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):	Tavares; Francis X. (Durham, NC), Strum; Jay C. (Hillsborough, NC)
Assignee:	G1 Therapeutics, Inc. (Chapel Hill, NC)
Application Number:	13/869,576
Patent Claims:	1. A compound of formula: ##STR00210## or a pharmaceutically acceptable salt thereof, wherein: Z is --(CH.sub.2).sub.x-- wherein x is 1, 2, 3 or 4 or --O--(CH.sub.2).sub.z-- wherein z is 2, 3 or 4; each X is independently CH or N; each of R and R.sup.8 are independently H, C.sub.1-C.sub.3 alkyl or haloalkyl; each R.sup.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.sup.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.sup.2 is -(alkylene).sub.m-heterocyclo, -(alkylene).sub.m-heteroaryl, -(alkylene).sub.m-NR.sup.3R.sup.4, -(alkylene).sub.m-C(O)--NR.sup.3R.sup.4; -(alkylene).sub.m-C(O)--O-alkyl; -(alkylene).sub.m-O--R.sup.5, -(alkylene).sub.m-S(O).sub.n--R.sup.5, or -(alkylene).sub.m-S(O).sub.n--NR.sup.3R.sup.4 any of which may be optionally independently substituted with one or more R.sup.x groups as allowed by valance, and wherein two R.sup.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.sup.3 and R.sup.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.sup.x groups as allowed by valance, and wherein two R.sup.x groups bound to the same or adjacent atom may optionally combine to form a ring; or R.sup.3 and R.sup.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.sup.x groups as allowed by valance, and wherein two R.sup.x groups bound to the same or adjacent atom may optionally combine to form a ring; R.sup.5 and R.sup.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.sup.x groups as allowed by valance; R.sup.x at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene).sub.m-OR.sup.5, -(alkylene).sub.m-O-alkylene-OR.sup.5, -(alkylene).sub.m-S(O).sub.n--R.sup.5, -(alkylene).sub.m-NR.sup.3R.sup.4, -(alkylene).sub.m-CN, -(alkylene).sub.m-C(O)--R.sup.5, -(alkylene).sub.m-C(S)--R.sup.5, -(alkylene).sub.m-C(O)--OR.sup.5, -(alkylene).sub.m-O--C(O)--R.sup.5, -(alkylene).sub.m-C(S)--OR.sup.5, -(alkylene).sub.m-C(O)-(alkylene).sub.m-NR.sup.3R.sup.4, -(alkylene).sub.m-C(S)--NR.sup.3R.sup.4, -(alkylene).sub.m-N(R.sup.3)--C(O)--NR.sup.3R.sup.4, -(alkylene).sub.m-N(R.sup.3)--C(S)--NR.sup.3R.sup.4, -(alkylene).sub.m-N(R.sup.3)--C(O)--R.sup.5, -(alkylene).sub.m-N(R.sup.3)--C(S)--R.sup.5, -(alkylene).sub.m-O--C(O)--NR.sup.3R.sup.4, -(alkylene).sub.m-O--C(S)--NR.sup.3R.sup.4, -(alkylene).sub.m-SO.sub.2--NR.sup.3R.sup.4, -(alkylene).sub.m-N(R.sup.3)--SO.sub.2--R.sup.5, -(alkylene).sub.m-N(R.sup.3)--SO.sub.2--NR.sup.3R.sup.4, -(alkylene).sub.m-N(R.sup.3)--C(O)--OR.sup.5)-(alkylene).sub.m-N(R.sup.3)- --C(S)--OR.sup.5, or -(alkylene).sub.m-N(R.sup.3)--SO.sub.2--R.sup.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).sub.m-CN, -(alkylene).sub.m-OR.sup.5*, -(alkylene).sub.m-S(O).sub.n--R.sup.5*, -(alkylene).sub.m-NR.sup.3*R.sup.4*, -(alkylene).sub.m-C(O)--R.sup.5*, -(alkylene).sub.m-C(.dbd.S)R.sup.5*, -(alkylene).sub.m-C(.dbd.O)OR.sup.5*, -(alkylene).sub.m-OC(.dbd.O)R.sup.5*, -(alkylene).sub.m-C(S)--OR.sup.5*, -(alkylene).sub.m-C(O)--NR.sup.3*R.sup.4*, -(alkylene).sub.m-C(S)--NR.sup.3*R.sup.4*, -(alkylene).sub.m-N(R.sup.3*)--C(O)--NR.sup.3*R.sup.4*, -(alkylene).sub.m-N(R.sup.3*)--C(S)--NR.sup.3*R.sup.4*, (alkylene).sub.m-N(R.sup.3*)--C(O)--R.sup.5*, -(alkylene).sub.m-N(R.sup.3*)--C(S)--R.sup.5*, -(alkylene).sub.m-O--C(O)--NR.sup.3*R.sup.4*, -(alkylene).sub.m-O--C(S)--NR.sup.3*R.sup.4*, -(alkylene).sub.m-SO.sub.2--NR.sup.3*R.sup.4*, -(alkylene).sub.m-N(R.sup.3*)--SO.sub.2--R.sup.5*, -(alkylene).sub.m-N(R.sup.3*)--SO.sub.2--NR.sup.3*R.sup.4*, -(alkylene).sub.m-N(R.sup.3*)--C(O)--OR.sup.5*, -(alkylene).sub.m-N(R.sup.3*)--C(S)--OR.sup.5*, or -(alkylene).sub.m-N(R.sup.3*)--SO.sub.2--R.sup.5*, n is 0, 1 or 2, and m is 0 or 1; and R.sup.3* and R.sup.