 mg, 301 mol, 1.0 eq.) in DCM (10 mL) was added a solution of BCl 3 (1M, 3.1 mL, 10.0 equiv) in DCM, stirred at 0 °C 2 h, warmed to Stir at 15-25 ° C for 12 hours. The reaction mixture was cooled to 0.degree. C., MeOH (6 mL) was then evaporated and evaporated. The mixture was concentrated to give a crude material.
- Step C Metal sodium (10.2 g, 445 mmol, 3.0 eq.) was added portionwise to ethanol (400 mL) under a nitrogen atmosphere at 20 ° C and stirred for 1 hour. Subsequently, 1-(2,4-dibenzyloxy-5-bromo-phenyl)ethanone (61.0 g, 148 mmol, 1.0 eq.) was added portionwise, and finally dimethyl oxalate (32.5 g, 222 mmol). , 1.5 equivalents). The reaction mixture was stirred at 80 ° C for further 2 hours and then cooled to 65 ° C. EtOAc (30 mL). The solid was collected by filtration.
- Step D To a solution of 2-hydroxy-4-(5-bromo-2,4-dimethoxy-phenyl)-4-oxo-butyric acid ethyl ester (32 g, 63 mmol) To a solution of 1.00 eq. of EtOH (320 mL) was added NH ? The mixture was heated to 80 degrees Celsius and stirred for 3 hours. The mixture was cooled to room temperature, and a solid was collected by filtration.
- Step E To a solution of ethyl 5-(5-bromo-2,4-dimethoxy-phenyl)-isoxazole-3-carboxylate (23 g, 45 mmol, 1.00 eq.) in EtOH. Ethylamine (17 g, 384 mmol, 8.5 equivalents) was added to a solution (200 mL). The reaction mixture was stirred at 80 ° C for 12 hours. . The reaction mixture was cooled to room temperature and a solid was precipitated. The solid was collected by filtration.
- Step F N 2 protection at room temperature, a solution of 5- (2,4-benzyloxy-5-bromo - phenyl) -N- ethyl - isoxazole-3-carboxamide (2.0 g, 3.9 mmol)
- EtOAc EtOAc, EtOAc, EtOAc, EtOAc
- EtOAc EtOAc
- Step G to 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 under nitrogen at 25 ° C, 2,3,4-tetrahydroisoquinoline (1.8 g, 4 mmol) and 5-(2,4-dibenzyloxy 5-bromo-phenyl)-N-ethyl-4-iodo-isophor -3-carboxamide (2.5 g, 3.9 mmol) in DMF (25.0 mL) was added the mixture solution of NaHCO 3 (1.3 g, 15.5 mmol), H 2 O (2.5 mL) and Pd (PPh 3) 2 Cl 2 (407 mg, 580 micromolar).
- Step H to 5-(2,4-dibenzyloxy-5-bromo-phenyl)-N-ethyl-4-(2-methyl-1,2,3, under nitrogen at 0 ° C.
- 4-tetrahydro-isoquinolin-6-yl) isoxazole-3-carboxamide (300 mg, 345 mol) in dichloromethane (20.00 mL) was added dropwise a solution of BCl 3 /DCM(1.3 mL, 1.0 Moore / liter). The mixture was stirred at 0 ° C for 1 hour. Methanol (3 ml) was added dropwise to the mixture and evaporated.
- Step A The title compound of this example was prepared according to the procedure of Steps B, C, D, E, F, G, and H of Example 30, wherein NBS was replaced with NCS in step B as a white solid.
- Step A N-ethyl-5-(5-bromo-2,4-dimethoxyphenyl)isoxazole-3-carboxamide (1.0 g, 2.0 ⁇ mol) under nitrogen at 25 ° C.
- Cs 2 CO 3 1.3 g, 4 mmol
- Pd(dppf) 2 Cl 2 288 mg, 400 Micromolar
- Step B 5-(5-Methyl-2,4-dibenzyloxyphenyl)-N-ethyl-isoxazole-3-carboxamide (740 mg, 1.7 mM) under N 2 at room temperature
- EtOAc EtOAc
- EtOAc EtOAc
- the mixture was heated to 80 degrees Celsius and stirred for 12 hours.
- the mixture was cooled to room temperature and poured into water (30 mL).
- the combined organic phases were washed with EtOAc EtOAc m.
- the residue was purified by silica gel chromatography (EtOAc/EtOAc/EtOAc) 3-Carboxamide (450 mg, 792 mmol, 47.0% yield) as a yellow oil.
- Step C to 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 under nitrogen at 25 ° C, 2,3,4-tetrahydroisoquinoline (309 mg, 679 ⁇ mol) and 5-(5-methyl-2,4-dibenzyloxyphenyl)-N-ethyl-4-iodo-iso 3-carboxamide (450 mg, 721 mol) in dioxane (5.0 ml) was added the mixture solution of NaHCO 3 (228 mg, 2.7 mmol), H 2 O (1.0 mL) and Pd (PPh 3 ) 2 Cl 2 (71 mg, 102 ⁇ mol).
- Step D 5-(5-methyl-2,4-dibenzyloxyphenyl)-N-ethyl-4-(2-methyl-1,2,3, under nitrogen at 0 ° C.
- a solution of a mixture of 4-tetrahydroisoquinolin-6-yl)isoxazole-3-carboxamide (280 mg 476 ⁇ mol) in dichloromethane (10.00 mL) was added dropwise BCI 3 / DCM (1. /Rise). The mixture was stirred at 0 ° C for 1 hour. Methanol (4 ml) was added dropwise to the mixture and evaporated.
- Step A 5-(2,4-Dibenzyloxy-5-bromo-phenyl)-N-ethyl-isoxazole-3-carboxamide (2.00 g, 3.94 m) under nitrogen at 25 ° C. Mole, 1 eq.) and a mixture of isobutylboronic acid (803.67 mg, 7.88 mmol, 2 eq.) in toluene (50 ml), Na 2 CO 3 ( 835.60 mg, 7.88 mmol, 2 eq.), H 2 O (2.0 ml) and Pd(dppf) 2 Cl 2 (576.86 mg, 788.00 mmol, 0.2 eq.). The mixture was heated to 120 ° C and stirred for 18 hours.
- Step B To a solution of 5-(2,4-dibenzyloxy-5-isobutyl-phenyl)-N-ethyl-isoxazole-3-carboxamide (500.00 mg, under N 2 at room temperature, To a solution of 1.03 mmol (1.0 eq.) in EtOAc (50 mL), EtOAc (EtOAc, EtOAc, EtOAc, The mixture was heated to 10 degrees Celsius and stirred for 18 hours. The mixture was cooled to rt and poured into Na 2 SO 3 in water (40 ml), the aqueous phase with EA (30 mL x3) and extracted.
