Discovery of 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis

Abstract

Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition and for the treatment of B cell related diseases. We report a series of compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with excellent kinase selectivity. Selectivity is achieved through specific interactions of the ligand with the kinase hinge and driven by aminopyridine hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of trifluoropyridine in the back pocket. These interactions are evident in the X-ray crystal structure of the lead compounds 1 and 3 in the complex with the BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the preclinical rat collagen induced arthritis model.

Computational studies on the conformational preference of N‐(Thiazol‐2‐yl) benzamide

“…Scheme 2 presents the examples of co-crystals of the ligand bearing the 1 backbone in their structures. [3][4][5][6][7][8][9] Although close proximity of O and S atoms is counterintuitive due to the expected lone-pair repulsion between the two atoms, this phenomenon had been noted by Angyán and coworkers in 1987. 10 The intramolecular interaction of carbonyl O atom of proteins with S atom of the ligands was studied by Zhang et al 11 and the strength of the interaction was found to be as strong as a regular H-bond.…”

“…In all of the known co‐crystal substructures of 1 with proteins, the 1 moiety adopts a conformer in which the amide O and the thiazole S atoms get close to each other. Scheme 2 presents the examples of co‐crystals of the ligand bearing the 1 backbone in their structures 3–9 …”

Investigation of rotameric conformations of substituted imidazo-[1,2-a]pyrazine: experimental and theoretical approaches

“…The heterocyclic compounds are essential candidates in the chemical, biological, agricultural, and veterinary elds. 1,2 Among the various heterocycles, imidazo [1,2-a]pyrazine is an aza-heterocyclic compound that has applications as an anticancer agent, 3 cardiac stimulating agent and uterine relaxant, 4 antihyperglycemic agent, 5 antihypertensive agent, 6 antiulcer agent, 7 antibronchospastic agent 8 etc., [9][10][11] The properties of compounds as an application candidate depend upon the molecular structure of the compound and can be tuned by altering the molecular modication, and orientation of the compound. 12 The spatial and chemical constraints in molecular systems give rise to different spatial arrangements or conformations.…”

A novel synthetic approach to hydroimidazo[1,5-b]pyridazines by the recyclization of itaconimides and HPLC–HRMS monitoring of the reaction pathway

“…The presence of a bridgehead nitrogen atom is a common structural motif of these heterocyclic systems. For example, compounds with the imidazo[1,5- a ]pyrazine structure show inhibitory activity against kinases BTK [ 1 ], MEK [ 2 ], ACK1 [ 3 ], mTORC1(2) [ 4 ], c-Src [ 5 ], growth factor IGF-1R [ 6 ] and act as the antagonists of Hedgehog pathway dependent malignancies [ 7 ]. Imidazo[1,5- a ]pyrimidines are inhibitors of the bone morphogenic protein [ 8 ], antitumor agents [ 9 ], and are stimulators of guanylate cyclase [ 10 ], whereas imidazo[1,5- c ]pyrimidines demonstrate anti-infectious effects in the treatment of brucellosis [ 11 ], etc.…”