Imidazole derivatives as factor Xa inhibitors

A compound of the formula I,

• 32
• wherein,
• R0 is 1) a monocyclic or bicyclic 6- to 14-membered aryl, wherein, the aryl is mono-, di- or trisubstituted independently of one another by R8,
• 2) a monocyclic or bicyclic 4- to 15-membered heterocyclyl, selected from the group consisting of acridinyl, azaindole, azabenzimidazolyl, azaspirodecanyl, azepinyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, 1,3-benzodioxolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydrochinolinyl, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolyl, isothiazolyl, isothiazolidinyl, isothiazolinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopiperazinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2-oxathiepanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl, 1,4-oxazepinyl, oxazinyl, oxazolidinyl, oxazolinyl, oxazolyl, oxetanyl, oxocanyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phenylpyridyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyridopyridinyl, pyridopyrimidinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolyl, 4H-quinolizinyl, quinoxalinyl, 1,4,5,6-tetrahydropyridazinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, thiazolidinyl, thiazolinyl, thienyl, thietanyl, thienothiazolyl, thienooxazolyl,
• 33
• thienoimidazolyl, thietanyl, thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl, or
• 3) a monocyclic or bicyclic 4- to 15-membered heterocyclyl, containing one, two, three or four heteroatoms chosen from the group consisting of nitrogen, sulfur or oxygen, wherein, said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R8;
• R8 is 1) halogen,
• 2) —NO2,
• 3) —CN,
• 4) —C(O)—NH2,
• 5) —OH,
• 6) —NH2,
• 7) —O—CF3
• 8) a monocyclic or bicyclic 6- to 14-membered aryl, wherein aryl is mono-, di- or trisubstituted independently of one another by halogen or —O—(C1-C8)-alkyl,
• 9) —(C1-C8)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, NH2, —OH or a methoxy residue,
• 10) —O—(C1-C8)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, NH2, —OH or a methoxy residue,
• 11) —SO2—CH3 or
• 12) —SO2—CF3,
• provided that where R0 is a monocyclic or bicyclic 6- to 14-membered aryl, then R8 is at least one halogen, —C(O)—NH2 or —O—(C1-C8)-alkyl residue;
• Q is a direct bond, —(C0-C2)-alkylene-C(O)—NR10—, —NR10—C(O)—NR10—, —NR10—C(O)—, —SO2—, —(C1-C6)-alkylene, —(CH2)m—NR10—C(O)—NR10—(CH2)n—, —(CH2)m—NR10—C(O)—(CH2)n—, —(CH2)m—S—(CH2)n—, —(CH2)m—C(O)—(CH2)n—, —(CH2)m—SO2—NR10—(CH2)n—, —(CH2)m—NR10—SO2—(CH2)n—, —(CH2)m—NR10—SO2—NR10—(CH2)n—, —(CH2)m—CH(OH)—(CH2)n—, —(CH2)m—O—C(O)—NR10—(CH2)n—, —(C2-C3)-alkylene-O—(C0-C3)-alkylene-, —(C2-C3)-alkylene-S(O)—, —(C2-C3)-alkylene-S(O)2—, —(CH2)m—NR10—C(O)—O—(CH2)n—, —(C2-C3)-alkylene-S(O)2—NH—(R10), —(C2-C3)-alkylene-N(R10) or —(C0-C3)-alkylene-C(O)—O—,
• wherein R10 is as defined below, and wherein n and m are independently of one another identical or different and are the integers zero, 1, 2, 3, 4, 5 or 6, wherein the alkylene residues which are formed by —(CH2)m— or —(CH2)n— are unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, —NH2 or —OH;
• or —C3-C6)-cycloalkylene, wherein cycloalkylene is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, —NH2 or —OH;
• R1 is hydrogen, —(C1-C4)-alkyl, wherein alkyl is unsubstituted or substituted one to three times by R13;
• —(C1-C3)-alkylene-C(O)—NH—R0, —(C1-C3)-alkylene-C(O)—O—R10, a monocyclic or bicyclic 6- to 14-membered aryl, wherein aryl is mono-, di- or trisubstituted independently of one another by R8, a monocyclic or bicyclic 4- to 15-membered heterocyclyl, containing one, two, three or four heteroatoms chosen from nitrogen, sulfur or oxygen;
