CA2752114C - Fused pyrimidines as akt inhibitors - Google Patents
Fused pyrimidines as akt inhibitors Download PDFInfo
- Publication number
- CA2752114C CA2752114C CA2752114A CA2752114A CA2752114C CA 2752114 C CA2752114 C CA 2752114C CA 2752114 A CA2752114 A CA 2752114A CA 2752114 A CA2752114 A CA 2752114A CA 2752114 C CA2752114 C CA 2752114C
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- CA
- Canada
- Prior art keywords
- alkyl
- salt
- hydrogen
- compound
- halogen
- 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
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- 239000003197 protein kinase B inhibitor Substances 0.000 title description 11
- 150000003230 pyrimidines Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 321
- 150000003839 salts Chemical class 0.000 claims abstract description 108
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 50
- 238000004519 manufacturing process Methods 0.000 claims abstract description 19
- 230000008569 process Effects 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims description 99
- 229910052739 hydrogen Inorganic materials 0.000 claims description 99
- 206010028980 Neoplasm Diseases 0.000 claims description 89
- -1 hydroxy, amino Chemical group 0.000 claims description 89
- 229910052736 halogen Inorganic materials 0.000 claims description 78
- 150000002367 halogens Chemical group 0.000 claims description 78
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 72
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 58
- 229910052757 nitrogen Inorganic materials 0.000 claims description 58
- 201000010099 disease Diseases 0.000 claims description 46
- 201000011510 cancer Diseases 0.000 claims description 44
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 43
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 33
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims description 31
- 150000002431 hydrogen Chemical class 0.000 claims description 29
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 29
- 239000004480 active ingredient Substances 0.000 claims description 28
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- 125000005842 heteroatom Chemical group 0.000 claims description 27
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 26
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 26
- 230000009826 neoplastic cell growth Effects 0.000 claims description 26
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- 239000001301 oxygen Substances 0.000 claims description 26
- 230000003211 malignant effect Effects 0.000 claims description 25
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- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 21
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- 125000005549 heteroarylene group Chemical group 0.000 claims description 19
- 150000001412 amines Chemical class 0.000 claims description 17
- 208000035475 disorder Diseases 0.000 claims description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 230000000973 chemotherapeutic effect Effects 0.000 claims description 15
- 230000003463 hyperproliferative effect Effects 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
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- 125000002971 oxazolyl group Chemical group 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
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- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
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- 125000003118 aryl group Chemical group 0.000 claims description 6
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- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 4
- 229910052717 sulfur Chemical group 0.000 claims description 3
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 abstract 3
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 229960005419 nitrogen Drugs 0.000 description 21
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- 230000005764 inhibitory process Effects 0.000 description 16
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
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- 241000124008 Mammalia Species 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
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- 101150107888 AKT2 gene Proteins 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
