Cyclin dependent kinase (CDK2) inhibitors

By designing new CDK2 inhibitor compounds, the problems of insufficient selectivity and in vivo PK properties of existing inhibitors were solved, efficient targeted regulation of CDK2 was achieved, and the therapeutic effect on specific cancers was significantly improved.

CN120659790APending Publication Date: 2025-09-16NOVARTIS AG
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Patent Information

Application Number
CN202480011605.2
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Priority Date
2023-09-01
Filing Date
2024-02-15
Publication Date
2025-09-16

AI Technical Summary

Technical Problem

Existing CDK2 inhibitors have problems with selectivity and in vivo PK properties in cancer treatment, and are unable to effectively target and regulate CDK2 activity, resulting in poor therapeutic effects.

Method used

Provided is a new class of CDK2 inhibitor compounds having a specific structural formula (Formula I), which enhance the selectivity and in vivo pharmacokinetic properties of the compounds through a unique binding mode to the CDK2 ATP binding site, including compounds having a 5-membered heteroaryl motif.

Benefits of technology

The selectivity and in vivo pharmacokinetic properties of CDK2 inhibitors are improved, and the therapeutic effect on CDK2-mediated cancers is enhanced, especially the therapeutic potential for cancers such as uterine carcinosarcoma, ovarian cancer, gastric cancer, endometrial cancer and breast cancer.

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Abstract

The present invention relates to compounds that inhibit CDK2 (cyclin dependent kinase 2 or cell division protein kinase 2), and to processes for the preparation of said compounds, pharmaceutical compositions comprising said compounds and the use of said compounds in the treatment of conditions, diseases and conditions mediated by CDK2.
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Claims

1. A compound according to formula (I), (I); wherein: Y 1 is a bond or CH2 (e.g. Y 1 is a key); Y 2 It is a bond, O, NR 5 or CR 6 R 7 (For example, Y 2 is a key); R 1 and R 2 are each independently selected from the group consisting of H, halo, C1-C6 alkyl and C1-C6 haloalkyl, or R 1 and R 2 linked together to form a C3-C4 cycloalkyl group or a C3-C4 cyclohaloalkyl group; Each R 3 independently selected from the group consisting of hydroxy, halo, C1-C6 alkyl and C1-C6 haloalkyl; R 4 Selected from the group consisting of H, halo, C1-C6 alkyl and C1-C6 haloalkyl; R 5 Selected from the group consisting of H, C1-C6 alkyl, C(=O)-C1-C6 alkyl or C(=O)-O-C1-C6 alkyl; R 6 and R 7 are linked together to form, together with the carbon atoms to which they are attached, a C3-C6 cycloalkyl group or a 3-6 membered heterocyclic group containing 1-3 heteroatoms independently selected from the group consisting of O, N and S, wherein the C3-C6 cycloalkyl group or the 3-6 membered heterocyclic group is substituted by 0-3 substituents R 8 replace; Each R 8 independently selected from the group consisting of C1-C6 alkyl, C(=O)C1-C6 alkyl, halo, C1-C6 haloalkyl, S-C1-C6 alkyl, SO-C1-C6 alkyl, SO2-C1-C6 alkyl, cyano, hydroxyl, or two R on the same ring atom 8 The substituents are linked together to form =0; n is 0 to 3; m is 1 to 5; is a 5-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from N, O and S, which is substituted by 0 to 3 substituents R A replace; Each R A Independently L 1 -X 1 ,in Instructions and Attachment point, each L 1 are independently selected from a bond, O, S, SO, SO2, C≡C, C(=O), C(=O)-O , C1-C6 alkylene, C1-C6 haloalkylene, O-C1-C6 alkylene 、 O-C1-C6 haloalkylene 、 O-C1-C6 hydroxyalkylene , C1-C6 alkylene-O-C1-C6 alkylene, O-C3-C6 cycloalkylene 、 O-3-6 membered heterocyclylene , C1-C6 hydroxyalkylene, C3-C6 cycloalkylene, 3-6 membered heterocyclic group (e.g., containing 1 heteroatom which is O), O-C1-C6 alkylene-O, O-C1-C6 alkylene-O-C3-C6 cycloalkylene and O-C1-C6 alkylene-O-3-6 membered heterocyclylene ,in Instructions and attachment points, and Instructions and X 1 attachment points; And each X 1 independently selected from H, halo, cyano, hydroxy, C1-C6 alkyl, C(=O)-C1-C6 alkyl, C1-C6 haloalkyl, 0-3 R 8 C3-C6 cycloalkyl, O-C1-C6 alkyl, S-C1-C6 alkyl, S(O)-C1-C6 alkyl, S(O)2-C1-C6 alkyl, N(C1-C6 alkyl)2, C(=O)N(C1-C6 alkyl)2, C1-C6 hydroxyalkyl, 0-3 R 8 substituted 3-6 membered heterocyclic group (eg containing 1 or 2 heteroatoms independently selected from O, N and S), substituted by 0-3 R 8 substituted 5-10 membered heteroaryl (e.g., 5-, 6-, 9-, or 10-membered heteroaryl) containing 1-4 heteroatoms independently selected from O, N, and S, substituted by 0-3 R 8 A 5-10 membered partially saturated heterocyclic group containing 1 to 4 heteroatoms independently selected from the group consisting of O, N and S, substituted by 0-3 R 8 A 7-10 membered spiroheterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S and substituted by 0-3 R 8 C7-C 10 spirocycloalkyl; or Two R on adjacent ring atoms A The substituents are joined together to form with the adjacent ring atoms a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, provided that at least one heteroatom is N; or a pharmaceutically acceptable salt and / or tautomer thereof.