- EtOAc EtOAc
- EtOAc EtOAc
- Step C 5-(2,4-Dibenzyloxy-5-isobutyl-phenyl)-N-ethyl-4-iodo-isoxazole-3-carboxamide under nitrogen at 25 ° C (400 mg, 655.22 mmol, 1 equivalent) and 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 , 2,3,4-tetrahydroisoquinoline (268.49 mg, 982.83 mol, 1.5 eq.) in dioxane (2.50 ml) was added NaHCO 3 (165.14 mg, 7.88 mmol, 2 eq.), H 2 O (0.5 ml) and Pd(PPh 3 ) 2 Cl 2 (45.99 mg, 65.52 micromoles, 0.10 equivalents).
- Step D 5-(5-isobutyl-2,4-dibenzyloxy-phenyl)-N-ethyl-4-(2-methyl-1,2) under nitrogen at -20 °C , 3,4-tetrahydroisoquinolin-6-yl)isoxazole-3-carboxamide (150.00 mg 238.17 ⁇ mol) in dichloromethane (10.00 mL) mixture was added dropwise to BCl 3 /DCM (1 mL) , 1.0 mole / liter). The mixture was stirred at -20 ° C for 1 hour. Methanol (2 ml) was added dropwise to the mixture and evaporated.
- Step A 5-(2,4-Dibenzyloxy-5-bromo-phenyl)-N-ethyl-isoxazole-3-carboxamide (1 g, 1.97 m) under nitrogen at 25 ° C.
- ethyl chlorotrifluoroborate 316.81 mg, 2.36 mmol
- cesium carbonate 1.93 g, 5.91 mmol.
- the mixture was heated to 80 ° C and stirred for 12 hours.
- the mixture was cooled to 25 <0>C and poured into water (30 mL).
- the combined organic phases were washed with EtOAcq. It was concentrated under reduced pressure.
- Step B 5-(2,4-Dibenzyloxy-5-vinyl-phenyl)-N-ethyl-isoxazole-3-carboxamide (0.7 g, 1.54) under hydrogen at 25 ° C.
- Step C 5-(2,4-Dibenzyloxy-5-ethyl-phenyl)-N-ethyl-isoxazole-3-carboxamide (0.6 g, 1.31) under nitrogen at 25 ° C.
- iodosuccinimide 442.09 mg, 1.96 mmol.
- the mixture was stirred at 25 ° C for 12 hours.
- the mixture was cooled to 25 ° C, filtered and concentrated under reduced pressure and then sodium sulfate (30mL).
- the aqueous phase was extracted with EA (20 mL x 2).
- the combined organic layers were washed with EtOAc EtOAc m. It was concentrated under reduced pressure.
- Step D To 5-(2,4-dibenzyloxy-5-ethyl-phenyl)-N-ethyl-4-iodo-isoxazole-3-carboxamide under nitrogen at 25 ° C ( 320 mg, 549 micromoles, 1 equivalent) and 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1, 2,3,4-tetrahydroisoquinoline (250 mg, 549 mol, 1.0 eq.) in dioxane (5.0 mL) was added NaHCO 3 (184 mg, 220 mol, 4.0 eq.), H 2 O (1.0 mL) and Pd(PPh 3 ) 2 Cl 2 (39 mg, 55 ⁇ mol, 0.10 eq.).
- Step E 5-(5-ethyl-2,4-dibenzyloxy-phenyl)-N-ethyl-4-(2-methyl-1,2,3) under nitrogen at 25 ° C , a solution of 4-tetrahydroisoquinolin-6-yl)isoxazole-3-carboxamide (100.00 mg 166 ⁇ mol) in dichloromethane (10.00 mL) was added dropwise to a solution of BCl 3 /DCM (5 mL, 1.0) Moore / liter). The mixture was stirred at 25 ° C for 0.5 hours. Methanol (10 ml) was added dropwise to the mixture and evaporated.
- Step A 5-(2,4-benzyloxy-5-bromo-phenyl)-N-ethyl-4-(2-methyl-1,2,3 was dissolved in a nitrogen atmosphere at 25 °C. , 4-tetrahydroisoquinolin-6-yl)-isoxazole-3-carboxamide (1.10 g, 1.69 mmol, 1.00 equiv) in a mixed solution of PhMe (10.00 mL) and H 2 O (2.1 mL) Cyclopropylboronic acid (217.76 mg, 2.54 mmol, 1.50 equiv) K3PO4 (717.47 mg, 3.38 mmol, 2.00 equiv) and Pd(OAc)2 (75.88 mg, 338.00 micromoles, 0.20 eq.).
- the mixture was stirred at 25 ° C for 20 minutes, then heated to 90 ° C and stirred for 12 hours.
- the mixture was cooled to 25 ° C, and the reaction solution was poured into a solution of ammonium chloride (20 ml) and stirred for 10 min.
- the aqueous phase was extracted with ethyl acetate (10 mL x liter).
- the combined organic phases were dried with EtOAc EtOAc m.
- Step B to 5-(2,4-benzyloxy-5-cyclopropyl-phenyl)-N-ethyl-4-(2-methyl-1,2,3 under nitrogen at 0 °C , a mixture of 4-tetrahydroisoquinolin-6-yl)-isoxazole-3-carboxamide (300 mg 489 ⁇ mol) in dichloromethane (30.00 ml) was added dropwise with BCI 3 / DCM (1.9 mL, 1 mole / liter). The mixture was stirred at 0 ° C for 1 hour. Methanol (4 ml) was added dropwise to the mixture and evaporated.
- Step A N 2 protection at room temperature, a solution of ethyl 5- (2,4-dibenzyl-5-isopropyl-phenyl) - isoxazole-3-carboxylate (4.00 g, 8.5 mmol To a solution of MoCN (1.0 eq.) in MeCN (50 mL), EtOAc (465 mg, EtOAc. The mixture was heated to 90 degrees Celsius and stirred for 12 hours. The mixture was cooled to room temperature and poured into water (40 mL). The combined organic layers were washed with EtOAc EtOAc m.
- Step B to 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 under nitrogen at 25 ° C, 2,3,4-tetrahydroisoquinoline (2.47 g, 9.0 mmol) and ethyl-5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-4-iodo-iso oxazole-3-carboxylate (2.70 g, 4.5 mmol) in dioxane (30 ml) mixture was added a solution of NaHCO 3 (1.52 g, 18.0 mmol), H 2 O (6.0 mL) and Pd ( PPh 3 ) 4 (1.26 g, 1.80 mmol).
