Claims for Patent: 9,388,140

Summary for Patent: 9,388,140

Title:	Substituted benzimidazoles
Abstract:	The present invention relates to substituted benzimidazole compounds of general formula (I) in which R.sup.3, R.sup.5 and A are as defined in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients. ##STR00001##
Inventor(s):	Klar; Ulrich (Berlin, DE), Koppitz; Marcus (Berlin, DE), Nguyen; Duy (Berlin, DE), Kosemund; Dirk (Berlin, DE), Neuhaus; Roland (Berlin, DE), Siemeister; Gerhard (Berlin, DE)
Assignee:	Bayer Intellectual Property GmbH (Monheim, DE)
Application Number:	14/008,981
Patent Claims:	1. A compound of general formula (I): ##STR00213## in which: A represents ##STR00214## wherein * indicates the point of attachment of said groups with the rest of the molecule; Z represents a --C(.dbd.O)N(H)R.sup.1 or --C(.dbd.S)N(H)R.sup.1 group; R.sup.1 represents a hydrogen atom or a C.sub.1-C.sub.6-alkyl- or C.sub.3-C.sub.6-cycloalkyl-group; wherein said C.sub.1-C.sub.6-alkyl- or C.sub.3-C.sub.6-cycloalkyl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 groups selected from: halogen, --OH, --CN, C.sub.1-C.sub.6-alkyl-, C.sub.1-C.sub.6-alkoxy-; R.sup.2 represents a hydrogen atom or a C.sub.1-C.sub.6-alkyl- or C.sub.3-C.sub.6-cycloalkyl-group; wherein said C.sub.1-C.sub.6-alkyl- or C.sub.3-C.sub.6-cycloalkyl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 groups selected from: halogen, OH, --CN, C.sub.1-C.sub.6-alkyl-, C.sub.1-C.sub.6-alkoxy-; R.sup.3 represents a hydrogen atom or a halogen atom or a --CN, C.sub.1-C.sub.6-alkyl-, --(CH.sub.2).sub.m--C.sub.2-C.sub.6-alkenyl, --(CH.sub.2).sub.m--C.sub.4-C.sub.8-cycloalkenyl, --(CH.sub.2).sub.m--C.sub.2-C.sub.6-alkynyl, --(CH.sub.2).sub.m--C.sub.3-C.sub.6-cycloalkyl, --(CH.sub.2).sub.m-(3- to 7-membered heterocycloalkyl), --(CH.sub.2).sub.m-(4- to 8-membered heterocycloalkenyl), aryl-C.sub.1-C.sub.6-alkyl-, heteroaryl-C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.6-alkyl-, R.sup.6a(R.sup.6b)N--C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C.sub.2-C.sub.6-alkenyl-, C.sub.4-C.sub.8-cycloalkenyl-, C.sub.2-C.sub.6-alkynyl-, aryl-, --C.sub.1-C.sub.6-alkyl-aryl, --C.sub.1-C.sub.6-alkyl-heteroaryl, heteroaryl-, C.sub.1-C.sub.6-alkyl-X--, --X--(CH.sub.2).sub.m--C.sub.2-C.sub.6-alkenyl, --X--(CH.sub.2).sub.m--C.sub.4-C.sub.8-cycloalkenyl, --X--(CH.sub.2).sub.m--C.sub.2-C.sub.6-alkynyl, --X--(CH.sub.2).sub.m--C.sub.3-C.sub.6-cycloalkyl, --X--(CH.sub.2).sub.m-(3- to 7-membered heterocycloalkyl), --X--(CH.sub.2).sub.m-(4- to 8-membered heterocycloalkenyl), aryl-X--, heteroaryl-X--, --C(.dbd.O)R.sup.6, --C(.dbd.O)N(H)R.sup.6a, --C(.dbd.O)N(R.sup.6a)R.sup.6b, --C(.dbd.O)O--R.sup.6, --N(R.sup.6a)R.sup.6b, --NO.sub.2, --N(H)C(.dbd.O)R.sup.6, --OR.sup.6, --SR.sup.6, --S(.dbd.O)R.sup.6, --S(.dbd.O).sub.2R.sup.6, --S(.dbd.O)(.dbd.NR.sup.6a)R.sup.6b, --S(.dbd.O).sub.2N(R.sup.6b)R.sup.6c, --S--(CH.sub.2).sub.n--N(R.sup.6a)R.sup.6b, or --S--(CH.sub.2).sub.n-(3- to 7-membered heterocycloalkyl) group; said C.sub.1-C.sub.6-alkyl-, --(CH.sub.2).sub.m--C.sub.2-C.sub.6-alkenyl, --(CH.sub.2).sub.m--C.sub.2-C.sub.6-alkynyl, --(CH.sub.2).sub.m--C.sub.3-C.sub.6-cycloalkyl, aryl-C.sub.1-C.sub.6-alkyl-, heteroaryl-C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C.sub.2-C.sub.6-alkenyl-, C.sub.4-C.sub.8-cycloalkenyl-, C.sub.2-C.sub.6-alkynyl-, aryl-, C.sub.1-C.sub.6-alkyl-X--, --X--(CH.sub.2).sub.m--C.sub.2-C.sub.6-alkenyl, --X--(CH.sub.2).sub.m--C.sub.4-C.sub.8-cycloalkenyl, --X--(CH.sub.2).sub.m--C.sub.2-C.sub.6-alkynyl, --X--(CH.sub.2).sub.m--C.sub.3-C.sub.6-cycloalkyl, --X--(CH.sub.2).sub.m-(3- to 7-membered