Kinase inhibitor and use thereof
View Patent ↗The invention relates to a CDK4/6 kinase inhibitor, or a pharmaceutically acceptable salt, ester, or solvate thereof, or their isomers; a pharmaceutical formulation, pharmaceutical composition and kit comprising said CDK4/6 kinase inhibitor, or a pharmaceutically acceptable salt, ester, or solvate thereof, or their isomers, and use of said CDK4/6 kinase inhibitor, or a pharmaceutically acceptable salt, ester, or solvate thereof, or their isomers. For example, the compounds of the invention are useful for reducing or inhibiting the activity of CDK4/6 kinase in a cell, and/or treating and/or preventing a cancer-related disease mediated by CDK4/6 kinase.
1. A method for treating a cancer-related disease mediated by CDK4/6 kinase, comprising the step of administering to a subject in need thereof a therapeutically effective amount of the compound of Formula (I′), or a pharmaceutically acceptable salt, ester, or solvate thereof, or their stereoisomers,
wherein:
each of A 1 and A 2 is nitrogen;
R 1 is selected from C 1-6 alkyl, C 1-6 alkoxy, or 3-8 membered cycloalkyl optionally substituted by Q 1 , wherein Q 1 is selected from C 1-6 alkyl or C 1-6 alkoxy;
R 2 is selected from C 1-6 alkyl, C 1-6 alkoxy, cyano, carbamoyl or C 1-6 alkylcarbonylamino;
R 3 and R 5 are independently selected from halogen or hydrogen, and at least one of R 3 and R 5 is halogen;
R 4 is selected from 3-8 membered heterocyclyl, 6-14 membered fused heterocyclyl, 5-8 membered heteroaryl, 6-14 membered fused heteroaryl, phenyl, naphthyl, 6-12 membered bridged heterocyclyl or 6-12 membered spiroheterocyclyl, each of which is optionally substituted by Q 2 ;
Q 2 is selected from amino, hydroxyl, halogen, trifluoromethyl, cyano, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonylamino, or di-C 1-6 alkylamino; or C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl or 6-9 membered bridged heterocyclyl, each of which is optionally substituted by a substituent, wherein the substituent is selected from amino, hydroxyl, halogen, trifluoromethyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, C 1-6 alkylsulfonyl, 3-8 membered heterocyclyl or 3-8 membered cycloalkyl;
n is selected from 0, 1, 2, 3, 4 or 5; and
wherein the cancer-related disease is selected from lung cancer, prostate cancer, lymphoma, leukemia, bladder carcinoma, esophageal cancer, liver cancer, pancreatic carcinoma and gastric cancer.
2. The method of claim 1 , wherein
each of A 1 and A 2 is nitrogen;
le is selected from C 1-4 alkyl or C 1-4 alkoxy;
R 2 is selected from C 1-4 alkyl, C 1-4 alkoxy, cyano, carbamoyl or C 1-4 alkylcarbonylamino;
each of R 3 and R 5 is halogen;
R 4 is selected from a nitrogen-containing 5-6 membered heterocyclyl optionally substituted by Q 2 ;
Q 2 is selected from amino, hydroxyl, halogen, trifluoromethyl, cyano, C 1-4 alkoxy, or di-C 1-4 alkylamino; or C 1-4 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, each of which is optionally substituted by a substituent, wherein the substituent is selected from amino, hydroxyl, halogen, trifluoromethyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, or 3-6 membered cycloalkyl; and
n is 0.
3. The method of claim 2 wherein the nitrogen-containing 5-6 membered heterocyclyl is a nitrogen-containing 6 membered heterocyclyl.
4. The method of claim 1 , wherein the compound has the structure of Formula (I),
wherein:
each of A 1 and A 2 is nitrogen;
R 1 is selected from C 1-6 alkyl, C 1-6 alkoxy, or 3-8 membered cycloalkyl optionally substituted by Q 1 , wherein Q 1 is selected from C 1-6 alkyl or C 1-6 alkoxy;
R 2 is selected from C 1-6 alkyl, C 1-6 alkoxy, cyano, carbamoyl or C 1-6 alkylcarbonylamino;
R 3 and R 5 are independently selected from halogen or hydrogen, and at least one of R 3 and R 5 is halogen; and
R 4 is selected from 3-8 membered heterocyclyl, 6-14 membered fused heterocyclyl, 5-8 membered heteroaryl, 6-14 membered fused heteroaryl, phenyl, naphthyl, 6-12 membered bridged heterocyclyl or 6-12 membered spiroheterocyclyl, each of which is optionally substituted by Q 2 ; wherein Q 2 is selected from amino, hydroxyl, halogen, trifluoromethyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, 3-8 membered heterocyclyl or 6-9 membered bridged heterocyclyl.
5. The method of claim 4 , wherein
each of A 1 and A 2 is nitrogen;
R 1 is selected from C 1-4 alkyl or C 1-4 alkoxy;
R 2 is selected from C 1-4 alkyl, C 1-4 alkoxy, cyano, carbamoyl or C 1-4 alkylcarbonylamino;
each of R 3 and R 5 is halogen; and
R 4 is selected from 5-7 membered heterocyclyl, 6-11 membered fused heterocyclyl, 6-11 membered bridged heterocyclyl or 6-11 membered spiroheterocyclyl, each of which is optionally substituted by Q 2 ; wherein Q 2 is selected from amino, hydroxyl, trifluoromethyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, 5-6 membered heterocyclyl or 7-9 membered bridged heterocyclyl.
