Aminopyrimidine derivatives as cyclin-dependent kinase inhibitors
The present disclosure relates to novel CDK inhibitors, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of diseases and conditions associated with CDK.
1. A compound, wherein the compound is represented by Formula IA or is a pharmaceutically acceptable salt thereof:
wherein:
is a single bond or a double bond;
R 1 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cyclic haloalkyl, C 5 -C 8 bicyclic alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, an oxo group, cyano, a 3-7 membered heterocyclic group, 6-10 membered aryl, and a 5-10 membered heteroaryl, wherein each of the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cyclic haloalkyl, C 5 -C 8 bicyclic alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, 3-7 membered heterocyclic group, 6-10 membered aryl, and 5-10 membered heteroaryl is independently substituted with 0, 1, 2, or 3 R 1A ;
each R 1A is independently selected from halogen, hydroxyl, an oxo group, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cyclic alkoxy, —C(═O)OR 1B , —C(═O)N(R 1B ) 2 , —NHC(═O)OR 1B , and a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted with 1, 2, or 3 R 1C ;
each R 1B is independently selected from hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
each R 1C is independently selected from hydrogen, hydroxyl, halogen, an oxo group, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
R 2 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cyclic haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cyclic alkoxy, C 1 -C 6 haloalkoxy, and a 3-7 membered heterocyclic group;
X 1 and X 2 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, and C 3 -C 6 cyclic haloalkyl;
Q is N or CR O , wherein R Q is independently selected from hydrogen, halogen, and cyano;
Z is C;
W is selected from C(R W1 ) 2 , O, S, N, and NR W2 ; wherein
R w1 is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 5-8 membered bicyclic carbocyclic group, 5-8 membered bicyclic heterocyclic group, and a 3-8 membered heterocyclic group, wherein each of the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl is optionally substituted with 1, 2, or 3 R 1D ;
R W2 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 5-8 membered bicyclic carbocyclic group, 5-8 membered bicyclic heterocyclic group, and a 3-8 membered heterocyclic group, wherein each of the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl is optionally substituted with 1, 2, or 3 R 1D ; and
each R 1D is independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and hydroxyl; or
W and R 1 may be taken together with the C atom to which both are attached to form a carbocyclic ring of 5-8 atoms or a heterocyclic ring of 5-8 atoms, wherein the carbocyclic ring and heterocyclic ring is each optionally substituted with 1, 2, 3, or 4 R 1E ; or
W, Z, R 2 , and the C atom to which R 2 is attached may be taken together to form a carbocyclic ring of 5-8 atoms or a heterocyclic ring of 5-8 atoms, wherein each of the carbocyclic ring and heterocyclic ring is optionally substituted with 1, 2, 3, or 4 R 1E ;
each R 1E is independently selected from C 1 -C 6 alkyl, hydroxyl, and an oxo group;
Ring A is
wherein:
R 3 and R 4 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; or R 3 and R 4 may be taken together with the carbon atom to which both are attached to form a 3-7 membered cycloalkyl;
R 5 and R 6 are independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and aryl, wherein the C 1 -C 6 alkyl is optionally substituted with hydroxyl;
X is O or N—S(O) 2 —R X , wherein R X is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, a 3-7 membered heterocyclic group, aryl, and heteroaryl, and wherein each of the C 3 -C 6 cycloalkyl, 3-7 membered heterocyclic group, aryl, and heteroaryl is optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxyl, and cyano;
U is O or C(R U ) 2 , wherein R U is independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein each of the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl is optionally substituted with hydroxyl; and
V is O, C, or C(R V ) 2 , wherein R Y is independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein each of the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl is optionally substituted with hydroxyl;
with the proviso that one but not both of U and V is O.
