OA13027A - Substituted N-arylheterocycles, method for production end use thereof as medicaments. - Google Patents
Substituted N-arylheterocycles, method for production end use thereof as medicaments. Download PDFInfo
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- OA13027A OA13027A OA1200500227A OA1200500227A OA13027A OA 13027 A OA13027 A OA 13027A OA 1200500227 A OA1200500227 A OA 1200500227A OA 1200500227 A OA1200500227 A OA 1200500227A OA 13027 A OA13027 A OA 13027A
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to N-arylheterocycles and the physiologically-acceptable salts and physiologically-functional derivatives thereof. Compounds of formula (I), where the groups have the given meanings, the N-oxides and the physiologically-acceptable salts and methods for production thereof are disclosed. The compounds are suitable as anorectics for example.
Description
1 013027
Substituted N-aryl heterocycles, process fortheir préparation and their useas médicaments
The invention relates to substituted N-aryl heterocycles and to thephysiologically tolerated salts and physiologically functional dérivativesthereof.
Compounds having a pharmacological effect and similar in their overallstructure to the N-aryl heterocycles described hereih hâve already beendescribed in the prior art. Thus, for example, WO 00/35454 describesureido-substituted phenylpiperidines and -pyrrolidines as agents for thetreatment of inflammatory and autoimmune diseases. Acylamido-substituted phenylpyrrolidines are proposed in WO 02/042271 for thetreatment of diabètes, obesity and disorders of lipid metabolism.
The invention was based on the object of providing compounds which bringabout a weight réduction in mammals and are suitable for preventing andtreating obesity and diabètes.
The invention therefore relates to compounds of the formula I R7 R6
O
R3 •NR^ R4 R9 R8 R5 in which the meanings are R1, R2 independently of one another H, (C-i-CsJ-alkyl, -(CR78R79)O-R12, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, aryloxy-(Ci-C4)-alkyl,(C3-Cg)-alkenyl, (C3-C8)-alkynyl, CO-fCrCgJ-alkyl, -CO-(CH2)o-R12, CO-aryloxy-(Ci-C4)-alkyl, CO-(C2-Cg)-alkenyl,CO-(C2-Cg)-alkynyl, COCH=CH(R13), COCC(R14), CO-(Ci-C4)-alkyl-S(O)p-(Ci-C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), 013027 2 CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))SO(R25);or R1 and R2 form together with the nitrogen atom to which theyare bonded a 4 to 10-membered mono-, bi- or spirocyclic ringwhich, apart from the nitrogen atom, may comprise 0 to 4additional heteroatoms selected from the group of oxygen,nitrogen and sulfur, where the heterocyclic ring System mayadditionally be substituted by F, Cl, Br, CF3, NO2, CN, (C-1-C6)-alkyl, O-(Ci-Cs)-alkyl, (C-|-C4)-alkoxy-(Ci-C4)-alkyl, hydroxy-(Ci-C4)-alkyl, (Co-C8)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28),hydroxy, COO(R29), N(R30)CO(Ci-C6)-alkyl, N(R31)(R32) orSO2CH3; o 0,1,2,3,4,5,6; P 0,1,2 q, r, s independently of one another 0, 1,2, 3, 4; R13, R14 independently of one another a 5-10 membered aromatic ring
System which may comprise 0-2 further heteroatoms from thegroup of nitrogen, oxygen and sulfur and may be substituted byF, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkyl, O-(Ci-C8)-alkyl; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29,R30, R31.R32 independently of one another H, (C-|-C6)-alkyl; R18 H, (Ci-C6)-alkyl, CO(Ci-C6)-alkyl, ÇO(R33); or R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(C-|-C6)-alkyl, oxygenand sulfur; R33 a 5-10 membered aromatic ring System which may comprise 0-2further heteroatoms from the group of nitrogen, oxygen and 3 013027 sulfur and may be substituted by F, Cl, Br, CF3, NO2, CN,(Ci-CeJ-alkyl, O-(Ci-C8)-alkyl; R12 OH, O-^-CeMkyl, O(C0-C8)-alkylene-aryl, CN, S-(Ci-C6)-alkyl, COO(R80), CON(R81)(R93), N(R82)(R83), 3-12membered mono-, bi- or spirocyclic ring which may comprise oneor more heteroatoms from the group of N, O and S, and the 3-12membered ring may comprise further substituents such as F, Cl,Br, I, OH, CF3, NO2i CN, OCF3> oxo, O-(Ci-C6)-alkyl,(Ci-C4)-alkoxy-(C-|-C4)-alkyl, S-(C-|-C6)-alkyl, (Ci-C8)-alkyl,(C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O-(C3-C8)-cycloalkyl,(C3-C8)-cycloalkenyl, O-(C3-C8)-cycloalkenyl, (C2-C8)-alkynyl,0-(Co-C8)-alkylene-aryl, N(R34)(R35), COCH=CH(R36),(C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(Ci-C8)-alkyl,COCOO(Ci-C6)-alkyl, COO(R40), S(O)U(R41 ) and COOH; t 0,1,2,3,4,5,6; u 0,1,2; R34, R35, R37, R38 independently of one another H, (Ci-C8)-alkyl;or R34 and R35 optionally together with the nitrogen atom to which they arebonded a 5-6 membered ring which, apart from the nitrogenatom, may also comprise 0-1 further heteroatoms from the groupof N-(C-|-C6)-alkyl, oxygen and sulfur and may optionally besubstituted by 1-2 oxo groups; R36, R39 independently of one another (C3-C8)-cycloalkyl, 5-10 memberedaromatic ring System which may comprise 0-2 furtherheteroatoms from the group of nitrogen, oxygen and sulfur andmay be substituted by F, Cl, Br, CF3, ΝΟ2, CN, (Ci-C6)-alkyl,O-(Ci-C8)-alkyl; R40 H, (Ci-C8)-alkyl, (C2-C8)-alkenyl, (Co-C8)-alkylene-aryl; 013027 4 R41 (C-j-Ce)-alkyl, 5-10 membered aromatic ring System which maycomprise 0-2 further heteroatoms from the group of nitrogen,oxygen and sulfur and may be substituted by F, Cl, Br, CF3,NO2, CN, (Ci-C6)-alkyl, O-(Ci-Ce)-alkyl; R78, R79 independently of one another H, (C-i-CsJ-alkyl, hydroxy-(Ci-C4)-alkyl, OH, (Ci-C4)-alkoxy-(C-|-C4)-alkyl; R80, R81 R93 independently of one another H, (Ci-Cs)-alkyl, (C2-C6)-alkenyl,(Co-C8)-alkylene-aryl; R82, R83 independently of one another H, (Ci-C6)-alkyl; or R82 and R83 optionally together with the nitrogen atom to which they arebonded a 5-6 membered ring which, apart from the nitrogenatom, may also comprise 0-1 further heteroatoms from the groupof N-(C-i-C6)-alkyl, oxygen and sulfur and may optionally besubstituted by 1-2 oxo groups; R3 H, (Ci-C6)-alkyl; R4, R5 independently of one another H, (Ci-C6)-alkyl, OH,O-(Ci-C6)-alkyl, O-CO(Ci-C6)-alkyl, S-(C-|-C6)-alkyl; R6, R7, R8, R9 independently of one another H, (C-i-C8)-alkyl;or R6 and R7, R8 and R9 independently of one another optionally oxo; n, m independently of one another 0, 1,2; A, B, D, G independently of one another N, C(R42);or the groups A and B or the groups D and G are each C(R42) andtogether form a 5- or 6 membered carbocyclic or heterocyclic 013027 5 radical to resuit overall in a bicyclic System; R42 H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-alkyl, O-(C-|-C4)-alkoxy-(Ci-C4)-alkyl, S-(Ci-C6)-alkyl, (Ci-C6)-alkyl,(C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O-(C3-C8)-cycloalkyl,(C3-C8)-cycloalkenyl, O-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl,(Co-C8)-alkylene-aryl, 0-(Co-C8)-alkylene-aryl, S-aryl,N(R43)(R44), SO2-CH3, COOH, COO-(C-|-C6)-alkyl,CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51),-(CR84R85)x-O(R86); R43, R44, R45, R46, R47, R49 independently of one another H, (Ci-C8)-alkyl; or R43 and R44, R45 and R46 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(C-|-C6)-alkyI, oxygenand sulfur; R48, R50, R51 independently of one another H, (Ci-Cs)-alkyl, aryl; R84, R85 independently of one another H, (Ci-Cs)-alkyl; R86 H, (Ci-C6)-alkyl, aryl; x 1,2,3,4,5,6; R10 H, (Ci-C8)-alkyl, (C3-C6)-alkenyl, (C3-C6)-alkynyl; X N(R52), O, a bond, C=C, C(R53)(R54), C(R55)(R56)O, CO, C=C, a group of the formula -(CR87R88)y- in which one or more-(CR87R88)- groups may be replaced by Y to resuit in achemically reasonable radical; O, S, N(R89); 013027 6 R52, R53, R54, R55, R56 independently of one another H, (Ci-Cg)-alkyl; R87, R88 independently of one another H, (Ci-C4)-alkyl, where R87 andR88 in the y groups may in each case hâve the same or differentmeanings; y 2, 3, 4, 5, 6; R89 H, (Ci-C8)-alkyl; E 3-14 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, O and S, which mayoptionally hâve substituents from the group of H, F, Cl, Br, I, OH,CF3, NO2, CN, OCF3, oxo, O-(C-|-C6)-alkyl, O-(C-|-C4)-alkoxy-(Ci-C4)-alkyl, S-(C-]-C6)-alkyl, (C-]-C6)-alkyl, (C2-C6)-alkenyl,(C3-C8)-cycloalkyl, O-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl,O-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (Co-Cs)-alkylene-aryl,0-(Co-C8)-alkylene-aryl, S-aryl, N(R57)(R58), SO2-CH3, COOH,COO-(C-|-C6)-alkyl, CON(R59)(R60), N(R61)CO(R62),N(R63)SO2(R64), CO(R65) and may be mono- or bicyclic; R57, R58, R59, R60, R61, R63 independently of one another H, (C-|-C8)-alkyl; or R57 and R58, R59 and R60 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(C-|-C6)-alkyl, oxygenand sulfur; R62, R64, R65 independently of one another H, (Ci-C8)-alkyl,aryl; a bond, O, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO,CON(R68), (C(R69)(R70))v, CO, C=C, C=C, a group of the 013027 7 formula -(CR90R91)z- in which one or more -(CR90R91)- groupsmay be replaced by Z to resuit in a chemically reasonableradical; v 1,2,3,4 R66, R67, R68, R69, R70 independently of one another H, (Ci-Cs)-alkyl; Z O, S, N(R92), CO, SO, SO2; R90, R91 independently of one another H, (Ci-C8)-alkyl, hydroxy-(Ci-C4)-alkyl, hydroxy, (Ci-C4)-aIkoxy-(Ci-C4)-alkyl, where R90 and R91in the z groups may in each case hâve the same of differentmeanings; z 2, 3,4, 5, 6; R92 H, (Ci-C8)-alkyl; R11 H, (Ci-C8)-alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, a 3 to 10-membered mono-, bi- or spirocyclicring which may comprise 0 to 4 heteroatoms selected from thegroup of oxygen, nitrogen and sulfur, where the ring System mayadditionally be substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl, O-(Ci-Cs)-alkyl, (C-|-C4)-alkoxy-(Ci-C4)-alkyl, (Co-Cs)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, hydroxy-(Ci-C4)-alkyl, COO(R74), N(R75)CO(Ci-C6)-alkyl, N(R76)(R77)or SO2CH3i SCF3; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (Ci-Cs)-alkyl; or R72 and R73, R76 and R77 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(Ci-C6)-alkyl, oxygen 013027 8 and sulfur; or E, K and R11 together form a tricyclic System where the rings mayindependently of one another [lacuna] saturated, partiallysaturated or unsaturated and may each comprise 3-8 ring atoms; and the N-oxides and physiologically tolerated salts thereof.
In a further embodiment, the invention therefore relates to compounds ofthe formula I in which the meanings are:
R9 R8 R5 R1, R2 independently of one another H, (C-|-C8)-alkyl, -(CH2)o-R12,(C-|-C4)-alkoxy-(C-|-C4)-alkyl, aryloxy-(Ci-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, CO-(Ci-C8)-alkyl, -CO-(CH2)o-R12,CO-aryloxy-(C-|-C4)-alkyl, CO-(C2*C8)-alkenyl, CO-(C2-C8)-alkynyl, COCH=CH(R13), COCC(R14), CO-(Ci-C4)-alkyl-S(O)p-(Ci-C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))SO(R25);or R1 and R2 form together with the nitrogen atom to which theyare bonded a 4 to 10-membered mono-, bi- or spirocyclic ringwhich, apart from the nitrogen atom, may comprise 0 to 4additional heteroatoms selected from the group of oxygen,nitrogen and sulfur, where the heterocyclic ring System mayadditionally be substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl, O-(Ci-C8)-alkyl, (C-j-C4)-alkoxy-(Ci-C4)-alkyl,(Co-C8)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy,COO(R29), N(R30)CO(Ci-C6)-alkyl, N(R31)(R32)orSO2CH3; o 0,1,2,3,4,5,6; 0,1,2 013027 9 q, r, s independently of one another 0,1,2, 3, 4; R13, R14 independently of one another a 5-10 membered aromatic ringSystem which may comprise 0-2 further heteroatoms from thegroup of nitrogen, oxygen and sulfur and may be substituted byF, Cl, Br, CF3, NO2i CN, (Ci-C6)-alkyl, O-(Ci-C8)-alkyl; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29,R30, R31, R32 independently of one another H, (Ci-C6)-alkyl; R18 H, (C-i-CeJ-alkyl, CO(Ci-Ce)-alkyl, CO(R33); R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(C-|-C6)-alkyl, oxygenand sulfur; R33 a 5-10 membered aromatic ring System which may comprise 0-2further heteroatoms from the group of nitrogen, oxygen andsulfur and may be substituted by F, Cl, Br, CF3, ΝΟ2, CN,(Ci-Ce)-alkyl, O-(Ci-C8)-alkyl; R12 OH, 3-12 membered mono-, bi- or spirocyclic ring which maycomprise one or more heteroatoms from the group of N, O andS, and the 3-12 membered ring may comprise furthersubstituents such as F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, oxo,O-(Ci-C6)-alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, S-(C-|-C6)-alkyl,(Ci-C6)-alkyl, (C2-C8)-alkenyl, (C3-C8)-cycloalkyl, O-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, 0-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, 0-(Co-C8}-alkylene-aryl, N(R34)(R35),COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39),CO(Ci-C6)-alkyl, COCOO(Ci-C6)-alkyl, COO(R40), S(O)U(R41)and COOH; 0,1,2, 3,4, 5, 6; 013027 10 U 0,1,2; R34, R35, R37, R38 independently of one another H, (Ci-Cs)-alkyl; R34 and R35 optionaiiy together with the nitrogen atom to which they arebonded a 5-6 membered ring which, apart from the nitrogenatom, may also comprise 0-1 further heteroatoms from the groupof N-(C-|-C6)-alkyl, oxygen and sulfur and may optionaiiy besubstituted by 1-2 oxo groups; R36, R39 independently of one another (C3-C8)-cycloalkyl, 5-10 memberedaromatic ring System which may comprise 0-2 furtherheteroatoms from the group of nitrogen, oxygen and sulfur andmay be substituted by F, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkyl,O-(Ci-C8)-alkyl; R40 H, (Ci-Ce)-alkyl, (C2-C6)-alkenyl, (Co-C8)-alkylene-aryl; R41 (Ci-C6)-alkyl, 5-10 membered aromatic ring System which maycomprise 0-2 further heteroatoms from the group of nitrogen,oxygen and sulfur and may be substituted by F, Cl, Br, CF3, NO2,CN, (Ci-C6)-alkyl, O-(Ci-C8)-alkyl; R3 H, (CrCeJ-alkyl; R4, R5 independently of one another H, (Ci-C6)-alkyl, OH,O-{Ci-C6)-alkyl, O-CO(Ci-C6)-alkyl, S-(C-|-C6)-alkyl; R6, R7, R8, R9 independently of one another H, (C-|-C8)-alkyl; R6 and R7, R8 and R9 independently of one another optionaiiy oxo; n, m independently of one another 0,1,2; 013027 11 A, B, D, G independently of one another N, C(R42); R42 H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-alkyl, O-(Ci-C4)-alkoxy-(Ci-C4)-alkyl, S-(C-|-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, (C3-Cs)-cycloalkyl, O-(C3-C8)-cycloalkyl, (C3-C8)-cyçloalkenyl, O-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (Co-Cs)-alkylene-aryl, 0-(Co-C8)-alkylene-aryl, S-aryl, N(R43)(R44), SO2-CH3, COOH, COO-(Ci-C6)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51) R43, R44, R45, R46, R47, R49 independently of one another H, (C-j-C8)-alkyl; R43 and R44, R45 and R46 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(Ci-C6)-alkyl, oxygenand sulfur; R48, R50, R51 independently of one another H, (Ci-CsJ-alkyl, aryl; R10 H, (Ci-C8)-alkyl, (C3-C6)-alkenyl, (C3-C6)-alkynyl; X N(R52), O, a bond, C=C, C(R53)(R54), C(R55)(R56)O; R52, R53, R54, R55, R56 independently of one another H, (Ci-C8)-alkyl; E 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, O and S, which mayoptionally hâve substituents from the group of H, F, Cl, Br, I, OH,CF3, NO2i CN, OCF3, O-(Ci-C6)-alkyl, O-(Ci-C4)-alkùxy-(Ci-C4)-alkyl, S-(C-|-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O-(C3-C8)-cycloalkyl, (C3-Cs)-cycloalkenyl, O-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (Co-Cs)-alkylene-aryl, O- 013027 12 (C0-C8)-alkylene-aryl, S-aryl, N(R57)(R58), SO2-CH3, COOH,COO-(Ci-C6)-alkyl, CON(R59)(R60), N(R61 )CO(R62),N(R63)SO2(R64)„ CO(R65) and may be mono- or bicyclic; R57, R58, R59, R60, R61, R63 independently of one another H, (Ci-CsJ-alkyl; R57 and R58, R59 and R60 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ring-which, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(Ci-C6)-alkyl, oxygenand sulfur; R62, R64, R65 independently of one another H, (C-|-C8)-alkyl, aryl; K a bond, O, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C=C; v 1,2,3,4; R66, R67, R68, R69, R70 independently of one another H, (Ci-C8)-alkyl; R11 H, (C-|-C8)-alkyl, (C-|-C4)-alkoxy-(C-|-C4)-alkyl, (C3-C8)-alkenyl,(C3-C8)-alkynyl, a 3 to 10-membered mono-, bi- or spirocyclicring which may comprise 0 to 4 heteroatoms selected from thegroup of oxygen, nitrogen and sulfur, where the ring System mayadditionally be substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl, O-(Ci-Cs)-alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, (Co-Cs)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy,COO(R74), N(R75)CO(Ci-C6)-alkyl, N(R76)(R77) or SO2CH3; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (Ci-C8)-alkyl; R72 and R73, R76 and R77 013027 13 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(Ci-C6)-alkyl, oxygenand sulfur; or E, K and R11 together form a tricyclic System where the rings may independently of one another [lacuna] saturated, partiallysaturated or unsaturated and may each comprise 3-8 ring atoms; and the physiologically tolerated salts thereof.
The invention relates to compounds of the formula I in the form of theirracemates, enantiomer-enriched mixtures and pure enantiomers, and totheir diastereomers and mixtures thereof.
The alkyl, alkenyl and alkynyl radicale in the substituents R1, R2, R3, R4,R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19,R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92 and R93 may be either straight-chain, branched oroptionally halogenated.
The term “aryl” means in particular a phenyl or naphthyl group. A “tricyclic System” means structures having 3 rings which are connectedtogether by more than one bond. Examples of such Systems are fusedSystems with 3 rings and spirocycles with a ring System fused on.
In the case where R1 and R2 form together with the nitrogen atom to whichthey are bonded a ring, this ring may be substituted by one or more of thesubstituents mentioned.
The bivalent carbo- or heterocyclic ring structure E includes structureswhich are linked by one and the same atom to the two adjacent groups K 013027 14 and X.
Pharmaceutically acceptable salts are, because their solubility in water isgreaterthan that of the initial or basic compounds, particularly suitable formedical applications. These salts must hâve a pharmaceutically acceptableanion or cation. Suitable pharmaceutically acceptable acid addition salts ofthe compounds of the invention are salts of inorganic acids such ashydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonicand sulfuric acid, and of organic acids such as, for example, acetic acid,benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic,isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic,p-toluenesulfonic, tartaric and trifluoroacetic acid. For medical purposes thechlorine sait is particularly preferably used. Suitable pharmaceuticallyacceptable basic salts are ammonium salts, alkali métal salts (such assodium and potassium salts), alkaline earth métal salts (such asmagnésium and calcium salts).
Salts with a pharmaceutically unacceptabie anion likewise beiong within theframework of the invention as useful intermediates for the préparation orpurification of pharmaceutically acceptable salts and/or for use innontherapeutic, for example in vitro, applications.
The term “physiologically functional dérivative” used herein refers to anyphysiologically tolerated dérivative of a compound of the formula I of theinvention, for example an ester, which on administration to a mammal suchas, for example, a human is able to form (directly or indirectly) a compoundof the formula I or an active métabolite thereof.
Physiologically functional dérivatives include prodrugs of the compounds ofthe invention. Such prodrugs can be metabolized in vivo to a compound ofthe invention. These prodrugs may themselves be active or not.
The compounds of the invention may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Ailpolymorphous forms of the compounds of the invention beiong within theframework of the invention and are a further aspect of the invention.
Ail references to “compound(s) of formula (I)” hereinafter refer tocompound(s) of the formula (I) as described above, and their salts, solvatés 013027 15 and physiologically functional dérivatives as described herein.
If radicals or substituents can occur more than once in the compounds ofthe formula I, they may ail hâve independently of one another the statedmeanings and be identical or different.
In a particularly preferred embodiment, the présent invention relates tocompounds of the formula I in which the meanings are: R1, R2 independently of one another, H, (Ci-C8)-alkyl, -(CH2)o -R12, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, CO-(Ci-C8)-alkyl, -CO-(CH2)o -R12, COCH=CH(R13), COCC(R14), CO-(C-t-C4)-alkyl-S(O)p-(Ci-C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))SO(R25); or R1 and R2 form together withthe nitrogen atom to which they are bonded a 4 to10-membered mono-, bi- or spirocyclic ring which, apart fromthe nitrogen atom, may comprise 0 to 2 additionalheteroatoms selected from the group of oxygen, nitrogen andsulfur, where the heterocyclic ring System may additionally besubstituted by F, (Ci-C6)-alkyl, O-(Ci-Cs)-alkyl, (Co-Cs)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy,COO(R29), N(R30)CO(Ci-C6)-alkyl, N(R31)(R32) orSO2CH3, where R1 and R2 are preferably not both H, and R1 and R2 together with the nitrogen atom are preferably not amorpholino radical; 0 0,1,2,3,4; 0,1,2; 013027 16 q, r, s independently of one another 0,1,2, 3, preferably q, s areindependently of one another 1,2,3 and r is 0,1,2, 3; R13, R14 independently of one another a 5-10 membered aromatic ringSystem which may comprise a further heteroatom from thegroup of nitrogen, oxygen and sulfur and may be substitutedby F, Cl, (C-i-CeJ-alkyl, O-(Ci-C8)-alkyl; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26,R27, R28, R29, R30, R31, R32independently of one another H, (C-t-Cel-alkyl; R18 H, (C«|-C6)-alkyl, CCXCvCe^alkyl, CO(R33); R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(C-|-C6)-alkyl, oxygenand sulfur; R33 a 5-10 membered aromatic ring System which may comprise a further heteroatom from the group of nitrogen, oxygen andsulfur and may be substituted by F, Cl, (Ci-C6)-aIkyl, O-(Ci-C8)-alkyl; R12 OH, 3-12 membered mono-, bi- or spirocyclic ring which may comprise one or more heteroatoms from the group of N, Oand S, and the 3-12 membered ring may comprise furthersubstituents such as F, Cl, CF3, CN, oxo, O-(Ci-C6)-alkyl,(Ci-C6)-alkyl, O-(C0-C8)-alkylene-aryl, N(R34)(R35), 17 013027 COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t(R39), CO(C-|-C6)-alkyl, COCOO(Ci-C6)-alkyl, COO(R40)and S(O)U (R41), where in a preferred embodiment the substituent O-(Ci-C6)-alkyl is excluded when the 3-12membered ring is phenyl; t 0,1,2,3,4: u 0,1,2; R34, R35, R37, R38 independently of one another H, (Ci-Cs)-alkyl; R34andR35 optionally together with the nitrogen atom to which they arebonded a 5-6 membered ring which, apart from the nitrogenatom, may also comprise 0-1 further heteroatoms from thegroup of N-(Ci-C6)-alkyl, oxygen and sulfur and mayoptionally be substituted by 1-2 oxo groups; R36, R39 independently of one another (C3-Cs)-cycloalkyl, 5-10membered aromatic ring System which may comprise afurther heteroatom from the group of nitrogen, oxygen andsulfur and may be substituted by F, Cl, (Ci-Ce)-alkyl, O-(Ci-Cebalkyl; R40 H, (Ci-C8)-alkyl, (C2-C6)-alkenyl, (Co-Cs)-alkylene-aryl; R41 (Ci-C6)-alkyl, 5-10 membered aromatic ring System which may comprise 0-2 further heteroatoms from the group ofnitrogen, oxygen and sulfur and may be substituted by F, Cl, 013027 18 (Ci-C6)-alkyl, O-(CvC8)-alkyl; R3 H, (C-|-C6)-alkyi; 5 R4, R5 independently of one another H, (Ci-C6)-aIkyl, OH, O-(Ci-C6)-alkyl, O-CO(Ci-C6)-alkyl; R6, R7, R8, R9 independently of one another H, (Ct-Cs)-Alkyl; 10 R6 and R7, R8 and R9 independently of one another optionally oxo; n, ‘m independently of one another 0, 1,2, preferably m is 0, 1,2 15 and n is 1; A, B, D, G independently of one another N, C(R42); R42 is H, F, Cl, Br, CF3, CN, O-(Ci-C6)-alkyl, (C^J-alkyl, 20 (C3-C8)-cycloalkyl, (Co-C2)-alkylene-aryl, 0-(Co-C2)-alkylene- aryl, N(R43)(R44), SO2-CH3, COO-(Ci-C6)-alkyl,CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51) 25 R43, R44, R45, R46, R47, R49 independently of one another H, (Ci-C8)-alkyl; R43 and R44, R45 and R46 independently of one another optionally together with the30 nitrogen atom to which they are bonded a 5-6 membered ring 013027 19 which, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(C-|-C6)-alkyl, oxygenand sulfur; R48, R50, R51 independently of one another H, (Ci-Cs)-alkyl, aryl; R10 H, (Ci-C8)-alkyl; X N(R52), O, a bond, C=C, C(R53)(R54), C(R55)(R56)O; R52, R53, R54, R55, R56 independently of one another H, (Ci-C8)-alkyl E 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, O and S, whichmay optionally hâve substituents from the group of H, F, Cl,CF3, NO2i OH, CN, O-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C0-C8)-alkylene-aryl, 0-(Co-C8)-alkylene-aryl, N(R57)(R58), SO2-CH3, COO-(Ci-C8)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO2(R64), CO(R65) and may be mono- or bicyclic,preferably the group E has no substituents from the group of(Co-C8)-alkylene-aryl, 0-(Co-C8)-alkylene-aryl and N(R57)(R58), in which R57 and R58 form together with thenitrogen atom a 5-6 membered ring, in the position ortho tothe point of attachaient of X; particularly preferably E ismonocyclic; R57, R58, R59, R60, R61, R63 independently of one another H, (Ci-C8)-alkyl; 013027 20 R57 and R58, R59 and R60 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(Ci-C6)-alkyl, oxygenand sulfur, where R59 and R60 are preferably not both H; R62, R64, R65 independently of one another H, (Ci-C8)-alkyl, aryl; K a bond, O, CH2O, N(R66), (C(R69)(R70))v, C=C, OCH2, CON(R68), preferably a bond, O, CH2O, ((CR69)(R70))v, CEC, N(R66); v 1,2; R66, R68, R69, R70 independently of one another H, (Ci-C8)-alkyl; R11 H, (Ci-C8)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, (C3-C8)- alkenyl, a 3 to 10-membered mono-, bi- or spirocyclic ringwhich may comprise 0 to 4 heteroatoms selected from thegroup of oxygen, nitrogen and sulfur, where the ring Systemmay additionally be substituted by F, Cl, Br, CF3, NO2, CN,(Ci-C6)-aIkyl, O-(Ci-C8)-alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl,(C0-C8)-alkylene-aryl, oxo, CO(R71 ), CON(R72)(R73),hydroxy, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) orSO2CH3, preferably R11 is not COO(R74); 013027 21 R71, R72, R73, R74, R75, R76, R77 independently of one another H, (Ci-Ce)-alkyl; R72 and R73, R76 and R77 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(Ci-C6)-alkyl, oxygenand sulfur.
Particularly preferred compounds of the formula I are those in which A, B, D, G are independently of one another N or C(R42), and the totalnumber of nitrogen atoms in this ring is 0-2, preferably 0 or 1.
Very particularly preferred compounds of the formula I are those in which n is 1 and m is 1 or 2.
Especially preferred compounds of the formula I are those in which A, B, D, G are independently of one another N or C(R42). and the totalnumber of nitrogen atoms in this ring is 0-2, preferably 0 or 1 ; n is 1 and m is 1 or 2.
In a further preferred embodiment, the présent invention relates tocompounds of the formula I in which the meanings are: 013027 22 R1, R2 independently of one another are H, (Ci-C8)-alkyl, - (CR78R79)o -R12, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, (C3-C8)-alkenyl, CO-(Ci-Cg)-alkyl, -CO-(CH2)O7R12, CO-aryloxy-(Ci-C4)-alkyl, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))SO(R25); or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to10-membered mono-, bi- or spirocyclic ring which, apartfromthe nitrogen atom, may comprise 0 to 2 additionalheteroatoms selected from the group of oxygen, nitrogen andsulfur, where the heterocyclic ring System may additionally besubstituted by F, Cl, CF3, (C-|-C6)-alkyl, O-(C-|-C4)-alkyl, (C-|-C4)-alkoxy-(Ci-C4)-alkyl, hydroxy-(C-i-C4)-alkyl, (C0-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy,COO(R29), N(R30)CO(Ci-C6)-alkyl, N(R31)(R32) orSO2CH3; preferably independently of one another H, (Ci-Cs)-alkyl,-(CR78R79)O -R12, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, CO-(C-|-C8)-alkyl, -CO-(CH2)o -R12, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R23)(R24))SO(R25);or R1 and R2 form together with the nitrogen atom to whichthey are bonded a 4 to 10-membered mono- or bicyclic ringwhich, apart from the nitrogen atom, may comprise 0 to 2additional heteroatoms selected from the group of oxygen,nitrogen and sulfur, where the heterocyclic ring System mayadditionally be substituted by F, Cl, CF3, (Ci-C6)-alkyl, O-(Ci-C4)-alkyl, (Ci-C4)-alkoxy-(Ci_C4)-alkyl, (Co-C2)-alkylene-aryl, 013027 23 oxo, CO(R26), hydroxy, N(R31)(R32) or SO2CH3;particularly preferably independently of one another H,(Ci-C8)-alkyl, -(CR78R79)O -R12, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, CO-(C-|-C8)-alkyl, -CO-(CH2)o -R12, CO(C(R15)(R16))qN(R17)(R18), or R1 and R2 form togetherwith the nitrogen atom to which they are bonded a 4 to 10-membered mono - or bicyclic ring which, apart from thenitrogen atom, may comprise 0 to 2 additional heteroatomsselected from the group of oxygen and nitrogen, where theheterocyclic ring System may be additionally substituted by F,(Ci-C6)-alkyl, (C-|-C4)-alkoxy-(C-|-C4)-alkyl, oxo, CO(R26),hydroxy, N(R31)(R32); o 0, 1, 2, 3, 4, 5, 6; preferably 0, 1, 2, 3, 4; particularly preferably 0,1, 2, 3; q, r independently of one another 1, 2, 3; preferably q is 1 or 2; s 0, 1,2, 3, 4; preferably 0,1,2, 3; particularly preferably 0, 1, 2; R13, R14 independently of one another are a phenyl ring which maycomprise 0-1 nitrogen atoms; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29,R30, R31, R32 independently of one another H, (Ci-C6)-alkyl; R18 H, (Ci-C6)-alkyl, CO(Ci-C6)-alkyl, CO(R33); preferably H,(C-|-C6)-alkyl, CO(Ci-C6)-alkyl; particularly preferably H,(Ci-C6)-alkyl; 013 0 2 7 24 or R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally form together with thenitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(Ci-C6)-alkyl, oxygenand sulfur; preferably the ring is pyrrolidine, piperidine, N-methylpiperazine, morphoiine; R33 a 5-10 membered aromatic ring System which may comprise a further heteroatom from the group of nitrogen, oxygen andsulfur and may be substituted by F, Cl, (Ci-C6)-alkyl,O-(Ci-C8)-alkyl; R12 OH, O-(Ci-C6)-alkyl, O-(C0-C8)-alkylene-aryl, CN, S-(C-|-C6)- alkyl, COO(R80), CON(R81)(R82), 3-12 membered mono-, bi-or spirocyclic ring which may comprise one or moreheteroatoms from the group of N, O and S, and the 3-12membered ring may comprise further substituents such as F,Cl, Br, OH, CF3, CN, oxo, O-(C-|-C6)-alkyl, (Ci-C4)-alkoxy-(C-i-C4)-alkyl, (Ci-C8)-alkyl, 0-(Co-C8)-alkylene-aryl, (Co-C8)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t (R39), CO(Ci-C6)-alkyl,COCOO(Ci-C6)-alkyl, COO(R40), S(O)U(R41);preferably OH, O-(C-|-C8)-alkyl, 0-(Co-C8)-alkylene-aryl, CN, 3-10 membered mono- or bicyclic ring which may comprise 1-3 heteroatoms from the group of N, O and S, and the 3-10membered ring may comprise further substituents such as F,Cl, Br, OH, CF3, CN, oxo, O-(Ci-C6)-aIkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, (C-|-C8)-alkyl, (Co-C2)-alkylene-aryl, 013027 25 N(R34)(R35), CO(Ci-C6)-alkyl; particularly preferably OH, O-(Ci-C6)-alkyl, 3-10 memberedmono- or bicyclic ring which may comprise 1-2 heteroatomsfrom the group of N, O and S, and the 3-10 membered ringmay comprise further substituents such as F, OH, oxo,(Ci-C6)-alkyl, COiCvCeJ-alkyl; t 0,1,2,3,4,5,6; u 0,1,2; preferably 0 or 2; particularly preferably 2; R34, R35, R37, R38 independently of one another H, (Ci-C8)-alkyl;or R34 and R35 optionally together with the nitrogen atom to which they arebonded a 5-6 membered ring which, apart from the nitrogenatom, may also comprise 0-1 further heteroatoms from thegroup of N-(Ci-C6)-alkyl, oxygen and sulfur and mayoptionally be substituted by 1-2 oxo groups; R36, R39 independently of one another (C3-C8)-cycloalkyl, 5-10 membered aromatic ring System which may comprise 0-2further heteroatoms from the group of nitrogen, oxygen andsulfur and may be substituted by F, Cl, (C-|-C6)-alkyl, O-(C-j-Csbalkyl; R40 H, (Ci-C8)-alkyl, (C2-C6)-alkenyl, (Co-Cs)-alkylene-aryl: R41 (Ci-C6)-alkyl, 5-10 membered aromatic ring System which may comprise 0-2 further heteroatoms from the group of 013027 26 nitrogen, oxygen and sulfurand may be substituted by F, Cl, (C-|-C6)-alkyl, O-(Ci-Cs)-alkyl; R78, R79 independently of one another H, (C-i-CsJ-alkyl, hydroxy- (Ci-C4)-alkyl, OH, (Ci-C4)-alkoxy-(C-|-C4)-alkyl; R80, R81 independently of one another H, (Ci-C8)-alkyl; R3 H, (C-|-C6)-alkyl; preferably H; R4, R5 independently of one another H, (C-|-C6)-aIkyl, OH, O-(Ci-C6)-alkyl, O-CO-(C-|-C6)-alkyl, S-(C-|-C6)-alkyl; preferably independently of one another H, (Ci-C6)-alkyl, OH, O-(C-|-C6)-alkyl, O-CO-(C-|-C6)-alkyl; particularly preferably independently of one another H, OH, O-(Ci-C6)-alkyl; R6, R7, R8, R9H; or R6 and R7, R8 and R9 independently of one another optionally oxo; preferably R6, R7, R8, R9 are H; n 1 m 1 or 2; preferably 1 ; A, B, D, G independently of one another N, C(R42); or the groups A and B or D and G are each C(R42) and togetherform an ortho-phenylene unit to resuit overall in a 1,4- bisubstituted naphthalene System; preferably 013027 27 B is N, C(R42); and A, D, G C(R42); particularly preferably A, B, D, G are C(R42); R42 H, F, Cl, Br, CF3, CN, O-(Ci-C6)-alkyl, O-(Ci-C4)-alkoxy-(Ci- C4)-alkyl, S-(C-|-C6)-alkyl, (Ci-C6)-alkyl, (Co-Cs)-alkylene-aryl, 0-(Co-C8)-alkylene-aryl, N(R43)(R44), SO2-CH3, CON(R45)(R46), N(R47)CO(R48), CO(R51 ), -(CR84R85)X-O(R86); preferably H, F, Cl, Br, CF3, CN, 0-(Ci-C6)-alkyl, (C-i-Cg)-alkyl, SO2-CH3, CON(R45)(R46), N(R47)CO(R48), CO(R51),-(CR84R85)X-O(R86); particularly preferably H, F, Cl, CF3, CN, (Ci-C6)-alkyl,-(CR84R85)X-O(R86); R43, R44, R45, R46, R47 independently of one another H, (Ci-Cs)-alkyl; or R43 and R44, R45 and R46 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(Ci-C6)-alkyl, oxygenand sulfur; R48, R50, R51 independently of one another H, (Ci-C8)-alkyl, aryl; preferably independently of one another H, (Ci-Cs)-alkyi; R84, R85 H; 013027 28 R86 x
R1O
X
Y R89 R52, R53,
E H, (Ci-Ce)-alkyl; 0,1, 2; preferably 0, 1; particularly preferably 1;H, (Ci-C8)-alkyl; N(R52), a bond, C=C, C(R53)(R54), C(R55)(R56)O, C=C,CH2-CH2) YCH2; preferably N(R52), a bond, C=C,C(R53)(R54), CH2-CH2; particularly preferably a bond, C=C, C(R53)(R54), CH2-CH2; O, S, N(R89); H, (Ci-C8)-alkyl; R54, R55, R56 independently of one another H, (C-|-C8)-alkyl; 3-8 membered bivalent carbo- or heterocyclic ring structurewith 0-4 heteroatoms from the group of N, O and S, whichmay optionally hâve substituents from the group of H, F, Cl,Br, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-alkyl, O-(Ci-C4)-alkoxy-(C-i-C4)-alkyl, S-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, O-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (Co-C8)-alkylene-aryl, 0-(Co-C8)-alkylene-aryl, S-aryl, N(R57)(R58), SO2-CH3, N(R61)CO(R62), N(R63)SO2(R64),CO(R65) and may be mono- or bicyclic;preferably 5-7 membered bivalent carbo- or heterocyclic ringstructure with 0-3 heteroatoms from the group of N, O and S,which may optionally hâve substituents from the group of H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-ÎCvCeJ-alkyl, 013027 29 S-(Ci-C6)-alkyl, (C-|-C6)-alkyl, (C2-C6)-alkenyl, O-(Co-Cs)-alkylene-aryl, S-aryl, N(R57)(R58), SO2-CH3, N(R61)CO(R62), CO(R65) and may be mono- or bicyclic;particularly preferably 5-7 membered bivalent carbo- or 5 heterocyclic ring structure with 0-2 heteroatoms from the group of N, O and S, which may optionally hâve substituentsfrom the group of H, F, Cl, Br, OH, CF3, NO2, OCF3,O-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58),SO2-CH3, CO(R65) 10 e.g. E is selected from the group consisting of
which may optionally hâve substituents from the group of H, F, Cl, Br, OH,15 CF3, NO2i OCF3j O-(Ci-C6)-alkyl, (Ci-Ç6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2-CH3, CO(R65); preferably 013027
which may optionally hâve the aforementioned substituents; 5 R57, R58, R61, R63 independently of one another H, (Ci-Ce)-alkyl; R62, R64, R65 independently of one another H, (Ci-Cs)-alkyl, aryl; preferably 10 independently of one another H, (Ci-Cs)-alkyl; K a bond, O, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C=C, C=C, SCH2, SO2CH2;preferably a bond, O, OCH2, CH2O, N(R66), CON(R68), 15 (C(R69)(R70))v, CO, C=C, SCH2; particularly preferably a bond, O, OCH2, CH2O, CON(R68), (C(R69)(R70))v, CO, C^C; v 1, 2, 3, 4; preferably 1, 2, 3; particularly preferably 1,2; 20 R66, R67, R68, R69, R70 independently of one another H, (Ci-Cs)-alkyl; R11 H, (Ci-C8)-alkyh (Ci-C4)-alkoxy-(C-|-C4)-alkyl, (C3-C8)- 25 alkenyl, (C3-C8)-alkynyl, a 3 to 10-membered mono-, bi-, tri- 013027 31 or spirocyclic ring, which may comprise 0 to 4 heteroatomsselected from the group of oxygen, nitrogen and sulfur,where the ring System may additionally be substituted by F,
Cl, Br, CF3, CN, (CrCeJ-alkyl, O-fCrCsi-alkyl, (C1-C4)- alkoxy-(C-|-C4)-alkyl, hydroxy-(C-|-C4)-alkyl, (Co-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74),N(R75)CO(Ci-C6)-alkyl, N(R76)(R77) or SO2CH3; preferably (C-|-C8)-alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, a 3 to10-membered mono-, bi-, tri- or spirocyclic ring which maycomprise 0 to 3 heteroatoms selected from the group ofoxygen, nitrogen and sulfur, where the ring System mayadditionally be substituted by F, Cl, Br, CF3, CN, (Ο-ι-Οθ)-alkyl, O-(C-|-C8)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R71),CON(R72)(R73), hydroxy, N(R75)CO(Ci-C6)-alkyl,N(R76)(R77) or SO2CH3; particularly preferably (Ci-C8)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, a3to 10-membered mono-or bicyclic ring which maycomprise 0 to 2 heteroatoms selected from the group ofoxygen, nitrogen and sulfur, where the ring System mayadditionally be substituted by F, Cl, Br, CF3, CN, (C-j-Ce)-alkyl, O-(Ci-Cs)-alkyl, oxo, CO(R71 ), CON(R72)(R73),N(R75)CO(C1-C6)-alkyl, or SO2CH3; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (C-i-Cs)-alkyl; or R72 and R73, R76 and R77 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ring 013027 32 which, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(Ci-C6)-alkyl, oxygenand sulfur; or 5 the N-oxides and the physiologicaliy tolerated salts thereof.
