Arylamino N-heteroaryl compounds as MEK inhibitors
View Patent ↗The invention provides novel arylamino N-heteroaryl MEK inhibitors of Formula (I): 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),
or a tautomer or pharmaceutically acceptable salt thereof, wherein:
Het is:
wherein:
* is the connecting position;
W is selected from: 1) heteroaryl containing 1-4 heteroatoms or heterocycloalkyl containing 1-4 heteroatoms, wherein the heteroaryl or the heterocycloalkyl represented by W is optionally substituted by 1 to 5 substituents R 11 ; and 2) aryl, halogen, C 1 -C 10 -alkyl-OR 6 , C 1 -C 10 -alkyl-NR 7 R 8 , —C═NNR 6 R 7 , —C═NOR 7 , C 1 -C 10 alkyl(NR 7 )(NR 7 R 8 ), —C(O)R 6 , —C(O)OR 6 , —C(O)NR 7 R 8 , —C(O)NR 7 OR 6 , —C(O)(C 3 -C 10 -cycloalkyl), —C(O)(C 1 -C 10 -alkyl), —C(O)(aryl), —C(O)NR 7 (C 1 -C 10 -alkyl)heterocycloalkyl, —C(O)(heteroaryl), —C(O)(heterocycloalkyl), —CN, —C(O)NR 7 NR 8 R 6 , —C(O)C(O)R 6 , —NR 7 R 8 , —C(O)CR 6 R 7 C(O)R 8 , —NR 7 C(O)R 8 , —NRC(O)NR 7 R 8 or —C(O)NR 7 NR 8 C(O)R 6 ;
R 1 and R 9 are independently selected from: hydrogen, halogen, cyano, azido, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C 1 -C 4 -alkyl-C(O)OR 6 , C 1 -C 4 -alkyl-OR 6 , C 1 -C 4 -alkyl-C(O)NR 7 R 8 , —C(O)OR 6 , —C(O)R 6 , —NR 7 C(O)OR 6 , —OC(O)R 6 , —NR 7 R 8 , —SR 6 , and —NR 7 S(O) 2 R 6 ,
R 2 and R 3 are independently halogen;
R 4 and R 5 are independently selected from: hydrogen, halogen, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 -alkyl, C 3 -C 10 -cycloalkyl, aryl, arylalkyl, heteroaryl, heterocycloalkyl, C 1 -C 4 -alkyl-C(O)OR′, C 1 -C 4 -alkyl-OR′, C 1 -C 4 -alkyl-(heterocycloalkyl), C 1 -C 4 -alkyl-diol, and 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 heteroaryl or heterocycloalkyl ring, with 1 or 2-nitrogen atoms and optionally an oxygen atom;
R 10 is selected from hydrogen, halogen or C 1 -C 6 -alkyl;
R 11 is selected from hydrogen, C 1 -C 6 -alkyl, —OR 6 , —NR 7 R 8 , —SR 6 , and —NR 7 S(O)(O)R′; and
R′ and R″ are independently selected from hydrogen, C 1 -C 6 -alkyl and aryl.
2. The compound according to claim 1 , wherein
W is selected from: 1) heteroaryl containing 1-4 heteroatoms, wherein the heteroaryl represented by W is optionally substituted by 1 to 5 substituents R 11 ; and 2) aryl, C 1 -C 10 -alkyl -OR 6 , C 1 -C 10 -alkyl-NR 7 R 8 , —C═NNR 7 R 8 , —C═NOR 7 , C 1 -C 10 alkyl(NR 7 )(NR 7 R 8 ), —C(O)R 6 , —C(O)OR 6 , —C(O)NR 7 R 6 , —C(O)NR 7 OR 6 , —C(O)(C 3 -C 10 cycloalkyl), —C(O)(C 1 -C 10 alkyl), —C(O)(aryl), —C(O)NR 7 (C 1 -C 10 alkyl)heterocycloalkyl, —C(O)(heteroaryl), —C(O)(heterocyclyl), —CN, —C(O)NR 7 NR 8 R 6 , —C(O)C(O)R 6 , —C(O)CR 6 R 7 C(O)R 8 , —NR 7 R 8 , —NR 7 C(O)R 8 , —NRC(O)NR 7 R 8 , or —C(O)NR 7 NR 8 C(O)R 6 ;
R 1 is selected from: halogen, cyano, azido, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR 6 , C 1 -C 4 alkyl-OR 6 , C 1 -C 4 alkyl -C(O)NR 7 R 8 , —C(O)OR 6 , —C(O)R 6 , —NR 7 C(O)OR 6 , —OC(O)R 6 , —NR 7 R 8 , —SR 6 and —NR 7 S(O);R 6 ;
R 2 is selected from F, Cl, I, Br;
R 3 is selected from F, Cl, 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′, C 1 -C 4 alkyl-(heterocycloalkyl), C 1 -C 4 alkyl-diol, and 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 heterocycloalkyl ring, with 1 or 2 nitrogen atoms and optionally an oxygen atom,
R 9 is selected from: hydrogen, halogen, C 1 -C 10 alkyl, and C 1 -C 4 alkoxy;
R 10 is selected from: Cl, I, F, and Br;
R 11 is selected from: —OR 6 , —NR 7 R 8 , —SR 6 and —NR 7 S(O) 2 R′; and
R′ and R″ are independently either hydrogen, or C 1 -C 6 -alkyl.
