Benzoimidazole-carboxylic acid amide derivatives as APJ receptor modulators

A compound of the formula I,

• wherein
• R′, R″, and R′″ are independently of each other H, halogen, CF3, OCF3, or O—(C1-C3)-alkyl;
• R1 is
• a) (C4-C7)-alkyl;
• b) (C5-C7)-cycloalkyl, which is unsubstituted or mono-substituted by (C1-C2)-alkyl or CF3;
• c) methylene-cyclohexyl;
• or
• d) phenyl, which is unsubstituted or mono-substituted by methyl or Cl;
• R2 is
• a) a 5-membered heteroaryl which contains 1 or 2 identical or different ring heteroatoms selected from the group consisting of N, O and S, wherein said 5-membered heteroaryl is unsubstituted or mono-substituted by Cl or (C1-C4)-alkyl;
• b) phenyl;
• c) (C5-C6)-cycloalkyl;
• or
• d) tetrahydrofuranyl;
• R3 is H or (C1-C2)-alkyl;
• and
• R4 is
• a) (C3-C5)-alkyl, which may be optionally substituted by 1-3 F or S—(C1-C4)-alkyl,
• b) (C0-C1)-alkylene-(C3-C7)-cycloalkyl, wherein said cycloalkyl is unsubstituted or mono- or di-substituted by methyl;
• c) (C0-C2)-alkylene-phenyl, wherein said phenyl is unsubstituted or mono- or di-substituted by F, Cl, (C1-C4)-alkyl or CF3;
• or
• d) thienyl;
• or
• R3 and R4
• are, together with the carbon atom to which they are attached, a 5- to 7-membered cycloalkyl ring, which is unsubstituted or mono-substituted by (C1-C4)-alkyl;
• R5 is H, (C1-C4)-alkyl or OH;
• R6 is H or (C1-C4)-alkyl;
• n is 0, 1 or 2;
• and
• Z is
• CO2—R7, OR8, C(O)NR9R10, S(O)2NR11R12,
• wherein
• v is 0 or 2;
• R7 is H or (C1-C4)-alkyl;
• R8 is H or (C1-C4)-alkyl;
• R9 is H, (C1-C4)-alkyl or ethylene-O—(C1-C4)-alkyl;
• and
• R10 is
• a) H;
• b) (C1-C6)-alkyl, which is unsubstituted or mono-substituted by CF3;
• c) (C1-C2)-alkyl, which is substituted by CN or CO2R19;
• wherein
• R19 is H or (C1-C6)-alkyl;
• d) (C2-C4)-alkyl, which is mono-substituted by a substituent selected from the group consisting of S-methyl, SO2NR20R21, O—R22 and NR23R24;
• wherein
• R20 is H;
• R21 is H;
• R22 is H, (C1-C3)-alkyl, methylene-cyclopropyl, methylene-phenyl, or methylene-2-tetrahydrofurane;
• R23 is H or (C1-C2)-alkyl;
• and
• R24 is (C1-C2)-alkyl or SO2-methyl;
• e) (C3-C5)-cycloalkyl, which is unsubstituted or mono-substituted by phenyl;
• f) (C0-C2)-alkylene-heterocycloalkyl, wherein said heterocycloalkyl is five or six membered and contains 1 or 2 O atoms in non-adjacent positions, and wherein said heterocycloalkyl is unsubstituted or geminally disubstituted with a spiro cyclopentyl ring or a spiro cyclohexyl ring;
• g) (C2-C5)-alkylene-heterocycloalkyl, wherein said heterocycloalkyl is a five-, six- or seven-membered ring, which contains at least one N atom, and which is attached via said N-atom, and which may additionally contain one heteroatom selected from the group consisting of O, S(O)x and NR25 in a position not adjacent to the N atom by which the ring is attached to the alkylene, and wherein any carbon atom within said heterocycloalkyl is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of (C1-C3)alkyl and methylene-phenyl;
• wherein
• x is 2;
• and
• R25 is H, (C1-C2)alkyl, methylene-phenyl or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl and O—(C1-C4)-alkyl;
