CDK inhibitors
Compounds of formulae I, II or III, and pharmaceutically acceptable salts thereof, are useful as CDK inhibitors.
1. A compound of formula:
or a pharmaceutically acceptable salt thereof, wherein:
Z is —(CH 2 ) x — wherein x is 2 or 3;
each X is independently CH or N;
each R 1 is independently aryl, alkyl, or cycloalkyl, wherein two R 1 s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle;
y is 0, 1, 2, or 3;
R 2 is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 , -(alkylene) m -C(O)—O-alkyl, -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valence;
m is 0 or 1;
n is 1 or 2;
R 3 and R 4 at each occurrence are independently:
(i) hydrogen or
(ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, or R 3 and R 4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring;
R 5 is:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl;
R x at each occurrence is independently, halo, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkyl; and
R 6 is a lower alkyl or absent.
2. The compound of claim 1 having formula:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 having formula:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 having formula:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 having formula:
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 having formula:
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 having formula:
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 having formula:
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 having formula:
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 having formula:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 having formula:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , wherein x 2.
13. The compound of claim 1 , wherein y is 0, 1, or 2.
14. The compound of claim 1 , wherein R 2 is -(alkylene) m -heterocyclo, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -C(O)—O-alkyl, or -(alkylene) m -O—R 5 .
15. The compound of claim 1 , wherein R 2 is -(alkylene) m -heterocyclo or -(alkylene) m -heteroaryl.
16. The compound of claim 1 , wherein R 2 is -(alkylene) m -heterocyclo.
17. The compound of claim 16 , wherein m is 0.
18. The compound of claim 1 , wherein R 2 is substituted with one R x group.
19. The compound of claim 1 , wherein R x is selected from alkyl, cycloalkyl, and heterocyclo.
20. The compound of claim 1 , wherein R 6 is absent.
21. The compound of claim 1 , wherein both of X are N.
22. The compound of claim 1 , wherein one X is N and the other is CH.
23. The compound of claim 22 , wherein x is 2.
24. The compound of claim 23 , wherein y is 0, 1, or 2.
25. The compound of claim 24 , wherein R 2 is -(alkylene) m -heterocyclo.
26. The compound of claim 25 , wherein m is 0.
27. The compound of claim 26 , wherein R 2 is substituted with one R x group.
28. The compound of claim 27 , wherein R x is selected from alkyl, cycloalkyl, and heterocyclo.
29. The compound of claim 28 , wherein R 6 is absent.
30. The compound of claim 29 , wherein y is 2.
31. The compound of claim 30 , wherein two R 1 s on the same ring atom together with the ring atom to which they are attached form a 3-8-membered cycle.
32. The compound of claim 31 , wherein the 3-8-membered cycle is a 6-membered cycle.
33. A compound of formula:
or a pharmaceutically acceptable salt thereof, wherein:
Z is —(CH 2 ) x — wherein x is 2 or 3;
each X is independently CH or N;
each R 1 is independently aryl, alkyl, or cycloalkyl, wherein two R 1 s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle;
y is 0, 1, 2, or 3;
R 6 is a lower alkyl or absent;
R 2 is
R 2 * is a bond, alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m - or -(alkylene) m -NH-(alkylene) m -;
P is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group;
each R x1 is independently —(C(O))—O-alkyl, -(alkylene) m -cycloalkyl, —N(R N )-cycloalkyl, —C(O)-cycloalkyl, -(alkylene) m -heterocyclyl, —N(R N )-heterocyclyl, —C(O)-heterocyclyl, or —S(O) 2 -(alkylene) m ;
R N is H, C 1 to C 4 alkyl or C 1 to C 6 heteroalkyl;
m is 0 or 1; and
t is 0, 1 or 2.
34. The compound of claim 33 , wherein x is 2.
35. The compound of claim 33 , wherein y is 0, 1, or 2.
36. The compound of claim 33 , wherein R 6 is absent.
37. The compound of claim 33 , wherein one X is N and the other is CH.
38. The compound of claim 37 , wherein x is 2.
39. The compound of claim 38 , wherein y is 0, 1, or 2.
40. The compound of claim 39 , wherein R 6 is absent.
41. The compound of claim 40 , wherein y is 2.
42. The compound of claim 41 , wherein two R 1 s on the same ring atom together with the ring atom to which they are attached form a 3-8-membered cycle.
43. The compound of claim 42 , wherein the 3-8-membered cycle is a 6-membered cycle.
44. The compound of claim 43 , wherein R 2 is
45. The compound of claim 43 , wherein R 2 is
46. A compound of formula:
or a pharmaceutically acceptable salt thereof, wherein:
Z is —(CH 2 ) x — wherein x is 2 or 3;
each X is independently CH or N;
each R 1 is independently aryl, alkyl, or cycloalkyl, wherein two R 1 s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle;
y is 0, 1, 2, or 3;
R 6 is a lower alkyl or absent;
R 2 is
R 2 * is a bond, alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m - or -(alkylene) m -NH-(alkylene) m -;
P is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group;
P1 is a 4- to 6-membered monocyclic saturated heterocyclyl group;
each R x2 is independently hydrogen or alkyl;
m is 0 or 1; and
s is 0, 1 or 2.
47. The compound of claim 46 , wherein x is 2.
48. The compound of claim 46 , wherein y is 0, 1, or 2.
49. The compound of claim 46 , wherein R 6 is absent.
50. The compound of claim 46 , wherein one X is N and the other is CH.
51. The compound of claim 50 , wherein x is 2.
52. The compound of claim 51 , wherein y is 0, 1, or 2.
53. The compound of claim 52 , wherein R 6 is absent.
54. The compound of claim 53 , wherein y is 2.
55. The compound of claim 54 , wherein two R 1 s on the same ring atom together with the ring atom to which they are attached form a 3-8-membered cycle.
56. The compound of claim 55 , wherein the 3-8-membered cycle is a 6-membered cycle.
57. The compound of claim 56 , wherein R 2 is