5-anilinoimidazo[1,5-a]-pyridines inhibitors of MEK kinase
The invention relates to imidazopyridines of formula I with anti-cancer and/or anti-inflammatory activity and more specifically to imidazopyridines which inhibit MEK kinase activity. The invention provides compositions and methods useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder, or treating an inflammatory disease in a mammal. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.
1. A compound of formula I:
and pharmaceutically acceptable salts thereof, wherein:
Z 1 is CR 1 ;
R 1 is H, C 1 -C 3 alkyl, halo, CF 3 , CHF 2 , CN, OR A or NR A R A ;
R 1′ is H, C 1 -C 3 alkyl, halo, CF 3 , CHF 2 , CN, OR A , or NR A R A ;
wherein each R A is independently H or C 1 -C 3 alkyl;
Z 2 is CR 2 ;
Z 3 is CR 3 ;
R 2 and R 3 are independently selected from H, halo, CN, CF 3 , —OCF 3 , —NO 2 , —(CR 14 R 15 ) n C(═Y′)R 11 , —(CR 14 R 15 ) n C(═Y′)OR 11 , —(CR 14 R 15 ) n C(═Y′)NR 11 R 12 , —(CR 14 R 15 ) n NR 11 R 12 , —(CR 14 R 15 ) n OR 11 , —(CR 14 R 15 ) n SR 11 , —(CR 14 R 15 ) n NR 12 C(═Y′)R 11 , —(CR 14 R 15 ) n NR 12 C(═Y′)OR 11 , —(CR 14 R 15 ) n NR 13 C(═Y′)NR 11 R 12 , —(CR 14 R 15 ) n NR 12 SO 2 R 11 , —(CR 14 R 15 ) n OC(═Y′)R 11 , —(CR 14 R 15 ) n OC(═Y′)OR 11 , —(CR 14 R 15 ) n OC(═Y′)NR 11 R 12 , —(CR 14 R 15 ) n OS(O) 2 (OR 11 ), —(CR 14 R 15 ) n OC(═Y′)(OR 11 )(OR 12 ), —(CR 14 R 15 ) n OP(OR 11 )(OR 12 ), —(CR 14 R 15 ) n S(O)R 11 , —(CR 14 R 15 ) n S(O) 2 R 11 , —(CR 14 R 15 ) n S(O) 2 NR 11 R 12 , —(CR 14 R 15 ) n S(O)(OR 11 ), —(CR 14 R 15 ) n S(O) 2 (OR 11 ), —(CR 14 R 15 ) n SC(═Y″)R 11 , —(CR 14 R 15 ) n SC(═Y′)OR 11 , —(CR 14 R 15 ) n SC(═Y′)NR 11 R 12 , C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl;
R 4 is H, C 1 -C 6 alkyl or C 3 -C 4 carbocyclyl;
Y is W—C(O)— or W′;
W is
R 5 is H or C 1 -C 12 alkyl;
X 1 is selected from R 11′ and —OR 11′ ; when X 1 is R 11′ , X 1 is optionally taken together with R 5 and the nitrogen atom to which they are bound to form a 4-7 membered saturated or unsaturated ring having 0-2 additional heteroatoms selected from 0, S and N, wherein said ring is optionally substituted with one or more groups selected from halo, CN, CF 3 , —OCF 3 , —NO 2 , oxo, —(CR 19 R 20 ) n C(═Y′)R 16 , —(CR 19 R 20 ) n C(═Y′)OR 16 , —(CR 19 R 20 ) n C(═Y′)NR 16 R 17 , —(CR 19 R 20 )—NR 16 R 17 , —(CR 19 R 20 ) n OR 16 , —(CR 19 R 20 ) n —SR 16 , —(CR 19 R 20 ) n NR 16 C(═Y′)R 17 , —(CR 19 R 20 ) n NR 16 C(═Y′)OR 17 , —(CR 19 R 20 ) n NR 18 C(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n NR 17 SO 2 R 16 , —(CR 19 R 20 ) n OC(═Y′)R 16 , —(CR 19 R 20 ) n OC(═Y′)OR 16 , —(CR 19 R 20 ) n OC(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n OS(O) 2 (OR 16 ), —(CR 19 R 20 ) n OP(═Y′)(OR 16 )(OR 17 ), —(CR 19 R 20 ) n OP(OR 16 )(OR 17 ), —(CR 19 R 20 ) n S(O)R 16 , —(CR 19 R 20 ) n S(O) 2 R 16 , —(CR 19 R 20 ) n S(O) 2 NR 16 R 17 , —(CR 19 R 20 ) n S(O)(OR 16 ), —(CR 19 R 20 ) n S(O) 2 (OR 16 ), —(CR 19 R 20 ) n SC(═Y′)R 16 , —(CR 19 R 20 ) n SC(═Y′)OR 16 , —(CR 19 R 20 ) n SC(═Y′)NR 16 R 17 , and R 21 ;
each R 11′ is independently H, C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
R 11 , R 12 and R 13 are independently H, C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl,
