JP2017504650A5 - - Google Patents
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- JP2017504650A5 JP2017504650A5 JP2016549416A JP2016549416A JP2017504650A5 JP 2017504650 A5 JP2017504650 A5 JP 2017504650A5 JP 2016549416 A JP2016549416 A JP 2016549416A JP 2016549416 A JP2016549416 A JP 2016549416A JP 2017504650 A5 JP2017504650 A5 JP 2017504650A5
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- Prior art keywords
- substituted
- unsubstituted
- disease
- alkyl
- protecting group
- 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.)
- Pending
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- 125000000217 alkyl group Chemical group 0.000 claims 54
- 229910052739 hydrogen Inorganic materials 0.000 claims 51
- 239000001257 hydrogen Substances 0.000 claims 51
- 150000002431 hydrogen Chemical class 0.000 claims 51
- 125000001072 heteroaryl group Chemical group 0.000 claims 47
- 125000000623 heterocyclic group Chemical group 0.000 claims 47
- 150000003839 salts Chemical class 0.000 claims 45
- 201000010099 disease Diseases 0.000 claims 41
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 41
- 125000003342 alkenyl group Chemical group 0.000 claims 34
- 125000000304 alkynyl group Chemical group 0.000 claims 34
- 125000003118 aryl group Chemical group 0.000 claims 34
- 125000004452 carbocyclyl group Chemical group 0.000 claims 34
- 150000001875 compounds Chemical class 0.000 claims 30
- 229910052736 halogen Inorganic materials 0.000 claims 25
- 150000002367 halogens Chemical group 0.000 claims 25
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 24
- 229910052757 nitrogen Inorganic materials 0.000 claims 22
- 125000002252 acyl group Chemical group 0.000 claims 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 18
- 102000001805 Bromodomains Human genes 0.000 claims 17
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 17
- 238000000034 method Methods 0.000 claims 15
- 108090000623 proteins and genes Proteins 0.000 claims 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 13
- 239000008194 pharmaceutical composition Substances 0.000 claims 13
- 229910052717 sulfur Inorganic materials 0.000 claims 13
- 125000004430 oxygen atom Chemical group O* 0.000 claims 12
- 108091005575 Bromodomain-containing proteins Proteins 0.000 claims 11
- 102000004169 proteins and genes Human genes 0.000 claims 11
- 125000004434 sulfur atom Chemical group 0.000 claims 11
- 230000000694 effects Effects 0.000 claims 9
- 208000015181 infectious disease Diseases 0.000 claims 8
- 108050009021 Bromodomains Proteins 0.000 claims 6
- 206010028980 Neoplasm Diseases 0.000 claims 6
- 229910052760 oxygen Inorganic materials 0.000 claims 6
- 239000001301 oxygen Substances 0.000 claims 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 5
- 208000030507 AIDS Diseases 0.000 claims 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 4
- 208000009329 Graft vs Host Disease Diseases 0.000 claims 4
- 241000711549 Hepacivirus C Species 0.000 claims 4
- 241000725303 Human immunodeficiency virus Species 0.000 claims 4
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 claims 4
- 230000002159 abnormal effect Effects 0.000 claims 4
- 201000011510 cancer Diseases 0.000 claims 4
- 208000024908 graft versus host disease Diseases 0.000 claims 4
- 125000006239 protecting group Chemical group 0.000 claims 4
- 201000001320 Atherosclerosis Diseases 0.000 claims 3
- 241000701806 Human papillomavirus Species 0.000 claims 3
- VEYYWZRYIYDQJM-ZETCQYMHSA-N N(2)-acetyl-L-lysine Chemical group CC(=O)N[C@H](C([O-])=O)CCCC[NH3+] VEYYWZRYIYDQJM-ZETCQYMHSA-N 0.000 claims 3
- 241000700584 Simplexvirus Species 0.000 claims 3
- 125000002837 carbocyclic group Chemical group 0.000 claims 3
- 238000000338 in vitro Methods 0.000 claims 3
