Substituted sulphoximines as TIE2 inhibitors and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same
View Patent ↗The invention relates to substituted sulphoximines according to the general formula (I): in which A, E, G, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , m, p, q, are given in the claims, and salts thereof, to pharmaceutical compositions comprising said substituted sulphoximines, to methods of preparing said substituted sulphoximines as well as the use thereof for manufacturing a pharmaceutical composition for the treatment of diseases of dysregulated vascular growth or of diseases which are accompanied with dysregulated vascular growth, wherein the compounds effectively interfere with Tie2 signalling.
1. A compound of Formula I:
in which:
A and E are the same or different, and are each, independently from each other, phenylene or a five- or six-membered heteroarylene;
G is selected from —C(O)NR 9 —, —S(O) 2 —, and —C(O)—Y—;
X is selected from —O—, —S—, and —NR 10 —;
Y is selected from —C 1 -C 6 -alkylene and —C 3 -C 8 -cycloalkylene;
R 1 is selected from hydrogen, halogen, nitro, cyano, —C 1 -C 6 -alkyl, —(CH 2 ) n OR 11 , —(CH 2 ) n NR 11 R 12 , —(CH 2 ) n C(O)R 13 , —(CH 2 ) n NHC(O)R 13 , —(CH 2 ) n NHC(O)NR 11 R 12 , —(CH 2 ) n NHS(O) 2 R 14 , and —(CH 2 ) n C(O)NR 11 R 12 ;
R 2 is hydrogen, —C(O)R 13a , —S(O) 2 R 14a , or —S(O) 2 —(CH 2 ) r —Si(R 15 R 16 R 17 ), or is selected from —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —(CH 2 ) s -aryl and —(CH 2 ) s -heteroaryl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —OR 11a , —NR 11a R 12a , C 1 -C 6 -haloalkyl, —C(O)R 13a , or —S(O) 2 R 14a ;
R 3 is selected from —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —(CH 2 ) t -aryl and —(CH 2 ) t -heteroaryl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —OR 11b , —NR 11b R 12b , —C 1 -C 6 -haloalkyl, —C(O)R 13b , or —S(O) 2 R 14b ;
R 4 is selected from —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —(CH 2 ) u -aryl and —(CH 2 ) u -heteroaryl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —OR 11c , —NR 11c R 12c , C 1 -C 6 -haloalkyl, —C(O)R 13c , or —S(O) 2 R 14c ;
R 5 is selected from hydrogen, halogen, nitro, cyano, —C 1 -C 6 -alkyl, —OR 11d , —NR 11d R 12d , —C 1 -C 6 -haloalkyl, —C 1 -C 6 -alkylthio and —C 1 -C 6 -alkylcarbonyl;
R 6 is hydrogen or —C 1 -C 6 -alkyl;
R 7 , R 8 are the same or different, and are each independently selected from hydrogen, halogen, nitro, cyano, —(CH 2 ) v OR 11e , —(CH 2 ) v NR 11e R 12e , C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —C 1 -C 6 -haloalkyl, —C 1 -C 6 -alkylthio, —(CH 2 ) v C(O)R 13e , —(CH 2 ) v C(O)NR 11e R 12e and —(CH 2 ) v S(O) 2 NR 11e R 12e ;
R 9 and R 10 are the same or different, and are each independently selected from hydrogen and —C 1 -C 6 -alkyl;
R 11 , R 11a ,
R 11b , R 11c ,
R 11d , R 11e ,
R 11f , R 11g ,
R 12 , R 12a ,
R 12b , R 12c ,
R 12d , R 12e , and
R 12f are each, independently from each other, hydrogen, —C(O)R 13f , or —S(O) 2 R 14f , or are selected from —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —(CH 2 ) x -aryl and —(CH 2 ) x -heteroaryl, wherein R 11 , R 11a ; R 11b ; R 11c ; R 11d ; R 11e ; R 11g , R 12 ; R 12a ; R 12b ; R 12c ; R 12d ; R 12e ; are in each case unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —OR 11f ; —NR 11f R 12f , —C 1 -C 6 -haloalkyl, —C 1 -C 6 -haloalkoxy, —C 1 -C 6 -alkylthio, —C(O)OR 18 , —C(O)NR 18 R 18a , or —S(O) 2 NR 18 R 18a , and wherein R 11f and R 12f are in each case unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, —C 1 -C 6 -haloalkoxy, —C 1 -C 6 -alkylthio, —C(O)OR 18 , —C(O)NR 18 R 18a , or —S(O) 2 NR 18 R 18a , or substituted one time with —OR 11f or —NR 11f R 12f ; or
R 11 and R 12 ,
R 11a and R 12a ,
R 11b and R 12b ,
R 11c and R 12c ,
R 11d and R 12d ,
R 11e and R 12e ,
and
R 12f and R 12f independently from each other, together with the nitrogen atom to which they are attached in groups —NR 11 R 12 , —NR 11a R 12a , —NR 11b R 12b , —NR 11c R 12c , —NR 11d R 12d , —NR 11e R 12e , and —NR 11f R 12f , each form a 3 to 10 membered heterocycloalkyl ring, wherein the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group —NR 11g —, —O—, —S—, —C(O)—, —S(O)—, and —S(O) 2 —, and optionally contains one or more double bonds;
R 13 ; R 13a ;
R 13b ; R 13c ;
R 13e ;
and R 13f are each, independently from each other, hydrogen, hydroxy or —NR 19 R 20 , or are, independently from each other, selected from —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 3 -C 10 -cycloalkyl and —C 3 -C 10 -heterocycloalkyl, which in each is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, aryl, or heteroaryl, wherein aryl or heteroaryl are unsubstituted or substituted one or more times with halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 1 -C 6 -haloalkyl, or —C 1 -C 6 -haloalkoxy;
R 14 , R 14a ,
R 14b , R 14c ,
and R 14f are each, independently from each other, hydrogen or —NR 19a R 20a , or are, independently from each other, selected from —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl and —C 3 -C 10 -heterocycloalkyl, which in each is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, aryl, or heteroaryl, wherein aryl or heteroaryl are unsubstituted or substituted one or more times with halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 1 -C 6 -haloalkyl, or —C 1 -C 6 -haloalkoxy;