- Step C To ethyl 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-4-(2-methyl-1,2,3,4- at 20 °C To a solution of a mixture of tetrahydroisoquinolin-6-yl)isoxazole-3-carboxylate in THF (15 mL) /EtOAc (EtOAc) The mixture was stirred at 20 ° C for 2 hours. The mixture was adjusted to pH 6 with HCl and extracted with EA (30 mL).
- Step D to 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-4-(2-methyl-1,2,3,4-tetrahydroiso) at 20 °C
- DIPEA 220 mg, 1.7 mmol
- HATU a solution of quinoline-6-yl)isoxazole-3-carboxylic acid (200 mg, 340 ⁇ mol) in DMF (5 mL) .
- the mixture was stirred at 20 ° C for 0.5 hours.
- Methylamine hydrochloride (30 mg, 441 micromoles) was then added and the reaction was stirred at 20 ° C for 1 hour.
- Step E to 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-N-methyl-4-(2-methyl-1,2,3, at 0 °C 4-tetrahydro-isoquinolin-6-yl) isoxazole-3-carboxamide (120 mg, 199 mol, 1.0 eq.) in DCM (5 mL) was added a solution of BCl 3 (1M, 2 mL, 10.0 eq. ).
- Step A The title compound of this example was prepared according to the procedure of Steps D and E of Example 36, wherein the methylamine hydrochloride salt was replaced with the propylamine in the step D, which was a pale yellow solid.
- MS (ESI) M/Z 450 (M+1).
- Step A The title compound of this example was prepared according to the procedure of Steps D and E of Example 36, wherein the methylamine hydrochloride was replaced with propane-2-amine in step D, which was a pale yellow solid.
- Step A The title compound of this example was prepared according to the procedure of Steps D and E of Example 36, wherein the methylamine hydrochloride was replaced with 2,2,2-trifluoroethylamine in step D.
- Step A The title compound of this example was prepared according to the procedure of Steps D and E of Example 36, wherein the methylamine hydrochloride was replaced with 2-fluoroethylamine in step D.
- Step A The title compound of this example was prepared according to the procedure of Steps D and E of Example 36, wherein the methylamine hydrochloride was replaced with 2-methoxyethylamine in step D.
- Step A The title compound of this example was prepared according to the procedure of Steps D and E of Example 36, wherein the methylamine hydrochloride was replaced with 3-methoxypropan-1-amine in step D.
- Step A The title compound of this example was prepared according to the sequence of Steps D and E of Example 36, wherein the methylamine hydrochloride was replaced with N',N'-dimethylethane-1,2-di in step D. amine.
- Step A tert-Butyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2 under nitrogen , 3,4-tetrahydroisoquinoline-2-carboxylate (4.00 g, 11.1 mmol, 1.6 equivalents), 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)- Ethyl 4-iodo-isoxazole-3-carboxylate (4.10 g, 6.9 mmol, 1.0 eq.), Pd(PPh 3 ) 2 Cl 2 (723 mg, 1.0 mmol, 0.15 eq.) and NaHCO 3 (2.31) Gram, 27.5 mmol, 4.0 eq.) was added to a mixed solution of dioxane (40 mL) and water (8 mL).
- Step B tert-Butyl 6-[5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-3-(ethylcarbamoyl)isoxazol-4-yl]-
- the mixture was concentrated at 40 ° C to give the product 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(1,2,3,4-tetrahydroiso Quinoline-6-yl)isoxazole-3-carboxamide (630 mg, 1.07 mmol, 98% yield) as a yellow solid.
- Step C 5-(2,4-Dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(1,2,3,4-tetrahydroisoquinoline-6- Isooxazol-3-carboxamide (4.00 g, 382 ⁇ mol, 1.0 eq.), K 2 CO 3 (158 mg, 1.2 mmol, 3.0 eq.), 2-bromoethanol (72 mg, 570 ⁇ mol, 1.5 equivalents) was added to ethanol (5 ml). The mixture was heated to 50 ° C and stirred for 12 hours. After cooling, the reaction mixture was evaporated to dryness.
- Step D 5-(2,4-Dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4[2-(2-hydroxyethyl)-(1) at 0 °C , 2,3,4-tetrahydro-isoquinolin-6-yl)] isoxazole-3-carboxamide (132 mg, 204 mol, 1.0 eq.) in DCM (5.0 ml) was added dropwise a solution of BCl 3 of DCM solution (1 M, 2.0 mL, 10.0 eq.) over 5 min. The suspension was stirred at 0 ° C for 30 minutes, then warmed to 25 ° C and stirred for 2 hours. The mixture was cooled to 0.
- Step A The title compound of this example was prepared according to the procedure of Steps C and D of Example 44, wherein 2-bromoethanol was replaced with 1-bromo 2-methoxyethane in Step C.
- Step A 5-(2,4-Dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(1,2,3,4-,tetrahydroisoquinoline-6 -yl)isoxazole-3-carboxamide (150 mg, 250 micromolar, 1.0 equivalent), triethylamine (63 mg, 623 micromoles, 2.5 equivalents), 1-bromo-2-fluoroethane (44 mg) , 350 ⁇ mol, 1.4 eq.) was added to acetonitrile (3 mL). The mixture was heated to 50 ° C and stirred for 5 hours. After cooling, the reaction mixture was concentrated in vacuo to give a crystal.
- Step B to 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4[2-(2-fluoroethyl)-(1) at 0 °C 1,2,3,4, tetrahydro-isoquinolin-6-yl)] isoxazole-3-carboxamide (120 mg, 185 mol, 1.0 eq.) in DCM (8.0 ml) was added dropwise a solution of BCl 3 The DCM solution (1 M, 1.9 mL, 10.0 eq.) was taken for 5 min. The suspension was stirred at 0 ° C for 30 minutes, then warmed to 25 ° C and stirred for 2 hours. The mixture was cooled to 0.
- Step A The title compound of this example was prepared according to the procedure of Steps A and B of Example 46, in which 1-bromo-2-fluoroethane was replaced by 1-bromo-3-methoxypropane, triethyl The amine is replaced by cesium carbonate.
- Step A The title compound of this example was prepared according to the procedure of Steps A and B of Example 46, wherein, in Step A, 1-bromo-2-fluoroethane was replaced by 1-vinyl-sulfonylethane.
- Step A To 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(1,2,3,4-tetrahydroisoquinoline-6- Add acetaldehyde (274 mg, 433.3 ⁇ mol, 10.00 eq.), acetic acid (1.3 mg, 21.7 ⁇ m) to a solution of isoxazole-3-carboxamide (150 mg, 250 ⁇ mol, 1.0 eq.) in methanol (3 mL) Mole, 0.50 equivalents), tetraisopropoxytitanium (6.2 mg, 2.5 mmol, 10 equivalents).