- 230000002401 inhibitory effect Effects 0.000 claims 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 3
- 230000001105 regulatory effect Effects 0.000 claims 3
- 208000023275 Autoimmune disease Diseases 0.000 claims 2
- 206010060999 Benign neoplasm Diseases 0.000 claims 2
- 102100033641 Bromodomain-containing protein 2 Human genes 0.000 claims 2
- 101710126816 Bromodomain-containing protein 2 Proteins 0.000 claims 2
- 102100033642 Bromodomain-containing protein 3 Human genes 0.000 claims 2
- 101710126814 Bromodomain-containing protein 3 Proteins 0.000 claims 2
- 102100029895 Bromodomain-containing protein 4 Human genes 0.000 claims 2
- 101710126815 Bromodomain-containing protein 4 Proteins 0.000 claims 2
- 108010040163 CREB-Binding Protein Proteins 0.000 claims 2
- 102100021975 CREB-binding protein Human genes 0.000 claims 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims 2
- 206010009944 Colon cancer Diseases 0.000 claims 2
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 claims 2
- 208000017701 Endocrine disease Diseases 0.000 claims 2
- 102100038885 Histone acetyltransferase p300 Human genes 0.000 claims 2
- 108010033040 Histones Proteins 0.000 claims 2
- 101000882390 Homo sapiens Histone acetyltransferase p300 Proteins 0.000 claims 2
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 2
- 208000034578 Multiple myelomas Diseases 0.000 claims 2
- 206010029260 Neuroblastoma Diseases 0.000 claims 2
- 208000008589 Obesity Diseases 0.000 claims 2
- 206010033128 Ovarian cancer Diseases 0.000 claims 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 2
- 208000034038 Pathologic Neovascularization Diseases 0.000 claims 2
- 108091000080 Phosphotransferase Proteins 0.000 claims 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 2
- 206010039710 Scleroderma Diseases 0.000 claims 2
- 206010040047 Sepsis Diseases 0.000 claims 2
- 102000006467 TATA-Box Binding Protein Human genes 0.000 claims 2
- 108010044281 TATA-Box Binding Protein Proteins 0.000 claims 2
- 208000024313 Testicular Neoplasms Diseases 0.000 claims 2
- 206010057644 Testis cancer Diseases 0.000 claims 2
- 208000036142 Viral infection Diseases 0.000 claims 2
- 125000004429 atom Chemical group 0.000 claims 2
- 125000001246 bromo group Chemical group Br* 0.000 claims 2
- 208000029742 colonic neoplasm Diseases 0.000 claims 2
- 206010012601 diabetes mellitus Diseases 0.000 claims 2
- 208000016097 disease of metabolism Diseases 0.000 claims 2
- 208000030172 endocrine system disease Diseases 0.000 claims 2
- 230000003176 fibrotic effect Effects 0.000 claims 2
- 208000004104 gestational diabetes Diseases 0.000 claims 2
- 208000027866 inflammatory disease Diseases 0.000 claims 2
- 206010022000 influenza Diseases 0.000 claims 2
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims 2
- 208000032839 leukemia Diseases 0.000 claims 2
- 201000005202 lung cancer Diseases 0.000 claims 2
- 208000020816 lung neoplasm Diseases 0.000 claims 2
- 208000030159 metabolic disease Diseases 0.000 claims 2
- 235000020824 obesity Nutrition 0.000 claims 2
- 102000020233 phosphotransferase Human genes 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- 230000002062 proliferating effect Effects 0.000 claims 2
- 230000005855 radiation Effects 0.000 claims 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 2
- 239000011593 sulfur Substances 0.000 claims 2
- 201000003120 testicular cancer Diseases 0.000 claims 2
- 231100000419 toxicity Toxicity 0.000 claims 2
- 230000001988 toxicity Effects 0.000 claims 2
- 238000013518 transcription Methods 0.000 claims 2
- 230000035897 transcription Effects 0.000 claims 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims 2
- 230000009385 viral infection Effects 0.000 claims 2
- 206010003210 Arteriosclerosis Diseases 0.000 claims 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 claims 1
