发明名称 CCR2 antagonists
摘要 The present invention relates to novel antagonists for CCR2 (CC chemokine receptor 2) of formula (Ia) and their use for providing medicaments for treating conditions and diseases, especially pulmonary diseases like asthma and COPD.;
申请公布号 US8962656(B2) 申请公布日期 2015.02.24
申请号 US201113700752 申请日期 2011.05.26
申请人 Boehringer Ingelheim International GmbH 发明人 Ebel Heiner;Frattini Sara;Giovannini Riccardo;Hoenke Christoph;Scheuerer Stefan
分类号 A61K31/44;C07D211/72;C07D405/14;C07D401/06;C07D401/14 主分类号 A61K31/44
代理机构 代理人 Morris Michael P.;Lazer Edward S.
主权项 1. A compound according to formula (Ia), wherein A′ is —NH-L1-R7, wherein L1 is a linker selected from a bond or —C1-C2-alkylene, wherein R7 is a ring selected from among —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C5-C10-aryl, and -C5-C10-heteroaryl, wherein the ring R7 is optionally substituted with one or more groups selected from among —CF3, —C1-C6-alkyl, —O—CF3, —CN, —O—C1-C6-alkyl, —C1-C6-alkenyl, and —C1-C6-alkynyl, and -halogen, or wherein the ring R7 is optionally substituted with one or more groups selected from among -C5-C10-aryl, -C5-C10-heteroaryl, —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, optionally being substituted by one or more groups selected from among —OH, —NH2, —C1-C4-alkyl, —O—C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, and ═O, or wherein the ring R7 is optionally further bi-valently substituted on two neighbouring ring atoms, such that an annellated ring is formed by one or more groups selected from among —C1-C6-alkylene, —C2-C6-alkenylene and —C4-C6-alkynylene, in which one or two carbon centers may optionally be replaced by 1 or 2 hetero atoms selected from N, O and S, the bivalent group being optionally substituted by one or more groups selected from —OH, —NH2, —C1-C4-alkyl, —O—C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, and ═O, wherein R1 is —H; wherein R2 is selected from among —H, -halogen, —CN, —O—C1-C4-alkyl, —C1-C4-alkyl, —CH═CH2, —C≡CH, -cyclopropyl, —CF3, —OCF3, —OCF2H, and —OCFH2; wherein R3 is —H; wherein R6 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3; wherein Z is C; wherein n is 2; wherein R4 and R5 are independently selected from among an electron pair, —H, and a group selected from among —C1-C6-alkyl, —NH2, —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C5-C10-aryl, -C5-C10-heteroaryl, and —C(O)—N(R8,R8′), with R8 and R8′ independently being selected from among —H, and —C1-C6-alkyl, and wherein R4 and R5 if different from an electron pair or —H are optionally independently substituted with one or more groups selected from among -halogen, —OH, —CF3, —CN, —C1-C6-alkyl, —O—C1-C6-alkyl, —O—C3-C8-cycloalkyl, —O—C3-C8-heterocyclyl, —O—C5-C10-aryl, —O—C5-C10-heteroaryl, —C0-C6-alkylene-CN, —C0-C4-alkylene-O—C1-C4-alkyl, —C0-C4-alkylene-O—C3-C8-cycloalkyl, —C0-C4-alkylene-O—C3-C8-heterocyclyl, —C0-C4-alkylene-O-C5-C10-aryl, —C0-C4-alkylene-O-C5-C10-heteroaryl, —C0-C4-alkylene-Q-C0-C4-alkyl-N(R9,R9′), —C0-C4-alkylene-N(R10)-Q-C1-C4-alkyl, —C0-C4-alkylene-N(R10)-Q-C3-C8-cycloalkyl, —C0-C4-alkylene-N(R10)-Q-C3-C8-heterocyclyl, —C0-C4-alkylene-N(R10)-Q-C5-C10-aryl, —C0-C4-alkylene-N(R10)-Q-C5-C10-heteroaryl, —C0-C4-alkylene-Q-N(R11,R11′), —C0-C4-alkylene-N(R12)-Q-N(R13,R13′), —C0-C4-alkylene-R14, —C0-C4-alkylene-Q-C1-C6-alkyl, —C0-C4-alkylene-Q-C3-C8-cycloalkyl, —C0-C4-alkylene-Q-C3-C8-heterocyclyl, —C0-C4-alkylene-Q-C5-C10-aryl, —C0-C4-alkylene-Q-C5-C10-heteroaryl, —C0-C4-alkylene-O-Q-N(R15,R15′), and —C0-C4-alkylene-N(R16)-Q-O—(R17), wherein Q is selected from among —C(O)—, and —SO2—, wherein R12, R16, are independently selected from among —H, —C1-C6-alkyl, and —C3-C6-cycloalkyl, wherein R9, R9′, R10, R11, R11′, R13, R13′, R15, R15′, are independently selected from among —H, —C1-C6-alkyl, and —C3-C6-cycloalkyl, or wherein R9 and R9′, R11 and R11′, R13 and R13′, R15 and R15′ together form a —C2-C6-alkylene group, wherein R14 and R17 are independently selected from among —H, —C1-C6-alkyl, —C5-C10-aryl, —C5-C10-heteroaryl, —C3-C8-cycloalkyl, and —C3-C8-heterocyclyl, wherein said —C3-C8-heterocyclyl optionally comprises nitrogen and/or —SO2— in the ring, and wherein R14 and R17 are optionally substituted with one or more groups selected from among —OH, —OCH3, —CF3, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —SO2—C1-C4-alkyl, or wherein R4 and/or R5 are independently selected from among an electron pair, —H, and a group of the structure -L2-R18, wherein L2 is selected from among —NH— and —N(C1-C4-alkyl)-, wherein R18 is selected from among —C5-C10-aryl, —C5-C10-heteroaryl, —C3-C8-cycloalkyl, and —C3-C8-heterocyclyl, wherein R18 is optionally substituted by one or more groups selected from among halogen, —CF3, —OCF3, —CN, —OH, —O—C1-C4-alkyl, —C1-C6-alkyl, —NH—C(O)—C1-C6-alkyl, —N(C1-C4-alkyl)-C(O)—C1-C6-alkyl, —C(O)—C1-C6-alkyl, —S(O)2—C1-C6-alkyl, —NH—S(O)2—C1-C6-alkyl, —N(C1-C4-alkyl)-S(O)2—C1-C6-alkyl, and —C(O)—O—C1-C6-alkyl, and wherein R4, R5 and R18 are optionally further substituted by spiro-C3-C8-cycloalkyl or spiro-C3-C8-heterocyclyl such that together with R4, R5 and/or R18 a spirocycle is formed, wherein said spiro-C3-C8-heterocyclyl optionally comprises one or more groups selected from among nitrogen, —C(O)—, —SO2—, and —N(SO2—C1-C4-alkyl)- in the ring, or wherein R4, R5 and R18 are optionally further bi-valently substituted by one or more spirocyclic or annellated ring forming groups selected from among —C1-C6-alkylene, —C2-C6-alkenylene, and —C4-C6-alkynylene, in which one or two carbon centers may optionally be replaced by one or two hetero atoms selected from among N, O and S and which may optionally be substituted by one or more groups on one ring atom or on two neighbouring ring atoms selected from among —OH, —NH2, —C1-C3-alkyl, O—C1-C6-alkyl, —CN, —CF3, —OCF3, and halogen; or a pharmacologically acceptable salt thereof.
地址 Ingelheim am Rhein DE
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