High affinity quinoline-based kinase ligands
View Patent ↗Quinoline-based inhibitors of cyclin dependent kinase 2, compositions including the inhibitors, and methods of using the inhibitors and inhibitor compositions are described. The inhibitors and compositions including them are useful for treating disease or disease symptoms. The invention also provides for methods of making CDK-2 inhibitor compounds, methods of inhibiting CDK-2, and methods for treating disease or disease symptoms.
1. A compound of the formula (I)
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
R 0 is arylalkyl, wherein said aryl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different and are independently selected from Q 0 ;
R 1 is hydrogen, alkyl, aryl, alkylaryl, arylalkyl, alkylheteroaryl, alkoxy, alkoxyalkyl, alkoxyoxo, amino, aminoalkyl, alkylamino, alkylheterocyclyl, carboxy, cyanoalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, oxo, —CO 2 R 5 , —C(O)N(R 5 ) 2 , or —C═(NOR 5 ), where each of said R 5 is independently hydrogen, alkyl, aryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, alkoxyalkyl, aminoalkyl, cyanoalkyl, oxo, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, or alkylamino; further wherein each of said alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different and are independently selected from Q 1 ;
R 2 is hydrogen, akyl, aryl, alkylaryl, arylalkyl, carboxy, alkoxyoxo, alkylsulfonamido, heterocyclyl, heteroaryl, heteroarylalkyl, —CO 2 R 6 , —N(R 6 )SO 2 R 6 , —C(O)NHSO 2 R 6 , —SO 2 R 6 , —C(O)N(R 6 ) 2 , or —C(O)NHC(R 6 )C(O)R 6 ; where each of said R 6 is independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl alkylheteroaryl, alkoxyalkyl, aminoalkyl, cyanoalkyl, alkyloxo, cycloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, alkylheterocyclyl, or alkylamino; further wherein each of said alkyl, aryl, heteroaryl, and cycloalkyl and heterocyclyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different and are independently selected from Q 2 ;
R 3 is aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or heteroaryl, further wherein each of said aryl, and heteroaryl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different and are independently selected from Q 3 ;
Q 0 is alkyl, hydroxy, amino, halo, alkoxy, alkylamino, dialkylamino, aminoalkyl, hydroxyalkyl, haloalkyl, arylalkyl, heteroarylalkyl, aryl, haloaryl, alkylaryl, aryloxy, heteroaryl, haloheteroaryl, alkylheteroaryl, hydroxyheteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, alkylamido, oxo, alkylsulfonamido, alkyloxo, alkoxyoxo, nitro, cyano, haloalkoxy, —C(O)NH, —NHC(O), —S(O) 2 NH, or —NHS(O) 2 ;
Q 1 is hydrogen, alkyl, hydroxy, amino, halo, alkoxy, alkylamino, dialkylamino, aminoalkyl, hydroxyalkyl, haloalkyl, arylalkyl, heteroarylalkyl, aryl, haloaryl. alkylaryl, aryloxy, cycloalkyl, heteroaryl, haloheteroaryl, alkylheteroaryl, hydroxyheteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, alkylamido oxo, alkylsulfonamido, alkyloxo, alkoxyoxo, nitro, cyano, haloalkoxy-C(O)NH, —NHC(O), —S(O) 2 NH, or —NHS(O) 2 ;
Q 2 is hydrogen, alkyl, alkyloxo, alkylsulfonyl, aryl, arylsulfonyl, hydroxy, hydroxyalkyl, amino, halo, alkoxy, alkoxyoxo, alkylamino, dialkylamino, aminoalkyl, hydroxyalkyl, haloalkyl, arylalkyl, heteroarylalkyl, heteroarylsulfonyl, haloaryl, hydroxysulfonyl, alkylaryl, aryloxy cycloalkyl, heteroaryl, haloheteroaryl, alkylheteroaryl, hydroxyheteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, alkylamido, oxo, alkylsulfonamido, alkyloxo, alkoxyoxo, nitro, cyano, haloalkoxy, —C(O)NH, —NHC(O), —S(O) 2 NH, or —NHS(O) 2 ; and
Q 3 is hydrogen, alkyl, alkylamido, alkyloxo, alkylsulfonyl, alkoxyoxo, alkylaryl, alkylheteroaryl, amino, aryloxy, aryl, arylsulfonyl, alkylsulfonamido, halo, alkoxy, alkoxyoxo, alkylamino, aminoakyl, arylalkyl, cycloalkyl, cyano, dialkylamino, dialkylaminoalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, haloaryl, heteroarylalkyl, heteroarylsulfonyl, hydroxy, hydroxyalkyl, hydroxysulfonyl, heteroaryl, haloheteroaryl, hydroxyheteroaryl, hydroxyheterocyclyl, heteroaryloxy, heterocyclyl, heterocyclyloxy, oxo, nitro, —C(O)NH, —NHC(O), —S(O) 2 NH, or —NHS(O) 2 .