- 101000596093 Homo sapiens Transcription initiation factor TFIID subunit 1 Proteins 0.000 claims 1
- 101000596092 Homo sapiens Transcription initiation factor TFIID subunit 1-like Proteins 0.000 claims 1
- 241000726306 Irus Species 0.000 claims 1
- 102100035222 Transcription initiation factor TFIID subunit 1 Human genes 0.000 claims 1
- 102100035238 Transcription initiation factor TFIID subunit 1-like Human genes 0.000 claims 1
- 230000036523 atherogenesis Effects 0.000 claims 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims 1
- 208000003154 papilloma Diseases 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 208000011580 syndromic disease Diseases 0.000 claims 1
- 241001529453 unidentified herpesvirus Species 0.000 claims 1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201461934668P | 2014-01-31 | 2014-01-31 | |
| US61/934,668 | 2014-01-31 | ||
| PCT/US2015/014109 WO2015117083A1 (en) | 2014-01-31 | 2015-02-02 | Diazepane derivatives and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2017504650A JP2017504650A (ja) | 2017-02-09 |
| JP2017504650A5 true JP2017504650A5 (enExample) | 2018-08-30 |
Family
ID=53757810
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016549416A Pending JP2017504650A (ja) | 2014-01-31 | 2015-02-02 | ジアゼパン誘導体およびその使用 |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US9695172B2 (enExample) |
| EP (1) | EP3099696A4 (enExample) |
| JP (1) | JP2017504650A (enExample) |
| KR (1) | KR20160111036A (enExample) |
| CN (1) | CN105940005A (enExample) |
| BR (1) | BR112016017045A2 (enExample) |
| CA (1) | CA2936256A1 (enExample) |
| HK (1) | HK1225383A1 (enExample) |
| MX (1) | MX2016009976A (enExample) |
| RU (1) | RU2016134941A (enExample) |
| WO (1) | WO2015117083A1 (enExample) |
Families Citing this family (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2937345B1 (en) | 2009-12-29 | 2018-03-21 | Dana-Farber Cancer Institute, Inc. | Type ii raf kinase inhibitors |
| CN103180318B (zh) | 2010-05-14 | 2017-05-10 | 达那-法伯癌症研究所 | 雄性避孕组合物以及使用方法 |
| ES2606958T3 (es) | 2010-05-14 | 2017-03-28 | Dana-Farber Cancer Institute, Inc. | Compuestos de tienotriazolodiazepina para tratar una neoplasia |
| CN103154246B (zh) | 2010-05-14 | 2015-11-25 | 达那-法伯癌症研究所 | 用于治疗白血病的组合物和方法 |
| JP6106685B2 (ja) | 2011-11-17 | 2017-04-05 | ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッド | Ｃ−ｊｕｎ−ｎ−末端キナーゼ（ｊｎｋ）の阻害剤 |
| EP2909194A1 (en) | 2012-10-18 | 2015-08-26 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinase 7 (cdk7) |
| US10000483B2 (en) | 2012-10-19 | 2018-06-19 | Dana-Farber Cancer Institute, Inc. | Bone marrow on X chromosome kinase (BMX) inhibitors and uses thereof |
| USRE48175E1 (en) | 2012-10-19 | 2020-08-25 | Dana-Farber Cancer Institute, Inc. | Hydrophobically tagged small molecules as inducers of protein degradation |
| BR112016001457A2 (pt) | 2013-07-25 | 2017-08-29 | Dana Farber Cancer Inst Inc | Inibidores de fatores de transcrição e usos dos mesmos |
| WO2015058126A1 (en) | 2013-10-18 | 2015-04-23 | Syros Pharmaceuticals, Inc. | Heteroaromatic compounds useful for the treatment of prolferative diseases |
| AU2014337044A1 (en) | 2013-10-18 | 2016-05-05 | Dana-Farber Cancer Institute, Inc. | Polycyclic inhibitors of cyclin-dependent kinase 7 (CDK7) |
| US11446309B2 (en) | 2013-11-08 | 2022-09-20 | Dana-Farber Cancer Institute, Inc. | Combination therapy for cancer using bromodomain and extra-terminal (BET) protein inhibitors |
| MX2016009974A (es) | 2014-01-31 | 2016-10-31 | Dana Farber Cancer Inst Inc | Derivados de diaminopirimidina bencensulfona y sus usos. |
| EP3099693A4 (en) * | 2014-01-31 | 2017-08-16 | Dana-Farber Cancer Institute, Inc. | Uses of diazepane derivatives |
| WO2015131113A1 (en) | 2014-02-28 | 2015-09-03 | Tensha Therapeutics, Inc. | Treatment of conditions associated with hyperinsulinaemia |
