Heteroaryl-substituted arylaminopyridine derivatives as MEK inhibitors
View Patent ↗The invention provides novel heteroaryl-substituted arylaminopyridine derivative MEK inhibitors of Formula (Ia) Such compounds are MEK inhibitors that are useful in the treatment of hyperproliferative diseases, such as cancer and inflammation. Also disclosed is the treatment of a hyperproliferative disease in mammals, and pharmaceutical compositions containing such compounds.
1. A compound of Formula (I),
as well as tautomers- and pharmaceutically acceptable salts thereof, wherein:
Y is independently selected from NR′, CR′, S or O, whereby at least one Y is NR′;
R 1 is selected from hydrogen, trimethylsilyl, C 1 -C 6 -alkyl, OR 6 , C(O)OR 6 , NR 7 R 8 , SR 6 , NR 7 S(O)(O)R′, NR 7 C(O)R 6 , NR 7 C(O)NR 7 R 6 , NR 7 C(O)OR 6 , NR 7 C(O)C(O)OR 6 , C 1 -C 4 -alkyl-NR′R″, C 1 -C 4 -alkyl-heterocycloalkyl or C 1 -C 4 alkyl-(OR′) n ;
R 2 is halogen;
R 3 is selected from Cl, F or I;
R 4 and R 5 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein said alkyl or alkoxy is substituted or unsubstituted;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′, C 1 -C 4 -alkyl-NR′R″, C 1 -C 4 -alkyl-heterocycloalkyl, C 1 -C 4 alkyl-(OR′) n or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, and alkyl-heterocycloalkyl is substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 4 to 10-membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted;
R′ and R″ are independently selected from hydrogen, C 1 -C 6 -alkyl or aryl, wherein said alkyl or aryl is substituted or unsubstituted; or
R′ and R″ can be taken together with the atom to which they are attached to form a 4 to 10-membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted; and
n is 0 to 2.
2. The compound according to claim 1 , wherein:
R 1 is selected from hydrogen, trimethylsilyl, OR 6 , NR 7 R 8 , NR 7 C(O)R 6 , NR 7 C(O)OR 6 , or C 1 -C 4 alkyl-(OR′) n ;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′, C 1 -C 4 -alkyl-NR′R″, C 1 -C 4 -alkyl-heterocycloalkyl, or C 1 -C 4 alkyl-C(O)NR′R″; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 6-membered heterocyclic ring with 1 or 2 N atoms and optionally an O atom; and
R′ and R″ are either hydrogen or C 1 -C 6 -alkyl; or
R′ and R″ can be taken together with the atom to which they are attached to form a 6-membered heterocyclic ring with 1 or 2 N atoms and optionally an O atom.
3. The compound according to claim 1 wherein:
R 1 is selected from hydrogen, C 1 -C 6 -alkyl, OR 6 , NR 7 R 8 , SR 6 , NR 7 S(O)(O)R′, NR 7 C(O)R 6 , NR 7 C(O)NR 7 R 6 , or NR 7 C(O)OR 6 ;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′ or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 4 to 10-membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted; and
R′ and R″ are independently selected from hydrogen, C 1 -C 6 -alkyl or aryl, wherein said alkyl or aryl is substituted or unsubstituted.
4. The compound according to claim 3 , wherein:
R 1 is selected from OR 6 , NR 7 R 8 or SR 6 ;
R 2 is selected from F, Cl, I or Br;
R 3 is selected from F, Cl or I;
R 4 and R 5 are independently either hydrogen or C 1 -C 6 alkyl;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′ or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl is substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 6-membered heterocyclic ring with 1 or 2 N atoms and optionally an O atom, which is substituted or unsubstituted; and
R′ and R″ are either hydrogen or C 1 -C 6 -alkyl.
5. The compound according to claim 4 , wherein:
R 2 is F;
R 3 is I;
R 4 and R 5 are hydrogen;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′ or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl is substituted or unsubstituted; or
R 7 and R 8 form a 6-membered heterocyclic ring with 1 or 2 N atoms and optionally an 0 atom, which is substituted or unsubstituted.
6. A compound of Formula (II),
as well as tautomers and pharmaceutically acceptable thereof, wherein:
Y is either NR′ or O;
R 1 is selected from hydrogen, C 1 -C 6 -alkyl, OR 6 , NR 7 R 8 , SR 6 , NR 7 S(O)(O)R′, NR 7 C(O)R 6 , NR 7 C(O)NR 7 R 6 , or NR 7 C(O)OR 6 ;
R 2 is halogen;
R 3 is selected from Cl, F or I;
R 4 and R 5 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein said alkyl or alkoxy is substituted or unsubstituted;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′ or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 4 to 10-membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted; and
R′ and R″ are independently selected from hydrogen, C 1 -C 6 -alkyl or aryl, wherein said alkyl or aryl is substituted or unsubstituted.