R 15 , R 16 ,
and R 17 are each, independently from each other, —C 1 -C 6 -alkyl or phenyl;
R 18 and R 18a are each, independently from each other, hydrogen, or are selected from —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —(CH 2 ) y -aryl and —(CH 2 ) y -heteroaryl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, or —C 1 -C 6 -haloalkyl; or
R 18 and R 18a , together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocycloalkyl ring, wherein the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group —NR 11g —, —O—, —S—, —C(O)—, —S(O)—, and —S(O) 2 —, and optionally contains one or more double bonds;
R 19 , R 19a ,
R 20 ,
and R 20a are each, independently from each other, hydrogen, —C 1 -C 6 -alkyl or —(CH 2 ) z -phenyl;
m and r are each, independently from each other, 1 or 2;
n, p, q,
r, s, t,
u, v, x,
y and z are each, independently from each other, 0, 1, 2, 3 or 4,
wherein when m is 2, each of the R 1 substituents is independent of the others,
heterocycloalkyl, unless otherwise indicated, is a cycloalkyl group wherein one or more ring atoms are selected from —NR 11g —, O, S, and carbonyl, and
heteroaryl is a monocyclic, bicyclic, or tricyclic aromatic ring having 3-16 ring atoms which contains at least one heteroatom, said heteroatom each being selected from oxygen, nitrogen and sulfur;
or a salt or N-oxide thereof.
2. A compound according to claim 1 , wherein:
A and E are the same or different and are each phenylene or a five- or six-membered heteroarylene;
G is selected from —C(O)NR 9 —, —S(O) 2 —, and —C(O)—Y—;
X is selected from —O—, —S—, and —NR 10 —;
Y is selected from —C 1 -C 6 -alkylene and —C 3 -C 8 -cycloalkylene;
R 1 is selected from hydrogen, halogen, nitro, cyano, —C 1 -C 6 -alkyl, —(CH 2 ) n OR 11 , —(CH 2 ) n NHC(O)R 13 , —(CH 2 ) n NHC(O)NR 11 R 12 , and —(CH 2 ) n NHS(O) 2 R 14 ;
R 2 is hydrogen, —C(O)R 13a , —S(O) 2 R 14a , or —S(O) 2 —(CH 2 ) r —Si(R 15 R 16 R 17 ), or is selected from —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, and —(CH 2 ) s -aryl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —OR 11a , —NR 11a R 12a , —C 1 -C 6 -haloalkyl, —C(O)R 13a , or —S(O) 2 R 14a ;
R 3 is selected from —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, and —(CH 2 ) t -aryl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —OR 11b , —NR 11b R 12b , —C 1 -C 6 -haloalkyl, —C(O)R 13b , or —S(O) 2 R 14b ;
R 4 is selected from —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —(CH 2 ) u -aryl and —(CH 2 ) u -heteroaryl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —OR 11c , —NR 11c R 12c , —C 1 -C 6 -haloalkyl, —C(O)R 13c , or —S(O) 2 R 14c ;
R 5 is selected from hydrogen, halogen, —C 1 -C 6 -alkyl, —OR 11d , and —NR 11d R 12d ;
R 6 is hydrogen or —C 1 -C 6 -alkyl;
R 7 , R 8 are the same or different, and are independently selected from hydrogen, halogen, nitro, cyano, —(CH 2 ) v OR 11e , —(CH 2 ) v NR 11e R 12e , —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —C 1 -C 6 -haloalkyl, —C 1 -C 6 -alkylthio, —(CH 2 ) v C(O)R 13e , —(CH 2 ) v C(O)NR 11e R 12e and —(CH 2 ) v S(O) 2 NR 11e R 12e ;
R 9 and R 10 are the same or different, and are independently selected from hydrogen and —C 1 -C 6 -alkyl;
R 11 , R 11a ,
R 11b , R 11c ,
R 11d , R 11e ,
R 11f , R 11g ,
R 12 , R 12a ,
R 12b , R 12c ,
R 12d , R 12e , and
R 12f are, independently from each other, hydrogen, —C(O)R 13f , or —S(O) 2 R 14f , or are selected from —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —(CH 2 ) x -aryl and —(CH 2 ) x -heteroaryl, wherein said R 11 , R 11a , R 11b , R 11c , R 11d , R 11e , R 11g , R 12 , R 12a , R 12b , R 12c , R 12d , R 12e , are in each case unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —OR 11f , —NR 11f R 12f , C 1 -C 6 -haloalkyl, —C 1 -C 6 -haloalkoxy, —C 1 -C 6 -alkylthio, —C(O)OR 18 , —C(O)NR 18 R 18a , or —S(O) 2 NR 18 R 18a , and R 11f and R 12f are in each case unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, —C 1 -C 6 -haloalkoxy, —C 1 -C 6 -alkylthio, —C(O)OR 18 , —C(O)NR 18 R 18a , or —S(O) 2 NR 18 R 18a , or substituted one time with —OR 11f or —NR 11f R 12f ; or
R 11 and R 12 ,
R 11a and R 12a ,
R 11b and R 12b ,
R 11c and R 12c ,
R 11d and R 12d ,
R 11e and R 12e ,
and
R 12f and R 12f independently from each other, together with the nitrogen atom to which they are attached in groups —NR 11 R 12 , —NR 11a R 12a , —NR 11b R 12b , —NR 11c R 12c , —NR 11d R 12d , NR 11e R 12e , and —NR 11f R 12f , and each form a 3 to 10 membered heterocycloalkyl ring, wherein the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group —NR 11g —, —O, S, C(O)—, —S(O)—, and —S(O) 2 —, and optionally contains one or more double bonds;
R 13 , R 13a ,
R 13b , R 13c ,
R 13e ,
and R 13f are each, independently from each other, hydrogen, hydroxy or —NR 19 R 20 , or are each, independently from each other, selected from —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 3 -C 10 -cycloalkyl, and —C 3 -C 10 -heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, aryl, or heteroaryl, wherein aryl or heteroaryl are each unsubstituted or substituted one or more times with halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 1 -C 6 -haloalkyl, or —C 1 -C 6 -haloalkoxy;
R 14 , R 14a ,
R 14b , R 14c ,
