Substituted phenylamino-benzene derivatives useful for treating hyper-proliferative disorders and diseases associated with mitogen extracellular kinase activity
This invention relates to novel substituted phenylamino-benzene compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for treating hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients.
1 . A compound of general formula (I):
in which:
R 1 and R 2 are the same or different and are independently a hydrogen atom, a halogen atom, a C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, or —CN group, in which at least one of R 1 and R 2 is a halogen atom;
each occurrence of R 3 is independently a halogen atom, a C 1 -C 4 -alkyl or —CN group q is an integer of 0, 1, 2, or 3;
R 4 is a hydrogen atom or a C 1 -C 6 -alkyl group
R 5 is a —C(═O)R 7 , —C(═O)OR 7 , —C(═O)N(R 7 )(R 8 ), —NHC(═O)R 7 , —S(═O) 2 R 7 , —NHS(═O) 2 R 7 , —S(═O) 2 NR 7 R 8 , —NO 2 , —CN, or a
group,
in which
each of Z 1 , Z 2 , Z 3 and Z 4 is independently —CH—, —C(C 1 -C 6 -alkyl)-, —C(═O)—, —S—, —O—, —N— or —NH, such that at least one of Z 1 , Z 2 , Z 3 and Z 4 is —N— or —NH—;
X is —O—, —NH—, —N(C 1 -C 6 -alkyl)-, —S—, —S(═O) 2 —, —C(═O)—, —C(═O)O—, —C(═O)NH—, or —NHC(═O)—;
R 6 is —(CH 2 ) n —(CH(OR 11 ))—(CH 2 ) m —R 9 , —(CR 15 2 ) n —(CR 15 (OR 11 ))—(CR 15 2 ) m —R 9 , —(CH 2 ) n —(CHN((R 12 )(R 13 )))—(CH 2 ) m —R o , —(CR 15 2 ) n —(CR 15 N((R 12 )(R 13 )))—(CR 15 2 ) m —R 10 , —(CH 2 ) n —Y, —(CH 2 ) n —CH(OH)—CH(OH)—CH 2 (OH), or —(CH 2 ) n —CH(OH)—C(═O)OH;
Y is —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1 -C 3 -alkyl), —N(R 12 )(R 13 ), aryl, heteroaryl, C 2 -C 10 -alkenyl, C 5 -C 10 -cycloalkenyl, cycloalkyl or heterocycloalkyl group, in which aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more —(CH 2 ) o R 14 groups;
R 7 and R 8 are independently a hydrogen atom, a —N(R 12 )(R 13 ), —OH, —C 1 -C 6 -alkoxy, —C 1 -C 6 -alkyl, —CF 3 , —O—(CH 2 ) n —(CH(OR 11 ))—(CH 2 ) m —R 9 , —O— (CH 2 ) n -cycloalkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, in which aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are, independently of each other, optionally substituted with one or more halogen atoms, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy groups;
R 9 and R 10 are independently —OH, —C 1 -C 6 -alkoxy, halogen, heteroaryl, —NR d1 R d2 or —N(R 12 )(R 13 );
R 11 , R 12 and R 13 are independently a hydrogen atom, a C 1 -C 6 -alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, in which C 1 -C 6 -alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are, independently of each other, optionally substituted with one or more —(CH 2 ) o R 14 groups,
or
R 12 and R 13 , together with the N atom to which they are bound, form a 5-, 6-, or 7-membered heterocyclic ring which optionally comprises one or more additional heteroatoms, which optionally comprises one or more —C(═O)— or —S(═O) 2 groups, and which is optionally substituted with one or more —(CH 2 ) o R 14 groups;
each occurrence of R 14 is, independently, a halogen atom, a C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxyalkyl, cycloalkyl, heterocycloalkyl, —OR c , —NR d1 R d2 , —CN, —NHS(═O) 2 H, —NR a S(═O) 2 R b , —S(═O) 2 R b or —C(═O)R b group;
each occurrence of R 15 is, independently, a hydrogen atom or a C 1 -C 6 -alkyl group;
each occurrence of n is, independently, an integer of 0, 1, 2, 3, or 4;
each occurrence of m is, independently, an integer of 0, 1, or 2; and
each occurrence of o is, independently, an integer of 0, 1, or 2;
each occurrence of R a is, independently, a hydrogen atom or a C 1 -C 6 -alkyl group;
each occurrence of R b is, independently, an —OH, —OR c , —SR c , —NR d1 R d2 , a C 1 -C 6 -alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, in which C 1 -C 6 -alkyl, cycloalkyl and heterocycloalkyl are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH or C 1 -C 6 -alkoxy group;
each occurrence of R c is, independently, a hydrogen atom, a —C(═O)R e , —S(═O) 2 R e , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, in which C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH, aryl, —OR f , —NR d1 R d2 , or —OP(═O)(OR f ) 2 group;
in each occurrence of R d1 , R d2 , R d1 , R d2 are, independently of each other, a hydrogen atom, a C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C(═O)R e , —S(═O) 2 R e , or —C(═O)NR g1 R g2 group, in which C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are, independently of each other, optionally substituted one or more times, the same way or differently, with a halogen atom, an —OH or aryl, —NR g1 R g2 , —OR f , —C(═O)R e , —S(═O) 2 R e , or —OP(═O)(OR f ) 2 group;
or
