JP2017510595A5 - - Google Patents
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- Publication number
- JP2017510595A5 JP2017510595A5 JP2016560952A JP2016560952A JP2017510595A5 JP 2017510595 A5 JP2017510595 A5 JP 2017510595A5 JP 2016560952 A JP2016560952 A JP 2016560952A JP 2016560952 A JP2016560952 A JP 2016560952A JP 2017510595 A5 JP2017510595 A5 JP 2017510595A5
- Authority
- JP
- Japan
- Prior art keywords
- carboxamide
- anilino
- dihydropyrimido
- indolizine
- methoxy
- 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.)
- Granted
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- 150000001875 compounds Chemical class 0.000 claims description 52
- -1 homopiperazinyl Chemical group 0.000 claims description 52
- 125000003635 2-dimethylaminoethoxy group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- VNEZLSKCYNTZLU-UHFFFAOYSA-N C1(CC1)C(=O)N1CCN(CC1)C1=CC(=C(NC=2N=CC3=C(N4C=CC(=C4CC3)C(=O)NC3=C(C=CC=C3C)C)N=2)C=C1)OC Chemical compound C1(CC1)C(=O)N1CCN(CC1)C1=CC(=C(NC=2N=CC3=C(N4C=CC(=C4CC3)C(=O)NC3=C(C=CC=C3C)C)N=2)C=C1)OC VNEZLSKCYNTZLU-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 59
- 125000003545 alkoxy group Chemical group 0.000 claims 34
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 19
- URGAFFAIKGXTJC-UHFFFAOYSA-N indolizine-7-carboxamide Chemical compound C1=C(C(=O)N)C=CN2C=CC=C21 URGAFFAIKGXTJC-UHFFFAOYSA-N 0.000 claims 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 16
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 15
- 229910052736 halogen Inorganic materials 0.000 claims 15
- 150000002367 halogens Chemical class 0.000 claims 15
- 125000001153 fluoro group Chemical group F* 0.000 claims 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims 8
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims 8
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 6
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 6
- 125000001072 heteroaryl group Chemical group 0.000 claims 6
- 125000004043 oxo group Chemical group O=* 0.000 claims 6
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 6
- 150000003839 salts Chemical class 0.000 claims 5
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 4
- 125000003282 alkyl amino group Chemical group 0.000 claims 4
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 4
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 4
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 3
- 125000003342 alkenyl group Chemical group 0.000 claims 3
- 125000002393 azetidinyl group Chemical group 0.000 claims 3
- 125000003566 oxetanyl group Chemical group 0.000 claims 3
- 125000003386 piperidinyl group Chemical group 0.000 claims 3
- UYPNZGVGCJECJV-UHFFFAOYSA-N CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC12)C=NC(=N3)NC3=C(C=C(C=C3)N3CCNCC3)OC Chemical compound CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC12)C=NC(=N3)NC3=C(C=C(C=C3)N3CCNCC3)OC UYPNZGVGCJECJV-UHFFFAOYSA-N 0.000 claims 2
- XPORPDHLTHKBQR-UHFFFAOYSA-N N-(2,6-dimethylphenyl)-2-[2-methoxy-4-[4-(2-methoxyacetyl)piperazin-1-yl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C(COC)=O)OC XPORPDHLTHKBQR-UHFFFAOYSA-N 0.000 claims 2
- CMSARXIYXRBTSN-UHFFFAOYSA-N N-(3,5-diethyl-1H-pyrazol-4-yl)-2-[2-(difluoromethoxy)-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound C(C)C1=NNC(=C1NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC(F)F)CC CMSARXIYXRBTSN-UHFFFAOYSA-N 0.000 claims 2
- PXOSVHWTKXCACO-UHFFFAOYSA-N N-[3,5-diethyl-1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl]-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound C(C)C1=NN(C(=C1NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC)CC)CCOCCOC PXOSVHWTKXCACO-UHFFFAOYSA-N 0.000 claims 2
- 125000003118 aryl group Chemical group 0.000 claims 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 2
- 201000010099 disease Diseases 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 125000005842 heteroatom Chemical group 0.000 claims 2