and R 14f are each, independently from each other, hydrogen or —NR 19a R 20a , or are each, independently from each other, selected from —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, and —C 3 -C 10 -heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, aryl, or heteroaryl, wherein aryl or heteroaryl are each unsubstituted or substituted one or more times with halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 1 -C 6 -haloalkyl, or —C 1 -C 6 -haloalkoxy;
R 15 , R 16 ,
and R 17 are each, independently from each other, —C 1 -C 6 -alkyl or phenyl;
R 18 and R 18a are each, independently from each other, hydrogen, or are selected each from —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —(CH 2 ) y -aryl, and —(CH 2 ) y -heteroaryl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, or —C 1 -C 6 -haloalkyl; or
R 18 and R 18a , together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocycloalkyl ring, wherein the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group —NR 11g —, —O—, —S—, —C(O)—, —S(O)—, and —S(O) 2 —, and optionally contains one or more double bonds;
R 19 , R 19a ,
R 20 ,
and R 20a are each, independently from each other, hydrogen, —C 1 -C 6 -alkyl or —(CH 2 ) z -phenyl;
m is 1 or 2;
r is 2;
s and t are each, independently from each other, 0, 1, or 2;
n is 0 or 1;
p, q,
u, v, x
y and z are each, independently from each other, 0, 1, 2, 3 or 4,
wherein when m is 2, each of the R 1 substituents are independent of each other.
3. A compound according to claim 1 , wherein:
A is phenylene;
E is phenylene or a five- or six-membered heteroarylene;
G is selected from —C(O)NR 9 —, —S(O) 2 —, and —C(O)—Y—;
X is selected from —O—, —S—, and —NR 10 —;
Y is selected from —C 1 -C 6 -alkylene and —C 3 -C 8 -cycloalkylene;
R 1 is hydrogen;
R 2 is hydrogen or —C(O)R 13a , or is selected from —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, and —(CH 2 ) s -aryl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, C 1 -C 6 alkyl, OR 11a , —NR 11a R 12a , or —C 1 -C 6 -haloalkyl;
R 3 is selected from a group comprising, preferably consisting of —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, and —(CH 2 ) t -aryl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, or —C 1 -C 6 -haloalkyl;
R 4 is selected from —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —(CH 2 ) u -aryl and —(CH 2 ) u -heteroaryl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —OR 11c , —NR 11c R 12c , —C 1 -C 6 -haloalkyl, —C(O)R 13c , or —S(O) 2 R 14c ;
R 5 is selected from hydrogen, methyl, fluoro, and chloro;
R 6 is hydrogen or methyl;
R 7 , R 8 are the same or different, and are each independently selected from hydrogen, halogen, nitro, cyano, —(CH 2 ) v OR 11e , —(CH 2 ) v NR 11e R 12e , C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —C 1 -C 6 -haloalkyl, —C 1 -C 6 -alkylthio, —(CH 2 ) v C(O)R 13e , —(CH 2 ) v C(O)NR 11e R 12e , and —(CH 2 ) v S(O) 2 NR 11e R 12e ;
R 9 is hydrogen or methyl;
R 10 is hydrogen;
R 11a , R 11b ,
R 11c , R 11e ,
R 11f , R 11g ,
R 12a , R 12b ,
R 12c , R 12e , and
R 12f are each, independently from each other, hydrogen, —C(O)R 13f , or —S(O) 2 R 14f , or are selected from —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, and —(CH 2 ) x -aryl, wherein R 11 , R 11a , R 11b , R 11c , R 11d , R 11e , R 11g , R 12 , R 12a , R 12b , R 12c , R 12d , R 12e , are each unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —OR 11f , —NR 11f R 12f , —C 1 -C 6 -haloalkyl, or —C 1 -C 6 -haloalkoxy, and R 11f and R 12f are each unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, or —C 1 -C 6 -haloalkoxy, or substituted one time with —OR 11f or —NR 11f R 12f ; or
R 11a and R 12a ,
R 11b and R 12b ,
R 11c and R 12c ,
R 11e and R 12e ,
and
R 12f and R 12f independently from each other, together with the nitrogen atom to which they are attached in groups —NR 11a R 12a , —NR 11b R 12b , —NR 11c R 12c , —NR 11e R 12e , and NR 11f R 12f , each form a 3 to 7 membered heterocycloalkyl ring, wherein the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group —NR 11g — and —O—;
R 13a , R 13c ,
R 13e ,
and R 13f are each, independently from each other, hydrogen, hydroxy or —NR 19 R 20 , or are, independently from each other, selected from —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 3 -C 10 -cycloalkyl, and —C 3 -C 10 -heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, or aryl, wherein aryl is unsubstituted or substituted one or more times with halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 1 -C 6 -haloalkyl, or —C 1 -C 6 -haloalkoxy;
R 14c and R 14f are each, independently from each other, hydrogen or —NR 19a R 20a , or are, independently from each other, selected from —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl and —C 3 -C 10 -heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, —C 1 -C 6 -alkyl, or aryl, wherein aryl is unsubstituted or substituted one or more times with halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 1 -C 6 -haloalkyl, or —C 1 -C 6 -haloalkoxy;
R 19 , R 19a ,
R 20 ,
and R 20a are each, independently from each other, hydrogen, —C 1 -C 6 -alkyl or —(CH 2 ) z -phenyl;
s, t and x are each, independently from each other, 0, 1, or 2;
p, q,
u, and v are each, independently from each other, 0, 1, 2, 3 or 4;
z is 0 or 1.
