Substituted N-aryl heterocycles, process for their preparation and their use as medicaments

Abstract

The invention relates to substituted N-aryl heterocycles and to the physiologically tolerated salts and physiologically functional derivatives thereof.

Description

[0001] The invention relates to substituted N-aryl heterocycles and to the physiologically tolerated salts and physiologically functional derivatives thereof.

[0002] Compounds having a pharmacological effect and similar in their overall structure to the N-aryl heterocycles described herein have already been described in the prior art. Thus, for example, WO 00/35454 describes ureido-substituted phenylpiperidines and -pyrrolidines as agents for the treatment of inflammatory and autoimmune diseases. Acylamido-substituted phenylpyrrolidines are proposed in WO 02/042271 for the treatment of diabetes, obesity and disorders of lipid metabolism.

[0003] The invention was based on the object of providing compounds which bring about a weight reduction in mammals and are suitable for preventing and treating obesity and diabetes.

[0004] The invention therefore relates to compounds of the formula I 2

[0005] wherein

[0006] R1, R2 are each independently H, (C1-C8)-alkyl, —(CR78R79)o—R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, aryloxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, CO—(C1-C8)-alkyl, —CO—(CH2)o—R12, CO-aryloxy-(C1-C4)-alkyl, CO—(C2-C8)-alkenyl, CO—(C2-C8)-alkynyl, COCH═CH(R13), COCC(R14), CO—(C1-C4)-alkyl-S(O)p—(C1-C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22) or CO(C(R23)(R24))sO(R25); or

[0007] R1 and R2, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered mono-, bi- or spirocyclic ring which, apart from said nitrogen atom of attachment, optionally contains 1, 2, 3 or 4 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, and is optionally substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C1-C6)-alkyl, N(R31)(R32) or SO2CH3;

[0008] wherein

[0009] o is 0, 1, 2, 3, 4, 5 or 6;

[0010] p is 0, 1 or 2

[0011] q, r, s are each independently 0, 1, 2, 3 or 4;

[0012] R13, R14 are each independently a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system optionally containing 1 or 2 heteroatoms selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl or O—(C1-C8)-alkyl;

[0013] R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 are each independently H or (C1-C6)-alkyl;

[0014] R18 is H, (C1-C6)-alkyl, CO(C1-C6)-alkyl or CO(R33); or

[0015] substituent pairs R17 and R18, R21 and R22, R27 and R28, and R31 and R32, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur;

[0016] R33 is a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system which optionally contains 1 or 2 heteroatoms selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl or O—(C1-C8)-alkyl;

[0017] R12 is OH, O—(C1-C6)-alkyl, O(C0-C8)-alkylene-aryl, CN, S—(C1-C6)-alkyl, COO(R80), CON(R81)(R93), N(R82)(R83) or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered mono-, bi- or spirocyclic ring which optionally contains one or more heteroatoms selected from the group of N, O and S, and is optionally substituted with F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, oxo, O—(C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O—(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, O—(C0-C8)-alkylene-aryl, N(R34)(R35), COCH═CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(C1-C6)-alkyl, COCOO(C1-C6)-alkyl, COO(R40), S(O)u(R41) or COOH;

[0018] t is 0, 1, 2, 3, 4, 5 or 6;

[0019] u is 0, 1 or 2;

[0020] R34, R35, R37, R38 are each independently H or (C1-C8)-alkyl; or

[0021] R34 and R35, taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur, and is optionally substituted by 1 or 2 oxo groups;

[0022] R36, R39 are each independently (C3-C8)-cycloalkyl or a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system wherein said aromatic ring system optionally contains one or two additional heteroatoms selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl or O—(C1-C8)-alkyl;

[0023] R40 is H, (C1-C8)-alkyl, (C2-C6)-alkenyl or (C0-C8)-alkylene-aryl;

[0024] R41 is (C1-C6)-alkyl or a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring system optionally containing one or two heteroatoms from the group of nitrogen, oxygen and sulfur, and optionally substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl or O—(C1-C8)-alkyl;

[0025] R78, R79 are each independently H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, OH or (C1-C4)-alkoxy-(C1-C4)-alkyl;

[0026] R80, R81, R93 are each independently (C1-C8)-alkyl, (C2-C6)-alkenyl or (C0-C8)-alkylene-aryl;

[0027] R82, R83 are each independently H or (C1-C6)-alkyl; or

[0028] R82 and R83, taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur, and is optionally substituted by 1 or 2 oxo groups;

[0029] R3 is H or (C1-C6)-alkyl;

[0030] R4, R5 are each independently H, (C1-C6)-alkyl, OH, O—(C1-C6)-alkyl, O—CO(C1-C6)-alkyl or S—(C1-C6)-alkyl;

[0031] R6, R7, R8, R9 are each independently H or (C1-C8)-alkyl; or

[0032] substituent pairs R6 and R7, and R8 and R9, optionally form, independently of one another, an oxo group;

[0033] n, m are each independently 0, 1 or 2;

[0034] A, B, D, G are each independently N or C(R42); or

[0035] said radicals A and B, or said radicals D and G are each C(R42) and, taken together, optionally form a 5- or 6 membered carbocyclic or heterocyclic radical resulting in an overall bicyclic ring system;

[0036] wherein

[0037] R42 is H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O—(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl, S-aryl, N(R43)(R44), SO2—CH3, COOH, COO—(C1-C6)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51) or —(CR84R85)x—O(R86);

[0038] wherein

[0039] R43, R44, R45, R46, R47, R49 are each independently H or (C1-C8)-alkyl; or

[0040] substituent pairs R43 and R44, and R45 and R46, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains an additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur;

[0041] R48, R50, R51 are each independently H, (C1-C8)-alkyl or aryl;

[0042] R84, R85 are each independently H or (C1-C8)-alkyl;

[0043] R86 is H, (C1-C6)-alkyl or aryl;

[0044] x is 1, 2, 3, 4, 5 or 6;

[0045] R10 is H, (C1-C8)-alkyl, (C3-C6)-alkenyl or (C3-C6)-alkynyl;

[0046] X is N(R52), O, a bond, C═C, C(R53)(R54), C(R55)(R56)O, CO, C═C, or a group of the formula —(CR87R88)Y— wherein one or more —(CR87R88)— units contained in said group of formula —(CR87R88)Y— is optionally replaced by Y;

[0047] wherein

[0048] Y is O, S or N(R89) wherein R89 is H or (C1-C8)-alkyl;

[0049] R52, R53, R54, R55, R56 are each independently H or (C1-C8)-alkyl;

[0050] R87, R88 are each independently H or (C1-C4)-alkyl, and may be defined the same or differently in each of said —(CR87R88)— units contained in said group of formula —(CR87R88)Y—;

[0051] y is 2, 3, 4, 5 or 6;

[0052] E is a 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13- or 14-membered bivalent carbo- or heterocyclic ring structure with 0, 1, 2, 3 or 4 heteroatoms selected from the group of N, O and S, and optionally substituted with H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, oxo, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O—(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl, S-aryl, N(R57)(R58), SO2—CH3, COOH, COO—(C1-C6)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO2(R64) or CO(R65), and wherein said bivalent carbo- or heterocyclic ring structure is mono- or bicyclic;

[0053] wherein

[0054] R57, R58, R59, R60, R61, R63 are each independently H or (C1-C8)-alkyl; or

[0055] substituent pairs R57 and R58, and R59 and R60, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one further heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur;

[0056] R62, R64, R65 are each independently H, (C1-C8)-alkyl or aryl;

[0057] K is a bond, O, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C≡C, C═C or a group of the formula —(CR90R91)Z— in which one or more of the —(CR90R91)— units contained in said group of the formula —(CR90R91)Z— is optionally replaced by Z;

[0058] wherein

[0059] v is 1, 2, 3 or 4

[0060] R66, R67, R68, R69, R70 are each independently H or (C1-C8)-alkyl;

[0061] Z is O, S, N(R92), CO, SO or SO2;

[0062] R90, R91 are each independently H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, hydroxy or (C1-C4)-alkoxy-(C1-C4)-alkyl, and wherein R90 and R91 may be defined the same or differently in each of said —(CR90R91)— units contained in said group of formula —(CR90R91)Z—;

[0063] z is 2, 3, 4, 5 or 6;

[0064] R92 is H or (C1-C8)-alkyl;

[0065] R11 is H, (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl or a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered mono-, bi- or spirocyclic ring, optionally containing 1, 2, 3 or 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, and optionally substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, hydroxy-(C1-C4)-alkyl, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77), SO2CH3 or SCF3;

[0066] wherein

[0067] R71, R72, R73, R74, R75, R76, R77 are each independently H or (C1-C8)-alkyl; or

[0068] substituent pairs R72 and R73, and R76 and R77, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from the nitrogen atom, optionally contain one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur; or

[0069] E, K and R11 taken together form a tricyclic system where each of the rings in said tricyclic system are, independently of one another, saturated, partially saturated or unsaturated, and wherein each ring is comprised of 3-8 ring atoms;

[0070] and the N-oxides and pharmaceutically acceptable salts thereof.

[0071] In a further embodiment, the invention therefore relates to compounds of the formula I in which the meanings are: 3

[0072] wherein

[0073] R1, R2 are each independently H, (C1-C8)-alkyl, —(CR78R79)o—R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, aryloxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, CO—(C1-C8)-alkyl, —CO—(CH2)o—R12, CO-aryloxy-(C1-C4)-alkyl, CO—(C2-C8)-alkenyl, CO—(C2-C8)-alkynyl, COCH═CH(R13), COCC(R14), CO—(C1-C4)-alkyl-S(O)p—(C1-C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21 )(R22) or CO(C(R23)(R24))sO(R25); or

[0074] R1 and R2, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered mono-, bi- or spirocyclic ring which, apart from said nitrogen atom of attachment, optionally contains 1, 2, 3 or 4 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, and is optionally substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C1-C6)-alkyl, N(R31 )(R32) or SO2CH3;

[0075] wherein

[0076] o is, 0, 1, 2, 3, 4, 5 or 6;

[0077] p is 0, 1 or 2

[0078] q, r, s are each independently 0, 1, 2, 3 or 4;

[0079] R13, R14 are each independently a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system optionally containing 1 or 2 heteroatoms selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl or O—(C1-C8)-alkyl;

[0080] R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 are each independently H or (C1-C6)-alkyl;

[0081] R18 is H, (C1-C6)-alkyl, CO(C1-C6)-alkyl or CO(R33); or

[0082] substituent pairs R17 and R18, R21 and R22, R27 and R28, and R31 and R32, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur;

[0083] R33 is a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system which optionally contains 1 or 2 heteroatoms selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl or O—(C1-C8)-alkyl;

[0084] R12 is OH or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered mono-, bi- or spirocyclic ring which optionally contains one or more heteroatoms selected from the group of N, O and S, and is optionally substituted with F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, oxo, O—(C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O—(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, O—(C0-C8)-alkylene-aryl, N(R34)(R35), COCH═CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(C1-C6)-alkyl, COCOO(C1-C6)-alkyl, COO(R40), S(O)u(R41) or COOH;

[0085] t is 0, 1, 2, 3, 4, 5 or 6;

[0086] u is 0, 1 or 2;

[0087] R34, R35, R37, R38 are each independently H or (C1-C8)-alkyl; or

[0088] R34 and R35, taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur, and is optionally substituted by 1 or 2 oxo groups;

[0089] R36, R39 are each independently (C3-C8)-cycloalkyl or a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system wherein said aromatic ring system optionally contains one or two additional heteroatoms selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl or O—(C1-C8)-alkyl;

[0090] R40 is H, (C1-C8)-alkyl, (C2-C6)-alkenyl or (C0-C8)-alkylene-aryl;

[0091] R41 is (C1-C6)-alkyl or a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring system optionally containing one or two heteroatoms from the group of nitrogen, oxygen and sulfur, and optionally substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl or O—(C1-C8)-alkyl;

[0092] R3 is H or (C1-C6)-alkyl;

[0093] R4, R5 are each independently H, (C1-C6)-alkyl, OH, O—(C1-C6)-alkyl, O—CO(C1-C6)-alkyl or S—(C1-C6)-alkyl;

[0094] R6, R7, R8, R9 are each independently H or (C1-C8)-alkyl; or

[0095] substituent pairs R6 and R7, and R8 and R9, optionally form, independently of one another, an oxo group;

[0096] n, m are each independently 0, 1 or 2;

[0097] A, B, D, G are each independently N or C(R42);

[0098] wherein

[0099] R42 is H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O—(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl, S-aryl, N(R43)(R44), SO2-CH3, COOH, COO—(C1-C6)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50) or CO(R51);

[0100] wherein

[0101] R43, R44, R45, R46, R47, R49 are each independently H or (C1-C8)-alkyl; or

[0102] substituent pairs R43 and R44, and R45 and R46, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains an additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur;

[0103] R48, R50, R51 are each independently H, (C1-C8)-alkyl or aryl;

[0104] R10 is H, (C1-C8)-alkyl, (C3-C6)-alkenyl or (C3-C6)-alkynyl;

[0105] X is N(R52), O, a bond, C═C, C(R53)(R54) or C(R55)(R56)O;

[0106] wherein

[0107] R52, R53, R54, R55, R56 are each independently H or (C1-C8)-alkyl;

[0108] E is a 3, 4, 5, 6, 7 or 8-membered bivalent carbo- or heterocyclic ring structure with 0, 1, 2, 3 or 4 heteroatoms selected from the group of N, O and S, and optionally substituted with H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O—(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl, S-aryl, N(R57)(R58), SO2—CH3, COOH, COO—(C1-C6)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO2(R64) or CO(R65), and wherein said bivalent carbo- or heterocyclic ring structure is mono- or bicyclic;

[0109] wherein

[0110] R57, R58, R59, R60, R61, R63 are each independently H or (C1-C8)-alkyl; or

[0111] substituent pairs R57 and R58, and R59 and R60, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one further heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur;

[0112] R62, R64, R65 are each independently H, (C1-C8)-alkyl or aryl;

[0113] K is a bond, O, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO or C≡C;

[0114] wherein

[0115] v is 1, 2, 3 or 4

[0116] R66, R67, R68, R69, R70 are each independently H or (C1-C8)-alkyl;

[0117] R11 is H, (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl or a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered mono-, bi- or spirocyclic ring, optionally containing 1, 2, 3 or 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, and optionally substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO2CH3;

[0118] wherein

[0119] R71, R72, R73, R74, R75, R76, R77 are each independently H or (C1-C8)-alkyl; or

[0120] substituent pairs R72 and R73, and R76 and R77, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from the nitrogen atom, optionally contain one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur; or

[0121] E, K and R11 taken together form a tricyclic system where each of the rings in said tricyclic system are, independently of one another, saturated, partially saturated or unsaturated, and wherein each ring is comprised of 3-8 ring atoms;

[0122] and the N-oxides and pharmaceutically acceptable salts thereof.

[0123] The invention relates to compounds of the formula I in the form of their racemates, enantiomer-enriched mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.

[0124] The alkyl, alkenyl and alkynyl radicals 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 or optionally halogenated.

[0125] The term “aryl” means in particular a phenyl or naphthyl group.

[0126] A “tricyclic system” means structures having 3 rings which are connected together by more than one bond. Examples of such systems are fused systems with 3 rings and spirocycles with a ring system fused on.

[0127] In the case where R1 and R2 form together with the nitrogen atom to which they are bonded a ring, this ring may be substituted by one or more of the substituents mentioned.

[0128] The bivalent carbo- or heterocyclic ring structure E includes structures which are linked by one and the same atom to the two adjacent groups K and X.

[0129] Pharmaceutically acceptable salts are, because their solubility in water is greater than that of the initial or basic compounds, particularly suitable for medical applications. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic and 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 the chlorine salt is particularly preferably used. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts).

[0130] Salts with a pharmaceutically unacceptable anion likewise belong within the framework of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.

[0131] The term “physiologically functional derivative” used herein refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for example an ester, which on administration to a mammal such as, for example, a human is able to form (directly or indirectly) a compound of the formula I or an active metabolite thereof.

[0132] Physiologically functional derivatives include prodrugs of the compounds of the invention. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or not.

[0133] The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention.

[0134] All references to “compound(s) of formula (I)” hereinafter refer to compound(s) of the formula (I) as described above, and their salts, solvates and physiologically functional derivatives as described herein.

[0135] If radicals or substituents can occur more than once in the compounds of the formula I, they may all have independently of one another the stated meanings and be identical or different.

[0136] In a particularly preferred embodiment, the present invention relates to compounds of the formula I in which the meanings are:

[0137] R1, R2 are each independently H, (C1-C8)-alkyl, —(CH2)o—R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, CO—(C1-C8)-alkyl, —CO—(CH2)o—R12, COCH═CH(R13), COCC(R14), CO—(C1-C4)-alkyl-S(O)p—(C1-C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22) or CO(C(R23)(R24))sO(R25); or R1 and R2 together with the nitrogen atom to which they are attached, optionally form a 4-, 5-, 6-, 7, 8-, 9- or 10-membered mono-, bi- or spirocyclic ring which, apart from he nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C1-C6)-alkyl, N(R31)(R32) or SO2CH3, where R1 and R2 are preferably not both H, and R1 and R2 together with the nitrogen atom are preferably not a morpholino radical;

[0138] o 0, 1, 2, 3, 4;

[0139] p 0, 1, 2;

[0140] q, r, s independently of one another 0, 1, 2, 3, preferably q, s are independently of one another 1, 2, 3 and r is 0, 1, 2, 3;

[0141] R13, R14 independently of one another a 5-10 membered aromatic ring system which may comprise a further heteroatom from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1-C6)-alkyl, O—(C1-C8)-alkyl; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 independently of one another H, (C1-C6)-alkyl;

[0142] R18 H, (C1-C6)-alkyl, CO(C1-C6)-alkyl, CO(R33);

[0143] R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another 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—(C1-C6)-alkyl, oxygen and sulfur;

[0144] R33 a 5-10 membered aromatic ring system which may comprise a further heteroatom from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1-C6)-alkyl, O—(C1-C8)-alkyl;

[0145] R12 OH, 3-12 membered mono-, bi- or spirocyclic ring which may comprise one or more heteroatoms from the group of N, O and S, and the 3-12 membered ring may comprise further substituents such as F, Cl, CF3, CN, oxo, O—(C1-C6)-alkyl, (C1-C6)-alkyl, O—(C0-C8)-alkylene-aryl, N(R34)(R35), COCH═CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t (R39), CO(C1-C6)-alkyl, COCOO(C1-C6)-alkyl, COO(R40) and S(O)u (R41), where in a preferred embodiment the substituent O—(C1-C6)-alkyl is excluded when the 3-12 membered ring is phenyl;

[0146] t 0, 1, 2, 3, 4;

[0147] u 0, 1, 2;

[0148] R34, R35, R37, R38

[0149] independently of one another H, (C1-C8)-alkyl;

[0150] R34 and R35

[0151] 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—(C1-C6)-alkyl, oxygen and sulfur and may optionally be substituted by 1-2 oxo groups;

[0152] R36, R39 independently of one another (C3-C8)-cycloalkyl, 5-10 membered aromatic ring system which may comprise a further heteroatom from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1-C6)-alkyl, O—(C1-C8)-alkyl;

[0153] R40 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (C0-C8)-alkylene-aryl;

[0154] R41 (C1-C6)-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, (C1-C6)-alkyl, O—(C1-C8)-alkyl;

[0155] R3 H, (C1-C6)-alkyl;

[0156] R4, R5 independently of one another H, (C1-C6)-alkyl, OH, O—(C1-C6)-alkyl, O—CO(C1-C6)-alkyl;

[0157] R6, R7, R8, R9

[0158] independently of one another H, (C1-C8)-Alkyl;

[0159] R6 and R7, R8 and R9

[0160] independently of one another optionally oxo;

[0161] n, m independently of one another 0, 1, 2, preferably m is 0, 1, 2 and n is 1;

[0162] A, B, D, G independently of one another N, C(R42);

[0163] R42 is H, F, Cl, Br, CF3, CN, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C0-C2)-alkylene-aryl, O—(C0-C2)-alkylene-aryl, N(R43)(R44), SO2—CH3, COO—(C1-C6)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51)

[0164] R43, R44, R45, R46, R47, R49

[0165] independently of one another H, (C1-C8)-alkyl;

[0166] R43 and R44, R45 and R46

[0167] independently of one another 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—(C1-C6)-alkyl, oxygen and sulfur;

[0168] R48, R50, R51

[0169] independently of one another H, (C1-C8)-alkyl, aryl;

[0170] R10 H, (C1-C8)-alkyl;

[0171] X N(R52), O, a bond, C═C, C(R53)(R54), C(R55)(R56)O;

[0172] R52, R53, R54, R55, R56

[0173] independently of one another H, (C1-C8)-alkyl

[0174] E 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, O and S, which may optionally have substituents from the group of H, F, Cl, CF3, NO2, OH, CN, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl, N(R57)(R58), SO2—CH3, COO—(C1-C6)-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 (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl and N(R57)(R58), in which R57 and R58 form together with the nitrogen atom a 5-6 membered ring, in the position ortho to the point of attachment of X; particularly preferably E is monocyclic;

[0175] R57, R58, R59, R60, R61, R63

[0176] independently of one another H, (C1-C8)-alkyl;

[0177] R57 and R58, R59 and R60

[0178] independently of one another 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—(C1-C6)-alkyl, oxygen and sulfur, where R59 and R60 are preferably not both H;

[0179] R62, R64, R65

[0180] independently of one another H, (C1-C8)-alkyl, aryl;

[0181] K a bond, O, CH2O, N(R66), (C(R69)(R70))v, C≡C, OCH2, CON(R68), preferably a bond, O, CH2O, ((CR69)(R70))v, C≡C, N(R66);

[0182] v 1, 2;

[0183] R66, R68, R69, R70

[0184] independently of one another H, (C1-C8)-alkyl;

[0185] R11 H, (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, a 3 to 10-membered mono-, bi- or spirocyclic ring which may comprise 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO2CH3, preferably R11 is not COO(R74);

[0186] R71, R72, R73, R74, R75, R76, R77

[0187] independently of one another H, (C1-C8)-alkyl;

[0188] R72 and R73, R76 and R77

[0189] independently of one another 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—(C1-C6)-alkyl, oxygen and sulfur.

[0190] Particularly preferred compounds of the formula I are those in which

[0191] A, B, D, G are independently of one another N or C(R42), and the total number of nitrogen atoms in this ring is 0-2, preferably 0 or 1.

[0192] Very particularly preferred compounds of the formula I are those in which n is 1 and

[0193] m is 1 or 2.

[0194] Especially preferred compounds of the formula I are those in which

[0195] A, B, D, G are independently of one another N or C(R42) and the total number of nitrogen atoms in this ring is 0-2, preferably 0 or 1;

[0196] n is 1 and

[0197] m is 1 or 2.

[0198] In a further preferred embodiment, the present invention relates to compounds of the formula I in which the meanings are:

[0199] R1, R2 independently of one another are H, (C1-C8)-alkyl, —(CR78R79)o—R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, CO—(C1-C8)-alkyl, —CO—(CH2)o—R12, CO-aryloxy-(C1-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 spirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, CF3, (C1-C6)-alkyl, O—(C1-C4)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C0-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C1-C6)-alkyl, N(R31)(R32) or SO2CH3;

[0200] preferably independently of one another H, (C1-C8)-alkyl, —(CR78R79)o—R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, CO—(C1-C8)-alkyl, —CO—(CH2)o—R12, COCH═CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R23)(R24))sO(R25);

[0201] or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 1 0-membered mono- or bicyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, CF3, (C1-C6)-alkyl, O—(C1-C4)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C0-C2)-alkylene-aryl, oxo, CO(R26), hydroxy, N(R31)(R32) or SO2CH3;

[0202] particularly preferably independently of one another H, (C1-C8)-alkyl, —(CR78R79)o—R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, CO—(C1-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 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, (C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, oxo, CO(R26), hydroxy, N(R31)(R32);

[0203] o 0, 1, 2, 3, 4, 5, 6; preferably 0, 1, 2, 3, 4; particularly preferably 0, 1, 2, 3;

[0204] q, r independently of one another 1, 2, 3; preferably q is 1 or 2;

[0205] s 0, 1, 2, 3, 4; preferably 0, 1, 2, 3; particularly preferably 0, 1, 2;

[0206] R13, R14 independently of one another are a phenyl ring which may comprise 0-1 nitrogen atoms;

[0207] R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32

[0208] independently of one another H, (C1-C6)-alkyl;

[0209] R18 H, (C1-C6)-alkyl, CO(C1-C6)-alkyl, CO(R33); preferably H, (C1-C6)-alkyl, CO(C1-C6)-alkyl; particularly preferably H, (C1-C6)-alkyl; or

[0210] R17 and R18, R21 and R22, R27 and R28, R31 and R32

[0211] independently of one another optionally form 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—(C1-C6)-alkyl, oxygen and sulfur; preferably the ring is pyrrolidine, piperidine, N-methylpiperazine, morpholine;

[0212] R33 a 5-10 membered aromatic ring system which may comprise a further heteroatom from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1-C6)-alkyl, O—(C1-C8)-alkyl;

[0213] R12 OH, O—(C1-C6)-alkyl, O—(C0-C8)-alkylene-aryl, CN, S—(C1-C6)-alkyl, COO(R80), CON(R81)(R82), 3-12 membered mono-, bi- or spirocyclic ring which may comprise one or more heteroatoms from the group of N, O and S, and the 3-12 membered ring may comprise further substituents such as F, Cl, Br, OH, CF3, CN, oxo, O—(C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C6)-alkyl, O—(C0-C8)-alkylene-aryl, (C0-C8)-alkylene-aryl, N(R34)(R35), COCH═CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t (R39), CO(C1-C6)-alkyl, COCOO(C1-C6)-alkyl, COO(R40), S(O)u (R41);

[0214] preferably OH, O—(C1-C6)-alkyl, O—(C0-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 3-10 membered ring may comprise further substituents such as F, Cl, Br, OH, CF3, CN, oxo, O—(C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C6)-alkyl, (C0-C2)-alkylene-aryl, N(R34)(R35), CO(C1-C6)-alkyl;

[0215] particularly preferably OH, O—(C1-C6)-alkyl, 3-10 membered mono- or bicyclic ring which may comprise 1-2 heteroatoms from the group of N, O and S, and the 3-10 membered ring may comprise further substituents such as F, OH, oxo, (C1-C6)-alkyl, CO(C1-C6)-alkyl;

[0216] t 0, 1, 2, 3, 4, 5, 6;

[0217] u 0, 1, 2; preferably 0 or 2; particularly preferably 2;

[0218] R34, R35, R37, R38

[0219] independently of one another H, (C1-C8)-alkyl;

[0220] or

[0221] R34 and R35

[0222] 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—(C1-C6)-alkyl, oxygen and sulfur and may optionally be substituted by 1-2 oxo groups;

[0223] R36, R39 independently of one another (C3-C8)-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, (C1-C6)-alkyl, O—(C1-C8)-alkyl;

[0224] R40 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (C0-C8)-alkylene-aryl;

[0225] R41 (C1-C6)-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, (C1-C6)-alkyl, O—(C1-C8)-alkyl;

[0226] R78, R79 independently of one another H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, OH, (C1-C4)-alkoxy-(C1-C4)-alkyl;

[0227] R80, R81 independently of one another H, (C1-C8)-alkyl;

[0228] R3 H, (C1-C6)-alkyl; preferably H;

[0229] R4, R5 independently of one another H, (C1-C6)-alkyl, OH, O—(C1-C6)-alkyl, O—CO—(C1-C6)-alkyl, S—(C1-C6)-alkyl;

[0230] preferably independently of one another H, (C1-C6)-alkyl, OH, O—(C1-C6)-alkyl, O—CO—(C1-C6)-alkyl; particularly preferably independently of one another H, OH, O—(C1-C6)-alkyl;

[0231] R6, R7, R8, R9

[0232] H;

[0233] or

[0234] R6 and R7, R8 and R9

[0235] independently of one another optionally oxo;

[0236] preferably R6, R7, R8, R9 are H;

[0237] n 1

[0238] m 1 or 2; preferably 1;

[0239] A, B, D, G independently of one another N, C(R42);

[0240] or

[0241] the groups A and B or D and G are each C(R42) and together form an ortho-phenylene unit to result overall in a 1,4-bisubstituted naphthalene system;

[0242] preferably

[0243] B is N, C(R42); and A, D, G C(R42);

[0244] particularly preferably

[0245] A, B, D, G are C(R42);

[0246] R42 H, F, Cl, Br, CF3, CN, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl, N(R43)(R44), SO2—CH3, CON(R45)(R46), N(R47)CO(R48), CO(R51), —(CR84R85)x—O(R86);

[0247] preferably H, F, Cl, Br, CF3, CN, O—(C1-C6)-alkyl, (C1-C6)-alkyl, SO2—CH3, CON(R45)(R46), N(R47)CO(R48), CO(R51), —(CR84R85)x—O(R86);

[0248] particularly preferably H, F, Cl, CF3, CN, (C1-C6)-alkyl, —(CR84R85)x—O(R86);

[0249] R43, R44, R45, R46, R47

[0250] independently of one another H, (C1-C8)-alkyl;

[0251] or

[0252] R43 and R44, R45 and R46

[0253] independently of one another 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—(C1-C6)-alkyl, oxygen and sulfur;

[0254] R48, R50, R51

[0255] independently of one another H, (C1-C8)-alkyl, aryl; preferably independently of one another H, (C1-C8)-alkyl;

[0256] R84, R85 H;

[0257] R86 H, (C1-C6)-alkyl;

[0258] x 0, 1, 2; preferably 0, 1; particularly preferably 1;

[0259] R10 H, (C1-C8)-alkyl;

[0260] x 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;

[0261] y O, S, N(R89);

[0262] R89 H, (C1-C8)-alkyl;

[0263] R52, R53, R54, R55, R56

[0264] independently of one another H, (C1-C8)-alkyl;

[0265] E 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, O and S, which may optionally have substituents from the group of H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O—(C0-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;

[0266] preferably 5-7 membered bivalent carbo- or heterocyclic ring structure with 0-3 heteroatoms from the group of N, O and S, which may optionally have substituents from the group of H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, O—(C0-C8)-alkylene-aryl, S-aryl, N(R57)(R58), SO2—CH3, N(R61)CO(R62), CO(R65) and may be mono- or bicyclic;

[0267] particularly preferably 5-7 membered bivalent carbo- or heterocyclic ring structure with 0-2 heteroatoms from the group of N, O and S, which may optionally have substituents from the group of H, F, Cl, Br, OH, CF3, NO2, OCF3, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2—CH3, CO(R65)

[0268] e.g. E is selected from the group consisting of 4

[0269] which may optionally have substituents from the group of H, F, Cl, Br, OH, CF3, NO2, OCF3, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2—CH3, CO(R65);

[0270] preferably 5

[0271] which may optionally have the aforementioned substituents;

[0272] R57, R58, R61, R63

[0273] independently of one another H, (C1-C8)-alkyl;

[0274] R62, R64, R65

[0275] independently of one another H, (C1-C8)-alkyl, aryl; preferably independently of one another H, (C1-C8)-alkyl;

[0276] 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;

[0277] preferably a bond, O, OCH2, CH2O, N(R66), CON(R68), (C(R69)(R70))v, CO, C≡C, SCH2; particularly preferably a bond, O, OCH2, CH2O, CON(R68), (C(R69)(R70))v, CO, C≡C;

[0278] v 1, 2, 3, 4; preferably 1, 2, 3; particularly preferably 1, 2;

[0279] R66, R67, R68, R69, R70

[0280] independently of one another H, (C1-C8)-alkyl;

[0281] R11 H, (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-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 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO2CH3;

[0282] preferably (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may comprise 0 to 3 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C0-C2)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO2CH3;

[0283] particularly preferably (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, a 3 to 10-membered mono- or bicyclic ring which may comprise 0 to 2 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, oxo, CO(R71), CON(R72)(R73), N(R75)CO(C1-C6)-alkyl, or SO2CH3;

[0284] R71, R72, R73, R74, R75, R76, R77

[0285] independently of one another H, (C1-C8)-alkyl;

[0286] or

[0287] R72 and R73, R76 and R77

[0288] independently of one another 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—(C1-C6)-alkyl, oxygen and sulfur; or

[0289] the N-oxides and the physiologically tolerated salts thereof.

[0290] In a further preferred embodiment, A, B, G and D in formula I are CH or:

[0291] If E is 1,4-phenylene, the preferred meanings for A, B, G and D are furthermore those listed in table I below:

	TABLE I
	A	B	G	D
	N	CH	CH	CH
	CH	N	CH	CH
	C—Cl	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—Cl	CH	CH
	CH	CH	C—Cl	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
	CH	C—F	CH	C—F
	CH	C—F	C—F	CH
	CH	CH	C—F	C—F
	CH	CH	C—F	C—Cl
	CH	CH	C—Cl	C—CN
	CH	C—CH3	C—Cl	CH
	CH	N	CH	C—CH3
	CH	C—CH3	CH	N
	CH	N	C—CH3	CH
	CH	CH	6

[0292] If E is 7

[0293] the preferred meanings for A, B, G and D are furthermore those listed in table 11 below:

	TABLE II
	A	B	G	D
	CH	C—CH3	CH	CH
	CH	C—F	CH	CH
	CH	CH	C—CH3	CH
	CH	CH	C—F	CH
	CH	N	CH	CH
	CH	CH	CH	N
	C—F	CH	C—F	CH

[0294] If E is 8

[0295] the preferred meanings for A, B, G and D are furthermore those listed in table III below:

	TABLE III
	A	B	G	D
	CH	CH	C—F	CH
	CH	N	CH	CH
	CH	CH	CH	N

[0296] Further preferred combinations for E and A, B, G and D are listed in table IV.

	TABLE IV
	E	A	B	G	D
	9	CH	C—F	CH	CH
	10	CH	CH	C—F	CH
	11	CH	C—F	CH	CH
	12	CH	C—F	CH	CH
	13	CH	CF	CH	CH
	14	CH	CF	CH	CH
	15	CH	C—F	CH	CH
	16	CH	C—F	CH	CH
	17	CH	C—F	CH	CH
	18	CH	C—F	CH	CH
	19	CH	C—F	CH	CH
	20	CH	C—F	CH	CH
	21	CH	C—F	CH	CH
	22	CH	C—F	CH	CH
	23	CH	C—F	CH	CH
	24	CH	C—F	CH	CH

[0297] The radicals R11, K, X and E in formula I have in a particularly preferred embodiment one of the following meanings:

[0298] R11is preferably selected from the group consisting of:

[0299] 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-methylthiophenyl, o-fluorophenyl, o-chlorophenyl, o-cyanophenyl, m-fluorophenyl, 2,4-difluorophenyl, 3-fluoro-4-methylphenyl, 2-nitro-4-methylphenyl, 2-amino-4-methylphenyl, 25

[0300] K is preferably selected from the group consisting of:

[0301] —O—, bond, C≡C, CH2, CH2O, CONH, OCH2, CO, SCH2 and (CH2)2O.

[0302] X is preferably selected from the group consisting of bond, NH and CH2.

