CA2651136C - Substituted thieno-fused pyrimidines as p13k inhibitors - Google Patents
Substituted thieno-fused pyrimidines as p13k inhibitors Download PDFInfo
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- CA2651136C CA2651136C CA2651136A CA2651136A CA2651136C CA 2651136 C CA2651136 C CA 2651136C CA 2651136 A CA2651136 A CA 2651136A CA 2651136 A CA2651136 A CA 2651136A CA 2651136 C CA2651136 C CA 2651136C
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- acid
- substituted
- alkyl
- unsubstituted
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- 239000003112 inhibitor Substances 0.000 title abstract description 8
- 150000003230 pyrimidines Chemical class 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 126
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 47
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 44
- 230000008569 process Effects 0.000 claims abstract description 35
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 31
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 18
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 18
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 17
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 16
- 201000011510 cancer Diseases 0.000 claims abstract description 15
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 15
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 13
- 150000002367 halogens Chemical class 0.000 claims abstract description 13
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 11
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 8
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- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 230000000694 effects Effects 0.000 claims abstract description 7
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- 125000006347 bis(trifluoromethyl)hydroxymethyl group Chemical group [H]OC(*)(C(F)(F)F)C(F)(F)F 0.000 claims abstract 3
- 239000000203 mixture Substances 0.000 claims description 47
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 21
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 14
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
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- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 10
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
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- 125000004452 carbocyclyl group Chemical group 0.000 claims description 9
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
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- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 8
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 7
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims description 6
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 claims description 6
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- FNQJDLTXOVEEFB-UHFFFAOYSA-N 1,2,3-benzothiadiazole Chemical compound C1=CC=C2SN=NC2=C1 FNQJDLTXOVEEFB-UHFFFAOYSA-N 0.000 claims description 5
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical compound C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 claims description 5
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 5
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical compound C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 claims description 5
- JBYRSSMFLXQHKH-UHFFFAOYSA-N 2-amino-1h-pyrazol-3-one Chemical compound NN1NC=CC1=O JBYRSSMFLXQHKH-UHFFFAOYSA-N 0.000 claims description 5
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims description 5
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 claims description 5
- 239000005964 Acibenzolar-S-methyl Substances 0.000 claims description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 5
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 5
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| GB0608820.7 | 2006-05-04 | ||
| PCT/GB2007/001644 WO2007132171A1 (en) | 2006-05-04 | 2007-05-04 | Pharmaceutical compounds |
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| AR064155A1 (es) | 2006-12-07 | 2009-03-18 | Piramed Ltd | Compuestos de inhibidores de fosfoinositido-3 quinasa y metodos de uso |
| WO2008073785A2 (en) | 2006-12-07 | 2008-06-19 | Genentech, Inc. | Phosphoinositide 3-kinase inhibitor compounds and methods of use |
| EP2173722B1 (en) * | 2007-07-26 | 2012-08-29 | Novartis AG | Pyrimidine derivatives useful for the treatment of inflammatory or allergic conditions |
