1128075-31-9

Upstream product

• 179232-29-2 methyl 4-bromo-2-fluorobenzoate 
• 135884-31-0 N-boc-2-pyrroleboronic acid 

Downstream Products

• 934162-68-2 tert-butyl 2-(3-fluoro-4-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate 

Relevant academic research and scientific papers

N, C-Disubstituted Biarylpalladacycles as Precatalysts for ppm Pd-Catalyzed Cross Couplings in Water under Mild Conditions

Various monosubstitution and disubstitution patterns on the parent biarylamine skeleton characteristic of palladacycles, as well as the counterion effect, have been studied while looking for ways to increase the effectiveness of the catalyst formed under micellar catalysis conditions in water, with the goal of reducing the amount of Pd needed for coupling reactions. Several substituted palladacycles containing readily accessible ligands were chosen for evaluation. The results indicate that (1) preactivation of Pd(II) salts as precursors for Suzuki-Miyaura (SM) couplings via treatment with a reducing agent is not required; (2) reactions could be performed with approximately half the loading of Pd, relative to that previously required based on a combination of a Pd(II) salt and ligand; and (3) the most effective palladacycle precatalyst has been identified as that containing an isopropyl group on both an aryl ring and on nitrogen, together with the ligand EvanPhos and triflate as the counterion (P13). This precatalyst is also effective in other C-C bond-forming reactions, such as Heck and Sonogashira couplings. No organic solvents were needed for these processes, while the aqueous reaction medium could be recycled several times. A one-pot, four-step sequence involving Suzuki-Miyaura, reduction, alkylation, and acylation reactions highlights the potential for this precatalyst to maximize synthetic gain while minimizing costs and waste generation.

Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: Identification of (S)-2-(2-fluoro-4- (pyrrolidin-2-yl)phenyl)-1 H -benzimidazole-4-carboxamide (A-966492), a highly potent and efficacious inhibitor

We have developed a series of phenylpyrrolidine- and phenylpiperidine- substituted benzimidazole carboxamide poly(ADP-ribose) polymerase (PARP) inhibitors with excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (22b, A-966492). Compound 22b displayed excellent potency against the PARP-1 enzyme with a Ki of 1 nM and an EC50 of 1 nM in a whole cell assay. In addition, 22b is orally bioavailable across multiple species, crosses the blood-brain barrier, and appears to distribute into tumor tissue. It also demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide and in an MX-1 breast cancer xenograft model both as a single agent and in combination with carboplatin.

1H-BENZIMIDAZOLE-4-CARBOXAMIDES SUBSTITUTED WITH PHENYL AT THE 2-POSITION ARE POTENT PARP INHIBITORS

Compounds having formula (I), inhibit the PARP enzyme and are useful for treating a disease or a disorder associated with PARP. Also disclosed are pharmaceutical compositions comprising compounds having formula (I), methods of treatment comprising compounds having formula (I), and methods of inhibiting the PARP enzyme comprising compounds having formula (I).