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 1, 2, 3 or 4 or —O—(CH 2 ) z — wherein z is 2, 3 or 4;
each X′ is independently, CH or N;
X″ is CH 2 , S or NH;
each of R and R 8 are independently H, C 1 -C 3 alkyl or haloalkyl;
each R 1 is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and 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, 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
(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;
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; and
R 6 is a lower alkyl or absent.
2. The compound of claim 1 , wherein R 8 is hydrogen or C 1 -C 3 alkyl.
3. The compound of claim 1 , wherein R 2 is selected from any one of the structures of FIG. 1 .
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
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:
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.
6. The compound of claim 5 , 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.
7. The compound of claim 5 , wherein R 2 is
8. The compound of claim 6 , wherein R 2 is
9. The compound of claim 5 , wherein each R x1 is only optionally substituted by C 1 -C 4 alkyl, halogen or hydroxy.
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 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.
14. The compound of claim 13 , wherein R 2 is
15. The compound of claim 1 , wherein R x is not further substituted.
16. The compound of claim 5 , wherein R 2 * is an 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, and wherein any alkylene is not further substituted.
17. The compound of claim 6 , wherein R 2 * is an 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, and wherein any alkylene is not further substituted.
18. The compound of claim 7 , wherein R 2 * is an 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, and wherein any alkylene is not further substituted.
19. The compound of claim 8 , wherein R 2 * is an 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, and wherein any alkylene is not further substituted.
20. The compound of claim 9 , wherein R 2 * is an 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, and wherein any alkylene is not further substituted.
21. The compound of claim 10 wherein R 2 * is an 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, and wherein any alkylene is not further substituted.
22. The compound of claim 11 wherein R 2 * is an 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, and wherein any alkylene is not further substituted.
23. The compound of claim 12 , wherein R 2 * is an 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, and wherein any alkylene is not further substituted.
24. The compound of claim 13 , wherein R 2 * is an 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, and wherein any alkylene is not further substituted.
25. The compound of claim 14 , wherein R 2 * is an 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, and wherein any alkylene is not further substituted.
26. The compound of claim 1 , wherein R is hydrogen or C 1 -C 3 alkyl.
27. The compound of claim 4 , wherein the alkylene in R 2 is methylene.
28. The compound of claim 5 , wherein the alkylene in R 2 is methylene.
29. The compound of claim 13 , 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.
37. The compound of claim 31 , wherein the heterocyclo is not substituted.
38. The compound of claim 30 , wherein R 2 is
39. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
40. The compound of claim 1 , wherein R 2 is selected from any one of the structures of FIG. 2 .
41. The compound of claim 1 , wherein R 2 is selected from any one of the structures of FIG. 3 .
42. The compound of claim 1 , wherein R 6 is absent.