In a further preferred embodiment, A, B, G and D in formula I are CH or:
If E is 1,4-phenylene, the preferred meanings for A, B, G and D are10 furthermore those listed in table I below:
Table I: A B G D N CH CH CH CH N CH CH C-CI N CH CH C-F CH C-F CH CH CH C-F CH CH C-F CH CH CH CH CH CF CH C-Br CH CH CH CH C-Br CH CH C-CI CH CH CH CH C-CI CH CH CH C-CN CH CH CH CH C-CN CH CH c-ch3 CH CH CH CH c-ch3 CH CH c-cf3 CH CH CH CH C-CF3 CH CH CH ch2oh 013027
CH CH CH CH CH CH C-F C-F CH CH CH c-ch3 N CH C-F C-F C-F C-CI C-CI C-F CH C-F C-CI C-CN CH CH CH C-CH3 CH C-CH3 N CH N CH C-CH3 CH CH CH
If E is , the preferred meanings for A, B, G and D are furthermore those listed in table II below:
Tabte.ll:
the preferred meanings for A, B, G and D arefurthermore those listed in table III below: 10 01302*7 34
Table III:
A
CH
CH
CH
B G
CH C-F
N CH
CH CH
D
CH
CH
N
Further preferred combinations for E and A, B, G and D are listed in table5 IV.
Table IV:
CH
C-F
CH
CH
CH
CF
CH
CH
CH
CF
CH
CH
CH
C-F
CH
CH
CH
C-F
CH
CH
CH
C-F
CH
CH
CH C-F CH CH
CH C-F | CH B CH 013027 35
The radicals R11, K, X and E in formula I hâve in a particularly preferredembodiment one of the following meanings: R11 is preferably selected from the group consisting of:n-propyl, n-butyl, iso-butyl, iso-pentyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohex-(1)-enyl, phenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-tolyl, p-methoxyphenyl, p-trifluoromethylphenyl, p- 10 methylthiophenyl, o-fluorophenyl, o-chlorophenyl, o-cyanophenyl, m-fluorophenyl, 2,4-difluorophenyl, 3-fluoro-4-methylphenyl, 2-nitro-4-methylphenyl, 2-amino-4-methylphenyl,
15 K is preferably selected from the group consisting of: -O-, bond, C=C, CH2, CH2O, CONH, OCH2, CO, SCH2 and (CH2)2O. X is preferably selected from the group consisting of bond, NH and CH2. 36 013027 E is preferably selected from the group consisting of:
Preferred combinations of R11, K, X and E are listed below: 10 If K and X are each a bond, the particularly preferred meanings for E andR11 are as follows:
If E is 1,4-phenylene, R11 ts selected from the group consisting of:cyclohexyl, p-tolyl, p-fluorophenyi, o-fluorophenyl, p-methoxyphenyl, 15 p-chlorophenyl, o-chlorophenyl, 2,4-difluorophenyl, 3-fluoro-4- methylphenyl, o-cyanophenyl,
and
20
If E is '—' , R11 selected from the group consisting of: p-chlorophenyl, p-tolyl, p-fluorophenyl, p-methoxyphenyl,trifluoromethylphenyl, o-fluorophenyl, phenyl and P- 013027 37
Further combinations of E and R11 for the case where K and X are each abond are listed in table V:
Table V: R11 p-Chlorophenyl 2-Nitro-4-methylphenyl p-Chlorophenyl p-Bromophenyl p-Fluorophenyl p-Chlorophenyl p-Tolyl n-Butyl
E 1,4-Cyclohexylene p-Chlorophenyl 0130 38 p-Methylthiophenyl 2-Amino-4-methylphenyl
If K is -O- and X is a bond, NH or CH2, the particularly preferred meanings for E and R11 are as follows: 5
If E is 1,4-phenylene, R11 is selected from the group consisting of:phenyl, cyclopentyl, n-butyl, iso-butyl, iso-pentyl, 2,4-difluorophenyland p-fiuorophenyl. 10 Further combinations of E and R11 for the case where K is -O- and X is abond, NH or CH2 are listed in table VI:
Table VI:
R11 E
Phenyl I
Cyclopentyl I
Phenyl I n-Butyl^^^^^| 15
If K is CsC and X is a bond, the particularly preferred meanings of E andR11 are as follows: 013027 39
If E is ° , R11 is selected from the group consisting of: phenyl, p-fluorophenyl and p-chlorophenyl.
If K is CH2 and X is a bond, the particularly preferred meanings of E andR11 are indicated in table VII below:
Table VII: 10
If K is CH2O and X is a bond, the particularly preferred meanings of E andR11 are as follows: 15 If E is 1,4-phenylene, R11 is selected from the group consisting of: phenyl, cyclopropyl and cyclohexyl.
If K is CONH and X is a bond, the particularly preferred meanings of E and20 R11 are indicated in table VIII below:
Table VIII:
R11 ! E
Cyclopentyl I 1,4-Phenylene
Cyclohex-(1)-enyl I 1,4-Phenylene 013027 40
Cyclopentyl
If K is OCH2 and X is a bond, the particularlÿ preferred meanings of E andR11 are indicated in table IX below:
1,4-Phenylene 1,4-Phenylene 1,4-Phenylene
The combinations of R11, K and E listed in table X below are furthermoreparticularlÿ preferred in addition to the aforementioned combinations, with 10 X very particularlÿ preferably being a bond:
Table X: R11 o-Fluorophenyl
Phenyl
Cyclopropyl
K
CO sch2
(CH2)2O 1,4-Phenylene
15 The compounds of the formula I are in a very particularlÿ preferredembodiment compounds of the formula la 013027 41 R42 Ο r11^kxE"x
NR1R2 R42' la in which the radicals R1, R2, R10, R11, R42, and groups X, E, K hâve theaforementioned meanings, and R42’ is defined as R42, where R42 andR42’ in the compounds of the formula la may be identical or different, or theN-oxides and the physiologically tolerated salts thereof.
In a preferred embodiment of the invention, the radicals R1, R2, R10, R11,R42, R42’ and groups X, E, K hâve the following meanings: R1, R2 independently of one another H, (Ci-Cs)-alkyl, -(CR78R79)O-R12, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, or R1 and R2 form together with the nitrogen atom to which they are bonded a 4to 10-membered mono-, bi- or spirocyclic ring which, apartfrom the nitrogen atom, may comprise 0 to 2 additionalheteroatoms selected from the group of oxygen, nitrogen andsulfur, where the heterocyclic ring System may additionally besubstituted by F, (C<|-C6)-alkyl, O-(C-|-C4)-alkyl, (C1-C4)- alkoxy-(Ci-C4)-alkyl, hydroxy-(C-|-C4)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, N(R31)(R32)or SO2CH3; where R1 and R2 are not both CO(R26), preferably H, (Ci-C8)-alkyl, -(CR78R79)O-R12, (C1-C4)-alkoxy-(C-|-C4)-alkyl, or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 10-memberedmono- or bicyclic ring which, apart from the nitrogen atom,may comprise 0 to 2 additional heteroatoms selected from thegroup of oxygen and nitrogen, where the heterocyclic ring 013027 42
System may additionally be substituted by F, (C-|-C6)-alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, oxo, CO(R26), hydroxy,N(R31)(R32); o 0, 1,2, 3, 4, preferably 0,1,2,3; q 1, 2, 3, preferably 1 or 2; s ................. 0,1,2; R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32independently of one another H, (Ci-C6)-alkyl; or R17 and R18, R27 and R28, R31 and R32 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(Ci-C6)-alkyl, oxygenand sulfur, preferably the ring is a pyrrolidine, piperidine,N-methylpiperazine, morpholine ring; R12 OH, O-(C-|-C6)-alkyl, 0-(Co-C2)-alkyIene-aryl, CN, S-(Ci-C6)- alkyl, 3-12 membered mono-, bi- or spirocyclic ring which maycomprise 1 to 3 heteroatoms from the group of N, O and S,and the 3-12 membered ring may comprise furthersubstituents such as F, OH, CF3, CN, oxo, (Ci-Ce)-alkyl, (Co-C2)-alkylene-aryl, N(R34)(R35), COO(R40), CO(Ci-C6)-alkyl, preferably OH, O-(Ci-C6)-alkyl, 3-10 membered mono- orbicyclic ring which may comprise 1 -2 heteroatoms from the 013027 43 group of N, O and S, and the 3-10 membered ring maycomprise further substituents sucb as F, OH, oxo, (Οι-Οθ)-alkyl, CO(C-|-C6)-alkyl; R34, R35 independently of one another H, (Ci-C4)-alkyl; R40 H, (Ci-C6)-alkyl, (Co-C2)-alkyIene-aryl; R78, R79 independently of one another H, (C-|-C8)-alkyl, hydroxy-(Ci-C4)-alkyl, OH, (Ci-C4)-alkoxy-(Ci-C4)-alkyl; R42, R42’ independently of one another H, F, Cl, Br, CF3, CN, (C1-C6)-alkyl; R10 H, (Ci-C8)-alkyl; X N(R52), a bond, C=C, C(R53)(R54), CH2CH2; R52, R53, R54 independently of one another H, (Ci-C8)-alkyl; E 5-7 membered bivalent carbo- or heterocyclic ring structure with 0-3 heteroatoms from the group of N, O and S, whichmay optionally hâve substituents from the group of H, F, Cl,Br, CF3, OH, CN, OCF3, NO2, O-(Ci-C6)-alkyl, (Ci-C6)-alkyl,SO2-CH3, CO(R65); preferably 5-7 membered bivalent carbo- or heterocyclic ring 44
rO structure with 0-2 heteroatoms from the group of N, O and S,which may optionally hâve substituents from the group of H,F, Cl, Br, OH, CF3, NO2, OCF3, O-(Ci-C6)-alkyl, (CrCe)- alkyl, (C2-C6)-alkenyl, N(R57)(R58), SÔ2-CH3, CO(R65) e.g. E is selected from the group consisting of
10 which may optionally hâve substituents from the group of H, F, Cl, Br, OH,CF3, NO2, OCF3, O-CCvCeJ-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl,N(R57)(R58), SO2-CH3, CO(R65); preferably 15 013027 45
—N
N -o
and
which may optionally hâve the aforementioned substituents; R65 H, (Ci-C8)-alkyl; a bond, O, OCH2> CH2O, S, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C=C, SCH2, SO2CH2;preferably a bond, O, OCH2, CH2O, CON(R68),(C(R69)(R70))v, particularly preferably CH2, CO, C=C; 1, 2, 3, preferably1 2’ R66, R67, R68, R69, R70 independently of one another H, (Ci-Cs)-alkyl; R11 (C-|-C8)-alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, a 3 to 10- membered mono-, bi-, tri- or spirocyclic ring which maycomprise 0 to 4 heteroatoms selected from the group ofoxygen, nitrogen and sulfur, where the ring System mayadditionally be substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O-(Ci-Cs)-alkyl, oxo, CO(R71), hydroxy,N(R75)CO(Ci-C6)-alkyl, or SO2CH3; preferably (C-|-C8)-alkyl, (C-|-C4)-alkoxy-(Ci-C4)-aIkyl, a 3 to 46 013027 10-membered mono- or bicyclic ring which may comprise 0 to2 heteroatoms selected from the group of oxygen, nitrogenand sulfur, where the ring System may additionally besubstituted by F, Cl, Br, CF3, CN, (Ci-C6)-alkyl, O-(Ci-Cs)-alkyl, oxo, CO(R71), CON(R72)(R73), N(R75)CO(C1-C6)-alkyl, or SO2CH3; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (Ci-Cs)-alkyl; or R72 and R73, R76 and R77 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(C-|-C6)-alkyl, oxygenand sulfur.
In a preferred embodiment, the présent invention relates to compounds ofthe formula la, in which X is CH2CH2, N(R52), CH2, OCH2i SCH2, CH=CH, preferably CH2CH2, CH=CH; E is 47
preferably K is a bond, O or C(R69)(R70); 5 and the other symbols R1, R2, R10, R11, R42, R42’, R52, R69 and R70hâve the meanings indicated above in relation to a définition of the radicaisof the compound of the formula la. 10 In a further preferred embodiment, the présent invention relates tocompounds of the formula la, in which 15 X is N(R52), preferably NH, or C(R53)(R54); E is
20 K is a bond, O or C(R69)(R70), preferably 0; 013027 48 preferably Ο and the other symbols R1, R2, R10, R11, R42, R42’,R52, R53, R54, R69and R70 hâve the meanings indicated above in relation to a définition of theradicals of the compound of the formula la.
In a further particularly preferred embodiment, the compounds of theformula I are compounds of the formula Ib
in which the radicals R1, R2, R10 and R11 and the groups E and D hâvethe aforementioned meanings, or the N-oxides and the physiologicallytolerated salts thereof.
In a preferred embodiment, the radicals R1, R2, R10 and R11 the groups Eand D hâve the following meanings:
R1, R2 independently of one another H, (C-i-Cs)-alkyl, -(CR78R79)O -R12, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, (C3-Cs)-alkenyl, CO- (C-|-C8)-alkyl, -CO-(CH2)o -R12, CO-aryloxy-(C-|-C4)-alkyl,COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18),CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))SO(R25); or R1 and R2 form together withthe nitrogen atom to which they are bonded a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from thenitrogen atom, may comprise 0 to 2 additional heteroatomsselected from the group of oxygen, nitrogen and sulfur, where 49 013027 the heterocyclic ring System may additionally be substitutedby F, Cl, CF3, (Ci-C6)-alkyl, O-(C-|-C4)-alkyl, (Ci-C4)-alkoxy- (C-|-C4)-alkyl, hydroxy-(Ci-C4)-alkyl, (Co-C2)-aikylene-aryl,oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29),N(R30)CO(C-|-C6)-alkyl, N(R31)(R32) or SO2CH3, where R1and R2 are not both CO(R26); preferably independently of one another H, (Ci-C8)-alkyl,-(CR78R79)O -R12, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, CO-(C-|-C8)-alkyl, -CO-(CH2)o -R12, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R23)(R24))SO(R25);or R1 and R2 form together with the nitrogen atom to whichthey are bonded a 4 to 10-membered mono- or bicyclic ringwhich, apart from the nitrogen atom, may comprise 0 to 2additional heteroatoms selected from the group of oxygen,nitrogen and sulfur, where the heterocyclic ring System mayadditionally be substituted by F, Cl, CF3, (Ci-Cg)-alkyl, O-(C-|-C4)-alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, (Co-C2)-alkylene-aryl,oxo, hydroxy, N(R31)(R32) or SO2CH3, where R1 and R2 arenot both CO-(C-|-C8)-alkyl; particularly preferably independently of one another H, (Ci-C8)-alkyl, -(CR78R79)O -R12, (Ci-C4)-alkoxy-(C1-C4)-alkyl, CO-(Ci-C8)-alkyl, -CO-(CH2)0 -R12, CO(C(R15)(R16))qN(R17)(R18), or R1 and R2 form togetherwith the nitrogen atom to which they are bonded a 4 to 10-membered mono- or bicyclic ring which, apart from thenitrogen atom, may comprise 0 to 2 additional heteroatomsselected from the group of oxygen and nitrogen, where theheterocyclic ring System may additionally be substituted by F,(Ci-C6)-alkyl, (C-|-C4)-alkoxy-(C-|-C4)-alkyl, oxo, CO(C-|-C8)- 50 013027 alkyl, hydroxy, N(R31)(R32), where R1 and R2 are not bothCO(Ci-C8)-alkyl; o 0, 1, 2, 3, 4, 5, 6; preferably 0, 1, 2, 3, 4; particularly preferably 0, 1, 2, 3; q, r independently of one another 1,2, 3; preferably q is 1 or 2; s 0, 1,2, 3, 4; preferably 0, 1, 2, 3; particularly preferably 0, 1, 2; R13, R14 independently of one another a phenyl ring which maycomprise 0-1 nitrogen atoms; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29,R30, R31, R32 independently of one another H, (Ci-C8)-alkyl; R18 H, (Ci-C6)-alkyl, CO(Ci-C6)-alkyl, CO(R33); preferably H, (C-|-C6)-alkyl, CO(Ci-C6)-alkyl; particularly preferably H,(Ci-C6)-alkyl; or R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also comprise 0-1further heteroatoms from the group of N-(C-i-C6)-alkyl, oxygen and sulfur; preferably the ring is pyrrolidine, piperidine,N-methylpiperazine, morpholine; R33 a 5-10 membered aromatic ring System which may comprise a further heteroatom from the group of nitrogen, oxygen and R12 013027 51 sulfur and may be substituted by F, Cl, (C-|-C6)-alkyl, O-(Ci-C8)-alkyl; is OH, O-(Ci-C6)-alkyl, 0-(Co-C8)-alkylene-aryl, CN, S- (Ci-C6)-alkyl, COO(R80), CON(R81)(R82), 3-12 membered mono-, bi- or spirocyclic ring which may comprise one or moreheteroatoms from the group of N, O and S and the 3-12membered ring may comprise further substituents such as F,
Cl, Br, OH, CF3, CN, oxo, O-(Ci-C6)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, (Ci-C6)-alkyl, 0-(Co-C8)-alkylene-aryi, (Co-Cs)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39),CO(C(R37XR38))t(R39),CO(Ci-C6)-alkyl,COCOO(Ci-C6)-alkyl, COO(R40), S(O)U(R41); preferably OH, O-(Ci-C6)-alkyl, 0-(Co-C8)-alkylene-aryl, CN, 3-10 membered mono- or bicyclic ring which may comprise Ι-Ο heteroatoms from the group of N, O and S, and the 3-10membered ring may comprise further substituents such as F,
Cl, Br, OH, CF3, CN, oxo, O-(C-|-C6)-alkyl, (C-|-C4)-alkoxy-(Ci-C4)-alkyl, (Ci-C6)-alkyl, (Co-C2)-alkylene-aryl, N(R34)(R35), CO(C1-C6)-alkyl; particularly preferably OH, O-(C-|-C6)-alkyl, 3-10 memberedmono- or bicyclic ring which may comprise 1-2 heteroatomsfrom the group of N, O and S and the 3-10 membered ringmay comprise further substituents such as F, OH, oxo, (C-|-C6)-alkyl, CO(C-|-C6)-alkyl; 0, 1,2, 3, 4, 5, 6; 0130? 52 u 0,1,2; preferably O or 2; particularly preferably 2; R34, R35, R37, R38 independently of one another H, (Ci-Cs)-alkyl;or 5 R34 and R35 optionally together with the nitrogen atom to which they arebonded a 5-6 membered ring which, apart from the nitrogenatom, may also comprise 0-1 further heteroatoms from thegroup of N-(Ci-C6)-alkyl, oxygen and sulfur and may 10 optionally be substituted by 1-2 oxo groups; R36, R39 independently of one another (C3-C8)-cycloalkyl, 5-10 membered aromatic ring System which may comprise 0-2further heteroatoms from the group of nitrogen, oxygen and 15 sulfur and may be substituted by F, Cl, (Ci-C6)-alkyl, O- (Ci-C8)-alkyl; R40 H, (Ci-C8)-alkyl, (C2-C6)-alkenyl, (Co-C8)-alkylene-aryl; 20 R41 (C-|-C6)-alkyl, 5-10 membered aromatic ring System which may comprise 0-2 further heteroatoms from the group ofnitrogen, oxygen and sulfur and may be substituted by F, Cl,(Ci-Ce)-alkyl, O-(Ci-C8)-alkyl; 25 R78, R79 independently of one another H, (Ci-Cs)-alkyl, hydroxy- (Ci-C4)-alkyl, OH, (C1-C4)-alkoxy-(Ci-C4)-alkyl; R80, R81 independently of one another H, (Ci-Cs)-alkyl; 30 R10 H, (Ci-C8)-alkyl; 53 073027 E 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteraatoms from the group of N, O and S, whichmay optionally hâve substituents from the group of H, F, Cl,Br, OH, CF3, NO2, CN, OCF3i O-(Ci-C6)-alkyl, O-(Ci-C4)-alkoxy-(Ci-C4)-alkyl, S-(C-|-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, O-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (Co-C8)-alkylene-aryl, 0-(Co-C8)-alkylene-aryl, S-aryl,N(R57)(R58), SO2-CH3) N(R61)CO(R62), N(R63)SO2(R64), CO(R65) and may be mono- or bicyclic;preferably 5-7 membered bivalent carbo- or heterocyclic ringstructure with 0-3 heteraatoms from the group of N, Θ and S,which may optionally hâve substituents from the group of H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-alkyl, S-(Ci-C6)-alkyl, (C-|-C6)-alkyl, (C2-C6)-alkenyl, 0-(Co-C8)-alkylene- aryl, S-aryl, N(R57)(R58), SO2-CH3, N(R61)CO(R62),CO(R65) and may be mono- or bicyclic;particularly preferably 5-7 membered bivalent carbo- orheterocyclic ring structure with 0-2 heteraatoms from thegroup of N, O and S, which may optionally hâve substituentsfrom the group of H, F, Cl, Br, OH, CF3, NO2, OCF3, O-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58),SO2-CH3, CO(R65) e.g. E is selected from the group consisting of 013027 54
which may optionally hâve substitueras from the group of H, F, Cl, Br, OH,5 CF3, NO2, OCF3, O-(Ci-C6)-alkyl, (C-|-C6)-alkyl, (C2-C6)-aIkenyl, N(R57)(R58), SO2-CH3, CO(R65); preferably 10 //
which may optionally hâve the aforementioned substituents; 013027 55 R57, R58, R61, R63 independently of one another H, (Ci-Cs)-alkyl; R62, R64, R65 independently of one another H, (Ci-Cs)-alkyl, aryl; preferablyindependently of one another H, (Ci-Cs)-alkyl; K a bond, O, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C=C, C=C, SCH2, SO2CH2;preferably a bond, O, OCH2, CH2O, N(R66), CON(R68),(C(R69)(R70))v, CO, C=C, SCH2; particularly preferably abond, O, OCH2, CH2O, CON(R68), (C(R69)(R70))v, CO, C^C; v 1,2, 3,4; preferably 1, 2, 3; particularly preferably 1,2; R66, R67, R68, R69, R70 independently of one another H, (Ci-Cs)-alkyl; R11 H, (Ci-C8)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, (C3-C8)- alkenyl, (C3-C8)-alkynyl, a 3 to 10-membered mono-, bi-, tri-or spirocyclic ring which may comprise 0 to 4 heteroatomsselected from the group of oxygen, nitrogen and sulfur, wherethe ring System may additionally be substituted by F, Cl, Br,CF3, CN, (Ci-C6)-alkyl, O-(C-|-C8)-alkyl, (C-|-C4)-alkoxy-(Ci-C4)-alkyl, hydroxy-(C-|-C4)-alkyl, (Co-Cs)-alkylene-aryl,oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74),N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO2CH3 SCF3; 56 013027 preferably (Ci-C8)-alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, a 3 to10-membered mono-, bi-, tri- or spirocyclic ring which maycomprise 0 to 3 heteroatoms selected from the group ofoxygen, nitrogen and sulfur, where the ring System mayadditionally be substituted by F, Cl, Br, CF3, CN, (Ο-ι-Οθ)-alkyl, O-(Ci-C8)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R71),CON(R72)(R73), hydroxy, N(R75)CO(Ci-C6)-alkyl, N(R76)(R77) or SO2CH3; particularly preferably (C-i-CsJ-alkyl, (C-|-C4)-alkoxy-(Ci-C4)-alkyl, a 3 to 10-membered mono- or bicyclic ring which maycomprise 0 to 2 heteroatoms selected from the group ofoxygen, nitrogen and sulfur, where the ring System mayadditionally be substituted by F, Cl, Br, CF3, CN, (C-i-Ce)-alkyl, O-(Ci-C8)-alkyl, oxo, CO(R71), CON(R72)(R73),N(R75)CO(Ci-C6)-alkyl, orSO2CH3; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (Ci-Cs)-alkyl; or R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atom towhich they are bonded a 5-6 membered ring which, apart from the nitrogenatom, may also comprise 0-1 further heteroatoms from the group ofN-(Ci-C6)-alkyl, oxygen and sulfur.
In a preferred embodiment, the présent invention relates to compounds ofthe formula Ib in which 013027 57 X is a bond,
N—O where the aforementioned groupe may optionally hâve substituents from thegroup of H, F, Cl, Br, OH, CF3, NO2, OCF3, O^CvCeJ-alkyl, (Ci-C6)-alkyl, 10 (C2-C6)-alkenyl, N(R57)(R58), SO2-CH3, CO(R65); preferably E is 013027 58
N—
Ν·
or
in which the groups may hâve the aforementioned substituents; K is a bond; and the other radicals R1, R2, R10 and R11 and the group D hâve themeanings indicated above in relation to the définition of the radicals of thecompound of the formula Ib. R11 in the aforementioned compounds of the formula Ib is particularlypreferably a substituted mono- or bicyclic ring System with 5-10 members,which may hâve 0-3 heteroatoms, in particular N, O and/or S, particularlypreferably phenyl with 0-1 N atom, cyclohexyl or a bicyclic System with 8-10members and 1-2 heteroatoms, in particular N, O and/or S.
In a further preferred embodiment, the présent invention relates tocompounds of the formula Ib in which is a bond; 59 is
O
N or .s ir where the aforementioned groupe may optionally hâve substituents fromthe group of H, F, Cl, Br, OH, CF3, NO2, OCF3, O-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2CH3 and CO(R65); preferably or in which the groups may hâve the aforementioned substituents; K is CH2, CH2CH2, O, CH2O, OCH2, CON(R68), N(R67)CO, S, SO2,SCH2, SO2, SO2CH2i CO or a triple bond; preferably CH2, O, CH2O, OCH2i CON(R68), SCH2, CO or a triplebond; and the other radicals R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R67 andR68 and the group D hâve the meanings indicated above in relation to thedéfinition of the radicals of the compound of the formula Ib.
The amount of a compound of formula (I) necessary to achieve the desiredbioiogical effect dépends on a numberof factors, for example the spécifiecompound chosen, the intended use, the mode of administration and the 013027 60 clinical condition of the patient. The daily dose is generally in the rangefrom 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day and perkilogram of bodyweight, for example 3-10 mg/kg/day. An intravenous dosemay be, for example, in the range from 0.3 mg to 1.0 mg/kg, which cansuitably be administered as infusion of 10 ng to 100 ng per kilogram andper minute. Suitable infusion solutions for these purposes may contain, forexample, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter.Single doses may contain, for example, from 1 mg to 10 g of the activeingrédient. Thus, ampoules for injections may contain, for example, from1 mg to 100 mg, and single-dose formulations which can be administeredorally, such as, for example, tablets or capsules, may contain, for example,from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case ofpharmaceutically acceptable salts, the aforementioned weight data arebased on the weight of the free compound from which the sait is derived.For the prophylaxis and therapy of the abovementioned conditions, thecompounds of formula (I) may be used as the compound itself, but they arepreferably in the form of a pharmaceutical composition with an acceptablecarrier. The carrier must, of course, be acceptable in the sense that it iscompatible with the other ingrédients of the composition and is not harmfulfor the patient’s health. The carrier may be a solid or a liquid or both and ispreferably formulated with the compound as a single dose, for example asa tablet, which may contain from 0.05% to 95% by weight of the activeingrédient. Other pharmaceutically active substances may likewise beprésent, including other compounds of formula (I). The pharmaceuticalcompositions of the invention can be produced by one of the knownpharmaceutical methods, which essentially consist of mixing theingrédients with pharmacologically acceptable carriers and/or excipients.
Pharmaceutical compositions of the invention are those suitable for oral,rectal, topical, pérorai (for example sublingual) and parentéral (for examplesubcutaneous, intramuscular, intradermal or intravenous) administration,although the most suitable mode of administration dépends in eachindividual case on the nature and severity of the condition to be treated andon the nature of the compound of formula (I) used in each case. Coatedformulations and coated slow-release formulations also belong within theframework of the invention. Préférence is given to acid- and gastric juice-resistant formulations. Suitable coatings résistant to gastric juice comprisecellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of 013027 61 methacrylic acid and methyl méthacrylate.
Suitable pharmaceutical corppounds for oral administration may be in theform of separate units such as, for example, capsules, cachets, suckabletablets or tablets, each of which contain a defined amount of the compoundof formula (I); as powders or granules; as solution or suspension in anaqueous or nonaqueous liquid; or as an oil-in-water or water-in-oilémulsion. These compositions may, as already mentioned, be prepared byany suitable pharmaceutical method which includes a step in which theactive ingrédient and the carrier (which may consist of one or moreadditional ingrédients) are brought into contact. The compositions aregenerally produced by uniform and homogeneous mixing of the activeingrédient with a liquid and/orfinely divided solid carrier, after which theproduct is shaped if necessary. Thus, for example, a tablet can beproduced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingrédients.Compressed tablets can be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one or moresurface-active/dispersing agent(s) in a suitable machine. Molded tabletscan be produced by molding the compound, which is in powder form and ismoistened with an inert liquid diluent, in a suitable machine.
Pharmaceutical compositions which are suitable for pérorai (sublingual)administration comprise suckable tablets which contain a compound offormula (I) with a flavoring, normally sucrose and gum arable or tragacanth,and pastilles which comprise the compound in an inert base such as gelatinand glycerol or sucrose and gum arabic.
Pharmaceutical compositions suitable for parentéral administrationcomprise preferably stérile aqueous préparations of a compound offormula (I), which are preferably isotonie with the blood of the intendedrécipient. These préparations are preferably administered intravenously,although administration may also take place by subeutaneous,intramuscular or intradermal injection. These préparations can preferablybe produced by mixing the compound with water and making the resultingsolution stérile and isotonie with blood. Injectable compositions of theinvention generally contain from 0.1 to 5% by weight of the activecompound. 013027 62
Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can be producedby mixing a compound of the formula (I) with one or more conventionalsolid carriers, for example cocoa butter, and shaping the resulting mixture.
Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aérosol oroil. Carriers which can be used are petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.
The active ingrédient is generalfy présent in a concentration of from 0.1 to15% by weight of the composition, for example from 0.5 to 2%.
TransdermaL administration is also possible. Pharmaceutical compositionssuitable for transdermal uses can be in the form of single plasters whichare suitable for long-term close contact with the patient’s epidermis. Suchplasters suitably contain the active ingrédient in an aqueous solution whichis buffered where appropriate, dissolved and/or dispersed in an adhesive ordispersed in a polymer. A suitable active ingrédient concentration is about1% to 35%, preferably about 3% to 15%. A particular possibility is for theactive ingrédient to be released by electrotransport or iontophoresis asdescribed, for example, in Pharmaceutical Research, 2(6): 318 (1986).
The compounds of the formula I are distinguished by bénéficiai effects onlipid metabolism, and they are particularly suitable for weight réduction andfor maintaining a reduced weight after weight réduction has taken place inmammals and as anorectic agents. The compounds are distinguished bytheir low toxicity and their few side effects. The compounds can beemployed alone or in combination with other weight-reducing or anorecticactive ingrédients. Further anorectic active ingrédients of this type arementioned, for example, in the Rote Liste, chapterOI under weight-reducing agents/appetite suppressants, and they also include activeingrédients which increase the energy turnover of the organism and thuslead to weight réduction or else those which influence the generalmetabolism of the organism in such a way that an increased calorie intakedoes not lead to an enlargement of the fat depots and a normal calorieintake leads to a réduction of the fat depots of the organism. Thecompounds are suitable for the prophylaxie and, in particular, for thetreatment of excessive weight or obesity. The compounds are further 63 013027 suitable for the prophylaxis and, in particular, for the treatment of type IIdiabètes, of arteriosclerosis and for normalizing lipid metabolism and forthe treatment of high blood pressure. The compounds act as MCHantagoniste and are also suitable for the treatment of disturbances ofwellbeing and of psychiatrie indications such as, for example, dépréssions,anxiety States, anxiety neuroses, schizophrenia and for the treatment ofdisorders associated with the circadian rhythm and for the treatment ofdrug abuse.
In a further aspect of the invention, the compounds of the formula I can beadministered in combination with one or more other pharmacologicallyactive substances which are selected, for example, from antidiabetics,antiobesity agents, active ingrédients which lower blood pressure, lipid-lowering agents and active ingrédients for the treatment and/or préventionof complications caused by diabètes or associated with diabètes.
Further pharmacologically active substances suitable in particular are:
ali antidiabetics mentioned in the Rote Liste 2001, chapter 12. They may becombined with the compounds of the formula I of the invention in particularfor a synergistic împrovement of the effect. Administration of the activeingrédient combination may take place either by separate administration ofthe active ingrédients to the patient or in the form of combination productsin which a plurality of active ingrédients are présent in one pharmaceuticalpréparation. Most of the active ingrédients listed below are disclosed in theUSP Dictionary of USAN and International Drug Names, US
Pharmacopeia, Rockville 2001.
Suitable antidiabetics include insulin and insulin dérivatives such as, forexample, Lantus® or HMR 1964, fast-acting insulins (see US 6,221,633),amylin, GLP-1 and GLP-2 dérivatives such as, for exampie, thosedisclosed in WO 98/08871 of Novo Nordisk A/S, and orally effectivehypoglycémie active ingrédients.
The orally effective hypoglycémie active ingrédients include, preferably,sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones,thiazolidinediones, glucosidase inhibitors, glucagon receptor antagonists,GLP-1 agonists, potassium channel openers such as, for example, thosedisclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin 013027 64 sensitizers, activators of insulin receptor kinase, inhibitors of liver enzymesinvolved in the stimulation of gluconeogenesis and/or glycogenolysis, forexample inhibitors of glycogen phosphorylase, modulators of glucoseuptake and glucose excrétion, compounds which alter lipid metabolism,such as antihyperlipidemic active ingrédients and antilipidemic activeingrédients, e.g. HMGCoA reductase inhibitors, inhibitors of cholestéroltransport/of cholestérol uptake, inhibitors of bile acid reabsorption orinhibitors of microsomal triglycéride transfer protein (MTP), compoundswhich reduce food intake, PPAR and RXR agonists and active ingrédientswhich act on the ATP-dependent potassium channel of the beta cells.
In one embodiment of the invention, the présent compounds areadministered in combination with insulin.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with an HMGCoA reductase inhibitor such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin,rosuvastatin.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with a cholestérol absorption inhibitor such as,for example, ezetimibe, tiqueside, pamaqueside.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with a PPAR gamma agonist, such as, forexample, rosiglitazone, pioglitazone, JTT-501, Gl 262570.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with PPAR alpha agonist, such as, forexample, GW 9578, GW 7647.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with a mixed PPAR alpha/gamma agonist,such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, or asdescribed in PCT/US 11833, PCT/US 11490, DE10142734.4.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with a fibrate such as, for example,fenofibrate, clofibrate, bezafibrate. 013027 65
In one embodiment of the invention, the compounds of the formula I areadministered in combination, with an MTP inhibitor such as, for example,implitapide, BMS-201038, R-103757.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with bile acid absorption inhibitor (see, forexample, US 6,245,744 or US 6,221,897), such as, for example, HMR1741.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with a CETP inhibitor, such as, for example,JTT-705.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with a polymeric bile acid adsorbent such as,for example, cholestyramine, colesevelam.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with an LDL receptor inducer (see US6,342,512), such as, for example, HMR1171, HMR1586.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ACAT inhibitor, such as, for example,avasimibe.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with an antioxidant, such as, for example,OPC-14117.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein lipase inhibitor, such as, forexample, NO-1886.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ATP-citrate lyase inhibitor, such as, forexample, SB-204990.
In one embodiment of the invention, the compounds of the formula I are 013027 66 administered in combination with a squalene synthetase inhibitor, such as,for example, B MS-188494.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein(a) antagonist, such as, forexample, CI-1027 or nicotinic acid.
In one embodiment of the invention, the compounds ofthe formula I areadministered in combination with a lipase inhibitor, such as, for example,orlistat.
In one embodiment ofthe invention, the compounds ofthe formula I areadministered in combination with insulin.
In one embodiment, the compounds ofthe formula I are administered incombination with a sulfonylurea such as, for example, tolbutamide,glibenclamide, glipizide or glimepiride.
In one embodiment, the compounds ofthe formula I are administered incombination with a biguanide, such as, for example, metformin.
In one further embodiment, the compounds ofthe formula I areadministered in combination with a meglitinide, such as, for example,repaglinide.
In one embodiment, the compounds ofthe formula I are administered incombination with a thiazoiidinedione, such as, for example, troglitazone,ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed inWO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.
In one embodiment, the compounds ofthe formula I are administered incombination with an α-glucosidase inhibitor, such as, for example, miglitolor acarbose.
In one embodiment, the compounds ofthe formula I are administered incombination with an active ingrédient which acts on the ATP-dependentpotassium channel ofthe beta cells, such as, for example, tolbutamide, 013027 67 glibenclamide, glipizide, glimepiride or repaglinide.
In one embodiment, the compounds of the formula I are administered incombination with more than one of the aforementioned compounds, e.g. incombination with a sulfonylurea and metformin, with a sulfonylurea andacarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin andmetformin, insulin and troglitazone, insulin and lovastatin, etc. Thecompounds of the invention may moreover be administered in combinationwith one or more antiobesity agents or appetite-controlling activeingrédients.
In a further embodiment, the compounds of the formula I are administeredin combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastricemptying in mice" Asakawa, A, et aE, M.: Hormone and MetabolicResearch (2001), 33(9), 554-558), NPY antagonists, e.g. naphthalene-1-sulfonic acid {4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexyl-methyljamide; hydrochloride (CGP 71683A)), MC4 agonists (e.g. 1-amino- 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-amide; (WO 01/91752)), orexin antagonists (e.g. 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea; hydrochloride (SB-334867-A)), H3 agonists (3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic acid sait (WO00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine (WO 00/66585)),CRF BP antagonists (e.g. urocortin), urocortin agonists, β3 agonists (e.g. 1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-ethanol hydrochloride (WO 01/83451)), MSH(melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g. {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]- 5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid sait (WO 99/15525)),serotonin reuptake inhibitors (e.g. dexfenfluramine), mixed sertoninergicand noradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid sait (WO 01/09111), bombesinagonists, galanin antagonists, growth hormone (e.g. human growthhormone), growth hormone-releasing compounds (6-benzyloxy-1 -(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxyiicacid tert-butyl ester (WO 01/85695)), TRH agonists (see, for example, EP 0 013027 68 462 884), uncoupling protein 2 or 3 modulators, leptin agonists (see, forexample, Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena,Marina; Grasso, Patricia. Leptin agonists as a potential approach to thetreatment ofobesity. Drugs ofthe Future (2001), 26(9), 873-881), DAagonists (bromocriptine, Doprexin), lipase/amylase inhibitors (e.g. WO00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators orTR-β agonists.
In one embodiment ofthe invention, the otheractive ingrédient is leptin;see, for example, "Perspectives in the therapeutic use of leptin", Salvador,Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion onPharmacotherapy (2001), 2(10), 1615-1622.
In one embodiment, the other active ingrédient is dexamphatamine oramphétamine.
In one embodiment, the other active ingrédient is fenfluramine ordexfenfluramine.
In another embodiment, the other active ingrédient is sibutramine or themono- and bisdemethylated active métabolites of sibutramine.
In one embodiment, the other active ingrédient is orlistat.
In one embodiment, the other active ingrédient is mazindol or phentermine.
In one embodiment, the compounds ofthe formula I are administered incombination with bulking agents, preferably insoluble bulking agents (see,for example, carob/Caromax® (Zunft H J; et al., Carob pulp préparation fortreatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6.) Caromax is a carob-containing product fromNutrinova, Nutrition Specialties & Food Ingrédients GmbH, IndustrieparkHôchst, 65926 Frankfurt/Main)). Combination with Caromax® is possible inone préparation or by separate administration of compounds of the formulaI and Caromax®. Caromax® can in this connection also be administered inthe form of food products such as, for example, in bakery products ormuesli bars. 013027 69
JTT-501
The présent compounds may additionally be administered in combinationwith one or more antihypertensive active ingrédients. Examples of 5 antihypertensive active ingrédients are beta blockers such as alprenolol,atenol, timolol, pindolol, propanolol and metoproloi, ACE (angiotensinconverting enzyme) inhibitors such as, for example, benazeprii, captoprii,enalapril, fosinopril, lisinopril, quinapril and rampril, calcium channel 013027 70 blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine,diltiazem and verapamil, and alpha blockers such as doxazosin, urapidil,prazosin and terazosin. Référencé may furthermore be made toRemington: The Science and Practice of Pharmacy, 19th édition, Gennaro, 5 editor, Mack Publishing Co., Easton, PA, 1995.
It will be appreciated that every suitable combination of the compounds ofthe invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances is to be 10 regarded as covered by the scope of protection of the présent invention.