2. The compound according to claim 1 , wherein the compound of Formula IA is represented by Formula IA′:
wherein:
R 1 is selected from C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 5 haloalkyl, C 3 -C 6 cyclic haloalkyl, C 5 -C 7 bicyclic alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, an oxo group, a 4-6 membered heterocyclic group, 6-membered aryl, and 5-6 membered heteroaryl, wherein each of the C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 5 haloalkyl, C 3 -C 6 cyclic haloalkyl, C 5 -C 7 bicyclic alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, 4-6 membered heterocyclic group, 6-membered aryl, and 5-6 membered heteroaryl are independently substituted with 0, 1, 2, or 3 R 1A ;
each R 1A is independently selected from halogen, hydroxyl, oxo, amino, C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cyclic alkoxy, —C(═O)OR 1B , —C(═O)N(R 1B ) 2 , —NHC(═O)OR 1B , and 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted with 1, 2, or 3 R 1C ;
each R 1B is independently selected from hydrogen, C 1 -C 8 alkyl, and C 4 -C 6 cycloalkyl; and
each R 1C is independently selected from hydroxyl, halogen, an oxo group, C 1 -C 8 alkyl, and C 4 -C 6 cycloalkyl;
R 2 is selected from hydrogen, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl;
R 3 and R 4 are independently selected from hydrogen, hydroxyl, deuterium, halogen, and C 1 -C 3 alkyl; or R 3 and R 4 may be taken together with the carbon atom to which both are attached to form a 3-5 membered cycloalkyl;
R 5 and R 6 are independently selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, and aryl;
X is O or N—S(O) 2 —R X , wherein R X is selected from C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, a 3-6 membered heterocyclic group, 6-membered aryl, and 6-membered heteroaryl, and wherein each of the C 3 -C 6 cycloalkyl, 3-6 membered heterocyclic group, 6-membered aryl, and 6-membered heteroaryl is optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxyl, and cyano;
X 1 is selected from halogen, C 1 -C 8 alkyl, and C 1 -C 5 haloalkyl;
X 2 is selected from hydrogen, halogen, C 1 -C 8 alkyl, and C 1 -C 4 haloalkyl;
Q is N or CR O , wherein R Q is hydrogen or cyano;
W is NR W2 , wherein R W2 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 5-6 membered bicyclic carbocyclic group, and a 3-7 membered heterocyclic group, wherein each of the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl is optionally substituted with 1, 2, or 3 R 1D , wherein R 1D is independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 3 haloalkyl, and hydroxyl; or
W and R 1 are taken together with the C atom to which both are attached to form a heterocyclic ring of 6-7 atoms, wherein the ring has 1 to 3 heteroatoms independently selected from N, S, and O, and wherein the ring is optionally substituted with 1, 2, or 3 R 1E , wherein each R 1E is independently a C 1 -C 3 alkyl or an oxo group;
U is O or C(R U ) 2 , wherein R U is independently selected from hydrogen, deuterium, halogen, and C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is optionally substituted with hydroxyl; and
V is O or C(R V ) 2 , wherein R Y is independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1 -C 3 alkyl, and C 3 -C 6 cycloalkyl, and wherein the C 1 -C 3 alkyl is optionally substituted with hydroxyl.
3. The compound according to claim 2 , wherein X 1 and X 2 are independently selected from bromine, chlorine, fluorine, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
4. The compound according to claim 2 , wherein R 2 is hydrogen.
5. The compound according to claim 2 , wherein R 5 is selected from hydrogen, deuterium, and cyclopropyl, and R 6 is hydrogen.
6. The compound according to claim 1 , wherein W, Z, R 2 , and the C atom to which R 2 is attached are taken together to form a heterocyclic ring of 6 atoms, wherein the heterocyclic ring is optionally substituted with 1, 2, or 3 R 1E .