R d1 and R d2 , together with the nitrogen atom to which they are bound, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently, with a halogen atom, a C 1 -C 6 -alkyl, —NR g1 R g2 , —OR f , —C(═O)R e , —S(═O) 2 R e , or —OP(═O)(OR f ) 2 group; and the carbon backbone of which is optionally interrupted one or more times, in the same way or differently, with NH, NR d3 , O, or S, and is optionally interrupted one or more times, in the same way or differently, with a —C(═O)—, —S(═O)—, and/or —S(═O) 2 — group, and optionally contains one or more double bonds;
R d3 is a hydrogen atom, a C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, in which C 1 -C 6 -alkyl or cycloalkyl are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH, C 1 -C 6 -alkyl, cycloalkyl, C 1 -C 6 -haloalkyl or C 1 -C 6 -alkoxy group;
R e is an —NR g1 R g2 , C 1 -C 6 -alkyl, cycloalkyl, C 1 -C 6 -alkoxy, aryl or heteroaryl group
R f is a hydrogen atom, a —C(═O)R e , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, in which C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH, C 1 -C 6 -alkoxy, aryl, or —NR g1 R g2 group;
R g1 , R g2 , are, independently of each other, a hydrogen atom, a C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or
R g1 and R g2 , together with the nitrogen atom to which they are bound, form a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, in the same way or differently, with a halogen atom, an —OH, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy group; and the carbon backbone of which is optionally interrupted one or more times, in the same way or differently, with NH, NR a , O, S, and is optionally interrupted one or more times, in the same way or differently, with a —C(═O)—, —S(═O)—, and/or —S(═O) 2 — group, and optionally contains one or more double bonds;
with the proviso that:
X-R 6 is not (O or NH)—(CH 2 ) r —R r ,
where R r is NR s1 R s2 in which
r=1-4, and
R s1 , R s2 =independently hydrogen, C 1 -C 8 alkyl, or taken together with the nitrogen to which they are attached, form a 3-10 member cyclic ring optionally containing one oxygen atom or one sulfur atom or one NH or N—C 1 -C 8 alkyl group;
or a tautomer, stereoisomer, physiologically acceptable salt, hydrate, solvate, metabolite, or prodrug thereof.
2 . The compound according to claim 1 , wherein
R 1 and R 2 are the same or different and are independently a hydrogen atom, a halogen atom, a C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, or —CN group, in which at least one of R 1 and R 2 is a halogen atom;
each occurrence of R 3 is independently a halogen atom, a C 1 -C 4 -alkyl or —CN group q is an integer of 0, 1, 2, or 3;
R 4 is a hydrogen atom or a C 1 -C 6 -alkyl group;
R 5 is a —C(═O)R 7
R 6 is —(CH 2 ) n —(CH(OR 11 ))—(CH 2 ) m —R 9 , —(CR 15 2 ) n —(CR 15 (OR 11 ))—(CR 15 2 ) m —R 9 , —(CH 2 ) n —(CHN((R 12 )(R 13 )))—(CH 2 ) m —R 1 , —(CR 15 2 ) n —(CR 15 N((R 12 )(R 13 )))—(CR 15 2 ) m —R 10 , —(CH 2 ) n —Y, —(CH 2 ) n —CH(OH)—CH(OH)—CH 2 (OH), or —(CH 2 ) n —CH(OH)—C(═O)OH;
Y is —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1 -C 3 -alkyl), —N(R 12 )(R 13 ), aryl, heteroaryl, C 2 -C 10 -alkenyl, C 5 -C 10 -cycloalkenyl, cycloalkyl or heterocycloalkyl group, in which aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more —(CH 2 ) o R 14 groups;
R 7 is a —N(R 12 )(R 13 ), —OH, or a —C 1 -C 6 -alkoxy group;
R 8 is a hydrogen atom, a —N(R 12 )(R 13 ), —OH, —C 1 -C 6 -alkoxy, —C 1 -C 6 -alkyl, —CF 3 , —O—(CH 2 ) n —(CH(OR 11 ))—(CH 2 ) m —R 9 , —O—(CH 2 ) n -cycloalkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, in which aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are, independently of each other, optionally substituted with one or more halogen atoms, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy groups;
R 9 and R 10 are independently —OH, —C 1 -C 6 -alkoxy, halogen, heteroaryl, —NR d1 R d2 or —N(R 12 )(R 13 );
R 11 is a hydrogen atom, a C 1 -C 6 -alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, in which C 1 -C 6 -alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are, independently of each other, optionally substituted with one or more —(CH 2 ) o R 14 groups,
R 12 and R 13 are independently a hydrogen atom or a C 1 -C 6 -alkyl group, in which C 1 -C 6 -alkyl is optionally substituted with one R 14 group;
or
R 12 and R 13 , together with the N atom to which they are bound, form a 5-, 6-, or 7-membered heterocyclic ring which optionally comprises one or more additional heteroatoms, which optionally comprises one or more —C(═O)— or —S(═O) 2 groups, and which is optionally substituted with one or more —(CH 2 ) o R 14 groups;
each occurrence of R 14 is a halogen atom, a C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxyalkyl, cycloalkyl, heterocycloalkyl, —OR c , —NR d1 R d2 , —CN, —NR a S(═O) 2 R b , —S(═O) 2 R b or —C(═O)R b group;
each occurrence of R 15 is, independently, a hydrogen atom or a C 1 -C 6 -alkyl group;
each occurrence of n is, independently, an integer of 0, 1, 2, 3, or 4;
