Amines as small molecule inhibitors
View Patent ↗The present invention relates to compounds that are useful as inhibitors of protein arginine methyltransferase that have a formula selected from Formula (I), Formula (II) and Formula (III), as well as racemic mixtures, diastereomers, enantiomers and tautomers thereof and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof as defined herein. The compound are useful as inhibitors of PRMTs and/or CARM-I. The invention further relates to compositions comprising such compounds and methods for their use.
1. A compound of Formula (I),
or a pharmaceutically acceptable salt thereof, wherein
A is phenyl or piperidinyl;
B together with R 6 and Z is
M is selected from the group consisting of
or
M is selected from the group consisting of
or
M is selected from the group consisting of
or
M is selected from the group consisting of
wherein p is 1, 2 or 3;
each R 13 is independently selected from the group consisting of H and C 1 -C 4 alkyl;
each R 14 is independently selected from the group consisting of H and C 1 -C 4 alkyl; or alternatively,
R 8 and R 14 may join to form a 4-, 5- or 6-membered saturated ring containing one N atom; and
ring D is a heterocycle, preferably selected from the group consisting of
wherein the left side of ring D as shown is attached to ring A; and
wherein Q is selected from the group consisting of —N(R 15 )—, O and S; and
R 15 is C 1 -C 6 alkyl; and
each R 1 is independently selected from the group consisting of H, —OH, —CF 3 , —CHF 2 , —CH 2 F, halo, —CN, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, cycloalkyl, heterocyclyl, —O-alkyl, —S(O) 0-1 -alkyl, —O-cycloalkyl, —S(O) 0-1 -cycloalkyl, —O-heterocyclyl, —S(O) 0-1 -heterocyclyl, —O-aryl, —S(O) 0-1 aryl, —O-heteroaryl, —S(O) 0-1 -heteroaryl, -alkyl-cycloalkyl, -alkyl-heterocyclyl, -alkyl-aryl, -alkyl-heteroaryl and ═O;
R 2 is selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, -alkyl-aryl, -alkyl-heteroaryl, -alkyl-cycloalkyl and -alkyl-heterocycle, each of which is optionally substituted; or
R 1 and R 2 together form a 5-, 6- or 7-membered heterocycle, each of which is optionally substituted; or
R 2 optionally bonds with Ring A to form a 5 or 6 membered heterocycle fused to ring A;
R 3 is selected from the group consisting of H, —OH, —CF 3 , —CHF 2 , —CH 2 F, halo, —CN, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, cycloalkyl, heterocyclyl, —O-alkyl, —S(O) 0-1 -alkyl, —O-cycloalkyl, —S(O) 0-1 -cycloalkyl, —O-heterocyclyl, —S(O) 0-1 -heterocyclyl, —O-aryl, —S(O) 0-1 aryl, —O-heteroaryl, —S(O) 0-1 -heteroaryl, -alkyl-cycloalkyl, -alkyl-heterocyclyl, -alkyl-aryl, -alkyl-heteroaryl and ═O; or
R 2 together with R 3 optionally form a 4-, 5-, 6- or 7-membered heterocycle, each of which is optionally substituted;
R 4 is selected from the group consisting of H, —OH, halo, —CN, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, cycloalkyl, heterocyclyl, —O-alkyl, —S(O) 0-1 -alkyl, —O-cycloalkyl, —S(O) 0-1 -cycloalkyl, —O-heterocyclyl, —S(O) 0-1 -heterocyclyl, —O-aryl, —S(O) 0-1 aryl, —O-heteroaryl, —S(O) 0-1 -heteroaryl, -alkyl-cycloalkyl, -alkyl-heterocyclyl, -alkyl-aryl, -alkyl-heteroaryl and ═O, each of which is optionally substituted;
R 5 is selected from the group consisting of H, —NO 2 , halo, —CN, —CF 3 , —CHF 2 , —CH 2 F, —OH, —SH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —O-alkyl, —S(O) 0-1 -alkyl, —O-cycloalkyl, —S(O) 01 -cycloalkyl, —O-heterocyclyl, —S(O) 0-1 -heterocyclyl, ═O, —O-aryl, —S(O) 0-1 -aryl, —O-heteroaryl, —S(O) 0-1 -heteroaryl, —O—C(O)—N(R 2 ) 2 , —N(R 2 )—C(O)—O—R 2 , —C(O)—NH2, —C(O)—O—R 2 , —C(O)—N(R 2 ) 2 ;
