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Inhibitors of cyclin-dependent kinase 12 (CDK12) and uses thereof

a cyclin-dependent kinase and inhibitor technology, applied in the field of inhibitors of cyclin-dependent kinase 12 (cdk12), can solve the problems of prolonged disruption of transcription and induction of apoptosis of a diverse subset of cancer cell lines, unclear mechanism, and inability to precisely determine the site of cdk12 phosphorylation on ctd, etc., to achieve the effect of reducing or avoiding symptoms or

Active Publication Date: 2021-10-14
DANA FARBER CANCER INST INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compounds selectively inhibit CDK12, leading to prolonged disruption of transcription and induction of apoptosis in cancer cells, providing a viable therapeutic strategy for proliferative diseases, including cancers and inflammatory conditions.

Problems solved by technology

However, the detailed mechanism is not clear, and the exact site of phosphorylation on CTD by CDK12 is still controversial.
Without wishing to be bound by any particular theory, the irreversible inhibition of CDK12 by the inventive compounds results in prolonged disruption of transcription and induction of apoptosis of a diverse subset of cancer cell lines.

Method used

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  • Inhibitors of cyclin-dependent kinase 12 (CDK12) and uses thereof
  • Inhibitors of cyclin-dependent kinase 12 (CDK12) and uses thereof
  • Inhibitors of cyclin-dependent kinase 12 (CDK12) and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

of N-(4-((1R,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyloxy)phenyl)acrylamide (BSJ-01-033)

[0385]

(1R,3R)-3-(4-nitrophenoxy)cyclohexanamine

[0386]

[0387]To a suspension of NaH (0.8 g, 8.25 mmol) in 3.0 mL of anhydrous DMF was added (1R,3R)-3-aminocyclohexanol HCl salt (0.5 g, 3.3 mmol) slowly at 0° C. and kept stirring for 0.5 h, then 1-fluoro-4-nitrobenzene (0.465 g, 3.3 mmol) was added. The reaction mixture was kept stirring at 0° C. for another 0.5 h, then warm to room temperature and kept stirring for 2 h. 1.0 mL of H2O was added dropwise to quench the reaction. The mixture was extracted with DCM (100 mL), washed with brine (3×50 mL), dried (anhydrous Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (623 mg, 80%) as a brown solid. LC-MS (m / z): 237 [M+H]+.

5-chloro-N-((1R,3R)-3-(4-nitrophenoxy)cyclohexyl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-amine

[0388]

[0389]3-(...

example 2

of (E)-N-(4-((1R,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyloxy)phenyl)-4-(dimethylamino)but-2-enamide (BSJ-01-175)

[0396]

[0397]To a cold solution (0° C.) of N-((1R,3R)-3-(4-aminophenoxy)cyclohexyl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine (15 mg, 0.035 mmol) and 0.1 mL of DIPEA in 2.0 mL of anhydrous CH3CN was added a solution of (E)-4-bromobut-2-enoyl chloride (6.34 mg, 0.035 mmol) in 1.0 mL of DCM dropwise. After 0.5 h at 0° C., a 2M solution of dimethylamine in THF (1.0 mL) was added and the mixture was stirred for 1 h at 0° C. Then 1.5 mL of DMSO was added, followed by removal of the low boiling point solvents under reduced pressure. The residue was purified by prep-HPLC (MeOH / H2O, 0.05% TFA) to give the title compound (11 mg, 58%) as a light yellow solid after lyophilisation. LC-MS (m / z): 545 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 10.92 (dd, J=10.4, 5.6 Hz, 1H), 10.38 (s, 1H), 8.65 (d, J=8.4 Hz, 2H), 8.36 (s, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.54 (d, J=8.1 Hz, 1...

example 3

of (E)-N-(4-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyloxy)phenyl)-4-(dimethylamino)but-2-enamide (BSJ-01-193)

[0398]

3-(4-nitrophenoxy)cyclohexanamine

[0399]

[0400]To a suspension of NaH (0.8 g, 8.25 mmol) in 3.0 mL of anhydrous DMF was added 3-aminocyclohexanol HCl salt (0.5 g, 3.3 mmol) slowly at 0° C. and kept stirring for 0.5 h, then 1-fluoro-4-nitrobenzene (0.465 g, 3.3 mmol) was added. The reaction mixture was kept stirring at 0° C. for another 0.5 h, then warm to room temperature and kept stirring for 2 h. 1.0 mL of H2O was added dropwise to quench the reaction. The mixture was extracted with DCM (100 mL), washed with brine (3×50 mL), dried (anhydrous Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (623 mg, 80%) as a brown solid. LC-MS (m / z): 237 [M+H]+.

5-chloro-N-(3-(4-nitrophenoxy)cyclohexyl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-amine

[0401]

[0402]3-(2,5-dic...

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Abstract

The present invention provides novel compounds of Formulae (I′) and (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and / or preventing proliferative diseases (e.g., cancers (e.g., leukemia, acute lymphoblastic leukemia, lymphoma, Burkitt's lymphoma, melanoma, multiple myeloma, breast cancer, Ewing's sarcoma, osteosarcoma, brain cancer, ovarian cancer, neuroblastoma, lung cancer, colorectal cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase, such as a cyclin-dependent kinase (CDK) (e.g., CDK12), and therefore, induce cellular apoptosis and / or inhibit transcription in the subject.

Description

RELATED APPLICATIONS[0001]This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S. Ser. No. 62 / 425,519, filed Nov. 22, 2016, which is incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]The members of the cyclin-dependent kinase (CDK) family play critical regulatory roles in proliferation. There are currently 20 known mammalian CDKs.[0003]CDK12 and CDK13 were identified in cDNA screens for cell cycle regulators. Because their cyclin partners were not yet known, they were initially named CRKRS and CDC2L5 (Ko et al., J. Cell Sci., 2001, 114, 2591-2603; Marqués et al., Biochem Biophys Res Commun., 2000, 279(3):832-837), respectively. They were found to be 1490- and 1512-amino acid proteins, respectively, with a conserved central CTD kinase domain and degenerate RS domains identified in their N- and C-terminal regions (Even et al., J Cell Biochem., 2006, 99(3), 890-904).[0004]Evidence has shown CDK12 and CDK13 play an important role i...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D403/04C07D401/14
CPCC07D403/04C07D401/14A61P35/00
Inventor GRAY, NATHANAEL S.ZHANG, TINGHUJIANG, BAISHANKWIATKOWSKI, NICHOLAS PAUL
Owner DANA FARBER CANCER INST INC
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