Examples
The efficacy of the compounds was tested as follows: 15
Biological test mode!:
The anorectic effect was tested on female NMRI mice. After withdrawal offood for 17 hours, the test product was administered by gavage. The 20 animais were housed singly with free access to drinking water and wereoffered condensed milk 30 minutes after administration of the product. Thecondensed milk consumption was determined every half hour for 7 hours,and the general wellbeing of the animais was observed. The measured milkconsumption was compared with the vehicle-treated control animais. 25
Table 1: Anorectic effect measured as the réduction in the cumulative milkconsumption of treated compared with control animais
Example Oral Number of Number of Réduction in dose animais/- animais/- the cumulative milk cumulative milk cumulative [mg/kg] consumption of consumption of milk the treated the control consumption animais animais as % of thecontrol N/[ml] N/[ml] Example 4 30 5/3.55 5/1.76 50 Example 13 30 5/3.70 5/1.34 64 013027 71
DESCRIPTION OF EXPERIMENTS
Functional measurements to find IC50 values
The cloning of the cDNA forthe human MCH receptor, préparation of arecombinant HEK293 cell line which expresses the human MCH receptor,and functional measurements with the recombinant cell line took place inanalogy to the description by Audinot et al. (J. Biol. Chem. 276, 13554-13562, 2001). A différence from the référencé was, however, the use of theplasmid pEAK8 from EDGE Biosystems (USA) to construct the expressionvector. The host used for the transfection was a transformed HEK cell linenamed “PEAK Stable Cells” (likewise from EDGE Biosystems). Thefunctional measurements of the cellular calcium flux after addition ofagonist (MCH) in the presence of ligand of the invention took place with theaid of the FLIPR apparatus from Molecular Devices (USA) using theprotoçols of the apparatus manufacturer.
The examples and préparation methods detailed below serve to illustratethe invention without, however, restricting it.
The compounds of the formula I of the invention can be prepared with theaid of réactions which are known in principle. For example, the compoundswere obtained in accordance with the following general reaction schemes. 013027 72 2 NO,
NH
R1 = H -1 Alkyl-X, NaH
I Method F R1 = Alkyl «·-' (tor R2 “ Boc) CDI, NHR3R4 R3x ,Ν—
* ,N-( '—S R4 q
Method A
-Ί NaOH
R2 = H —_I Method D
R2 = Boc 1 TFAR2 = H —J MethodG
R3COOK, TOTU
Method E
R2COOH
TOTU
Method E
Other compounds of the invention can be obtained by further routes whichare outlined by way of exemple in the following scheme. 013027 73
2) R3-X, Cs2CO3Method H
R Methods J
013027 74
Yet other examples were obtained as indicated in the following scheme. R’ //
1) Nu-
2) MOHMethods P
3) A, Methods E (M = MétalNir = nucleophile) HNR1R2
Method L
5 Descriptions of the general methods used are to be found by way ofexample described at the following places:
Methods A, B and C in example 1 ; 10 Method D in example 2;
Method E in example 3;
Method E-a in example 275; 15
Method E-b in example 286; 75
Method F in example 4;
Method F-a in example 264;, 5 Method G in example 15;
Method H in example 237;
Method H-a in example 298;
Method I in example 238;
Method J in example 245; 10 Method J-a in example 297;
Method K in example 250;
Method L in example 254;
Method M in example 274;
Method N in example 277; 15 Method O in example 279;
Method O-a in example 292;
Method O-b in example 280;
Method P in example 285;
Method Q in example 290; 20 Method R in example 309.
General explanations a) Mode of drawing the structural formulae25 Only non-hydrogen atoms are depicted for clarity in the structurai formulae of the given examples. 013027 76
In tables 6-13, enantiomer-enriched compounds are identified by a markedhydrogen atom on the stereogenic center. Unless expressly notedotherwise, the enantiomer-enriched examples shown hâve the (R)configuration on the 3-aminopyrrolidine stereocenter. b) Sait forme
Many of the compounds of the invention are bases and can form salts withappropriately strong acids. In particular, after purification of the compoundsby HPLC chromatography using a trifluoroacetic acid-containing mobilephase they may be in the form of hydrotrifluoroacetates. These can beconverted into the free bases shown by simple treatment of a solution ofthe salts for example with sodium carbonate solution. c) Units of the characterizing data
The unit of the stated molecular weight is “g/mol”. Peaks observed in themass spectrum are indicated as the intégral quotient of the molar molecularion mass and the charge of the molecular ion (m/z).
Example 1 N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin- 3-yl)acetamide
Method A A solution of 4-phenoxyaniline (3.33 g) in DMF (10 ml) was added dropwiseto a solution of carbonyldiimidazole (2.92g) in DMF (12 ml) cooled to 0°C.After 30 minutes, N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide(3.80 g) in DMF (10 ml) was added dropwise. The reaction solution waskept initially at room température for 2 hours and then at 80°C for30 minutes. The mixture was added dropwise to water (600 ml) and theresulting precipitate was fïltered off with su.ction and washed with water.Altematively, the product can also be extracted with ethyl acetate and 013027 77 purified by chromatography after concentration. This resulted in the product with the molecular weight of 444.54 (C26H28N4O3); MS (ESI): 445 (M+H+).
5 N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamideMethod B A suspension of N-methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide(3.5 g) and palladium(ll) hydroxide (20% on carbon; 0.9 g) in éthanol(150 ml) and ethyl acetate (300 ml) was vigorously stirred under a 10 hydrogen atmosphère (atmospheric pressure) for 3 hours. The catalyst wasthen removed by filtration, and the filtrate was concentrated. This resultedin the product with the molecular weight of 233.32 (C13H19N3O); MS(ESI): 234 (M+H+).
15 N-Methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamideMethod C 4-Fluoronitrobenzene (25.0 g) was slowly added to a suspension ofN-methyl-N-pyrrolidin-3-ylacetamide (25.2 g) and césium carbonate(57.6 g) in DMF (300 ml). After 2 hours, the reaction mixture was poured 20 into water, and the résultant precipitate was filtered off with suction.Alternatively, the product can also be extracted with ethyl acetate andpurified by chromatography after concentration. This résulte in the productwith the molecular weight of 263.30 (C13H17N3O3): MS (ESI): 264(M+H+). 25
Example 2 1-[4-(3-Methylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea
Method D A mixture of N-methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrroldin- 3-yl)acetamide (6.0 g), éthanol (250 ml), water (60 ml) and sodiumhydroxide solution (10 M; 80 ml) was heated under reflux for 12 hours. The 35 alcohol was distilled out and the resulting precipitate was filtered off with 013027 78 suction and washed with dichloromethane. Additional product was obtainedby concentration of the organic phase and chromatography (silica gel,dichloromethane/methanol 9:1 with 1% triethylamine). This resulted in theproduct with the molecular weight of 402.50 (C24H26N4O2); MS (ESI): 403(M+H+).
Example 3 N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)- 2-phenylacetamide o
Method E TOTU (327 mg) was added to a solution of 1-[4-(3-methylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea (402 mg) in DMF (3 ml) at 0°C. After10 minutes, Hünig’s base (130 mg) and then a solution of phenylacetic acid(136 mg) in DMF (1 ml) was added. After a reaction tifne of 12 hours atroom température, water was added to the mixture, and it was extractedwith ethyl acetate. The organic phase was dried over magnésium sulfateand concentrated. The residue was purified by préparative HPLC. Thisresulted in the product with the molecular weight of 520.64 (C32H32N4O3);MS (ESI): 521 (M+H+) as hydrotrifluoroacetate.
Example 4 f/?)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ure.ido]phenyl}pyrrolidin- 3-yl)acetamide (7?)-N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted 013027 79 with 4-phenoxyaniline by method A. This resulted in the product with the molecular weight of 444.54 (C26H28N4O3); MS (ESI): 445 (M+H+). (7?J-N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide (7?j-N-MethyI-N-[1 -(4-nitrophenyl)pyrrolidin-3-yl]acetamide washydrogenated by method B. This resulted in the product with the molecularweight of 233.32 (C13H19N3O); MS (ESI): 234 (M+H+). f/?J-N-Methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide
Method F (R)-N-[1-(4-Nitrophenyl)pyrrolidin-3-yl]acetamide (1.3 g) was added inportions to a suspension of sodium hydride (50% in oil; 0.25 g) in DMF(50 ml). After gas évolution had ceased, iodomethane (0.82 g) was added.After one hour, the reaction mixture was cautiously hydrolyzed with waterand extracted with ethyl acetate. The organicphase was dried overmagnésium sulfate and concentrated. This resulted in the product with themolecular weight of 263.30 (C13H17N3O3); MS (ESI): 264 (M+H+). ('R)-N-[1-(4-Nitrophenyl)pyrrolidin-3-yl]acetamide (f?)-N-pyrrolidin-3-ylacetamide was reacted with 4-fluoronitrobenzene bymethod C. This resulted in the product with the molecular weight of 249.27(C12H15N3O3); MS (ESI): 250 (M+H+).
Example 5 (S}-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyI)ureido]phenyl}pyrrolidin- 3-yl)acetamide
The sequence described in example 4 was applied to fS)-N-pyrrolidin- 3-ylacetamide. This resulted in the product with the molecular weight of444.54 (C26H28N4O3); MS (ESI): 445 (M+H+). 013027 80
Example 6 (RJ-1-[4-(3-Methylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea
5 (R)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin- 3-yl)acetamide was reacted by method D. This resulted in the product withthe molecularweight of 402.50 (C24H26N4O2); MS (ESI): 403 (M+H+). 10 Example 7 (S}-1-[4-(3-Methylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea
(S)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin- 3-yl)acetamide was reacted by method D. This resulted in the product withthe molecularweight of 402.50 (C24H26N4O2); MS (ESI): 403 (M+H+).
Example 8 (R)-N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N- methylacetamide
(R)-N-[1 -(4-Aminophenyl)pyrrolidin-3-yl)-N-methylacetamide was reacted 013027 81 with 4-cyclopentyloxyaniline by method A. This résultée! in the product with the molecular weight of 436.56 (C25H32N4O3); MS (ESI): 437 (M+H+). (S)-N-(1-{4-[3-(4-cyclopentyloxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-N-methyl-acetamide was obtained analogously from (S)-N-[1-(4-amino-phenyI)-pyrrolidin-3-yl]-N-methyl-acetamide. 4-Cyclopentyloxyaniline A mixture of 4-nitrophenol (63.7 g), bromocyclopentane (68.2 g), potassiumcarbonate (63.3 g) and DMF (300 ml) was heated at 80°C for 24 hours.After cooling, it was diluted with water and extracted with ethyl acetate. Theorganic phase was washed with water, dried over magnésium sulfate andconcentrated. The residue was hydrogenated by method B. This resulted inthe product with the molecular weight of 177.25 (C11H15NO); MS (ESI):178(M+H+).
Example 9 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide was reacted by method D. This resulted in the productwith the molecular weight of 394.52 (C23H30N4O2); MS (ESI): 395(M+H+). (R)- and (S)-1 -(4-cyclopentyloxy-phenyl)-3-[4-(3-methylamino-pyrrolidin-1 -yl)-phenyl]-urea was obtained analogously from (R)- and (S)-N-(1-{4-[3-(4-cyclopentyloxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-N-methyl-acetamide. Êxample 10
Ethyl (1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrro!idin-3-yl)methyl-carbamate 013027 82
Ethyl chloroformate (8 μΙ) was added dropwise to a solution of1-(4-cycIopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea 5 (20 mg) and Hünig’s base (10 mg) in dichloromethane (3 ml). After 12 hours, the reaction mixture was concentrated and the residue waspurified by préparative HPLC. This resulted in the product with themolecular weight of 466.59 (C26H34N4O4); MS (ESI): 467 (M+H+) ashydrotrifluoroacetate. 10
Example 11 1-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-3-ethyl-1- methylurea 15
Ethyl isocyanate (7 μΙ) was added dropwise to a solution of 1-(4-cyclo-pentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1 -yl)phenyl]urea (20 mg)and Hünig’s base (10 mg) in dichloromethane (3 ml). After 12 hours, the 20 reaction mixture was concentrated and the residue was purified by préparative HPLC. This resulted in the product with the molecular weight of465.60 (C26H35N5O3); MS (ESI): 466 (M+H+) as hydrotrifluoroacetate. 25 Example 12 1-(4-Cyclopentyloxyphenyl)-3-(4-{3-[methyl-((R)-5-oxo-pyrrolidin-2- ylmethyl)amino]pyrrolidin-1-yl}phenyl)urea 013027 83
(R/5-Bromomethylpyrrolidin-2-one (15 mg) was added to a suspension of1-(4-cyclopentyloxyphenyl)-3-[4-(3-methyaminopyrrolidin-1-yl)phenyl]urea 5 (30 mg) and potassium carbonate (20 mg) in DMF (3 ml). After 2 hours, the reaction mixture was filtered and concentrated, and the residue waspurified by préparative HPLC. This resulted in the product with themolecular weight of 491.64 (C28H37N5O3); MS (ESI): 492 (M+H+) ashydrotrifluoroacetate. 10
Example 13 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1 -yl]phenyl}amide 15
N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted withcarbonyldiimidazole and then with 4-(4-chlorophenyl)piperidine by 20 method A. This resulted in the product with the molecular weight of 455.00(C25H31CIN4O2); MS (ESI): 455 (M+H+). (R)-and (S)-4-(4-chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]phenyl}amide were obtained analogously from(R)- and (S)-N-[1 -(4-aminophenyl)pyrroiidin-3-yl]-N-methyacetamide. 25
Example 14 tert-Butyl (R)-[1-(4-{[4-(4-chlorophenyl)piperidine-1-carbonyl]amino}-phenyl)pyrrolidin-3-yl]methylcarbamate 013027 84 cl^yC”x°“O'"CÎ'”M· tert-Butyl (Y?J-[1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate wasreacted with carbonyldiimidazole and then with 4-(4-chlorophenyl)piperidineby method A. This resulted in the product with the molecular weight of513.09 (C28H37CIN4O3); MS (ESI): 513 (M+H+). tert-Butyl f/?J-[1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate tert-Butyl (R)-methyl-[1 -(4-nitrophenyl)pyrrolidin-3-yl]carbamate washydrogenated by method B. This resulted in the product with the molecularweight of 291.40 (C16H25N3O2); MS (ESI): 292 (M+H+). tert-Butyl (R)-methyl-[1 -(4-nitrophenyl)pyrrolidin-3-yl]carbamate tert-Butyl f/?)-[1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate was alkylated withiodomethane by method F. This resulted in the product with the molecularweight of 321.38 (C16H23N3O4); MS (ESI): 322 (M+H+). tert-Butyl (Æ)-[1 -(4-nitrophenyl)pyrrolidin-3-yl]carbamate tert-Butyl (7?J-pyrrolidin-3-ylcarbamate was reacted with 4-fluoronitro-benzene by method C. This resulted in the product with the molecularweight of 307.35 (C15H21N3O4); MS (ESI): 308 (M+H+).
Example 15 (7?)-4-(4-Chlorophenyl)piperidine-1 -carboxylic acid [4-(3-methylamino-pyrrolidin-1 -yl)phenyl]amide 013027
Method G 5 Trifluoroacetic acid (6.67 g) was added to a solution of tert-butyl (R)-[1-(4-{[4-(4-chlorophenyl)piperidin-1-carbonyl]amino}phenyl)pyrrolidin- 3-yl]methylcarbamate (1.5 g) in dichloromethane (50 ml). After 3 hours,volatile fractions were removed and the residue was taken up indichloromethane. After washing with sodium carbonate solution, the 10 organic phase was dried over magnésium sulfate and concentrated. Thisresulted in the product with the molecular weight of 412.97(C23H29CIN4O); MS (ESI): 413 (M+H+).
Example 16 15 4-(4-Chlorophenyl)piperidine-1-carboxylic acid (4-{(R)-3-[methyl-(1-methyl-piperidin-3-ylcart>onyl)amino]pyrrolidin-1-yl}phenyl)amide
20 (R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid [4-(3-methylamino-pyrrolidin-1-yl)phenyl]amide was reacted with 1-methylpiperidine-3-carboxylic acid by method E. This resulted in the product with the molecularweight of 538.14 (C30H40CIN502); MS (ESI): 538 (M+H+). 25
Example 17 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid (4-(R>{3-[methyl-(2-piperidin-1-ylacetyl)amino]pyrrolidin-1-yl}phenyl)amide 013027 86 10 10 Ο
CI
Κ/Ν (R)-4-(4-Chlorophenyl)piperidine-1 -carboxylic acid [4-(3-methylamino-pyrrolidin-1-yl)phenyl]amide was reacted with piperidin-1-ylacetic acid bymethod E. This resulted in the product with the molecular weight of 538.14(C30H40CIN502); MS (ESI): 538 (M+H+).
Example 18 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid (4-('R)-{3-[methyl-(2-oxo-thiazolidine-4-carbonyl)amino]pyrrolidin-1 -yl}phenyl)amide 15 15 20 20 (R)-4-(4-Chlorophenyl)piperidin-1 -carboxylic acid [4-(3-methylamino-pyrrolidin-1-yl)phenyl]amide was reacted with 2-oxothiazolidine-4-carboxylic acid by method E. This resulted in the product with themolecular weight of 542.10 (C27H32CIN5O3S); MS (ESI): 542 (M+H+).
Example 19 (7?)-4-(4-Chlorophenyl)piperidine-1 -carboxylic acid (4-{3-[methyl-(2,2,2-trifluoroacetyl)amino]pyrrolidin-1-yl}phenyl)amide
Cl
F (/?)-[N-[1-(4-aminophenyl)pyrrolidin-3-yl]-2,2,2-trifluoro-N-methylacetamidewas reacted with carbonyldiimidazole and then with 4-(4-chlorophenyl)-piperidine by method A. This resulted in the product with the molecular 013027 87 weightof 508.98 (C25H28CIF3N4O2); MS (ESI): 509 (M+H+). (/?7-[N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-2,2,2-trifluoro-N-methylacetamide f/?)-2,2,2-Trifluoro-N-methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamidewas hydrogenated by method B. This resulted in the product with themolecular weight of 287.29 (C13H16F3N3O); MS (ESI): 288 (M+H+). f/?J-2,2,2-Trifluoro-N-methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide
Trifluoroacetic anhydride (0.5 ml) was added dropwise to a solution offR)-methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]amine (0.48 g) in pyridine (2 ml).After 3 hours, the reaction mixture was diluted with water and extractedwith ethyl acetate. The organic phase was washed with citric acid solution,dried over magnésium sulfate and concentrated. This resulted in theproduct with the molecular weight of 317.27 (C13H14F3N3O3); MS (ESI):318(M+H+). f/?)-Methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]amine A solution of tert-butyl (7?)-methyl-[1 -(4-nitrophenyl)pyrrolidin-3-yl]-carbamate (0.7 g) in dichloromethane (5 ml) was treated with trifluoroaceticacid (3 ml) for 1 hour. The reaction solution was concentrated and theresidue was taken up in dichloromethane. After washing with sodiumcarbonate solution, the organic phase was dried over magnésium sulfateand concentrated. This resulted in the product with the molecular weight of 221.26 (C11H15N3O2); MS (ESI): 222 (M+H+).
Example 20 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}methylamide 013027 88
Ci
K
N 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yljphenyl}amide was reacted wîth iodomethane by method F.This resulted in the product with the molecular weight of 469.03(C26H33CIN4O2); MS (ESI): 469 (M+H+).
Example 21 (R)-4-(4-Chlorophenyl)piperidine-1 -carboxylic acid (4-{3-[acetyl-(2-diethylaminoethyl)amino]pyrrolidin-1-yl}phenyl)amide
Cl fR)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-(2-diethylaminoethyl)acetamidewas reacted with 4-(4-chlorophenyl)piperidine by method A. This resulted inthe product with the molecular weight of 540.15 (C30H42CIN5O2); MS(ESI): 540 (M+H+). fR)-N-[1-(4-Aminophenyl)pyrrolidin-3-ylJ-N-(2-diethylaminoethyl)acetamidefR)-N-(2-Diethylaminoethyl)-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamidewas hydrogenated by method B. This resulted in the product with themolecular weight of 318.47 (C18H30N4O); MS (ESI): 319 (M+H+). (R)-N-(2-Diethylaminoethy!)-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide fR)-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide was reacted with2-chloroethyldiethylamine by method F. This resulted in the product withthe molecular weight of 348.45 (C18H28N4O3); MS (ESI): 349 (M+H+). 013027 89
Example 22 1-[4-(3-Dimethylaminopyrroljdin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea
Dimethylpyrrolidin-3-ylamine was reacted with 4-fluoronitrobenzene, theresulting nitro compound was reduced with hydrogen and finally the anilinewas reacted with CDI and 4-phenoxyaniline by method A, B and C. Thisresulted in the product with the molecular weight of 416.53 (C25H28N4O2);MS (ESI): 417 (M+H+).
Example 23 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-isobutoxy- phenyl)propionamide N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with2-(4-isobutoxyphenyl)propionic acid by method E. This resulted in theproduct with the molecular weight of 437.59 (C26H35N3O3); MS (ESI): 438(M+H+).
Example 24 N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide 013027 90
N-PyrroIidin-3-ylacetamide was reacted with 4-fluoronitrobenzene, theresulting nitro compound was reduced with hydrogen and finally the anilinewas reacted with CDI and 4-cyclopentyloxyaniline by method A, B and C.This resulted in the product with the molecular weight of 422.53(C24H30N4O3); MS (ESI): 423 (M+H+). (R)- and (SJ-N-(1 -{4-[3-(4-cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide were obtained in an analogous manner starting from (R)- and(S^-N-pyrrolidin-3-ylacetamide.
Example 25 N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N- ethylacetamide N-Ethyl-N-pyrroiidin-3-ylacetamide was reacted with 4-fluoronitrobenzene,the resulting nitro compound was reduced with hydrogen and finally theaniline was reacted with CDI and 4-cyclopentyloxyaniline by method A, Band C. This resulted in the product with the molecular weight of 450.59(C26H34N4O3); MS (ESI): 451 (M+H+).
Example 26 4-(4-Chlorophenyl)piperidin-1 -carboxylic acid {4-[3-(acetylmethyl-amino)pyrrolidin-1-yi]-3-methylphenyl}amide 013027 91
Ci
ο N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 1-fluoro-2-methyl- 4-nitrobenzene, the resulting nitro compound was reduced with hydrogenand finally the aniline was reacted with CDI and 4-(4- chlorophenyl)piperidine by method A, B and C. This resulted in the productwith the molecular weight of 469.03 (C26H33C1N4O2); MS (ESI): 469(M+H+).
Example 27 4-(4-Chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl)-3-fluorophenyl}amide
Cl N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 1,2-difluoro- 4-nitrobenzene, the resulting nitro compound was reduced with hydrogenand finally the aniline was reacted with CDI and 4-(4- chlorophenyl)piperidine by method A, B and C. This resulted in the productwith the molecular weight of 472.99 (C25H30CIFN4O2); MS (ESI): 473(M+H+).
Example 28 4-(4-Chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolid in-1 -yl]-2,6-difluorophenyl}amide 013027 92 .0 F.
Ο
F N-Methyl-N-pyrroIidin-3-ylacetamide was reacted with 1,3,5-trifluoro-2-nitrobenzene, the resulting nitro compound was reduced with hydrogen and 5 finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine bymethod A, B and C. This resulted in the product with the molecular weightof 490.99 (C25H29CIF2N4O2); MS (ESI): 491 (M+H+). 10 Example 29 4-(4-Chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]-2-methylphenyl}amide
Ci 15 N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 4-fIuoro-2-methyl-1 -nitrobenzene, the resulting nitro compound was reduced with hydrogen andfinally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine bymethod A, B and C. This resulted in the product with the molecular weightof 469.03 (C26H33CIN4O2); MS (ESI): 469 (M+H+). 20
Example 30 4-(4-Chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolid in-1 -yl]-2-fluorophenyl}amide 25
Cl N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 2,4-difluoro-1- 013027 93 nitrobenzene, the resulting nitro compound was reduced with hydrogen andfinally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine bymethod A, B and C. This resulted in the product with the molecular weightof 472.99 (C25H30CIFN4O2); MS (ESI): 473 (M+H+).
Example 31 tert-Butyl (Y?J-[1-(5-{[4-(4-Chlorophenyl)piperidin-1-carbonyl]amino}pyridin-2-yl)pyrrolidin-3-yl]methylcarbamate
The synthetic sequence for preparing tert-butyl (R)-[1-(4-{[4-(4-chloro-phenyl)piperidin-1-carbonyl]amino}phenyl)pyrrolidin-3-yl]methylcarbamatewas carried out starting from 2-chloro-5-nitropyridine instead of4-fluoronitrobenzene. This resulted in the product with the molecular weightof 514.07 (C27H36CIN5O3); MS (ESI): 514 (M+H+).
Example 32 (R)-[4-(4-Chlorophenyl)piperidine-1 -carboxylic acid [6-(3-methylamino-pyrrolidin-1-yl)pyridin-3-yl]amide
tert-Butyl (7?)-[1-(5-{[4-(4-chlorophenyl)piperidine-1-carbonyl]amino}pyridin-2-yl)pyrrolidin-3-yl]methylcarbamate was treated with trifluoroacetic acid bymethod G. This resulted in the product with the molecular weight of 413.95(C22H28CIN5O); MS (ESI): 414 (M+H+).
It was possible to obtain racemic [4-(4-chlorophenyl)piperidine-1 -carboxylicacid [6-(3-methylaminopyrrolidin-yl)pyridin-3-yl]amide in a similar manner. 013027 94
Example 33 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {6-[3-(acetylmethylamino)-pyrrolidin-1-yl]pyridin-3-yl}amide
Cl N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 2-chloro-5-nitro-pyridine, the resulting nitro compound was reduced with hydrogen andfinally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine bymethod A, B and C. This resulted in the product with the molecular weightof 490.99 (C25H29CIF2N4O2); MS (ESI): 491 (M+H+).
Example 34 1-[4-(4-Dimethylaminopiperidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea
Dimethylpiperidin-4-ylamine was reacted with 4-fluoronitrobenzene, theresulting nitro compound was reduced with hydrogen and finally the aniline([1-(4-aminophenyl)piperidin-4-yl]dimethylamihe) was reacted with CDI and4-phenoxyaniline by method A, B and C. This resulted in the product withthe molecular weight of 430.55 (C26H30N4O2); MS (ESI): 431 (M+H+).
Example 35 1-(4-Cyclopentyloxyphenyl)-3-[4-(4-morpholin-4-ylpiperidin-1-yI)phenyl]urea 013027 95 4-Piperidin-4-ylmorpholine was reacted with 4-fluoronitrobenzene, theresulting nitro compound wa,s reduced with hydrogen and finally the anilinewas reacted with CDI and 4-cyclopentyloxyaniline by method A, B and C. 5 This resulted in the product with the molecular weight of 464.61(C27H36N4O3); MS (ESI): 465 (M+H+).
Example 36 10 4-Butoxy-N-[4-(4-dimethylaminopiperidin-1-yl)phenyl]benzamide ([1-(4-Aminophenyl)piperidin-4-yl]dimethylamine) was reacted with 4-15 4-butoxybenzoic acid by method E. This resulted in the product with the molecular weight of 395.55 (C24H33N3O2); MS (ESI): 396 (M+H+).
Example 37 4-(4-Chlorophenyl)piperidin-1 -carboxylic acid {4-[3-(acetylmethyIamino)-20 azetidin-1-yl]phenyl}amide
Cl
O N-[1-(4-aminophenyl)azetidin-3-yl]-N-methylacetamide was reacted withcarbonyldiimidazole and 4-(4-chlorophenyl)piperidine by method A. This 25 resulted in the product with the molecular weight of 440.98(C24H29CIN4O2); MS (ESI): 441 (M+H+). N-[1-(4-AminophenyI)azetidin-3-yl]-N-methylacetamide30 N-Methyl-N-[1-(4-nitrophenyl)azetidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight pf 219.29(C12H17N3O); MS (ESI): 220 (M+H+). 96 013027 N-Methyl-N-[1-(4-nitrophenyl)azetidin-3-yl]acetamide N-[1-(4-nitrophenyl)azetidin-3-yl]acetamide was alkylated with iodomethaneby method F. This resulted in the product with the molecular weight of 249.27 (C12H15N3O3); MS (ESI): 250 (M+H+). N-[1-(4-Nitrophenyl)azetidin-3-yl]acetamide
Acetic anhydride (0.6 ml) was added to a solution of 1-(4-nitrophenyl)-azetidin-3-ylamine (0.5 g ) in pyridine (1.2 ml). After one hour, volatilefractions were removed. This resulted in the product with the molecularweight of 235.24 (C11H13N3O3); MS (ESI): 236 (M+H+). 1-(4-Nitrophenyl)azetidin-3-ylamine tert-Butyl [1-(4-nitrophenyl)azetidin-3-yl]carbamate was treated withtrifluoroacetic acid by method G. This resulted in the product with themolecular weight of 193.21 (C9H11N3O2); MS (ESI): 194 (M+H+). tert-Butyl [1 -(4-nitrophenyl)azetidin-3-yl]carbamate tert-Butyl azetidin-3-ylcarbamate was reacted with 4-fluoronitrobenzene bymethod C. This resulted in the product with the molecular weight of 293.33(C14H19N3O4); MS (ESI): 294 (M+H+).
Example 38 tert-Butyl [1 -(4-{[4-(4-Chlorophenyl)piperidin-1 -carbonyl]amino}-phenyl)azetidin-3-yl]methylcarbamate
Ci tert-Butyl [1-(4-aminophenyl)azetidin-3-yl]methylcarbamate was reactedwith carbonyldiimidazole and 4-(4-chlorophenyl)piperidine by method A.This resulted in the product with the molecular weight of 499.06(C27H35CIN4O3; MS (ESI): 499 (M+H+). 013027 97 tert-Butyl [1-(4-aminophenyl)azetidin-3-yl]methylcarbamatetert-Butyl methyl-[1-(4-nitrophenyl)azetidin-3-yl]carbamate was 5 hydrogenated by method B. This resulted in the product with the molecularweight of 277.37 (C15H23N3O2); MS (ESI): 278 (M+H+). tert-Butyl methyl-[1-(4-nitrophenyl)azetidin-3-yl]carbamate10 tert-Butyl [1-(4-nitrophenyl)azetidin-3-yl]carbamate was alkylated with iodomethane by method F. This resulted in the product with the molecularweight of 307.35 (C15H21N3O4); MS (ESI): 308 (M+H+). 15 Example 39 4-(4-Chlorophenyl)piperidin-1 -carboxylic acid [4-(3-methyIaminoazetidin-1-yl)phenyl]amide
CI
20 tert-Butyl [1-(4-{[4-(4-chlorophenyl)piperidin-1-carbonyl]amino}- phenyl)azetidin-3-yl]methylcarbamate was reacted with trifluoroacetic acidby method G. This resulted in the product with the molecular weight of398.94 (C22H27CIN4O); MS (ESI): 399 (M+H+). 25
Example 40 N-Methyl-N-[1-(4-{3-[4-(pyridin-3-yloxy)phenyl]ureido}phenyl)pyrrolidin- 3-yl]acetamide
30 N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 98
carbonyldiimidazole and then with 4-(pyridin-3-yloxy)phenylamine bymethod A. This resulted in the product with the molecuiar weight of 445.53(C25H27N5O3); MS (ESI): 446 (M+H+).
Example 41 N-Methyl-N-(1-{4-[3-(4-piperidin-1-ylphenyl)ureido]phenyl}pyrrolidin- 3-yl)acetamide
N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted withcarbonyldiimidazole and then with 4-piperidin-1-ylphenylamine bymethod A. This resulted in the product with the molecuiar weight of 435.57(C25H33N5O2); MS (ESI): 436 (M+H+).
Example 42 N-{4-[3-(Acetylmethylamino)pyrroIidin-1-yl]phenyl}-4-phenoxybenzamide
N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4-phenoxybenzoic acid by method E. This resulted in the product with themolecuiar weight of 429.52 (C26H27N3O3); MS (ESI): 430 (M+H+).
Example 43 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-butoxybenzamide 99 013027
N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4-butoxybenzoic acid by method E. This resulted in the product with themolecular weight of 409.53 (C24H31N3O3); MS (ESI): 410 (M+H+).
Example 44 4-(4-Chlorophenyl)cyclohexanecarboxylic acid {4-[3-(acetylmethylamino)-pyrrolid in-1 -yl]phenyl}amide
N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with4-(4-chlorophenyl)cyclohexanecarboxyIic acid by method E. This resultedin the product with the molecular weight of 454.02 (C26H32CIN3O2); MS(ESI): 454 (M+H+).
Example 45 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyI}-3-(4-isopropylphenyl)- acrylamide
N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with3-(4-isopropylphenyl)acrylic acid by method E. This resulted in the product 013027 100 with the molecular weight of 405.54 (C25H31N3O2); MS (ESI): 406(M+H+).
Example 46
Tetrahydrofuran-2-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylamide
1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]ureawas reacted with tetrahydrofuran-2-carboxylic acid by method E. Thisresulted in the product with the molecular weight of 492.62 (C28H36N4O4);MS (ESI): 493 (M+H+).
Example 47 1-Acetylpyrrolidin-2-carboxylic acid (1-{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylamide
1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]ureawas reacted with 1-acetylpyrrolidine-2-carboxylic acid by method E. Thisresulted in the product with the molecular weight of 533.68 (C30H39N5O4);MS (ESI): 534 (M+H+).
Example 48 5-Oxopyrrolidine-2-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylamide 101 013027
1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]ureawas reacted with 5-oxopyrrolidine-2-carboxylic acid by method E. Thisresulted in the product with the molecular weight of 505.62 (C28H35N5O4);MS (ESI): 506 (M+H+).
Example 49 2-Oxothiazolidine-4-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylamide
1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]ureawas reacted with 2-oxothiazolidine-4-carboxylic acid by method E. Thisresulted in the product with the molecular weight of 523.66(C27H33N5O4S); MS (ESI): 524 (M+H+).
Example 50 (R)-1 -Methylpiperidine-3-carboxylic acid {1 -[4-(4-cyclohexylbenzoyl-amino)phenyl]pyrrolidin-3-yl}methylamide
(R)-4-Cyclohexyl-N-[4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamide was 013027 102 reacted with 1-methylpiperidine-3-carboxylic acid by method E. Thisresulted in the product with the molecular weight of 502.71 (C31H42N4O2);MS (ESI): 503 (M+H+).
Example 51 N-(1-{4-[3-(6-Cyclopentyloxypyridin-3-yl)ureido]phenyl}pyrrolidin-3-yl)- N-methylacetamide
N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted withcarbonyldiimidazole and then 6-cyclopentyloxypyridin-3-ylamine bymethod A. This resulted in the product with the molecular weight of 437.55(C24H31N5O3); MS (ESI): 438 (M+H+). 6-Cyclopentyloxypyridin-3-ylamine A mixture of 5-nitropyridin-2-ol (14.0 g), bromocyclopentane (8.0 g),potassium carbonate (14 g) and DMF (200 ml) was heated at 80°C for6 hours. After cooling, the reaction mixture was diluted with water andextracted with ethyl acetate. The organic phase was washed with water,dried over magnésium sulfate and concentrated. The residue was purifiedby chromatography on silica gel. The resulting product (2-cyclopentyloxy- 5-nitropyridine) was hydrogenated by method B. This resulted in theproduct with the molecular weight of 178.24 (C10H14N2O); MS (ESI): 179(M+H+).
Example 52 1-(6-Cyclopentyloxypyridin-3-yl)-3-[4-(3-methylaminopyrrolidin-1-yl)- phenyl]urea 103 013027
N N
N \ N-(1-{4-[3-(6-Cyclopentyloxypyridin-3-yl)ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide was treated with sodium hydroxide solution by method D.This resulted in the product with the molecular weight of 395.51(C22H29N5O2); MS (ESI): 395 (M+H+).
Example 53 4’-Fluorobiphenyl-4-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide
F
N \ N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4’-fluorobiphenyl-4-carboxylic acid by method E. This resulted in the product withthe molecular weight of 431.51 (C26H26FN3O2); MS (ESI): 432 (M+H+).Example 54 4’-Trifluoromethylbiphenyl-4-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1 -yl]phenyl}amide
O
N
N \ N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methyIacetamide was reacted with4’-trifluoromethylbiphenyl-4-carboxylic acid by method E. This resulted in 013027 104 the product with the molecular weight of 481.52 (C27H26F3N3O2); MS(ESI): 482 (M+H+).
Examples 55-103 1-(4-Phenoxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea wasreacted with various carboxylic acids by method E. The products arecompiled in table 2.
Examples 104-144 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]ureawas reacted with various carboxylic acids by method E. The products arecompiled in table 3.
Examples 145-185 N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted withvarious carboxylic acids by method E. The products are compiled in table4.
Examples 186-234 N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted withcarbonyldiimidazole and then with various amines by method A. Theproducts are compiled in table 5.
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Example 235 N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N-methyl-2-piperidin-1 -yl-acetamide
1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]ureawas reacted with piperidin-1-ylacetic acid by method E. This resulted in theproduct with the molecular weight of 519.69 (C30H41N5O3); MS (ESI): 520(M+H+). 10
Example 236 1-Methylpiperidine-3-carboxylic acid {(R)-1-[5-(4- cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl)methylamide
(R)-4-Cyclohexyl-N-[6-(3-methylaminopyrrolidin-1-yl)pyridin-3-yljbenzamide was reacted with 1-methylpiperidin-3-carboxylic acid bymethod E. This resulted in the product with the molecular weight of 503.69(C30H41N5O2); MS (ESI): 504 (M+H+).
Example 237 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4- butoxyphenyl)propionamide 013027 155
Method H
Caesium carbonate (36 mg) and n-butyl bromide (15 mg) were added to asolution of N-{4-[3-(acetylmethylamino)pyrrolidin-1 -yI]phenyl}-2-(4-hydroxyphenyl)propionamide (27 mg) in DMF (1 ml). After a reaction timeof 2 hours at room température, water was added to the mixture, and it wasextracted with ethyl acetate. The organic phase was dried over sodiumsulfate and concentrated, and the residue was crystallized from diethylether/methanol. This resulted in the product with the molecular weight of437.59 (C26H35N3O3); MS(ESI): 438 (M+H+). N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4- hydroxyphenyl)propionamide N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamid was reacted with 2-(4-hydroxyphenyl)propionie acid by method I. This resulted in the productwith the molecular weight of 381.48 (C22H27N3O3); MS(ESI): 382 (M+H+).
Example 238 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4- isobutoxyphenyl)acetamide
N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4- hydroxyphenyl)acetamide was reacted with isobutyl bromide by method H.This resulted in the product with the molecular weight of 423.56(C25H33N3O3); MS(ESI): 424 (M+H+). 013027 156
N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)acetamideMethod I 4-Hydroxyphenylacetic acid (305 mg), 1-hydroxybenzotriazole (300 mg) 5 and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (480 mg) in DMF (5 ml) were stirred with N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide (470 mg) at room température for 3 hours. Water wasthen added to the mixture, which was extracted with ethyl acetate. Theorganic phase was washed with saturated sodium chloride solution, dried 10 over sodium sulfate, concentrated and crystallized from diethyl ether. Thisresulted in the product with the molecular weight of 367.45 (C21H25N3O3);MS(ESI): 368 (M+H+). 15 Example 239 (/?)-N-{4-[3-(Acetylmethylamino)pyrrolidin-1 -yl]phenyl}-2-(4-butoxyphenyl)acetamide
(R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted20 with 4-butoxypheny!acetic acid by method E. This resulted in the product with the molecular weight of 423.56 (C25H33N3O3); MS(ESI): 424 (M+H+).
Example 240 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4- cyclopropylmethoxyphenyl)propionamide
25 013027 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4- hydroxyphenyl)propionamide was reacted with bromomethylcyclopropaneby method H. This resulted in the product with the molecular weight of435.57 (C26H33N3O3); MS(ESI): 436 (M+H+).
Example 241 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4- cyclobutylmethoxyphenyl)propionamide 10
N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4- hydroxyphenyl)propionamide was reacted with bromomethylcyclobutane bymethod H. This resulted in a product with the molecular weight 449.60(C27H35N3O3); MS(ESI): 450 (M+H+). 15
Example 242 1 -(4-Methoxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethyl-amino)pyrrolidin-1-yl]phenyl}amide
N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with1-(4-methoxyphenyl)-1-cyclopropanecarboxylic acid by method E. Thisresulted in the product with the molecular weight of 407.52 (C24H29N3O3);MS(ESI): 408 (M+H+). 20 25 013027 158
Example 243 1-(4-Butoxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1 -yl]phenyl}amide
1 -(4-Hydroxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethyl-amino)pyrrolidin-1yl]phenyl}amide was reacted with n-butyl bromide bymethod H. This resulted in the product with the molecular weight of 449.60(C27H35N3O3); MS(ESI): 450 (M+H+). 1-(4-Hydroxyphenyl)cyclopropanecarboxylicacid {4-[3-(acetylmethyl-amino)pyrrolidin-1-yl]phenyl}amide
Boron tribromide-dimethyl sulfide (460 mg) was added to a solution of 1-(4-methoxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide (540 mg) indichloromethane (5.5 ml) at 0°C. After a reaction time of 12 hours at roomtempérature, water was added to the mixture, the phases were separated,and the aqueous phase was extracted with dichloromethane. Thecombined organic phases were dried over sodium sulfate, concentratedand purified by chromatography (silica gel, toluene/ethanol/ethyl acetate8:1:1 with addition of 0.1 % triethylamine). This resulted in the product withthe molecular weight of 393.49 (C23H27N3O3); MS(ESI): 394 (M+H+).
Example 244 (/?)-4-(4-Fluorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethyl-amino)pyrrolidin-1-yl]phenyl}-N-methylamide
N \
O
013027 159 (/?)-4-(4-Fluorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethyl-amino)pyrrolidin-1-yl]phenyl}amide (22 mg) was added to a suspension ofsodium hydride (95% in oil; 0.005 g) in DMF (1 ml). After évolution of gasceased, iodomethane (0.02 ml) was added. After two hours, the reaction 5 mixture was cautiously hydrolyzed with water and extracted with dichloromethane. The organic phase was dried over magnésium sulfateand concentrated, and the residue was crystallized from pentane. Thisresulted in the product with the molecular weight of 452,58(C26H33FN4O2); MS (ESI): 453 (M+H+).
Example 245 5-2-[(2-Fluorophenyl)ethynyl]furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide
Firstly diisopropylamine (14.9 mg) and then a solution of 5-bromofuran-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide(50.0 mg) and 1-ethynyl-2-fluorobenzene (17.7 mg) in dioxane (0.5 ml) and 20 DMF (0.2 ml) were added under inert conditions to a suspension ofpalladium bis(tri-tert-butylphosphine) dichloride (3.8 mg) and copper(l)iodide (0.9 mg) in DMF (0.5 ml). After a reaction time of 12 hours at roomtempérature, the mixture was diluted with ethyl acetate and filtered throughsilica gel, and the filtrate was concentrated and purified by préparative 25 HPLC. This resulted in the product with the molecular weight of 445.18(C26H24FN3O3); MS(ESI): 446 (M+H+) as hydrotrifluoroacetate. 5-Bromofuran-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide 013027 160 N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with5-bromo-2-furancarboxylic acid by method E. This resulted in the productwith the molecular weight of 406.28 (C18H20BrN3O3); MS(ESI): 407(M+H+).