or R 11 and R 12 together with the nitrogen to which they are attached form a 3-8 membered saturated, unsaturated or aromatic ring having 0-2 heteroatoms selected from O, S and N, wherein said ring is optionally substituted with one or more groups selected from halo, CN, CF 3 , —NO 2 , C 1 -C 6 alkyl, —OH, —SH, —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —SO 2 (C 1 -C 6 alkyl), —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHSO 2 (C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)SO 2 (C 1 -C 6 alkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 , —OC(O)NH 2 , —OC(O)NH(C 1 -C 6 alkyl), —OC(O)N(C 1 -C 6 alkyl) 2 , —OC(O)O(C 1 -C 6 alkyl), —NHC(O)NH(C 1 -C 6 alkyl), —NHC(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)C(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)N(C 1 -C 6 alkyl) 2 , —NHC(O)NH(C 1 -C 6 alkyl), —NHC(O)N(C 1 -C 6 alkyl) 2 , —NHC(O)O(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl)C(O)O(C 1 -C 6 alkyl);
R 14 and R 15 are independently selected from H, C 1 -C 12 alkyl, aryl, carbocyclyl, heterocyclyl, and heteroaryl;
W′ is
wherein
each X 2 is independently O, S, or NR 9 ;
each R 7 is independently selected from H, halo, CN, CF 3 , —OCF 3 , —NO 2 , —(CR 14 R 15 ) n C(═Y′)R 11 , —(CR 14 R 15 ) n C(═Y′)OR 11 , —(CR 14 R 15 ) n C(═Y′)NR 11 R 12 , —(CR 14 R 15 ) n NR 11 R 12 , —(CR 14 R 15 ) n OR 11 , —(CR 14 R 15 ) n SR 11 , —(CR 14 R 15 ) n NR 12 C(═Y′)R 11 , —(CR 14 R 15 ) n NR 12 C(═Y′)OR 11 , —(CR 14 R 15 ) n NR 13 C(═Y′)NR 11 R 12 , —(CR 14 R 15 ) n NR 12 SO 2 R 11 , —(CR 14 R 15 ) n OC(═Y′)R 11 , —(CR 14 R 15 ) n OC(═Y′)OR 11 , —(CR 14 R 15 ) n OC(═Y′)NR 11 R 12 , —(CR 14 R 15 ) n OS(O) 2 (OR 11 ), —(CR 14 R 15 ) n OP(═Y′)(OR 11 )(OR 12 ), —(CR 14 R 15 ) n OP(OR 11 )(OR 12 ), —(CR 14 R 15 ) n S(O)R 11 , —(CR 14 R 15 ) n S(O) 2 R 11 , —(CR 14 R 15 ) n S(O) 2 NR 11 R 12 , —(CR 14 R 15 ) n S(O)(OR 11 ), —(CR 14 R 15 ) n S(O) 2 (OR 11 ), —(CR 14 R 15 ) n SC(═Y′)R 11 , —(CR 14 R 15 ) n SC(═Y′)OR 11 , —(CR 14 R 15 ) n SC(═Y′)NR 11 R 12 , C 1 -C 2 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl;
each R 8 is independently selected from C 1 -C 12 alkyl, aryl, carbocyclyl, heterocyclyl, and heteroaryl;
R 9 is selected from H, —(CR 14 R 15 ) n C(═Y′)R 11 , —(CR 14 R 15 ) n C(═Y′)OR 11 , —(CR 14 R 15 ) n C(═Y′)NR 11 R 12 , —(CR 14 R 15 ) q NR 11 R 12 , —(CR 14 R 15 ) q OR 11 , —(CR 14 R 15 ) q SR 11 , —(CR 14 R 15 ) q NR 12 C(═Y′)R 11 , —(CR 14 R 15 ) q NR 12 C(═Y′)OR 11 , —(CR 14 R 15 ) q NR 13 C(═Y′)NR 11 R 12 , —(CR 14 R 15 ) q NR 12 SO 2 R 11 , —(CR 14 R 15 ) q OC(≡Y′)R 11 , —(CR 14 R 15 ) q OC(═Y′)OR 11 , —(CR 14 R 15 ) q OC(═Y′)NR 11 R 12 , —(CR 14 R 15 ) q OS(O) 2 (OR 11 ), —(CR 14 R 15 ) q OP(═Y′)(OR 11 )(OR 12 ), —(CR 14 R 15 ) q OP(OR 11 )(OR 12 ), —(CR 14 R 15 ) n S(O)R 11 , —(CR 14 R 15 ) n S(O) 2 R 11 , —(CR 14 R 15 ) n S(O) 2 NR 11 R 12 , C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl;
R 10 is H, C 1 -C 6 alkyl or C 3 -C 4 carbocyclyl;
X 4 is
R 6 is H, halo, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, carbocyclyl, heteroaryl, heterocyclyl, —OCF 3 , —NO 2 , —Si(C 1 -C 6 alkyl), —(CR 19 R 20 ) n NR 16 R 17 , —(CR 19 R 20 ) n OR 16 , or —(CR 19 R 20 ) n —SR 16 ;
