Compounds, compositions, and methods of use thereof

Selective CDK2 inhibitors address the need for targeted treatment of CDK2-mediated diseases by minimizing interference with other CDKs, offering effective therapeutic outcomes for conditions like cancer.

HK40134659APending Publication Date: 2026-07-10TYPE6 THERAPEUTICS INC
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Patent Information

Authority / Receiving Office
HK · HK
Patent Type
Applications
Current Assignee / Owner
TYPE6 THERAPEUTICS INC
Filing Date
2026-04-09
Publication Date
2026-07-10

AI Technical Summary

Technical Problem

Existing treatments lack selective inhibitors for CDK2 to effectively treat or prevent diseases mediated by cyclin-dependent kinase 2 (CDK2), particularly in the context of cancer.

Method used

Development of compounds and compositions that selectively inhibit CDK2 activity while minimizing interference with other cyclin-dependent kinases (CDKs), which are used in methods to treat, prevent, or reduce the severity of CDK2-mediated diseases such as cancer.

Benefits of technology

The compounds and compositions effectively inhibit CDK2 activity with minimal impact on other CDKs, providing therapeutic benefits for CDK2-related diseases.

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Abstract

The present disclosure provides, in part, compounds of formula: (I) and pharmaceutically acceptable salts thereof, and compositions comprising said compounds or salts thereof and a pharmaceutically acceptable excipient. In some embodiments, the compounds or salts thereof and compositions disclosed herein are effective at inhibiting CDK2 activity. In some embodiments, the compounds or salts thereof and compositions disclosed herein are selective at inhibiting CDK2 over other CDKs. Thus, also provided herein are uses of the compounds or salts thereof and compositions in methods of treating, preventing, or reducing the risk or severity of certain diseases or disorders mediated by CDK2, such as cancer.
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Description

This disclosure partially provides compounds of formula (I): and pharmaceutically acceptable salts thereof, and compositions comprising said compound or salt thereof and pharmaceutically acceptable excipients. In some embodiments, the disclosed compounds or salts thereof and compositions thereof are effective in inhibiting CDK2 activity. In some embodiments, the disclosed compounds or salts thereof and compositions thereof are selective relative to other CDKs in inhibiting CDK2. Therefore, the use of said compounds or salts thereof and compositions thereof in methods of treating, preventing, or reducing the risk or severity of certain diseases or disorders mediated by CDK2, such as cancer, is also provided herein.Abstract COMPOUNDS, COMPOSITIONS, AND METHODS OF USE THEREOF The present disclosure provides, in part, compounds of formula: (I) and pharmaceutically acceptable salts thereof, and compositions comprising said compounds or salts thereof and a pharmaceutically acceptable excipient. In some embodiments, the compounds or salts thereof and compositions disclosed herein are effective at inhibiting CDK2 activity. In some embodiments, the compounds or salts thereof and compositions disclosed herein are selective at inhibiting CDK2 over other CDKs. Thus, also provided herein are uses of the compounds or salts thereof and compositions in methods of treating, preventing, or reducing the risk or severity of certain diseases or disorders mediated by CDK2, such as cancer. Abstract.

