New indole derivatives as factor Xa inhibitors

A compound of the formula I,

• 322
• wherein
• R0 is selected from the group consisting of
• 1) monocyclic and bicyclic 6- to 14-membered aryl radicals, said aryl radicals being substituted with one two or three substituents independently selected from the R8 substituents defined below, provided that at least one R8 is halogen, —C(O)—NH2 or —O—(C1-C8)-alkyl;
• 2) monocyclic and bicyclic 4- to 14-membered heteroaryl radicals selected from the group consisting of pyridyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, benzothiophen, quinazolinyl and phenylpyridyl radicals, said heteroaryl radicals being unsubstituted or substituted with one two or three substituents independently selected from the R8 substituents defined below;
• 3) monocyclic or bicyclic 4- to 14-membered heteroaryl radicals containing one, two, three or four heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, said heteroaryl radicals being unsubstituted or substituted with one two or three substituents independently selected from the R8 substituents defined below, as well as by a monocyclic or bicyclic 4- to 14-membered heteroaryl, containing one, two, three or four heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, which heteroaryl radical is unsubstituted or substituted with one two or three substituents independently selected from the R8 substituents defined below;
• R8 is selected from the group consisting of
• halogen, —NO2;
• —CN;
• —C(O)—NH2;
• —OH;
• —NH2;
• —OCF3;
• monocyclic and bicyclic 4- to 14-membered aryl radicals, said aryl radicals being substituted with one, two, or three substituents independently selected from halogen and —O—(C1-C8)-alkyl;
• —(C1-C8)-alkyl, said alkyl being unsubstituted or substituted with up to three substituents independently selected from halogen, NH2, —OH and methoxy;
• and —O—(C1-C8)-alkyl, said alkyl being unsubstituted or substituted with up to three substituents independently selected from halogen, NH2, —OH and methoxy;
• Q is selected from the group consisting of
• a direct bond;
• —C(O)—;
• —(C0-C2)-alkylene-C(O)—NR10—;
• —NR10—C(O)—NR10—;
• —NR10—C(O)—;
• —SO2—;
• —(C1-C6)-alkylene, wherein alkylene is unsubstituted or substituted with up to three substituents independently selected from halogen, —NH2 and —OH;
• and (C3-C6)-cycloalkylene, wherein cycloalkylene is unsubstituted or substituted with up to three substituents independently selected from halogen, —NH2 and —OH;
• R1 is selected from the group consisting of
• hydrogen;
• —(C1-C4)-alkyl radicals, said alkyl radicals being unsubstituted or substituted with one two or three substituents independently selected from the R13 substituents defined below;
• and monocyclic or bicyclic 4- to 14-membered heteroaryl radicals said heteroaryl radical is unsubstituted or substituted with one two or three substituents independently selected from the R14 substituents defined below;
• R2 is a direct bond or —(C1-C4)-alkylene;
• provided that:
• a) R1 and R7 together with the atoms to which they are bonded can form a 4- to 7-membered cyclic group, which may contain 1, 2, 3 or 4 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, said cyclic group being unsubstituted or substituted with one two or three substituents independently selected from the R14 substituents defined below;
• b) R1—N—R2—V can form a 4- to 7-membered cyclic group, which may contain 1, 2, 3 or 4 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, said cyclic group being unsubstituted or substituted with one two or three substituents independently selected from the R14 substituents defined below;
• R14 is selected from the group consisting of