[0303] E is preferably selected from the group consisting of: 26

[0304] Preferred combinations of R11, K, X and E are listed below:

[0305] If K and X are each a bond, the particularly preferred meanings for E and R11 areas follows:

[0306] If E is 1,4-phenylene, R11 is selected from the group consisting of:

[0307] cyclohexyl, p-tolyl, p-fluorophenyl, o-fluorophenyl, p-methoxyphenyl, p-chlorophenyl, o-chlorophenyl, 2,4-difluorophenyl, 3-fluoro-4-methylphenyl, o-cyanophenyl, 27

[0308] If E is 28

[0309] R 11 selected from the group consisting of:

[0310] p-chlorophenyl, p-tolyl, p-fluorophenyl, p-methoxyphenyl, p-trifluoromethylphenyl, o-fluorophenyl, phenyl and 29

[0311] Further combinations of E and R11 or the case where K and X are each a bond are listed in table V:

TABLE V
R11                    E
p-Chlorophenyl         1,4-Cyclohexylene
2-Nitro-4-methylphenyl 30
p-Chlorophenyl         31
p-Bromophenyl          32
p-Fluorophenyl         33
p-Chlorophenyl         34
35                     36
p-Tolyl                37
n-Butyl                38
p-Chlorophenyl         39
40                     41
42                     43
p-Methylthiophenyl     44
2-Amino-4-methylphenyl 45

[0312] If K is —O— and X is a bond, NH or CH2, the particularly preferred meanings for E and R11 are as follows:

[0313] If E is 1,4-phenylene, R11 is selected from the group consisting of:

[0314] phenyl, cyclopentyl, n-butyl, iso-butyl, iso-pentyl, 2,4-difluorophenyl and p-fluorophenyl.

[0315] Further combinations of E and R11 for the case where K is —O— and X is a bond, NH or CH2 are listed in table VI:

TABLE VI
R11         E
Phenyl      46
Cyclopentyl 47
Phenyl      48
n-Butyl     49
n-Butyl     50

[0316] If K is C≡C and X is a bond, the particularly preferred meanings of E and R11 are as follows:

[0317] If E is 51

[0318] R11 is selected from the group consisting of:

[0319] phenyl, p-fluorophenyl and p-chlorophenyl.

[0320] If K is CH2 and X is a bond, the particularly preferred meanings of E and R11 are indicated in table VlI below:

TABLE VII
R11            E
Phenyl         1,4-Phenylene
52             1,4-Phenylene
p-Chlorophenyl 53

[0321] If K is CH2O and X is a bond, the particularly preferred meanings of E and R11 areas follows:

[0322] If E is 1,4-phenylene, R11 is selected from the group consisting of:

[0323] phenyl, cyclopropyl and cyclohexyl.

[0324] If K is CONH and X is a bond, the particularly preferred meanings of E and R11 are indicated in table VIII below:

TABLE VIII
R11               E
Cyclopentyl       1,4-Phenylene
Cyclohex-(1)-enyl 1,4-Phenylene
Cyclopentyl       54

[0325] If K is OCH2 and X is a bond, the particularly preferred meanings of E and R11 are indicated in table IX below:

TABLE IX
R11            E
o-Chlorophenyl 55
p-Tolyl        1,4-Phenylene
n-Propyl       1,4-Phenylene
Cyclobutyl     1,4-Phenylene

[0326] The combinations of R11, K and E listed in table X below are furthermore particularly preferred in addition to the aforementioned combinations, with X very particularly preferably being a bond:

	TABLE X
	R11	K	E
	o-Fluorophenyl	CO	56
	Phenyl	SCH2	1,4-Phenylene
	Cyclopropyl	(CH2)2O	57

[0327] The compounds of the formula I are in a very particularly preferred embodiment compounds of the formula Ia 58

[0328] in which the radicals R1, R2, R10, R11, R42, and groups X, E, K have the aforementioned meanings, and R42′ is defined as R42, where R42 and R42′ in the compounds of the formula Ia may be identical or different, or the N-oxides and the physiologically tolerated salts thereof.

[0329] In a preferred embodiment of the invention, the radicals R1, R2, R10, R11, R42, R42′ and groups X, E, K have the following meanings:

[0330] R1, R2 independently of one another H, (C1-C8)-alkyl, —(CR78R79)o—R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, (C1-C6)-alkyl, O—(C1-C4)-alkyl, (C1-C4)-alkoxy-(C1-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 CO(R26),

[0331] preferably H, (C1-C8)-alkyl, —(CR78R79)o—R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 10-membered mono- or 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 additionally be substituted by F, (C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, oxo, CO(R26), hydroxy, N(R31)(R32);

[0332] o 0, 1, 2, 3, 4, preferably

[0333] 0, 1, 2, 3;

[0334] q 1, 2, 3, preferably

[0335] 1 or 2;

[0336] s 0, 1, 2;

[0337] R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32

[0338] independently of one another H, (C1-C6)-alkyl;

[0339] or

[0340] R17 and R18, R27 and R28, R31 and R32

[0341] independently of one another 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—(C1-C6)-alkyl, oxygen and sulfur, preferably the ring is a pyrrolidine, piperidine, N-methylpiperazine, morpholine ring;

[0342] R12 OH, O—(C1-C6)-alkyl, O—(C0-C2)-alkylene-aryl, CN, S—(C1-C6)-alkyl, 3-12 membered mono-, bi- or spirocyclic ring which may comprise 1 to 3 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(C1-C6)-alkyl, preferably OH, O—(C1-C6)-alkyl, 3-10 membered mono- or bicyclic ring which may comprise 1-2 heteroatoms from the group of N, O and S, and the 3-10 membered ring may comprise further substituents such as F, OH, oxo, (C1-C6)-alkyl, CO(C1-C6)-alkyl;

[0343] R34, R35

[0344] independently of one another H, (C1-C4)-alkyl;

[0345] R40 H, (C1-C6)-alkyl, (C0-C2)-alkylene-aryl;

[0346] R78, R79 independently of one another H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, OH, (C1-C4)-alkoxy-(C1-C4)-alkyl;

[0347] R42, R42′ independently of one another H, F, Cl, Br, CF3, CN, (C1-C6)-alkyl;

[0348] R10 H, (C1-C8)-alkyl;

[0349] X N(R52), a bond, C═C, C(R53)(R54), CH2CH2;

[0350] R52, R53, R54

[0351] independently of one another H, (C1-C8)-alkyl;

[0352] E 5-7 membered bivalent carbo- or heterocyclic ring structure with 0-3 heteroatoms from the group of N, O and S, which may optionally have substituents from the group of H, F, Cl, Br, CF3, OH, CN, OCF3, NO2, O—(C1-C6)-alkyl, (C1-C6)-alkyl, SO2—CH3, CO(R65);

[0353] preferably 5-7 membered bivalent carbo- or heterocyclic ring structure with 0-2 heteroatoms from the group of N, O and S, which may optionally have substituents from the group of H, F, Cl, Br, OH, CF3, NO2, OCF3, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2—CH3, CO(R65) e.g. E is selected from the group consisting of 59

[0354] which may optionally have substituents from the group of H, F, Cl, Br, OH, CF3, NO2, OCF3, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2—CH3, CO(R65);

[0355] preferably 60

[0356] which may optionally have the aforementioned substituents;

[0357] R65 H, (C1-C8)-alkyl;

[0358] K a bond, O, OCH2, CH2O, S, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C≡C, SCH2, SO2CH2;

[0359] preferably a bond, O, OCH2, CH2O, CON(R68), (C(R69)(R70))v, particularly preferably CH2, CO, C≡C;

[0360] v 1, 2, 3, preferably

[0361] 1, 2;

[0362] R66, R67, R68, R69, R70

[0363] independently of one another H, (C1-C8)-alkyl;

[0364] R11 (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may comprise 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, oxo, CO(R71), hydroxy, N(R75)CO(C1-C6)-alkyl, or SO2CH3;

[0365] preferably (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, a 3 to 10-membered mono- or bicyclic ring which may comprise 0 to 2 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, oxo, CO(R71), CON(R72)(R73), N(R75)CO(C1-C6)-alkyl, or SO2CH3;

[0366] R71, R72, R73, R74, R75, R76, R77

[0367] independently of one another H, (C1-C8)-alkyl;

[0368] or

[0369] R72 and R73, R76 and R77

[0370] independently of one another 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—(C1-C6)-alkyl, oxygen and sulfur.

[0371] In a preferred embodiment, the present invention relates to compounds of the formula Ia,

[0372] in which

[0373] X is CH2CH2, N(R52), CH2, OCH2, SCH2, CH═CH, preferably CH2CH2, CH═CH;

[0374] E is 61

[0375] K is a bond, O or C(R69)(R70);

[0376] and the other symbols R1, R2, R10, R11, R42, R42′, R52, R69 and R70 have the meanings indicated above in relation to a definition of the radicals of the compound of the formula Ia.

[0377] In a further preferred embodiment, the present invention relates to compounds of the formula Ia,

[0378] in which

[0379] X is N(R52), preferably NH, or C(R53)(R54);

[0380] E is 62

[0381] K is a bond, O or C(R69)(R70), preferably 0;

[0382] preferably O

[0383] and the other symbols R1, R2, R10, R11, R42, R42′, R52, R53, R54, R69 and R70 have the meanings indicated above in relation to a definition of the radicals of the compound of the formula Ia.

[0384] In a further particularly preferred embodiment, the compounds of the formula I are compounds of the formula Ib 63

[0385] in which the radicals R1, R2, R10 and R11 and the groups E and D have the aforementioned meanings, or the N-oxides and the physiologically tolerated salts thereof.

[0386] In a preferred embodiment, the radicals R1, R2, R10 and R11 the groups E and D have the following meanings:

[0387] R1, R2 independently of one another H, (C1-C8)-alkyl, —(CR78R79)o—R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, CO—(C1-C8)-alkyl, —CO—(CH2)o—R12, CO-aryloxy-(C1-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 spirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, CF3, (C1-C6)-alkyl, O—(C1-C4)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C0-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C1-C6)-alkyl, N(R31)(R32) or SO2CH3, where R1 and R2 are not both CO(R26);

[0388] preferably independently of one another H, (C1-C8)-alkyl, —(CR78R79)o—R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, CO—(C1-C8)-alkyl, —CO—(CH2)o—R12, COCH═CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R23)(R24))sO(R25);

[0389] or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 10-membered mono- or bicyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, CF3, (C1-C6)-alkyl, O—(C1-C4)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C0-C2)-alkylene-aryl, oxo, hydroxy, N(R31)(R32) or SO2CH3, where R1 and R2 are not both CO—(C1-C8)-alkyl;

[0390] particularly preferably independently of one another H, (C1-C8)-alkyl, —(CR78R79)o—R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, CO—(C1-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 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 additionally be substituted by F, (C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, oxo, CO(C1-C8)-alkyl, hydroxy, N(R31)(R32), where R1 and R2 are not both CO(C1-C8)-alkyl;

[0391] o 0, 1, 2, 3, 4, 5, 6; preferably 0, 1, 2, 3, 4; particularly preferably 0, 1, 2, 3;

[0392] q, r independently of one another 1, 2, 3; preferably q is 1 or 2;

[0393] s 0, 1, 2, 3, 4; preferably 0, 1, 2, 3; particularly preferably 0, 1, 2;

[0394] R13, R14 independently of one another a phenyl ring which may comprise 0-1 nitrogen atoms;

[0395] R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32

[0396] independently of one another H, (C1-C6)-alkyl;

[0397] R18 H, (C1-C6)-alkyl, CO(C1-C6)-alkyl, CO(R33); preferably H, (C1-C6)-alkyl, CO(C1-C6)-alkyl; particularly preferably H, (C1-C6)-alkyl;

[0398] or

[0399] R17 and R18, R21 and R22, R27 and R28, R31 and R32

[0400] independently of one another 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—(C1-C6)-alkyl, oxygen and sulfur; preferably the ring is pyrrolidine, piperidine, N-methylpiperazine, morpholine;

[0401] R33 a 5-10 membered aromatic ring system which may comprise a further heteroatom from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1-C6)-alkyl, O—(C1-C8)-alkyl;

[0402] R12 is OH, O—(C1-C6)-alkyl, O—(C0-C8)-alkylene-aryl, CN, S—(C1-C6)-alkyl, COO(R80), CON(R81)(R82), 3-12 membered mono-, bi- or spirocyclic ring which may comprise one or more heteroatoms from the group of N, O and S and the 3-12 membered ring may comprise further substituents such as F, Cl, Br, OH, CF3, CN, oxo, O—(C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C6)-alkyl, O—(C0-C8)-alkylene-aryl, (C0-C8)-alkylene-aryl, N(R34)(R35), COCH═CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38)) (R39), CO(C1-C6)-alkyl, COCOO(C1-C6)-alkyl, COO(R40), S(O)u (R41);

[0403] preferably OH, O—(C1-C6)-alkyl, O—(C0-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 3-10 membered ring may comprise further substituents such as F, Cl, Br, OH, CF3, CN, oxo, O—(C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C6)-alkyl, (C0-C2)-alkylene-aryl, N(R34)(R35), CO(C1-C6)-alkyl;

[0404] particularly preferably OH, O—(C1-C6)-alkyl, 3-10 membered mono- or bicyclic ring which may comprise 1-2 heteroatoms from the group of N, O and S and the 3-10 membered ring may comprise further substituents such as F, OH, oxo, (C1-C6)-alkyl, CO(C1-C6)-alkyl;

[0405] t 0, 1, 2, 3, 4, 5, 6;

[0406] u 0, 1, 2; preferably 0 or 2; particularly preferably 2;

[0407] R34, R35, R37, R38

[0408] independently of one another H, (C1-C8)-alkyl;

[0409] or

[0410] R34 and R35

[0411] 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—(C1-C6)-alkyl, oxygen and sulfur and may optionally be substituted by 1-2 oxo groups;

[0412] R36, R39 independently of one another (C3-C8)-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, (C1-C6)-alkyl, O—(C1-C8)-alkyl;

[0413] R40 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (C0-C8)-alkylene-aryl;

[0414] R41 (C1-C6)-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, (C1-C6)-alkyl, O—(C1-C8)-alkyl;

[0415] R78, R79 independently of one another H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, OH, (C1-C4)-alkoxy-(C1-C4)-alkyl;

[0416] R80, R81 independently of one another H, (C1-C8)-alkyl;

[0417] R10 H, (C1-C8)-alkyl;

[0418] E 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, O and S, which may optionally have substituents from the group of H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O—(C0-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;

[0419] preferably 5-7 membered bivalent carbo- or heterocyclic ring structure with 0-3 heteroatoms from the group of N, O and S, which may optionally have substituents from the group of H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, O—(C0-C8)-alkylene-aryl, S-aryl, N(R57)(R58), SO2—CH3, N(R61 )CO(R62), CO(R65) and may be mono- or bicyclic;

[0420] particularly preferably 5-7 membered bivalent carbo- or heterocyclic ring structure with 0-2 heteroatoms from the group of N, O and S, which may optionally have substituents from the group of H, F, Cl, Br, OH, CF3, NO2, OCF3, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2—CH3, CO(R65)

[0421] e.g. E is selected from the group consisting of 64

[0422] which may optionally have substituents from the group of H, F, Cl, Br, OH, CF3, NO2, OCF3, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2—CH3, CO(R65);

[0423] preferably 65

[0424] which may optionally have the aforementioned substituents;

[0425] R57, R58, R61, R63

[0426] independently of one another H, (C1-C8)-alkyl;

[0427] R62, R64, R65

[0428] independently of one another H, (C1-C8)-alkyl, aryl; preferably independently of one another H, (C1-C8)-alkyl;

[0429] 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;

[0430] preferably a bond, O, OCH2, CH2O, N(R66), CON(R68), (C(R69)(R70))v, CO, C≡C, SCH2; particularly preferably a bond, O, OCH2, CH2O, CON(R68), (C(R69)(R70))v, CO, C≡C;

[0431] v 1, 2, 3, 4; preferably 1, 2, 3; particularly preferably 1, 2;

[0432] R66, R67, R68, R69, R70

[0433] independently of one another H, (C1-C8)-alkyl;

[0434] R11 H, (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-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 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO2CH3SCF3;

[0435] preferably (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may comprise 0 to 3 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C0-C2)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO2CH3;

[0436] particularly preferably (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, a 3 to 10-membered mono- or bicyclic ring which may comprise 0 to 2 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, oxo, CO(R71), CON(R72)(R73), N(R75)CO(C1-C6)-alkyl, or SO2CH3;

[0437] R71, R72, R73, R74, R75, R76, R77

[0438] independently of one another H, (C1-C8)-alkyl;

[0439] or

[0440] R72 and R73, R76 and R77

[0441] independently of one another 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—(C1-C6)-alkyl, oxygen and sulfur.

[0442] In a preferred embodiment, the present invention relates to compounds of the formula Ib

[0443] in which

[0444] X is a bond,

[0445] E is 66

[0446] where the aforementioned groups may optionally have substituents from the group of H, F, Cl, Br, OH, CF3, NO2, OCF3, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2—CH3, CO(R65);

[0447] preferably E is 67

[0448] in which the groups may have the aforementioned substituents;

[0449] K is a bond; and

[0450] the other radicals R1, R2, R10 and R11 and the group D have the meanings indicated above in relation to the definition of the radicals of the compound of the formula Ib.

[0451] R11 in the aforementioned compounds of the formula Ib is particularly preferably a substituted mono- or bicyclic ring system with 5-10 members, which may have 0-3 heteroatoms, in particular N, O and/or S, particularly preferably phenyl with 0-1 N atom, cyclohexyl or a bicyclic system with 8-10 members and 1-2 heteroatoms, in particular N, O and/or S.

[0452] In a further preferred embodiment, the present invention relates to compounds of the formula Ib

[0453] in which

[0454] X is a bond;

[0455] E is 68

[0456] where the aforementioned groups may optionally have substituents from the group of H, F, Cl, Br, OH, CF3, NO2, OCF3, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2CH3 and CO(R65);

[0457] preferably 69

[0458] in which the groups may have the aforementioned substituents;

[0459] K is CH2, CH2CH2, O, CH2O, OCH2, CON(R68), N(R67)CO, S, SO2, SCH2, SO2, SO2CH2, CO or a triple bond;

[0460] preferably CH2, O, CH2O, OCH2, CON(R68), SCH2, CO or a triple bond; and

[0461] the other radicals R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R67 and R68 and the group D have the meanings indicated above in relation to the definition of the radicals of the compound of the formula Ib.

[0462] The amount of a compound of formula (I) necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day and per kilogram of bodyweight, for example 3-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.3 mg to 1.0 mg/kg, which can suitably be administered as infusion of 10 ng to 100 ng per kilogram and per minute. Suitable infusion solutions for these purposes may contain, for example, 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 active ingredient. Thus, ampoules for injections may contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, 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 of pharmaceutically acceptable salts, the aforementioned weight data are based on the weight of the free compound from which the salt is derived. For the prophylaxis and therapy of the abovementioned conditions, the compounds of formula (I) may be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient's health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances may likewise be present, including other compounds of formula (I). The pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.

[0463] Pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula (I) used in each case. Coated formulations and coated slow-release formulations also belong within the framework of the invention. Preference is given to acid- and gastric juice-resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

[0464] Suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, cachets, suckable tablets or tablets, each of which contain a defined amount of the compound of formula (I); as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact. The compositions are generally produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets can be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one or more surface-active/dispersing agent(s) in a suitable machine. Molded tablets can be produced by molding the compound, which is in powder form and is moistened with an inert liquid diluent, in a suitable machine.

[0465] Pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula (I) with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.

[0466] Pharmaceutical compositions suitable for parenteral administration comprise preferably sterile aqueous preparations of a compound of formula (I), which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place by subcutaneous, intramuscular or intradermal injection. These preparations can preferably be produced by mixing the compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.

[0467] Pharmaceutical compositions suitable for rectal administration are preferably in the form of single-dose suppositories. These can be produced by mixing a compound of the formula (I) with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.

[0468] Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%.

[0469] Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis. Such plasters suitably contain the active ingredient in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%. A particular possibility is for the active ingredient to be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2(6): 318 (1986).

[0470] As used herein, the following definitions apply:

[0471] “Patient” means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.

[0472] “Treat” or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.

[0473] “Therapeutically effective amount” means a quantity of the compound which is effective in treating the named disorder or condition.

[0474] “Pharmaceutically acceptable carrier” is a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration.

[0475] The compounds of the formula I are distinguished by beneficial effects on lipid metabolism, and they are particularly suitable for weight reduction and for maintaining a reduced weight after weight reduction has taken place in mammals and as anorectic agents. The compounds are distinguished by their low toxicity and their few side effects. The compounds can be employed alone or in combination with other weight-reducing or anorectic active ingredients. Further anorectic active ingredients of this type are mentioned, for example, in the Rote Liste, chapter 01 under weight-reducing agents/appetite suppressants, and they also include active ingredients which increase the energy turnover of the organism and thus lead to weight reduction or else those which influence the general metabolism of the organism in such a way that an increased calorie intake does not lead to an enlargement of the fat depots and a normal calorie intake leads to a reduction of the fat depots of the organism. The compounds are suitable for the prophylaxis and, in particular, for the treatment of excessive weight or obesity. The compounds are further suitable for the prophylaxis and, in particular, for the treatment of type II diabetes, of arteriosclerosis and for normalizing lipid metabolism and for the treatment of high blood pressure. The compounds act as MCH antagonists and are also suitable for the treatment of disturbances of wellbeing and of psychiatric indications such as, for example, depressions, anxiety states, anxiety neuroses, schizophrenia and for the treatment of disorders associated with the circadian rhythm and for the treatment of drug abuse.

[0476] In a further aspect of the invention, the compounds of the formula I can be administered in combination with one or more other pharmacologically active substances which are selected, for example, from antidiabetics, antiobesity agents, active ingredients which lower blood pressure, lipid-lowering agents and active ingredients for the treatment and/or prevention of complications caused by diabetes or associated with diabetes.

[0477] Further pharmacologically active substances suitable in particular are:

[0478] all antidiabetics mentioned in the Rote Liste 2001, chapter 12. They may be combined with the compounds of the formula I of the invention in particular for a synergistic improvement of the effect. Administration of the active ingredient combination may take place either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation. Most of the active ingredients listed below are disclosed in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.

[0479] Suitable antidiabetics include insulin and insulin derivatives such as, for example, Lantus® or HMR 1964, fast-acting insulins (see U.S. Pat. No. 6,221,633), amylin, GLP-1 and GLP-2 derivatives such as, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S, and orally effective hypoglycemic active ingredients.

[0480] The orally effective hypoglycemic active ingredients include, preferably, sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon receptor antagonists, GLP-1 agonists, potassium channel openers such as, for example, those disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers, activators of insulin receptor kinase, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, for example inhibitors of glycogen phosphorylase, modulators of glucose uptake and glucose excretion, compounds which alter lipid metabolism, such as antihyperlipidemic active ingredients and antilipidemic active ingredients, e.g. HMGCoA reductase inhibitors, inhibitors of cholesterol transport/of cholesterol uptake, inhibitors of bile acid reabsorption or inhibitors of microsomal triglyceride transfer protein (MTP), compounds which reduce food intake, PPAR and RXR agonists and active ingredients which act on the ATP-dependent potassium channel of the beta cells.

[0481] In one embodiment of the invention, the present compounds are administered in combination with insulin.

[0482] In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.

[0483] In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor such as, for example, ezetimibe, tiqueside, pamaqueside.

[0484] In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR gamma agonist, such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570.

[0485] In one embodiment of the invention, the compounds of the formula I are administered in combination with PPAR alpha agonist, such as, for example, GW 9578, GW 7647.

[0486] In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR alpha/gamma agonist, such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in PCT/US 11833, PCT/US 11490, DE10142734.4.

[0487] In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate such as, for example, fenofibrate, clofibrate, bezafibrate.

[0488] In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor such as, for example, implitapide, BMS-201038, R-103757.

[0489] In one embodiment of the invention, the compounds of the formula I are administered in combination with bile acid absorption inhibitor (see, for example, U.S. Pat. No. 6,245,744 or U.S. Pat. No. 6,221,897), such as, for example, HMR 1741.

[0490] In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, such as, for example, JTT-705.

[0491] In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine, colesevelam.

[0492] In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer (see U.S. Pat. No. 6,342,512), such as, for example, HMR1171, HMR1586.

[0493] In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, such as, for example, avasimibe.

[0494] In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant, such as, for example, OPC-14117.

[0495] In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor, such as, for example, NO-1886.

[0496] In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP-citrate lyse inhibitor, such as, for example, SB-204990.

[0497] In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor, such as, for example, BMS-188494.

[0498] In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist, such as, for example, CI-1027 or nicotinic acid.

[0499] In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, such as, for example, orlistat.

[0500] In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.

[0501] In one embodiment, the compounds of the formula I are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.

[0502] In one embodiment, the compounds of the formula I are administered in combination with a biguanide, such as, for example, metformin.

[0503] In one further embodiment, the compounds of the formula I are administered in combination with a meglitinide, such as, for example, repaglinide.

[0504] In one embodiment, the compounds of the formula I are administered in combination with a thiazolidinedione, such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 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.

[0505] In one embodiment, the compounds of the formula I are administered in combination with an α-glucosidase inhibitor, such as, for example, miglitol or acarbose.

[0506] In one embodiment, the compounds of the formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

[0507] In one embodiment, the compounds of the formula I are administered in combination with more than one of the aforementioned compounds, e.g. in combination with a sulfonylurea and metformin, with a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. The compounds of the invention may moreover be administered in combination with one or more antiobesity agents or appetite-controlling active ingredients.

[0508] In a further embodiment, the compounds of the formula I are administered in combination with CART modulators (see “Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice” Asakawa, A, et al., M.: Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists, e.g. naphthalene-1-sulfonic acid {4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexyl-methyl}amide; 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 salt (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 salt (WO 99/15525)), serotonin reuptake inhibitors (e.g. dexfenfluramine), mixed sertoninergic and noradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (e.g. human growth hormone), growth hormone-releasing compounds (6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH agonists (see, for example, EP 0 462 884), uncoupling protein 2 or 3 modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881), DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or TR-β agonists.

[0509] In one embodiment of the invention, the other active ingredient is leptin; see, for example, “Perspectives in the therapeutic use of leptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622.

[0510] In one embodiment, the other active ingredient is dexamphatamine or amphetamine.

[0511] In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine.

[0512] In another embodiment, the other active ingredient is sibutramine or the mono- and bisdemethylated active metabolites of sibutramine.

[0513] In one embodiment, the other active ingredient is orlistat.

[0514] In one embodiment, the other active ingredient is mazindol or phentermine.

[0515] In one embodiment, the compounds of the formula I are administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob/Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 September-October), 18(5), 230-6.) Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt/Main)). Combination with Caromax® is possible in one preparation or by separate administration of compounds of the formula I and Caromax®. Caromax® can in this connection also be administered in the form of food products such as, for example, in bakery products or muesli bars. 7071

[0516] The present compounds may additionally be administered in combination with one or more antihypertensive active ingredients. Examples of antihypertensive active ingredients are beta blockers such as alprenolol,atenol, timolol, pindolol, propanolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as, for example, benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and rampril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and alpha blockers such as doxazosin, urapidil, prazosin and terazosin. Reference may furthermore be made to Remington: The Science and Practice of Pharmacy, 19th edition, Gennaro, editor, Mack Publishing Co., Easton, Pa., 1995.

[0517] It will be appreciated that every suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is to be regarded as covered by the scope of protection of the present invention.

[0518] The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.

[0519] The present invention is not to be limited in scope by the specific embodiments describe herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[0520] Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties.

EXAMPLES

[0521] The efficacy of the compounds was tested as follows:

[0522] Biological Test Model:

[0523] The anorectic effect was tested on female NMRI mice. After withdrawal of food for 17 hours, the test product was administered by gavage. The animals were housed singly with free access to drinking water and were offered condensed milk 30 minutes after administration of the product. The condensed milk consumption was determined every half hour for 7 hours, and the general wellbeing of the animals was observed. The measured milk consumption was compared with the vehicle-treated control animals.

TABLE 1
Anorectic effect measured as the reduction in the cumulative milk
consumption of treated compared with control animals
		Number of	Number of	Reduction in
		animals/-	animals/-	the
		cumulative milk	cumulative milk	cumulative
		consumption of	consumption of	milk
	Oral	the treated	the control	consumption
	dose	animals	animals	as % of the
Example	[mg/kg]	N/[ml]	N/[ml]	control
Example 4	30	5/3.55	5/1.76	50
Example	30	5/3.70	5/1.34	64
13

[0524] Description of Experiments

[0525] Functional Measurements to Find IC50 Values

[0526] The cloning of the cDNA for the human MCH receptor, preparation of a recombinant HEK293 cell line which expresses the human MCH receptor, and functional measurements with the recombinant cell line took place in analogy to the description by Audinot et al. (J. Biol. Chem. 276, 13554-13562, 2001). A difference from the reference was, however, the use of the plasmid pEAK8 from EDGE Biosystems (USA) to construct the expression vector. The host used for the transfection was a transformed HEK cell line named “PEAK Stable Cells” (likewise from EDGE Biosystems). The functional measurements of the cellular calcium flux after addition of agonist (MCH) in the presence of ligand of the invention took place with the aid of the FLIPR apparatus from Molecular Devices (USA) using the protocols of the apparatus manufacturer.

[0527] The examples and preparation methods detailed below serve to illustrate the invention without, however, restricting it.

[0528] The compounds of the formula I of the invention can be prepared with the aid of reactions which are known in principle. For example, the compounds were obtained in accordance with the following general reaction schemes. 7273

[0529] Other compounds of the invention can be obtained by further routes which are outlined by way of example in the following scheme. 7475

[0530] Yet other examples were obtained as indicated in the following scheme. 76

[0531] Descriptions of the general methods used are to be found by way of example described at the following places:

[0532] Methods A, B and C in example 1;

[0533] Method D in example 2;

[0534] Method E in example 3;

[0535] Method E-a in example 275;

[0536] Method E-b in example 286;

[0537] Method F in example 4;

[0538] Method F-a in example 264;

[0539] Method G in example 15;

[0540] Method H in example 237;

[0541] Method H-a in example 298;

[0542] Method I in example 238;

[0543] Method J in example 245;

[0544] Method J-a in example 297;

[0545] Method K in example 250;

[0546] Method L in example 254;

[0547] Method M in example 274;

[0548] Method N in example 277;

[0549] Method O in example 279;

[0550] Method O-a in example 292;

[0551] Method O-b in example 280;

[0552] Method P in example 285;

[0553] Method Q in example 290;

[0554] Method R in example 309.

[0555] General Explanations

[0556] a) Mode of Drawing the Structural Formulae

[0557] Only non-hydrogen atoms are depicted for clarity in the structural formulae of the given examples.

[0558] In tables 6-13, enantiomer-enriched compounds are identified by a marked hydrogen atom on the stereogenic center. Unless expressly noted otherwise, the enantiomer-enriched examples shown have the (R) configuration on the 3-aminopyrrolidine stereocenter.

[0559] b) Salt Forms

[0560] Many of the compounds of the invention are bases and can form salts with appropriately strong acids. In particular, after purification of the compounds by HPLC chromatography using a trifluoroacetic acid-containing mobile phase they may be in the form of hydrotrifluoroacetates. These can be converted into the free bases shown by simple treatment of a solution of the salts for example with sodium carbonate solution.

[0561] c) Units of the Characterizing Data

[0562] The unit of the stated molecular weight is “g/mol”. Peaks observed in the mass spectrum are indicated as the integral quotient of the molar molecular ion 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

[0563] 77

[0564] Method A

[0565] A solution of 4-phenoxyaniline (3.33 g) in DMF (10 ml) was added dropwise to a solution of carbonyldiimidazole (2.92 g) 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 was kept initially at room temperature for 2 hours and then at 80° C. for 30 minutes. The mixture was added dropwise to water (600 ml) and the resulting precipitate was filtered off with suction and washed with water. Alternatively, the product can also be extracted with ethyl acetate and purified by chromatography after concentration. This resulted in the product with the molecular weight of 444.54 (C26H28N4O3); MS (ESI): 445 (M+H+).

[0566] N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide

[0567] Method B

[0568] A suspension of N-methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide (3.5 g) and palladium(II) hydroxide (20% on carbon; 0.9 g) in ethanol (150 ml) and ethyl acetate (300 ml) was vigorously stirred under a hydrogen atmosphere (atmospheric pressure) for 3 hours. The catalyst was then removed by filtration, and the filtrate was concentrated. This resulted in the product with the molecular weight of 233.32 (C13H19N3O); MS (ESI): 234 (M+H+).

[0569] N-Methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide

[0570] Method C

[0571] 4-Fluoronitrobenzene (25.0 g) was slowly added to a suspension of N-methyl-N-pyrrolidin-3-ylacetamide (25.2 g) and cesium carbonate (57.6 g) in DMF (300 ml). After 2 hours, the reaction mixture was poured into water, and the resultant precipitate was filtered off with suction. Alternatively, the product can also be extracted with ethyl acetate and purified by chromatography after concentration. This results in the product with the molecular weight of 263.30 (C13H17N3O3): MS (ESI): 264 (M+H+).

Example 2

1-[4-(3-Methylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea

[0572] 78

[0573] Method D

[0574] A mixture of N-methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrroldin-3-yl)acetamide (6.0 g), ethanol (250 ml), water (60 ml) and sodium hydroxide solution (10 M; 80 ml) was heated under reflux for 12 hours. The alcohol was distilled out and the resulting precipitate was filtered off with suction and washed with dichloromethane. Additional product was obtained by concentration of the organic phase and chromatography (silica gel, dichloromethane/methanol 9:1 with 1% triethylamine). This resulted in the product 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

[0575] 79

[0576] Method E

[0577] 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. After 10 minutes, Hünig's base (130 mg) and then a solution of phenylacetic acid (136 mg) in DMF (1 ml) was added. After a reaction time of 12 hours at room temperature, water was added to the mixture, and it was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 520.64 (C32H32N4O3); MS (ESI): 521 (M+H+) as hydrotrifluoroacetate.

Example 4

(R)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide

[0578] 80

[0579] (R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4-phenoxyaniline by method A. This resulted in the product with the molecular weight of 444.54 (C26H28N4O3); MS (ESI): 445 (M+H+).

[0580] (R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide

[0581] (R)-N-Methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight of 233.32 (C13H19N3O); MS (ESI): 234 (M+H+).

[0582] (R)-N-Methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide

[0583] Method F

[0584] (R)-N-[1-(4-Nitrophenyl)pyrrolidin-3-yl]acetamide (1.3 g) was added in portions to a suspension of sodium hydride (50% in oil; 0.25 g) in DMF (50 ml). After gas evolution had ceased, iodomethane (0.82 g) was added. After one hour, the reaction mixture was cautiously hydrolyzed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 263.30 (C13H17N3O3); MS (ESI): 264 (M+H+).

[0585] (R)-N-[1-(4-Nitrophenyl)pyrrolidin-3-yl]acetamide

[0586] (R)-N-pyrrolidin-3-ylacetamide was reacted with 4-fluoronitrobenzene by method 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-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide

[0587] 81

[0588] The sequence described in example 4 was applied to (S)-N-pyrrolidin-3-ylacetamide. This resulted in the product with the molecular weight of 444.54 (C26H28N4O3); MS (ESI): 445 (M+H+).

Example 6

(R)-1-[4-(3-Methylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea

[0589] 82

[0590] (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 with the molecular weight of 402.50 (C24H26N4O2); MS (ESI): 403 (M+H+).

Example 7

(S)-1-[4-(3-Methylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea

[0591] 83

[0592] (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 with the molecular weight 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

[0593] 84

[0594] (R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl)-N-methylacetamide was reacted with 4-cyclopentyloxyaniline by method A. This resulted in the product with the molecular weight of 436.56 (C25H32N4O3); MS (ESI): 437 (M+H+).

[0595] (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-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide.

[0596] 4-Cyclopentyloxyaniline

[0597] A mixture of 4-nitrophenol (63.7 g), bromocyclopentane (68.2 g), potassium carbonate (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. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was hydrogenated by method B. This resulted in the 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

[0598] 85

[0599] N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide was reacted by method D. This resulted in the product with the molecular weight of 394.52 (C23H30N4O2); MS (ESI): 395 (M+H+).

[0600] (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.