Claims

CLAIMS 1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: A2is phenyl, 2,3-naphthyl, or 5 or 6-membered heteroaryl; A4is aryl, heteroaryl, C3-12 carbocyclyl, or 4-12 membered heterocyclyl; L1is -O-, -S-, -NH-, -S(=O)1-2-, -S(=O)(=NR5)-, -C(R6)2-, or -C(=O)-; L2is -NR7SO2-, -C(R8)2SO2-, -NR7SO2-C(R8)2-, -C(R8)2C(=O)-, - C(=O)C(R8)2-, -C(=O)O-, -OC(=O)-, -C(R8)2O-, -OC(R8)2-, -C(=O)NR7-, - NR7C(=O)-, -C(R8)2NR7-, -NR7C(R8)2-, -C(R8)2S(=O)0-2-, -S(=O)0-2C(R8)2-, - C(R8)2S(=O)NR7-, S(=O)NR7C(R8)2-, or -C(R8)2C(R8)2-; R1is C3-12 carbocyclyl, 4-12 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -(C1-6alkylene)-(C3-10carbocyclyl), -(C1-6alkylene)-(4-12 membered heterocyclyl), -(C1-6alkylene)-(phenyl), -(C1-6alkylene)-(5-12 membered heteroaryl), - (C1-6alkylene)-OR9, or -(C1-6alkylene)-NR7R10, wherein R1is optionally substituted by 0-5 R11; R2is each independently H, halogen, cyano, nitro, hydroxy, -NR7R10, - NHCOR9, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, COR9, CON(R9)2, CF3, CF2H, CF3CF2, CF3CH2, C1-6haloalkyl, CF3O, CF2HO, CF3CF2O, CF3CH2O, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6 alkylthio, C2-6alkenylthio, C1-6alkylsulfonyl, aryl, or heteroaryl, wherein R2is each independently optionally substituted by 0-4 R11; R3is each independently H, halogen, cyano, nitro, hydroxy, -NR7R10, - NHCOR9, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, COR9, CON(R9)2, CF3, CF2H, CF3CF2, CF3CH2, C1-6haloalkyl, CF3O, CF2HO, CF3CF2O, CF3CH2O, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6alkylthio, C2-6alkenylthio, or C1-6alkylsulfonyl, wherein R3is each independently optionally substituted by 0-4 R11; R4is each independently H, halogen, cyano, nitro, hydroxy, NR7R10, NHCOR9, NR7CONR7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, COR9, CO2R9, CONR7R10, C1-6alkoxy, C2-6alkenoxy, C2-6alkynoxy, CF3, CF2H, CF3CF2, CF3CH2, C1-6 haloalkyl, CF3O, CF2HO, CF3CF2O, CF3CH2O, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8cycloalkenyl, C1-6alkylthio, C2-6alkenylthio, C1-6alkylsulfonyl, SO2N(R7)2, or phenyl, or any two occurrences of R4on contiguous atoms, taken together with the contiguous atoms to which the two occurrences of R4are attached, form a saturated or unsaturated 5-7 membered ring comprising 0-2 heteroatoms each independently selected from O, S(=O)0-2, P(=O)R12, N, and NR10, wherein R4is each independently optionally substituted by 0-4 R11; R5is each independently H or C1-4alkyl; R6is each independently H, F, OH, cyano, or C1-6 alkyl; R7is each independently H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6 cycloalkyl, C4-6 heterocycloalkyl, aryl, 5-10 membered heteroaryl, C1-3 alkylene-C3-6cycloalkyl, or C1-3alkylene-C4-6heterocycloalkyl, or two R7s along with the N atom to which they are attached form a 4-7 membered ring comprising an additional 0-1 heteroatoms selected from NR5, O and S(=O)0-2; R8is each independently H, halogen, cyano, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C2-6cycloalkyl, C4-6heterocycloalkyl, C1-3alkylene-C3-6cycloalkyl, C1-3alkylene-C4-6heterocycloalkyl, or two R8s taken together with the C atom to which they are attached form a 4-7 membered ring comprising 0-1 heteroatom selected from O, S(=O)0-2, P(=O)R12, and NR5, wherein R8is optionally substituted by 1-3 R11; each R9is H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10heterocycloalkyl, C1-3alkylene-C3-6cycloalkyl, C1-3alkylene-C4-6heterocycloalkyl, C1-6acyl, phenyl, or 5-12 membered heteroaryl, wherein R9is optionally substituted by 1-3 R11; each R10is independently H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene-C4-6heterocycloalkyl, C1-6acyl, C1-6alkylsulfonyl, phenyl, or 5-12 membered heteroaryl, wherein R10is optionally substituted by 1-3 R11;or R7and R10on the same N atom may be taken together with the N atom to which they are attached form a 4-7 membered ring comprising an additional 0-1 heteroatoms selected from NR5, O, S(=O)0-2, P(=O)R12, and NR13; R11is each independently R6, oxo, nitro, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, 4- 6 membered heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene-C4-6 heterocycloalkyl, C6-10aryl, C5-10heteroaryl, SO2R7, S(=O)NR5, SO2N(R7)2, CON(R7)2, or N(R7)2; R12is each independently H, OH, C1-6alkyl, C1-6alkoxy, or -N(R7)2; R13is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6cycloalkyl, C4-6heterocycloalkyl, C1-3alkylene-C3-6cycloalkyl, or C1-3alkylene-C4-6 heterocycloalkyl, C1-6 acyl, aroyl, or heteroaroyl; m is an integer 0, 1 or 2; n is an integer 0, 1, 2, or 3; and p is an integer 0, 1, 2, or 3, provided that the A1ring and the L1linker are on contiguous C atoms of A2, whereas L1and L2are not situated on contiguous atoms of the A3ring; and when A2is, not -O-, wherein * is the site covalently linked to the A1ring, and *** is the site covalently linked to L1.