- 230000001404 mediated effect Effects 0.000 claims 2
- 125000002757 morpholinyl group Chemical group 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- FPZWZCWUIYYYBU-UHFFFAOYSA-N 2-(2-ethoxyethoxy)ethyl acetate Chemical group CCOCCOCCOC(C)=O FPZWZCWUIYYYBU-UHFFFAOYSA-N 0.000 claims 1
- FEPTTWBIJAOREA-UHFFFAOYSA-N BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)C Chemical compound BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)C FEPTTWBIJAOREA-UHFFFAOYSA-N 0.000 claims 1
- SCNJHTNENAOJON-UHFFFAOYSA-N BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC Chemical compound BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC SCNJHTNENAOJON-UHFFFAOYSA-N 0.000 claims 1
- LNYQMDKVTIRBIZ-UHFFFAOYSA-N BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCNCC1)C Chemical compound BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCNCC1)C LNYQMDKVTIRBIZ-UHFFFAOYSA-N 0.000 claims 1
- SMTVCUWSXLIKHQ-UHFFFAOYSA-N BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)OC1CCN(CC1)C)OC Chemical compound BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)OC1CCN(CC1)C)OC SMTVCUWSXLIKHQ-UHFFFAOYSA-N 0.000 claims 1
- SKOVQURQPGBBNK-UHFFFAOYSA-N BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC=1C(=NC(=CC=1)N1CCOCC1)C Chemical compound BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC=1C(=NC(=CC=1)N1CCOCC1)C SKOVQURQPGBBNK-UHFFFAOYSA-N 0.000 claims 1
- LBDJJKHJZVLVBY-UHFFFAOYSA-N C(#N)C1(CCN(CC1)C(=O)C1=CC(=C(NC=2N=CC3=C(N4C=CC(=C4CC3)C(=O)NC3=C(C=CC=C3C)C)N=2)C=C1)OC)C Chemical compound C(#N)C1(CCN(CC1)C(=O)C1=CC(=C(NC=2N=CC3=C(N4C=CC(=C4CC3)C(=O)NC3=C(C=CC=C3C)C)N=2)C=C1)OC)C LBDJJKHJZVLVBY-UHFFFAOYSA-N 0.000 claims 1
- KKPQZYIFMSQJBT-UHFFFAOYSA-N C(#N)C1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC Chemical compound C(#N)C1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC KKPQZYIFMSQJBT-UHFFFAOYSA-N 0.000 claims 1
- QSHOMXOBJBDIRW-UHFFFAOYSA-N C(C)C1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)C Chemical compound C(C)C1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)C QSHOMXOBJBDIRW-UHFFFAOYSA-N 0.000 claims 1
- BOBDWLYTHZDBMJ-UHFFFAOYSA-N C(C)C1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCNCC1)C Chemical compound C(C)C1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCNCC1)C BOBDWLYTHZDBMJ-UHFFFAOYSA-N 0.000 claims 1
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- DPRUUGIKMIGILV-UHFFFAOYSA-N C(C)C1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC=1C(=NC(=CC=1)N1CCOCC1)C Chemical compound C(C)C1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC=1C(=NC(=CC=1)N1CCOCC1)C DPRUUGIKMIGILV-UHFFFAOYSA-N 0.000 claims 1
- ZBODMVDQKFDZCC-UHFFFAOYSA-N C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CC(NCC1)C)OC Chemical compound C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CC(NCC1)C)OC ZBODMVDQKFDZCC-UHFFFAOYSA-N 0.000 claims 1
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- 125000003226 pyrazolyl group Chemical group 0.000 claims 1
- BBQZWKVMDCAMHS-UHFFFAOYSA-N pyrimido[4,5-e]indolizine-7-carboxamide Chemical compound N1=CN=CC2=C1N1C=CC(=C1C=C2)C(=O)N BBQZWKVMDCAMHS-UHFFFAOYSA-N 0.000 claims 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 2
- FOYHNROGBXVLLX-UHFFFAOYSA-N 2,6-diethylaniline Chemical compound CCC1=CC=CC(CC)=C1N FOYHNROGBXVLLX-UHFFFAOYSA-N 0.000 description 1
- LDUCMSVRKKDATH-UHFFFAOYSA-N 2-bromo-6-methylaniline Chemical compound CC1=CC=CC(Br)=C1N LDUCMSVRKKDATH-UHFFFAOYSA-N 0.000 description 1
- WFNLHDJJZSJARK-UHFFFAOYSA-N 2-chloro-6-methylaniline Chemical compound CC1=CC=CC(Cl)=C1N WFNLHDJJZSJARK-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- FZIMDRORYRFCMW-UHFFFAOYSA-N C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)OCCN(C)C)OC Chemical compound C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)OCCN(C)C)OC FZIMDRORYRFCMW-UHFFFAOYSA-N 0.000 description 1
