AU2014225155B2 - Pyridopyrimidine or pyrimidopyrimidine compound, preparation method, pharmaceutical composition and use thereof - Google Patents
Pyridopyrimidine or pyrimidopyrimidine compound, preparation method, pharmaceutical composition and use thereof Download PDFInfo
- Publication number
- AU2014225155B2 AU2014225155B2 AU2014225155A AU2014225155A AU2014225155B2 AU 2014225155 B2 AU2014225155 B2 AU 2014225155B2 AU 2014225155 A AU2014225155 A AU 2014225155A AU 2014225155 A AU2014225155 A AU 2014225155A AU 2014225155 B2 AU2014225155 B2 AU 2014225155B2
- Authority
- AU
- Australia
- Prior art keywords
- oxa
- azabicyclo
- compound
- title compound
- octanyl
- 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.)
- Ceased
Links
- -1 pyrimidopyrimidine compound Chemical class 0.000 title claims abstract description 63
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title abstract description 23
- BWESROVQGZSBRX-UHFFFAOYSA-N pyrido[3,2-d]pyrimidine Chemical compound C1=NC=NC2=CC=CN=C21 BWESROVQGZSBRX-UHFFFAOYSA-N 0.000 title abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 163
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 150000002148 esters Chemical class 0.000 claims abstract description 23
- 229940002612 prodrug Drugs 0.000 claims abstract description 23
- 239000000651 prodrug Substances 0.000 claims abstract description 23
- 239000012453 solvate Substances 0.000 claims abstract description 23
- 229940124302 mTOR inhibitor Drugs 0.000 claims abstract description 12
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 claims abstract description 12
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 80
- 229910052736 halogen Chemical group 0.000 claims description 46
- 150000002367 halogens Chemical group 0.000 claims description 46
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 16
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 16
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 230000019491 signal transduction Effects 0.000 claims description 13
- 229910003827 NRaRb Chemical group 0.000 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
- 125000006413 ring segment Chemical group 0.000 claims description 10
- 230000004064 dysfunction Effects 0.000 claims description 6
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical group C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims description 5
- ZNGWEEUXTBNKFR-UHFFFAOYSA-N 1,4-oxazepane Chemical group C1CNCCOC1 ZNGWEEUXTBNKFR-UHFFFAOYSA-N 0.000 claims description 5
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical group CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 230000007257 malfunction Effects 0.000 abstract description 2
- 208000024891 symptom Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- 238000004949 mass spectrometry Methods 0.000 description 64
- 239000007787 solid Substances 0.000 description 45
- QCOHPFLNQAVPJE-UHFFFAOYSA-N 3-oxa-8-azabicyclo[3.2.1]octane;hydrochloride Chemical compound Cl.C1OCC2CCC1N2 QCOHPFLNQAVPJE-UHFFFAOYSA-N 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 23
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- SFWWGMKXCYLZEG-YFKPBYRVSA-N (3s)-3-methylmorpholine Chemical group C[C@H]1COCCN1 SFWWGMKXCYLZEG-YFKPBYRVSA-N 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- XADOTNAXKKFKDY-UHFFFAOYSA-N 8-oxa-3-azabicyclo[3.2.1]octane;hydrochloride Chemical group Cl.C1NCC2CCC1O2 XADOTNAXKKFKDY-UHFFFAOYSA-N 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
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- 238000000034 method Methods 0.000 description 15
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- 125000000217 alkyl group Chemical group 0.000 description 13
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- HNVIQLPOGUDBSU-OLQVQODUSA-N (2s,6r)-2,6-dimethylmorpholine Chemical group C[C@H]1CNC[C@@H](C)O1 HNVIQLPOGUDBSU-OLQVQODUSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
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- NEAANVGSZBCRKC-UHFFFAOYSA-N (5-ethynyl-2-methoxyphenyl)methyl 2,2-dimethylpropanoate Chemical compound C(C(C)(C)C)(=O)OCC1=C(C=CC(=C1)C#C)OC NEAANVGSZBCRKC-UHFFFAOYSA-N 0.000 description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 8
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
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- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 6
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical group COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 5
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical group C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 5
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- 230000035755 proliferation Effects 0.000 description 5
