Inhibitors of the human aldosterone synthase CYP11B2

A method of treating hyperaldosteronism in a mammal in need thereof, the method comprising administering to the mammal a pharmaceutically effective amount of a compound of formula (I):

• wherein:
• Z is C═O or C═S;
• U is CR5R6, NR7, O, S, SO, or SO2;
• X is independently CR5R6, NR7, O, or S;
• Y is CR5R6, NR7, O, or S;
• b is 0;
• n is 0;
• m is 0 or 1;
• provided that when U is SO or SO2:
• not more than one of U, X, and Y is NR7,O, or S;
• and X and Y are not O or S;
• and X or Y is NR7 in a position vicinal to U,
• wherein, when m is 1, the bond between U and X or U and Y, respectively, or X and Y can be a C═C or C═N double bond;
• Het is a ring system containing 1 or 2 rings, and at least one of the rings is aromatic and contains 5 or 6 ring atoms, of which at least one is nitrogen, and the other ring can be saturated or unsaturated and comprises from 5 to 7 ring atoms;
• while the ring system can contain additional 1 to 5 heteroatoms selected from the group consisting of N, S, and O, provided that not more than two heteroatoms are selected from the group consisting of S and O;
• and the ring system can be substituted by from one to four substituents R11,
• with the provisos that:
• 3-pyridyl has at position 6 no substituents other than H, when Het is 3-pyridyl;
• and,
• when Z is C═O;
• m is 1;
• X is CR5R6 and U is CR5R6;
• or the bond between U and X is a C═C double bond;
• R1 is H, C1-4 alkyl or 2-hydroxyethyl;
• and R2 is other than NO2;
• then Het is not an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group;
• R1 is selected from the group consisting of H;
• C1-4 alkyl;
• C2-4 alkenyl;
• C3-7 cycloalkyl;
• C1-4 alkylcarbonyl;
• and C1-4 alkoxycarbonyl;
• each of which can be substituted by from one to three substituents Ra, wherein Ra is independently selected from the group consisting of optionally partially or completely halogenated C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, and C1-4 alkylcarbonyl and also hydroxyl, nitro, and cyano, or can be partially or completely halogenated with independent halogen atoms;
• aryl C1-4 alkyl and heterocyclyl C1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents Rb, wherein Rb is selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylcarbonyl, C1-4 alkylsulfonyl, whose alkyl moieties may be partially or completely halogenated with independent halogen atoms, halogen, hydroxyl, nitro, cyano, —NRc2, —CONRc2, and SO2NRc2,
• wherein Rc is independently selected from the group consisting of H and C1-4 alkyl;
• R2, R3 and R4 are independently selected from the group consisting of H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, C1-4 alkoxy, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylsulfonyl, which in each case can be substituted by from one to three substituents Ra, or can be partially or completely halogenated with independent halogen atoms;
• aryl C1-4 alkyl, aryl C0-4 alkylsulfonyl, heterocyclyl C1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents Rb;
• halogen, hydroxyl, nitro, cyano, —NRc2, —CONRc2, and —SO2NRc2;
• or
• R1 and R2 form, together with the atoms to which they are bonded, an unsaturated nitrogen-containing five membered to seven membered ring comprising 1 or 2 unsaturated bonds and may, in addition to the nitrogen atom to which the R1 group is bonded, also contain a hetero atom or a heteroatom-containing group selected from the group consisting of O, S and NR7, and can be substituted by from one to four substituents R12;
• R5 and R6 are independently selected from the group consisting of H, C1-4 alkyl, C3-7 cycloalkyl, hydroxyl C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, C1-4 alkylthio, whose alkyl moieties can be partially or completely halogenated with independent halogen atoms;
• halogen, hydroxyl, nitro, cyano, —NRc2, and NRcCORd, and Rd is selected from the group consisting of C1-4 alkyl, C3-7 cycloalkyl, C1-4 alkoxy, whose alkyl moieties can be partially or completely halogenated with independent halogen atoms, and wherein R5 or R6 may be bonded to a carbon atom forming part of a double bond,
• R7 is selected from the group consisting of H, C1-4 alkyl, and C3-7 cycloalkyl, which in each case can be substituted by from one to three substituents Ra, or can be partially or completely halogenated with independent halogen atoms;
• and aryl C1-4 alkyl, which can be substituted on the ring or at least on one ring by from one to four substituents Rb;
• R8 and R9 are independently selected from the group consisting of H;
• C1-4 alkyl, C3-7 cycloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, which can in each case be substituted by from one to three substituents Ra, or can be partially or completely halogenated with independent halogen atoms;
• halogen, hydroxyl;
• aryl, aryl C1-4 alkyl, heterocyclyl, heterocyclyl C1-4 alkyl, which can be substituted on the ring or at least on one ring by from one to four substituents Rb;
• or
• R8 and R9 form, together with the carbon atom to which they are bonded, a cyclopropane ring;
• R10 is selected from the group consisting of H;
• C1-4 alkyl, C3-7 cycloalkyl, which in each case can be substituted by from one to three substituents Ra, or can be partially or completely halogenated with independent halogen atoms;
• aryl, aryl C1-4 alkyl, heterocyclyl, and heterocyclyl C1-4 alkyl, each of which can be substituted on the or at least one ring by from one to four substituents Rb;
• R11 is independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylsulfonyl, which can in each case be substituted by from one to three substituents Ra, or can be partially or completely halogenated with independent halogen atoms;
• aryl, heterocyclyl, aryl C0-4 alkylsulfonyl, aryl C1-4 alkyl, and heterocyclyl C1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents Rb, halogen, hydroxyl, nitro, cyano, —NRc2, —CONRc2, and —SO2NRc2;
• and
• R12 is independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, which can in each case be substituted by from one to three substituents Ra, or can be partially or completely halogenated with independent halogen atoms;
• aryl, heterocyclyl, aryl C1-4 alkyl, and heterocyclyl C1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents Rb;
• optionally partially or completely halogenated C1-4 alkoxy, hydroxyl, halogen, nitro, cyano, and NRc2 when R12 is bonded to a carbon atom;
• or a pharmaceutically acceptable salt thereof.