R 7 is selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl and substituted heteroaryl, alkyl, optionally substituted alkyl;
each R 8 is independently selected from the group consisting of H and C 1 -C 4 alkyl;
Y is —H, O, S or —N(R 8 );
G 1 is O, S or NR 8 ;
G 2 is N or CH;
G 3 is N or CH;
wherein
R 10 is selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, -alkyl-aryl, -alkyl-heteroaryl, -alkyl-cycloalkyl and -alkyl-heterocycle, each of which is optionally substituted;
W is selected from the group consisting of a bond, an optionally substituted C 1 -C 4 alkyl, —O—, —S(O) 0-2 —, —N(R 10 )—, —O—C(O)—N(R 10 )—, —N(R 10 )—C(O)—O—, —O—C(S)—N(R 10 )—, —N(R 10 )—C(S)—O—, —N(R 10 )—S(O) 2 —, —S(O) 2 —N(R 10 )—, —C(O)—, —C(S)—, —O—C(O)— and —C(O)—O—; or
u is 0 or 1;
s is 0, 1, 2 or 3; and
n is 0 or 1.
2. The compound according to claim 1 , wherein ring A is selected from the group consisting of
wherein group M is attached via the N atom of ring A;
Q is selected from the group consisting of —N(R 15 )—, O and S; and
R 15 is C 1 -C 6 alkyl.
3. The compound according to claim 1 , wherein ring A is phenyl.
4. The compound according to claim 1 , wherein ring A is
wherein group M is attached via the N atom of ring A.
5. The compound according to claim 1 , wherein R 7 is aryl, heteroaryl, substituted aryl or substituted heteroaryl.
6. The compound according to claim 1 , wherein R 7 is selected from the group consisting of phenyl, pyridine, napthylene and cyclohexyl, each of is optionally substituted.
7. The compound according to claim 1 , wherein R 7 is an optionally substituted heterocycle.
8. The compound according to claim 1 , wherein R 7 is selected from the group consisting of
each of which is optionally substituted.
9. The compound according to claim 1 , wherein M is
10. The compound according to claim 1 , wherein M is
11. The compound according to claim 1 , wherein M is
12. The compound according to claim 1 , wherein M is
13. The compound according to claim 1 , wherein M is
14. The compound according to claim 1 , wherein W is —O—.
15. The compound according to claim 1 , wherein R 4 is halo or alkyl.
16. The compound according to claim 1 , wherein X 4 is a bond, X 1 and X 2 are each N, and X 3 and X 5 are each C, wherein X 3 is substituted with —CF 3 .
17. The compound according to claim 1 , wherein R 7 is substituted with a substituent selected from the group consisting of alkoxy, alkyl, halo, —CO 2 -alkyl, —CF 3 , —C(O)—O-alkyl, fused heterocycle, —O—CF 3 , —O—CHF 2 , —NH 2 , —NH-alkyl, —N(alkyl) 2 and —O-phenyl.
18. The compound according to claim 1 , wherein each R 8 is independently selected from the group consisting of H, methyl, ethyl and isopropyl.
19. The compound according to claim 1 , wherein D is
wherein * represents the point of attachment to ring A.
20. The compound according to claim 1 , wherein M and ring B are in a meta or para position on ring A.
21. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
22. The composition according to claim 21 , further comprising an additional therapeutic agent.
23. An N-oxide, prodrug or complex of the compound according to claim 1 and racemic mixtures, diastereomers, enantiomers and tautomers thereof.
24. A prodrug of the compound of claim 1 .
25. A racemic mixture, diastereomer, enantiomer or tautomer of the compound according to claim 1 .