Example 246 5-2-[(4-FluorophenyI)ethynyl]furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide
5-Bromofuran-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide was reacted with 1-ethynyl-4-fluorobenzene by method J.This resulted in the product with the molecular weight of 445.18(C26H24FN3O3); MS(ESI): 446 (M+H+) as hydrotrifluoroacetate.
Example 247 5-2-[(2-ChIorophenyl)ethynyl]furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide
5-Bromofuran-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide was reacted with 1-ethynyl-2-chlorobenzene by method J.This resulted in the product with the molecular weight of 461.15(C26H24CIN3O3); MS(ESI): 462 (M+H+) as hydrotrifluoroacetate. 161
Example 248 R-4-Butoxy-N-(3-fluoro-4-{3-[(2-hydroxy-2-methylpropyl)methylamino]- pyrrolidin-1-yl}-phenyl)benzamide A solution of (R)-4-butoxy-N-[3-fluoro-4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamide (0,03 g) and isobutylene oxide in éthanol (5 ml) wereheated under reflux for 3 hours. It was then concentrated in vacuo. Thisresulted in the product with the molecular weight of 457.59 (C26H36FN3O3); MS (ESI): 458 (M+H+):
Example 249 R-4-Butoxy-N-(3-fluoro-4-{3-[(3-hydroxy-3- methylbutyl)methylamino]pyrrolidin-1-yl}-phenyl)-N-methylbenzamide A solution of (R)-4-butoxy-N-[3-fluoro-4-(3-methylaminopynrolidin-1 -yl)phenyl]benzamide (0.03 g), triethylamine (0.02 g) and 4-bromo-2-methylbutan-2-ol (0.03 g) in DMF (2 ml) was heated at 80°C for 16 hours.After cooling, ethyl acetate (100 ml) was added, the mixture was washedwith water (2 x 50 ml), and the organic phase was dried with sodiumsulfate, filtered and concentrated. The residue was purified by préparativeHPLC. This resulted in the product with the molecular weight of 471.62(C27H38FN3O3); MS (ESI): 472 (M+H+). 013027 162 4-Bromo-2-methylbutan-2-ol Méthylmagnésium bromide (3M in diethyl ether, 46 ml) was added to asolution of ethyl 3-bromopropionate (10 g) in diethyl ether (100 ml) at roomtempérature under argon. During this, the mixture was kept at above 20°Cand below 35°C. After 2 hours, the mixture was pourèd into a saturatedammonium chloride solution. This was followed by extraction with diethylether, drying with sodium sulfate, filtration and concentration. This resultedin the desired product.
Example 250 R-4-Butoxy-N-[6-(3-dicyclopropylaminopyrrolidin-1-yl)-pyridin-3- yljbenzamide
Method K A solution of (R)-N-[6-(3-aminopyrrolidin-1-yl)pyridin-3-yl]-4- butoxybenzamide (0.065 g) in methanol (2 ml) was mixed with glacialacetic acid (0.11 ml) and [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.19 g).Then sodium cyanoborohydride (0.051 g) was added and the mixture washeated under reflux for 16 hours. The mixture was then filtered,concentrated, taken up in dichloromethane, washed with sodium hydroxide(2N; 20 ml) and sodium chloride solution (20 ml), dried with magnésiumsulfate and concentrated. The residue was purified by préparative HPLC.This resulted in the product with the molecular weight of 434.59(C26H34N4O2); MS (ESI): 435 (M+H+).
Example 251 R-4-Butoxy-N-[6-(3-dicyclopropylaminopyrrolidin-1-yl)pyridin-3-yl]-N- methylbenzamide 013027 163
(R)-4-Butoxy-N-[6-(3-dicyclopropylaminopyrrolidin-1-yl)pyridin-3-yljbenzamide was methylated by method F. This resulted in the productwith the molecular weight of 448.61 (C27H36N4O2); MS (ESI): 449 5 (M+H+).
Example 252 R-4-Butoxy-N-{6-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]pyridin-3-10 yljbenzamide
N \ (R)-4-Butoxy-N-[6-(3-methylaminopyrrolidin-1-yl)pyridin-3-yl]benzamidewas cyclopropylated by method K. This resulted in the product with themolecular weight of 408.551 (C24H32N4O2); MS (ESI): 409 (M+H+). 15
Example 253 tert-Butyl {1-[4-(2-amino-4-butoxybenzoylamino)-3-fluorophenyl]pyrrolidin-3-yl)methylcarbamate
tert-Butyl [1 -(4-amino-3-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was 20 013027 164 reacted with 4-butoxy-2-nitrobenzoic acid by method E, followed byhydrogénation. This resulted in the product with the molecular weight of500.62 (C27H37FN4O4); MS (ESI): 501 (M+H+). 4-Butoxy-2-nitrobenzoic acid A solution of 4-fluoro-2-nitrobenzoic acid (1.81 g) in butanol (20 ml) wasmixed with sulfuric acid (3 ml) and stirred at 110°C for 4 hours. Ethylacetate (100 ml) was added, and the mixture was washed with saturatedsodium bicarbonate solution (3 χ 50 ml), dried with sodium sulfate, filteredand concentrated in vacuo. The residue (2.2 g) was added dropwise at-10°C to a sodium butoxylate solution prepared from butanol (20 ml) andsodium hydride (2.18 g) at -10°C under argon and then stirred for 20hours. Ethyl acetate (100 ml) was added, and the mixture was washed withwater (2 χ 50 ml), dried over sodium sulfate, filtered and concentrated invacuo. The residue was purified by préparative HPLC. The butyl 4-butoxy-2-nitrobenzoate was hydrolyzed with sodium hydoxide (5N; 100 ml) inéthanol at room température for 3 hours. The mixture was acidified withhydrochloric acid (10N; 100 ml) and extracted with dichloromethane, andthe organic phase was dried over sodium sulfate, filtered and concentrated.This resulted in the product with the molecular weight of 239.23(C11H13NO5); MS (ESI): 240 (M+H+).
Example 254 N-{4-[3-(7-Azabicyclo[2.2.1]hept-7-yl)-2-oxopyrrolidin-1-yl]phenyl}-4-cyclo hexyl-N-methy I benza mid e
Method L A mixture of N-[4-(3-bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide (100 mg), potassium carbonate (60 mg), 7-azabicyclo[2.2.1]heptane (44 mg) and DMF (2 ml) was kept at 50°C for 6hours. The mixture was diluted with water and extracted with ethyl acetate. 165
The organic phase was dried over magnésium sulfate and concentrated.The residue was purified by préparative HPLC. This resulted in the productwith the molecular weight of 471.65 (C30H37N3O2); MS (ESI): 472(M+H+). N-[4-(3-Bromo-2-oxo-pyrrolidin-1-yl)phenyl]-4-cyclohexyi-N- methylbenzamide N-(4-Aminophenyl)-4-cyclohexyl-N-methylbenzamide (3.0 g) in acetonitrile(30 ml) was mixed with trisodium phosphate (0.95 g) and, at 0°C, 2-bromo-4-chlorobutyryl bromide (2.9 g) was added. After one hour, a solution ofsodium hydroxide (0.85 g) in water (10 ml) was added and the mixture wasstirred vigorously at room température for 6 hours. The same amount ofsodium hydroxide solution was then added, and stirring was continued for48 hours. The reaction solution was diluted with water and extracted withethyl acetate. The organic phase was dried over magnésium sulfate andconcentrated. The residue was purified by chromatography on silica gel(mobile phase ethyl acetate/heptane 1:2). This resulted in the product withthe molecular weight of 455.40 (C24H27BrN2O2); MS (ESI): 456 (M+H+). N-(4-Aminophenyl)-4-cyclohexyI-N-methylbenzamide 4-Cyclohexylcarboxylic acid (5.0 g) and 4-nitrophenylisocyanate (4.0 g)were stirred in toluene (150 ml) for 3 hours and then left to stand overnight.The precipitate was filtered off with suction and washed with diethyl ether.The resulting amide was ethylated by method F and hydrogenated bymethod B. This resulted in the product with the molecular weight of 308.43(C20H24N2O); MS (ESI): 309 (M+H+).
Example 255 4-Cyclohexyl-N-methyl-N-[4-(3-morpholin-4-yl-2-oxopyrrolidin-1- yl)phenyl]benzamide
166 N-[4-(3-Bromo-2-oxo-pyrrolidin-1-yl)phenyl]-4-cyclohexyl-N- methylbenzamide was reacted with morpholine by method L. This resultedin the product with the molecularweight461.61 (C28H35N3O3); MS (ESI):462 (M+H+).
Example 256 4-Cyclohexyl-N-methyl-N-[4-(2-oxo-3-piperidin-1 -ylpy rrolidin-1 -yl)phenyl]benzamide 10 10 15 15 N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N- methylbenzamide was reacted with piperidine by method L. This resulted inthe product with the molecular weight of 459.64 (C29H37N3O2); MS (ESI):460 (M+H+).
Example 257 4-Cyclohexyl-N-methyl-N-[4-(2'-oxo[1,3']bipy rrol id inyl-1 yl)phenyl]benzamide
O
N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N- methylbenzamide was reacted with pyrrolidine by method L. This resultedin the product with the molecular weight of 445.61 (C28H35N3O2); MS(ESI): 446 (M+H+). 167
Example 258 4-Cyclohexyl-N-methyl-N-[4-(3-methylamino-2-oxopyrrolidin-1- yl)phenyl]benzamide
H
N \ N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with methylamine by method L. Thisresulted in the product with the molecular weight of 405.54 (C25H31N3O2); 10 MS (ESI): 406 (M+H+).
Example 259 4-Cyclohexyl-N-[4-(3-cyclohexylamino-2-oxopyrrolidin-1-yl)phenyl]-N-15 methylbenzamide N-[4-(3-Bromo-2-oxo-pyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with cyclohexylamine by method L. Thisresulted in the product with the molecular weight of 473.66 (C30H39N3O2); 20 MS (ESI): 474 (M+H+).
Example 260 4-Cyclohexyl-N-{4-[3-(cyclopropylmethylamino)-2-oxopyrrolidin-1- 013027 168 yl]phenyl}-N-methylbenzamide
N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyI]-4-cyclohexyl-N-methylbenzamide was reacted with cyclopropylmethylamine by method L. 5 This resulted in the product with the molecular weight of 445.61(C28H35N3O2); MS (ESI): 446 (M+H+).
Example 261 10 N-{4-[3-(Acetylmethylamino)-2-oxopyrrolidin-1 -yl]phenyl}-4-cyclohexyl-N-methyl-benzamide 4-Cyclohexyl-N-methyl-N-[4-(3-methylamino-2-oxopyrrolidin-1-yl)phenyl]benzamide (52 mg) was mixed with pyridine (0.5 ml) and acetic 15 anhydride (130 mg) and, after 3 hours, volatile fractions were removed invacuo. This resulted in the product with the molecular weight of 447.58(C27H33N3O3); MS (ESI): 448 (M+H+).
Example 262 20 4-Cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxopyrrolidin-1-yl)phenyl]benzamide 013027
tert-Butanol (8 ml), triethylamine (350 mg) and finally diphenylphosphorylazide (1.18 g) were added to 1 -{4-[(4- cyclohexylbenzoyl)methylamino]phenyl}-5-oxo-pyrrolidin-3-carboxylic acid(1.5 g), and the mixture was heated at 95°C for 48 hours. The reactionsolution was diluted with ethyl acetate and washed twice with water. Theorganic phase was dried over magnésium sulfate and concentrated. Thecrude product was reacted further by method G. This resulted in theproduct with the molecular weight of 405.54 (C25H31N3O2); MS (ESI): 406(M+H+). 1-{4-[(4-Cyclohexylbenzoyl)methylamino]phenyl}-5-oxo-pyrrolidine-3-carboxylic acid N-(4-Aminophenyl)-4-cyclohexyl-N-methylbenzamide (3.0 g) was heatedwith itaconic acid (1.27 g) at 100°C for 3 hours. Purification took place byfiltration through silica gel (mobile phase ethyl acetate/methanol 5:1). Thisresulted in the product with the molecular weight of 420.51 (C25H28N2O4);MS (ESI): 421 (M+H+).
Example 263 N-{4-[4-(AcetyImethylamino)-2-oxopyrrolidin-1-yl]phenyl}-4-cyclohexyl-N- methylbenzamide
4-Cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxo-pyrrolidin-1 -.yl)phenyl]benzamide (101 mg) was mixed with pyridine (20 mg) and acetic 170 013027 anhydride (25 mg) and, after 3 hours, volatile fractions were removed invacuo. This resulted in the product with the molecular weight of 447.58(C27H33N3O3); MS (ESI): 448 (M+H+).
Example 264 tert-Butyl (1-{5-[(4-cyclohexyIbenzoyl)propylamino]pyridin-2-yl}pyrrolidin-3-
tert-Butyl {1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yljmethylcarbamate (50 mg), césium carbonate (249 mg), potassium iodide(17 mg), N-methylpyrrolidone (1.5 ml) and propyl iodide (40 mg) werestirred at 60°C for 5 hours. If conversion was incomplète, the mixture washeated to 100°C and, after addition of further propyl iodide (40 mg), heatedat 140°C for 12 hours. The reaction mixture was diluted with ethyl acetate,washed with water and sodium bicarbonate solution, dried overChromabond XTR and concentrated. The residue was purified bypréparative HPLC. This resulted in the product with the molecular weight of520.72 (C31H44N4O3); MS (ESI): 521 (M+H+).
Example 265 tert-Butyl (1 -{5-[(4-cyclohexylbenzoyl)-(1 -ethylpropyl)amino]pyridin-2-yl)pyrrolidin-3-yl)-methylcarbamate 171
tert-Butyl {1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yljmethylcarbamate was reacted with 2-ethylbutyl bromide by method F-a.This resulted in the product with the molecular weight of 548.78 5 (C33H48N4O3); MS (ESI): 549 (M+H+).
Example 266 tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)-(3-methylbut-2-enyl)amino]pyridin-2
tert-Butyl {1 -[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylcarbamate was reacted with 3-methyl-2-butenyl bromide bymethod F-a. This resulted in the product with the molecular weight of 15 546.76-(C33H46N4O3); MS (ESI): 547 (M+H+).
Example 267 tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)methylamino]pyridin-2-yl}pyrrolidin-320 yl)methylcarbamate 013027 172
tert-Butyl {1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yljmethylcarbamate was reacted with methyl iodide by method F-a. Thisresulted in the product with the molecular weight of 492.67 (C29H40N4O3); 5 MS (ESI): 493 (M+H+).
The following further compounds were obtained by method F-a from tert-butyl {1 -[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylcarbamate and the appropriate alkylating agent: tert-Butyl (1-{5-[sec-butyl-(4-cyclohexylbenzoyl)amino]pyridin-2-10 yl}pyrrolidin-3-yl)methylcarbamate tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)isopropylamino]pyridin-2-yl}pyrrolidin- 3-yl)methylcarbamate tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)prop-2-inylamino]pyridin-2-yl}pynOlidin-3-yl)-methylcarbamate 15
Example 268 5-p-Tolylethinylfuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide 20
0.042 ml of diisopropylamine was added under argon to 3.8 mg ofPd(tBu)2Cl2 and 0.95 mg of Cul in 0.2 ml of DMF. A solution of 94.6 mg of 013027 173 5-bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide in 0.3 ml of DMF and a solution of 4-ethynyltoluene in 0.3 ml of DMFwere then added dropwise. The solution was stirred at room températureovernight. The precipitate which had separated out was filtered off with 5 suction and the filtrate purified by préparative HPLC. The desired productwith the molecular weight of 413.52; MS (ESI): 414 was obtained ashydrotrifluoroacetate. 5-Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-10 yl)phenyl]amide [1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with 5-bromo-2-furancarboxylic acid by method E. The product with a molecular weight of378.27 (C17H20BrN3O2); MS (ESI): 379 (M+H+) was obtained ashydrotrifluoroacetate. 15
Examples 269-273 were prepared analogously:
Ex. No. Structure Molecular formula Molecular weight M+H+ 269 ° C26H27N3O3 429.21 430 270 ° Uï> C25H23F2N3O2 435.18 436 271 / o < C26H27N3O3 429.21 430 174 013027 272 F 0 uï>' C25H24FN3O2 417.19 418 273 C25H24CIN3O2 433.16 434
Example 274 (R)-4’-Fluorobiphenyl-4-carboxylic acid [6-(3-dimethylaminopyrrolidin-1-
Method M (R)-4'-Fluorobiphenyl-4-carboxylic acid [6-(3-methylaminopyrrolidin-1-yl)pyridin-3-yl]-amide (390 mg) dissolved in formic acid (230 mg) was 10 mixed with formaldéhyde solution (37% aq.; 0.4 ml) and the mixture washeated at 80°C for 3 hours. The cooled reaction solution was concentratedand partitioned between ethyl acetate and a saturated sodium carbonatesolution. The organic phase was dried over magnésium sulfate andconcentrated. The crude product was purified by préparative HPLC. This 15 resulted in the product with the molecular weight of 404.49 (C24H25FN4O);MS (ESI): 405 (M+H+).
Example 275 1-(4-Fluorophenyl)piperidine-4-carboxylic acid {4-[3- 20 (acetylmethylamino)pyrrolidin-l -yl]phenyl}amide 013027 175
Ν Ο
Method E-a A mixture of 0.048 g of 1-(4-fluorophenyl)piperidine-4-carboxylic acid and0.5 ml of SOCI2 and one drop of DMF were stirred at room température for2 hours. The excess SOCI2 was then removed in vacuo. The residue wasdissolved in 0.4 ml of DMF, and 0.033 ml of triethylamine and 0.048 g of N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide were added. Thesolution was stirred at room température overnight. The solution was thenfiltered and purified by préparative HPLC. This resulted in the product withthe molecular weight of 438.20 (C25H31FN4O2); MS (ESI): 439 (M+H+) ashydrotrifluoroacetate. 1 -(4-Fluorophenyl)piperidine-4-carboxylic acid 0.875 g of 4-bromofluorobenzene, 0.016 g of Pd(dba)3*CHCI3, 0.022 g2-(dicyclohexylphosphino)biphenyl and 2.28 g of césium carbonate wereput in a heat-dried and argon-flushed flask, and 0.943 g of ethyl 4-piperidinecarboxylate in 5 ml of degassed toluene was added. The solutionwas heated at 100°C overnight. The mixture was cooled and thenconcentrated in vacuo. The residue was taken up in ethyl acetate/water.The organic phase was washed with 10% NaHCO3 solution, dried oversodium sulfate and concentrated in vacuo. The residue was purified bypréparative HPLC. 4.4 ml of a 2N potassium hydroxide solution were added to a solution of 1.1g of ethyl 1-(4-fluorophenyl)piperidine-4-carboxylate in 100 ml of methanol.The mixture was stirred at room température overnight. The pH was thenadjusted to 6 with 5% hydrochloric acid, and the solution was concentrated 176 in vacuo. The residue was purified by préparative HPLC.
Example 276 5 4-Phenoxycyclohexanecarboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide
O
0.251 g of PyBOP and 0.135 ml of triethylamine were added to a solution of0.106 g of 4-phenoxycyclohexanecarboxylic acid and 0.113 g of N-[1-(4- 10 aminophenyl)pyrrolidin-3-yl]-N-methylacetamide in 9 ml of DMF at 0°C.After 10 minutes, the solution was allowed to reach room température andwas stirred at this température ovemight. The solvent was then removed invacuo, and the residue was taken up in water/ethyl acetate. The ethylacetate phase was washed with 10% citric acid and 10% NaHCO3 solution 15 and dried over sodium sulfate, and the solvent was removed in vacuo. Theresidue was purified by préparative HPLC. The desired product wasobtained. Molecular weight 435.25 (C26H33N3O3), MS: 436 (M+H+). 4-Phenoxycyclohexanecarboxylic acid 20 0.63 g of p-toluenesulfonyl chloride was added to a solution of 0.522 g of
ethyl 4-hydroxycyclohexanecarboxylate in 5.0 ml of pyridine. The reactionwas stirred at room température for 3 hours. The reaction mixture wasconcentrated in vacuo. The resulting solid was taken up in water and ethylacetate, and the organic phase was washed three times with 2N 25 hydrochloric acid and once with saturated NaCI solution. The organicphase was dried over sodium sulfate and concentrated in vacuo. Theresulting product was employed without further purification in the next step.The resulting product (0.55 g) was dissolved in 11.2 ml of DMF, and 0.159g of phénol and 0.549 g of césium carbonate were added. The solution was 013027 177 then heated at 80°C for 6 hours. After cooling, the mixture wasconcentrated in vacuo and purified by column chromatography on silica gel(eluent: ethyl acetate Zn-heptane 1:1). The desired product was obtained.Molecular weight 248.32 (015H20O3), MS: 249 (M+H+). 0.06 ml of 2N potassium hydroxide solution was added to a solution of 0.12g of ethyl 4-phenoxycyclohexanecarboxylate in 8 ml of water/THF (1:1).
The solution was heated at 60°C for 3 hours. Ethyl acetate and 10% citricacid were added to the mixture. The aqueous phase was extracted threetimes with ethyl acetate, dried over sodium sulfate and concentrated invacuo. The resulting compound was employed without further purification inthe next stage.
Example 277 N-[4-(3-Cyclohexylaminopyrrolidin-1-yl)phenyl]-4-isobutoxybenzamide
Method N (4-lsobutoxy-N-[4-(3-oxopyrrolidin-1-yl)phenyl]benzamide (50 mg) inmethanol (2 ml) was mixed with aminocyclohexane (28 mg) and glacialacetic acid (10 mg), and a solution of sodium cyanoborohydride (1M intoluene; 0.17 ml) was added. After 8 hours, the reaction solution wasconcentrated and partitioned between ethyl acetate and water. The organicphase was dried over magnésium sulfate and concentrated. The crudeproduct was purified by préparative HPLC. This resulted in the product withthe molecular weight of 435.61 (C27H37N3O2); MS (ESI): 436 (M+H+). 4-lsobutoxy-N-[4-(3-oxopyrrolidin-1-yl)phenyl]benzamide 4-lsobutoxybenzoic acid was reacted with 4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)phenylamine by method E-a. The resulting amide (0.25 g) in acetone(10 ml) was mixed with para-toluene sulfonic acid (monohydrate, 109 mg),and the mixture was boiled under reflux for 8 hours. After addingtriethylamine (0.5 ml), the mixture was diluted with water and extracted withethyl acetate. The organic phase was dried over magnésium sulfate andconcentrated. This resulted in the product with the molecular weight of 013027 178 352.44 (C21H24N2O3); MS (ESI): 353 (M+H+). 4-Butoxy-N-[4-(3-oxopyrrolidin-1-yl)-phenyl]benzamide was obtained using4-butoxybenzoic acid in an analogous way. Likewise, 4-butoxybenzoic acidand 4-(1,4-dioxa-7-azaspiroÎ4.4]non-7-yl)-3-fluorophenylamine initiallyresulted in 4-butoxy-N-[4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenyi]benzamide which, after méthylation by method F andtreatment with para-toluenesulfonic acid as described àbove, afforded4-butoxy-N-[3-fluoro-4-(3-oxopyrrolidin-1-yl)phenyl]benzamide. 4-(1,4-Dioxa-7-azaspiro[4.4]non-7-yl)phenylamine
Trimethylchlorosilane (9.3 g) was slowly added to a solution of 1-benzyl-3-pyrrolidinone (5.0 g) in dichloromethane (30 ml) and ethylene glycol (2.67g). After 18 hours, the mixture was poured into sodium hydroxide solution(1N). The organic phase was separated off, dried over magnésium sulfateand concentrated. The residue was dissolved in methanol (30 ml) andammonium formate (5.2 g) and palladium hydroxide (10% on carbon, 300mg) were added. The mixture was boiled under reflux for 8 hours, filteredand concentrated. The residue was reacted with 4-fluoronitrobenzene bymethod C. Hydrogénation was finally carried out by method B. Thisresulted in the product with the molecular weight of 220.27 (C12H16N2O2); MS (ESI): 221 (M+H+). 4-(1,4-Dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenylamine was obtainedanalogously using 3,4-difluoronitrobenzene.
Example 278 (R)-4-(4-Chlorophenyl)piperidin-1-carboxylic acid {4-[3-(methylpyrimidin-2-yl-amino)pyrrolidin-1-yl]-phenyl}amide
(R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid [4-(3- methylaminopyrrolidin-1-yl)phenyl]amide (100 mg) was reacted withpotassium carbonate (100 mg) and 2-bromopyrimidine (50 mg) ίπ N-methylpyrrolidone (3 ml) at 100°C for 4 hours. The reaction solution wasthen partitioned between ethyl acetate and water. The organic phase wasdried over magnésium sulfate and concentrated. The crude product was 013027 179 purified by préparative HPLC. This resulted in the product with themolecular weight of 491.04 (C27H31CIN6O); MS (ESI): 491 (M+H+).
Example 279 tert-Butyl [1-(4-{[5-(2-fluorophenyl)furan-2-carbonyl]amino}phenyl)pyrrolidin-3-yl]rnethylcarbamate
Method O
Tetrakis(triphenylphosphine)pailadium(0) (20 mg) was added to a solutionof tert-butyl (1 -{4-[(5-bromofuran-2-carbonyl)amino]phenyl}pyrrolidin-3-yl)methylcarbamate (252 mg) in degassed touene (4 ml) under argon in a10 ml two-necked flask and stirred at room température for 10 minutes.Then a solution of 2-fluorobenzeneboronic acid (73 mg in 1 ml of éthanol)and 0.35 ml of 2M sodium carbonate solution were added, and the mixturewas stirred at 100°C for 24 hours.
Then water (5 ml) and ethyl acetate (5 ml) were added to the reactionmixture, the organic phase was separated off, and the aqueous phase wasextracted 2 χ with ethyl acetate (10 ml). The combined organic phaseswere concentrated and the residue was purified by préparative HPLC. Thedesired product with the molecular weight of 479.56 (C27H30FN3O4); MS(ESI): 480 (M+H+) was obtained as hydrotrifluoroacetate. It is alternativelypossible to use césium carbonate as base and to heat the reaction at150°C in a microwave apparatus for 3 minutes. tert-Butyl (1-{4-[(5-bromofuran-2-carbonyl)amino]phenyl}pyrrolidin-3-yl)methylcarbamate 5-Bromofuran-2-carboxylic acid was reacted with tert-butyl [1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate by method E. This resulted in 013027 180
the product with the molecular weight of 464.36 (C21 H26BrN3O4); MS (ESI): 464 (M+H+).
The following compounds were prepared analogously: 5-Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-5 yl)phenyl]amide tert-Butyl (1-{4-[(5-bromothiophene-2-carbonyl)amino]phenyl}pyrrolidin-3-yl)methylcarbamate 2-Bromothiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]amide 10 4-lodo-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl3benzamide (R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-iodobenzamide 4-Bromo-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-3-fluorobenzamide 15 Example 280 (3R)-3'-Cyanobiphenyl-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]amide
F
N
Method O-b 20 0.002 mg of Pd(PPh3)4 were added to a solution of 0.022 g of (R)-N-[4-(3-
dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-iodobenzamide in 0.45 mlof degassed DMF and stirred at room température for 10 minutes. 0.035 mlof water, 0.021 g of K3PO4 and 0.008 g of 3-cyanophenylboronic acid werethen added to the solution. The reaction solution was heated at 80°C 25 overnight. The solution was then filtered and purified by préparative HPLC.This resulted in the product with the molecular weight of 428.20 013027 181 (C26H25FIN4O); MS (ESI): 429 (M+H+) as hydrotrifluoroacetate.
Example 281 5 3,2',4'-Trifluorobiphenyl-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide
1-Bromo-2,4-difluorobenzene was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic acid benzamide by 10 method O-b. This resulted in the product with the molecular weight of439.19 (C25H24F3N3O); MS (ESI): 440 (M+H+) as hydrotrifluoroacetate. N-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]-2-fluoro-4-boronic acidbenzamide 15 4-Carboxy-3-fluorophenylboronic acid was reacted with [1-(4- aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted inthe product with the molecular weight of 371.18 (C19H23BFN3O3); MS(ESI): 372 (M+H+) as hydrotrifluoroacetate.
Example 282 5-(2,4-Difluorophenyl)thiophen-2-carboxylic acid [4-(3- dimethylaminopyrrolidin-1-yl)-phenyl]amide
25 1-Bromo-2,4-difluorobenzene was reacted with 2-boronic acid thiophen-5- 013027 182 carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide by methodO-b. This resulted in the product with molecular weight of 427.52(C23H23F2N3OS); MS (ESI): 428 (M+H+) as hydrotrifluoroacetate. 2-Boronic acid thiophene-5-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide 5-Carboxy-2-thiopheneboronic acid was reacted with [1-(4-aminophenyl)pyrroIidin-3-yl]-dimethylamine by method E-b. This resulted inthe product with the molecular weight of 359.15 (C17H22BN3O3S); MS(ESI): 360 (M+H+) as hydrotrifluoroacetate.
Example 283 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-6-(4- fluorophenyl)nicotinamide
methanesulfonate was reacted with 4-fluorobenzeneboronic acid under theconditions of method O-b. (Heating at 140°C in a microwave apparatus for15 minutes). This resulted in the product with the molecular weight of404.20 (C24H25FN4O); MS (ESI): 405 (M+H+) as hydrotrifluoroacetate. 5-[4-(3-Dimethylaminopyrrolidin-1-yl)phenylcarbamoyl]pyridin-2-yl[trifluoro methanesulfonate A suspension of 0.0.5 g of N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-6-hydroxynicotinamide in 0.4 ml of DME was added to a solution of 0.084 mlof LDA solution (2M) in 0.4 ml of DME at 0°C. The mixture was stirred at0°C for 2 hours. A solution of 0.055 g of N-phenyltrifluoromethanesulfonimide in 0.2 ml of DME was then added to themixture. The reaction solution was allowed to reach room température and 183 was heated at 80°C for 3 hours. After cooling, the solution wasconcentrated in vacuo. The residue was taken up in ethyl acetate/water,and the aqueous phase was extracted three times with ethyl acetate. Thecombined organic phases were dried over sodium sulfate, concentrated in 5 vacuo and purified by préparative HPLC. N-[4-(3-Dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide 6-Hydroxynicotinic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the 10 molecular weight of 326.17 (C18H22N4O2); MS (ESI): 327 (M+H+) ashydrotrifluoroacetate.
Example 284 15 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-6-(2,4-difluorophenyl)nicotinamide
2,4-Difluorophenylboronic acid was reacted with 5-[4-(3-20 dimethylaminopyrrolidin-1-yl)-phenylcarbamoyl]pyridin-2-yl [trifluoromethanesulfonate by method O-b. This resulted in the product withthe molecular weight of 422.00 (C24H24F2N4O); MS (ESI): 423 (M+H+) ashydrotrifluoroacetate.
Example 285 2,,4'-Difluorobiphenyl-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide 013027 184
2',4'-Difluorobiphenyl-4-carboxylic acid was reacted with [1-(4-aminophenyl)pyirolidin-3-yl]dimethylamine by method E-a. This resulted inthe product with the molecular weight of 421.20 (C25H25F2N3O); MS(ESI): 422 (M+H+) as hydrotrifluoroacetate. 2',4'-Difluorobiphenyl-4-carboxylic acid
Method P 0.098 ml of 1 N lithium hydroxide solution was added to a solution of 0.051g of ethyl 2,,4'-difluorobiphenyl-4-carboxylate in 1 ml THF/water (1:1), andthe mixture was stirred at room température ovemight. 5% hydrochloricacid was used to neutralize the solution, which was concentrated in vacuo,and the residue was purified by préparative HPLC.
Ethyl 2,,4'-difluorobiphenyl-4-carboxylate 0.009 g of Pd(PPh3)4 was added to a solution of 0.091 g of ethyl4-iodobenzoate in 0.96 ml of degassed toluene and stirred at roomtempérature for 10 minutes. Then a solution of 0.047 g of 2,4-difiuorophenylboronic acid in 0.114 ml of éthanol and 0.201 ml of a 2NNa2CO3 solution was added to the reaction solution. The solution washeated at 100°C ovemight. The reaction mixture was then concentrated invacuo, and water/ethyl acetate were added to the residue. The aqueousphase was extracted three times with ethyl acetate and dried over sodiumsulfate, and the solvent was removed in vacuo and purified by préparativeHPLC. 013027 185
Example 286 2',4,-Difluorobiphenyl-4-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}-amide 5 Method E-b 0.095 g of HATU, 0.068 g of HOBT and 0.035 ml of triethylamine wereadded to a solution of 0.047 g of 2',4'-difluorobiphenyl-4-carboxylic acid and0.058 g of N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide in 2 mlof DMF at 0°C. After 10 minutes, the solution was allowed to reach room 10 température and was stirred at this température ovemight. The solvent wasthen removed in vacuo, and the residue was taken up in water/ethylacetate. The ethyl acetate phase was washed with 10% NaHCO3 solutionand water. The ethyl acetate phase was dried over sodium sulfate, and thesolvent was removed in vacuo. The residue was purified by préparative 15 HPLC. The desired product was obtained. Molecular weight 449.19(C26H25F2N3O2), MS: 450 (M+H+).
Example 287 20 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-3-fluoro-4-(4-methylpiperidin-1-yl)-benzamide 013027 186
N- 3-Fluoro-4-(4-methylpiperidin-1-yl)benzoic acid was reacted with [1-(4-aminophenyl)-pyrrolidin-3-yl]dimethylamine by method E-a. This resulted inthe product with the molecular weight of 424.00 (C25H33FN4O); MS (ESI): 5 425 (M+H+) as hydrotrifluoroacetate. 3-Fluoro-4-(4-methylpiperidin-1 -yl)benzoic acid
Methyl 3-fluoro-4-(4-methylpiperidin-1-yl)benzoate was treated with lithiumhydroxide by method P. This resulted in the product with the molecular 10 weight of 237.28 (C13H16FNO2); MS (ESI): 238 (M+H+).
Methyl 3-fluoro-4-(4-methylpiperidin-1-yl)benzoate 0.076 g of potassium carbonate was added to a solution of 0.086 g ofmethyl 3,4-difluorobenzoate and 0.050 g of 4-methylpiperidine in 0.5 ml of 15 DMF. The reaction was heated at 60°C for 2 days, filtered and purified bypréparative HPLC. This resulted in the product with the molecular weight of251.3 (C14H18FNO2); MS (ESI): 252 (M+H+) as hydrotrifluoroacetate. 20 Example 288 4-Butoxy-N-(4-{3-[(2-dimethylaminoacetyl)methylamino]pyrrolidin-1- yl}phenyl)-N-methylbenzamide 187
/
N \ 4-Butoxy-N-methyl-N-[4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamidewas reacted with Ν,Ν-dimethylglycine by method E. This resulted in theproduct with the molecular weight of 466.63 (C27H38N4O3); MS (ESI): 467 5 (M+H+). (R)-4-Butoxy-N-(4-{3-[(2-dimethylaminoacetyl)methylamino]pyrrolidin-1-yl}phenyl)-N-methylbenzamide was obtained analogously. 10 Example 289 N-{4-[3-(Acetylmethylamino)pyrrolidin-1 -yl]phenyl}-4-butoxy-N-methylbenzamide 4-Butoxy-N-methyl-N-[4-(3-methylaminopyrrolidin-1-yI)phenyl]benzamide15 was mixed with pyridine and acetic anhydride. Volatile fractions were removed after 2 hours. This resulted in the product with the molecularweight of 423.56 (C25H33N3O3); MS (ESI): 424 (M+H+). 20 Example 290 4-Butyrylamino-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]benzamide 188
Method Q 4-Amino-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]benzamide (32 mg) indichloromethane (2 ml) was mixed with potassium carbonate (50 mg) andbutyryl chloride (11 mg). The mixture was filtered and concentrated after 12hours. The residue was purified by préparative HPLC. This resulted in theproduct with the molecular weight of 394.52 (C23H30N4O3); MS (ESI): 395(M+H+).
An alternative possibility is to react 4-amino-N-[4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]benzamide with butyric acid bymethod E. 4-Amino-N-[4-(3-dimethylaminopyriOlidin-1-yl)phenyl]benzamide 4-tert-Butoxycarbonylaminobenzoic acid was reacted with 1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E, and the productwas treated by method G. This resulted in the product with the molecularweight of 324.43 (C19H24N4O); MS (ESI): 325 (M+H+).
Example 291 2-Phenylethynylthiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]-amide 2-Bromothiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (100 mg) was dissolved in tetrahydrofuran (2 ml), andphenylacetylene (52 mg), triethylamine (52 mg), triphenylphosphine (17mg), bis(triphenylphosphine)palladium dichloride (89 mg) and copper (I)iodide (9.6 mg) were added. The reaction mixture was heated at 150°C in amicrowave apparatus for 3 minutes and then concentrated. The residuewas purified by préparative HPLC. This resulted in the product with the 013027 189 molecular weight of416.55 (C24H24N4OS); MS (ESI): 417 (M+H+).
Example 292 5-(4-Fluorophenyl)pyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]-amide
Method O-a 5-Chloropyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (100 mg) dissolved in toluene was mixed with 4-fluorophenylboronic acid (81 mg), POPD (15 mg) and césium carbonate(2M aq.; 0.5 ml). The réaction was heated at 150°C in a microwaveapparatus for 10 minutes and then concentrated. The residue was purifiedby préparative HPLC. This resulted in the product with the molecular weightof 404.49 (C24H25FN4O); MS (ESI): 405 (M+H+). 5-Chloropyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]amide [1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with 5-chloropyridine-2-carboxylic acid by method E. This resulted in the productwith the molecular weight of 344.85 (C18H21CIN4O); MS (ESI): 345(M+H+).
Example 293 5-(4-Fluorophenyl)pyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]-amide 013027 190
5-Chloropyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 4-methylphenylboronic acid by methodO-a. This resulted in the product with the molecular weight of 400.53 5 (C25H28N4O); MS (ESI): 401 (M+H+).
Example 294 1-Benzenesulfonylpiperidine-4-carboxylic acid [4-(3-10 dimethylaminopyrroiidin-1-yl)-phenyl]amide
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyi]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixedwith potassium carbonate (45 mg) and benzenesulfonyl chloride (35 mg). 15 After 12 hours, the mixture was filtered and the filtrate was purified by préparative HPLC. This resulted in the product with the molecular weight of456.61 (C24H32N4O3S); MS (ESI): 457 (M+H+). 20 Example 295 1-(4-Fluorobenzenesulfonyl)piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]amide 191 013027
Piperidine-4-carboxylic acid [4-(3-dimethyIaminopyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixedwith potassium carbonate (45 mg) and 4-fluorobenzenesulfonyl chloride (40 5 mg). After 12 hours, the mixture was filtered and the filtrate was purified bypréparative HPLC. This resulted in the product with the molecular weight of474.60 (C24H31FN4O3S); MS (ESI): 475 (M+H+).
Example 296 10 1-(Butane-1-sulfonyl)piperidine-4-carboxylic acid [4-(3- dimethylaminopyrrolidin-1 -yl)-phenyl]amide
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed 15 with potassium carbonate (45 mg) and butylsulfonyl chloride (30 mg). After12 hours, the mixture was filtered and the filtrate was purified bypréparative HPLC. This resulted in the product with the molecular weight of436.62 (C22H36N4O3S); MS (ESI): 437 (M+H+).
Example 297 5-(4-Butoxyphenylethynyl)furan-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]amide 20 013027 192
— Ο
Method J-a 5-Bromofuran-2-carboxyIic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]amide (75 mg) was dissolved together with 1-butoxy-4-ethynylbenzene (35 mg) in N,N-dimethy|formamide (1 ml) and, underargon, added dropwise to a suspension of Pd(tBu3P)2Cl2 (4 mg), copper(I) iodide (75 mg) and N,N-düsopropylamine (20 mg) in anhydroustetrahydrofuran (3 ml). The mixture was stirred at room température for8 hours. The reaction was worked up by filtration through a syringe filterand concentrated, and the crude product was purified by préparativeHPLC. This resulted in the product with the molecular weight of 471.6(C29H33N3O3); MS (ESI): 472 (M+H+) as hydrotrifluoroacetate.
Example 298 6-Butoxy-N-[4-(3~dimethylaminopyrrolidin-1-yl)phenyl]nicotinamide
O
Method H-a A solution of 0.1 g of potassium hydroxide in 1 ml of DMSO was stirred atroom température for 10 minutes and then 0.1 g of N-[4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide was added.The reaction solution was stirred for 10 minutes and then 0.084 g of 1-bromobutane was added. The mixture was stirred at room températureovemight. After addition of water and ethyl acetate, the aqueous phase wasextracted three times with ethyl acetate. The combined organic phaseswere dried over sodium sulfate, concentrated in vacuo and purified by 013027 193 préparative HPLC. This resulted in the product with the molecular weight of382.24 (C22H30N4O2); MS (ESI): 383 (M+H+) as hydrotrifluoroacetate. 5 Example 299 6-Cyclopropylmethoxy-N-[4-(3-dimethylaminopyrrolidin-1- yl)phenyl]nicotinamide
(Bromomethyl)cyclopropane was reacted with N-[4-(3-10 dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide by method H-a. This resulted in the product with the molecular weight of 380.22 (C22H28N4O2); MS (ESI): 381 (M+H+) as hydrotrifluoroacetate. 15 Example 300 N-[4-(3-DimethylaminopyrroIidin-1-yl)phenyl]-6-isobutoxynicotinamide
dimethylaminopyrroIidin-1-yI)-phenyl]-6-hydroxynicotinamide by method H-20 a. This resulted in the product with the molecular weight of 382.24 (C22H30N4O2); MS (ESI): 383 (M+H+) as hydrotrifluoroacetate.