2. The compound according to claim 1 or its pharmaceutically acceptable salt and / or tautomer, wherein Y 1 It is a key.

3. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein Y 2 It is a key.

4. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein m is 4.

5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein n is 1 to 3, for example n is 1.

6. The compound according to claim 5 or a pharmaceutically acceptable salt and / or tautomer thereof, wherein at least one R 3 It's OH.

7. The compound according to claim 1 or a pharmaceutically acceptable salt and / or tautomer thereof, wherein the compound having formula (I) is a compound having formula (Ia): (Ia), where R 1 、R 2 、R 3 、R 4 and As defined in claim 1.

8. The compound according to claim 1 or a pharmaceutically acceptable salt and / or tautomer thereof, wherein the compound having formula (I) is a compound having formula (Ib): (Ib), where R 1 、R 2 、R 3 、R 4 and As defined in claim 1.

9. The compound according to claim 1 or a pharmaceutically acceptable salt and / or tautomer thereof, wherein the compound having formula (I) is a compound having formula (Ic): (Ic), where R 1 、R 2 、R 3 、R 4 and As defined in claim 1.

10. The compound according to claim 1 or a pharmaceutically acceptable salt and / or tautomer thereof, wherein the compound having formula (I) is a compound having formula (Id): (Id), where R 1 、R 2 、R 4 and As defined in claim 1.

11. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein R 1 and R 2 are linked together to form a C3-C4 cycloalkyl group or a C3-C4 cyclohaloalkyl group.

12. The compound according to claim 11 or a pharmaceutically acceptable salt and / or tautomer thereof, wherein R 1 and R 2 linked together to form a C3-C4 cycloalkyl group.

13. The compound according to claim 12 or a pharmaceutically acceptable salt and / or tautomer thereof, wherein R 1 and R 2 linked together to form a C3 cycloalkyl group.

14. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein R 4 It’s H.

15. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is a 5-membered heteroaryl group containing 2 heteroatoms independently selected from N, O and S, which is substituted by 0 to 3 substituents R A Substituted, where R A As defined in any one of the preceding claims.

16. The compound according to claim 15 or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is a 5-membered heteroaryl group containing 2 heteroatoms independently selected from N and O, the 5-membered heteroaryl group being substituted by 0 to 3 substituents R A Substituted, where R A As defined in any one of the preceding claims.

17. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is a 5-membered heteroaryl group containing 1 to 3 heteroatoms each of which is N, the 5-membered heteroaryl group being substituted by 0 to 3 substituents R A Substituted, where R A As defined in any one of the preceding claims.

18. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is a 5-membered heteroaryl group containing 2 heteroatoms each of which is N, which is substituted by 0 to 3 substituents R A Substituted, where R A As defined in any one of the preceding claims.

19. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is a 5-membered heteroaryl group containing 2 heteroatoms each of which is N, the 5-membered heteroaryl group being substituted by 0 to 2 substituents R A Substituted, where R A As defined in any one of the preceding claims.

20. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is a 5-membered heteroaryl group containing 2 heteroatoms each of which is N, and the 5-membered heteroaryl group is substituted by 0 or 1 substituents R A Substituted, where R A yes L 1 -X 1 , and L 1 and X 1 As defined in any one of the preceding claims.

21. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein Selected from the group consisting of: 、 、 、 、 and .

22. A compound according to any one of claims 1 to 14 and 21 or a pharmaceutically acceptable salt and / or tautomer thereof, wherein Selected from the group consisting of: 、 and .

23. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt and / or tautomer thereof, wherein Selected from the group consisting of: 1) 、2) 3) 、4) 、5) 、6) 7) 、8) 、9) 、10) 、11) 、12) 、13) 、14) 、15) 、16) 、17) 、18) 、19) 、20) ,twenty one) ,twenty two) ,twenty three) ,twenty four) 、25) 、26) 、27) 、28) 、29) , 30) 、31) 、32) 、33) 、34) 、35) 、36) 、37) 、38) 、39) , 40) 、41) , 42) , 43) , 44) , 45) , 46) 、47) and 48) ,and wherein X is selected from O, NH and S (eg, X is NH).

24. A compound according to any one of claims 1 to 14 and 22, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein Selected from the group consisting of: 1) 、2) 3) 、4) 、5) 、6) 7) 、8) 、9) 、10) 、11) 、12) 、13) 、14) 、15) 、16) 、17) 、18) 、19) 、20) ,twenty one) ,twenty two) ,twenty three) ,twenty four) 、25) 、26) 、27) 、28) 、29) , 30) 、31) 、32) 、33) 、34) 、35) 、36) 、37) 、38) 、39) , 40) 、41) , 42) , 43) , 44) , 45) , 46) 、47) and 48) .

25. A compound according to any one of claims 1 to 14 and 23, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein Selected from the group consisting of: 、 、 、 and , and wherein X is selected from O, NH and S.

26. A compound according to any one of claims 1 to 14 and 25, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein Selected from the group consisting of: 、 、 、 and .

27. A compound according to any one of claims 1 to 14 and 26, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein: i) Selected from the group consisting of: 、 、 and (For example yes ) and R A Selected from a) halogenated, b) a cyano group, c) C1-C6 alkyl, d) C1-C6 haloalkyl, e) C1-C6 hydroxyalkyl, f) O-C1-C6 alkyl, g) C(=O)-O-C1-C6 alkyl, h) C1-C6 alkylene-O-C1-C6 alkyl, i) O-C1-C6 alkylene-O-C1-C6 alkyl, j) 0-3 R 8 a C3-C6 cycloalkyl group substituted with a group, k) 0-3 R 8 a 5-10 membered heteroaryl group substituted with 1-4 heteroatoms independently selected from N, O and S, l) 0-3 R 8 a 5-10 membered partially saturated heterocyclic group containing 1-4 heteroatoms independently selected from N, O and S, m) 0-3 R 8 O-C3-C6 cycloalkyl substituted with a group, n) 0-3 R 8 a C≡C-5-10 membered heteroaryl group substituted with 1 to 4 heteroatoms independently selected from N, O and S, o) 0-3 R 8 S-5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, p) 0-3 R 8 a C1-C6 alkylene-5-10 membered heteroaryl group substituted with 1-4 heteroatoms independently selected from N, O and S, q) O-C1-C6 haloalkyl, r) O-C1-C6 alkylene-N(C1-C6 alkyl)2, s) O-C1-C6 hydroxyalkylene-O-C1-C6 alkyl, t) 0-3 R 8 O-C1-C6 alkylene-C3-C6 cycloalkyl substituted with a group, u) 0-3 R 8 O-C1-C6 alkylene-3-6 membered heterocyclic group containing 1 or 2 heteroatoms independently selected from O, N and S, v) O-C1-C6 alkylene-C(=O)-N(C1-C6 alkyl)2, w) 0-3 R 8 a C1-C6 alkylene-5-10 membered partially saturated heterocyclic group containing 1-4 heteroatoms independently selected from N, O and S, x) 0-3 R 8 O-C1-C6 alkylene-7-10 membered spiroheterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, y) O-C1-C6 alkylene-S(O)2-C1-C6 alkyl, z) O-C1-C6 hydroxyalkyl, aa) 0-3 R 8 O-C1-C6 alkylene-5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, bb) 0-3 R 8 O-5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, cc) 0-3 R 8 O-3-6 membered heterocyclic group containing 1 or 2 heteroatoms independently selected from O, N and S, dd) 0-3 R 8 C≡C-C3-C6 cycloalkyl substituted with a group, ee) S-C1-C6 haloalkyl, ff) 0-3 R 8 O-C1-C6 alkylene-O-3-6 membered heterocyclic group containing 1 or 2 heteroatoms independently selected from O, N and S gg) and 0-3 R 8 a 3- to 6-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S; or ii) yes And R A The substituents are joined together to form, with the ring atoms to which they are attached, a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S.

