Cyclin dependent kinase degraders and methods of use thereof

Abstract

The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for degrading CDK2 and / or CCNE1 with the compounds and compositions of the disclosure. The present disclosure further relates to, but is not limited to, methods for treating disorders associated with CDK2 and / or CCNE1 with the compounds and compositions of the disclosure.

Description

CN Title: Cyclin-Dependent Kinase Degraders and Their Use CN Abstract This disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for degrading CDK2 and / or CCNE1 using the compounds and compositions disclosed herein. This disclosure further relates to, but is not limited to, methods for treating conditions related to CDK2 and / or CCNE1 using the compounds and compositions disclosed herein. 1 Abstract

Claims

CLAIMS1. A compound of Formula A:A or a pharmaceutically acceptable salt thereof, wherein:Ring A is phenyl, a 3-14 membered cycloalkyl or 4-14 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S;R1is selected from -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C1-6 haloalkyl, -C1-6 heteroalkyl, -C3-14 cycloalkyl, 6-14 membered aryl, 4-14 membered heterocyclyl, 5-14 membered heteroaryl, -C1-4 alkyl-Cs-14 cycloalkyl, -C1-4 alkyl-(6-14 membered aryl), -C1-4 alkyl-(4-14 membered heterocyclyl), and -C1-4 alkyl (5-14 membered heteroaryl), wherein each heterocyclyl and heteroaryl contains 1-3 heteroatoms independently selected from N, O and S, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl is substituted with 0, 1, 2, 3 or 4 instances of R6; each R2and R3is independently selected from -C1-6 alkyl, -C1-6 haloalkyl, -C1-6 heteroalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1-3 heteroatoms independently selected from N, O and S, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl is substituted with 0, 1, 2, 3 or 4 instances of RB; or R2and R3, together with the carbon atom to which they are attached, form Ring B, wherein Ring B is a 3-7 membered cycloalkyl ring or a 4-7 membered heterocyclyl ring containing 1 or 3 heteroatoms independently selected from N, O and S, wherein Ring B is substituted with 0, 1, 2, 3, or 4 instances of RB;L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, - CH(R)-, -C(R)2-, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRS(=O)2- -S(=O)2NR- -NRC(=O)-, -C(=O)NR-, -OC(=O)NR- or -NRC(=O)O- wherein: each -Cy- is independently a bivalent ring selected from phenylene, an 8-10 membered bicyclic arylene, a 4-7 membered monocyclic carbocyclylene, a 5-11 membered spiro carbocyclylene, a 4-10 membered bicyclic carbocyclylene, a 5-10 membered bridged carbocyclylene, a 4-7 membered monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-11 membered spiro heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 4-10 membered bicyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each phenylene, arylene, carbocyclylene, heterocyclylene and heteroarylene is substituted with 0, 1, 2, 3, or 4 instances of Rc;each instance of RA, RB, Rc, R4, R5and R6is independently selected from oxo, deuterium, halogen, -Ci-6 alkyl, -Ci-6 heteroalkyl, -Ci-6 haloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, - S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, - OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, - N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR -C3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1-3 heteroatoms independently selected from N, O and S;each instance of R is independently hydrogen, -C1-6 alkyl, -C1-6 haloalkyl, -C1-6 heteroalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1-3 heteroatoms independently selected from N, O and S, or two R groups attached to the same nitrogen are optionally taken together with nitrogen to which they are attached to form an optionally substituted 4-7 heterocyclyl having 0, 1 or 2 additional heteroatoms independently selected from N, O and S; n is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula B:wherein Ring B is a 3-7 membered cycloalkyl ring or a 4-7 membered heterocyclyl ring containing 1 or 3 heteroatoms independently selected from N, O and S.