7. The compound according to claim 6 , wherein W, R 2 , and the C atom to which R 2 is attached are taken together to form a ring selected from:
8. The compound according to claim 2 , wherein W is selected from:
NH,
9. The compound according to claim 2 , wherein R 1 is selected from C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 5 haloalkyl, C 3 -C 6 cyclic haloalkyl, C 5 -C 7 bicyclic alkyl, C 1 -C 4 aminoalkyl, C 1 -C 6 alkoxy, an oxo group, a 4-6 membered heterocyclic group, 6-membered aryl and 5-6 membered heteroaryl, wherein each of the C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 5 haloalkyl, C 3 -C 6 cyclic haloalkyl, C 5 -C 7 bicyclic alkyl, C 1 -C 4 aminoalkyl, C 1 -C 6 alkoxy, 4-6 membered heterocyclic group, 6-membered aryl, and 5-6 membered heteroaryl is independently substituted with 0, 1, 2, or 3 R 1A .
10. The compound according to claim 9 , wherein R 1 is selected from:
11. The compound according to claim 2 , wherein X is selected from:
O,
12. The compound according to claim 2 , wherein U is selected from:
O,
13. The compound according to claim 2 , wherein V is selected from:
O,
14. The compound according to claim 1 , wherein Ring A is selected from:
15. The compound according to claim 14 , wherein Ring A is selected from:
16. The compound according to claim 1 , wherein the compound is selected from:
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or a pharmaceutically acceptable salt of any of the above.
17. The compound according to claim 16 , wherein the compound is selected from:
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or a pharmaceutically acceptable salt of any of the above.
18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 16 and one or more pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, pharmaceutically acceptable excipients, or combinations thereof.
19. A method of treating a disease or condition modulated at least in part by a cyclin-dependent kinase (CDK) in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound according to claim 16 .
20. A method for inhibiting a CDK in a subject, comprising administering to the subject an effective amount of at least one compound according to claim 16 .
21. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound according to claim 16 .
22. A compound, wherein the compound is represented by Formula (IB) or is a pharmaceutically acceptable salt thereof:
wherein:
is a single bond or a double bond;
R 1 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cyclic haloalkyl, C 5 -C 8 bicyclic alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, an oxo group, cyano, a 3-7 membered heterocyclic group, 6-10 membered aryl, and a 5-10 membered heteroaryl, wherein each of the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cyclic haloalkyl, C 5 -C 8 bicyclic alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, 3-7 membered heterocyclic group, 6-10 membered aryl, and 5-10 membered heteroaryl is independently substituted with 0, 1, 2, or 3 R 1A ;
each R 1A is independently selected from halogen, hydroxyl, an oxo group, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cyclic alkoxy, —C(═O)OR 1B , —C(═O)N(R 1B ) 2 , —NHC(═O)OR 1B , and a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted with 1, 2, or 3 R 1C ;
each R 1B is independently selected from hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
each R 1C is independently selected from hydrogen, hydroxyl, halogen, an oxo group, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
X 1 and X 2 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, and C 3 -C 6 cyclic haloalkyl;
Q is CR O , N, or NR O , wherein R Q is selected from hydrogen, halogen, C 1 -C 4 alkyl, and an oxo group;
Q′ is CR Q′ , N, NR Q′ , wherein R Q′ is selected from hydrogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl;
T is CR T1 or NR T2 , wherein R T1 is halogen or R T2 , and R T2 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1, 2, or 3 groups independently selected from halogen, C 1 -C 6 alkyl, and hydroxyl;
Ring A is
wherein:
R 3 and R 4 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; or R 3 and R 4 may be taken together with the carbon atom to which both are attached to form a 3-7 membered cycloalkyl;
R 5 and R 6 are independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and aryl, wherein the C 1 -C 6 alkyl is optionally substituted with hydroxyl;
X is O or N—S(O) 2 —R X , wherein R X is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, a 3-7 membered heterocyclic group, aryl, and heteroaryl, and wherein each of the C 3 -C 6 cycloalkyl, 3-7 membered heterocyclic group, aryl, and heteroaryl is optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxyl, and cyano;
U is O or C(R U ) 2 , wherein R U is independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein each of the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl is optionally substituted with hydroxyl; and
V is O, C, or C(R V ) 2 , wherein R V is independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein each of the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl is optionally substituted with hydroxyl;
with the proviso that one but not both of U and V is O.
