CA2864672C - Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme - Google Patents
Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme Download PDFInfo
- Publication number
- CA2864672C CA2864672C CA2864672A CA2864672A CA2864672C CA 2864672 C CA2864672 C CA 2864672C CA 2864672 A CA2864672 A CA 2864672A CA 2864672 A CA2864672 A CA 2864672A CA 2864672 C CA2864672 C CA 2864672C
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- CA
- Canada
- Prior art keywords
- pyrimidin
- sulfamate
- pyrazolo
- rac
- ylamino
- 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.)
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- -1 Pyrazolopyrimidinyl Chemical group 0.000 title claims description 337
- 108010091546 Ubiquitin-Activating Enzymes Proteins 0.000 title abstract description 50
- 102000018478 Ubiquitin-Activating Enzymes Human genes 0.000 title abstract description 50
- 239000003112 inhibitor Substances 0.000 title description 19
- 150000005829 chemical entities Chemical class 0.000 claims abstract description 236
- 150000001875 compounds Chemical class 0.000 claims abstract description 224
- 150000003839 salts Chemical class 0.000 claims abstract description 167
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 50
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 40
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 271
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 152
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 150
- 125000005843 halogen group Chemical group 0.000 claims description 124
- 125000001931 aliphatic group Chemical group 0.000 claims description 118
- FIYXUOWXHWJDAM-UHFFFAOYSA-N methyl sulfamate Chemical compound COS(N)(=O)=O FIYXUOWXHWJDAM-UHFFFAOYSA-N 0.000 claims description 102
- 125000003118 aryl group Chemical group 0.000 claims description 56
- 125000000623 heterocyclic group Chemical group 0.000 claims description 53
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 49
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 38
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 38
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 36
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 33
- 125000001072 heteroaryl group Chemical group 0.000 claims description 32
- 201000011510 cancer Diseases 0.000 claims description 31
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 30
- 125000002947 alkylene group Chemical group 0.000 claims description 23
- 230000005764 inhibitory process Effects 0.000 claims description 20
- 238000011282 treatment Methods 0.000 claims description 19
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 16
- 239000003937 drug carrier Substances 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000006706 (C3-C6) carbocyclyl group Chemical group 0.000 claims description 14
- 125000001188 haloalkyl group Chemical group 0.000 claims description 13
- 125000004474 heteroalkylene group Chemical group 0.000 claims description 13
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 8
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- 101000983970 Conus catus Alpha-conotoxin CIB Proteins 0.000 claims description 7
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
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- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
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- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
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- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
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- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 229910007161 Si(CH3)3 Inorganic materials 0.000 claims description 2
- 125000004145 cyclopenten-1-yl group Chemical group [H]C1=C(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 3