R 6′ is H, halo, C 1 -C 6 alkyl, carbocyclyl, CF 3 , —OCF 3 , —NO 2 , —Si(C 1 -C 6 alkyl), —(CR 19 R 20 ) n NR 16 R 17 , —(CR 19 R 20 ) n OR 16 , —(CR 19 R 20 ) n —SR 16 , C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, heterocyclyl, aryl, or heteroaryl;
p is 0, 1, 2 or 3;
n is 0, 1, 2 or 3;
q is 2 or 3;
wherein each said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6′ , R 7 , R 8 , R 9 , R 10 , R 11 , R 11′ , R 12 , R 13 , R 14 , R 15 , and R A is independently optionally substituted with one or more groups independently selected from halo, CN, CF 3 , —OCF 3 , —NO 2 , oxo, —Si(C 1 -C 6 alkyl) —(CR 19 R 20 ) n C(═Y′)R 16 , —(CR 19 R 20 ) n C(═Y′)OR 16 , —(CR 19 R 20 ) n C(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n NR 16 R 17 , —(CR 19 R 20 ) n OR 16 , —(CR 19 R 20 ) n SR 16 , —(CR 19 R 20 ) n NR 16 C(═Y′)R 17 , —(CR 19 R 20 ) n NR 16 C(═Y′)OR 17 , —(CR 19 R 20 ) n NR 18 C(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n NR 17 SO 2 R 16 , —(CR 19 R 20 ) n OC(═Y′)R 16 , —(CR 19 R 20 ) n OC(═Y′)OR 16 , —(CR 19 R 20 ) n OC(═y′)NR 16 R 17 , —(CR 19 R 20 ) n OS(O) 2 (OR 16 ), —(CR 19 R 20 ) n OP(═Y′)(OR 16 )(OR 17 ), —(CR 19 R 20 ) n OP(OR 16 )(OR 17 ), —(CR 19 R 20 ) n S(O)R 16 , —(CR 19 R 20 ) n S(O) 2 R 16 , —(CR 19 R 20 ) n S(O) 2 NR 16 R 17 , —(CR 19 R 20 ) n S(O)(OR 16 ), —(CR 19 R 20 ) n S(O) 2 (OR 16 ), —(CR 19 R 20 ) n SC(═Y′)R 16 , —(CR 19 R 20 ) n SC(═Y′)OR 16 , —(CR 19 R 20 ) n SC(═Y′)NR 16 R 17 , and R 21 ;
each R 16 , R 17 and R 18 is independently H, C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups selected from halo, CN, —OCF 3 , CF 3 , —NO 2 , C 1 -C 6 alkyl, —OH, —SH, —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —SO 2 (C 1 -C 6 alkyl), —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHSO 2 (C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)SO 2 (C 1 -C 6 alkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 , —OC(O)NH 2 ; —OC(O)NH(C 1 -C 6 alkyl), —OC(O)N(C 1 -C 6 alkyl) 2 , —OC(O)O(C 1 -C 6 alkyl), —NHC(O)NH(C 1 -C 6 alkyl), —NHC(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)C(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)N(C 1 -C 6 alkyl) 2 , —NHC(O)NH(C 1 -C 6 alkyl), —NHC(O)N(C 1 -C 6 alkyl) 2 , —NHC(O)O(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl)C(O)O(C 1 -C 6 alkyl);
or R 16 and R 17 together with the nitrogen to which they are attached form a 3-8 membered saturated, unsaturated or aromatic ring having 0-2 heteroatoms selected from 0, S and N, wherein said ring is optionally substituted with one or more groups selected from halo, CN, —OCF 3 , CF 3 , —NO 2 , C 1 -C 6 alkyl, —OH, —SH, —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —SO 2 (C 1 -C 6 alkyl), —CO 2 H, —OC 2 (C 1 -C 6 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHSO 2 (C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)SO 2 (C 1 -C 6 alkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 , —OC(O)NH 2 , —OC(O)NH(C 1 -C 6 alkyl), —OC(O)N(C 1 -C 6 alkyl) 2 , —OC(O)O(C 1 -C 6 alkyl), —NHC(O)NH(C 1 -C 6 alkyl), —NHC(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)C(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)N(C 1 -C o alkyl) 2 , —NHC(O)NH(C 1 -C 6 alkyl), —NHC(O)N(C 1 -C 6 alkyl) 2 , —NHC(O)O(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl)C(O)O(C 1 -C 6 alkyl);
