Heteroaryl-carboxylic acid (sulfamoyl alkyl) amide - derivatives as factor xa inhibitors

A compound of the formula I,

• wherein
• R1 is halogen, methyl or ethynyl,
• X is sulfur, nitrogen, oxygen or the residues —CH═CH— or —CH═N—,
• V is hydrogen atom or one or two times halogen or —(C1-C4)-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times by R8,
• R2 and R3 are independent of one another are identical or different and are a hydrogen atom, —(C0-C3)-alkylene-C(O)—NH—R6, —(C0-C3)-alkylene-C(O)—N(R21)-R22,
• —(C0-C3)-alkylene-C(O)—R10, —(C0-C3)-alkylene-C(O)—O—R10, —(C1-C3)-alkylene-S(O)—R10,
• —(C1-C3)-alkylene-S(O)2—R10, —(C1-C5)-alkylene-S(O)2—N(R4)-R5,
• —(C1-C3)-alkylene-O—(C1-C4)-alkyl, —(C0-C5)-alkylene-(C1-C3)-perfluoroalkyl,
• —(C0-C5)-alkylene-(C3-C8)-cycloalkyl-R23,
• —(C1-C4)-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times by R8,
• —(C0-C4)-alkylene-aryl, wherein aryl is selected out of the group phenyl, naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl or fluorenyl, wherein aryl is mono-, di- or trisubstituted independently of one another by R7, or
• —(C0-C4)-alkylene-heterocyclyl, wherein heterocyclyl is as defined below and is unsubstituted or mono-, di- or trisubstituted independently of one another by R8,
• R4 and R5 are independent of one another are identical or different and are hydrogen atom or —(C1-C4)-alkyl,
• R6 is 1) a heterocyclyl selected out of the group acridinyl, azabenzimidazolyl, azaspirodecanyl, azepinyl, azetidinyl, aziridinyl, benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzothienyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydrochinolinyl, 4,5-dihydrooxa-zolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, indanyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolidinyl, isothiazolinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopiperazinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxa-thiepanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl, 1,4-oxazepinyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolinyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phenylpyridyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoimidazolyl, pyridooxazolyl, pyridopyrimidinyl, pyridothiazolyl, pyridothienyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinolyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 1,4,5,6-tetrahydro-pyridazinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 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, thienoimidazolyl, thietanyl, thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstitutedindependently of one another by R7 or
• 2) a 6- to 14-membered aryl selected out of the group phenyl, naphthyl, biphenylyl,
• 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl or fluorenyl, wherein aryl is mono-, di- or trisubstituted independently of one another by R7,
• R7 is halogen, carbamimidoyl, —NO2, ═O, —CF3, —C(O)—O—R10, —CN, —C(O)—NH2, —OH, —NH2,
• —O—CF3, —C(O)—N(R10)-R20, —N(R10)-R20, —(C3-C8)-cycloalkyl, —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, or —(C1-C8)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, NH2, —OH or a methoxy residue, or —SO2—CH3 or —SO2—CF3,
• R8 is halogen, —NO2, —CN, ═O, —OH, —CF3, —C(O)—O—R10, —C(O)—N(R21)-R22, —N(R21)-R22,
• —(C3-C8)-cycloalkyl, —(C0-C3)-alkylene-O—R10, —Si—(CH3)3, —N(R10)-S(O)u—R10, wherein u is 1 or 2, —S—R10, —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-, —(C1-C3)-perfluoroalkyl,
• —(C0-C4)-alkyl-C(O)—O—C(R9,R11)-O—C(O)—R12, —O—R9, —NH—C(O)—NH—R10, —NH—C(O)—NH—R6,
• —N(R21)-C(O)—R22, —O—CF3, —(C0-C4)-alkyl-C(O)—O—C(R9,R11)-O—C(O)—O—R12, —NH—C(O)—O—R10, heterocyclyl, wherein heterocyclyl is defined above and is unsubstituted mono-, di- or trisubstituted independently of one another by R7, or a residue from the following list
• wherein Me is methyl,
• R10 and R20 are the same or different and are independently of one another hydrogen, halogen, —(C1-C6)-alkyl, —(C0-C4)-alkyl-OH, —(C0-C4)-alkyl-O—(C1-C4)-alkyl, —(C1-C3)-perfluoroalkyl, —(C0-C5)-alkyl-(C3-C8)-cycloalkyl, —(C0-C2)-alkylene-aryl, wherein aryl is as defined above and aryl is unsubstituted or substituted one, two or three times independent of each other by —(C1-C6)-alkyl, halogen or —(C3-C8)-cycloalkyl, or —(C0-C2)-alkylene-heterocyclyl, wherein heterocyclyl is as defined above and heterocyclyl is unsubstituted or substituted one, two or three times independent of each other by —(C1-C6)-alkyl, halogen or —(C3-C8)-cycloalkyl,
• R9 and R11 are the same or different and 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, two or three times by R10, R12 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,
• G1 is —(C1-C5)-alkylene or —(C3-C8)-cycloalkyl, wherein methylene is unsubstituted or mono- or disubstituted independently of one another by R13, or —(C2-C5)-alkylene or
