JP5859454B2 - Mk2インヒビター - Google Patents
Mk2インヒビター Download PDFInfo
- Publication number
- JP5859454B2 JP5859454B2 JP2012542575A JP2012542575A JP5859454B2 JP 5859454 B2 JP5859454 B2 JP 5859454B2 JP 2012542575 A JP2012542575 A JP 2012542575A JP 2012542575 A JP2012542575 A JP 2012542575A JP 5859454 B2 JP5859454 B2 JP 5859454B2
- Authority
- JP
- Japan
- Prior art keywords
- pyrrolo
- pyridine
- piperidine
- alkyl
- cycloalkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 229940124789 MK2 inhibitor Drugs 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims description 186
- 229910052739 hydrogen Inorganic materials 0.000 claims description 75
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 25
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 201000010099 disease Diseases 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical group 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 230000001363 autoimmune Effects 0.000 claims description 8
- 208000023275 Autoimmune disease Diseases 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 208000026278 immune system disease Diseases 0.000 claims description 7
- 208000027866 inflammatory disease Diseases 0.000 claims description 7
- 230000004770 neurodegeneration Effects 0.000 claims description 7
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 208000006386 Bone Resorption Diseases 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
- 208000035473 Communicable disease Diseases 0.000 claims description 6
- 230000024279 bone resorption Effects 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 230000002062 proliferating effect Effects 0.000 claims description 6
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 230000005784 autoimmunity Effects 0.000 claims 1
- 230000036039 immunity Effects 0.000 claims 1
- 238000000034 method Methods 0.000 description 160
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 130
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 65
- 238000011894 semi-preparative HPLC Methods 0.000 description 61
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 55
- 239000000203 mixture Substances 0.000 description 51
- 238000005481 NMR spectroscopy Methods 0.000 description 48
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 47
- 239000000243 solution Substances 0.000 description 43
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 37
- 235000019439 ethyl acetate Nutrition 0.000 description 37
- 239000011541 reaction mixture Substances 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- -1 pyrrolopyridine compound Chemical class 0.000 description 24
- 239000000047 product Substances 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 239000012043 crude product Substances 0.000 description 18
- 238000003818 flash chromatography Methods 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 17
- 239000011734 sodium Substances 0.000 description 16
- 238000003556 assay Methods 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- 239000012453 solvate Substances 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- 229940002612 prodrug Drugs 0.000 description 13
- 239000000651 prodrug Substances 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 12
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 201000008482 osteoarthritis Diseases 0.000 description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 description 8
- 102000004127 Cytokines Human genes 0.000 description 7
- 108090000695 Cytokines Proteins 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 102000004889 Interleukin-6 Human genes 0.000 description 7
- 108090001005 Interleukin-6 Proteins 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000002158 endotoxin Substances 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 6
- ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2 ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 0.000 description 6
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 125000003003 spiro group Chemical group 0.000 description 6