2. The compound of claim 1 , wherein R 0 is —(CH 2 ) n R 4 ; where n=1-3 and R 4 is aryl.
3. The compound of claim 1 , wherein R 1 is —CO 2 R 5 , —(CH 2 ) n OR 5 , —(CH 2 ) n N(R 5 ) 2 , —C(O)N(R 5 ) 2 , or —C═NOR 5 ; where n=1-3 and each R 5 is independently hydrogen, alkyl, aryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, alkoxyalkyl, aminoalkyl, cyanoalkyl, oxo, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, or alkylamino.
4. The compound of claim 1 , wherein R 2 is hydrogen, —CO 2 R 6 , —N(R 6 )SO 2 R 6 , —C(O)NHSO 2 R 6 , —SO 2 R 6 , —(C(O)N(R 6 ) 2 ), heterocyclyl, or heteroaryl; where each R 6 is independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkylheteroaryl, alkoxyalkyl, aminoalkyl, cyanoalkyl, alkyloxo, cycloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, alkylheterocyclyl, or alkylamino.
5. The compound of claim 1 wherein R 3 is heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, phenyl, aryl, heteroaryl, or arylalkyl.
6. The compound of claim 1 , wherein:
R 0 is —(CH 2 ) n R 4 ; where n=1-3 and R 4 is aryl;
R 1 is —CO 2 R 5 , —(CH 2 ) n OR 5 , —(CH 2 ) n N(R 5 ) 2 , —C(O)N(R 5 ) 2 , or —C═NOR 5 ; where n=1-3 and R 5 is each, independently, hydrogen, alkyl, aryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, alkoxyalkyl, aminoalkyl, cyanoalkyl, oxo, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, or alkylamino;
R 2 is hydrogen, —CO 2 R 6 , —N(R 6 )SO 2 R 6 , —C(O)NHSO 2 R 6 , —SO 2 R 6 , —(C(O)N(R 6 ) 2 ), heterocyclyl, or heteroaryl; where R 6 is each, independently, hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkylheteroaryl, alkoxyalkyl, aminoalkyl, cyanoalkyl, alkyloxo, cycloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, alkylheterocyclyl, or alkylamino; and
R 3 is heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, phenyl, aryl, heteroaryl, or arylalkyl.
7. The compound of claim 2 , wherein R 0 is —(CH 2 ) n -phenyl.
8. The compound of claim 7 , wherein said phenyl is optionally substituted with 1 or 2 moieties which are hydroxy, alkoxy, nitro or halo.
9. The compound of claim 8 , wherein R 0 is:
where each R 8 is hydrogen, or alkyl.
10. The compound of claim 7 , wherein R 0 is:
11. The compound of claim 10 , wherein R 0 is:
12. The compound of claim 1 , wherein R 1 is hydrogen, alkyl, aryl, alkylaryl, arylalkyl, alkylheteroaryl, alkoxy, alkoxyalkyl, alkoxyoxo, aminoalkyl, alkylheterocyclyl, carboxy, cyanoalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, oxo, —CO 2 R 5 , —C(O)N(R 5 ) 2 —CH 2 NHCH 2 CH 2 N(CH 3 ) 2 , or —C═NOR 5 , where R 5 is hydrogen, alkyl, aryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, alkoxyalkyl, cycloalkyl, or heterocyclyl.
13. The compound of claim 12 , wherein R 1 is —CO 2 R 5 , —(CH 2 ) n OR 5 , —(CH 2 ) n N(R 5 ) 2 , —C(O)N(R 5 ) 2 , or —C═NOR 5 , where n=1-3.
14. The compound of claim 13 , wherein R 1 is:
15. The compound of claim 12 , wherein R 1 is:
16. The compound of claim 12 , wherein R 1 is:
17. The compound of claim 12 , wherein R 1 is —C(O)OCH 3 .
18. The compound of claim 12 , wherein R 1 is —CH 2 OCH 3 .
19. The compound of claim 1 , wherein R 2 is hydrogen, alkyl, aryl, alkylaryl, arylalkyl, carboxy, alkoxyoxo, alkylsulfonamido, heterocyclyl, heteroaryl, heteroarylalkyl, —CO 2 R 6 , —N(R 6 )SO 2 R 6 , —C(O)NHSO 2 R 6 , —SO 2 R 6 , —C(O)N(R 6 ) 2 , or —C(O)NHC(R 6 )C(O)R 6 ; where R 6 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkylheteroaryl, alkoxyalkyl, aminoalkyl, cyanoalkyl, alkyloxo, cycloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, alkylheterocyclyl, or alkylamino.