heterocycloalkyl), --X--(CH.sub.2).sub.m-(4- to 8-membered heterocycloalkenyl), aryl-X--, heteroaryl-X--, --C.sub.1-C.sub.6-alkyl-aryl, --C.sub.1-C.sub.6-alkyl-heteroaryl or heteroaryl-group being optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R.sup.7 groups; R.sup.4a, R.sup.4b, R.sup.4c, R.sup.4d represent, independently from each other, a hydrogen or halogen atom, or a --CN, C.sub.1-C.sub.6-alkyl-, C.sub.1-C.sub.6-alkoxy-, halo-C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.6-alkoxy-, R.sup.6a(R.sup.6b)N--C.sub.1-C.sub.6-alkyl-, HO--C.sub.1-C.sub.6-alkyl-, NC--C.sub.1-C.sub.6-alkyl-, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl-group; R.sup.5 represents a hydrogen atom or a C.sub.1-C.sub.6-alkyl-, --(CH.sub.2).sub.n--C.sub.2-C.sub.6-alkenyl, --(CH.sub.2).sub.n--C.sub.2-C.sub.6-alkynyl, --(CH.sub.2).sub.m--C.sub.3-C.sub.6-cycloalkyl, --(CH.sub.2).sub.m-(3- to 7-membered heterocycloalkyl), aryl-C.sub.1-C.sub.6-alkyl-, heteroaryl-C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.6-alkyl-, R.sup.6a(R.sup.6b)N--C.sub.1-C.sub.6-alkyl-, HO--C.sub.1-C.sub.6-alkyl-, --C.sub.1-C.sub.6-alkyl-CN, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C.sub.4-C.sub.8-cycloalkenyl-, aryl- or heteroaryl-group; said C.sub.1-C.sub.6-alkyl-, --(CH.sub.2).sub.n--C.sub.2-C.sub.6-alkenyl, --(CH.sub.2).sub.n--C.sub.2-C.sub.6-alkynyl, --(CH.sub.2).sub.m--C.sub.3-C.sub.6-cycloalkyl, --(CH.sub.2).sub.m-(3- to 7-membered heterocycloalkyl), aryl-C.sub.1-C.sub.6-alkyl-, heteroaryl-C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.6-alkyl-, R.sup.6a(R.sup.6b)N--C.sub.1-C.sub.6-alkyl-, HO--C.sub.1-C.sub.6-alkyl-, --C.sub.1-C.sub.6-alkyl-CN, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C.sub.4-C.sub.8-cycloalkenyl-, aryl- or heteroaryl- group being optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R.sup.8 groups; R.sup.6, R.sup.6a, R.sup.6b, R.sup.6c represent, independently from each other, a hydrogen atom or a C.sub.1-C.sub.6-alkyl-, HO--C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-cycloalkyl-, C.sub.2-C.sub.6-alkenyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, aryl-C.sub.1-C.sub.6-alkyl- or heteroaryl-C.sub.1-C.sub.6-alkyl-group; R.sup.7 represents a hydrogen or halogen atom or a HO--, --CN, C.sub.1-C.sub.6-alkoxy-, halo-C.sub.1-C.sub.6-alkoxy-, C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.6-alkyl-, R.sup.6a(R.sup.6b)N--C.sub.1-C.sub.6-alkyl-, HO--C.sub.1-C.sub.6-alkyl-, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl-, C.sub.2-C.sub.6-alkenyl-, C.sub.2-C.sub.6-alkynyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, --C(.dbd.O)R.sup.6, --C(.dbd.O)N(H)R.sup.6a, --C(.dbd.O)N(R.sup.6a)R.sup.6b, --C(.dbd.O)O--R.sup.6, --N(R.sup.6a)R.sup.6b, --NO.sub.2, --N(H)C(.dbd.O)R.sup.6, --N(R.sup.6c)C(.dbd.O)R.sup.6, --N(H)C(.dbd.O)N(R.sup.6a)R.sup.6b, --N(R.sup.6c)C(.dbd.O)N(R.sup.6a)R.sup.6b, --N(H)C(.dbd.O)OR.sup.6, --N(R.sup.6c)C(.dbd.O)OR.sup.6, --N(H)S(.dbd.O)R.sup.6, --N(R.sup.6c)S(.dbd.O)R.sup.6, --N(H)S(.dbd.O).sub.2R.sup.6, --N(R.sup.6c)S(.dbd.O).sub.2R.sup.6, --N.dbd.S(.dbd.O)(R.sup.6a)R.sup.6b, --OR.sup.6, --O(C.dbd.O)R.sup.6, --O(C.dbd.O)N(R.sup.6a)R.sup.6b, --O(C.dbd.O)OR.sup.6, --SR.sup.6, --SF.sub.5, --S(.dbd.O)R.sup.6, --S(.dbd.O)N(H)R.sup.6, --S(.dbd.O)N(R.sup.6a)R.sup.6b, --S(.dbd.O).sub.2R.sup.6, --S(.dbd.O).sub.2N(H)R.sup.6, --S(.dbd.O).sub.2N(R .sup.6a)R.sup.6b or --S(.dbd.O)(.dbd.NR.sup.6c)R.sup.6 group; wherein said aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2 or 3 C.sub.1-C.sub.6-alkyl-groups; or when 2 R.sup.7 groups are present ortho- to each other on an aryl ring, said 2 R.sup.7 groups together