3. A compound of Formula I or Formula 1-1 :1-1 or a pharmaceutically acceptable salt thereof, wherein: R1is selected from -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C1-6 haloalkyl, -C1-6 heteroalkyl, -C3-14 cycloalkyl, 6-14 membered aryl, 4-14 membered heterocyclyl, 5-14 membered heteroaryl, -C1-4 alkyl-Cs-14 cycloalkyl, -C1-4 alkyl-(6-14 membered aryl), -C1-4 alkyl-(4-14 membered heterocyclyl), and -C1-4 alkyl (5-14 membered heteroaryl), wherein each heterocyclyl and heteroaryl contains 1-3 heteroatoms independently selected from N, O and S, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl is substituted with 0, 1, 2, 3 or 4 instances of R6;L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, - CH(R)-, -C(R)2-, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRS(=O)2- -S(=O)2NR- -NRC(=O)-, -C(=O)NR-, -OC(=O)NR- or -NRC(=O)O- wherein: each -Cy- is independently a bivalent ring selected from phenylene, an 8-10 membered bicyclic arylene, a 4-7 membered monocyclic carbocyclylene, a 5-11 membered spiro carbocyclylene, a 4-10 membered bicyclic carbocyclylene, a 5-10 membered bridged carbocyclylene, a 4-7 membered monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-11 membered spiro heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 4-10 membered bicyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each phenylene, arylene, carbocyclylene, heterocyclylene and heteroarylene is substituted with 0, 1, 2, 3, or 4 instances of Rc;each instance of RA, RB, Rc, R4, R5and R6is independently selected from oxo, deuterium, halogen, -Ci-6 alkyl, -Ci-6 heteroalkyl, -Ci-6 haloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, - S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, - OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, - N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -C3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1-3 heteroatoms independently selected from N, O and S;each instance of R is independently hydrogen, -C1-6 alkyl, -C1-6 haloalkyl, -C1-6 heteroalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said each heterocyclyl and heteroaryl contains 1-3 heteroatoms independently selected from N, O and S, or two R groups attached to the same nitrogen are optionally taken together with nitrogen to which they are attached to form an optionally substituted 4-7 heterocyclyl having 0, 1 or 2 additional heteroatoms independently selected from N, O and S; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula I.

5. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula 1-1.

6. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula I- A:

7. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula I-B:

8. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound is of F ormula I- C :

9. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula I-l-B:

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1is selected from -C3-7 cycloalkyl, phenyl and -C1-4 alkyl-Cs-14 cycloalkyl, each of which is substituted with 0, 1, 2, 3 or 4 instances of R6.

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1is C3-7 cycloalkyl substituted with 0, 1, 2, 3 or 4 instances of R6.

12. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1is cyclopentyl, cyclohexyl, phenyl or -CH(CH3)-cyclopropyl, each substituted with 0, 1, 2, 3 or 4 instances of R6.

13. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1is cyclopentyl or cyclohexyl, each substituted with 0, 1, 2, 3 or 4 instances of R6.

14. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1is cyclopentyl substituted with 0, 1, 2, 3 or 4 instances of R6.

15. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula II- A:wherein p is 0, 1, 2, 3 or 4.

16. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula II-B:wherein p is 0, 1, 2, 3 or 4.

17. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula II-C:wherein p is 0, 1, 2, 3 or 4.

18. The compound of claim 3 or 5, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula II-l-B:wherein p is 0, 1, 2, 3 or 4.

19. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1is cyclohexyl substituted with 0, 1, 2, 3 or 4 instances of R6.

20. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula K:wherein p is 0, 1, 2, 3 or 4.

21. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula IV- A:wherein p is 0, 1, 2, 3 or 4.

22. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula IV-B:wherein p is 0, 1, 2, 3 or 4.

23. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula IV-C:wherein p is 0, 1, 2, 3 or 4.

24. The compound of claim 3 or 5, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula IV-l-B:wherein p is 0, 1, 2, 3 or 4.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R6is selected from halo, -OH and -Ci-6 alkyl.

26. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R6is selected from -OH and -Me.

27. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R6is -OH.

28. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R6is -Me.

29. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1is selected from 2-methylcyclopentyl and 3 -hydroxy cyclohexyl.

30. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1is 3 -hydroxy cyclohexyl.

31. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1is 2-methylcyclopentyl.

32. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:

33. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:

34. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:

35. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:

36. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula M:

37. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula III- A:

38. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula III-B:

39. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula III-F:

40. The compound of claim 3 or 5, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula III-l-B:

41. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula V-D:

42. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula V-E:

43. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula V-G:

44. The compound of claim 3 or 5, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula V-l-E:

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein RAis selected from halogen and -Ci-6 alkyl.

46. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein RAis selected from -F and -Me.

47. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein RAis -F.

48. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein the moiety representedselected from49. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein the moiety represented50. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein the moiety represented51. The compound of any one of claims 1-50, or a pharmaceutically acceptable saltach substituted with 0, 1, 2 or 3 instances of R7, wherein each R7is independently selected from -Ci-4 alkyl and halo; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM;L1and L2are each independently selected from a bond and -N(R’), wherein R’ is selected from H and Ci-6 alkyl; and q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

52. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein each R7is independently selected from -Me, - Pr and -F.

53. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein each R7is independently selected from -Me and -F.

