2-aminothiazole-4-carboxylic amides as protein kinase inhibitors
View Patent ↗The present invention relates to novel Anilinopiperazine Derivatives of formula (I), compositions comprising the Anilinopiperazine Derivatives, and methods for using the Anilinopiperazine Derivatives for treating or preventing a proliferative disorder, an anti-proliferative disorder, inflammation, arthritis, a central nervous system disorder, a cardiovascular disease, alopecia, a neuronal disease, an ischemic injury, a viral disease, a fungal infection, or a disorder related to the activity of a protein kinase.
1. A compound having the formula:
or a pharmaceutically acceptable salt, ester, prodrug or stereoisomer thereof, wherein the dashed line indicates an optional and additional bond, and wherein:
R 1 is nitrogen-containing heteroaryl, nitrogen-containing heterocyclyl, nitrogen-containing benzofused heteroaryl or nitrogen-containing benzofused heterocyclyl, wherein R 1 is joined to the rest of the compound of formula (I) via a ring nitrogen atom, and wherein one or more ring carbon atoms of the nitrogen-containing heteroaryl, nitrogen-containing heterocyclyl, nitrogen-containing benzofused heteroaryl or nitrogen-containing benzofused heterocyclyl group can be substituted with up to 5 substituents, which may be the same or different, and are independently selected from alkyl, aryl, halo, —OH, —O-alkyl, —O-aryl, —N(R 8 ) 2 —CF 3 , —NO 2 , —C(O)R 8 , —C(O)OR 8 , —C(O)N(R 8 ) 2 , —OC(O)R 8 or —NHC(O)R 8 ;
R 2 is —H, -alkyl, —NH 2 or —CH 2 NH 2 ;
R 3 is —H, -alkyl, —NH 2 or —CH 2 NH 2 ;
each occurrence of R 4 is independently —H, -alkyl, —NH 2 , —OH, -alkylene-OH, —CH 2 NH 2 , —C(O)R 5 , —C(O)NH 2 , —C(O)NH-alkyl, —C(O)N(alkyl) 2 , —NHC(O)R 6 or —NHS(O) 2 R 6 ;
R 5 is —H, -alkyl, -aryl, -heteroaryl, —NHOH;
R 6 is —H, -alkyl or —CF 3 ;
R 7 is —H, —OH, —C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl), or —CF 3 ;
R 8 is —H, alkyl, aryl, heterocyclyl, heteroaryl or cycloalkyl;
Ar is -arylene- or -heteroarylene-, wherein the arylene or heteroarylene is joined via 2 of its adjacent ring carbon atoms, and wherein the -arylene- or -heteroarylene- can be substituted with up to 4 substituents, which may be the same or different, and are independently selected from -halo, alkyl, alkoxy, aryloxy, —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , —C(O)R 8 , —C(O)OR 8 , —C(O)N(R 8 ) 2 , —NHC(O)R 8 , —CF 3 , —CN or NO 2 , and such that when Ar is tetrahydronaphthylene, R 1 and R 2 cannot both be hydrogen
W is —NH— or —C(R 4 ) 2 —, wherein both R 4 groups and the carbon atom to which they are attached can combine to form a five to seven membered heterocyclyl or heteroaryl group;
Y is —H, -halo, -alkyl or —CN; and
Z is —CR 7 — or —N—, when the optional additional bond is absent, and —C— when the optional additional bond is present.
2. The compound of claim 1 , wherein R 1 is nitrogen-containing heteroaryl.
3. The compound of claim 1 , wherein R 1 is nitrogen-containing heterocyclyl.
4. The compound of claim 1 , wherein R 1 is nitrogen-containing benzofused heteroaryl.
5. The compound of claim 1 , wherein R 1 is nitrogen-containing benzofused heterocyclyl.
6. The compound of claim 1 , wherein R 1 is
7. The compound of claim 1 , wherein R 2 and R 3 are each —H; and Z is —N—.
8. The compound of claim 7 , wherein W is —(CR 4 ) 2 —.
9. The compound of claim 7 , wherein W is NH.
10. The compound of claim 1 , wherein Ar is:
11. The compound of claim 8 , wherein Ar is:
12. The compound of claim 1 having the formula:
or a pharmaceutically acceptable salt, ester, prodrug or stereoisomer thereof, wherein X is N or CH; and R 1 is as defined in claim 1 .
13. The compound of claim 12 , wherein X is N.
14. A compound of claim 1 in purified form.
15. A pharmaceutical composition comprising an effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, ester, prodrug or stereoisomer thereof, and a pharmaceutically acceptable carrier.
16. A pharmaceutical composition comprising an effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, ester, prodrug or stereoisomer thereof, and a pharmaceutically acceptable carrier, further comprising an effective amount of at least one anticancer agent, wherein the anticancer agent is different from the compound of claim 1 .