each occurrence of m is, independently, an integer of 0, 1, or 2; and
each occurrence of o is, independently, an integer of 0, 1, or 2;
each occurrence of R a is, independently, a hydrogen atom or a C 1 -C 6 -alkyl group;
each occurrence of R b is, independently, an —OH, —OR c , —SR c , —NR d1 R d2 , a C 1 -C 6 -alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, in which C 1 -C 6 -alkyl, cycloalkyl and heterocycloalkyl are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH or C 1 -C 6 -alkoxy group;
each occurrence of R c is, independently, a hydrogen atom, a —C(═O)R e , —S(═O) 2 R e , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, in which C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH, aryl, —OR f , —NR d1 R d2 , or —OP(═O)(OR f ) 2 group;
in each occurrence of R d1 , R d2 , R d1 , R d2 are, independently of each other, a hydrogen atom, a C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C(═O)R e , —S(═O) 2 R e , or —C(═O)NR g1 R g2 group, in which C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are, independently of each other, optionally substituted one or more times, the same way or differently, with a halogen atom, an —OH or aryl, —NR g1 R g2 , —OR f , —C(═O)R e , —S(═O) 2 R e , or —OP(═O)(OR f ) 2 group;
or
R d1 and R d2 , together with the nitrogen atom to which they are bound, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently, with a halogen atom, a C 1 -C 6 -alkyl, —NR g1 R g2 , —OR f , —C(═O)R e , —S(═O) 2 R e , or —OP(═O)(OR f ) 2 group; and the carbon backbone of which is optionally interrupted one or more times, in the same way or differently, with NH, NR d3 , O, or S, and is optionally interrupted one or more times, in the same way or differently, with a —C(═O)—, —S(═O)—, and/or —S(═O) 2 — group, and optionally contains one or more double bonds;
R d3 is a hydrogen atom, a C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, in which C 1 -C 6 -alkyl or cycloalkyl are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH, C 1 -C 6 -alkyl, cycloalkyl, C 1 -C 6 -haloalkyl or C 1 -C 6 -alkoxy group;
R e is an —NR g1 R g2 C 1 -C 6 -alkyl, cycloalkyl, C 1 -C 6 -alkoxy, aryl or heteroaryl group;
R f is a hydrogen atom, a —C(═O)R e , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, in which C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH, C 1 -C 6 -alkoxy, aryl, or —NR g1 R g2 group;
R g1 , R g2 , are, independently of each other, a hydrogen atom, a C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or
R g1 and R g2 , together with the nitrogen atom to which they are bound, form a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, in the same way or differently, with a halogen atom, an —OH, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy group; and the carbon backbone of which is optionally interrupted one or more times, in the same way or differently, with NH, NR a , O, S, and is optionally interrupted one or more times, in the same way or differently, with a —C(═O)—, —S(═O)—, and/or —S(═O) 2 — group, and optionally contains one or more double bonds;
with the proviso that:
X-R 6 is not (O or NH)—(CH 2 ) r —R r ,
where R r is NR s1 R s2 in which
r=1-4, and
R s1 , R s2 =independently hydrogen, C 1 -C 8 alkyl, or taken together with the nitrogen to which they are attached, form a 3-10 member cyclic ring optionally containing one oxygen atom or one sulfur atom or one NH or N—C 1 -C 8 alkyl group;
or a tautomer, stereoisomer, physiologically acceptable salt, hydrate, solvate, metabolite, or prodrug thereof.
3 . The compound according to claim 1 , wherein
R 1 and R 2 are the same or different and are independently a hydrogen atom, a halogen atom, a C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, or —CN group, in which at least one of R 1 and R 2 is a halogen atom;
each occurrence of R 3 is independently a halogen atom, a C 1 -C 4 -alkyl or —CN group q is an integer of 0, 1, 2, or 3;
R 4 is a hydrogen atom or a C 1 -C 6 -alkyl group;
R 5 is a —C(═O)R 7
R 6 is —(CH 2 ) n —(CH(OR 11 ))—(CH 2 ) m —R 9 , —(CR 15 2 ) n —(CR 15 (OR 11 ))—(CR 15 2 ) m —R 9 , —(CH 2 ) n —(CHN((R 12 ) (R 13 )))—(CH 2 ) m —R 10 , —(CR 15 2 ) n —(CR 15 N((R 12 )(R 13 )))—(CR 15 2 ) m —R 10 , —(CH 2 ) n —Y, (CH 2 ) n —CH(OH)—CH(OH)—CH 2 (OH), or —(CH 2 ) n —CH(OH)—C(═O)OH;
Y is —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1 -C 3 -alkyl), —N(R 12 )(R 13 ), C 2 -C 10 -alkenyl, C 5 -C 10 -cycloalkenyl, cycloalkyl or heterocycloalkyl group, in which cycloalkyl or heterocycloalkyl is optionally substituted with one or more —(CH 2 ) o R 14 groups R 7 is a —N(R 12 )(R 13 ), —OH, or a —C 1 -C 6 -alkoxy group;
R 8 is a hydrogen atom, a —N(R 12 )(R 13 ), —OH, —C 1 -C 6 -alkoxy, —C 1 -C 6 -alkyl, —CF 3 , —O—(CH 2 ) n —(CH(OR 11 ))—(CH 2 ) m —R 9 , —O—(CH 2 ) n -cycloalkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, in which aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are, independently of each other, optionally substituted with one or more halogen atoms, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy groups;