- YHGJHTMBMIUDIY-UHFFFAOYSA-N C(C)C1=NNC(=C1NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)OCCN(C)C)OC)CC Chemical compound C(C)C1=NNC(=C1NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)OCCN(C)C)OC)CC YHGJHTMBMIUDIY-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
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| PCT/EP2015/056839 WO2015155042A1 (en) | 2014-04-07 | 2015-03-30 | (5,6-dihydro)pyrimido[4,5-e]indolizines |
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| CA2944610C (en) * | 2014-04-07 | 2024-01-09 | Netherlands Translational Research Center B.V. | (5,6-dihydro)pyrimido[4,5-e]indolizines |
| CA2981844A1 (en) | 2015-04-17 | 2016-10-20 | Netherlands Translational Research Center B.V. | Prognostic biomarkers for ttk inhibitor chemotherapy |
| US9771366B2 (en) * | 2016-02-19 | 2017-09-26 | Phoenix Molecular Design | Substituted tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamides as RSK inhibitors |
| EA202092442A3 (ru) | 2016-06-07 | 2021-08-31 | Джакобио Фармасьютикалс Ко., Лтд. | Новые гетероциклические производные, применимые в качестве ингибиторов shp2 |
| CN106551938B (zh) * | 2016-11-26 | 2017-11-24 | 广东安诺药业股份有限公司 | 一种治疗非酒精性脂肪肝的药物及其应用 |
| KR102317480B1 (ko) | 2017-03-23 | 2021-10-25 | 자코바이오 파마슈티칼스 컴퍼니 리미티드 | Shp2 억제제로서 유용한 신규한 헤테로환형 유도체 |
| WO2020063760A1 (en) | 2018-09-26 | 2020-04-02 | Jacobio Pharmaceuticals Co., Ltd. | Novel heterocyclic derivatives useful as shp2 inhibitors |
| EP3924352A4 (en) | 2019-02-11 | 2022-11-16 | Phoenix Molecular Designs | CRYSTALLINE FORMS OF AN RSK INHIBITOR |
| CA3241213A1 (en) * | 2021-12-15 | 2023-06-22 | Heidi Lane | Pharmaceutical combinations for use in the treatment of neoplastic diseases |
| JP2024544083A (ja) * | 2021-12-15 | 2024-11-27 | シルラジェン，インコーポレイテッド | 修飾ベータ－シクロデキストリンを含む医薬組成物 |
| KR20240107329A (ko) * | 2021-12-15 | 2024-07-09 | 신라젠(주) | 신생물성 질환을 치료하는 방법 |
| AU2023228543A1 (en) * | 2022-03-04 | 2024-08-22 | Sillajen, Inc. | Pharmaceutical combinations for use in the treatment of neoplastic diseases. |
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| WO2003024967A2 (en) * | 2001-09-19 | 2003-03-27 | Aventis Pharma S.A. | Indolizines as kinase protein inhibitors |
| RS20050944A (sr) | 2003-05-22 | 2008-06-05 | Nerviano Medical Sciences S.R.L., | Derivati pirazolo- hinazolina,postupci za njihovo dobijanje i njihova upotreba kao inhibitora kinaze |
| WO2008065054A1 (en) | 2006-11-28 | 2008-06-05 | Nerviano Medical Sciences S.R.L. | Tricyclic indoles and (4,5-dihydro) indoles |
| WO2009156315A1 (en) | 2008-06-26 | 2009-12-30 | Nerviano Medical Sciences S.R.L. | Pyrazolo-quinazolines |
| WO2010111406A2 (en) | 2009-03-24 | 2010-09-30 | Myriad Pharmaceuticals, Inc. | Compounds and therapeutic uses thereof |
| ES2660146T3 (es) | 2009-04-29 | 2018-03-21 | Nerviano Medical Sciences S.R.L. | Sales del inhibidor de cdk |
| CN103626777B (zh) | 2009-07-29 | 2015-10-21 | 内尔维阿诺医学科学有限公司 | Plk抑制剂的盐类 |
| TW201107329A (en) | 2009-07-30 | 2011-03-01 | Oncotherapy Science Inc | Fused imidazole derivative having ttk inhibitory action |
| EP2343297A1 (en) | 2009-11-30 | 2011-07-13 | Bayer Schering Pharma AG | Triazolopyridines |
| CA2821829A1 (en) | 2010-12-17 | 2012-06-21 | Bayer Intellectual Property Gmbh | Imidazopyrazines for use as mps-1 and tkk inhibitors in the treatment of hyperproliferative disorders |
| EP2668190B1 (en) | 2011-01-26 | 2016-08-17 | Nerviano Medical Sciences S.r.l. | Tricyclic pyrrolo derivatives, process for their preparation and their use as kinase inhibitors |
| CN105658650B (zh) | 2013-06-24 | 2019-01-08 | 默克专利有限公司 | 用作卵泡刺激素受体调节剂的咪唑化合物及其用途 |
| CA2944610C (en) * | 2014-04-07 | 2024-01-09 | Netherlands Translational Research Center B.V. | (5,6-dihydro)pyrimido[4,5-e]indolizines |
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- 2015-03-30 CN CN201580017365.8A patent/CN106132963B/zh active Active
- 2015-03-30 MX MX2016012997A patent/MX368767B/es active IP Right Grant
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