1260667-65-9

Upstream product

• 659731-48-3 5-chloro-2-fluoro-4-iodopyridine 

Downstream Products

• 1339129-46-2 5-chloro-3-(2-methoxyphenyl)pyridin-2-amine 
• 1270077-79-6 (R)-3-[5'-chloro-6-(cyclohexylmethylamino)-[2,4,]bipyridinyl-2'-ylcarbamoyl]piperidine-1-carboxylic acid tert-butyl ester 
• 1269815-52-2 (R)-tert-butyl 3-(5-chloro-4-phenylpyridin-2-ylcarbamoyl)piperidine-1-carboxylate trifluoroacetate 
• 2057509-72-3 (1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexane-1-carboxamide 
• 2057509-72-3 (1R,3S)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide 
• 2057509-72-3 cis-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide 

Relevant academic research and scientific papers

From Milligram to Kilogram Manufacture of AZD4573: Making It Possible by Application of Enzyme-, Iridium-, and Palladium-Catalyzed Key Transformations

With the first generation medicinal chemistry synthesis as a starting point, we describe herein process development of AZD4573, an oncology drug candidate. In addition to improved yields and removal of chromatographic steps, we have addressed other factors such as availability of starting materials as well as safety of the chemistry involved. With several steps involving volatile, reactive, and non-UV active materials, reaction optimization was facilitated by implementing off-line 1H NMR analysis of crude mixtures. Key transformations targeted for process development included a Wolff-Kishner reduction, an iridium-catalyzed borylation, and enzymatic resolution of a racemic amino-ester.

Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies

A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.

Preparation method and application of N-(pyrimidine-2-yl) coumarin-7-amine derivative as protein kinase inhibitor

The invention discloses a cyclin-dependent kinase inhibitor. The cyclin-dependent kinase inhibitor comprises an N-(pyrimidine-2-yl) coumarin-7-amine derivative shown as a general formula (I). In-vitropharmacodynamic tests prove that the compound has a high-selectivity inhibition effect on CDK9 kinase, and can be applied to reducing or inhibiting the activity of CDK9 kinase in cells. The inventionalso discloses a preparation method of the inhibitor and application of the inhibitor in drugs for CDK family kinase mediated diseases, especially hyperproliferative diseases, virus-induced infectious diseases and cardiovascular diseases.

Chemical Compounds

Provided are a series of novel pyridine or pyrimidine derivatives which inhibit CDK9 and may be useful for the treatment of hyperproliferative diseases. In particular the compounds are of use in the treatment of proliferative disease such as cancer including hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt's lymphoma, follicular lymphoma and solid tumors such as breast cancer, lung cancer, neuroblastoma and colon cancer.

N-ACYL PYRIDINE BIARYL COMPOUNDS AND THEIR USES

The present invention provides a compound of general formula:wherein Z2-Z6 include one or two nitrogen atoms as described herein, including pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof. These compounds inhibit the activity of CDK9 and are thus useful as pharmaceuticals. Also provided are methods of treating a disease or condition mediated by CDK9 using the compounds of Formula I and isomers thereof, and pharmaceutical compositions comprising such compounds.

N-ACYL PYRIMIDINE BIARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS

The present invention provides a compound of the general formula (1): wherein one of X and Y is N and the other is an optionally substituted carbon atom, and Z2-Z5 represent one or two nitrogen atoms, as further described herein, including pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof. These compounds inhibit the activity of CDK9 and are thus useful as pharmaceuticals and as components of pharmaceutical compositions. Also provided are methods of treating a disease or condition mediated by CDK9 using the compounds described herein or pharmaceutical compositions comprising such compounds.

PYRAZINYLPYRIDINES USEFUL FOR THE TREATMENT OF PROLIFERATIVE DISEASES

The present invention provides a compound of Formula (I) and pharmaceutically acceptable salts thereof. Also provided is a method of using a compound of Formula I for treating a disease or condition mediated by a CDK inhibitor.

HETEROARYL COMPOUNDS AS KINASE INHIBITORS

The present invention provides a compound of Formula (I): and pharmaceutically acceptable salts thereof. Also provided is a method of using a compound of Formula I for treating a disease or condition mediated by a CDK inhibitor