R 9 and R 10 are independently —OH, —C 1 -C 6 -alkoxy, halogen, heteroaryl, —NR d1 R d2 or —N(R 12 )(R 13 );
R 11 is a hydrogen atom, a C 1 -C 6 -alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, in which C 1 -C 6 -alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are, independently of each other, optionally substituted with one or more —(CH 2 ) o R 14 groups,
R 12 and R 13 are independently a hydrogen atom or a C 1 -C 6 -alkyl group; in which C 1 -C 6 -alkyl is optionally substituted with one R 14 group;
or
R 12 and R 13 , together with the N atom to which they are bound, form a 5-, 6-, or 7-membered heterocyclic ring which optionally comprises one or more additional heteroatoms, which optionally comprises one or more —C(═O)— or —S(═O) 2 groups, and which is optionally substituted with one or more —(CH 2 ) o R 14 groups;
each occurrence of R 14 is a halogen atom, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or (C 1 -C 6 -alkyl) 2 -amino;
each occurrence of R 15 is, independently, a hydrogen atom or a C 1 -C 6 -alkyl group;
each occurrence of n is, independently, an integer of 0, 1, 2, 3, or 4;
each occurrence of m is, independently, an integer of 0, 1, or 2; and
each occurrence of o is, independently, an integer of 0, 1, or 2;
each occurrence of R a is, independently, a hydrogen atom or a C 1 -C 6 -alkyl group;
each occurrence of R b is, independently, an —OH, —OR c , —SR c , —NR d1 R d2 , a C 1 -C 6 -alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, in which C 1 -C 6 -alkyl, cycloalkyl and heterocycloalkyl are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH or C 1 -C 6 -alkoxy group;
each occurrence of R c is, independently, a hydrogen atom, a —C(═O)R e , —S(═O) 2 R e , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, in which C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH, aryl, —OR f , —NR d1 R d2 , or —OP(═O)(OR f ) 2 group;
in each occurrence of R d1 , R d2 , R d1 , R d2 are, independently of each other, a hydrogen atom, a C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C(═O)R e , —S(═O) 2 R e , or —C(═O)NR g1 R g2 group, in which C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are, independently of each other, optionally substituted one or more times, the same way or differently, with a halogen atom, an —OH or aryl, —NR g1 R g2 , —OR f , —C(═O)R e , —S(═O) 2 R e , or —OP(═O)(OR f ) 2 group;
or
R d1 and R d2 , together with the nitrogen atom to which they are bound, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently, with a halogen atom, a C 1 -C 6 -alkyl, —NR g1 R g2 , —OR f , —C(═O)R e , —S(═O) 2 R e , or —OP(═O)(OR f ) 2 group; and the carbon backbone of which is optionally interrupted one or more times, in the same way or differently, with NH, NR d3 , O, or S, and is optionally interrupted one or more times, in the same way or differently, with a —C(═O)—, —S(═O)—, and/or —S(═O) 2 — group, and optionally contains one or more double bonds;
R d3 is a hydrogen atom, a C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, in which C 1 -C 6 -alkyl or cycloalkyl are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH, C 1 -C 6 -alkyl, cycloalkyl, C 1 -C 6 -haloalkyl or C 1 -C 6 -alkoxy group;
R e is an —NR g1 R g2 , C 1 -C 6 -alkyl, cycloalkyl, C 1 -C 6 -alkoxy, aryl or heteroaryl group;
R f is a hydrogen atom, a —C(═O)R e , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, in which C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH, C 1 -C 6 -alkoxy, aryl, or —NR g1 R g2 group;
R g1 , R g2 , are, independently of each other, a hydrogen atom, a C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or
R g1 and R g2 , together with the nitrogen atom to which they are bound, form a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, in the same way or differently, with a halogen atom, an —OH, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy group; and the carbon backbone of which is optionally interrupted one or more times, in the same way or differently, with NH, NR a , O, S, and is optionally interrupted one or more times, in the same way or differently, with a —C(═O)—, —S(═O)—, and/or —S(═O) 2 — group, and optionally contains one or more double bonds;
with the proviso that
X-R 6 is not (O or NH)—(CH 2 ) r —R r ,
where R r is NR s1 R s2 in which
r=1-4, and
R s1 , R s2 =independently hydrogen, C 1 -C 8 alkyl, or taken together with the nitrogen to which they are attached, form a 3-10 member cyclic ring optionally containing one oxygen atom or one sulfur atom or one NH or N—C 1 -C 8 alkyl group;
or a tautomer, stereoisomer, physiologically acceptable salt, hydrate, solvate, metabolite, or prodrug thereof.