28. The compound according to claim 27 or a pharmaceutically acceptable salt and / or tautomer thereof, wherein each R 8 Independently selected from the group consisting of: halo (e.g. fluorine), C1-C6 alkyl (e.g. methyl), hydroxy, cyano, S(O2)-C1-C6 alkyl (e.g. S(O2)CH3), C(=O)-C1-C6 alkyl (e.g. C(=O)CH3), O-C1-C6 alkyl (e.g. OCH3) and C1-C6 haloalkyl (e.g. C1 haloalkyl, e.g. CHF2), or two R on the same ring atom 8 The substituents are linked together to form =0.

29. The compound according to claim 27 or a pharmaceutically acceptable salt and / or tautomer thereof, wherein: i) Selected from the group consisting of: 、 、 and , and R A is selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, O-C1-C6 alkyl, C(=O)-O-C1-C6 alkyl, C1-C6 alkylene-O-C1-C6 alkyl, O-C1-C6 alkylene-O-C1-C6 alkyl, C3-C6 cycloalkyl and a 3- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S; or ii) yes And R A The substituents are joined together to form, with the ring atoms to which they are attached, a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S.

30. A compound according to any one of claims 1 to 14, 28 and 29, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein yes And R A It is CH3, OCH3 or OCH2CH3.

31. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein each L 1 are independently selected from a bond, O, C(=O), C(=O)-O , C1-C6 alkylene, C1-C6 haloalkylene, O-C1-C6 alkylene , C1-C6 alkylene-O-C1-C6 alkylene, C1-C6 hydroxyalkylene, C3-C6 cycloalkylene, 3-6 membered heterocyclyl (e.g., containing 1 heteroatom which is O) and O-C1-C6 alkylene-O, wherein Instructions and attachment points, and Instructions and X 1 attachment points; And each X 1 Independently selected from H, halo, cyano, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, O-C1-C6 alkyl, C1-C6 hydroxyalkyl and 3-6 membered heterocyclyl (e.g., containing 1 heteroatom which is O).

32. A compound according to any one of claims 1 to 27 and 31, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein R A Selected from the following list, said list consisting of: C1-C6 alkyl, C1-C6 alkylene-O-C1-C6 alkyl, C1-C6 haloalkyl, C(=O)-O-C1-C6 alkyl, C1-C6 hydroxyalkyl, 3-6 membered heteroatoms containing 1 heteroatom which is O, halo, O-C1-C6 alkyl, C3-C6 cycloalkyl, cyano and O-C1-C6 alkylene-O-C1-C6 alkyl.

33. A compound selected from any one of the following: 1) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((1-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 2) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 3) 2'-((3-(difluoromethyl)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 4) methyl 4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazole-3-carboxylate; 5) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methyl-1H-pyrazol-5-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 6) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(hydroxymethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 7) 7'-((1R,5R)-5-hydroxy-3,3-dimethylcyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 8) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 9) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 10) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 11) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((2-(methoxymethyl)-1H-imidazol-5-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 12) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methoxy-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 13) 2'-((3-chloro-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 14) 2'-((3-cyclopropyl-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 15) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(trifluoromethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 16) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 17) 7'-(3-hydroxycycloheptyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 18) 7'-((1R,3R)-3-hydroxycycloheptyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 19) 2'-((3-chloro-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycycloheptyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 20) 4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazole-3-carbonitrile; 21) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(methoxymethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 22) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(2-methoxyethoxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 23) 2'-((3-ethoxy-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; or a pharmaceutically acceptable salt and / or tautomer thereof.

34. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt and / or tautomer thereof.

35. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt and / or tautomer thereof.

36. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt and / or tautomer thereof.

37. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt and / or tautomer thereof.

38. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt and / or tautomer thereof.

39. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt and / or tautomer thereof.

40. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt and / or tautomer thereof, and one or more pharmaceutically acceptable carriers.

41. A combination comprising a compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt and / or tautomer thereof, and one or more therapeutically active agents.

42. A method of modulating CDK2 activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt and / or tautomer thereof.

43. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt and / or tautomer thereof.

44. A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt and / or tautomer thereof, for use as a medicament.

45. A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt and / or tautomer thereof, for use in treating cancer.

46. ​​Use of a compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt and / or tautomer thereof, in the treatment of cancer.

47. Use of a compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt and / or tautomer thereof, in the manufacture of a medicament for treating cancer.

48. The method of claim 43, the compound for use according to claim 45, or the use according to claim 46 or claim 47, wherein the cancer is selected from ovarian cancer, gastric cancer, uterine cancer, breast cancer (e.g., ER+ breast cancer, e.g., ER+ / Her2- breast cancer), lung cancer, and endometrial cancer.

49. The method of claim 43 or claim 48, the compound for use according to claim 45 or claim 48, or the use of any one of claims 46 to 48, wherein the cancer is a cyclin E amplified cancer.

Citation Information

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