1284940-16-4

Upstream product

• 95798-22-4 3-hydroxy-piperidine-1-carboxylic acid benzyl ester 
• 501-53-1 benzyl chloroformate 
• 61995-20-8 N-(benzyloxycarbonyl)-3-piperidone 
• 1609467-42-6 3-(tert-butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acid benzyl ester 
• 870-46-2 t-butoxycarbonylhydrazine 

Downstream Products

• 1609467-63-1 benzyl 3-(5-amino-3-(4-(4-chlorophenoxy)phenyl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate 
• 1609467-64-2 5-amino-3-(4-(4-chlorophenoxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide 
• 1609465-76-0 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-(1-cyanopiperidin-3-yl)-1H-pyrazole-4-carboxamide 
• 1609465-77-1 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-[(3S)-1-cyanopiperidin-3-yl]-1H-pyrazole-4-carboxamide 
• 1609465-78-2 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-[(3R)-1-cyanopiperidin-3-yl]-1H-pyrazole-4-carboxamide 
• 1609467-67-5 benzyl 3-(5-amino-4-cyano-3-(4-(2,4-difluorophenoxy)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 
• 1609467-68-6 5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide 
• 1609465-88-4 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(2,4-difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide 
• 1609465-89-5 5-amino-1-[(3S)-1-cyanopiperidin-3-yl]-3-[4-(2,4-difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide 
• 1609286-06-7 5-amino-1-[(3R)-1-cyanopiperidin-3-yl]-3-[4-(2,4-difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide 
• 1609467-05-1 1-[(3R)-1-acryloyl piperidin-3-yl]-5-amino-3-[4-(4-chlorophenoxy)phenyl]-1H-pyrazole-4-carboxamide 
• 1609468-24-7 (R)-5-amino-3-(4-(4-chlorophenoxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide 
• 1609467-06-2 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-{(3R)-1-[(2E)-4-hydroxybut-2-enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide 
• 1609467-07-3 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-{(3R)-1-[(2E)-4-fluorobut-2-enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide 

Relevant academic research and scientific papers

Aminopyrazole Carboxamide Bruton's Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group Tuning

Potent covalent inhibitors of Bruton's tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties.

PROCESSES AND INTERMEDIATES FOR PREPARING A MEDICAMENT

Disclosed is a process for the preparation of the following compounds: (I), (II) where R1, R1a and R2a have the definitions in the description, as well as a process to prepare other intermediates that may be useful to synthesise downstream products, especially compounds that are useful as medicaments, for instance Bruton's tyrosine kinase (Btk) inhibitors such as ibrutinib. Also disclosed are other processes, other intermediates and compounds per se.

BRUTON'S TYROSINE KINASE INHIBITORS

Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (BTK). Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the BTK inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions. (Formula I)