Glucagon antagonists/inverse agonists

A compound of formula (I6):

• wherein R46 and R47 are selected from hydrogen, halogen, —CN, —CF3, —OCF3, —NO2, —OR10, —NR10R11 and C1-6-alkyl,
• wherein R10 and R11 independently are hydrogen or C1-6-alkyl;
• R1 is hydrogen or C1-6-alkyl;
• X is
• wherein
• r is 0 or 1,
• q and s independently are 0, 1, 2 or 3,
• R12, R13, R14 and R15 independently are hydrogen or C1-6-alkyl;
• D is
• wherein
• W is —O—, —S—, —S(O)2— or —NR20—,
• W′ is ═CR20′— or ═N—,
• R16, R17, R18 and R19 independently are
• hydrogen, halogen, —CN, —CH2CN, —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —OS(O)2CF3, —SCF3, —NO2, —OR21, —NR21R22, —SR21, —NR21S(O)2R22, —S(O)2NR21R22, —S(O)NR21R22, —S(O)R21, —S(O)2R21, —OS(O)2R21, —C(O)NR21R22, —OC(O)NR21R22, —NR21C(O)R22, —CH2C(O)NR21R22, —OCH2C(O)NR21R22, —CH2OR21, —CH2NR21R22, —OC(O)R21, —C(O)R21 or —C(O)OR21,
• C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
• which may optionally be substituted with one or more substituents selected from —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR21, —NR21R22, —SR21, —S(O)R21, —S(O)2R21, —C(O)NR21R22, —OC(O)NR21R22, —NR21C(O)R22, —OCH2C(O)NR21R22, —C(O)R21 and —C(O)OR21,
• C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkoxy, C3-8-cycloalkyloxy, C3-8-cycloalkyl-C1-6-alkylthio, C3-8-cycloalkylthio, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl or heterocyclyl-C2-4-alkynyl,
• of which the cyclic moieties optionally may be substituted with one or more substituents selected from
• —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR21, —NR21R22, —SR21, —S(O)R21, —S(O)2R21, —C(O)NR21R22, —OC(O)NR21R22, —NR21C(O)R22, —OCH2C(O)NR21R22, —C(O)R21 and —C(O)OR21,
• C1-6-alkyl, C2-6-alkenyl and C2-6-alkynyl,
• which may optionally be substituted with one or more substituents selected from —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR21, —NR21R22, —SR21, —S(O)R21, —S(O)2R21, —C(O)NR21R22, —OC(O)NR21R22, —NR21C(O)R22, —OCH2C(O)NR21R22, —C(O)R21 and —C(O)OR21,
• aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl,
• of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from
• halogen, —CN, —CH2CN, —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —OS(O)2CF3, —SCF3, —NO2, —OR21, —NR21R22, —SR21, —NR21S(O)2R22, —S(O)2NR21R22, —S(O)NR21R22, —S(O)R21, —S(O)2R21, —OS(O)2R21, —C(O)NR21R22, —OC(O)NR21R22, —NR21C(O)R22, —CH2C(O)NR21R22, —OCH2C(O)NR21R22, —CH2OR21, —CH2NR21R22, —OC(O)R21, —C(O)R21 and —C(O)OR21,
• C1-6-alkyl, C2-6-alkenyl and C2-6-alkynyl,
• which may optionally be substituted with one or more substituents selected from —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR21, —NR21R22, —SR21, —S(O)R21, —S(O)2R21, —C(O)NR21R22, —OC(O)NR21R22, —NR21C(O)R22, —OCH2C(O)NR21R22, —C(O)R21 and —C(O)OR21,
• wherein R21 and R22 independently are hydrogen, —CF3, C1-6-alkyl, tri-C1-6-alkylsilyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, aryl, aryl-C1-6-alkyl or heteroaryl,
• or R21 and R22 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R16 to R19 when placed in adjacent positions together may form a bridge —(CR16′R17′)a—O—(CR18′R19′)c—O—,
• wherein
• a is 0, 1 or 2,
• c is 1 or 2,
• R16′, R17′, R18′and R19′ independently are hydrogen, C1-6-alkyl or halogen,
• R20 and R20′ independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl or C3-8-cycloalkyl-C1-6-alkyl;
• E is a 3 to 9 membered mono- or bicyclic ring which may optionally contain one or two double bonds and which may optionally contain one or two heteroatoms selected from nitrogen, oxygen and sulfur, wherein one or two groups R23 and R24 may be attached to the same or different ring carbon atoms and wherein a group R31 may be attached to a ring nitrogen atom when present, or
• wherein
• m and p independently are 0, 1, 2, 3 or 4, with the proviso that when both m and p are present in the same formula at least one of m and p is different from 0,