Example 10

Ethyl (1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)methylcarbamate

[0601] 86

[0602] Ethyl chloroformate (8 μl) was added dropwise to a solution of 1-(4-cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea (20 mg) and Hünig's base (10 mg) in dichloromethane (3 ml). After 12 hours, the reaction mixture was concentrated and the residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 466.59 (C26H34N4O4); MS (ESI): 467 (M+H+) as hydrotrifluoroacetate.

Example 11

1-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-3-ethyl-1-methylurea

[0603] 87

[0604] Ethyl isocyanate (7 μl) was added dropwise to a solution of 1-(4-cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea (20 mg) and Hünig's base (10 mg) in dichloromethane (3 ml). After 12 hours, the reaction mixture was concentrated and the residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 465.60 (C26H35N5O3); MS (ESI): 466 (M+H+) as hydrotrifluoroacetate.

Example 12

1-(4-Cyclopentyloxyphenyl)-3-(4-{3-[methyl-((R)-5-oxopyrrolidin-2-ylmethyl)amino]pyrrolidin-1-yl}phenyl)urea

[0605] 88

[0606] (R)-5-Bromomethylpyrrolidin-2-one (15 mg) was added to a suspension of 1-(4-cyclopentyloxyphenyl)-3-[4-(3-methyaminopyrrolidin-1-yl)phenyl]urea (30 mg) and potassium carbonate (20 mg) in DMF (3 ml). After 2 hours, the reaction mixture was filtered and concentrated, and the residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 491.64 (C28H37N5O3); MS (ESI): 492 (M+H+) as hydrotrifluoroacetate.

Example 13

4-(4-Chlorophenyl)piperidine-1-carboxylic Acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide

[0607] 89

[0608] N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyidiimidazole and then with 4-(4-chlorophenyl)piperidine by method A. This resulted in the product with the molecular weight of 455.00 (C25H31ClN4O2); MS (ESI): 455 (M+H+).

[0609] (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)pyrrolidin-3-yl]-N-methylacetamide.

Example 14

tert-Butyl (R)-[1-(4-{[4-(4-chlorophenyl)piperidine-1-carbonyl]amino}-phenyl)pyrrolidin-3-yl]methylcarbamate

[0610] 90

[0611] tert-Butyl (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate was reacted with carbonyidiimidazole and then with 4-(4-chlorophenyl)piperidine by method A. This resulted in the product with the molecular weight of 513.09 (C28H37ClN4O3); MS (ESI): 513 (M+H+).

[0612] tert-Butyl (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate

[0613] tert-Butyl (R)-methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate was hydrogenated by method B. This resulted in the product with the molecular weight of 291.40 (C16H25N3O2); MS (ESI): 292 (M+H+).

[0614] tert-Butyl (R)-methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate

[0615] tert-Butyl (R)-[1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate was alkylated with iodomethane by method F. This resulted in the product with the molecular weight of 321.38 (C16H23N3O4); MS (ESI): 322 (M+H+).

[0616] tert-Butyl (R)-[1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate

[0617] tert-Butyl (R)-pyrrolidin-3-ylcarbamate was reacted with 4-fluoronitro-benzene by method C. This resulted in the product with the molecular weight of 307.35 (C15H21N3O4); MS (ESI): 308 (M+H+).

Example 15

(R)-4-(4-Chlorophenyl)piperidine-1-carboxylic Acid [4-(3-methylamino-pyrrolidin-1-yl)phenyl]amide

[0618] 91

[0619] Method G

[0620] 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 in dichloromethane. After washing with sodium carbonate solution, the organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 412.97 (C23H29ClN4O); MS (ESI): 413 (M+H+).

Example 16

4-(4-Chlorophenyl)piperidine-1-carboxylic Acid (4-{(R)-3-[methyl-(1-methyl-piperidin-3-ylcarbonyl)amino]pyrrolidin-1-yl}phenyl)amide

[0621] 92

[0622] (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 molecular weight of 538.14 (C30H40ClN5O2); MS (ESI): 538 (M+H+).

Example 17

4-(4-Chlorophenyl)piperidine-1-carboxylic Acid (4-(R)-{3-[methyl-(2-piperidin-1-ylacetyl)amino]pyrrolidin-1-yl}phenyl)amide

[0623] 93

[0624] (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 (C30H40ClN5O2); 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

[0625] 94

[0626] (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 the molecular weight of 542.10 (C27H32ClN5O3S); MS (ESI): 542 (M+H+).

Example 19

(R)-4-(4-Chlorophenyl)piperidine-1-carboxylic Acid (4-{3-[methyl-(2,2,2-trifluoroacetyl)amino]pyrrolidin-1-yl}phenyl)amide

[0627] 95

[0628] (R)-[N-[1-(4-aminophenyl)pyrrolidin-3-yl]-2,2,2-trifluoro-N-methylacetamide was reacted with carbonyldiimidazole and then with 4-(4-chlorophenyl)-piperidine by method A. This resulted in the product with the molecular weight of 508.98 (C25H28ClF3N4O2); MS (ESI): 509 (M+H+).

[0629] (R)-[N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-2,2,2-trifluoro-N-methylacetamide

[0630] (R)-2,2,2-Trifluoro-N-methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight of 287.29 (C13H16F3N3O); MS (ESI): 288 (M+H+).

[0631] (R)-2,2,2-Trifluoro-N-methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide

[0632] Trifluoroacetic anhydride (0.5 ml) was added dropwise to a solution of (R)-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 extracted with ethyl acetate. The organic phase was washed with citric acid solution, dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 317.27 (C13H14F3N3O3); MS (ESI): 318 (M+H+).

[0633] (R)-Methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]amine

[0634] A solution of tert-butyl (R)-methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]-carbamate (0.7 g) in dichloromethane (5 ml) was treated with trifluoroacetic acid (3 ml) for 1 hour. The reaction solution was concentrated and the residue was taken up in dichloromethane. After washing with sodium carbonate solution, the organic phase was dried over magnesium sulfate and 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

[0635] 96

[0636] 4-(4-Chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide was reacted with iodomethane by method F. This resulted in the product with the molecular weight of 469.03 (C26H33ClN4O2); 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

[0637] 97

[0638] (R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-(2-diethylaminoethyl)acetamide was reacted with 4-(4-chlorophenyl)piperidine by method A. This resulted in the product with the molecular weight of 540.15 (C30H42ClN5O2); MS (ESI): 540 (M+H+).

[0639] (R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-(2-diethylaminoethyl)acetamide (R)-N-(2-Diethylaminoethyl)-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight of 318.47 (C18H30N4O); MS (ESI): 319 (M+H+).

[0640] (R)-N-(2-Diethylaminoethyl)-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide

[0641] (R)-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide was reacted with 2-chloroethyldiethylamine by method F. This resulted in the product with the molecular weight of 348.45 (C18H28N4O3); MS (ESI): 349 (M+H+).

Example 22

1-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea

[0642] 98

[0643] Dimethylpyrrolidin-3-ylamine was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-phenoxyaniline by method A, B and C. This resulted 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-isobutoxyphenyl)propionamide

[0644] 99

[0645] N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 2-(4-isobutoxyphenyl)propionic acid by method E. This resulted in the product 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

[0646] 100

[0647] N-Pyrrolidin-3-ylacetamide was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was 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+).

[0648] (R)- and (S)-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

[0649] 101

[0650] N-Ethyl-N-pyrrolidin-3-ylacetamide was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-cyclopentyloxyaniline by method A, B and 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-(acetylmethylamino)pyrrolidin-1-yl]-3-methylphenyl}amide

[0651] 102

[0652] N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 1-fluoro-2-methyl-4-nitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 469.03 (C26H33ClN4O2); MS (ESI): 469 (M+H+).

Example 27

4-(4-Chlorophenyl)piperidine-1-carboxylic Acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl)-3-fluorophenyl}amide

[0653] 103

[0654] N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 1,2-difluoro-4-nitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 472.99 (C25H30ClFN4O2); MS (ESI): 473 (M+H+).

Example 28

4-(4-Chlorophenyl)piperidine-1-carboxylic Acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]-2,6-difluorophenyl}amide

[0655] 104

[0656] N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 1,3,5-trifluoro-2-nitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 490.99 (C25H29ClF2N4O2); MS (ESI): 491 (M+H+).

Example 29

4-(4-Chlorophenyl)piperidine-1-carboxylic Acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]-2-methylphenyl}amide

[0657] 105

[0658] N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 4-fluoro-2-methyl-1-nitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 469.03 (C26H33ClN4O2); MS (ESI): 469 (M+H+).

Example 30

4-(4-Chlorophenyl)piperidine-1-carboxylic Acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]-2-fluorophenyl}amide

[0659] 106

[0660] N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 2,4-difluoro-1-nitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 472.99 (C25H30ClFN4O2); MS (ESI): 473 (M+H+).

Example 31

tert-Butyl (R)-[1-(5-{[4-(4-Chlorophenyl)piperidin-1-carbonyl]amino}pyridin-2-yl)pyrrolidin-3-yl]methylcarbamate

[0661] 107

[0662] The synthetic sequence for preparing tert-butyl (R)-[1-(4-{[4-(4-chlorophenyl)piperidin-1-carbonyl]amino}phenyl)pyrrolidin-3-yl]methylcarbamate was carried out starting from 2-chloro-5-nitropyridine instead of 4-fluoronitrobenzene. This resulted in the product with the molecular weight of 514.07 (C27H36ClN5O3); 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

[0663] 108

[0664] tert-Butyl (R)-[1-(5-{[4-(4-chlorophenyl)piperidine-1-carbonyl]amino}pyridin-2-yl)pyrrolidin-3-yl]methylcarbamate was treated with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 413.95 (C22H28ClN5O); MS (ESI): 414 (M+H+).

[0665] It was possible to obtain racemic [4-(4-chlorophenyl)piperidine-1-carboxylic acid [6-(3-methylaminopyrrolidin-yl)pyridin-3-yl]amide in a similar manner.

Example 33

4-(4-Chlorophenyl)piperidine-1-carboxylic Acid {6-[3-(acetylmethylamino)-pyrrolidin-1-yl]pyridin-3-yl}amide

[0666] 109

[0667] N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 2-chloro-5-nitro-pyridine, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 490.99 (C25H29ClF2N4O2); MS (ESI): 491 (M+H+).

Example 34

1-[4-(4-Dimethylaminopiperidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea

[0668] 110

[0669] Dimethylpiperidin-4-ylamine was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline ([1-(4-aminophenyl)piperidin-4-yl]dimethylamine) was reacted with CDI and 4-phenoxyaniline by method A, B and C. This resulted in the product with the molecular weight of 430.55 (C26H30N4O2); MS (ESI): 431 (M+H+).

Example 35

1-(4-Cyclopentyloxyphenyl)-3-[4-(4-morpholin-4-ylpiperidin-1-yl)phenyl]urea

[0670] 111

[0671] 4-Piperidin-4-ylmorpholine was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-cyclopentyloxyaniline by method A, B and C. This resulted in the product with the molecular weight of 464.61 (C27H36N4O3); MS (ESI): 465 (M+H+).

Example 36

4-Butoxy-N-[4-(4-dimethylaminopiperidin-1-yl)phenyl]benzamide

[0672] 112

[0673] ([1-(4-Aminophenyl)piperidin-4-yl]dimethylamine) was reacted with 4-4-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-(acetylmethylamino)-azetidin-1-yl]phenyl}amide

[0674] 113

[0675] N-[1-(4-aminophenyl)azetidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and 4-(4-chlorophenyl)piperidine by method A. This resulted in the product with the molecular weight of 440.98 (C24H29ClN4O2); MS (ESI): 441 (M+H+).

[0676] N-[1-(4-Aminophenyl)azetidin-3-yl]-N-methylacetamide

[0677] N-Methyl-N-[1-(4-nitrophenyl)azetidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight of 219.29 (C12H17N3O); MS (ESI): 220 (M+H+).

[0678] N-Methyl-N-[1-(4-nitrophenyl)azetidin-3-yl]acetamide

[0679] N-[1-(4-nitrophenyl)azetidin-3-yl]acetamide was alkylated with iodomethane by method F. This resulted in the product with the molecular weight of 249.27 (C12H15N3O3); MS (ESI): 250 (M+H+).

[0680] N-[1-(4-Nitrophenyl)azetidin-3-yl]acetamide

[0681] 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, volatile fractions were removed. This resulted in the product with the molecular weight of 235.24 (C11H13N3O3); MS (ESI): 236 (M+H+).

[0682] 1-(4-Nitrophenyl)azetidin-3-ylamine

[0683] tert-Butyl [1-(4-nitrophenyl)azetidin-3-yl]carbamate was treated with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 193.21 (C9H11N3O2); MS (ESI): 194 (M+H+).

[0684] tert-Butyl [1-(4-nitrophenyl)azetidin-3-yl]carbamate

[0685] tert-Butyl azetidin-3-ylcarbamate was reacted with 4-fluoronitrobenzene by method 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

[0686] 114

[0687] tert-Butyl [1-(4-aminophenyl)azetidin-3-yl]methylcarbamate was reacted with carbonyidiimidazole and 4-(4-chlorophenyl)piperidine by method A. This resulted in the product with the molecular weight of 499.06 (C27H35ClN4O3; MS (ESI): 499 (M+H+).

[0688] tert-Butyl [1-(4-aminophenyl)azetidin-3-yl]methylcarbamate

[0689] tert-Butyl methyl-[1-(4-nitrophenyl)azetidin-3-yl]carbamate was hydrogenated by method B. This resulted in the product with the molecular weight of 277.37 (C15H23N3O2); MS (ESI): 278 (M+H+).

[0690] tert-Butyl methyl-[1-(4-nitrophenyl)azetidin-3-yl]carbamate

[0691] tert-Butyl [1-(4-nitrophenyl)azetidin-3-yl]carbamate was alkylated with iodomethane by method F. This resulted in the product with the molecular weight of 307.35 (C15H21N3O4); MS (ESI): 308 (M+H+).

Example 39

4-(4-Chlorophenyl)piperidin-1-carboxylic Acid [4-(3-methylaminoazetidin-1-yl)phenyl]amide

[0692] 115

[0693] tert-Butyl [1-(4-{[4-(4-chlorophenyl)piperidin-1-carbonyl]amino}-phenyl)azetidin-3-yl]methylcarbamate was reacted with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 398.94 (C22H27ClN4O); MS (ESI): 399 (M+H+).

Example 40

N-Methyl-N-[1-(4-{3-[4-(pyridin-3-yloxy)phenyl]ureido}phenyl)pyrrolidin-3-yl]acetamide

[0694] 116

[0695] N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then with 4-(pyridin-3-yloxy)phenylamine by method A. This resulted in the product with the molecular 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

[0696] 117

[0697] N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then with 4-piperidin-1-ylphenylamine by method A. This resulted in the product with the molecular weight of 435.57 (C25H33N5O2); MS (ESI): 436 (M+H+).

Example 42

N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-phenoxybenzamide

[0698] 118

[0699] N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4-phenoxybenzoic acid by method E. This resulted in the product with the molecular weight of 429.52 (C26H27N3O3); MS (ESI): 430 (M+H+).

Example 43

N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-butoxybenzamide

[0700] 119

[0701] N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4-butoxybenzoic acid by method E. This resulted in the product with the molecular weight of 409.53 (C24H31N3O3); MS (ESI): 410 (M+H+).

Example 44

4-(4-Chlorophenyl)cyclohexanecarboxylic Acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide

[0702] 120

[0703] N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4-(4-chlorophenyl)cyclohexanecarboxylic acid by method E. This resulted in the product with the molecular weight of 454.02 (C26H32ClN3O2); MS (ESI): 454 (M+H+).

Example 45

N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-3-(4-isopropylphenyl)-acrylamide

[0704] 121

[0705] N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 3-(4-isopropylphenyl)acrylic acid by method E. This resulted in the product 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

[0706] 122

[0707] 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with tetrahydrofuran-2-carboxylic acid by method E. This resulted 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

[0708] 123

[0709] 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with 1-acetylpyrrolidine-2-carboxylic acid by method E. This resulted 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

[0710] 124

[0711] 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with 5-oxo-pyrrolidine-2-carboxylic acid by method E. This resulted 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

[0712] 125

[0713] 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with 2-oxothiazolidine-4-carboxylic acid by method E. This resulted 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

[0714] 126

[0715] (R)4-Cyclohexyl-N-[4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamide was reacted with 1-methylpiperidine-3-carboxylic acid by method E. This resulted 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

[0716] 127

[0717] N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then 6-cyclopentyloxypyridin-3-ylamine by method A. This resulted in the product with the molecular weight of 437.55 (C24H31N5O3); MS (ESI): 438 (M+H+).

[0718] 6-Cyclopentyloxypyridin-3-ylamine

[0719] 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. for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel. The resulting product (2-cyclopentyloxy-5-nitropyridine) was hydrogenated by method B. This resulted in the product with the molecular weight of 178.24 (C10H14N20); MS (ESI): 179 (M+H+).

Example 52

1-(6-Cyclopentyloxypyridin-3-yl)-3-[4-(3-methylaminopyrrolidin-1-yl)-phenyl]urea

[0720] 128

[0721] 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

[0722] 129

[0723] 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 with the 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

[0724] 130

[0725] N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4′-trifluoromethylbiphenyl-4-carboxylic acid by method E. This resulted in the product with the molecular weight of 481.52 (C27H26F3N3O2); MS (ESI): 482 (M+H+).

Examples 55-103

[0726] 1-(4-Phenoxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with various carboxylic acids by method E. The products are compiled in table 2.

Examples 104-144

[0727] 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with various carboxylic acids by method E. The products are compiled in table 3.

Examples 145-185

[0728] N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with various carboxylic acids by method E. The products are compiled in table 4.

Examples 186-234

[0729] N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then with various amines by method A. The products are compiled in table 5.

TABLE 2
				Molecu-
Ex.			Molecular	lar
No.	Structure	Name	formula	weight	M + H+
55	131	Cyclopropanecarboxylic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl)pyrrolidin-3-yl)amide	C28H30N4O3	470.58	471
56	132	3,N-Dimethyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)butyramide	C29H34N4O3	486.62	487
57	133	2,N-Dimethyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)butyramide	C29H34N4O3	486.62	487
58	134	N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)benzamide	C31H30N4O3	506.61	507
59	135	(E)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)-3-phenylacrylamide	C33H32N4O3	532.65	533
60	136	2-Cyclopentyl-N-methyl-N-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide	C31H36N4O3	512.66	513
61	137	Cyclohexanecarboxylic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)amide	C31H36N4O3	512.66	513
62	138	N-Methyl-2-methylsulfanyl-N-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenylpyrrolidin-3-yl)acetamide	C27H30N4O3S	490.63	491
63	139	N-Methoxy-N-methyl-N-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenylpyrrolidin-3-yl)acetamide	C27H30N4O4	474.56	475
64	140	2-Oxothiazolidine-4-carboxylic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)amide	C28H29N5O4S	531.64	532
65	141	4-Fluoro-N-methyl-N-(1-{4-[3-(4-phenoxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)benzamide	C31H29FN4O3	524.60	525
66	142	Pyridine-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)amide	C30H29N5O3	507.60	508
67	143	2-Acetylamino-N-methyl-N-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide	C28H31N5O4	501.59	502
68	144	2,2,3,3-Tetramethylcyclopropanecarboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}-pyr- rolidin-3-yl)amide	C32H38N4O3	526.68	527
69	145	3,5-Dimethylisoxazole-4-carboxylic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)amide	C30H31N5O4	525.61	526
70	146	2-Ethoxy-N-methyl-N-(1-{4-[3-(4-phenoxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)acetamide	C28H32N4O4	488.59	489
71	147	3-Methoxy-N-methyl-N-(1-{4-[3-(4-phenoxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)propionamide	C28H32N4O4	488.59	489
72	148	2,2,N-Trimethyl-N-(1-{4-[3-(4-phenoxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)butyramide	C30H36N4O3	500.65	501
73	149	1-Methylcyclopropanecarboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}-pyro- rolidin-3-yl)amide	C29H32N4O3	484.60	485
74	150	Cyclobutanecarboxylic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)amide	C29H32N4O3	484.60	485
75	151	N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)isonicotinamide	C30H29N5O3	507.60	508
76	152	Pyrazine-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)amide	C29H28N6O3	508.58	509
77	153	5-Oxopyrrolidine-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)amide	C29H31N5O4	513.60	514
78	154	Thiophene-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)amide	C29H28N4O3S	512.64	513
79	155	Furan-3-carboxylic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)amide	C29H28N4O4	496.57	497
80	156	N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)nicotinamide	C30H29N5O3	507.60	508
81	157	4-Cyano-N-methyl-(1-{4-[3-(4-phenoxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)benzamide	C32H29N5O3	531.62	532
82	158	1-Methyl-1H-pyrrole-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)amide	C30H31N5O3	509.61	510
83	159	3-Cyclopentyl-N-methyl-N-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)propionamide	C32H38N4O3	526.68	527
84	160	N,N,N′-Trimethyl-N′-(1-{4-[3-(4-phenoxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)succinamide	C30H35N5O4	529.64	530
85	161	3-Phenylpropynoic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)amide	C33H30N4O3	530.63	531
86	162	(1R,4S)-Bicyclo[2.2.1]heptane-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}-pyr- rolidin-3-yl)amide	C32H36N4O3	524.67	525
87	163	[1,2,3]Thiadiazol-4-carboxylic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)amide	C27H26N6O3S	514.61	515
88	164	Isoxazole-5-carboxylic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)amide	C28H27N5O4	497.56	498
89	165	2,N-Dimethyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)benzamide	C32H32N4O3	520.64	521
90	166	2-Methanesulfonyl-N-methyl-N-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)-aceta- mide	C27H30N4O5S	522.63	523
91	167	(E)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)-3-pyridin-3-ylacrylamide	C32H31N5O3	533.64	534
92	168	4,4,4-Trifluoro-N-methyl-N-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)butyramide	C28H29F3N4O3	526.56	527
93	169	2-Dimethylamino-N-methyl-N-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide	C28H33N5O3	487.61	488
94	170	3-Acetylamino-N-methyl-N-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)propionamide	C29H33N5O4	515.62	516
95	171	Tetrahydrofuran-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)-amide	C29H32N4O4	500.60	501
96	172	N-Methyl-2-(3-methylisoxazol-5-yl)-N-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)-ace- tamide	C30H31N5O4	525.61	526
97	173	(S)-1-Acetylpyrrolidine-2-carboxylic acid methyl-(1-{4-[3-(4-phe- noxyphenyl)ureido]phenyl}pyrrolidin-3-yl)amide	C31H35N5O4	541.66	542
98	174	4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe- nyl}pyrrolidine-3-yl)amide	C28H28N6O3S	528.64	529
99	175	1,5-Dimethyl-1H-pyrazole-3-carboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}-pyr- rolidin-3-yl)amide	C30H32N6O3	524.63	525
100	176	5-Methylhexanoic acid methyl-(1-{4-[3-(4-phenoxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)amide	C31H38N4O3	514.67	515
101	177	Tetrahydropyran-4-carboxylic acid methyl-(1-{4-[3-(4-phe- noxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-amide	C30H34N4O4	514.63	515
102	178	N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)-2-piperi- din-1ylacetamide	C31H37N5O3	527.67	528
103	179	1,3-Dimethyl-1H-pyrazole-4-carboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)amide	C30H32N6O3	524.63	525

[0730]

TABLE 3
				Molecu-
Ex.			Molecular	lar
No.	Structure	Name	formula	weight	M + H+
104	180	Benzyl(S)-5-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-2-oxo- imidazolidine-1-carboxylate	C35H40N6O6	640.75	641
105	181	Benzyl(R)-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-pyr- rolidine-1-carboxylate	C36H43N5O5	625.77	626
106	182	N-(1-{4-[3-(4-cyclopentyloxyphenyl)ureido]-phe- nyl]pyrrolidin-3-yl)-3-dimethylamino-N-methyl- benzamide	C32H39N5O3	541.70	542
107	183	Benzyl(S)-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-5-oxo- pyrrolidine-1-carboxylate	C36H41N5O6	639.76	640
108	184	tert-Butyl 3-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methyl- carbamoyl]piperidine-1-carboxylate	C34H47N5O5	605.78	606
109	185	Benzyl 5-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-2-oxo- imidazolidine-1-carboxylate	C35H40N6O6	640.75	641
110	186	1-Methylpiperidine-3-carboxylic acid (1-{4-[3-(4-cyclo- pentyloxyphenyl)ureido]phenyl}pyr- rolidin-3-yl)methyl- amide	C30H41N5O3	519.69	520
111	187	2,6-Dioxohexahydropyrimidine-4-carboxylic acid (1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methylamide	C28H34N6O5	534.62	535
112	188	2-Methyl-5-oxopyrrolidine-2-carboxylic acid (1-{4-[3-(4-cyclo- pentyloxyphenyl)ureido]phenyl}-pyr- rolidin-3-yl)methylamide	C29H37N5O4	519.65	520
113	189	tert-Butyl 4-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-thia- zolidine-3-carboxylate	C32H43N5O5S	609.79	610
114	190	Benzyl(2S,4R)-4-tert-butoxy-2-[(1-{4-[3-(4-cyclo- pentyloxyphenyl)ureido]phenyl}pyr- rolidin-3-yl)methyl- carbamoyl]pyrrolidine-1-carboxylate	C40H51N5O6	697.88	698
115	191	N-(1-{4-[3-(4-Cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)-3-(2,5-di- oxopyrrolidin-1-yl)-N-methyl-5-tri- fluoromethylbenzamide	C35H36F3N5O5	663.70	664
116	192	tert-Butyl-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-mor- pholine-4-carboxylate	C33H45N5O6	607.76	608
117	193	(R)-1-(Toluene-4-sulfonyl)pyrrolidine-2-carboxylic acid(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methylamide	C35H43N5O5S	645.83	646
118	194	{(3aS,6aS)-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-hexa- hydrocyclopenta[b]pyrrol-1-yl}oxoacetic acid methyl ester	C34H43N5O6	617.75	618
119	195	(S)-1-(2,2,2,-Trifluoroacetyl)pyrrolidine-2-carboxylic acid(1-{4-[3-(4-cyclopentyloxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)methylamide	C30H36F3N5O4	587.65	588
120	196	2-Chloro-N-{[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methyl- carbamoyl]-methyl}benzamide	C32H36ClN5O4	590.13	590
121	197	N-{1-[(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)methylcarbamoyl]ethyl}-4-methyl- benzamide	C34H41N5O4	583.74	584
122	198	N-{[(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)methylcarbamoyl]methyl}-3,3-di- methylbutyramide	C31H43N5O4	549.72	550
123	199	N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)-2-(1H-imidazol-4-yl)-N-methyl- acetamide	C28H34N6O3	502.62	503
124	200	Benzyl 3-[(1-(4-[3-(4-cyclo- pentyloxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)methylcarbamoyl]piperidine-1-car- boxylate	C37H45N5O5	639.80	640
125	201	1-(Furan-2-carbonyl)piperidine-3-carboxylic acid (1-{4-[3-(4-cyclopentyloxyphenyl)ureido]phenyl}-pyr- rolidin-3-yl)methylamide	C34H41N5O5	599.74	600
126	202	(E)-N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)-N-methyl-3-pyridin-2-yl-acryl- amide	C31H35N5O3	525.66	526
127	203	(E)-N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)-N-methyl-3-pyridin-4-yl-acryl- amide	C31H35N5O3	525.66	526
128	204	N-(1-{4-[3-(4-Cyclopentyl- oxyphenyl)ureido]phenyl}-pyr- rolidin-3-yl)-N-methyl-2-pyridin-3-ylacetamide	C30H35N5O3	513.65	514
129	205	4-Methyl-3-oxo-3,4-dihy- dro-2H-benzo[1,4]thiazine-6-car- boxylic acid(1-{4-[3-(4-cyclopentyloxy- phenyl)ureido]phenyl}pyrrolidin-3-yl)methylamide	C33H37N5O4S	599.76	600
130	206	Benzyl 2-[(1-{4-[3-(4-cyclo- pentyloxyphenyl)ureido]-phe- nyl}pyrrolidin-3-yl)methylcarbamoyl]piperidin-1-car- boxylate	C37H45N5O5	639.80	640
131	207	Benzyl(S)-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-pipe- ridin-1-carboxylate	C36H43N5O5	625.77	626
132	208	(R)-1-Acetylpyrrolidine-2-carboxylic acid(1-{4-[3-(4-cyclo- pentyloxyphenyl)ureido]phenyl}pyr- rolidin-3-yl)methyl- amide	C30H39N5O4	533.68	534
133	209	(S)-1-((E)-3-Furan-2-ylacryloyl)pyrrolidine-2-car- boxylic acid(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methylamide	C35H41N5O5	611.75	612
134	210	1-(2,2-Dimethylpropionyl)pyrrolidine-2-carboxylic acid(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methylamide	C33H45N5O4	575.76	576
135	211	(trans)-1-Methyl-5-oxo-2-py- ridin-3-ylpyrrolidine-3-car- boxylic acid(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methylamide	C34H40N5O4	596.74	597
136	212	(S)-1-Benzylpyrrolidine-2-carboxylic acid (1-{4-[3-(4-cyclo- pentyloxyphenyl)ureido]phenyl}pyr- rolidin-3-yl)methyl- amide	C35H43N5O3	581.76	582
137	213	Isobutyl 2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-pyr- rolidine-1-carboxylate	C33H45N5O5	591.76	592
138	214	Allyl(S)-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei- do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-pyr- rolidine-1-carboxylate	C32H41N5O5	575.71	576
139	215	2-Oxoimidazolidine-4-carboxylic acid(1-{4-[3-(4-cyclo- pentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)meth- ylamide	C27H34N6O4	506.61	507
140	216	(R)-5-Oxopyrrolidine-2-carboxylic acid(1-{4-[3-(4-cyclo- pentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)meth- ylamide	C28H35N5O4	505.62	506
141	217	1-Methyl-5-oxopyrrolidine-3-carboxylic acid(1-{4-[3-(4-cyclo- pentyloxyphenyl)ureido]phenyl}-pyr- rolidin-3-yl)methylamide	C29H37N5O4	519.65	520
142	218	1-Benzyl-5-oxopyrrolidine-3-carboxylic acid(1-{4-[3-(4-cyclo- pentyloxyphenyl)ureido]phenyl}-pyr- rolidine-3-yl)methylamide	C35H41N5O4	595.75	596
143	219	5-Oxo-1-phenylpyrrolidine-3-carboxylic acid(1-{4-[3-(4-cyclo- pentyloxyphenyl)ureido]phenyl}-pyr- rolidin-3-yl)methylamide	C34H39N5O4	581.72	582
144	220	5-Oxo-1-p-tolylpyrrolidine-3-carboxylic acid(1-{4-[3-(4-cyclopentyloxy- phenyl)ureido]phenyl}-pyr- rolidin-3-yl)methylamide	C35H41N5O4	595.75	596

[0731]

TABLE 4
Ex. No.	Structure	Name	Molecular formula	Molecular weight	M + H+
145	221	(E)-N-{4-[3-(Acetylmethylamin- o)pyrrolidin-1-yl]-phenyl}-3-(5, 6-dimethylbenzooxazol-2-yl)-a- crylamide	C25H28N4O3	432.53	433
146	222	4′-Ethylbiphenyl-4-carboxylic acid {4-[3-(acetyl-methylamino) pyrrolidin-1-yl]phenyl}amide	C28H31N3O2	441.58	442
147	223	4′-Propylbiphenyl-4-carboxylic acid {4-[3-(acetyl-methylamino) pyrrolidin-1-yl]phenyl}amide	C29H33N3O2	455.61	456
148	224	2′-Fluorobiphenyl-4-carboxylic acid {4-[3-(acetyl-methylamino) pyrrolidin-1-yl]phenyl}amide	C26H26FN3O2	431.51	432
149	225	4′-Cyanobiphenyl-4-carboxylic acid {4-[3-(acetyl-methylamino) pyrrolidin-1-yl]phenyl}amide	C27H26N4O2	438.53	439
150	226	4′-Bromobiphenyl-4-carboxylic acid {4-[3-(acetyl-methylamino) pyrrolidin-1-yl]phenyl}amide	C26H26BrN3O2	492.42	492
151	227	4′-Ethoxybiphenyl-4-carboxylic acid {4-[3-(acetyl-methylamino) pyrrolidin-1-yl]phenyl}amide	C28H31N3O3	457.58	458
152	228	3′,4′-Dichlorobiphenyl-4-car- boxylic acid {4-[3-(acetylme- thylamino)pyrrolidin-1-yl]phenyl}amide	C26H25Cl2N3O2	482.41	482
153	229	2-Ethylbiphenyl-4-carboxylic acid {4-[3-(acetyl-methylamino) pyrrolidin-1-yl]phenyl}amide	C28H31N3O2	441.58	442
154	230	N-{4-[3-(Acetylmethyla- mino)pyrrolidin-1-yl]phenyl}- 4-benzenesulfonylbenzamide	C26H27N3O4S	477.59	478
155	231	N-{4-[3-(Acetylmethyla- mino)pyrrolidin-1-yl]phenyl}- 4-cyclopentyloxybenzamide	C25H31N3O3	421.54	422
156	232	N-{4-[3-(Acetylmethyla- mino)pyrrolidin-1-yl]phenyl}- 4-(4-chlorophenoxy)-3-nitro- benzamide	C26H25ClN4O5	508.97	509
157	233	N-{4-[3-(Acetylmethyla- mino)pyrrolidin-1-yl]phenyl}- 4-(4-fluorophenoxy)benzamide	C26H26FN3O3	447.51	448
158	234	N-{4-[3-(Acetylmethyla- mino)pyrrolidin-1-yl]phenyl}- 4-(4-chlorophenoxy)benzamide	C26H26ClN3O3	463.97	464
159	235	N-{4-[3-(Acetylmethyla- mino)pyrrolidin-1-yl]phenyl}- 4-cyclohexylbenzamide	C26H33N3O2	419.57	420
160	236	1-(4-Nitrophenyl)piperidine- 4-carboxylic acid {4-[3- (acetylmethylamino)pyrro- lidin-1-yl]phenyl}amide	C25H31N5O4	465.56	466
161	237	N-{4-[3-(Acetylmethyla- mino)pyrrolidin-1-yl]phenyl}- 3-phenoxybenzamide	C26H27N3O3	429.52	430
162	238	N-{4-[3-(Acetylmethyla- mino)pyrrolidin-1-yl]phenyl}- 4-propoxybenzamide	C23H29N3O3	395.51	396
163	239	N-{4-[3-(Acetylmethyla- mino)pyrrolidin-1-yl]phenyl}- 4-(cyclohex-2-enyloxy) benzamide	C26H31N3O3	433.56	434
164	240	N-{4-[3-(Acetylmethyla- mino)pyrrolidin-1-yl]phenyl}- 4-(3-methylbutoxy)benzamide	C25H33N3O3	423.56	424
165	241	N-{4-[3-(Acetylmethyla- mino)pyrrolidin-1-yl]phenyl}- 4-isobutoxybenzamide	C24H31N3O3	409.53	410
166	242	5-(4-Chlorophenyl)furan-2- carboxylic acid {4-[3-(ace- tylmethylamino)pyrrolidin-1- yl]phenyl}amide	C24H24ClN3O3	437.93	438
167	243	5-(4-Methoxyphenyl)thiophene- 2-carboxylic acid {4-[3-(ace- tylmethylamino)pyrrolidin-1-yl]phenyl}-amide	C25H27N3O3S	449.58	450
168	244	5-(4-Chloro-2-nitrophenyl) furan-2-carboxylic acid {4- [3-(acetylmethylamino)pyrroli- din-1-yl]phenyl}-amide	C24H23ClN4O5	482.93	483
169	245	5-(4-Methyl-2-nitrophenyl) furan-2-carboxylic acid {4- [3-(acetylmethylamino)pyrroli- din-1-yl]phenyl}-amide	C25H26N4O5	462.51	463
170	246	5-(4-Fluorophenyl)thiophene- 2-carboxylic acid {4-[3- (acetylmethylamino)pyrrolidin- 1-yl]phenyl}-amide	C24H24FN3O2S	437.54	438
171	247	5-(2,4-Dichlorophenyl)furan- 2-carboxylic acid {4-[3- (acetylmethylamino)pyrrolidin- 1-yl]phenyl}amide	C24H23Cl2N3O3	472.38	472
172	248	4-Methyl-2-(4-trifluoromethyl phenyl)thiazole-5-carboxylic acid {4-[3-(acetylmethylamino) pyrrolidin-1-yl]phenyl}amide	C25H25F3N4O2S	502.56	503
173	249	2-(4-Chlorophenyl)-4-methyl thiazole-5-carboxylic acid {4-[3-(acetylmethylamino) pyrrolidin-1-yl]phenyl}amide	C24H25ClN4O2S	469.01	469
174	250	5-Benzyloxy-1H-indole-2- carboxylic acid {4-[3- (acetylmethylamino)pyr- rolidin-1-yl]phenyl}amide	C29H30N4O3	482.59	483
175	251	N-{4-[3-(Acetylmethylamino) pyrrolidin-1-yl]phenyl}- 4-benzyloxybenzamide	C27H29N3O3	443.55	444
176	252	5-Phenylethynylfuran-2- carboxylic acid {4-[3- (acetylmethylamino)pyr- rolidin-1-yl]phenyl}amide	C26H25N3O3	427.51	428
177	253	N-{4-[3-(Acetylmethylamino) pyrrolidin-1-yl]phenyl}- 2-biphenyl-4-ylacetamide	C27H29N3O2	427.55	428
178	254	N-{4-[3-(Acetylmethylamino) pyrrolidin-1-yl]phenyl}- 2-(4-butoxyphenyl)acetamide	C25H33N3O3	423.56	424
179	255	N-{4-[3-(Acetylmethylamino) pyrrolidin-1-yl]phenyl}- 2-(4-benzyloxyphenyl)acetamide	C28H31N3O3	457.58	458
180	256	N-{4-[3-(Acetylmethylamino) pyrrolidin-1-yl]phenyl}- 2-(4-phenoxyphenyl)acetamide	C27H29N3O3	443.55	444
181	257	N-{4-[3-(Acetylmethylamino) pyrrolidin-1-yl]phenyl}- 2-(4-benzyloxy-3-methoxy- phenyl)acetamide	C29H33N3O4	487.60	488
182	258	N-{4-[3-(Acetylmethylamino) pyrrolidin-1-yl]phenyl}- 2-(4′-fluorobiphenyl-4- yl)acetamide	C27H28FN3O2	445.54	446
183	259	N-{4-[3-(Acetylmethylamino) pyrrolidin-1-yl]phenyl}- 2-[4-(2,5-dimethylpyrrol- 1-yl)phenyl]acetamide	C27H32N4O2	444.58	445
184	260	N-{4-[3-(Acetylmethylamino) pyrrolidin-1-yl]phenyl}- 2-(4-isopropylphenoxy) acetamide	C24H31N3O3	409.53	410
185	261	N-{4-[3-(Acetylmethylamino) pyrrolidin-1-yl]phenyl}- 2-(4-ethylphenoxy)acetamide	C23H29N3O3	395.51	396