2. The compound of claim 1, wherein A4is phenyl, naphthyl, 5-10 membered heteroaryl, C3-10carbocyclyl, or 5-10 membered heterocyclyl.

3. The compound of claim 1, wherein A4is phenyl, naphthyl, thiophenyl, cyclopropyl, O cyclobutyl, cyclopentyl, cyclohexyl,, , ,O,4. The compound of claim 1, wherein A4is phenyl.

5. The compound of any one of claims 1-4, wherein A2is phenyl, 2,3-naphthyl, pyridinyl, or pyrimidinyl.

6. The compound of claim 5, wherein A2is 1,2-linked phenylene, 2,3-linked- naphthylene, 2-L1-3-biaryl linked pyridylene, 4-L1-3-biaryl linked pyridylene or 4-L1- 5-biaryl linked pyrimidylene.

7. The compound of claim 5, wherein A2is 1,2-linked phenylene.

8. The compound of any one of claims 1-7, wherein R1is C6-10carbocyclyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -(C1-6alkylene)-(C3- 10carbocyclyl), -(C1-6alkylene)-(4-8 membered heterocyclyl), -(C1-6alkylene)-(5-6 membered heteroaryl), -(C1-6alkylene)-OR9, or -(C1-6alkylene)-NR7R10, wherein R1is optionally substituted by 1-2 R11.

9. The compound of claim 8, wherein R1is C6-10carbocyclyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -(C1-6alkylene)-(C3-10carbocyclyl), - (C1-6alkylene)-(4-8 membered heterocyclyl), -(C1-6alkylene)-(5-6 membered heteroaryl), -(C1-6alkylene)-OR9, or -(C1-6alkylene)-NR7R10, wherein R1is optionally substituted by 1 R11.

10. The compound of claim 8, wherein R1is cyclohexyl optionally substituted with 1 R11.

11. The compound of claim 8, wherein R1is piperidinyl, oxetanyl, azetidinyl, pyrrolidinyl, or azaspiroheptanyl, optionally substituted with 1 R11.

12. The compound of claim 8, wherein R1is –(C1-3alkylene)-OR9optionally substituted with 1 R11.

13. The compound of claim 8, wherein R1is -(C1-3alkylene)-NR7R10optionally substituted with 1 R11.

14. The compound of claim 8, wherein R1is -(C1-3alkylene)-(4-6 membered heterocyclyl containing 1-2 heteroatoms selected from the group consisting of O, S, and N) optionally substituted by 1 R11.

15. The compound of claim 8, wherein R1is -(C1-3alkylene)-(5-6 membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of O, S, and N) optionally substituted by 1 R11.

16. The compound of any one of claims 1-15, wherein L1is -O-, -S-, -NH-, -S(=O)1-2, - S(=O)(=NR5)-, -CHR6-, or -CF2-.

17. The compound of claim 16, wherein L1is -O- or -S-.

18. The compound of claim 17, wherein L1is -O-.

19. The compound of claim 17, wherein L1is -S-.

20. The compound of any one of claims 1-19, wherein L2-NHSO2-, -NHSO2-CH2-, - C(=O)NH-, or -NHC(=O)-.

21. The compound of any one of claims 1-19, wherein L2is -NR7SO2-.

22. The compound of claim 21, wherein L2is -NHSO2-.

23. The compound of any one of claims 1-22, wherein R6is each independently H, methyl, ethyl, fluoro, chloro, cyano, CF3, CHF2, or CH2F.

24. The compound of any one of claims 1-23, wherein R8is each independently H, methyl, ethyl, fluoro, chloro, cyano, CF3, CHF2, CH2F, methoxy, or ethoxy.

25. The compound of any one of claims 1-24, wherein m is 0.

26. The compound of any one of claims 1-24, wherein m is 1.

27. The compound of any one of claims 1-24 and 26, wherein R2is each independently H, halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-6cycloalkyl, aryl or heteroaryl.

28. The compound of any one of claims 1-24 and 26, wherein R2is each independently H, halogen, cyano, C1-6 alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, or C3-6cycloalkyl.

29. The compound of any one of claims 1-28, wherein n is 0, 1, or 2.

30. The compound of claim 29, wherein n is 1 or 2.

31. The compound of any one of claims 1-30, wherein R3is each independently H, halogen, cyano, C1-4alkyl, or C1-4haloalkyl.

32. The compound of any one of claims 1-30, wherein R3is each independently H, halogen, cyano, or C1-2haloalkyl.

33. The compound of any one of claims 1-32, wherein p is 0, 1, or 2.

34. The compound of claim 33, wherein p is 1 or 2.

35. The compound of any one of claims 1-34, wherein R4is each H, halogen, cyano, nitro, hydroxy, NR7R10, NHCOR9, NR7CONR7, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, COR9, CO2R9, CONR7R10, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, or C3-8cycloalkyl, wherein R4is each independently optionally substituted by 0-1 R11.

36. The compound of claim 35, wherein R4is each independently H, halogen, cyano, nitro, C1-6 alkyl optionally substituted with R11, C2-6alkenyl, C2-6alkynyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, or CONR7R10.

37. The compound of any one of claims 1-36, wherein R9is H, C3-10cycloalkyl, C4-10heterocycloalkyl, phenyl, or 5-12 membered heteroaryl, wherein R9is optionally substituted by 1-2 R11.

38. The compound of any one of claims 1-36, wherein R9is C1-6alkyl optionally substituted by 1 R11.

39. The compound of any one of claims 1-38, wherein R7is H or C1-6alkyl.

40. The compound of any one of claims 1-39, wherein R10is H or C1-6alkyl, wherein the R10is optionally substituted by 1-2 R11.

41. The compound of any one of claims 1-40, wherein R11is each independently R6, nitro, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene-C4-6 heterocycloalkyl, C6-10 aryl, C5-6 heteroaryl, SO2R7, S(=O)NR5, SO2N(R7)2, CON(R7)2, or N(R7)2.

42. The compound of claim 31, wherein R11is each independently R6, C1-6alkoxy, C1-6haloalkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C6-10 aryl, C5-6 heteroaryl, SO2R7, S(=O)NR5, SO2N(R7)2, CON(R7)2, or N(R7)2.