- 239000011550 stock solution Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- CMHPUBKZZPSUIQ-UHFFFAOYSA-N 1,3-benzodioxol-5-ylboronic acid Chemical compound OB(O)C1=CC=C2OCOC2=C1 CMHPUBKZZPSUIQ-UHFFFAOYSA-N 0.000 description 5
- DOMXASMASBMLJQ-UHFFFAOYSA-N 1-o-tert-butyl 3-o-ethyl 3-(iodomethyl)piperidine-1,3-dicarboxylate Chemical compound CCOC(=O)C1(CI)CCCN(C(=O)OC(C)(C)C)C1 DOMXASMASBMLJQ-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 108091000080 Phosphotransferase Proteins 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000002875 fluorescence polarization Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000011813 knockout mouse model Methods 0.000 description 5
- 102000020233 phosphotransferase Human genes 0.000 description 5
- 230000000770 proinflammatory effect Effects 0.000 description 5
- 125000004076 pyridyl group Chemical group 0.000 description 5
- BWCCJYUBHIGKIY-UHFFFAOYSA-N pyrrolo[3,2-c]pyridine Chemical compound N1=C[CH]C2=NC=CC2=C1 BWCCJYUBHIGKIY-UHFFFAOYSA-N 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- OBPYPRPHENQCSZ-UHFFFAOYSA-N tert-butyl 2-[2-(1-benzofuran-2-yl)pyrimidin-4-yl]-5-[(4-methoxyphenyl)methyl]-4-oxospiro[1,6-dihydropyrrolo[3,2-c]pyridine-7,4'-piperidine]-1'-carboxylate Chemical compound C1=CC(OC)=CC=C1CN1C(=O)C(C=C(N2)C=3N=C(N=CC=3)C=3OC4=CC=CC=C4C=3)=C2C2(CCN(CC2)C(=O)OC(C)(C)C)C1 OBPYPRPHENQCSZ-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- RZIYWKZWSSFEFI-UHFFFAOYSA-N 4-o-tert-butyl 2-o-methyl morpholine-2,4-dicarboxylate Chemical compound COC(=O)C1CN(C(=O)OC(C)(C)C)CCO1 RZIYWKZWSSFEFI-UHFFFAOYSA-N 0.000 description 4
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 4
- KEOOKHRRAZRWGJ-UHFFFAOYSA-N 8-o-tert-butyl 4-o-methyl 2-[(4-methoxyphenyl)methyl]-3,5-dioxo-2,8-diazaspiro[5.5]undecane-4,8-dicarboxylate Chemical compound C1C2(CN(CCC2)C(=O)OC(C)(C)C)C(=O)C(C(=O)OC)C(=O)N1CC1=CC=C(OC)C=C1 KEOOKHRRAZRWGJ-UHFFFAOYSA-N 0.000 description 4
- HLFFEUPYFUYFHZ-UHFFFAOYSA-N 9-o-tert-butyl 4-o-methyl 2-[(4-methoxyphenyl)methyl]-3,5-dioxo-2,9-diazaspiro[5.5]undecane-4,9-dicarboxylate Chemical compound C1C2(CCN(CC2)C(=O)OC(C)(C)C)C(=O)C(C(=O)OC)C(=O)N1CC1=CC=C(OC)C=C1 HLFFEUPYFUYFHZ-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 4
- 239000005695 Ammonium acetate Substances 0.000 description 4
- 0 C*C(N=CC)=NC[C@@](C1)[C@]1C([C@@](NCCCN(CC(C)(C)C)CC1)O)=C1N Chemical compound C*C(N=CC)=NC[C@@](C1)[C@]1C([C@@](NCCCN(CC(C)(C)C)CC1)O)=C1N 0.000 description 4
- 102100034069 MAP kinase-activated protein kinase 2 Human genes 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- 239000012346 acetyl chloride Substances 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 235000019257 ammonium acetate Nutrition 0.000 description 4
- 229940043376 ammonium acetate Drugs 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
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- 229940079593 drug Drugs 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 4
- 125000002541 furyl group Chemical group 0.000 description 4
- 125000002883 imidazolyl group Chemical group 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- 238000012799 strong cation exchange Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- FOWWXWNWWPCXLN-UHFFFAOYSA-N tert-butyl 2-(2-chloropyrimidin-4-yl)-5-[(4-methoxyphenyl)methyl]-4-oxospiro[1,6-dihydropyrrolo[3,2-c]pyridine-7,4'-piperidine]-1'-carboxylate Chemical compound C1=CC(OC)=CC=C1CN1C(=O)C(C=C(N2)C=3N=C(Cl)N=CC=3)=C2C2(CCN(CC2)C(=O)OC(C)(C)C)C1 FOWWXWNWWPCXLN-UHFFFAOYSA-N 0.000 description 4
- ANZRJLQTCXTVHS-UHFFFAOYSA-N tert-butyl 2-[(4-methoxyphenyl)methyl]-3,5-dioxo-2,8-diazaspiro[5.5]undecane-8-carboxylate Chemical compound C1=CC(OC)=CC=C1CN1C(=O)CC(=O)C2(CN(CCC2)C(=O)OC(C)(C)C)C1 ANZRJLQTCXTVHS-UHFFFAOYSA-N 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000000335 thiazolyl group Chemical group 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 3
- PKRRNTJIHGOMRC-UHFFFAOYSA-N 1-benzofuran-2-ylboronic acid Chemical compound C1=CC=C2OC(B(O)O)=CC2=C1 PKRRNTJIHGOMRC-UHFFFAOYSA-N 0.000 description 3