3. The compound according to claim 1 , wherein
R 1 is halogen, C 1 -C 6 alkoxy or —NR 7 R 8 ;
R 2 is F;
R 3 is I;
R 4 and R 5 are each hydrogen;
R 9 is hydrogen; and
R 10 is F.
4. A compound of Formula (II),
or a pharmaceutically acceptable salt thereof, wherein:
Het is
wherein
* is the connecting position;
W is selected from: 1) heteroaryl containing 1-4 heteroatoms or heterocycloalkyl containing 1-4 heteroatoms, wherein the heteroaryl or the heterocycloalkyl represented by W is optionally substituted by 1 to 5 substituents R 11 ; and 2) aryl, halogen, C 1 -C 10 -alkyl-OR 6 , C 1 -C 10 -alkyl-NR 7 R 8 , —C═NNR 6 R 7 , —C═NOR 7 , C 1 -C 10 alkyl(NR 7 )(NR 7 R 8 ), —C(O)R 6 , —C(O)OR 6 , —C(O)NR 7 R 8 , —C(O)NR 7 OR 6 , —C(O)(C 3 -C 10 cycloalkyl), —C(O)(C 1 -C 10 alkyl), —C(O)NR 7 (C 1 -C 10 alkyl)-heterocycloalkyl, —C(O)(heteroaryl), —C(O)(heterocycloalkyl), —CN, —C(O)NR 7 NR 8 R 6 , —C(O)C(O)R 6 , —NR 7 R 8 , C(O)CR 6 R 7 C(O)R 8 , —NR 7 C(O)R 8 , —NRC(O)NR 7 R 8 or —C(O)NR 7 NR 8 C(O)R 6 ;
R 1 and R 9 are independently selected from: hydrogen, halogen, cyano, azido, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR 6 , C 1 -C 4 alkyl-C(O)NR 7 R 8 , —C(O)OR 6 , —C(O)R 6 , —NR 7 C(O)OR 6 , —OC(O)R 6 , —NR 7 R 8 , —SR 6 and —NR 7 S(O) 2 R 6 ,
R 4 and R 5 are independently selected from: hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy;
R 6 , R 7 and R 8 are independently selected from: hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, arylalkyl, heteroaryl, or heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′, C 1 -C 4 alkyl-(heterocycloalkyl), C 1 -C 4 alkyl-diol, and 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 4 to 10 membered heteroaryl or heterocycloalkyl ring, with 1-4 heteroatoms;
R 10 is selected from: hydrogen, halogen and C 1 -C 6 alkyl; and
R 11 is selected from: hydrogen, C 1 -C 6 -alkyl, —OR 6 , —NR 7 R 8 , —SR 6 and —NR 7 S(O) 2 R′;
R′ and R″ are independently selected from hydrogen, C 1 -C 6 -alkyl or aryl.