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.sup.x groups as allowed by valance; or R.sup.3* and R.sup.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 Rx groups as allowed by valance, and R.sup.6 is a lower alkyl or absent. 2. The compound of claim 1, wherein R.sup.8 is hydrogen or C.sub.1-C.sub.3 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: ##STR00211## 5. The compound of claim 1 having formula: ##STR00212## 6. The compound of claim 1 having formula: ##STR00213## 7. The compound of claim 1 having formula: ##STR00214## 8. The compound of claim 1 having formula: ##STR00215## 9. The compound of claim 1 having formula: ##STR00216## 10. The compound of claim 1 having formula: ##STR00217## 11. The compound of claim 1 having formula: ##STR00218## 12. The compound of claim 1 having formula: ##STR00219## 13. The compound of claim 1 having formula: ##STR00220## 14. The compound of claim 1, wherein both of X are N. 15. The compound of claim 1, wherein R.sup.2 is selected from the structures of FIG. 1. 16. The compound of claim 1, wherein R.sup.2 is -(alkylene).sub.m-heterocyclo, -(alkylene).sub.m-NR.sup.3R.sup.4, -(alkylene).sub.m-C(O)--NR.sup.3R.sup.4, -(alkylene).sub.m-C(O)--O-alkyl or -(alkylene).sub.m-OR.sup.5 any of which may be optionally independently substituted with one or more R.sup.x groups as allowed by valance, and wherein two R.sup.x groups bound to the same or adjacent atom may optionally combine to form a ring. 17. The compound of claim 1, wherein R.sup.2 is ##STR00221## wherein: R.sup.2* is a bond, alkylene, -(alkylene).sub.m-O-(alkylene).sub.m-, -(alkylene).sub.m-C(O)-(alkylene).sub.m-, -(alkylene).sub.m-S(O).sub.2-(alkylene).sub.m- or -(alkylene).sub.m-NH-(alkylene).sub.m- wherein each m is independently 0 or 1; P is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group; each R.sup.x1 is independently -(alkylene).sub.m-(C(O)).sub.m-(alkylene).sub.m-(N(R.sup.N)).sub.m-(alkyl- ).sub.m wherein each m is independently 0 or 1 provided at least one m is 1, --(C(O))--O-alkyl, -(alkylene).sub.m-cycloalkyl wherein m is 0 or 1, --N(R.sup.N)-cycloalkyl, --C(O)-cycloalkyl, -(alkylene).sub.m-heterocyclyl wherein m is 0 or 1, or --N(R.sup.N)-heterocyclyl, --C(O)-heterocyclyl, --S(O).sub.2-(alkylene).sub.m wherein: R.sup.N is H, C.sub.1 to C.sub.4 alkyl or C.sub.1 to C.sub.6 heteroalkyl, and wherein two R.sup.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. 18. The compound of claim 17, wherein R.sup.2 is ##STR00222## wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R.sup.2*, R.sup.x1 and t are as previously defined. 19. The compound of claim 17, wherein R.sup.2 is ##STR00223## 20. The compound of claim 18, wherein R.sup.2 is ##STR00224## 21. The compound of claim 17, wherein each R.sup.x1 is only optionally substituted by C.sub.1-C.sub.4 alkyl, halogen or hydroxy. 22. The compound of claim 18, wherein each R.sup.x1 is only optionally substituted by C.sub.1-C.sub.4 alkyl, halogen or hydroxy. 23. The compound of claim 19, wherein each R.sup.x1 is only optionally substituted by C.sub.1-C.sub.4 alkyl, halogen or hydroxy. 24. The compound of claim 20, wherein each R.sup.x1 is only optionally substituted by C.sub.1-C.sub.4 alkyl, halogen or hydroxy. 25. The compound of claim 1, wherein R.sup.2 is ##STR00225## wherein: R.sup.2* is a bond, alkylene, -(alkylene).sub.m-O-(alkylene).sub.m-, -(alkylene).sub.m-C(O)-(alkylene).sub.m-, -(alkylene).sub.m-S(O)-2-(alkylene).sub.m or -(alkylene).sub.m-NH-(alkylene).sub.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.sup.x2 is independently hydrogen or alkyl; and s is 0, 1 or 2. 26. The compound of claim 25, wherein R.sup.2 is ##STR00226## 27. The compound of claim 1, wherein R.sup.x is not further substituted. 