7. A compound according to claim 6 , wherein:
R 1 is selected from OR 6 , NR 7 R 8 or SR 6 ;
R 2 is selected from F, Cl, I or Br;
R 3 is selected from F, Cl or I;
R 4 and R 5 are independently either hydrogen or C 1 -C 6 alkyl;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′ or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl is substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 6-membered heterocyclic ring with 1 or 2 N atoms and optionally an O atom, which is substituted or unsubstituted; and
R′ and R″ are either hydrogen or C 1 -C 6 -alkyl.
8. The compound according claim 7 , wherein:
R 2 is F;
R 3 is I;
R 4 and R 5 are hydrogen;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′ or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl is substituted or unsubstituted; or
R 7 and R 8 form a 6-membered heterocyclic ring with 1 or 2 N atoms and optionally an 0 atom, which is substituted or unsubstituted.
9. A compound of Formula (IIa) or Formula (IIb),
as well as tautomers and pharmaceutically acceptable salts thereof, wherein:
R 1 is selected from hydrogen, trimethylsilyl, C 1 -C 6 -alkyl, OR 6 , C(O)OR 6 , NR 7 R 8 , SR 6 , NR 7 S(O)(O)R′, NR 7 C(O)R 6 , NR 7 C(O)NR 7 R 6 , NR 7 C(O)OR 6 , NR 7 C(O)C(O)OR 6 , C 1 -C 4 -alkyl-NR′R″, C 1 -C 4 -alkyl-heterocycloalkyl or C 1 -C 4 alkyl-(OR′) n ;
R 2 is selected from halogen, C 1 -C 6 -alkyl or OR 6 ;
R 3 is halogen, trimethylsilyl, C 1 -C 6 -alkyl or OR 6 ;
R 4 and R 5 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein said alkyl or alkoxy is substituted or unsubstituted;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′, C 1 -C 4 -alkyl-NR′R″, C 1 -C 4 -alkyl-heterocycloalkyl, C 1 -C 4 alkyl-(OR′) n or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, and alkyl-heterocycloalkyl is substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 4 to 10-membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted;
R′ and R″ are independently selected from hydrogen, C 1 -C 6 -alkyl or aryl, wherein said alkyl or aryl is substituted or unsubstituted; or
R′ and R″ can be taken together with the atom to which they are attached to form a 4 to 10-membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted; and
n is 0 to 2.
10. The compound according to claim 9 , wherein:
R 1 is selected from hydrogen, trimethylsilyl, OR 6 , NR 7 R 8 , NR 7 C(O)R 6 , NR 7 C(O)OR 6 , or C 1 -C 4 alkyl-(OR′) n ;
R 2 is selected from F or Cl;
R 3 is I;
R 4 and R 5 are hydrogen;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′, C 1 -C 4 -alkyl-NR′R″, C 1 -C 4 -alkyl-heterocycloalkyl, or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl and alkyl-heterocycloalkyl is substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 6-membered heterocyclic ring with 1 or 2 N atoms and optionally an O atom, which is substituted or unsubstituted; and
R′ and R″ are either hydrogen or C 1 -C 6 -alkyl; or
R′ and R″ can be taken together with the atom to which they are attached to form a 6-membered heterocyclic ring with 1 or 2 N atoms and optionally an O atom, which is substituted or unsubstituted.
11. A compound of Formula (III)
as well as tautomers and pharmaceutically acceptable salts thereof, wherein:
Y is either O, or NR';
R 1 is selected from hydrogen, C 1 -C 6 -alkyl, OR 6 , NR 7 R 8 or SR 6 or NR 7 S(O)(O)R′;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′, C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 4 to 10 membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted; and
R′ and R″ are independently selected from hydrogen, C 1 -C 6 -alkyl or aryl, wherein said alkyl or aryl is substituted or unsubstituted.
12. A compound according to claim 11 , wherein:
R 1 is selected from OR 6 , NR 7 R 8 or SR 6 ;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′ or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl is substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 6 membered heterocyclic ring with 1 or 2 N atoms and optionally an O atom, which is substituted or unsubstituted; and
R′ and R″ are independently either hydrogen or C 1 -C 6 -alkyl.
13. A compound of Formula (IIIa) or Formula (IIIb)
as well as tautomers and pharmaceutically acceptable salts thereof, wherein:
R 1 is selected from hydrogen, trimethylsilyl, C 1 -C 6 -alkyl, OR 6 , C(O)OR 6 , NR 7 R 8 , SR 6 , NR 7 S(O)(O)R′, NR 7 C(O)R 6 , NR 7 C(O)NR 7 R 6 , NR 7 C(O)OR 6 , NR 7 C(O)C(O)OR 6 , C 1 -C 4 -alkyl-NR′R″, C 1 -C 4 -alkyl-heterocycloalkyl or C 1 -C 4 alkyl-(OR′) n ;
R 4 and R 5 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein said alkyl or alkoxy is substituted or unsubstituted;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′, C 1 -C 4 -alkyl-NR′R″, C 1 -C 4 -alkyl-heterocycloalkyl, C 1 -C 4 alkyl-(OR′) n or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, and alkyl-heterocycloalkyl is substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 4 to 10-membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted;
R′ and R″ are independently selected from hydrogen, C 1 -C 6 -alkyl or aryl, wherein said alkyl or aryl is substituted or unsubstituted; or
R′ and R″ can be taken together with the atom to which they are attached to form a 4 to 10-membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted; and
n is 0 to 2.