form a bridge: *O(CH.sub.2).sub.2O*, *O(CH.sub.2)O*, *NH(C(.dbd.O))NH*, wherein * represent the point of attachment to said aryl ring; R.sup.8 represents a hydrogen or halogen atom or a --CN, C.sub.1-C.sub.6-alkoxy-, C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.6-alkyl-, R.sup.6a(R.sup.6b)N--C.sub.1-C.sub.6-alkyl, HO--C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl-, C.sub.2-C.sub.6-alkenyl-, C.sub.2-C.sub.6-alkynyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, --C(.dbd.O)R.sup.6, --C(.dbd.O)N(H)R.sup.6a, --C(.dbd.O)N(R.sup.6a)R.sup.6b, --C(.dbd.O)O--R.sup.6, --N(R.sup.6a)R.sup.6b, --NO.sub.2, --N(H)C(.dbd.O)R.sup.6, --N(R.sup.6c)C(.dbd.O)R.sup.6, --N(H)C(.dbd.O)N(R.sup.6a)R.sup.6b, --N(R.sup.6c)C(.dbd.O)N(R.sup.6a)R.sup.6b, --N(H)C(.dbd.O)OR.sup.6, --N(R.sup.6c)C(.dbd.O)OR.sup.6, --N(H)S(.dbd.O)R.sup.6, --N(R.sup.6c)S(.dbd.O)R.sup.6, --N(H)S(.dbd.O).sub.2R.sup.6, --N(R.sup.6c)S(.dbd.O).sub.2R.sup.6, --N.dbd.S(.dbd.O)(R.sup.6a)R.sup.6b, --OR.sup.6, --O(C.dbd.O)R.sup.6, --O(C.dbd.O)N(R.sup.6a)R.sup.6b, --O(C.dbd.O)OR.sup.6, --SR.sup.6, --S(.dbd.O)R.sup.6, --S(.dbd.O)N(H)R.sup.6, --S(.dbd.O)N(R.sup.6a)R.sup.6b, --S(.dbd.O).sub.2R.sup.6, --S(.dbd.O).sub.2N(H)R.sup.6, --S(.dbd.O).sub.2N(R.sup.6a)R.sup.6b, --S(.dbd.O)(.dbd.NR.sup.6c)R.sup.6 or --S(.dbd.O).sub.2-(3- to 7-membered heterocycloalkyl) group; wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group, is optionally substituted, identically or differently, with 1, 2, 3 or 4 C.sub.1-C.sub.6-alkyl-groups; m is an integer of 0, 1, 2, 3, 4, 5, or 6; n is an integer of 0, 1, 2, 3, 4, or 5; and X is S, S(.dbd.O), S(.dbd.O).sub.2, O, NR.sup.6, CR.sup.6aR.sup.6b, C(.dbd.CR.sup.6aR.sup.6b), C(.dbd.O) or C(OH)(R.sup.6a); or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 2. A compound according to claim 1, wherein: R.sup.4a and R.sup.4d represent hydrogen; R.sup.4b and R.sup.4c are selected, independently from each other, from hydrogen, halogen, --CN, C.sub.1-C.sub.6-alkyl-, C.sub.1-C.sub.6-alkoxy-, halo-C.sub.1-C.sub.6-alkyl-, or halo-C.sub.1-C.sub.6-alkoxy-; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 3. A compound according to claim 1, wherein: A represents ##STR00215## wherein * indicates the point of attachment of said group with the rest of the molecule; Z represents a --C(.dbd.O)N(H)R.sup.1 group; R.sup.1 represents a C.sub.1-C.sub.6-alkyl- or C.sub.3-C.sub.6-cycloalkyl-group; wherein said C.sub.1-C.sub.6-alkyl- or C.sub.3-C.sub.6-cycloalkyl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 groups selected from: halogen, OH, --CN, C.sub.1-C.sub.6-alkyl-, C.sub.1-C.sub.6-alkoxy-; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 4. A compound according to claim 1, wherein: R.sup.3 represents a hydrogen atom or a halogen atom or an aryl-, heteroaryl-, aryl-X-- or heteroaryl-X-- group; said aryl-, heteroaryl-, aryl-X-- or heteroaryl-X-- group being optionally substituted, identically or differently, with 1, 2 or 3 R.sup.7 groups; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 5. A compound according to claim 1, wherein: R.sup.7 represents a halogen atom, or a HO--, --CN, C.sub.1-C.sub.6-alkoxy-, halo-C.sub.1-C.sub.6-alkoxy-, C.sub.1-C.sub.6-alkyl-, HO--C.sub.1-C.sub.6-alkyl-, 3- to 7-membered heterocycloalkyl-, heteroaryl-, --C(.dbd.O)N(H)R.sup.6a, --OR.sup.6, --SR.sup.6, --SF.sub.5 or --S(.dbd.O).sub.2R.sup.6 group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 6. A compound according to claim 1, wherein: R.sup.5 represents a C.sub.1-C.sub.6-alkyl-, --(CH.sub.2).sub.m-(3- to 7-membered heterocycloalkyl) or halo-C.sub.1-C.sub.6-alkyl-group; said