| TWI471134B (zh) | 2007-09-12 | 2015-02-01 | Genentech Inc | 肌醇磷脂３－激酶抑制劑化合物及化療劑之組合及使用方法 |
| CA2701292C (en) * | 2007-10-25 | 2015-03-24 | Genentech, Inc. | Process for making thienopyrimidine compounds |
| GB0721095D0 (en) * | 2007-10-26 | 2007-12-05 | Piramed Ltd | Pharmaceutical compounds |
| CA2710194C (en) | 2007-12-19 | 2014-04-22 | Amgen Inc. | Inhibitors of p13 kinase |
| US8415376B2 (en) | 2008-05-30 | 2013-04-09 | Amgen Inc. | Inhibitors of PI3 kinase |
| US8163743B2 (en) * | 2008-06-05 | 2012-04-24 | GlaxoGroupLimited | 4-carboxamide indazole derivatives useful as inhibitors of PI3-kinases |
| ES2383246T3 (es) | 2008-06-05 | 2012-06-19 | Glaxo Group Limited | 4-amino-indazoles |
| JP5502076B2 (ja) | 2008-06-05 | 2014-05-28 | グラクソ グループ リミテッド | 新規化合物 |
| WO2009147188A1 (en) | 2008-06-05 | 2009-12-10 | Glaxo Group Limited | Benzpyrazol derivatives as inhibitors of pi3 kinases |
| KR20110046514A (ko) | 2008-07-31 | 2011-05-04 | 제넨테크, 인크. | 피리미딘 화합물, 조성물 및 사용 방법 |
| JP5656880B2 (ja) | 2009-03-09 | 2015-01-21 | グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ | Ｐｉ３キナーゼの阻害剤としての４−オキサジアゾール−２−イル−インダゾール |
| MX2011009796A (es) | 2009-03-20 | 2011-12-14 | Amgen Inc | Inhibidores de la cinasa pi3. |
| CN102361878A (zh) | 2009-03-24 | 2012-02-22 | 住友化学株式会社 | 用于制备硼酸酯化合物的方法 |
| MY160454A (en) | 2009-04-30 | 2017-03-15 | Glaxo Group Ltd | Oxazole substituted indazoles as pi3-kinase inhibitors |
| EP2451811A1 (en) | 2009-05-27 | 2012-05-16 | F. Hoffmann-La Roche AG | Bicyclic indole-pyrimidine pi3k inhibitor compounds selective for p110 delta, and methods of use |
| CA2761445A1 (en) | 2009-05-27 | 2010-12-02 | Genentech, Inc. | Bicyclic pyrimidine pi3k inhibitor compounds selective for p110 delta, and methods of use |
| WO2011011550A1 (en) | 2009-07-21 | 2011-01-27 | Calistoga Pharmaceuticals Inc. | Treatment of liver disorders with pi3k inhibitors |
| MX2012005463A (es) | 2009-11-12 | 2012-09-12 | Hoffmann La Roche | Compuestos de purina n/9 sustituida, composiciones y metodos de uso. |
| BR112012011147A2 (pt) | 2009-11-12 | 2021-09-08 | F.Hoffmann-La Roche Ag | Composto, composição farmacêutica e uso de um composto. |
| GB201018124D0 (en) | 2010-10-27 | 2010-12-08 | Glaxo Group Ltd | Polymorphs and salts |
| EP3053925A1 (en) | 2010-12-16 | 2016-08-10 | F. Hoffmann-La Roche AG | Tricyclic pi3k inhibitor compounds and methods of use |
| WO2013152717A1 (zh) * | 2012-04-10 | 2013-10-17 | 上海昀怡健康管理咨询有限公司 | 稠合嘧啶类化合物，其制备方法，中间体，组合物和应用 |
| KR20160027218A (ko) | 2012-05-23 | 2016-03-09 | 에프. 호프만-라 로슈 아게 | 내배엽 및 간세포를 수득하고 사용하는 조성물 및 방법 |
| US9745321B2 (en) | 2013-09-30 | 2017-08-29 | Shanghai Yingli Pharmaceutical Co., Ltd | Fused pyrimidine compound, intermediate, preparation method therefor, and composition and application thereof |
| AU2016378723B2 (en) | 2015-12-22 | 2021-09-30 | SHY Therapeutics LLC | Compounds for the treatment of cancer and inflammatory disease |
| MA49458A (fr) | 2017-06-21 | 2020-04-29 | SHY Therapeutics LLC | Composés interagissant avec la superfamille ras destinés à être utilisés dans le traitement de cancers, de maladies inflammatoires, de rasopathies et de maladies fibrotiques |
| EP3898609A1 (en) | 2018-12-19 | 2021-10-27 | Shy Therapeutics LLC | Compounds that interact with the ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease |
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| US6187777B1 (en) * | 1998-02-06 | 2001-02-13 | Amgen Inc. | Compounds and methods which modulate feeding behavior and related diseases |
| JP3810017B2 (ja) * | 2000-04-27 | 2006-08-16 | アステラス製薬株式会社 | 縮合ヘテロアリール誘導体 |
| CN1186324C (zh) | 2000-04-27 | 2005-01-26 | 山之内制药株式会社 | 稠合杂芳基衍生物 |
| ES2217956B1 (es) * | 2003-01-23 | 2006-04-01 | Almirall Prodesfarma, S.A. | Nuevos derivados de 4-aminotieno(2,3-d)pirimidin-6-carbonitrilo. |
| AR045445A1 (es) * | 2003-08-05 | 2005-10-26 | Vertex Pharma | Compuestos ihinibidores de canales ionicos regulados por voltaje |
| GB0423653D0 (en) * | 2004-10-25 | 2004-11-24 | Piramed Ltd | Pharmaceutical compounds |
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| US20090209559A1 (en) | 2009-08-20 |
| CA2651136A1 (en) | 2007-11-22 |
| ES2562935T3 (es) | 2016-03-09 |
| EP2035431B1 (en) | 2016-02-03 |
| CN101479276B (zh) | 2012-11-14 |
| JP5329395B2 (ja) | 2013-10-30 |
| CN101479276A (zh) | 2009-07-08 |
| JP2009535390A (ja) | 2009-10-01 |
| GB0608820D0 (en) | 2006-06-14 |
| US8153639B2 (en) | 2012-04-10 |
| WO2007132171A1 (en) | 2007-11-22 |
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