28. The compound of claim 17, wherein R.sup.2* is alkylene, -(alkylene).sub.m-O-(alkylene).sub.m- , -(alkylene).sub.m-C(O)-(alkylene).sub.m-, -(alkylene).sub.m-S(O).sub.2-(alkylene).sub.m- and or -(alkylene).sub.m-NH-(alkylene).sub.m- wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted. 29. The compound of claim 18, wherein R.sup.2* is alkylene, -(alkylene).sub.m-O-(alkylene).sub.m- , -(alkylene).sub.m-C(O)-(alkylene).sub.m-, -(alkylene).sub.m-S(O).sub.2-(alkylene).sub.m- and or -(alkylene).sub.m-NH-(alkylene).sub.m- wherein each m is independently 0 or 1, and wherein any alkyleneis not further substituted. 30. The compound of claim 19, wherein R.sup.2* is alkylene, -(alkylene).sub.m-O-(alkylene).sub.m-, -(alkylene).sub.m-C(O)-(alkylene).sub.m-, -(alkylene).sub.m-S(O).sub.2-(alkylene).sub.m- and or -(alkylene).sub.m-NH-(alkylene).sub.m- wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted. 31. The compound of claim 20, wherein R.sup.2* is alkylene, -(alkylene).sub.m-O-(alkylene).sub.m-, -(alkylene).sub.m-C(O)-(alkylene).sub.m-, -(alkylene).sub.m-S(O).sub.2-(alkylene).sub.m- and or -(alkylene).sub.m-NH-(alkylene).sub.m- wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted. 32. The compound of claim 21, wherein R.sup.2* is alkylene, -(alkylene).sub.m-O-(alkylene).sub.m-, -(alkylene).sub.m-C(O)-(alkylene).sub.m-, -(alkylene).sub.m-S(O).sub.2-(alkylene).sub.m- and or -(alkylene).sub.m-NH-(alkylene).sub.m- wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted. 33. The compound of claim 22 wherein R.sup.2* is alkylene, -(alkylene).sub.m-O-(alkylene).sub.m-, -(alkylene).sub.m-C(O)-(alkylene).sub.m-, -(alkylene).sub.m-S(O).sub.2-(alkylene).sub.m- and or -(alkylene).sub.m-NH-(alkylene).sub.m- wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted. 34. The compound of claim 23 wherein R.sup.2* is alkylene, -(alkylene).sub.m-O-(alkylene).sub.m-, -(alkylene).sub.m-C(O)-(alkylene).sub.m-, -(alkylene).sub.m-S(O).sub.2-(alkylene).sub.m- and or -(alkylene).sub.m-NH-(alkylene).sub.m- wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted. 35. The compound of claim 24, wherein R.sup.2* is alkylene, -(alkylene).sub.m-O-(alkylene).sub.m-, -(alkylene).sub.m-C(O)-(alkylene).sub.m-, -(alkylene).sub.m-S(O).sub.2-(alkylene).sub.m- and or -(alkylene).sub.m-NH-(alkylene).sub.m- wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted. 36. The compound of claim 25, wherein R.sup.2* is alkylene, -(alkylene).sub.m-O-(alkylene).sub.m-, -(alkylene).sub.m-C(O)-(alkylene).sub.m-, -(alkylene).sub.m-S(O).sub.2-(alkylene).sub.m- and or -(alkylene).sub.m-NH-(alkylene).sub.m- wherein each m is independently 0 or 1, and wherein any alkylene is not further substituted. 37. The compound of claim 26 wherein R.sup.2* is alkylene, -(alkylene).sub.m-O-(alkylene).sub.m-, -(alkylene).sub.m-C(O)-(alkylene).sub.m-, -(alkylene).sub.m-S(O)2-(alkylene).sub.m- and or -(alkylene).sub.m-NH-(alkylene).sub.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 C.sub.1-C.sub.3 alkyl. 39. The compound of claim 16, wherein the alkylene in R.sup.2 is methylene. 40. The compound of claim 17, wherein the alkylene in R.sup.2 is methylene. 41. The compound of claim 25, wherein the alkylene in R.sup.2 is methylene. 42. The compound of claim 1, wherein R.sup.2 is -(alkylene).sub.m-heterocyclo or -(alkylene).sub.m-heteroaryl, R is hydrogen, and, X is independently CH or N. 43. The compound of claim 42, wherein R.sup.2 is -(alkylene).sub.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 R.sup.2 is ##STR00227## 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 R.sup.2 is selected from the structures of FIG. 2. 57. The compound of claim 1, wherein R.sup.2 is selected from the structures of FIG. 3. 58. The compound of claim 1, wherein R.sup.6 is absent.