23. The compound according to claim 22 , wherein the compound is selected from:
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or a pharmaceutically acceptable salt of any of the above.
24. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound according to claim 23 .
25. A compound, wherein the compound is represented by Formula (IC) or is a pharmaceutically acceptable salt thereof:
wherein:
is a single bond or a double bond;
R 1 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cyclic haloalkyl, C 5 -C 8 bicyclic alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, an oxo group, cyano, a 3-7 membered heterocyclic group, 6-10 membered aryl, and a 5-10 membered heteroaryl, wherein each of the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cyclic haloalkyl, C 5 -C 8 bicyclic alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, 3-7 membered heterocyclic group, 6-10 membered aryl, and 5-10 membered heteroaryl is independently substituted with 0, 1, 2, or 3 R 1A ;
each R 1A is independently selected from halogen, hydroxyl, an oxo group, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cyclic alkoxy, —C(═O)OR 1B , —C(═O)N(R 1B ) 2 , —NHC(═O)OR 1B , and a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted with 1, 2, or 3 R 1C ;
each R 1B is independently selected from hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
each R 1C is independently selected from hydrogen, hydroxyl, halogen, an oxo group, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
R 2 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cyclic haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cyclic alkoxy, C 1 -C 6 haloalkoxy, and a 3-7 membered heterocyclic group;
X 1 and X 2 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, and C 3 -C 6 cyclic haloalkyl;
Q is N, O, or CR O , wherein R Q is selected from hydrogen, halogen, and an oxo group;
Q′ is CH, CH 2 , CR Q′ , N, or NR″, wherein R Q is halogen or R″, and R″ is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, and a 3-8 membered heterocyclic group, wherein each of the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl are each optionally substituted with 0, 1, 2, or 3 groups independently selected from halogen, C 1 -C 6 alkyl, and hydroxyl;
Z is C;
W is CR W1 , N, or NR W2 ; wherein
R W1 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and a 3-8 membered heterocyclic group, wherein each of the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl is optionally substituted with 1, 2, or 3 R 1D ,
R W2 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and a 3-8 membered heterocyclic group, wherein each of the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl is optionally substituted with 1, 2, or 3 R 1D , and
each R 1D is independently selected from halogen, C 1 -C 6 alkyl, and hydroxyl; or
W, Z, R 2 , and the C atom to which R 2 is attached may be taken together to form a carbocyclic ring of 5-8 atoms or a heterocyclic ring of 5-8 atoms, wherein each of the carbocyclic ring and heterocyclic ring is optionally substituted with 1, 2, 3, or 4 R 1E , and wherein each R 1E is independently selected from C 1 -C 6 alkyl, hydroxyl, and an oxo group;
Ring A is
wherein:
R 3 and R 4 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; or R 3 and R 4 may be taken together with the carbon atom to which both are attached to form a 3-7 membered cycloalkyl;
R 5 and R 6 are independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and aryl, wherein the C 1 -C 6 alkyl is optionally substituted with hydroxyl;
X is O or N—S(O) 2 —R X , wherein R X is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, a 3-7 membered heterocyclic group, aryl, and heteroaryl, and wherein each of the C 3 -C 6 cycloalkyl, 3-7 membered heterocyclic group, aryl, and heteroaryl is optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxyl, and cyano;
U is O or C(R U ) 2 , wherein R u is independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein each of the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl is optionally substituted with hydroxyl; and
V is O, C, or C(R Y ) 2 , wherein R Y is independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein each of the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl is optionally substituted with hydroxyl;
with the proviso that one but not both of U and V is O.
26. The compound according to claim 25 , wherein the compound is selected from:
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or a pharmaceutically acceptable salt of any of the above.
27. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound according to claim 26 .
