# Patent

## Title
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.
Compounds of the formula I




in which the radicals have the stated meanings, the N-oxides and the physiologically tolerated salts thereof and process for the preparation thereof are described. The compounds are suitable for example as anorectic agents.

## Background
This application claims priority from Provisional Application 60/488,545 filed Jul. 18, 2003.


The invention relates to substituted N-aryl heterocycles and to the physiologically tolerated salts and physiologically functional derivatives thereof.
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.
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.
The invention therefore relates to compounds of the formula I




wherein

    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
    
        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;
        wherein
        
            o is 0, 1, 2, 3, 4, 5 or 6;
            p is 0, 1 or 2
            q, r, s are each independently 0, 1, 2, 3 or 4;
            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;
            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 additional 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 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;
            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;
            t is 0, 1, 2, 3, 4, 5 or 6;
            u is 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 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-, 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;
        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 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;
        R78, R79 are each independently H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, OH or (C1-C4)-alkoxy-(C1-C4)-alkyl;
        R80, R81, R93 are each independently (C1-C8)-alkyl, (C2-C6)-alkenyl or (C0-C8)-alkylene-aryl;
        R82, R83 are each independently H or (C1-C6)-alkyl; or
        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;
    
    
    R3 is H or (C1-C6)-alkyl;
    R4, R5 are each independently H, (C1-C6)-alkyl, OH, O—(C1-C6)-alkyl, O—CO(C1-C6)-alkyl or S—(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); or
    
        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;
        wherein
        
            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);
            
                wherein
                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;
                R84, R85 are each independently H or (C1-C8)-alkyl;
                R86 is H, (C1-C6)-alkyl or aryl;
                x is 1, 2, 3, 4, 5 or 6;
            
            
        
        
    
    
    R10 is H, (C1-C8)-alkyl, (C3-C6)-alkenyl or (C3-C6)-alkynyl;
    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;
    
        wherein
        
            Y is O, S or N(R89) wherein R89 is H or (C1-C8)-alkyl;
            R52, R53, R54, R55, R56 are each independently H or (C1-C8)-alkyl;
            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-;
            y is 2, 3, 4, 5 or 6;
        
        
    
    
    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;
    
        wherein
        
            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, 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;
    
        wherein
        
            v is 1, 2, 3 or 4
            R66, R67, R68, R69, R70 are each independently H or (C1-C8)-alkyl;
            Z is O, S, N(R92), CO, SO or SO2;
            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-;
            z is 2, 3, 4, 5 or 6;
            R92 is H or (C1-C8)-alkyl;
        
        
    
    
    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;
    
        wherein
        
            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 the nitrogen atom, optionally contain one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur; or
        
        
    
    
    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;
    and the N-oxides and pharmaceutically acceptable salts thereof.


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




wherein

    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-CCO(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, 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;
        wherein
        
            o is, 0, 1, 2, 3, 4, 5 or 6;
            p is 0, 1 or 2
            q, r, s are each independently 0, 1, 2, 3 or 4;
            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;
            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 additional 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 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;
            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;
            t is 0, 1, 2, 3, 4, 5 or 6;
            u is 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 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-, 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;
        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 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;
    
    
    R3 is H or (C1-C6)-alkyl;
    R4, R5 are each independently H, (C1-C6)-alkyl, OH, O—(C1-C6)-alkyl, O—CO(C1-C6)-alkyl or S—(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);
    
        wherein
        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);
        
            wherein
            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, (C1-C8)-alkyl, (C3-C6)-alkenyl or (C3-C6)-alkynyl;
    X is N(R52), O, a bond, C═C, C(R53)(R54) or C(R55)(R56)O;
    
        wherein
        
            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 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;
    
        wherein
        
            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, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO or C≡C;
    
        wherein
        
            v is 1, 2, 3 or 4
            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, (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;
    
        wherein
        
            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 the nitrogen atom, optionally contain one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur; or
        
        
    
    
    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;

and the N-oxides and pharmaceutically acceptable salts thereof.



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.
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.
The term “aryl” means in particular a phenyl or naphthyl group.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
In a particularly preferred embodiment, the present invention relates to compounds of the formula I in which the meanings are:

    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;
    o 0, 1, 2, 3, 4;
    p 0, 1, 2;
    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;
    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;
    
    
    R18 H, (C1-C6)-alkyl, CO(C1-C6)-alkyl, CO(R33);
    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;
    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;
    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;
    t 0, 1, 2, 3, 4;
    u 0, 1, 2;
    R34, R35, R37, R38
    
        independently of one another H, (C1-C8)-alkyl;
    
    
    R34 and R35
    
        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;
    
    
    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;
    R40 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (C0-C8)-alkylene-aryl;
    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;
    R3 H, (C1-C6)-alkyl;
    R4, R5 independently of one another H, (C1-C6)-alkyl, OH, O—(C1-C6)-alkyl, O—CO(C1-C6)-alkyl;
    R6, R7, R8, R9
    
        independently of one another H, (C1-C8)-Alkyl;
    
    
    R6 and R7, R8 and R9
    
        independently of one another optionally oxo;
    
    
    n, m independently of one another 0, 1, 2, preferably m is 0, 1, 2 and n is 1;
    A, B, D, G independently of one another N, 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), CO(R51)
    R43, R44, R45, R46, R47, R49
    
        independently of one another H, (C1-C8)-alkyl;
    
    
    R43 and R44, R45 and R46
    
        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;
    
    
    R48, R50, R51
    
        independently of one another H, (C1-C8)-alkyl, aryl;
    
    
    R10 H, (C1-C8)-alkyl;
    X N(R52), O, a bond, C═C, C(R53)(R54), C(R55)(R56)O;
    R52, R53, R54, R55, R56
    
        independently of one another H, (C1-C8)-alkyl
    
    
    E 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, O and S, which 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;
    R57, R58, R59, R60, R61, R63
    
        independently of one another H, (C1-C8)-alkyl;
    
    
    R57 and R58, R59 and R60
    
        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;
    
    
    R62, R64, R65
    
        independently of one another H, (C1-C8)-alkyl, aryl;
    
    
    K a bond, O, CH2O, N(R66), (C(R69)(R70))v, C≡C, OCH2, CON(R68), preferably a bond, O, CH2O, ((CR69)(R70))v, C≡C, N(R66);
    v 1, 2;
    R66, R68, R69, R70
    
        independently of one another H, (C1-C8)-alkyl;
    
    
    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);
    R71, R72, R73, R74, R75, R76, R77
    
        independently of one another H, (C1-C8)-alkyl;
    
    
    R72 and R73, R76 and R77
    
        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.
    
    


Particularly preferred compounds of the formula I are those in which

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


Very particularly preferred compounds of the formula I are those in which

    n is 1 and
    m is 1 or 2.


Especially preferred compounds of the formula I are those in which

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


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

    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;
    
        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);
        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, CO(R26), hydroxy, N(R31)(R32) or SO2CH3;
        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);
    
    
    o 0, 1, 2, 3, 4, 5, 6; preferably 0, 1, 2, 3, 4; particularly preferably 0, 1, 2, 3;
    q, r independently of one another 1, 2, 3; preferably q is 1 or 2;
    s 0, 1, 2, 3, 4; preferably 0, 1, 2, 3; particularly preferably 0, 1, 2;
    R13, R14 independently of one another are a phenyl ring which may comprise 0-1 nitrogen atoms;
    R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32
    
        independently of one another H, (C1-C6)-alkyl;
    
    
    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

    R17 and R18, R21 and R22, R27 and R28, R31 and R32
    
        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;
    
    
    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;
    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);
    
        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;
        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;
    
    
    t 0, 1, 2, 3, 4, 5, 6;
    u 0, 1, 2; preferably 0 or 2; particularly preferably 2;
    R34, R35, R37, R38
    
        independently of one another H, (C1-C8)-alkyl;

or

    
    
    R34 and R35
    
        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;
    
    
    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;
    R40 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (C0-C8)-alkylene-aryl;
    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;
    R78, R79 independently of one another H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, OH, (C1-C4)-alkoxy-(C1-C4)-alkyl;
    R80, R81 independently of one another H, (C1-C8)-alkyl;
    R3 H, (C1-C6)-alkyl; preferably H;
    R4, R5 independently of one another H, (C1-C6)-alkyl, OH, O—(C1-C6)-alkyl, O—CO—(C1-C6)-alkyl, S—(C1-C6)-alkyl;
    
        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;
    
    
    R6, R7, R8, R9
    
        H;

or

    
    
    R6 and R7, R8 and R9
    
        independently of one another optionally oxo;
    
    
    preferably R6, R7, R8, R9 are H;
    n 1
    m 1 or 2; preferably 1;
    A, B, D, G independently of one another N, C(R42);
    
        or
        the groups A and B or D and G are each C(R42) and together form an ortho-phenylene unit to result overall in a 1,4-bisubstituted naphthalene system;
        preferably
        B is N, C(R42); and A, D, G C(R42);
        particularly preferably
        A, B, D, G are C(R42);
    
    
    R42 H, F, Cl, Br, CF3, CN, O—(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);
    
        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);
        particularly preferably H, F, Cl, CF3, CN, (C1-C6)-alkyl, —(CR84R85)x—O(R86);
    
    
    R43, R44, R45, R46, R47
    
        independently of one another H, (C1-C8)-alkyl;

or

    
    
    R43 and R44, R45 and R46
    
        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;
    
    
    R48, R50, R51
    
        independently of one another H, (C1-C8)-alkyl, aryl; preferably independently of one another H, (C1-C8)-alkyl;
    
    
    R84, R85 H;
    R86 H, (C1-C6)-alkyl;
    x 0, 1, 2; preferably 0, 1; particularly preferably 1;
    R10 H, (C1-C8)-alkyl;
    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; 
    y O, S, N(R89);
    R89 H, (C1-C8)-alkyl;
    R52, R53, R54, R55, R56
    
        independently of one another H, (C1-C8)-alkyl;
    
    
    E 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, O and S, which 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;
    
        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; 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)
        e.g. E is selected from the group consisting of
    
    






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);

preferably





which may optionally have the aforementioned substituents;

    R57, R58, R61, R63
    
        independently of one another H, (C1-C8)-alkyl;
    
    
    R62, R64, R65
    
        independently of one another H, (C1-C8)-alkyl, aryl; preferably independently of one another H, (C1-C8)-alkyl;
    
    
    K a bond, O, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C═C, C≡C, SCH2, SO2CH2; preferably a bond, O, OCH2, CH2O, N(R66), CON(R68), (C(R69)(R70))v, CO, C≡C, SCH2; particularly preferably a bond, O, OCH2, CH2O, CON(R68), (C(R69)(R70))v, CO, C≡C;
    v 1, 2, 3, 4; preferably 1, 2, 3; particularly preferably 1, 2;
    R66, R67, R68, R69, R70
    
        independently of one another H, (C1-C8)-alkyl;
    
    
    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;
    
        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;
        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;
    
    
    R71, R72, R73, R74, R75, R76, R77
    
        independently of one another H, (C1-C8)-alkyl;

or

    
    
    R72 and R73, R76 and R77
    
        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

the N-oxides and the physiologically tolerated salts thereof.

    
    


In a further preferred embodiment, A, B, G and D in formula I are CH or:
If E is 1,4-phenylene, the preferred meanings for A, B, G and D 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














If E is




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










If E is




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










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













TABLE IV







E
A
B
G
D













CH
C—F
CH
CH



 







CH
CH
C—F
CH



 







CH
C—F
CH
CH



 







CH
C—F
CH
CH



 







CH
CF
CH
CH



 







CH
CF
CH
CH



 







CH
C—F
CH
CH



 







CH
C—F
CH
CH



 







CH
C—F
CH
CH



 







CH
C—F
CH
CH



 







CH
C—F
CH
CH



 







CH
C—F
CH
CH



 







CH
C—F
CH
CH



 







CH
C—F
CH
CH



 







CH
C—F
CH
CH



 







CH
C—F
CH
CH










The radicals R11, K, X and E in formula I have in a particularly preferred embodiment one of the following meanings:
R11is preferably selected from the group consisting of:

    n-propyl, n-butyl, iso-butyl, iso-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohex-(1)-enyl, phenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-tolyl, p-methoxyphenyl, p-trifluoromethylphenyl, p-methylthiophenyl, o-fluorophenyl, o-chlorophenyl, o-cyanophenyl, m-fluorophenyl, 2,4-difluorophenyl, 3-fluoro-4-methylphenyl, 2-nitro-4-methylphenyl, 2-amino-4-methylphenyl,






K is preferably selected from the group consisting of:

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


X is preferably selected from the group consisting of bond, NH and CH2.
E is preferably selected from the group consisting of:




Preferred combinations of R11, K, X and E are listed below:
If K and X are each a bond, the particularly preferred meanings for E and R11 areas follows:

    
    
        If E is 1,4-phenylene, R11 is selected from the group consisting of:
        
            cyclohexyl, p-tolyl, p-fluorophenyl, o-fluorophenyl, p-methoxyphenyl, p-chlorophenyl, o-chlorophenyl, 2,4-difluorophenyl, 3-fluoro-4-methylphenyl, o-cyanophenyl,
        
        
    
    






    
    
        If E is
    
    






R 11 selected from the group consisting of: p-chlorophenyl, p-tolyl, p-fluorophenyl, p-methoxyphenyl, p-trifluoromethylphenyl, o-fluorophenyl, phenyl and





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







 



p-Chlorophenyl







 



p-Bromophenyl







 



p-Fluorophenyl







 



p-Chlorophenyl







 














 



p-Tolyl







 



n-Butyl







 



p-Chlorophenyl







 














 














 



p-Methylthiophenyl







 



2-Amino-4-methylphenyl














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

    
    
        If E is 1,4-phenylene, R11 is selected from the group consisting of:
        phenyl, cyclopentyl, n-butyl, iso-butyl, iso-pentyl, 2,4-difluorophenyl and p-fluorophenyl.
    
    


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







 



Cyclopentyl







 



Phenyl







 



n-Butyl







 



n-Butyl














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

    
    
        If E is
    
    






R11 is selected from the group consisting of:

    
    
        phenyl, p-fluorophenyl and p-chlorophenyl.
    
    


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










TABLE VII







R11
E









Phenyl
1,4-Phenylene



 







1,4-Phenylene



 



p-Chlorophenyl














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

    
    
        If E is 1,4-phenylene, R11 is selected from the group consisting of:
        
            phenyl, cyclopropyl and cyclohexyl.
        
        
    
    


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










TABLE VIII







R11
E









Cyclopentyl
1,4-Phenylene



Cyclohex-(1)-enyl
1,4-Phenylene



 



Cyclopentyl














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







 



p-Tolyl
1,4-Phenylene



n-Propyl
1,4-Phenylene



Cyclobutyl
1,4-Phenylene










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







 



Phenyl
SCH2
1,4-Phenylene



 



Cyclopropyl
(CH2)2O














The compounds of the formula I are in a very particularly preferred embodiment compounds of the formula Ia




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.

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

    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),
    
        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);
    
    
    o 0, 1, 2, 3, 4, preferably
    
        0, 1, 2, 3;
    
    
    q 1, 2, 3, preferably
    
        1 or 2;
    
    
    s 0, 1, 2;
    R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32
    
        independently of one another H, (C1-C6)-alkyl;

or

    
    
    R17 and R18, 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, preferably the ring is a pyrrolidine, piperidine, N-methylpiperazine, morpholine ring;
    
    
    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;
    R34, R35
    
        independently of one another H, (C1-C4)-alkyl;
    
    
    R40 H, (C1-C6)-alkyl, (C0-C2)-alkylene-aryl;
    R78, R79 independently of one another H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, OH, (C1-C4)-alkoxy-(C1-C4)-alkyl;
    R42, R42′ independently of one another H, F, Cl, Br, CF3, CN, (C1-C6)-alkyl;
    R10 H, (C1-C8)-alkyl;
    X N(R52), a bond, C═C, C(R53)(R54), CH2CH2;
    R52, R53, R54
    
        
    
    


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

    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);
    
        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
    
    






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);

preferably





which may optionally have the aforementioned substituents;

    R65 H, (C1-C8)-alkyl;
    K a bond, O, OCH2, CH2O, S, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C≡C, SCH2, SO2CH2;
    
        preferably a bond, O, OCH2, CH2O, CON(R68), (C(R69)(R70))v, particularly preferably CH2, CO, C≡C;
    
    
    v 1, 2, 3, preferably
    
        1, 2;
    
    
    R66, R67, R68, R69, R70
    
        independently of one another H, (C1-C8)-alkyl;
    
    
    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;
    
        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;
    
    
    R71, R72, R73, R74, R75, R76, R77
    
        independently of one another H, (C1-C8)-alkyl;

or

    
    
    R72 and R73, R76 and R77
    
        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.
    
    


In a preferred embodiment, the present invention relates to compounds of the formula Ia,
in which


    X is CH2CH2, N(R52), CH2, OCH2, SCH2, CH═CH, preferably CH2CH2, CH═CH;
    E is






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

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.



In a further preferred embodiment, the present invention relates to compounds of the formula Ia,
in which


    X is N(R52), preferably NH, or C(R53)(R54);
    E is






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

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.

    
    


In a further particularly preferred embodiment, the compounds of the formula I are compounds of the formula Ib




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.

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

    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);
    
        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);
        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;
        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;
    
    
    o 0, 1, 2, 3, 4, 5, 6; preferably 0, 1, 2, 3, 4; particularly preferably 0, 1, 2, 3;
    q, r independently of one another 1, 2, 3; preferably q is 1 or 2;
    s 0, 1, 2, 3, 4; preferably 0, 1, 2, 3; particularly preferably 0, 1, 2;
    R13, R14 independently of one another a phenyl ring which may comprise 0-1 nitrogen atoms;
    R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32
    
        independently of one another H, (C1-C6)-alkyl;
    
    
    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

    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; preferably the ring is pyrrolidine, piperidine, N-methylpiperazine, morpholine;
    R33 a 5-10 membered aromatic ring system which may comprise a further heteroatom from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1-C6)-alkyl, 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), 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);
    
        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;
        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;
    
    
    t 0, 1, 2, 3, 4, 5, 6;
    u 0, 1, 2; preferably 0 or 2; particularly preferably 2;
    R34, R35, R37, R38
    
        independently of one another H, (C1-C8)-alkyl;

or

    
    
    R34 and R35
    
        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;
    
    
    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;
    R40 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (C0-C8)-alkylene-aryl;
    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;
    R78, R79 independently of one another H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, OH, (C1-C4)-alkoxy-(C1-C4)-alkyl;
    R80, R81 independently of one another H, (C1-C8)-alkyl;
    R10 H, (C1-C8)-alkyl;
    E 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, O and S, which 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)-alky 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;
    
        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;
        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)
        e.g. E is selected from the group consisting of
    
    






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);

preferably





which may optionally have the aforementioned substituents;

    R57, R58, R61, R63
    
        independently of one another H, (C1-C8)-alkyl;
    
    
    R62, R64, R65
    
        independently of one another H, (C1-C8)-alkyl, aryl; preferably independently of one another H, (C1-C8)-alkyl;
    
    
    K a bond, O, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C═C, C≡C, SCH2, SO2CH2;
    
        preferably a bond, O, OCH2, CH2O, N(R66), CON(R68), (C(R69)(R70))v, CO, C≡C, SCH2; particularly preferably a bond, O, OCH2, CH2O, CON(R68), (C(R69)(R70))v, CO, C≡C;
    
    
    v 1, 2, 3, 4; preferably 1, 2, 3; particularly preferably 1, 2;
    R66, R67, R68, R69, R70
    
        independently of one another H, (C1-C8)-alkyl;
    
    
    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;
    
        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;
        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;
    
    
    R71, R72, R73, R74, R75, R76, R77
    
        independently of one another H, (C1-C8)-alkyl;

or

    
    
    R72 and R73, R76 and R77
    
        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.
    
    


In a preferred embodiment, the present invention relates to compounds of the formula Ib
in which


    X is a bond,
    E is






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);

preferably E is





in which the groups may have the aforementioned substituents;

    K is a bond; and

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.



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.
In a further preferred embodiment, the present invention relates to compounds of the formula Ib
in which


    X is a bond;
    E is






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);

preferably





in which the groups may have the aforementioned substituents;

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

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.

    
    


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.
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.
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.
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.
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.
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.
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%.
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).
As used herein, the following definitions apply:
“Patient” means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.
“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.
“Therapeutically effective amount” means a quantity of the compound which is effective in treating the named disorder or condition.
“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.
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.
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.
Further pharmacologically active substances suitable in particular are:

    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.


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.
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.
In one embodiment of the invention, the present compounds are administered in combination with insulin.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.
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.
In one embodiment, the compounds of the formula I are administered in combination with a biguanide, such as, for example, metformin.
In one further embodiment, the compounds of the formula I are administered in combination with a meglitinide, such as, for example, repaglinide.
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-thiazolidined
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.
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.
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.
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-oxoethy]-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.
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.
In one embodiment, the other active ingredient is dexamphatamine or amphetamine.
In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine.
In another embodiment, the other active ingredient is sibutramine or the mono- and bisdemethylated active metabolites of sibutramine.
In one embodiment, the other active ingredient is orlistat.
In one embodiment, the other active ingredient is mazindol or phentermine.
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.







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


EXAMPLES
The efficacy of the compounds was tested as follows:
Biological Test Model:
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









DESCRIPTION OF EXPERIMENTS
Functional Measurements to Find IC50 Values
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.
The examples and preparation methods detailed below serve to illustrate the invention without, however, restricting it.
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.







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







Yet other examples were obtained as indicated in the following scheme.




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

    Methods A, B and C in example 1;
    Method D in example 2;
    Method E in example 3;
    Method E-a in example 275;
    Method E-b in example 286;
    Method F in example 4;
    Method F-a in example 264;
    Method G in example 15;
    Method H in example 237;
    Method H-a in example 298;
    Method I in example 238;
    Method J in example 245;
    Method J-a in example 297;
    Method K in example 250;
    Method L in example 254;
    Method M in example 274;
    Method N in example 277;
    Method O in example 279;
    Method O-a in example 292;
    Method O-b in example 280;
    Method P in example 285;
    Method Q in example 290;
    Method R in example 309.

General Explanations

a) Mode of Drawing the Structural Formulae



Only non-hydrogen atoms are depicted for clarity in the structural formulae of the given examples.
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.
b) Salt Forms
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.
c) Units of the Characterizing Data
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 




Method A

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+).
N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide
Method B
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+).
N-Methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide
Method C
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




Method D

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




Method E

TOTU (327 mg) was added to a solution of 1-[4-(3-methylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea (402 mg) in DMF (3 ml) at 0° C. 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




(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+).
(R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide
(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+).
(R)-N-Methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide
Method F
(R)-N-[1-(4-Nitrophenyl)pyrrolidin-3-yl]acetamide (1.3 g) was added 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+).
(R)-N-[1-(4-Nitrophenyl)pyrrolidin-3-yl]acetamide
(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




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




(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




(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




(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+).
(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.
4-Cyclopentyloxyaniline
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




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+).
(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)methyl-carbamate




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




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-oxo-pyrrolidin-2-ylmethyl)amino]pyrrolidin-1-yl}phenyl)urea




(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




N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-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 455.00 (C25H31ClN4O2); MS (ESI): 455 (M+H+).
(R)- and (S)-4-(4-chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]phenyl}amide were obtained analogously from (R)- and (S)-N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide.
Example 14 
tert-Butyl (R)-[1-(4-{[4-(4-chlorophenyl)piperidine-1-carbonyl]amino}-phenyl)pyrrolidin-3-yl]methylcarbamate




tert-Butyl (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate was reacted with carbonyldiimidazole 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+).
tert-Butyl (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate
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+).
tert-Butyl (R)-methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate
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+).
tert-Butyl (R)-[1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate
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




Method G

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




(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




(R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid [4-(3-methylamino-pyrrolidin-1-yl)phenyl]amide was reacted with piperidin-1-ylacetic acid by method 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




(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




(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+).
(R)-[N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-2,2,2-trifluoro-N-methylacetamide
(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+).
(R)-2,2,2-Trifluoro-N-methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide
Trifluoroacetic anhydride (0.5 ml) was added dropwise to a solution 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+).
(R)-Methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]amine
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




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




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




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




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




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+).
(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




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




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




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




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




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




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-3yl]methylcarbamate




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




tert-Butyl (R)-[1-(5-{[4-(4-chlorophenyl)piperidine-1-carbonyl]amino}pyridin-2-yl)pyrrolidin-3yl]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+).
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




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




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




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




([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




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+).
N-[1-(4-Aminophenyl)azetidin-3-yl]-N-methylacetamide
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+).
N-Methyl-N-[1-(4-nitrophenyl)azetidin-3-yl]acetamide
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+).
N-[1-(4-Nitrophenyl)azetidin-3-yl]acetamide
Acetic anhydride (0.6 ml) was added to a solution of 1-(4-nitrophenyl)-azetidin-3-ylamine (0.5 g ) in pyridine (1.2 ml). After one hour, volatile fractions were removed. This resulted in the product with the molecular weight of 235.24 (C11H13N3O3); MS (ESI): 236 (M+H+).
1-(4-Nitrophenyl)azetidin-3-ylamine
tert-Butyl [1-(4-nitrophenyl)azetidin-3-yl]carbamate was treated with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 193.21 (C9H11N3O2); MS (ESI): 194 (M+H+).
tert-Butyl [1-(4-nitrophenyl)azetidin-3-yl]carbamate
tert-Butyl azetidin-3-ylcarbamate was reacted with 4-fluoronitrobenzene 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




tert-Butyl [1-(4-aminophenyl)azetidin-3-yl]methylcarbamate was reacted with carbonyldiimidazole 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+).
tert-Butyl [1-(4-aminophenyl)azetidin-3-yl]methylcarbamate
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+).
tert-Butyl methyl-[1-(4-nitrophenyl)azetidin-3-yl]carbamate
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




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




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




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




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




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




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




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




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




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




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




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




(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




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+).
6-Cyclopentyloxypyridin-3-ylamine
A mixture of 5-nitropyridin-2-ol (14.0 g), bromocyclopentane (8.0 g), potassium carbonate (14 g) and DMF (200 ml) was heated at 80° C. 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




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




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




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
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
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 
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 
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




Cyclopropanecarboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl)pyrrolidin-3-yl)amide
C28H30N4O3
470.58
471


 


56




3,N-Dimethyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)butyramide
C29H34N4O3
486.62
487


 


57




2,N-Dimethyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)butyramide
C29H34N4O3
486.62
487


 


58




N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)benzamide
C31H30N4O3
506.61
507


 


59




(E)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)-3-phenylacrylamide
C33H32N4O3
532.65
533


 


60




2-Cyclopentyl-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide
C31H36N4O3
512.66
513


 


61




Cyclohexanecarboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide
C31H36N4O3
512.66
513


 


62




N-Methyl-2-methylsulfanyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenylpyrrolidin-3-yl)acetamide
C27H30N4O3S
490.63
491


 


63




N-Methoxy-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenylpyrrolidin-3-yl)acetamide
C27H30N4O4
474.56
475


 


64




2-Oxothiazolidine-4-carboxylicacid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide
C28H29N5O4S
531.64
532


 


65




4-Fluoro-N-methyl-N-(1-{4-[3-(4-phenoxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)benzamide
C31H29FN4O3
524.60
525


 


66




Pyridine-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide
C30H29N5O3
507.60
508


 


67




2-Acetylamino-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide
C28H31N5O4
501.59
502


 


68




2,2,3,3-Tetramethylcyclopropanecarboxylic acidmethyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)amide
C32H38N4O3
526.68
527


 


69




3,5-Dimethylisoxazole-4-carboxylicacid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide
C30H31N5O4
525.61
526


 


70




2-Ethoxy-N-methyl-N-(1-{4-[3-(4-phenoxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)acetamide
C28H32N4O4
488.59
489


 


71




3-Methoxy-N-methyl-N-(1-{4-[3-(4-phenoxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)propionamide
C28H32N4O4
488.59
489


 


72




2,2,N-Trimethyl-N-(1-{4-[3-(4-phenoxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)butyramide
C30H36N4O3
500.65
501


 


73




1-Methylcyclopropanecarboxylic acidmethyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)amide
C29H32N4O3
484.60
485


 


74




Cyclobutanecarboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide
C29H32N4O3
484.60
485


 


75




N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)isonicotinamide
C30H29N5O3
507.60
508


 


76




Pyrazine-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide
C29H28N6O3
508.58
509


 


77




5-Oxopyrrolidine-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide
C29H31N5O4
513.60
514


 


78




Thiophene-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide
C29H28N4O3S
512.64
513


 


79




Furan-3-carboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide
C29H28N4O4
496.57
497


 


80




N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)nicotinamide
C30H29N5O3
507.60
508


 


81




4-Cyano-N-methyl-(1-{4-[3-(4-phenoxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)benzamide
C32H29N5O3
531.62
532


 


82




1-Methyl-1H-pyrrole-2-carboxylicacid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide
C30H31N5O3
509.61
510


 


83




3-Cyclopentyl-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)propionamide
C32H38N4O3
526.68
527


 


84




N,N,N′-Trimethyl-N′-(1-{4-[3-(4-phenoxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)succinamide
C30H35N5O4
529.64
530


 


85




3-Phenylpropynoic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide
C33H30N4O3
530.63
531


 


86




(1R,4S)-Bicyclo[2.2.1]heptane-2-carboxylic acidmethyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)amide
C32H36N4O3
524.67
525


 


87




[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




Isoxazole-5-carboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide
C28H27N5O4
497.56
498


 


89




2,N-Dimethyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)benzamide
C32H32N4O3
520.64
521


 


90




2-Methanesulfonyl-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)-aceta-mide
C27H30N4O5S
522.63
523


 


91




(E)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)-3-pyridin-3-ylacrylamide
C32H31N5O3
533.64
534


 


92




4,4,4-Trifluoro-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)butyramide
C28H29F3N4O3
526.56
527


 


93




2-Dimethylamino-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide
C28H33N5O3
487.61
488


 


94




3-Acetylamino-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)propionamide
C29H33N5O4
515.62
516


 


95




Tetrahydrofuran-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)-amide
C29H32N4O4
500.60
501


 


96




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




(S)-1-Acetylpyrrolidine-2-carboxylicacid methyl-(1-{4-[3-(4-phe-noxyphenyl)ureido]phenyl}pyrrolidin-3-yl)amide
C31H35N5O4
541.66
542


 


98




4-Methyl-[1,2,3]thiadiazole-5-carboxylic acidmethyl-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidine-3-yl)amide
C28H28N6O3S
528.64
529


 


99




1,5-Dimethyl-1H-pyrazole-3-carboxylic acidmethyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)amide
C30H32N6O3
524.63
525


 


100




5-Methylhexanoic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide
C31H38N4O3
514.67
515


 


101




Tetrahydropyran-4-carboxylic acid methyl-(1-{4-[3-(4-phe-noxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-amide
C30H34N4O4
514.63
515


 


102




N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)-2-piperi-din-1ylacetamide
C31H37N5O3
527.67
528


 


103




1,3-Dimethyl-1H-pyrazole-4-carboxylic acidmethyl-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)amide
C30H32N6O3
524.63
525





















TABLE 3









Molecu-



Ex.


Molecular
lar


No.
Structure
Name
formula
weight
M + H+







104




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




Benzyl(R)-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-pyr-rolidine-1-carboxylate
C36H43N5O5
625.77
626


 


106




N-(1-{4-[3-(4-cyclopentyloxyphenyl)ureido]-phe-nyl]pyrrolidin-3-yl)-3-dimethylamino-N-methyl-benzamide
C32H39N5O3
541.70
542


 


107




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




tert-Butyl 3-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methyl-carbamoyl]piperidine-1-carboxylate
C34H47N5O5
605.78
606


 


109




Benzyl 5-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-2-oxo-imidazolidine-1-carboxylate
C35H40N6O6
640.75
641


 


110




1-Methylpiperidine-3-carboxylicacid (1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}pyr-rolidin-3-yl)methyl-amide
C30H41N5O3
519.69
520


 


111




2,6-Dioxohexahydropyrimidine-4-carboxylic acid(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylamide
C28H34N6O5
534.62
535


 


112




2-Methyl-5-oxopyrrolidine-2-carboxylicacid (1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)methylamide
C29H37N5O4
519.65
520


 


113




tert-Butyl 4-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-thia-zolidine-3-carboxylate
C32H43N5O5S
609.79
610


 


114




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




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




tert-Butyl-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-mor-pholine-4-carboxylate
C33H45N5O6
607.76
608


 


117




(R)-1-(Toluene-4-sulfonyl)pyrrolidine-2-carboxylicacid(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylamide
C35H43N5O5S
645.83
646


 


118




{(3aS,6aS)-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-hexa-hydrocyclopenta[b]pyrrol-1-yl}oxoacetic acidmethyl ester
C34H43N5O6
617.75
618


 


119




(S)-1-(2,2,2,-Trifluoroacetyl)pyrrolidine-2-carboxylicacid(1-{4-[3-(4-cyclopentyloxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)methylamide
C30H36F3N5O4
587.65
588


 


120




2-Chloro-N-{[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methyl-carbamoyl]-methyl}benzamide
C32H36ClN5O4
590.13
590


 


121




N-{1-[(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)methylcarbamoyl]ethyl}-4-methyl-benzamide
C34H41N5O4
583.74
584


 


122




N-{[(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)methylcarbamoyl]methyl}-3,3-di-methylbutyramide
C31H43N5O4
549.72
550


 


123




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




Benzyl 3-[(1-(4-[3-(4-cyclo-pentyloxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)methylcarbamoyl]piperidine-1-car-boxylate
C37H45N5O5
639.80
640


 


125




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




(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




(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




N-(1-{4-[3-(4-Cyclopentyl-oxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)-N-methyl-2-pyridin-3-ylacetamide
C30H35N5O3
513.65
514


 


129




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




Benzyl 2-[(1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)methylcarbamoyl]piperidin-1-car-boxylate
C37H45N5O5
639.80
640


 


131




Benzyl(S)-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-pipe-ridin-1-carboxylate
C36H43N5O5
625.77
626


 


132




(R)-1-Acetylpyrrolidine-2-carboxylicacid(1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}pyr-rolidin-3-yl)methyl-amide
C30H39N5O4
533.68
534


 


133




(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




1-(2,2-Dimethylpropionyl)pyrrolidine-2-carboxylicacid(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylamide
C33H45N5O4
575.76
576


 


135




(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
C34H40N6O4
596.74
597


 


136




(S)-1-Benzylpyrrolidine-2-carboxylicacid (1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}pyr-rolidin-3-yl)methyl-amide
C35H43N5O3
581.76
582


 


137




Isobutyl 2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-pyr-rolidine-1-carboxylate
C33H45N5O5
591.76
592


 


138




Allyl (S)-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-pyr-rolidine-1-carboxylate
C32H41N5O5
575.71
576


 


139




2-Oxoimidazolidine-4-carboxylicacid(1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)meth-ylamide
C27H34N6O4
506.61
507


 


140




(R)-5-Oxopyrrolidine-2-carboxylicacid(1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)meth-ylamide
C28H35N5O4
505.62
506


 


141




1-Methyl-5-oxopyrrolidine-3-carboxylicacid(1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)methylamide
C29H37N5O4
519.65
520


 


142




1-Benzyl-5-oxopyrrolidine-3-carboxylicacid(1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}-pyr-rolidine-3-yl)methylamide
C35H41N5O4
595.75
596


 


143




5-Oxo-1-phenylpyrrolidine-3-carboxylicacid(1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)methylamide
C34H39N5O4
581.72
582


 


144




5-Oxo-1-p-tolylpyrrolidine-3-carboxylicacid(1-{4-[3-(4-cyclopentyloxy-phenyl)ureido]phenyl}-pyr-rolidin-3-yl)methylamide
C35H41N5O4
595.75
596





















TABLE 4





Ex. No.
Structure
Name
Molecular formula
Molecular weight
M + H+




















145




(E)-N-{4-[3-(Acetylmethylamin-o)pyrrolidin-1-yl]-phenyl}-3-(5,6-dimethylbenzooxazol-2-yl)-a-crylamide
C25H28N4O3
432.53
433


 


146




4′-Ethylbiphenyl-4-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide
C28H31N3O2
441.58
442


 


147




4′-Propylbiphenyl-4-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide
C29H33N3O2
455.61
456


 


148




2′-Fluorobiphenyl-4-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide
C26H26FN3O2
431.51
432


 


149




4′-Cyanobiphenyl-4-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide
C27H26N4O2
438.53
439


 


150




4′-Bromobiphenyl-4-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide
C26H26BrN3O2
492.42
492


 


151




4′-Ethoxybiphenyl-4-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide
C28H31N3O3
457.58
458


 


152




3′,4′-Dichlorobiphenyl-4-car-boxylic acid {4-[3-(acetylme-thylamino)pyrrolidin-1-yl]-phenyl}amide
C26H25Cl2N3O2
482.41
482


 


153




2-Ethylbiphenyl-4-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide
C28H31N3O2
441.58
442


 


154




N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-benzenesulfonylbenzamide
C26H27N3O4S
477.59
478


 


155




N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-cyclopentyloxybenzamide
C25H31N3O3
421.54
422


 


156




N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-(4-chlorophenoxy)-3-nitro-benzamide
C26H25ClN4O5
508.97
509


 


157




N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-(4-fluorophenoxy)benzamide
C26H26FN3O3
447.51
448


 


158




N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-(4-chlorophenoxy)benzamide
C26H26ClN3O3
463.97
464


 


159




N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-cyclohexylbenzamide
C26H33N3O2
419.57
420


 


160




1-(4-Nitrophenyl)piperidine-4-carboxylic acid {4-[3-(acetylmethylamino)pyrro-lidin-1-yl]phenyl}amide
C25H31N5O4
465.56
466


 


161




N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-3-phenoxybenzamide
C26H27N3O3
429.52
430


 


162




N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-propoxybenzamide
C23H29N3O3
395.51
396


 


163




N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-(cyclohex-2-enyloxy)-benzamide
C26H31N3O3
433.56
434


 


164




N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-(3-methylbutoxy)benzamide
C25H33N3O3
423.56
424


 


165




N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-isobutoxybenzamide
C24H31N3O3
409.53
410


 


166




5-(4-Chlorophenyl)furan-2-carboxylic acid {4-[3-(ace-tylmethylamino)pyrrolidin-1-yl]phenyl}amide
C24H24ClN3O3
437.93
438


 


167




5-(4-Methoxyphenyl)thiophene-2-carboxylic acid {4-[3-(ace-tylmethylamino)pyrrolidin-1-yl]-phenyl}amide
C25H27N3O3S
449.58
450


 


168




5-(4-Chloro-2-nitrophenyl)-furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrroli-din-1-yl]phenyl}amide
C24H23ClN4O5
482.93
483


 


169




5-(4-Methyl-2-nitrophenyl)furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrroli-din-1-yl]phenyl}-amide
C25H26N4O5
462.51
463


 


170




5-(4-Fluorophenyl)thiophene-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}-amide
C24H24FN3O2S
437.54
438


 


171




5-(2,4-Dichlorophenyl)furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide
C24H23Cl2N3O3
472.38
472


 


172




4-Methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-carboxylicacid{ 4-[ 3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide
C25H25F3N4O2S
502.56
503


 


173




2-(4-Chlorophenyl)-4-methyl-thiazole-5-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide
C24H25ClN4O2S
469.01
469


 


174




5-Benzyloxy-1H-indole-2-carboxylic acid {4-[3-(acetylmethylamino)pyr-rolidin-1-yl]phenyl}amide
C29H30N4O3
482.59
483


 


175




N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-4-benzyloxybenzamide
C27H29N3O3
443.55
444


 


176




5-Phenylethynylfuran-2-carboxylic acid {4-[3-(acetylmethylamino)pyr-rolidin-1-yl]phenyl}amide
C26H25N3O3
427.51
428


 


177




N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-biphenyl-4-ylacetamide
C27H29N3O2
427.55
428


 


178




N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-(4-butoxyphenyl)acetamide
C25H33N3O3
423.56
424


 


179




N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-(4-benzyloxyphenyl)acetamide
C28H31N3O3
457.58
458


 


180




N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-(4-phenoxyphenyl)acetamide
C27H29N3O3
443.55
444


 


181




N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-(4-benzyloxy-3-methoxy-phenyl)acetamide
C29H33N3O4
487.60
488


 


182




N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-(4′-fluorobiphenyl-4-yl)acetamide
C27H28FN3O2
445.54
446


 


183




N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-[4-(2,5-dimethylpyrrol-1-yl)phenyl]acetamide
C27H32N4O2
444.58
445


 


184




N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-(4-isopropylphenoxy)-acetamide
C24H31N3O3
409.53
410


 


185




N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-(4-ethylphenoxy)acetamide
C23H29N3O3
395.51
396





















TABLE 5





Ex. No.
Structure
Name
Molecular formula
Molecular weight
M + H+




















186




N-Methyl-N-(1-{4-[3-(6-phe-noxypyridin-3-yl)ureido]phenyl}-pyrrolidin-3-yl)acetamide
C25H27N5O3
445.53
446


 


187




N-[1-(4-{3-[4-(2-Chlorophe-noxy)phenyl]ureido}-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide
C26H27ClN4O3
478.98
479


 


188




N-[1-(4-{3-[4-(3-Chlorophe-noxy)phenyl]ureido}-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide
C26H27ClN4O3
478.98
479


 


189




N-Methyl-N-[1-{4-[3-(4-o-tolyloxyphenyl)ureido}-phenyl)-pyrrolidin-3-yl)acetamide
C27H30N4O3
458.57
459


 


190




N-Methyl-N-[1-{4-[3-(4-m-tolyloxyphenyl)ureido}-phenyl)-pyrrolidin-3-yl)acetamide
C27H30N4O3
458.57
459


 


191




N-[1-{4-{3-[4-(2-Fluorophen-oxy)phenyl)ureido}-phenyl)-pyrrolidin-3-yl)-N-methyl-acetamide
C26H27FN4O3
462.53
463


 


192




N-{1-{4-[3-Biphenyl-4-yl-ureido}phenyl]pyrrolidin-3-yl}-N-methylacetamide
C26H28N4O2
428.54
429


 


193




N-[1-(4-{3-[4-(2-Methoxyphe-noxy)phenyl]ureido}-phenyl)-pyrrolidin-3-yl]methyl-acetamide
C27H30N4O4
474.56
475


 


194




N-(1-{4-[3-(4-Isobutoxyphenyl)-ureido}phenyl)pyrrolidin-3-yl]-N-methylacetamide
C24H32N4O3
424.55
425


 


195




N-(1-{4-[3-(4-Cyclopentyloxy-phenyl)ureido}phenyl)pyrro-lidin-3-yl]-N-methylacet-amide
C25H32N4O3
436.56
437


 


196




N-[1-(4-{3-[4-(4-Fluorophe-noxy)phenyl]ureido}-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide
C26H27FN4O3
462.53
463


 


197




N-[1-(4-{3-[4-(3-Methoxyphe-noxy)phenyl]ureido}-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide
C27H30N4O4
474.56
475


 


198




4-(3-Acetylaminophenyl)piperi-dine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]-phenylamide
C27H35N5O3
477.61
478


 


199




N-Methyl-N-(1-{4-[3-(5-phenyl-pyridin-2-yl)ureido]-phenyl}-pyrrolidin-3-yl)acetamide
C25H27N5O2
429.53
430


 


200




N-(1-{4-[3-(2-Acetylamino-4-phenylsulfanylphenyl)-ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide
C28H31N5O3S
517.65
518


 


201




N-(1-{4-[3-(4′-Cyanobiphenyl-4-yl)ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide
C27H27N5O2
453.55
454


 


202




N-(1-{4-[3-(2-Methoxybiphenyl-4-yl)ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide
C27H30N4O3
458.57
459


 


203




4-(2-Chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyr-rolidin-1-yl]phenyl}amide
C25H31ClN4O2
455.00
455


 


204




N-(1-{4-[3-(4-Benzene-sulfonyl-3-chlorophenyl)-ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide
C26H27ClN4O4S
527.05
527


 


205




4-(4-Chlorophenyl)-4-hydroxy-piperidine-1-carboxylicacid {4-[3-(acetylmethyl-amino)pyrrolidin-1-yl]phenyl}amide
C25H31ClN4O3
471.00
471


 


206




4-Phenylpiperidine-1-carboxylicacid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide
C25H32N4O2
420.56
421


 


207




4-Cyano-4-phenylpiperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrro-lidin-1-yl]phenyl}amide
C26H31N5O2
445.57
446


 


208




4-Acetyl-4-phenylpiperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrro-lidin-1-yl]phenyl}amide
C27H34N4O3
462.60
463


 


209




4-(2-Methoxyphenyl)piperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}amide
C26H34N4O3
450.59
451


 


210




4-(4-Fluorophenyl)piperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}amide
C25H31FN4O2
438.55
439


 


211




4-(3-Fluorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrro-lidin-1-yl]phenyl}amide
C25H31FN4O2
438.55
439


 


212




4-(2-Fluorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrro-lidin-1-yl]phenyl}amide
C25H31FN4O2
438.55
439


 


213




4-p-Tolylpiperidine-1-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide
C26H34N4O2
434.59
435


 


214




4-(4-Trifluoromethylphenyl)pi-peridine-1-carboxylic acid{4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}-amide
C26H31F3N4O2
488.56
489


 


215




4-(3-Trifluoromethylphenyl)pi-peridine-1-carboxylic acid{4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}-amide
C26H31F3N4O2
488.56
489


 


216




4-(2-Trifluoromethylphenyl)pi-peridine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide
C26H31F3N4O2
488.56
489


 


217




4-(4-Methoxyphenyl)piperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}-amide
C26H34N4O3
450.59
451


 


218




4-(3-Methoxyphenyl)piperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}-amide
C26H34N4O3
450.59
451


 


219




4-Naphthalen-2-ylpiperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}amide
C29H34N4O2
470.62
471


 


220




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




N-(1-{4-[3-(9-Ethyl-9H-carbazol-3-yl)ureido]-phenyl}-pyrrolidin-3-yl)-N-methyl-acetamide
C28H31N5O2
469.59
470


 


222




N-(1-(4-{3-[4-(4-Chloro-phenoxy)phenyl]ureido}-phenyl)pyrrolidin-3-yl)-N-methylacetamide
C26H27ClN4O3
478.98
479


 


223




N-(1-{4-[3-(4-Benzylphenyl)-ureido]phenyl}-pyrrolidin-3-yl)-N-methylacetamide
C27H30N4O2
442.57
443


 


224




N-Methyl-N-(1-{4-[3-(4-Pyri-din-4-ylmethylphenyl)-ureido]-phenyl}pyrrolidin-3-yl)aceta-mide
C28H30F3N5O4
443.55
444


 


225




N-[1-(4-{3-[6-(2-Fluorophe-noxy)pyridin-3-yl]ureido}-phenyl}pyrrolidin-3-yl)-N-methylacetamide
C25H26FN5O3
463.52
464


 


226




N-Methyl-N-(1-{4-[3-(4-phenyl-sulfanylphenyl)-ureido]phenyl}-pyrrolidin-3-yl)acetamide
C26H28N4O2S
460.60
461


 


227




N-Methyl-N-[1-(4-{3-[4-(3-tri-fluoromethylphenoxy)-phenyl]-ureido}phenyl)pyrrolidin-3-yl]-acetamide
C27H27F3N4O3
512.54
513


 


228




N-Methyl-N-[1-(4-{3-[6-(pyridin-2-ylsulfanyl)pyridin-3-yl]ureido}phenyl)pyrrolidin-3-yl]acetamide
C26H27F3N6O4S
462.58
463


 


229




N-(1-{4-[3-(4-Butoxyphenyl)-ureido]phenyl}-pyrrolidin-3-yl)-N-methylacetamide
C24H32N4O3
424.55
425


 


230




4-Benzylpiperidine-1-carboxylicacid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide
C26H34N4O2
434.59
435


 


231




Benzo-8-azaspiro[4.5]decane-8-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}amide
C27H34N4O2
446.60
447


 


232




4-Benzofuran-3-ylpiperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}amide
C27H32N4O3
460.58
461


 


233




4-p-Tolyloxypiperidine-1-car-boxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}amide
C26H34N4O3
450.59
451


 


234




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




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




(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




Method H

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+).
N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)propionamide 
N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide 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




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+).
N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)acetamide
Method I
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




(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




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




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




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




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+).
1-(4-Hydroxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide
Boron tribromide-dimethyl sulfide (460 mg) was added to a solution of 1-(4-methoxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide (540 mg) 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




(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




Method J

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




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




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




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




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+).
4-Bromo-2-methylbutan-2-ol
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




Method K

A solution of (R)-N-[6-(3-aminopyrrolidin-1-yl)pyridin-3-yl]-4-butoxybenzamide (0.065 g) in methanol (2 ml) was mixed with 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




(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




(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




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+).
4-Butoxy-2-nitrobenzoic acid
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




Method L

A mixture of N-[4-(3-bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide (100 mg), potassium carbonate (60 mg), 7-azabicyclo[2.2.1]heptane (44 mg) and DMF (2 ml) was kept at 50° C. for 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+).
N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide
N-(4-Aminophenyl)-4-cyclohexyl-N-methylbenzamide (3.0 g) in acetonitrile (30 ml) was mixed with trisodium phosphate (0.95 g) and, at 0° C., 2-bromo-4-chlorobutyryl bromide (2.9 g) was added. After one hour, a solution 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+).
N-(4-Aminophenyl)-4-cyclohexyl-N-methylbenzamide
4-Cyclohexylcarboxylic acid (5.0 g) and 4-nitrophenylisocyanate (4.0 g) were stirred in toluene (150 ml) for 3 hours and then left to stand overnight. The precipitate was filtered off with suction and washed with diethyl ether. The resulting amide was ethylated by method F and hydrogenated 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




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




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




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




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




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




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-methyl-benzamide




4-Cyclohexyl-N-methyl-N-[4-(3-methylamino-2-oxopyrrolidin-1-yl)phenyl]benzamide (52 mg) was mixed with pyridine (0.5 ml) and acetic 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




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+).
1-{4-[(4-Cyclohexylbenzoyl)methylamino]phenyl}-5-oxo-pyrrolidine-3-carboxylic acid
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




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




Method F-a

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




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




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




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+).
The following further compounds were obtained by method F-a from tert-butyl {1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylcarbamate and the appropriate alkylating agent:

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


Example 268
5-p-Tolylethinylfuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide




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.
5-Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide
[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with 5-bromo-2-furancarboxylic acid by method E. The product with a molecular weight of 378.27 (C17H20BrN3O2); MS (ESI): 379 (M+H+) was obtained as hydrotrifluoroacetate.
Examples 269-273 were prepared analogously:
















Molecular
Molecular



Ex. No.
Structure
formula
weight
M+H+







269




C26H27N303
429.21
430


 


270




C25H23F2N3O2
435.18
436


 


271




C26H27N3O3
429.21
430


 


272




C25H24FN3O2
417.19
418


 


273




C25H24CIN3O2
433.16
434









Example 274 
(R)-4′-Fluorobiphenyl-4-carboxylic acid [6-(3-dimethylaminopyrrolidin-1-yl)pyridin-3-yl]-amide




Method M

(R)-4′-Fluorobiphenyl-4-carboxylic acid [6-(3-methylaminopyrrolidin-1-yl)pyridin-3-yl]-amide (390 mg) dissolved in formic acid (230 mg) was 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




Method E-a

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.
1-(4-Fluorophenyl)piperidine-4-carboxylic acid
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.
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




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+).
4-Phenoxycyclohexanecarboxylic acid
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+).
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




Method N

(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+).
4-Isobutoxy-N-[4-(3-oxopyrrolidin-1-yl)phenyl]benzamide 
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+).
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.
4-(1,4-Dioxa-7-azaspiro[4.4]non-7-yl)phenylamine
Trimethylchlorosilane (9.3 g) was slowly added to a solution of 1-benzyl-3-pyrrolidinone (5.0 g) in dichloromethane (30 ml) and ethylene glycol (2.67 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+).
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




(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




Method O

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.
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.

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


The following compounds were prepared analogously:

    5-Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide
    tert-Butyl (1-{4-[(5-bromothiophene-2-carbonyl)amino]phenyl}pyrrolidin-3-yl)methylcarbamate
    2-Bromothiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide
    4-Iodo-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]benzamide
    (R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-iodobenzamide
    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




Method O-b

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




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.
N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic acid benzamide
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




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.
2-Boronic acid thiophene-5-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide
5-Carboxy-2-thiopheneboronic acid was reacted with [1-(4-aminophenyl)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




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.
5-[4-(3-Dimethylaminopyrrolidin-1-yl)phenylcarbamoyl]pyridin-2-yl [trifluoromethanesulfonate
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.
N-[4-(3-Dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide
6-Hydroxynicotinic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the 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




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




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.
2′,4′-Difluorobiphenyl-4-carboxylic acid
Method P
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.
Ethyl 2′,4′-difluorobiphenyl-4-carboxylate
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




Method E-b

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




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.
3-Fluoro-4-(4-methylpiperidin-1-yl)benzoic acid
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+).
Methyl 3-fluoro-4-(4-methylpiperidin-1-yl)benzoate
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




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+).
(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




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




Method Q

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




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




Method O-a

5-Chloropyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (100 mg) dissolved in toluene was mixed with 4-fluorophenylboronic acid (81 mg), POPD (15 mg) and 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+).
5-Chloropyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide
[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with 5-chloropyridine-2-carboxylic acid by method E. This resulted in the 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




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




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




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




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




Method J-a

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




Method H-a

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




(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




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




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.
6-Chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]nicotinamide
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.
The following examples were prepared analogously.
















Molecular
Molecular



Ex. No.
Structure
formula
weight
M+H+







302




C24H26N4O2
402.21
403


 


303




C24H25ClN4O2
436.17
437


 


304




C25H28N4O2
416.22
417









Example 305 
N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-phenoxybenzamide




Powdered molecular sieves (4 A), 0.01 g of copper acetate and 0.02 g 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.
N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic acid benzamide
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




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+)
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
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




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




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




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.
Method R
A solution of 0.05 g of N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-4-hydroxybenzamide, 0.017 g of 2,5-dichloropyridine and 0.064 g of 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.
4-[4-(3-Dimethylaminopyrrolidin-1-yl)phenylcarbamoyl]phenyl Acetate
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




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




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




[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+).
5-Chloro-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridine
A solution of tert-butyl 5-chloro-3′,6′-dihydro-2′H-[2,4′]bipyridine-1′-carboxylate (50 mg) in chloroform (2.4 ml) was mixed with 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+).
tert-Butyl 5-chloro-3′,6′-dihydro-2′H-[2,4′]bipyridine-1′-carbamate
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




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




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




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




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+).
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]methylamide
tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]methylcarbamoyl}-piperidine-1-carboxylate was treated with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 330.48 (C19H30N4O); MS (ESI): 331 (M+H+).
Piperidine-4-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]-amide can be prepared analogously.
tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]methylcarbamoyl}-piperidine-1-carboxylate
A solution of N-Boc-piperidine-4-carboxylic acid (550 mg) and pyridine (0.47 ml) in dichloromethane (15 ml) was mixed with 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+).
tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]carbamoyl}piperidin-1-carboxylate can be prepared analogously.
The following examples were prepared analogously.
















Molecular
Molecular



Ex. No.
Structure
formula
weight
M+H+







317




C25H30ClN5O
466.03
466


 


318




C24H30ClN5O3
471.99
472


 


319




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




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+).
The following examples were prepared analogously.
















Molecular
Molecular



Ex. No.
Structure
formula
weight
M+H+







321




C25H32ClN5O3
486.02
486


 


322




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




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




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




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+).
The following examples were prepared analogously.
















Molecular
Molecular



Ex. No.
Structure
formula
weight
M+H+







326




C27H36FN5O2
481.62
482


 


327




C26H34ClN5O2
484.05
484


 


328




C26H34FN5O3
467.59
468









Example 329 
(R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-(4-phenylpiperidin-1-yl)acetamide




Cesium carbonate (100 mg) and 4-phenylpiperidine (48 mg) were added to a 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+).
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.
(R)-2-Chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]acetamide
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+).
The following were obtained analogously:

    N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-chloroacetamide
    2-Chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]acetamide
    (R)-2-Chloro-N-[6-(3-dimethylaminopyrrolidin-1-yl)pyridin-3-yl]acetamide


The following examples were prepared in analogy to the method given in example 329:
















Molecular
Molecular



Ex. No.
Structure
formula
weight
M+H+







330




C25H34N4O
406.58
407


 


331




C26H34N4O2
434.59
435


 


332




C26H33ClN4O2
469.03
469


 


333




C27H30N4O3
458.57
459


 


334




C25H29N5O2
431.54
432


 


335




C25H28ClN5O2
465.99
466


 


336




C26H33N5O3
463.59
464


 


337




C25H33ClN4O2
441.02
441


 


338




C25H34N4O2
422.58
423


 


339




C24H33N5O2
423.56
424









Example 340 
(R)-4-Benzylpiperidine-1-carboxylic acid [6-(3-dimethylaminopyrrolidin-1-yl)pyridin-3-yl]-amide




(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+).
The following examples were prepared analogously:
















Molecular
Molecular



Ex. No.
Structure
formula
weight
M+H+







341




C24H31N5O2
421.55
422


 


342




C24H33N5O
407.56
408


 


343




C26H34N4O3
450.59
451


 


344




C25H31ClN4O2
455.00
455


 


345




C26H30N4O
414.56
415


 


346




C24H39N5O
413.61
414


 


347




C26H37N5O
435.62
436









Example 348
(R)-4-Cyclopropylmethoxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-benzamide




(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 cyclopropylmethyl bromide by method H. This resulted in the product with the molecular weight of 397.50 (C23H28N3O2); MS (ESI): 398 (M+H+).
The following examples were likewise obtained by method H:
















Molecular
Molecular



Ex. No.
Structure
formula
weight
M+H+







349




C26H34FN3O2
439.58
440


 


350




C25H32FN3O3
441.55
442


 


351




C24H30FN3O2
411.52
412









Example 352
(R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-(pyridin-2-yloxy)benzamide




(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
Various pyrrolidinylanilines were reacted with diverse amines by method A. The resulting products are summarized in table 6.
Example 508-Example 1130
Various pyrrolidinylanilines were reacted with diverse acids by methods E. The resulting products are summarized in table 7.
Example 1131-Example 1232
Various (hetero)aryl halides were reacted with diverse boronic acids by methods O. The resulting products are summarized in table 8.
Example 1233-Example 1237
Various aryl halides were reacted with diverse acetylenes by methods J. The resulting products are summarized in table 9.
Example 1238-Example 1403
Various aminopyrrolidines and N-arylpyrrolidinones were reacted with diverse aldehydes, ketones and amines by method N. The resulting products are summarized in table 10.
Example 1404-Example 1423
Various aminopyrrolidines were reductively methylated with formaldehyde by method E. The resulting products are summarized in table 11.
Example 1424-Example 1443
Various amides were alkylated by method F. The resulting products are summarized in table 12.
Example 1444-Example 1618
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




C25H31FN4O2
438.24
439


 


354




C25H30N4O4
450.23
451


 


355




C25H31ClN4O3
470.21
471


 


356




C26H30N4O2
430.24
431


 


357




C24H29ClN4O
424.20
425


 


358




C25H35N5O
421.28
422


 


359




C23H3OBrN5O
471.16
472


 


360




C24H34N4O
394.27
395


 


361




C26H28N4O3
444.22
445


 


362




C24H29N5O
403.24
404


 


363




C27H29N5OS
471.21
472


 


364




C26H30N4O2
430.24
431


 


365




C25H30N6O3
462.24
463


 


366




C22H25N5O2
391.20
392


 


367




C26H28N6O
440.23
441


 


368




C24H29FN4O
408.23
409


 


369




C26H30N4O3
446.23
447


 


370




C25H27ClN4O2
450.18
451


 


371




C25H27FN4O2
434.21
435


 


372




C26H30N4O2
430.24
431


 


373




C26H30N4O2
430.24
431


 


374




C26H30N4O3
446.23
447


 


375




C25H27ClN4O2
450.18
451


 


376




C23H32N4O2
396.25
397


 


377




C25H29N5O2
431.23
432


 


378




C24H27N5O2
417.22
418


 


379




C25H35N5O2
437.28
438


 


380




C25H27FN4O2
434.21
435


 


381




C26H27F3N4O2
484.21
485


 


382




C26H27F3N4O
468.21
469


 


383




C24H31ClN4O2
442.21
443


 


384




C25H28N4O
400.23
401


 


385




C26H30N4O2
430.24
431


 


386




C23H32N4O2
396.25
397


 


387




C25H34N4O2
422.27
423


 


388




C24H31ClN4O
426.22
427


 


389




C25H34N4O
406.27
407


 


390




C25H31F3N4O
460.24
461


 


391




C25H31F3N4O2
476.24
477


 


392




C23H31N5O4
441.24
442


 


393




C24H30N4O3
422.23
423


 


394




C24H32ClN5O
441.23
442


 


395




C25H27ClN4O
434.19
435


 


396




C25H28N4O
400.23
401


 


397




C24H28N6O
416.23
417


 


398




C25H34N4O2
422.27
423


 


399




C28H34N4O
442.27
443


 


400




C25H27N5O3
445.21
446


 


401




C25H27ClN4O
434.19
435


 


402




C24H31ClN4O2
442.21
443


 


403




C24H33N5O
407.27
408


 


404




C22H30N4O2
382.24
383


 


405




C25H34N4O
406.27
407


 


406




C22H22Cl2F6N4O2
558.10
559


 


407




C26H27F3N4O2
484.21
485


 


408




C24H31FN4O
410.25
411


 


409




C24H31FN4O
410.25
411


 


410




C24H31FN4O
410.25
411


 


411




C25H34N4O
406.27
407


 


412




C25H34N4O
406.27
407


 


413




C24H32N4O2
408.25
409


 


414




C22H26N6O
390.22
391


 


415




C26H27BrN4O
490.14
491


 


416




C21H24N6OS
408.17
409


 


417




C26H27N5O
425.22
426


 


418




C24H32N4O
392.26
393


 


419




C25H27ClN4O2
450.18
451


 


420




C24H30N4O3
422.23
423


 


421




C24H29ClN4O2
440.20
441


 


422




C26H31ClN4O2
466.21
467


 


423




C28H35ClN4O
478.25
479


 


424




C28H38N4O4
494.29
495


 


425




C24H31ClN4O2
442.21
443


 


426




C25H33ClN4O2
456.23
457


 


427




C25H28N4O3
432.22
433


 


428




C25H29FN4O2
436.23
437


 


429




C24H30BrN5O2
499.16
500


 


430




C25H29ClN4O2
452.20
453


 


431




C25H32N4O3
436.25
437


 


432




C24H32BrN5O2
501.17
502


 


433




C22H30N6O
394.25
395


 


434




C24H30F3N5O
461.24
462


 


435




C21H29N7O
395.24
396


 


436




C23H31N5O
393.25
394


 


437




C22H30N6O
394.25
395


 


438




C21H29N7O
395.24
396


 


439




C23H30ClN5O
427.21
428


 


440




C23H30ClN5O
427.21
428


 


441




C23H30ClN5O
427.21
428


 


442




C23H30FN5O
411.24
412


 


443




C23H30FN5O
411.24
412


 


444




C24H33N5O
407.27
408


 


445




C24H33N5O
407.27
408


 


446




C24H33N5O
407.27
408


 


447




C24H33N5O
407.27
408


 


448




C24H30F3N5O
461.24
462


 


449




C24H30F3N5O
461.24
462


 


450




C24H30N6O
418.25
419


 


451




C24H33N5O2
423.26
424


 


452




C24H33N5O2
423.26
424


 


453




C24H33N5O2
423.26
424


 


454




C25H33N5O2
435.26
436


 


455




C24H29ClF3N5O
495.20
496


 


456




C24H32ClN5O
441.23
442


 


457




C25H35N5O
421.28
422


 


458




C23H29Cl2N5O
461.17
462


 


459




C23H29F3N6O
462.24
463


 


460




C23H29F3N6O
462.24
463


 


461




C23H28ClF3N6O
496.20
497


 


462




C25H35N5O2
437.28
438


 


463




C23H29Cl2N5O
461.17
462


 


464




C25H35N5O
421.28
422


 


465




C23H29Cl2N5O
461.17
462


 


466




C25H35N5O3
453.27
454


 


467




C24H32ClN5O2
457.22
458


 


468




C23H38N6O
414.31
415


 


469




C23H29F2N5O
429.23
430


 


470




C24H30N6O
418.25
419


 


471




C25H35N5O
421.28
422


 


472




C23H37N5O
399.30
400


 


473




C23H32N6O
408.26
409


 


474




C23H32N6O
408.26
409


 


475




C26H37N5O
435.30
436


 


476




C28H36ClN5O2
509.26
510


 


477




C25H34N4O
406.27
407


 


478




C25H31FN4O2
438.24
439


 


479




C23H27ClFN5O
443.96
444


 


480




C23H30FN5O2
427.53
428


 


481




C23H29F2N5O2
445.52
446


 


482




C23H27F2N5O
427.50
428


 


483




C23H29ClFN5O2
461.97
462


 


484




C28H37FN4O4
512.28
513


 


485




C28H32FN5O4
521.24
522


 


486




C23H30ClN5O2
443.98
444


 


487




C23H29ClFN5O2
461.97
462


 


488




C26H34N4O2
434.27
435


 


489




C30H36N4O
468.29
469


 


490




C26H34N4O3
450.26
451


 


491




C25H32N4O2
420.25
421


 


492




C26H34N4O3
450.26
451


 


493




C25H30N4O3
434.23
435


 


494




C26H35N5O2
449.28
450


 


495




C25H30FN5O2
451.24
452


 


496




C25H31N5OS
449.23
450


 


497




C26H33N5O
431.27
432


 


498




C27H35N5O
445.28
446


 


499




C25H31F3N4O2
476.24
477


 


500




C26H35N5O3S
497.25
498


 


501




C25H31N5O3
449.24
450


 


502




C23H29ClN4O
412.20
413


 


503




C23H29FN4O
396.23
397


 


504




C25H31N5O
417.25
418


 


505




C24H30N6O3
450.24
451


 


506




C24H31FN4O2
426.24
427


 


507




C25H31FN4O
422.25
423




















TABLE 7





Ex.

Molecular
Monoisotopic
M +


No.
Structure
formula
molecular wt.
H+



















508




C26H33N3O2
419.26
420


 


509




C26H34N4O2
434.27
435


 


510




C26H27N3O2
413.21
414


 


511




C30H35N3O2
469.27
470


 


512




C27H29N3O2
427.23
428


 


513




C27H28N4O6S
536.17
537


 


514




C25H33N3O3
423.25
424


 


515




C24H29N3O3
407.22
408


 


516




C25H33N3O3
423.25
424


 


517




C27H29N3O3
443.22
444


 


518




C27H29N3O2
427.23
428


 


519




C27H29N3O2
427.23
428


 


520




C27H29N3O2
427.23
428


 


521




C27H26F3N3O2
481.20
482


 


522




C27H26F3N3O2
481.20
482


 


523




C28H31N3O4
473.23
474


 


524




C27H28N4O4S
504.18
505


 


525




C26H25ClFN3O3
481.16
482


 


526




C24H25N3O3
403.19
404


 


527




C24H25N3O2S
419.17
420


 


528




C25H28N4O2
416.22
417


 


529




C24H24ClN3O3
437.15
438


 


530




C24H24FN3O3
421.18
422


 


531




C25H33N3O
391.26
392


 


532




C25H27N3O2
401.21
402


 


533




C25H27N3O
385.21
386


 


534




C23H31N3O2
381.24
382


 


535




C26H29N3O2
415.23
416


 


536




C25H27N3O
385.21
386


 


537




C24H31N3O
377.25
378


 


538




C25H26N4O4
446.20
447


 


539




C26H29N3O
399.23
400


 


540




C26H29N3O2
415.23
416


 


541




C28H33N3O2
443.26
444


 


542




C25H29N5O4
463.22
464


 


543




C23H31N3O2
381.24
382


 


544




C25H27N3O2
401.21
402


 


545




C25H31N3O2
405.24
406


 


546




C27H31N3O
413.25
414


 


547




C28H33N3O
427.26
428


 


548




C21H22FN5O2
395.18
396


 


549




C25H25N3O2
399.20
400


 


550




C29H35N3O
441.28
442


 


551




C23H23ClN4O4
454.14
455


 


552




C25H26FN3O2
419.20
420


 


553




C26H29N3O
399.23
400


 


554




C27H29N3O2
427.23
428


 


555




C28H38N4O3
478.29
479


 


556




C25H26FN3O
403.21
404


 


557




C23H24FN3OS
409.16
410


 


558




C26H26F3N3O2
469.20
470


 


559




C29H34N4O2
470.27
471


 


560




C25H26N4O4
446.20
447


 


561




C24H33N3O2
395.26
396


 


562




C24H33N3O2
395.26
396


 


563




C25H26FN3O
403.21
404


 


564




C26H29N3O2
415.23
416


 


565




C25H26ClN30
419.18
420


 


566




C26H29N3O2
415.23
416


 


567




C26H29N3O2
415.23
416


 


568




C25H26FN3O
403.21
404


 


569




C26H27N3O3
429.20
430


 


570




C26H29N3O
399.23
400


 


571




C26H29N3O
399.23
400


 


572




C26H26F3N3O
453.20
454


 


573




C26H26F3N3O
453.20
454


 


574




C26H35N3O2
421.27
422


 


575




C27H31N3O2
429.24
430


 


576




C25H26ClN3O
419.18
420


 


577




C25H25Cl2N3O
453.14
454


 


578




C24H28N4O2
404.22
405


 


579




C27H31N3O3S
477.21
478


 


580




C25H31N5O3
449.24
450


 


581




C24H31N3O2
393.24
394


 


582




C23H31N3O2
381.24
382


 


583




C25H25F3N4O2
470.19
471


 


584




C24H39N3O
385.31
386


 


585




C25H25Cl2N3O
453.14
454


 


586




C25H26BrN3O
463.13
464


 


587




C25H32ClN3O
425.22
426


 


588




C25H32N4O2
420.25
421


 


589




C24H26N4O4
434.20
435


 


590




C24H30FN3O2
411.23
412


 


591




C26H28FN3O
417.22
418


 


592




C25H25N5O2
427.20
428


 


593




C26H26N4O
410.21
411


 


594




C26H32FN3O2
437.25
438


 


595




C25H26ClN3O
419.18
420


 


596




C24H26N4O
386.21
387


 


597




C26H26F3N3O
453.20
454


 


598




C27H31N3O3
445.24
446


 


599




C28H29N3O3
455.22
456


 


600




C24H33N3O2
395.26
396


 


601




C25H27N3O
385.21
386


 


602




C28H30N4O2
454.24
455


 


603




C26H36N4O4
468.27
469


 


604




C28H38N4O3
478.29
479


 


605




C22H28FN3O2S
417.55
418


 


606




C23H29N3O3
395.22
396


 


607




C27H33N3O3
447.25
448


 


608




C27H37N3O4
467.28
468


 


609




C29H39N3O3
477.30
478


 


610




C27H29FN4O3
476.22
477


 


611




C25H34N4O4
454.26
455


 


612




C27H35N3O2
433.27
434


 


613




C25H31N3O3
421.24
422


 


614




C28H32N4O4
488.24
489


 


615




C27H35ClN4O3
498.24
499


 


616




C26H29N5O4
475.22
476


 


617




C28H36F3N3O4
535.27
536


 


618




C27H38N4O4
482.29
483


 


619




C27H38N4O4
482.29
483


 


620




C28H39N3O5
497.29
498


 


621




C23H23N5O3
417.18
418


 


622




C25H26N4O2
414.21
415


 


623




C28H35ClN4O4
526.23
527


 


624




C28H39N3O4
481.29
482


 


625




C27H36ClN3O4
501.24
502


 


626




C27H35F2N3O4
503.26
504


 


627




C27H36FN3O4
485.27
486


 


628




C27H36FN3O4
485.27
486


 


629




C28H39N3O4
481.29
482


 


630




C28H36F3N3O4
535.27
536


 


631




C27H35ClFN3O4
519.23
520


 


632




C28H36N4O4
492.27
493


 


633




C28H38ClN3O4
515.26
516


 


634




C31H39N3O4
517.29
518


 


635




C27H36BrN3O4
545.19
546


 


636




C28H36N4O4
492.27
493


 


637




C26H35ClN4O4
502.23
503


 


638




C27H35F2N3O4
503.26
504


 


639




C27H36BrN3O4
545.19
546


 


640




C27H35F2N3O4
503.26
504


 


641




C23H31N3O3
397.24
398


 


642




C24H33N3O3
411.25
412


 


643




C27H37N3O5
483.27
484


 


644




C25H34N4O4
454.26
455


 


645




C27H36FN3O4
485.27
486


 


646




C27H24FN3O3
457.18
458


 


647




C27H33N3O2
431.26
432


 


648




C23H31N3O3
397.24
398


 


649




C25H24FN3O2
417.18
418


 


650




C27H36N4O3
464.28
465


 


651




C25H26N4O2
414.21
415


 


652




C31H33FN4O3
528.25
529


 


653




C32H38N4O2
510.30
511


 


654




C28H38N4O2
462.30
463


 


655




C29H34N4O2
470.27
471


 


656




C26H26ClN3O2
447.17
448


 


657




C29H38N4O2
474.30
475


 


658




C27H29N3O3
443.22
444


 


659




C24H29N5O4
451.22
452


 


660




C25H33N3O2
407.26
408


 


661




C25H30N4O3S2
498.18
499


 


662




C28H29FN4O3
488.22
489


 


663




C31H44N4O2
504.35
505


 


664




C32H40N4O2
512.32
513


 


665




C25H30N6O3
462.24
463


 


666




C25H30N6O3
462.24
463


 


667




C30H33N5O4
527.25
528


 


668




C27H27N3O4
457.20
458


 


669




C26H31N5O3
461.24
462


 


670




C21H27N3O4
385.20
386


 


671




C25H30N6O3
462.24
463


 


672




C31H35FN4O3
530.27
531


 


673




C26H32N6O3
476.25
477


 


674




C27H42FN3O4
491.32
492


 


675




C25H32N4O
404.26
405


 


676




C27H30N4O2
442.24
443


 


677




C29H34N4O2
470.27
471


 


678




C26H28FN3O
417.22
418


 


679




C25H32FN3O2
425.55
426


 


680




C23H30N4O2
394.24
395


 


681




C25H32N4O2
420.25
421


 


682




C24H30N4O2
406.24
407


 


683




C26H28N4O2
428.22
429


 


684




C23H28N4O2
392.22
393


 


685




C26H34N4O2
434.27
435


 


686




C24H27N5O3
433.21
434


 


687




C24H32N4O2
408.25
409


 


688




C22H30N4O2
382.24
383


 


689




C24H33N5O
407.27
408


 


690




C25H28N4O2
416.22
417


 


691




C24H26N4O
386.21
387


 


692




C22H24N4OS
392.17
393


 


693




C21H24N4OS
380.17
381


 


694




C19H21N3OS2
371.11
372


 


695




C23H24ClN3O2
409.16
410


 


696




C22H24ClN3OS
413.13
414


 


697




C21H21ClFN3OS
417.11
418


 


698




C21H21Cl2N3OS
433.08
434


 


699




C21H21ClN4O3S
444.10
445


 


700




C22H23Cl2N3O2S
463.09
464


 


701




C22H24ClN3O2S
429.13
430


 


702




C23H26ClN3OS
427.15
428


 


703




C24H26ClN3O2S
455.14
456


 


704




C22H24F3N5OS
463.17
464


 


705




C24H23ClF3N3O2
477.14
478


 


706




C24H24F3N3O2
443.18
444


 


707




C23H28BrN5O2
485.14
486


 


708




C24H25F3N4O2S
490.17
491


 


709




C22H22N4OS
390.15
391


 


710




C23H25N3O2
375.20
376


 


711




C24H27N3O2S
421.18
422


 


712




C24H26ClN3O3
439.17
440


 


713




C21H22ClN3OS
399.12
400


 


714




C25H23F6N3O2
511.17
512


 


715




C23H30FN3O2
399.51
400


 


716




C26H34FN3O4
471.25
472


 


717




C26H29N3O2
415.23
416


 


718




C27H31N3O2
429.24
430


 


719




C26H33N3O2
419.26
420


 


720




C25H28N4O4
448.21
449


 


721




C24H33N3O2
395.26
396


 


722




C26H28FN3O2
433.22
434


 


723




C26H27N3O2
413.21
414


 


724




C25H33N3O2
407.26
408


 


725




C26H28BrN3O
477.14
478


 


726




C24H26FN3OS
423.18
424


 


727




C26H28FN3O
417.22
418


 


728




C27H31N3O2
429.24
430


 


729




C26H28ClN3O
433.19
434


 


730




C26H28ClN3O
433.19
434


 


731




C26H28ClN3O
433.19
434


 


732




C24H25ClN4O4
468.16
469


 


733




C26H28FN3O
417.22
418


 


734




C27H29N3O3
443.22
444


 


735




C27H31N3O
413.25
414


 


736




C27H31N3O
413.25
414


 


737




C26H26FN3O2
431.20
432


 


738




C27H29N3O2
427.23
428


 


739




C25H35N3O2
409.27
410


 


740




C26H34ClN3O
439.24
440


 


741




C32H36N6O3
552.28
553


 


742




C26H36FN3O2
411.59
412


 


743




C25H32N4O2
420.25
421


 


744




C24H30N4O2
406.24
407


 


745




C26H28N4O2
428.22
429


 


746




C27H30N4O2
442.24
443


 


747




C24H32N4O2
408.25
409


 


748




C24H30N4O2
406.24
407


 


749




C24H32N4O2
408.25
409


 


750




C25H32N4O2
420.25
421


 


751




C24H30N4O2
406.24
407


 


752




C25H34N4O2
422.27
423


 


753




C22H30N4O2
382.24
383


 


754




C27H35FN4O6
530.25
531


 


755




C24H32N4O2
408.25
409


 


756




C26H27FN4O2
446.21
447


 


757




C25H34N4O2
422.27
423


 


758




C24H32N4O2
408.25
409


 


759




C24H26N4O3
418.20
419


 


760




C24H30N4O2
406.24
407


 


761




C26H32N4O2
432.25
433


 


762




C26H34N4O2
434.27
435


 


763




C26H34N4O3
450.26
451


 


764




C25H31ClN4O2
454.21
455


 


765




C24H30N4O2
406.24
407


 


766




C25H34N4O2
422.27
423


 


767




C24H26N4O2S
434.18
435


 


768




C26H34N4O2
434.27
435


 


769




C23H30ClN3O2
415.20
416


 


770




C24H32FN3O2
413.25
414


 


771




C23H28FN3O2
397.22
398


 


772




C24H30FN3O2
411.23
412


 


773




C24H30FN3O2
411.23
412


 


774




C25H33FN4O2
440.26
441


 


775




C26H33FN4O3
468.25
469


 


776




C23H26N4O
374.21
375


 


777




C28H30N4O
438.24
439


 


778




C21H25N5O2
379.20
380


 


779




C26H27N3O2
413.21
414


 


780




C26H26N4O
410.21
411


 


781




C25H31N5O
417.25
418


 


782




C21H24N6OS
408.17
409


 


783




C22H25N5O
375.21
376


 


784




C24H28F3N5O
459.23
460


 


785




C25H30N6O
430.25
431


 


786




C26H32N6O
444.26
445


 


787




C25H27N3OS
417.19
418


 


788




C30H34N4O
466.27
467


 


789




C24H30N4OS
422.21
423


 


790




C24H26ClN3O3S2
503.11
504


 


791




C23H23Cl2N3O3
459.11
460


 


792




C24H26ClN3O2
423.17
424


 


793




C23H26N4OS
406.18
407


 


794




C25H27N3O3S
449.18
450


 


795




C23H25ClN4OS
440.14
441


 


796




C23H25N3O3
391.19
392


 


797




C23H23F3N4O2
444.18
445


 


798




C23H28N4O3
408.22
409


 


799




C25H30N4O
402.24
403


 


800




C26H29N3O2
415.23
416


 


801




C27H29N5O
439.24
440


 


802




C22H24F3N3O2
419.18
420


 


803




C22H25N3O3
379.19
380


 


804




C22H24N4O
360.20
361


 


805




C22H23F4N3O
421.18
422


 


806




C23H29N3O2
379.23
380


 


807




C26H29N3O2
415.23
416


 


808




C27H30FN3O
431.24
432


 


809




C22H23F3N4O2
432.18
433


 


810




C25H25N3O2
399.20
400


 


811




C25H28N40
400.23
401


 


812




C21H24F3N3O3
423.18
424


 


813




C22H30N4O
366.24
367


 


814




C24H31FN4O2
426.24
427


 


815




C25H31FN4O3
454.24
455


 


816




C25H30FN3O2
423.23
424


 


817




C23H30N4O
378.24
379


 


818




C24H27N3O4
421.20
422


 


819




C30H34FN3O4
519.25
520


 


820




C30H34FN3O4
519.25
520


 


821




C29H34FN3O4S
539.22
540


 


822




C29H38FN3O3
495.29
496


 


823




C30H40FN3O3
509.30
510


 


824




C31H35F2N3O3
535.27
536


 


825




C28H38FN3O4
499.29
500


 


826




C30H39ClFN3O3
543.27
544


 


827




C29H33ClFN3O5
557.21
558


 


828




C29H38FN3O4
511.29
512


 


829




C29H33FN4O6
552.24
553


 


830




C28H38FN3O4
499.29
500


 


831




C30H34FN3O3
503.26
504


 


832




C31H36FN3O4
533.27
534


 


833




C33H37FN4O4
572.28
573


 


834




C31H36FN3O3
517.27
518


 


835




C29H40FN3O4
513.30
514


 


836




C30H33F2N3O3
521.25
522


 


837




C25H32N4O2
420.25
421


 


838




C23H30N4O2S
426.21
427


 


839




C23H30N4O3
410.23
411


 


840




C25H36N4O2
424.28
425


 


841




C24H36N4O2
412.28
413


 


842




C23H34N4O2
398.27
399


 


843




C23H34N4O2
398.27
399


 


844




C25H31FN4O2
438.24
439


 


845




C26H34N4O2
434.27
435


 


846




C25H31ClN4O2
454.21
455


 


847




C23H36N4O2
400.28
401


 


848




C23H36N4O2
400.28
401


 


849




C26H25N3O4S
475.16
476


 


850




C21H23N3O
333.18
334


 


851




C22H25N5O
375.21
376


 


852




C21H23N5OS
393.16
394


 


853




C20H22N6OS
394.16
395


 


854




C20H25N5OS
383.18
384


 


855




C23H29N5O4
439.22
440


 


856




C25H32N4O3S
468.22
469


 


857




C22H30N4OS2
430.19
431


 


858




C24H31BrN4OS
502.14
503


 


859




C24H24FN3O3
421.18
422


 


860




C28H27ClN4O
470.19
471


 


861




C23H31N5OS
425.23
426


 


862




C22H30N4O5S
462.19
463


 


863




C23H32N4O4S
460.21
461


 


864




C27H29N5O
439.24
440


 


865




C22H25N5O2
391.20
392


 


866




C26H29N3O4S
479.19
480


 


867




C23H23F3N4OS
460.15
461


 


868




C22H29N7O2
423.24
424


 


869




C25H26N6O
426.22
427


 


870




C26H32N4O2
432.25
433


 


871




C24H27N3O2
389.21
390


 


872




C27H29N5O
439.24
440


 


873




C23H28N4O3S
440.19
441


 


874




C28H34N4OS
474.24
475


 


875




C24H28N4O3S
452.19
453


 


876




C23H23ClN4O3
438.15
439


 


877




C23H26FN5O
407.21
408


 


878




C25H27ClN4O2
450.18
451


 


879




C24H27N5O
401.22
402


 


880




C24H30F3N5O
461.24
462


 


881




C22H23ClN4O2
410.15
411


 


882




C23H26N4OS
406.18
407


 


883




C24H26N4O
386.21
387


 


884




C24H26N4O
386.21
387


 


885




C24H26N4O
386.21
387


 


886




C21H23F3N6OS
464.16
465


 


887




C23H30N4O3S
442.20
443


 


888




C24H26N4O2
402.21
403


 


889




C24H25F3N4OS
474.17
475


 


890




C27H29N3O
411.23
412


 


891




C26H29N3O
399.23
400


 


892




C28H31N3O2
441.24
442


 


893




C23H28N4O2
392.22
393


 


894




C27H29N3O2
427.23
428


 


895




C21H25N7O
391.21
392


 


896




C21H28N4OS
384.20
385


 


897




C23H26ClN5O
423.18
424


 


898




C21H23N5OS
393.16
394


 


899




C26H26ClN5O
459.18
460


 


900




C23H27N5O
389.22
390


 


901




C25H34N4O
406.27
407


 


902




C24H30N4O2
406.24
407


 


903




C23H30ClN3O2
415.20
416


 


904




C25H25F2N3O2
437.19
438


 


905




C29H39FN4O2
494.31
495


 


906




C29H32F2N4O2
506.25
507


 


907




C30H35FN4O2
502.27
503


 


908




C27H37FN4O3
484.29
485


 


909




C27H37FN4O3
484.29
485


 


910




C25H34FN3O3
443.26
444


 


911




C24H30Cl2FN3O2
481.17
482


 


912




C24H31FN4O4
458.23
459


 


913




C24H31ClFN3O2
447.21
448


 


914




C26H36FN3O2
441.28
442


 


915




C25H32Cl2FN3O3
511.18
512


 


916




C24H28F5N3O2
485.21
486


 


917




C24H31F2N3O2
431.24
432


 


918




C26H34FN3O3
455.26
456


 


919




C28H40FN3O3
485.30
486


 


920




C25H34FN5O
439.27
440


 


921




C23H31FN4O2
414.24
415


 


922




C24H26FN3O3
423.20
424


 


923




C26H28FN3O2
433.22
434


 


924




C26H33FN4O2
452.26
453


 


925




C26H32ClFN4O2
486.22
487


 


926




C25H31FN4O2
438.24
439


 


927




C26H31F3N4O3
504.23
505


 


928




C26H33ClN4O3
484.22
485


 


929




C25H31ClN4O2
454.21
455


 


930




C24H31ClFN3O2
447.21
448


 


931




C25H34FN3O2
427.26
428


 


932




C27H33FN4O2
464.26
465


 


933




C26H28FN3O2
433.22
434


 


934




C25H28FN3O2S
453.19
454


 


935




C25H32FN3O
409.25
410


 


936




C26H34FN3O
423.27
424


 


937




C27H29F2N3O
449.23
450


 


938




C24H32FN3O2
413.25
414


 


939




C26H33ClFN3O
457.23
458


 


940




C24H32FN3O2
413.25
414


 


941




C26H28FN3O
417.22
418


 


942




C27H30FN3O2
447.23
448


 


943




C29H31FN4O2
486.24
487


 


944




C27H30FN3O
431.24
432


 


945




C25H34FN3O2
427.26
428


 


946




C26H27F2N3O
435.21
436


 


947




C25H27FN4O2
434.52
435


 


948




C25H27FN4O4
466.20
467


 


949




C24H29FN4O3
440.22
441


 


950




C27H30FN3O2
447.23
448


 


951




C23H31FN4O
398.25
399


 


952




C24H26ClFN4OS
472.15
473


 


953




C25H25F2N3O3
453.19
454


 


954




C24H27F2N5O
439.22
440


 


955




C26H31F2N3O2
455.24
456


 


956




C23H31N3O2
381.24
382


 


957




C24H33N3O2
395.26
396


 


958




C24H33N3O2
395.26
396


 


959




C26H29N3O2
415.23
416


 


960




C25H29N5O2
431.23
432


 


961




C24H24ClFN4O3
470.15
471


 


962




C27H36FN3O2
453.61
454


 


963




C24H30N4O2
406.24
407


 


964




C24H28N4O2
404.22
405


 


965




C27H29N5O
439.24
440


 


966




C25H28N4O4S
480.18
481


 


967




C24H26N4O2
402.21
403


 


968




C27H27BrN4O2
518.13
519


 


969




C22H24ClN5O
409.17
410


 


970




C22H23F2N3O3
415.17
416


 


971




C21H23N5OS
393.16
394


 


972




C23H24ClN3OS
425.13
426


 


973




C22H24N4O3
392.18
393


 


974




C25H27ClN4O2
450.18
451


 


975




C25H30N4O
402.24
403


 


976




C22H25N5O
375.21
376


 


977




C22H27N3O3S
413.18
414


 


978




C20H23F3N4OS
424.15
425


 


979




C21H24F3N3OS
423.16
424


 


980




C26H24BrF3N6O
572.11
573


 


981




C23H25ClN4OS
440.14
441


 


982




C24H32N4O3S
456.22
457


 


983




C24H31ClN4O3S
490.18
491


 


984




C23H25N3O4S
439.16
440


 


985




C26H32N4O3
448.25
449


 


986




C26H32N4O
416.26
417


 


987




C22H27N3OS
381.19
382


 


988




C24H31N3O2
393.24
394


 


989




C22H24F3N3OS
435.16
436


 


990




C24H33N3O
379.26
380


 


991




C22H29N3O2
367.23
368


 


992




C25H35N3O
393.28
394


 


993




C25H30N4O
402.24
403


 


994




C22H26N4OS2
426.15
427


 


995




C29H32N4O2
468.25
469


 


996




C23H26FN5O
407.21
408


 


997




C28H28ClN5O
485.20
486


 


998




C20H23N5O2S
397.16
398


 


999




C25H26N6O
426.22
427


 


1000




C22H24N4O2
376.19
377


 


1001




C26H35FN4O2
454.27
455


 


1002




C25H34FN3O2
427.57
428


 


1003




C24H25FN4O
404.20
405


 


1004




C25H30N4O2
418.24
419


 


1005




C26H31FN4O2
450.24
451


 


1006




C25H34N4O2
422.27
423


 


1007




C24H30N4O2
406.24
407


 


1008




C27H30N4O2
442.24
443


 


1009




C27H29FN4O2
460.23
461


 


1010




C26H34N4O2
434.27
435


 


1011




C26H26ClFN4O2
480.17
481


 


1012




C26H27FN4O2
446.21
447


 


1013




C25H27N5O2
429.22
430


 


1014




C27H36N4O2
448.28
449


 


1015




C25H29N5O3
447.23
448


 


1016




C29H32N4O2
468.25
469


 


1017




C26H27FN4O2
446.21
447


 


1018




C23H30N4O3
410.23
411


 


1019




C23H30N4O3
410.23
411


 


1020




C24H30N4O2
406.24
407


 


1021




C24H28N6O2
432.23
433


 


1022




C25H27N5O2
429.22
430


 


1023




C25H34N4O2
422.27
423


 


1024




C25H28N4O2S
448.19
449


 


1025




C25H29N5O2
431.23
432


 


1026




C26H26F2N4O2
464.20
465


 


1027




C24H27N5O2
417.22
418


 


1028




C29H38N4O2
474.30
475


 


1029




C27H36N4O3
464.28
465


 


1030




C24H27N5O2
417.22
418


 


1031




C27H36N4O2
448.28
449


 


1032




C27H36N4O2
448.28
449


 


1033




C27H38N4O2
450.30
451


 


1034




C29H32N4O2
468.25
469


 


1035




C27H34N4O2
446.27
447


 


1036




C26H27ClN4O2
462.18
463


 


1037




C22H24N6O2S
436.17
437


 


1038




C23H25N5O3
419.20
420


 


1039




C25H32N4O2
420.25
421


 


1040




C26H27ClN4O2
462.18
463


 


1041




C27H30N4O2
442.24
443


 


1042




C24H30N4O3
422.23
423


 


1043




C27H30N4O2
442.24
443


 


1044




C30H38N4O2
486.30
487


 


1045




C29H34N4O3
486.26
487


 


1046




C27H28F2N4O3
494.21
495


 


1047




C25H32N4O3
436.25
437


 


1048




C27H36N4O2
448.28
449


 


1049




C23H27F3N4O2
448.21
449


 


1050




C26H32N4O2
432.25
433


 


1051




C26H36N4O2
436.28
437


 


1052




C22H28FN3O2
385.22
386


 


1053




C27H30N4O2
442.24
443


 


1054




C21H24N6O
376.20
377


 


1055




C25H27N5OS
445.19
446


 


1056




C24H26N4O
386.21
387


 


1057




C22H24N4O2
376.19
377


 


1058




C27H30N4O
426.24
427


 


1059




C24H32N4O
392.26
393


 


1060




C22H26N6O
390.22
391


 


1061




C24H27N5O2
417.22
418


 


1062




C23H26ClN5O
423.18
424


 


1063




C24H26ClN3O2
423.17
424


 


1064




C24H25ClN6O2
464.17
465


 


1065




C24H27N3OS
405.19
406


 


1066




C20H21ClN4O2S
416.11
417


 


1067




C25H26N4O3S
462.17
463


 


1068




C26H28N4O4
460.21
461


 


1069




C30H42FN3O4
527.32
528


 


1070




C31H42FN3O4
539.32
540


 


1071




C27H30N4O2
442.24
443


 


1072




C28H32N4O3
472.25
473


 


1073




C25H32FN3O2
425.25
426


 


1074




C27H30FN3O2
447.23
448


 


1075




C27H30FN3O
431.24
432


 


1076




C28H27FN4O3
486.21
487


 


1077




C28H28BrFN4O2
550.14
551


 


1078




C28H31FN4O2
474.24
475


 


1079




C26H31FN4O
434.25
435


 


1080




C26H29FN4O2
448.23
449


 


1081




C28H30FN5O
471.24
472


 


1082




C29H31FN4O
470.25
471


 


1083




C27H30FN3OS
463.21
464


 


1084




C25H28FN5OS
465.20
466


 


1085




C26H29FN4OS
464.20
465


 


1086




C28H29FN4O2
472.23
473


 


1087




C27H30FN3O2
447.23
448


 


1088




C27H29ClFN3O2
481.19
482


 


1089




C25H34FN3O
411.27
412


 


1090




C25H34FN3O2
427.26
428


 


1091




C23H30FN3O2
399.23
400


 


1092




C24H32FN3O2
413.25
414


 


1093
—
C26H32FN3O2
437.25
438


 


1094
—
C30H36N4O4
516.27
517


 


1095




C25H31F2N3O2
443.24
444


 


1096




C25H31F2N3O2
443.24
444


 


1097




C26H27F2N3O2
451.21
452


 


1098




C26H34F2N4O
456.27
457


 


1099




C27H27FN4O2
458.21
459


 


1100




C27H27FN4O2
458.21
459


 


1101




C24H30FN3O2
411.23
412


 


1102




C23H25FN4OS
424.17
425


 


1103




C28H29FN4O2
472.23
473


 


1104




C25H32FN3O2
425.25
426


 


1105




C24H27FN4OS
438.19
439


 


1106




C25H34FN3O3
443.26
444


 


1107




C26H27F2N3O2
451.21
452


 


1108




C27H36FN3O2
453.28
454


 


1109




C26H26F3N3O2
469.20
470


 


1110




C25H27FN4O2
434.21
435


 


1111




C25H34FN3O2
427.26
428


 


1112




C26H34FN3O2
439.26
440


 


1113




C27H36FN3O2
453.28
454


 


1114




C25H34FN3O2
427.26
428


 


1115




C25H33ClFN3O3
477.22
478


 


1116




C24H31F2N3O2
431.24
432


 


1117




C25H32FN3O2
425.25
426


 


1118




C27H30FN3O3S
495.62
496


 


1119




C23H27F4N3O
437.21
438


 


1120




C26H36FN3O2
441.28
442


 


1121




C25H27FN4O2
434.21
435


 


1122




C25H33N3O2
407.26
408


 


1123




C24H31N3O2
393.24
394


 


1124




C25H34FN3O2
427.26
428


 


1125




C23H30FN3O2
399.23
400


 


1126




C27H29ClFN3O2
481.19
482


 


1127




C22H25F4N3OS
455.17
456


 


1128




C25H32FN3O2
425.25
426


 


1129




C25H32F2N4O
442.25
443


 


1130




C26H29FN4O2
448.23
449




















TABLE 8





Ex.

Molecular
Monoisotopic
M +


No.
Structure
formula
molecular wt.
H+



















1131




C23H23Cl2N3O2
443.12
444


 


1132




C23H23ClFN3O2
427.15
428


 


1133




C24H26FN3O2
407.20
408


 


1134




C28H33N3O4
475.25
476


 


1135




C29H34N4O5
518.25
519


 


1136




C33H41N3O4
543.31
544


 


1137




C29H36N4O4
504.27
505


 


1138




C29H32N4O4
500.24
501


 


1139




C28H30F3N3O4
529.22
530


 


1140




C22H22Cl2N4OS
460.09
461


 


1141




C22H23ClN4OS
426.13
427


 


1142




C22H23FN4OS
410.16
411


 


1143




C23H25FN4OS
424.17
425


 


1144




C23H22ClF3N4OS
494.12
495


 


1145




C26H26N4OS
442.18
443


 


1146




C25H25Cl2N3O
453.14
454


 


1147




C23H25N3OS
391.17
392


 


1148




C23H23F3N4OS
460.15
461


 


1149




C22H23N5O3S
437.15
438


 


1150




C22H24N4OS
392.17
393


 


1151




C22H22Cl2N4OS
460.09
461


 


1152




C22H22ClFN4OS
444.12
445


 


1153




C20H22N4OS2
398.12
399


 


1154




C23H26N4O2S
422.18
423


 


1155




C23H23F3N4OS
460.15
461


 


1156




C23H26N4OS
406.18
407


 


1157




C23H26N4O2S
422.18
423


 


1158




C24H27N5O2S
449.19
450


 


1159




C22H23ClN4OS
426.13
427


 


1160




C22H23FN4OS
410.16
411


 


1161




C26H26N4OS
442.18
443


 


1162




C23H26N4OS2
438.15
439


 


1163




C22H22Cl2N4OS
460.09
461


 


1164




C24H28N4O2S
436.19
437


 


1165




C24H28N4O2S
436.19
437


 


1166




C26H32N4OS
448.23
449


 


1167




C23H23N5OS
417.16
418


 


1168




C28H28N4OS
468.20
469


 


1169




C24H28N4O2S
436.19
437


 


1170




C23H24N4O3S
436.16
437


 


1171




C26H32N4O2S
464.23
465


 


1172




C23H26N4OS2
438.15
439


 


1173




C24H28N4OS2
452.17
453


 


1174




C24H28N4OS
420.20
421


 


1175




C23H23F3N4O2S
476.15
477


 


1176




C24H28N4O3S
452.19
453


 


1177




C25H30N4OS
434.21
435


 


1178




C25H30N4OS
434.21
435


 


1179




C23H26N4O2S
422.18
423


 


1180




C22H25N5O2S
423.17
424


 


1181




C24H24N4OS2
448.14
449


 


1182




C23H23F3N4O2S
476.15
477


 


1183




C24H22F6N4OS
528.14
529


 


1184




C23H25FN4OS
424.17
425


 


1185




C24H28N4OS
420.20
421


 


1186




C24H28N4OS
420.20
421


 


1187




C25H26N4O3
430.20
431


 


1188




C27H31N3O2
429.24
430


 


1189




C25H25ClFN3O
437.17
438


 


1190




C25H25Cl2N3O
453.14
454


 


1191




C26H26N4O
410.21
411


 


1192




C27H29N3O2
427.23
428


 


1193




C27H29N3O2
427.23
428


 


1194




C25H25F2N3O
421.20
422


 


1195




C25H25F2N3O
421.20
422


 


1196




C26H28N4O3
444.22
445


 


1197




C27H32N4O
428.26
429


 


1198




C25H28N4O2
416.22
417


 


1199




C27H29N3O3
443.22
444


 


1200




C24H28N4O2
404.22
405


 


1201




C23H25N3O2
375.20
376


 


1202




C24H25FN4O
404.20
405


 


1203




C22H25N5O
375.21
376


 


1204




C26H28FN3O
417.22
418


 


1205




C26H28FN3O
417.22
418


 


1206




C24H25ClN4O
420.17
421


 


1207




C24H25FN4O
404.20
405


 


1208




C24H25FN4O
404.20
405


 


1209




C26H28FN3O2
433.22
434


 


1210




C27H30N4O2
442.24
443


 


1211




C25H26N4O3
430.20
431


 


1212




C26H25FN4O
428.20
429


 


1213




C24H25FN4O
404.20
405


 


1214




C24H25FN4O
404.20
405


 


1215




C26H28FN3O3S
481.18
482


 


1216




C27H29FN4O2
460.23
461


 


1217




C28H31FN4O2
474.24
475


 


1218




C26H25F4N3O2
487.19
488


 


1219




C26H28FN3O3S
481.18
482


 


1220




C26H25F4N3O2
487.19
488


 


1221




C26H25FN4O
428.20
429


 


1222




C27H29FN4O2
460.23
461


 


1223




C26H25F4N3O2
487.19
488


 


1224




C25H25F2N3O
421.20
422


 


1225




C25H32N4O3S
468.22
469


 


1226




C24H31N5O
405.25
406


 


1227




C24H31N5O2
421.25
422


 


1228




C23H28FN5O
409.23
410


 


1229




C26H31N5O
429.25
430


 


1230




C25H29N5OS
447.21
448


 


1231




C26H34N4O
418.27
419


 


1232




C26H32N4O2
432.25
433




















TABLE 9





Ex.

Molecular
Monoisotopic
M +


No.
Structure
formula
molecular wt.
H+



















1233




C31H29N3O2
475.23
476


 


1234




C30H35N3O2
469.27
470


 


1235




C28H30N4O3S
502.20
503


 


1236




C29H30FN3O3S
519.20
520


 


1237




C28H30N4O3S
502.20
503




















TABLE 10





Ex.

Molecular
Monoisotopic
M +


No.
Structure
formula
molecular wt.
H+



















1238




C26H35N3O2
421.27
422


 


1239




C26H35N3O2
421.27
422


 


1240




C25H31F2N3O2
443.24
444


 


1241




C27H35N3O2
433.27
434


 


1242




C26H35N3O2
421.27
422


 


1243




C25H36N4O2
424.28
425


 


1244




C24H33N3O3
411.25
412


 


1245




C26H37N3O3
439.28
440


 


1246




C27H37N3O2
435.29
436


 


1247




C27H37N3O2
435.29
436


 


1248




C27H33N5O2
459.26
460


 


1249




C26H35N3O3
437.27
438


 


1250




C29H34FN3O2
475.26
476


 


1251




C27H32N4O2
444.25
445


 


1252




C24H33N3O2
395.26
396


 


1253




C23H31N3O2
381.24
382


 


1254




C25H33N3O3
423.25
424


 


1255




C23H28F3N3O2
435.21
436


 


1256




C23H30FN3O2
399.23
400


 


1257




C27H37N3O3
451.28
452


 


1258




C24H33N3O3
411.25
412


 


1259




C25H33N3O2
407.26
408


 


1260




C25H33N3O2
407.26
408


 


1261




C25H35N3O2
409.27
410


 


1262




C25H35N3O2
409.27
410


 


1263




C25H35N3O2
409.27
410


 


1264




C25H35N3O2
409.27
410


 


1265




C27H35N5O2
461.28
462


 


1266




C28H38N4O3
478.29
479


 


1267




C26H36N4O2
436.28
437


 


1268




C26H38N4O2
438.30
439


 


1269




C30H35N3O2
469.27
470


 


1270




C27H32N4O2
444.25
445


 


1271




C27H36N4O3
464.28
465


 


1272




C27H37N3O2
435.29
436


 


1273




C30H35N3O2
469.27
470


 


1274




C26H35N3O2
421.27
422


 


1275




C29H39N3O2
461.30
462


 


1276




C29H43N3O2
465.34
466


 


1277




C28H39N3O2
449.30
450


 


1278




C28H37N3O2
447.29
448


 


1279




C28H40N4O2
464.32
465


 


1280




C30H35N3O2
469.27
470


 


1281




C30H34N4O2
482.27
483


 


1282




C30H35N3O3
485.27
486


 


1283




C25H33N3O4S
471.22
472


 


1284




C29H39N3O2
461.30
462


 


1285




C26H33N3O3
435.25
436


 


1286




C27H35N5O2
461.28
462


 


1287




C25H35N3O2
409.27
410


 


1288




C26H35N3O4S
485.23
486


 


1289




C27H38N4O2
450.30
451


 


1290




C26H31N3O2S
449.21
450


 


1291




C29H41N3O2
463.32
464


 


1292




C25H32N4O3
436.25
437


 


1293




C26H35N3O3
437.27
438


 


1294




C25H30N4O2S
450.21
451


 


1295




C24H31N3O2
393.24
394


 


1296




C25H35N5O2
437.28
438


 


1297




C27H37N5O2
463.30
464


 


1298




C26H32N6O2S
492.23
493


 


1299




C24H33N5O3
439.26
440


 


1300




C28H40FN3O3
485.30
486


 


1301




C27H36FN3O2
453.28
454


 


1302




C31H37N5O2
511.30
512


 


1303




C28H39N5O2
477.31
478


 


1304




C27H39N5O2
465.31
466


 


1305




C27H39N5O2
465.31
466


 


1306




C26H35N5O2S
481.25
482


 


1307




C26H33N7O2
475.27
476


 


1308




C26H35N5O2
449.28
450


 


1309




C26H37N5O3
467.29
468


 


1310




C26H37N5O3
467.29
468


 


1311




C26H37N5O3
467.29
468


 


1312




C27H37N5O3
479.29
480


 


1313




C27H39N5O3
481.30
482


 


1314




C28H38N6O2
490.31
491


 


1315




C28H39N5O4
509.30
510


 


1316




C28H39N5O2
477.31
478


 


1317




C29H40N6O3
520.32
521


 


1318




C30H44N6O2
520.35
521


 


1319




C30H44N6O3
536.35
537


 


1320




C30H34N6O2
510.27
511


 


1321




C33H42N6O2
554.34
555


 


1322




C27H35N7O2
489.29
490


 


1323




C29H38F3N5O2
545.30
546


 


1324




C29H39N7O2
517.32
518


 


1325




C31H37N7O2
539.30
540


 


1326




C26H33N7O2
475.27
476


 


1327




C26H37N5O2S
483.27
484


 


1328




C26H35N5O2
449.28
450


 


1329




C27H35N7O2
489.29
490


 


1330




C28H41N5O3
495.32
496


 


1331




C25H31N7O2S
493.23
494


 


1332




C31H39N5O3
529.30
530


 


1333




C30H42N6O4
550.33
551


 


1334




C28H41N5O2
479.33
480


 


1335




C29H30F2N4O2
504.58
505


 


1336




C25H32FN3O2
425.25
426


 


1337




C25H34FN3O2
427.26
428


 


1338




C24H32FN3O3
429.24
430


 


1339




C26H34FN3O2
439.26
440


 


1340




C26H34FN3O2
439.26
440


 


1341




C25H34FN3O3
443.26
444


 


1342




C25H34FN3O3
443.26
444


 


1343




C25H34FN3O3
443.26
444


 


1344




C27H36FN3O2
453.28
454


 


1345




C27H38FN3O2
455.30
456


 


1346




C27H38FN3O2
455.30
456


 


1347




C27H38FN3O2
455.30
456


 


1348




C26H36FN3O3
457.27
458


 


1349




C26H36FN3O3
457.27
458


 


1350




C25H34FN3O4
459.25
460


 


1351




C25H34FN3O4
459.25
460


 


1352




C28H38FN3O2
467.30
468


 


1353




C27H38FN3O3
471.29
472


 


1354




C27H38FN3O3
471.29
472


 


1355




C27H34FN5O2
479.27
480


 


1356




C29H40FN3O2
481.31
482


 


1357




C29H40FN3O2
481.31
482


 


1358




C28H39FN4O2
482.31
483


 


1359




C28H38FN3O3
483.29
484


 


1360




C28H38FN3O3
483.29
484


 


1361




C28H36FN5O2
493.29
494


 


1362




C27H35FN6O2
494.28
495


 


1363




C28H37FN4O3
496.29
497


 


1364




C29H41FN4O2
496.32
497


 


1365




C28H39FN4O3
498.30
499


 


1366




C26H32FN3O4
469.24
470


 


1367




C29H40FN3O3
497.30
498


 


1368




C25H31FN4O2
438.24
439


 


1369




C26H34FN3O2
439.26
440


 


1370




C26H36FN3O2
441.28
442


 


1371




C25H34FN3O3
443.26
444


 


1372




C27H36FN3O2
453.28
454


 


1373




C26H34FN3O3
455.26
456


 


1374




C28H38FN3O2
467.30
468


 


1375




C27H37FN4O2
468.29
469


 


1376




C26H34FN3O2S
471.24
472


 


1377




C26H36FN3O4
473.27
474


 


1378




C28H41FN4O2
484.32
485


 


1379




C28H37FN4O3
496.29
497


 


1380




C28H37FN4O3
496.29
497


 


1381




C32H38FN3O2
515.29
516


 


1382




C31H38FN3O3
519.29
520


 


1383




C31H43FN4O2
522.34
523


 


1384




C27H36FN3O3
469.27
470


 


1385




C27H36FN3O3
469.27
470


 


1386




C28H34F3N3O3
517.26
518


 


1387




C27H36FN3O4S
517.24
518


 


1388




C30H41FN4O3
524.32
525


 


1389




C27H36FN3O3
469.27
470


 


1390




C22H28FN3O2
385.22
386


 


1391




C29H38FN3O4
511.29
512


 


1392




C26H36FN3O3
457.27
458


 


1393




C25H34FN3O3
443.26
444


 


1394




C27H36FN3O3
469.27
470


 


1395




C26H34FN3O3
455.26
456


 


1396




C28H38FN3O3
483.29
484


 


1397




C26H36FN3O3
457.27
458


 


1398




C26H34FN3O4
471.25
472


 


1399




C28H38FN3O4
499.29
500


 


1400




C27H38FN3O3
471.29
472


 


1401




C28H40FN3O3
485.30
486


 


1402




C27H36FN3O4
485.27
486


 


1403




C27H36FN3O3
469.27
470




















TABLE 11








Mono-






isotopic


Ex.

Molecular
molecular


No.
Structure
formula
wt.
M + H+







1404




C22H30N4O2
382.24
383


 


1405




C24H31ClN4O
426.22
427


 


1406




C23H32N4O2
396.25
397


 


1407




C25H27FN4O
418.22
410


 


1408




C23H32N4O2
396.25
397


 


1409




C22H30N4O2
382.24
383


 


1410




C23H25N5O2
403.20
404


 


1411




C24H33N3O2
395.26
396


 


1412




C23H31N3O2(S)-Konfiguration
381.24
382


 


1413




C23H31N3O2
381.24
382


 


1414




C23H30FN3O2
399.23
400


 


1415




C24H32FN3O2
413.25
414


 


1416




C24H32N4O
392.26
393


 


1417




C24H32FN3O2
413.25
414


 


1418




C24H32FN3O2(S)-configuration
413.25
414


 


1419




C25H34FN3O2
427.26
428


 


1420




C26H36FN3O2
441.28
442


 


1421




C26H36FN3O2
441.28
442


 


1422




C27H36FN3O2
453.28
454


 


1423




C27H38FN3O3
471.29
472




















TABLE 12








Mono-






isotopic


Ex.

Molecular
molecular


No.
Structure
formula
wt.
M + H+







1424




C27H35N3O2
433.27
434


 


1425




C28H39N3O4
481.29
482


 


1426




C27H38N4O4
482.29
483


 


1427




C24H32N4O3
424.25
425


 


1428




C24H33N3O2
395.26
396


 


1429




C24H31N3O3
409.24
410


 


1430




C29H33FN4O3
504.25
505


 


1431




C27H38N4O4
482.29
483


 


1432




C30H43N3O5
525.32
526


 


1433




C25H33N3O3
423.25
424


 


1434




C29H41N3O5
511.30
512


 


1435




C26H28FN3O
417.22
418


 


1436




C27H30FN3O
431.24
432


 


1437




C28H38FN3O4
499.29
500


 


1438




C28H38FN3O4
499.29
500


 


1439




C28H38FN3O4(S)-Konfiguration
499.29
500


 


1440




C25H32N4O2
420.25
421


 


1441




C24H32C1N3O2
429.22
430


 


1442




C29H40FN3O4
513.30
514


 


1443




C30H42FN3O4
527.32
528




















TABLE 13








Mono-






isotopic


Ex.

Molecular
molecular


No.
Structure
formula
wt.
M + H+







1444




C23H30N4O
378.24
379


 


1445




C23H30N4O
378.24
379


 


1446




C21H28N4O2
368.22
369


 


1447




C27H38N4O
434.30
435


 


1448




C26H36N4O
420.29
421


 


1449




C29H42N4O
462.34
463


 


1450




C28H38N4O
446.30
447


 


1451




C24H32N4O
392.26
393


 


1452




C26H36N4O
420.29
421


 


1453




C26H32N4O
416.26
417


 


1454




C23H31N3O2
381.24
382


 


1455




C24H31N3O
377.25
378


 


1456




C22H29N3O2
367.23
368


 


1457




C22H21FN4O
376.17
377


 


1458




C20H26N4O2
354.21
355


 


1459




C23H24N4O2
388.19
389


 


1460




C22H27ClN4O
398.19
399


 


1461




C22H30N4O2
382.24
383


 


1462




C21H21N5O2
375.17
376


 


1463




C22H27F2N3O2
403.21
404


 


1464




C22H28FN3O2
385.22
386


 


1465




C22H28ClN3O2
401.19
402


 


1466




C23H31N3O2
381.24
382


 


1467




C23H28F3N3O2
435.21
436


 


1468




C23H28F3N3O2
435.21
436


 


1469




C22H27F2N3O2
403.21
404


 


1470




C22H27ClFN3O2
419.18
420


 


1471




C23H28N4O2
392.22
393


 


1472




C23H27C1N4O2
426.18
427


 


1473




C22H28BrN3O2
445.14
446


 


1474




C26H31N3O2
417.24
418


 


1475




C22H27F2N3O2
403.21
404


 


1476




C22H28BrN3O2
445.14
446


 


1477




C23H30ClN3O2
415.20
416


 


1478




C21H27ClN4O2
402.18
403


 


1479




C22H30N4O2
382.24
383


 


1480




C22H30N4O2
382.24
383


 


1481




C22H30N4O2
382.24
383


 


1482




C24H25FN4O
404.20
405


 


1483




C22H29N3O3
383.22
384


 


1484




C20H26N4O2
354.21
355


 


1485




C22H28FN3O2
385.22
386


 


1486




C22H29N3O2
367.23
368


 


1487




C22H28N4O
364.23
365


 


1488




C25H35N3O3
425.27
426


 


1489




C24H33N3O3
411.25
412


 


1490




C22H29N5O2
395.23
396


 


1491




C23H25N5O2
403.20
404


 


1492




C23H25N5O2
403.20
404


 


1493




C20H22N6O
362.19
363


 


1494




C25H25N5O2
427.20
428


 


1495




C23H25N3O2
375.20
376


 


1496




C19H21N5O2
351.17
352


 


1497




C20H22N4OS2
398.12
399


 


1498




C21H23N5O
361.19
362


 


1499




C20H22N6O
362.19
363


 


1500




C22H28FN3O2
385.22
386


 


1501




C23H29FN4O2
412.23
413


 


1502




C22H34FN3O2
391.26
392


 


1503




C23H30FN3O2
399.23
400


 


1504




C22H28FN5O2
413.22
414


 


1505




C23H24FN5O2
421.19
422


 


1506




C23H22F3N3O2
429.17
430


 


1507




C24H28N4O2
404.22
405


 


1508




C28H33N3O2
443.26
444


 


1509




C24H24N4O2
400.19
401


 


1510




C24H26N4O3
418.20
419


 


1511




C23H30FN3O2
399.23
400


 


1512




C22H27FN4O4
430.20
431


 


1513




C22H29FN4O2
400.23
401


 


1514




C24H26N4O3
418.20
419


 


1515




C23H30FN3O2
399.23
400


 


1516




C24H29FN4O
408.23
409


 


1517




C25H26FN3O2
419.20
420


 


1518




C25H26FN3O2
419.20
420


 


1519




C24H26FN3O2S
439.17
440


 


1520




C24H30FN3O
395.24
396


 


1521




C25H32FN3O
409.25
410


 


1522




C26H27F2N3O
435.21
436


 


1523




C22H21ClFN3O2
413.13
414


 


1524




C22H22FN3O2
379.17
380


 


1525




C23H25N3O3
391.19
392


 


1526




C23H25N3O3
391.19
392


 


1527




C22H22FN3O2
379.17
380


 


1528




C23H25N3O2S
407.17
408


 


1529




C23H25N3O2
375.20
376


 


1530




C24H27N3O3
405.20
406


 


1531




C23H30FN3O2
399.23
400


 


1532




C25H31ClFN3O
443.21
444


 


1533




C24H25ClFN3O3
457.16
458


 


1534




C24H30FN3O2
411.23
412


 


1535




C24H27N3O3
405.20
406


 


1536




C23H22N4O2
386.17
387


 


1537




C24H25N3O3
403.19
404


 


1538




C24H27N3O4
421.20
422


 


1539




C24H25N3O3
403.19
404


 


1540




C24H25FN4O4
452.19
453


 


1541




C23H3OFN3O2
399.23
400


 


1542




C25H26FN3O
403.21
404


 


1543




C26H28FN3O2
433.22
434


 


1544




C28H29FN4O2
472.23
473


 


1545




C26H28FN3O
417.22
418


 


1546




C24H32FN3O2
413.25
414


 


1547




C22H18F5N3O2
451.13
452


 


1548




C24H25N3O3
403.19
404


 


1549




C22H21F2N3O2
397.16
398


 


1550




C22H21F2N3O2
397.16
398


 


1551




C22H21F2N3O2
397.16
398


 


1552




C23H23N3O4
405.17
406


 


1553




C28H26FN3O2
455.20
456


 


1554




C26H31N3O3
433.24
434


 


1555




C25H25F2N3O
421.20
422


 


1556




NC23H25N3O2S
407.17
408


 


1557




C24H27N3O2S
421.18
422


 


1558




C24H27N3O2
389.21
390


 


1559




C24H27N3O2
389.21
390


 


1560




C23H22F3N3O3
445.16
446


 


1561




C25H29N3O2
403.23
404


 


1562




C25H29N3O2
403.23
404


 


1563




C21H22N4O2
362.17
363


 


1564




C22H21F2N3O2
397.16
398


 


1565




C22H24N4O3
392.18
393


 


1566




C23H25N3O4S
439.16
440


 


1567




C22H21F2N3O2
397.16
398


 


1568




C23H22F3N3O3
445.16
446


 


1569




C23H24FN3O2
393.18
394


 


1570




C20H21N5O2
363.17
364


 


1571




C21H21FN4O2
380.17
381


 


1572




C23H30FN3O2
399.23
400


 


1573




C22H22N4O3S
422.14
423


 


1574




C23H25N3O2S
407.17
408


 


1575




C23H25N3O2S
407.17
408


 


1576




C23H25N3OS2
423.14
424


 


1577




C24H27N3O2S
421.18
422


 


1578




C24H27N3O2S
421.18
422


 


1579




C23H22N4OS
402.15
403


 


1580




C24H27N3O3S
437.18
438


 


1581




C24H25N3O2S
419.17
420


 


1582




C24H25N3O2S
419.17
420


 


1583




C23H23N3O3S
421.15
422


 


1584




C23H25N3OS2
423.14
424


 


1585




C24H27N3OS2
437.16
438


 


1586




C24H27N3OS
405.19
406


 


1587




C24H27N3OS
405.19
406


 


1588




C23H22F3N3O2S
461.14
462


 


1589




C25H29N3OS
419.20
420


 


1590




C25H29N3OS
419.20
420


 


1591




C24H25N3O3S
435.16
436


 


1592




C22H24N4O2S
408.16
409


 


1593




C23H22F3N302S
461.14
462


 


1594




C24H26N4O2S
434.18
435


 


1595




C21H24N4O2S
396.16
397


 


1596




C21H21FN4OS
396.14
397


 


1597




C25H27N3O3S
449.18
450


 


1598




C28H33N3OS
459.23
460


 


1599




C24H26N4O2S
434.18
435


 


1600




C25H28N4O2S
448.19
449


 


1601




C25H28N4O2S
448.19
449


 


1602




C24H28N4OS
420.20
421


 


1603




C24H26N4O2S
434.18
435


 


1604




C24H25N3O2S
419.17
420


 


1605




C20H21N3OS2
383.11
384


 


1606




C26H28FN3O2
433.22
434


 


1607




C26H27ClFN3O2
467.18
468


 


1608




C21H21FN4OS
396.14
397


 


1609




C24H32FN3O2
413.25
414


 


1610




C25H34FN3O2
427.26
428


 


1611




C25H34FN3O2
427.26
428


 


1612




C26H34FN3O2
439.26
440


 


1613




C25H25N3OS
415.17
416


 


1614




C23H22N4OS
402.15
403


 


1615




C24H22FN3OS
419.15
420


 


1616




C23H22N4OS
402.15
403


 


1617




C21H27N5O3
397.21
398


 


1618




C25H28N4O2
416.22
417









Synthesis of Pyrrolidinylanilines Required as Intermediates
[1-Amino-2-chlorophenyl)pyrrolidin-3-yl]dimethylamine
Method C-a
3-Dimethylaminopyrrolidine (0.34 g) was slowly added to a solution of 2-chloro-1 fluoro-4-nitrobenzene (0.52 g) in DMF (5 ml). After 1 hour, 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+),
5-Amino-2-(3-dimethylaminopyrrolidin-1-yl)benzonitrile
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+),
[1-(4-Amino-3-chlorophenyl)pyrrolidin-3-yl]dimethylamine
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+),
[1-(4-Amino-3-methylphenyl)pyrrolidin-3-yl]dimethylamine
Dimethylaminopyrrolidine was treated with 4-fluoro-2-methyl-1-nitrobenzene and subsequently reduced by method C-a. This resulted in the product with the molecular weight of 219.33 (C13H21N3); MS (ESI): 220 (M+H+).
tert-Butyl (R)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate
Method C-b
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+).
tert-Butyl (S)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was obtained analogously.
tert-Butyl (R)-[1-(2-fluoro-4-isopropylaminophenyl)pyrrolidin-3-yl]methylcarbamate
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+).
tert-Butyl (R)-[1-(2-Fluoro-4-cyclobutylaminophenyl)pyrrolidin-3-yl]methylcarbamate
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+).
tert-Butyl (R)-[1-(2-fluoro-4-methylaminophenyl)pyrrolidin-3-yl]methylcarbamate
tert-Butyl (R)-{1-[4-(benzyloxycarbonylmethylamino)-2-fluorophenyl]pyrrolidin-3-yl}-methylcarbamate was treated as described for method B. This resulted in the product with the molecular weight of 323.41 (C17H26FN3O2); MS (ESI): 324 (M+H+).
tert-Butyl (R)-{1-[4-(benzyloxycarbonylmethylamino)-2-fluorophenyl]pyrrolidin-3-yl}-methylcarbamate
tert-Butyl (R)-(+)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate (0.93 g) was added to a solution of N-(benzyloxycarbonyloxy)succinimide (2.49 g) in dichloromethane (30 ml). After 12 hours, the mixture was washed with water (2×30 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+).
(R)-[1-(2-Fluoro-4-methylaminophenyl)pyrrolidin-3-yl]dimethylamine
(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+).
Dimethyl-[1-(4-methylaminophenyl)pyrrolidin-3-yl]amine can be prepared analogously.
2-Dimethylamino-N-[1-(2-fluoro-4-methylaminophenyl)pyrrolidin-3-yl]-N-methylacetamide
(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+).
tert-Butyl (R)-[1-(4-amino-3-fluorophenyl)pyrrolidin-3-yl]methylcarbamate
2,4-Difluoronitrobenzene was treated with tert-butyl (R)-(+)-pyrrolidin-3-ylcarbamate, methylated and subsequently hydrogenated by method C-b. This resulted in the product with the molecular weight of 309.39 (C16H24FN3O2); MS (ESI): 310 (M+H+).
tert-Butyl [1-(4-aminonaphthalen-1-yl)pyrrolidin-3-yl]methylcarbamate
Method C-c
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+).
tert-Butyl [1-(4-amino-3-bromophenyl)pyrrolidin-3-yl]methylcarbamate
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+).
Tert-butyl [1-(4-amino-3-cyanophenyl)pyrrolidin-3-yl]methylcarbamate
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+).
tert-Butyl [1-(5-amino-6-chloropyridin-2-yl)pyrrolidin-3-yl]methylcarbamate
2-Chloro-6-fluoro-3-nitropyridine was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently reduced by method C-c. This resulted in the product with the molecular weight of 326.83 (C15H23ClN4O2); MS (ESI): 326 (M+H+), 327 (M+H+).
tert-Butyl [1-(4-amino-2,3-difluorophenyl)pyrrolidin-3-yl]methylcarbamate
2,3,4-Trifluoronitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently reduced by method C-c. This resulted in the product with the molecular weight of 327.38 (C16H23F2N3O2); MS (ESI): 328 (M+H+).
tert-Butyl [1-(4-amino-2-bromophenyl)pyrrolidin-3-yl]methylcarbamate
3-Bromo-4-fluoro-1-nitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently reduced by method C-a. This resulted in the product with the molecular weight of 370.29 (C16H24BrN3O2); MS (ESI): 370 (M+H+), 372 (M+H+).
tert-Butyl [1-(4-amino-2,6-difluorophenyl)pyrrolidin-3-yl]methylcarbamate
3,4,5-Trifluoronitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 327.38 (C16H23F2N3O2); MS (ESI): 328 (M+H+).
tert-Butyl (R)-[1-(4-amino-2-hydroxymethylphenyl)pyrrolidin-3-yl]carbamate
(2-Fluoro-5-nitrophenyl)methanol was treated with tert-butyl (R)-(+)-pyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 307.40 (C16H25N3O3); MS (ESI): 308 (M+H+).
tert-Butyl [1-(4-amino-2-chlorophenyl)pyrrolidin-3-yl]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+).
tert-Butyl [1-(4-amino-2,5-difluorophenyl)pyrrolidin-3-yl]methylcarbamate
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+).
tert-Butyl [1-(4-amino-2-methylphenyl)pyrrolidin-3-yl]methylcarbamate
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+).
tert-Butyl [1-(4-amino-3-trifluoromethylphenyl)pyrrolidin-3-yl]methylcarbamate
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+).
tert-Butyl [1-(4-amino-2-chloro-3-fluorophenyl)pyrrolidin-3-yl]methylcarbamate
2,4-Difluoro-3-chloronitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 329.80 (C15H21ClN3O2); MS (ESI): 329 (M+H+), 330 (M+H+).
tert-Butyl [1-(4-amino-2-cyanophenyl)pyrrolidin-3-yl]methylcarbamate
3-Cyano-4-fluoronitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 302.38 (C16H22N4O2); MS (ESI): 303 (M+H+).
tert-Butyl [1-(4-amino-5-chloro-2-methylphenyl)pyrrolidin-3-yl]methylcarbamate
1-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+).
tert-Butyl (R)-[1-(5-aminopyridin-2-yl)pyrrolidin-3-yl]methylcarbamate
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+).
tert-Butyl [1-(5-aminopyridin-2-yl)pyrrolidin-3-yl]methylcarbamate
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+).
tert-Butyl (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate
4-Fluoronitrobenzene was treated with tert-butyl (R)-(+)-pyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-b. This resulted in the product with the molecular weight of 291.40 (C16H25N3O2); MS (ESI): 292 (M+H+).
tert-Butyl [1-(4-amino-2-trifluoromethylphenyl)pyrrolidin-3-yl]methylcarbamate
4-Fluoro-3-trifluoromethylnitrobenzene was treated with tert-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+).
tert-Butyl [1-(5-amino-4-methylpyridin-2-yl)pyrrolidin-3-yl]methylcarbamate
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+).
tert-Butyl [1-(5-amino-3-methylpyridin-2-yl)pyrrolidin-3-yl]methylcarbamate
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+).
tert-Butyl [1-(4-amino-2-hydroxymethylphenyl)pyrrolidin-3-yl]methylcarbamate
(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+).
tert-Butyl [1-(4-amino-3-chloro-2-cyanophenyl)pyrrolidin-3-yl]methylcarbamate
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+).
tert-Butyl [1-(4-amino-3-methylphenyl)pyrrolidin-3-yl]methylcarbamate
4-Fluoro-2-methylnitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 291.40 (C16H25N3O2); MS (ESI): 292 (M+H+).
tert-Butyl [1-(5-aminopyridin-2-yl)pyrrolidin-3-yl]carbamate
2-Chloro-5-nitropyridine was treated with tert-butyl (R)-(+)-pyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 278.36 (C14H22N4O2); MS (ESI): 279 (M+H+).
5-(3-Dimethylaminopyrrolidin-1-yl)pyridin-2-ylamine
A suspension of 5-bromo-2-nitropyridine (2 g), 3-(dimethylamino)pyrrolidine (1.14 g), (R)-(+)2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.5 g), palladium(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+).
N-[1-(4-Aminophenyl)-4-hydroxypyrrolidin-3-yl]-N-methylacetamide
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+).
trans-N-(4-Hydroxypyrrolidin-3-yl)-N-methylacetamide
tert-Butyl trans-3-hydroxy-4-methylaminopyrrolidin-1-carboxylate (1.0 g, tetrahedron: Asymmetry 2001, 12, 2989) was mixed with pyridine (1.5 g) and acetic anhydride (0.567 g). After 3 hours, volatile fractions 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+).
trans-1-(4-Aminophenyl)-4-dimethylaminopyrrolidin-3-ol
tert-Butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.0 g, tetrahedron: Asymmetry 2001, 12, 2989) was stirred with dimethylamine (40% aq., 10 ml) for 12 hours. The mixture was concentrated 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+).
[1-(4-Aminophenyl)-4-methoxypyrrolidin-3-yl]dimethylamine
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+).
[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine
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+).
1-(4-Aminophenyl)-3-dimethylaminopyrrolidin-2-one
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+).
1-(4-Aminophenyl)-3-(7-azabicyclo[2.2.1]hept-7-yl)pyrrolidin-2-one was obtained in an analogous manner.
4-[3-(7-Azabicyclo[2.2.1 ]hept-7-yl)pyrrolidin-1-yl]phenylamine
1-(4-Nitrophenyl)-3-(7-azabicyclo[2.2.1]hept-7-yl)pyrrolidin-2-one (0.25 g) 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+).
(R)-1′-(4-Aminophenyl)-[1,3′]bipyrrolidinyl-2-one
tert-Butyl [1-(4-Nitrophenyl)pyrrolidin-3-yl]carbamate was treated by method G. The crude product (1.4 g) was dissolved in acetonitrile (20 ml) and mixed with trisodium phosphate (0.67 g) and 4-chlorobutyryl chloride (1.1 g). After 2 hours, sodium hydroxide (0.6 g) in water (10 ml) was 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+).
1-Methylpiperidine-3-carboxylic acid [(R)-1-(4-aminophenyl)pyrrolidin-3-yl]methylamide
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+).
(R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-2-dimethylamino-N-methylacetamide was obtained in an analogous manner using N,N-dimethylglycine.
N-[(R)-1-(4-Aminophenyl)pyrrolidin-3-yl]-N-(2-diethylaminoethyl)acetamide
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+).
N-(2-Diethylaminoethyl)-N-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide
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+).
N,N-Diethyl-N′-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]ethane-1,2-diamine
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+).
tert-Butyl (2-diethylaminoethyl)-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate
tert-Butyl [(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate (6.0 g) 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+).
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester was reacted with [1-(4-aminophenyl)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+).
Synthesis of Amines Required as Intermediates
Spiro[1,3-benzodioxol-2,1′-cyclopentane]-5-amine
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+).
Spiro[5-nitro-1,3-benzodioxol-2,1′-cyclopentane]
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+).
Spiro[1,3-benzodioxol-2,1′-cyclopentane]
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+).
5-Chloro-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol
Butyllithium (15% in hexane; 7.6 ml) was added dropwise to a solution of 2-bromo-5-chloropyridine (2.0 g) in diethyl ether (50 ml) at −78° C. and, 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+).
The following were obtained analogously:

    5-Fluoro-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol
    6-Chloro-2′,3′,5′,6′-tetrahydro-1′H-[3,4′]bipyridinyl-4′-ol.


6-Cyclopentyloxypyridin-3-ylamine
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+).
6-(4-Fluorophenyl)-3-azabicyclo[4.1.0]heptane
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+).
Synthesis of Carboxylic Acids Required as Intermediates
4-(4-Methylpiperidin-1-yl)benzoic acid
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+).
4-(4-Methylpiperidin1-yl)benzonitrile
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+).
4-Butoxycyclohexanecarboxylic acid
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+).
1-Benzyl-1H-[1,2,3]triazole-4-carboxylic acid
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+).
Methyl 1-benzyl-1H-[1,2,3]triazole-4-carboxylate
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+).
1-Biphenyl-4-yl-1H-[1,2,3]triazole-4-carboxylic acid was prepared analogously from 4-Ethynylbiphenyl and ethyl azidoacetate.
1-Butyl-1H-indole-5-carboxylic acid
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+).
3′-Acetylaminobiphenyl-4-carboxylic acid
3′-Aminobiphenyl-4-carboxylic acid (0.2 g) was mixed with pyridine (0.7 g) and acetic anhydride (180 mg) and, after 14 hours, volatile fractions 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+).
3′-Isobutyrylaminobiphenyl-4-carboxylic acid
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+).
5-Butoxypyridine-2-carboxylic acid
Sodium hydride (50% in oil, 250 mg) was added to benzhydryl 5-hydroxypyridine-2-carboxylate (2.0 g) dissolved in DMF (20 ml) and, 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+).
4-Methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-carboxylic acid
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+).
N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]terephthalamic acid
Method P-a
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+).
N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]terephthalamic acid methyl ester
[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with terephthalic acid monomethyl ester by method E. This resulted in the product with the molecular weight of 367.45 (C21H25N3O3); MS (ESI): 368 (M+H+).
4-(Cyclopentanecarbonylmethylamino)benzoic acid
Methyl 4-methylaminobenzoate was reacted with 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+).
The following compounds were obtained analogously:

    4-(Cyclopentanecarbonylamino)-3-methoxybenzoic acid
    2-Chloro-4-(cyclopentanecarbonylamino)benzoic acid
    2-Fluoro-4-(cyclopentanecarbonylamino)benzoic acid
    4-(Cyclopentanecarbonylamino)-3-methylbenzoic acid
    4-(Cyclopentanecarbonylamino)benzoic acid
    4-(Cyclopentanecarbonylamino)-3-trifluoromethoxybenzoic acid
    3-Chloro-4-(cyclopentanecarbonylamino)benzoic acid
    5-Chloro-4-(cyclopentanecarbonylamino)-2-methoxybenzoic acid
    4-[(Cyclohex-1-enecarbonyl)amino]benzoic acid
    4-[(Cyclopent-1-enecarbonyl)amino]benzoic acid


3-Fluoro-4-(1-methylbutoxy)benzoic Acid
A solution of 0.449 g of 1-[3-fluoro-4-(1-methylbutoxy)phenyl]ethanone 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+).
1-[3-Fluoro-4-(1-methylbutoxy)phenyl]ethanone
0.058 g of NaH was added to a solution of 0.176 g of 2-pentanol in 2 ml 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.
The following compounds were obtained analogously:

    4-Cyclobutoxy-3-fluorobenzoic acid
    3-Fluoro-4-(2-methylcyclopropylmethoxy)benzoic acid
    4-(2-Cyclopropylethoxy)-3-fluorobenzoic acid
    3-Fluoro-4-(1-methylpiperidin-3-yloxy)benzoic acid
    4-(1-Acetylpiperidin-3-yloxy)-3-fluorobenzoic acid
    3-Fluoro-4-(1-methylpyrrolidin-3-yloxy)benzoic acid
    4-(1-Acetylpyrrolidin-3-yloxy)-3-fluorobenzoic acid
    3-Fluoro-4-(1-methylpiperidin-3-ylmethoxy)benzoic acid


4-(2,4-Difluorophenoxy)benzoic Acid
0.518 g of potassium hydroxide was added to a 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+).
Ethyl 4-(2,4-difluorophenoxy)benzoate
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+)
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.
4-Butoxy-3-methoxybenzoic acid
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+).
The following compounds were prepared analogously:

    4-Butoxy-3,5-dichlorobenzoic acid
    4-Butoxy-3-nitrobenzoic acid
    4-Butoxy-3-chlorobenzoic acid
    4-Butoxy-3,5-dimethylbenzoic acid
    4-Butoxy-2,3-dichloro-5-methoxybenzoic acid
    4-Butoxy-2,3,5,6-tetrafluorobenzoic acid
    4-Butoxy-3-fluorobenzoic acid
    3-Acetyl-4-butoxybenzoic acid
    2,4-Dibutoxybenzoic acid
    4-Butoxy-2-chlorobenzoic acid


4-Propoxymethylbenzoic Acid
Sodium hydride (50% in oil; 0.42 g) was cautiously added to a solution 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+).
The following compounds were prepared analogously:

    4-Ethoxymethylbenzoic acid
    4-Butoxymethylbenzoic acid
    4-Isobutoxymethylbenzoic acid
    4-Phenoxymethylbenzoic acid
    4-(Pyridin-3-yloxymethyl)benzoic acid
    4-(Pyridin-2-yloxymethyl)benzoic acid
    4-Benzoimidazol-1-ylmethylbenzoic acid
    4-Indol-1-ylmethylbenzoic acid
    4-Phenylsulfanylmethylbenzoic acid
    4-(Pyrimidin-2-ylsulfanylmethyl)benzoic acid
    4-(Pyridin-2-ylsulfanylmethyl)benzoic acid
    4-(2-Cyanophenoxymethyl)benzoic acid
    4-(2-Chlorophenoxymethyl)benzoic acid
    4-Cyclobutoxymethylbenzoic acid
    4-Cyclopentyloxymethylbenzoic acid
    4-Cyclohexyloxymethylbenzoic acid
    4-sec-Butoxymethylbenzoic acid
    4-Pentoxymethylbenzoic acid


4-(3-Oxo-3a,4,5,6-tetrahydro-3H-cyclopentapyrazol-2-yl)benzoic acid
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+).
4-Butoxy-2-methoxybenzoic acid
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.
4-(1-Propoxyethyl)benzoic acid
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




wherein
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
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;
wherein
o is 0, 1, 2, 3, 4, 5 or 6;
p is 0, 1 or 2
q, r, s are each independently 0, 1, 2, 3 or 4;
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;
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 additional 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 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;
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;
t is 0, 1, 2, 3, 4, 5 or 6;
u is 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 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-, 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;
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 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;
R78, R79 are each independently H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, OH or (C1-C4)-alkoxy-(C1-C4)-alkyl;
R80, R81, R93 are each independently (C1-C8)-alkyl, (C2-C6)-alkenyl or (C0-C8)-alkylene-aryl;
R82, R83 are each independently H or (C1-C6)-alkyl; or
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;

R3 is H or (C1-C6)-alkyl;
R4, R5 are each independently H, (C1-C6)-alkyl, OH, O—(C1-C6)-alkyl, O—CO(C1-C6)-alkyl or S—(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); or
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;
wherein
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);
wherein
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;
R84, R85 are each independently H or (C1-C8)-alkyl;
R86 is H, (C1-C6)-alkyl or aryl;
x is 1, 2, 3, 4, 5 or 6;



R10 is H, (C1-C8)-alkyl, (C3-C6)-alkenyl or (C3-C6)-alkynyl;
X is N(R52) or O;
wherein
R52 is H or (C1-C8)-alkyl;


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;
wherein
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, 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;
wherein
v is 1, 2, 3 or 4
R66, R67, R68, R69, R70 are each independently H or (C1-C8)-alkyl;
Z is O, S, N(R92), CO, SO or SO2;
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-;
z is 2, 3, 4, 5 or 6;
R92 is H or (C1-C8)-alkyl;


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;
wherein
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 the nitrogen atom, optionally contain one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur; or


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;
and the N-oxides and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 of formula 1:




wherein
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
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;
wherein
o is 0, 1, 2, 3, 4, 5 or 6;
p is 0, 1 or 2
q, r, s are each independently 0, 1, 2, 3 or 4;
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;
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 additional 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 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;
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;
t is 0, 1, 2, 3, 4, 5 or 6;
u is 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 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-, 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;
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 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;

R3 is H or (C1-C6)-alkyl;
R4, R5 are each independently H, (C1-C6)-alkyl, OH, O—(C1-C6)-alkyl, O—CO(C1-C6)-alkyl or S—(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);
wherein
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);
wherein
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, (C1-C8)-alkyl, (C3-C6)-alkenyl or (C3-C6)-alkynyl;
X is N(R52) or O;
wherein
R52 is 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 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;
wherein
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, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO or C≡C;
wherein
v is 1, 2, 3 or 4
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, (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;
wherein
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 the nitrogen atom, optionally contain one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur; or


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;

and the N-oxides and pharmaceutically acceptable salts thereof.

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) or O;
R52 is 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 1 and
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) or a bond;
R52 is 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




wherein
R1, R2 are 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);
o is 0, 1, 2, 3 or 4;
q is 1, 2 or 3;
s 0, 1 or 2;
R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32 are independently of one another H or (C1-C6)-alkyl; or
substituent pairs R17 and R18, 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 5-6 membered ring which, apart from said nitrogen atom of attachment, optionally comprises one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur;

R12 is OH, O—(C1-C6)-alkyl, O—(C0-C2)-alkylene-aryl, CN, S—(C1-C6)-alkyl, 3-12 membered mono-, bi- or spirocyclic ring which optionally comprises 1 to 3 heteroatoms selected from the group of N, O and S, and optionally substituted by F, OH, CF3, CN, oxo, (C1-C6)-alkyl, (C0-C2)-alkylene-aryl, N(R34)(R35), COO(R40) or CO(C1-C6)-alkyl;
R34, R35 are independently of one another H or (C1-C4)-alkyl;
R40 is H, (C1-C6)-alkyl or (C0-C2)-alkylene-aryl;
R78, R79 are each independently H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, OH or (C1-C4)-alkoxy-(C1-C4)-alkyl;
R42, R42′ are each independently H, F, Cl, Br, CF3, CN or (C1-C6)-alkyl;
R10 is H or (C1-C8)-alkyl;
X is N(R52);
R52 is H or (C1-C8)-alkyl;
E is a 5-7 membered bivalent carbo- or heterocyclic ring structure with 0-3 heteroatoms from the group of N, O and S, and optionally substituted by H, F, Cl, Br, CF3, OH, CN, OCF3, NO2, O—(C1-C6)-alkyl, (C1-C6)-alkyl, SO2—CH3 or CO(R65);
R65 is H or (C1-C8)-alkyl;
K is a bond, O, OCH2, CH2O, S, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C≡C, SCH2 or SO2CH2;
v is 1, 2 or 3,
R66, R67, R68, R69, R70 are each independently H or (C1-C8)-alkyl;
R11 is (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring optionally comprising 1 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, and optionally 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;
R71, R72, R73, R74, R75, R76, R77 is 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 contains one additional heteroatom component selected from the group of N—(C1-C6)-alkyl, oxygen and sulfur; or
the N-oxides or pharmaceutically acceptable salts thereof.

8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8 further comprising one or more anorectic active ingredients.

10. A method of treating obesity comprising administering to a patient in need thereof a compound of claim 1.

11. 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.

12. A method of treating type II diabetes comprising administering to a patient in need thereof a compound of claim 1.

13. 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.

14. A method of reducing weight in mammals comprising administering to a patient in need thereof a compound of claim 1.