14. The compound according to claim 13 , wherein:
R 1 is selected from hydrogen, trimethylsilyl, OR 6 , NR 7 R 8 , NR 7 C(O)R 6 , NR 7 C(O)OR 6 , or C 1 -C 4 alkyl-(OR′) n ;
R 4 and R 5 are hydrogen;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′, C 1 -C 4 -alkyl-NR′R″, C 1 -C 4 -alkyl-heterocycloalkyl, or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl and alkyl-heterocycloalkyl is substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 6-membered heterocyclic ring with 1 or 2 N atoms and optionally an O atom, which is substituted or unsubstituted; and
R′ and R″ are either hydrogen or C 1 -C 6 -alkyl; or
R′ and R″ can be taken together with the atom to which they are attached to form a 6-membered heterocyclic ring with 1 or 2 N atoms and optionally an O atom, which is substituted or unsubstituted.
15. The compound according to claim 13 , wherein:
R 1 is selected from hydrogen, C 1 -C 6 -alkyl, OR 6 , NR 7 R 8 or SR 6 or NR 7 S(O)(O)R′;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′, C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 4 to 10 membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted; and
R′ and R″ are independently selected from hydrogen, C 1 -C 6 -alkyl or aryl, wherein said alkyl or aryl is substituted or unsubstituted.
16. The compound according to claim 15 , wherein:
R 1 is selected from OR 6 , NR 7 R 8 or SR 6 ;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′ or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl is substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 6 membered heterocyclic ring with 1 or 2 N atoms and optionally an O atom, which is substituted or unsubstituted; and
R′ and R″ are independently either hydrogen or C 1 -C 6 -alkyl.
17. A compound of Formulae (IVa) or (IVb)
as well as tautomers and pharmaceutically acceptable salts thereof, wherein:
R 1 is selected from hydrogen, C 1 -C 6 -alkyl, OR 6 , NR 7 R 8 or SR 6 or NR 7 S(O)(O)R′;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′ or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 4 to 10-membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted; and
R′ and R″ are independently selected from hydrogen, C 1 -C 6 -alkyl or aryl, wherein said alkyl or aryl is substituted or unsubstituted.
18. A compound according to claim 17 , wherein:
R 1 is selected from OR 6 , NR 7 R 8 or SR 6 ;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′ or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl is substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 6-membered heterocyclic ring with 1 or 2 N atoms and optionally an O atom, which is substituted or unsubstituted; and
R′ and R″ are independently either hydrogen or C 1 -C 6 -alkyl.
19. A compound of Formulae (IVa) or (IVb)
as well as tautomers and pharmaceutically acceptable salts thereof, wherein:
R 1 is selected from hydrogen, trimethylsilyl, C 1 -C 6 -alkyl, OR 6 , C(O)OR 6 , NR 7 R 8 , SR 6 , NR 7 S(O)(O)R′, NR 7 C(O)R 6 , NR 7 C(O)NR 7 R 6 , NR 7 C(O)OR 6 , NR 7 C(O)C(O)OR 6 , C 1 -C 4 -alkyl-NR′R″, C 1 -C 4 -alkyl-heterocycloalkyl or C 1 -C 4 alkyl-(OR′) n ;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′, C 1 -C 4 -alkyl-NR′R″, C 1 -C 4 -alkyl-heterocycloalkyl, C 1 -C 4 alkyl-(OR′) n or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, and alkyl-heterocycloalkyl is substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 4 to 10-membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted;
R′ and R″ are independently selected from hydrogen, C 1 -C 6 -alkyl or aryl, wherein said alkyl or aryl is substituted or unsubstituted; or
R′ and R″ can be taken together with the atom to which they are attached to form a 4 to 10-membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted; and
n is 0 to 2.
20. The compound according to claim 19 , wherein:
R 1 is selected from hydrogen, trimethylsilyl, OR 6 , NR 7 R 8 , NR 7 C(O)R 6 , NR 7 C(O)OR 6 , or C 1 -C 4 alkyl-(OR′) n ;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′, C 1 -C 4 -alkyl-NR′R″, C 1 -C 4 -alkyl-heterocycloalkyl, or C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl and alkyl-heterocycloalkyl is substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 6-membered heterocyclic ring with 1 or 2 N atoms and optionally an O atom, which is substituted or unsubstituted; and
R′ and R″ are either hydrogen or C 1 -C 6 -alkyl; or
R′ and R″ can be taken together with the atom to which they are attached to form a 6-membered heterocyclic ring with 1 or 2 N atoms and optionally an O atom, which is substituted or unsubstituted.
21. A pharmaceutical composition, which comprises a compound of claim 1 and a pharmaceutically acceptable carrier.