N-substituted azaindoles and methods of use
The invention relates to N-substituted azaindolyl compounds of Formula I with anti-cancer and/or anti-inflammatory activity and more specifically to N-substituted azaindolyl compounds 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 selected from Formula I:
or a salt thereof, wherein:
Z 1 is CR 1 ;
Z 2 is N;
Z 3 is CR 3 ;
Z 4 is CR 4 ;
R 1 , R 3 and R 4 are independently selected from H or halo;
W is
R 5 , R 6 and R 7 are independently selected from H or C 1 -C 6 alkyl;
or R 6 and R 7 together with the carbon atom to which they are attached form a 3-6 membered saturated ring having 0-1 heteroatoms selected from O, S and N, wherein said ring is optionally substituted with one or more groups selected from halo, CN, CF 3 , —OCF 3 , C 1 -C 6 alkyl, —OH, —O(C 1 -C 6 alkyl);
X 1 is selected from —OR 11 , —NR 11 R 12 , and —S(O) 2 R 11 ; when X 1 is —OR 11 , said —OR 11 and R 5 optionally taken together with the nitrogen atom to which they are attached form a 4-7 membered saturated or unsaturated ring having 0-2 additional heteroatoms selected from O, 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, —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 ;
X 2 is phenyl;
X 3 is selected from H;
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 , —OCF 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;
each n is independently selected from 0, 1, 2, 3, 4, 5, or 6;
Y is independently 0, NR 11 , or S;
wherein each said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , R 11 , R 12 , R 13 , R 14 , and R 15 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 O, 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, —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 , 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 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 X 1 is selected from:
3. The compound of claim 2 wherein X 1 is selected from:
4. The compound of claim 1 wherein X 2 is selected from:
5. The compound of claim 1 wherein R 3 is selected from H.
6. The compound of claim 1 wherein R 4 is selected from Cl, Br, F.
7. The compound of claim 1 wherein R 5 is H.
8. The compound of claim 1 wherein R 6 is H or methyl.
9. The compound of claim 1 wherein R 7 is H or methyl.
10. The compound of claim 1 wherein R 6 and R 7 are taken together with the carbon atom to which they are attached to form a cyclopropyl or cyclobutyl ring.
11. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.