4 . The compound according to claim 1 , wherein
R 1 and R 2 are the same or different and are independently a hydrogen atom, a halogen atom, a C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, or —CN group, in which at least one of R 1 and R 2 is a halogen atom;
each occurrence of R 3 is independently a halogen atom, a C 1 -C 4 -alkyl or —CN group;
q is an integer of 0, 1, 2, or 3;
R 4 is a hydrogen atom or a C 1 -C 6 -alkyl group;
R 5 is a —C(═O)R 7
R 6 is —(CH 2 ) n —Y;
Y is aryl, heteroaryl, in which aryl, heteroaryl is optionally substituted with one or more —(CH 2 ) o R 14 groups;
R 7 is a —N(R 12 )(R 13 ), —OH, or a —C 1 -C 6 -alkoxy group;
R 8 is a hydrogen atom, a —N(R 12 )(R 13 ), —OH, —C 1 -C 6 -alkoxy, —C 1 -C 6 -alkyl, —CF 3 , —O—(CH 2 ) n —(CH(OR 11 ))—(CH 2 ) m —R 9 , —O—(CH 2 ) n -cycloalkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, in which aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are, independently of each other, optionally substituted with one or more halogen atoms, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy groups;
R 9 and R 10 are independently —OH, —C 1 -C 6 -alkoxy, halogen, heteroaryl, —NR d1 R d2 or —N(R 12 )(R 13 );
R 11 is a hydrogen atom, a C 1 -C 6 -alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, in which C 1 -C 6 -alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are, independently of each other, optionally substituted with one or more —(CH 2 ) o R 14 groups,
R 12 and R 13 are independently a hydrogen atom or a C 1 -C 6 -alkyl group, in which C 1 -C 6 -alkyl is optionally substituted with one R 14 group;
or
R 12 and R 13 , together with the N atom to which they are bound, form a 5-, 6-, or 7-membered heterocyclic ring which optionally comprises one or more additional heteroatoms, which optionally comprises one or more —C(═O)— or —S(═O) 2 groups, and which is optionally substituted with one or more —(CH 2 ) o R 14 groups;
each occurrence of R 14 is a halogen atom, a C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxyalkyl, cycloalkyl, heterocycloalkyl, —OR c , —NR d1 R d2 , —CN, —NR a S(═O) 2 R b , —S(═O) 2 R b or —C(═O)R b group;
a halogen atom, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or (C 1 -C 6 -alkyl) 2 -amino each occurrence of R 15 is, independently, a hydrogen atom or a C 1 -C 6 -alkyl group;
each occurrence of n is, independently, an integer of 0, 1, 2, 3, or 4;
each occurrence of m is, independently, an integer of 0, 1, or 2; and
each occurrence of o is, independently, an integer of 0, 1, or 2;
each occurrence of R a is, independently, a hydrogen atom or a C 1 -C 6 -alkyl group;
each occurrence of R b is, independently, an —OH, —OR c , —SR c , —NR d1 R d2 , a C 1 -C 6 -alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, in which C 1 -C 6 -alkyl, cycloalkyl and heterocycloalkyl are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH or C 1 -C 6 -alkoxy group;
each occurrence of R c is, independently, a hydrogen atom, a —C(═O)R e , —S(═O) 2 R e , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, in which C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH, aryl, —OR f , —NR d1 R d2 , or —OP(═O)(OR f ) 2 group;
in each occurrence of R d1 , R d2 , R d1 , R d2 are, independently of each other, a hydrogen atom, a C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C(═O)R e , —S(═O) 2 R e , or —C(═O)NR g1 R g2 group, in which C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are, independently of each other, optionally substituted one or more times, the same way or differently, with a halogen atom, an —OH or aryl, —NR g1 R g2 , —OR f , —C(═O)R e , —S(═O) 2 R e , or —OP(═O)(OR f ) 2 group;
or
R d1 and R d2 , together with the nitrogen atom to which they are bound, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently, with a halogen atom, a C 1 -C 6 -alkyl, —NR g1 R g2 , —OR f , —C(═O)R e , —S(═O) 2 R e , or —OP(═O)(OR f ) 2 group; and the carbon backbone of which is optionally interrupted one or more times, in the same way or differently, with NH, NR d3 , O, or S, and is optionally interrupted one or more times, in the same way or differently, with a —C(═O)—, —S(═O)—, and/or —S(═O) 2 — group, and optionally contains one or more double bonds;
R d3 is a hydrogen atom, a C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, in which C 1 -C 6 -alkyl or cycloalkyl are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH, C 1 -C 6 -alkyl, cycloalkyl, C 1 -C 6 -haloalkyl or C 1 -C 6 -alkoxy group;
R e is an —NR g1 R g2 , C 1 -C 6 -alkyl, cycloalkyl, C 1 -C 6 -alkoxy, aryl or heteroaryl group;
R f is a hydrogen atom, a —C(═O)R e , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, in which C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are, independently of each other, optionally substituted one or more times with a halogen atom, an —OH, C 1 -C 6 -alkoxy, aryl, or —NR g1 R g2 group;
R g1 , R g2 , are, independently of each other, a hydrogen atom, a C 1 -C 6 -alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or
R g1 and R g2 , together with the nitrogen atom to which they are bound, form a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, in the same way or differently, with a halogen atom, an —OH, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy group; and the carbon backbone of which is optionally interrupted one or more times, in the same way or differently, with NH, NR a , O, S, and is optionally interrupted one or more times, in the same way or differently, with a —C(═O)—, —S(═O)—, and/or —S(═O) 2 — group, and optionally contains one or more double bonds;
with the proviso that:
X-R 6 is not (O or NH)—(CH 2 ) r —R r ,
where R r is NR s1 R s2 in which
r=1-4, and
R s1 , R s2 =independently hydrogen, C 1 -C 8 alkyl, or taken together with the nitrogen to which they are attached, form a 3-10 member cyclic ring optionally containing one oxygen atom or one sulfur atom or one NH or N—C 1 -C 8 alkyl group;
or a tautomer, stereoisomer, physiologically acceptable salt, hydrate, solvate, metabolite, or prodrug thereof.