[0732]

TABLE 5
Ex. No.	Structure	Name	Molecular formula	Molecular weight	M + H+
186	262	N-Methyl-N-(1-{4-[3-(6-phe- noxypyridin-3-yl)ureido]phenyl}pyrrolidin-3-yl)acetamide	C25H27N5O3	445.53	446
187	263	N-[1-(4-{3-[4-(2-Chlorophe- noxy)phenyl]ureido}-phenyl) pyrrolidin-3-yl]-N-methyl- acetamide	C26H27ClN4O3	478.98	479
188	264	N-[1-(4-{3-[4-(3-Chlorophe- noxy)phenyl]ureido}-phenyl) pyrrolidin-3-yl]-N-methyl- acetamide	C26H27ClN4O3	478.98	479
189	265	N-Methyl-N-[1-{4-[3-(4-o- tolyloxyphenyl)ureido}-phenyl) pyrrolidin-3-yl)acetamide	C27H30N4O3	458.57	459
190	266	N-Methyl-N-[1-{4-[3-(4-m- tolyloxyphenyl)ureido}-phenyl) pyrrolidin-3-yl)acetamide	C27H30N4O3	458.57	459
191	267	N-[1-{4-{3-[4-(2-Fluorophen- oxy)phenyl)ureido}-phenyl) pyrrolidin-3-yl)-N-methyl- acetamide	C26H27FN4O3	462.53	463
192	268	N-{1-{4-[3-Biphenyl-4-yl- ureido}phenyl]pyrrolidin-3- yl}-N-methylacetamide	C26H28N4O2	428.54	429
193	269	N-[1-(4-{3-[4-(2-Methoxyphe- noxy)phenyl]ureido}-phenyl) pyrrolidin-3-yl]methyl- acetamide	C27H30N4O4	474.56	475
194	270	N-(1-{4-[3-(4-Isobutoxyphenyl) ureido}phenyl)-pyrrolidin-3- yl]-N-methylacetamide	C24H32N4O3	424.55	425
195	271	N-(1-{4-[3-(4-Cyclopentyloxy- phenyl)ureido}phenyl)-pyrro- lidin-3-yl]-N-methylacet- amide	C25H32N4O3	436.56	437
196	272	N-[1-(4-{3-[4-(4-Fluorophe- noxy)phenyl]ureido}-phenyl) pyrrolidin-3-yl]-N-methyl- acetamide	C26H27FN4O3	462.53	463
197	273	N-[1-(4-{3-[4-(3-Methoxyphe- noxy)phenyl]ureido}-phenyl) pyrrolidin-3-yl]-N-methyl- acetamide	C27H30N4O4	474.56	475
198	274	4-(3-Acetylaminophenyl)piperi- dine-1-carboxylic acid {4-[3- (acetylmethylamino)pyrrolidin- 1-yl]-phenylamide	C27H35N5O3	477.61	478
199	275	N-Methyl-N-(1-{4-[3-(5-phenyl- pyridin-2-yl)ureido]-phenyl}pyrrolidin-3-yl)acetamide	C25H27N5O2	429.53	430
200	276	N-(1-{4-[3-(2-Acetylamino-4- phenylsulfanylphenyl)-ureido]phenyl}pyrrolidin-3-yl)-N- methylacetamide	C28H31N5O3S	517.65	518
201	277	N-(1-{4-[3-(4′-Cyanobiphenyl- 4-yl)ureido]-phenyl}pyrrolidin- 3-yl)-N-methylacetamide	C27H27N5O2	453.55	454
202	278	N-(1-{4-[3-(2-Methoxybiphenyl- 4-yl)ureido]-phenyl}pyrrolidin- 3-yl)-N-methylacetamide	C27H30N4O3	458.57	459
203	279	4-(2-Chlorophenyl)piperidine- 1-carboxylic acid {4-[3- (acetylmethylamino)pyr- rolidin-1-yl]phenyl}amide	C25H31ClN4O2	455.00	455
204	280	N-(1-{4-[3-(4-Benzene- sulfonyl-3-chlorophenyl)- ureido]phenyl}pyrrolidin- 3-yl)-N-methylacetamide	C26H27ClN4O4S	527.05	527
205	281	4-(4-Chlorophenyl)-4-hydroxy- piperidine-1-carboxylic acid {4-[3-(acetylmethyl- amino)pyrrolidin- 1-yl]phenyl}amide	C25H31ClN4O3	471.00	471
206	282	4-Phenylpiperidine-1-carboxylic acid {4-[3-(acetylmethylamino) pyrrolidin-1-yl]phenyl}amide	C25H32N4O2	420.56	421
207	283	4-Cyano-4-phenylpiperidine- 1-carboxylic acid {4-[3- (acetylmethylamino)pyrro- lidin-1-yl]phenyl}amide	C26H31N5O2	445.57	446
208	284	4-Acetyl-4-phenylpiperidine- 1-carboxylic acid {4-[3- (acetylmethylamino)pyrro- lidin-1-yl]phenyl}amide	C27H34N4O3	462.60	463
209	285	4-(2-Methoxyphenyl)piperidine- 1-carboxylic acid {4-[3-(acetyl- methylamino)pyrrolidin-1-yl]phenyl}-amide	C26H34N4O3	450.59	451
210	286	4-(4-Fluorophenyl)piperidine- 1-carboxylic acid {4-[3-(acetyl- methylamino)pyrrolidin-1-yl]phenyl}amide	C25H31FN4O2	438.55	439
211	287	4-(3-Fluorophenyl)piperidine- 1-carboxylic acid {4-[3- (acetylmethylamino)pyrro- lidin-1-yl]phenyl}amide	C25H31FN4O2	438.55	439
212	288	4-(2-Fluorophenyl)piperidine- 1-carboxylic acid {4-[3- (acetylmethylamino)pyrro- lidin-1-yl]phenyl}amide	C25H31FN4O2	438.55	439
213	289	4-p-Tolylpiperidine-1-carboxylic acid {4-[3-(acetyl-methylamino) pyrrolidin-1-yl]phenyl}amide	C26H34N4O2	434.59	435
214	290	4-(4-Trifluoromethylphenyl)pi- peridine-1-carboxylic acid {4-[3-(acetylmethylamino) pyrrolidin-1-yl]phenyl}amide	C26H31F3N4O2	488.56	489
215	291	4-(3-Trifluoromethylphenyl)pi- peridine-1-carboxylic acid {4-[3-(acetylmethylamino) pyrrolidin-1-yl]phenyl}amide	C26H31F3N4O2	488.56	489
216	292	4-(2-Trifluoromethylphenyl)pi- peridine-1-carboxylic acid {4-[3- (acetylmethylamino)pyrrolidin- 1-yl]phenyl}amide	C26H31F3N4O2	488.56	489
217	293	4-(4-Methoxyphenyl)piperidine- 1-carboxylic acid {4-[3-(acetyl- methylamino)pyrrolidin-1-yl]phenyl}-amide	C26H34N4O3	450.59	451
218	294	4-(3-Methoxyphenyl)piperidine- 1-carboxylic acid {4-[3-(acetyl- methylamino)pyrrolidin-1-yl]phenyl}-amide	C26H34N4O3	450.59	451
219	295	4-Naphthalen-2-ylpiperidine- 1-carboxylic acid {4-[3-(acetyl- methylamino)pyrrolidin-1-yl]phenyl}amide	C29H34N4O2	470.62	471
220	296	Benzo[c]-1-oxa-8-aza-spiro [4,5]decane-8-car {4-[3-(acetyl- methylamino)pyrrolidin-1-yl]phenyl}amide	C26H32N4O3	448.57	449
221	297	N-(1-{4-[3-(9-Ethyl-9H- carbazol-3-yl)ureido]-phenyl}pyrrolidin-3-yl)-N-methyl- acetamide	C28H31N5O2	469.59	470
222	298	N-(1-(4-{3-[4-(4-Chloro- phenoxy)phenyl]ureido}- phenyl)pyrrolidin-3-yl)- N-methylacetamide	C26H27ClN4O3	478.98	479
223	299	N-(1-{4-[3-(4-Benzylphenyl) ureido]phenyl}-pyrrolidin-3-yl)- N-methylacetamide	C27H30N4O2	442.57	443
224	300	N-Methyl-N-(1-{4-[3-(4-Pyri- din-4-ylmethylphenyl)-ureido]phenyl}pyrrolidin-3-yl)aceta- mide	C28H30F3N5O4	443.55	444
225	301	N-[1-(4-{3-[6-(2-Fluorophe- noxy)pyridin-3-yl]ureido}- phenyl}pyrrolidin-3-yl)-N- methylacetamide	C25H26FN5O3	463.52	464
226	302	N-Methyl-N-(1-{4-[3-(4-phenyl- sulfanylphenyl)-ureido]phenyl}pyrrolidin-3-yl)acetamide	C26H28N4O2S	460.60	461
227	303	N-Methyl-N-[1-(4-{3-[4-(3-tri- fluoromethylphenoxy)-phenyl]ureido}phenyl)pyrrolidin-3-yl]acetamide	C27H27F3N4O3	512.54	513
228	304	N-Methyl-N-[1-(4-{3-[6- (pyridin-2-ylsulfanyl)pyridin- 3-yl]ureido}phenyl)pyrrolidin- 3-yl]acetamide	C26H27F3N6O4S	462.58	463
229	305	N-(1-{4-[3-(4-Butoxyphenyl) ureido]phenyl}-pyrrolidin- 3-yl)-N-methylacetamide	C24H32N4O3	424.55	425
230	306	4-Benzylpiperidine-1-carboxylic acid {4-[3-(acetylmethylamino) pyrrolidin-1-yl]phenyl}amide	C26H34N4O2	434.59	435
231	307	Benzo-8-azaspiro[4.5]decane- 8-carboxylic acid {4-[3-(acetyl- methylamino)pyrrolidin-1-yl]phenyl}amide	C27H34N4O2	446.60	447
232	308	4-Benzofuran-3-ylpiperidine-1- carboxylic acid {4-[3-(acetyl- methylamino)pyrrolidin-1-yl]phenyl}amide	C27H32N4O3	460.58	461
233	309	4-p-Tolyloxypiperidine-1-car- boxylic acid {4-[3-(acetyl- methylamino)pyrrolidin-1-yl]phenyl}amide	C26H34N4O3	450.59	451
234	310	4-(2-Chlorophenoxy)piperidine- 1-carboxylic acid {4-[3-(acetyl- methylamino)pyrrolidin-1-yl]phenyl}-amide	C25H31ClN4O3	471.00	471

Example 235

N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N-methyl-2-piperidin-1-yl-acetamide

[0733] 311

[0734] 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with piperidin-1-ylacetic acid by method E. This resulted in the product with the molecular weight of 519.69 (C30H41N5O3); MS (ESI): 520 (M+H+).

Example 236

1-Methylpiperidine-3-carboxylic Acid {(R)-1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylamide

[0735] 312

[0736] (R)-4-Cyclohexyl-N-[6-(3-methylaminopyrrolidin-1-yl)pyridin-3-yl]benzamide was reacted with 1-methylpiperidin-3-carboxylic acid by method 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

[0737] 313

[0738] Method H

[0739] Caesium carbonate (36 mg) and n-butyl bromide (15 mg) were added to a solution of N-{4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)propionamide (27 mg) in DMF (1 ml). After a reaction time of 2 hours at room temperature, water was added to the mixture, and it was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated, and the residue was crystallized from diethyl ether/methanol. This resulted in the product with the molecular weight of 437.59 (C26H35N3O3); MS(ESI): 438 (M+H+).

[0740] N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)propionamide

[0741] N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamid was reacted with 2-(4-hydroxyphenyl)propionic acid by method I. This resulted in the product with 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

[0742] 314

[0743] 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+).

[0744] N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)acetamide

[0745] Method I

[0746] 4-Hydroxyphenylacetic acid (305 mg), 1-hydroxybenzotriazole (300 mg) 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 temperature for 3 hours. Water was then added to the mixture, which was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated and crystallized from diethyl ether. This resulted in the product with the molecular weight of 367.45 (C21H25N3O3); MS(ESI): 368 (M+H+).

Example 239

(R)-N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-butoxyphenyl)acetamide

[0747] 315

[0748] (R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4-butoxyphenylacetic 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

[0749] 316

[0750] N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)propionamide was reacted with bromomethylcyclopropane by method H. This resulted in the product with the molecular weight of 435.57 (C26H33N3O3); MS(ESI): 436 (M+H+).

Example 241

N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-cyclobutylmethoxyphenyl)propionamide

[0751] 317

[0752] N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)propionamide was reacted with bromomethylcyclobutane by method H. This resulted in a product with the molecular weight 449.60 (C27H35N3O3); MS(ESI): 450 (M+H+).

Example 242

1-(4-Methoxyphenyl)cyclopropanecarboxylic Acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

[0753] 318

[0754] N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 1-(4-methoxyphenyl)-1-cyclopropanecarboxylic acid by method E. This resulted in the product with the molecular weight of 407.52 (C24H29N3O3); MS(ESI): 408 (M+H+).

Example 243

1-(4-Butoxyphenyl)cyclopropanecarboxylic Acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide

[0755] 319

[0756] 1-(4-Hydroxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1yl]phenyl}amide was reacted with n-butyl bromide by method H. This resulted in the product with the molecular weight of 449.60, (C27H35N3O3); MS(ESI): 450 (M+H+).

[0757] 1-(4-Hydroxyphenyl)cyclopropanecarboxylic Acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

[0758] 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) in dichloromethane (5.5 ml) at 0° C. After a reaction time of 12 hours at room temperature, water was added to the mixture, the phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, concentrated and purified by chromatography (silica gel, toluene/ethanol/ethyl acetate 8:1:1 with addition of 0.1% triethylamine). This resulted in the product with the molecular weight of 393.49 (C23H27N3O3); MS(ESI): 394 (M+H+).

Example 244

(R)-4-(4-Fluorophenyl)piperidine-1-carboxylic Acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}-N-methylamide

[0759] 320

[0760] (R)-4-(4-Fluorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide (22 mg) was added to a suspension of sodium hydride (95% in oil; 0.005 g) in DMF (1 ml). After evolution of gas ceased, iodomethane (0.02 ml) was added. After two hours, the reaction mixture was cautiously hydrolyzed with water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated, and the residue was crystallized from pentane. This resulted 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

[0761] 321

[0762] Method J

[0763] 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 DMF (0.2 ml) were added under inert conditions to a suspension of palladium bis(tri-tert-butylphosphine) dichloride (3.8 mg) and copper(I) iodide (0.9 mg) in DMF (0.5 ml). After a reaction time of 12 hours at room temperature, the mixture was diluted with ethyl acetate and filtered through silica gel, and the filtrate was concentrated and purified by preparative HPLC. This resulted in the product with the molecular weight of 445.18 (C26H24FN3O3); MS(ESI): 446 (M+H+) as hydrotrifluoroacetate.

[0764] 5-Bromofuran-2-carboxylic Acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

[0765] N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 5-bromo-2-furancarboxylic acid by method E. This resulted in the product with the molecular weight of 406.28 (C18H20BrN3O3); MS(ESI): 407 (M+H+).

Example 246

5-2-[(4-Fluorophenyl)ethynyl]furan-2-carboxylic Acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

[0766] 322

[0767] 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-Chlorophenyl)ethynyl]furan-2-carboxylic Acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

[0768] 323

[0769] 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 (C26H24ClN3O3); MS(ESI): 462 (M+H+) as hydrotrifluoroacetate.

Example 248

R-4-Butoxy-N-(3-fluoro-4-{3-[(2-hydroxy-2-methylpropyl)methylamino]-pyrrolidin-1-yl}-phenyl)benzamide

[0770] 324

[0771] A solution of (R)-4-butoxy-N-[3-fluoro-4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamide (0.03 g) and isobutylene oxide in ethanol (5 ml) were heated under reflux for 3 hours. It was then concentrated in vacuo. This resulted 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

[0772] 325

[0773] A solution of (R)-4-butoxy-N-[3-fluoro-4-(3-methylaminopyrrolidin-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 washed with water (2×50 ml), and the organic phase was dried with sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 471.62 (C27H38FN3O3); MS (ESI): 472 (M+H+).

[0774] 4-Bromo-2-methylbutan-2-ol

[0775] Methylmagnesium bromide (3M in diethyl ether, 46 ml) was added to a solution of ethyl 3-bromopropionate (10 g) in diethyl ether (100 ml) at room temperature under argon. During this, the mixture was kept at above 20° C. and below 35° C. After 2 hours, the mixture was poured into a saturated ammonium chloride solution. This was followed by extraction with diethyl ether, drying with sodium sulfate, filtration and concentration. This resulted in the desired product.

Example 250

R-4-Butoxy-N-[6-(3-dicyclopropylaminopyrrolidin-1-yl)-pyridin-3-yl]benzamide

[0776] 326

[0777] Method K

[0778] 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 glacial acetic acid (0.11 ml) and [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.19 g). Then sodium cyanoborohydride (0.051 g) was added and the mixture was heated 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 magnesium sulfate and concentrated. The residue was purified by preparative 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

[0779] 327

[0780] (R)-4-Butoxy-N-[6-(3-dicyclopropylaminopyrrolidin-1-yl)pyridin-3-yl]benzamide was methylated by method F. This resulted in the product with the molecular weight of 448.61 (C27H36N4O2); MS (ESI): 449 (M+H+).

Example 252

R-4-Butoxy-N-{6-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]pyridin-3-yl}benzamide

[0781] 328

[0782] (R)-4-Butoxy-N-[6-(3-methylaminopyrrolidin-1-yl)pyridin-3-yl]benzamide was cyclopropylated by method K. This resulted in the product with the molecular weight of 408.551 (C24H32N4O2); MS (ESI): 409 (M+H+).

Example 253

tert-Butyl {1-[4-(2-amino-4-butoxybenzoylamino)-3-fluorophenyl]pyrrolidin-3-yl}methylcarbamate

[0783] 329

[0784] tert-Butyl [1-(4-amino-3-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was reacted with 4-butoxy-2-nitrobenzoic acid by method E, followed by hydrogenation. This resulted in the product with the molecular weight of 500.62 (C27H37FN4O4); MS (ESI): 501 (M+H+).

[0785] 4-Butoxy-2-nitrobenzoic Acid

[0786] A solution of 4-fluoro-2-nitrobenzoic acid (1.81 g) in butanol (20 ml) was mixed with sulfuric acid (3 ml) and stirred at 110° C. for 4 hours. Ethyl acetate (100 ml) was added, and the mixture was washed with saturated sodium bicarbonate solution (3×50 ml), dried with sodium sulfate, filtered and concentrated in vacuo. The residue (2.2 g) was added dropwise at −10° C. to a sodium butoxylate solution prepared from butanol (20 ml) and sodium hydride (2.18 g) at −10° C. under argon and then stirred for 20 hours. Ethyl acetate (100 ml) was added, and the mixture was washed with water (2×50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC. The butyl 4-butoxy-2-nitrobenzoate was hydrolyzed with sodium hydoxide (5N; 100 ml) in ethanol at room temperature for 3 hours. The mixture was acidified with hydrochloric acid (10N; 100 ml) and extracted with dichloromethane, and the 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-cyclohexyl-N-methylbenzamide

[0787] 330

[0788] Method L

[0789] 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 6 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 471.65 (C30H37N3O2); MS (ESI): 472 (M+H+).

[0790] N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide

[0791] 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 of sodium hydroxide (0.85 g) in water (10 ml) was added and the mixture was stirred vigorously at room temperature for 6 hours. The same amount of sodium hydroxide solution was then added, and stirring was continued for 48 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/heptane 1:2). This resulted in the product with the molecular weight of 455.40 (C24H27BrN2O2); MS (ESI): 456 (M+H+).

[0792] N-(4-Aminophenyl)-4-cyclohexyl-N-methylbenzamide

[0793] 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 by method 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

[0794] 331

[0795] N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with morpholine by method L. This resulted in the product with the molecular weight 461.61 (C28H35N3O3); MS (ESI): 462 (M+H+).

Example 256

4-Cyclohexyl-N-methyl-N-[4-(2-oxo-3-piperidin-1-ylpyrrolidin-1-yl)phenyl]benzamide

[0796] 332

[0797] N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with piperidine by method L. This resulted in the 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′]bipyrrolidinyl-1′-yl)phenyl]benzamide

[0798] 333

[0799] N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with pyrrolidine by method L. This resulted in the product with the molecular weight of 445.61 (C28H35N3O2); MS (ESI): 446 (M+H+).

Example 258

4-Cyclohexyl-N-methyl-N-[4-(3-methylamino-2-oxopyrrolidin-1-yl)phenyl]benzamide

[0800] 334

[0801] N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with methylamine by method L. This resulted in the product with the molecular weight of 405.54 (C25H31N3O2); MS (ESI): 406 (M+H+).

Example 259

4-Cyclohexyl-N-[4-(3-cyclohexylamino-2-oxopyrrolidin-1-yl)phenyl]-N-methylbenzamide

[0802] 335

[0803] N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with cyclohexylamine by method L. This resulted in the product with the molecular weight of 473.66 (C30H39N3O2); MS (ESI): 474 (M+H+).

Example 260

4-Cyclohexyl-N-{4-[3-(cyclopropylmethylamino)-2-oxopyrrolidin-1-yl]phenyl}-N-methylbenzamide

[0804] 336

[0805] N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with cyclopropylmethylamine by method L. This resulted in the product with the molecular weight of 445.61 (C28H35N3O2); MS (ESI): 446 (M+H+).

Example 261

N-{4-[3-(Acetylmethylamino)-2-oxopyrrolidin-1-yl]phenyl}-4-cyclohexyl-N-methylbenzamide

[0806] 337

[0807] 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 anhydride (130 mg) and, after 3 hours, volatile fractions were removed in vacuo. This resulted in the product with the molecular weight of 447.58 (C27H33N3O3); MS (ESI): 448 (M+H+).

Example 262

4-Cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxopyrrolidin-1-yl)phenyl]benzamide

[0808] 338

[0809] tert-Butanol (8 ml), triethylamine (350 mg) and finally diphenylphosphoryl azide (1.18 g) were added to 1-{4-[(4-cyclohexylbenzoyl)methylamino]phenyl}-5-oxopyrrolidin-3-carboxylic acid (1.5 g), and the mixture was heated at 95° C. for 48 hours. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was reacted further by method G. This resulted in the product with the molecular weight of 405.54 (C25H31N3O2); MS (ESI): 406 (M+H+).

[0810] 1-{4-[(4-Cyclohexylbenzoyl)methylamino]phenyl}-5-oxo-pyrrolidine-3-carboxylic Acid

[0811] N-(4-Aminophenyl)-4-cyclohexyl-N-methylbenzamide (3.0 g) was heated with itaconic acid (1.27 g) at 100° C. for 3 hours. Purification took place by filtration through silica gel (mobile phase ethyl acetate/methanol 5:1). This resulted in the product with the molecular weight of 420.51 (C25H28N2O4); MS (ESI): 421 (M+H+).

Example 263

N-{4-[4-(Acetylmethylamino)-2-oxopyrrolidin-1-yl]phenyl}-4-cyclohexyl-N-methylbenzamide

[0812] 339

[0813] 4-Cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxopyrrolidin-1-yl)phenyl]benzamide (101 mg) was mixed with pyridine (20 mg) and acetic anhydride (25 mg) and, after 3 hours, volatile fractions were removed in vacuo. 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-cyclohexylbenzoyl)propylamino]pyridin-2-yl}pyrrolidin-3-yl)methylcarbamate

[0814] 340

[0815] Method F-a

[0816] tert-Butyl {1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylcarbamate (50 mg), cesium carbonate (249 mg), potassium iodide (17 mg), N-methylpyrrolidone (1.5 ml) and propyl iodide (40 mg) were stirred at 60° C. for 5 hours. If conversion was incomplete, the mixture was heated to 100° C. and, after addition of further propyl iodide (40 mg), heated at 140° C. for 12 hours. The reaction mixture was diluted with ethyl acetate, washed with water and sodium bicarbonate solution, dried over Chromabond XTR and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 520.72 (C31H44N4O3); MS (ESI): 521 (M+H+).

Example 265

tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)-(1-ethylpropyl)amino]pyridin-2-yl}pyrrolidin-3-yl)-methylcarbamate

[0817] 341

[0818] tert-Butyl {1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylcarbamate was reacted with 2-ethylbutyl bromide by method F-a. This resulted in the product with the molecular weight of 548.78 (C33H48N4O3); MS (ESI): 549 (M+H+).

Example 266

tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)-(3-methylbut-2-enyl)amino]pyridin-2-yl}pyrrolidin-3-yl)methylcarbamate

[0819] 342

[0820] tert-Butyl {1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylcarbamate was reacted with 3-methyl-2-butenyl bromide by method F-a. This resulted in the product with the molecular weight of 546.76 (C33H46N4O3); MS (ESI): 547 (M+H+).

Example 267

tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)methylamino]pyridin-2-yl}pyrrolidin-3-yl)methylcarbamate

[0821] 343

[0822] tert-Butyl {1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylcarbamate was reacted with methyl iodide by method F-a. This resulted in the product with the molecular weight of 492.67 (C29H40N4O3); MS (ESI): 493 (M+H+).

[0823] 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:

[0824] tert-Butyl (1-{5-[sec-butyl-(4-cyclohexylbenzoyl)amino]pyridin-2-yl}pyrrolidin-3-yl)methylcarbamate

[0825] tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)isopropylamino]pyridin-2-yl}pyrrolidin-3-yl)methylcarbamate

[0826] tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)prop-2-inylamino]pyridin-2-yl}pyrrolidin-3-yl)-methylcarbamate

Example 268

5-p-Tolylethinylfuran-2-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[0827] 344

[0828] 0.042 ml of diisopropylamine was added under argon to 3.8 mg of Pd(tBu)2Cl2 and 0.95 mg of Cul in 0.2 ml of DMF. A solution of 94.6 mg of 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 DMF were then added dropwise. The solution was stirred at room temperature overnight. The precipitate which had separated out was filtered off with suction and the filtrate purified by preparative HPLC. The desired product with the molecular weight of 413.52; MS (ESI): 414 was obtained as hydrotrifluoroacetate.

[0829] 5-Bromofuran-2-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[0830] [1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with 5-bromo-2-furancarboxylic acid by method E. The product with a molecular weight of 378.27 (C17H20BrN3O2); MS (ESI): 379 (M+H+) was obtained as hydrotrifluoroacetate.

[0831] Examples 269-273 were prepared analogously:

		Molecular	Molecular
Ex. No.	Structure	formula	weight	M+H+
269	345	C26H27N303	429.21	430
270	346	C25H23F2N302	435.18	436
271	347	C26H27N303	429.21	430
272	348	C25H24FN302	417.19	418
273	349	C25H24CIN302	433.16	434

Example 274

(R)-4′-Fluorobiphenyl-4-carboxylic Acid [6-(3-dimethylaminopyrrolidin-1-yl)pyridin-3-yl]-amide

[0832] 350

[0833] Method M

[0834] (R)-4′-Fluorobiphenyl-4-carboxylic acid [6-(3-methylaminopyrrolidin-1-yl)pyridin-3-yl]-amide (390 mg) dissolved in formic acid (230 mg) was mixed with formaldehyde solution (37% aq.; 0.4 ml) and the mixture was heated at 80° C. for 3 hours. The cooled reaction solution was concentrated and partitioned between ethyl acetate and a saturated sodium carbonate solution. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. This 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-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

[0835] 351

[0836] Method E-a

[0837] A mixture of 0.048 g of 1-(4-fluorophenyl)piperidine-4-carboxylic acid and 0.5 ml of SOCl2 and one drop of DMF were stirred at room temperature for 2 hours. The excess SOCl2 was then removed in vacuo. The residue was dissolved 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. The solution was stirred at room temperature overnight. The solution was then filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 438.20 (C25H31FN4O2); MS (ESI): 439 (M+H+) as hydrotrifluoroacetate.

[0838] 1-(4-Fluorophenyl)piperidine-4-carboxylic Acid

[0839] 0.875 g of 4-bromofluorobenzene, 0.016 g of Pd(dba)3*CHCl3, 0.022 g 2-(dicyclohexylphosphino)biphenyl and 2.28 g of cesium carbonate were put 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 solution was heated at 100° C. overnight. The mixture was cooled and then concentrated in vacuo. The residue was taken up in ethyl acetate/water. The organic phase was washed with 10% NaHCO3 solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC.

[0840] 4.4 ml of a 2N potassium hydroxide solution were added to a solution of 1.1 g of ethyl 1-(4-fluorophenyl)piperidine-4-carboxylate in 100 ml of methanol. The mixture was stirred at room temperature overnight. The pH was then adjusted to 6 with 5% hydrochloric acid, and the solution was concentrated in vacuo. The residue was purified by preparative HPLC.

Example 276

4-Phenoxycyclohexanecarboxylic Acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

[0841] 352

[0842] 0.251 g of PyBOP and 0.135 ml of triethylamine were added to a solution of 0.106 g of 4-phenoxycyclohexanecarboxylic acid and 0.113 g of N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide in 9 ml of DMF at 0° C. After 10 minutes, the solution was allowed to reach room temperature and was stirred at this temperature overnight. The solvent was then removed in vacuo, and the residue was taken up in water/ethyl acetate. The ethyl acetate phase was washed with 10% citric acid and 10% NaHCO3 solution and dried over sodium sulfate, and the solvent was removed in vacuo. The residue was purified by preparative HPLC. The desired product was obtained. Molecular weight 435.25 (C26H33N3O3), MS: 436 (M+H+).

[0843] 4-Phenoxycyclohexanecarboxylic Acid

[0844] 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 reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The resulting solid was taken up in water and ethyl acetate, and the organic phase was washed three times with 2N hydrochloric acid and once with saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting 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 0.159 g of phenol and 0.549 g of cesium carbonate were added. The solution was then heated at 80° C. for 6 hours. After cooling, the mixture was concentrated in vacuo and purified by column chromatography on silica gel (eluent: ethyl acetate/n-heptane 1:1). The desired product was obtained. Molecular weight 248.32 (C15H20O3), MS: 249 (M+H+).

[0845] 0.06 ml of 2N potassium hydroxide solution was added to a solution of 0.12 g 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% citric acid were added to the mixture. The aqueous phase was extracted three times with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The resulting compound was employed without further purification in the next stage.

Example 277

N-[4-(3-Cyclohexylaminopyrrolidin-1-yl)phenyl]-4-isobutoxybenzamide

[0846] 353

[0847] Method N

[0848] (4-Isobutoxy-N-[4-(3-oxopyrrolidin-1-yl)phenyl]benzamide (50 mg) in methanol (2 ml) was mixed with aminocyclohexane (28 mg) and glacial acetic acid (10 mg), and a solution of sodium cyanoborohydride (1M in toluene; 0.17 ml) was added. After 8 hours, the reaction solution was concentrated and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. This resulted in the. product with the molecular weight of 435.61 (C27H37N3O2); MS (ESI): 436 (M+H+).

[0849] 4-Isobutoxy-N-[4-(3-oxopyrrolidin-1-yl)phenyl]benzamide

[0850] 4-Isobutoxybenzoic 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 adding triethylamine (0.5 ml), the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 352.44 (C21H24N2O3); MS (ESI): 353 (M+H+).

[0851] 4-Butoxy-N-[4-(3-oxopyrrolidin-1-yl)-phenyl]benzamide was obtained using 4-butoxybenzoic acid in an analogous way. Likewise, 4-butoxybenzoic acid and 4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenylamine initially resulted in 4-butoxy-N-[4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenyl]benzamide which, after methylation by method F and treatment with para-toluenesulfonic acid as described above, afforded 4-butoxy-N-[3-fluoro-4-(3-oxopyrrolidin-1-yl)phenyl]benzamide.

[0852] 4-(1,4-Dioxa-7-azaspiro[4.4]non-7-yl)phenylamine

[0853] 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 (2.67 g). After 18 hours, the mixture was poured into sodium hydroxide solution (1N). The organic phase was separated off, dried over magnesium sulfate and concentrated. The residue was dissolved in methanol (30 ml) and ammonium formate (5.2 g) and palladium hydroxide (10% on carbon, 300 mg) were added. The mixture was boiled under reflux for 8 hours, filtered and concentrated. The residue was reacted with 4-fluoronitrobenzene by method C. Hydrogenation was finally carried out by method B. This resulted in the product with the molecular weight of 220.27 (C12H16N2O2); MS (ESI): 221 (M+H+).

