CDK2 inhibitors
The present disclosure provides a compound represented by structural Formula (I): or a pharmaceutically acceptable salt thereof useful for treating a cancer.
1. A compound of Formula (Ia),
or a pharmaceutically acceptable salt thereof, wherein
R 1 is C 1 -C 4 alkyl optionally substituted with 1 to 4 groups each independently selected from halo and D;
R 2 is C 1 -C 4 alkyl or Ring A, wherein the C 1 -C 4 alkyl is optionally substituted with 1 to 4 groups each independently selected from halo, D, CN, and OH and/or 1 group of 5 to 6 membered heteroaryl having 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR d ; and
R 3 is selected from the group consisting of H, D, C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl, and 4 to 12-membered heterocyclyl, wherein the C 1 -C 4 alkyl and C 3 -C 10 cycloalkyl are each optionally substituted with 1 to 4 R c , wherein the 4 to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR d and then is optionally substituted on a ring carbon with 1 to 4 R c ; or
R 2 and R 3 are taken together with the carbon atom to which they are attached to form Ring B, wherein Ring B is C 3 -C 10 cycloalkyl or 4 to 12-membered heterocyclyl, wherein the C 3 -C 10 cycloalkyl is optionally substituted with 1 to 4 R b , wherein the 4 to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of NR d , N, O, and S and then is optionally substituted on a ring carbon by 1 to 4 R b ;
Ring A is selected from the group consisting of C 3 -C 10 cycloalkyl, phenyl, naphthyl, 4 to 12-membered heterocyclyl, and 4 to 12-membered heteroaryl, wherein the C 3 -C 10 cycloalkyl, phenyl, and naphthyl are each optionally substituted with 1 to 4 R a , wherein the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR d and then are optionally substituted on a ring carbon with 1 to 4 R a ;
Each R a is independently selected from the group consisting of D, halo, OH, CN, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, or two R a , attached to the same atom, form a ═O, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN;
Each R b is independently selected from the group consisting of D, halo, OH, CN, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, or two R b , attached to the same atom, form a ═O, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN;
Each R c is independently selected from the group consisting of D, halo, OH, CN, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, or two R c , attached to the same atom, form a ═O, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, and CN; or
Each R d is independently selected from the group consisting of H, D, and C 1 -C 6 alkyl;
R 4 is selected from the group consisting of H, D, and C 1 -C 4 alkyl optionally substituted with 1 to 4 groups each independently selected from halo, D and OH;
R 5 is selected from the group consisting of H, D, halo, CN, and C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is optionally substituted with 1 to 4 groups each independently selected from halo and OH;
R 6 is H or D; and
R 7 is H or D.
2. The compound of claim 1 , wherein R 1 is methyl or ethyl, each optionally substituted with 1 to 4 halo or D.
3. The compound of claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl, CF 3 , CH 2 F, and CHF 2 .
4. The compound of claim 1 , wherein the compound is of Formula (IIa):
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein Ring A is 4 to 10-membered heterocyclyl, optionally substituted on a ring carbon with 1 to 3 groups each independently selected from the group consisting of D, halo, OH, ═O, CN, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN.
6. The compound of claim 1 , wherein Ring A is 4 to 10-membered heteroaryl, optionally substituted on a ring carbon with 1 to 3 groups each independently selected from the group consisting of D, halo, OH, ═O, CN, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN.
7. The compound of claim 1 , wherein the compound is of Formula IIIa:
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7 , wherein Ring B is C 3 -C 8 cycloalkyl, optionally substituted with 1 to 3 groups each independently selected from the group consisting of D, halo, OH, ═O, CN, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN.
9. The compound of claim 1 , wherein R 3 is selected from the group consisting of H, D, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, and 4 to 10-membered heterocyclyl are each optionally substituted (on a ring carbon if R 3 is 4 to 10-membered heterocyclyl) with 1 to 3 groups each independently selected from the group consisting of D, halo, and OH.
10. The compound of claim 1 , wherein R 3 is selected from the group consisting of H, D, methyl, ethyl, cyclopropyl, and oxetanyl, each of which is optionally substituted (on a ring carbon if R 3 is oxetanyl) with 1 to 3 groups each independently selected from the group consisting of D, halo, and OH.
11. The compound of claim 1 , wherein R 4 is selected from the group consisting of H, D, and CH 3 .
12. The compound of claim 1 , wherein R 5 is H.
13. The compound of claim 1 , wherein the compound is of Formula IVa-1 or IVb-1:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , wherein the compound is selected from a compound of Formula Va-1, Vb-1, Vc-1, and Vd-1:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , wherein R 6 is H.
16. The compound of claim 1 , wherein R 7 is H.
17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
18. A compound of Formula (I),
or a pharmaceutically acceptable salt thereof, wherein
R 1 is C 1 -C 4 alkyl optionally substituted with 1 to 4 halo;
R 2 is C 1 -C 4 alkyl or Ring A, wherein the C 1 -C 4 alkyl is optionally substituted with 1 to 4 groups each independently selected from halo, CN, and OH and/or 1 group of 5 to 6 membered heteroaryl having 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR d ; and
R 3 is selected from the group consisting of H, C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl, and 4 to 12-membered heterocyclyl, wherein the C 1 -C 4 alkyl and C 3 -C 10 cycloalkyl are each optionally substituted with 1 to 4 R c , wherein the 4 to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR d and then is optionally substituted on a ring carbon with 1 to 4 R c ; or
R 2 and R 3 are taken together with the carbon atom to which they are attached to form Ring B, wherein Ring B is C 3 -C 10 cycloalkyl or 4 to 12-membered heterocyclyl, wherein the C 3 -C 10 cycloalkyl is optionally substituted with 1 to 4 R b , wherein the 4 to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of NR d , N, O, and S and then is optionally substituted on a ring carbon by 1 to 4 R b ;
Ring A is selected from the group consisting of C 3 -C 10 cycloalkyl, phenyl, naphthyl, 4 to 12-membered heterocyclyl, and 4 to 12-membered heteroaryl, wherein the C 3 -C 10 cycloalkyl, phenyl, and naphthyl are each optionally substituted with 1 to 4 R a , wherein the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR d and then are optionally substituted on a ring carbon with 1 to 4 R a ;
Each R a is independently selected from the group consisting of halo, OH, CN, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, or two R a , attached to the same atom, form a ═O, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN;
Each R b is independently selected from the group consisting of halo, OH, CN, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, or two R b , attached to the same atom, form a ═O, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN;
Each R c is independently selected from the group consisting of halo, OH, CN, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, or two R c , attached to the same atom, form a ═O, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, and CN; or
Each R d is independently H or C 1 -C 6 alkyl;
R 4 is H or C 1 -C 4 alkyl optionally substituted with 1 to 4 groups each independently selected from halo and OH; and
R 5 is selected from the group consisting of H, halo, CN, and C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is optionally substituted with 1 to 4 groups each independently selected from halo and OH.