R 19 and R 20 are independently selected from H, C 1 -C 12 alkyl, —(CH 2 ) n -aryl, —(CH 2 ) n -carbocyclyl, —(CH 2 ) n -heterocyclyl, and —(CH 2 ) n -heteroaryl;
R 21 is C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein each member of R 21 is optionally substituted with one or more groups selected from halo, oxo, CN, —OCF 3 , CF 3 , —NO 2 , C 1 -C 6 alkyl, —OH, —SH, —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —SO 2 (C 1 -C 6 alkyl), —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHSO 2 (C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)SO 2 (C 1 -C 6 alkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 , —OC(O)NH 2 , —OC(O)NH(C 1 -C 6 alkyl), —OC(O)N(C 1 -C 6 alkyl) 2 , —OC(O)O(C 1 -C 6 alkyl), —NHC(O)NH(C 1 -C 6 alkyl), —NHC(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)C(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)N(C 1 -C 6 alkyl) 2 , —NHC(O)NH(C 1 -C 6 alkyl), —NHC(O)N(C 1 -C 6 alkyl) 2 , —NHC(O)O(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl)C(O)O(C 1 -C 6 alkyl);
each Y′ is independently O, NR 22 , or S; and
R 22 is H or C 1 -C 12 alkyl.
2. The compound of claim 1 wherein R 2 is H, methyl, CF 3 , Cl, or F.
3. The compound of claim 2 wherein R 2 is H, Cl or F.
4. The compound of claim 1 wherein R 3 is H, methyl, CF 3 , Cl, or F.
5. The compound of claim 4 wherein R 3 is H, Cl or F.
6. The compound of claim 1 wherein R 1 is H or methyl.
7. The compound of claim 6 wherein R 1 is H.
8. The compound of claim 1 wherein R 1′ is H.
9. The compound of claim 8 wherein Y is W—C(O), W is X 1 —N(R 5 )—, and X 1 is selected from:
10. The compound of claim 8 wherein Y is W—C(O), W is X 1 —N(R 5 )—, and X 1 is selected from:
11. The compound of claim 9 or 10 wherein X 4 is selected from:
12. The compound of claim 11 wherein R 4 is H or methyl.
13. The compound of claim 12 wherein R 4 is H.
14. The compound of claim 12 wherein R 5 is H or methyl.
15. The compound of claim 14 wherein R 5 is H.
16. The compound of claim 1 where the compound is selected from the group consisting of:
5-(2-fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-hydroxyethoxy)-amide;
5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((R)-2,3-dihydroxy-propoxy)-amide;
5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((S)-2-hydroxy-propoxy)-amide;
5-(4-bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-hydroxyethoxy)-amide;
5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((S)-2-hydroxy-propoxy)-amide;
5-(4-bromo-2-fluoro-phenylamino)-8-fluoro-imidazo[1,5-a]pyridine-6-carboxylic acid ((S)-2-hydroxy-propoxy)-amide;
8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-hydroxy-ethoxy)-amide;
8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((R)-2,3-dihydroxy-propoxy)-amide;
8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((S)-2-hydroxy-propoxy)-amide;
5-(2-fluoro-methanesulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-hydroxy-ethoxy)-amide; and,
5-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-hydroxy-ethoxy)-amide.
17. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.