ZA200700060B - 2, 4, 6-Trisubstituted pyrimidines as phosphotidylinositol (PI) 3-kinase inhibitors and their use in the treatment of cancer - Google Patents
2, 4, 6-Trisubstituted pyrimidines as phosphotidylinositol (PI) 3-kinase inhibitors and their use in the treatment of cancer Download PDFInfo
- Publication number
- ZA200700060B ZA200700060B ZA200700060A ZA200700060A ZA200700060B ZA 200700060 B ZA200700060 B ZA 200700060B ZA 200700060 A ZA200700060 A ZA 200700060A ZA 200700060 A ZA200700060 A ZA 200700060A ZA 200700060 B ZA200700060 B ZA 200700060B
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- ZA
- South Africa
- Prior art keywords
- alkyl
- group
- ylmethyl
- formula
- hydroxy
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- -1 2, 4, 6-Trisubstituted pyrimidines Chemical class 0.000 title claims description 240
- 206010028980 Neoplasm Diseases 0.000 title description 24
- 201000011510 cancer Diseases 0.000 title description 12
- 229940043355 kinase inhibitor Drugs 0.000 title 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims description 173
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 23
- 150000003230 pyrimidines Chemical class 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 125000005281 alkyl ureido group Chemical group 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 229940002612 prodrug Drugs 0.000 claims description 13
- 239000000651 prodrug Substances 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 239000012453 solvate Substances 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000004423 acyloxy group Chemical group 0.000 claims description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
- 125000003282 alkyl amino group Chemical group 0.000 claims description 9
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 9
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 9
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 125000001589 carboacyl group Chemical group 0.000 claims description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 239000003446 ligand Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 2
- 230000001028 anti-proliverative effect Effects 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 claims 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 13
- 125000001153 fluoro group Chemical group F* 0.000 claims 8
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 7
- 125000006239 protecting group Chemical group 0.000 claims 7
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims 6
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 6
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 claims 6
- 150000001412 amines Chemical class 0.000 claims 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 4
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims 4
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims 3
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims 3
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 3
- 230000010933 acylation Effects 0.000 claims 3
- 238000005917 acylation reaction Methods 0.000 claims 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 3
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims 3
- 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 3
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 3
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims 3
- 125000006534 ethyl amino methyl group Chemical group [H]N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 3
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 3
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims 2
- 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 2
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims 2
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 2
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 2
- 235000015164 Iris germanica var. florentina Nutrition 0.000 claims 2
- 235000015265 Iris pallida Nutrition 0.000 claims 2
- 244000050403 Iris x germanica Species 0.000 claims 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 2
- 125000002947 alkylene group Chemical group 0.000 claims 2
- 125000004273 azetidin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])C1([H])* 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- 239000003153 chemical reaction reagent Substances 0.000 claims 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims 2
- 238000003780 insertion Methods 0.000 claims 2
- 230000037431 insertion Effects 0.000 claims 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims 2
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- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims 2
- LJCJRRKKAKAKRV-UHFFFAOYSA-N (2-amino-2-methylpropyl) 3-(3,5-ditert-butyl-4-hydroxyphenyl)propanoate Chemical group CC(C)(N)COC(=O)CCC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 LJCJRRKKAKAKRV-UHFFFAOYSA-N 0.000 claims 1
- 125000001506 1,2,3-triazol-5-yl group Chemical group [H]N1N=NC([H])=C1[*] 0.000 claims 1
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- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 claims 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 1
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- 241000252095 Congridae Species 0.000 claims 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims 1
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- 125000002393 azetidinyl group Chemical group 0.000 claims 1
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- 150000002391 heterocyclic compounds Chemical class 0.000 claims 1
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Families Citing this family (20)
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|---|---|---|---|---|
| GB0415364D0 (en) | 2004-07-09 | 2004-08-11 | Astrazeneca Ab | Pyrimidine derivatives |
| GB0520657D0 (en) | 2005-10-11 | 2005-11-16 | Ludwig Inst Cancer Res | Pharmaceutical compounds |
| GB0525081D0 (en) * | 2005-12-09 | 2006-01-18 | Astrazeneca Ab | Pyrimidine derivatives |
| GB0525080D0 (en) * | 2005-12-09 | 2006-01-18 | Astrazeneca Ab | Pyrimidine derivatives |
| GB0616747D0 (en) * | 2006-08-24 | 2006-10-04 | Astrazeneca Ab | Novel compounds |
| WO2007080382A1 (en) * | 2006-01-11 | 2007-07-19 | Astrazeneca Ab | Morpholino pyrimidine derivatives and their use in therapy |
| CA2660758A1 (en) | 2006-08-24 | 2008-02-27 | Astrazeneca Ab | Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders |
| JP2010501537A (ja) * | 2006-08-24 | 2010-01-21 | アストラゼネカ アクチボラグ | 増殖性障害の治療に有用なモルホリノピリミジン誘導体 |
| WO2008032041A1 (en) * | 2006-09-14 | 2008-03-20 | Astrazeneca Ab | Pyrimidine derivatives having inhibitory activity against pi3k enzymes |
| CA2692720A1 (en) * | 2007-07-09 | 2009-01-15 | Astrazeneca Ab | Morpholino pyrimidine derivatives used in diseases linked to mtor kinase and/or pi3k |
| TWI555746B (zh) * | 2009-12-28 | 2016-11-01 | 財團法人生物技術開發中心 | 作為ｍＴＯＲ及ＰＩ３Ｋ抑制劑之新穎嘧啶化合物 |
| SA111320519B1 (ar) | 2010-06-11 | 2014-07-02 | Astrazeneca Ab | مركبات بيريميدينيل للاستخدام كمثبطات atr |
| 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 |
| HK1213251A1 (zh) | 2013-03-14 | 2016-06-30 | Novartis Ag | 作为突变idh抑制剂的3-嘧啶-4-基-恶唑烷-2-酮化合物 |
| US9242969B2 (en) * | 2013-03-14 | 2016-01-26 | Novartis Ag | Biaryl amide compounds as kinase inhibitors |
| UY36294A (es) | 2014-09-12 | 2016-04-29 | Novartis Ag | Compuestos y composiciones como inhibidores de quinasa |
| CA3037456A1 (en) | 2016-09-19 | 2018-03-22 | Novartis Ag | Therapeutic combinations comprising a raf inhibitor and a erk inhibitor |
| IL270224B1 (en) | 2017-05-02 | 2024-04-01 | Novartis Ag | Combination therapy employing trametinib and a defined raf inhibitor |
| JP2021510152A (ja) * | 2018-01-04 | 2021-04-15 | 北京大学深▲ヂェン▼研究生院Ｐｅｋｉｎｇ Ｕｎｉｖｅｒｓｉｔｙ Ｓｈｅｎｚｈｅｎ Ｇｒａｄｕａｔｅ Ｓｃｈｏｏｌ | Ｌｓｄ１とｈｄａｃとを標的として同時に阻害する化合物及びその用途 |
| EP4563150A3 (en) | 2019-05-13 | 2025-07-23 | Novartis AG | New crystalline forms of n-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methvlphenyl)-2(trifluoromethyl) isonicotinamide as raf inhibitors for the treatment of cancer |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19836697A1 (de) * | 1998-08-13 | 2000-02-17 | Hoechst Marion Roussel De Gmbh | Substituierte 4-Amino-2-aryl-pyrimidine, ihre Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate |
| CN1186324C (zh) * | 2000-04-27 | 2005-01-26 | 山之内制药株式会社 | 稠合杂芳基衍生物 |
-
2004
- 2004-07-09 GB GBGB0415367.2A patent/GB0415367D0/en not_active Ceased
-
2005
- 2005-07-07 MX MX2007000118A patent/MX2007000118A/es not_active Application Discontinuation
- 2005-07-07 BR BRPI0513056-5A patent/BRPI0513056A/pt not_active Application Discontinuation
- 2005-07-07 KR KR1020077003207A patent/KR20070032810A/ko not_active Withdrawn
- 2005-07-07 US US11/630,676 patent/US20080051401A1/en not_active Abandoned
- 2005-07-07 CA CA002571756A patent/CA2571756A1/en not_active Abandoned
- 2005-07-07 AU AU2005261555A patent/AU2005261555A1/en not_active Abandoned
- 2005-07-07 WO PCT/GB2005/002678 patent/WO2006005918A1/en not_active Ceased
- 2005-07-07 EP EP05759085A patent/EP1778681A1/en not_active Withdrawn
- 2005-07-07 CN CNA2005800297623A patent/CN101010317A/zh active Pending
- 2005-07-07 RU RU2007104838/04A patent/RU2007104838A/ru not_active Application Discontinuation
- 2005-07-07 JP JP2007519885A patent/JP2008505877A/ja active Pending
- 2005-07-08 TW TW094123251A patent/TW200618801A/zh unknown
- 2005-07-08 AR ARP050102852A patent/AR049712A1/es unknown
- 2005-07-08 UY UY29009A patent/UY29009A1/es not_active Application Discontinuation
-
2006
- 2006-12-17 IL IL180138A patent/IL180138A0/en unknown
-
2007
- 2007-01-02 ZA ZA200700060A patent/ZA200700060B/en unknown
- 2007-02-06 NO NO20070681A patent/NO20070681L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| UY29009A1 (es) | 2006-02-24 |
| NO20070681L (no) | 2007-03-21 |
| AU2005261555A1 (en) | 2006-01-19 |
| RU2007104838A (ru) | 2008-08-27 |
| CA2571756A1 (en) | 2006-01-19 |
| EP1778681A1 (en) | 2007-05-02 |
| WO2006005918A1 (en) | 2006-01-19 |
| TW200618801A (en) | 2006-06-16 |
| GB0415367D0 (en) | 2004-08-11 |
| MX2007000118A (es) | 2007-03-09 |
| CN101010317A (zh) | 2007-08-01 |
| KR20070032810A (ko) | 2007-03-22 |
| JP2008505877A (ja) | 2008-02-28 |
| BRPI0513056A (pt) | 2008-04-22 |
| US20080051401A1 (en) | 2008-02-28 |
| AR049712A1 (es) | 2006-08-30 |
| IL180138A0 (en) | 2007-06-03 |
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