Example 301 25 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-6-(4- 013027 194
49 mg of potassium carbonate were added to a solution of 0.041 g of 6-chloro-N-[4-(3-dimethylaminopyrrolidin-î-yl)phenyI]nicotinamide and 4- 5 fluorophenol (30 mg) in 0.8 ml of DMF, and the reaction was heated at140°C in a microwave apparatus for 90 minutes. After addition of water andethyl acetate, the aqueous phase was extracted three times with ethylacetate. The combined organic phases were dried over sodium sulfate,concentrated in vacuo and purified by préparative HPLC. This resulted in 10 the product with the molecular weight of 420.2 (C24H25FN4O2); MS (ESI):421 (M+H+) as hydrotrifluoroacetate. 6-Chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]nicotinamide 6-Chloronicotinic acid was reacted with [1-(4-amino-phenyl)pyrrolidin-3- 15 yl]dimethylamine by method E-b. This resulted in the product with themolecular weight of 344.14 (C18H21CIN4O); MS (ESI): 345 (M+H+) ashydrotrifluoroacetate. 20 The following examples were prepared analogously.
Ex. No. Structure Molecular formula Mole- cular weight M+H+ 302 O C24H26N4O2 402.21 403 303 O C24H25CIN4O2 436.17 437 013027 195 304 0 C25H28N4O2 416.22 417
Example 305 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-phenoxybenzamide
Powdered molecular sieves (4 A), 0.01 g of copper acetate and 0.02 g ofN-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic acid benzamide were added to a solution of 0.008 g of phénol in 0.5 ml ofmethylene chloride and stirred at 40°C for 24 hours. The solvent was thenremoved in vacuo, the residue was taken up in water/ethyl acetate, and theaqueous phase was extracted three times with ethyl acetate. The combinedorganic phases were dried over sodium sulfate, concentrated in vacuo andpurified by préparative HPLC. This resulted in the product with themolecular weight of 419.2 (C25H26FN3O2); MS (ESI): 420 (M+H+) ashydrotrifluoroacetate. N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic acid benzamide 4-Carboxy-3-fluorophenyIboronic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted inthe product with the molecular weight of 371.18 (C19H23BFN3O3); MS(ESI): 372 (M+H+) as hydrotrifluoroacetate.
Example 306 196 4-(3-Cyanophenyl)-3,6-dihydiO-2H-pyridine-1-carboxylicdimethylaminopyrrolidin-1 -yl)phenyl]amide 013027 acid [4-(3-
4-(4,4)5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopynOlidin-1-yl)phenyl]amide wasreacted with 3-bromobenzonitriIe by method O-a. This resulted in theproduct with the molecular weight of 415.54 (G25H29N5O); MS (ESI): 416(M+H+) 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinewas reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine bymethod A. This resulted in the product with the molecular weight of 440.40(C24H37BN4O3); MS (ESI): 441 (M+H+)
Example 307 4-(2-Cyanophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]amide
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide wasreacted with 2-bromobenzonitrile by method O-a. This resulted in theproduct with the molecular weight of 415.54 (C25H29N5O); MS (ESI): 416(M+H+) 013027 197
Example 308 4-(3-Methylsulfanylphenyl)-3,6-d ihyd ro-2H-pyridi ne-1 -carboxylic acid [4-(3-dimethylaminopyrroirdin-1-yl)phenyl]amide
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide wasreacted with 3-bromothioanisole by method O-a. This resulted in theproduct with the molecular weight of 436.62 (C25H32N4OS); MS (ESI):437 (M+H+)
Example 309 4-(5-Chloropyridin-2-yloxy)-N-[4-(3-dimethylaminopyrrolidin-1- yl)phenyl]benzamide
Cl
0.143 g of potassium carbonate was added to a solution of 0.19 g of 4-[4-(3-dimethylaminopyrrolidin-1-yl)phenylcarbamoyl]phenyl acetate in 2 ml ofDMF, and the solution was heated at 130°C in a microwave apparatus for15 minutes. The solution was then mixed with water and ethyl acetate, theaqueous phase was freeze-dried, and the residue was employed withoutfurther purification in the next stage.
Method R A solution of 0.05 g of N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-4-hydroxybenzamide, 0.017 g of 2,5-dichloropyridine and 0.064 g of 013027 198 potassium carbonate in 0.8 ml of DMF was heated at 230°C in a microwaveapparatus for 30 minutes. The solution was filtered and purified bypréparative HPLC. This resulted in the product with the molecular weight of436.17 (C24H25CIN4O2); MS (ESI): 437 (M+H+) as hydrotrifluoroacetate. 4-[4-(3-Dimethylaminopyrrolidin-1-yl)phenylcarbamoyl]phenyl acetate 4-Acetoxybenzoic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yljdimethylamine by method E-b. This resulted in the product with themolecular weight of 367.19 (C21H25N3O3); MS (ESI): 368 (M+H+) ashydrotrifluoroacetate.
Example 310 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-4-(5-fiuoropyridin-2- yloxy)benzamide
2-Chloro-5-fluoropyridine was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-4-hydroxybenzamide by method R. This resulted in the productwith the molecular weight of 420.2 (C24H25FN4O2); MS (ESI): 421(M+H+) as hydrotrifluoroacetate.
Example 311 4-(6-Chloropyridin-3-yloxy)-N-[4-(3-dimethylaminopyrrolidin-1- yl)phenyl]benzamide
was obtained as by-product of the reaction in example 310. This resulted in 013027 199 the product with the molecular weight of 436.95 (C24H25CIN4O2); MS(ESI): 437 (M+H+) as hydrotrifluoroacetate.
Example 312 5-Chloro<3\6'<iihydro-2'l-|-[2,4']bipyridinyl-1 '-carboxylic acid [4-(3- dimethylamino- pyrrol id in-1 -yl)phenyl]amide
[1-(4-Aminopheny!)pyrTOlidin-3-yl]dirnethyIamine (32 mg) andcarbonyldiimidazole (27.1 mg) were dissolved in acetonitrile (1.5 ml), andthe mixture was stirred for 3 hours. Triethylamine (63.4 μΙ) was added to asolution of δ-οήΙοΓΟ-Γ^'^',δ'- tetrahydro~[2,4']bipyridine (40.7 mg) in THF(1 ml) and chloroform (0.5 ml). After 15 minutes, the mixture was addeddropwise to the first solution and stirred overnight. The mixture wasconcentrated and the residue was partitioned between dichloromethaneand water. The organic phase was dried over sodium sulfate, filtered andconcentrated. Contamination by the primary and/or secondary amine wasremoved by dissolving the residue in dichloromethane (1.5 ml) and addingthe solution to a stirred suspension of polymer-bound p-toluenesulfonylchloride (0.5 g) in dichloromethane (6 ml) and triethylamine (128 pl). After 3hours, the resin was filtered Off and washed several times withdichloromethane. The combined organic phases were concentrated. Theresidue was purified by chromatography (silica gel, mobile phase: ethylacetate/dichloromethane (5%), ammonia (7N in methanol, 2%), later ethylacetate/dichloromethane (5%), ammonia (7N in methanol, 3%). Thisresulted in the product with the molecular weight of 425.97(C23H28CIN5O); MS (ESI): 426 (M+H+). 5-Chloro-r,2',3',6'-tetrahydro-[2,4']bipyridine A solution of tert-butyl 5-chloro-3',6'-dihydro-2'H-[2,4']bipyridine-1'-carboxylate (50 mg) in chloroform (2.4 ml) was mixed with hydrogenchloride (4N in dioxane; 0.8 ml) and the mixture was concentrated after 13 013027 200 hours. This resulted in the product with the molecular weight of 194.67(C10H11CIN2); MS (ESI): 195 (M+H+). tert-Butyl S-chloro-S'.e'-dihydro^'H-^^'Jbipyridine-l '-carbamateA solution of 2-bromo-5-chloropyridine (131 mg) in DMF (degassed withnitrogen; 4.5 ml) was added to a mixture of tert-butyl 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-carbamate(Eastwood, Paul R., Tetrahedron Lett, 41, 19, 2000, 3705-3708; 200 mg),potassium carbonate (0.265 g) and Pd(dppf)Cl2 (50 mg). The mixture was heated at 80°C for 8 hours. After cooling, the mixture was diluted withdichloromethane and washed with sodium carbonate solution and water.The organic phase was dried over sodium sulfate, filtered andconcentrated. The residue was purified by chromatography (silica gel,mobile phase: heptane/ethyl acetate (2%)/dichloromethane (5%), laterheptane/ethyl acetate (5%)/dichloromethane (5%).
Example 313 5-(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)- phenyljamide 5-(2-Nitro-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)- phenyljamide was hydrogenated by method B. Thisresulted in the product with the molecular weight of 404.22 (C24H28N4O2);MS (ESI): 405 (M+H+).
Example 314 5-(2-Acetylamino-4-methyIphenyl)furan-2-carboxylic acid [4-(3-dimethylaminopyrrolidin- 1-yl)phenyljamide 013027 201 Ο
Ο 5-(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidïn-1 -yl)- phenyl]amide was reacted with acetyl chloride by methodQ. This resulted in the product with the molecular weight of 446.23 5 (C26H30N4O3); MS (ESI): 447 (M+H+).
Example 315 5-(2-lsobutyrylamino-4-methy!phenyl)furan-2-carboxylic acid [4-(3-10 dimethylamino- pyrrolidin-1-yl)phenyl]amide
O
O 5-(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)- phenyljamide was reacted with isobutyryl chloride bymethod Q. This resulted in the product with the molecular weight of 474.26 15 (C28H34N4O3); MS (ESI): 475 (M+H+).
Example 316 5'-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid [4-(3-20 dimethylamino- pyrrolidin-1-yl)phenyl]methylamide .0
Cl
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenylj-methylamide (44.4 mg) and 2,5-dichloropyridine (60 mg) were heated at160°C for 15 minutes. o-Xylene (0.5 ml) was added and heating at 160°C 013027 202 was continuée! for 2 hours. The cooled crude mixture was purified bychromatography (silica gel, eluent: ethyl acetate/ammonia (7N inmethanol)). This resulted in the product with the molecular weight of 442.01(C24H32CIN5O); MS (ESI): 442 (M+H+).
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1- yl)phenyl]methylamide tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]methylcarbamoyl}-piperidine-1-carboxylate was treated with trifluoroacetic acid by method G.This resulted in the product with the molecular weight of 330.48(C19H30N4O); MS (ESI): 331 (M+H+).
Piperidine-4-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1 -yl)phenyl]-amide can be prepared analogously. tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]methylcarbamoyl}-piperidine-1 -carboxylate A solution of N-Boc-piperidine-4-carboxylic acid (550 mg) and pyridine(0.47 ml) in dichloromethane (15 ml) was mixed with thinoyl chloride (0.21ml) and, after 30 minutes, a solution of dimethyl[1-(4-methylaminophenyl)pyrrolidin-3-yl]amine (0.5 g), triethylamine (1.17 ml),DMAP (0.44 g) and dichloromethane (10 ml) was added dropwise. After 16hours, the mixture was diluted with dichloromethane, washed with waterand saturated brine, dried over sodium sulfate and concentrated. Theresidue was purified by chromatography (silica gel, eluent: ethylacetate/ammonia (7N in methanol)). This resulted in the product with themolecular weight of 430.60 (C24H38N4O3); MS (ESI): 431 (M+H+).tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1-yl)phenyI]carbamoyl}piperidin-1-carboxylate can be prepared analogously.
The following examples were prepared analogously. 013027 203
Ex. No. Structure Molecular formula Mole- cular weight M+H+ 317 \ W N' C25H30CIN5O 466.03 466 318 N°J ν- Ι C24H30CIN5O3 471.99 472 319 ^n— 2 Ν'" I C24H30FN5O3 455.54 456
Example 320 3,4,5,6-Tetrahydro-2H-[1,2']bipyriclinyl-4-carboxylic aciddimethylaminopyrrolidin-1-yl)phenyl]amide [4-(3-
10
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]-amide (30 mg) and 2-chloropyridine (90 mg) were heated at 160°C for 2hours. 2-Chloropyridine (0.2 ml) was added and the mixture was againheated at 160°C for 4 hours. The cooled crude mixture was purified bychromatography (silica gel, eluent: ethyl acetate/ammonia (3N inmethanol)). This resulted in the product with the molecular weight of393.54(C23H31N5O); MS (ESI): 394 (M+H+).
The following examples were prepared analogously. 15 073027 204
Ex. No. Structure Molecular formula Mole- cular weight M+H+ 321 2 N" I C25H32CIN5O3 486.02 486 322 N°2 ^^N-' I C24H30FN5O3 469.56 470
Example 323 5 5’-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxyiic acid [4-(3-dimethylamino- pyrrolidin-1-yl)phenyl]amid
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1- yl)phenyl]amide (30 mg), 2,5-dichloropyridine (30 mg) and tributylamine 10 (0.2 ml) were heated at 160°C for 2 hours. The cooled crude mixture was washed with heptane and purified by chromatography (silica gel, eluent:ethyl acetate/ammonia (3N in methanol)). This resulted in the product withthe molecular weight of 427.98 (C23H30CIN5O); MS (ESI): 428 (M+H+). 15
Example 324 1-(4-Chloro-2-cyanophenyl)piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 - yl)phenyl]amide 013027 205
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1- yl)phenyl]amide was reacted with 2,5-dichlorobenzonitrile as described inexample 323. This resulted in the product with the molecular weight of 5 452.00 (C25H30CIN5O); MS (ESI): 452 (M+H+).
Example 325 1-(2-Acetylamino-4-chlorophenyt)piperidine-4-carbôxylic acid [4-(3-10 dimethylamino- pyrrolidin-1-yl)phenyl]methylamide
Palladium on carbon (10%; 10 mg) was added to a solution of 1-(4-chloro-2-nitro-phenyl)piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]methylamide (50 mg) in glacial acetic acid (5 ml). The solution 15 was stirred under a hydrogen atmosphère (1 bar), and acetic anhydride (14μΙ) was added. Aller one hour, further acetic anhydride (6 μΙ) were addedand the mixture was stirred for 15 minutes. The suspension was filteredand the filtrate was concentrated. The residue was purified bychromatography (silica gel, eluent: ethyl acetate/ammonia (7N in 20 methanol)). This resulted in the product with the molecular weight of 498.07(C27H36CIN5O2); MS (ESI): 498 (M+H+).
The following examples were prepared analogously.
Ex. Structure Molecular Mole- M+H+ No. formula cular weight 013027 206 326 ^0 C27H36FN5O2 481.62 482 327 o=< 1 C26H34CIN5O2 484.05 484 328 °={ 1 C26H34FN5O3 467.59 468
Example 329 (R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-(4-phenylpiperidin-1-5 yl)acetamide
Césium carbonate (100 mg) and 4-phenylpiperidine (48 mg) were added toa solution of (R)-2-chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]acetamide (80 mg) in acetonitrile (5 ml) and DMF (1 ml), and the 10 mixture was kept at 65°C for 12 hours. The mixture was freed of volatilefractions and the residue was partitioned between water anddichloromethane. The organic phase was dried over sodium sulfate, filteredand concentrated. The residue was purified by chromatography (silica gel,eluent: methanol/dichloromethane). This resulted in the product with the 15 molecular weight of 406.58 (C25H34N4O); MS (ESI): 407 (M+H+).
It is altematively possible to use potassium carbonate or pyridine asauxiliary bases, to add potassium iodide as catalyst, or to carry out thereaction at 150°C in a microwave apparatus. 20 013027 207 (R)-2-Chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]acetamideTriethylamine (2.03 g) was added to a solution of (R)- [1-(4-aminophenyl)pyrrolidin-3-yl]-dimethylamine (3.15 g) in dichloromethane(120 ml), and then chloroacetyl chloride (2.26 g) was added dropwise. After 5 3 hours, the mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried over sodium sulfate, fîlteredand concentrated. The residue was purified by chromatography (silica gel,eluent: methanol/dichloromethane). This resulted in the product with themolecular weight of 281.79 (C14H20CIN3O); MS (ESI): 282 (M+H+). 10 The following were obtained analogously: N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-chloroacetamide 2-Chloro-N-[4-(3-dimethyIaminopyrrolidin-1-yl)phenyl]acetamide (R)-2-Chloro-N-[6-(3-dimethylaminopyrrolidin-1-yl)pyridin-3-ylïacetamide 15 The following examples were prepared in analogy to the method given inexample 329:
Ex. No. Structure Molecular formula Mole- cular weight M+H+ 330 C25H34N4O 406.58 407 331 C26H34N4O2 434.59 435 332 C26H33CIN4O2 469.03 469 333 γύΛ O αοπ C27H30N4O3 458.57 459 013027 208 334 o αοαΝ^"χ" C25H29N5O2 431.54 432 335 s X"’ C25H28CIN5O2 465.99 466 336 r\ V C26H33N5O3 463.59 464 337 C25H33CIN4O 441.02 441 338 j /γθΧ C25H34N4O2 422.58 423 339 ο C24H33N5O2 423.56 424
Example 340 (R)-4-Benzylpiperidine-1 -carboxylic acid [6-(3-dimethylaminopyrrolidin-1-yl)pyridin-3-yl]-amide
N
/
N \ (R)-6-(3-Dimethylaminopyrrolidin-1-yl)pyridin-3-ylamine was added to asolution of carbonyldiimidazole (53 mg) in DMF (0.5 ml) at 0°C. After 15minutes, 4-benzylpiperidine (57 mg) was added and the mixture was 10 heated at 90°C for one hour. The cooled mixture was freed of volatilefractions. The residue was purified by chromatography (silica gel, eluent:methanol/dichloromethane). This resulted in the product with the molecularweight of 407.56 (C24H33N5O); MS (ESI): 408 (M+H+). 013027 209
The following examples were prepared analogously:
Ex. No. Structure Molecular formula Molecu lar weight M+H+ 341 0 C24H31N5O2 421.55 422 342 0 n r-AXï C24H33N5O 407.56 408 343 0 C26H34N4O3 450.59 451 344 0 C25H31CIN4O2 455.00 455 345 ««-A C26H30N4O 414.56 415 346 0 exA0 C24H39N5O 413.61 414 347 0 q^qxXT C26H37N5O 435.62 436 5 Example 348 (R)-4-Cyclopropylmethoxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]- benzamide 013027 210
(R)-4-Benzyloxy-N-[4-(3-dimethylaminopyrrolidin-1 -y!)-3-fluorophenyljbenzamide underwent debenzylating hydrogénation bymethod B. The resulting (R)-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3- 5 fluorophenyI]-4-hydroxybenzamide was alkylated with cyclopropylmethylbromide by method H. This resulted in the product with the molecularweight of 397.50 (C23H28N3O2); MS (ESI): 398 (M+H+).
The following examples were likewise obtained by method H:
Ex. No. Structure Molecular formula Mole- cular weight M+H+ 349 0 C26H34FN3O2 439.58 440 350 o C25H32FN3O3 441.55 442 351 jqvX C24H30FN3O2 411.52 4Î2
Example 352 (R)-N-[4-(3-DimethylaminopynOlidin-1-yl)-3-fluorophenyl]-4-(pyridin-2- yloxy)benzamide 013027
(R)-N-[4-(3-Dimethylaminopyrrolidin-1 -yl)-3-fluorophenyl]-4- hydroxybenzamide was reacted with 2-chloropyridine by method R. Thisresulted in the product with the molecular weight of 434.52 (C25H27N4O2);MS (ESI): 435 (M+H+).
Example 353 - example 507
Various pyrrolidinylanilines were reacted with diverse amines by method A.The resulting products are summarized in table 6.
Example 508 - example 1130
Various pyrrolidinylanilines were reacted with diverse acids by methods E.The resulting products are summarized in table 7.
Example 1131 - example 1232
Various (hetero)aryl halides were reacted with diverse boronic acids bymethods O. The resulting products are summarized in table 8.
Example 1233 - example 1237
Various aryl halides were reacted with diverse acetylenes by methods J.The resulting products are summarized in table 9.
Example 1238 - example 1403
Various aminopyrrolidines and N-arylpyrrolidinones were reacted withdiverse aldéhydes, ketones and amines by method N. The resultingproducts are summarized in table 10.
Example 1404 - example 1423
Various aminopyrrolidines were reductively methylated with formaldéhydeby method E. The resulting products are summarized in table 11. 212
Example 1424 - example 1443
Various amides were alkylated by method F. The resulting products aresummarized in table 12. 5 Example 1444-example 1618
Various tert-butyl carbamates were cleaved by method G. The resultingproducts were summarized in table 13.
Table 6
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 353 η 0 C25H31FN4O2 438.24 439 354 C25H30N4O4 450.23 451 355 η C25H31CIN4O3 470.21 471 356 \ Ο'θΛ-Ο'"^ C26H30N4O2 430.24 431 357 C24H29CIN4O 424.20 425 358 C25H35N5O 421.28 422 359 C23H30BrN5O 471.16 472 360 C24H34N4O 394.27 395 361 %σχοΝ,>< C26H28N4O3 444.22 445 013027 213
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 362 C24H29N5O 403.24 404 363 C27H29N5OS 471.21 472 364 çAAvU C26H30N4O2 430.24 431 365 A N- C25H30N6O3 462.24 463 366 \i— WT C22H25N5O2 391.20 392 367 ΡΓΝύ° Ό-,ρ N~ z C26H28N6O 440.23 441 368 λ F<yO^œ°N' C24H29FN4O 408.23 409 369 C26H30N4O3 446.23 447 370 Çr0O-N è» c/n'U C25K27CIN4O2 450.18 451 371 C25H27FN4O2 434.21 435 372 N— V’-ClAO'^ C26H30N4O2 430.24 431 373 N— ά°Τ>Α-Ο^ C26H30N4O2 430.24 431 013027 214
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 374 N— C26H30N4O3 446.23 447 375 &°o-N C25H27CIN4O2 450.18 451 376 N— λοΌΛΟ^ C23H32N4O2 396.25 397 377 N- C25H29N5O2 431.23 432 378 \ N— αθταΑΌΓ^ C24H27N5O2 417.22 418 379 C25H35N5O2 437.28 438 380 ά0ΟΑ-0^ C25H27FN4O2 434.21 435 381 C26H27F3N4O2 484.21 485 382 kAN^NAJ C26H27F3N4O 468.21 469 383 N— ορ<-ξχ><3 cA C24H31CIN4O2 442.21 443 384 \ Λ N- d '"S C25H28N4O 400.23 401 385 C\ À Wr C26H30N4O2 430.24 431 013027 215
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 386 N- C23H32N4O2 396.25 397 387 C25H34N4O2 422.27 423 388 C24H31CIN4O 426.22 427 389 C25H34N4O 406.27 407 390 F C25H31F3N4O 460.24 461 391 \ N— C25H31F3N4O2 476.24 477 392 C23H31N5O4 441.24 442 393 C24H30N4O3 422.23 423 394 0Aao&·'· C24H32CIN5O 441.23 442 395 '^Aâ-û^ C25H27CIN4O 434.19 435 396 \ N- C25H28N4O 400.23 401 013027 216
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 397 C24H28N6O 416.23 417 398 C25H34N4O2 422.27 423 399 C28H34N4O 442.27 443 400 A S Xra C25H27N5O3 445.21 446 401 AA C25H27CIN4O 434.19 435 402 po-c<<>'0 C24H31CIN4O2 442.21 443 403 rA N“ A/r C24H33N5O 407.27 408 404 N- ϊ°Χ>αΆ C22H30N4O2 382.24 383 405 \ N- ΆαΑ C25H34N4O 406.27 407 406 C22H22CI2F6N4O2 558.10 559 407 f/TOA#' F F C26H27F3N4O2 484.21 485 408 C24H31FN4O 410.25 411 013027 217
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 409 \ FçyO-'0N-O"°" C24H31FN4O 410.25 411 410 \ C24H31FN4O 410.25 411 411 \ C25H34N4O 406.27 407 412 C25H34N4O 406.27 407 413 αΟΛΟ-^ 0 C24H32N4O2 408.25 409 414 C22H26N6O 390.22 391 415 C26H27BrN4O 490.14 491 416 C21H24N6OS 408.17 409 417 zv( C26H27N5O 425.22 426 418 q/Z-o*0" C24H32N4O 392.26 393 419 C25H27CIN4O2 450.18 451 420 \ N- oçoao^ C24H30N4O3 422.23 423 013027 218
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 421 C24H29CIN4O2 440.20 441 422 - C26H31CIN4O2 466.21 467 423 C28H35CIN4O 478.25 479 424 π~ C28H38N4O4 494.29 495 425 ο,,ζγΌ^^ο C24H31CIN4O2 442.21 443 426 C25H33CIN4O2 456.23 457 427 ηΝ- σ°θΑ-σΝ^° C25H28N4O3 432.22 433 428 ρ^><Λο-ν0^ C25H29FN4O2 436.23 437 429 Ν-/ γ-'ν-? Fyf0 0Br-O^ Ν<Ζ C24H30BrN5O2 499.16 500 430 Ν-/ ° C25H29CIN4O2 452.20 453 431 O-C^N-O-^ ό C25H32N4O3 436.25 437 013027 219
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 432 C24H32BrN5O2 501.17 502 433 C22H30N6O 394.25 395 434 \ C24H30F3N5O 461.24 462 435 λ/ΛΟ·*0 Vn C21H29N7O 395.24 396 436 aojU>N°N C23H31N5O 393.25 394 437 C22H30N6O 394.25 395 438 \ N- \»N C21H29N7O 395.24 396 439 C23H30CIN5O 427.21 428 440 C23H30CIN5O 427.21 428 441 \ C23H30CIN5O 427.21 428 442 C23H30FN5O 411.24 412 013027 220
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 443 C23H30FN5O 411.24 412 444 qûW C24H33N5O 407.27 408 445 C24H33N5O 407.27 408 446 C24H33N5O 407.27 408 447 N- C24H33N5O 407.27 408 448 ÿo^-O-’0’' C24H30F3N5O 461.24 462 449 fV>O^n° F C24H30F3N5O 461.24 462 450 \ O-rAcA *N C24H30N6O 418.25 419 451 q-o4cA" <0 i C24H33N5O2 423.26 424 452 \ O C24H33N5O2 423.26 424 013027 221
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 453 G24H33N5O2 423.26 424 454 νσθ^Ν°Ν' 0 C25H33N5O2 435.26 436 455 α^ο^-σ^Ν' C24H29CIF3N5O 495.20 496 456 C24H32CIN5O 441.23 442 457 C25H35N5O 421.28 422 458 \ Q^oto°N' Cl C23H29CI2N5O 461.17 462 459 K C23H29F3N6O 462.24 463 460 K F C23H29F3N6O 462.24 463 461 \ F Cl C23H28CIF3N6O 496.20 497 462 \ C25H35N5O2 437.28 438 013027 222
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 463 Cl Cl C23H29CI2N5O 461.17 462 464 C25H35N5O 421.28 422 465 Cl C23H29CI2N5O 461.17 462 466 \ ' 0/ C25H35N5O3 453.27 454 467 \ a^OtoN°N O ! C24H32CIN5O2 457.22 458 468 \ C23H38N6O 414.31 415 469 C23H29F2N5O 429.23 430 470 C24H30N6O 418.25 419 471 \ C25H35N5O 421.28 422 472 \ N— οθΛ-œ0 C23H37N5O 399.30 400 013027 223
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 473 C23H32N6O 408.26 409 474 \»N C23H32N6O 408.26 409 475 N- C26H37N5O 435.30 436 476 o C28H36CIN5O2 509.26 510 477 C25H34N4O 406.27 407 478 CVo-vo-'ô 0 C25H31FN4O2 438.24 439 479 F î1 C23H27CIFN5O 443.96 444 480 C23H30FN5O2 427.53 428 481 F C23H29F2N5O2 445.52 446 482 F C23H27F2N5O 427.50 428 483 CK ,bl· I II /---- Jl ί/Ά^Ν. k / ^z\ Ν”^ν—\_Ζ F C23H29CIFN5O2 461.97 462 484 o^AÇ^ÿ0 C28H37FN4O4 512.28 513 013027 224
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 485 F C28H32FN5O4 521.24 522 486 C23H30CIN5O2 443.98 444 487 F C23H29CIFN5O2 461.97 462 488 \ 0-o-?o-nO C26H34N4O2 434.27 435 489 C30H36N4O 468.29 469 490 c 0 "s C26H34N4O3 450.26 451 491 \ C25H32N4O2 420.25 421 492 C26H34N4O3 450.26 451 493 \ N- C25H30N4O3 434.23 435 494 C26H35N5O2 449.28 450 495 ÎVc^hO-^ O-N C25H30FN5O2 451.24 452 013027 225
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 496 C25H31N5OS 449.23 450 497 \ N- N-» C26H33N5O 431.27 432 498 \ C27H35N5O 445.28 446 499 C25H31F3N4O2 476.24 477 500 C26H35N5O3S 497.25 498 501 Po-vo-n°n Jr° o C25H31N5O3 449.24 450 502 C23H29CIN4O 412.20 413 503 F'Ckû-51<>C C23H29FN4O 396.23 397 504 \ N- C25H31N5O 417.25 418 505 PoW' ür° o C24H30N6O3 450.24 451 506 C24H31FN4O2 426.24 427 013027 226
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 507 C25H31FN4O 422.25 423
Table 7
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 508 C26H33N3O2 419.26 420 509 o 0 C26H34N4O2 434.27 435 510 ° O C26H27N3O2 413.21 414 511 nY C30H35N3O2 469.27 470 512 -O"0 C27H29N3O2 427.23 428 513 O - o-V C27H28N4O6S 536.17 537 514 C25H33N3O3 423.25 424 013027 227
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 515 N-/ yCUf0 ° C24H29N3O3 407.22 408 516 N-/ 0 C25H33N3O3 423.25 424 517 N-/ οΌΥζΥ ° C27H29N3O3 443.22 444 518 C27H29N3O2 427.23 428 519 O C27H29N3O2 427.23 428 520 C27H29N3O2 427.23 428 521 F 'NY _θ-Ό ° C27H26F3N3O2 481.20 482 522 N-/ -θ'Ό θ C27H26F3N3O2 481.20 482 523 nY À 0 _ r~< 7^Ό^νΌ·ν^ C28H31N3O4 473.23 474 524 °S> C27H28N4O4S 504.18 505 525 Ck N< ’Ά-ο'ν-ο-'0 0 C26H25CIFN3O3 481.16 482 013027 228
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 526 N-/ OHrO*5' ° C24H25N3O3 403.19 404 527 C24H25N3O2S 419.17 420 528 Λ C25H28N4O2 416.22 417 529 C24H24CIN3O3 437.15 438 530 C24H24FN3O3 421.18 422 531 \ 0 r^i" C25H33N3O 391.26 392 532 \ oûW Ô C25H27N3O2 401.21 402 533 \ 0 C25H27N3O 385.21 386 534 \ N- P-O^-O^5 C23H31N3O2 381.24 382 535 \ N- O-cOW C26H29N3O2 415.23 416 536 ° θ'1" C25H27N3O 385.21 386 537 γΟ^Λ-Ο-'θ ' C24H31N3O 377.25 378 013027 229
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 538 G-° C25H26N4O4 446.20 447 539 \ N- C26H29N3O 399.23 400 540 C26H29N3O2 415.23 416 541 \ N- C28H33N3O2 443.26 444 542 C25H29N5O4 463.22 464 543 γΟ'θΛ-Ο-'0 C23H31N3O2 381.24 382 544 θ'οΛ-Ο-'θ C25H27N3O2 401.21 402 545 Qo-<y°-0-NO C25H31N3O2 405.24 406 546 K ° r^i" C27H31N3O 413.25 414 547 \ C28H33N3O 427.26 428 548 C21H22FN5O2 395.18 396 549 N~ P -vO C25H25N3O2 399.20 400 013027 230
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 550 \ N- C29H35N3O 441.28 442 551 q: x CI^NO Q N’ C23H23CIN4O4 454.14 455 552 'N~ C25H26FN3O2 419.20 420 553 ° oN' C26H29N3O 399.23 400 554 \ ^o-CW°n-O-O C27H29N3O2 427.23 428 555 C28H38N4O3 478.29 479 556 ° C25H26FN3O 403.21 404 557 f<\^0n-O~3n' Ç23H24FN3OS 409.16 410 558 θο-ρΛ-θ-Ν° C26H26F3N3O2 469.20 470 559 ('Ί N- οΟ^Ό"0 ό C29H34N4O2 470.27 471 560 θο-οΛ-Ο-’0 0*ς C25H26N4O4 446.20 447 013027 231
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 561 \ N- C24H33N3O2 395.26 396 562 ο-οΛΟ"0 C24H33N3O2 395.26 396 563 \ ° oN" C25H26FN3O 403.21 404 564 .0^θΛ-θ-θΝ C26H29N3O2 415.23 416 565 \ N- C25H26CIN3O 419.18 420 566 '° ° oN~ C26H29N3O2 415.23 416 567 \ 1 o r-^" C26H29N3O2 415.23 416 568 \ N— C25H26FN3O 403.21 404 569 \ N- C26H27N3O3 429.20 430 570 \ ° oN" C26H29N3O 399.23 400 571 0 r^i~ C26H29N3O 399.23 400 013027 232
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 572 C26H26F3N3O 453.20 454 573 \ N- C26H26F3N3O 453.20 454 574 N Cro-œ°N-0-N° C26H35N3O2 421.27 422 575 \ N- C27H31N3O2 429.24 430 576 \ N- C25H26CIN3O 419.18 420 577 \ N- Cl C25H25CI2N3O 453.14 454 578 \ N- C24H28N4O2 404.22 405 579 \ N— -^p-VO- C27H31N3O3S 477.21 478 580 ciy"0^' C25H31N5O3 449.24 450 581 \ ΛΟ^Λο-Ό C24H31N3O2 393.24 394 582 \ N— ο-οΛ-Ο-*0 C23H31N3O2 381.24 382 013027 233
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 583 fXÙ N- C25H25F3N4O2 470.19 471 584 \ N— /ΟΛ-0-Ν^ C24H39N3O 385.31 386 585 N-- c, Cl C25H25CI2N3O 453.14 454 586 0 r^i" C25H26BrN3O 463.13 464 587 \ N- C25H32CIN3O 425.22 426 588 ckx^V· C25H32N4O2 420.25 421 589 C24H26N4O4 434.20 435 590 C24H30FN3O2 411.23 412 591 /Ύθ^° 'θ'Ό·^ ρΛ> C26H28FN3O 417.22 418 592 ^Ν-θΛ-Ο',σ C25H25N5O2 427.20 428 593 0 C26H26N4O 410.21 411 013027 234
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 594 F o N— VfM n C26H32FN3O2 437.25 438 595 \ N- C25H26CIN3O 419.18 420 596 V N- C24H26N4O 386.21 387 597 \ 0 N" C26H26F3N3O 453.20 454 598 V C27H31N3O3 445.24 446 599 0 C28H29N3O3 455.22 456 600 ^TXUOr"^ C24H33N3O2 395.26 396 601 \ 0 O~ C25H27N3O 385.21 386 602 0-=-0^-0-° C28H30N4O2 454.24 455 603 C26H36N4O4 468.27 469 604 C28H38N4O3 478.29 479 605 Go^sJ’^nO F C22H28FN3O2S 417.55 418 013027 235
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 606 / ο 1 C23H29N3O3 395.22 396 607 ^0 0 HyjH C27H33N3O3 447.25 448 608 O O s -h C27H37N3O4 467.28 468 609 s C29H39N3O3 477.30 478 610 \=/ \=Z & | C27H29FN4O3 476.22 477 611 C25H34N4O4 454.26 455 612 Ο-Ο’θ-Ο-'θ'Ν^ C27H35N3O2 433.27 434 613 α-οΛο^ο y O C25H31N3O3 421.24 422 614 ο-θΛ-0-Ν>ί ό -£° C28H32N4O4 488.24 489 615 C27H35CIN4O3 498.24 499 616 wm N-? O C26H29N5O4 475.22 476 617 ÏM0 οΟ^-Ο-*0 * y FA C28H36F3N3O4 535.27 536 618 C27H38N4O4 482.29 483 013027 236
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 619 —x /=N. C27H38N4O4 482.29 483 620 0?< C28H39N3O5 497.29 498 621 N-* O C23H23N5O3 417.18 418 622 W Ο θ C25H26N4O2 414.21 415 623 σΟΛ-Ο:'0 θ* CI^N C28H35CIN4O4 526.23 527 624 'n-<o ρ-Ο^-ρ·*0 o< C28H39N3O4 481.29 482 625 \ 0 Cl N^u □OW0 0/" C27H36CIN3O4 501.24 502 626 \ 0 F N-{ 0-0^° C27H35F2N3O4 503.26 504 627 ο-οΛρ-^ 0?< S C27H36FN3O4 485.27 486 628 F N^° yCr^-Ô^ 0;< C27H36FN3O4 485.27 486 Ο 130ζ7 237
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 629 C28H39N3O4 481.29 482 630 ' o Λ= C28H36F3N3O4 535.27 536 631 0< crG^Q-'0-^0 F Cl C27H35CIFN3O4 519.23 520 632 oP^-Cp3 0?< N C28H36N4O4 492.27 493 633 , N-f° ο-ΟΛ-^"0 S ° C28H38CIN3O4 515.26 516 634 'N-t° 0/ C31H39N3O4 517.29 518 635 ο-ΟΛ-Ρ^3 ^y-7 Br C27H36BrN3O4 545.19 546 636 k^° ο-οΛ-Ο-'0 0/i N C28H36N4O4 492.27 493 637 °χ C26H35CIN4O4 502.23 503 638 ο-Ο’θΡ^ P C27H35F2N3O4 503.26 504 013027 238
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 639 ' 0 Br C27H36BrN3O4 545.19 546 640 \ o F N^u y C27H35F2N3O4 503.26 504 641 \ H ο-ΟΛ-Ο'^ C23H31N3O3 397.24 398 642 C24H33N3O3 411.25 412 643 C27H37N3O5 483.27 484 644 -V, - 0Ό0 C25H34N4O4 454.26 455 645 \ 0 C27H36FN3O4 485.27 486 646 F'|^"S . H.W C27H24FN3O3 457.18 458 647 C27H33N3O2 431.26 432 648 οΌΛ-<>4° C23H31N3O3 397.24 398 649 Fyi n- C25H24FN3O2 417.18 418 239
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 650 C27H36N4O3 464.28 465 651 O__. η N-yO^!N-O'N^ C25H26N4O2 414.21 415 652 \ N"\ Frv 0 C31H33FN4O3 528.25 529 653 C32H38N4O2 510.30 511 654 qO7O"°X0 C28H38N4O2 462.30 463 655 „N. C29H34N4O2 470.27 471 656 Χολ-Ον7^ C26H26CIN3O2 447.17 448 657 ! C29H38N4O2 474.30 475 658 N-/ C27H29N3O3 443.22 444 659 C24H29N5O4 451.22 452 660 θα-ΟΛ-Ο-"9 C25H33N3O2 407.26 408 661 JXs? rvoTc S N-V C25H30N4O3S2 498.18 499 240