• —(C1-C3)-perfluoroalkyl, —(C1-C3)-alkylene-S(O)—(C1-C4)-alkyl, —(C1-C3)-alkylene-S(O)2—(C1-C3)-alkyl, —(C1-C3)-alkylene-S(O)2—N(R4′)-R5′, —(C1-C3)-alkylene-O—(C1-C4)-alkyl, —(C0-C3)-alkylene-(C3-C8)-cycloalkyl, or —(C0-C3)-alkylene-het, wherein het is unsubstituted or mono-, di- or trisubstituted independently of one another by R14, and;
• R4′ and R5′ are independent of one another are identical or different and are hydrogen or —(C1-C4)-alkyl;
• R2 is a direct bond or —(C1-C4)-alkylene, or
• R1 and R3 together with the atoms to which they are bonded form a 6- to 8-membered cyclic group, containing 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur or oxygen, and wherein, said cyclic group is unsubstituted or mono-, di- or trisubstituted independently of one another by R14;
• or
• R1—N—R2—V form a 4- to 8-membered cyclic group, containing 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur or oxygen, wherein said cyclic group is unsubstituted or mono-, di- or trisubstituted independently of one another by R14,
• R14 halogen, —OH, ═O, —(C1-C8)-alkyl, —(C1-C4)-alkoxy, —NO2, —(C0-C4)-alkyl-C(O)—O—R18, —CN, —(C0-C4)-alkyl-N(R18)—R21, —(C0-C4)-alkyl-O—R18, —(C0-C4)-alkyl-het, —(C0-C8)-alkyl-SO2, —SO2—(C1-C4)-alkyl, —SO2—N(R18)—R21, —C(O)—NH—(C1-C8)-alkyl, —C(O)—N—[(C1-C8)-alkyl]2, —NR18—C(O)—NH—(C1-C8)-alkyl, —C(O)—NH2, —S—R18, or —NR18—C(O)—NH—[(C1-C8)-alkyl]2,
• wherein R18 and R21 are independently from each other hydrogen atom, —(C1-C3)-perfluoroalkyl or —(C1-C6)-alkyl;
• V is 1) a 3- to 7-membered cyclic residue, containing 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur or oxygen, wherein said cyclic residue is unsubstituted or mono-, di- or trisubstituted independently of one another by R14,
• 2) a 6- to14-membered aryl, wherein aryl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14, or
• 3) a monocyclic or bicyclic 4- to 15-membered heterocyclyl, wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14;
• G is 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)—NR10CH2)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— or —CH2)m—NR10—C(O)—O—(CH2)n—;
• n and m are independently of one another identical or different and are the integers zero, 1, 2, 3,4,5 or 6;
• M is 1) hydrogen,
• 2) —(C1-C8)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14,
• 3) —C(O)—N(R11)-R12,
• 4) —(CH2)m—NR10,
• 5) a 6- to 14-membered aryl, wherein aryl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14,
• 6) a monocyclic or bicyclic 4- to 15-membered heterocyclyl, wherein heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14,
• 7) —(C3-C8)-cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14, or
• 8) a 3- to 7-membered cyclic residue, containing 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur or oxygen, wherein said cyclic residue is unsubstituted or mono-, di- or trisubstituted independently of one another by R14;
• R3 and R4 are independent of one another are identical or different and are
• 1) hydrogen,
• 2) halogen,
• 3) —(C1-C4)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• 4) —(C1-C3)-perfluoroalkyl,
• 5) phenyl, wherein phenyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• 6) —(C0-C4)-alkylene-O—R19, wherein R19 is
• a) hydrogen,
• b) —(C1-C4)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13, or
• c) phenyl, wherein phenyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• d) —CF3, or
• e) —CHF2,
• 7) —NO2,
• 8) —CN,
• 9) —SOS—R11, wherein s is 1 or 2,
• 10) —SOt—N(R11)—R12, wherein t is 1 or 2,