4. A compound according to claim 1 , wherein:
A and E are each phenylene;
G is selected from —C(O)NR 9 —, —S(O) 2 —, and —C(O)—Y—;
X is selected from —O—, —S—, and —NR 10 —;
Y is selected —C 1 -C 3 -alkylene and —C 3 -cycloalkylene;
R 1 is hydrogen;
R 2 is hydrogen, or —C(O)R 13a ;
R 3 is selected from —C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, and phenyl;
R 4 is selected from —C 1 -C 6 -alkyl, and —(CH 2 ) u -aryl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —OR 11c , or —NR 11c R 12c ;
R 5 is selected from hydrogen, methyl, fluoro, and chloro;
R 6 is hydrogen;
R 7 is selected from hydrogen, halogen, cyano, hydroxyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, —C 1 -C 6 -alkyl, and —C 1 -C 6 -haloalkyl;
R 8 is selected from hydrogen, halogen, cyano, —(CH 2 ) v OR 11e , —(CH 2 ) v NR 11e R 12e , —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —C 1 -C 6 -haloalkyl, —(CH 2 ) v C(O)R 13e , —(CH 2 ) v C(O)NR 11e R 12e and —(CH 2 ) v S(O) 2 NR 11e R 12e ;
R 9 and R 10 are each hydrogen;
R 11c , R 11e ,
R 11f , R 11g ,
R 12c , R 12e ,
and R 12f are each, independently from each other, hydrogen, or —C(O)R 13f , or are selected from —C 1 -C 6 -alkyl, and —C 3 -C 10 -cycloalkyl, wherein R 11 , R 11a , R 11b , R 11c , R 11d , R 11e , R 11g , R 12 , R 12a , R 12b , R 12c , R 12d , R 12e , are each unsubstituted or substituted one or more times, independently from each other, by halogen, —OR 11f , or —NR 11f R 12f , and R 11f and R 12f are each unsubstituted or substituted one or more times, independently from each other, with halogen, or substituted one time with —OR 11f or —NR 11f R 12f ; or
R 11c and R 12c ,
R 11e and R 12e ,
and
R 12f and R 12f independently from each other, together with the nitrogen atom to which they are attached in groups —NR 11c R 12c , —NR 11e R 12e , and —NR 11f R 12f , each form a 3 to 7 membered heterocycloalkyl ring, wherein the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group —NR 11g — and —O—;
R 13a , R 13e ,
and R 13f are each, independently from each other, hydrogen, hydroxy or —NR 19 R 20 , or are, independently from each other, selected from —C 1 -C 6 -alkyl or —C 1 -C 6 -alkoxy, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen or phenyl;
R 19 and R 20 are each, independently from each other, hydrogen, —C 1 -C 6 -alkyl or —(CH 2 ) z -phenyl;
p, q,
and z, are each, independently of each other, 0 or 1;
u, and v are each, independently of each other, 0, 1, 2, 3, or 4.
5. A compound according to claim 1 , wherein:
A and E are each phenylene;
G is selected from —C(O)NR 9 —, —S(O) 2 —, and —C(O)—Y—;
X is selected from —O—, —S—, and —NR 10 —;
Y is selected from —C 1 -C 3 -alkylene and —C 3 -cycloalkylene;
R 1 is hydrogen;
R 2 is hydrogen, or —C(O)R 13a ;
R 3 is selected from —C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, and phenyl;
R 4 is selected from —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —(CH 2 ) u -aryl and —(CH 2 ) u -heteroaryl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —OR 11c , —NR 11c R 12c , C 1 -C 6 -haloalkyl, —C(O)R 13c , or —S(O) 2 R 14c ;
R 5 is selected from hydrogen, methyl, fluoro, and chloro;
R 6 is hydrogen;
R 7 is hydrogen, halogen, C 1 -C 6 -alkyl, or C 1 -C 6 -haloalkyl;
R 8 is selected from hydrogen, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkyl, and C 1 -C 6 -haloalkoxy;
R 9 and R 10 are each hydrogen;
R 11a , R 11c ,
R 11e , R 11f ,
R 11g , R 12c ,
R 12e , R 12f are each, independently from each other, hydrogen or —C(O)R 13f , or are selected from —C 1 -C 6 -alkyl and —C 3 -C 10 -cycloalkyl, wherein R 11 , R 11a , R 11b , R 11c , R 11d , R 11e , R 11g , R 12 , R 12a , R 12b , R 12c , R 12d , R 12e , are unsubstituted or substituted one or more times, independently from each other, by halogen, —OR 11f , or —NR 11f R 12f , and wherein R 11f and R 12f are unsubstituted or substituted one or more times, independently from each other, with halogen, or substituted one time with —OR 11f or —NR 11f R 12f ; or
R 11c and R 12c ,
R 11e and R 12e ,
and
R 12f and R 12f independently from each other, together with the nitrogen atom to which they are attached in groups —NR 11c R 12c , —NR 11e R 12e , and —NR 11f R 12f , each form a 3 to 7 membered heterocycloalkyl ring, wherein the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group —NR 11g — and —O—;
R 13a , R 13e ,
and R 13f are each, independently from each other, hydrogen, hydroxy or —NR 19 R 20 , or are, independently from each other, selected from —C 1 -C 6 -alkyl, and —C 1 -C 6 -alkoxy, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen or phenyl;
R 14c is hydrogen, —NR 19a R 20a , or —C 1 -C 6 -alkyl, wherein —C 1 -C 6 -alkyl is unsubstituted or substituted one or more times with halogen or phenyl;
R 19 , R 19a ,
R 20 ,
and R 20a are each, independently from each other, hydrogen, —C 1 -C 6 -alkyl or —(CH 2 ) z -phenyl;
p, q,
and z, are each, independently of each other, 0 or 1;
u, and v are each, independently of each other, 0, 1, 2, 3, or 4.