[0854] 4-(1,4-Dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenylamine was obtained analogously 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

[0855] 354

[0856] (R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid [4-(3-methylaminopyrrolidin-1-yl)phenyl]amide (100 mg) was reacted with potassium carbonate (100 mg) and 2-bromopyrimidine (50 mg) in N-methylpyrrolidone (3 ml) at 100° C. for 4 hours. The reaction solution was then partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. This resulted in the product with the molecular weight of 491.04 (C27H31ClN6O); MS (ESI): 491 (M+H+).

Example 279

tert-Butyl [1-(4-{[5-(2-fluorophenyl)furan-2-carbonyl]amino}phenyl)pyrrolidin-3-yl]methylcarbamate

[0857] 355

[0858] Method O

[0859] Tetrakis(triphenylphosphine)palladium(0) (20 mg) was added to a solution of tert-butyl (1-{4-[(5-bromofuran-2-carbonyl)amino]phenyl}pyrrolidin-3-yl)methylcarbamate (252 mg) in degassed toluene (4 ml) under argon in a 10 ml two-necked flask and stirred at room temperature for 10 minutes. Then a solution of 2-fluorobenzeneboronic acid (73 mg in 1 ml of ethanol) and 0.35 ml of 2M sodium carbonate solution were added, and the mixture was stirred at 100° C. for 24 hours.

[0860] Then water (5 ml) and ethyl acetate (5 ml) were added to the reaction mixture, the organic phase was separated off, and the aqueous phase was extracted 2× with ethyl acetate (10 ml). The combined organic phases were concentrated and the residue was purified by preparative HPLC. The desired product with the molecular weight of 479.56 (C27H30FN3O4); MS (ESI): 480 (M+H+) was obtained as hydrotrifluoroacetate. It is alternatively possible to use cesium carbonate as base and to heat the reaction at 150° C. in a microwave apparatus for 3 minutes.

[0861] tert-Butyl (1-{4-[(5-bromofuran-2-carbonyl)amino]phenyl}pyrrolidin-3-yl)methylcarbamate

[0862] 5-Bromofuran-2-carboxylic acid was reacted with tert-butyl [1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate by method E. This resulted in the product with the molecular weight of 464.36 (C21H26BrN3O4); MS (ESI): 464 (M+H+).

[0863] The following compounds were prepared analogously:

[0864] 5-Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[0865] tert-Butyl (1-{4-[(5-bromothiophene-2-carbonyl)amino]phenyl}pyrrolidin-3-yl)methylcarbamate

[0866] 2-Bromothiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[0867] 4-Iodo-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]benzamide

[0868] (R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-iodobenzamide

[0869] 4-Bromo-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-3-fluorobenzamide

Example 280

(3R)-3′-Cyanobiphenyl-4-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]amide

[0870] 356

[0871] Method O-b

[0872] 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 ml of degassed DMF and stirred at room temperature for 10 minutes. 0.035 ml of water, 0.021 g of K3PO4 and 0.008 g of 3-cyanophenylboronic acid were then added to the solution. The reaction solution was heated at 80° C. overnight. The solution was then filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 428.20 (C26H25FlN4O); MS (ESI): 429 (M+H+) as hydrotrifluoroacetate.

Example 281

3,2′,4′-Trifluorobiphenyl-4-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide

[0873] 357

[0874] 1-Bromo-2,4-difluorobenzene was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic acid benzamide by method O-b. This resulted in the product with the molecular weight of 439.19 (C25H24F3N3O); MS (ESI): 440 (M+H+) as hydrotrifluoroacetate.

[0875] N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic Acid Benzamide

[0876] 4-Carboxy-3-fluorophenylboronic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the 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

[0877] 358

[0878] 1-Bromo-2,4-difluorobenzene was reacted with 2-boronic acid thiophen-5-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide by method O-b. This resulted in the product with molecular weight of 427.52 (C23H23F2N3OS); MS (ESI): 428 (M+H+) as hydrotrifluoroacetate.

[0879] 2-Boronic Acid thiophene-5-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[0880] 5-Carboxy-2-thiopheneboronic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]-dimethylamine by method E-b. This resulted in the 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

[0881] 359

[0882] 5-[4-(3-Dimethylaminopyrrolidin-1-yl)phenylcarbamoyl]pyridin-2-yl [trifluoro-methanesulfonate was reacted with 4-fluorobenzeneboronic acid under the conditions of method O-b. (Heating at 140° C. in a microwave apparatus for 15 minutes). This resulted in the product with the molecular weight of 404.20 (C24H25FN4O); MS (ESI): 405 (M+H+) as hydrotrifluoroacetate.

[0883] 5-[4-(3-Dimethylaminopyrrolidin-1-yl)phenylcarbamoyl]pyridin-2-yl[trifluoromethanesulfonate

[0884] A suspension of 0.05 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 ml of LDA solution (2M) in 0.4 ml of DME at 0° C. The mixture was stirred at 0° C. for 2 hours. A solution of 0.055 g of N-phenyltrifluoromethanesulfonimide in 0.2 ml of DME was then added to the mixture. The reaction solution was allowed to reach room temperature and was heated at 80° C. for 3 hours. After cooling, the solution was concentrated in vacuo. The residue was taken up in ethyl acetate/water, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC.

[0885] N-[4-(3-Dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide

[0886] 6-Hydroxynicotinic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 326.17 (C18H22N4O2); MS (ESI): 327 (M+H+) as hydrotrifluoroacetate.

Example 284

N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-6-(2,4-difluorophenyl)nicotinamide

[0887] 360

[0888] 2,4-Difluorophenylboronic acid was reacted with 5-[4-(3-dimethylaminopyrrolidin-1-yl)-phenylcarbamoyl]pyridin-2-yl[trifluoromethanesulfonate by method O-b. This resulted in the product with the molecular weight of 422.00 (C24H24F2N4O); MS (ESI): 423 (M+H+) as hydrotrifluoroacetate.

Example 285

2′,4′-Difluorobiphenyl-4-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[0889] 361

[0890] 2′,4′-Difluorobiphenyl-4-carboxylic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-a. This resulted in the product with the molecular weight of 421.20 (C25H25F2N3O); MS (ESI): 422 (M+H+) as hydrotrifluoroacetate.

[0891] 2′,4′-Difluorobiphenyl-4-carboxylic Acid

[0892] Method P

[0893] 0.098 ml of 1 N lithium hydroxide solution was added to a solution of 0.051 g of ethyl 2′,4′-difluorobiphenyl-4-carboxylate in 1 ml THF/water (1:1), and the mixture was stirred at room temperature overnight. 5% hydrochloric acid was used to neutralize the solution, which was concentrated in vacuo, and the residue was purified by preparative HPLC.

[0894] Ethyl 2′,4′-difluorobiphenyl-4-carboxylate

[0895] 0.009 g of Pd(PPh3)4 was added to a solution of 0.091 g of ethyl 4-iodobenzoate in 0.96 ml of degassed toluene and stirred at room temperature for 10 minutes. Then a solution of 0.047 g of 2,4-difluorophenylboronic acid in 0.114 ml of ethanol and 0.201 ml of a 2N Na2CO3 solution was added to the reaction solution. The solution was heated at 100° C. overnight. The reaction mixture was then concentrated in vacuo, and water/ethyl acetate were added to the residue. The aqueous phase was extracted three times with ethyl acetate and dried over sodium sulfate, and the solvent was removed in vacuo and purified by preparative HPLC.

Example 286

2′,4′-Difluorobiphenyl-4-carboxylic Acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}-amide

[0896] 362

[0897] Method E-b

[0898] 0.095 g of HATU, 0.068 g of HOBT and 0.035 ml of triethylamine were added to a solution of 0.047 g of 2′,4′-difluorobiphenyl-4-carboxylic acid and 0.058 g of N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide in 2 ml of DMF at 0° C. After 10 minutes, the solution was allowed to reach room temperature and was stirred at this temperature overnight. The solvent was then removed in vacuo, and the residue was taken up in water/ethyl acetate. The ethyl acetate phase was washed with 10% NaHCO3 solution and water. The ethyl acetate phase was dried over sodium sulfate, and the solvent was removed in vacuo. The residue was purified by preparative HPLC. The desired product was obtained. Molecular weight 449.19 (C26H25F2N3O2), MS: 450 (M+H+).

Example 287

N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-3-fluoro-4-(4-methylpiperidin-1-yl)-benzamide

[0899] 363

[0900] 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 in the product with the molecular weight of 424.00 (C25H33FN4O); MS (ESI): 425 (M+H+) as hydrotrifluoroacetate.

[0901] 3-Fluoro-4-(4-methylpiperidin-1-yl)benzoic Acid

[0902] Methyl 3-fluoro-4-(4-methylpiperidin-1-yl)benzoate was treated with lithium hydroxide by method P. This resulted in the product with the molecular weight of 237.28 (C13H16FNO2); MS (ESI): 238 (M+H+).

[0903] Methyl 3-fluoro-4-(4-methylpiperidin-1-yl)benzoate

[0904] 0.076 g of potassium carbonate was added to a solution of 0.086 g of methyl 3,4-difluorobenzoate and 0.050 g of 4-methylpiperidine in 0.5 ml of DMF. The reaction was heated at 60° C. for 2 days, filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 251.3 (C14H18FNO2); MS (ESI): 252 (M+H+) as hydrotrifluoroacetate.

Example 288

4-Butoxy-N-(4-{3-[(2-dimethylaminoacetyl)methylamino]pyrrolidin-1-yl}phenyl)-N-methylbenzamide

[0905] 364

[0906] 4-Butoxy-N-methyl-N-[4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamide was reacted with N,N-dimethylglycine by method E. This resulted in the product with the molecular weight of 466.63 (C27H38N4O3); MS (ESI): 467 (M+H+).

[0907] (R)-4-Butoxy-N-(4-{3-[(2-dimethylaminoacetyl)methylamino]pyrrolidin-1-yl}phenyl)-N-methylbenzamide was obtained analogously.

Example 289

N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-butoxy-N-methylbenzamide

[0908] 365

[0909] 4-Butoxy-N-methyl-N-[4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamide was mixed with pyridine and acetic anhydride. Volatile fractions were removed after 2 hours. This resulted in the product with the molecular weight of 423.56 (C25H33N3O3); MS (ESI): 424 (M+H+).

Example 290

4-Butyrylamino-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]benzamide

[0910] 366

[0911] Method Q

[0912] 4-Amino-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]benzamide (32 mg) in dichloromethane (2 ml) was mixed with potassium carbonate (50 mg) and butyryl chloride (11 mg). The mixture was filtered and concentrated after 12 hours. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 394.52 (C23H30N4O3); MS (ESI): 395 (M+H+).

[0913] An alternative possibility is to react 4-amino-N-[4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]benzamide with butyric acid by method E.

[0914] 4-Amino-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]benzamide

[0915] 4-tert-Butoxycarbonylaminobenzoic acid was reacted with 1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E, and the product was treated by method G. This resulted in the product with the molecular weight of 324.43 (C19H24N4O); MS (ESI): 325 (M+H+).

Example 291

2-Phenylethynylthiazole-4-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide

[0916] 367

[0917] 2-Bromothiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (100 mg) was dissolved in tetrahydrofuran (2 ml), and phenylacetylene (52 mg), triethylamine (52 mg), triphenylphosphine (17 mg), bis(triphenylphosphine)palladium dichloride (89 mg) and copper (I) iodide (9.6 mg) were added. The reaction mixture was heated at 150° C. in a microwave apparatus for 3 minutes and then concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 416.55 (C24H24N4OS); MS (ESI): 417 (M+H+).

Example 292

5-(4-Fluorophenyl)pyridine-2-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide

[0918] 368

[0919] Method O-a

[0920] 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 cesium carbonate (2M aq.; 0.5 ml). The reaction was heated at 150° C. in a microwave apparatus for 10 minutes and then concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 404.49 (C24H25FN4O); MS (ESI): 405 (M+H+).

[0921] 5-Chloropyridine-2-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[0922] [1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with 5-chloropyridine-2-carboxylic acid by method E. This resulted in the product with the molecular weight of 344.85 (C18H21 ClN4O); MS (ESI): 345 (M+H+).

Example 293

5-(4-Fluorophenyl)pyridine-2-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide

[0923] 369

[0924] 5-Chloropyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 4-methylphenylboronic acid by method O-a. This resulted in the product with the molecular weight of 400.53 (C25H28N4O); MS (ESI): 401 (M+H+).

Example 294

1-Benzenesulfonylpiperidine-4-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]amide

[0925] 370

[0926] Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and benzenesulfonyl chloride (35 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This resulted in the product with the molecular weight of 456.61 (C24H32N4O3S); MS (ESI): 457 (M+H+).

Example 295

1-(4-Fluorobenzenesulfonyl)piperidine-4-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[0927] 371

[0928] Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and 4-fluorobenzenesulfonyl chloride (40 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This resulted in the product with the molecular weight of 474.60 (C24H31FN4O3S); MS (ESI): 475 (M+H+).

Example 296

1-(Butane-1-sulfonyl)piperidine-4-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]amide

[0929] 372

[0930] Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and butylsulfonyl chloride (30 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This resulted in the product with the molecular weight of 436.62 (C22H36N4O3S); MS (ESI): 437 (M+H+).

Example 297

5-(4-Butoxyphenylethynyl)furan-2-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]amide

[0931] 373

[0932] Method J-a

[0933] 5-Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (75 mg) was dissolved together with 1-butoxy-4-ethynylbenzene (35 mg) in N,N-dimethylformamide (1 ml) and, under argon, added dropwise to a suspension of Pd(tBu3P)2Cl2 (4 mg), copper (I) iodide (75 mg) and N,N-diisopropylamine (20 mg) in anhydrous tetrahydrofuran (3 ml). The mixture was stirred at room temperature for 8 hours. The reaction was worked up by filtration through a syringe filter and concentrated, and the crude product was purified by preparative HPLC. 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

[0934] 374

[0935] Method H-a

[0936] A solution of 0.1 g of potassium hydroxide in 1 ml of DMSO was stirred at room temperature 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 temperature overnight. After addition of water and ethyl acetate, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 382.24 (C22H30N4O2); MS (ESI): 383 (M+H+) as hydrotrifluoroacetate.

Example 299

6-Cyclopropylmethoxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]nicotinamide

[0937] 375

[0938] (Bromomethyl)cyclopropane was reacted with N-[4-(3-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.

Example 300

N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-6-isobutoxynicotinamide

[0939] 376

[0940] 1-Bromo-2-methylpropane was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide by method H-a. This resulted in the product with the molecular weight of 382.24 (C22H30N4O2); MS (ESI): 383 (M+H+) as hydrotrifluoroacetate.

Example 301

N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-6-(4-fluorophenoxy)nicotinamide

[0941] 377

[0942] 49 mg of potassium carbonate were added to a solution of 0.041 g of 6-chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]nicotinamide and 4-fluorophenol (30 mg) in 0.8 ml of DMF, and the reaction was heated at 140° C. in a microwave apparatus for 90 minutes. After addition of water and ethyl acetate, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 420.2 (C24H25FN4O2); MS (ESI): 421 (M+H+) as hydrotrifluoroacetate.

[0943] 6-Chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]nicotinamide

[0944] 6-Chloronicotinic acid was reacted with [1-(4-amino-phenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 344.14 (C18H21ClN4O); MS (ESI): 345 (M+H+) as hydrotrifluoroacetate.

[0945] The following examples were prepared analogously.

		Molecular	Molecular
Ex. No.	Structure	formula	weight	M+H+
302	378	C24H26N402	402.21	403
303	379	C24H25CIN402	436.17	437
304	380	C25H28N402	416.22	417

Example 305

N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-phenoxybenzamide

[0946] 381

[0947] Powdered molecular sieves (4 A), 0.01 g of copper acetate and 0.02 g of N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic acid benzamide were added to a solution of 0.008 g of phenol in 0.5 ml of methylene chloride and stirred at 40° C. for 24 hours. The solvent was then removed in vacuo, the residue was taken up in water/ethyl acetate, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 419.2 (C25H26FN3O2); MS (ESI): 420 (M+H+) as hydrotrifluoroacetate.

[0948] N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic Acid Benzamide

[0949] 4-Carboxy-3-fluorophenylboronic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 371.18 (C19H23BFN3O3); MS (ESI): 372 (M+H+) as hydrotrifluoroacetate.

Example 306

4-(3-Cyanophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[0950] 382

[0951] 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 was reacted with 3-bromobenzonitrile by method O-a. This resulted in the product with the molecular weight of 415.54 (C25H29N5O); MS (ESI): 416 (M+H+)

[0952] 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

[0953] 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method 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

[0954] 383

[0955] 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 was reacted with 2-bromobenzonitrile by method O-a. This resulted in the product with the molecular weight of 415.54 (C25H29N5O); MS (ESI): 416 (M+H+)

Example 308

4-(3-Methylsulfanylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[0956] 384

[0957] 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 was reacted with 3-bromothioanisole by method O-a. This resulted in the product 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

[0958] 385

[0959] 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 of DMF, and the solution was heated at 130° C. in a microwave apparatus for 15 minutes. The solution was then mixed with water and ethyl acetate, the aqueous phase was freeze-dried, and the residue was employed without further purification in the next stage.

[0960] Method R

[0961] 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 potassium carbonate in 0.8 ml of DMF was heated at 230° C. in a microwave apparatus for 30 minutes. The solution was filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 436.17 (C24H25ClN4O2); MS (ESI): 437 (M+H+) as hydrotrifluoroacetate.

[0962] 4-[4-(3-Dimethylaminopyrrolidin-1-yl)phenylcarbamoyl]phenyl Acetate

[0963] 4-Acetoxybenzoic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 367.19 (C21H25N3O3); MS (ESI): 368 (M+H+) as hydrotrifluoroacetate.

Example 310

N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-4-(5-fluoropyridin-2-yloxy)benzamide

[0964] 386

[0965] 2-Chloro-5-fluoropyridine was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-4-hydroxybenzamide by method R. This resulted in the product with 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

[0966] 387

[0967] was obtained as by-product of the reaction in example 310. This resulted in the product with the molecular weight of 436.95 (C24H25ClN4O2); MS (ESI): 437 (M+H+) as hydrotrifluoroacetate.

Example 312

5-Chloro-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic Acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]amide

[0968] 388

[0969] [1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine (32 mg) and carbonyldiimidazole (27.1 mg) were dissolved in acetonitrile (1.5 ml), and the mixture was stirred for 3 hours. Triethylamine (63.4 μl) was added to a solution of 5-chloro-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridine (40.7 mg) in THF (1 ml) and chloroform (0.5 ml). After 15 minutes, the mixture was added dropwise to the first solution and stirred overnight. The mixture was concentrated and the residue was partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate, filtered and concentrated. Contamination by the primary and/or secondary amine was removed by dissolving the residue in dichloromethane (1.5 ml) and adding the solution to a stirred suspension of polymer-bound p-toluenesulfonyl chloride (0.5 g) in dichloromethane (6 ml) and triethylamine (128 μl). After 3 hours, the resin was filtered off and washed several times with dichloromethane. The combined organic phases were concentrated. The residue was purified by chromatography (silica gel, mobile phase: ethyl acetate/dichloromethane (5%), ammonia (7N in methanol, 2%), later ethyl acetate/dichloromethane (5%), ammonia (7N in methanol, 3%). This resulted in the product with the molecular weight of 425.97 (C23H28ClN5O); MS (ESI): 426 (M+H+).

[0970] 5-Chloro-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridine

[0971] 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 hydrogen chloride (4N in dioxane; 0.8 ml) and the mixture was concentrated after 13 hours. This resulted in the product with the molecular weight of 194.67 (C10H11ClN2); MS (ESI): 195 (M+H+).

[0972] tert-Butyl 5-chloro-3′,6′-dihydro-2′H-[2,4′]bipyridine-1′-carbamate

[0973] A solution of 2-bromo-5-chloropyridine (131 mg) in DMF (degassed with nitrogen; 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 with dichloromethane and washed with sodium carbonate solution and water. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, mobile phase: heptane/ethyl acetate (2%)/dichloromethane (5%), later heptane/ethyl acetate (5%)/dichloromethane (5%).

Example 313

5-(2-Amino-4-methylphenyl)furan-2-carboxylic Acid [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]amide

[0974] 389

[0975] 5-(2-Nitro-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]amide was hydrogenated by method B. This resulted in the product with the molecular weight of 404.22 (C24H28N4O2); MS (ESI): 405 (M+H+).

Example 314

5-(2-Acetylamino-4-methylphenyl)furan-2-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[0976] 390

[0977] 5-(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]amide was reacted with acetyl chloride by method Q. This resulted in the product with the molecular weight of 446.23 (C26H30N4O3); MS (ESI): 447 (M+H+).

Example 315

5-(2-Isobutyrylamino-4-methylphenyl)furan-2-carboxylic Acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]amide

[0978] 391

[0979] 5-(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]amide was reacted with isobutyryl chloride by method Q. This resulted in the product with the molecular weight of 474.26 (C28H34N4O3); MS (ESI): 475 (M+H+).

Example 316

5′-Chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic Acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]methylamide

[0980] 392

[0981] Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-methylamide (44.4 mg) and 2,5-dichloropyridine (60 mg) were heated at 160° C. for 15 minutes. o-Xylene (0.5 ml) was added and heating at 160° C. was continued for 2 hours. The cooled crude mixture was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). This resulted in the product with the molecular weight of 442.01 (C24H32ClN5O); MS (ESI): 442 (M+H+).

[0982] Piperidine-4-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]methylamide

[0983] 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+).

[0984] Piperidine-4-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]-amide can be prepared analogously.

[0985] tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]methylcarbamoyl}-piperidine-1-carboxylate

[0986] A solution of N-Boc-piperidine-4-carboxylic acid (550 mg) and pyridine (0.47 ml) in dichloromethane (15 ml) was mixed with thionyl chloride (0.21 ml) 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 16 hours, the mixture was diluted with dichloromethane, washed with water and saturated brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). This resulted in the product with the molecular weight of 430.60 (C24H38N4O3); MS (ESI): 431 (M+H+).

[0987] tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]carbamoyl}piperidin-1-carboxylate can be prepared analogously.

[0988] The following examples were prepared analogously.

		Molecular	Molecular
Ex. No.	Structure	formula	weight	M+H+
317	393	C25H30CIN5O	466.03	466
318	394	C24H30CIN5O3	471.99	472
319	395	C24H30FN5O3	455.54	456

Example 320

3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[0989] 396

[0990] Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide (30 mg) and 2-chloropyridine (90 mg) were heated at 160° C. for 2 hours. 2-Chloropyridine (0.2 ml) was added and the mixture was again heated at 160° C. for 4 hours. The cooled crude mixture was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (3N in methanol)). This resulted in the product with the molecular weight of 393.54(C23H31N5O); MS (ESI): 394 (M+H+).

[0991] The following examples were prepared analogously.

		Molecular	Molecular
Ex. No.	Structure	formula	weight	M+H+
321	397	C25H32CIN5O3	486.02	486
322	398	C24H30FN5O3	469.56	470

Example 323

5′-Chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic Acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]amid

[0992] 399

[0993] Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (30 mg), 2,5-dichloropyridine (30 mg) and tributylamine(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 with the molecular weight of 427.98 (C23H30ClN5O); MS (ESI): 428 (M+H+).

Example 324

1-(4-Chloro-2-cyanophenyl)piperidine-4-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[0994] 400

[0995] Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 2,5-dichlorobenzonitrile as described in example 323. This resulted in the product with the molecular weight of 452.00 (C25H30ClN5O); MS (ESI): 452 (M+H+).

Example 325

1-(2-Acetylamino-4-chlorophenyl)piperidine-4-carboxylic Acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]methylamide

[0996] 401

[0997] 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 was stirred under a hydrogen atmosphere (1 bar), and acetic anhydride (14 μl) was added. After one hour, further acetic anhydride (6 μl) were added and the mixture was stirred for 15 minutes. The suspension was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). This resulted in the product with the molecular weight of 498.07 (C27H36ClN5O2); MS (ESI): 498 (M+H+).

[0998] The following examples were prepared analogously.

		Molecular	Molecular
Ex. No.	Structure	formula	weight	M+H+
326	402	C27H36FN5O2	481.62	482
327	403	C26H34CIN5O2	484.05	484
328	404	C26H34FN5O3	467.59	468

Example 329

(R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-(4-phenylpiperidin-1-yl)acetamide

[0999] 405

[1000] Cesium 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 mixture was kept at 65° C. for 12 hours. The mixture was freed of volatile fractions and the residue was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 406.58 (C25H34N4O); MS (ESI): 407 (M+H+).

[1001] It is alternatively possible to use potassium carbonate or pyridine as auxiliary bases, to add potassium iodide as catalyst, or to carry out the reaction at 150° C. in a microwave apparatus.

[1002] (R)-2-Chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]acetamide

[1003] Triethylamine (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 3 hours, the mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 281.79 (C14H20ClN3O); MS (ESI): 282 (M+H+).

[1004] The following were obtained analogously:

[1005] N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-chloroacetamide

[1006] 2-Chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]acetamide

[1007] (R)-2-Chloro-N-[6-(3-dimethylaminopyrrolidin-1-yl)pyridin-3-yl]acetamide

[1008] The following examples were prepared in analogy to the method given in example 329:

		Molecular	Molecular
Ex. No.	Structure	formula	weight	M+H+
330	406	C25H34N4O	406.58	407
331	407	C26H34N4O2	434.59	435
332	408	C26H33CIN4O2	469.03	469
333	409	C27H30N4O3	458.57	459
334	410	C25H29N5O2	431.54	432
335	411	C25H28CIN5O2	465.99	466
336	412	C26H33N5O3	463.59	464
337	413	C25H33CIN4O2	441.02	441
338	414	C25H34N4O2	422.58	423
339	415	C24H33N5O2	423.56	424

Example 340

(R)-4-Benzylpiperidine-1-carboxylic Acid [6-(3-dimethylaminopyrrolidin-1-yl)pyridin-3-yl]-amide

[1009] 416

[1010] (R)-6-(3-Dimethylaminopyrrolidin-1-yl)pyridin-3-ylamine was added to a solution of carbonyldiimidazole (53 mg) in DMF (0.5 ml) at 0° C. After 15 minutes, 4-benzylpiperidine (57 mg) was added and the mixture was heated at 90° C. for one hour. The cooled mixture was freed of volatile fractions. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 407.56 (C24H33N5O); MS (ESI): 408 (M+H+).

[1011] The following examples were prepared analogously:

		Molecular	Molecular
Ex. No.	Structure	formula	weight	M+H+
341	417	C24H31N5O2	421.55	422
342	418	C24H33N5O	407.56	408
343	419	C26H34N4O3	450.59	451
344	420	C25H31CIN4O2	455.00	455
345	421	C26H30N4O	414.56	415
346	422	C24H39N5O	413.61	414
347	423	C26H37N5O	435.62	436

Example 348

(R)-4-Cyclopropylmethoxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-benzamide

[1012] 424

[1013] (R)-4-Benzyloxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]benzamide underwent debenzylating hydrogenation by method B. The resulting (R)-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-hydroxybenzamide was alkylated with cyclopropylmethylbromide by method H. This resulted in the product with the molecular weight of 397.50 (C23H28N3O2); MS (ESI): 398 (M+H+).

[1014] The following examples were likewise obtained by method H:

		Molecular	Molecular
Ex. No.	Structure	formula	weight	M+H+
349	425	C26H34FN3O2	439.58	440
350	426	C25H32FN3O3	441.55	442
351	427	C24H30FN3O2	411.52	412

Example 352

(R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-(pyridin-2-yloxy)benzamide

[1015] 428

[1016] (R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-hydroxybenzamide was reacted with 2-chloropyridine by method R. This resulted in the product with the molecular weight of 434.52 (C25H27N4O2); MS (ESI): 435 (M+H+).

Example 353-Example 507

[1017] Various pyrrolidinylanilines were reacted with diverse amines by method A. The resulting products are summarized in table 6.

Example 508-Example 1130

[1018] Various pyrrolidinylanilines were reacted with diverse acids by methods E. The resulting products are summarized in table 7.

Example 1131-Example 1232

[1019] Various (hetero)aryl halides were reacted with diverse boronic acids by methods O. The resulting products are summarized in table 8.

Example 1233-Example 1237

[1020] Various aryl halides were reacted with diverse acetylenes by methods J. The resulting products are summarized in table 9.

Example 1238-Example 1403

[1021] Various aminopyrrolidines and N-arylpyrrolidinones were reacted with diverse aldehydes, ketones and amines by method N. The resulting products are summarized in table 10.

Example 1404-Example 1423

[1022] Various aminopyrrolidines were reductively methylated with formaldehyde by method E. The resulting products are summarized in table 11.

Example 1424-Example 1443

[1023] Various amides were alkylated by method F. The resulting products are summarized in table 12.

Example 1444-Example 1618

[1024] Various tert-butyl carbamates were cleaved by method G. The resulting products were summarized in table 13.

TABLE 6
		Molecular	Monoisotopic
Ex. No.	Structure	formula	molecular wt.	M+H+
353	429	C25H31FN4O2	438.24	439
354	430	C25H30N4O4	450.23	451
355	431	C25H31CIN4O3	470.21	471
356	432	C26H30N4O2	430.24	431
357	433	C24H29CIN4O	424.20	425
358	434	C25H35N5O	421.28	422
359	435	C23H3OBrN5O	471.16	472
360	436	C24H34N4O	394.27	395
361	437	C26H28N4O3	444.22	445
362	438	C24H29N5O	403.24	404
363	439	C27H29N5OS	471.21	472
364	440	C26H30N4O2	430.24	431
365	441	C25H30N6O3	462.24	463
366	442	C22H25N5O2	391.20	392
367	443	C26H28N6O	440.23	441
368	444	C24H29FN4O	408.23	409
369	445	C26H30N4O3	446.23	447
370	446	C25H27CIN4O2	450.18	451
371	447	C25H27FN4O2	434.21	435
372	448	C26H30N4O2	430.24	431
373	449	C26H30N4O2	430.24	431
374	450	C26H30N4O3	446.23	447
375	451	C25H27CIN4O2	450.18	451
376	452	C23H32N4O2	396.25	397
377	453	C25H29N5O2	431.23	432
378	454	C24H27N5O2	417.22	418
379	455	C25H35N5O2	437.28	438
380	456	C25H27FN4O2	434.21	435
381	457	C26H27F3N4O2	484.21	485
382	458	C26H27F3N4O	468.21	469
383	459	C24H31CIN4O2	442.21	443
384	460	C25H28N4O	400.23	401
385	461	C26H30N4O2	430.24	431
386	462	C23H32N4O2	396.25	397
387	463	C25H34N4O2	422.27	423
388	464	C24H31CIN4O	426.22	427
389	465	C25H34N4O	406.27	407
390	466	C25H31F3N4O	460.24	461
391	467	C25H31F3N4O2	476.24	477
392	468	C23H31N5O4	441.24	442
393	469	C24H30N4O3	422.23	423
394	470	C24H32CIN5O	441.23	442
395	471	C25H27CIN4O	434.19	435
396	472	C25H28N4O	400.23	401
397	473	C24H28N6O	416.23	417
398	474	C25H34N4O2	422.27	423
399	475	C28H34N4O	442.27	443
400	476	C25H27N5O3	445.21	446
401	477	C25H27CIN4O	434.19	435
402	478	C24H31CIN4O2	442.21	443
403	479	C24H33N5O	407.27	408
404	480	C22H30N4O2	382.24	383
405	481	C25H34N4O	406.27	407
406	482	C22H22CI2F6N4O2	558.10	559
407	483	C26H27F3N4O2	484.21	485
408	484	C24H31FN4O	410.25	411
409	485	C24H31FN4O	410.25	411
410	486	C24H31FN4O	410.25	411
411	487	C25H34N4O	406.27	407
412	488	C25H34N4O	406.27	407
413	489	C24H32N4O2	408.25	409
414	490	C22H26N6O	390.22	391
415	491	C26H27BrN4O	490.14	491
416	492	C21H24N6OS	408.17	409
417	493	C26H27N5O	425.22	426
418	494	C24H32N4O	392.26	393
419	495	C25H27CIN4O2	450.18	451
420	496	C24H30N4O3	422.23	423
421	497	C24H29CIN4O2	440.20	441
422	498	C26H31CIN4O2	466.21	467
423	499	C28H35CIN4O	478.25	479
424	500	C28H38N4O4	494.29	495
425	501	C24H31CIN4O2	442.21	443
426	502	C25H33CIN4O2	456.23	457
427	503	C25H28N4O3	432.22	433
428	504	C25H29FN4O2	436.23	437
429	505	C24H30BrN5O2	499.16	500
430	506	C25H29CIN4O2	452.20	453
431	507	C25H32N4O3	436.25	437
432	508	C24H32BrN5O2	501.17	502
433	509	C22H30N6O	394.25	395
434	510	C24H30F3N5O	461.24	462
435	511	C21H29N7O	395.24	396
436	512	C23H31N5O	393.25	394
437	513	C22H30N6O	394.25	395
438	514	C21H29N7O	395.24	396
439	515	C23H30CIN5O	427.21	428
440	516	C23H30CIN5O	427.21	428
441	517	C23H30CIN5O	427.21	428
442	518	C23H30FN5O	411.24	412
443	519	C23H30FN5O	411.24	412
444	520	C24H33N5O	407.27	408
445	521	C24H33N5O	407.27	408
446	522	C24H33N5O	407.27	408
447	523	C24H33N5O	407.27	408
448	524	C24H30F3N5O	461.24	462
449	525	C24H30F3N5O	461.24	462
450	526	C24H30N6O	418.25	419
451	527	C24H33N5O2	423.26	424
452	528	C24H33N5O2	423.26	424
453	529	C24H33N5O2	423.26	424
454	530	C25H33N5O2	435.26	436
455	531	C24H29CIF3N5O	495.20	496
456	532	C24H32CIN5O	441.23	442
457	533	C25H35N5O	421.28	422
458	534	C23H29CI2N5O	461.17	462
459	535	C23H29F3N6O	462.24	463
460	536	C23H29F3N6O	462.24	463
461	537	C23H28CIF3N6O	496.20	497
462	538	C25H35N5O2	437.28	438
463	539	C23H29CI2N5O	461.17	462
464	540	C25H35N5O	421.28	422
465	541	C23H29CI2N5O	461.17	462
466	542	C25H35N5O3	453.27	454
467	543	C24H32CIN5O2	457.22	458
468	544	C23H38N6O	414.31	415
469	545	C23H29F2N5O	429.23	430
470	546	C24H30N6O	418.25	419
471	547	C25H35N5O	421.28	422
472	548	C23H37N5O	399.30	400
473	549	C23H32N6O	408.26	409
474	550	C23H32N6O	408.26	409
475	551	C26H37N5O	435.30	436
476	552	C28H36CIN5O2	509.26	510
477	553	C25H34N4O	406.27	407
478	554	C25H31FN4O2	438.24	439
479	555	C23H27CIFN5O	443.96	444
480	556	C23H30FN5O2	427.53	428
481	557	C23H29F2N5O2	445.52	446
482	558	C23H27F2N5O	427.50	428
483	559	C23H29CIFN5O2	461.97	462
484	560	C28H37FN4O4	512.28	513
485	561	C28H32FN5O4	521.24	522
486	562	C23H30CIN5O2	443.98	444
487	563	C23H29CIFN5O2	461.97	462
488	564	C26H34N4O2	434.27	435
489	565	C30H36N4O	468.29	469
490	566	C26H34N4O3	450.26	451
491	567	C25H32N4O2	420.25	421
492	568	C26H34N4O3	450.26	451
493	569	C25H30N4O3	434.23	435
494	570	C26H35N5O2	449.28	450
495	571	C25H30FN5O2	451.24	452
496	572	C25H31N5OS	449.23	450
497	573	C26H33N5O	431.27	432
498	574	C27H35N5O	445.28	446
499	575	C25H31F3N4O2	476.24	477
500	576	C26H35N5O3S	497.25	498
501	577	C25H31N5O3	449.24	450
502	578	C23H29CIN4O	412.20	413
503	579	C23H29FN4O	396.23	397
504	580	C25H31N5O	417.25	418
505	581	C24H30N6O3	450.24	451
506	582	C24H31FN4O2	426.24	427
507	583	C25H31FN4O	422.25	423