20. The compound of claim 19 , wherein R 2 is hydrogen, —CO 2 R 6 , —N(R 6 )SO 2 R 6 , —C(O)NHSO 2 R 6 , —SO 2 R 6 , —C(O)N(R 6 ) 2 , or —C(O)NHC(R 6 )C(O)R 6 ; where R 6 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkylheteroaryl, alkoxyalkyl aminoalkyl, cyanoalkyl, alkyloxo, cycloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, alkylheterocyclyl, or alkylamino.
21. The compound of claim 19 , wherein R 2 is:
22. The compound of claim 19 , wherein R 2 is:
23. The compound of claim 19 , wherein R 2 is
24. The compound of claim 19 , wherein R 2 is
25. The compound of claim 19 , wherein R 2 is —COOH.
26. The compound of claim 19 , wherein R 2 is —NHS(O) 2 C(CH 3 ) 3 .
27. The compound of claim 1 , wherein R 3 is aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or heteroaryl, wherein each of said aryl, heteroaryl, and heteroarylalkyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different and is independently selected from Q 3 .
28. The compound of claim 27 , wherein R 3 is:
where n is 1 or 2 and Q 1 is hydrogen, alkyl, hydroxy, amino, halo, alkoxy, alkylamino, dialkylamino, aminoalkyl, hydroxyalkyl, haloalkyl, arylalkyl, heteroarylalkyl, aryl, haloaryl, alkylaryl, aryloxy, cycloalkyl, heteroaryl, haloheteroaryl, alkylheteroaryl, hydroxyheteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, alkylamido, oxo, alkylsulfonamido, alkyloxo, alkoxyoxo, nitro, cyano, haloalkoxy-C(O)NH, —NHC(O), —S(O) 2 NH, or —NHS(O) 2 .
29. The compound of claims 27 , wherein R 3 is:
where n is 1 or 2; Q 1 is hydrogen, alkyl, hydroxy, amino, halo, alkoxy, alkylamino, Dialkylamino, aminoalkyl, hydroxyalkyl, haloalkyl, arylalkyl, heteroarylalkyl, aryl, haloaryl, alkylaryl, aryloxy, cycloalkyl, heteroaryl, haloheteroaryl, alkylheteroaryl, hydroxyheteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, alkylamido, oxo, alkylsulfonamido, alkyloxo, alkoxyoxo, nitro, cyano, haloalkoxy-C(O)NH, —NHC(O), —S(O) 2 NH, or —NHS(O) 2 ; and L is —CH 2 CH 2 —, —CH═CH—, —C≡C—, —CH 2 O—, or —OCH 2 —.
30. The compound of claim 27 , wherein R 3 is:
31. The compound of claim 27 , wherein R 3 is:
32. The compound of claim 27 , wherein R 3 is:
where A is O or S.
33. The compound of claim 27 , wherein R 3 is:
where X is halo.
34. The compound of claim 27 , wherein R 3 is:
where X is halo or CF 3 and A is O or S.
35. The compound of claim 27 , wherein R 3 is:
36. The compound of claim 27 , wherein R 3 is
37. The compound of claim 27 , wherein R 3 is:
38. The compound of claim 27 , wherein R 3 is:
39. The compound of claim 27 , wherein R 3 is:
40. The compound of claim 27 , wherein R 3 is:
41. The compound of claims 1 , wherein:
R 0 is hydroxyarylalkyl;
R 1 is —CO 2 R 5 , where R 5 is alkyl;
R 2 is —CO 2 H; and
R 3 is haloalkylaryl.
42. The compound of claim 1 , wherein:
R 0 is hydroxyarylalkyl;
R 1 is —CO 2 R 5 , where R 5 is alkyl;
R 2 is —CO 2 H; and
R 3 is haloalkoxyaryl.
43. The compound of claim 1 , wherein:
R 0 is hydroxyarylalkyl;
R 1 is —CO 2 R 5 , where R 5 is alkyl;
R 2 is —CO 2 H; and
R 3 is haloarylalkyl.
44. The compound of claim 1 , wherein:
R 0 is hydroxyarylalkyl;
R 1 is —CO 2 R 5 , where R 5 is alkyl;
R 2 is —CO 2 H; and
R 3 is haloarylalkenyl.
45. The compound of claim 1 , wherein:
R 0 is hydroxyarylalkyl;
R 1 is —CO 2 R 5 , where R 5 is alkyl;
R 2 is —CO 2 H; and
R 3 is haloarylalkyl.
46. The compound of claim 1 , wherein:
R 0 is hydroxyarylalkyl;
R 1 is —CO 2 R 5 , where R 5 is alkyl;
R 2 is —CO 2 H; and
R 3 is heteroarylalkylaryl.
47. The compound of claim 1 , wherein the compound is selected from:
48. A pharmaceutical composition, comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.
49. The pharmaceutical composition of claim 48 that is formulated for single dosage administration.
50. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in combination with at least one pharmaceutically acceptable carrier.
51. A compound of claim 1 in purified form.