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 662 k. 0 l· H N-f C28H29FN4O3 488.22 489 663 C31H44N4O2 504.35 505 664 C32H40N4O2 512.32 513 665 fl P _ >ζζ N-N C25H30N6O3 462.24 463 666 0Â N-N C25H30N6O3 462.24 463 667 /s θ'Ν^θ-Ο'Ο °7< Ço C30H33N5O4 527.25 528 668 O O Q F’V'CJ/ N-Ç-y 'S Lo C27H27N3O4 457.20 458 669 0 'N~?° OvM ryO θ/ N-N N·^-» C26H31N5O3 461.24 462 670 φΛ-Ο-0' C21H27N3O4 385.20 386 671 ΰΛ-Ο^ 0?< N=/ C25H30N6O3 462.24 463 672 '^NZ~~ ύκ „ i"-/ C31H35FN4O3 530.27 531 013027 241
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 673 'n^° C26H32N6O3 476.25 477 674 k-t0 s F C27H42FN3O4 491.32 492 675 N C25H32N4O 404.26 405 676 \ N— < n-\J C27H30N4O2 442.24 443 677 \ / N— C29H34N4O2 470.27 471 678 C26H28FN3O 417.22 418 679 \ N- F C25H32FN3O2 425.55 426 680 N ν-ΟΛ-Ο"0 H, C23H30N4O2 394.24 395 681 û^o C25H32N4O2 420.25 421 682 ο-?<Κ<χΛ C24H30N4O2 406.24 407 683 \ εΛ-ο^ο-*0" C26H28N4O2 428.22 429 684 C23H28N4O2 392.22 393 013027 242
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 685 \ C26H34N4O2 434.27 435 686 N C24H27N5O3 433.21 434 687 \zο λ- 2*° $ Z / C24H32N4O2 408.25 409 688 \ Ο-ζΤ^Ν-Ο-^ C22H30N4O2 382.24 383 689 \ N- C24H33N5O 407.27 408 690 C25H28N4O2 416.22 417 691 \ N- C24H26N4O 386.21 387 692 οΛο-Ό O C22H24N4OS 392.17 393 693 \ N- φΛ-Ο'’0 0 C21H24N4OS 380.17 381 694 \ N- C19H21N3OS2 371.11 372 695 \ CL N-» ru η ο Π ^s/U°-rJÎ!N'Cy’N^ C23H24CIN3O2 409.16 410 013027 243
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 696 Cl ° oN" C22H24CIN3OS 413.13 414 697 \ N— C21H21CIFN3OS 417.11 418 698 Q| i_N-- cr^~S C21H21CI2N3OS 433.08 434 699 Cl C21H21CIN4O3S 444.10 445 700 C22H23CI2N3O2 S 463.09 464 701 N s C22H24CIN3O2S 429.13 430 702 \ Cl N~ C23H26CIN3OS 427.15 . 428 703 ^S'^N-O-'0 C24H26CIN3O2S 455.14 456 704 C22H24F3N5OS 463.17 464 705 F C24H23CIF3N3O 2 477.14 478 706 F f-J-f \ C24H24F3N3O2 443.18 444 013027 244
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 707 C23H28BrN5O2 485.14 486 708 C24H25F3N4O2S 490.17 491 709 \ N- C22H22N4OS 390.15 391 710 C23H25N3O2 375.20 376 711 \ N< Ç) \ C24H27N3O2S 421.18 422 712 C24H26CIN3O3 439.17 440 713 \ N— C21H22CIN3OS 399.12 400 714 F f4-f \ C25H23F6N3O2 511.17 512 715 \ N- —θ-οΛ-Ο'0 F C23H30FN3O2 399.51 400 716 ° C26H34FN3O4 471.25 472 717 θο-οΛΟ'^ C26H29N3O2 415.23 416 013027 245
Ex. No. Structure Molecular formula Monoisotopiçmolecular wt. M+H+ 718 œ C27H31N3O2 429.24 430 719 Qo<K<-o-^ C26H33N3O2 419.26 420 720 C25H28N4O4 448.21 449 721 C24H33N3O2 395.26 396 722 F N- ^o-O'rÛ'’0 C26H28FN3O2 433.22 434 723 C26H27N3O2 413.21 414 724 C25H33N3O2 407.26 408 725 C26H28BrN3O 477.14 478 726 \ ^jO C24H26FN3OS 423.18 424 727 \ ° oN~ C26H28FN3O 417.22 418 728 \ O r~^~ C27H31N3O2 429.24 430 013027 246
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 729 \ N— C26H28CIN3O 433.19 434 730 \ N- C26H28CIN3O 433.19 434 731 \ ° oN~ C26H28CIN3O 433.19 434 732 07 v “fl* ° , nN~ C24H25CIN4O4 468.16 469 733 0 ry" C26H28FN3O 417.22 418 734 \ ° r^i" C27H29N3O3 443.22 444 735 C27H31N3O 413.25 414 736 qO^nO"0 C27H31N3O 413.25 414 737 C26H26FN3O2 431.20 432 738 iy?o-cN' C27H29N3O2 427.23 428 739 \ χ-0-θΛθ,σ C25H35N3O2 409.27 410 013027 247
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 740 0 r-^" C26H34CIN3O 439.24 440 741 a® + C32H36N6O3 552.28 553 742 C26H36FN3O2 411.59 412 743 N- VQ-W''0 Û"N C25H32N4O2 420.25 421 744 \ N- <rN C24K30N4O2 406.24 407 745 N- “rCrtO-10 0~N C26H28N4O2 428.22 429 746 W-<0-nO O'N' C27H30N4O2 442.24 443 747 C24H32N4O2 408.25 409 748 iKXoH.ÿ*' C24H30N4O2 406.24 407 749 > vM-œ0 0 C24H32N4O2 408.25 409 750 \ N- vO^n-O-'0 û C25H32N4O2 420.25 421 013027 248
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 751 \ N- νθΛ-Ο-Ν3 0 C24H30N4O2 406.24 407 752 N 0 C25H34N4O2 422.27 423 753 —, ν-^Λ-νΤΊ C22H30N4O2 382.24 383 754 %&" cS- F C27H35FN4O6 530.25 531 755 \ Ν-θΛ-Ό-°Ν y° C24H32N4O2 408.25 409 756 N d^-o^-o-"0 C26H27FN4O2 446.21 447 757 ν-οΛ-ο-° Z° C25H34N4O2 422.27 423 758 η-ΟΛΟ-*0 z° C24H32N4O2 408.25 409 759 \ o N-O-U)-0 οΛ C24H26N4O3 418.20 419 760 C24H30N4O2 406.24 407 761 οΛ-Ο^ν-Ο'^ C26H32N4O2 432.25 433 013027 249
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 762 C26H34N4O2 434.27 435 763 CTo C26H34N4O3 450.26 451 764 Ν<Τ°ν-Ο-Ν°Νû^o α C25H31CIN4O2 454.21 455 765 νΛ-αΛ-Ό-"0 C24H30N4O2 406.24 407 766 ν-ΟΛό-^ C25H34N4O2 422.27 423 767 \ ô^-CrVO-’0” C24H26N4O2S 434.18 435 768 \ N- C26H34N4O2 434.27 435 769 S a C23H30CIN3O2 415.20 416 770 \ N- O-Vj N-^ss/ F C24H32FN3O2 413.25 414 771 N— □> ry«° zvO oA/ N-V? F C23H28FN3O2 397.22 398 013027 250
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 772 0 N" o-CZÿ C24H30FN3O2 411.23 412 773 \ N- C24H30FN3O2 411.23 412 774 r-, o '^o-Ç^N-O-'0 F C25H33FN4O2 440.26 441 775 YnQ 0 O-\J NAes/ F C26H33FN4O3 468.25 469 776 N ο-ΟΛ-Ο-^ C23H26N4O 374.21 375 777 N ίΛΡ <vn~5 C28H30N4O 438.24 439 778 N C21H25N5O2 379.20 380 779 \ N- C26H27N3O2 413.21 414 780 \ CrtO-G C26H26N4O 410.21 411 781 N- C25H31N5O 417.25 418 013027 251
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 782 \ N- ΛΓ'θ-Ο''0 O C21H24N6OS 408.17 409 783 N=, C22H25N5O 375.21 376 784 \ 0 N" f2*n FF C24H28F3N5O 459.23 460 785 4¾ C25H30N6O 430.25 431 786 N 'ν-οΛ-ο-^ C26H32N6O 444.26 445 787 ^S-O^N-O^ C25H27N3OS 417.19 418 788 C30H34N4O 466.27 467 789 \ N- C24H30N4OS 422.21 423 790 C24H26CIN3O3S 2 503.11 504 791 “V C23H23CI2N3O3 459.11 460 013027 252
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 792 όΛ-Ο’θ C24H26CIN3O2 423.17 424 793 C23H26N4OS 406.18 407 794 C25H27N3O3S 449.18 450 795 ci. N— C23H25CIN4OS 440.14 441 796 o.^ C23H25N3O3 391.19 392 797 F \ f4~f n~ ϊΗ-ο-φ o C23H23F3N4O2 444.18 445 798 O'C^°N<>-'0 C23H28N4O3 408.22 409 799 \ λ-Λ~- rV0 C25H30N4O 402.24 403 800 0" C26H29N3O2 415.23 416 801 \ N- σ:» C27H29N5O 439.24 440 802 X C22H24F3N3O2 419.18 420 013027 253
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 803 C22H25N3O3 379.19 380 804 XHo-o C22H24N4O 360.20 361 805 C22H23F4N3O 421.18 422 806 'οΟ-^νΟ-νΟ C23H29N3O2 379.23 380 807 X /=χ -À Ο ν-ΟΌ C26H29N3O2 415.23 416 808 C27H30FN3O 431.24 432 809 \ Ν- 0 C22H23F3N4O2 432.18 433 810 \ ο Γ^" C25H25N3O2 399.20 400 811 °OJXr·^ C25H28N4O 400.23 401 812 C21H24F3N3O3 423.18 424 813 C22H30N4O 366.24 367 013027 254
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 814 \ N- 'Όο-ρΛ-Ο-^ F C24H31FN4O2 426.24 427 815 \ o v_(h jtVnA F C25H31FN4O3 454.24 455 816 ° h° F'^ C25H30FN3O2 423.23 424 817 \ C23H30N4O 378.24 379 818 \ 'çP'A-O'*0 O C24H27N3O4 421.20 422 819 \ 0 F HN-t Cj^n-àr^ A o-° ' C30H34FN3O4 519.25 520 820 \ 0 p HN-f Qo<K-<yN^ C30H34FN3O4 519.25 520 821 Y, θ F Η,Ή Ci \ C29H34FN3O4S 539.22 540 822 ν-ΟΌ °?< C29H38FN3O3 495.29 496 823 ' 0 F KN-i ryQAj'Ô'^ 0?< C30H40FN303 509.30 510 013027 255
Ex. No. Structure Molecuiar formula Monoisotopicmolecuiar wt. M+H+ 824 F C31H35F2N3O3 535.27 536 825 C28H38FN3O4 499.29 500 826 \ 0 F KN^ C30H39CIFN3O3 543.27 544 827 α ο Λ C29H33CIFN3O5 557.21 558 828 C29H38FN3O4 511.29 512 829 C29H33FN4O6 552.24 553 830 \ 0 F HN-f wW ο?< C28H38FN3O4 499.29 500 831 C30H34FN3O3 503.26 504 832 θ'θΠ ο J Λ^θζο?< C31H36FN3O4 533.27 534 833 \ 0 η F >1Ν-ί ζ O-XûVM5 C33H37FN4O4 572.28 573 834 \ 0 0 -θ'’ ^"θ^· C31H36FN3O3 517.27 518 835 C29H40FN3O4 513.30 514 013027 256
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 836 \ 0 Λ F Η,Ν·^ Z C30H33F2N3O3 521.25 522 837 \ N— O C25H32N4O2 420.25 421 838 \ N- °rOÂO-,cs o C23H30N4O2S 426.21 427 839 \ N- °o C23H30N4O3 410.23 411 840 N- γΟΛτΟ-Φ C25H36N4O2 424.28 425 841 N— γΟΛ-Ο''0 0 C24H36N4O2 412.28 413 842 N— C23H34N4O2 398.27 399 843 ^O-vCr9 0 C23H34N4O2 398.27 399 844 F_. N— ΗνΟΛ-Ο^ 0 C25H31FN4O2 438.24 439 845 \ N— γΟΛ-Ο-’0 0 C26H34N4O2 434.27 435 013027 257
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 846 0 C25H31CIN4O2 454.21 455 847 0 C23H36N4O2 400.28 401 848 \ N- C23H36N4O2 400.28 401 849 0 C26H25N3O4S 475.16 476 850 Q— C21H23N3O 333.18 334 851 ο-θΛ-Ο-Ν°Ν C22H25N5O 375.21 376 852 C21H23N5OS 393.16 394 853 0 r^i~ C20H22N60S 394.16 395 854 N 1 C20H25N5OS 383.18 384 855 \ 0-œ°-o-’0 C23H29N5O4 439.22 440 856 ÔyN P FVnO C25H32N4O3S 468.22 469 013027 258
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 857 s ' V C22H30N4OS2 430.19 431 858 Br^ C24H31BrN4OS 502.14 503 859 C24H24FN3O3 421.18 422 860 PS n- V n ci C28H27CIN4O 470.19 471 861 7-lN~ C23H31N5OS 425.23 426 862 q£O i?so ’ÛC" C22H30N4O5S 462.19 463 863 N cf° C23H32N4O4S 460.21 461 864 \ ^-ΟΛ-Ο''0 C27H29N5O 439.24 440 865 \ □vCrU^ >N C22H25N5O2 391.20 392 866 \ N- Οο-οΛ-Ο-*0 °K N ' C26H29N3O4S 479.19 480 013027 259
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 867 F \ F-/-F N— σ C23H23F3N4OS 460.15 461 868 N-i N 0 C22H29N7O2 423.24 424 869 C25H26N6O 426.22 427 870 \ N ° r-^" C26H32N4O2 432.25 433 871 \ C24H27N3O2 389.21 390 872 ô C27H29N5O 439.24 440 873 οξΧ, n- C23H28N4O3S 440.19 441 874 N C28H34N4OS 474.24 475 875 "θ'/οΛ-Ο-'θ C24H28N4O3S 452.19 453 876 α$όΛ-Ο^ C23H23CIN4O3 438.15 439 877 \ N— Ny°N-çyO G F C23H26FN5O 407.21 408 013027 260
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 878 \ N- C25H27CIN4O2 450.18 451 879 Cr5^*’0*' C24H27N5O 401.22 402 880 F C24H30F3N5O 461.24 462 881 ^νό o crClNO-,β-Ί C22H23CIN4O2 410.15 411 882 Xk, ' ^N~ C23H26N4OS 406.18 407 883 C24H26N4O 386.21 387 884 £5*~Ο~ν2τν' C24H26N4O 386.21 387 885 ΰ^~ C24H26N4O 386.21 387 886 \ N~ F F S^-ξ, ZV^Of^>N N<Z C21H23F3N6OS 464.16 465 887 \ N- C23H30N4O3S 442.20 443 888 \ N- θ~~ο"^ C24H26N4O2 402.21 403 013027 261
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 889 N- F kj C24H25F3N4OS 474.17 475 890 0 C27H29N3O 411.23 412 891 ^LAJO^' C26H29N3O 399.23 400 892 N— ✓ C28H31N3O2 441.24 442 893 C23H28N4O2 392.22 393 894 σ° C27H29N3O2 427.23 428 895 çr C21H25N7O 391.21 392 896 CS C21H28N4OS 384.20 385 897 C23H26CIN5O 423.18 424 898 ^Ao-10"' C21H23N5OS 393.16 394 899 O N~~ Cl C26H26CIN5O 459.18 460 013027 262
Ex. No. Structure Moleeular formula Monoisotopicmoleeular wt. M+H+ 900 N C23H27N5O 389.22 390 901 C25H34N4O 406.27 407 902 \ 0-θΛ<^Ν^ s 'N C24H30N4O2 406.24 407 903 Cl N- p-O-’n-Ô"0 C23H30CIN3O2 415.20 416 904 Po-oVo’0 C25H25F2N3O2 437.19 438 905 ' O C29H39FN4O2 494.31 495 906 C29H32F2N4O2 506.25 507 907 1, o C30H35FN4O2 502.27 503 908 L o C27H37FN4O3 484.29 485 909 C27H37FN4O3 484.29 485 910 ^-0-05-0-^ O C25H34FN3O3 443.26 444 013027 263
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 911 t •V 1 C24H30CI2FN3O 2 481.17 482 912 °S> C24H31FN4O4 458.23 459 913 C24H31CIFN3O2 447.21 448 914 C26H36FN3O2 441.28 442 915 °r C25H32CI2FN3O 3 511.18 512 916 F fo °f f r ' C24H28F5N3O2 485.21 486 917 F C24H31F2N3O2 431.24 432 918 -^ο-ρΛ-ό-^ "o C26H34FN3O3 455.26 456 919 C28H40FN3O3 485.30 486 920 ^y0^y<5'N~ C25H34FN5O 439.27 440 013027 264
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 921 C23H31FN4O2 414.24 415 922 Οίτ.ύ·^ C24H26FN3O3 423.20 424 923 C26H28FN3O2 433.22 434 924 Ν-α<-ώ0'Ν' C26H33FN4O2 452.26 453 925 a 0 F ÿ o-V' ' ' C26H32CIFN4O2 486.22 487 926 \ N-Qto°N OS F C25H31FN4O2 438.24 439 927 \ N~ 0 0 r( °xF F F C26H31F3N4O3 504.23 505 928 \ 'o 0 J’ 0 On-ÇJ Cl C26H33CIN4O3 484.22 485 929 \ N— /Ά-^ '/*Μ0On'Ç/nAX Cl C25H31CIN4O2 454.21 455 930 Cl 0 / λ'ν- - C24H31CIFN3O2 447.21 448 013027 265
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 931 C25H34FN3O2 427.26 428 932 C27H33FN4O2 464.26 465 933 C26H28FN3O2 433.22 434 934 C25H28FN3O2S 453.19 454 935 xx^T C25H32FN3O 409.25 410 936 οόΛ^ν C26H34FN3O 423.27 424 937 C27H29F2N3O 449.23 450 938 C24H32FN3O2 413.25 414 939 C26H33CIFN3O 457.23 458 940 C24H32FN3O2 413.25 414 941 C26H28FN3O 417.22 418 013027 266
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 942 I C27H30FN3O2 447.23 448 943 C29H31FN4O2 486.24 487 944 C27H30FN3O 431.24 432 945 C25H34FN3O2 427.26 428 946 F-a<dd^ C26H27F2N3O 435.21 436 947 ι^σΟψ0" C25H27FN4O2 434.52 435 948 Q7 x F N~ 0 c> _/"ViOH C25H27FN4O4 466.20 467 949 '°Ow4°AnT N O ,N C24H29FN4O3 440.22 441 950 dbdcdr C27H30FN3O2 447.23 448 951 C23H31FN4O 398.25 399 952 f-v^b0 Λ ,cXrs -no-nj< C24H26CIFN4OS 472.15 473 953 y O C25H25F2N3O3 453.19 454 013027 267
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 954 O J P' F C24H27F2N5O 439.22 440 955 Z 0 C26H31F2N3O2 455.24 456 956 N- C23H31N3O2 381.24 382 957 N Z C24H33N3O2 395.26 396 958 \ N~ Z C24H33N3O2 395.26 396 959 \ N- C26H29N3O2 415.23 416 960 ς^-ΟΛ-Ο-Ζ C25H29N5O2 431.23 432 961 C24H24CIFN4O3 470.15 471 962 ζθ-οΛ-οΖ ' F C27H36FN3O2 453.61 454 963 \ N-. °ρΛ<Ζ P C24H30N4O2 406.24 407 013027 268
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 964 n-OU C24H28N4O2 404.22 405 965 0 N Τ-ΟΛ-Ο-'0 C27H29N5O 439.24 440 966 \ N- Ό-ρΛ-ο-Ό °’S-0 C25H28N4O4S 480.18 481 967 \ N- ζ^Ο^Ν-Ο'1® C24H26N4O2 402.21 403 968 Br θ C27H27BrN4O2 518.13 519 969 N-N o crO^ 'C=\n2/'Nx C22H24CIN5O 409.17 410 970 .P00·’- f4-o F C22H23F2N3O3 415.17 416 971 \ N- ρρΛο-’0 C21H23N5OS 393.16 394 972 j>W Cl^ C23H24CIN3OS 425.13 426 973 o. ^<r°N N>° C22H24N4O3 392.18 393 013027 269
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 974 \ N- o-O^-O-10 Çr" Cl C25H27CIN4O2 450.18 451 975 C25H30N4O 402.24 403 976 \ N- C22H25N5O 375.21 376 977 ό C22H27N3O3S 413.18 414 978 C20H23F3N4OS 424.15 425 979 Λθ-«,- F C21H24F3N3OS 423.16 424 980 i^»-o-’c5 0 N Br C26H24BrF3N6O 572.11 573 981 Z C23H25CIN4OS 440.14 441 982 (Σ C24H32N4O3S 456.22 457 983 \ N— o rvO a-O-ïN-^N<Z C24H31CIN4O3S 490.18 491 984 C23H25N3O4S 439.16 440 013027 270
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 985 C26H32N4O3 448.25 449 986 C26H32N4O 416.26 417 987 C22H27N3OS 381.19 382 988 C24H31N3O2 393.24 394 989 FAX C22H24F3N3OS 435.16 436 990 \ C24H33N3O 379.26 380 991 C22H29N3O2 367.23 368 992 C25H35N3O 393.28 394 993 _/-N C25H30N4O 402.24 403 994 0 C_.S-7—Î X’ n<Xq N- ! C22H26N4OS2 426.15 427 995 dtN<rX>Ni>< C29H32N4O2 468.25 469 996 C23H26FN5O 407.21 408 013027 271
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 997 C28H28CIN5O 485.20 486 998 N- C20H23N5O2S 397.16 398 999 ^-ΟΛ-Ο-'0 C25H26N6O 426.22 427 1000 \ C22H24N4O2 376.19 377 1001 Λ N— O-p^N-O" Ν'7 / C26H35FN4O2 454.27 455 1002 \ Xo<^X>fN°N C25H34FN3O2 427.57 428 1003 \ N— C24H25FN4O 404.20 405 1004 ,-ΟΛ-Ο"'0" C25H30N4O2 418.24 419 1005 O^o C26H31FN4O2 450.24 451 1006 \ N-O-W-’0 Z° C25H34N4O2 422.27 423 013027 272
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 1007 n-ca-O'’0 C24H30N4O2 406.24 407 1008 N-ZX-f0 Z C27H30N4O2 442.24 443 1009 \ F C27H29FN4O2 460.23 461 1010 C26H34N4O2 434.27 435 1011 C26H26CIFN4O2 480.17 481 1012 \ F-O^-O^-O"0 C26H27FN4O2 446.21 447 1013 <H-o^O'n°n C25H27N5O2 429.22 430 1014 N 4/0¼0 Λ 0 C27H36N4O2 448.28 449 1015 \ N- , Ν-θΛ-Ο-Ν° O-^° C25K29N5O3 447.23 448 1016 C29H32N4O2 468.25 469 1017 ΡθΛ-0^-0-° C26H27FN4O2 446.21 447 013027 273
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1018 r° C23H30N4O3 410.23 411 1019 \ <z° Z C23H30N4O3 410.23 411 1020 C24H30N4O2 406.24 407 1021 C24H28N6O2 432.23 433 1022 οΛό^ν-Ο-’0 G25H27N5O2 429.22 430 1023 y° C25H34N4O2 422.27 423 1024 C25H28N4O2S 448.19 449 1025 όΛ-α^Ό'^ C25H29N5O2 431.23 432 1026 \ C26H26F2N4O2 464.20 465 1027 \ Υν-οΛ-ο-^ N C24H27N5O2 417.22 418 013027 274
Ex. No. Structure Moiecular formula Monoisotopic moiecular wt. M+H+ 1028 ,hh-OJ’~<7n°N C29H38N4O2 474.30 475 1029 C27H36N4O3 464.28 465 1030 C24H27N5O2 417.22 418 1031 \ θΛ-0^-0"0 C27H36N4O2 448.28 449 1032 Ν-θΛ·Ο-Ν° CF0 C27H36N4O2 448.28 449 1033 C27H38N4O2 450.30 451 1034 0 N" Qu N-O^ N-Ç/ O C29H32N4O2 468.25 469 1035 H/VN-A.0 i C27H34N4O2 446.27 447 1036 Cl n O /—fN~ οΛ-Ο^ν-Ο-'0 C26H27CIN4O2 462.18 463 1037 C22H24N6O2S 436.17 437 1038 0 -CH C23H25N5O3 419.20 420 275 013027
Ex. No. Structure Molecuiar formula Monoisotopicmolecuiar wt. M+H+ 1039 N— Ν-αΛ-Ο-"0 yjr4 0 C25H32N4O2 420.25 421 1040 C26H27CIN4O2 462.18 463 1041 C27H30N4O2 442.24 443 1042 C24H30N4O3 422.23 423 1043 \ C27H30N4O2 442.24 443 1044 WW H C30H38N4O2 486.30 487 1045 C29H34N4O3 486.26 487 1046 C27H28F2N4O3 494.21 495 1047 \ οΟΛ-ΟΛΌ"-^ C25H32N4O3 436.25 437 1048 -ΟΛ-Ο^-Ο-^ C27H36N4O2 448.28 449 1049 N- F ηΟΛ/Ρ0 h F 0 C23H27F3N4O2 448.21 449 013027 276
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 1050 \ C26H32N4O2 432.25 433 1051 r C26H36N4O2 436.28 437 1052 C22H28FN3O2 385.22 386 1053 C27H30N4O2 442.24 443 1054 \ N- ν·Μ°ΖΥν^ C21H24N6O 376.20 377 1055 C25H27N5OS 445.19 446 1056 ° oN" C24H26N4O 386.21 387 1057 N θ'ο-Ν^Ν-^^" C22H24N4O2 376.19 377 1058 C27H30N4O 426.24 427 1059 Q u τοΛ-θ"σ C24H32N4O 392.26 393 1060 Çn C22H26N6O 390.22 391 013027 277
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 1061 N- N-C y C24H27N5O2 417.22 418 1062 \ N- & CI'"'* C23H26CIN5O 423.18 424 1063 \ N- C24H26CIN3O2 423.17 424 1064 ci-Q"N C24H25CIN6O2 464.17 465 1065 \ N— ΟΛ-Ο"0 C24H27N3OS 405.19 406 1066 N ίΛ-Ο"0 ci-Ax C20H21CIN4O2S 416.11 417 1067 Qs^’n-O-'0 °S> C25H26N4O3S 462.17 463 1068 'QoOJ>nO'N° °S> C26H28N4O4 460.21 461 1069 O r, 0-05-0-4¾ °s Λ C30H42FN3O4 527.32 528 013027 278
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 1070 y ό F C31H42FN3O4 539.32 540 1071 N C27H30N4O2 442.24 443 1072 te C28H32N4O3 472.25 473 1073 C25H32FN3O2 425.25 426 1074 ο-οΛ<^ œ C27H30FN3O2 447.23 448 1075 N C27H30FN3O 431.24 432 1076 C28H27FN4O3 486.21 487 1077 ? AA" C28H28BrFN4O2 550.14 551 1078 C28H31FN4O2 474.24 475 1079 Α-χΡ C26H31FN4O 434.25 435 1080 cy° C26H29FN4O2 448.23 449 013027 279
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1081 ω C28H30FN5O 471.24 472 1082 C29H31FN4O 470.25 471 1083 o-s C27H30FN3OS 463.21 464 1084 cr C25H28FN5OS 465.20 466 1085 rys . ' . \=N C26H29FN4OS 464.20 465 1086 0>gW'n’ C28H29FN4O2 472.23 473 1087 o° C27H30FN3O2 447.23 448 1088 0-0° C27H29CIFN3O2 481.19 482 1089 C25H34FN3O 411.27 412 1090 C25H34FN3O2 427.26 428 1091 C23H30FN3O2 399.23 400 013027 230 1092 0 F μ?1'1-' C24H32FN3O2 413.25 414 1093 C26H32FN3O2 437.25 438 1094 Ci r-v / A-/~ VJ N*8* C30H36N4O4 516.27 517 1095 / C25H31F2N3O2 443.24 444 1096 C25H31F2N3O2 443.24 444 1097 C26H27F2N3O2 451.21 452 1098 C26H34F2N4O 456.27 457 1099 C27H27FN4O2 45S.21 459 1100 C27H27FN4O2 458.21 459 1101 C24H30FN3O2 411.23 412 1102 C23H25FN4OS 424.17 425 1103 ,Η C28H29FN4O2 472.23 473 1104 J C25H32FN3O2 425.25 426 013027 281
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1105 0 / C24H27FN4OS 438.19 439 1106 C25H34FN3O3 443.26 444 1107 C26H27F2N3O2 451.21 452 1108 C27H36FN3O2 453.28 454 1109 C26H26F3N3O2 469.20 470 1110 Z C25H27FN4O2 434.21 435 1111 C25H34FN3O2 427.26 428 1112 /0Z0"C0. C26H34FN3O2 439.26 440 1113 àcS. C27H36FN3O2 453.28 454 1114 C25H34FN3O2 427.26 428 1115 Cl C25H33CIFN3O3 477.22 478 1116 C24H31F2N3O2 431.24 432 1117 C25H32FN3O2 425.25 426 013027 282
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 1118 C27H30FN3O3S 495.62 496 1119 C23H27F4N3O 437.21 438 1120 Γ C26H36FN3O2 441.28 442 1121 c^-^ar C25H27FN4O2 434.21 435 1122 C25H33N3O2 407.26 408 1123 C24H31N3O2 393.24 394 1124 y* I C25H34FN3O2 427.26 428 1125 C23H30FN3O2 399.23 400 1126 I C27H29CIFN3O2 481.19 482 1127 C22H25F4N3OS 455.17 456 1128 ΟΧίΑ,ίΓ^ H C25H32FN3O2 425.25 426 1129 <XHckv I C25H32F2N4O 442.25 443 1130 CV - C26H29FN4O2 448.23 449 5 013027 283
Table 8
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H + 1131 Ck^ci N- vOCoj5 rvO C23H23CI2N3O2 443.12 444 1132 Ck^zF N- C23H23CIFN3O2 427.15 428 1133 o'N~ C24H26FN3O2 407.20 408 1134 C28H33N3O4 475.25 476 1135 o rS-T. ô-W-0? 0 C29H34N4O5 518.25 519 1136 N^° C33H41N3O4 543.31 544 1137 'M° ΰΛ-Ο'"^ Oz< "N K C29H36N4O4 504.27 505 1138 C29H32N4O4 500.24 501 1139 C28H30F3N3O4 529.22 530 013027 284
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H + 1140 N- cA C22H22CI2N4OS 460.09 461 1141 A» A § ù, Z / C22H23CIN4OS 426.13 427 1142 \ N- m-O'c o F C22H23FN4OS 410.16 411 1143 \ N- A F C23H25FN4OS 424.17 425 1144 \ N— s-vL/V^ >n A FF C23H22CIF3N4OS 494.12 495 1145 A^-O''0 C26H26N4OS 442.18 443 1146 \ 0 r^i" C25H25CI2N3O 453.14 454 1147 0 rJ^i~ C23H25N3OS 391.17 392 1148 \ F j.yto-'0Fto C23H23F3N4OS 460.15 461 01302? 285
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H + 1149 \ N— o; >n C22H23N5O3S 437.15 438 1150 N C22H24N4OS 392.17 393 1151 \ N- a~Q Cl C22H22CI2N4OS 460.09 461 1152 \ N— CO F C22H22CIFN4OS 444.12 445 1153 C20H22N4OS2 398.12 399 1154 N C23H26N4O2S 422.18 423 1155 0 'N" Fp FF C23H23F3N4OS 460.15 461 1156 \ Ç^N-O'"0 C23H26N4OS 406.18 407 1157 C23H26N4O2S 422.18 423 1158 N XjOvM0 Γ\-νΟ C24H27N5O2S 449.19 450 013027 286
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H + 1159 \ N- a~O C22H23CIN4OS 426.13 427 1160 \ N— F-O C22H23FN4OS 410.16 411 1161 \ C26H26N4OS 442.18 443 1162 C23H26N4OS2 438.15 439 1163 \ N- “ci C22H22CI2N4OS 460.09 461 1164 C24H28N4O2S 436.19 437 1165 C24H28N4O2S 436.19 437 1166 C26H32N4OS 448.23 449 1167 N P ΓΧ-νΟ\\ N-XZ C23H23N5OS 417.16 418 1168 C28H28N4OS 468.20 469 1169 N nûn^ C24H28N4O2S 436.19 437 013027 287
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H + 1170 o k N~ C23H24N4O3S 436.16 437 1171 C26H32N4O2S . 464.23 465 1172 N C23H26N4OS2 438.15 439 1173 C24H28N4OS2 452.17 453 1174 C24H28N4OS 420.20 421 1175 \ N- F C23H23F3N4O2S 476.15 477 1176 θ N~ IÀ/o jTVnO C24H28N4O3S 452.19 453 1177 C25H30N4OS 434.21 435 1178 N C25H30N4OS 434.21 435 1179 N C23H26N4O2S 422.18 423 1180 N 70^^---^^^--^0 C22H25N5O2S 423.17 424 1181 C24H24N4OS2 448.14 449 013027 288
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H + 1182 C23H23F3N4O2S 476.15 477 1183 \ N- οΛ-Ο-*0 F F C24H22F6N4OS 528.14 529 1184 \ M F C23H25FN4OS 424.17 425 1185 N C24H28N4OS 420.20 421 1186 Ç^’rO'’0 C24H28N4OS 420.20 421 1187 0" 0 _ r-CN- ° N?sy-C^JÎN-C^N'^ C25H26N4O3 430.20 431 1188 \ N- iV C27H31N3O2 429.24 430 1189 \ N- C25H25CIFN3O 437.17 438 1190 \ N- γ%-/ύ^ν-Ο'ν^ Cl Cl C25H25CI2N3O 453.14 454 1191 \ N 0 r^>" C26H26N4O 410.21 411 013027 2 89 Ex No. Structure Molecular formula Monoisotopic molecular wt. M+H + 1192 \ 0 0 C27H29N3O2 427.23 428 1193 \ 0 C27H29N3O2 427.23 428 1194 0 F C25H25F2N3O 421.20 422 1195 0 oN~ F C25H25F2N3O 421.20 422 1196 °S> C26H28N4O3 444.22 445 1197 ° oN~ C27H32N4O 428.26 429 1198 ° o" C25H28N4O2 416.22 417 1199 ?5yO'°~-0"°N C27H29N3O3 443.22 444 1200 \ N— C24H28N4O2 404.22 405 013027 290
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H + 1201 N- C23H25N3O2 375.20 376 1202 \ N- C24H25FN4O 404.20 405 1203 \ ° oN~ C22H25N5O 375.21 376 1204 0 N" F C26H28FN3O 417.22 418 1205 0 ON~ C26H28FN3O 417.22 418 1206 \ 0 N~ Cl C24H25CIN4O 420.17 421 1207 N- C24H25FN4O 404.20 405 1208 \ F^y^N' C24H25FN4O 404.20 405 1209 \ N- 0 F C26H28FN3O2 433.22 434 1210 0 \ -4 N- C27H30N4O2 442.24 443 1211 \ 0 N"~ *0* " C25H26N4O3 430.20 431 013027 291
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H + 1212 C26H25FN4O 428.20 429 1213 C24H25FN4O 404.20 405 1214 C24H25FN4O 404.20 405 1215 ”ô " C26H28FN3O3S 481.18 482 1216 0 ' 0 -Cy r^i" C27H29FN4O2 460.23 461 1217 C28H31FN4O2 474.24 475 1218 FÎF P Γ-ί'Ϋ' C26H25F4N3O2 487.19 488 1219 N C26H28FN3O3S 481.18 482 1220 V n F λ'“- fPï-y? zS-O C26H25F4N3O2 487.19 488 1221 \ C26H25FN4O 428.20 429 013027 292
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H + 1222 N C27H29FN4O2 460.23 461 1223 C26H25F4N3O2 487.19 488 1224 \ N- C25H25F2N3O 421.20 422 1225 \ «^Q-O-VO-'C C25H32N4O3S 468.22 469 1226 //oW C24H31N5O 405.25 406 1227 \ ' ^XyO^-O'^ C24H31N5O2 421.25 422 1228 C23H28FN5O 409.23 410 1229 \ N- /vOkyO N-V# C26H31N5O 429.25 430 1230 C25H29N5OS 447.21 448 1231 \ N- C26H34N4O 418.27 419 013027 293
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H + 1232 C26H32N4O2 432.25 433
Table 9
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 1233 N- C31H29N3O2 475.23 476 1234 C30H35N3O2 469.27 470 1235 'N~t° C28H30N4O3S 502.20 503 1236 C29H30FN3O3S 519.20 520 1237 Ν<Χτ!Λ-σΛ C28H30N4O3S 502.20 503
Table 10
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 1238 c-O^O-^-O C26H35N3O2 421.27 422 1239 C26H35N3O2 421.27 422 013027 294
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1240 C25H31F2N3O2 443.24 444 1241 C27H35N3O2 433.27 434 1242 C26H35N3O2 421.27 422 1243 ο-ΟΛ-0-0 C25H36N4O2 424.28 425 1244 N^°Z ο-θΛ-0-0 C24H33N3O3 411.25 412 1245 N yO^O^ C26H37N3O3 439.28 440 1246 C27H37N3O2 435.29 436 1247 ^eW0 C27H37N3O2 . 435.29 436 1248 C27H33N5O2 459.26 460 1249 yO^O^Ô C26H35N3O3 437.27 438 1250 C29H34FN3O2 475.26 476 013027 295
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1251 C27H32N4O2 444.25 445 1252 C24H33N3O2 395.26 396 1253 N-/ o-o-W-'0 C23H31N3O2 381.24 382 1254 C25H33N3O3 423.25 424 1255 0-0^-0-¾y r C23H28F3N3O2 435.21 436 1256 f C23H30FN3O2 399.23 400 1257 1 ^οΛ-Ο-0^0 C27H37N3O3 451.28 452 1258 ο-αΛ-Ο-'0 Ύ° C24H33N3O3 411.25 412 1259 o-cyw-O'^ C25K33N3O2 407.26 408 1260 C25H33N3O2 407.26 408 1261 n3~~ o-o^-cy0 C25H35N3O2 409.27 410 013027 296
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1262 O-m-O''0 C25H35N3O2 409.27 410 1263 "n o-θΛ-Ο*0 Λ C25H35N3O2 409.27 410 1264 IW / C25H35N3O2 409.27 410 1265 σΟΛ-Ο-'0'') C27H35N5O2 461.28 462 1266 N~^ 0 ^ρ-ΟΛ-Ο’’0 C28H38N4O3 478.29 479 1267 C26H36N4O2 436.28 437 1268 0-O^N-O^ C26H38N4O2 438.30 439 1269 ο-ο-’θ-Ο'"0 B C30H35N3O2 469.27 470 1270 C27H32N4O2 444.25 445 1271 C27H36N4O3 464.28 465 1272 C27H37N3O2 435.29 436 013027 297
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 1273 C30H35N3O2 469.27 470 1274 ^ο-θΛ-O-"^ Ό C26H35N3O2 421.27 422 1275 Ο-Ο^Ν-Ο'^'ζ^ K C29H39N3O2 461.30 462 1276 O-O^N -Ο"0 C29H43N3O2 465.34 466 1277 C28H39N3O2 449.30 450 1278 o oOW·0 C28H37N3O2 447.29 448 1279 θΧ>?Ν-0-’0ΐ C28H40N4O2 464.32 465 1280 ^οΌΛΌ-νΟ C30H35N3O2 469.27 470 1281 y' w C30H34N4O2 482.27 483 1282 00^-0-°¾ Y « C30H35N3O3 485.27 486 1283 C25H33N3O4S 471.22 472 013027 298
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1284 C29H39N3O2 461.30 462 1285 C26H33N3O3 435.25 436 1286 C27H35N5O2 461.28 462 1287 C25H35N3O2 409.27 410 1288 C26H35N3O4S 485.23 486 1289 ο-αΛ-Ο-^ο-’-' y C27H38N4O2 450.30 451 1290 C26H31N3O2S 449.21 450 1291 o-CrUr^-Q^ C29H41N3O2 463.32 464 1292 o-O^n-O'^Ç, C25H32N4O3 436.25 437 1293 C26H35N3O3 437.27 438 1294 O-O^N-O'’0'^ C25H30N4O2S 450.21 451 1295 οΟΛ-Ο^-ο y C24H31N3O2 393.24 394 013027 299
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1296 C25H35N5O2 437.28 438 1297 C27H37N5O2 463.30 464 1298 <A>a<Æ C26H32N6O2S 492.23 493 1299 C24H33N5O3 439.26 440 1300 o f 0 C28H40FN3O3 485.30 486 1301 C27H36FN3O2 453.28 454 1302 C31H37N5O2 511.30 512 1303 £W crWo C28H39N5O2 477.31 478 1304 σθΟΑΟ0* ' C27H39N5O2 465.31 466 1305 σ°α A-û^f C27H39N5O2 465.31 466 1306 a°ajN<r°“b C26H35N5O2S 481.25 482 1307 <AaAJûr'°'VNÎ C26H33N7O2 475.27 470 1308 C26H35N5O2 449.28 450 013027 300
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1309 O C26H37N5O3 467.29 468 1310 ✓ C26H37N5O3 467.29 468 1311 n _ fW er°ONîNJa f 0 C26H37N5O3 467.29 468 1312 aYxACr% C27H37N5O3 479.29 480 1313 C27H39N5O3 481.30 482 1314 Ns~y C28H38N6O2 490.31 491 1315 O ? C28H39N5O4 509.30 510 1316 a„üïCL, C28H39N5O2 477.31 478 1317 ?° C29H40N6O3 520.32 521 1318 Λ C30H44N6O2 520.35 521 1319 αθύΥο. M Ohn> C30H44N6O3 536.35 537 1320 ^Υαλιυ^-ρ ν' C30H34N6O2 510.27 511 013027 301
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1321 0.01¾ O C33H42N6O2 554.34 555 1322 hk C27H35N7O2 489.29 490 1323 F F C29H38F3N5O2 545.30 546 1324 Λχΐ/τ' C29H39N7O2 517.32 518 1325 C31H37N7O2 539.30 540 1326 C26H33N7O2 475.27 476 1327 C26H37N5O2S 483.27 484 1328 C26H35N5O2 449.28 450 1329 C27H35N7O2 489.29 490 1330 σθΟΑ-σ0^ C28H41N5O3 495.32 496 1331 ^ΠΛΟ'0*0'" C25H31N7O2S 493.23 494 1332 C31H39N5O3 529.30 530 013027 302
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 1333 owy >0 C30H42N6O4 550.33 551 1334 C28H41N5O2 479.33 480 1335 Ογ C29H30F2N4O2 504.58 505 1336 5- C25H32FN3O2 425.25 426 1337 F N-Z C25H34FN3O2 427.26 428 1338 F N^0 ^0-040-^ C24H32FN3O3 429.24 430 1339 ; C26H34FN3O2 439.26 440 1340 Z -^-0-0^0-^ C26H34FN3O2 439.26 440 1341 F N-Z~° ^-οΌΛ-ό"0 C25H34FN3O3 443.26 444 1342 F N-^~° -^-0-000-'° C25H34FN3O3 443.26 444 1343 C25H34FN3O3 443.26 444 1344 F N~<0 C27H36FN3O2 453.28 454 013027 303
Ex. No. Structure Molecufar formula Monoisotopic molecular wt. M+H+ 1345 C27H38FN3O2 455.30 456 1346 C27H38FN3O2 455.30 456 1347 F C27H38FN3O2 455.30 456 1348 C26H36FN3O3 457.27 458 1349 F C26H36FN3O3 457.27 458 1350 F nJ-° '^ο-οΛ-ό-^ C25H34FN3O4 459.25 460 1351 -^-Ό-οΛ-ό·^ C25H34FN3O4 459.25 460 1352 F Ν-ΖΛ C28H38FN3O2 467.30 468 1353 v° F N -^ο-οΛ-ό-^ C27H38FN3O3 471.29 472 1354 -^'ο-οΛ-ΰ'0" C27H38FN3O3 471.29 472 1355 O27H34FN5O2 479.27 480 013027 304
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1356 C29H40FN3O2 481.31 482 1357 C29H40FN3O2 481.31 482 1358 C28H39FN4O2 482.31 483 1359 C28H38FN3O3 483.29 484 1360 0 0 J nN~Ô C28H38FN3O3 483.29 484 1361 --Ό-Ο^νΛ0 C28H36FN5O2 493.29 494 1362 Λ N-> F N—/ C27H35FN6O2 494.28 495 1363 F ν-ΛΝ) C28H37FN4O3 496.29 497 1364 F "^O '^o<K--ô-N° C29H41FN4O2 496.32 497 1365 N C28H39FN4O3 498.30 499 1366 O J ^nbQ'^oO’N-œ^ ° C26H32FN3O4 469.24 470 1367 -^ο-οΛ-^'^ό0 C29H40FN3O3 497.30 498 013027 305
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1368 C25H31FN4O2 438.24 439 1369 p C26H34FN3O2 439.26 440 1370 C26H36FN3O2 441.28 442 1371 C25H34FN3O3 443.26 444 1372 F N-/ C27H36FN3O2 453.28 454 1373 -^o-OV^’û-0 C26H34FN3O3 455.26 456 1374 F Ό C28H38FN3O2 467.30 468 1375 C27H37FN4O2 468.29 469 1376 C26H34FN3O2S 471.24 472 1377 ^ο-Ο^ηΛ’0'^ O C26H36FN3O4 473.27 474 1378 C28H41FN4O2 484.32 485 013027 306
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1379 r}N C28H37FN4O3 496.29 497 1380 C28H37FN4O3 496.29 497 1381 -^-O<K-0'N'ÿ C32H38FN3O2 515.29 516 1382 F Ν·>Ο C31H38FN3O3 519.29 520 1383 0 C31H43FN4O2 522.34 523 1384 F οφ C27H36FN3O3 469.27 470 1385 0 C27H36FN3O3 469.27 470 1386 -^o-OO-O^ F F C28H34F3N3O3 517.26 518 1387 \ O F N-Z^S'o C27H36FN3O4S 517.24 518 1388 -''-οΟΛ^'0 C30H41FN4O3 524.32 525 1389 -o-Ch-^'0 C27H36FN3O3 469.27 470 013027 307
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1390 C22H28FN3O2 385.22 386 1391 C29H38FN3O4 511.29 512 1392 C26H36FN3O3 457.27 458 1393 F N-^°Z - C25H34FN3O3 443.26 444 1394 C27H36FN3O3 469.27 470 1395 F 0^-o-o-Vo'*0 C26H34FN3O3 455.26 456 1396 Λ° F 0- C28H38FN3O3 483.29 484 1397 _0- C26H36FN3O3 457.27 458 1398 C26H34FN3O4 471.25 472 1399 cXo z C28H38FN3O4 499.29 500 1400 C27H38FN3O3 471.29 472 013027 308
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1401 ^-0-0-0-"° C28H40FN3O3 485.30 486 1402 5° F N-s C27H36FN3O4 485.27 486 1403 F C27H36FN3O3 469.27 470 5 Table 11
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1404 C22H30N4O2 382.24 383 1405 C24H31CIN4O 426.22 427 1406 C23H32N4O2 396.25 397 1407 C25H27FN4O 418.22 419 1408 C23H32N4O2 396.25 397 013027 309 1409 °<Po C22H30N4O2 382.24 383 1410 o C23H25N5O2 403.20 404 1411 C24H33N3O2 395.26 396 1412 C23H31N3O2 (S)- Konfiguration 381.24 382 1413 C23H31N3O2 381.24 382 1414 O-O^N-Ô-^ C23H30FN3O2 399.23 400 1415 C24H32FN3O2 413.25 414 1416 C24H32N4O 392.26 393 1417 -^ο-οΛ-ό-^ C24H32FN3O2 413.25 414 1418 C24H32FN3O2 (S)-configuration 413.25 414 1419 0-0^0-;% C25H34FN3O2 427.26 428 1420 C26H36FN3O2 441.28 442 013027 310 1421 ο-οΛη-^' y Λ F C26H36FN3O2 441.28 442 1422 0-θΛ<ζΝ% C27H36FN3O2 453.28 454 1423 o ijy— C27H38FN3O3 471.29 472
Table 12
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1424 C27H35N3O2 433.27 434 1425 4- C28H39N3O4 481.29 482 1426 C27H38N4O4 482.29 483 1427 C24H32N4O3 424.25 425 1428 yo-OVO'"0 C24H33N3O2 395.26 396 1429 C24H31N3O3 409.24 410 1430 n hIH° θ/· C29H33FN4O3 504.25 505 013027 311
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1431 0 0i C27H38N4O4 482.29 483 1432 °' -b C30H43N3O5 525.32 526 1433 C25H33N3O3 423.25 424 1434 0 -b C29H41N3O5 511.30 512 1435 \ ° σ' C26H28FN3O 417.22 418 1436 C27H30FN3O 431.24 432 1437 F C28H38FN3O4 499.29 500 1438 \ 0 F hN-Ç -^o-θΛ-ό-^ C28H38FN3O4 499.29 500 1439 F hW -^oO^-C-*0 0?< C28H38FN3O4 (S)- Konfiguration 499.29 500 1440 n C25H32N4O2 420.25 421 1441 C24H32CIN3O2 429.22 430 1442 c o 0*' jzO^n-Q-Q^0 C29H40FN3O4 513.30 514 01302? 312
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 1443 \ 0 F H C30H42FN3O4 527.32 528 5 Table 13
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1444 C23H30N4O 378.24 379 1445 C23H30N4O 378.24 379 1446 0 HN C21H28N4O2 368.22 369 1447 C27H38N4O 434.30 435 1448 C26H36N4O 420.29 421 1449 \ C29H42N4O 462.34 463 1450 O \ q-ovc/-S À C28H38N4O 446.30 447 013027 313
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1451 OûW C24H32N4O 392.26 393 1452 C26H36N4O 420.29 421 1453 C26H32N4O 416.26 417 1454 '-ο-ΟΛ-Ο-^ C23H31N3O2 381.24 382 1455 C24H31N3O 377.25 378 1456 o-θΛθ"^ C22H29N3O2 367.23 368 1457 η,ν C22H21FN4O 376.17 377 1458 o-OW^ y C20H26N4O2 354.21 355 1459 ό C23H24N4O2 388.19 389 1460 Η,Ν C22H27CIN4O 398.19 399 1461 ο -Η,Ν o^rO-rO C22H30N4O2 382.24 383 013027 314
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1462 ο-ΟΛ-Ο-^ 0 C21H21N5O2 375.17 376 1463 N ο-οΛ^·^ C22H27F2N3O2 403.21 404 1464 N C22H28FN3O2 385.22 386 1465 O Cl ^-('N C22H28CIN3O2 401.19 402 1466 \ o-œONp-^N C23H31N3O2 381.24 382 1467 C23H28F3N3O2 435.21 436 1468 o-Oto"0" s C23H28F3N3O2 435.21 436 1469 \ o€r*°-Çr'°N ^y"7 F F C22H27F2N3O2 403.21 404 1470 οΟΛ-Ο^-ί ^y-7 F Cl C22H27CIFN3O2 419.18 420 1471 oûW *N C23H28N4O2 392.22 393 013027 315
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1472 C23H27CIN4O2 426.18 427 1473 C22H28BrN3O2 445.14 446 1474 C26H31N3O2 417.24 418 1475 N C22H27F2N3O2 403.21 404 1476 \ N Br C22H28BrN3O2 445.14 446 1477 S C23H30CIN3O2 415.20 416 1478 Cl N C21H27CIN4O2 402.18 403 1479 C22H30N4O2 382.24 383 1480 C22H30N4O2 382.24 383 1481 \ 'το-οΛ-α^" C22H30N4O2 382.24 383 1482 Ky-CH-ô^ C24H25FN4O 404.20 405 013027 316
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1483 0 C22H29N3O3 383.22 384 1484 ο ΛΝ C20H26N4O2 354.21 355 1485 ο-οΛ-ό-^ C22H28FN3O2 385.22 386 1486 C22H29N3O2 367.23 368 1487 C22H28N4O 364.23 365 1488 0 -χ ^-oyQr ο C25H35N3O3 425.27 426 1489 ο C24H33N3O3 411.25 412 1490 ηΝ σ°θΑ£ϊ^ C22H29N5O2 395.23 396 1491 ÀN O^OAJCj C23H25N5O2 403.20 404 1492 Ν σθαΑΠ^ C23H25N5O2 403.20 404 1493 C20H22N6O 362.19 363 013027 317
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1494 Ço C25H25N5O2 427.20 428 1495 C23H25N3O2 375.20 376 1496 C19H21N5O2 351.17 352 1497 C20H22N4OS2 398.12 399 1498 n-'Q'1'1 C21H23N5O 361.19 362 1499 N λΛο-’Ο N==/ C20H22N6O 362.19 363 1500 \ o<n-p-N°" s C22H28FN3O2 385.22 386 1501 N σθ-ΟΑΨ^ F C23H29FN4O2 412.23 413 1502 \ o-O^-Q-0 F C22H34FN3O2 391.26 392 1503 N C23H30FN3O2 399.23 400 013027 318
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1504 N F C22H28FN5O2 413.22 414 1505 N F C23H24FN5O2 421.19 422 1506 C23H22F3N3O2 429.17 430 1507 "N C24H28N4O2 404.22 405 1508 C28H33N3O2 443.26 444 1509 <^0^Cy° ^0Η0Ν C24H24N4O2 400.19 401 1510 O °TNXJ 0 νη0Όν. C24H26N4O3 418.20 419 1511 F C23H30FN3O2 399.23 400 1512 F C22H27FN4O4 430.20 431 1513 N o N θΌ^N-C/ A r C22H29FN4O2 400.23 401 013027 319
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1514 N C24H26N4O3 418.20 419 1515 C23H30FN3O2 399.23 400 1516 Ρ<λ£Λ·Ο-Ν° C24H29FN4O 408.23 409 1517 œ C25H26FN3O2 419.20 420 1518 C25H26FN3O2 419.20 420 1519 <c C24H26FN3O2S 439.17 440 1520 C24H30FN3O 395.24 396 1521 o-o-V^" C25H32FN3O 409.25 410 1522 F C26H27F2N3O 435.21 436 1523 ΡΊ^όΛ-θ-Ν° C22H21CIFN3O2 413.13 414 1524 N C22H22FN3O2 379.17 380 01302? 320
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1525 C23H25N3O3 391.19 392 1526 0 Z C23H25N3O3 391.19 392 1527 F \ C22H22FN3O2 379.17 380 1528 s N C23H25N3O2S 407.17 408 1529 N C23H25N3O2 375.20 376 1530 οΛ-Ο-'0'-' 0 C24H27N3O3 405.20 406 1531 C23H30FN3O2 399.23 400 1532 C25H31CIFN3O 443.21 444 1533 C24H25CIFN3O3 457.16 458 1534 C24H30FN3O2 411.23 412 1535 C24H27N3O3 405.20 406 1536 r\ _N' C23H22N4O2 386.17 387 013027 321
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1537 Q C24H25N3O3 403.19 404 1538 0 / C24H27N3O4 421.20 422 1539 \ C24H25N3O3 403.19 404 1540 o; , C24H25FN4O4 452.19 453 1541 C23H30FN3O2 399.23 400 1542 C25H26FN3O 403.21 404 1543 I C26H28FN3O2 433.22 434 1544 C28H29FN4O2 472.23 473 1545 C26H28FN3O 417.22 418 1546 C24H32FN3O2 413.25 414 1547 F L.F n C22H18F5N3O2 451.13 452 013027 322
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1548 \ N C24H25N3O3 403.19 404 1549 C22H21F2N3O2 397.16 398 1550 C22H21F2N3O2 397.16 398 1551 ?n C22H21F2N3O2 397.16 398 1552 c^-σΑ - C23H23N3O4 405.17 406 1553 C28H26FN3O2 455.20 456 1554 C26H31N3O3 433.24 434 1555 C25H25F2N3O 421.20 422 1556 o'N C23H25N3O2S 407.17 408 1557 0 'N C24H27N3O2S 421.18 422 1558 \ jy0N-o-A C24H27N3O2 389.21 390 013027 323
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1559 C24H27N3O2 389.21 390 1560 F F+F kl C23H22F3N3O3 445.16 446 1561 C25H29N3O2 403.23 404 1562 οΛ-Ο-^'ί C25H29N3O2 403.23 404 1563 K '®Ν C21H22N4O2 362.17 363 1564 C22H21F2N3O2 397.16 398 1565 οΛ-Ο-"0 Χ=Ν-~o IN C22H24N4O3 392.18 393 1566 ^.Q N C23H25N3O4S 439.16 440 1567 rnrF o z-?N C22H21F2N3O2 397.16 398 1568 Xf^N-V C23H22F3N3O3 445.16 446 013027 324
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1569 N C23H24FN3O2 393.18 394 1570 νΠ '“N C20H21N5O2 363.17 364 1571 C21H21FN4O2 380.17 381 1572 C23H30FN3O2 399.23 400 1573 °"n®‘ 'N C22H22N4O3S 422.14 423 1574 \ N οΛο-'0 C) \ C23H25N3O2S 407.17 408 1575 \ o- C23H25N3O2S 407.17 408 1576 \ N ΟΛ-0-C S C23H25N3OS2 423.14 424 1577 N οΛ-ζ>^ O C24H27N3O2S 421.18 422 013027 325
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 1578 z-o" C24H27N3O2S 421.18 422 1579 n' C23H22N4OS 402.15 403 1580 N C24H27N3O3S 437.18 438 1581 0 G24H25N3O2S 419.17 420 1582 \ οΛΟ'0 " 0 C24H25N3O2S 419.17 420 1583 λ οΛο40 C23H23N3O3S 421.15 422 1584 βΛ-θ-Ν° \=sZ S C23H25N3OS2 423.14 424 1585 \ N οΛ-Ο-’0 C24H27N3OS2 437.16 438 326
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 1586 \ N οΛ-Ο-'0 C24H27N3OS 405.19 406 1587 \ N C24H27N3OS 405.19 406 1588 F F+F k. C23H22F3N3O2S 461.14 462 1589 C25H29N3OS 419.20 420 1590 \ N C25H29N3OS 419.20 420 1591 0 C24H25N3O3S 435.16 436 1592 N o-to-^3 (S C22H24N4O2S 408.16 409 1593 fi ί\Λο<3" C23H22F3N3O2S 461.14 462 013027 327
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1594 >0 C24H26N4O2S 434.18 435 1595 N C21H24N4O2S 396.16 397 1596 C21H21FN4OS 396.14 397 1597 \ N z-o 0 C25H27N3O3S 449.18 450 1598 tyZCr’O C28H33N3OS 459.23 460 1599 \ j^Njyc o^N~~ C24H26N4O2S 434.18 435 1600 οΛ-Ο-^ \ C25H28N4O2S 448.19 449 1601 \ N-/*' ' 0 C25H28N4O2S 448.19 449 013027 328
Ex. No. Structure Molecular formula Monoisotopicmolecular wt. M+H+ 1602 \ C24H28N4OS 420.20 421 1603 \ N οΛ-Ο0 N 0 C24H26N4O2S 434.18 435 1604 \ /=O C24H25N3O2S 419.17 420 1605 οΛ-Ο-’0 v C20H21N3OS2 383.11 384 1.606 O / γΨ1 o° C26H28FN3O2 433.22 434 1607 xd-d^ oO0 C26H27CIFN3O2 467.18 468 1608 \ C21H21FN4OS 396.14 397 1609 y ς F C24H32FN3O2 413.25 414 1610 C25H34FN3O2 427.26 428 013027 329
Ex. No. Structure Molecular formula Monoisotopic molecular wt. M+H+ 1611 C25H34FN3O2 427.26 428 1612 S O F C26H34FN3O2 439.26 440 1613 C25H25N3OS 415.17 416 1614 C23H22N4OS 402.15 403 1615 C24H22FN3OS 419.15 420 1616 C23H22N4OS 402.15 403 1617 / O '—' C21H27N5O3 397.21 398 1618 C25H28N4O2 416.22 417
Synthèses of pyrrolidinvlanilines required as intermediates [1-(4-Amino-2-chlorophenyl)pyrrolidin-3-yl]dimethylamine 5 Method C-a 3-Dimethylaminopyrrolidine (0.34 g) was slowly added to a solution of 2-chloro-1 fluoro-4-nitrobenzene (0.52 g) in DMF (5 ml). After 1 hour, ethylacetate (30 mi) was added to the reaction mixture, and it was extractedwith 10% hydrochloric acid (2 χ 20 ml). The aqueous phase was washed 10 with ethyl acetate (2 x 20 ml), adjusted to pH > 10 with 10% ammonia andextracted with ethyl acetate. The yellow solution was dried with sodiumsulfate, filtered and concentrated in a rotary evaporator. The residue wasthen dissolved in dichloromethane (50 ml), zinc (10 g) was added, and 013027 330 glacial acetic acid (5 ml) was slowly added dropwise while cooling in ice.The suspension was stirred for 15 minutes, filtered, washed with 10%ammonia (2 χ 20 ml) and concentrated. This resulted in the product withthe molecular weight of 239.75 (C12H18CIN3); MS (ESI): 239 (M+H+), 240(M+H+), 5-Amino-2-(3-dimethylaminopyrrolidin-1-yl)benzonitrile
Dimethylaminopyrrolidine was treated with 2-fluoro-5-nitrobenzonitrile andsubsequently reduced by method C-a. This resulted in the product with themolecular weight of 230.32 (C13H18N4); MS (ESI): 231 (M+H+), [1-(4-Amino-3-chlorophenyl)pyrrolidin-3-yl]dimethylamine
Dimethylaminopyrrolidine was treated with 3-chloro-1-fluoro-4-nitrobenzeneand subsequently reduced by method C-a. This resulted in the product withthe molecular weight of 239.75 (C12H18CIN3); MS (ESI): 239 (M+H+), 240(M+H+), [1-(4-Amino-3-methylphenyl)pyrrolidin-3-yl]dimethylamine
Dimethylaminopyrrolidine was treated with 4-fluoro-2-methyl-1-nitrobenzene and subsequently reduced by method C-a. This resulted inthe product with the molecular weight of 219.33 (C13H21N3); MS (ESI):220 (M+H+). tert-Butyl (R)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamateMethod C-b tert-Butyl (R)-(+)-pyrrolidin-3-ylcarbamate (1.86 g) was slowly added to asuspension of 3,4-difluoronitrobenzene (1.59 g) and potassium carbonate(2.8 g) in DMF (10 ml). After 10 minutes, ethyl acetate (50 ml) was added,and the mixture was washed with water (3 χ 50 ml) in a separating funnel,dried with sodium sulfate, filtered and concentrated. The residue wasdissolved in DMF (10 ml), and sodium hydride (0.48 g) was added. After 15minutes, methyl iodide (1.41 g) was then added while cooling in ice. After30 minutes, ethyl acetate (50 ml) was added, and the mixture was washedwith water (3 χ 50 ml) in a separating funnel, dried with sodium sulfate,filtered and concentrated. The substance was then treated as described formethod B. This resulted in the product with the molecular weight of 309.39(C16H24FN3O2); MS (ESI): 310 (M+H+). tert-Butyl (S)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate 013027 331 was obtained analogously. tert-Butyl (R)-[1 -(2-fluoro-4-isopropylaminophenyI)pyrrolidin-3- yl]methylcarbamate tert-Butyl (R)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamatewas alkylated with acetone using triacetoxyborohydride as reducing agentby method N. This resulted in the product with the molecular weight of351.47 (C19H30FN3O2); MS (ESI): 352 (M+H+). tert-Butyl (R)-[1-(2-Fluoro-4-cyclobutylaminophenyl)pyrrolidin-3-yl]methyl-carbamate tert-Butyl (R)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamatewas alkylated with cyclobutanone using triacetoxyborohydride as reducingagent by method N. This resulted in the product with the molecular weightof 363.48 (C20H30FN302); MS (ESI): 364 (M+H+). tert-Butyl (R)-[1-(2-fluoro-4-methylaminophenyl)pyrrolidin-3- yl]methylcarbamate tert-Butyl (R)-{1-[4-(benzyloxycarbonylmethylamino)-2- fluorophenyl]pyrrolidin-3-yl}-methylcarbamate was treated as described formethod B. This resulted in the product with the molecular weight of 323.41(C17H26FN3O2); MS (ESI): 324 (M+H+). tert-Butyl (R)-{1 -[4-(benzyloxycarbonylmethylamino)-2- fluorophenyl]pyrrolidin-3-yl}-methylcarbamate tert-Butyl (R)-(+)-[1 -(4-amino-2-fluorophenyl)pyrrolidin-3- yl]methylcarbamate (0.93 g) was added to a solution of N- (benzyloxycarbonyloxy)succinimide (2.49 g) in dichloromethane (30 ml).After 12 hours, the mixture was washed with water (2 x 30 ml), driedsodium sulfate, filtered and concentrated. The residue was recrystallizedfrom acetonitrile. The product obtained in this way was dissolved in DMF(10 ml), and sodium hydride (0.24 g) was added. After 15 minutes, methyliodide (0.71 g) was added while cooling in ice. After 15 minutes, ethylacetate (50 ml) was added, and the mixture was washed with water (3 χ 30ml), dried sodium sulfate, filtered and concentrated. This resulted in theproduct with the molecular weight of 457.55 (C25H32FN3O4); MS (ESI):458 (M+H+). (R)-[1-(2-Fluoro-4-methylaminophenyl)pyrrolidin-3-yl]dimethylamine 013027 332 (R)-{1-[4-(Benzyloxycarbonylmethylamino)-2-fluorophenyl]pyrrolidin-3-yl}methylcarbamic acid tert-butyl ester was treated by method G, and theresulting amine was methylated by method M. Finally, hydrogénation wascarried out by method B. This resulted in the product with the molecularweight of 237.32 (Cl 3H20FN3); MS (ESI): 238 (M+H+).
Dimethyl-[1-(4-methylaminophenyl)pyrrolidin-3-yl]amine can be preparedanalogously. 2-Dimethylamino-N-[1-(2-fluoro-4-methylaminophenyl)pyrrolidin-3-yl]-N- methylacetamide (R)-{1-[4-(Benzyloxycarbonylmethylamino)-2-fliiorophenyl]pyrrolidin-3-yljmethylcarbamic acid tert-butyl ester was treated by method G, and theresulting amine was reacted with Ν,Ν-dimethylglycine by method E. Finally,hydrogénation was carried out by method B. This resulted in the productwith the molecular weight of 308.40 (C16H25FN4O); MS (ESI): 309(M+H+). tert-Butyl (R)-[1-(4-amino-3-fluorophenyl)pyrrolidin-3-yl]methylcarbamate 2,4-Difluoronitrobenzene was treated with tert-butyl (R)-(+)-pyrrolidin-3-ylcarbamate, methylated and subsequently hydrogenated by method C-b.
This resulted in the product with the molecular weight of 309.39(C16H24FN3O2); MS (ESI): 310 (M+H+). tert-Butyl [1-(4-aminonaphthalen-1-yl)pyrrolidin-3-yl]methylcarbamateMethod C-c tert-Butyl methylpyrrolidin-3-ylcarbamate (1.86 g) was slowly added to asuspension of 4-fluoro-1-nitronaphthalene (1.91 g) and potassiumcarbonate (2.8 g) in DMF (10 ml). After 10 minutes, ethyl acetate (50 ml)was added, and the mixture was washed with water (3 χ 50 ml) in aseparating funnel, dried with sodium sulfate, filtered and concentrated. Thesubstance was then treated as described for method B. This resulted in theproduct with the molecular weight of 341.46 (C20H27N3O2); MS (ESI): 342(M+H+). tert-Butyl [1-(4-amino-3-bromophenyl)pyrrolidin-3-yl]methylcarbamate 2-Bromo-4-fluoro-1 -nitrobenzene was treated with tert-butylmethylpyrrolidin-3-ylcarbamate and subsequently reduced by method C-a.
This resulted in the product with the molecular weight of 370.29(C16H24BrN3O2); MS (ESI): 370 (M+H+), 372 (M+H+). 013027 333
Tert-butyl [1-(4-amino-3-cyanophenyl)pyrrolidin-3-yl]methylcarbamate 2-Cyano-4-fluoro-1-nitrobenzene was treated with tert-butylmethylpyrrolidin-3-yl-carbamate and subsequently reduced by method C-a.This resulted in the product with the molecular weight of 316.41(C17H24N4O2); MS (ESI): 317 (M+H+). tert-Butyl [1-(5-amino-6-chloropyridin-2-yl)pyrrolidin-3-yl]methylcarbamate 2- Chloro-6-fluoro-3-nitropyridine was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently reduced by method C-c.This resulted in the product with the molecular weight of 326.83(C15H23CIN4O2); MS (ESI): 326 (M+H+), 327 (M+H+). tert-Butyl [1-(4-amino-2,3-difluorophenyl)pyrrolidin-3-yl]methylcarbamate 2.3.4- Trifluoronitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently reduced by method C-c. This resulted in theproduct with the molecular weight of 327.38 (C16H23F2N3O2); MS (ESI):328 (M+H+). tert-Butyl [1 -(4-amino-2-bromophenyl)pyrrolidin-3-yl]methylcarbamate 3- Bromo-4-fluoro-1-nitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently reduced by method C-a.This resulted in the product with the molecular weight of 370.29(C16H24BrN3O2); MS (ESI): 370 (M+H+), 372 (M+H+). tert-Butyl [1-(4-amino-2,6-difluorophenyl)pyrrolidin-3-yl]methylcarbamate 3.4.5- Trifluoronitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted inthe product with the molecular weight of 327.38 (C16H23F2N3O2); MS(ESI): 328 (M+H+). tert-Butyl (R)-[1-(4-amino-2-hydroxymethylphenyl)pyrrolidin-3-yl]carbamate(2-Fluoro-5-nitrophenyl)methanol was treated with tert-butyl (R)-(+)-pyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c.This resulted in the product with the molecular weight of 307.40(C16H25N3O3); MS (ESI): 308 (M+H+). tert-Butyl [1-(4-amino-2-chlorophenyl)pyrrolidin-3-yl]methylcarbamate2-Chloro-1 -fluoro-4-nitrobenzene was treated with tert-butyl 013027 334 methylpyrrolidin-3-ylearbamate and subsequently hydrogenated by methodC-c. This resulted in the product with the molecular weight of 311.81(C15H22CIN3O2); MS (ESI): 311 (M+H+), 312 (M+H+). tert-Butyl [1-(4-amino-2,5-difluorophenyl)pyrrolidin-3-yl]methyIcarbamate 3,4,6-Trifluoronitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resultedin the product with the molecular weight of 327.38 (C16H23F2N3O2); MS(ESI): 328 (M+H+). tert-Butyl [1-(4-amino-2-methylphenyl)pyrrolidin-3-yl]methylcarbamatetert-Butyl 4-fluoro-3-methylnitrobenzene was treated with tert-butylmethylpyrrolidin-3-yl-carbamate and subsequently hydrogenated bymethod C-c. This resulted in the product with the molecular weight of291.40 (C16H25N3O2); MS (ESI): 292 (M+H+). tert-Butyl [1-(4-amino-3-trifluoromethylphenyl)pyrrolidin-3- yl]methylcarbamate 4-Fluoro-2-trifluoromethylnitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of345.37 (C16H22F3N3O2); MS (ESI): 346 (M+H+). tert-Butyl [1 -(4-amino-2-chloro-3-fluorophenyl)pyrrolidin-3- yl]methylcarbamate 2,4-Difluoro-3-chloronitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of329.80 (C15H21CIN3O2); MS (ESI): 329 (M+H+), 330 (M+H+). tert-Butyl [1-(4-amino-2-cyanophenyl)pyrrolidin-3-yl]methylcarbamate 3-Cyano-4-fluoronitrobenzene was treated with tert-butyl methylpyrrolidin- 3-yl-carbamate and subsequently hydrogenated by method C-c. Thisresulted in the product with the molecular weight of 302.38 (C16H22N4O2); MS (ESI): 303 (M+H+). tert-Butyl [1 -(4-amino-5-chloro-2-methylphenyl)pyrrolidin-3- yl]methylcarbamate 1-Chioro-5-fluoro-4-methyl-2-nitrobenzene was treated with tert-butyl 013027 335 methylpyrrolidin-3-ylcarbamate ànd subsequently hydrogenated by methodC-c. This resulted in the product with the molecular weight of 325.84(C16H24CIN3O2); MS (ESI): 325 (M+H+), 326 (M+H+). tert-Butyl (R)-[1-(5-aminopyridin-2-yl)pyrrolidin-3-yl]methylcarbamate2-Chloro-5-nitropyridine was treated with tert-butyl (R)-(+)-pyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-b. This resulted inthe product with the molecular weight of 322.37 (C16H24FN3O2); MS(ESI): 323 (M+H+). tert-Butyl [1-(5-aminopyridin-2-yl)pyrTOlidin-3-yl]methylcarbamate2-Chloro-5-nitropyridine was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted inthe product with the molecular weight of 322.37 (C16H24FN3O2); MS(ESI): 323 (M+H+). tert-Butyl (R)-[1 -(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate 4-Fluoronitrobenzene was treated with tert-butyl (R)-(+)-pyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-b. This resulted inthe product with the molecular weight of 291.40 (C16H25N3O2); MS (ESI):292 (M+H+). tert-Butyl [1-(4-amino-2-trifluoromethylphenyl)pyrrolidin-3- yl]methylcarbamate 4-Fluoro-3-trifluoromethylnitrobenzene was treated with tert-butylmethylpyrrolidin-3-yl-carbamate and subsequently hydrogenated bymethod C-c. This resulted in the product with the molecular weight of345.37 (C16H22F3N3O2); MS (ESI): 346 (M+H+). tert-Butyl [1-(5-amino-4-methylpyridin-2-yl)pyrrolidin-3-yl]methylcarbamate2-Chloro-4-methyl-5-nitropyridine was treated with tert-butylmethylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by methodC-c. This resulted in the product with the molecular weight of 306.419(C16H26N4O2); MS (ESI): 306 (M+H+), 307 (M+H+). tert-Butyl [1-(5-amino-3-methylpyridin-2-yl)pyrrolidin-3-yl]methylcarbamate2-Chloro-3-methyl-5-nitropyridine was treated with tert-butylmethylpyrrolidin-3-yl-carbamate and subsequently hydrogenated bymethod C-c. This resulted in the product with the molecular weight of 013027 336 306.419 (C16H26N4O2); MS (ESI): 306 (M+H+), 307 (M+H+). tert-Butyl [1-(4-amino-2-hydroxymethylphenyl)pyrrolidin-3- yl]methylcarbamate (2-Fluoro-5-nitrophenyl)methanol was trèated with tert-butylmethylpyrrolidin-3-yl-carbamate and subsequently hydrogenated bymethod C-c. This resulted in the product with the molecular weight of321.42 (C17H27N3O3); MS (ESI): 322 (M+H+). tert-Butyl [1 -(4-amino-3-chloro-2-cyanophenyl)pyrrolidin-3- yljmethylcarbamate 2- Chloro-6-fluoro-3-nitrobenzonitrile was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated bymethod C-c. This resulted in the product with the molecular weight of 350.5(C17H23CIN4O2); MS (ESI): 350 (M+H+), 351 (M+H+). tert-Butyl [1-(4-amino-3-methylphenyl)pyrrolidin-3-yl]methylcarbamate 4- Fluoro-2-methylnitrobenzene was treated with tert-butyl methylpyrrolidin- 3- ylcarbamate and subsequently hydrogenated by method C-c. Thisresulted in the product with the molecular weight of 291.40 (C16H25N3O2);MS (ESI): 292 (M+H+). tert-Butyl [1-(5-aminopyridin-2-yl)pyrrolidin-3-yl]carbamate 2-Chloro-5-nitropyridine was treated with tert-butyl (R)-(+)-pyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resultedin the product with the molecular weight of 278.36 (C14H22N4O2); MS(ESI): 279 (M+H+). 5- (3-Dimethylaminopyrrolidin-1-yl)pyridin-2-ylamine A suspension of 5-bromo-2-nitropyridine (2 g), 3-(dimethylamino)pyrrolidine(1.14 g), (R)-(+)2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (0.5 g),palladium(ll) acetate (0.09 g), césium carbonate (4.5 g) in toluene (20 ml)was heated at 100°C for 3 hours. Cooling to room température wasfollowed by extraction with 1N hydrochloric acid (2 χ 100 ml). The aqueousphase was adjusted to pH > 10 with ammonia, extracted with ethyl acetate(2 χ 100 ml), dried with sodium sulfate, filtered and concentrated. Thesubstance was then treated as described for method B. This resulted in theproduct with the molecular weight of 206.29 (C11H18FN4); MS (ESI): 207(M+H+). 0T3027 337 N-[1-(4-Aminophenyl)-4-hydroxypyrrolidin-3-yl]-N-methylacetamidetrans-N-(4-Hydroxypyrrolidin-3-yl)-N-methylacetamide was reacted with 4-fluoronitrobenzene by method C, and the product was subsequentlyhydrogenated by method B. This resulted in the product with the molecularweight of 249.32 (C13H19N3O2); MS (ESI): 250 (M+H+). trans-N-(4-Hydroxypyrrolidin-3-yl)-N-methylacetamide tert-Butyl trans-3-hydroxy-4-methylaminopyrrolidin-1-carboxylate (1.0 g,tetrahedron: Asymmetry 2001,12, 2989) was mixed with pyridine (1.5 g)and acetic anhydride (0.567 g). After 3 hours, volatile fractions wereremoved under high vacuum. The residue was treated by method G. Thisresulted in the product with the molecular weight of 158.20 (C7H14N2O2);MS (ESI): 159 (M+H+). trans-1-(4-Aminophenyl)-4-dimethylaminopyrTolidin-3-ol tert-Butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.0 g,tetrahedron: Asymmetry 2001,12, 2989) was stirred with dimethylamine(40% aq., 10 ml) for 12 hours. The mixture was concentrated andpartitioned between water and ethyl acetate. The organic phase was driedover magnésium sulfate and concentrated. The crude product was treatedby method G. The resulting amine was reacted with 4-fluoronitrobenzeneby method C. The resulting nitro compound was hydrogenated by methodB. This resulted in the product with the molecular weight of 221(C12H19N3O); MS (ESI): 222 (M+H+).
[1-(4-Aminophenyl)-4-methoxypyrrolidin-3-yl]dimethylamine
An alternative possibility is for the nitro compound prepared in thepreceding method to be alkylated with methyl iodide by method F and thenhydrogenated by method B. This resulted in the product with the molecularweight of 235 (C13H21N3O); MS (ESI): 236 (M+H+).
[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine
Dimethylpyrrolidin-3-ylamine was reacted with 4-fluoronitrobenzene bymethod C, and the product was subsequently hydrogenated by method B.This resulted in the product with the molecular weight of 205.31(C12H19N3); MS (ESI): 206 (M+H+). 1-(4-Aminophenyl)-3-dimethylaminopyrrolidin-2-one 013027 338
Trisodium phosphate (3.56 g) was added to a solution of 4-nitroaniline (5.0g) in acetonitrile (30 ml) and, at 0°C, 2-bromo-4-chlorobutyryl bromide (11g) was added. After one hour, a solution of sodium hydroxide (3.2 g) inwater (10 ml) was added, and the mixture was vigorously stirred at roomtempérature. After 6 hours, the same amount of sodium hydroxide solutionwas again added, and the mixture was left to stand overnight. The reactionsolution was diluted with water and extracted with ethyl acetate. Theorganic phase was dried over magnésium sulfate and concentrated. Thecrude product (0.5 g) was heated with dimethylamine (160 mg) in toluene(20 ml) at 80°C for 3 hours. The reaction solution was diluted with waterand extracted with ethyl acetate. The organic phase was dried overmagnésium sulfate and concentrated. The crude product washydrogenated by method B. This resulted in the product with the molecularweightof 219.29 (C12H17N3O); MS (ESI): 220 (M+H+). 1 -(4-Aminophenyl)-3-(7-azabicyclo[2.2.1 ]hept-7-yl)pyrrolidin-2-one wasobtained in an analogous manner. 4-[3-(7-Azabicyclo[2.2.1]hept-7-yl)pyrrolidin-1-yl]phenylamine 1-(4-Nitrophenyl)-3-(7-azabicyclo[2.2.1]hept-7-yl)pyrrolidin-2-one (0.25 g) inTHF (10 ml) was mixed with borane-THF complex (1M in THF, 0.83 ml)and boiled under reflux for 3 hours. After the reaction was complété, themixture was diluted with water and adjusted to pH 9-10 with hydrochloricacid (4N). Extraction in ethyl acetate, drying and concentration of theorganic phase afforded a crude product that was hydrogenated by methodB. This resulted in the product with the molecular weight of 257.38(C16H23N3); MS (ESI): 258 (M+H+). (R)-1 '-(4-Aminophenyl)-[1,3']bipyrrolidinyl-2-one tert-Butyl [1-(4-Nitrophenyl)pyrrolidin-3-yl]carbamate was treated by method G. The crude product (1.4 g) was dissolved in acetonitrile (20 ml)and mixed with trisodium phosphate (0.67 g) and 4-chlorobutyryl chloride(1.1 g). After 2 hours, sodium hydroxide (0.6 g) in water (10 ml) was addedand the mixture was vigorously stirred. After 12 hours, the same amount ofsodium hydroxide solution was again added, and the mixture was stirred fora further 24 hours. The concentrated reaction solution was partitionedbetween water and ethyl acetate, and the organic phase was dried andconcentrated. The residue was hydrogenated by method B. This resulted inthe product with the molecular weight of 245.33 (C14H19N3O); MS (ESI): 246 (M+H+). 01302/ 339 1-Methylpiperidine-3-carboxylic acid [(R)-1-(4-aminophenyl)pyrrolidin-3-yljmethylamide tert-Butyl (R)-[1-(4-nitrophenyl)pyrrolidin-3-yl]methylcarbamate was treatedby method G and reacted with 1-methylpiperidine-3-carboxylic acid bymethod E. Finally, hydrogénation was also carried out by method E. Thisresuited in the product with the moleGular weight of 316.45 (€18H28N4O);MS (ESI): 317 (M+H+). (R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-2-dimethylamino-N-methylacetamide was obtained in an analogous manner using N,N-dimethylglycine. N-[(R)-1-(4-Aminophenyl)pyrrolidin-3-yl]-N-(2-diethylaminoethyl)acetamideN-(2-Diethylaminoethyl)-N-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]acetamidewas hydrogenated by method B. This resuited in the product with themolecular weight of 318.47 (C18H30N4O); MS (ESI): 319 (M+H+). N-(2-Diethylaminoethyl)-N-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]acetamideAcetyl chloride (2.9 g) was dissolved in 50 ml of dry dichloromethane,mixed with 5.3 ml of triethylamine, and after addition of N,N-diethyl-N'-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]-ethane-1,2-diamine (5.8 g), stirred at roomtempérature for 30 minutes. Subsequently, (LCMS check), water(10 ml)was added to the reaction, and the mixture was extracted withdichloromethane (2x10 ml). The combined organic phases were driedover magnésium sulfate, the solvent was removed, and the crude productwas separated by chromatography on silica gel (dichloromethane/methanol10:1). This resuited in the product with the molecular weight of 348.45(C18H28N4O3); MS (ESI): 349 (M+H+). N,N-Diethyl-N'-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]ethane-1,2-diaminetert-Butyl (2-diethylaminoethyl)-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate (7.9 g) was reacted with trifluoroacetic acid by method G. Thisresuited in the product with the molecular weight of 306.41 (C16H26N4O2);MS (ESI): 307 (M+H+). 013027 340 tert-Butyl (2-diethylaminoethyl)-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate tert-Butyl [(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate (6.0 g) wasdissolved in 50 ml of Ν,Ν-dimethylformamide and, after addition of sodiumhydride (1.1 g), stirred at room température for 30 minutes, andsubsequently chlorethyldiethylamine hydrochloride (4.1 g) was added. Themixture was subsequently stirred at room température with exclusion ofmoisture for 4 hours. The reaction was stopped by adding water (50 ml),and this was followed by extraction with ethyl acetate (3 x 50 ml) anddrying of the combined organic phases over magnésium sulfate, andremoval of the solvent. This resulted in the product with the molecularweight of 406.53 (C21H34N4O4); MS (ESI): 407 (M+H+).
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1- yl)phenyl]amide
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester was reacted with [1-(4-aminophenyl)pyriOlidin-3-yl]dimethylamine by method E, and the productwas then treated by method G. This resulted in the product with themolecular weight of 316.45 (C18H28N4O); MS (ESI): 317 (M+H+).
Svnthesis of amines required as intermediates
Spiro[1,3-benzodioxol-2,T-cyclopentane]-5-amine A solution of spiro[5-nitro-1,3-benzodioxol-2,1'-cyclopentane] (8.8 g) inmethanol (90 ml) was hydrogenated under 6 bar in the presence ofpalladium on carbon (10%, 0.1 g). After 30 minutes at room température,the mixture was filtered and concentrated. This resulted in the product withthe molecular weight of 191.23 (C11H13NO2); MS(ESI): 192 (M+H+).
Spiro[5-nitro-1,3-benzodioxol-2,T-cyclopentane] A solution of spiro[1,3-benzodioxol-2,T-cyclopentane] (8.5 g) in 20 ml ofdichloromethane was added dropwise at 10°G to 65% strength nitric acid(65 ml). After 2 hours at 5-10°C, the mixture was diluted with water, theorganic phase was separated off, and the aqueous phase was extracted 013027 341 twice with dichloromethane. The combined organic phases were washedwith water until neutral, dried over sodium sulfate, concentrated andcrystallized from heptane. This resulted in the product with the molecularweight of 221.21 (C11H11NO4); MS(ESI): 222 (M+H+).
Spire [ 1,3-benzodioxol-2,1 -cyclopentane]
Catechol (11g) and cyclopentanone (9 ml) were heated under reflux intoluene (150 ml) with p-toluenesulfonic acid (0.18 g) with a water trap. After18 hours, the mixture was concentrated and purified by chromatography(silica gel, heptane/ethyl acetate 4:1). This resulted in the product with themolecular weight of 176.22 (C11H12O2); MS(ESI): 177 (M+H+). S-Chloro-Z.S'.ô'.e'-tetrahydro-ri-l-l^'lbipyridinyM'-ol
Butyllithium (15% in hexane; 7.6 ml) was added dropwise to a solution of 2-bromo-5-chloropyridine (2.0 g) in diethyl ether (50 ml) at -78°C and, afterone hour, a solution of N-tert-butoxycarbonyR-piperidinone (2.1 g) indiethyl ether (10 ml) was added dropwise. After 30 minutes, water wascautiously added, and the mixture was extracted with ethyl acetate. Theorganic phase was dried over sodium sulfate, filtered and concentrated.
The residue was treated by method G. This resulted in the product with themolecular weight of 212.68 (C10H13CIN2O); MS(ESI): 213 (M+H+).