[1025]

TABLE 7
Ex.		Molecular	Monoisotopic	M +
No.	Structure	formula	molecular wt.	H+
508	584	C26H33N3O2	419.26	420
509	585	C26H34N4O2	434.27	435
510	586	C26H27N3O2	413.21	414
511	587	C30H35N3O2	469.27	470
512	588	C27H29N3O2	427.23	428
513	589	C27H28N4O6S	536.17	537
514	590	C25H33N3O3	423.25	424
515	591	C24H29N3O3	407.22	408
516	592	C25H33N3O3	423.25	424
517	593	C27H29N3O3	443.22	444
518	594	C27H29N3O2	427.23	428
519	595	C27H29N3O2	427.23	428
520	596	C27H29N3O2	427.23	428
521	597	C27H26F3N3O2	481.20	482
522	598	C27H26F3N3O2	481.20	482
523	599	C28H31N3O4	473.23	474
524	600	C27H28N4O4S	504.18	505
525	601	C26H25ClFN3O3	481.16	482
526	602	C24H25N3O3	403.19	404
527	603	C24H25N3O2S	419.17	420
528	604	C25H28N4O2	416.22	417
529	605	C24H24ClN3O3	437.15	438
530	606	C24H24FN3O3	421.18	422
531	607	C25H33N3O	391.26	392
532	608	C25H27N3O2	401.21	402
533	609	C25H27N3O	385.21	386
534	610	C23H31N3O2	381.24	382
535	611	C26H29N3O2	415.23	416
536	612	C25H27N3O	385.21	386
537	613	C24H31N3O	377.25	378
538	614	C25H26N4O4	446.20	447
539	615	C26H29N3O	399.23	400
540	616	C26H29N3O2	415.23	416
541	617	C28H33N3O2	443.26	444
542	618	C25H29N5O4	463.22	464
543	619	C23H31N3O2	381.24	382
544	620	C25H27N3O2	401.21	402
545	621	C25H31N3O2	405.24	406
546	622	C27H31N3O	413.25	414
547	623	C28H33N3O	427.26	428
548	624	C21H22FN5O2	395.18	396
549	625	C25H25N3O2	399.20	400
550	626	C29H35N3O	441.28	442
551	627	C23H23ClN4O4	454.14	455
552	628	C25H26FN3O2	419.20	420
553	629	C26H29N3O	399.23	400
554	630	C27H29N3O2	427.23	428
555	631	C28H38N4O3	478.29	479
556	632	C25H26FN3O	403.21	404
557	633	C23H24FN3OS	409.16	410
558	634	C26H26F3N3O2	469.20	470
559	635	C29H34N4O2	470.27	471
560	636	C25H26N4O4	446.20	447
561	637	C24H33N3O2	395.26	396
562	638	C24H33N3O2	395.26	396
563	639	C25H26FN3O	403.21	404
564	640	C26H29N3O2	415.23	416
565	641	C25H26ClN30	419.18	420
566	642	C26H29N3O2	415.23	416
567	643	C26H29N3O2	415.23	416
568	644	C25H26FN3O	403.21	404
569	645	C26H27N3O3	429.20	430
570	646	C26H29N3O	399.23	400
571	647	C26H29N3O	399.23	400
572	648	C26H26F3N3O	453.20	454
573	649	C26H26F3N3O	453.20	454
574	650	C26H35N3O2	421.27	422
575	651	C27H31N3O2	429.24	430
576	652	C25H26ClN3O	419.18	420
577	653	C25H25Cl2N3O	453.14	454
578	654	C24H28N4O2	404.22	405
579	655	C27H31N3O3S	477.21	478
580	656	C25H31N5O3	449.24	450
581	657	C24H31N3O2	393.24	394
582	658	C23H31N3O2	381.24	382
583	659	C25H25F3N4O2	470.19	471
584	660	C24H39N3O	385.31	386
585	661	C25H25Cl2N3O	453.14	454
586	662	C25H26BrN3O	463.13	464
587	663	C25H32ClN3O	425.22	426
588	664	C25H32N4O2	420.25	421
589	665	C24H26N4O4	434.20	435
590	666	C24H30FN3O2	411.23	412
591	667	C26H28FN3O	417.22	418
592	668	C25H25N5O2	427.20	428
593	669	C26H26N4O	410.21	411
594	670	C26H32FN3O2	437.25	438
595	671	C25H26ClN3O	419.18	420
596	672	C24H26N4O	386.21	387
597	673	C26H26F3N3O	453.20	454
598	674	C27H31N3O3	445.24	446
599	675	C28H29N3O3	455.22	456
600	676	C24H33N3O2	395.26	396
601	677	C25H27N3O	385.21	386
602	678	C28H30N4O2	454.24	455
603	679	C26H36N4O4	468.27	469
604	680	C28H38N4O3	478.29	479
605	681	C22H28FN3O2S	417.55	418
606	682	C23H29N3O3	395.22	396
607	683	C27H33N3O3	447.25	448
608	684	C27H37N3O4	467.28	468
609	685	C29H39N3O3	477.30	478
610	686	C27H29FN4O3	476.22	477
611	687	C25H34N4O4	454.26	455
612	688	C27H35N3O2	433.27	434
613	689	C25H31N3O3	421.24	422
614	690	C28H32N4O4	488.24	489
615	691	C27H35ClN4O3	498.24	499
616	692	C26H29N5O4	475.22	476
617	693	C28H36F3N3O4	535.27	536
618	694	C27H38N4O4	482.29	483
619	695	C27H38N4O4	482.29	483
620	696	C28H39N3O5	497.29	498
621	697	C23H23N5O3	417.18	418
622	698	C25H26N4O2	414.21	415
623	699	C28H35ClN4O4	526.23	527
624	700	C28H39N3O4	481.29	482
625	701	C27H36ClN3O4	501.24	502
626	702	C27H35F2N3O4	503.26	504
627	703	C27H36FN3O4	485.27	486
628	704	C27H36FN3O4	485.27	486
629	705	C28H39N3O4	481.29	482
630	706	C28H36F3N3O4	535.27	536
631	707	C27H35ClFN3O4	519.23	520
632	708	C28H36N4O4	492.27	493
633	709	C28H38ClN3O4	515.26	516
634	710	C31H39N3O4	517.29	518
635	711	C27H36BrN3O4	545.19	546
636	712	C28H36N4O4	492.27	493
637	713	C26H35ClN4O4	502.23	503
638	714	C27H35F2N3O4	503.26	504
639	715	C27H36BrN3O4	545.19	546
640	716	C27H35F2N3O4	503.26	504
641	717	C23H31N3O3	397.24	398
642	718	C24H33N3O3	411.25	412
643	719	C27H37N3O5	483.27	484
644	720	C25H34N4O4	454.26	455
645	721	C27H36FN3O4	485.27	486
646	722	C27H24FN3O3	457.18	458
647	723	C27H33N3O2	431.26	432
648	724	C23H31N3O3	397.24	398
649	725	C25H24FN3O2	417.18	418
650	726	C27H36N4O3	464.28	465
651	727	C25H26N4O2	414.21	415
652	728	C31H33FN4O3	528.25	529
653	729	C32H38N4O2	510.30	511
654	730	C28H38N4O2	462.30	463
655	731	C29H34N4O2	470.27	471
656	732	C26H26ClN3O2	447.17	448
657	733	C29H38N4O2	474.30	475
658	734	C27H29N3O3	443.22	444
659	735	C24H29N5O4	451.22	452
660	736	C25H33N3O2	407.26	408
661	737	C25H30N4O3S2	498.18	499
662	738	C28H29FN4O3	488.22	489
663	739	C31H44N4O2	504.35	505
664	740	C32H40N4O2	512.32	513
665	741	C25H30N6O3	462.24	463
666	742	C25H30N6O3	462.24	463
667	743	C30H33N5O4	527.25	528
668	744	C27H27N3O4	457.20	458
669	745	C26H31N5O3	461.24	462
670	746	C21H27N3O4	385.20	386
671	747	C25H30N6O3	462.24	463
672	748	C31H35FN4O3	530.27	531
673	749	C26H32N6O3	476.25	477
674	750	C27H42FN3O4	491.32	492
675	751	C25H32N4O	404.26	405
676	752	C27H30N4O2	442.24	443
677	753	C29H34N4O2	470.27	471
678	754	C26H28FN3O	417.22	418
679	755	C25H32FN3O2	425.55	426
680	756	C23H30N4O2	394.24	395
681	757	C25H32N4O2	420.25	421
682	758	C24H30N4O2	406.24	407
683	759	C26H28N4O2	428.22	429
684	760	C23H28N4O2	392.22	393
685	761	C26H34N4O2	434.27	435
686	762	C24H27N5O3	433.21	434
687	763	C24H32N4O2	408.25	409
688	764	C22H30N4O2	382.24	383
689	765	C24H33N5O	407.27	408
690	766	C25H28N4O2	416.22	417
691	767	C24H26N4O	386.21	387
692	768	C22H24N4OS	392.17	393
693	769	C21H24N4OS	380.17	381
694	770	C19H21N3OS2	371.11	372
695	771	C23H24ClN3O2	409.16	410
696	772	C22H24ClN3OS	413.13	414
697	773	C21H21ClFN3OS	417.11	418
698	774	C21H21Cl2N3OS	433.08	434
699	775	C21H21ClN4O3S	444.10	445
700	776	C22H23Cl2N3O2S	463.09	464
701	777	C22H24ClN3O2S	429.13	430
702	778	C23H26ClN3OS	427.15	428
703	779	C24H26ClN3O2S	455.14	456
704	780	C22H24F3N5OS	463.17	464
705	781	C24H23ClF3N3O2	477.14	478
706	782	C24H24F3N3O2	443.18	444
707	783	C23H28BrN5O2	485.14	486
708	784	C24H25F3N4O2S	490.17	491
709	785	C22H22N4OS	390.15	391
710	786	C23H25N3O2	375.20	376
711	787	C24H27N3O2S	421.18	422
712	788	C24H26ClN3O3	439.17	440
713	789	C21H22ClN3OS	399.12	400
714	790	C25H23F6N3O2	511.17	512
715	791	C23H30FN3O2	399.51	400
716	792	C26H34FN3O4	471.25	472
717	793	C26H29N3O2	415.23	416
718	794	C27H31N3O2	429.24	430
719	795	C26H33N3O2	419.26	420
720	796	C25H28N4O4	448.21	449
721	797	C24H33N3O2	395.26	396
722	798	C26H28FN3O2	433.22	434
723	799	C26H27N3O2	413.21	414
724	800	C25H33N3O2	407.26	408
725	801	C26H28BrN3O	477.14	478
726	802	C24H26FN3OS	423.18	424
727	803	C26H28FN3O	417.22	418
728	804	C27H31N3O2	429.24	430
729	805	C26H28ClN3O	433.19	434
730	806	C26H28ClN3O	433.19	434
731	807	C26H28ClN3O	433.19	434
732	808	C24H25ClN4O4	468.16	469
733	809	C26H28FN3O	417.22	418
734	810	C27H29N3O3	443.22	444
735	811	C27H31N3O	413.25	414
736	812	C27H31N3O	413.25	414
737	813	C26H26FN3O2	431.20	432
738	814	C27H29N3O2	427.23	428
739	815	C25H35N3O2	409.27	410
740	816	C26H34ClN3O	439.24	440
741	817	C32H36N6O3	552.28	553
742	818	C26H36FN3O2	411.59	412
743	819	C25H32N4O2	420.25	421
744	820	C24H30N4O2	406.24	407
745	821	C26H28N4O2	428.22	429
746	822	C27H30N4O2	442.24	443
747	823	C24H32N4O2	408.25	409
748	824	C24H30N4O2	406.24	407
749	825	C24H32N4O2	408.25	409
750	826	C25H32N4O2	420.25	421
751	827	C24H30N4O2	406.24	407
752	828	C25H34N4O2	422.27	423
753	829	C22H30N4O2	382.24	383
754	830	C27H35FN4O6	530.25	531
755	831	C24H32N4O2	408.25	409
756	832	C26H27FN4O2	446.21	447
757	833	C25H34N4O2	422.27	423
758	834	C24H32N4O2	408.25	409
759	835	C24H26N4O3	418.20	419
760	836	C24H30N4O2	406.24	407
761	837	C26H32N4O2	432.25	433
762	838	C26H34N4O2	434.27	435
763	839	C26H34N4O3	450.26	451
764	840	C25H31ClN4O2	454.21	455
765	841	C24H30N4O2	406.24	407
766	842	C25H34N4O2	422.27	423
767	843	C24H26N4O2S	434.18	435
768	844	C26H34N4O2	434.27	435
769	845	C23H30ClN3O2	415.20	416
770	846	C24H32FN3O2	413.25	414
771	847	C23H28FN3O2	397.22	398
772	848	C24H30FN3O2	411.23	412
773	849	C24H30FN3O2	411.23	412
774	850	C25H33FN4O2	440.26	441
775	851	C26H33FN4O3	468.25	469
776	852	C23H26N4O	374.21	375
777	853	C28H30N4O	438.24	439
778	854	C21H25N5O2	379.20	380
779	855	C26H27N3O2	413.21	414
780	856	C26H26N4O	410.21	411
781	857	C25H31N5O	417.25	418
782	858	C21H24N6OS	408.17	409
783	859	C22H25N5O	375.21	376
784	860	C24H28F3N5O	459.23	460
785	861	C25H30N6O	430.25	431
786	862	C26H32N6O	444.26	445
787	863	C25H27N3OS	417.19	418
788	864	C30H34N4O	466.27	467
789	865	C24H30N4OS	422.21	423
790	866	C24H26ClN3O3S2	503.11	504
791	867	C23H23Cl2N3O3	459.11	460
792	868	C24H26ClN3O2	423.17	424
793	869	C23H26N4OS	406.18	407
794	870	C25H27N3O3S	449.18	450
795	871	C23H25ClN4OS	440.14	441
796	872	C23H25N3O3	391.19	392
797	873	C23H23F3N4O2	444.18	445
798	874	C23H28N4O3	408.22	409
799	875	C25H30N4O	402.24	403
800	876	C26H29N3O2	415.23	416
801	877	C27H29N5O	439.24	440
802	878	C22H24F3N3O2	419.18	420
803	879	C22H25N3O3	379.19	380
804	880	C22H24N4O	360.20	361
805	881	C22H23F4N3O	421.18	422
806	882	C23H29N3O2	379.23	380
807	883	C26H29N3O2	415.23	416
808	884	C27H30FN3O	431.24	432
809	885	C22H23F3N4O2	432.18	433
810	886	C25H25N3O2	399.20	400
811	887	C25H28N40	400.23	401
812	888	C21H24F3N3O3	423.18	424
813	889	C22H30N4O	366.24	367
814	890	C24H31FN4O2	426.24	427
815	891	C25H31FN4O3	454.24	455
816	892	C25H30FN3O2	423.23	424
817	893	C23H30N4O	378.24	379
818	894	C24H27N3O4	421.20	422
819	895	C30H34FN3O4	519.25	520
820	896	C30H34FN3O4	519.25	520
821	897	C29H34FN3O4S	539.22	540
822	898	C29H38FN3O3	495.29	496
823	899	C30H40FN3O3	509.30	510
824	900	C31H35F2N3O3	535.27	536
825	901	C28H38FN3O4	499.29	500
826	902	C30H39ClFN3O3	543.27	544
827	903	C29H33ClFN3O5	557.21	558
828	904	C29H38FN3O4	511.29	512
829	905	C29H33FN4O6	552.24	553
830	906	C28H38FN3O4	499.29	500
831	907	C30H34FN3O3	503.26	504
832	908	C31H36FN3O4	533.27	534
833	909	C33H37FN4O4	572.28	573
834	910	C31H36FN3O3	517.27	518
835	911	C29H40FN3O4	513.30	514
836	912	C30H33F2N3O3	521.25	522
837	913	C25H32N4O2	420.25	421
838	914	C23H30N4O2S	426.21	427
839	915	C23H30N4O3	410.23	411
840	916	C25H36N4O2	424.28	425
841	917	C24H36N4O2	412.28	413
842	918	C23H34N4O2	398.27	399
843	919	C23H34N4O2	398.27	399
844	920	C25H31FN4O2	438.24	439
845	921	C26H34N4O2	434.27	435
846	922	C25H31ClN4O2	454.21	455
847	923	C23H36N4O2	400.28	401
848	924	C23H36N4O2	400.28	401
849	925	C26H25N3O4S	475.16	476
850	926	C21H23N3O	333.18	334
851	927	C22H25N5O	375.21	376
852	928	C21H23N5OS	393.16	394
853	929	C20H22N6OS	394.16	395
854	930	C20H25N5OS	383.18	384
855	931	C23H29N5O4	439.22	440
856	932	C25H32N4O3S	468.22	469
857	933	C22H30N4OS2	430.19	431
858	934	C24H31BrN4OS	502.14	503
859	935	C24H24FN3O3	421.18	422
860	936	C28H27ClN4O	470.19	471
861	937	C23H31N5OS	425.23	426
862	938	C22H30N4O5S	462.19	463
863	939	C23H32N4O4S	460.21	461
864	940	C27H29N5O	439.24	440
865	941	C22H25N5O2	391.20	392
866	942	C26H29N3O4S	479.19	480
867	943	C23H23F3N4OS	460.15	461
868	944	C22H29N7O2	423.24	424
869	945	C25H26N6O	426.22	427
870	946	C26H32N4O2	432.25	433
871	947	C24H27N3O2	389.21	390
872	948	C27H29N5O	439.24	440
873	949	C23H28N4O3S	440.19	441
874	950	C28H34N4OS	474.24	475
875	951	C24H28N4O3S	452.19	453
876	952	C23H23ClN4O3	438.15	439
877	953	C23H26FN5O	407.21	408
878	954	C25H27ClN4O2	450.18	451
879	955	C24H27N5O	401.22	402
880	956	C24H30F3N5O	461.24	462
881	957	C22H23ClN4O2	410.15	411
882	958	C23H26N4OS	406.18	407
883	959	C24H26N4O	386.21	387
884	960	C24H26N4O	386.21	387
885	961	C24H26N4O	386.21	387
886	962	C21H23F3N6OS	464.16	465
887	963	C23H30N4O3S	442.20	443
888	964	C24H26N4O2	402.21	403
889	965	C24H25F3N4OS	474.17	475
890	966	C27H29N3O	411.23	412
891	967	C26H29N3O	399.23	400
892	968	C28H31N3O2	441.24	442
893	969	C23H28N4O2	392.22	393
894	970	C27H29N3O2	427.23	428
895	971	C21H25N7O	391.21	392
896	972	C21H28N4OS	384.20	385
897	973	C23H26ClN5O	423.18	424
898	974	C21H23N5OS	393.16	394
899	975	C26H26ClN5O	459.18	460
900	976	C23H27N5O	389.22	390
901	977	C25H34N4O	406.27	407
902	978	C24H30N4O2	406.24	407
903	979	C23H30ClN3O2	415.20	416
904	980	C25H25F2N3O2	437.19	438
905	981	C29H39FN4O2	494.31	495
906	982	C29H32F2N4O2	506.25	507
907	983	C30H35FN4O2	502.27	503
908	984	C27H37FN4O3	484.29	485
909	985	C27H37FN4O3	484.29	485
910	986	C25H34FN3O3	443.26	444
911	987	C24H30Cl2FN3O2	481.17	482
912	988	C24H31FN4O4	458.23	459
913	989	C24H31ClFN3O2	447.21	448
914	990	C26H36FN3O2	441.28	442
915	991	C25H32Cl2FN3O3	511.18	512
916	992	C24H28F5N3O2	485.21	486
917	993	C24H31F2N3O2	431.24	432
918	994	C26H34FN3O3	455.26	456
919	995	C28H40FN3O3	485.30	486
920	996	C25H34FN5O	439.27	440
921	997	C23H31FN4O2	414.24	415
922	998	C24H26FN3O3	423.20	424
923	999	C26H28FN3O2	433.22	434
924	1000	C26H33FN4O2	452.26	453
925	1001	C26H32ClFN4O2	486.22	487
926	1002	C25H31FN4O2	438.24	439
927	1003	C26H31F3N4O3	504.23	505
928	1004	C26H33ClN4O3	484.22	485
929	1005	C25H31ClN4O2	454.21	455
930	1006	C24H31ClFN3O2	447.21	448
931	1007	C25H34FN3O2	427.26	428
932	1008	C27H33FN4O2	464.26	465
933	1009	C26H28FN3O2	433.22	434
934	1010	C25H28FN3O2S	453.19	454
935	1011	C25H32FN3O	409.25	410
936	1012	C26H34FN3O	423.27	424
937	1013	C27H29F2N3O	449.23	450
938	1014	C24H32FN3O2	413.25	414
939	1015	C26H33ClFN3O	457.23	458
940	1016	C24H32FN3O2	413.25	414
941	1017	C26H28FN3O	417.22	418
942	1018	C27H30FN3O2	447.23	448
943	1019	C29H31FN4O2	486.24	487
944	1020	C27H30FN3O	431.24	432
945	1021	C25H34FN3O2	427.26	428
946	1022	C26H27F2N3O	435.21	436
947	1023	C25H27FN4O2	434.52	435
948	1024	C25H27FN4O4	466.20	467
949	1025	C24H29FN4O3	440.22	441
950	1026	C27H30FN3O2	447.23	448
951	1027	C23H31FN4O	398.25	399
952	1028	C24H26ClFN4OS	472.15	473
953	1029	C25H25F2N3O3	453.19	454
954	1030	C24H27F2N5O	439.22	440
955	1031	C26H31F2N3O2	455.24	456
956	1032	C23H31N3O2	381.24	382
957	1033	C24H33N3O2	395.26	396
958	1034	C24H33N3O2	395.26	396
959	1035	C26H29N3O2	415.23	416
960	1036	C25H29N5O2	431.23	432
961	1037	C24H24ClFN4O3	470.15	471
962	1038	C27H36FN3O2	453.61	454
963	1039	C24H30N4O2	406.24	407
964	1040	C24H28N4O2	404.22	405
965	1041	C27H29N5O	439.24	440
966	1042	C25H28N4O4S	480.18	481
967	1043	C24H26N4O2	402.21	403
968	1044	C27H27BrN4O2	518.13	519
969	1045	C22H24ClN5O	409.17	410
970	1046	C22H23F2N3O3	415.17	416
971	1047	C21H23N5OS	393.16	394
972	1048	C23H24ClN3OS	425.13	426
973	1049	C22H24N4O3	392.18	393
974	1050	C25H27ClN4O2	450.18	451
975	1051	C25H30N4O	402.24	403
976	1052	C22H25N5O	375.21	376
977	1053	C22H27N3O3S	413.18	414
978	1054	C20H23F3N4OS	424.15	425
979	1055	C21H24F3N3OS	423.16	424
980	1056	C26H24BrF3N6O	572.11	573
981	1057	C23H25ClN4OS	440.14	441
982	1058	C24H32N4O3S	456.22	457
983	1059	C24H31ClN4O3S	490.18	491
984	1060	C23H25N3O4S	439.16	440
985	1061	C26H32N4O3	448.25	449
986	1062	C26H32N4O	416.26	417
987	1063	C22H27N3OS	381.19	382
988	1064	C24H31N3O2	393.24	394
989	1065	C22H24F3N3OS	435.16	436
990	1066	C24H33N3O	379.26	380
991	1067	C22H29N3O2	367.23	368
992	1068	C25H35N3O	393.28	394
993	1069	C25H30N4O	402.24	403
994	1070	C22H26N4OS2	426.15	427
995	1071	C29H32N4O2	468.25	469
996	1072	C23H26FN5O	407.21	408
997	1073	C28H28ClN5O	485.20	486
998	1074	C20H23N5O2S	397.16	398
999	1075	C25H26N6O	426.22	427
1000	1076	C22H24N4O2	376.19	377
1001	1077	C26H35FN4O2	454.27	455
1002	1078	C25H34FN3O2	427.57	428
1003	1079	C24H25FN4O	404.20	405
1004	1080	C25H30N4O2	418.24	419
1005	1081	C26H31FN4O2	450.24	451
1006	1082	C25H34N4O2	422.27	423
1007	1083	C24H30N4O2	406.24	407
1008	1084	C27H30N4O2	442.24	443
1009	1085	C27H29FN4O2	460.23	461
1010	1086	C26H34N4O2	434.27	435
1011	1087	C26H26ClFN4O2	480.17	481
1012	1088	C26H27FN4O2	446.21	447
1013	1089	C25H27N5O2	429.22	430
1014	1090	C27H36N4O2	448.28	449
1015	1091	C25H29N5O3	447.23	448
1016	1092	C29H32N4O2	468.25	469
1017	1093	C26H27FN4O2	446.21	447
1018	1094	C23H30N4O3	410.23	411
1019	1095	C23H30N4O3	410.23	411
1020	1096	C24H30N4O2	406.24	407
1021	1097	C24H28N6O2	432.23	433
1022	1098	C25H27N5O2	429.22	430
1023	1099	C25H34N4O2	422.27	423
1024	1100	C25H28N4O2S	448.19	449
1025	1101	C25H29N5O2	431.23	432
1026	1102	C26H26F2N4O2	464.20	465
1027	1103	C24H27N5O2	417.22	418
1028	1104	C29H38N4O2	474.30	475
1029	1105	C27H36N4O3	464.28	465
1030	1106	C24H27N5O2	417.22	418
1031	1107	C27H36N4O2	448.28	449
1032	1108	C27H36N4O2	448.28	449
1033	1109	C27H38N4O2	450.30	451
1034	1110	C29H32N4O2	468.25	469
1035	1111	C27H34N4O2	446.27	447
1036	1112	C26H27ClN4O2	462.18	463
1037	1113	C22H24N6O2S	436.17	437
1038	1114	C23H25N5O3	419.20	420
1039	1115	C25H32N4O2	420.25	421
1040	1116	C26H27ClN4O2	462.18	463
1041	1117	C27H30N4O2	442.24	443
1042	1118	C24H30N4O3	422.23	423
1043	1119	C27H30N4O2	442.24	443
1044	1120	C30H38N4O2	486.30	487
1045	1121	C29H34N4O3	486.26	487
1046	1122	C27H28F2N4O3	494.21	495
1047	1123	C25H32N4O3	436.25	437
1048	1124	C27H36N4O2	448.28	449
1049	1125	C23H27F3N4O2	448.21	449
1050	1126	C26H32N4O2	432.25	433
1051	1127	C26H36N4O2	436.28	437
1052	1128	C22H28FN3O2	385.22	386
1053	1129	C27H30N4O2	442.24	443
1054	1130	C21H24N6O	376.20	377
1055	1131	C25H27N5OS	445.19	446
1056	1132	C24H26N4O	386.21	387
1057	1133	C22H24N4O2	376.19	377
1058	1134	C27H30N4O	426.24	427
1059	1135	C24H32N4O	392.26	393
1060	1136	C22H26N6O	390.22	391
1061	1137	C24H27N5O2	417.22	418
1062	1138	C23H26ClN5O	423.18	424
1063	1139	C24H26ClN3O2	423.17	424
1064	1140	C24H25ClN6O2	464.17	465
1065	1141	C24H27N3OS	405.19	406
1066	1142	C20H21ClN4O2S	416.11	417
1067	1143	C25H26N4O3S	462.17	463
1068	1144	C26H28N4O4	460.21	461
1069	1145	C30H42FN3O4	527.32	528
1070	1146	C31H42FN3O4	539.32	540
1071	1147	C27H30N4O2	442.24	443
1072	1148	C28H32N4O3	472.25	473
1073	1149	C25H32FN3O2	425.25	426
1074	1150	C27H30FN3O2	447.23	448
1075	1151	C27H30FN3O	431.24	432
1076	1152	C28H27FN4O3	486.21	487
1077	1153	C28H28BrFN4O2	550.14	551
1078	1154	C28H31FN4O2	474.24	475
1079	1155	C26H31FN4O	434.25	435
1080	1156	C26H29FN4O2	448.23	449
1081	1157	C28H30FN5O	471.24	472
1082	1158	C29H31FN4O	470.25	471
1083	1159	C27H30FN3OS	463.21	464
1084	1160	C25H28FN5OS	465.20	466
1085	1161	C26H29FN4OS	464.20	465
1086	1162	C28H29FN4O2	472.23	473
1087	1163	C27H30FN3O2	447.23	448
1088	1164	C27H29ClFN3O2	481.19	482
1089	1165	C25H34FN3O	411.27	412
1090	1166	C25H34FN3O2	427.26	428
1091	1167	C23H30FN3O2	399.23	400
1092	1168	C24H32FN3O2	413.25	414
1093		C26H32FN3O2	437.25	438
1094		C30H36N4O4	516.27	517
1095	1169	C25H31F2N3O2	443.24	444
1096	1170	C25H31F2N3O2	443.24	444
1097	1171	C26H27F2N3O2	451.21	452
1098	1172	C26H34F2N4O	456.27	457
1099	1173	C27H27FN4O2	458.21	459
1100	1174	C27H27FN4O2	458.21	459
1101	1175	C24H30FN3O2	411.23	412
1102	1176	C23H25FN4OS	424.17	425
1103	1177	C28H29FN4O2	472.23	473
1104	1178	C25H32FN3O2	425.25	426
1105	1179	C24H27FN4OS	438.19	439
1106	1180	C25H34FN3O3	443.26	444
1107	1181	C26H27F2N3O2	451.21	452
1108	1182	C27H36FN3O2	453.28	454
1109	1183	C26H26F3N3O2	469.20	470
1110	1184	C25H27FN4O2	434.21	435
1111	1185	C25H34FN3O2	427.26	428
1112	1186	C26H34FN3O2	439.26	440
1113	1187	C27H36FN3O2	453.28	454
1114	1188	C25H34FN3O2	427.26	428
1115	1189	C25H33ClFN3O3	477.22	478
1116	1190	C24H31F2N3O2	431.24	432
1117	1191	C25H32FN3O2	425.25	426
1118	1192	C27H30FN3O3S	495.62	496
1119	1193	C23H27F4N3O	437.21	438
1120	1194	C26H36FN3O2	441.28	442
1121	1195	C25H27FN4O2	434.21	435
1122	1196	C25H33N3O2	407.26	408
1123	1197	C24H31N3O2	393.24	394
1124	1198	C25H34FN3O2	427.26	428
1125	1199	C23H30FN3O2	399.23	400
1126	1200	C27H29ClFN3O2	481.19	482
1127	1201	C22H25F4N3OS	455.17	456
1128	1202	C25H32FN3O2	425.25	426
1129	1203	C25H32F2N4O	442.25	443
1130	1204	C26H29FN4O2	448.23	449

[1026]

TABLE 8
Ex.		Molecular	Monoisotopic	M +
No.	Structure	formula	molecular wt.	H+
1131	1205	C23H23Cl2N3O2	443.12	444
1132	1206	C23H23ClFN3O2	427.15	428
1133	1207	C24H26FN3O2	407.20	408
1134	1208	C28H33N3O4	475.25	476
1135	1209	C29H34N4O5	518.25	519
1136	1210	C33H41N3O4	543.31	544
1137	1211	C29H36N4O4	504.27	505
1138	1212	C29H32N4O4	500.24	501
1139	1213	C28H30F3N3O4	529.22	530
1140	1214	C22H22Cl2N4OS	460.09	461
1141	1215	C22H23ClN4OS	426.13	427
1142	1216	C22H23FN4OS	410.16	411
1143	1217	C23H25FN4OS	424.17	425
1144	1218	C23H22ClF3N4OS	494.12	495
1145	1219	C26H26N4OS	442.18	443
1146	1220	C25H25Cl2N3O	453.14	454
1147	1221	C23H25N3OS	391.17	392
1148	1222	C23H23F3N4OS	460.15	461
1149	1223	C22H23N5O3S	437.15	438
1150	1224	C22H24N4OS	392.17	393
1151	1225	C22H22Cl2N4OS	460.09	461
1152	1226	C22H22ClFN4OS	444.12	445
1153	1227	C20H22N4OS2	398.12	399
1154	1228	C23H26N4O2S	422.18	423
1155	1229	C23H23F3N4OS	460.15	461
1156	1230	C23H26N4OS	406.18	407
1157	1231	C23H26N4O2S	422.18	423
1158	1232	C24H27N5O2S	449.19	450
1159	1233	C22H23ClN4OS	426.13	427
1160	1234	C22H23FN4OS	410.16	411
1161	1235	C26H26N4OS	442.18	443
1162	1236	C23H26N4OS2	438.15	439
1163	1237	C22H22Cl2N4OS	460.09	461
1164	1238	C24H28N4O2S	436.19	437
1165	1239	C24H28N4O2S	436.19	437
1166	1240	C26H32N4OS	448.23	449
1167	1241	C23H23N5OS	417.16	418
1168	1242	C28H28N4OS	468.20	469
1169	1243	C24H28N4O2S	436.19	437
1170	1244	C23H24N4O3S	436.16	437
1171	1245	C26H32N4O2S	464.23	465
1172	1246	C23H26N4OS2	438.15	439
1173	1247	C24H28N4OS2	452.17	453
1174	1248	C24H28N4OS	420.20	421
1175	1249	C23H23F3N4O2S	476.15	477
1176	1250	C24H28N4O3S	452.19	453
1177	1251	C25H30N4OS	434.21	435
1178	1252	C25H30N4OS	434.21	435
1179	1253	C23H26N4O2S	422.18	423
1180	1254	C22H25N5O2S	423.17	424
1181	1255	C24H24N4OS2	448.14	449
1182	1256	C23H23F3N4O2S	476.15	477
1183	1257	C24H22F6N4OS	528.14	529
1184	1258	C23H25FN4OS	424.17	425
1185	1259	C24H28N4OS	420.20	421
1186	1260	C24H28N4OS	420.20	421
1187	1261	C25H26N4O3	430.20	431
1188	1262	C27H31N3O2	429.24	430
1189	1263	C25H25ClFN3O	437.17	438
1190	1264	C25H25Cl2N3O	453.14	454
1191	1265	C26H26N4O	410.21	411
1192	1266	C27H29N3O2	427.23	428
1193	1267	C27H29N3O2	427.23	428
1194	1268	C25H25F2N3O	421.20	422
1195	1269	C25H25F2N3O	421.20	422
1196	1270	C26H28N4O3	444.22	445
1197	1271	C27H32N4O	428.26	429
1198	1272	C25H28N4O2	416.22	417
1199	1273	C27H29N3O3	443.22	444
1200	1274	C24H28N4O2	404.22	405
1201	1275	C23H25N3O2	375.20	376
1202	1276	C24H25FN4O	404.20	405
1203	1277	C22H25N5O	375.21	376
1204	1278	C26H28FN3O	417.22	418
1205	1279	C26H28FN3O	417.22	418
1206	1280	C24H25ClN4O	420.17	421
1207	1281	C24H25FN4O	404.20	405
1208	1282	C24H25FN4O	404.20	405
1209	1283	C26H28FN3O2	433.22	434
1210	1284	C27H30N4O2	442.24	443
1211	1285	C25H26N4O3	430.20	431
1212	1286	C26H25FN4O	428.20	429
1213	1287	C24H25FN4O	404.20	405
1214	1288	C24H25FN4O	404.20	405
1215	1289	C26H28FN3O3S	481.18	482
1216	1290	C27H29FN4O2	460.23	461
1217	1291	C28H31FN4O2	474.24	475
1218	1292	C26H25F4N3O2	487.19	488
1219	1293	C26H28FN3O3S	481.18	482
1220	1294	C26H25F4N3O2	487.19	488
1221	1295	C26H25FN4O	428.20	429
1222	1296	C27H29FN4O2	460.23	461
1223	1297	C26H25F4N3O2	487.19	488
1224	1298	C25H25F2N3O	421.20	422
1225	1299	C25H32N4O3S	468.22	469
1226	1300	C24H31N5O	405.25	406
1227	1301	C24H31N5O2	421.25	422
1228	1302	C23H28FN5O	409.23	410
1229	1303	C26H31N5O	429.25	430
1230	1304	C25H29N5OS	447.21	448
1231	1305	C26H34N4O	418.27	419
1232	1306	C26H32N4O2	432.25	433

[1027]

TABLE 9
Ex.		Molecular	Monoisotopic	M +
No.	Structure	formula	molecular wt.	H+
1233	1307	C31H29N3O2	475.23	476
1234	1308	C30H35N3O2	469.27	470
1235	1309	C28H30N4O3S	502.20	503
1236	1310	C29H30FN3O3S	519.20	520
1237	1311	C28H30N4O3S	502.20	503

[1028]

TABLE 10
Ex.		Molecular	Monoisotopic	M +
No.	Structure	formula	molecular wt.	H+
1238	1312	C26H35N3O2	421.27	422
1239	1313	C26H35N3O2	421.27	422
1240	1314	C25H31F2N3O2	443.24	444
1241	1315	C27H35N3O2	433.27	434
1242	1316	C26H35N3O2	421.27	422
1243	1317	C25H36N4O2	424.28	425
1244	1318	C24H33N3O3	411.25	412
1245	1319	C26H37N3O3	439.28	440
1246	1320	C27H37N3O2	435.29	436
1247	1321	C27H37N3O2	435.29	436
1248	1322	C27H33N5O2	459.26	460
1249	1323	C26H35N3O3	437.27	438
1250	1324	C29H34FN3O2	475.26	476
1251	1325	C27H32N4O2	444.25	445
1252	1326	C24H33N3O2	395.26	396
1253	1327	C23H31N3O2	381.24	382
1254	1328	C25H33N3O3	423.25	424
1255	1329	C23H28F3N3O2	435.21	436
1256	1330	C23H30FN3O2	399.23	400
1257	1331	C27H37N3O3	451.28	452
1258	1332	C24H33N3O3	411.25	412
1259	1333	C25H33N3O2	407.26	408
1260	1334	C25H33N3O2	407.26	408
1261	1335	C25H35N3O2	409.27	410
1262	1336	C25H35N3O2	409.27	410
1263	1337	C25H35N3O2	409.27	410
1264	1338	C25H35N3O2	409.27	410
1265	1339	C27H35N5O2	461.28	462
1266	1340	C28H38N4O3	478.29	479
1267	1341	C26H36N4O2	436.28	437
1268	1342	C26H38N4O2	438.30	439
1269	1343	C30H35N3O2	469.27	470
1270	1344	C27H32N4O2	444.25	445
1271	1345	C27H36N4O3	464.28	465
1272	1346	C27H37N3O2	435.29	436
1273	1347	C30H35N3O2	469.27	470
1274	1348	C26H35N3O2	421.27	422
1275	1349	C29H39N3O2	461.30	462
1276	1350	C29H43N3O2	465.34	466
1277	1351	C28H39N3O2	449.30	450
1278	1352	C28H37N3O2	447.29	448
1279	1353	C28H40N4O2	464.32	465
1280	1354	C30H35N3O2	469.27	470
1281	1355	C30H34N4O2	482.27	483
1282	1356	C30H35N3O3	485.27	486
1283	1357	C25H33N3O4S	471.22	472
1284	1358	C29H39N3O2	461.30	462
1285	1359	C26H33N3O3	435.25	436
1286	1360	C27H35N5O2	461.28	462
1287	1361	C25H35N3O2	409.27	410
1288	1362	C26H35N3O4S	485.23	486
1289	1363	C27H38N4O2	450.30	451
1290	1364	C26H31N3O2S	449.21	450
1291	1365	C29H41N3O2	463.32	464
1292	1366	C25H32N4O3	436.25	437
1293	1367	C26H35N3O3	437.27	438
1294	1368	C25H30N4O2S	450.21	451
1295	1369	C24H31N3O2	393.24	394
1296	1370	C25H35N5O2	437.28	438
1297	1371	C27H37N5O2	463.30	464
1298	1372	C26H32N6O2S	492.23	493
1299	1373	C24H33N5O3	439.26	440
1300	1374	C28H40FN3O3	485.30	486
1301	1375	C27H36FN3O2	453.28	454
1302	1376	C31H37N5O2	511.30	512
1303	1377	C28H39N5O2	477.31	478
1304	1378	C27H39N5O2	465.31	466
1305	1379	C27H39N5O2	465.31	466
1306	1380	C26H35N5O2S	481.25	482
1307	1381	C26H33N7O2	475.27	476
1308	1382	C26H35N5O2	449.28	450
1309	1383	C26H37N5O3	467.29	468
1310	1384	C26H37N5O3	467.29	468
1311	1385	C26H37N5O3	467.29	468
1312	1386	C27H37N5O3	479.29	480
1313	1387	C27H39N5O3	481.30	482
1314	1388	C28H38N6O2	490.31	491
1315	1389	C28H39N5O4	509.30	510
1316	1390	C28H39N5O2	477.31	478
1317	1391	C29H40N6O3	520.32	521
1318	1392	C30H44N6O2	520.35	521
1319	1393	C30H44N6O3	536.35	537
1320	1394	C30H34N6O2	510.27	511
1321	1395	C33H42N6O2	554.34	555
1322	1396	C27H35N7O2	489.29	490
1323	1397	C29H38F3N5O2	545.30	546
1324	1398	C29H39N7O2	517.32	518
1325	1399	C31H37N7O2	539.30	540
1326	1400	C26H33N7O2	475.27	476
1327	1401	C26H37N5O2S	483.27	484
1328	1402	C26H35N5O2	449.28	450
1329	1403	C27H35N7O2	489.29	490
1330	1404	C28H41N5O3	495.32	496
1331	1405	C25H31N7O2S	493.23	494
1332	1406	C31H39N5O3	529.30	530
1333	1407	C30H42N6O4	550.33	551
1334	1408	C28H41N5O2	479.33	480
1335	1409	C29H30F2N4O2	504.58	505
1336	1410	C25H32FN3O2	425.25	426
1337	1411	C25H34FN3O2	427.26	428
1338	1412	C24H32FN3O3	429.24	430
1339	1413	C26H34FN3O2	439.26	440
1340	1414	C26H34FN3O2	439.26	440
1341	1415	C25H34FN3O3	443.26	444
1342	1416	C25H34FN3O3	443.26	444
1343	1417	C25H34FN3O3	443.26	444
1344	1418	C27H36FN3O2	453.28	454
1345	1419	C27H38FN3O2	455.30	456
1346	1420	C27H38FN3O2	455.30	456
1347	1421	C27H38FN3O2	455.30	456
1348	1422	C26H36FN3O3	457.27	458
1349	1423	C26H36FN3O3	457.27	458
1350	1424	C25H34FN3O4	459.25	460
1351	1425	C25H34FN3O4	459.25	460
1352	1426	C28H38FN3O2	467.30	468
1353	1427	C27H38FN3O3	471.29	472
1354	1428	C27H38FN3O3	471.29	472
1355	1429	C27H34FN5O2	479.27	480
1356	1430	C29H40FN3O2	481.31	482
1357	1431	C29H40FN3O2	481.31	482
1358	1432	C28H39FN4O2	482.31	483
1359	1433	C28H38FN3O3	483.29	484
1360	1434	C28H38FN3O3	483.29	484
1361	1435	C28H36FN5O2	493.29	494
1362	1436	C27H35FN6O2	494.28	495
1363	1437	C28H37FN4O3	496.29	497
1364	1438	C29H41FN4O2	496.32	497
1365	1439	C28H39FN4O3	498.30	499
1366	1440	C26H32FN3O4	469.24	470
1367	1441	C29H40FN3O3	497.30	498
1368	1442	C25H31FN4O2	438.24	439
1369	1443	C26H34FN3O2	439.26	440
1370	1444	C26H36FN3O2	441.28	442
1371	1445	C25H34FN3O3	443.26	444
1372	1446	C27H36FN3O2	453.28	454
1373	1447	C26H34FN3O3	455.26	456
1374	1448	C28H38FN3O2	467.30	468
1375	1449	C27H37FN4O2	468.29	469
1376	1450	C26H34FN3O2S	471.24	472
1377	1451	C26H36FN3O4	473.27	474
1378	1452	C28H41FN4O2	484.32	485
1379	1453	C28H37FN4O3	496.29	497
1380	1454	C28H37FN4O3	496.29	497
1381	1455	C32H38FN3O2	515.29	516
1382	1456	C31H38FN3O3	519.29	520
1383	1457	C31H43FN4O2	522.34	523
1384	1458	C27H36FN3O3	469.27	470
1385	1459	C27H36FN3O3	469.27	470
1386	1460	C28H34F3N3O3	517.26	518
1387	1461	C27H36FN3O4S	517.24	518
1388	1462	C30H41FN4O3	524.32	525
1389	1463	C27H36FN3O3	469.27	470
1390	1464	C22H28FN3O2	385.22	386
1391	1465	C29H38FN3O4	511.29	512
1392	1466	C26H36FN3O3	457.27	458
1393	1467	C25H34FN3O3	443.26	444
1394	1468	C27H36FN3O3	469.27	470
1395	1469	C26H34FN3O3	455.26	456
1396	1470	C28H38FN3O3	483.29	484
1397	1471	C26H36FN3O3	457.27	458
1398	1472	C26H34FN3O4	471.25	472
1399	1473	C28H38FN3O4	499.29	500
1400	1474	C27H38FN3O3	471.29	472
1401	1475	C28H40FN3O3	485.30	486
1402	1476	C27H36FN3O4	485.27	486
1403	1477	C27H36FN3O3	469.27	470

[1029]

TABLE 11
			Mono-
			isotopic
Ex.		Molecular	molecular
No.	Structure	formula	wt.	M + H+
1404	1478	C22H30N4O2	382.24	383
1405	1479	C24H31ClN40	426.22	427
1406	1480	C23H32N4O2	396.25	397
1407	1481	C25H27FN4O	418.22	410
1408	1482	C23H32N4O2	396.25	397
1409	1483	C22H30N4O2	382.24	383
1410	1484	C23H25N5O2	403.20	404
1411	1485	C24H33N3O2	395.26	396
1412	1486	C23H31N3O2 (S)- Konfiguration	381.24	382
1413	1487	C23H31N3O2	381.24	382
1414	1488	C23H30FN3O2	399.23	400
1415	1489	C24H32FN3O2	413.25	414
1416	1490	C24H32N4O	392.26	393
1417	1491	C24H32FN3O2	413.25	414
1418	1492	C24H32FN3O2 (S)-configuration	413.25	414
1419	1493	C25H34FN3O2	427.26	428
1420	1494	C26H36FN3O2	441.28	442
1421	1495	C26H36FN3O2	441.28	442
1422	1496	C27H36FN3O2	453.28	454
1423	1497	C27H38FN3O3	471.29	472

[1030]

TABLE 12
			Mono-
			isotopic
Ex.		Molecular	molecular
No.	Structure	formula	wt.	M + H+
1424	1498	C27H35N3O2	433.27	434
1425	1499	C28H39N3O4	481.29	482
1426	1500	C27H38N4O4	482.29	483
1427	1501	C24H32N4O3	424.25	425
1428	1502	C24H33N3O2	395.26	396
1429	1503	C24H31N3O3	409.24	410
1430	1504	C29H33FN4O3	504.25	505
1431	1505	C27H38N4O4	482.29	483
1432	1506	C30H43N3O5	525.32	526
1433	1507	C25H33N3O3	423.25	424
1434	1508	C29H41N3O5	511.30	512
1435	1509	C26H28FN3O	417.22	418
1436	1510	C27H30FN3O	431.24	432
1437	1511	C28H38FN3O4	499.29	500
1438	1512	C28H38FN3O4	499.29	500
1439	1513	C28H38FN3O4 (S)- Konfiguration	499.29	500
1440	1514	C25H32N4O2	420.25	421
1441	1515	C24H32C1N3O2	429.22	430
1442	1516	C29H40FN3O4	513.30	514
1443	1517	C30H42FN3O4	527.32	528

[1031]

TABLE 13
			Mono-
			isotopic
Ex.		Molecular	molecular
No.	Structure	formula	wt.	M + H+
1444	1518	C23H30N4O	378.24	379
1445	1519	C23H30N4O	378.24	379
1446	1520	C21H28N4O2	368.22	369
1447	1521	C27H38N4O	434.30	435
1448	1522	C26H36N4O	420.29	421
1449	1523	C29H42N4O	462.34	463
1450	1524	C28H38N4O	446.30	447
1451	1525	C24H32N4O	392.26	393
1452	1526	C26H36N4O	420.29	421
1453	1527	C26H32N4O	416.26	417
1454	1528	C23H31N3O2	381.24	382
1455	1529	C24H31N3O	377.25	378
1456	1530	C22H29N3O2	367.23	368
1457	1531	C22H21FN4O	376.17	377
1458	1532	C20H26N4O2	354.21	355
1459	1533	C23H24N4O2	388.19	389
1460	1534	C22H27ClN4O	398.19	399
1461	1535	C22H30N4O2	382.24	383
1462	1536	C21H21N5O2	375.17	376
1463	1537	C22H27F2N3O2	403.21	404
1464	1538	C22H28FN3O2	385.22	386
1465	1539	C22H28ClN3O2	401.19	402
1466	1540	C23H31N3O2	381.24	382
1467	1541	C23H28F3N3O2	435.21	436
1468	1542	C23H28F3N3O2	435.21	436
1469	1543	C22H27F2N3O2	403.21	404
1470	1544	C22H27ClFN3O2	419.18	420
1471	1545	C23H28N4O2	392.22	393
1472	1546	C23H27C1N4O2	426.18	427
1473	1547	C22H28BrN3O2	445.14	446
1474	1548	C26H31N3O2	417.24	418
1475	1549	C22H27F2N3O2	403.21	404
1476	1550	C22H28BrN3O2	445.14	446
1477	1551	C23H30ClN3O2	415.20	416
1478	1552	C21H27ClN4O2	402.18	403
1479	1553	C22H30N4O2	382.24	383
1480	1554	C22H30N4O2	382.24	383
1481	1555	C22H30N4O2	382.24	383
1482	1556	C24H25FN4O	404.20	405
1483	1557	C22H29N3O3	383.22	384
1484	1558	C20H26N4O2	354.21	355
1485	1559	C22H28FN3O2	385.22	386
1486	1560	C22H29N3O2	367.23	368
1487	1561	C22H28N4O	364.23	365
1488	1562	C25H35N3O3	425.27	426
1489	1563	C24H33N3O3	411.25	412
1490	1564	C22H29N5O2	395.23	396
1491	1565	C23H25N5O2	403.20	404
1492	1566	C23H25N5O2	403.20	404
1493	1567	C20H22N6O	362.19	363
1494	1568	C25H25N5O2	427.20	428
1495	1569	C23H25N3O2	375.20	376
1496	1570	C19H21N5O2	351.17	352
1497	1571	C20H22N4OS2	398.12	399
1498	1572	C21H23N5O	361.19	362
1499	1573	C20H22N6O	362.19	363
1500	1574	C22H28FN3O2	385.22	386
1501	1575	C23H29FN4O2	412.23	413
1502	1576	C22H34FN3O2	391.26	392
1503	1577	C23H30FN3O2	399.23	400
1504	1578	C22H28FN5O2	413.22	414
1505	1579	C23H24FN5O2	421.19	422
1506	1580	C23H22F3N3O2	429.17	430
1507	1581	C24H28N4O2	404.22	405
1508	1582	C28H33N3O2	443.26	444
1509	1583	C24H24N4O2	400.19	401
1510	1584	C24H26N4O3	418.20	419
1511	1585	C23H30FN3O2	399.23	400
1512	1586	C22H27FN4O4	430.20	431
1513	1587	C22H29FN4O2	400.23	401
1514	1588	C24H26N4O3	418.20	419
1515	1589	C23H30FN3O2	399.23	400
1516	1590	C24H29FN4O	408.23	409
1517	1591	C25H26FN3O2	419.20	420
1518	1592	C25H26FN3O2	419.20	420
1519	1593	C24H26FN3O2S	439.17	440
1520	1594	C24H30FN3O	395.24	396
1521	1595	C25H32FN3O	409.25	410
1522	1596	C26H27F2N3O	435.21	436
1523	1597	C22H21ClFN3O2	413.13	414
1524	1598	C22H22FN3O2	379.17	380
1525	1599	C23H25N3O3	391.19	392
1526	1600	C23H25N3O3	391.19	392
1527	1601	C22H22FN3O2	379.17	380
1528	1602	C23H25N3O2S	407.17	408
1529	1603	C23H25N3O2	375.20	376
1530	1604	C24H27N3O3	405.20	406
1531	1605	C23H30FN3O2	399.23	400
1532	1606	C25H31ClFN3O	443.21	444
1533	1607	C24H25ClFN3O3	457.16	458
1534	1608	C24H30FN3O2	411.23	412
1535	1609	C24H27N3O3	405.20	406
1536	1610	C23H22N4O2	386.17	387
1537	1611	C24H25N3O3	403.19	404
1538	1612	C24H27N3O4	421.20	422
1539	1613	C24H25N3O3	403.19	404
1540	1614	C24H25FN4O4	452.19	453
1541	1615	C23H3OFN3O2	399.23	400
1542	1616	C25H26FN3O	403.21	404
1543	1617	C26H28FN3O2	433.22	434
1544	1618	C28H29FN4O2	472.23	473
1545	1619	C26H28FN3O	417.22	418
1546	1620	C24H32FN3O2	413.25	414
1547	1621	C22H18F5N3O2	451.13	452
1548	1622	C24H25N3O3	403.19	404
1549	1623	C22H21F2N3O2	397.16	398
1550	1624	C22H21F2N3O2	397.16	398
1551	1625	C22H21F2N3O2	397.16	398
1552	1626	C23H23N3O4	405.17	406
1553	1627	C28H26FN3O2	455.20	456
1554	1628	C26H31N3O3	433.24	434
1555	1629	C25H25F2N3O	421.20	422
1556	1630	NC23H25N3O2S	407.17	408
1557	1631	C24H27N3O2S	421.18	422
1558	1632	C24H27N3O2	389.21	390
1559	1633	C24H27N3O2	389.21	390
1560	1634	C23H22F3N3O3	445.16	446
1561	1635	C25H29N3O2	403.23	404
1562	1636	C25H29N3O2	403.23	404
1563	1637	C21H22N4O2	362.17	363
1564	1638	C22H21F2N3O2	397.16	398
1565	1639	C22H24N4O3	392.18	393
1566	1640	C23H25N3O4S	439.16	440
1567	1641	C22H21F2N3O2	397.16	398
1568	1642	C23H22F3N3O3	445.16	446
1569	1643	C23H24FN3O2	393.18	394
1570	1644	C20H21N5O2	363.17	364
1571	1645	C21H21FN4O2	380.17	381
1572	1646	C23H30FN3O2	399.23	400
1573	1647	C22H22N4O3S	422.14	423
1574	1648	C23H25N3O2S	407.17	408
1575	1649	C23H25N3O2S	407.17	408
1576	1650	C23H25N3OS2	423.14	424
1577	1651	C24H27N3O2S	421.18	422
1578	1652	C24H27N3O2S	421.18	422
1579	1653	C23H22N4OS	402.15	403
1580	1654	C24H27N3O3S	437.18	438
1581	1655	C24H25N3O2S	419.17	420
1582	1656	C24H25N3O2S	419.17	420
1583	1657	C23H23N3O3S	421.15	422
1584	1658	C23H25N3OS2	423.14	424
1585	1659	C24H27N3OS2	437.16	438
1586	1660	C24H27N3OS	405.19	406
1587	1661	C24H27N3OS	405.19	406
1588	1662	C23H22F3N3O2S	461.14	462
1589	1663	C25H29N3OS	419.20	420
1590	1664	C25H29N3OS	419.20	420
1591	1665	C24H25N3O3S	435.16	436
1592	1666	C22H24N4O2S	408.16	409
1593	1667	C23H22F3N302S	461.14	462
1594	1668	C24H26N4O2S	434.18	435
1595	1669	C21H24N4O2S	396.16	397
1596	1670	C21H21FN4O2S	396.14	397
1597	1671	C25H27N3O3S	449.18	450
1598	1672	C28H33N3OS	459.23	460
1599	1673	C24H26N4O2S	434.18	435
1600	1674	C25H28N4O2S	448.19	449
1601	1675	C25H28N4O2S	448.19	449
1602	1676	C24H28N4OS	420.20	421
1603	1677	C24H26N4O2S	434.18	435
1604	1678	C24H25N3O2S	419.17	420
1605	1679	C20H21N3OS2	383.11	384
1606	1680	C26H28FN3O2	433.22	434
1607	1681	C26H27ClFN3O2	467.18	468
1608	1682	C21H21FN4OS	396.14	397
1609	1683	C24H32FN3O2	413.25	414
1610	1684	C25H34FN3O2	427.26	428
1611	1685	C25H34FN3O2	427.26	428
1612	1686	C26H34FN3O2	439.26	440
1613	1687	C25H25N3OS	415.17	416
1614	1688	C23H22N4OS	402.15	403
1615	1689	C24H22FN3OS	419.15	420
1616	1690	C23H22N4OS	402.15	403
1617	1691	C21H27N5O3	397.21	398
1618	1692	C25H28N4O2	416.22	417

[1032] Synthesis of Pyrrolidinylanilines Required as Intermediates

[1033] [1-Amino-2-chlorophenyl)pyrrolidin-3-yl]dimethylamine

[1034] Method C-a

[1035] 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, ethyl acetate (30 ml) was added to the reaction mixture, and it was extracted with 10% hydrochloric acid (2×20 ml). The aqueous phase was washed with ethyl acetate (2×20 ml), adjusted to pH>10 with 10% ammonia and extracted with ethyl acetate. The yellow solution was dried with sodium sulfate, filtered and concentrated in a rotary evaporator. The residue was then dissolved in dichloromethane (50 ml), zinc (10 g) was added, and 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 (2×20 ml) and concentrated. This resulted in the product with the molecular weight of 239.75 (C12H18ClN3); MS (ESI): 239 (M+H+), 240 (M+H+),

[1036] 5-Amino-2-(3-dimethylaminopyrrolidin-1-yl)benzonitrile

[1037] Dimethylaminopyrrolidine was treated with 2-fluoro-5-nitrobenzonitrile and subsequently reduced by method C-a. This resulted in the product with the molecular weight of 230.32 (C13H18N4); MS (ESI): 231 (M+H+),

[1038] [1-(4-Amino-3-chlorophenyl)pyrrolidin-3-yl]dimethylamine

[1039] Dimethylaminopyrrolidine was treated with 3-chloro-1-fluoro-4-nitrobenzene and subsequently reduced by method C-a. This resulted in the product with the molecular weight of 239.75 (C12H18ClN3); MS (ESI): 239 (M+H+), 240 (M+H+),

[1040] [1-(4-Amino-3-methylphenyl)pyrrolidin-3-yl]dimethylamine

[1041] Dimethylaminopyrrolidine was treated with 4-fluoro-2-methyl-1-nitrobenzene and subsequently reduced by method C-a. This resulted in the product with the molecular weight of 219.33 (C13H21N3); MS (ESI): 220 (M+H+).

[1042] tert-Butyl (R)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate

[1043] Method C-b

[1044] tert-Butyl (R)-(+)-pyrrolidin-3-ylcarbamate (1.86 g) was slowly added to a suspension 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 (3×50 ml) in a separating funnel, dried with sodium sulfate, filtered and concentrated. The residue was dissolved in DMF (10 ml), and sodium hydride (0.48 g) was added. After 15 minutes, methyl iodide (1.41 g) was then added while cooling in ice. After 30 minutes, ethyl acetate (50 ml) was added, and the mixture was washed with water (3×50 ml) in a separating funnel, dried with sodium sulfate, filtered and concentrated. The substance was then treated as described for method B. This resulted in the product with the molecular weight of 309.39 (C16H24FN3O2); MS (ESI): 310 (M+H+).

[1045] tert-Butyl (S)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was obtained analogously.

[1046] tert-Butyl (R)-[1-(2-fluoro-4-isopropylaminophenyl)pyrrolidin-3-yl]methylcarbamate

[1047] tert-Butyl (R)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was alkylated with acetone using triacetoxyborohydride as reducing agent by method N. This resulted in the product with the molecular weight of 351.47 (C19H30FN3O2); MS (ESI): 352 (M+H+).

[1048] tert-Butyl (R)-[1-(2-Fluoro-4-cyclobutylaminophenyl)pyrrolidin-3-yl]methylcarbamate

[1049] tert-Butyl (R)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was alkylated with cyclobutanone using triacetoxyborohydride as reducing agent by method N. This resulted in the product with the molecular weight of 363.48 (C20H30FN3O2); MS (ESI): 364 (M+H+).

[1050] tert-Butyl (R)-[1-(2-fluoro-4-methylaminophenyl)pyrrolidin-3-yl]methylcarbamate

[1051] tert-Butyl (R)-{1-[4-(benzyloxycarbonylmethylamino)-2-fluorophenyl]pyrrolidin-3-yl}-methylcarbamate was treated as described for method B. This resulted in the product with the molecular weight of 323.41 (C17H26FN3O2); MS (ESI): 324 (M+H+).

[1052] tert-Butyl (R)-{1-[4-(benzyloxycarbonylmethylamino)-2-fluorophenyl]pyrrolidin-3-yl}-methylcarbamate

[1053] 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 (2×30 ml), dried sodium sulfate, filtered and concentrated. The residue was recrystallized from acetonitrile. The product obtained in this way was dissolved in DMF (10 ml), and sodium hydride (0.24 g) was added. After 15 minutes, methyl iodide (0.71 g) was added while cooling in ice. After 15 minutes, ethyl acetate (50 ml) was added, and the mixture was washed with water (3×30 ml), dried sodium sulfate, filtered and concentrated. This resulted in the product with the molecular weight of 457.55 (C25H32FN3O4); MS (ESI): 458 (M+H+).

[1054] (R)-[1-(2-Fluoro-4-methylaminophenyl)pyrrolidin-3-yl]dimethylamine

[1055] (R)-{1-[4-(Benzyloxycarbonylmethylamino)-2-fluorophenyl]pyrrolidin-3-yl}methylcarbamic acid tert-butyl ester was treated by method G, and the resulting amine was methylated by method M. Finally, hydrogenation was carried out by method B. This resulted in the product with the molecular weight of 237.32 (C13H20FN3); MS (ESI): 238 (M+H+).

[1056] Dimethyl-[1-(4-methylaminophenyl)pyrrolidin-3-yl]amine can be prepared analogously.

[1057] 2-Dimethylamino-N-[1-(2-fluoro-4-methylaminophenyl)pyrrolidin-3-yl]-N-methylacetamide

[1058] (R)-{1-[4-(Benzyloxycarbonylmethylamino)-2-fluorophenyl]pyrrolidin-3-yl}methylcarbamic acid tert-butyl ester was treated by method G, and the resulting amine was reacted with N,N-dimethylglycine by method E. Finally, hydrogenation was carried out by method B. This resulted in the product with the molecular weight of 308.40 (C16H25FN4O); MS (ESI): 309 (M+H+).

[1059] tert-Butyl (R)-[1-(4-amino-3-fluorophenyl)pyrrolidin-3-yl]methylcarbamate

[1060] 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+).

[1061] tert-Butyl [1-(4-aminonaphthalen-1-yl)pyrrolidin-3-yl]methylcarbamate

[1062] Method C-c

[1063] tert-Butyl methylpyrrolidin-3-ylcarbamate (1.86 g) was slowly added to a suspension of 4-fluoro-1-nitronaphthalene (1.91 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 (3×50 ml) in a separating funnel, dried with sodium sulfate, filtered and concentrated. The substance was then treated as described for method B. This resulted in the product with the molecular weight of 341.46 (C20H27N3O2); MS (ESI): 342 (M+H+).

[1064] tert-Butyl [1-(4-amino-3-bromophenyl)pyrrolidin-3-yl]methylcarbamate

[1065] 2-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+).

[1066] Tert-butyl [1-(4-amino-3-cyanophenyl)pyrrolidin-3-yl]methylcarbamate

[1067] 2-Cyano-4-fluoro-1-nitrobenzene was treated with tert-butyl methylpyrrolidin-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+).

[1068] tert-Butyl [1-(5-amino-6-chloropyridin-2-yl)pyrrolidin-3-yl]methylcarbamate

[1069] 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 (C15H23ClN4O2); MS (ESI): 326 (M+H+), 327 (M+H+).

[1070] tert-Butyl [1-(4-amino-2,3-difluorophenyl)pyrrolidin-3-yl]methylcarbamate

[1071] 2,3,4-Trifluoronitrobenzene 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 327.38 (C16H23F2N3O2); MS (ESI): 328 (M+H+).

[1072] tert-Butyl [1-(4-amino-2-bromophenyl)pyrrolidin-3-yl]methylcarbamate

[1073] 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+).

[1074] tert-Butyl [1-(4-amino-2,6-difluorophenyl)pyrrolidin-3-yl]methylcarbamate

[1075] 3,4,5-Trifluoronitrobenzene 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 of 327.38 (C16H23F2N3O2); MS (ESI): 328 (M+H+).

[1076] tert-Butyl (R)-[1-(4-amino-2-hydroxymethylphenyl)pyrrolidin-3-yl]carbamate

[1077] (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+).

[1078] tert-Butyl [1-(4-amino-2-chlorophenyl)pyrrolidin-3-yl]methylcarbamate 2-Chloro-1-fluoro-4-nitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 311.81 (C15H22ClN3O2); MS (ESI): 311 (M+H+), 312 (M+H+).

[1079] tert-Butyl [1-(4-amino-2,5-difluorophenyl)pyrrolidin-3-yl]methylcarbamate

[1080] 3,4,6-Trifluoronitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 327.38 (C16H23F2N3O2); MS (ESI): 328 (M+H+).

[1081] tert-Butyl [1-(4-amino-2-methylphenyl)pyrrolidin-3-yl]methylcarbamate

[1082] tert-Butyl 4-fluoro-3-methylnitrobenzene 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 of 291.40 (C16H25N3O2); MS (ESI): 292 (M+H+).

[1083] tert-Butyl [1-(4-amino-3-trifluoromethylphenyl)pyrrolidin-3-yl]methylcarbamate

[1084] 4-Fluoro-2-trifluoromethyinitrobenzene 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 of 345.37 (C16H22F3N3O2); MS (ESI): 346 (M+H+).

[1085] tert-Butyl [1-(4-amino-2-chloro-3-fluorophenyl)pyrrolidin-3-yl]methylcarbamate

[1086] 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 of 329.80 (C15H21ClN3O2); MS (ESI): 329 (M+H+), 330 (M+H+).

[1087] tert-Butyl [1-(4-amino-2-cyanophenyl)pyrrolidin-3-yl]methylcarbamate

[1088] 3-Cyano-4-fluoronitrobenzene 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 of 302.38 (C16H22N4O2); MS (ESI): 303 (M+H+).

[1089] tert-Butyl [1-(4-amino-5-chloro-2-methylphenyl)pyrrolidin-3-yl]methylcarbamate

[1090] 1-Chloro-5-fluoro-4-methyl-2-nitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 325.84 (C16H24ClN3O2); MS (ESI): 325 (M+H+), 326 (M+H+).

[1091] tert-Butyl (R)-[1-(5-aminopyridin-2-yl)pyrrolidin-3-yl]methylcarbamate

[1092] 2-Chloro-5-nitropyridine was treated with tert-butyl (R)-(+)-pyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-b. This resulted in the product with the molecular weight of 322.37 (C16H24FN3O2); MS (ESI): 323 (M+H+).

[1093] tert-Butyl [1-(5-aminopyridin-2-yl)pyrrolidin-3-yl]methylcarbamate

[1094] 2-Chloro-5-nitropyridine 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 of 322.37 (C16H24FN3O2); MS (ESI): 323 (M+H+).

[1095] tert-Butyl (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate

[1096] 4-Fluoronitrobenzene was treated with tert-butyl (R)-(+)-pyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-b. This resulted in the product with the molecular weight of 291.40 (C16H25N3O2); MS (ESI): 292 (M+H+).

[1097] tert-Butyl [1-(4-amino-2-trifluoromethylphenyl)pyrrolidin-3-yl]methylcarbamate

[1098] 4-Fluoro-3-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 of 345.37 (C16H22F3N3O2); MS (ESI): 346 (M+H+).

[1099] tert-Butyl [1-(5-amino-4-methylpyridin-2-yl)pyrrolidin-3-yl]methylcarbamate

[1100] 2-Chloro-4-methyl-5-nitropyridine was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 306.419 (C16H26N4O2); MS (ESI): 306 (M+H+), 307 (M+H+).

[1101] tert-Butyl [1-(5-amino-3-methylpyridin-2-yl)pyrrolidin-3-yl]methylcarbamate

[1102] 2-Chloro-3-methyl-5-nitropyridine 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 of 306.419 (C16H26N4O2); MS (ESI): 306 (M+H+), 307 (M+H+).

[1103] tert-Butyl [1-(4-amino-2-hydroxymethylphenyl)pyrrolidin-3-yl]methylcarbamate

[1104] (2-Fluoro-5-nitrophenyl)methanol 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 of 321.42 (C17H27N3O3); MS (ESI): 322 (M+H+).

[1105] tert-Butyl [1-(4-amino-3-chloro-2-cyanophenyl)pyrrolidin-3-yl]methylcarbamate

[1106] 2-Chloro-6-fluoro-3-nitrobenzonitrile 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 of 350.5 (C17H23ClN4O2); MS (ESI): 350 (M+H+), 351 (M+H+).

[1107] tert-Butyl [1-(4-amino-3-methylphenyl)pyrrolidin-3-yl]methylcarbamate

[1108] 4-Fluoro-2-methylnitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 291.40 (C16H25N3O2); MS (ESI): 292 (M+H+).

[1109] tert-Butyl [1-(5-aminopyridin-2-yl)pyrrolidin-3-yl]carbamate

[1110] 2-Chloro-5-nitropyridine 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 278.36 (C14H22N4O2); MS (ESI): 279 (M+H+).

[1111] 5-(3-Dimethylaminopyrrolidin-1-yl)pyridin-2-ylamine

[1112] 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(II) acetate (0.09 g), cesium carbonate (4.5 g) in toluene (20 ml) was heated at 100° C. for 3 hours. Cooling to room temperature was followed by extraction with 1N hydrochloric acid (2×100 ml). The aqueous phase was adjusted to pH>10 with ammonia, extracted with ethyl acetate (2×100 ml), dried with sodium sulfate, filtered and concentrated. The substance was then treated as described for method B. This resulted in the product with the molecular weight of 206.29 (C11H18FN4); MS (ESI): 207 (M+H+).

[1113] N-[1-(4-Aminophenyl)-4-hydroxypyrrolidin-3-yl]-N-methylacetamide

[1114] trans-N-(4-Hydroxypyrrolidin-3-yl)-N-methylacetamide was reacted with 4-fluoronitrobenzene by method C, and the product was subsequently hydrogenated by method B. This resulted in the product with the molecular weight of 249.32 (C13H19N3O2); MS (ESI): 250 (M+H+).

[1115] trans-N-(4-Hydroxypyrrolidin-3-yl)-N-methylacetamide

[1116] 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 were removed under high vacuum. The residue was treated by method G. This resulted in the product with the molecular weight of 158.20 (C7H14N2O2); MS (ESI): 159 (M+H+).