C.sub.1-C.sub.6-alkyl-, --(CH.sub.2).sub.m-(3- to 7-membered heterocycloalkyl) or halo-C.sub.1-C.sub.6-alkyl-group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R.sup.8 groups; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 7. A compound according to claim 1, wherein: m is an integer of 0 or 1; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 8. A compound according to claim 1, wherein: X is O, NR.sup.6, CR.sup.6aR.sup.6b, C(.dbd.CR.sup.6aR.sup.6b), C(.dbd.O) or C(OH)(R.sup.6a); or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 9. A compound according to claim 1, which is selected from the group consisting of: N-cyclopropyl-4-{4-[(2-methylpropyl)amino]-1H-benzimidazol-1-yl}benzamide- , N-cyclopropyl-2-methyl-4-{6-(pyridin-4-yl)-4-[(3,3,3-trifluoropropyl)ami- no]-1H-benzimida zol-1-yl}benzamide, N-cyclopropyl-4-{6-[(5-fluoro-2-methylphenyl)amino]-4-[(3,3,3-trifluoropr- opyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3-fluorophenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-- benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[(2,3-difluorophenyl)amino]-4-[(3,3,3-trifluoropropyl)- amino]-1H-benzi midazol-1-yl}-2-methylbenzamide, 4-{6-bromo-4-[(2-methylpropyl)amino]-1H-benzimidazol-1-yl}-N-cyclopropylb- enzamide, N-cyclopropyl-4-{6-(4-fluorophenyl)-4-[(2-methylpropyl)amino]-1H- -benzimidazol-1-yl}benzamide, N-cyclopropyl-4-{4-[(2-methylpropyl)amino]-6-phenyl-1H-benzimidazol-1-yl}- benzamide, N-cyclopropyl-4-{6-(3-fluorophenoxy)-4-[(tetrahydro-2H-pyran-4-- ylmethyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(3-fluorophenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-1- -yl}-N,2-dimethylbenzamide, N-ethyl-4-{6-(3-fluorophenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzim- idazol-1-yl}-2-methylbenzamide, 4-{6-(3-fluorophenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-1- -yl}-2-methyl-N-(1-methylcyclopropyl)benzamide, N-(1-cyanocyclopropyl)-4-{6-(3-fluorophenoxy)-4-[(3,3,3-trifluoropropyl)a- mino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(2,3-difluorophenoxy)-4-[(3,3,3-trifluoropropyl)amino]- -1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3-fluoro-5-methylphenoxy)-4-[(tetrahydro-2H-pyran-4-y- lmethyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(5-fluoro-2-methylphenoxy)-4-[(tetrahydro-2H-pyran-4-y- lmethyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3,4-difluorophenoxy)-4-[(tetrahydro-2H-pyran-4-ylmeth- yl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(4-chlorophenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-1- -yl}-N-cyclopropyl-2-methylbenzamide, N-cyclopropyl-4-{6-[(5-fluoro-2-methylphenyl)amino]-4-[(tetrahydro-2H-pyr- an-4-ylmethyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[2-(hydroxymethyl)phenyl]-4-[(tetrahydro-2H-pyran-4-yl- methyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[2-(hydroxymethyl)phenyl]-4-[(3,3,3-trifluoropropyl)am- ino]-1H-benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(4-chloro-3-fluorophenoxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]- -1H-benzimidazol-1-yl}-N-cyclopropyl-2-methylbenzamide, 