- HYYSNOLMHGTLTG-UHFFFAOYSA-N 1-o-tert-butyl 3-o-ethyl 3-[[(4-methoxyphenyl)methylamino]methyl]piperidine-1,3-dicarboxylate Chemical compound C=1C=C(OC)C=CC=1CNCC1(C(=O)OCC)CCCN(C(=O)OC(C)(C)C)C1 HYYSNOLMHGTLTG-UHFFFAOYSA-N 0.000 description 3
- RYBQZBHSPICRJK-UHFFFAOYSA-N 1-o-tert-butyl 4-o-methyl 4-[[(3-ethoxy-3-oxopropanoyl)-[(4-methoxyphenyl)methyl]amino]methyl]piperidine-1,4-dicarboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1(C(=O)OC)CN(C(=O)CC(=O)OCC)CC1=CC=C(OC)C=C1 RYBQZBHSPICRJK-UHFFFAOYSA-N 0.000 description 3
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 3
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| US28609109P | 2009-12-14 | 2009-12-14 | |
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| EP09179043.6 | 2009-12-14 | ||
| US61/286,091 | 2009-12-14 | ||
| PCT/EP2010/069465 WO2011073119A1 (en) | 2009-12-14 | 2010-12-13 | Mk2 inhibitors |
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| JP2016128412A (ja) * | 2009-12-14 | 2016-07-14 | メルク・シャープ・エンド・ドーム・ベー・フェー | Mk2インヒビター |
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| CN102936216B (zh) * | 2012-12-05 | 2015-03-04 | 南京药石药物研发有限公司 | 7,9-二氧代-2,6-氮杂-螺[3.5]壬-2-甲酸叔丁酯及其中间体的制备方法 |
| CA2908098A1 (en) | 2013-03-15 | 2014-09-25 | Celgene Avilomics Research, Inc. | Mk2 inhibitors and uses thereof |
| JP6552061B2 (ja) | 2014-06-10 | 2019-07-31 | サンフォード−バーンハム メディカル リサーチ インスティテュート | 代謝型グルタミン酸受容体の負のアロステリックモジュレーター(nams)とその使用 |
| CN108794496B (zh) * | 2018-04-28 | 2020-04-24 | 北京施安泰医药技术开发有限公司 | 一类cdk抑制剂、其药物组合物、制备方法及用途 |
| US11458124B2 (en) | 2018-07-12 | 2022-10-04 | UCBBiopharma Srl | Spirocyclic indane analogues as IL-17 modulators |
| CN114105834B (zh) * | 2022-01-26 | 2023-04-25 | 寿光诺盟化工有限公司 | 一种n,n,n,n-四烯丙基氧代双苯磺酰胺的制备方法 |
| WO2024125464A1 (en) * | 2022-12-11 | 2024-06-20 | Jiangsu Hansoh Pharmaceutical Group Co., Ltd. | Tetrahydroisoquinolin-one derivatives, preparation methods and medicinal uses thereof |
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| BRPI0413438A (pt) * | 2003-08-08 | 2006-10-17 | Pharmacia Italia Spa | derivados de pirimidilpirrol ativos como inibidores de cinase |
| US20050043346A1 (en) * | 2003-08-08 | 2005-02-24 | Pharmacia Italia S.P.A. | Pyridylpyrrole derivatives active as kinase inhibitors |
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| CA2693904A1 (en) * | 2007-07-16 | 2009-01-22 | Novartis Ag | Heterocyclic compounds useful as mk2 inhibitors |
| US8772286B2 (en) * | 2009-12-14 | 2014-07-08 | Merck Sharp & Dohme B.V. | MK2 inhibitors |
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- 2010-12-13 CN CN201510037679.6A patent/CN104710423A/zh active Pending
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- 2010-12-13 IN IN4978DEN2012 patent/IN2012DN04978A/en unknown
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2014
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2015
- 2015-07-09 US US14/795,085 patent/US20160159800A1/en not_active Abandoned
- 2015-11-06 HK HK15110942.1A patent/HK1210159A1/xx unknown
- 2015-12-16 JP JP2015245246A patent/JP2016128412A/ja active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2016128412A (ja) * | 2009-12-14 | 2016-07-14 | メルク・シャープ・エンド・ドーム・ベー・フェー | Mk2インヒビター |
Also Published As
| Publication number | Publication date |
|---|---|
| US9102676B2 (en) | 2015-08-11 |
| US20140288109A1 (en) | 2014-09-25 |
| CA2780290A1 (en) | 2011-06-23 |
| HK1210159A1 (en) | 2016-04-15 |
| US20120245175A1 (en) | 2012-09-27 |
| BR112012013199A2 (pt) | 2016-03-01 |
| EP2513111A1 (en) | 2012-10-24 |
| JP2013513585A (ja) | 2013-04-22 |
| CN102712641B (zh) | 2015-12-09 |
| CN104710423A (zh) | 2015-06-17 |
| WO2011073119A1 (en) | 2011-06-23 |
| JP2016128412A (ja) | 2016-07-14 |
| US8772286B2 (en) | 2014-07-08 |
| AU2010333024A1 (en) | 2012-06-14 |
| AU2010333024B2 (en) | 2014-09-18 |
| RU2012129887A (ru) | 2014-01-27 |
| BR112012013199A8 (pt) | 2018-01-02 |
| IN2012DN04978A (enExample) | 2015-09-25 |
| KR20120104241A (ko) | 2012-09-20 |
| CA2780290C (en) | 2018-01-02 |
| US20160159800A1 (en) | 2016-06-09 |
| MX2012006778A (es) | 2012-07-23 |
| EP2513111B1 (en) | 2013-10-02 |
| CN102712641A (zh) | 2012-10-03 |
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