- 201000009613 breast lymphoma Diseases 0.000 claims 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- GUAHEWCHNSONQK-SRBBEKPSSA-N 5-[7-[[(1r,2s,3r,4r)-2,3-dihydroxy-4-(sulfamoyloxymethyl)cyclopentyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]naphthalene-2-carboxylic acid Chemical compound O[C@@H]1[C@H](O)[C@@H](COS(=O)(=O)N)C[C@H]1NC1=CC=NC2=CC(C=3C4=CC=C(C=C4C=CC=3)C(O)=O)=NN12 GUAHEWCHNSONQK-SRBBEKPSSA-N 0.000 claims 1
- XDXPCTFDYJMPLE-IXZQUYOESA-N [(1r,2r,3s,4r)-2,3-dihydroxy-4-[(2-pyridin-2-ylpyrazolo[1,5-a]pyrimidin-7-yl)amino]cyclopentyl]methyl sulfamate Chemical compound O[C@@H]1[C@H](O)[C@@H](COS(=O)(=O)N)C[C@H]1NC1=CC=NC2=CC(C=3N=CC=CC=3)=NN12 XDXPCTFDYJMPLE-IXZQUYOESA-N 0.000 claims 1
- UPUSYLJKPLQMMM-UWIFEVILSA-N [(1r,2r,3s,4r)-2,3-dihydroxy-4-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]cyclopentyl]methyl sulfamate Chemical compound CC=1C=NC2=CC(C=3C=CC=CC=3)=NN2C=1N[C@@H]1C[C@H](COS(N)(=O)=O)[C@@H](O)[C@H]1O UPUSYLJKPLQMMM-UWIFEVILSA-N 0.000 claims 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 1
- OBTLKLQNAGSDFP-VKZMIXJFSA-N methyl 5-[7-[[(1r,2s,3r,4r)-2,3-dihydroxy-4-(sulfamoyloxymethyl)cyclopentyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]naphthalene-2-carboxylate Chemical compound C=1C=CC2=CC(C(=O)OC)=CC=C2C=1C(=NN12)C=C1N=CC=C2N[C@@H]1C[C@H](COS(N)(=O)=O)[C@@H](O)[C@H]1O OBTLKLQNAGSDFP-VKZMIXJFSA-N 0.000 claims 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 69
- 208000035269 cancer or benign tumor Diseases 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 225
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 146
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- HUMMCEUVDBVXTQ-UHFFFAOYSA-N naphthalen-1-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=CC=CC2=C1 HUMMCEUVDBVXTQ-UHFFFAOYSA-N 0.000 description 74
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 64
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 29
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- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
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| US61/600,070 | 2012-02-17 | ||
| PCT/US2013/026113 WO2013123169A1 (en) | 2012-02-17 | 2013-02-14 | Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme |
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| CA2864672A1 CA2864672A1 (en) | 2013-08-22 |
| CA2864672C true CA2864672C (en) | 2018-01-09 |
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| US8008307B2 (en) | 2006-08-08 | 2011-08-30 | Millennium Pharmaceuticals, Inc. | Heteroaryl compounds useful as inhibitors of E1 activating enzymes |
| WO2013123169A1 (en) | 2012-02-17 | 2013-08-22 | Millennium Pharmaceuticals, Inc. | Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme |
| EP2879681A4 (en) | 2012-08-03 | 2015-12-23 | Millennium Pharm Inc | INDOINDUBSTITUTED PYRROLOPYRIMIDINYL HIBITORS OF UBA6 |
| JP6378759B2 (ja) | 2013-07-02 | 2018-08-22 | ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． | Ｓｕｍｏ活性化酵素阻害剤として有用なヘテロアリール化合物 |
| JP6603712B2 (ja) | 2014-07-01 | 2019-11-06 | ミレニアム ファーマシューティカルズ， インコーポレイテッド | Ｓｕｍｏ活性化酵素の阻害薬として有用なヘテロアリール化合物 |
| JP6697453B2 (ja) * | 2014-10-29 | 2020-05-20 | ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． | ユビキチン活性化酵素阻害物質及び放射線の投与 |
| WO2016069392A1 (en) | 2014-10-29 | 2016-05-06 | Millennium Pharmaceuticals, Inc. | Administration of ubiquitin-activating enzyme inhibitor and chemotherapeutic agents |
| JP7385658B2 (ja) | 2018-10-30 | 2023-11-22 | クロノス バイオ インコーポレイテッド | Ｃｄｋ９活性を調節するための化合物、組成物、および方法 |
| CN117412973A (zh) * | 2021-05-31 | 2024-01-16 | 上海瑛派药业有限公司 | 含氮稠合杂芳双环化合物作为usp1抑制剂及其应用 |
| WO2023021498A1 (en) * | 2021-08-16 | 2023-02-23 | Moya Bio Ltd. | Fused azole and furan based nucleoside analogs and uses thereof |
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| CA2477795A1 (en) | 2002-02-28 | 2003-09-12 | Kandasamy Sakthivel | Nucleoside 5'-monophosphate mimics and their prodrugs |
| MXPA05002573A (es) | 2002-09-04 | 2005-09-08 | Schering Corp | Pirazolopirimidinas como inhibidores de cinasa dependientes de ciclina. |
