Azaindole compounds, synthesis thereof, and methods of using the same

Inventors

Shirude, Pravin S. • Naik, Maruti N. • Shinde, Vikas Narayan • Peer Mohamed, Shahul Hameed • Chatterji, Monalisa • Shindil, Radha K.

Assignees

FOUNDATION FOR NEGLECTED DISEASE RESEARCH • Global Alliance for TB Drug Development

Abstract

The invention provides compounds of formula (I) and methods of treating a Mycobacterium infection or tuberculosis, or inhibiting DprE1 with the same.

Core Innovation

The invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, including defined substituent options for R1, R2, R3, X, R4, R5, Y, Z, R6, R7, R8, n, and R9. The disclosure includes heteroaromatic carboxamide compounds featuring a pyrrolo[3,2-b]pyridine scaffold and substituted pyrimidinyl groups, with substituents such as hydrogen, halogen, methoxy, methyl, trifluoromethyl, cyclopropyl, fluorination, difluoromethoxy, trifluoromethoxy, fluoroethyl, and other fluoroalkyl substituents.

The invention further provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt and a pharmaceutically acceptable diluent or carrier. The disclosure includes acid addition salts and base salts, and the compounds are framed in relation to DprE1 target specificity and resistance behavior, including a DprE1 resistance mutation (Y314H) and resistance context involving dprE1 (Rv3790).

The document also includes evaluation of antimicrobial activity against Mycobacterium tuberculosis and associated cell models, including hypoxic NRP Mtb cells, together with MIC and MBC measurements using a resazurin assay. It further reports downstream characterization including DMPK/PK parameters, solubility, equilibrium dialysis protein binding, Caco-2 permeability, CYP inhibition, hERG, and in vivo efficacy in acute and chronic mouse and rat TB models.

Claims Coverage

The independent claims include a compound of formula (I) with specific substituent constraints and a second independent claim directed to a compound of a specified formula. Across the claim set, the coverage focuses on the defined chemical structures and pharmaceutically acceptable salts, with further claimed coverage in dependent claims for pharmaceutical compositions and therapeutic methods centered on DprE1 inhibition in tuberculosis or Mycobacterium infections, including drug-resistant forms. The claim coverage presents two independent inventive feature groupings.

The claim coverage is anchored by structurally constrained compounds under formula (I) and an additional independent coverage for a compound of a specified formula. Dependent claim scope further connects the compounds to pharmaceutical compositions and methods directed to DprE1 inhibition for tuberculosis and Mycobacterium infections, including drug-resistant infections.

Stated Advantages

Documented Applications