• —(C3-C8)-cycloalkyl are unsubstituted or mono- di-, tri- or tetrasubstituted independently of one another by R13,
• R13 is 1) hydrogen atom,
• 2) halogen,
• 3) —(C1-C4)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R8,
• 4) —(C1-C3)-perfluoroalkyl,
• 5) phenyl, wherein phenyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R8,
• 6) —(C0-C4)-alkylene-O—R19, wherein R19 is
• a) hydrogen atom,
• b) —(C1-C4)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R8, or
• c) phenyl, wherein phenyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R8,
• d) —CF3, or
• e) —CHF2,
• f) heterocyclyl, wherein heterocyclyl is as defined above and is unsubstituted or mono-, di- or trisubstituted independently of one another by R8,
• 7) —NO2,
• 8) —CN,
• 9) —SOs—R21, wherein s is 1 or 2,
• 10) —SOt—N(R21)-R22, wherein t is 1 or 2,
• 11) —(C0-C4)-alkylene-C(O)—O—R21,
• 12) —(C0-C4)-alkylene-C(O)—N(R21)-R22,
• 13) —(C0-C4)-alkylene-N(R21)-R22,
• 14) —NR21-SO2—R22,
• 15) —S—R10,
• 16) —(C0-C2)alkylene-C(O)—O—(C2-C4)-alkylene-O—C(O)—(C1-C4)-alkyl,
• 17) —C(O)—O—C(R9,R11)-O—C(O)—R12,
• 18) —(C0-C2)alkylene-C(O)—O—(C2-C4)-alkylene-O—C(O)—O—(C1-C6)-alkyl,
• 19) —C(O)—O—C(R9,R11)-O—C(O)—O—R12,
• 20) —(C0-C4)-alkylene-(C6-C14)-aryl, wherein aryl is as defined above and alkylene and aryl are independently of one another unsubstituted or mono-, di- or trisubstituted by R8,
• 21) —(C0-C4)-alkylene-heterocyclyl, wherein heterocyclyl is as defined above and alkylene and heterocyclyl are independently of one another unsubstituted or mono-, di- or trisubstituted by R8,
• 22) —(C0-C4)-alkylene-(C3-C8)-cycloalkyl, wherein alkylene and cycloalkyl are independently of one another unsubstituted or mono-, di- or trisubstituted by R8,
• 23) —(C1-C4)-alkylene-heterocyclyl, wherein heterocyclyl is as defined above and is unsubstituted or mono-, di- or trisubstituted independently of one another by R8,
• 24) —(C0-C4)-alkylene-O—CH2—(C1-C3)-perfluoroalkylene-CH2—O—(C0-C4)-alkyl,
• 25) —SOw—N(R21)-R8, wherein w is 1 or 2,
• 26) —(C0-C4)-alkylene-N(R21)-C(O)—R22,
• 27) —(C0-C4)-alkylene-N(R21)-C(O)—O—R22 or
• 28) a residue from the following list
• wherein Me is methyl, or
• if two —OR19 residues are attached to adjacent atoms they can form together with the atoms which they are attached to a 5- or 6-membered ring, which is unsubstituted or substituted one, two, three or four times by R8, or
• if two R13 are attached to the same carbon atom they can form together a 3- to 8-membered carbocyclic ring, which is unsubstituted or substituted one, two or three times by R10, or
• if two R13 are attached to the same carbon atom they can form together a 3- to 8-membered heterocyclic ring, which is unsubstituted or substituted one, two or three times by R10, or
• R13 and R3 together with the atoms to which they are bonded form a 5- to 7-membered cyclic group, wherein one of the carbon atoms within said cyclic group can be replaced by nitrogen, oxygen or sulphur and wherein said cyclic group is unsubstituted or substituted one, two or three times by R7,
• R21 and R22 are the same or different and are independently of one another
• 1) hydrogen atom,
• 2) —(C1-C6)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R7,
• 3) —(C0-C6)-alkylene-(C3-C8)-cycloalkyl,
• 4) —SOt—R10, wherein t is 1 or 2,
• 5) —(C0-C6)-alkylene-(C6-C14)-aryl, wherein aryl is as defined above and alkylene and aryl independently from one another are unsubstituted or mono-, di- or trisubstituted by R7,
• 6) —(C1-C3)-perfluoroalkyl,
• 7) —O—R12 or
• 8) —(C0-C6)-alkylene-heterocyclyl, wherein heterocyclyl is as defined above and alkylene and heterocyclyl independently from one another are unsubstituted or mono-, di- or trisubstituted by R7, or
• R21 and R22 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 R7,
• R23 is hydrogen atom, —OH or —O—(C1-C4)-alkyl,
• G2 is azetidine, pyrrolidine, piperidine, azepane, hexahydro-pyridazine, hexahydro-pyrimidine, piperazine, [1,2]diazepane, [1,3]diazepane or [1,4]diazepane,
• wherein G2 is unsubstituted or mono-, di-, tri or tetrasubstituted independently of one another by M or Y,
• M is —(C1-C6)-alkyl, —(C2-C6)-alkenyl, —(C2-C6)-alkinyl, —(C3-C6)-cycloalkyl, —(C0-C2)-alkylene-aryl, wherein aryl is as defined above, —(C1-C4)-alkyl-(C3-C6)-cycloalkyl, pyridyl or piperidinyl, wherein piperidinyl is unsubstituted or substituted by —(C1-C6)-alkyl,
• Y is hydrogen atom, halogen, ═O, —OH, —CF3, —C(O)—O—R10, —C(O)—N(R10)-R20, —N(R10)-R20,
• —(C3-C8)-cycloalkyl, —(C0-C3)-alkylene-O—R10, phenyl, —(C1-C8)-alkyl, —(C1-C8)-alkoxy, —(C0-C4)-alkyl-C(O)—O—C(R9,R11)-O—C(O)—R12, —O—R9, —O—CF3, —(C1-C3)-perfluoroalkyl, or
• —(C0-C4)-alkyl-C(O)—O—C(R9, R1)-O—C(O)—O—R12,
• in all its stereoisomeric forms and mixtures thereof in any ratio, and its physiologically tolerable salts.