CA2692720A1 - Morpholino pyrimidine derivatives used in diseases linked to mtor kinase and/or pi3k - Google Patents
Morpholino pyrimidine derivatives used in diseases linked to mtor kinase and/or pi3k Download PDFInfo
- Publication number
- CA2692720A1 CA2692720A1 CA 2692720 CA2692720A CA2692720A1 CA 2692720 A1 CA2692720 A1 CA 2692720A1 CA 2692720 CA2692720 CA 2692720 CA 2692720 A CA2692720 A CA 2692720A CA 2692720 A1 CA2692720 A1 CA 2692720A1
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- Canada
- Prior art keywords
- 6alkyl
- 6alkoxy
- amino
- bis
- formula
- 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.)
- Abandoned
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 40
- 201000010099 disease Diseases 0.000 title claims abstract description 38
- 108091000080 Phosphotransferase Proteins 0.000 title description 18
- 102000020233 phosphotransferase Human genes 0.000 title description 18
- DUIMWXDLDBNUFD-UHFFFAOYSA-N 4-pyrimidin-2-ylmorpholine Chemical class C1COCCN1C1=NC=CC=N1 DUIMWXDLDBNUFD-UHFFFAOYSA-N 0.000 title description 6
- 101150097381 Mtor gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 302
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- 238000000034 method Methods 0.000 claims abstract description 56
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- 230000002062 proliferating effect Effects 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- -1 nitro, hydroxy Chemical group 0.000 claims description 355
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 320
- 125000005843 halogen group Chemical group 0.000 claims description 213
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 167
- 125000001424 substituent group Chemical group 0.000 claims description 160
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 148
- 229910052739 hydrogen Inorganic materials 0.000 claims description 146
- 239000001257 hydrogen Substances 0.000 claims description 145
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 137
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 128
- 125000000623 heterocyclic group Chemical group 0.000 claims description 95
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 84
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 81
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 81
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 74
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 72
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 70
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 63
- 229910052757 nitrogen Inorganic materials 0.000 claims description 45
- 125000005647 linker group Chemical group 0.000 claims description 39
- 241001465754 Metazoa Species 0.000 claims description 35
- 125000004429 atom Chemical group 0.000 claims description 34
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 33
- 150000002431 hydrogen Chemical class 0.000 claims description 33
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 33
- 125000004076 pyridyl group Chemical group 0.000 claims description 30
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 28
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 27
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 24
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 19
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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 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 11