• halogen, —OH, ═O, —(C1-C8)-alkyl, —(C1-C4)-alkoxy, —NO2, —C(O)—OH, —CN, —NH2, —C(O)—O—(C1-C4)-alkyl, —(C1-C8)-alkylsulfonyl, —SO2, —C(O)—NH—(C1-C8)-alkyl, —C(O)—N—[(C1-C8)-alkyl]2, —NR10—C(O)—NH—(C1-C8)-alkyl, —C(O)—NH2, —SR10, and —NR10—C(O)—NH—[(C1-C8)-alkyl]2, said R10 being selected from hydrogen, —(C1-C3)-perfluoroalkyl and —(C1-C6)-alkyl;
• V is selected from the group consisting of
• a 3- to 7-membered cyclic group, which may contain 1, 2, 3 or 4 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, said cyclic group being unsubstituted or substituted with one two or three substituents independently selected from the R14 substituents defined above;
• a 6- to 14-membered aryl, said aryl being unsubstituted or substituted with one two or three substituents independently selected from the R14 substituents defined above;
• and a monocyclic or bicyclic 4- to 14-membered heteroaryl, said heteroaryl being unsubstituted or substituted with one two or three substituents independently selected from the R14 substituents defined above;
• G is selected from the group consisting of:
• a direct bond, —(CH2)m—NR10—SO2—NR10—(CH2)n—, —(CH2)m—CH(OH)—(CH2)n—, —(CH2)m—, —(CH2)m—O—(CH2)n—, —(CH2)m—C(O)—NR10—(CH2)n—, —(CH2)—SO2—(CH2)n—, —(CH2)m—NR10—C(O)—NR10—(CH2)n—, —(CH2)m—NR10—C(O)—(CH2)n—, —(CH2)m—C(O)—(CH2)n—, —(CH2)—S—(CH2)n—, —(CH2)m—SO2—NR10—(CH2)n—, —(CH2)m—NR10—SO2—(CH2)n—, —(CH2)m—NR10—, —(CH2)m—O—C(O)—NR10—(CH2)n— and —(CH2)m—NR10—C(O)—O—(CH2)n—,
• n and m are independently selected from zero and the integers 1, 2, 3, 4, 5 and 6,
• R10 is hydrogen, —(C1-C3)-perfluoroalkyl or —(C1-C6)-alkyl,
• M is selected from the group consisting of
• hydrogen;
• —(C1-C8)-alkyl, said alkyl being unsubstituted or substituted with one two or three substituents independently selected from the R14 substituents defined above;
• —C(O)—NR11R12;
• —(CH2)m—NR10;
• —(C6-C14)-aryl, said aryl being unsubstituted or substituted with one two or three substituents independently selected from the R14 substituents defined above;
• —(C4-C14)-heteroaryl, said heteroaryl being unsubstituted or substituted with one two or three substituents independently selected from the R14 substituents defined above;
• (C3-C7)-cycloalkyl, said cycloalkyl being unsubstituted or substituted with one two or three substituents independently selected from the R14 substituents defined above;
• a 3- to 7-membered cyclic residue, optionally containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur and oxygen, said cyclic residue being unsubstituted or substituted with one two or three substituents independently selected from the R14 substituents defined above;
• R11 and R12 are independently selected from the group consisting of:
• hydrogen;.—(C1-C6)-alkyl, said alkyl being unsubstituted or substituted with one two or three substituents independently selected from the R13 substituents defined below;
• —(C6-C14)-aryl-(C1-C4)-alkyl-, wherein said alkyl and said aryl are each independently unsubstituted or substituted with one two or three substituents independently selected from the R13 substituents defined below;
• —(C6-C14)-aryl-, said aryl being unsubstituted or substituted with one two or three substituents independently selected from the R13 substituents defined below;
• —(C4-C14)-heteroaryl, said heteroaryl being unsubstituted or substituted with one two or three substituents independently selected from the R13 substituents defined below;
• —(C4-C14)-heteroaryl-(C1-C4)-alkyl-, wherein said alkyl and said heteroaryl are each independently unsubstituted or substituted with one two or three substituents independently selected from the R13 substituents defined below;
