Compounds that are ERK inhibitors
Disclosed are the ERK inhibitors of formula (1): and the pharmaceutically acceptable salts thereof. Also disclosed are methods of treating cancer using the compounds of formula (I).
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
Q is selected from the group consisting of: —(CR 3 )— and N;
X is selected from the group consisting of: NH and N—O; Y is —N(R 9 )—;
Z is selected from the group consisting of: —C(═O)—, —C(R 7 R 8 )— and —C(R 7 R 8 )—C(R 7 R 8 )— wherein each R 7 and each R 8 is independently selected;
R 1 is selected from the group consisting of: —NR 12 R 13 , —OR 10 , —O—(R 10 )—O—R 10 , —O—R 10 —OH, —O—R 11 , (C 3 -C 7 )cycloalkyl, substituted (C 3 -C 7 )cycloalkyl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, (C 6 -C 14 )aryl, substituted (C 6 -C 14 )aryl, fused arylheteroaryl, substituted fused arylheteroaryl, fused heterocycloalkylheteroaryl, and substituted fused heterocycloalkylheteroaryl;
and wherein said substituted R 1 groups are substituted with 1 to 3 substituents independently selected from the group consisting of: —(C 1 -C 6 )alkyl, halo, CN, —OH, —OR 10 , —CF 3 , ═O, —NH 2 , —NH(C 1 -C 6 )alkyl, —S(O) 2 (C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —((C 1 -C 6 )alkyl)OH, —(C 3 -C 6 )cycloalkyl-S—(C 3 -C 6 )cycloalkyl, —N((C 1 -C 6 )alkyl) 2 wherein each alkyl is independently selected, —C(O)O—(C 1 -C 6 )alkyl, —C(O)OH, —OCF 3 , —C(O)NH(C 1 -C 6 )alkyl, heteroaryl, —(C 1 -C 6 )alkyl)-O—(C 1 -C 6 )alkyl, fused heteroarylaryl-, heterocycloalkyl, and heterocycloalkenyl;
and wherein the alkyl moieties of the R 1 groups, are optionally substituted with 1 to 3 substituents independently selected from the group consisting of: (C 1 -C 6 )alkoxy, halo, CN, —OH, ═O, —CF 3 , —NH 2 , —NH(C 1 -C 6 )alkyl, —S(O) 2 (C 1 -C 6 )alkyl, fused heteroarylaryl-, heterocycloalkyl, and heterocycloalkenyl;
and wherein said heteroaryl moiety of said R 1 groups is a 5-10 membered ring comprising 1-3 heteroatoms independently selected from the group consisting of: N, O and S, and wherein the remaining ring atoms are carbon (and wherein said heteroaryl definition applies to the heteroaryl moieties in the R 1 fused heteroarylheteroaryl, substituted fused heteroarylheteroaryl, fused arylheteroaryl, fused heterocycloalkyl-heteroaryl, substituted fused heterocycloalkylheteroaryl, and fused heteroarylaryl- groups); and wherein said heterocycloalkyl moiety of said R 1 groups is a 3-10 membered ring comprising 1-3 heteroatoms independently selected from the group consisting of: N, O and S, and wherein the remaining ring atoms are carbon (and wherein said heterocycloalkyl definition applies to the heterocycloalkyl moieties in the R 1 fused heterocycloalkylheteroaryl and substituted fused heterocycloalkylheteroaryl groups;
and wherein said fused arylheteroaryl moiety of said R 1 groups comprises a C 6 -C 10 aryl fused to a heteroaryl, as defined above, wherein the aryl and the heteroaryl have 2 ring atoms in common;
R 2 is selected from the group consisting of: H, halo, —NH 2 , —OH and —(C 1 -C 3 )alkyl;
R 3 is selected from the group consisting of: H, halo, (C 1 -C 6 alkyl), and (C 1 -C 6 alkyl) substituted with 1-2 —OH groups, —(C 3 -C 6 cycloalkyl), —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-N(C 1 -C 6 alkyl) 2 wherein each alkyl is independently selected, and -(C 1 -C 6 alkyl)-heterocycloalkyl, wherein said heterocycloalkyl is as defined above for R 1 ;