The following were obtained analogously: 5- Fluoro-2',3’,5',6'-tetrahydro-1 ’H-p^'lbipyridinyM'-ol e-Chloro^'.S'.S'.e'-tetrahydro-rH-P^'lbipyridinyM'-ol. 6- Cyclopentyloxypyridin-3-yIamine A mixture of 2-hydroxy-5-nitropyridine (1.4 g), cyclopentyl bromide (1.5 g)and potassium carbonate (3 g) was heated in DMF (20 ml) at 80°C for 6hours. The mixture was diluted with water and extracted with ethyl acetate.The organic phase was dried over magnésium sulfate and concentrated.The residue was purified by chromatography on silica gel (mobile phaseethyl acetate/heptane 1:2). The nitro compound obtained in this way washydrogenated by method B. This resulted in the product with the molecularweight of 178.24 (C10H14N2O2); MS(ESI): 179 (M+H+). 013027 342 6-(4-Fluorophenyl)-3-azabicyclo[4.1 .OJheptane
Diethylzinc (1M in hexane, 19 ml) in dichloromethane (100 ml) was mixedwith trifluoroacetic acid (3 ml) at 0°C. After 20 minutes, diiodomethane (3ml) in dichloromethane (10 ml) was added. Then 4-(4-fluorophenyi)-1,2,3,6-tetrahydropyridine (3.0 g) in dichloromethane (10 ml) was added, and themixture was stirred at room température overnight. After addition ofhydrochloric acid (1N), the phases were separated and the organic phasewas washed with water, dried over magnésium sulfate and concentrated.This resulted in the product with the molecular weight of 191.25(C12H14FN); MS(ESI): 192 (M+H+).
Synthesis of carboxvlic acids required as intermediates 4-(4-Methylpiperidin-1-yl)benzoic acid 4-(4-Methylpiperidin1-yl)benzonitrile (1.2 g) was heated to reflux withpotassium hydroxide (0.7 g) in water (2 ml) and ethylene glycol (8 ml) for 3hours. The mixture was diluted with water, washed with ethyl acetate andacidified with 2N hydrochloric acid. The precipitated product was filtered offwith suction, dissolved in dichloromethane, dried over sodium sulfate,concentrated and crystallized from diethyl ether. This resulted in theproduct with the molecular weight of 219.29 (C13H17NO2); MS(ESI): 220(M+H+). 4-(4-Methylpiperidin1-yl)benzonitrile 4-Fluorobenzonitrile (1.21 g) was heated with 4-methylpiperidine (1.00 g) at180°C for 1 hour. The mixture was then taken up in ethyl acetate, washedwith water, 2N sodium hydroxide solution and saturated sodiumbicarbonate solution, dried over sodium sulfate, concentrated andcrystallized from n-pentane. This resulted in the product with the molecularweight of 200.29 (C13H16N2); MS(ESI): 201 (M+H+). 4-Butoxycyclohexanecarboxylic acid 013027 343
Sodium hydride (2.78 g) was added to a solution of ethyl 4- hydroxycyclocarboxylate (10 g) and butyl iodide (10.6 g) in DMF whilecooling in ice under argon. After 12 hours, the mixture was poured onto ice(200 g), extracted with ethyl acetate (100 ml) and then washed with water(3 x 50 ml). The organic phase was concentrated and mixed with éthanol(50 ml) and 5N sodium hydroxide (30 ml). The solution was heated at 60°Cfor 4 hours. Cooling to room température was followed by adjustment to pH< 2 with 2N hydrochloric acid, extraction with ethyl acetate (3 χ 50 ml),drying with magnésium sulfate, filtration and concentration. This resulted inthe product with the molecular weight of 200.28 (C11H20O3); MS (ESI): 201 (M+H+). 1-Benzyl-1 H-[1,2,3]triazole-4-carboxylic acid
Methyl 1-benzyl-1 H-[1,2,3]triazol-4-carboxylate (217 mg) was dissolved in 4ml of methanol and hydrolyzed with 2 ml of 2N sodium hydroxide solution.After acidification with 4 ml of 2N hydrochloric acid, the resulting precipitatewas filtered off, taken up in 5 ml of ethyl acetate and purified by préparativeHPLC. This resulted in the product with the molecular weight of 203.2(C10H9N3O2); MS (ESI): 204 (M+H+).
Methyl 1 -benzyl-1 H-[1,2,3]triazole-4-carboxylate
Benzyl azide (266 mg) was dissolved together with sodium ascorbate (20mg) and copper sulfate (5 mg) in 8 ml of the solvent mixture (tert-butanol/water 3:1), and methyl propionate (336 mg) was added. Thesolution was stirred at room température for 2 hours. A white precipitateseparated out and was filtered off with suction on a frit and subsequentlydried. This resulted in the product with the molecular weight of 217.23(C11H11N3O2); MS (ESI): 218 (M+H+). 1-Biphenyl-4-yl-1H-[1,2,3]triazole-4-carboxylic acid was preparedanalogously from 4-Ethynylbiphenyl and ethyl azidoacetate. 1-Butyl-1 H-indole-5-carboxylic acid
Sodium hydride (50% in oil, 1.4 g) was added to methyl 1 H-indole-5-carboxylate (5.0 g) in DMF (100 ml) and, after gas évolution ceased,bromobutane (3.9 g) was added. After 12 hours, the reaction solution wasdiluted with ethyl acetate and washed three times with water. The organic 013027 344 phase was dried over magnésium sulfate and concentrated. The residuewas purified by chromatography on silica gel (mobile phase ethylacetate/heptane 1:6). The resulting ester was dissolved in methanol (10 ml)and boiled under reflux with sodium hydroxide (0.6 g ) in water (10 ml) for12 hours. The mixture was diluted with water and acidified with hydrochloricacid, followed by extraction with ethyl acetate. The organic phase was driedover magnésium sulfate and concentrated. This resulted in the product withthe molecular weight of 217.27 (C13H15NO2); MS (ESI): 218 (M+H+). 3'-Acetylaminobiphenyl-4-carboxylic acid 3'-Aminobiphenyl-4-carboxylic acid (0.2 g) was mixed with pyridine (0.7 g)and acetic anhydride (180 mg) and, after 14 hours, volatile fractions wereremoved. The residue was taken up in sodium hydroxide solution (2N) andwashed with diethyl ether. The aqueous phase was acidified withhydrochloric acid and extracted with ethyl acetate. The organic phase wasdried over magnésium sulfate and concentrated. This resulted in theproduct with the molecular weight of 255.28 (C15H13NO3); MS (ESI): 256(M+H+). 3'-lsobutyrylaminobiphenyl-4-carboxylic acid 3’-Aminobiphenyl-4-carboxylic acid (0.2 g) was mixed in dichloromethanewith potassium carbonate (121 mg) and isobutyryl chloride (94 mg). After12 hours, the mixture was diluted with sodium hydroxide solution andwashed with diethyl ether. The aqueous phase was acidified withhydrochloric acid and extracted with ethyl acetate. The organic phase wasdried over magnésium sulfate and concentrated. This resulted in theproduct with the molecular weight of 283.33 (C17H17NO3); MS (ESI): 284(M+H+). 5-Butoxypyridine-2-carboxylic acid
Sodium hydride (50% in oil, 250 mg) was added to benzhydryl 5-hydroxypyridine-2-carboxylate (2.0 g) dissolved in DMF (20 ml) and, aftergas évolution ceased, 1-bromobutane (0.72 g) was added. The mixturewas heated at 90°C for 6 hours. It was diluted with water and extracted withethyl acetate. The organic phase was dried over magnésium sulfate and 013027 345 concentrated. The residue was hydrogenated in analogy to method B. Thisresulted in the product with the molecular weight of 195.22 (C10H13NO3); MS (ESI): 196 (M+H+). 4-Methyl-3,4,5,6-tetrahydro-2H-[1 .Slbipyridinyl-e’-carboxylic acid
Benzhydryl 5-trifluoromethanesulfonyloxypyridine-2-carboxylate (3.0 g) washeated with 4-methylpiperidine (1.4 g) at 80°C for one hour. The reactionmixture was immediately purified by préparative HPLC and thenhydrogenated in analogy to method. This resulted in the product with themolecular weight of 220.27 (C12H16N2O2); MS (ESI): 221 (M+H+). N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]terephthalamic acid
Method P-a N-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]terephthalamic acid methylester (1.7 g) dissolved in methanol (20 ml) was stirred with sodiumhydroxide solution (2N, 15 ml) at room température for 24 hours. Ifconversion is incomplète, it is also possible to heat to reflux. The organicsolvent was distilled off, and the mixture was acidified with hydrochloricacid. The precipitate which separated out was filtered off with suction anddried. This resulted in the product with the molecular weight of 353.42(C20H23N3O3); MS (ESI): 354 (M+H+). N-[4-(3-Dimethylaminopyrrolidin-1 -yl)pheny1]terephthalamic acid methylester [1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with terephthalic acid monomethyl ester by method E. This resulted in the product with the molecular weight of 367.45 (C21H25N3O3); MS (ESI): 368(M+H+). 4-(Cyclopentanecarbonylmethylamino)benzoic acid
Methyl 4-methylaminobenzoate was reacted with cyclopentanecarboxylicacid by method E and then hydrolyzed by method P-a. This resulted in theproduct with the molecular weight of 247.30 (C14H17NO3); MS (ESI): 248(M+H+).
The following compounds were obtained analogously: 4-(Cyclopentanecarbonylamino)-3-methoxybenzoic acid 2-Chloro-4-(cyclopentanecarbonylamino)benzoic acid 2-Fluoro-4-(cyclopentanecarbonylamino)benzoic acid 4-(Cyclopentanecarbonylamino)-3-methylbenzoic acid 013027 346 4-(Cyclopentanecarbonylamino)benzoic acid 4- (Cyclopentanecarbonylamino)-3-trifluoromethoxybenzoic acid 3- Chloro-4-(cyclopentanecarbonylamino)benzoic acid 5- Chioro-4-(cyclopentanecarbonylamino)-2-methoxybenzoic acid 4- [(Cyclohex-1-enecarbonyl)amino]benzoic acid 4-[(Cyclopent-1 -enecarbonyl)amino]benzoic acid 3- Fluoro~4-(1 -methylbutoxy)benzoic acid A solution of 0.449 g of 1-[3-fluoro-4-(1-methylbutoxy)phenyl]ethanone in6.8 ml of dioxane was dropped dropwise into 1.36 g of NaOH, 1.6 g ofbromine in 6.8 ml of water. The mixture was stirred at room température for30 minutes and then heated at 50°C for 1 h. The excess bromide wasdecomposed by adding a sodium disulfite solution, and then the solutionwas poured into 25% strength hydrochloric acid solution and stirred for 20minutes. The solution was extracted with ethyl acetate. The combinedorganic phases dried over sodium sulfate, concentrated in vacuo andpurified by préparative HPLC. This resulted in the product with themolecular weight of 226.1 (C12H15FO3); MS (ESI): 227 (M+H+). 1-[3-Fluoro-4-(1-methylbutoxy)phenyl]ethanone 0.058 g of NaH was added to a solution of 0.176 g of 2-pentanol in 2 ml ofDMF, and the solution was stirred at room température for 1 hour. Then0.312 g of 3,4-difluoroacetophenone was added, and the mixture wasstirred at room température overnight. The reaction solution was taken upin ethyl acetate and washed twice with water. The organic phase was driedover sodium sulfate and concentrated in vacuo. The resulting compoundwas reacted further without further purification.
The following compounds were obtained analogously: 4- Cyclobutoxy-3-fluorobenzoic acid 3- Fluoro-4-(2-methylcyclopropylmethoxy)benzoic acid 4- (2-Cyclopropylethoxy)-3-fluorobenzoic acid 3- Fluoro-4-( 1 -methylpiperidin-3-yloxy)benzoic acid 4- (1 -Acetylpiperidin-3-yloxy)-3-fluorobenzoic acid 3- Fluoro-4-(1-methylpyrrolidin-3-yloxy)benzoic acid 4- (1-Acetylpyrrolidin-3-yloxy)-3-fluorobenzoic acid 013027 347 3-Fluoro-4-( 1 -methylpiperidin-3-ylmethoxy)benzoic acid 4-(2,4-Difluorophenoxy)benzoic acid 0.518 g of potassium hydroxide was added to a solûtion of 0.428 g of ethyl4-(2,4-difiuorophenoxy)benzoate in 2 ml of THF/water (1:1). The solutionwas heated at 110°C for 6 hours. The THF was then removed in vacuo,and the aqueous phase was freeze dried and purified by préparative HPLO.This resulted in the product with the molecular weight of 250.04(C13H8F2O3); MS (ESI): 251 (M+H+).
Ethyl 4-(2,4-difluorophenoxy)benzoate 0.018 g of NaH was added to a solution of 0.1 g of 2,4-difIuorophenol in 0.5ml of DMF. The reaction was stirred at room température for 45 minutes.Then 0.129 g of ethyl 4-fluorobenzoate in 0.5 ml of DMF was addeddropwise. The reaction was heated at 110°C overnight. After coolingconcentrated in vacuo and the residue taken up in ethyl acetate/water. Theethyl acetate phase was washed three times with water, dried over sodiumsulfate, concentrated in vacuo and purified by préparative HPLC. Thisresulted in the product with the molecular weight of 278.08 (C15H12F2O3);MS (ESI): 279 (M+H+) 4-(2,4-Difluorophenoxy)benzoic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]-dimethylamine by method E-b. This resulted inthe product with the molecular weight of 437.19 (C25H25F2N3O2); MS(ESI): 438 (M+H+) as hydrotrifluoroacetate. 4-Butoxy-3-methoxybenzoic acid
Methyl 4-hydroxy-3-methoxybenzoate was alkylated with bromobutane bymethod H and hydrolyzed by method P-a. This resulted in the product withthe molecular weight of 224.26 (C12H16O4); MS (ESI): 225 (M+H+).
The following compounds were prepared analogously: 4-Butoxy-3,5-dichlorobenzoic acid 4-Butoxy-3-nitrobenzoic acid 4-Butoxy-3-chlorobenzoic acid 4-B utoxy-3,5-dimethylbenzoic acid 013027 348 4-Butoxy-2,3-dichloro-5-methoxybenzoic acid 4-Butoxy-2>3,5,6-tetrafluorobenzoic acid 4-Butoxy-3-fluorobenzoic acid 3- Acetyl-4-butoxybenzoic acid 2,4-Dibutoxybenzoic acid 4- Butoxy-2-chlorobenzoic acid 4-Propoxymethylbenzoic acid
Sodium hydride (50% in oil; 0.42 g) was cautiously added to a solution ofpropanol (0.6 g) in DMF (8 ml). After gas évolution ceased, methyl 4-bromomethylbenzoate (1.0 g) was added. After 4 hours, the mixture waspartitioned between water and ethyl acetate. The organic phase was driedover magnésium sulfate and concentrated. The residue was hydrolyzed bymethod P-a. This resulted in the product with the molecular weight of194.23 (C11H14O3); MS (ESI): 195 (M+H+).
The following compounds were prepared analogously: 4-Ethoxymethylbenzoic acid 4-Butoxymethylbenzoic acid 4-lsobutoxymethylbenzoic acid 4-Phenoxymethylbenzoic acid 4-(Pyridin-3-yloxymethyI)benzoic acid 4-(Pyridin-2-yloxymethyl)benzoic acid 4-Benzoimidazol-1 -ylmethylbenzoic acid 4-lndol-i-ylmethylbenzoic acid 4-Phenylsulfanylmethylbenzoic acid 4-(Pyrimidin-2-ylsulfanylmethyl)benzoic acid 4-(Pyridin-2-ylsulfanylmethyl)benzoic acid 4-(2-Cyanophenoxymethyl)benzoic acid 4-(2-Chlorophenoxymethyl)benzoic acid 4-Cyclobutoxymethylbenzoic acid 4-Cyclopentyloxymethylbenzoic acid 4-Cyclohexyloxymethylbenzoic acid 4-sec-Butoxymethylbenzoic acid 4-Pentoxymethylbenzoic acid 4-(3-Oxo-3a,415,6-tetrahydro-3H-cyclopentapyrazol-2-yl)benzoic acidA solution of 4-hydrazinobenzoic acid (0.3 g), ethyl-2-oxocyclopentanecarboxylate (0.31 g) and p-toluenesulfonic acid (340 mg) 013027 349 in éthanol (12 ml) was boiled under reflux for 12 hours. The concentratedreaction solution was purified by préparative HPLC. The isoiated reactionproduct (as ethyl ester) was hydrolyzed by method P-a. This resulted in theproduct with the molecularweight of 244.25 (C13H12N2O3); MS (ESI): 245(M+H+). 4-Butoxy-2-methoxybenzoic acid 4-Hydroxy-2-methoxybenzaldehyde was alkylated with 1-bromobutane bymethod H. The resulting aldéhyde (6.4 g) in dioxane (100 ml) was mixedwith sodium dihydrogen phosphate (14.4 g) and sulfuric acid (2.4 ml), andthe solution was cooled to 10°C. A solution of sodium chlorite (3.61 g) inwater (100 ml) was added in such a way that the température did notexceed 10°C. 15 minutes afterthe addition was complété, sodium sulfite(4.6 g) was added. After a further 15 minutes, the pH was adjusted to 2with hydrochloric acid and the dioxane was removed in a rotary evaporator.The aqueous phase was extracted with ethyl acetate. The organic phasewas dried over magnésium sulfate, filtered and concentrated. The residuewas purified by préparative HPLC. This resulted in the product with the molecular weight of 224.26 (C12H16O4); MS (ESI): 225 (M+H+).4-Butoxy-5-chloro-2-methoxybenzoic acid was obtained as by-product. 4-(1-Propoxyethyl)benzoic acid
Methyl 4-(1-hydroxyethyl)benzoate (2.0 g) dissolved in DMF (30 ml) wasmixed with propyl iodide (3.8 g), and then sodium hydride (50% in oïl, 0.53g) was added. Afterthe end of the exothermic reaction, the mixture wasstirred for 1 hour and then water was cautiously added. It was extractedwith ethyl acetate, and the organic phase was dried over sodium sulfate,filtered and concentrated. The residue was hydrolyzed by method P-a.This resulted in the product with the molecularweight of 208.26(C12H16O3); MS (ESI): 209 (M+H+).
Claims (16)
- 013027 350 Claims
- 2. A compound of formula I as claimed in claim 1, in which the meanings are R1, R2 independently of one another are H, (Ci-C8)-alkyl, -(CR78R79)O -R12, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, CO-(C-|-C8)-alkyl,-CO-(CH2)o -R12, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R23)(R24))SO(R25); or R1 andR2 form together with the nitrogen atom to which they are bonded a 4 to10-membered mono- or bicyclic ring which, apart from the nitrogenatom, may comprise 0 to 2 additional heteroatoms selected from thegroup of oxygen, nitrogen and sulfur, where the heterocyclic ringSystem may additionally be substituted by F, Cl, CF3, (Ci-C6)-alkyl, O-(Ci-C4)-alkyl, (Ci-C4)-alkoxy-(Ci.C4)-alkyl, (Co-C2)-alkylene-aryl, oxo,CO(R26), hydroxy, N(R31 )(R32) or SO2CH3; o 0,1,2,3,4; 1 or 2; 356 013027 s 0, 1,2,3; R13, R14 independently of one another are a phenyl ring which may comprise 0-1nitrogen atoms; R15, R16, R17, R23, R24, R26, R31, R32 5 independently of one another H, (Ci-C6)-alkyl; R18 H,(Ci-C6)-alkyl,CO(Ci-C6)-alkyl; or R17 and R18, R31 and R32 independently of one another optionally form together with the nitrogen 10 atom to which they are bonded a 5-6 membered ring selected from pyrrolidine, piperidine, N-methylpiperazine, morpholine; R12 OH, O-(C-|-C6)-alkyl, 0-(Co-C8)-alkylene-aryl, CN, 3-10 membered mono- or bicyclic ring which may comprise 1-3 heteroatoms from thegroup of N, O and S, and the 3-10 membered ring may comprise further 15 substituents such as F, Cl, Br, OH, CF3, CN, oxo, O-(Ci-C6)-alkyl, (C1- C4)-alkoxy-(C-|-C4)-alkyl, (Ci-C6)-alkyl, (Co-C2)-alkylene-aryl,N(R34)(R35), CO(Ci-C6)-alkyl; t 0,1,2,3,4,5,6; u 0or2; 20 R34, R35 independently of one another H, (C-j-Cs)-alkyl;or R34 and R35 optionally together with the nitrogen atom to which they are bonded a 5- 25 6 membered ring which, apartfrom the nitrogen atom, may also 357 013027 comprise 0-1 further heteroatoms from the group of N-(Ci-C6)-alkyl,oxygen and sulfur and may optionally be substituted by 1-2 oxo groups; R78, R79 independently of one another H, (Ci-Cs)-alkyl,· hydroxy-(C-|-C4)-alkyl,OH, (C-]-C4)-alkoxy-(Ci-C4)-alkyl; 5 R3 H; R4, R5 independently of one another H, (C-(-Ce)-alkyl, OH, O-(C-|-C6)-alkyl, O- CO-(Ci-C6)-alkyl; R6, R7, R8, R9H; 10 n 1 m 1; A, B, D, G B is N, C(R42); and A, D, G C(R42); R42 H, F, Cl, Br, CF3, CN, 0-(0^06)-311^1, (Ci-C6)-aIkyl, SO2-CH3, CON(R45)(R46), N(R47)CO(R48), CO(R51), 15 -(CR84R85)X-O(R86); R45, R46, R47 independently of one another H, (Ci-C8)-alkyl; or R45 and R46 20 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from thenitrogen atom, may also comprise 0-1 further heteroatoms from the 358 013027 group of N-(Ci-C6)-alkyl, oxygen and sulfur; R48, R51 independently of one ânother H, (C-i-CsJ-aikyl; R84, R85 H; R86 H, (Ci-C6)-alkyl; 5 x 0,1; R10 H, (Ci-Cg)-alkyl; X N(R52), a bond, C=C, C(R53)(R54), CH2-CH2; R52, R53, R54 independently of one another H, (Ci-Cs)-alkyl; 10 E is selected from the group consisting of359 013027 which may optionally hâve substitueras from the group of H, F, Cl, Br,OH, CF3, NO2i OCF3i O-ÎC-i-Cg^alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl,N(R57)(R58), SO2-CH3, CO(R65); R57, R58 independently of one another H, (Ci-Cs)-alkyl; 5 R65 independently of one another H, (Ci-C8)-alkyl; K a bond, O, OCH2, CH2O, N(R66), CON(R68), (C(R69)(R70))v, CO, C=C, SCH2; v 1,2,3; R66, R68, R69, R70 10 independently of one another H, (Ci-Cs)-alkyl; R11 (Ci-C8)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may comprise 0 to 3heteroatoms selected from the group of oxygen, nitrogen and sulfur,where the ring System may additionally be substituted by F, Cl, Br, CF3, 15 CN, (Ci-C6)-alkyl, O-(Ci-Cs)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R71 ), CON(R72)(R73), hydroxy, N(R75)CO(Ci-C6)-alkyl,N(R76)(R77) or SO2CH3; R71, R72, R73, R75, R76, R77 independently of one another H, (Ci-C8)-alkyl; 20 or R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atomto which they are bonded a 5-6 membered ring which, apart from the 360 013027 nitrogen atom, may also comprise 0-1 further heteroatoms from thegroup of N-(Ci-C6)-alkyl, oxygen and sulfur; or the N-oxides and the physiologically tolerated salts thereof. ·
- 3. A compound of formula I as claimed in claim 1, 5 in which the meanings are R1, R2 independently of one anotherare H, (Ci-C8)-alkyl, -(CR78R79)O-R12,(Ci-C4)-alkoxy-(Ci-C4)-alkyl, CO-(Ci-C8)-alkyl, -CO-(CH2)o -R12,CO(C(R15)(R16))qN(R17)(R18), or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 10-membered mono - or -1 θ bicyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen and nitrogen,where the heterocyclic ring System may be additionally substituted by F,(Ci-C6)-alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, oxo, CO(R26), hydroxy,N(R31)(R32); 15 o 0,1,2,3; q 1 or 2; R15, R16, R17, R26, R31, R32 independently of one another H, (C-|-C8)-alkyl; R18 H, (Ci-C6)-alkyl; 20 or R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally form together with the nitrogenatom to which they are bonded a 5-6 membered ring selected frompyrrolidine, piperidine, N-methylpiperazine, morpholine; 361 013027 R12 OH, O-(Ci-C6)-alkyl, 3-10 membered mono- or bicyçlic ring which may comprise 1-2 heteroatoms from the group of N, O and S, and the 3-10membered ring may comprise further substituents such as F, OH, oxo, (Ci-C6)-alkyl, CO(Ci-C6)-alkyl; 5 R78, R79 independently of one another H, (Ci-C8)-alkyl, hydroxy-(Ci-C4)-alkyl, OH, (Ci-C4)-alkoxy-(Ci-C4)-alkyl; R3 H; R4, R5 independently of one another H, OH, O-(Ci-C6)-alkyl; R6, R7, R8, R9H; 10 n 1 1; A, B, D, G are C(R42); 15 R42 H, F, Cl, -(CR84R85)X-O(R86); R84, R85 H; R86 H, (Ci-C6)-alkyl; cf3, CN, (CvCeJ-alkyl, 0, 1, 2; preferably 0, 1; particularly preferably 1; R10 H, (Ci-C8)-alkyl; 362 X a bond, C=C, C(R53)(R54), CH2-CH2; R53, R54 independently of one another H, (Ci-Cs)-alkyl;which may optionally hâve substituents from the group of H, F, Cl, Br,OH, CF3, NO2, OCF3, O-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl,N(R57)(R58), SO2-CH3, CO(R65); R57, R58 independently of one another H, (Ci-Cg)-alkyl; 10 R65 independently of one another H, (Ci-C8)-alkyl; K a bond, O, OCH2, ΟΗ2Ο, CON(R68), (C(R69)(R70))v, CO, C=C; v 1,2; R68, R69, R70 independently of one another H, (Ci-Cs)-alkyl; R11 (C-]-C8)-alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, a 3 to 10-membered mono-or bicyclic ring which may comprise 0 to 2 heteroatoms selected fromthe group of oxygen, nitrogen and sulfur, where the ring System may 15 363 013027 additionally be substituted by F, Cl, Br, CF3, CN, (C-|-C6)-alkyl, O-(C-|-C8)-alkyl, oxo, CO(R71), CON(R72)(R73), N(R75)CO(C1-C6)-alkyl, orSO2CH3; R71.R72, R75 independently of one another H, (C-|-C8)-alkyl; or R72 and R73 independently of one another optionally together with the nitrogen atomto which they are bonded a 5-6 membered ring which, apart from thenitrogen atom, may also comprise 0-1 further heteroatoms from thegroup of N-(Ci-C6)-alkyl, oxygen and sulfur; or the N-oxides and the physiologically tolerated salts thereof.
- 4. A compound as claimed in claim ï, characterized in that it has the formula la R11-KNR1R2 la in which R1, R2 independently of one another H, (Ci-C8)-alkyl, -(CR78R79)O -R12, (C-|-C4)-alkoxy-(C-|-C4)-alkyl, or R1 and R2 form together with the nitrogenatom to which they are bonded a 4 to 10-membered mono-, bi- orspirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 2additional heteroatoms selected from the group of oxygen, nitrogen andsulfur, where the heterocyclic ring System may additionally be substitutedby F, (Ci-C6)-alkyl, O-(C-i-C4)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C0-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28),hydroxy, N(R31 )(R32) or SO2CH3; where R1 and R2 are not both 364 013027 CO(R26); o 0,1,2,3,4: q 1,2,3; s 0,1,2; 5 R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32 independently of one another H, (Ci-C6)-alkyl; or R17 and R18, R27 and R28, R31 and R32 independently of one another optionally together with the nitrogen atom 10 to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from thegroup of N-(Ci-C6)-alkyl, oxygen and sulfur; R12 OH, O-(Ci-C6)-alkyl, O-(C0-C2)-alkylene-aryl, CN, S-(Ci-C6)-alkyl, 3-12 membered mono-, bi- or spirocyclic ring which may comprise 1 to 3 15 heteroatoms from the group of N, O and S, and the 3-12 membered ring may comprise further substituents such as F, OH, CF3, CN, oxo, (C1- C6)-alkyl, (C0-C2)-alkylene-aryl, N(R34)(R35), COO(R40), CO(Ci-C6)-alkyl; R34, R35 20 independently of one another H, (Ci-C4)-alkyl; R40 H, (Ci-C6)-alkyl, (Co-C2)-alkylene-aryl; R78, R79 independently of one another H, (Ci-Cs)-alkyl, hydroxy-(Ci-C4)-alkyl,OH, (Ci-C4)-alkoxy-(C-|-C4)-alkyl; R42, R42’ independently of one another H, F, Cl, Br, CF3, CN, (Ci-C6)-alkyl; 365 013027 R1O H, (C-|-C8)-alkyl; X N(R52), a bond, C=C, C(R53)(R54), CH2CH2;‘ R52, R53, R54 independently of one another H, (Ci-Cs)-alkyl;10 which may optionally hâve substituents from the group of H, F, Cl, Br, OH, CF3, NO2, OCF3i O-(Ci-C6)-alkyl, (C-j-Ce^alkyl, (C2-C6)-alkenyl,N(R57)(R58), SO2-CH3, CO(R65); R57, R58 independently of one another H, (C1-C8)-alkyl; R65 H, (Ci-C8)-alkyl; 366 013027 K a bond, O, OCH2) CH2O, S, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C=C, SCH2, SO2CH2; v 1,2,3, R66, R67, R68, R69, R70 5 independently of one another H, (C1 -Cs)-alkyl; R11 (Ci-C8)-alkyl, (C-|-C4)-alkoxy-(C-i-C4)-alkyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may comprise 0 to 4heteroatoms selected from the group of oxygen, nitrogen and sutfur,where the ring System may additionally be substituted by F, Ci, Br, CF3, 10 CN, (Ci-C6)-alkyl, O-(Ci-Cs)-alkyl, oxo, CO(R71), hydroxy, N(R75)CO(Ci-C6)-alkyl, or SO2CH3; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (C4-C8)-alkyl; or 15 R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atomto which they are bonded a 5-6 membered ring which, apart from thenitrogen atom, may also comprise 0-1 further heteroatoms from thegroup of N-(Ci-C6)-alkyl, oxygen and sulfur; or 20 the N-oxides or the physiologically tolerated salts thereof.
- 5. Compounds as claimed in claim 1, characterized in that they hâve the formulaIb 013027 367 R11 Οnr.,r2 (lb) in which: R1, R2 in which: R1, R2 o 0. r s R13, R14 0 q. r s R13, R14 independently of one another H, (Ci-C8)-alkyl, -(CR78R79)O -R12,(Ci-C4)-alkoxy-(C-i-C4)-alkyl, (C3-Cs)-alkenyl, CO-(C-|-C8)-alkyl, -CO-(CH2)o -R12, CO-aryloxy-(Ci-C4)-alkyl, COCH=CH(R13), COCC(R14),CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21 )(R22),CO(C(R23)(R24))SO(R25); or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 10-membered mono-, bi-or spirocyciic ring which, apart from the nitrogen atom, may comprise 0to 2 additional heteroatoms selected from the group of oxygen, nitrogenand sulfur, where the heterocyclic ring System may additionally besubstituted by F, Cl, CF3, (C-]-C6)-alkyl, O-(Ci-C4)-alkyî, (C1-C4)-alkoxy-(Ci-C4)-alkyl, hydroxy-(C-|-C4)-alkyl, (Co-C2)-alkylene-aryl, oxo,CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C-|-C6)- alkyl, N(R31)(R32) or SO2CH3, where R1 and R2 are not bothCO(R26); 0,1,2, 3, 4, 5, 6; independently of one another 1,2, 3; 0,1,2,3,4; independently of one another a phenyl ring which may comprise 0-1nitrogen atoms; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, 368 013027 R31, R32 independently of one another H, (C-|-C6)-alkyl; R18 H, (Ci-C6)-alkyl, CO(Ci-C6)-alkyl, CO(R33);; ' or 5 R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally together with the nitrogen atomto which they are bonded a 5-6 membered ring which, apart from thenitrogen atom may, also comprise 0-1 further heteroatoms from thegroup of N-(Ci-C6)-alkyl, oxygen and sulfur; 10 R33 a 5-10 membered aromatic ring System which may comprise a further heteroatom from the group of nitrogen, oxygen and sulfur and may besubstituted by F, Cl, (C-|-C6)-alkyl, O-(C-|-Cg)-alkyl; R12 is OH, O-(C-|-C6)-alkyl, 0-(Co-Cg)-alkylene-aryl, CN, S-(C-|-C6)-alkyl, COO(R80), CON(R81)(R82), 3-12 membered mono-, bi- or spirocyclic15 ring which may comprise one or more heteroatoms from the group of N, O and S and the 3-12 membered ring may comprise furthersubstituents such as F, Cl, Br, OH, CF3, CN, oxo, O-(Ci-C6)-alkyl, (C1-C4)-alkoxy-(Ci-C4)-alkyl, (Ci-Cg)-alkyl, 0-(Co-Cg)-alkylene-aryl, (Co-Cg)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t 20 (R39)r CO(C(R37)(R38))t (R39), CO(Ci-C6)-alkyl, COCOO(Ci-C6)- alkyl, COO(R40), S(O)U (R41); t 0,1,2,3,4,5,6; u 0,1,2; R34, R35, R37, R38 25 independently of one another H, (C-i-Cg)-alkyl; or R34 and R35 013027 369 optionally together with the nitrogen atom to which they are bonded a 5- 6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further.heteroatoms from the group of N-(Ci-C6)-alkyl, oxygen and sulfur and may optionally be substituted by 1-2 oxo groupe; 5 R36, R39 independently of one another (C3-Cs)-cycloalkyl, 5-10 membered aromatic ring System which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (Ci-C6)-alkyl, O-(Ci-C8)-alkyl; R40 H, (Ci-C8)-alkyl, (C2-C6)-alkenyl, (Co-Cs)-alkylene-aryl; 10 R41 (Ci-Csj-alkyl, 5-10 membered aromatic ring System which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (Ci-Cg)-alkyl, O-(C-i-Cg)- alkyl; R78, R79 independently of one another H, (Ci-C8)-alkyl, hydroxy-(Ci-C4)-alkyl, 15 OH, (Ci-C4)-alkoxy-(Ci-C4)-alkyl; R80, R81 independently of one another H,· (Ci-Cs)-alkyl; R1O H, (Ci-C8)-alkyl; 013027 3705 which may optionally hâve substituents from the group of H, F, Cl, Br, OH, CF3, NO2i OCF3i O-iCrCe^alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl,N(R57)(R58), SO2-CH3, CO(R65); R57, R58 independently of one another H, (Ci-Cs)-alkyl; R65 independently of one another H, (Ci-C8)-alkyl, aryl; 10 K a bond, O, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C=C, C^C, SCH2, SO2CH2; v 1,2,3,4; R66, R67, R68, R69, R70 independently of one another H, (Ci-Cs)-alkyl; 15 R11 H, (Ci-C8>-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, (C3-Cs)-alkenyl, (C3- C8)-alkynyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which 371 013027 may comprise 0 to 4 heteroatoms selected from the group of oxygen,nitrogen and sulfur, where the ring System may additionaily besubstituted by F, Cl, Br, CF3, CN, (Ci-C6)-alkyl, O-(Ci-C8)-alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, hydroxy-(Ci-C4)-alkyl, (Co-C8)-alkylene-aryl, 5 oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(Ci- C6)-alkyl, N(R76)(R77) or SO2CH3; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (Ci-C8)-alkyl; or 10 R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atomto which they are bonded a 5-6 membered ring which, apart from thenitrogen atom, may also comprise 0-1 further heteroatoms from thegroup of N-(C-|-C6)-alkyl, oxygen and sulfur; 15 the N-oxides and the physiologically tolerated salts thereof.
- 6. A médicament comprising one or more of the compounds as claimed in daims1 to 5.
- 7. A médicament comprising one or more of the compounds as claimed in one ofdaims 1 to 5 and one or more anorectic active ingrédients. 20 8. A compound of the formula I as claimed in one of daims 1 to 5 for use as médicament for the prophylaxis or treatment of obesity.
- 9. A compound of the formula I as claimed in one of daims 1 to 5 for use asmédicament for the prophylaxis or treatment of type II diabètes.
- 10. A compound of the formula I as claimed in one of daims 1 to 5 in combination25 with at least one further anorectic active ingrédient for use as médicament for the prophylaxis or treatment of obesity.
- 11. A compound of the formula I as claimed in one of daims 1 to 5 in combinationwith at least one further anorectic active ingrédient for use as médicament for the 013027 prophylaxis or treatment of of type II diabètes.
- 12. A process for producing a médicament comprising one or more of thecompounds of the formula I as claimed in one of daims 1 to 5, which comprisesmixing the active ingrédient with a pharmaceutically suitable carrier and converting 5 this mixture into a form suitable for administration.
- 13. The use of the compounds of the formula I as claimed in one of daims 1 to 5for producing a médicament for weight réduction in mammals.
- 14. The use of the compounds of the formula I as claimed in one of daims 1 to 5for producing a médicament for the prophylaxis or treatment of obesity.
- 15. The use of the compounds of the formula I as claimed in one of daims 1 to 5 for producing a médicament for the prophylaxis or treatment of type II diabètes.
- 16. The use of the compounds of the formula I as claimed in any of daims 1 to 5for producing a médicament for the treatment of disturbances of well being and otherpsychiatrie indications, and for the treatment of disorders associated with the 15 circadian rhythm and for the treatment of drug abuse.
- 17. The use of the compounds of the formula I as claimed in any of daims 1 to 5for preparing a médicament having a MCH-receptor antagonistic activity.
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| DE10306250A DE10306250A1 (en) | 2003-02-14 | 2003-02-14 | Substituted N-aryl heterocycles, processes for their preparation and their use as pharmaceuticals |
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| DE602004017316D1 (en) | 2003-07-24 | 2008-12-04 | Euro Celtique Sa | HETEROARYL TETRAHYDROPYRIDYL COMPOUNDS RELATING TO THE TREATMENT THE PREVENTION OF PAIN EQUIPMENTS |
| EP1657240A4 (en) * | 2003-08-18 | 2009-04-08 | Fujifilm Finechemicals Co Ltd | Pyridyltetrahydropyridines, pyridylpiperidines, and process for the production of both |
| DE10360745A1 (en) * | 2003-12-23 | 2005-07-28 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New amide compounds having MCH antagonist activity and medicaments containing these compounds |
| US7592373B2 (en) | 2003-12-23 | 2009-09-22 | Boehringer Ingelheim International Gmbh | Amide compounds with MCH antagonistic activity and medicaments comprising these compounds |
| US7319108B2 (en) | 2004-01-25 | 2008-01-15 | Sanofi-Aventis Deutschland Gmbh | Aryl-substituted heterocycles, process for their preparation and their use as medicaments |
| DE102004003812A1 (en) * | 2004-01-25 | 2005-08-11 | Aventis Pharma Deutschland Gmbh | Aryl-substituted heterocycles, methods of their preparation and their use as pharmaceuticals |
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| TW200626138A (en) * | 2004-09-20 | 2006-08-01 | Xenon Pharmaceuticals Inc | Heterocyclic derivatives and their use as therapeutic agents |
| AU2005290436A1 (en) * | 2004-10-01 | 2006-04-13 | Banyu Pharmaceutical Co.,Ltd | 2-arylcarboxamide-nitrogeneous heterocycle compound |
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- 2004-02-13 AU AU2004212145A patent/AU2004212145B2/en not_active Ceased
- 2004-02-13 UA UAA200508733A patent/UA86760C2/en unknown
- 2004-02-13 PE PE2004000158A patent/PE20040952A1/en not_active Application Discontinuation
- 2004-02-13 NZ NZ541823A patent/NZ541823A/en unknown
- 2004-02-13 CN CNB2004800098606A patent/CN100506792C/en not_active Expired - Fee Related
- 2004-02-13 TW TW093103412A patent/TW200510297A/en unknown
- 2004-02-13 BR BRPI0407504-8A patent/BRPI0407504A/en not_active IP Right Cessation
- 2004-02-13 CA CA002516118A patent/CA2516118A1/en not_active Abandoned
- 2004-02-13 EP EP04710808A patent/EP1597228A2/en not_active Withdrawn
- 2004-02-13 RS YUP-2005/0666A patent/RS20050666A/en unknown
- 2004-02-13 UY UY28186A patent/UY28186A1/en unknown
- 2004-02-13 RU RU2005128551/04A patent/RU2005128551A/en not_active Application Discontinuation
- 2004-02-13 OA OA1200500227A patent/OA13027A/en unknown
- 2004-02-16 AR ARP040100469A patent/AR044496A1/en unknown
-
2005
- 2005-08-10 ZA ZA200506369A patent/ZA200506369B/en unknown
- 2005-08-11 EC EC2005005967A patent/ECSP055967A/en unknown
- 2005-08-11 MA MA28430A patent/MA27735A1/en unknown
- 2005-08-11 CO CO05079788A patent/CO5690548A2/en not_active Application Discontinuation
- 2005-08-12 TN TNP2005000194A patent/TNSN05194A1/en unknown
- 2005-08-12 HR HR20050710A patent/HRP20050710A2/en not_active Application Discontinuation
- 2005-09-12 NO NO20054220A patent/NO20054220L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0407504A (en) | 2006-02-14 |
| AR044496A1 (en) | 2005-09-14 |
| NO20054220D0 (en) | 2005-09-12 |
| KR20050101215A (en) | 2005-10-20 |
| MXPA05008449A (en) | 2006-05-25 |
| CN100506792C (en) | 2009-07-01 |
| RS20050666A (en) | 2007-12-31 |
| NO20054220L (en) | 2005-10-28 |
| CO5690548A2 (en) | 2006-10-31 |
| HRP20050710A2 (en) | 2006-07-31 |
| UY28186A1 (en) | 2004-09-30 |
| JP2006517563A (en) | 2006-07-27 |
| NZ541823A (en) | 2009-01-31 |
| MA27735A1 (en) | 2006-02-01 |
| ECSP055967A (en) | 2006-01-16 |
| TW200510297A (en) | 2005-03-16 |
| ZA200506369B (en) | 2006-07-26 |
| AU2004212145A1 (en) | 2004-08-26 |
| EP1597228A2 (en) | 2005-11-23 |
| RU2005128551A (en) | 2006-02-10 |
| AU2004212145B2 (en) | 2010-06-17 |
| CN1774418A (en) | 2006-05-17 |
| PA8595901A1 (en) | 2004-09-16 |
| WO2004072025A2 (en) | 2004-08-26 |
| DE10306250A1 (en) | 2004-09-09 |
| TNSN05194A1 (en) | 2007-06-11 |
| MY139102A (en) | 2009-08-28 |
| PL378065A1 (en) | 2006-02-20 |
| PE20040952A1 (en) | 2005-02-08 |
| UA86760C2 (en) | 2009-05-25 |
| WO2004072025A3 (en) | 2004-12-23 |
| CA2516118A1 (en) | 2004-08-26 |
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