• or, alternatively,
• R11 and R12,, together with the nitrogen atom to which they are bonded, form a saturated 5- to 7-membered monocyclic heterocyclic ring which, in addition to said nitrogen atom, may contain one or two identical or different ring heteroatoms selected from oxygen, sulfur and nitrogen;
• said heterocyclic ring being unsubstituted or substituted with one two or three substituents independently selected from the R13substituents defined below;
• R13 is selected from the group consisting of:
• halogen;
• —NO2;
• —CN;
• ═O;
• —OH;
• —(C1-C8)-alkyl;
• —(C1-C8)-alkoxy;
• —CF3;
• phenyl;
• phenyloxy-;
• —C(O)—O—R11;
• phenyl-(C1-C4)-alkoxy-;
• —C(O)—N—R11R12;
• —NR11R12;
• —NR10—SO2—R10;
• —S—R10;
• —SOn—R10;
• wherein n is 1 or 2;
• —SO2—NR11R12;
• —C(O)—R10;
• —(C0-C4)-alkyl-C(O)—O—C(R15R16)—O—C(O)—R17;
• —(C0-C4)-alkyl-C(O)—O—C(R15R16)—O—C(O)O—R17, and a residue of formula Va,
• 323
• wherein R10, R11, R12 are as defined above and R15, R16 or R17 are as defined below;
• R15 and R16 are independently selected from hydrogen, and —(C1-C6)-alkyl, or, alternatively, together with the carbon atom to which they are bonded, form a 3- to 6 membered carbocyclic ring, said carbocyclic ring being unsubstituted or substituted with one, two or three substituents independently selected from the R10 substituents defined above;
• R17 is selected from the group consisting of —(C1-C6)-alkyl, —(C1-C8)-cycloalkyl, and —(C1-C6)-alkyl-(C1-C8)-cycloalkyl, each said cycloalkyl ring being unsubstituted or substituted with one, two or three substituents independently selected from the R10 substituents defined above;
• R3, R4, R5, R6 and R7 are each independently selected from the group consisting of:
• hydrogen;
• halogen;
• —(C1-C4)-alkyl, said alkyl being unsubstituted or substituted with one two or three substituents independently selected from the R13 substituents defined above;
• —(C1-C3)-perfluoroalkyl;
• phenyl, said phenyl being unsubstituted or substituted with one, two or three substituents independently selected from the R13 substituents defined above;
• —O—(C1-C4)-alkyl, said alkyl being unsubstituted or substituted with one two or three substituents independently selected from the R13 substituents defined above;
• —NO2;
• —CN;
• —OH;
• phenyloxy-, said phenyloxy being unsubstituted or substituted with one two or three substituents independently selected from the R13 substituents defined above;
• benzyloxy-, said benzyloxy being unsubstituted or substituted with one two or three substituents independently selected from the R13 substituents defined above;
• —C(O)—O—R11, wherein R11 is as defined above;
• —C(O)—N—R11R12, wherein R11 and R12 are as defined above;
• —NR11R12, wherein R11 and R12 are as defined above;
• —NR10—SO2—R10, wherein R10 is as defined above;
• —SR10, wherein R10 is as defined above;
• —SOn—R10, wherein n is 1 or 2 and R10 is as defined above;
• —SO2—NR11R12, wherein R11 and R12 are as defined above;
• —C(O)—R10, wherein R10 is as defined above;
• —C(O)—O—C(R15R16)—O—C(O)—R17, wherein R15, R16 and R17 are as defined above;
• —C(O)—O—C(R15R16)—O—C(O)O—R17, wherein R15, R16 and R17 are as defined above;
• a residue of formula Va,
• 324
• wherein
• R10 is as defined above;
• a residue of formula Vb or Vc,
• 325
• —NR10—(C1-C4)-alkyl, said alkyl being unsubstituted or substituted with one two or three substituents independently selected from the R13 substituents defined above;
• —O—CF3;
• and a residue selected from the group consisting of:
• 326
• wherein
• R10, R11, R12 and R13 are as defined above;
• in all its stereoisomeric forms and mixtures thereof in any ratio, and its physiologically tolerable salts.