4-{6-(4-chlorophenoxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-1H-benzi- midazol-1-yl}-N-cyclopropyl-2-methylbenzamide, N-cyclopropyl-4-{6-(2-fluoro-4-methoxyphenoxy)-4-[(tetrahydro-2H-pyran-4-- ylmethyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(2,3-difluorophenoxy)-4-[(tetrahydro-2H-pyran-4-ylmeth- yl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3-fluoro-5-methylphenoxy)-4-[(3,3,3-trifluoropropyl)a- mino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3,4-difluorophenoxy)-4-[(3,3,3-trifluoropropyl)amino]- -1H-benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(4-chloro-3-fluorophenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzi- midazol-1-yl}-N-cyclopropyl-2-methylbenzamide, N-cyclopropyl-4-{6-(2-fluoro-4-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)- amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-2-methyl-4-{6-(1-methyl-1H-pyrazol-5-yl)-4-[(3,3,3-trifluor- opropyl)amino]-1H-benzimidazol-1-yl}benzamide, N-ethyl-2-methyl-4-{6-(1-methyl-1H-pyrazol-5-yl)-4-[(3,3,3-trifluoropropy- l)amino]-1H-benzimidazol-1-yl}benzamide, N,2-dimethyl-4-{6-(1-methyl-1H-pyrazol-5-yl)-4-[(3,3,3-trifluoropropyl)am- ino]-1H-benzimidazol-1-yl}benzamide, N-cyclopropyl-4-{6-(3-fluoro-4-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)- amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-ethyl-4-{6-(3-fluoro-4-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]- -1H-benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(3-fluoro-4-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benz- imidazol-1-yl}-N,2-dimethylbenzamide, N-cyclopropyl-4-{6-(2,3-difluorophenoxy)-4-[(3,3,3-trifluoropropyl)amino]- -1H-benzimidazol-1-yl}benzamide, N-cyclopropyl-4-{6-phenoxy-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidaz- ol-1-yl}benzamide, N-cyclopropyl-4-{6-(3-fluoro-4-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)- amino]-1H-benzimidazol-1-yl}benzamide, 4-{6-(2-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-- 1-yl}-N,2-dimethylbenzamide, N-ethyl-4-{6-(2-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzi- midazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(2-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H- -benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(3-fluoro-4-methoxyphenoxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino- ]-1H-benzimidazol-1-yl}-N,2-dimethylbenzamide, N-ethyl-4-{6-(3-fluoro-4-methoxyphenoxy)-4-[(tetrahydro-2H-pyran-4-ylmeth- yl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3-fluoro-4-methoxyphenoxy)-4-[(tetrahydro-2H-pyran-4-- ylmethyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, 4-{6-[4-(benzyloxy)phenoxy]-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimida- zol-1-yl}-N-cyclopropyl-2-methylbenzamide, 4-{6-[4-(benzyloxy)phenoxy]-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimida- zol-1-yl}-N-ethyl-2-methylbenzamide, 4-{6-[4-(benzyloxy)phenoxy]-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimida- zol-1-yl}-N,2-dimethylbenzamide, 4-{6-(4-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-- 1-yl}-N,2-dimethylbenzamide, N-ethyl-4-{6-(4-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzi- midazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(4-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H- -benzimidazol-1-yl}-2-methylbenzamide, 4,4'-{4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazole-1,6-diyl}bis(N-cy- clopropyl-2-methylbenzamide), 4-{1-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-4-[(3,3,3-trifluoropropyl)- amino]-1H-benzimidazol-6-yl}-N,2-dimethylbenzamide, 4-{1-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-4-[(3,3,3-trifluoropropyl)- amino]-1H-benzimidazol-6-yl}-N-ethyl-2-methylbenzamide, N-cyclopropyl-4-{6-(2-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H- -benzimidazol-1-yl}-2-methylbenzamide, N-ethyl-4-{6-(2-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzi- midazol-1-yl}-2-methylbenzamide, 4-{6-(2-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-- 1-yl}-N,2-dimethylbenzamide, N-cyclopropyl-4-{6-(3-fluoro-2-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)- amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-2-methyl-4-{6-[3-(trifluoromethoxy)phenoxy]-4-[(3,3,3-trifl- uoropropyl)amino]-1H-benzimidazol-1-yl}benzamide, N-cyclopropyl-2-methyl-4-{6-[4-(morpholin-4-yl)phenoxy]-4-[(3,3,3-trifluo- ropropyl)amino]-1H-benzimidazol-1-yl}benzamide, N-cyclopropyl-4-{6-[4-(difluoromethoxy)phenoxy]-4-[(3,3,3-trifluoropropyl- )amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[3-(difluoromethoxy)phenoxy]-4-[(3,3,3-trifluoropropyl- )amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[(2-methoxyphenyl)amino]-4-[(3,3,3-trifluoropropyl)ami- no]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-2-methyl-4-{6-[3-(methylsulfonyl)phenoxy]-4-[(3,3,3-trifluo- ropropyl)amino]-1H-benzimidazol-1-yl}benzamide, N-cyclopropyl-4-{6-[(3-methoxy-2-methylphenyl)amino]-4-[(3,3,3-trifluorop- ropyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(2,3-difluorophenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidaz- ol-1-yl}-N-ethyl-2-methylbenzamide, 4-{6-(2,3-difluorophenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidaz- ol-1-yl}-N,2-dimethylbenzamide, 4-{6-(3-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-- 1-yl}-N,2-dimethylbenzamide, N-ethyl-4-{6-(3-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzi- midazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H- -benzimidazol-1-yl}-2-methylbenzamide, N-ethyl-4-{6-(3-fluoro-2-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]- -1H-benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(3-fluoro-2-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benz- imidazol-1-yl}-N,2-dimethylbenzamide, 4-{6-(4-cyano-2-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzi- midazol-1-yl}-N-cyclopropyl-2-methylbenzamide, N-cyclopropyl-2-methyl-4-{6-[4-(methylsulfonyl)phenoxy]-4-[(3,3,3-trifluo- ropropyl)amino]-1H-benzimidazol-1-yl}benzamide, N-cyclopropyl-2-methyl-4-{6-[4-(1,3-oxazol-2-yl)phenoxy]-4-[(3,3,3-triflu- oropropyl)amino]-1H-benzimidazol-1-yl}benzamide, N-cyclopropyl-4-{6-[4-fluoro-3-(trifluoromethyl)phenoxy]-4-[(3,3,3-triflu- oropropyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(3-cyanophenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-1-- yl}-N-cyclopropyl-2-methylbenzamide, N-cyclopropyl-2-methyl-4-{6-[4-(1H-1,2,4-triazol-1-yl)phenoxy]-4-[(3,3,3-- trifluoropropyl)amino]-1H-benzimidazol-1-yl}benzamide, N-cyclopropyl-4-{6-[3-(cyclopropylcarbamoyl)phenoxy]-4-[(3,3,3-trifluorop- ropyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[(2-hydroxyphenyl)amino]-4-[(3,3,3-trifluoropropyl)ami- no]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3-fluoro-4-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)- amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(2,3-difluorophenoxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-1H-b- enzimidazol-1-yl}-N,2-dimethylbenzamide, 4-{6-(2,3-difluorophenoxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-1H-b- enzimidazol-1-yl}-N-ethyl-2-methylbenzamide, 4-{6-(2-fluoro-4-methoxyphenoxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino- ]-1H-benzimidazol-1-yl}-N,2-dimethylbenzamide, N-ethyl-4-{6-(2-fluoro-4-methoxyphenoxy)-4-[(tetrahydro-2H-pyran-4-ylmeth- yl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(2-fluoro-4-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benz- imidazol-1-yl}-N,2-dimethylbenzamide, N-ethyl-4-{6-(2-fluoro-4-methoxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]- -1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(2-fluoro-4-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)- amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3-fluoro-2-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)- amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(3-fluoro-2-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benz- imidazol-1-yl}-N,2-dimethylbenzamide, N-ethyl-4-{6-(3-fluoro-2-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]- -1H-benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(3-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-- 1-yl}-N,2-dimethylbenzamide, N-ethyl-4-{6-(3-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzi- midazol-1-yl}-2-methylbenzamide, N-cyclopropyl-2-methyl-4-{6-[3-(pentafluoro-lambda6-sulfanyl)phenoxy]-4-[- (3,3,3-trifluoropropyl)amino]-1H-benzimidazol-1-yl}benzamide, 4-{6-(2-fluoro-4-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benz- imidazol-1-yl}-N,2-dimethylbenzamide, N-ethyl-4-{6-(2-fluoro-4-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]- -1H-benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(3-fluoro-4-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benz- imidazol-1-yl}-N,2-dimethylbenzamide, N-ethyl-4-{6-(3-fluoro-4-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]- -1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3-fluoro-4-methoxybenzoyl)-4-[(3,3,3-trifluoropropyl)- amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[(3-fluoro-4-methoxyphenyl)(hydroxy)methyl]-4-[(3,3,3-- trifluoropropyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[(1RS)-1-(3-fluoro-4-methoxyphenyl)-1-hydroxyethyl]-4-- [(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[(1RS)-1-(3-fluoro-4-methoxyphenyl)-1-hydroxyethyl]-4-- [(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-1-yl}-2-(hydroxymethyl)benz- amide, N-cyclopropyl-4-{6-[1-(3-fluoro-4-methoxyphenyl)vinyl]-4-[(3,3,3-tr- ifluoropropyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[(1RS)-1-(3-fluoro-4-methoxyphenyl)ethyl]-4-[(3,3,3-tr- ifluoropropyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3-fluoro-4-methoxybenzyl)-4-[(3,3,3-trifluoropropyl)a- mino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(5-fluoro-2-methylphenoxy)-4-[(3,3,3-trifluoropropyl)a- mino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3-fluoro-4-hydroxybenzoyl)-4-[(3,3,3-trifluoropropyl)- amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[3-(difluoromethyl)phenoxy]-4-[(3,3,3-trifluoropropyl)- amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(2-methoxybenzoyl)-4-[(3,3,3-trifluoropropyl)amino]-1H- -benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3-hydroxyphenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H- -benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(3-fluoro-4-hydroxyphenoxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino- ]-1H-benzimidazol-1-yl}-N,2-dimethylbenzamide, N-ethyl-4-{6-(3-fluoro-4-hydroxyphenoxy)-4-[(tetrahydro-2H-pyran-4-ylmeth- yl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-ethyl-4-{6-[4-methoxy-3-(methylsulfanyl)phenoxy]-4-[(tetrahydro-2H-pyra- n-4-ylmethyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3-fluoro-4-hydroxyphenoxy)-4-[(tetrahydro-2H-pyran-4-- ylmethyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[4-methoxy-3-(methylsulfanyl)phenoxy]-4-[(tetrahydro-2- H-pyran-4-ylmethyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, 4-{6-(2-fluoro-4-hydroxyphenoxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino- ]-1H-benzimidazol-1-yl}-N,2-dimethylbenzamide, 4-{6-[4-methoxy-2-(methylsulfanyl)phenoxy]-4-[(tetrahydro-2H-pyran-4-ylme- thyl)amino]-1H-benzimidazol-1-yl}-N,2-dimethylbenzamide, N-cyclopropyl-4-{6-(2-fluoro-4-hydroxyphenoxy)-4-[(tetrahydro-2H-pyran-4-- ylmethyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[4-methoxy-2-(methylsulfanyl)phenoxy]-4-[(tetrahydro-2- H-pyran-4-ylmethyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-ethyl-4-{6-(2-fluoro-4-hydroxyphenoxy)-4-[(tetrahydro-2H-pyran-4-ylmeth- yl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, N-ethyl-4-{6-[4-methoxy-2-(methylsulfanyl)phenoxy]-4-[(tetrahydro-2H-pyra- n-4-ylmethyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzamide, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 10. A method of preparing a compound according to claim 1, said method comprising the step: allowing an intermediate compound of general formula (II): ##STR00216## in which R.sup.5 and A are as defined in claim 1; R.sup.3' is a halogen atom; to react with a compound of general formula (IIa): R.sup.3--Y (IIa) in which R.sup.3 is as defined in claim 1; Y is a substituent which is displaced in a coupling reaction; thereby giving a compound of general formula (I): ##STR00217## in which R.sup.3, R.sup.5 and A are as defined in claim 1. 11. A method of preparing a compound according to claim 1, said method comprising the step: allowing an intermediate compound of general formula (IV): ##STR00218## in which R.sup.3 and R.sup.5 are as defined in claim 1; to react with a compound of general formula (IVa): A-Y (IVa) in which A is as defined in claim 1; Y is a substituent which is displaced in a coupling reaction; thereby giving a compound of general formula (I): ##STR00219## in which R.sup.3, R.sup.5 and A are as defined in claim 1. 12. A pharmaceutical composition comprising a compound according to claim 1, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same, and a pharmaceutically acceptable diluent or carrier. 13. A pharmaceutical composition comprising: one or more compounds according to claim 1, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same; and one or more agents selected from: a taxane, Docetaxel, Paclitaxel, Taxol; an epothilone, Ixabepilone, Patupilone, Sagopilone; Mitoxantrone; Predinisolone; Dexamethasone; Estramustin; Vinblastin; Vincristin; Doxorubicin; Adriamycin; Idarubicin; Daunorubicin; Bleomycin; Etoposide; Cyclophosphamide; Ifosfamide; Procarbazine; Melphalan; 5-Fluorouracil; Capecitabine; Fludarabine; Cytarabine; Ara-C; 2-Chloro-2'-deoxyadenosine; Thioguanine; an anti-androgen, Flutamide, Cyproterone acetate, Bicalutamide; Bortezomib; a platinum derivative, Cisplatin, Carboplatin; Chlorambucil; Methotrexate; and Rituximab. 14. A method for inhibiting monopolar spindle 1 kinase activity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to claim 1. 15. A compound of general formula (II): ##STR00220## in which R.sup.5 and A are as defined in claim 1 and R.sup.3' is a halogen atom. 16. The method of claim 14, wherein the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by the mitogen-activated protein kinase (MEK-ERK) pathway. 17. The method of claim 14, wherein the disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is a haematological tumour, a solid tumour and/or metastases thereof. 18. The method of claim 17, wherein the haematological tumour, solid tumour and/or metastases thereof, is selected from leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours, brain tumours and brain metastases, tumours of the thorax, non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours, renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

Details for Patent 9,388,140

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2031-03-31
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2031-03-31
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2031-03-31