5. A compound according to claim 4 , wherein
W is selected from: 1) heteroaryl containing 1-4 heteroatoms, wherein the heteroaryl represented by W is optionally substituted by substituted by 1 to 5 substituents R 11 ; and 2) aryl, C 1 -C 10 -alkyl -OR 6 , C 1 -C 10 -alkyl-NR 7 R 8 , —C═NNR 7 R 8 , —C═NOR 7 , C 1 -C 10 alkyl(NR 7 )(NR 7 R 8 ), —C(O)R 6 , —C(O)OR 6 , —C(O)NR 7 R 6 , —C(O)NR 7 OR 6 , —C(O)(C 3 -C 10 cycloalkyl), —C(O)(C 1 -C 10 alkyl), —C(O)(aryl), —C(O)NR 7 (C 1 -C 10 alkyl)heterocycloalkyl, —C(O)(heteroaryl), —C(O)(heterocyclyl), —CN, —C(O)NR 7 NR 8 R 6 , —C(O)C(O)R 6 , —C(O)CR 6 R 7 C(O)R 8 , —NR 7 R 8 , —NR 7 C(O)R 8 , —NRC(O)NR 7 R 8 , or —C(O)NR 7 NR 8 C(O)R 6 ;
R 1 is halogen, C 1 -C 6 alkoxy or —NR 7 R 8 ;
R 4 and R 5 are each 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-(heterocycloalkyl), C 1 -C 4 alkyl-diol and 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 heterocycloalkyl ring with 1 or 2 nitrogen atoms and optionally an oxygen atom;
R 9 is hydrogen;
R 10 is F;
R 11 is selected from: —OR 6 , —NR 7 R 8 , —SR 6 and —NR 7 S(O) 2 R′; and
R′ and R″ are independently either hydrogen, C 1 -C 6 -alkyl.
6. A compound of Formula (IIIa):
or a pharmaceutically acceptable salt thereof, wherein:
W is selected from: 1) a heteroaryl containing 1-4 heteroatoms or a heterocycloalkyl containing 1-4 heteroatoms, wherein the heteroaryl or the heterocycloalkyl represented by W is optionally substituted by 1 to 5 substituents R 11 ; and 2) aryl, halogen, C 1 -C 10 -alkyl-OR 6 , C 1 -C 10 -alkyl-NR 7 R 8 , —C═NNR 6 R 7 , —C═NOR 7 , C 1 -C 10 alkyl(NR 7 )(NR 7 R 8 ), —C(O)R 6 , —C(O)OR 6 , —C(O)NR 7 R 8 , —C(O)NR 7 OR 6 , —C(O)(C 3 -C 10 cycloalkyl), —C(O)(C 1 -C 10 alkyl), —C(O)(aryl), —C(O)NR 7 (C 1 -C 10 alkyl)heterocycloalkyl, —C(O)(heteroaryl), —C(O)(heterocycloalkyl), —CN, —C(O)NR 7 NR 8 R 6 , —C(O)C(O)R 6 , —C(O)CR 6 R 7 C(O)R 8 , —NR 7 R 8 , —NR 7 C(O)R 8 , —NRC(O)NR 7 R 8 or —C(O)NR 7 NR 8 C(O)R 6 ;
R 1 is selected from: hydrogen, halogen, cyano, azido, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR 6 , C 1 -C 4 alkyl-OR 6 , C 1 -C 4 alkyl -C(O)NR 7 R 8 , —C(O)OR 6 , —C(O)R 6 , —NR 7 C(O)OR 6 , —OC(O)R 6 , —NR 7 R 8 , —SR 6 and —NR 7 S(O) 2 R 6 ;
R 6 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, arylalkyl, heteroaryl, or heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′, C 1 -C 4 alkyl-(heterocycloalkyl), C 1 -C 4 alkyl-diol and 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 4 to 10 membered heteroaryl or heterocycloalkyl ring, with 1-4 heteroatoms;
R 10 is selected from: hydrogen, halogen and C 1 -C 6 alkyl;
R 11 is selected from: hydrogen, C 1 -C 6 -alkyl, —OR 6 , —NR 7 R 8 , —SR 6 and —NR 7 S(O) 2 R′; and
R′ and R″ are independently selected from: hydrogen, C 1 -C 6 -alkyl and aryl.