- Step B to 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(2-ethyl-1,2,3, at 0 °C 4-tetrahydroisoquinolin-6-yl)isoxazole-3-carboxamide (60 mg, 95 ⁇ mol, 1.0 eq.) in anhydrous DCM (8 mL) was slowly dropped into solution and dropped into DCM of BCl 3 Solution (1 M, 1.0 mL, 10.0 eq.) over 5 min. The suspension was stirred at 0 ° C for 30 minutes, then warmed to 25 ° C and stirred for 2 hours. The mixture was cooled to 0.
- Step A The title compound of this example was prepared according to the procedure of Steps A and B of Example 49, in which acetaldehyde was replaced with propionaldehyde in step B.
- Step A The title compound of this example was prepared according to the procedure of Steps A and B of Example 49, in which acetaldehyde was replaced with acetone in step B.
- Step A The title compound of this example was prepared according to the procedure of Steps A and B of Example 49, wherein acetaldehyde was replaced with 2-methylpropanal in step B.
- Step A 5-(2,4-Dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(1,2,3,4-,tetrahydroisoquinoline-6 -yl)isoxazole-3-carboxamide (300 mg, 499 ⁇ mol, 1.0 eq.), cesium carbonate (244 mg, 748 ⁇ mol, 1.5 eq.), tert-butyl N-(2-bromoethyl)amino Formate (168 mg, 748 micromoles, 1.5 equivalents) was added to acetonitrile (5 mL). The mixture was heated to 50 ° C and stirred for 25 hours. After cooling, the reaction mixture was concentrated in vacuo to give a crystal.
- Step B tert-Butyl N-[2-[6-[5-(2,4-benzyloxy-5-isopropylphenyl)-3-(ethylcarbamoyl)isoxazole-4 a mixture of -1,2,3,4-tetrahydroisoquinolin-2-yl]ethyl]formate (250 mg, 336 ⁇ mol, 1.00 eq.) in HCl/MeOH (4M, EtOAc) Stir at 25 ° C for 2 hours.
- Step C Acetyl chloride (39 mg, 496 ⁇ mol, 2.0 eq.) was added to 4-(2-(2-aminoethyl)-1,2,3,4-tetrahydroisoquinoline at 0 °C. 2-yl)-5-(2,4-benzyloxy-5-isopropylphenyl)-N-ethylisoxazole-3-carboxamide (170 mg, 248 ⁇ mol, 1.0 eq.), three Ethylamine (100 mg, 991 micromoles, 4.0 eq.) in DCM (6 mL). The mixture is stirred at 0 ° C 2 hours. The reaction mixture was concentrated in vacuo to give a crystal.
- Step D 4-(2-(2-Acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2,4-benzyloxy at 0 °C
- a solution of BCl 3 in DCM was added dropwise to a solution of benzyl-5-isopropylphenyl)-N-ethylisoxazole-3-carboxamide (100 mg, 146 ⁇ mol, 1.0 eq.) in DCM (5.0 mL) 1 M, 1.5 ml, 10.0 eq.), used for 5 minutes.
- the suspension was stirred at 0 ° C for 30 minutes, then warmed to 25 ° C and stirred for 2 hours.
- the mixture was cooled to 0.
- Step A The title compound of this example was prepared according to the procedure of Steps A, B, and C of Example 53, wherein in step A, tert-butyl N-(2-bromoethyl)carbamate was replaced with t-butyl N -(3-Bromopropyl)carbamate.
- Step A 2-Chloroacetyl chloride (3.00 g, 26.6 mmol, 1.6 eq.), dimethylamine hydrochloride (2.38 g, 29.2 mmol, 1.1 eq.) and triethylamine (8.0 g, 79.7 mmol, 3.0 eq.) was added to DCM (30 mL). The mixture was stirred at 15 ° C for 3 hours.
- Step B 5-(2,4-Dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(1,2,3,4-,tetrahydroisoquinoline-6 - yl) isoxazole-3-carboxamide (200 mg, 313 mol, 1.0 eq.), K2CO 3 (130 mg, 940 mol, 3.0 eq), 2-chloro -N, N- dimethylacetamide (114 mg, 940 micromoles, 3.0 eq.) was added to DMF (4 mL). The mixture was stirred at 15 ° C for 16 hours.
- reaction mixture was taken up in water (30 mL) and filtered and evaporated to give 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-4-(2-(2-(dimethylamino)) 2-acetyl)-(1,2,3,4-,tetrahydroisoquinolin-6-yl)-N-ethylisoxazole-3-carboxamide (195 mg, crude, 74% purity) , as a white solid.
- Step C To 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-4-(2-(2-(dimethylamino))-2-acetyl group at 0 °C )-(1,2,3,4-,tetrahydroisoquinolin-6-yl)-N-ethylisoxazole-3-carboxamide (190 mg, 277 ⁇ mol, 1.0 eq.) of DCM (10.0) ml) was added dropwise BCl DCM 3 solution (1M, 3.0 mL, 10.0 equiv), when over 5 minutes. the suspension was stirred for 30 min at 0 deg.] C, then warmed to 25 deg.] C and stirred for 2 hours.
- Step A acryloyl chloride (5.0 g, 55 mmol, 1.0 eq.), dimethylamine hydrochloride (4.95 g, 60.8 mmol, 1.1 eq.) and triethylamine (16.8 g, 166 mmol, 3.0 eq.) Add to DCM (50 mL). The mixture was stirred at 15 ° C for 3 hours. The reaction mixture was poured into water (30 mL) The organic phase was washed with dilute hydrochloric acid (30mLx2,1M), dried over anhydrous Na 2 SO 4, and concentrated in vacuo to give N, N- dimethylacrylamide (3.0 g, 30 mmol, 55% yield) as a yellow oil Things.
- Step B 5-(2,4-Dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(1,2,3,4-,tetrahydroisoquinoline-6 -yl)isoxazole-3-carboxamide (100 mg, 157 micromolar, 1.0 equivalent), triethylamine (48 mg, 470 micromoles, 3.0 equivalents), N,N-dimethylacrylamide (155 mg) , 1.57 mmol, 10.0 eq.) was added to ethanol (2 mL). The mixture was stirred at 15 ° C for 2 hours. The reaction mixture was taken up in water (30 mL) andEtOAc.
- Step C To 5-(2,4-dibenzyloxy-5-isopropylphenyl)-4-(2-(2-(dimethylamino)-3-propanoyl) at 0 °C -1,2,3,4-tetrahydroisoquinolin-6-yl)-N-ethylisoxazole-3-carboxamide (105 mg, 149 ⁇ mol, 1.0 eq.) in DCM (15.0 mL) BCl DCM was added dropwise a solution of 3 (1M, 3.0 mL, 20.0 equiv), when 5 minutes. The suspension was stirred at 0 ° C for 30 minutes, then warmed to 25 ° C and stirred for 2 hours. The mixture was cooled to 0.
