1387561-09-2

Basic information

• Product Name: 2-bromo-5-fluoro-4-(triethylsilyl)pyridine
• Synonyms: 2-bromo-5-fluoro-4-(triethylsilyl)pyridine
• CAS NO: 1387561-09-2
• Molecular Formula: C₁₁H₁₇BrFNSi
• Molecular Weight: 290.2472832
• Mol File: 1387561-09-2.mol

Chemical Properties

• Appearance: /
• CAS DataBase Reference: 2-bromo-5-fluoro-4-(triethylsilyl)pyridine(CAS DataBase Reference)
• NIST Chemistry Reference: 2-bromo-5-fluoro-4-(triethylsilyl)pyridine(1387561-09-2)
• EPA Substance Registry System: 2-bromo-5-fluoro-4-(triethylsilyl)pyridine(1387561-09-2)

Safety Data

• Hazardous Substances Data: 1387561-09-2(Hazardous Substances Data)

Upstream product

• 41404-58-4 2-bromo-5-fluoropyridine 
• 994-30-9 triethylsilyl chloride 

Downstream Products

• 1387561-10-5 1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)ethan-1-one 
• 1425841-72-0 [(R)-4-(6-amino-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine 
• 1425841-69-5 [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(6-bromo-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine 
• 1425841-66-2 5-cyano-3-methyl-pyridine-2-carboxylic acid {6-[(R)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-5,5-difluoro-4-(2-methoxy-ethyl)-5,6-dihydro-4H-[1,3]oxazin-4-yl]-5-fluoro-pyridin-2-yl}-amide 
• 1425841-63-9 [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(6-bromo-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-(2-methoxy-ethyl)-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine 
• 1425841-57-1 N-[(R)-4-(6-bromo-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-(2-methoxy-ethyl)-5,6-dihydro-4H-[1,3]oxazin-2-yl]-4-nitro-benzamide 
• 1387561-17-2 N-[(R)-1-(6-bromo-3-fluoropyridin-2-yl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methylethoxy)-1-methylethyl]-4-nitrobenzenesulfonamide 
• 1387561-16-1 (R)-2-[(R)-2-(6-bromo-3-fluoropyridin-2-yl)-2-(4-nitrobenzenesulfonylamino)propoxy]-3,3,3-trifluoro-2-methylpropionamide 
• 1387561-15-0 6-bromo-3-fluoro-2-[(2S)-2-methyl-1-(4-nitrobenzenesulfonyl)aziridin-2-yl]pyridine 
• 1387561-14-9 6-bromo-3-fluoro-2-[(2S)-2-methyl-1-(4-nitrobenzenesulfonyl)aziridin-2-yl]-4-triethylsilanylpyridine 
• 1387561-13-8 (R)-N-(2-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-hydroxypropyl)-4-nitrobenzenesulfonamide 

Relevant articles and documents

Modulating physicochemical properties of tetrahydropyridine-2-amine BACE1 inhibitors with electron-withdrawing groups: A systematic study

A common challenge for medicinal chemists is to reduce the pKa of strongly basic groups' conjugate acids into a range that preserves the desired effects, usually potency and/or solubility, but avoids undesired effects like high volume of distribution (Vd), limited membrane permeation, and off-target binding to, notably, the hERG channel and monoamine receptors. We faced this challenge with a 3,4,5,6-tetrahydropyridine-2-amine scaffold harboring an amidine, a key structural component of potential inhibitors of BACE1, the rate-limiting enzyme in the production of Aβ species that make up amyloid plaques in Alzheimer's disease. In our endeavor to balance potency with desirable properties to achieve brain penetration, we introduced a diverse set of groups in beta position of the amidine that modulate logD, PSA and pKa. Given the synthetic challenge to prepare these highly functionalized warheads, we first developed a design flow including predicted physicochemical parameters which allowed us to select only the most promising candidates for synthesis. For this we evaluated a set of commercial packages to predict physicochemical properties, which can guide medicinal chemists in their endeavors to modulate pKa values of amidine and amine bases.

Discovery of Umibecestat (CNP520): A Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor for the Prevention of Alzheimer's Disease

After identification of lead compound 6, 5-amino-1,4-oxazine BACE1 inhibitors were optimized in order to improve potency, brain penetration, and metabolic stability. Insertion of a methyl and a trifluoromethyl group at the 6-position of the 5-amino-1,4-oxazine led to 8 (NB-360), an inhibitor with a pKa of 7.1, a very low P-glycoprotein efflux ratio, and excellent pharmacological profile, enabling high central nervous system penetration and exposure. Fur color changes observed with NB-360 in efficacy studies in preclinical animal models triggered further optimization of the series. Herein, we describe the steps leading to the discovery of 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide 15 (CNP520, umibecestat), an inhibitor with superior BACE1/BACE2 selectivity and pharmacokinetics. CNP520 reduced significantly Aβ levels in mice and rats in acute and chronic treatment regimens without any side effects and thus qualified for Alzheimer's disease prevention studies in the clinic.

PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease

Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clinical candidate PF-07059013 (23). The seminal hit molecule was discovered by virtual screening and confirmed through a series of biochemical and biophysical studies. After a significant optimization effort, we arrived at 23, a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-week multiple dose study using Townes SCD mice, 23 showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. 23 (PF-07059013) has advanced to phase 1 clinical trials.

SALT FORMS OF AN OXAZINE DERIVATIVE BACE INHIBITOR

The present invention relates to salt forms of an oxazine derivative BACE-1 inhibitor for use in the treatment or prevention of Alzheimer's disease and/or cerebral amyloid angiopathy and the advantageous properties associated with said salt forms.

AN OXAZINE DERIVATIVE FOR USE IN THE PREVENTION OF ALZHEIMER'S DISEASE IN AT RISK PATIENTS

The present invention relates to an oxazine derivative BACE-1 inhibitor and pharmaceutical compositions comprising such oxazine derivative for use in the prevention of Alzheimer's disease in a patient at risk of developing clinical symptoms of Alzheimer's

AN OXAZINE DERIVATIVE FOR USE IN THE TREATMENT OR PREVENTION OF CEREBRAL AMYLOID ANGIOPATHY

The present invention relates to an oxazine derivative BACE-1 inhibitor and pharmaceutical compositions comprising such oxazine derivative for use in the treatment or prevention of cerebral amyloid angiopathy and, in particular, wherein the patient carries one or two copies of the ApoE4 allele.

A PHARMACEUTICAL COMPOSITION COMPRISING AN OXAZINE DERIVATIVE AND ITS USE IN THE TREATMENT OR PREVENTION OF ALZHEIMER'S DISEASE

The present invention relates to a pharmaceutical composition comprising an oxazine derivative BACE-1 inhibitor, a process for the preparation thereof, and its use in the treatment or prevention of Alzheimer's disease.

BACE1 INHIBITORS

The present invention provides a compound of formula I, having BACE1 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer's disease.

BACE1 INHIBITORS

The present invention provides a compound of formula (I), having BACE1 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention ar

2 -AMINO-4 - (PYRIDIN- 2 -YL) - 5, 6 -DIHYDRO-4H- 1, 3 -OXAZINE DERIVATIVES AND THEIR USE AS BACE-1 AND/OR BACE - 2 INHIBITORS

The invention relates to novel oxazine derivatives of formula (I), and pharmaceutically acceptable salts thereof, in which all of the variables are as defined in the specification, pharmaceutical compositions thereof, combinations thereof, and their use as medicaments, particularly for the treatment of Alzheimer's Disease or diabetes via inhibition of BACE-1 or BACE-2.