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- 108010034057 Mechanistic Target of Rapamycin Complex 2 Proteins 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- A—HUMAN NECESSITIES
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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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
- A61P35/02—Antineoplastic agents specific for leukemia
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310068888.8 | 2013-03-04 | ||
| CN201310068888.8A CN103588792B (zh) | 2013-03-04 | 2013-03-04 | 吡啶并嘧啶或嘧啶并嘧啶类化合物、其制备方法、药物组合物及其用途 |
| PCT/CN2014/072678 WO2014135028A1 (zh) | 2013-03-04 | 2014-02-28 | 吡啶并嘧啶或嘧啶并嘧啶类化合物、其制备方法、药物组合物及其用途 |
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| AU2014225155A1 AU2014225155A1 (en) | 2015-10-15 |
| AU2014225155B2 true AU2014225155B2 (en) | 2017-11-23 |
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| AU2014225155A Ceased AU2014225155B2 (en) | 2013-03-04 | 2014-02-28 | Pyridopyrimidine or pyrimidopyrimidine compound, preparation method, pharmaceutical composition and use thereof |
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| CN103588792B (zh) * | 2013-03-04 | 2016-03-23 | 中国科学院上海药物研究所 | 吡啶并嘧啶或嘧啶并嘧啶类化合物、其制备方法、药物组合物及其用途 |
| CN106008559B (zh) * | 2015-03-25 | 2020-10-16 | 中国科学院上海药物研究所 | 取代吡啶并嘧啶类化合物的合成工艺 |
| US10722484B2 (en) | 2016-03-09 | 2020-07-28 | K-Gen, Inc. | Methods of cancer treatment |
| WO2019091400A1 (zh) * | 2017-11-07 | 2019-05-16 | 中国科学院上海药物研究所 | 吡啶并嘧啶类化合物的盐型和晶型及其制备方法 |
| CN109867667B (zh) * | 2017-12-05 | 2021-06-11 | 中国药科大学 | 含有吡啶并嘧啶结构的parp和pi3k双靶点抑制剂 |
| US20220306622A1 (en) * | 2019-05-06 | 2022-09-29 | Medshine Discovery Inc. | Salt and crystal form of mtorc1/2 dual kinase activity inhibitor and preparation method therefor |
| US20240208964A1 (en) * | 2020-06-03 | 2024-06-27 | Pyridopyrimidines And Methods Of Their Use | Pyridopyrimidines and methods of their use |
| WO2022061251A1 (en) * | 2020-09-18 | 2022-03-24 | Plexxikon Inc. | Compounds and methods for kras modulation and indications therefor |
| WO2022228576A1 (zh) * | 2021-04-30 | 2022-11-03 | 上海医药集团股份有限公司 | 一种靶向蛋白调节剂的化合物及其应用 |
| JP2024532735A (ja) * | 2021-08-10 | 2024-09-10 | アムジエン・インコーポレーテツド | 複素環式化合物及び使用方法 |
| TW202330529A (zh) * | 2021-08-10 | 2023-08-01 | 美商安進公司 | 雜環化合物及使用方法 |
| JP2025519743A (ja) * | 2022-06-15 | 2025-06-26 | ミラティ セラピューティクス， インコーポレイテッド | 汎ＫＲａｓ阻害剤のプロドラッグ |
| WO2024057013A1 (en) * | 2022-09-12 | 2024-03-21 | Exscientia Ai Limited | Nlrp3 modulators |
Citations (2)
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| CN102887895A (zh) * | 2011-07-22 | 2013-01-23 | 山东轩竹医药科技有限公司 | 吡啶并嘧啶类mTOR抑制剂 |
| WO2013016999A1 (zh) * | 2011-08-04 | 2013-02-07 | 江苏豪森药业股份有限公司 | 杂芳基并嘧啶类衍生物、其制备方法和用途 |
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| JP2008531538A (ja) * | 2005-02-25 | 2008-08-14 | クドス ファーマシューティカルズ リミテッド | ２，４−ジアミノ−ピリドピリミジン誘導体とｍＴＯＲ阻害剤としてのその使用 |
| UA96745C2 (en) * | 2005-11-22 | 2011-12-12 | Кудос Фармасьютикалз Лимитед | PYRIDO-, PYRAZO- AND PYRIMIDO-PYRIMIDINE DERIVATIVES AS mTOR INHIBITORS |
| AU2007282535B9 (en) * | 2006-08-08 | 2013-06-20 | Chugai Seiyaku Kabushiki Kaisha | Pyrimidine derivative as PI3K inhibitor and use thereof |
| CN101558067B (zh) * | 2006-08-23 | 2014-05-28 | 库多斯药物有限公司 | 作为mtor抑制剂的2-甲基吗啉吡啶并、吡唑并和嘧啶并-嘧啶衍生物 |
| US20080233127A1 (en) * | 2007-03-21 | 2008-09-25 | Wyeth | Imidazolopyrimidine analogs and their use as pi3 kinase and mtor inhibitors |
| WO2010120987A1 (en) * | 2009-04-17 | 2010-10-21 | Wyeth Llc | Ring fused, ureidoaryl- and carbamoylaryl-bridged morpholino-pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their syntheses |
| CN103588792B (zh) * | 2013-03-04 | 2016-03-23 | 中国科学院上海药物研究所 | 吡啶并嘧啶或嘧啶并嘧啶类化合物、其制备方法、药物组合物及其用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102887895A (zh) * | 2011-07-22 | 2013-01-23 | 山东轩竹医药科技有限公司 | 吡啶并嘧啶类mTOR抑制剂 |
| WO2013016999A1 (zh) * | 2011-08-04 | 2013-02-07 | 江苏豪森药业股份有限公司 | 杂芳基并嘧啶类衍生物、其制备方法和用途 |
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| DK2966079T3 (da) | 2022-02-14 |
| RU2662713C2 (ru) | 2018-07-27 |
| HK1217197A1 (en) | 2016-12-30 |
| ES2572105T1 (es) | 2016-05-30 |
| EP2966079B1 (en) | 2021-11-24 |
| JP2016510042A (ja) | 2016-04-04 |
| CN103588792B (zh) | 2016-03-23 |
| AU2014225155A1 (en) | 2015-10-15 |
| EP2966079A1 (en) | 2016-01-13 |
| US20150368274A1 (en) | 2015-12-24 |
| US9796732B2 (en) | 2017-10-24 |
| DE14760712T1 (de) | 2017-12-14 |
| ES2572105T3 (es) | 2022-04-13 |
| EP2966079A4 (en) | 2016-11-09 |
| RU2015140387A (ru) | 2017-03-30 |
| DK2966079T1 (da) | 2016-05-17 |
| CN103588792A (zh) | 2014-02-19 |
| WO2014135028A1 (zh) | 2014-09-12 |
| CA2903072C (en) | 2019-05-07 |
| CA2903072A1 (en) | 2014-09-12 |
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