5 . The compound according to claim 1 , which is selected from the group consisting of 5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-2-nitrophenoxybutane-1,2-diol;
5-fluoro-N-(2-fluoro-4-iodophenyl)-2-nitro-3-(2-piperidin-4-ylethoxy)aniline;
2-(3,4-dihydroxybutoxy)-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]benzonitrile
2-[2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]benzamide;
2-(3,4-dihydroxybutoxy)-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]benzamide;
5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-2-nitrophenoxypropane-1,2-diol;
5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-2-nitrophenoxypentane-1,2-diol;
2-(2,3-dihydroxypropoxy)-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]benzonitrile;
2-[(4,5-dihydroxypentyl)oxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]benzonitrile;
2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]propoxy-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]benzamide;
2-[(3R)-3,4-dihydroxybutyl]oxy-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]benzamide;
2-[(3S)-3,4-dihydroxybutyl]oxy-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]benzamide;
2-[(4S)-4,5-dihydroxypentyl]oxy-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]benzamide;
2-{[(3R)-3,4-dihydroxybutyl]oxy}-4-fluoro-6-[(4-iodophenyl)amino]benzamide;
2-[(2-chloro-4-iodophenyl)amino]-6-{[(3R)-3,4-dihydroxybutyl]oxy}-4-fluorobenzamide;
2-{[(3R)-3,4-dihydroxybutyl]oxy}-4-fluoro-6-[(4-iodo-2-methylphenyl)amino]benzamide;
2-[(2-cyano-4-iodophenyl)amino]-6-{[(3R)-3,4-dihydroxybutyl]oxy}-4-fluorobenzamide;
2-[(4-bromo-2-fluorophenyl)amino]-6-{[(3R)-3,4-dihydroxybutyl]oxy}-4-fluorobenzamide;
2-[(4-bromo-2-chlorophenyl)amino]-6-{[(3R)-3,4-dihydroxybutyl]oxy}-4-fluorobenzamide;
2-{[(3R)-3,4-dihydroxybutyl]oxy}-6-[(4-ethynyl-2-fluorophenyl)amino]-4-fluorobenzamide;
2-{[(3R)-3,4-dihydroxybutyl]oxy}-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-N-methylbenzamide;
2-{[(3R)-3,4-dihydroxybutyl]oxy}-N-ethyl-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]benzamide;
2-{[(3R)-3,4-dihydroxybutyl]amino}-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]benzamide;
2-{[(3R)-3,4-dihydroxybutyl](methyl)amino}-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]benzamide;
4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-{[(2S,3S)-2,3,4-trihydroxybutyl]oxy}benzamide; or
4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-{[(2R,3R)-2,3,4-trihydroxybutyl]oxy}benzamide;
or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof.
6 . The compound according to claim 1 , which is selected from the group consisting of:
N′-[3-[2-cyano-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy]phenyl]-N,N-dimethyl-sulfamide;
{3-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-carbamic acid tert-butyl ester;
2-(Cyclopent-3-enyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzonitrile;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzonitrile;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(4-methyl-pent-3-enyloxy)-benzonitrile;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-methyl-but-3-enyloxy)-benzonitrile;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(2-imidazol-1-yl-ethoxy)-benzonitrile;
2-[3-(1,1-Dioxo-1λ 6 -thiomorpholin-4-yl)-propoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzonitrile;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(2-pyridin-3-yl-ethoxy)-benzonitrile;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(2-oxo-pyrrolidin-1-yl)-propoxy]-benzonitrile;
3-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester;
2-{2-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester;
3-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester;
2-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-morpholine-4-carboxylic acid tert-butyl ester;
3-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-azetidine-1-carboxylic acid tert-butyl ester;
4-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester;
{3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-carbamic acid tert-butyl ester;
2-[3-[[(di methylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(2-oxo-pyrrolidin-1-yl)-propoxy]-benzamide;
2-[3-(1,1-Dioxo-1λ 6 -thiomorpholin-4-yl)-propoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(2-pyridin-3-yl-ethoxy)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(4-methyl-pent-3-enyloxy)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-methyl-but-3-enyloxy)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-((2S,3S)-2,3,4-trihydroxy-butoxy)-benzamide;
2-(Cyclopent-3-enyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester;
2-{2-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester;
3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester;
2-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-morpholine-4-carboxylic acid tert-butyl ester;
3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-azetidine-1-carboxylic acid tert-butyl ester;
{3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-propyl}-carbamic acid tert-butyl ester;
4-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-((2R,3R)-2,3,4-trihydroxy-butoxy)-benzamide;
2-(3-Amino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(pyrrolidin-3-ylmethoxy)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(piperidin-3-ylmethoxy)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(morpholin-2-ylmethoxy)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(2-piperidin-2-yl-ethoxy)-benzamide;
2-(Azetidin-3-ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(piperidin-4-yloxy)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(1H-indol-6-yloxy)-benzamide;
2-[3-(3,3-Dimethyl-ureido)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-(3,3-Dioxo-2,3-dihydro-3λ 6 -benzo[1,3]oxathiol-5-yloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-phenoxy-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-((1S,2S)-2-hydroxy-cyclopentyloxy)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(4-imidazol-1-yl-phenoxy)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-nitro-phenoxy)-benzamide;
2-(Benzo[1,3]dioxol-5-yloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
Dimethyl-carbamic acid 3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl ester;
2-(4-Acetylamino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(1-methyl-piperidin-4-yloxy)-benzamide;
4-{2-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester;
6-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-indole-1-carboxylic acid tert-butyl ester;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[4-(methanesulfonyl-methyl-amino)-phenoxy]-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(pyridin-4-yloxy)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-hydrazinocarbonyl-phenoxy)-benzamide;
Acetic acid 4-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-cyclopent-2-enyl ester;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(4-hydroxy-cyclopent-2-enyloxy)-benzamide;
Dimethyl-sulfamic acid 3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl ester;