[1117] trans-1-(4-Aminophenyl)-4-dimethylaminopyrrolidin-3-ol

[1118] 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 and partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The crude product was treated by method G. The resulting amine was reacted with 4-fluoronitrobenzene by method C. The resulting nitro compound was hydrogenated by method B. This resulted in the product with the molecular weight of 221 (C12H19N3O); MS (ESI): 222 (M+H+).

[1119] [1-(4-Aminophenyl)-4-methoxypyrrolidin-3-yl]dimethylamine

[1120] An alternative possibility is for the nitro compound prepared in the preceding method to be alkylated with methyl iodide by method F and then hydrogenated by method B. This resulted in the product with the molecular weight of 235 (C13H21N3O); MS (ESI): 236 (M+H+).

[1121] [1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine

[1122] Dimethylpyrrolidin-3-ylamine was reacted with 4-fluoronitrobenzene by method 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+).

[1123] 1-(4-Aminophenyl)-3-dimethylaminopyrrolidin-2-one

[1124] Trisodium phosphate (3.56 g) was added to a solution of 4-nitroaniline (5.0 g) in acetonitrile (30 ml) and, at 0° C., 2-bromo-4-chlorobutyryl bromide (11 g) was added. After one hour, a solution of sodium hydroxide (3.2 g) in water (10 ml) was added, and the mixture was vigorously stirred at room temperature. After 6 hours, the same amount of sodium hydroxide solution was again added, and the mixture was left to stand overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The crude 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 water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The crude product was hydrogenated by method B. This resulted in the product with the molecular weight of 219.29 (C12H17N3O); MS (ESI): 220 (M+H+).

[1125] 1-(4-Aminophenyl)-3-(7-azabicyclo[2.2.1]hept-7-yl)pyrrolidin-2-one was obtained in an analogous manner.

[1126] 4-[3-(7-Azabicyclo[2.2.1 ]hept-7-yl)pyrrolidin-1-yl]phenylamine

[1127] 1-(4-Nitrophenyl)-3-(7-azabicyclo[2.2.1]hept-7-yl)pyrrolidin-2-one (0.25 g) in THF (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 complete, the mixture was diluted with water and adjusted to pH 9-10 with hydrochloric acid (4N). Extraction in ethyl acetate, drying and concentration of the organic phase afforded a crude product that was hydrogenated by method B. This resulted in the product with the molecular weight of 257.38 (C16H23N3); MS (ESI): 258 (M+H+).

[1128] (R)-1′-(4-Aminophenyl)-[1,3′]bipyrrolidinyl-2-one

[1129] 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 added and the mixture was vigorously stirred. After 12 hours, the same amount of sodium hydroxide solution was again added, and the mixture was stirred for a further 24 hours. The concentrated reaction solution was partitioned between water and-ethyl acetate, and the organic phase was dried and concentrated. The residue was hydrogenated by method B. This resulted in the product with the molecular weight of 245.33 (C14H19N3O); MS (ESI): 246 (M+H+).

[1130] 1-Methylpiperidine-3-carboxylic Acid [(R)-1-(4-aminophenyl)pyrrolidin-3-yl]methylamide

[1131] tert-Butyl (R)-[1-(4-nitrophenyl)pyrrolidin-3-yl]methylcarbamate was treated by method G and reacted with 1-methylpiperidine-3-carboxylic acid by method E. Finally, hydrogenation was also carried out by method E. This resulted in the product with the molecular weight of 316.45 (C18H28N4O); MS (ESI): 317 (M+H+).

[1132] (R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-2-dimethylamino-N-methylacetamide was obtained in an analogous manner using N,N-dimethylglycine.

[1133] N-[(R)-1-(4-Aminophenyl)pyrrolidin-3-yl]-N-(2-diethylaminoethyl)acetamide

[1134] N-(2-Diethylaminoethyl)-N-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight of 318.47 (C18H30N4O); MS (ESI): 319 (M+H+).

[1135] N-(2-Diethylaminoethyl)-N-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide

[1136] Acetyl 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 room temperature for 30 minutes. Subsequently, (LCMS check), water (10 ml)was added to the reaction, and the mixture was extracted with dichloromethane (2×10 ml). The combined organic phases were dried over magnesium sulfate, the solvent was removed, and the crude product was separated by chromatography on silica gel (dichloromethane/methanol 10:1). This resulted in the product with the molecular weight of 348.45 (C18H28N4O3); MS (ESI): 349 (M+H+).

[1137] N,N-Diethyl-N′-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]ethane-1,2-diamine

[1138] tert-Butyl (2-diethylaminoethyl)-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate (7.9 g) was reacted with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 306.41 (C16H26N4O2); MS (ESI): 307 (M+H+).

[1139] tert-Butyl (2-diethylaminoethyl)-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate

[1140] tert-Butyl [(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate (6.0 g) was dissolved in 50 ml of N,N-dimethylformamide and, after addition of sodium hydride (1.1 g), stirred at room temperature for 30 minutes, and subsequently chlorethyldiethylamine hydrochloride (4.1 g) was added. The mixture was subsequently stirred at room temperature with exclusion of moisture for 4 hours. The reaction was stopped by adding water (50 ml), and this was followed by extraction with ethyl acetate (3×50 ml) and drying of the combined organic phases over magnesium sulfate, and removal of the solvent. This resulted in the product with the molecular weight of 406.53 (C21H34N4O4); MS (ESI): 407 (M+H+).

[1141] Piperidine-4-carboxylic Acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[1142] Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E, and the product was then treated by method G. This resulted in the product with the molecular weight of 316.45 (C18H28N4O); MS (ESI): 317 (M+H+).

[1143] Synthesis of Amines Required as Intermediates

[1144] Spiro[1,3-benzodioxol-2,1′-cyclopentane]-5-amine

[1145] A solution of spiro[5-nitro-1,3-benzodioxol-2,1′-cyclopentane] (8.8 g) in methanol (90 ml) was hydrogenated under 6 bar in the presence of palladium on carbon (10%, 0.1 g). After 30 minutes at room temperature, the mixture was filtered and concentrated. This resulted in the product with the molecular weight of 191.23 (C11H13NO2); MS(ESI): 192 (M+H+).

[1146] Spiro[5-nitro-1,3-benzodioxol-2,1′-cyclopentane]

[1147] A solution of spiro[1,3-benzodioxol-2,1′-cyclopentane] (8.5 g) in 20 ml of dichloromethane was added dropwise at 10° C. to 65% strength nitric acid (65 ml). After 2 hours at 5-10° C., the mixture was diluted with water, the organic phase was separated off, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with water until neutral, dried over sodium sulfate, concentrated and crystallized from heptane. This resulted in the product with the molecular weight of 221.21 (C11H11NO4); MS(ESI): 222 (M+H+).

[1148] Spiro[1,3-benzodioxol-2,1′-cyclopentane]

[1149] Catechol (11 g) and cyclopentanone (9 ml) were heated under reflux in toluene (150 ml) with p-toluenesulfonic acid (0.18 g) with a water trap. After 18 hours, the mixture was concentrated and purified by chromatography (silica gel, heptane/ethyl acetate 4:1). This resulted in the product with the molecular weight of 176.22 (C11H12O2); MS(ESI): 177 (M+H+).

[1150] 5-Chloro-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol

[1151] 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, after one hour, a solution of N-tert-butoxycarbonyl-4-piperidinone (2.1 g) in diethyl ether (10 ml) was added dropwise. After 30 minutes, water was cautiously added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was treated by method G. This resulted in the product with the molecular weight of 212.68 (C10H13ClN2O); MS(ESI): 213 (M+H+).

[1152] The following were obtained analogously:

[1153] 5-Fluoro-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol

[1154] 6-Chloro-2′,3′,5′,6′-tetrahydro-1′H-[3,4′]bipyridinyl-4′-ol.

[1155] 6-Cyclopentyloxypyridin-3-ylamine

[1156] 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 6 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/heptane 1:2). The nitro compound obtained in this way was hydrogenated by method B. This resulted in the product with the molecular weight of 178.24 (C10H14N2O2); MS(ESI): 179 (M+H+).

[1157] 6-(4-Fluorophenyl)-3-azabicyclo[4.1.0]heptane

[1158] Diethylzinc (1M in hexane, 19 ml) in dichloromethane (100 ml) was mixed with trifluoroacetic acid (3 ml) at 0° C. After 20 minutes, diiodomethane (3 ml) in dichloromethane (10 ml) was added. Then 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (3.0 g) in dichloromethane (10 ml) was added, and the mixture was stirred at room temperature overnight. After addition of hydrochloric acid (1N), the phases were separated and the organic phase was washed with water, dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 191.25 (C12H14FN); MS(ESI): 192 (M+H+).

[1159] Synthesis of Carboxylic Acids Required as Intermediates

[1160] 4-(4-Methylpiperidin-1-yl)benzoic Acid

[1161] 4-(4-Methylpiperidin1-yl)benzonitrile (1.2 g) was heated to reflux with potassium hydroxide (0.7 g) in water (2 ml) and ethylene glycol (8 ml) for 3 hours. The mixture was diluted with water, washed with ethyl acetate and acidified with 2N hydrochloric acid. The precipitated product was filtered off with suction, dissolved in dichloromethane, dried over sodium sulfate, concentrated and crystallized from diethyl ether. This resulted in the product with the molecular weight of 219.29 (C13H17NO2); MS(ESI): 220 (M+H+).

[1162] 4-(4-Methylpiperidin1-yl)benzonitrile

[1163] 4-Fluorobenzonitrile (1.21 g) was heated with 4-methylpiperidine (1.00 g) at 180° C. for 1 hour. The mixture was then taken up in ethyl acetate, washed with water, 2N sodium hydroxide solution and saturated sodium bicarbonate solution, dried over sodium sulfate, concentrated and crystallized from n-pentane. This resulted in the product with the molecular weight of 200.29 (C13H16N2); MS(ESI): 201 (M+H+).

[1164] 4-Butoxycyclohexanecarboxylic Acid

[1165] Sodium hydride (2.78 g) was added to a solution of ethyl 4-hydroxycyclocarboxylate (10 g) and butyl iodide (10.6 g) in DMF while cooling 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 (3×50 ml). The organic phase was concentrated and mixed with ethanol (50 ml) and 5N sodium hydroxide (30 ml). The solution was heated at 60° C. for 4 hours. Cooling to room temperature was followed by adjustment to pH<2 with 2N hydrochloric acid, extraction with ethyl acetate (3×50 ml), drying with magnesium sulfate, filtration and concentration. This resulted in the product with the molecular weight of 200.28 (C11H20O3); MS (ESI): 201 (M+H+).

[1166] 1-Benzyl-1H-[1,2,3]triazole-4-carboxylic Acid

[1167] Methyl 1-benzyl-1H-[1,2,3]triazol-4-carboxylate (217 mg) was dissolved in 4 ml of methanol and hydrolyzed with 2 ml of 2N sodium hydroxide solution. After acidification with 4 ml of 2N hydrochloric acid, the resulting precipitate was filtered off, taken up in 5 ml of ethyl acetate and purified by preparative HPLC. This resulted in the product with the molecular weight of 203.2 (C10H9N3O2); MS (ESI): 204 (M+H+).

[1168] Methyl 1-benzyl-1H-[1,2,3]triazole-4-carboxylate

[1169] Benzyl azide (266 mg) was dissolved together with sodium ascorbate (20 mg) and copper sulfate (5 mg) in 8 ml of the solvent mixture (tert-butanol/water 3:1), and methyl propionate (336 mg) was added. The solution was stirred at room temperature for 2 hours. A white precipitate separated out and was filtered off with suction on a frit and subsequently dried. This resulted in the product with the molecular weight of 217.23 (C11H11N3O2); MS (ESI): 218 (M+H+).

[1170] 1-Biphenyl-4-yl-1H-[1,2,3]triazole-4-carboxylic acid was prepared analogously from 4-Ethynylbiphenyl and ethyl azidoacetate.

[1171] 1-Butyl-1H-indole-5-carboxylic Acid

[1172] Sodium hydride (50% in oil, 1.4 g) was added to methyl 1H-indole-5-carboxylate (5.0 g) in DMF (100 ml) and, after gas evolution ceased, bromobutane (3.9 g) was added. After 12 hours, the reaction solution was diluted with ethyl acetate and washed three times with water. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/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) for 12 hours. The mixture was diluted with water and acidified with hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 217.27 (C13H15NO2); MS (ESI): 218 (M+H+).

[1173] 3′-Acetylaminobiphenyl-4-carboxylic Acid

[1174] 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 were removed. The residue was taken up in sodium hydroxide solution (2N) and washed with diethyl ether. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 255.28 (C15H13NO3); MS (ESI): 256 (M+H+).

[1175] 3′-Isobutyrylaminobiphenyl-4-carboxylic Acid

[1176] 3′-Aminobiphenyl-4-carboxylic acid (0.2 g) was mixed in dichloromethane with potassium carbonate (121 mg) and isobutyryl chloride (94 mg). After 12 hours, the mixture was diluted with sodium hydroxide solution and washed with diethyl ether. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 283.33 (C17H17NO3); MS (ESI): 284 (M+H+).

[1177] 5-Butoxypyridine-2-carboxylic Acid

[1178] Sodium hydride (50% in oil, 250 mg) was added to benzhydryl 5-hydroxypyridine-2-carboxylate (2.0 g) dissolved in DMF (20 ml) and, after gas evolution ceased, 1-bromobutane (0.72 g) was added. The mixture was heated at 90° C. for 6 hours. It was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was hydrogenated in analogy to method B. This resulted in the product with the molecular weight of 195.22 (C10H13NO3); MS (ESI): 196 (M+H+).

[1179] 4-Methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-carboxylic Acid

[1180] Benzhydryl 5-trifluoromethanesulfonyloxypyridine-2-carboxylate (3.0 g) was heated with 4-methylpiperidine (1.4 g) at 80° C. for one hour. The reaction mixture was immediately purified by preparative HPLC and then hydrogenated in analogy to method. This resulted in the product with the molecular weight of 220.27 (C12H16N2O2); MS (ESI): 221 (M+H+).

[1181] N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]terephthalamic Acid

[1182] Method P-a

[1183] N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]terephthalamic acid methyl ester (1.7 g) dissolved in methanol (20 ml) was stirred with sodium hydroxide solution (2N, 15 ml) at room temperature for 24 hours. If conversion is incomplete, it is also possible to heat to reflux. The organic solvent was distilled off, and the mixture was acidified with hydrochloric acid. The precipitate which separated out was filtered off with suction and dried. This resulted in the product with the molecular weight of 353.42 (C20H23N3O3); MS (ESI): 354 (M+H+).

[1184] N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]terephthalamic Acid Methyl Ester

[1185] [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+).

[1186] 4-(Cyclopentanecarbonylmethylamino)benzoic Acid

[1187] Methyl 4-methylaminobenzoate was reacted with cyclopentanecarboxylic acid by method E and then hydrolyzed by method P-a. This resulted in the product with the molecular weight of 247.30 (C14H17NO3); MS (ESI): 248 (M+H+).

[1188] The following compounds were obtained analogously:

[1189] 4-(Cyclopentanecarbonylamino)-3-methoxybenzoic acid

[1190] 2-Chloro-4-(cyclopentanecarbonylamino)benzoic acid

[1191] 2-Fluoro-4-(cyclopentanecarbonylamino)benzoic acid

[1192] 4-(Cyclopentanecarbonylamino)-3-methylbenzoic acid

[1193] 4-(Cyclopentanecarbonylamino)benzoic acid

[1194] 4-(Cyclopentanecarbonylamino)-3-trifluoromethoxybenzoic acid

[1195] 3-Chloro-4-(cyclopentanecarbonylamino)benzoic acid

[1196] 5-Chloro-4-(cyclopentanecarbonylamino)-2-methoxybenzoic acid

[1197] 4-[(Cyclohex-1-enecarbonyl)amino]benzoic acid

[1198] 4-[(Cyclopent-1-enecarbonyl)amino]benzoic acid

[1199] 3-Fluoro-4-(1-methylbutoxy)benzoic Acid

[1200] A solution of 0.449 g of 1-[3-fluoro-4-(1-methylbutoxy)phenyl]ethanone in 6.8 ml of dioxane was dropped dropwise into 1.36 g of NaOH, 1.6 g of bromine in 6.8 ml of water. The mixture was stirred at room temperature for 30 minutes and then heated at 50° C. for 1 h. The excess bromide was decomposed by adding a sodium disulfite solution, and then the solution was poured into 25% strength hydrochloric acid solution and stirred for 20 minutes. The solution was extracted with ethyl acetate. The combined organic phases dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 226.1 (C12H15FO3); MS (ESI): 227 (M+H+).

[1201] 1-[3-Fluoro-4-(1-methylbutoxy)phenyl]ethanone

[1202] 0.058 g of NaH was added to a solution of 0.176 g of 2-pentanol in 2 ml of DMF, and the solution was stirred at room temperature for 1 hour. Then 0.312 g of 3,4-difluoroacetophenone was added, and the mixture was stirred at room temperature overnight. The reaction solution was taken up in ethyl acetate and washed twice with water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting compound was reacted further without further purification.

[1203] The following compounds were obtained analogously:

[1204] 4-Cyclobutoxy-3-fluorobenzoic acid

[1205] 3-Fluoro-4-(2-methylcyclopropylmethoxy)benzoic acid

[1206] 4-(2-Cyclopropylethoxy)-3-fluorobenzoic acid

[1207] 3-Fluoro-4-(1-methylpiperidin-3-yloxy)benzoic acid

[1208] 4-(1-Acetylpiperidin-3-yloxy)-3-fluorobenzoic acid

[1209] 3-Fluoro-4-(1-methylpyrrolidin-3-yloxy)benzoic acid

[1210] 4-(1-Acetylpyrrolidin-3-yloxy)-3-fluorobenzoic acid

[1211] 3-Fluoro-4-(1-methylpiperidin-3-ylmethoxy)benzoic acid

[1212] 4-(2,4-Difluorophenoxy)benzoic Acid

[1213] 0.518 g of potassium hydroxide was added to a solution of 0.428 g of ethyl 4-(2,4-difluorophenoxy)benzoate in 2 ml of THF/water (1:1). The solution was heated at 110° C. for 6 hours. The THF was then removed in vacuo, and the aqueous phase was freeze dried and purified by preparative HPLC. This resulted in the product with the molecular weight of 250.04 (C13H8F2O3); MS (ESI): 251 (M+H+).

[1214] Ethyl 4-(2,4-difluorophenoxy)benzoate

[1215] 0.018 g of NaH was added to a solution of 0.1 g of 2,4-difluorophenol in 0.5 ml of DMF. The reaction was stirred at room temperature for 45 minutes. Then 0.129 g of ethyl 4-fluorobenzoate in 0.5 ml of DMF was added dropwise. The reaction was heated at 110° C. overnight. After cooling concentrated in vacuo and the residue taken up in ethyl acetate/water. The ethyl acetate phase was washed three times with water, dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 278.08 (C15H12F2O3); MS (ESI): 279 (M+H+)

[1216] 4-(2,4-Difluorophenoxy)benzoic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]-dimethylamine by method E-b. This resulted in the product with the molecular weight of 437.19 (C25H25F2N3O2); MS (ESI): 438 (M+H+) as hydrotrifluoroacetate.

[1217] 4-Butoxy-3-methoxybenzoic Acid

[1218] Methyl 4-hydroxy-3-methoxybenzoate was alkylated with bromobutane by method H and hydrolyzed by method P-a. This resulted in the product with the molecular weight of 224.26 (C12H16O4); MS (ESI): 225 (M+H+).

[1219] The following compounds were prepared analogously:

[1220] 4-Butoxy-3,5-dichlorobenzoic acid

[1221] 4-Butoxy-3-nitrobenzoic acid

[1222] 4-Butoxy-3-chlorobenzoic acid

[1223] 4-Butoxy-3,5-dimethylbenzoic acid

[1224] 4-Butoxy-2,3-dichloro-5-methoxybenzoic acid

[1225] 4-Butoxy-2,3,5,6-tetrafluorobenzoic acid

[1226] 4-Butoxy-3-fluorobenzoic acid

[1227] 3-Acetyl-4-butoxybenzoic acid

[1228] 2,4-Dibutoxybenzoic acid

[1229] 4-Butoxy-2-chlorobenzoic acid

[1230] 4-Propoxymethylbenzoic Acid

[1231] Sodium hydride (50% in oil; 0.42 g) was cautiously added to a solution of propanol (0.6 g) in DMF (8 ml). After gas evolution ceased, methyl 4-bromomethylbenzoate (1.0 g) was added. After 4 hours, the mixture was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was hydrolyzed by method P-a. This resulted in the product with the molecular weight of 194.23 (C11H14O3); MS (ESI): 195 (M+H+).

[1232] The following compounds were prepared analogously:

[1233] 4-Ethoxymethylbenzoic acid

[1234] 4-Butoxymethylbenzoic acid

[1235] 4-Isobutoxymethylbenzoic acid

[1236] 4-Phenoxymethylbenzoic acid

[1237] 4-(Pyridin-3-yloxymethyl)benzoic acid

[1238] 4-(Pyridin-2-yloxymethyl)benzoic acid

[1239] 4-Benzoimidazol-1-ylmethylbenzoic acid

[1240] 4-Indol-1-ylmethylbenzoic acid

[1241] 4-Phenylsulfanylmethylbenzoic acid

[1242] 4-(Pyrimidin-2-ylsulfanylmethyl)benzoic acid

[1243] 4-(Pyridin-2-ylsulfanylmethyl)benzoic acid

[1244] 4-(2-Cyanophenoxymethyl)benzoic acid

[1245] 4-(2-Chlorophenoxymethyl)benzoic acid

[1246] 4-Cyclobutoxymethylbenzoic acid

[1247] 4-Cyclopentyloxymethylbenzoic acid

[1248] 4-Cyclohexyloxymethylbenzoic acid

[1249] 4-sec-Butoxymethylbenzoic acid

[1250] 4-Pentoxymethylbenzoic acid

[1251] 4-(3-Oxo-3a,4,5,6-tetrahydro-3H-cyclopentapyrazol-2-yl)benzoic Acid

[1252] A solution of 4-hydrazinobenzoic acid (0.3 g), ethyl-2-oxocyclopentanecarboxylate (0.31 g) and p-toluenesulfonic acid (340 mg) in ethanol (12 ml) was boiled under reflux for 12 hours. The concentrated reaction solution was purified by preparative HPLC. The isolated reaction product (as ethyl ester) was hydrolyzed by method P-a. This resulted in the product with the molecular weight of 244.25 (C13H12N2O3); MS (ESI): 245 (M+H+).

[1253] 4-Butoxy-2-methoxybenzoic Acid

[1254] 4-Hydroxy-2-methoxybenzaldehyde was alkylated with 1-bromobutane by method H. The resulting aldehyde (6.4 g) in dioxane (100 ml) was mixed with sodium dihydrogen phosphate (14.4 g) and sulfuric acid (2.4 ml), and the solution was cooled to 10° C. A solution of sodium chlorite (3.61 g) in water (100 ml) was added in such a way that the temperature did not exceed 10° C. 15 minutes after the addition was complete, sodium sulfite (4.6 g) was added. After a further 15 minutes, the pH was adjusted to 2 with hydrochloric acid and the dioxane was removed in a rotary evaporator. The aqueous phase was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative 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.

[1255] 4-(1-Propoxyethyl)benzoic Acid

[1256] Methyl 4-(1-hydroxyethyl)benzoate (2.0 g) dissolved in DMF (30 ml) was mixed with propyl iodide (3.8 g), and then sodium hydride (50% in oil, 0.53 g) was added. After the end of the exothermic reaction, the mixture was stirred for 1 hour and then water was cautiously added. It was extracted with 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 molecular weight of 208.26 (C12H16O3); MS (ESI): 209 (M+H+).

Claims

1. A compound of the formula I

2. The compound of claim 1 of formula 1:

3. The compound of claim 2 wherein R1, R2 are each independently H, (C1-C8)-alkyl, —(CH2)o—R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, CO—(C1-C8)-alkyl, —CO—(CH2)o—R12, COCH═CH(R13), COCC(R14), CO—(C1-C4)-alkyl-S(O)p—(C1-C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22) or CO(C(R23)(R24))sO(R25); or R1 and R2, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered mono-, bi- or spirocyclic ring which, apart from said nitrogen atom of attachment, optionally contains 1 or 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, and is optionally substituted by F, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C1-C6)-alkyl, N(R31)(R32) or SO2CH3; o 0, 1, 2, 3 or 4; p 0, 1 or 2; q, r, s are each independently 0, 1, 2 or 3; R13, R14 are each independently a 5-, 6-, 7-, 8-, 9- or 10 membered aromatic ring system optionally containing a further heteroatom selected from the group of nitrogen, oxygen and sulfur and optionally substituted by F, Cl, (C1-C6)-alkyl, O—(C1-C8)-alkyl; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 are each independently H or (C1-C6)-alkyl; R18 is H, (C1-C6)-alkyl, CO(C1-C6)-alkyl or CO(R33); or substituent pairs R17 and R18, R21 and R22, R27 and R28, and R31 and R32, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains one further heteroatom selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur; R33 is a 5-, 6-, 7-, 8-, 9- or 10 membered aromatic ring system which optionally contains a further heteroatom selected from the group of nitrogen, oxygen and sulfur and is optionally substituted by F, Cl, (C1-C6)-alkyl or O—(C1-C8)-alkyl; R12 is OH or a 3-, 4-, 5-, 6, 7-, 8-, 9-, 10-, 11- or 12 membered mono-, bi- or spirocyclic ring which optionally contains one or more heteroatoms from the group of N, O and S, and is optionally substituted by F, Cl, CF3, CN, oxo, O—(C1-C6)-alkyl, (C1-C6)-alkyl, O—(C0-C8)-alkylene-aryl, N(R34)(R35), COCH═CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(C1-C6)-alkyl, COCOO(C1-C6)-alkyl, COO(R40) or S(O)u(R41); t 0, 1, 2, 3 or 4; u 0, 1 or 2; R34, R35, R37, R38 are each independently H or (C1-C8)-alkyl; or R34 and R35, taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one further heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur, and is optionally substituted by 1 or 2 oxo groups; R36, R39 are each independently (C3-C8)-cycloalkyl or a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system wherein said aromatic ring system optionally contains a further heteroatom selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by F, Cl, (C1-C6)-alkyl, O—(C1-C8)-alkyl; R40 is H, (C1-C8)-alkyl, (C2-C6)-alkenyl or (C0-C8)-alkylene-aryl; R41 is (C1-C6)-alkyl or a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system optionally containing one or two heteroatoms selected from the group of nitrogen, oxygen and sulfur, and optionally substituted by F, Cl, (C1-C6)-alkyl or O—(C1-C8)-alkyl; R3 is H or (C1-C6)-alkyl; R4, R5 are each independently H, (C1-C6)-alkyl, OH, O—(C1-C6)-alkyl or O—CO(C1-C6)-alkyl; R6, R7, R8, R9 are each independently H or (C1-C8)-alkyl; or substituent pairs R6 and R7, and R8 and R9, optionally form, independently of one another, an oxo group; n, m are each independently 0, 1 or 2; A, B, D, G are each independently N or C(R42); R42 is H, F, Cl, Br, CF3, CN, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C0-C2)-alkylene-aryl, O—(C0-C2)-alkylene-aryl, N(R43)(R44), SO2—CH3, COO—(C1-C6)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50) or CO(R51); R43, R44, R45, R46, R47, R49 are each independently H or (C1-C8)-alkyl; or substituent pairs R43 and R44, and R45 and R46, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains an additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur; R48, R50, R51 are each independently H, (C1-C8)-alkyl or aryl; R10 is H or (C1-C8)-alkyl; X is N(R52), O, a bond, C═C, C(R53)(R54) or C(R55)(R56)O; R52, R53, R54, R55, R56 are each independently H or (C1-C8)-alkyl; E is a 3-, 4-, 5-, 6-, 7- or 8 membered bivalent carbo- or heterocyclic ring structure with 0, 1, 2, 3, or 4 heteroatoms from the group of N, O and S, and optionally substituted with H, F, Cl, CF3, NO2, OH, CN, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl, N(R57)(R58), SO2—CH3, COO—(C1-C6)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO2(R64) or CO(R65), and wherein said bivalent carbo-or heterocyclic ring is mono- or bicyclic; R57, R58, R59, R60, R61, R63 are each independently H or (C1-C8)-alkyl; or substituent pairs R57 and R58, and R59 and R60, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains one further heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur; R62, R64, R65 are each independently H, (C1-C8)-alkyl or aryl; K is a bond, O, CH2O, N(R66), (C(R69)(R70)v or C≡C; v is 1 or 2; R66, R67, R68, R69, R70 are each independently H or (C1-C8)-alkyl; R11 is H, (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered mono-, bi- or spirocyclic ring, optionally containing 1, 2, 3 or 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, and optionally substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO2CH3; R71, R72, R73, R74, R75, R76, R77 are each independently H or (C1-C8)-alkyl; or substituent pairs R72 and R73, and R76 and R77, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contain one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur.

4. The compound of claim 3, wherein A, B, D, G are each independently N or C(R42), and the total number of nitrogen atoms in said ring is 0-2.

5. The compound of claim 4, wherein n is 1and m is 1 or 2.

6. The compound of claim 1 wherein R1, R2 are each independently H, (C1-C8)-alkyl, —(CR78R79)o—R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, CO—(C1-C8)-alkyl, —CO—(CH2)o—R12, CO-aryloxy-(C1-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, taken together with the nitrogen atom to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered mono-, bi- or spirocyclic ring which, apart from said nitrogen atom of attachment, optionally comprises one or two additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, and is optionally substituted by F, Cl, CF3, (C1-C6)-alkyl, O—(C1-C4)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C0-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C1-C6)-alkyl, N(R31)(R32) or SO2CH3; o is 0, 1, 2, 3, 4, 5 or 6; q, r are independently of one another 1, 2 or 3; s is 0, 1, 2, 3 or 4; R13, R14 are each independently an aryl ring optionally comprising one nitrogen atom; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 are each independently H or (C1-C6)-alkyl; R18 is H, (C1-C6)-alkyl, CO(C1-C6)-alkyl or CO(R33); or substituent pairs R17 and R18, R21 and R22, R27 and R28, R31 and R32, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains 1 further heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur; R33 is a 5-, 6-, 7-, 8-, 9- or 10 membered aromatic ring system optionally comprising one additional heteroatom selected from the group of nitrogen, oxygen and sulfur and optionally substituted by F, Cl, (C1-C6)-alkyl or O—(C1-C8)-alkyl; R12 is OH, O—(C1-C6)-alkyl, O—(C0-C8)-alkylene-aryl, CN, S—(C1-C6)-alkyl, COO(R80), CON(R81)(R82), or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10, 11- or 12 membered mono-, bi- or spirocyclic ring which optionally contains one or more heteroatoms from the group of N, O and S, and is optionally substituted by F, Cl, Br, OH, CF3, CN, oxo, O—(C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C6)-alkyl, O—(C0-C8)-alkylene-aryl, (C0-C8)-alkylene-aryl, N(R34)(R35), COCH═CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(C1-C6)-alkyl, COCOO(C1-C6)-alkyl, COO(R40) or S(O)u(R41); t is 0, 1, 2, 3, 4, 5 or 6; u is 0, 1 or 2; R34, R35, R37, R38 are independently of one another H or (C1-C8)-alkyl; or substituent pair R34 and R35, taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur, and is optionally substituted by 1 or 2 oxo groups; R36, R39 are each independently (C3-C8)-cycloalkyl or a 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, (C1-C6)-alkyl or O—(C1-C8)-alkyl; R40 is H, (C1-C8)-alkyl, (C2-C6)-alkenyl or (C0-C8)-alkylene-aryl; R41 is (C1-C6)-alkyl or a 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, (C1-C6)-alkyl, O—(C1-C8)-alkyl; R78, R79 are independently of one another H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, OH or (C1-C4)-alkoxy-(C1-C4)-alkyl; R80, R81 are independently of one another H or (C1-C8)-alkyl; R3 is H or (C1-C6)-alkyl; R4, R5 are independently of one another H, (C1-C6)-alkyl, OH, O—(C1-C6)-alkyl, O—CO(C1-C6)-alkyl or S—(C1-C6)-alkyl; R6, R7, R8, R9 is H; or substituent pairs R6 and R7, and R8 and R9, independently of one another, optionally form oxo; n is 1; m is 1 or 2; A, B, D, G are independently of one another N or C(R42); or the groups A and B or D and G are each C(R42) and together form an ortho-phenylene unit to result overall in a 1,4-bisubstituted naphthalene system; R42 is H, F, Cl, Br, CF3, CN, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl, N(R43)(R44), SO2—CH3, CON(R45)(R46), N(R47)CO(R48), CO(R51) or —(CR84R85)x—O(R86); R43, R44, R45, R46, R47 are independently of one another H, (C1-C8)-alkyl; or substituent pairs R43 and R44, and R45 and R46, independently of one another, taken together with the nitrogen atom to which they are attached, optionally form a 5-6 membered ring which, apart from said nitrogen atom of attachment, optionally contain one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur; R48, R50, R51 are each independently H, (C1-C8)-alkyl or aryl; R84, R85 are H; R86 is H or (C1-C6)-alkyl; x is 0, 1 or 2; R10 is H or (C1-C8)-alkyl; X is N(R52), a bond, C═C, C(R53)(R54), C(R55)(R56)O, C≡C, CH2—CH2 or YCH2; Y is O, S or N(R89); R89 is H or (C1-C8)-alkyl; R52, R53, R54, R55, R56 are each independently H or (C1-C8)-alkyl; E is a 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, O and S, which may optionally have substituents from the group of H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl, S-aryl, N(R57)(R58), SO2—CH3, N(R61)CO(R62), N(R63)SO2(R64) or CO(R65) and wherein said carbo- or heterocyclic ring structure may be mono- or bicyclic; R57, R58, R61, R63 are each independently H or (C1-C8)-alkyl; R62, R64, R65 are each independently H, (C1-C8)-alkyl or aryl; K is 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 or SO2CH2; v is 1, 2, 3 or 4; R66, R67, R68, R69, R70 are independently of one another H or (C1-C8)-alkyl; R11 is H, (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-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 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO2CH3; R71, R72, R73, R74, R75, R76, R77 are independently of one another H or (C1-C8)-alkyl; or substituent pairs R72 and R73, and R76 and R77, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5-6 membered ring which, apart from said nitrogen atom of attachment, optionally contains an additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur; or the N-oxides and the pharmaceutically acceptable salts thereof.

7. The compound of claim 6 having the formula Ia

8. The compound of claim 6 having the formula Ib

9. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition of claim 9 further comprising one or more anorectic active ingredients.

11. A method of treating obesity comprising administering to a patient in need thereof a compound of claim 1.

12. A method of treating obesity comprising administering to a patient in need thereof a compound of claim 1 in combination with at least one further anorectic active ingredient.

13. A method of treating type II diabetes comprising administering to a patient in need thereof a compound of claim 1.

14. A method of treating type II diabetes comprising administering to a patient in need thereof a compound of claim 1 in combination with at least one further anorectic active ingredient.

15. A method of reducing weight in mammals comprising administering to a patient in need thereof a compound of claim 1.

16. A method of treating disturbances of well being comprising administering to a patient in need thereof a compound of claim 1.

17. A method of treating disorders associated with circadian rhythm comprising administering to a patient in need thereof a compound of claim 1.

18. A method of antagonizing the MCH receptor comprising administering to a patient in need thereof a compound of claim 1.

19. A method of treating drug abuse comprising administering to a patient in need thereof a compound of claim 1.

20. A method of treating psychiatric indications comprising administering to a patient in need thereof a compound of claim 1.