6. A compound according to claim 1 , wherein:
A and E are each phenylene;
G is selected from —C(O)NR 9 —, —S(O) 2 —, and —C(O)—Y—;
X is —S— or —NR 10 —;
Y is C 3 -cycloalkylene;
R 1 is hydrogen;
R 2 is hydrogen or —C(O)OC 2 H 5 ;
R 3 is methyl;
R 4 is C 1 -C 6 -alkyl, which is unsubstituted or substituted one or more times, independently from each other, by —C 3 -C 10 -heterocycloalkyl, —OR 11c or —NR 11c R 12c ;
R 5 is hydrogen or fluoro;
R 6 is hydrogen;
R 7 is hydrogen or halogen;
R 8 is selected from hydrogen, halogen, —C 1 -C 3 -alkyl, and C 1 -C 3 -haloalkyl;
R 9 and R 10 are each hydrogen;
R 11c and R 12c are each, independently from each other, hydrogen or C 1 -C 6 -alkyl; or together with the nitrogen atom to which they are attached, form a 5- to 6-membered heterocycloalkyl ring, wherein the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group —NCH 3 — and —O—;
p, q are each 0.
7. A compound according to claim 1 , wherein said compound is selected from:
N-{4-[2-({4-[(RS)-N-(Ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[(R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-5-yl]phenyl}-1-phenylcyclopropanecarboxamide;
2,3-Dichloro-N-{4-[2-({3-[(RS)-N-(ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[(R)-2-hydroxy-1-methylethyl]amino}pyrimidin-5-yl]-phenyl}benzenesulfonamide;
N-{4-[2-({4-[(RS)-N-(Ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[(R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-5-yl]-phenyl}benzene-sulfonamide;
2,3-Dichloro-N-{4-[2-({4-[(RS)-N-(ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[(R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-5-yl]-phenyl}benzene-sulfonamide;
2,3-Dichloro-N-{4-[2-({4-[(RS)-N-(ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[(R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-5-yl]-2-fluorophenyl}-benzenesulfonamide;
1-{4-[2-({4-[(RS)-N-(Ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[(R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-5-yl]-phenyl}-3-[phenyl]urea;
1-{4-[2-({4-[(RS)-N-(Ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[(R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-5-yl]-phenyl}-3-[3-(trifluoromethyl)-phenyl]urea;
1-{4-[2-({3-[(RS)-N-(Ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[(R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
N-{4-[2-({3-[(RS)-N-(Ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[(R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-5-yl]phenyl}-1-phenylcyclopropane-carboxamide;
1-{4-[2-({3-[(RS)-N-(Ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[(R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-5-yl]-phenyl}-3-[3-(trifluoromethyl)-phenyl]urea;
N-{4-[2-({3-[(RS)-N-(Ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[(R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-5-yl]-phenyl}benzene-sulfonamide;
1-{4-[2-({3-[(RS)-N-(Ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[(R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-5-yl]-phenyl}-3-[phenyl]urea;
2,3-Dichloro-N-{4-[2-({3-[(RS)-N-(ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[(R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-5-yl]-2-fluorophenyl}-benzenesulfonamide;
1-{4-[4-{[(R)-2-hydroxy-1-methylethyl]amino}-2-({3-[(RS)-N-(isopropylcarbamoyl)-S-methylsulfonimidoyl]phenyl}amino)-pyrimidin-5-yl]phenyl}-3-[3-(trifluoromethyl)-phenyl]urea;
N-{4-[4-{[(R)-2-hydroxy-1-methylethyl]amino}-2-({3-[(RS)-N-(isopropylcarbamoyl)-S-methylsulfonimidoyl]phenyl}amino)-pyrimidin-5-yl]phenyl}-1-[3-(trifluoromethyl)-phenyl]cyclopropanecarboxamide;
2,3-dichloro-N-{4-[4-{[(1R)-2-hydroxy-1-methylethyl]amino}-2-({3-[(RS)-N-(isopropylcarbamoyl)-S-methylsulfonimidoyl]phenyl}amino)-pyrimidin-5-yl]phenyl}benzene-sulfonamide;
1-{4-[2-({3-[(RS)-N-(Ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-(methylsulfanyl)pyrimidin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea;
2,3-Dichloro-N-{4-[2-({3-[(RS)-N-(ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-(methoxy)-pyrimidin-5-yl]-2-fluorophenyl}-benzenesulfonamide;
N-{4-[4-{[(R)-2-Hydroxy-1-methylethyl]amino}-2-({3-[(RS)-S-methylsulfonimidoyl]phenyl}amino)pyrimidin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea;
N-[4-(4-{[(R)-2-hydroxy-1-methylethyl]amino}-2-{[4-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl)phenyl]benzene-sulfonamide;
1-[4-(4-{[(R)-2-hydroxy-1-methylethyl]amino}-2-{[4-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl)phenyl]-3-phenylurea;
1-[4-(4-{[(R)-2-hydroxy-1-methylethyl]amino}-2-{[4-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl)phenyl]-3-[3-(trifluoromethyl)-phenyl]urea;
