CDK inhibitors

Patent metadata

Field	Value
Publication number	US-9957276-B2
Application number	US-201615348770-A
Country	US
Kind code	B2
Filing date	Nov 10, 2016
Priority date	Oct 25, 2010
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

Compounds of formulae I, II or III, and pharmaceutically acceptable salts thereof, are useful as CDK inhibitors.

First claim

What is claimed is:

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

Assignees

• G1 Therapeutics Inc
• Gi Therapeutics Inc

Inventors

• Tavares Francis X
• Strum Jay C

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/14 Primary

  Ortho-condensed systems · CPC title

• A61K31/499

  Spiro-condensed pyrazines or piperazines · CPC title

• C07D487/20

  Spiro-condensed systems · CPC title

• C07D498/14

  Ortho-condensed systems · CPC title