2-[2-((S)-2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-methanesulfonylamino-phenoxy)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-bis-methanesulfonyl-amino-phenoxy)-benzamide;
2-{2-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-ethyl}-piperidine-1-carboxylic acid dimethylamide;
2-[3-[[(propylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-benzamide;
2-(3-Acetylamino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-[3-(3-Chloro-propane-1-sulfonylamino)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-[3-(1,1-Dioxo-1λ 6 -isothiazolidin-2-yl)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-[3-[[(amino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-formylamino-phenoxy)-benzamide;
2-[2-(1-Ethanesulfonyl-piperidin-2-yl)-ethoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-[2-(1-Dimethylsulfamoyl-piperidin-2-yl)-ethoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-(3-Benzenesulfonylamino-propoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-(3-Benzoylamino-propoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(3-phenyl-ureido)-propoxy]-benzamide;
2-(1-Benzenesulfonyl-piperidin-3-ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(1-methanesulfonyl-piperidin-3-ylmethoxy)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(pyridin-3-ylmethanesulfonylamino)-propoxy]-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(1-methyl-1H-imidazole-4-sulfonylamino)-propoxy]-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(1-methyl-1H-pyrazole-4-sulfonylamino)-propoxy]-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-trifluoromethanesulfonylamino-propoxy)-benzamide;
2-(1-Ethanesulfonyl-piperidin-3-ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-(1-Dimethylsulfamoyl-piperidin-3-ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[2-(1-methanesulfonyl-piperidin-2-yl)-ethoxy]-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(1-methanesulfonyl-pyrrolidin-3-ylmethoxy)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(1-methanesulfonyl-piperidin-4-yloxy)-benzamide;
4-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-piperidine-1-carboxylic acid dimethylamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(morpholine-4-sulfonylamino)-phenoxy]-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[1-(1H-imidazole-4-sulfonyl)-azetidin-3-ylmethoxy]-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(1-methanesulfonyl-azetidin-3-ylmethoxy)-benzamide;
2-(1-Dimethylsulfamoyl-azetidin-3-ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-(3,4-Dihydroxy-4-methyl-pentyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-(3,4-Dihydroxy-3-methyl-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-(3,4-Dihydroxy-4-methyl-pentyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide (Enantiomer 1);
2-(3,4-Dihydroxy-4-methyl-pentyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide (Enantiomer 2);
2-(3,4-Dihydroxy-3-methyl-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide (Enantiomer 1);
2-(3,4-Dihydroxy-3-methyl-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide (Enantiomer 2);
2-((1S,3S,4R)-3,4-Dihydroxy-cyclopentyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-((1S,3S,4R)-3,4-Dihydroxy-cyclopentyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-(3,4-Dihydroxy-4-methyl-pentyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzonitrile;
2-(3,4-Dihydroxy-3-methyl-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzonitrile;
2-((S)-3,4-Dihydroxy-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-((R)-3,4-Dihydroxy-butoxy)-4-fluoro-6-(2-fluoro-phenylamino)-benzamide;
2-(4-Chloro-2-fluoro-phenylamino)-6-((R)-3,4-dihydroxy-butoxy)-4-fluoro-benzamide;
2-(4-Bromo-2-fluoro-phenylamino)-6-((R)-3,4-dihydroxy-butoxy)-4-fluoro-benzamide;
2-((R)-3,4-Dihydroxy-butoxy)-4-fluoro-6-(4-iodo-phenylamino)-benzamide;
2-((R)-3,4-Dihydroxy-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-((R)-3,4-Dihydroxy-butoxy)-6-(4-ethynyl-2-fluoro-phenylamino)-4-fluoro-benzamide;
2-((R)-3,4-Dihydroxy-butoxy)-4-fluoro-6-[2-fluoro-4-(4-hydroxy-but-1-ynyl)-phenylamino]-benzamide;
2-((R)-3,4-Dihydroxy-4-methyl-pentyloxy)-6-(4-ethynyl-2-fluoro-phenylamino)-4-fluoro-benzamide;
2-[3-[[(dimethylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(4-ethynyl-2-fluorophenyl)amino]-benzamide;
2-[3-[[(propylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(4-ethynyl-2-fluorophenyl)amino]-benzamide;
Methanesulfonic acid (R)-4-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-2-hydroxy-butyl ester;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[(R)-3-hydroxy-4-(2-hydroxy-ethylamino)-butoxy]-benzamide;
2-((R)-4-Amino-3-hydroxy-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-{(R)-3-hydroxy-4-[(2-methoxy-ethyl)-methyl-amino]-butoxy}-benzamide;
2-((R)-4-Diethylamino-3-hydroxy-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-((R)-3-hydroxy-4-morpholin-4-yl-butoxy)-benzamide;
2-((R)-4-Ethylamino-3-hydroxy-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-((R)-3-hydroxy-4-piperidin-1-yl-butoxy)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[(R)-3-hydroxy-4-(2-methoxy-ethylamino)-butoxy]-benzamide;
2-((R)-3,4-Dihydroxy-butoxy)-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-Bromo-2-((R)-3,4-dihydroxy-butoxy)-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-Chloro-2-((R)-3,4-dihydroxy-butoxy)-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-((R)-3,4-Dihydroxy-butoxy)-6-(2-fluoro-4-iodo-phenylamino)-4-methoxy-benzamide;
3-Chloro-6-((R)-3,4-dihydroxy-butoxy)-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-((R)-3,4-Dihydroxy-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzoic acid;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(2,2,2-trifluoro-acetylamino)-phenoxy]-benzamide;
2-((R)-3,4-Dihydroxy-butoxy)-4-fluoro-6-(3-fluoro-biphenyl-4-ylamino)-benzamide;
2-((R)-4-Chloro-3-hydroxy-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-((R)-3-hydroxy-4-imidazol-1-yl-butoxy)-benzamide; compound with 2,4,6-triisopropyl-benzenesulfonic acid;
2-((R)-3,4-Dimethoxy-butoxy)-4-fluoro-6-[(2-fluoro-4-iodo-phenyl)-methyl-amino]-N,N-dimethyl-benzamide;
2-((R)-3,4-Dihydroxy-butoxy)-4-fluoro-6-[(2-fluoro-4-iodo-phenyl)-methyl-amino]-N,N-dimethyl-benzamide;
2-((R)-3,4-Dihydroxy-butoxy)-4-fluoro-6-[(2-fluoro-4-iodo-phenyl)-methyl-amino]-N-methyl-benzamide;
2-((R)-3,4-Dihydroxy-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-N-methyl-benzamide;
N-Benzyl-2-((R)-3,4-dihydroxy-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
2-((R)-3,4-Dihydroxy-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzonitrile;
Phthalic acid mono-{(R)-4-[2-cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-2-hydroxy-butyl}ester;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-oxo-butoxy)-benzonitrile;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-((2R,3R)-2,3,4-trihydroxy-butoxy)-benzonitrile;
2-(3,4-Dihydroxy-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide; and
2-[3-(3,3-Dimethyl-ureido)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide
or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof.
7 . A method of preparing a compound of general formula (I) according to claim 1 , said method comprising the step of allowing an intermediate compound of general formula Ia:
in which R 1 , R 2 , R 3 , R 5 , R 6a , X and q are as defined in claim 1 , to react with an acid, for example hydrochloric acid or TFA thereby giving a compound of formula I
in which R 1 , R 2 , R 3 , R 5 , R 6 , X and q are as defined in claim 1 .
8 . A method of preparing a compound of general formula (Ic) according to claim 1 , said method comprising the step of allowing an intermediate compound of general formula 1b:
in which R 1 , R 2 , R 3 , R 6a , X and q are as defined in claim 1 , to react with an acid, for example hydrochloric acid or TFA thereby giving a compound of formula Ic:
in which R 1 , R 2 , R 3 , R 6a , X and q are as defined in claim 1 .
9 . A method of preparing a compound of general formula (Ig) according to claim 1 , said method comprising the step of allowing an intermediate compound of general formula 1f:
in which R 1 , R 3 , R 5 , R 6 , X and q are as defined in claim 1 , to react with a deprotecting agent thereby giving a compound of formula Ig:
in which R 1 , R 3 , R 5 , R 6 , X and q are as defined in claim 1 .
10 . A method of preparing a compound of general formula (It) according to claim 1 , said method comprising the step of allowing an intermediate compound of general formula Is:
in which R 1 , R 2 , R 3 , R 5 and q are as defined in claim 1 , to react either in situ or after isolation with an amine of general formula (IX) to afford a compound of Formula (It):
in which R 1 , R 3 , R 3 , R 5 , R 6 , R 7 , X and q are as defined in claim 1 .
11 . A pharmaceutical composition comprising a compound according to claim 1 , or a tautomer, stereoisomer, physiologically acceptable salt, hydrate, solvate, metabolite, or prodrug thereof, and a pharmaceutically acceptable diluent or carrier.
12 . The pharmaceutical composition according to claim 11 wherein said compound is present in a therapeutically effective amount.
13 . The pharmaceutical composition according to claim 12 which further comprises at least one further active compound.
14 . The pharmaceutical composition according to claim 13 , in which said further active compound is an anti-hyperproliferative agent, an anti-angiogenic agent, a mitotic inhibitor, an alkylating agent, an anti-metabolite, a DNA-intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme inhibitor, a toposisomerase inhibitor, a biological response modifier, or an anti-hormone.
15 . A packaged pharmaceutical composition comprising a container, the pharmaceutical composition of claim 11 , and instructions for using the pharmaceutical composition to treat a disease or condition in a mammal.
16 . A method of inhibiting mitogen extracellular kinase enzymes in a cell comprising contacting a cell with one or more compounds according to claim 1 .
17 . The method according to claim 16 , wherein said cell is a mammalian cell.
18 . Use of a compound according to claim 1 for the preparation of a medicament for treating a hyperproliferative disorder or abnormal cell growth in a mammal.
19 . The use according to claim 18 , wherein said hyperproliferative disorder is cancer.
20 . The use according to claim 19 , wherein said cancer is a cancer of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, endocrine system or a distant metastasis of a solid tumor.
21 . The use according to claim 20 , wherein said cancer is a sarcoma, a melanoma or a hematological malignancy.
22 . The use according to claim 21 , wherein said haematological malignancy is lymphoma, leukaemia or multiple myeloma.
23 . Use of a compound according to claim 1 for the preparation of a medicament for treating an angiogenesis disorder in a mammal.
24 . The use according to claim 23 , wherein said hyperproliferative disorder is psoriasis, restenosis, autoimmune disease, atherosclerosis, rheumatoid arthritis, chronic pain, neuropathic pain, osteoarthritis, benign prostate hyperplasia, hyperproliferative disease of the eye.
25 . The use according to claim 24 , wherein said hyperproliferative disease of the eye is cataract, conjunctival epithelial cell hypermitosis or goblet cell hyperplasia.