- Step A Add HCl/MeOH (4M, 30.00 mL) to tert-butyl 6-bromo-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (5.0 g, at 20 ° C, The mixture was stirred at 25 ° C for 2 hours in a solution of EtOAc (20.0 mL). The mixture was concentrated at 40 ° C to give the product 6-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (4.5 g, crude).
- Step B Add acryloyl chloride (1.0 g, 11 mmol, 1.2 eq.) to 6-bromo-1,2,3,4-, tetrahydroisoquinoline isoquinoline hydrochloride at 0 °C (2.0 Gram, 9 mmol, 1 eq.) and triethylamine (2.9 g, 28 mmol, 3.0 eq.). The mixture was stirred at 15 ° C for 14 hours. The reaction mixture was poured into water (30 mL) The organic phase was dried over anhydrous Na 2 SO 4, and concentrated in vacuo.
- Step C 1-(6-Bromo-1,2,3,4-,tetrahydroisoquinolinyl)propyl-2-en-1-one (700 mg, 2.6 mmol, 1.0 eq.) Dimethylamine (1.1 g, 7.9 mmol, 3.0 eq.) was added to ethanol (10 mL). The mixture was stirred at 15 ° C for 12 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography to afford 1-(6-bromo-1,2,3,4-,tetrahydroisoquinolin-yl)-3-(dimethylamino)propan-1-one (700 mg, 2.3 mmol, 86% yield) as a yellow oil.
- Step D To 5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-N-ethyl-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)isoxazole-3-carboxamide (767 mg, 771 ⁇ mol, 1.0 eq.) in a mixture of DMF (2.5 mL) and water (0.5 mL) -(6-Bromo-1,2,3,4-,tetrahydroisoquinolinyl)-3-(dimethylamino)propan-1-one (200 mg, 643 ⁇ mol, 1.0 eq.) and NaHCO 3 (216 mg, 2.6 mmol, 4.0 eq.).
- Step E to 5-(2,4-dibenzyloxy-5-isopropylphenyl)-4-(2-(3-(dimethylamino)propanoyl)-1, at 0 °C, 2,3,4-Tetrahydroisoquinolin-6-yl)-N-ethylisoxazole-3-carboxamide (170 mg, 243 ⁇ mol, 1.0 eq.) in DCM (12.0 mL) BCl DCM 3 solution (1M, 2.4 mL, 10.0 equiv), when 5 minutes. The suspension was stirred at 0 ° C for 30 minutes, then warmed to 25 ° C and stirred for 2 hours. The mixture was cooled to 0.
- Step A According to Example 57, steps C, D and E
- Step A The title compound of this example was prepared according to the procedure of Steps D and E of Example 57, wherein 1-(6-bromo-1,2,3,4-tetrahydroisoquinolinyl)- 3-(Dimethylamino)propan-1-one was replaced by 1-(6-bromo-1,2,3,4-tetrahydroisoquinolinyl)-2-(dimethylamino)ethanone.
- Step A The title compound of this example was prepared according to the procedure of Steps D and E of Example 57, wherein 1-(6-bromo-1,2,3,4-tetrahydroisoquinolinyl)- 3-(Dimethylamino)propan-1-one was replaced by 1-(6-bromo-1,2,3,4-tetrahydroisoquinolinyl)-2-morpholine ethyl ketone.
- Step A 3-(2,4-Dibenzyloxy-5-isopropylphenyl)-4-iodo-isoxazol-5-carboxylic acid (300 mg, 527 ⁇ mol, 1.0 at 0 ° C) (COCl) 2 (134 mg, 1050 micromoles, 2 equivalents) and DMF (100.00 microliters) were added to a solution of EtOAc (10 mL). After the mixture was stirred at 0 ° C for 1 hour, the reaction mixture was concentrated in vacuo to give Intermediate. The intermediate was dissolved in DCM (10 ml), at 0 deg.] C, and to the solution was added NH 3 /THF(4M,1.32 mL, 10.00 eq).
- Step B to 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 under nitrogen at 25 ° C, 2,3,4-tetrahydroisoquinoline (103 mg, 377 ⁇ mol) and 3-(2,4-dibenzyloxy-5-isopropylphenyl)-4-iodo-isoxazole-5 NaHCO 3 (40 mg, 472 ⁇ mol), H 2 O (1.0 mL) and Pd(PPh 3 ) 2 Cl 2 (17) were added to a mixture of carbamide (134 mg, 236 ⁇ mol) in DMF (4 mL). Mg, 24 micromolar).
- Step C To a solution of 3-(2,4-dibenzyloxy-5-isopropylphenyl)-4-(2-methyl-1,2,3,4-tetrahydrogen under nitrogen at 0 °C To a solution of isoquinolin-6-yl)isoxazole-3-carboxamide (80 mg, 136 ⁇ mol) in DCM (15.00 mL) was slowly added BCI 3 (2 mL, 1 M. After the reaction mixture was further stirred at 0 ° C for 1 hour, the mixture was warmed to room temperature and stirred for two hours. The reaction was cooled to 0 ° C then quenched by MeOH (20 mL). The reaction mixture was concentrated in vacuo to give a crude material.
- Step A The title compound was prepared according to the sequence of the present embodiment in Example 61 Step A, B and C of the embodiment, wherein in step A NH 3 / THF replaced by methylamine.
- Step A The title compound was prepared according to the sequence of the present embodiment in Example 61 Step A, B and C of the embodiment, wherein in step A NH 3 / THF was replaced propyl-amine.
- Step A The title compound was prepared according to the sequence of the present embodiment in Example 61 Step A, B and C of the embodiment, wherein in step A NH 3 / THF replaced with 2-amino ethanol.
- Step A The title compound was prepared according to the sequence of the present embodiment in Example 61 Step A, B and C of the embodiment, wherein in step A NH 3 / THF replaced with 2-fluoro-ethylamine.
- Step A The title compound was prepared according to the sequence of the present embodiment in Example 61 Step A, B and C of the embodiment, wherein in step A NH 3 / THF replaced with 3-amino-1-ol.
- Step A To a solution of tert-butyl 6-bromo-1,2,3,4-tetrahydroisoquinoline-2-carboxamide (7.5 g, 24 mmol) in DMF (100 mL) To the solution was added bispinacol borate (7.3 g, 29 mmol) and KOAc (7.1 g, 72 mmol), followed by the addition of the catalyst Pd(dppf)Cl 2 .CH 2 Cl 2 (5.3 g, 7 m) Moore). The mixture was stirred at 25 ° C for 10 minutes, then heated to 80 ° C and stirred for 12 hours.