2,3-dichloro-N-[2-fluoro-4-(4-{[(R)-2-hydroxy-1-methylethyl]amino}-2-{[4-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl)phenyl]benzene-sulfonamide;
2,3-dichloro-N-[4-(4-{[(R)-2-hydroxy-1-methylethyl]amino}-2-{[4-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl)-phenyl]benzene-sulfonamide;
1-{4-[2-({3-[(RS)-N-(Ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[2-(pyrrolidin-1-yl)ethyl]amino}pyrimidin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea;
1-{4-[4-{[2-N,N-(Dimethylamino)ethyl]amino}2-({3-[(RS)-N-(ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)pyrimidin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
1-{4-[2-({3-[(RS)-N-(Ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[2-(N-methyl-piperazin-4-yl)ethyl]amino}pyrimidin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
1-{4-[2-({3-[(RS)-N-(Ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[2-(morpholin-4-yl)ethyl]amino}pyrimidin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
1-{4-[2-({3-[(RS)-N-(Ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-{[3-(morpholin-4-yl)propyl]amino}pyrimidin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
1-{4-[2-({3-[(RS)-N-(Ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}amino)-4-(methoxy)-pyrimidin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
N-{4-[4-{[(R)-2-Hydroxy-1-methylethyl]amino}-2-({4-[(RS)-S-methylsulfonimidoyl]phenyl}amino)pyrimidin-5-yl]phenyl}-1-phenylcyclopropanecarboxamide;
N-{4-[4-{[(R)-2-Hydroxy-1-methylethyl]amino}-2-({3-[(RS)-S-methylsulfonimidoyl]phenyl}amino)pyrimidin-5-yl]phenyl}-1-phenylcyclopropanecarboxamide;
1-{4-[2-({3-[(RS)-S-Methylsulfonimidoyl]phenyl}amino)-4-{[2-(pyrrolidin-1-yl)ethyl]amino}pyrimidin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
1-[4-(4-{[2-(Dimethylamino)ethyl]amino}-2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl)-2-fluorophenyl]-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
1-[2-Fluoro-4-(4-{[2-(4-methylpiperazin-1-yl)ethyl]amino}-2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
1-[2-Fluoro-4-(2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-4-[(2-morpholin-4-ylethyl)amino]-pyrimidin-5-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
2,3-Dichloro-N-[4-(4-{[(R)-2-hydroxy-1-methylethyl]amino}-2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl)phenyl]benzene-sulfonamide;
1-[4-(4-{[(R)-2-Hydroxy-1-methylethyl]amino}-2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl)phenyl]-3-[3-(trifluoromethyl)-phenyl]urea;
N-[4-(4-{[(R)-2-Hydroxy-1-methylethyl]amino}-2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl)phenyl]benzene-sulfonamide;
1-[4-(4-{[(R)-2-Hydroxy-1-methylethyl]amino}-2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl)phenyl]-3-phenylurea;
2,3-Dichloro-N-[2-fluoro-4-(4-{[(R)-2-hydroxy-1-methylethyl]amino}-2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl)phenyl]benzene-sulfonamide;
1-[2-Fluoro-4-(2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-4-[(3-morpholin-4-ylpropyl)amino]-pyrimidin-5-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
1-{2-Fluoro-4-[2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-4-(methylthio)-pyrimidin-5-yl]phenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
1-[2-Fluoro-4-(4-methoxy-2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]-amino}pyrimidin-5-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea;
2,3-Dichloro-N-[2-fluoro-4-(4-methoxy-2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}pyrimidin-5-yl)phenyl]benzenesulfonamide;
1-{2-Fluoro-4-[2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-4-(prop-2-yn-1-ylamino)pyrimidin-5-yl]phenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
1-[2-Fluoro-4-(2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-4-[(2-phenylethyl)amino]-pyrimidin-5-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
1-{2-Fluoro-4-[4-(methylamino)-2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl]phenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
1-{4-[4-(Dimethylamino)-2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
1-{4-[4-(Ethylamino)-2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea;
1-[4-(4-[(Cyanomethyl)-amino]-2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl)-2-fluorophenyl]-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea; and
1-[2-Fluoro-4-(4-[(2-furylmethyl)amino]-2-{[3-(RS)-(S-methylsulfonimidoyl)phenyl]amino}-pyrimidin-5-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea; and
salts thereof.
8. A compound of formula Ib:
in which
R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , A, E, G, m, p, and q are as defined in claim 1 ,
w is 1 or 2, and
R 4 is —C 1 -C 6 -alkyl or —(CH 2 ) u -aryl.
9. A compound according to claim 1 , wherein:
A is phenylene;
E is phenylene or pyridinyl;
G is selected from —C(O)NH—, —C(O)N(CH 3 )—, —S(O) 2 —, and —C(O)—Y—;
X is selected from —O—, —S—, —NH—, and —N(CH 3 )—;
Y is —C 3 -C 8 -cycloalkylene;
R 1 is hydrogen;
R 5 is hydrogen or halogen, —C 1 -C 6 -alkyl, —OR 11d , and —NR 11d R 12d ;
R 6 is hydrogen or —C 1 -C 6 -alkyl;
R 7 , R 8 are the same or different, and are independently selected from hydrogen, halogen, nitro, cyano, —(CH 2 ) v OR 11e , —(CH 2 ) v NR 11e R 12e , —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, —C 1 -C 6 -haloalkyl, —C 1 -C 6 -alkylthio, —(CH 2 ) v C(O)R 13e , —(CH 2 ) v C(O)NR 11e R 12e and —(CH 2 ) v S(O) 2 NR 11e R 12e ;
R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g , R 12a , R 12b , R 12c , R 12d , R 12e , and R 12f are, independently from each other, hydrogen, —C(O)R 13f , or —S(O) 2 R 14f , or are selected from —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —(CH 2 ) x -aryl and —(CH 2 ) x -heteroaryl,
wherein said R 11 , R 11a , R 11b , R 11c , R 11d , R 11e , R 11g , R 12 , R 12a , R 12b , R 12c , R 12d , R 12e , are in each case unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —OR 11f , —NR 11f R 12f , —C 1 -C 6 -haloalkyl, —C 1 -C 6 -haloalkoxy, —C 1 -C 6 -alkylthio, —C(O)OR 18 , —C(O)NR 18 R 18a , or —S(O) 2 NR 18 R 18a , and
R 11f and R 12f are in each case unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, —C 1 -C 6 -haloalkoxy, —C 1 -C 6 -alkylthio, —C(O)OR 18 , —C(O)NR 18 R 18a , or —S(O) 2 NR 18 R 18a ;
R 13a , R 13b , R 13c , R 13e , and R 13f are each, independently from each other, hydrogen, hydroxy or —NR 19 R 20 , or are each, independently from each other, selected from —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, and —C 3 -C 10 -cycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, or aryl, wherein aryl is unsubstituted or substituted one or more times with halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 1 -C 6 -haloalkyl, or —C 1 -C 6 -haloalkoxy;
R 14a , R 14b , R 14c , and R 14f are each, independently from each other, hydrogen or —NR 19a R 20a , or are each, independently from each other, selected from —C 1 -C 6 -alkyl, and —C 3 -C 10 -cycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, or aryl, wherein aryl is unsubstituted or substituted one or more times with halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 1 -C 6 -haloalkyl, or —C 1 -C 6 -haloalkoxy;
R 18 and R 18a are each, independently from each other, hydrogen, or are selected each from —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, and —(CH 2 ) y -aryl, which in each case is unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, or —C 1 -C 6 -haloalkyl;
R 19 , R 19a , R 20 , and R 20a are each, independently from each other, hydrogen, —C 1 -C 6 -alkyl or —(CH 2 ) z -phenyl; and
p and q are each 0.
10. A compound according to claim 1 , wherein
R 11 , R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g , R 12 , R 12a , R 12b , R 12c , R 12d , R 12e , and R 12f are each, independently from each other, hydrogen, —C(O)R 13f , or —S(O) 2 R 14f , or are selected from —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —(CH 2 ) x -aryl and —(CH 2 ) x -heteroaryl,
wherein R 11 , R 11a , R 11b , R 11c , R 11d , R 11e , R 11g , R 12 , R 12a , R 12b , R 12c , R 12d , R 12e , are in each case unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —OR 11f , —NR 11f R 12f , —C 1 -C 6 -haloalkyl, —C 1 -C 6 -haloalkoxy, —C 1 -C 6 -alkylthio, —C(O)OR 18 , —C(O)NR 18 R 18a , or —S(O) 2 NR 18 R 18a , and
wherein R 11f and R 12f are in each case unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, —C 1 -C 6 -haloalkoxy, —C 1 -C 6 -alkylthio, —C(O)OR 18 , —C(O)NR 18 R 18a , or —S(O) 2 NR 18 R 18a ; or
R 11 and R 12 , R 11a and R 12a , R 11b and R 12b , R 11c and R 12c , R 11d and R 12d , R 11e and R 12e , and R 12f and R 12f independently from each other, together with the nitrogen atom to which they are attached in groups —NR 11 R 12 , —NR 11a R 12a , —NR 11b R 12b , —NR 11c R 12c , —NR 11d R 12d , NR 11e R 12e , and —NR 11f R 12f , each form a 3 to 10 membered heterocycloalkyl ring, wherein the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group —NR 11g —, —O—, —S—, —C(O)—, —S(O)—, and —S(O) 2 —, and optionally contains one or more double bonds.
11. A compound according to claim 2 ,
wherein
R 11 , R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g , R 12 , R 12a , R 12b , R 12c , R 12d , R 12e , and R 12f are, independently from each other, hydrogen, —C(O)R 13f , or —S(O) 2 R 14f , or are selected from —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 10 -heterocycloalkyl, —(CH 2 ) x -aryl and —(CH 2 ) x -heteroaryl,
wherein said R 11 , R 11a , R 11b , R 11c , R 11d , R 11e , R 11g , R 12 , R 12a , R 12b , R 12c , R 12d , R 12e , are in each case unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —OR 11f , —NR 11f R 12f , —C 1 -C 6 -haloalkyl, —C 1 -C 6 -haloalkoxy, —C 1 -C 6 -alkylthio, —C(O)OR 18 , —C(O)NR 18 R 18a , or —S(O) 2 NR 18 R 18a , and
wherein R 11f and R 12f are in each case unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, —C 1 -C 6 -haloalkoxy, —C 1 -C 6 -alkylthio, —C(O)OR 18 , —C(O)NR 18 R 18a , or —S(O) 2 NR 18 R 18a , or substituted one time with —OR 11f or —NR 11f R 12f ; or
R 11 and R 12 , R 11a and R 12a , R 11b and R 12b , R 11c and R 12c , R 11d and R 12d , R 11e and R 12e , and R 12f and R 12f independently from each other, together with the nitrogen atom to which they are attached in groups —NR 11 R 12 , —NR 11a R 12a , —NR 11b R 12b , —NR 11c R 12c , —NR 11d R 12d , NR 11e R 12e , and —NR 11f R 12f , each form a 3 to 10 membered heterocycloalkyl ring, wherein the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group —NR 11g —, —O—, —S—, —C(O)—, —S(O)—, and —S(O) 2 —, and optionally contains one or more double bonds.
