2-H-indazole derivatives as cyclin-dependent kinase (CDK) inhibitors and therapeutic uses thereof
Indazole compounds of formula (I) as cyclin-dependent kinase (CDK) and cell-proliferation inhibitors, and therapeutic uses and methods of preparation thereof, are disclosed. These compounds, and pharmaceutically acceptable salts, solvates, prodrugs, and pharmaceutical compositions thereof, are useful for treating diseases and disorders associated with activity of cyclin-dependent kinases, in particular CDK4/6, including but not limited to various cancers and inflammation-related diseases or conditions.
1. A compound of formula (I)
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
R 1 is hydrogen, C 1 -C 8 alkyl, or C 3 -C 7 cycloalkyl;
R 2 and R 3 are each independently hydrogen, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, or C 3 -C 7 cycloalkylmethyl;
R 4 is hydrogen, halogen, C 1 -C 8 alkyl, or C 3 -C 7 cycloalkyl; and
R 5 is hydrogen or halogen.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 is C 1 -C 6 alkyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 is methyl, ethyl, propyl, or isopropyl.
4. The compound of claim 2 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 2 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkylmethyl.
5. The compound of claim 3 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 2 is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, or cyclopentylmethyl.
6. The compound of claim 4 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 3 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl.
7. The compound of claim 5 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 3 is methyl, ethyl, propyl, isopropyl, or cyclopropyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4 is located at the 7-position of the indazole ring, characterized by formula Ia:
9. The compound of claim 8 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4 is hydrogen or halogen.
10. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 5 is hydrogen or fluoro.
11. The compound of claim 8 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 is methyl or ethyl; R 2 is isopropyl, cyclopropyl, cyclopropylmethyl, or cyclopentyl; R 3 is methyl or ethyl; R 4 is hydrogen or fluoro; and R 5 is hydrogen or fluoro.
12. The compound of claim 6 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, selected from the group consisting of:
13. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, selected from the list in the table below:
Compound
No.
Structure
Name
1
N-(5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoro-4-(3-isopropyl-2- methyl-2H-indazol-5- yl)pyrimidin-2-amine
2
N-(5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoro-4-(7-fluoro-3- isopropyl-2-methyl-2H- indazol-5-yl)pyrimidin-2- amine
3
N-(5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-4-(7- fluoro-3-isopropyl-2-methyl- 2H-indazol-5-yl)pyrimidin- 2-amine
4
4-(3-cyclopentyl-2-methyl- 2H-indazol-5-yl)-N-(5-((4- ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
5
4-(3-cyclopentyl-7-fluoro-2- methyl-2H-indazol-5-yl)-N- (5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
6
4-(3-cyclopentyl-7-fluoro-2- methyl-2H-indazol-5-yl)-N- (5-((4-ethylpiperazin-1- yl)methyl)pyridin-2- yl)pyrimidin-2-amine
7
4-(3-cyclopropyl-2-methyl- 2H-indazol-5-yl)-N-(5-((4- ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
8
4-(3-cyclopropyl-7-fluoro-2- methyl-2H-indazol-5-yl)-N- (5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
9
4-(3-cyclohexyl-2-methyl- 2H-indazol-5-yl)-N-(5-((4- ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
10
4-(3-cyclohexyl-7-fluoro-2- methyl-2H-indazol-5-yl)-N- (5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
11
5-fluoro-4-(3-isopropyl-2- methyl-2H-indazol-5-yl)-N- (5-((4-isopropylpiperazin-1- yl)methyl)pyridin-2- yl)pyrimidin-2-amine
12
5-fluoro-4-(7-fluoro-3- isopropyl-2-methyl-2H- indazol-5-yl)-N-(5-((4- isopropylpiperazin-1- yl)methyl)pyridin-2- yl)pyrimidin-2-amine
13
4-(3-cyclopentyl-2-methyl- 2H-indazol-5-yl)-5-fluoro-N- (5-((4-isopropylpiperazin-1- yl)methyl)pyridin-2- yl)pyrimidin-2-amine
14
4-(3-cyclopentyl-7-fluoro-2- methyl-2H-indazol-5-yl)-5- fluoro-N-(5-((4- isopropylpiperazin-1- yl)methyl)pyridin-2- yl)pyrimidin-2-amine
15
5-fluoro-4-(3-isopropyl-2- methyl-2H-indazol-5-yl)-N- (5-((4-propylpiperazin-1- yl)methyl)pyridin-2- yl)pyrimidin-2-amine
16
5-fluoro-4-(7-fluoro-3- isopropyl-2-methyl-2H- indazol-5-yl)-N-(5-((4- propylpiperazin-1- yl)methyl)pyridin-2- yl)pyrimidin-2-amine
17
4-(3-cyclopentyl-2-methyl- 2H-indazol-5-yl)-5-fluoro-N- (5-((4-propylpiperazin-1- yl)methyl)pyridin-2- yl)pyrimidin-2-amine
18
4-(3-cyclopentyl-7-fluoro-2- methyl-2H-indazol-5-yl)-5- fluoro-N-(5-((4- propylpiperazin-1- yl)methyl)pyridin-2- yl)pyrimidin-2-amine
19
4-(3-ethyl-2-methyl-2H- indazol-5-yl)-N-(5-((4- ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
20
4-(3-ethyl-7-fluoro-2- methyl-2H-indazol-5-yl)-N- (5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
21
4-(3-(sec-butyl)-2-methyl- 2H-indazol-5-yl)-N-(5-((4- ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
22
4-(3-(sec-butyl)-7-fluoro-2- methyl-2H-indazol-5-yl)-N- (5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
23
4-(2-ethyl-3-isopropyl-2H- indazol-5-yl)-N-(5-((4- ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
24
4-(2-ethyl-7-fluoro-3- isopropyl-2H-indazol-5-yl)- N-(5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
25
4-(3-cyclopropyl-2-ethyl-2H- indazol-5-yl)-N-(5-((4- ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
26
4-(3-cyclopropyl-2-ethyl-7- fluoro-2H-indazol-5-yl)-N- (5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
27
4-(3-(cyclopropylmethyl)-2- methyl-2H-indazol-5-yl)-N- (5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
28
4-(3-(cyclopropylmethyl)-7- fluoro-2-methyl-2H-indazol- 5-yl)-N-(5-((4- ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
29
4-(3-cyclopropyl-2-ethyl-7- fluoro-2H-indazol-5-yl)-N- (5-((4-ethylpiperazin-1- yl)methyl)pyridin-2- yl)pyrimidin-2-amine
30
4-(3-(sec-butyl)-2-methyl- 2H-indazol-5-yl)-N-(5-((4- ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
31
4-(3-(sec-butyl)-7-fluoro-2- methyl-2H-indazol-5-yl)-N- (5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5- fluoropyrimidin-2-amine
14. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable adjuvants, diluents, and/or carriers.