7. A compound according to claim 6 , wherein
W is selected from: 1) a heteroaryl containing 1-4 heteroatoms, wherein the heteroaryl represented by W is optionally substituted by substituted by 1 to 5 substituents R 11 ; and 2) aryl, C 1 -C 10 -alkyl -OR 6 , C 1 -C 10 -alkyl-NR 7 R 8 , —C═NNR 7 R 8 , —C═NOR 7 , C 1 -C 10 alkyl(NR 7 )(NR 7 R 8 ), —C(O)R 6 , —C(O)OR 6 , —C(O)NR 7 R 6 , —C(O)NR 7 OR 6 , —C(O)(C 3 -C 10 cycloalkyl), —C(O)(C 1 -C 10 alkyl), —C(O)(aryl), —C(O)NR 7 (C 1 -C 10 alkyl)heterocycloalkyl, —C(O)(heteroaryl), —C(O)(heterocyclyl), —CN, —C(O)NR 7 NR 8 R 6 , —C(O)C(O)R 6 , —C(O)CR 6 R 7 C(O)R 8 , —NR 7 R 8 , —NR 7 C(O)R 8 , —NRC(O)NR 7 R 8 , or —C(O)NR 7 NR 8 C(O)R 6 ;
R 1 is halogen, C 1 -C 6 alkoxy or —NR 7 R 8 ;
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-(heterocycloalkyl), C 1 -C 4 alkyl-diol and 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 heterocycloalkyl ring with 1 or 2 nitrogen atoms and optionally an oxygen atom;
R 10 is F;
R 11 is selected from: —OR 6 , —NR 7 R 8 , —SR 6 and —NR 7 S(O) 2 R′; and
R′ and R″ are independently either hydrogen, C 1 -C 6 -alkyl.
8. A compound according to claim 1 , wherein the compound is selected from the group consisting of:
6-Chloro-3-(2-fluoro-4-iodo-phenylamino)-pyridazine-4-carboxylic acid;
3-(2-Fluoro-4-iodo-phenylamino)-6-morpholin-4-yl-pyridazine-4-carboxylic acid;
3-(2-Fluoro-4-iodo-phenylamino)-6-methoxy-pyridazine-4-carboxylic acid;
6-Chloro-3-(2-fluoro-4-iodo-phenylamino)-pyridazine-4-carboxylic acid (2,2-imethyl -[1,3]dioxolan-4-ylmethoxy)-amide;
6-Chloro-3-(2-fluoro-4-iodo-phenylamino)-pyridazine-4-carboxylic acid amide; and
6-Chloro-3-(2-fluoro-4-iodo-phenylamino)-pyridazine-4-carboxylic acid (2-morpholin-4-yl -ethyl)-amide;
or a pharmaceutically accepatabe salts thereof.
9. A pharmaceutical composition, which comprises a compound according to claim 1 and a pharmaceutically acceptable carrier.
10. A process for the manufacture of a compound of Formula (I):
said process comprising the step of reacting the starting material, B
with a substituted aniline, A:
in the presence of a base, and thereby forming the compound according to Formula I;
wherein
W is selected from: 1) heteroaryl containing 1-4 heteroatoms or heterocycloalkyl containing 1-4 heteroatoms, wherein the heteroaryl or the heterocycloalkyl represented by W is optionally substituted by 1 to 5 substituents R 11 ; and 2) aryl, halogen, C 1 -C 10 -alkyl-OR 6 , C 1 -C 10 -alkyl-NR 7 R 8 , C═NNR 6 R 7 , C═NOR 7 , C 1 -C 10 alkyl(NR 7 )(NR 7 R 8 ), —C(O)R 6 , —C(O)OR 6 , —C(O)NR 7 R 8 , —C(O)NR 7 OR 6 , —C(O)(C 3 -C 10 cycloalkyl), —C(O)(C 1 -C 10 alkyl), —C(O)(aryl), —C(O)NR 7 (C 1 -C 10 alkyl)heterocycloalkyl, —C(O)(heteroaryl), —C(O)(heterocycloalkyl), —CN, —C(O)NR 7 NR 8 R 6 , —C(O)C(O)R 6 , —NR 7 R 8 , —C(O)CR 6 R 7 C(O)R 8 , —NR 7 C(O)R 8 , —NRC(O)NR 7 R 8 or —C(O)NR 7 NR 8 C(O)R 6 ;
R 2 and R 3 are independently halogen;
R 6 , R 7 and R 8 are independently selected from: hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, arylalkyl, heteroaryl, or heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′, C 1 -C 4 alkyl-(heterocycloalkyl), C 1 -C 4 alkyl-diol and C 1 -C 4 alkyl-C(O); 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 heterocycloalkyl ring, with 1-4 heteroatoms; and
R′ and R″ are independently selected from: hydrogen, C 1 -C 6 -alkyl and aryl.
11. The process of claim 10 , wherein the base is a silazide base.
12. The process of claim 11 , wherein the base is lithium hexamethyldisilazide.
13. The compound 6-chloro-3-(2-fluoro-4-iodophenylamino)pyridazine-4-carboxylic acid amide, or a pharmaceutically acceptable salt thereof.