US 2007/0191604 A1 · Novel compounds that are ERK inhibitors

Abstract

Disclosed are the ERK inhibitors of formula 1.0: and the pharmaceutically acceptable salts and solvates thereof. Q is a piperidine or piperazine ring that can have a bridge or a fused ring. The piperidine ring can have a double bond in the ring. All other substitutents are as defined herein. Also disclosed are methods of treating cancer using the compounds of formula 1.0.

A compound of formula 1.0:

or the pharmaceutically acceptable salts thereof, wherein:
Y1, Y2, and Y3 are each independently selected from the group consisting of:
—CH═, —N═ and —CR9═;
z is 1 to 3;
Q is a substituent selected from the group consisting of:
Each Q1 represents a ring independently selected from the group consisting of:
cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, wherein said substituted rings are substituted with 1 to 3 substituents independently selected from the group consisting of:
the R10 moieties;
provided that when Q1 is aryl, heteroaryl, substituted aryl or substituted heteroaryl then the carbon atoms at the ring junction are not substituted;
Q2 represents a ring selected from the group consisting of:
cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl, wherein said substituted rings are substituted with 1 to 3 substituents independently selected from the group consisting of:
the R10 moieties;
Z1 represents —(C(R24)2)w— wherein each R24 is independently selected from the group consisting of:
H, alkyl and F, and wherein w is 1, 2 or 3;
Z2 is selected from the group consisting of:
—N(R44)—, —O— and —C(R46)2—;
m is 1 to 6;
n is 1 to 6;
p is 0 to 6;
t is 0, 1, or 2;
R1 is selected from the group consisting of:
(1) —CN,
(2) —NO2,
(3) —OR10,
(4) —SR10,
(5) —N(R10)2,
(6) R10,
(7) —C(O)R10,
(8) —(C(R30)2)n—NR32—C(O)—R10,
(9) —(C(R30)2)n—NR32—S(O)t—R10,
(10) —(C(R30)2)n—NR32—C(O)—N(R32)—R10,
(12) —CF3,
(13) —C(O)OR10,
(14) —(C(R30)2)nR13 (e.g., —(CH2)nR13),
(15) alkenyl,
(16) —NR32C(O)—R14,
wherein each R10 is independently selected,
wherein each R10 is independently selected,
(20) —C(O)—NR32—(C(R30)2)p—OR10,
(21) —C(O)N(R10)2 wherein each R10 is independently selected,
(22) —C(O)—NR32—C(R18)3,
(23) —C(O)—NR32—(C(R30)2)n—C(O)—N(R10)2,
(24) heterocycloalkenyl,
(26) arylalkenyl-;
R2 is selected from the group consisting of:
(1) H,
(2) —CN,
(3) halo,
(4) alkyl,
(5) substituted alkyl wherein said substituted alkyl is substituted with 1 to 3 substitutents selected from the group consisting of:
(a) —OH, (b) —O-alkyl (e.g., —O—(C1-C3alkyl), (c) —O-alkyl substituted with 1 to 3 F atoms, and (d) —N(R40)2 wherein each R40 is independently selected from the group consisting of:
(i) H, (ii) C1-C3 alkyl, (iii) —CF3, and (e) halo,
(6) alkynyl,
(7) alkenyl,
(8) —(CH2)mR11,
(9) —N(R26)2,
(10) —OR23,
(11) —N(R26)C(O)R42,
(12) cycloalkyl,
(13) cycloalkylalkyl,
(15) —O-(substituted alkyl) wherein said substituted alkyl is substituted with 1 to 3 F atoms,
(16) —S(O)t-alkyl,
(17) —C(O)-alkyl,
wherein each alkyl is independently selected,
which each alkyl is independently selected,
wherein each alkyl is independently selected,
(22) —N(R48)—C(O)—R48 wherein each R48 is independently selected from the group consisting of:
H and alkyl, and
(23) —C(O)-alkyl, such as, for example, —C(O)—(C1-C6 alkyl), such as, for example, —C(O)CH3;
each R3, R4, R5, R6 and R7 is independently selected from the group consisting of:
(1) H,
(2) alkenyl,
(3) substituted alkenyl,
(4) alkyl,
(5) substituted alkyl,
(6) cycloalkyl,
(7) substituted cycloalkyl,
(8) cycloalkylalkyl-,
(9) substituted cycloalkylalkyl-,
(10) heterocycloalkyl,
(11) substituted heterocycloalkyl,
(12) heterocycloalkylalkyl-,
(13) substituted heterocycloalkylalkyl-,
(14) —C(O)R10,
(15) arylheteroaryl-,
(16) substituted arylheteroaryl-,
(17) heteroarylaryl-,
(18) substituted heteroarylaryl-,
(19) aryl,
(20) substituted aryl,
(21) heteroaryl,
(22) substituted heteroaryl,
(23) heteroarylheteroaryl-,
(24) substituted heteroarylheteroaryl-,
(25) arylaminoheteroaryl-,
(26) substituted arylaminoheteroaryl-,
(27) arylalkynyl-,
(28) substituted arylalkynyl-,
(29) heteroarylalkynyl-,
(30) substituted heteroarylalkynyl-,