6. The method of claim 5 , wherein
each of A 1 and A 2 is nitrogen;
R 1 is isopropyl;
R 2 is selected from methyl, methoxy, cyano, carbamoyl, or acetylamino;
each of R 3 and R 5 is F; and
R 4 is selected from 5-6 membered heterocyclyl optionally substituted by Q 2 ; wherein Q 2 is selected from amino, hydroxyl, trifluoromethyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, 6 membered heterocyclyl or 8 membered bridged heterocyclyl.
7. The method of claim 6 , wherein
R 2 is methyl; and
R 4 is selected from a nitrogen-containing 5-6 membered heterocyclyl optionally substituted by Q 2 ; wherein the nitrogen-containing 5-6 membered heterocyclyl is linked to the methylene of Formula (I) via a nitrogen atom, wherein Q 2 is selected from amino, hydroxyl, trifluoromethyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, or a nitrogen-containing 8 membered bridged heterocyclyl.
8. The method of claim 7 wherein the nitrogen-containing 5-6 membered heterocyclyl is a nitrogen-containing 5-6 membered heterocyclyl containing 1 to 2 nitrogen atoms.
9. The method of claim 7 , wherein
R 4 is selected from
each of which is optionally substituted by Q 2 , wherein Q 2 is selected from C 1-4 alkyl or a nitrogen-containing 8 membered bridged heterocyclyl.
10. The method of claim 5 , wherein
each of A 1 and A 2 is nitrogen;
R 1 is isopropyl;
R 2 is selected from methyl, methoxy, cyano, carbamoyl, or acetylamino;
each of R 3 and R 5 is F; and
R 4 is selected from 7-9 membered bridged heterocyclyl optionally substituted by Q 2 ; wherein Q 2 is selected from amino, hydroxyl, trifluoromethyl, cyano, C 1-4 alkyl, 6 membered heterocyclyl or 8 membered bridged heterocyclyl.
11. The method of claim 10 , wherein
R 2 is methyl; and
R 4 is selected from a nitrogen-containing 7-9 membered bridged heterocyclyl optionally substituted by Q 2 ; wherein the nitrogen-containing 7-9 membered bridged heterocyclyl is linked to the methylene of Formula (I) via a nitrogen atom, wherein Q 2 is selected from amino, hydroxyl, trifluoromethyl, cyano, C 1-4 alkyl, or a nitrogen-containing 6 membered heterocyclyl.
12. The method of claim 11 wherein the nitrogen-containing 7-9 membered bridged heterocyclyl is a nitrogen-containing 7-9 membered bridged heterocyclyl containing 1 to 2 nitrogen atoms.
13. The method of claim 11 , wherein
R 4 is selected from
each of which is optionally substituted by Q 2 , wherein Q 2 is selected from C 1-4 alkyl or a nitrogen-containing 6 membered heterocyclyl.
14. The method of claim 5 , wherein
each of A 1 and A 2 is nitrogen;
R 1 is isopropyl;
R 2 is selected from methyl, methoxy, cyano, carbamoyl, or acetylamino;
each of R 3 and R 5 is F; and
R 4 is selected from 6-10 membered fused heterocyclyl optionally substituted by Q 2 ; wherein Q 2 is selected from amino, hydroxyl, trifluoromethyl, cyano, C 1-4 alkyl, 6 membered heterocyclyl or 8 membered bridged heterocyclyl.
15. The method of claim 14 , wherein
R 2 is methyl; and
R 4 is selected from a 6-10 membered fused heterocyclyl that contains 1, 2 or 3 identical or different heteroatoms and is optionally substituted by Q 2 .
16. The method of claim 15 wherein the heteroatoms are selected from nitrogen atom and oxygen atom, and contain at least one nitrogen atom, and the 6-10 membered fused heterocyclyl is linked to the methylene of Formula (I) via a nitrogen atom, wherein Q 2 is selected from amino, hydroxyl, trifluoromethyl, cyano, or C 1-4 alkyl.
17. The method of claim 15 , wherein
R 4 is selected from
each of which is optionally substituted by Q 2 , wherein Q 2 is selected from amino or C 1-4 alkyl.
18. The method of claim 5 , wherein
each of A 1 and A 2 is nitrogen;
R 1 is isopropyl;
R 2 is selected from methyl, methoxy, cyano, carbamoyl, or acetylamino;
each of R 3 and R 5 is F; and
R 4 is selected from 7-11 membered spiroheterocyclyl optionally substituted by Q 2 ; wherein Q 2 is selected from amino, hydroxyl, trifluoromethyl, cyano, C 1-4 alkyl, 6 membered heterocyclyl or 8 membered bridged heterocyclyl.
19. The method of claim 18 , wherein
R 2 is methyl; and
R 4 is selected from a nitrogen-containing 7-11 membered spiroheterocyclyl optionally substituted by Q 2 ; wherein the nitrogen-containing 7-11 membered spiroheterocyclyl is linked to the methylene of Formula (I) via a nitrogen atom, wherein Q 2 is selected from amino, hydroxyl, trifluoromethyl, cyano, or C 1-4 alkyl.
20. The method of claim 19 wherein the nitrogen-containing 7-11 membered spiroheterocyclyl is a nitrogen-containing 7-11 membered spiroheterocyclyl containing 1 to 2 nitrogen atoms.
21. The method of claim 19 , wherein
R 4 is selected from
each of which is optionally substituted by Q 2 , wherein Q 2 is selected from C 1-4 alkyl.
22. The method of claim 1 , wherein the compound is selected from: