发明名称 Pyrazolopyrrolidine compounds
摘要 The invention relates to compounds of formula (I) as described herein, pharmaceutical preparations comprising such compounds, uses and methods of use for such compounds in the treatment of a disorder or a disease mediated by the activity of MDM2 and/or MDM4, and combinations comprising such compounds.;
申请公布号 US8969341(B2) 申请公布日期 2015.03.03
申请号 US201214361068 申请日期 2012.11.28
申请人 Novartis AG 发明人 Furet Pascal;Guagnano Vito;Holzer Philipp;Mah Robert;Masuya Keiichi;Schlapbach Achim;Stutz Stefan;Vaupel Andrea
分类号 A61K31/5377;A61K31/497;A61K31/517;A61K31/519;A61K31/505;A61K31/4709;A61K31/4523;A61K31/4155;C07D413/14;C07D487/14;C07D239/02;C07D403/14;C07D215/00;C07D211/80;C07D401/14;C07D257/02;C07D487/04;A61K31/41;A61K31/4162;A61K31/4178;A61K31/4439;A61K31/454;A61K31/496;A61K31/506 主分类号 A61K31/5377
代理机构 代理人 Reid Scott W.
主权项 1. A compound of formula (I) or a salt thereof,whereinA is selected fromB is selected fromR1 is selected from chloro, fluoro and methyl;R2 is selected from chloro, fluoro, trifluoromethyl, methyl and cyano;R3 is selected from isopropyl, cyclopropyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, or R3 is:wherein R14 is selected from OH, methoxy, NH2, NMe2, NHMe, NHCOMe and NHCOH;R4 is selected from H, —(C0-C4)alkyl-phenyl, said phenyl being optionally substituted with 1, 2 or 3 substituents independently selected from: (C1-C4)alkyl, optionally substituted by NR9(R10) or —O—(C1-C4)alkyl or by 1, 2 or 3 halo substituents,—O—(C1-C4)alkyl, optionally substituted by NR9(R10), phenyl or —O—(C1-C4)alkyl, or by 1, 2 or 3 halo substituents,—C(O)NR9(R12),cyano,halo,—(CH2)m—S(O)vNR9(R10),—C(O)OH,—C(O)O—(C1-C4)alkyl,—(CH2)p—NR9(R12),heterocyclyl1, andphenyl and wherein —(C0-C4)alkyl of said —(C0-C4)alkyl-phenyl, when present, is optionally substituted by 1 or 2 OH, —(C0-C4)alkyl-C(O)-phenyl, said phenyl being optionally substituted with 1, 2 or 3 substituents independently selected from: (C1-C4)alkyl, optionally substituted with from 1 to 3 halo,—O—(C1-C4)alkyl,cyano, andhalo, naphthyl, —(C0-C4)alkyl-(C3-C6)cycloalkyl, said (C3-C6)cycloalkyl being optionally substituted with 1, 2 or 3 substituents independently selected from OH, —C(O)NR9(R10), —O—C(O)—(C1-C4)alkyl, halo, —(CH2)m—NR9(R10) and —C(O)—O(C1-C4)alkyl, —(C0-C4)alkyl-heteroaryl1, the heteroaryl1 of said —(C0-C4)alkyl-heteroaryl1 being optionally substituted by 1, 2, 3 or 4 substituents independently selected from —O—(C1-C4)alkyl, ═O, OH, cyano, (C1-C4)alkyl, halo and —NR9(R10), —(C0-C4)alkyl-C(O)NR9(R13), —(C0-C4)alkyl-NR9(R12), wherein —(C0-C4)alkyl of said —(C0-C4)alkyl-NR9(R12), when present, is optionally substituted with 1 or 2 OH, —(C0-C4)alkyl-heterocyclyl4, said heterocyclyl4 being optionally substituted by 1, 2, 3 or 4 substituents independently selected from —O—C(O)NR9(R12),OH,—C(O)(C1-C4)alkyl, optionally substituted by (C1-C4)alkoxy,—C(O)—O(C1-C4)alkyl, optionally substituted by (C1-C4)alkoxy,═O,halo,—C(O)— heteroaryl2, and(C1-C4)alkyl, optionally substituted by phenyl,and wherein the —(C0-C4)alkyl of —(C0-C4)alkyl-heterocyclyl4, when present, is optionally substituted with 1 or 2 OH, (C1-C8)alkyl, said (C1-C8)alkyl being optionally substituted by 1, 2 or 3 substituents independently selected from OH, halo, —O—(C1-C4)alkyl, —C(O)(C1-C4)alkyl, —C(O)O—-(C1-C4)alkyl, —C(O)OH, cyano and NR9(R10), (C1-C8)alkenyl, said (C1-C8)alkenyl being optionally substituted by 1, 2 or 3 substituents independently selected from OH, halo and —O—(C1-C4)alkyl;R5 is selected from: H, heterocyclyl1-C(O)—(CH2)n—, (C1-C4)alkyl-, said (C1-C4)alkyl- being optionally substituted with 1 or 2 substituents independently selected from OH, ═O, heterocyclyl1-(C1-C4)alkyl-, wherein said alkyl of heterocyclyl1-(C1-C4)alkyl- is optionally substituted by 1 or 2 OH, and said heterocyclyl1 can be optionally substituted by methyl or ethyl, (C1-C4)alkyl-O—C(O)—(CH2)m— and cyano;R6 is selected from H, (C1-C4)alkyl-, optionally substituted with (C1-C4)alkoxy, (C1-C4)alkoxy, optionally substituted with (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkoxy(C1-C4)alkyl-, halo, R9(R10)N—C(O)—(CH2)m—, cyano R9(R10)N—(CH2)m—, R9(R10)N—(CH2)n—O—(CH2)m—, (C1-C4)alkyl-C(O)—(R10)N—(CH2)m—, and —O—(CH2)p-heteroaryl2;R7 is selected from H, halo, (C1-C4)alkyl-, optionally substituted with (C1-C4)alkoxy, (C1-C4)alkoxy, optionally substituted with (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkoxy(C1-C4)alkyl-, R9(R10)N—(CH2)n—O—(CH2)m—, and (C1-C4)alkyl-C(O)O—(CH2)n—(R10)N—;R8 is selected from H, (C1-C4)alkoxy(C1-C4)alkyl-, (C1-C4)alkyl-, said (C1-C4)alkyl- being optionally substituted by 1, 2 or 3 substituents independently selected from OH, halo, —O—(C1-C4)alkyl, NR9(R10), and (C1-C4)alkyl-C(O)NR9(R10);R9 is H, methyl or ethyl;R10 is H, methyl or ethyl, wherein said methyl and ethyl can each independently be substituted by 1 or 2 substituents independently selected from methoxy, ethoxy and halo;R11 is H, methyl, methoxy or halo;R12 is selected from H, (C1-C4)alkyl-, optionally substituted with heterocyclyl3, —C(O)(C1-C4)alkyl, —C(O)O(C1-C4)alkyl, —C(O)H, and —C(O)-phenyl, optionally substituted with 1 or 2 substituents independently selected from (C1-C4)alkyl, —O—(C1-C4)alkyl, cyano, halo, —C(O)OH, —C(O)O—(C1-C4)alkyl and —C(O)—(C1-C4)alkyl;R13 is selected from —(C0-C3)alkyl-phenyl, said phenyl being optionally substituted with 1 or 2 substituents independently selected from (C1-C4)alkyl, —O—(C1-C4)alkyl, cyano, halo, —C(O)OH, —C(O)O—(C1-C4)alkyl and —C(O)—(C1-C4)alkyl, —(C0-C3)alkyl-heterocyclyl4, said heterocyclyl4 being optionally substituted by 1, 2 or 3 substituents independently selected from —O—(C1-C4)alkyl, C(O)(C1-C4)alkyl and C(O)O—(C1-C4)alkyl, (C1-C4)alkyl, said (C1-C4)alkyl being optionally substituted with a substituent independently selected from —O—(C1-C4)alkyl, C(O)(C1-C4)alkyl and C(O)O—(C1-C4)alkyl, —(C0-C3)alkyl-(C3-C6)cycloalkyl; or R9 and R13, together with the nitrogen to which they are attached form heterocyclyl3, said heterocyclyl3 being optionally substituted with 1, 2 or 3 substitutents selected independently from ═O, (C1-C4)alkyl, said (C1-C4)alkyl being optionally substituted with 1, 2 or 3 substitutents selected independently from halo and OH, OH, C(O)(C1-C4)alkyl, C(O)O—(C1-C4)alkyl and C(O)NR9R10;m is 0, 1 or 2;n is 1, 2 or 3;p is 0, 1, 2 or 3;v is 0, 1 or 2;heterocyclyl1 is a 3, 4, 5 or 6 membered fully saturated or partially unsaturated monocyclic group comprising ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S;heterocyclyl3 is a 4, 5 or 6 membered fully saturated or partially unsaturated monocyclic group comprising ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S;heterocyclyl4 is a 3, 4, 5, 6 or 7 membered fully saturated or partially unsaturated monocyclic group comprising carbon ring atoms and 1 or 2 ring atoms selected independently from N, O and S;heteroaryl1 is a 5, 6, 7, 8, 9 or 10 membered, mono or bicyclic, fully unsaturated or partially unsaturated group, comprising carbon ring atoms and 1, 2, 3 or 4 ring heteratoms independently selected from N, O and S, wherein the total number of S atoms does not exceed 1, and the total number of O atoms does not exceed 1;heteroaryl2 is 5 or 6 membered fully unsaturated monocyclic group comprising ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein the total number of ring S atoms does not exceed 1, and the total number of ring O atoms does not exceed 1;and * indicates the point of attachment to the remainder of the molecule.
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