- Step B To 3-(2,4-dibenzyloxy-5-isopropylphenyl)-4-iodo-isoxazole-5-carboxylic acid (5 g, 9 mmol, 1.0) at 0 °C (COCl) 2 (2.2 g, 18 mmol, 1.5 eq.) and DMF (100.00 ⁇ L) were added to aq. After the mixture was stirred at 0 ° C for 1 hour, the reaction mixture was concentrated in vacuo to give Intermediate. This was dissolved in DCM (80 mL) EtOAc (EtOAc) After the mixture was stirred at 0 ° C for 1 hour, it was poured into 100 ml of water.
- EtOAc EtOAc
- Step C To a tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2 under nitrogen at 25 ° C , 3,4-tetrahydroisoquinoline-2-carboxamide (3.2 g, 9 mmol) and 3-(2,4-dibenzyloxy-5-isopropylphenyl)-N-ethyl- 4-iodo - isoxazole-5-carboxamide (3.8 g, 6 mmol) in DMF (50 mL) was added the mixture solution of NaHCO 3 (1.6 g, 19 mmol), H 2 O (17.0 mL) and Pd (PPh 3 ) 2 Cl 2 (447 mg, 637 ⁇ mol).
- the mixture was stirred at 25 ° C for 10 minutes, then heated to 80 ° C and stirred for 12 hours.
- the mixture was cooled to 25 ° C and poured into water (100 mL).
- the mixture is then extracted with EA (150 mL X2), and the combined organic phases were washed with water (100 mL), dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo.
- Step D Add HCl/MeOH (4M, 20.00 mL) to tert-butyl 6-(3-(2,4-dibenzyloxy-5-isopropyl-phenyl)-5- at 25 °C. (ethylcarbamoyl)isoxazol-4-yl)-1,1,3,4-,tetrahydroisoquinoline-2-carboxylate (2.6 g, 3.7 mmol, 1.00 equiv) in MeOH ( In a solution of 20.00 ml), the mixture was stirred at 25 ° C for 30 minutes.
- Step E 3-(2,4-Dibenzyloxy-5-isopropylphenyl)-N-ethyl-4-(1,2,3,4-tetrahydro) under nitrogen at 0 °C isoquinolin-6-yl) isoxazole-5-carboxamide (1.0 g, 1.6 mmol) in DCM (50.00 mL) was slowly added BCl 3 (9.5 mL, 1 molar solution in DCM). After the reaction mixture was further stirred at 0 ° C for 1 hour, the mixture was warmed to room temperature and stirred for two hours. The reaction was cooled to 0 ° C then quenched by MeOH (20 mL). The reaction mixture was concentrated in vacuo to give a crude material.
- Step A To 3-(2,4-dibenzyloxy-5-isopropylphenyl)-N-ethyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl To a solution of isoxazole-5-carboxamide (100 mg, 166 ⁇ mol, 1.0 eq.) in MeOH (3 mL) EtOAc (EtOAc (EtOAc) 0.50 equivalent). After the mixture was stirred at 30 ° C for 0.5 hour, NaBH 3 CN (31 mg, 499 ⁇ mol, 3.0 eq.) was added, and the mixture was further stirred for 1 hour. The reaction was concentrated in vacuo.
- Step B To 3-(2,4-dibenzyloxy-5-isopropylphenyl)-N-ethyl-4-(2-isopropyl-1,2,3, at 0 °C 4-tetrahydroisoquinolin-6-yl)isoxazole-5-carboxamide (80 mg, 124 ⁇ mol, 1.0 eq.) in dry DCM (8 mL) was slowly dropped into solution and dropped into DCM of BCl 3 Solution (1 M, 1.2 mL, 10.0 eq.) over 5 min. The suspension was stirred at 0 ° C for 30 minutes, then warmed to 25 ° C and stirred for 2 hours. The mixture was cooled to 0.
- Step A 3-(2,4-Dibenzyloxy-5-isopropylphenyl)-N-ethyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl Isoxazol-5-carboxamide (150 mg, 249 ⁇ mol, 1.0 eq.), Cs 2 CO 3 (122 mg, 374 ⁇ mol, 1.5 eq.), 2-bromoethanol (32 mg, 249 ⁇ mol, 1.0) Equivalent) was added to acetonitrile (3 mL). The mixture was heated to 50 ° C and stirred for 12 hours. After cooling, the reaction mixture was concentrated to dryness.
- Step B To 3-(2,4-dibenzyloxy-5-isopropylphenyl)-N-ethyl-4-(2-(2-hydroxyethyl)-- under 0 ° C under nitrogen (1,2,3,4-tetrahydro-isoquinolin-6-yl) isoxazole-5-carboxamide (120 mg, 186 mol) in DCM (8.00 ml) was slowly added BCl 3 (1.9 mL The reaction mixture was stirred at 0 ° C for further 1 hour, then warmed to room temperature and stirred for two hours. The reaction mixture was cooled to 0 ° C, then MeOH (4 mL) The crude product was obtained. EtOAc m.
- Step A The title compound of this example was prepared according to the procedure of Steps A and B of Example 69, wherein 2-bromoethanol was replaced with 1-bromo 2-methoxyethane in Step A.
- Step A The title compound of this example was prepared according to the procedure of Steps A and B of Example 69, wherein 2-bromoethanol was replaced with 1-bromo 2-fluoroethane in Step A.
- a fluorescence polarization (FP) method is applied to construct a screening platform for HSP90-alpha inhibitors.
- the principle is based on the determination of the fluorescence polarization values in the horizontal and vertical directions by detecting the change in molecular weight before and after the interaction of fluorescein-labeled small molecules with other molecules. If the equilibrium of the binding between the fluorescently labeled small molecule and the macromolecule is established, it will move slowly when excited, and the measured fluorescence polarization value will increase.
- the binding between the fluorescently labeled small molecule and the macromolecule is replaced by another ligand, its rotation or flipping speed in the free state will be faster, the emitted light will be depolarized relative to the plane of the excitation light, and the measured polarization value Decrease to calculate the polarization value of the sample (polarization value unit mP).
- the fluorescently labeled small molecule to be used in the present invention is VER-00051001 (synthesized by the synthesis method described in JMC, 2008, 51, 196-218).
- the reaction was carried out in a 384-well blackboard using the reaction hydrophobin HFB buffer: 100 mM Tris. Cl pH 7.4, 20 mM KCl, 6 mM MgCl 2 , 5 ug/mL BSA, 25 nM full-length Hsp 90U, 10 nM VER-51001.
- the reaction system has a volume of 50 mL containing 5 nM GM-BODIPY (geldanamycin), 30 nM HSP90 and the measured small molecule compound or DMSO (dimethyl sulfoxide), and the content of DMSO is 2 Torr.