• R23 and R24 independently are
• hydrogen, —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR36, —NR36R37, —SR36, —S(O)R36, —S(O)2R36, —C(O)NR36R37, —OC(O)NR36R37, —NR36C(O)R37, —OCH2C(O)NR36R37, —C(O)R36 or —C(O)OR36,
• C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
• which may optionally be substituted with one or more substituents selected from —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR36, —NR36R37, —SR36, —S(O)R36, —S(O)2R36, —C(O)NR36R37, —OC(O)NR36R37, —NR36C(O)R37, —OCH2C(O)NR36R37, —C(O)R36 and —C(O)OR36,
• C3-8-cycloalkyl, C3-8-cycloalkylidene, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl or heterocyclyl-C2-6-alkynyl,
• of which the cyclic moieties optionally may be substituted with one or more substituents selected from
• —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR36, —NR36R37, —SR36, —S(O)R36, S(O)2R36, C(O)NR36R37, —OC(O)NR36R37, —NR36C(O)R37, —OCH2C(O)NR36R37, —C(O)R36 and —C(O)OR36,
• C1-6-alkyl, C2-6-alkenyl and C2-6-alkynyl,
• which may optionally be substituted with one or more substituents selected from —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR36, —NR36R37, —SR36, —S(O)R36, —S(O)2R36, —C(O)NR36R37,
• —OC(O)NR36R37, —NR36C(O)R37, —OCH2C(O)NR36R37, —C(O)R36 and —C(O)OR36,
• aryl, aryloxy, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl,
• of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from
• halogen, —CN, —CH2CN, —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —OS(O)2CF3, —SCF3, —NO2, —OR36, —NR36R37, —SR36—NR36S(O)2R37, —S(O)2NR36R37, —S(O)NR36R37, —S(O)R36, —S(O)2R36, —OS(O)2R36, —C(O)NR36R37, —OC(O)NR36R37, —NR36C(O)R37, —CH2C(O)NR36R37, —CH2C(O)NR36R37, —CH2OR36, —CH2NR36R37, —OC(O)R36, —C(O)R36 and —C(O)OR36,
• C1-6-alkyl, C2-6-alkenyl and C2-6-alkynyl,
• which may optionally be substituted with one or more substituents selected from —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR36, —NR36R37, —SR36, —S(O)R36, —S(O)2R36, —C(O)NR36R37, —OC(O)NR36R37, —NR36C(O)R37, —OCH2C(O)NR36R37, —C(O)R36 and —C(O)OR36,
• wherein R36 and R37 independently are hydrogen, C1-6-alkyl or aryl,
• of which the aryl moiety optionally may be substituted with one or more substituents selected from halogen, —CN, —CF3, —OCF3, —NO2, —OR38, —NR38R39 and C1-6-alkyl,
• wherein R38 and R39 independently are hydrogen or C1-6-alkyl,
• or R36 and R37 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
• or R23 and R24 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical —O—(CH2)t—CR40R41—(CH2)l—O—, —(CH2)t—CR40R41—(CH2)l— or —S—(CH2)t—CR40R41—(CH2)l—S—,
• wherein
• t and l independently are 0, 1, 2, 3, 4 or 5,
• R40 and R41 independently are hydrogen or C1-6-alkyl,
• R25 to R30 independently are hydrogen, halogen, —CN, —CF3, —NO2, —OR42, —NR42R43, C1-6-alkyl, C3-8-cycloalkyl or C4-8-cycloalkenyl,
• wherein R42 and R43 independently are hydrogen or C1-6-alkyl, or
• R42 and R43 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
• R31, R32 and R33 independently are hydrogen or C1-6-alkyl,
• R34 and R35 independently are
• hydrogen, C1-6-alkyl, C1-6-alkoxy, C1-6-alkanoyl, —C(O)NR44R45 or —S(O)2R45,
• aryl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkanoyl or aryl-C1-6-alkyl,
• of which the aryl moieties optionally may be substituted with one or more substituents selected from halogen, —CN, —CF3, —OCF3, —OR44, —NR44R45 and C1-6-alkyl,
• wherein R44 and R45 independently are hydrogen or C1-6-alkyl, or
• R34 and R35 when attached to a carbon atom together with the said carbon atom may form a 3 to 8 membered cyclic ring optionally containing one or two heteroatoms selected from nitrogen, oxygen or sulfur, and optionally containing one or two double bonds, or
• R34 and R35 when attached to a nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen or sulfur, and optionally containing one or two double bonds,
• as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.