12. A compound according to claim 3 ,
wherein
R 11a , R 11b , R 11c , R 11e , R 11f , R 11g , R 12a , R 12b , R 12c , R 12e , and R 12f are, are each independently from each other, hydrogen, —C(O)R 13f , or —S(O) 2 R 14f , or are selected from —C 1 -C 6 -alkyl, —C 3 -C 10 -cycloalkyl, and —(CH 2 ) x -aryl,
wherein R 11a , R 11b , R 11c , R 11d , R 11e , R 11g , R 12 , R 12a , R 12b , R 12c , R 12d , R 12e , are each unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —OR 11f , —NR 11f R 12f , —C 1 -C 6 -haloalkyl, or —C 1 -C 6 -haloalkoxy, and
wherein R 11f and R 12f are each unsubstituted or substituted one or more times, independently from each other, by halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, or —C 1 -C 6 -haloalkoxy, or substituted one time with —OR 11f or —NR 11f R 12f ; or
R 11a and R 12a , R 11b and R 12b , R 11c and R 12c , R 11e and R 12e , and R 12f and R 12f independently from each other, together with the nitrogen atom to which they are attached in groups —NR 11a R 12a , —NR 11b R 12b , —NR 11c R 12c , —NR 11e R 12e , and NR 11f R 12f , each form a 3 to 7 membered heterocycloalkyl ring, wherein the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group —NR 11g — and —O—.
13. A compound according to claim 4 ,
wherein
R 11c , R 11e , R 11f , R 11g , R 12c , R 12e , and R 12f are each, independently from each other, hydrogen, or —C(O)R 13f , or are selected from —C 1 -C 6 -alkyl, and —C 3 -C 10 -cycloalkyl,
wherein R 11c , R 11d , R 11e , R 11g , R 12c , and R 12e , are each unsubstituted or substituted one or more times, independently from each other, by halogen, —OR 11f , or —NR 11f R 12f , and
wherein R 11f and R 12f are each unsubstituted or substituted one or more times, independently from each other, with halogen, or substituted one time with —OR 11f or —NR 11f R 12f ; or
R 11c and R 12c , R 11e and R 12e , and R 12f and R 12f independently from each other, together with the nitrogen atom to which they are attached in groups —NR 11c R 12c , —NR 11e R 12e , and —NR 11f R 12f , each form a 3 to 7 membered heterocycloalkyl ring, wherein the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group —NR 11g — and —O—.
14. A compound according to claim 5 ,
wherein
R 11a , R 11c , R 11e , R 11f , R 11g , R 12c , R 12e , and R 12f are each, independently from each other, hydrogen or —C(O)R 13f , or are selected from —C 1 -C 6 -alkyl and —C 3 -C 10 -cycloalkyl,
wherein R 11a , R 11c , R 11e , R 11g , R 12c , and R 12e are unsubstituted or substituted one or more times, independently from each other, by halogen, —OR 11f , or —NR 11f R 12f , and
wherein R 11f and R 12f are unsubstituted or substituted one or more times, independently from each other, with halogen, or substituted one time with —OR 11f or —NR 11f R 12f ; or
R 11c and R 12c , R 11e and R 12e , and R 12f and R 12f independently from each other, together with the nitrogen atom to which they are attached in groups —NR 11c R 12c , —NR 11e R 12e , and —NR 11f R 12f , each form a 3 to 7 membered heterocycloalkyl ring, wherein the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group —NR 11g — and —O—.
15. A compound according to claim 1 , wherein said compound is of one of the following formulas:
16. A compound according to claim 1 , wherein heterocycloalkyl is, in each case, oxyranyl, oxetanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl or chinuclidinyl.
17. A compound according to claim 1 , wherein heteroaryl is, in each case, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, azocinyl, indolizinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl.
18. A method of preparing a compound according to claim 1 , wherein said method comprises:
reacting an intermediate compound of formula 5:
with an intermediate of formula 6:
to provide a compound of formula I:
19. A method of preparing a compound according to claim 1 , wherein said method comprises:
reacting an intermediate compound of formula I′:
with an intermediate of formula 14a:
to provide a compound of formula I:
wherein Elph is an electrophilic group suitable to act as a precursor of G.
20. A method of preparing a compound according to claim 1 , wherein said method comprises:
reacting an intermediate compound of formula Ib
wherein
w is 1 or 2,
R 4 forms, together with the —S(O) w — to which it is attached, a leaving group, with an intermediate of formula 7a:
HXR 4 7a,
to provide a compound of formula I:
21. A method according to claim 19 , wherein Elph is HOC(O)—Y—, ClS(O) 2 —, or OCN—.
22. A method according to claim 20 , wherein R 4 is —C 1 -C 6 -alkyl or —(CH 2 ) u -aryl.
23. A pharmaceutical composition comprising a compound according to claims 1 and a pharmaceutically-acceptable diluent or carrier.