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 11
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 10
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- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 9
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 8
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
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- MKMSWAKWCOVXBQ-KRWDZBQOSA-N 1-(4-methoxyphenyl)-3-[4-[4-[(3s)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]thiourea Chemical compound C1=CC(OC)=CC=C1NC(=S)NC1=CC=C(C=2N=C(C=C(CS(C)(=O)=O)N=2)N2[C@H](COCC2)C)C=C1 MKMSWAKWCOVXBQ-KRWDZBQOSA-N 0.000 claims description 2
- NOPFSYBMFRVQFJ-KRWDZBQOSA-N 1-[2-(dimethylamino)ethyl]-3-[4-[4-[(3s)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidin-2-yl]phenyl]thiourea Chemical compound C[C@H]1COCCN1C1=CC(C(C)(C)S(C)(=O)=O)=NC(C=2C=CC(NC(=S)NCCN(C)C)=CC=2)=N1 NOPFSYBMFRVQFJ-KRWDZBQOSA-N 0.000 claims description 2
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- TYSOCOFJTDKJAJ-KRWDZBQOSA-N 1-[4-[4-[(3s)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]-3-phenylthiourea Chemical compound C[C@H]1COCCN1C1=CC(CS(C)(=O)=O)=NC(C=2C=CC(NC(=S)NC=3C=CC=CC=3)=CC=2)=N1 TYSOCOFJTDKJAJ-KRWDZBQOSA-N 0.000 claims description 2
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- Health & Medical Sciences (AREA)
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- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Heart & Thoracic Surgery (AREA)
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| US60/948,539 | 2007-07-09 | ||
| PCT/GB2008/050548 WO2009007750A1 (en) | 2007-07-09 | 2008-07-08 | Morpholino pyrimidine derivatives used in diseases linked to mtor kinase and/or pi3k |
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| CA2692720A1 true CA2692720A1 (en) | 2009-01-15 |
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| CA 2692720 Abandoned CA2692720A1 (en) | 2007-07-09 | 2008-07-08 | Morpholino pyrimidine derivatives used in diseases linked to mtor kinase and/or pi3k |
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Families Citing this family (56)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010533158A (ja) * | 2007-07-09 | 2010-10-21 | アストラゼネカ アクチボラグ | 化合物類−９４５ |
| JP5599783B2 (ja) | 2008-05-30 | 2014-10-01 | アムジエン・インコーポレーテツド | Ｐｉ３キナーゼの阻害薬 |
| WO2010103094A1 (en) | 2009-03-13 | 2010-09-16 | Cellzome Limited | PYRIMIDINE DERIVATIVES AS mTOR INHIBITORS |
| UY32582A (es) | 2009-04-28 | 2010-11-30 | Amgen Inc | Inhibidores de fosfoinositida 3 cinasa y/u objetivo mamífero |
| PE20120640A1 (es) | 2009-07-02 | 2012-06-09 | Sanofi Sa | Nuevos derivados de (6-oxo-1,6-dihidro-pirimidin-2-il)-amida, su preparacion y su utilizacion farmaceutica como inhibidores de fosforilacion de akt (pkb) |
| AR077628A1 (es) | 2009-07-02 | 2011-09-14 | Sanofi Aventis | Derivados de 6-(morfolin-4-il)-pirimidin-4(3h)-ona, su preparacion y su utilizacion farmaceutica como inhibidores de la fosforilacion de akt(pkb) |
| PH12012500809A1 (en) | 2009-10-30 | 2012-11-26 | Ariad Pharma Inc | Methods and compositions for treating cancer |
| BR112012019459A2 (pt) | 2010-02-03 | 2017-10-17 | Signal Pharm Llc | identificação de mutação de lkb1 como um biomarcador preditivo para sensibilidade para inibidores de tor quinase. |