- Two wells with only HFB buffer were used as a blank control and 5 nM GM-BODIPY as a negative control.
- the reaction was carried out at 4 ° C for 12-16 hours, and detected under a Biotek microplate reader with an excitation wavelength of 485 nm and an emission wavelength of 535 nm, and the mP value was measured. Calculate the inhibition rate using the following formula:
- SRB sulforhodamine B staining.
- human colon cancer cell line HCT116 and human lung cancer cell line A549 purchased from American Type Culture Collection, ATCC
- ATCC American Type Culture Collection
- 100 ⁇ L of wells were cultured overnight, and different concentrations (100, 10, 1, 0.1, 0.01 ⁇ M) of compounds were added for 72 h, three wells were set for each concentration, and the corresponding concentration of vehicle control and cell-free zero-adjustment were set.
- the inhibition rate (%) of each compound against HCT116 and A549 cells is shown in Table 1 below:
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Claims (27)
- 式(Ⅰ)所示的化合物、其药学上可接受的盐或水合物,其中:X、Y分别独立地选自N、O或S;X1、X2、Y1、Y2和连接X1、X2的碳原子共同组成5-7元芳环、脂肪族饱和环或脂肪族不饱和环;X1、X2分别独立地选自C、O、S、N、-C=C-、-C=N-;X1或X2中的C可以是未取代的,也可以被R01或R02取代;R01、R02分别独立地选自卤素、CN、OH、SH、NH2、CHO、COOH、C1-10烷基、N-C1-10烷氨基、N,N-二(C1-10烷基)氨基、C1-10烷氧基、C1-10烷酰基、C1-10烷氧羰基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基、C3-10环烷氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧羰基、C3-10环烷基磺酰基、C3-10环烷基亚磺酰基、被C3-10环烷基取代的C1-10烷基;Y1、Y2分别独立地选自C或N;Y1与Y2上的两个取代基连在一起形成带有取代基R1,R2和R3的氮杂五元、六元或七元饱和环或芳香环;R1、R2、R3分别独立选自氢、C1-10烷基、羟基C1-10烷基、C1-6烷氧基-C1-6烷基、卤代C1-10烷基、C1-6烷基磺酰基-C1-6烷基、C1-6烷基酰胺基-C1-6烷基、N,N-二(C1-6烷基)氨基酰基-C1-6烷基、N,N-二(C1-6烷基)氨基-C1-6烷酰基、吗啉基-C1-6烷酰基、N-C1-10烷氨基、N,N-二(C1-10烷基)氨基、C1-10烷氧基、C1-10烷酰基、C1-10烷氧羰基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基、C3-10环烷基氨基、C3-10环烷基氧基、C3-10环烷基酰基、C3-10环烷氧羰基、C3-10环烷基磺酰基、C3-10环烷基亚磺酰基、C3-10环烷基-C1-5烷基;或R2和R3的取代基通过共价键相互连在一起形成带有取代基R03或不带有取代基的五元、六元或七元饱和环;R03选自C1-6烷基或卤素;R4选自H、卤素、C1-6烷基、C3-10环烷氧基、苯基取代的C1-6烷基、苯基取代的C2-6烯基、苯基、C1-6 烷基取代的苯基、C3-6环烷基;R5选自H、氰基、羧基、C1-6烷氧基酰基、C1-7烷基氨基羰基、卤代C1-6烷基氨基羰基、C1-6烷氧基-C1-6烷基氨基羰基、N,N-二(C1-6烷基)氨基-C1-6烷基氨基羰基、氨基羰基、羟C1-6烷基氨基羰基、羟基取代的卤代C1-6烷基、腈基取代的脒基,或选自任选被1个或多个R05取代的C3-10环烷基、C3-10环烯基或5~10元芳香环;R05选自C1-6烷基、C3-10环烷基。
- 根据权利要求1所述化合物、其药学上可接受的盐或水合物,其中,Y1和Y2均为C。
- 根据权利要求1所述化合物、其药学上可接受的盐或水合物,其中,R1、R2、R3分别独立选自氢、C1-10烷基、羟基C1-10烷基、C3-10环烷基、C1-6烷氧基-C1-6烷基、卤代C1-10烷基、C1-6烷基磺酰基-C1-6烷基、C1-6烷基酰胺基-C1-6烷基、N,N-二(C1-6烷基)氨基酰基-C1-6烷基、N,N-二(C1-6烷基)氨基-C1-6烷酰基、吗啉基-C1-6烷酰基、C3-10环烷基-C1-5烷基,或R2和R3的取代基通过共价键相互连在一起形成带有取代基R03或不带有取代基的五元、六元或七元饱和环。
- 根据权利要求3所述化合物、其药学上可接受的盐或水合物,其中,R1、R2、R3分别独立选自氢、C1-6烷基、羟基C1-6烷基、C3-10环烷基、C1-4烷氧基-C1-4烷基、卤代C1-4烷基、C1-4烷基磺酰基-C1-4烷基、C1-4烷基酰胺基-C1-4烷基、N,N-二(C1-4烷基)氨基酰基-C1-4烷基、N,N-二(C1-4烷基)氨基-C1-4烷酰基、吗啉基-C1-4烷酰基、C3-6环烷基-C1-4烷基,或R2和R3的取代基通过共价键相互连在一起形成带有取代基R03或不带有取代基的五元、六元或七元饱和环。
- 根据权利要求4所述化合物、其药学上可接受的盐或水合物,其中,R1选自氢、C1-6烷基、羟基C1-6烷基、C3-10环烷基、C1-4烷氧基-C1-4烷基、卤代C1-4烷基、C1-4烷基磺酰基-C1-4烷基、C1-4烷基酰胺基-C1-4烷基、N,N-二(C1-4烷基)氨基酰基-C1-4烷基、N,N-二(C1-4烷基)氨基-C1-4烷酰基、吗啉基-C1-4烷酰基、C3-6环烷基-C1-5烷基,R2和R3选自氢或甲基,或R2和R3的取代基通过共价键相互连在一起形成不带有取代基的五元、六元或七元饱和环。
- 根据权利要求1所述化合物、其药学上可接受的盐或水合物,其中,R4选自H、C1-6烷基、苯基取代的C1-6烷基、卤素、C3-6环烷基。
- 根据权利要求6所述化合物、其药学上可接受的盐或水合物,其中,R4选自C1-4烷基、Cl、Br或环丙基。
- 根据权利要求7所述化合物、其药学上可接受的盐或水合物,其中R4选自异丙基。
- 根据权利要求书1所述化合物、其药学上可接受的盐或水合物,其中,R5选自氰基、C1-6烷基氨基羰基、卤代C1-4烷基氨基羰基、C1-4烷氧基-C1-4烷基氨基羰基、N,N-二(C1-4烷基)氨基-C1-4烷基氨基羰基、氨基羰基、羟C1-4烷基氨基羰基、羟基取代的卤代C1-4烷基、腈基取代的脒基,被1个或多个R05取代的5~6元含氮杂芳环;R05选自C1-6烷基。
- 一种药物组合物,其包括治疗有效量的权利要求1~19任意一项所述化合物或其药学上可接受的盐、水合物以及药学上可接受的载体。