• 11) —(C0-C4)-alkylene-C(O)—R11,
• 12) —(C0-C4)-alkylene-C(O)—O—R11,
• 13) —(C0-C4)-alkylene-C(O)—N(R11)—R12,
• 14) —(C0-C4)-alkylene-N(R11)—R12,
• 15) —NR10—SO2—R10,
• 16) —S—R10,
• 17) —(C0-C2)alkylene-C(O)—O—(C2-C4)-alkylene-O—C(O)—(C1-C4)-alkyl,
• 18) —C(O)—O—C(R15, R16)-O—C(O)—R17,
• 19) —C0-C2)alkylene-C(O)—O—(C2-C4)-alkylene-O—C(O)—O—(C1-C6)-alkyl,
• 20) —C(O)—O—C(R15, R16)-O—C(O)—O—R17,
• 21) —(C0-C4)-alkylene-(C6-C14)-aryl, wherein aryl is mono-, di- or trisubstituted independently of one another by R13,
• 22) —(C0-C4)-alkylene-(C4-C15)-heterocyclyl, wherein heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13
• 23) —(C0-C4)-alkylene-(C3-C8)-cycloalkyl, wherein cycloalkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• 24) —(C0-C4)-alkylene-het, wherein het is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• 25) —(C0-C4)-alkylene-O—CH2—(C1-C3)-perfluoroalkylene-CH2—O—(C0-C4)-alkyl, or
• 26) a residue selected from the group consisting of
• 34
• wherein Me is methyl, or
• two —OR19 residues and adjacent atoms through which they are attached form together a 5- or 6-membered ring, that is unsubstituted or substituted one, two, three or four times by R13;
• R11 and R12 are independently of one another identical or different and are
• 1) hydrogen,
• 2) —(C1-C6)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• 3) —(C0-C6)-alkyl-(C3-C8)-cycloalkyl,
• 4) —SOt—R10, wherein t is 1 or 2,
• 5) —(C0-C6)-alkyl-(C6-C14)-aryl, wherein alkyl and aryl independently from one another are unsubstituted or mono-, di- or trisubstituted by R13,
• 6) —(C1-C3)-perfluoroalkyl,
• 7) —O—R17, or
• 8) —(C0-C6)-alkyl-(C4-C15)-heterocyclyl, wherein alkyl and heterocyclyl independently from one another are unsubstituted or mono-, di- or trisubstituted by R13, or
• R11 and R12 together with the nitrogen atom to which they are bonded can form a 4- to 8-membered monocyclic heterocyclic ring which in addition to the nitrogen atom can contain one or two identical or different ring heteroatoms chosen from oxygen, sulfur and nitrogen;
• wherein said heterocyclic ring is unsubstituted or mono-, di- or trisubstituted independently of one another by R13;
• R13 is halogen, —NO2, —CN, ═O, —OH, —CF3, —C(O)—O—R10, —C(O)—N(R10)—R20, —N(R10)—R20, —N(R10)—R20, —(C3-C8)-cycloalkyl, —(C0-C3)-alkylene-O—R10, —Si—(CH3)3, —N(R10)—S(O)u—R10, wherein u is 1 or 2, —S—R11, —SOr—R10, wherein r is 1 or 2, —S(O)v—N(R10)—R20, wherein v is 1 or 2, —C(O)—R10, —(C1-C8)-alkyl, —(C1-C8)-alkoxy, phenyl, phenyloxy-, —O—CF3, —(C0-C4)-alkyl-C(O)—O—C(R15, R16)-O—C(O)—R17, —(C1-C4)-alkoxy-phenyl, —(C0-C4)-alkyl-C(O)—O—C(R15, R16)-O—C(O)—O—R17, —(C1-C3)-perfluoroalkyl, —O—R15, —NH—C(O)—NH—R10, —NH—C(O)—O—R10, or a residue selected from the group consisting of
• 35
• R10 and R20 are independently of one another hydrogen, —(C1-C6)-alkyl, —(C0-C4)-alkyl-OH, —(C0-C4)-alkyl-O—(C1-C4)-akyl or —(C1-C3)-perfluoroalkyl;
• R15 and R16 are independently of one another hydrogen, —(C1-C6)-alkyl, or together with the carbon atom to which they are bonded they can form a 3- to 6 membered carbocyclic ring which is unsubstituted or substituted one to three times by R10;
• and
• R17 is —(C1-C6)-alkyl, —(C1-C6)-alkyl-OH, —(C1-C6)-alkyl-O—(C1-C6)-alkyl, —(C3-C8)-cycloalkyl, —(C1-C6)-alkyl-O—(C1-C8)-alkyl-(C3-C8)-cycloalkyl, —(C1-C6)-alkyl-(C3-C8)-cycloalkyl, wherein said cycloalkyl ring is unsubstituted or substituted one, two or three times by —OH, —O—(C1-C4)-alkyl or R10;
• or
• in all its stereoisomeric forms and mixtures thereof in any ratio, and its physiologically tolerable salts.