54. The compound of any one of claims 1-50, or a pharmaceutically acceptable saltwherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM; L1and L2are each independently selected from a bond and -N(R’), wherein R’ is selected from H and Ci-6 alkyl; and q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

55. The compound of any one of claims 51-53, or a pharmaceutically acceptable saltYr -a , Yr-Oy thereof, wherein L is selected from: ' , ' ,, each substituted with 0, 1, 2 or 3 instances of R7; wherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM.

56. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein L iswherein the left side attachment point connects to the -S(O)2- group and the right side attachment point connects to LBM.

57. The compound of any one of claims 1-54 and 56, or a pharmaceutically acceptable salt thereof, wherein Cy is selected from:each not further substituted, wherein the left side atachment point connects to L1group and the right side atachment point connects to L2.

58. The compound of any one of claims 51-54 and 56, or a pharmaceutically|— L acceptable salt thereof, wherein1— Cy— L2— | is selected fromthe left attachment point connects to -S(O)2- and the right atachment point connects to LBM.

59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from deuterium, halogen, -Ci-6 alkyl, -Ci- 6 haloalkyl, -CN, -OR, -Nib, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -C(O)NR2, -C(O)N(R)OR, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, - N(R)S(O)2NR2and -N(R)S(O)2R, wherein R is H or C1-6 alkyl.

60. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from -Me, -Et, -F, -Cl, -CF3, -CN, -OH, -OMe, -NH2, -NHMe and -NMe2.

61. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from -Me and -F.

62. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof, wherein each R5is independently selected from deuterium, C1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, -CN, -OR, -NR2, -S(O)2R, -S(O)2NR2. - S(O)R, -S(O)NR2, -S(O)(NR)R, -C(O)NR2, -C(O)N(R)OR, -OC(O)NR2, -N(R)C(O)OR, - N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2NR2and -N(R)S(O)2R, wherein R is H or C1-6 alkyl.

63. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof, wherein each R5is independently selected from -Me, -Et, -F, -Cl, -CF3, -CN, -OH, -OMe, -NH2, -NHMe and -NMe2.

64. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof, wherein each R5is independently selected from -Me and -F.

65. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, wherein r is 0, 1 or 2.

66. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, wherein r is 0.

67. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, wherein r is 1.

68. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, wherein r is 2.

69. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, wherein s is 0, 1 or 2.

70. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, wherein s is 0.

71. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, wherein s is 1.

72. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, wherein s is 2.

73. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt74. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt75. The compound of any one of claims 1-74, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from76. A pharmaceutical composition comprising a compound of any one of claims 1-75, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

77. A method of inhibiting CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling in a sample by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound of any one of claims 1-75, or a pharmaceutically acceptable salt thereof, or a composition of claim 76.

78. A method of inhibiting CDK2 signaling in a sample by contacting CDK2 with a compound of any one of claims 1-75, or a pharmaceutically acceptable salt thereof, or a composition of claim 76.

79. A method of inhibiting CCNE (CCNE1 and / or CCNE2) signaling in a sample by contacting CCNE (CCNE1 and / or CCNE2) with a compound of any one of claims 1-75, or a pharmaceutically acceptable salt thereof, or a composition of claim 76.

80. A method of inhibiting CDK2 and CCNE (CCNE1 and / or CCNE2) signaling in a sample by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound of any one of claims 1-75, or a pharmaceutically acceptable salt thereof, or a composition of claim 76.

81. A method of treating a CDK2 and / or CCNE (CCNE 1 and / or CCNE2)-mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of any one of claims 1-75, or a pharmaceutically acceptable salt thereof, or a composition of claim 76.

82. The method of claim 81, wherein the CDK2 and / or CCNE (CCNE1 and / or CCNE2)-mediated disorder is cancer.

83. A method of treating a CDK2 -mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of any one of claims 1-75, or a pharmaceutically acceptable salt thereof, or a composition of claim 76.

84. The method of claim 83, wherein the CDK2 -mediated disorder is cancer.

85. A method of treating a CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of any one of claims 1-75, or a pharmaceutically acceptable salt thereof, or a composition of claim 76.

86. The method of claim 85, wherein the CCNE (CCNE1 and / or CCNE2)-mediated disorder is cancer.

87. A method of treating a CDK2 and CCNE (CCNE1 and / or CCNE2) -mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of any one of claims 1-75, or a pharmaceutically acceptable salt thereof, or a composition of claim 76.

88. The method of claim 87, wherein the CCNE (CCNE1 and / or CCNE2)-mediated disorder is cancer.

89. The method of any one of claims 82, 84, 86 and 88, wherein the cancer is selected from ovarian cancer, gastric cancer, uterine cancer, and breast cancer.

90. The method of any one of claims 82, 84, 86, 88 and 89, wherein the cancer is resistant to treatment with CDK 4 / 6 inhibitors.