| US9862688B2 (en) | 2014-04-23 | 2018-01-09 | Dana-Farber Cancer Institute, Inc. | Hydrophobically tagged janus kinase inhibitors and uses thereof |
| WO2015164614A1 (en) | 2014-04-23 | 2015-10-29 | Dana-Farber Cancer Institute, Inc. | Janus kinase inhibitors and uses thereof |
| RU2017104897A (ru) | 2014-08-08 | 2018-09-10 | Дана-Фарбер Кэнсер Инститьют, Инк. | Производные диазепана и их применения |
| WO2016022970A1 (en) | 2014-08-08 | 2016-02-11 | Dana-Farber Cancer Institute, Inc. | Dihydropteridinone derivatives and uses thereof |
| UA122130C2 (uk) | 2014-10-27 | 2020-09-25 | Тенша Терапеутікс, Інк. | Інгібітори бромодомену |
| US10870651B2 (en) | 2014-12-23 | 2020-12-22 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinase 7 (CDK7) |
| CN107427521B (zh) | 2015-03-27 | 2021-08-03 | 达纳-法伯癌症研究所股份有限公司 | 细胞周期蛋白依赖性激酶的抑制剂 |
| CA2986441A1 (en) | 2015-06-12 | 2016-12-15 | Dana-Farber Cancer Institute, Inc. | Combination therapy of transcription inhibitors and kinase inhibitors |
| WO2017044858A2 (en) | 2015-09-09 | 2017-03-16 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinases |
| RU2018112953A (ru) | 2015-09-11 | 2019-10-14 | Дана-Фарбер Кэнсер Инститьют, Инк. | Ацетамидтиенотриазолодиазепины и пути их применения |
| US11306105B2 (en) | 2015-09-11 | 2022-04-19 | Dana-Farber Cancer Institute, Inc. | Cyano thienotriazolodiazepines and uses thereof |
| CR20180336A (es) | 2015-11-25 | 2018-08-06 | Dana Farber Cancer Inst Inc | Inhibidores de bromodominio bivalentes y usos de los mismos |
| CA3040173A1 (en) * | 2016-10-18 | 2018-04-26 | Dana-Farber Cancer Institute, Inc. | Pyrimido-diazepinone kinase scaffold compounds and methods of treating dclk1/2-mediated disorders |
| RU2664331C1 (ru) * | 2017-10-23 | 2018-08-16 | Федеральное государственное бюджетное учреждение науки Новосибирский институт органической химии им. Н.Н. Ворожцова Сибирского отделения Российской академии наук (НИОХ СО РАН) | 6,13,13-ТРИМЕТИЛ-6,8,9,12-ТЕТРАГИДРО-6,9-МЕТАНОАЗЕПИНО[2,1-b]ХИНАЗОЛИН-10(7Н)-ОН В КАЧЕСТВЕ ИНГИБИТОРА ВИРУСОВ ГРИППА А |
| US10632209B2 (en) * | 2017-11-10 | 2020-04-28 | The Regents Of The University Of Michigan | ASH1L inhibitors and methods of treatment therewith |
| EP3810132A4 (en) | 2018-06-25 | 2022-06-22 | Dana-Farber Cancer Institute, Inc. | TAIRE FAMILY KINASE INHIBITORS AND RELATED USES |
| WO2020093162A1 (en) * | 2018-11-07 | 2020-05-14 | Neomed Institute | Treatment of bet inhibitor-resistant cancers and other diseases responsive to dual bet and cbp/ep300 inhibition therapy |
| CN113164477A (zh) | 2018-12-14 | 2021-07-23 | 达纳-法伯癌症研究所股份有限公司 | C-jun-n-末端激酶的吡唑并吡啶抑制剂及其用途 |
| WO2020206608A1 (en) | 2019-04-09 | 2020-10-15 | Ranok Therapeutics (Hangzhou) Co., Ltd. | Methods and compositions for targeted protein degradation |
| GB202202199D0 (en) * | 2022-02-18 | 2022-04-06 | Cancer Research Tech Ltd | Compounds |
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| WO1994006802A1 (fr) | 1992-09-18 | 1994-03-31 | Yoshitomi Pharmaceutical Industries, Ltd. | Compose de thienodiazepine et son utilisation medicinale |
| WO1994022872A1 (fr) | 1993-03-30 | 1994-10-13 | Yoshitomi Pharmaceutical Industries, Ltd. | Inhibiteur d'adhesion cellulaire et compose a base de thienotriazolodiazepine |
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| US6552037B2 (en) | 2000-06-30 | 2003-04-22 | Neurogen Corporation | 2-Substituted imidazo[1,2-A]pyridine derivatives |
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| US6861422B2 (en) | 2003-02-26 | 2005-03-01 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Dihydropteridinones, processes for preparing them and their use as pharmaceutical compositions |
