174907-58-5

Upstream product

• 15366-34-4 methyl 1H-pyrazole 3-carboxylate 
• 100-44-7 benzyl chloride 
• 5932-27-4 ethyl 1H-pyrazole-3-carboxylate 
• 100-39-0 benzyl bromide 
• 21056-77-9 2H-pyrazole-3-carboxylic acid ethyl ester 

Downstream Products

• 1007306-14-0 1-benzyl-1H-pyrazole-3-carboxylic acid 
• 102846-11-7 (1-benzyl-1H-pyrazol-3-yl)-methanol 

Relevant academic research and scientific papers

Steric redirection of alkylation in 1H-pyrazole-3-carboxylate esters

The alkylation of ethyl 1H-pyrazole-3-carboxylate with a variety of alkylating agents in the presence of K2CO3 was found to largely favor the formation of ethyl 1-substituted pyrazole-3-carboxylates. The alkylation could be sterically redirected by the use of a triphenylsilyl group (ethyl 3-(triphenylsilyl)-1H-pyrazole-5-carboxylate) to provide synthetically useful yields of ethyl 1-substituted-3-(triphenylsilyl)-1H-pyrazole-5-carboxylates. The triphenylsilyl group could be removed with Bu4NF. Other triorganosilyl groups (TMS, TES, TBDMS) failed to provide significant redirection, while TIPS proved refractory to protodesilylation.

INHIBITORS OF RECEPTOR INTERACTING PROTEIN KINASE I FOR THE TREATMENT OF DISEASE

Disclosed herein are compounds which inhibit RIPK1, pharmaceutical compositions, and methods of treatment of RIPK1 -mediated diseases, such as neurodegenerative disorders, inflammatory disorders, and cancer.

KCNT1 INHIBITORS AND METHODS OF USE

The present invention is directed to, in part, compounds and compositions useful for preventing and/or treating a neurological disease or disorder, a disease or condition relating to excessive neuronal excitability, and/or a gain-of-function mutation in a gene (e.g., KCNT1). Methods of treating a neurological disease or disorder, a disease or condition relating to excessive neuronal excitability, and/or a gain-of-function mutation in a gene such as KCNT1 are also provided herein.

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.

Discovery of 7-Oxo-2,4,5,7-tetrahydro-6 H -pyrazolo[3,4- c] pyridine Derivatives as Potent, Orally Available, and Brain-Penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors: Analysis of Structure-Kinetic Relationships

We report the discovery of 7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine derivatives as a novel class of receptor interacting protein 1 (RIP1) kinase inhibitors. On the basis of the overlay study between HTS hit 10 and GSK2982772 (6) in RIP1 kinase, we designed and synthesized a novel class of RIP1 kinase inhibitor 11 possessing moderate RIP1 kinase inhibitory activity and P-gp mediated efflux. The optimization of the core structure and the exploration of appropriate substituents utilizing SBDD approach led to the discovery of 22, a highly potent, orally available, and brain-penetrating RIP1 kinase inhibitor with excellent PK profiles. Compound 22 significantly suppressed necroptotic cell death both in mouse and human cells. Oral administration of 22 (10 mg/kg, bid) attenuated disease progression in the mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Moreover, analysis of structure-kinetic relationship (SKR) for our novel chemical series was also discussed.

CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF

Disclosed herein are small molecule calpain modulator compositions, pharmaceutical compositions, the use and preparation thereof.

Regioselective Synthesis, NMR, and Crystallographic Analysis of N1-Substituted Pyrazoles

A systematic study of the N-substitution reactions of 3-substituted pyrazoles under basic conditions has been undertaken. Regioselective N1-alkylation, -arylation, and -heteroarylation of 3-substituted pyrazoles have been achieved using K2CO3-DMSO. The regioselectivity is justified by the DFT calculations at the B3LYP/6-31G??(d) level. A consistent steric effect on chemical shift has been observed for N-alkyl pyrazole analogues. Twenty-five X-ray crystallographic structures have been obtained to confirm the regiochemistry of the major products.

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.