IP Library › Granted Patent US 8,822,683

Granted Patent B2

US 8,822,683 · App. 14/162,649 · Granted Sep 2, 2014

CDK inhibitors

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Quick Facts

Patent No.: US 8,822,683
App. No.: 14/162,649
Granted: Sep 2, 2014
Kind: B2

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Abstract

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

Claims (72)

1. A compound of the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R is H or CH 3 ,

each X is independently CH or N;

each R 1 is independently alkyl, cycloalkyl or haloalkyl;

y is 0, 1, 2, 3 or 4;

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 valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0 or 1 and n is 0, 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 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring; or R 3 and R 4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring;

R 5 and R 5 * at each occurrence is:

(i) hydrogen or

R x at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene) m -OR 5 , -(alkylene) m -O-alkylene-OR 5 , -(alkylene) m -S(O) n —R 5 , -(alkylene) m -NR 3 R 4 , -(alkylene) m -CN, -(alkylene) m -C(O)—R 5 , -(alkylene) m -C(S)—R 5 , -(alkylene) m -C(O)—OR 5 , -(alkylene) m -O—C(O)—R 5 , -(alkylene) m -C(S)—OR 5 , -(alkylene) m -C(O)-(alkylene) m -NR 3 R 4 , -(alkylene) m -C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—R 5 , -(alkylene) m -N(R 3 )—C(S)—R 5 , -(alkylene) m -O—C(O)—NR 3 R 4 , -(alkylene) m -O—C(S)—NR 3 R 4 , -(alkylene) m -SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—SO 2 —R 5 , -(alkylene) m -N(R 3 )—SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—OR 5 ), -(alkylene) m -N(R 3 )—C(S)—OR 5 , or -(alkylene) m -N(R 3 )—SO 2 —R 5 ; wherein:

said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene) m -CN, -(alkylene) m -OR 5 *, -(alkylene) m -S(O) n —R 5 *, -(alkylene) m -NR 3 *R 4 *, -(alkylene) m -C(O)—R 5 *, -(alkylene) m -C(═S)R 5 *, -(alkylene) m -C(═O)OR 5 *, -(alkylene) m -OC(═O)R 5 *, -(alkylene) m -C(S)—OR 5 *, -(alkylene) m -C(O)—NR 3 *R 4 *, -(alkylene) m -C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—R 5 *, -(alkylene) m -N(R 3 *)—C(S)—R 5 *, -(alkylene) m -O—C(O)—NR 3 *R 4 *, -(alkylene) m -O—C(S)—NR 3 *R 4 *, -(alkylene) m -SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—SO 2 —R 5 *, -(alkylene) m -N(R 3 *)—SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—OR 5 *, -(alkylene) m -N(R 3 *)—C(S)—OR 5 *, or -(alkylene) m -N(R 3 *)—SO 2 —R 5 *,

n is 0, 1 or 2, and

m is 0 or 1; and

R 3 * and R 4 * at each occurrence are independently:

(i) hydrogen or

(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance; or R 3 * and R 4 * together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance.

2. The compound of claim 1 , wherein both of X are N.

3. The compound of claim 1 , wherein one X is N and one X is CH.

4. 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 -OR 5 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring.

5. The compound of claim 1 , wherein R 2 is selected from the group consisting of

6. The compound of claim 1 , wherein R 2 is

wherein:

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 - wherein each m is independently 0 or 1;

P is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group;

each R x1 is independently -(alkylene) m -(C(O)) m -(alkylene) m -(N(R N )) m -(alkyl) m wherein each m is independently 0 or 1 provided at least one m is 1, —(C(O))—O-alkyl, -(alkylene) m -cycloalkyl wherein m is 0 or 1, —N(R N )-cycloalkyl, —C(O)-cycloalkyl, -(alkylene) m -heterocyclyl wherein m is 0 or 1, or —N(R N )-heterocyclyl, —C(O)-heterocyclyl, —S(O) 2 -(alkylene) m wherein m is 0 or 1:

R N is H, C 1 to C 4 alkyl or C 1 to C 6 heteroalkyl, and

wherein two R x1 can, together with the atoms to which they attach on P, which may be the same atom, form a ring; and

t is 0, 1 or 2.

7. The compound of claim 6 , wherein R 2 is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R 2 *, R x1 , and t are as previously defined.

8. The compound of claim 6 , wherein R 2 is

9. The compound of claim 7 , wherein R 2 is

10. The compound of claim 6 , wherein each R x1 is only optionally substituted by C 1 -C 4 alkyl, halogen or hydroxy.

11. The compound of claim 7 , wherein each R x1 is only optionally substituted by C 1 -C 4 alkyl, halogen or hydroxy.

12. The compound of claim 8 , wherein each R x1 is only optionally substituted by C 1 -C 4 alkyl, halogen or hydroxy.

13. The compound of claim 9 , wherein each R x1 is only optionally substituted by C 1 -C 4 alkyl, halogen or hydroxy.

14. The compound of claim 1 , wherein R 2 is

wherein:

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 - wherein each m is independently 0 or 1;

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; and

s is 0, 1 or 2.

15. The compound of claim 14 , wherein R 2 is

16. The compound of claim 1 , wherein R x is not further substituted.

17. The compound of claim 6 , wherein R 2 * is alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m - and/or -(alkylene) m -NH-(alkylene) m - wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted.

18. The compound of claim 7 , wherein R 2 * is alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m - and/or -(alkylene) m -NH-(alkylene) m - wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted.

19. The compound of claim 8 , wherein R 2 * is alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m - and/or -(alkylene) m -NH-(alkylene) m - wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted.

20. The compound of claim 9 , wherein R 2 * is alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m - and/or -(alkylene) m -NH-(alkylene) m - wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted.

21. The compound of claim 10 , wherein R 2 * is alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m - and/or -(alkylene) m -NH-(alkylene) m - wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted.

22. The compound of claim 11 wherein R 2 * is alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m - and/or -(alkylene) m -NH-(alkylene) m - wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted.

23. The compound of claim 12 wherein R 2 * is alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m - and/or -(alkylene) m -NH-(alkylene) m - wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted.

24. The compound of claim 13 , wherein R 2 * is alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m - and/or -(alkylene) m -NH-(alkylene) m - wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted.

25. The compound of claim 14 , wherein R 2 * is alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m - and/or -(alkylene) m -NH-(alkylene) m - wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted.

26. The compound of claim 15 wherein R 2 * is alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m - and/or -(alkylene) m -NH-(alkylene) m - wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted.

27. The compound of claim 4 , wherein the alkylene in R 2 is methylene.

28. The compound of claim 6 , wherein the alkylene in R 2 is methylene.

29. The compound of claim 14 , wherein the alkylene in R 2 is methylene.

30. The compound of claim 1 , wherein R 2 is -(alkylene) m -heterocyclo or -(alkylene) m -heteroaryl,

R is hydrogen, and,

X is independently CH or N.

31. The compound of claim 30 , wherein R 2 is -(alkylene) m -heterocyclo.

32. The compound of claim 30 , wherein m is 0.

33. The compound of claim 31 , wherein m is 0.

34. The compound of claim 30 , wherein m is 1.

35. The compound of claim 31 , wherein m is 1.

36. The compound of claim 30 , wherein the heterocyclo is not substituted.