- 108091000080 Phosphotransferase Proteins 0.000 description 10
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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| EP09152805.9 | 2009-02-13 | ||
| EP09152805 | 2009-02-13 | ||
| PCT/EP2010/000717 WO2010091824A1 (en) | 2009-02-13 | 2010-02-05 | Fused pyrimidines as akt inhibitors |
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| CA2752114A1 CA2752114A1 (en) | 2010-08-19 |
| CA2752114C true CA2752114C (en) | 2017-06-20 |
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| CA2752114A Expired - Fee Related CA2752114C (en) | 2009-02-13 | 2010-02-05 | Fused pyrimidines as akt inhibitors |
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| ES (1) | ES2435804T3 (enExample) |
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| SG11201505631PA (en) | 2013-01-23 | 2015-08-28 | Astrazeneca Ab | Chemical compounds |
| US10526660B2 (en) | 2013-09-12 | 2020-01-07 | Dana-Farber Cancer Institute, Inc. | Methods for evaluating and treating Waldenstrom's macroglobulinemia |
| TWI720451B (zh) | 2014-02-13 | 2021-03-01 | 美商英塞特控股公司 | 作為lsd1抑制劑之環丙胺 |
| KR102421235B1 (ko) | 2014-02-13 | 2022-07-15 | 인사이트 코포레이션 | Lsd1 저해제로서 사이클로프로필아민 |
| US9527835B2 (en) | 2014-02-13 | 2016-12-27 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
| EP2907811A1 (en) | 2014-02-14 | 2015-08-19 | Actelion Pharmaceuticals Ltd. | Process for manufacturing pyrimidine sulfamide derivatives |
| WO2016007722A1 (en) | 2014-07-10 | 2016-01-14 | Incyte Corporation | Triazolopyridines and triazolopyrazines as lsd1 inhibitors |
| TWI687419B (zh) | 2014-07-10 | 2020-03-11 | 美商英塞特公司 | 作為ｌｓｄ１抑制劑之咪唑并吡啶及咪唑并吡嗪 |
| TW201613925A (en) | 2014-07-10 | 2016-04-16 | Incyte Corp | Imidazopyrazines as LSD1 inhibitors |
| SG11201708047UA (en) | 2015-04-03 | 2017-10-30 | Incyte Corp | Heterocyclic compounds as lsd1 inhibitors |
| CN110402244B (zh) | 2015-08-12 | 2023-02-03 | 因赛特公司 | Lsd1抑制剂的盐 |
| WO2020047198A1 (en) | 2018-08-31 | 2020-03-05 | Incyte Corporation | Salts of an lsd1 inhibitor and processes for preparing the same |
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| IL164703A0 (en) * | 2002-04-19 | 2005-12-18 | Cellular Genomics Inc | ImidazoÄ1,2-AÜpyrazin-8-ylamines method of making and method of use thereof |
| EP1622616B1 (en) | 2003-04-24 | 2011-06-15 | Merck Sharp & Dohme Corp. | Inhibitors of akt activity |
| AU2005233584B2 (en) | 2004-04-09 | 2010-12-09 | Merck Sharp & Dohme Corp. | Inhibitors of Akt activity |
| JP2008510823A (ja) | 2004-08-23 | 2008-04-10 | メルク エンド カムパニー インコーポレーテッド | Ａｋｔ活性阻害剤 |
| US7713973B2 (en) * | 2004-10-15 | 2010-05-11 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
| US7910561B2 (en) | 2004-12-15 | 2011-03-22 | Merck Sharp & Dohme Corp. | Inhibitors of Akt activity |
| JP2008530111A (ja) | 2005-02-14 | 2008-08-07 | メルク エンド カムパニー インコーポレーテッド | Ａｋｔ活性の阻害剤 |
| DK1898903T3 (da) | 2005-06-10 | 2013-07-01 | Merck Sharp & Dohme | Inhibitorer af Akt-aktivitet |
| DE102007012645A1 (de) * | 2007-03-16 | 2008-09-18 | Bayer Healthcare Ag | Substituierte Imidazo- und Triazolopyrimidine |
| PA8793301A1 (es) * | 2007-08-14 | 2009-04-23 | Bayer Schering Pharma Ag | Imidazoles bicíclicos fusionados |
| PL2188291T3 (pl) * | 2007-08-14 | 2013-06-28 | Bayer Ip Gmbh | Skondensowane bicykliczne pirymidyny |
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- 2010-02-05 EP EP10703022.3A patent/EP2396331B1/en not_active Not-in-force
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- 2010-02-05 CA CA2752114A patent/CA2752114C/en not_active Expired - Fee Related
- 2010-02-05 WO PCT/EP2010/000717 patent/WO2010091824A1/en not_active Ceased
- 2010-02-05 ES ES10703022T patent/ES2435804T3/es active Active
- 2010-02-05 US US13/201,227 patent/US20130310362A1/en not_active Abandoned
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| ES2435804T3 (es) | 2013-12-23 |
| CN102361872A (zh) | 2012-02-22 |
| HK1166984A1 (en) | 2012-11-16 |
| JP2012517965A (ja) | 2012-08-09 |
| JP5667085B2 (ja) | 2015-02-12 |
| CN102361872B (zh) | 2014-12-03 |
| EP2396331A1 (en) | 2011-12-21 |
| WO2010091824A1 (en) | 2010-08-19 |
| US20130310362A1 (en) | 2013-11-21 |
| CA2752114A1 (en) | 2010-08-19 |
| EP2396331B1 (en) | 2013-10-16 |
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