| US7196092B2 (en) | 2002-09-04 | 2007-03-27 | Schering Corporation | N-heteroaryl pyrazolopyrimidines as cyclin dependent kinase inhibitors |
| MXPA05002572A (es) | 2002-09-04 | 2005-09-08 | Schering Corp | Compuestos pirazolo[1,5-a]pirimidinas como inhibidores de cinasa depentes de ciclina. |
| US7563798B2 (en) | 2002-09-04 | 2009-07-21 | Schering Corporation | Substituted pyrazolo[1,5-a]pyrimidines as protein kinase inhibitors |
| US20070179161A1 (en) | 2003-03-31 | 2007-08-02 | Vernalis (Cambridge) Limited. | Pyrazolopyrimidine compounds and their use in medicine |
| JP2005008581A (ja) | 2003-06-20 | 2005-01-13 | Kissei Pharmaceut Co Ltd | 新規なピラゾロ［１，５−ａ］ピリミジン誘導体、それを含有する医薬組成物およびそれらの用途 |
| EP1680431A1 (en) | 2003-10-17 | 2006-07-19 | Rigel Pharmaceuticals, Inc. | Benzothiazole and thiazole'5,5-b!pyridine compositions and their use as ubiquitin ligase inhibitors |
| WO2006002284A1 (en) | 2004-06-22 | 2006-01-05 | Rigel Pharmaceuticals, Inc. | Ubiquitin ligase inhibitors |
| DK1848718T3 (da) | 2005-02-04 | 2012-08-27 | Millennium Pharm Inc | E1 aktiveringsenzymhæmmere |
| US7642266B2 (en) | 2005-10-06 | 2010-01-05 | Schering Corporation | Substituted pyrazolo[1,5-a]pyrimidines as protein kinase inhibitors |
| PT1989206E (pt) * | 2006-02-02 | 2012-10-15 | Millennium Pharm Inc | Inibidores da enzima de ativação e1 |
| EP1992008A1 (en) * | 2006-02-28 | 2008-11-19 | Sez Ag | Device and method for liquid treating disc-like articles |
| US8008307B2 (en) * | 2006-08-08 | 2011-08-30 | Millennium Pharmaceuticals, Inc. | Heteroaryl compounds useful as inhibitors of E1 activating enzymes |
| BRPI0715176A8 (pt) * | 2006-08-08 | 2018-04-10 | Millennium Pharm Inc | compostos de heteroarila utéis como inibidores de enzimas de ativação e1 |
| WO2008154642A2 (en) | 2007-06-12 | 2008-12-18 | Achaogen, Inc. | Antibacterial agents |
| RU2553476C2 (ru) | 2007-08-02 | 2015-06-20 | Миллениум Фармасьютикалз, Инк. | Способ синтеза ингибиторов е1-активирующего фермента |
| US9216983B2 (en) | 2007-12-21 | 2015-12-22 | Board Of Regents, University Of Texas System | Dihydroorotate dehydrogenase inhibitors with selective anti-malarial activity |
| WO2010086040A1 (en) | 2009-01-29 | 2010-08-05 | Biomarin Iga, Ltd. | Pyrazolo-pyrimidines for treatment of duchenne muscular dystrophy |
| WO2010088518A2 (en) | 2009-01-31 | 2010-08-05 | Kalypsys, Inc. | Heterocyclic modulators of gpr119 for treatment of disease |
| SG175929A1 (en) * | 2009-05-14 | 2011-12-29 | Millennium Pharm Inc | Hydrochloride salt of ((1s,2s,4r)-4-{4-[(1s)-2,3-dihydro-1h-inden-1-ylamino]-7h-pyrrolo [2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate |
| AU2010347233B2 (en) | 2010-03-01 | 2015-06-18 | Oncternal Therapeutics, Inc. | Compounds for treatment of cancer |
| US20120077814A1 (en) | 2010-09-10 | 2012-03-29 | Zhong Wang | Sulfonamide, sulfamate, and sulfamothioate derivatives |
| CN103889988B (zh) | 2011-08-24 | 2018-05-04 | 米伦纽姆医药公司 | Nedd8-活化酶的抑制剂 |
| WO2013123169A1 (en) | 2012-02-17 | 2013-08-22 | Millennium Pharmaceuticals, Inc. | Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme |
| EP2879681A4 (en) | 2012-08-03 | 2015-12-23 | Millennium Pharm Inc | INDOINDUBSTITUTED PYRROLOPYRIMIDINYL HIBITORS OF UBA6 |
| JP6378759B2 (ja) | 2013-07-02 | 2018-08-22 | ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． | Ｓｕｍｏ活性化酵素阻害剤として有用なヘテロアリール化合物 |
| JP6603712B2 (ja) | 2014-07-01 | 2019-11-06 | ミレニアム ファーマシューティカルズ， インコーポレイテッド | Ｓｕｍｏ活性化酵素の阻害薬として有用なヘテロアリール化合物 |
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2013
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- 2013-02-14 GE GEAP201313560A patent/GEP201706687B/en unknown
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2014
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2016
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2017
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