Claims for Patent: 8,598,197

Summary for Patent: 8,598,197

Title:	CDK inhibitors
Abstract:	Compounds of formulae I, II or III, and pharmaceutically acceptable salts thereof, are useful as CDK inhibitors.
Inventor(s):	Francis X. Tavares, Jay C. Strum
Assignee:	Pharmacosmos Holding AS, Pharmacosmos AS
Application Number:	US13/869,576
Patent Claims:	1. A compound of formula: or a pharmaceutically acceptable salt thereof, wherein: Z is —(CH2)x— wherein x is 1, 2, 3 or 4 or —O—(CH2)z— wherein z is 2, 3 or 4; each X is independently CH or N; each of R and R8 are independently H, C1-C3 alkyl or haloalkyl; each R1 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 R1'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; R2 is -(alkylene)m-heterocyclo, -(alkylene)m-heteroaryl, -(alkylene)m-NR3R4, -(alkylene)m-C(O)—NR3R4; -(alkylene)m-C(O)—O-alkyl; -(alkylene)m-O—R5, -(alkylene)m-S(O)n—R5, or -(alkylene)m-S(O)n—NR3R4 any of which may be optionally independently substituted with one or more Rx groups as allowed by valance, and wherein two Rx 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; R3 and R4 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 Rx groups as allowed by valance, and wherein two Rx groups bound to the same or adjacent atom may optionally combine to form a ring; or R3 and R4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more Rx groups as allowed by valance, and wherein two Rx groups bound to the same or adjacent atom may optionally combine to form a ring; R5 and R5* 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 Rx groups as allowed by valance; Rx at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)m-OR5, -(alkylene)m-O-alkylene-OR5, -(alkylene)m-S(O)n—R5, -(alkylene)m-NR3R4, -(alkylene)m-CN, -(alkylene)m-C(O)—R5, -(alkylene)m-C(S)—R5, -(alkylene)m-C(O)—OR5, -(alkylene)m-O—C(O)—R5, -(alkylene)m-C(S)—OR5, -(alkylene)m-C(O)-(alkylene)m-NR3R4, -(alkylene)m-C(S)—NR3R4, -(alkylene)m-N(R3)—C(O)—NR3R4, -(alkylene)m-N(R3)—C(S)—NR3R4, -(alkylene)m-N(R3)—C(O)—R5, -(alkylene)m-N(R3)—C(S)—R5, -(alkylene)m-O—C(O)—NR3R4, -(alkylene)m-O—C(S)—NR3R4, -(alkylene)m-SO2—NR3R4, -(alkylene)m-N(R3)—SO2—R5, -(alkylene)m-N(R3)—SO2—NR3R4, -(alkylene)m-N(R3)—C(O)—OR5)-(alkylene)m-N(R3)—C(S)—OR5, or -(alkylene)m-N(R3)—SO2—R5; 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-OR5*, -(alkylene)m-S(O)n—R5*, -(alkylene)m-NR3*R4*, -(alkylene)m-C(O)—R5*, -(alkylene)m-C(═S)R5*, -(alkylene)m-C(═O)OR5*, -(alkylene)m-OC(═O)R5*, -(alkylene)m-C(S)—OR5*, -(alkylene)m-C(O)—NR3*R4*, -(alkylene)m-C(S)—NR3*R4*, -(alkylene)m-N(R3*)—C(O)—NR3*R4*, -(alkylene)m-N(R3*)—C(S)—NR3*R4*, (alkylene)m-N(R3*)—C(O)—R5*, -(alkylene)m-N(R3*)—C(S)—R5*, -(alkylene)m-O—C(O)—NR3*R4*, -(alkylene)m-O—C(S)—NR3*R4*, -(alkylene)m-SO2—NR3*R4*, -(alkylene)m-N(R3*)—SO2—R5*, -(alkylene)m-N(R3*)—SO2—NR3*R4*, -(alkylene)m-N(R3*)—C(O)—OR5*, -(alkylene)m-N(R3*)—C(S)—OR5*, or -(alkylene)m-N(R3*)—SO2—R5*, n is 0, 1 or 2, and m is 0 or 1; and R3* and R4* 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 Rx groups as allowed by valance; or R3* and R4* together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more Rx groups as allowed by valance, and R6 is a lower alkyl or absent. 2. The compound of claim 1, wherein R8 is hydrogen or C1-C3 alkyl. 3. The compound of claim 1 having the formula selected from the structures shown in FIG. 4. 4. The compound of claim 1 having formula: 5. The compound of claim 1 having formula: 6. The compound of claim 1 having formula: 7. The compound of claim 1 having formula: 8. The compound of claim 1 having formula: 9. The compound of claim 1 having formula: 10. The compound of claim 1 having formula: 11. The compound of claim 1 having formula: 12. The compound of claim 1 having formula: 13. The compound of claim 1 having formula: 14. The compound of claim 1, wherein both of X are N. 15. The compound of claim 1, wherein R2 is selected from the structures of FIG. 1. 