43. The compound of claim 41, wherein R11is each independently N(R7)2.

44. A compound of Formula III:or a pharmaceutically acceptable salt thereof, wherein: 2A is , wherein * is the site covalently linked to the A1ring, and *** is the site covalently linked to L1; A4is aryl, heteroaryl, C3-12carbocyclyl, or 4-12 membered heterocyclyl; L1is -O-, -S-, -NH-, -S(=O)1-2-, -S(=O)(=NR5)-, -C(R6)2-, or -C(=O)-; L2is -NR7SO2-, -C(R8)2SO2-, -NR7SO2-C(R8)2-, -C(R8)2C(=O)-, - C(=O)C(R8)2-, -C(=O)O-, -OC(=O)-, -C(R8)2O-, -OC(R8)2-, -C(=O)NR7-, - NR7C(=O)-, -C(R8)2NR7-, -NR7C(R8)2-, -C(R8)2S(=O)0-2-, -S(=O)0-2C(R8)2-, - C(R8)2S(=O)NR7-, S(=O)NR7C(R8)2-, or -C(R8)2C(R8)2-; R1is C3-12carbocyclyl, 4-12 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -(C1-6 alkylene)-(C3-10 carbocyclyl), -(C1-6 alkylene)-(4-12 membered heterocyclyl), -(C1-6alkylene)-(phenyl), -(C1-6alkylene)-(5-12 membered heteroaryl), - (C1-6alkylene)-OR9, or -(C1-6alkylene)-NR7R10, wherein R1is optionally substituted by 0-5 R11; R2is each independently H, halogen, cyano, nitro, hydroxy, -NR7R10, - NHCOR9, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C2-6alkenoxy, C2-6alkynoxy, COR9, CON(R9)2, CF3, CF2H, CF3CF2, CF3CH2, C1-6haloalkyl, CF3O, CF2HO, CF3CF2O, CF3CH2O, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6 alkylthio, C2-6alkenylthio, C1-6alkylsulfonyl, aryl or heteroaryl, wherein R2is each independently optionally substituted by 0-4 R11; R3is each independently H, halogen, cyano, nitro, hydroxy, -NR7R10, - NHCOR9, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, COR9, CON(R9)2, CF3, CF2H, CF3CF2, CF3CH2, C1-6haloalkyl, CF3O, CF2HO, CF3CF2O, CF3CH2O, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6 alkylthio, C2-6alkenylthio, or C1-6alkylsulfonyl, wherein R3is each independently optionally substituted by 0-4 R11; R4is each independently H, halogen, cyano, nitro, hydroxy, NR7R10, NHCOR9, NR7CONR7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, COR9, CO2R9, CONR7R10, C1-6alkoxy, C2-6alkenoxy, C2-6alkynoxy, CF3, CF2H, CF3CF2, CF3CH2, C1-6 haloalkyl, CF3O, CF2HO, CF3CF2O, CF3CH2O, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8cycloalkenyl, C1-6alkylthio, C2-6alkenylthio, C1-6alkylsulfonyl, SO2N(R7)2, or phenyl, or any two occurrences of R4on contiguous atoms, taken together with the contiguous atoms to which the two occurrences of R4are attached, form a saturated or unsaturated 5-7 membered ring comprising 0-2 heteroatoms each independently selected from O, S(=O)0-2, P(=O)R12, N, and NR10, wherein R4is each independently optionally substituted by 0-4 R11; R5is each independently H or C1-4alkyl; R6is each independently H, F, OH, cyano, or C1-6alkyl; R7is each independently H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C4-6heterocycloalkyl, aryl, 5-10 membered heteroaryl, C1-3alkylene-C3-6cycloalkyl, or C1-3alkylene-C4-6heterocycloalkyl, or two R7s along with the N atom to which they are attached form a 4-7 membered ring comprising an additional 0-1 heteroatoms selected from NR5, O and S(=O)0-2; R8is each independently H, halogen, cyano, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6 alkynyl, C2-6 cycloalkyl, C4-6 heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3alkylene-C4-6heterocycloalkyl, or two R8s taken together with the C atom to which they are attached form a 4-7 membered ring comprising 0-1 heteroatom selected from O, S(=O)0-2, P(=O)R12, and NR5, wherein R8is optionally substituted by 1-3 R11;each R9is H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10 heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene-C4-6 heterocycloalkyl, C1-6acyl, phenyl, or 5-12 membered heteroaryl, wherein R9is optionally substituted by 1-3 R11; each R10is independently H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene-C4-6heterocycloalkyl, C1-6acyl, C1-6alkylsulfonyl, phenyl, or 5-12 membered heteroaryl, wherein R10is optionally substituted by 1-3 R11, or R7and R10on the same N atom may be taken together with the N atom to which they are attached form a 4-7 membered ring comprising an additional 0-1 heteroatoms selected from NR5, O, S(=O)0-2, P(=O)R12, and NR13; R11is each independently R6, oxo, nitro, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, 4- 6 membered heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene-C4-6 heterocycloalkyl, C6-10aryl, C5-10heteroaryl, SO2R7, S(=O)NR5, SO2N(R7)2, CON(R7)2, or N(R7)2; R12is each independently H, OH, C1-6alkyl, C1-6alkoxy, or -N(R7)2; R13is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6cycloalkyl, C4-6heterocycloalkyl, C1-3alkylene-C3-6cycloalkyl, or C1-3alkylene-C4-6 heterocycloalkyl, C1-6 acyl, aroyl, or heteroaroyl; m is an integer 0, 1 or 2; n is an integer 0, 1, 2, or 3; and p is an integer 0, 1, 2, or 3, provided that L1and L2are not situated on contiguous atoms of the A3ring; and when A2is, not -O-, wherein * is the site covalently linked to the A1ring, and *** is the site covalently linked to L1.

45. The compound of claim 44, wherein A4is phenyl, naphthyl, 5-10 membered heteroaryl, C3-10carbocyclyl, or 5-10 membered heterocyclyl.

46. The compound of claim 44, wherein A4is phenyl, naphthyl, thiophenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,, , , ,, , , .

47. The compound of claim 44, wherein A4is phenyl.

248. The compound of any one of claims 44-47, wherein A is phenyl, ,49. The compound of any one of claims 44-48, wherein R1is cyclohexyl optionally substituted with 1 R11.