15. A method of relieving, ameliorating, or modulating a disease, disorder, or condition mediated through activity of at least one cyclin-dependent kinase (CDK), comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
16. The method of claim 15 , wherein said at least one CDK is CDK4, CDK6, or a combination thereof.
17. The method of claim 15 , wherein said disease or disorder is cancer.
18. The method of claim 17 , wherein said cancer is selected from the group consisting of colorectal cancer, breast cancer, lung cancer, especially non-small cell lung cancer (NSCLC), prostate cancer, glioblastoma, mantel cell lymphoma (MCL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML), and complications thereof.
19. The method of claim 15 , wherein said disease or disorder is an inflammation-related disease or condition selected from arthritis and cystic fibrosis.
20. The method of claim 15 , in combination with administering to said subject a second therapeutic agent.
21. The method of claim 20 , wherein said second therapeutic agent is a different CDK inhibitor, HER2 inhibitor, mTOR inhibitor, or EGFR inhibitor.
22. A method of inhibiting cell proliferation comprising treating proliferative cells with an effective amount of a compound claim 1 , or a salt, solvate, or prodrug thereof.
23. A method of inhibiting a cyclin-dependent kinase (CDK) comprising treating said kinase with an effective amount of a compound of claim 1 , or a salt, solvate, prodrug, or composition thereof.
24. The method of claim 23 , wherein said cyclin-dependent kinase is CDK4, CDK6, or a combination thereof.
25. A method of relieving, ameliorating, or modulating a disease, disorder, or condition mediated through activity of at least one cyclin-dependent kinase (CDK), comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 14 .
26. The method of claim 25 , wherein said CDK is CDK4, CDK6, or a combination thereof.
27. The method of claim 25 , wherein said disease or disorder is selected from the group consisting of colorectal cancer, breast cancer, lung cancer, especially non-small cell lung cancer (NSCLC), prostate cancer, glioblastoma, mantel cell lymphoma (MCL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and inflammation-related diseases and conditions.
28. A method of preparing a compound of formula (I), comprising a step of coupling intermediate E with intermediate G:
wherein R 1 through R 5 are defined as in claim 1 , and X 3 is Cl, Br, or I.
29. The method of claim 28 , further comprising the steps of converting intermediate C to intermediate D and coupling the intermediate D with a pyrimidine compound H to form the intermediate E:
wherein R x and R y are independent alkyl, aryl, cycloalkyl, or alternatively together form an alkylene group, each optionally substituted by one or more substituents independently selected from C 1 -C 4 alkyl, halogen and phenyl; and wherein X 1 , X 2 , and X 3 are each independently Cl, Br, or I, on condition that the intermediate D couples with the compound H selectively at the X 2 site over the X 3 site.
30. The method of claim 28 , further comprising the steps of converting starting material S1 to intermediate A and converting the intermediate A to the intermediate C:
wherein X is Cl, Br, I, or MeSO 3 —; and R 2 and R 3 are defined as in claim 28 .
31. The method of claim 30 , wherein said converting the intermediate A to the intermediate C, alternatively, comprises converting the intermediate A to an alcohol intermediate B followed by reduction of the alcohol intermediate B to form the intermediate C:
wherein R 2a and R 2b are each independently hydrogen, alkyl, cycloalkyl, or together form an alkylene group so that the group
formed in the intermediate C is R 2 as defined in claim 30 .
32. The method of claim 28 , further comprising a step of forming the intermediate G through coupling the pyridine aldehyde compound S2 and the piperazine compound S3 to form an intermediate F, followed by converting the intermediate F to the intermediate G:
wherein X 4 is selected from the group consisting of Cl, Br, I, and —NO 2 ; and
wherein said converting the intermediate F to the intermediate G comprises replacing —X 4 with —NH 2 when X 4 is Cl, Br, or I; or reducing the nitro group (—NO 2 ) to amino group (—NH 2 ) when X 4 is NO 2 .