| EP2542536B1 (en) | 2010-03-04 | 2015-01-21 | Cellzome Limited | Morpholino substituted urea derivatives as mtor inhibitors |
| JO2998B1 (ar) | 2010-06-04 | 2016-09-05 | Amgen Inc | مشتقات بيبيريدينون كمثبطات mdm2 لعلاج السرطان |
| ES2612492T3 (es) | 2010-12-28 | 2017-05-17 | Sanofi | Nuevos derivados de piridiminas, su preparación y su utilización farmacéutica como inhibidores de fosforilación de AKT (PKB) |
| US20140163023A1 (en) | 2011-04-04 | 2014-06-12 | Cellzome Limited | Dihydropyrrolo pyrimidine derivatives as mtor inhibitors |
| CN107320734A (zh) | 2011-04-29 | 2017-11-07 | 西莱克塔生物科技公司 | 从合成纳米载体中控制释放免疫抑制剂 |
| CA2843887A1 (en) | 2011-08-03 | 2013-02-07 | Signal Pharmaceuticals, Llc | Identification of gene expression profile as a predictive biomarker for lkb1 status |
| BR112014006743A8 (pt) | 2011-09-21 | 2018-01-09 | Cellzome Ltd | composto, uso de um composto, e, método para tratar, controlar, retardar ou impedir uma ou mais condições |
| MX352672B (es) | 2011-09-27 | 2017-12-04 | Amgen Inc | Compuestos heterocíclicos como inhibidores de mdm2 para el tratamiento del cáncer. |
| MX341577B (es) | 2011-10-07 | 2016-08-25 | Cellzome Ltd | Derivados biciclicos de pirimidin-urea o carbamato sustituidos con morfolino como inhibidores del blanco de rapamicina de mamifero. |
| SG11201407420RA (en) | 2012-07-04 | 2015-02-27 | Hoffmann La Roche | Covalently linked antigen-antibody conjugates |
| FR2994572B1 (fr) * | 2012-08-17 | 2015-04-17 | Centre Nat Rech Scient | Pyrido[3,2-d]pyrimidines trisubstituees, leurs procedes de preparation et leurs utilisation en therapeutique |
| AU2013203714B2 (en) | 2012-10-18 | 2015-12-03 | Signal Pharmaceuticals, Llc | Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity |
| US20160002185A1 (en) * | 2013-02-19 | 2016-01-07 | Amgen Inc. | Cis-morpholinone and other compounds as mdm2 inhibitors for the treatment of cancer |
| US11407721B2 (en) | 2013-02-19 | 2022-08-09 | Amgen Inc. | CIS-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer |
| WO2014151863A1 (en) | 2013-03-14 | 2014-09-25 | Amgen Inc. | Heteroaryl acid morpholinone compounds as mdm2 inhibitors for the treatment of cancer |
| WO2014172436A1 (en) | 2013-04-17 | 2014-10-23 | Signal Pharmaceuticals, Llc | Combination therapy comprising a tor kinase inhibitor and a 5-substituted quinazolinone compound for treating cancer |
| JP6382946B2 (ja) | 2013-04-17 | 2018-08-29 | シグナル ファーマシューティカルズ，エルエルシー | ジヒドロピラジノ−ピラジンによる癌治療 |
| WO2014172425A1 (en) | 2013-04-17 | 2014-10-23 | Signal Pharmaceuticals, Llc | Treatment of cancer with dihydropyrazino-pyrazines |
| CA2908742C (en) | 2013-04-17 | 2021-06-01 | Signal Pharmaceuticals, Llc | Combination therapy comprising a tor kinase inhibitor and a cytidine analog for treating cancer |
| EP3549940A1 (en) | 2013-04-17 | 2019-10-09 | Signal Pharmaceuticals, LLC | Pharmaceutical formulations, of 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one |
| HK1221168A1 (zh) | 2013-04-17 | 2017-05-26 | 西格诺药品有限公司 | 用於治疗癌症的包括tor激酶抑制剂和n-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯基氨基)嘧啶-4-基氨基)苯基)丙烯醯胺的组合疗法 |
| MY189663A (en) | 2013-04-17 | 2022-02-23 | Signal Pharm Llc | Combination therapy comprising a dihydropyrazino-pyrazine compound and an androgen receptor antagonist for treating prostate cancer |
| CN105307641A (zh) | 2013-05-03 | 2016-02-03 | 西莱克塔生物科技公司 | 用于降低不期望体液免疫应答的给药组合 |
| CN107474051B (zh) | 2013-05-29 | 2020-10-30 | 西格诺药品有限公司 | 二氢吡嗪并吡嗪化合物的药物组合物、其固体形式和它们的用途 |
| MA53572A1 (fr) | 2013-06-10 | 2021-10-29 | Amgen Inc | Procédés de production et formes cristallines d'un inhibiteur mdm2 |
| WO2015101586A1 (en) | 2014-01-03 | 2015-07-09 | F. Hoffmann-La Roche Ag | Bispecific anti-hapten/anti-blood brain barrier receptor antibodies, complexes thereof and their use as blood brain barrier shuttles |
| WO2015160880A1 (en) | 2014-04-16 | 2015-10-22 | Signal Pharmaceuticals, Llc | SOLID FORMS COMPRISING 1-ETHYL-7-(2-METHYL-6-(1H-1,2,4-TRIAZOL-3-YL) PYRIDIN-3-YL)-3,4-DIHYDROPYRAZINO(2,3-b)PYRAZIN-2(1H)-ONE, AND A COFORMER, COMPOSITIONS AND METHODS OF USE THEREOF |
| NZ714742A (en) | 2014-04-16 | 2017-04-28 | Signal Pharm Llc | Solid forms of 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one, compositions thereof and methods of their use |
| CN106687476B (zh) | 2014-06-26 | 2020-11-13 | 豪夫迈·罗氏有限公司 | 抗brdu抗体及使用方法 |
| MY195016A (en) | 2014-08-04 | 2023-01-03 | Nuevolution As | Optionally Fused Heterocyclyl-Substituted Derivatives of Pyrimidine Useful for The Treatment of Inflammatory, Metabolic, Oncologic and Autoimmune Diseases |
| EA201790551A1 (ru) | 2014-09-07 | 2017-07-31 | Селекта Байосайенсиз, Инк. | Способы и композиции для ослабления иммунных ответов к пропускающему экзон вирусному трансферному вектору |
| TW201813963A (zh) | 2016-09-23 | 2018-04-16 | 美商基利科學股份有限公司 | 磷脂醯肌醇3-激酶抑制劑 |
| TW201825465A (zh) | 2016-09-23 | 2018-07-16 | 美商基利科學股份有限公司 | 磷脂醯肌醇3-激酶抑制劑 |
| TW201815787A (zh) | 2016-09-23 | 2018-05-01 | 美商基利科學股份有限公司 | 磷脂醯肌醇3-激酶抑制劑 |
| EP4599848A3 (en) | 2017-03-11 | 2025-12-03 | Cartesian Therapeutics, Inc. | Methods and compositions related to combined treatment with anti-inflammatories and synthetic nanocarriers comprising an immunosuppressant |
| WO2018218197A2 (en) | 2017-05-26 | 2018-11-29 | Board Of Regents, The University Of Texas System | Tetrahydropyrido[4,3-d]pyrimidine inhibitors of atr kinase |
| IL271491B2 (en) | 2017-06-22 | 2023-09-01 | Celgene Corp | Treatment of carcinoma of the liver characterized by hepatitis b virus infection |
| HRP20240368T1 (hr) | 2017-07-13 | 2024-08-30 | Board Of Regents, The University Of Texas System | Heterociklički inhibitori atr kinaze |
| JP7290627B2 (ja) | 2017-08-17 | 2023-06-13 | ボード オブ レジェンツ，ザ ユニバーシティ オブ テキサス システム | Ａｔｒキナーゼの複素環式阻害剤 |
| JP7341156B2 (ja) | 2018-03-16 | 2023-09-08 | ボード オブ レジェンツ，ザ ユニバーシティ オブ テキサス システム | Ａｔｒキナーゼの複素環式阻害剤 |
| HUE065486T2 (hu) * | 2019-05-10 | 2024-05-28 | Deciphera Pharmaceuticals Llc | Fenilaminopirimidinamid autophágia inhibitorok és azok felhasználási eljárásai |
| US12553041B2 (en) | 2019-06-04 | 2026-02-17 | Cartesian Therapeutics Inc. | Formulations and doses of pegylated uricase |
| AU2020405446A1 (en) | 2019-12-20 | 2022-05-26 | Nuevolution A/S | Compounds active towards nuclear receptors |
| BR112022012205A2 (pt) | 2019-12-20 | 2022-09-13 | Nuevolution As | Compostos ativos para receptores nucleares |
| CA3174252A1 (en) | 2020-03-31 | 2021-10-07 | Nuevolution A/S | Compounds active towards nuclear receptors |
| JP7713954B2 (ja) | 2020-03-31 | 2025-07-28 | ヌエヴォリューション・アクティーゼルスカブ | 核内受容体に対して活性な化合物 |
| CN111646985A (zh) * | 2020-06-01 | 2020-09-11 | 江苏集萃分子工程研究院有限公司 | 一种含嘧啶杂环抗肿瘤药物分子azd6738的合成方法 |
| WO2023091887A1 (en) | 2021-11-16 | 2023-05-25 | Genentech, Inc. | Methods and compositions for treating systemic lupus erythematosus (sle) with mosunetuzumab |
Family Cites Families (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3922735A1 (de) * | 1989-07-11 | 1991-01-24 | Hoechst Ag | Aminopyrimidin-derivate, verfahren zu ihrer herstellung, sie enthaltende mittel und ihre verwendung als fungizide |
| 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 |
| AU5261001A (en) | 2000-04-27 | 2001-11-12 | Imperial Cancer Research Technology Ltd | Condensed heteroaryl derivatives |
| ES2271100T3 (es) | 2000-11-10 | 2007-04-16 | F. Hoffman-La Roche Ag | Derivados de pirimidina y su empleo como ligandos del receptor de neuropeptido. |
| DK2316831T3 (da) | 2002-11-21 | 2013-06-10 | Novartis Ag | 2-(Morpholin-4-yl)pyrimidiner som phosphotidylinositol (PI)-3-kinaseinhibitorer samt deres anvendelse ved behandling af cancer |
| WO2005000404A2 (en) | 2003-05-29 | 2005-01-06 | Synta Pharmaceuticals, Corp. | Heterocyclic compounds for preventing and treating disorders associated with excessive bone loss |
| GB0415364D0 (en) * | 2004-07-09 | 2004-08-11 | Astrazeneca Ab | Pyrimidine derivatives |
| GB0415365D0 (en) * | 2004-07-09 | 2004-08-11 | Astrazeneca Ab | Pyrimidine derivatives |
| GB0415367D0 (en) * | 2004-07-09 | 2004-08-11 | Astrazeneca Ab | Pyrimidine derivatives |
| WO2007084413A2 (en) | 2004-07-14 | 2007-07-26 | Ptc Therapeutics, Inc. | Methods for treating hepatitis c |
| US7772271B2 (en) * | 2004-07-14 | 2010-08-10 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| JP2008519850A (ja) * | 2004-11-10 | 2008-06-12 | シンタ ファーマシューティカルズ コーポレーション | Ｉｌ−１２調節化合物 |
| WO2006124874A2 (en) | 2005-05-12 | 2006-11-23 | Kalypsys, Inc. | Inhibitors of b-raf kinase |
| TW200720256A (en) | 2005-05-13 | 2007-06-01 | Synta Pharmaceuticals Corp | IL-12 modulatory compounds |
| MX2007014617A (es) | 2005-05-20 | 2008-02-11 | Methylgene Inc | Inhibidores de senalizacion de receptor de factor de crecimiento endotelial bascular y receptor de factor de crecimiento de hepatocitos. |
| DE102005024494A1 (de) | 2005-05-27 | 2006-11-30 | Bayer Healthcare Ag | Verwendung von Cyanopyrimidinen |
| BRPI0613501A2 (pt) | 2005-07-01 | 2011-01-11 | Irm Llc | composto, composição farmacêutica e uso do mesmo |
| CA2617042A1 (en) | 2005-07-29 | 2007-02-01 | Takeda Pharmaceutical Company Limited | Spiro-cyclic compound |
| AU2006284751A1 (en) * | 2005-09-01 | 2007-03-08 | Array Biopharma Inc. | Raf inhibitor compounds and methods of use thereof |
| JP4531027B2 (ja) | 2005-09-29 | 2010-08-25 | 田辺三菱製薬株式会社 | 医薬組成物 |
| JP2007091649A (ja) | 2005-09-29 | 2007-04-12 | Taisho Pharmaceut Co Ltd | ピリミジン誘導体及びその使用に関連する治療方法 |
| CN101801971A (zh) | 2005-09-30 | 2010-08-11 | 沃泰克斯药物股份有限公司 | 可用作janus激酶抑制剂的脱氮嘌呤 |
| BRPI0616630B8 (pt) | 2005-09-30 | 2021-05-25 | Miikana Therapeutics Inc | compostos de pirazol substituídos |
| GB2431156A (en) * | 2005-10-11 | 2007-04-18 | Piramed Ltd | 1-cyclyl-3-substituted- -benzenes and -azines as inhibitors of phosphatidylinositol 3-kinase |
| GB0520657D0 (en) | 2005-10-11 | 2005-11-16 | Ludwig Inst Cancer Res | Pharmaceutical compounds |
| BRPI0618011A2 (pt) | 2005-10-28 | 2011-08-16 | Astrazeneca Ab | composto ou um sal farmaceuticamente aceitável do mesmo, processo para a preparação do mesmo, composição farmacêutica, uso de um composto ou um sal farmaceuticamente aceitável do mesmo, e, métodos para produzir um efeito anti-proliferativo e um efeito pró-apoptósico em um animal de sangue quente, para tratar doença e para produzir um efeito inibidor de jak em um animal de sangue quente |