wherein said R3, R4, R5, R6 and R7 substituted groups (7), (9), (11), (13), (16), (18), (20), (22), (24), (26), (28) and (30) are substituted with 1 to 3 substituents independently selected from the group consisting of:
—NH2, alkyl, alkenyl, halo, —C(O)—NH—R28, —C(O)OR28, and —C(O)R28, and
wherein said R3, R4, R5, R6 and R7 substituted groups (3) and (5) are substituted with 1 to 3 substituents independently selected from the group consisting of:
—NH2, halo (e.g., F, Cl and Br, and in another example F), —C(O)—NH—R28 (e.g., —C(O)—NH—CH3), —C(O)OR28 (e.g., —C(O)OC2H5), and —C(O)R28 (e.g., —C(O)CH3);
R5A is selected from the group consisting of:
halo, —OH, and —O-alkyl;
R8 is selected from the group consisting of:
H, —OH, —N(R10)2, —NR10C(O)R12, and alkyl;
each R9 is independently selected from the group consisting of:
halogen, —CN, —NO2, —OR10, —SR10, —N(R10)2, and R10;
each R10 is independently selected from the group consisting of:
H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylheteroaryl-, alkylaryl-, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl-, substituted alkylaryl-, heterocycloalkenyl, and substituted heterocycloalkenyl, and wherein:
said R10 substituted alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of:
—NH2, —NHR20, —NO2, —CN, —OR26, halo, —C(O)—NH—R26, —C(O)OR26, and —C(O)R26, and
said R10 substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl- are substituted with 1 to 3 substituents independently selected from the group consisting of:
(1) —NH2, (2) —NO2, (3) —CN, (4) —OH, (5) —OR20, (6) —OCF3, (7) alkyl substituted with 1 to 3 independently selec halo atoms, (8) —C(O)R38, (9) alkyl, (10) alkenyl, (11) halo, (12) —C(O)—NH—R26, (13) —C(O)OR38, (14) —C(O)—NR32—(C(R30)2)n—N(R38)2, (15) —S(O)tR38, (16) —C(O)—NR32—R38, (17) —NR32—C(O)—R38,
(19) —NHR20, and (20) cycloalkyl;
R11 is selected from the group consisting of:
F, —OH, —CN, —OR10, —NHNR1R10, —SR10 and heteroaryl;
R12 is selected from the group consisting of:
alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl and heterocycloalkylalkyl;
R14 is selected from the group consisting of:
alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl-, alkylheteroaryl- and alkylaryl-;
R15 is selected from the group consisting of:
H, —OH, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl and heterocycloalkylalkyl-, alkylheteroaryl- and alkylaryl-;
R20 represents alkyl;
R23 is selected from the group consisting of:
H, alkyl, aryl, cycloalkyl, and cycloalkylalkyl-;
each R26 is independently selected from the group consisting of:
H and alkyl;
R28 is alkyl;
each R30 is independently selected from the group consisting of:
H, alkyl, and F;
each R32 is independently selected from the group consisting of:
H and alkyl, and wherein each R is generally H;
each R35 is independently selected from the group consisting of:
H and C1 to C6 alkyl;
R36 is selected from the group consisting of:
H, alkyl, and —O-alkyl;
each R38 is independently selected from the group consisting of:
H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylheteroaryl-, alkylaryl-, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl-, and wherein:
said R38 substituted alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of:
—NH2, —NO2, —CN, —OR26, halo, —C(O)—NH—R28, —C(O)OR28, and —C(O)R28, and
said R38 substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl- are substituted with 1 to 3 substituents independently selected from the group consisting of:
(1) —NH2, (2) —NO2, (3) —CN, (4) —OH, (5) —OR20, (6) —OCF3, (7) —CF3, (8) —C(O)R26, (9) alkyl, (10) alkenyl, (11) halo, (12) —C(O)—NH—R26, (13) —C(O)OR26, (14) —C(O)—NR32—(C(R30)2)n—N(R26)2, (15) —S(O)tR26, (16) —C(O)N(R32)(R26), (17) —NR32C(O)R26,
(19) —NHR20;
R42 is selected from the group consisting of:
alkyl, aryl, heteroaryl, and cycloalkyl;
R44 is selected from the group consisting of:
H, alkyl, cycloalkyl, and cycloalkylalkyl;
and
Each R46 is independently selected from the group consisting of:
H, alkyl, cycloalkyl, and cycloalkylalkyl.

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Novel compounds that are ERK inhibitors

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Novel compounds that are ERK inhibitors

Life of this patent

Abstract

Claims139