each R 6 , R 7 and R 8 is independently selected from the group consisting of: H, halo, (C 6 -C 14 )aryl(C 1 -C 6 )-alkyl-, and substituted (C 6 -C 14 )aryl(C 1 -C 6 )alkyl-, heteroaryl, substituted heteroaryl, heteroaryl(C 1 -C 6 )alkyl-, substituted heteroaryl(C 1 -C 6 )alkyl-, fused (C 3 -C 7 )cycloalkyl(C 6 -C 14 )aryl, substituted fused (C 3 -C 7 )cycloalkyl(C 6 -C 14 )aryl, fused heterocycloalkyl(C 6 -C 14 )aryl, substituted fused heterocycloalkyl(C 6 -C 14 )aryl; wherein said substituted R 6 , R 7 , R 8 moieties are substituted with 1-3 substitutents independently selected from the group consisting of: halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl; and wherein said heteroaryl moiety and said heterocycloalkyl moiety is as defined above in R 1 ;
R 9 is selected from the group consisting of: (C 6 -C 10 )aryl(C 1 -C 6 )alkyl-, and substituted (C 6 -C 14 )aryl(C 1 -C 6 )alkyl-, heteroaryl(C 1 -C 6 )alkyl-, substituted heteroaryl(C 1 -C 6 )alkyl-, fused heterocycloalkyl(C 6 -C 14 )aryl, substituted fused heterocycloalkyl(C 6 -C 14 )aryl; wherein said substituted R 9 moieties are substituted with 1-3 substitutents independently selected from the group consisting of: halo, OH, CN, CF 3 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl- O—(C 1 -C 6 )alkyl; and wherein said heteroaryl moiety and said heterocycloalkyl moiety is as defined above for R 1 ;
each R 10 is independently selected from the group consisting of: C 1 -C 6 alkyl;
R 11 is selected from the group consisting of: a 4-7 membered heterocycloalkyl ring comprising 1-3 heteroatoms independently selected from the group consisting of: O, S and N; and
R 12 and R 13 are independently selected from the group consisting of: H, (C 1 -C 6 )alkyl, —C(O)OR 10 , —C(O)R 10 ; said alkyl group optionally substituted with 1-4 substitutents independently selected from the group consisting of halo.
2. The compound of claim 1 , wherein Q is —(CR 3 )—.
3. The compound of claim 1 , wherein Z is —C(R 7 R 8 )—.
4. The compound of claim 1 , wherein Z is —C(R 7 R 8 )—C(R 7 R 8 )—.
5. The compound of claim 1 , wherein R 7 and R 8 are H.
6. The compound of claim 1 , wherein Ring B is selected from the group consisting of: (d2), (d3), (e2), and (e3).
7. The compound of claim 1 , wherein Ring B is selected from the group consisting of: (d2), (e2), and (e3).
8. The compound of claim 7 wherein R 7 and R 8 are H.
9. The compound of claim 1 , wherein R 9 is selected from the group consisting of: heteroaryl(C 1 -C 6 )alkyl-, substituted heteroaryl(C 1 -C 6 )alkyl-, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl-, substituted (C 6 -C 10 )aryl(C 1 -C 6 )alkyl-, fused heterocycloalkyl(C 6 -C 10 )aryl, and fused substituted heterocycloalkyl(C 6 -C 10 )aryl.
10. The compound of claim 1 , wherein R 9 is selected from the group consisting of: (g1), (g2), (g3), (g4), (g6), (g7), (g8), (g9), (g10), (g11), (g12), (g13), (g14), and (g15).
11. The compound of claim 1 , wherein R 1 is selected from the group consisting of: —NR 12 R 13 , —OR 10 , —O—(R 10 )—O—R 10 , —O—R 10 —OH, (C 3 -C 7 )cycloalkyl, substituted (C 3 -C 7 )cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, —OR 11 , heteroaryl, substituted heteroaryl, fused arylheteroaryl, and fused substituted arylheteroaryl.
12. The compound of claim 1 , wherein R 1 is selected from the group consisting of: —NH 2 , —NHCH 2 CH 3 , —NHCH(CH 3 )C(F) 3 , —NHC(O)OCH 3 , —NHC(O)CH 3 , —OCH 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OH, —(CH 2 ) 3 —O—CH 3 , cyclopropyl, (f1), (f2), (f3), (f4), (f8), (f9), (f11), and (f12).
13. A compound selected from the group consisting of compounds (10)-(12), (14)-(23), (26)-(30), (32)-(42), (44), (45), and (47), or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.