16. The compound of claim 1, wherein R2 is -(alkylene)m-heterocyclo, -(alkylene)m-NR3R4, -(alkylene)m-C(O)—NR3R4, -(alkylene)m-C(O)—O-alkyl or -(alkylene)m-OR5 any of which may be optionally independently substituted with one or more Rx groups as allowed by valance, and wherein two Rx groups bound to the same or adjacent atom may optionally combine to form a ring. 17. The compound of claim 1, wherein R2 is wherein: R2* 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 Rx1 is independently -(alkylene)m-(C(O))m-(alkylene)m-(N(RN))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(RN)-cycloalkyl, —C(O)-cycloalkyl, -(alkylene)m-heterocyclyl wherein m is 0 or 1, or —N(RN)-heterocyclyl, —C(O)-heterocyclyl, —S(O)2-(alkylene)m wherein: RN is H, C1 to C4 alkyl or C1 to C6 heteroalkyl, and wherein two Rx1 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. 18. The compound of claim 17, wherein R2 is wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R2*, Rx1 and t are as previously defined. 19. The compound of claim 17, wherein R2 is 20. The compound of claim 18, wherein R2 is 21. The compound of claim 17, wherein each Rx1 is only optionally substituted by C1-C4 alkyl, halogen or hydroxy. 22. The compound of claim 18, wherein each Rx1 is only optionally substituted by C1-C4 alkyl, halogen or hydroxy. 23. The compound of claim 19, wherein each Rx1 is only optionally substituted by C1-C4 alkyl, halogen or hydroxy. 24. The compound of claim 20, wherein each Rx1 is only optionally substituted by C1-C4 alkyl, halogen or hydroxy. 25. The compound of claim 1, wherein R2 is wherein: R2* 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 Rx2 is independently hydrogen or alkyl; and s is 0, 1 or 2. 26. The compound of claim 25, wherein R2 is 27. The compound of claim 1, wherein Rx is not further substituted. 28. The compound of claim 17, wherein R2* 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. 29. The compound of claim 18, wherein R2* 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 alkyleneis not further substituted. 30. The compound of claim 19, wherein R2* 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. 31. The compound of claim 20, wherein R2* 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. 32. The compound of claim 21, wherein R2* 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. 33. The compound of claim 22 wherein R2* 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. 34. The compound of claim 23 wherein R2* 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. 35. The compound of claim 24, wherein R2* 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. 36. The compound of claim 25, wherein R2* 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. 37. The compound of claim 26 wherein R2* 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. 38. The compound of claim 1, wherein R is hydrogen or C1-C3 alkyl. 39. The compound of claim 16, wherein the alkylene in R2 is methylene. 40. The compound of claim 17, wherein the alkylene in R2 is methylene. 41. The compound of claim 25, wherein the alkylene in R2 is methylene. 42. The compound of claim 1, wherein R2 is -(alkylene)m-heterocyclo or -(alkylene)m-heteroaryl, R is hydrogen, and, X is independently CH or N. 43. The compound of claim 42, wherein R2 is -(alkylene)m-heterocyclo. 44. The compound of claim 42, wherein m is 0. 45. The compound of claim 43, wherein m is 0. 46. The compound of claim 42, wherein m is 1. 47. The compound of claim 43, wherein m is 1. 48. The compound of claim 42, wherein the heterocyclo is not substituted. 49. The compound of claim 43, wherein the heterocyclo is not substituted. 50. The compound of claim 42, wherein R2 is 51. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof. 52. The compound of claim 1 having the formula selected from the structures shown in FIG. 5. 53. The compound of claim 1 having the formula selected from the structures shown in FIG. 6. 54. The compound of claim 1 having the formula selected from the structures shown in FIG. 7. 55. The compound of claim 1 having the formula selected from the structures shown in FIG. 8, wherein the selected structure falls within claim 1. 56. The compound of claim 1, wherein R2 is selected from the structures of FIG. 2. 57. The compound of claim 1, wherein R2 is selected from the structures of FIG. 3. 58. The compound of claim 1, wherein R6 is absent.