50. The compound of any one of claims 44-48, wherein R1is piperidinyl, oxetanyl, azetidinyl, pyrrolidinyl, or azaspiroheptanyl, optionally substituted with 1 R11.

51. The compound of any one of claims 44-50, wherein L1is -O- or -S-.

52. The compound of any one of claims 44-51, wherein L2is -NHSO2-.

53. The compound of any one of claims 44-52, wherein m is 0.

54. The compound of any one of claims 44-52, wherein m is 1.

55. The compound of any one of claims 44-52 and 54, wherein R2is each independently H, halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-6cycloalkyl, aryl, or heteroaryl.

56. The compound of any one of claims 44-55, wherein n is 0, 1, or 2.

57. The compound of claim 56, wherein n is 1 or 2.

58. The compound of any one of claims 44-57, wherein R3is each independently H, halogen, cyano, C1-4alkyl, or C1-4haloalkyl.

59. The compound of claim 58, wherein R3is each independently halogen.

60. The compound of any one of claims 44-59, wherein p is 0, 1, or 2.

61. The compound of claim 60, wherein p is 1 or 2.

62. The compound of any one of claims 44-61, wherein R4is each H, halogen, cyano, nitro, hydroxy, NR7R10, NHCOR9, NR7CONR7, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, COR9, CO2R9, CONR7R10, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, or C3- 8cycloalkyl, wherein R4is each independently optionally substituted by 0-1 R11.

63. The compound of claim 62, wherein R4is each independently H, halogen, cyano, nitro, C1-6 alkyl optionally substituted with R11, C2-6alkenyl, C2-6alkynyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, or CONR7R10.

64. The compound of claim 63, wherein R4is each independently halogen.

65. A compound selected from the group consisting of:or pharmaceutically acceptable salts thereof.

66. A pharmaceutical composition, comprising:a) a compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient.

67. A compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 66 for use in inhibiting CDK2 in a subject in need thereof.

68. A compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 66 for use in treating a disease or disorder characterized by overexpression or amplification of cyclin E in a subject in need thereof.

69. The compound or composition for use of claim 68, wherein the cyclin E is CCNE1 or CCNE2.

70. A compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 66 for use in of treating a disease or disorder characterized by overexpression or amplification of cyclin A in a subject in need thereof.

71. A compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 66 for use in of treating cancer in a subject in need thereof.

72. The compound or composition for use of claim 71, wherein the cancer is associated with amplification or overexpression of cyclin E or cyclin A.

73. The compound or composition for use of claim 71 or claim 72, wherein the cancer is breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, melanoma, lung cancer, pancreatic cancer, stomach cancer, esophageal cancer, bladder cancer, colon cancer, rectal cancer, testicular cancer, prostate cancer, renal cancer, hepatic cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, lymphoma, or leukemia.

74. A compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 66 for use in of treating an autoimmune disorder or disease in a subject in need thereof.

75. The compound or composition for use of claim 74, wherein the autoimmune disorder or disease is associated with amplification or overexpression of cyclin E or cyclin A.

76. The compound or composition for use of claim 74 or 75, wherein the autoimmune disorder or disease is rheumatoid arthritis, Lupus, Crohn’s Disease, Addison disease,celiac disease, dermatomyositis, Graves’ disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, or pemphigus vulgaris.

77. A compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 66 for use in of treating an inflammatory disease or disorder in a subject in need thereof.

78. The compound or composition for use of claim 77, wherein the inflammatory disease or disorder is associated with amplification or overexpression of cyclin E or cyclin A.

79. The compound or composition for use of claim 77 or 78, wherein the inflammatory disease or disorder is asthma, chronic peptic ulcers, psoriasis, inflammatory bowel disease, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, or hepatitis.

80. A compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 66 for use in of treating a neurodegenerative disease or disorder in a subject in need thereof.

81. The compound or composition for use of claim 80, wherein the neurodegenerative disease or disorder is associated with amplification or overexpression of cyclin E or cyclin A.

82. The compound or composition for use of claim 80 or 81, wherein the neurodegenerative disease or disorder is Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, or cerebellar degeneration.

83. A conjugate, comprising a compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof, bound to CDK2.