• h) (C0-C3)-alkylene-heterocycloalkyl, wherein said heterocycloalkyl is a five- or six-membered ring, which contains at least one N atom, and which is not attached via said N-atom, and which may additionally contain one O atom in a position not adjacent to the N atom, and wherein said N-atom is unsubstituted or substituted by a substituent selected from the group consisting of
• i) (C1-C4)-alkyl, which is unsubstituted or mono-substituted by O(C1-C4)-alkyl;
• ii) methylene-cyclohexyl;
• iii) (C0-C2)-alkylene-phenyl, wherein said phenyl is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F and O(C1-C4)-alkyl;
• iv) (C0-C1)-alkylene-pyridyl;
• and
• v) pyrimidinyl;
• i) 8-methyl-8-aza-bicyclo[3.2.1]oct-3yl;
• j) 9-methyl-9-aza-bicyclo[3.3.1]non-3-yl;
• k) methylene-4-(octahydro-quinolizinyl);
• l) (C0-C2)-alkylene-phenyl, wherein phenyl is unsubstituted or monosubstituted by a substituent selected from the group consisting of F, O(C1-C4)-alkyl, N((C1-C4)-alkyl)2, 4-morpholinyl and methylene-(4-methyl-piperidin)-1-yl or disubstituted on adjacent positions by the group —O(CH2)O—;
• or
• m) (C1-C2)-alkylene-heteroaryl, wherein said heteroaryl ring is a five- or six-membered ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of O, S and N;
• and wherein said heteroaryl ring is unsubstituted;
• or
• R9 and R10 together with the N-atom carrying them are
• a) a four-, five- or six-membered heterocycloalkyl ring containing one heteroatom, which is the N atom to which R9 and R10 are attached, and wherein said heterocycloalkyl ring is unsubstituted or mono-substituted by a substituent selected from the group consisting of
• i) (C0-C1)-alkylene-OR26, wherein R26 is H, (C1-C3)alkyl or methylene-phenyl;
• ii) CO2R27, wherein R27 is H or (C1-C6)-alkyl;
• ii) NR28R29, wherein R28 is (C1-C2)-alkyl and R29 is (C1-C2)-alkyl, methylene-phenyl or ethylene-N((C1-C4)-alkyl)2;
• iii) 1-piperidinyl, which is unsubstituted or mono-substituted by methyl;
• iv) 1-piperazinyl, which is unsubstituted or mono-substituted by methyl;
• v) 4-morpholinyl;
• vi) 1-azepanyl;
• and
• vii) 2-(2,3-dihydro-1H-isoindolyl);
• b) a six- or seven-membered heterocycloalkyl ring containing the N atom to which R9 and R10 are attached and one additional heteroatom selected from O, S or NR30 in a position non-adjacent to the N atom to which R9 and R10 are attached, wherein the carbon atoms in said heterocycloalkyl ring are unsubstituted or mono- or disubstituted by methyl and wherein
• R30 is
• i) H;
• ii) (C1-C4)-alkyl;
• iii) (C5-C6)-cycloalkyl;
• iv) phenyl, which is unsubstituted or mono-substituted by F, CF3 or O—(C1-C4)-alkyl;
• v) methylene-phenyl, which is unsubstituted or mono- or di-substituted by F or Cl or disubstituted on adjacent positions by the group —O(CH2)O—;
• or
• vi) pyridyl;
• or
• c) a 2,5-diaza-bicyclo[2.2.1]heptyl-ring, which is unsubstituted or substituted on the N atom in the 5-position by a substituent selected from the group consisting of (C1-C4)-alkyl, methylene-cyclopentyl, phenyl, which is unsubstituted or mono-substituted by F, and methylene-phenyl, wherein said phenyl is unsubstituted or mono-substituted by O—(C1-C4)-alkyl or CF3;
• R11 is H;
• R12 is (C1-C4)-alkyl;
• R13 is H;
• R14 is CF3 or methylene-O—(C1-C4)-alkyl;
• R15 is cyclopropyl or phenyl;
• R16 is H or (C1-C4)-alkyl;
• R17 is H or (C1-C4)-alkyl;
• and
• R18 is (C1-C4)-alkyl;
• in any of its stereoisomeric forms, or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them.