- 权利要求1~19任意一项所述化合物或权利要求21所述组合物在制备治疗HSP90蛋白介导的疾病的药物中的应用。
- 根据权利要求22所述HSP90蛋白介导的疾病,其选自自癌症和神经变性障碍。
- 权利要求1~19任意一项所述化合物或权利要求21所述组合物在制备治疗治疗特定类型的癌症中的应用;所述癌症包括:癌例如膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、包括小细胞肺癌的肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、前列腺癌和包括鳞状细胞癌的皮肤癌;淋巴系的造血系统癌(hematopoietic tumor),所述癌包括白血病、急性淋巴细胞性白血病、急性淋巴母细胞白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、毛细胞淋巴瘤和伯基特氏淋巴瘤;髓系的造血系统癌,所述癌包括急性和慢性髓性白血病、骨髓增生异常综合症和前髓细胞性白血病;包括纤维肉瘤和横纹肌肉瘤的间充质来源的癌;中枢和外周神经系统癌症,所述癌症包括星形细胞瘤、神经细胞瘤、神经胶质瘤和神经鞘瘤;其它癌,所述癌包括黑色素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角化棘皮瘤(keratoxanthoma)、甲状腺毛囊癌和卡波西肉瘤。
- 权利要求1~19任意一项所述化合物或权利要求21所述组合物供制备治疗治疗特定类型的神经变性障碍的药物中的应用,所述障碍包括:阿尔茨海默病、帕金森病、亨廷顿病、多发性硬化和脊髓延髓肌肉萎缩症。
- 权利要求1~19任意一项所述化合物或权利要求21所述组合物在制备治疗连同放射治疗或化疗方案同时、单独或连续用于抗癌治疗的应用。
- 权利要求1~19任意一项所述化合物或权利要求21所述组合物在体外抑制HSP90蛋白活性的应用,其包括将所述蛋白与有效量的式(I)的化合物接触。
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WO2018014858A1 (zh) * | 2016-07-21 | 2018-01-25 | 正大天晴药业集团股份有限公司 | 间苯二酚类衍生物的结晶、盐及其制备方法 |
CN109020883A (zh) * | 2018-03-27 | 2018-12-18 | 广西民族大学 | 一种3-氰基-2-氨基吡啶类衍生物及其制备方法与应用 |
CN109879732A (zh) * | 2019-02-27 | 2019-06-14 | 上海卡洛化学有限公司 | 一种1-(5-异丙基-2,4-二甲氧基苯基)乙酮的制备方法 |
CN115124550A (zh) * | 2020-10-26 | 2022-09-30 | 山东大学 | 一种特异性热休克蛋白90α亚型抑制剂制备及其应用 |
CN115521306A (zh) * | 2022-09-26 | 2022-12-27 | 贵州大学 | 一种1,2,3,4-四氢-β-咔啉衍生物及其制备方法和应用 |
CN115645532A (zh) * | 2022-12-07 | 2023-01-31 | 中山大学附属第五医院 | 一种异噁唑衍生物在制备脑胶质瘤放疗增敏药物中的应用 |
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Cited By (12)
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WO2018014858A1 (zh) * | 2016-07-21 | 2018-01-25 | 正大天晴药业集团股份有限公司 | 间苯二酚类衍生物的结晶、盐及其制备方法 |
CN109641858A (zh) * | 2016-07-21 | 2019-04-16 | 正大天晴药业集团股份有限公司 | 间苯二酚类衍生物的结晶、盐及其制备方法 |
US10851071B2 (en) | 2016-07-21 | 2020-12-01 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | M-dihydroxybenzene derivative crystal and salt, and manufacturing method thereof |
CN109641858B (zh) * | 2016-07-21 | 2021-06-25 | 正大天晴药业集团股份有限公司 | 间苯二酚类衍生物的结晶、盐及其制备方法 |
CN109020883A (zh) * | 2018-03-27 | 2018-12-18 | 广西民族大学 | 一种3-氰基-2-氨基吡啶类衍生物及其制备方法与应用 |
CN109020883B (zh) * | 2018-03-27 | 2022-02-08 | 广西民族大学 | 一种3-氰基-2-氨基吡啶类衍生物及其制备方法与应用 |
CN109879732A (zh) * | 2019-02-27 | 2019-06-14 | 上海卡洛化学有限公司 | 一种1-(5-异丙基-2,4-二甲氧基苯基)乙酮的制备方法 |
CN115124550A (zh) * | 2020-10-26 | 2022-09-30 | 山东大学 | 一种特异性热休克蛋白90α亚型抑制剂制备及其应用 |
CN115124550B (zh) * | 2020-10-26 | 2024-04-02 | 山东大学 | 一种特异性热休克蛋白90α亚型抑制剂制备及其应用 |
CN115521306A (zh) * | 2022-09-26 | 2022-12-27 | 贵州大学 | 一种1,2,3,4-四氢-β-咔啉衍生物及其制备方法和应用 |
CN115521306B (zh) * | 2022-09-26 | 2024-03-26 | 贵州大学 | 一种1,2,3,4-四氢-β-咔啉衍生物及其制备方法和应用 |
CN115645532A (zh) * | 2022-12-07 | 2023-01-31 | 中山大学附属第五医院 | 一种异噁唑衍生物在制备脑胶质瘤放疗增敏药物中的应用 |
Also Published As
Publication number | Publication date |
---|---|
EP3248968A1 (en) | 2017-11-29 |
TW201629049A (zh) | 2016-08-16 |
JP2018504413A (ja) | 2018-02-15 |
RU2697703C2 (ru) | 2019-08-19 |
AU2016208863B2 (en) | 2020-01-16 |
TWI688562B (zh) | 2020-03-21 |
CN107108591A (zh) | 2017-08-29 |
RU2017129151A3 (zh) | 2019-02-22 |
AU2016208863A1 (en) | 2017-08-24 |
RU2017129151A (ru) | 2019-02-22 |
CN107108591B (zh) | 2020-05-05 |
EP3248968A4 (en) | 2018-11-07 |
KR20170113586A (ko) | 2017-10-12 |
US10035792B2 (en) | 2018-07-31 |
JP6760946B2 (ja) | 2020-09-23 |
US20180009794A1 (en) | 2018-01-11 |
CA2974756A1 (en) | 2016-07-28 |
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