| JPWO2007063868A1 (ja) | 2005-11-29 | 2009-05-07 | 東レ株式会社 | アリールメチレンウレア誘導体及びその用途 |
| GB0525083D0 (en) * | 2005-12-09 | 2006-01-18 | Astrazeneca Ab | Pyrimidine derivatives |
| GB0525080D0 (en) | 2005-12-09 | 2006-01-18 | Astrazeneca Ab | Pyrimidine derivatives |
| GB0525081D0 (en) | 2005-12-09 | 2006-01-18 | Astrazeneca Ab | Pyrimidine derivatives |
| NL2000323C2 (nl) | 2005-12-20 | 2007-11-20 | Pfizer Ltd | Pyrimidine-derivaten. |
| KR20080083188A (ko) | 2006-01-11 | 2008-09-16 | 아스트라제네카 아베 | 모르폴리노 피리미딘 유도체 및 요법에서의 그 유도체의용도 |
| JO2660B1 (en) | 2006-01-20 | 2012-06-17 | نوفارتيس ايه جي | Pi-3 inhibitors and methods of use |
| EA200870217A1 (ru) | 2006-01-30 | 2009-02-27 | Экселиксис, Инк. | 4-арил-2-аминопиримидины или 4-арил-2-аминоалкилпиримидины в качестве модуляторов jak-2 и содержащие их фармацевтические композиции |
| EP2008210A1 (en) | 2006-03-15 | 2008-12-31 | Csir | Modulation of phosphoryl transferase activity of glutamine synthetase |
| JP5243696B2 (ja) | 2006-03-17 | 2013-07-24 | 田辺三菱製薬株式会社 | ベンゼン誘導体 |
| EP2003131A4 (en) | 2006-04-04 | 2009-12-16 | Taisho Pharmaceutical Co Ltd | AMINOPYRROLIDINE COMPOUND |
| MX2008013430A (es) | 2006-04-19 | 2009-01-26 | Novartis Vaccines & Diagnostic | Compuestos de indazol y metodos para la inhibición de cdc7. |
| WO2007126043A1 (ja) | 2006-04-27 | 2007-11-08 | Mitsubishi Tanabe Pharma Corporation | チアゾール環を含むカルボン酸誘導体の医薬用途 |
| GB0610909D0 (en) | 2006-06-05 | 2006-07-12 | Merck Sharp & Dohme | Therapeutic treatment |
| AU2007269540B2 (en) | 2006-07-05 | 2013-06-27 | Exelixis, Inc. | Methods of using IGF1R and Abl kinase modulators |
| US20090325957A1 (en) | 2006-08-24 | 2009-12-31 | Astrazeneca Ab | Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders |
| WO2008023159A1 (en) | 2006-08-24 | 2008-02-28 | Astrazeneca Ab | Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders |
| US20080234262A1 (en) * | 2007-03-21 | 2008-09-25 | Wyeth | Pyrazolopyrimidine analogs and their use as mtor kinase and pi3 kinase inhibitors |
| JP2010523637A (ja) | 2007-04-12 | 2010-07-15 | エフ．ホフマン−ラ ロシュ アーゲー | 医薬化合物 |
| JP2010533161A (ja) | 2007-07-09 | 2010-10-21 | アストラゼネカ アクチボラグ | 化合物−９４６ |
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- 2008-07-08 EA EA201000091A patent/EA018708B1/ru not_active IP Right Cessation
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| ZA200909224B (en) | 2011-05-25 |
| CO6251364A2 (es) | 2011-02-21 |
| ES2385692T3 (es) | 2012-07-30 |
| JP5508260B2 (ja) | 2014-05-28 |
| HK1142906A1 (en) | 2010-12-17 |
| DOP2010000012A (es) | 2010-01-31 |
| CL2008003940A1 (es) | 2010-09-24 |
| JP2010533160A (ja) | 2010-10-21 |
| EA201000091A1 (ru) | 2010-06-30 |
| CN101809002B (zh) | 2013-03-27 |
| EA018708B1 (ru) | 2013-10-30 |
| NI201000002A (es) | 2010-10-12 |
| AR070079A1 (es) | 2010-03-10 |
| ECSP109935A (es) | 2010-03-31 |
| PE20100138A1 (es) | 2010-03-20 |
| AU2008273891A1 (en) | 2009-01-15 |
| US8138183B2 (en) | 2012-03-20 |
| EP2176238A1 (en) | 2010-04-21 |
| AU2008273891B2 (en) | 2012-01-12 |
| CR11200A (es) | 2010-06-17 |
| KR20100042280A (ko) | 2010-04-23 |
| ATE554075T1 (de) | 2012-05-15 |
| EP2176238B1 (en) | 2012-04-18 |
| BRPI0814688A2 (pt) | 2017-06-06 |
| CN101809002A (zh) | 2010-08-18 |
| US20100249131A1 (en) | 2010-09-30 |
| WO2009007750A1 (en) | 2009-01-15 |
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