28. A compound, wherein the compound is represented by Formula (ID) or is a pharmaceutically acceptable salt thereof:
wherein:
is a single bond or a double bond;
R 1 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cyclic haloalkyl, C 5 -C 8 bicyclic alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, an oxo group, cyano, a 3-7 membered heterocyclic group, 6-10 membered aryl, and a 5-10 membered heteroaryl, wherein each of the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cyclic haloalkyl, C 5 -C 8 bicyclic alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, 3-7 membered heterocyclic group, 6-10 membered aryl, and 5-10 membered heteroaryl is independently substituted with 0, 1, 2, or 3 R 1A ;
each R 1A is independently selected from halogen, hydroxyl, an oxo group, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cyclic alkoxy, —C(═O)OR 1B , —C(═O)N(R 1B ) 2 , —NHC(═O)OR 1B , and a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted with 1, 2, or 3 R 1C ;
each R 1B is independently selected from hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
each R 1C is independently selected from hydrogen, hydroxyl, halogen, an oxo group, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
R 2 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cyclic alkoxy, C 1 -C 6 haloalkoxy, and a 3-7 membered heterocyclic group;
X 1 and X 2 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, and C 3 -C 6 cyclic haloalkyl;
Q is N or CR O , wherein R Q is independently selected from hydrogen, halogen, and cyano;
D and E together with the carbon atom to which they are both attached form a carbocyclic ring of 5-8 atoms or a heterocyclic ring of 5-8 atoms containing 1 to 2 heteroatoms selected from O, S, and N, wherein any carbon ring may be optionally substituted with halogen, C 1 -C 4 alkyl, or hydroxyl;
Ring A is
wherein:
R 3 and R 4 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; or R 3 and R 4 may be taken together with the carbon atom to which both are attached to form a 3-7 membered cycloalkyl;
R 5 and R 6 are independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and aryl, wherein the C 1 -C 6 alkyl is optionally substituted with hydroxyl;
X is O or N—S(O) 2 —R X , wherein R X is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, a 3-7 membered heterocyclic group, aryl, and heteroaryl, and wherein each of the C 3 -C 6 cycloalkyl, 3-7 membered heterocyclic group, aryl, and heteroaryl is optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxyl, and cyano;
U is O or C(R U ) 2 , wherein R U is independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein each of the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl is optionally substituted with hydroxyl; and
V is O, C, or C(R V ) 2 , wherein R Y is independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein each of the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl is optionally substituted with hydroxyl;
with the proviso that one but not both of U and V is O.
29. The compound according to claim 28 , wherein the compound is selected from:
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or a pharmaceutically acceptable salt of any of the above.
30. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound according to claim 29 .
31. A compound, wherein the compound is selected from:
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or is a pharmaceutically acceptable salt thereof.
32. The compound of claim 31 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
33. The compound of claim 31 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
34. The compound of claim 31 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
35. The compound of claim 31 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
36. A compound, wherein the compound is selected from:
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or is a pharmaceutically acceptable salt thereof.
37. The compound of claim 36 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
38. The compound of claim 36 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
39. The compound of claim 36 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
40. The compound of claim 36 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
41. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 31 and one or more pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, pharmaceutically acceptable excipients, or combinations thereof.
42. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 36 and one or more pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, pharmaceutically acceptable excipients, or combinations thereof.
43. A method of treating a disease or condition modulated at least in part by a cyclin- dependent kinase (CDK) in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound according to claim 31 .
44. A method of treating a disease or condition modulated at least in part by a cyclin- dependent kinase (CDK) in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound according to claim 36 .
45. A method for inhibiting a CDK in a subject, comprising administering to the subject an effective amount of at least one compound according to claim 31 .
46. A method for inhibiting a CDK in a subject, comprising administering to the subject an effective amount of at least one compound according to claim 36 .
47. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 31 or a pharmaceutically acceptable salt thereof.
48. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 36 or a pharmaceutically acceptable salt thereof.