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| US20060058311A1 (en) | 2004-08-14 | 2006-03-16 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation |
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| WO2007053452A1 (en) | 2005-11-01 | 2007-05-10 | Targegen, Inc. | Bi-aryl meta-pyrimidine inhibitors of kinases |
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| KR101062583B1 (ko) | 2006-01-17 | 2011-09-06 | 에프. 호프만-라 로슈 아게 | Ｇａｂａ 수용체에 의해 알츠하이머병의 치료에 유용한아릴-아이속사졸-4-일-이미다조[1,2-ａ]피리딘 |
| ES2351367T3 (es) * | 2006-02-14 | 2011-02-03 | Vertex Pharmaceuticals Incorporated | Dihidrodiazepinas útiles como inhibidores de proteína quinasas. |
| ATE479434T1 (de) | 2006-02-14 | 2010-09-15 | Vertex Pharma | Als protein-kinase-inhibitoren nutzbare dyhydrodiazepine |
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| CN101910182B (zh) | 2007-12-28 | 2013-07-17 | 田边三菱制药株式会社 | 抗癌剂 |
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| EP2379559B1 (en) | 2009-01-06 | 2017-10-25 | Dana-Farber Cancer Institute, Inc. | Pyrimido-diazepinone kinase scaffold compounds and methods of treating disorders |
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| GB0919431D0 (en) | 2009-11-05 | 2009-12-23 | Glaxosmithkline Llc | Novel compounds |
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| AU2010317096B2 (en) | 2009-11-05 | 2015-03-26 | Glaxosmithkline Llc | Benzodiazepine bromodomain inhibitor |
| GB0919434D0 (en) | 2009-11-05 | 2009-12-23 | Glaxosmithkline Llc | Novel compounds |
| GB0919432D0 (en) | 2009-11-05 | 2009-12-23 | Glaxosmithkline Llc | Use |
| GB0919426D0 (en) | 2009-11-05 | 2009-12-23 | Glaxosmithkline Llc | Novel compounds |
| CA2779355C (en) | 2009-11-05 | 2018-01-16 | Glaxosmithkline Llc | Benzodiazepine bromodomain inhibitor |
| US20120329803A1 (en) | 2010-02-17 | 2012-12-27 | Boehringer Ingelheim International Gmbh | Dihydropteridinones, method for production and use thereof |
| ES2606958T3 (es) | 2010-05-14 | 2017-03-28 | Dana-Farber Cancer Institute, Inc. | Compuestos de tienotriazolodiazepina para tratar una neoplasia |
| EP2585465B1 (en) | 2010-06-22 | 2014-11-12 | GlaxoSmithKline LLC | Benzotriazolodiazepine compounds inhibitors of bromodomains |
| AR084070A1 (es) | 2010-12-02 | 2013-04-17 | Constellation Pharmaceuticals Inc | Inhibidores del bromodominio y usos de los mismos |
| EP2677865A4 (en) | 2011-02-23 | 2015-04-22 | Icahn School Med Mount Sinai | BROMODOMAIN INHIBITORS AS MODULATORS OF GENE EXPRESSION |
| WO2013097052A1 (en) | 2011-12-30 | 2013-07-04 | Abbott Laboratories | Bromodomain inhibitors |
| WO2014071247A1 (en) | 2012-11-02 | 2014-05-08 | Dana-Farber Cancer Institute, Inc. | Pyrrol-1 -yl benzoic acid derivates useful as myc inhibitors |
| WO2014159392A1 (en) | 2013-03-14 | 2014-10-02 | Dana-Farber Cancer Institute, Inc. | Bromodomain binding reagents and uses thereof |
| MX2016009974A (es) | 2014-01-31 | 2016-10-31 | Dana Farber Cancer Inst Inc | Derivados de diaminopirimidina bencensulfona y sus usos. |
-
2015
- 2015-02-02 WO PCT/US2015/014109 patent/WO2015117083A1/en not_active Ceased
- 2015-02-02 US US15/114,895 patent/US9695172B2/en active Active
- 2015-02-02 CA CA2936256A patent/CA2936256A1/en not_active Abandoned
- 2015-02-02 MX MX2016009976A patent/MX2016009976A/es unknown
- 2015-02-02 EP EP15744026.4A patent/EP3099696A4/en not_active Ceased
- 2015-02-02 CN CN201580006614.3A patent/CN105940005A/zh active Pending
- 2015-02-02 RU RU2016134941A patent/RU2016134941A/ru not_active Application Discontinuation
- 2015-02-02 KR KR1020167023460A patent/KR20160111036A/ko not_active Withdrawn
- 2015-02-02 BR BR112016017045A patent/BR112016017045A2/pt active Search and Examination
- 2015-02-02 JP JP2016549416A patent/JP2017504650A/ja active Pending
- 2015-02-02 HK HK16113707.9A patent/HK1225383A1/zh unknown
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