Described herein are orally-bioavailable nucleoside analogs and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of coronavirus infections, including SARS-CoV-2 infection.

The disclosure describes methods of synthesis of pyridazinone compounds as thyroid hormone analogs and their prodrugs. Preferred methods according to the disclosure allow for large-scale preparation of pyridazinone compounds having high purity. In some embodiments, preferred methods according to the disclosure also allow for the preparation of pyridazinone compounds in better yield than previously used methods for preparing such compounds. Also disclosed are morphic forms of a pyridazinone compound. Further disclosed is a method for treating resistance to thyroid hormone in a subject having at least one TRβ mutation.

The disclosure describes methods of synthesis of pyridazinone compounds as thyroid hormone analogs and their prodrugs. Preferred methods according to the disclosure allow for large-scale preparation of pyridazinone compounds having high purity. In some embodiments, preferred methods according to the disclosure also allow for the preparation of pyridazinone compounds in better yield than previously used methods for preparing such compounds. Also disclosed are morphic forms of a pyridazinone compound. Further disclosed is a method for treating resistance to thyroid hormone in a subject having at least one TRβ mutation.

A system and method configured to separate PFAS from expressed breast milk, thereby producing breast milk which is essentially free (or at least contains a lesser amount of) per- and polyfluorinated substances, the system and method including filtration device including an adapter configured to be at least one of positioned in-line in a breast pump or between breast milk containers, and including a replaceable cyclodextrin based filter for filtration of PFAS from pumped breast milk.

A system and method configured to separate PFAS from expressed breast milk, thereby producing breast milk which is essentially free (or at least contains a lesser amount of) per- and polyfluorinated substances, the system and method including filtration device including an adapter configured to be at least one of positioned in-line in a breast pump or between breast milk containers, and including a replaceable cyclodextrin based filter for filtration of PFAS from pumped breast milk.

A small molecule compound IODVA1 has been found to have cellular inhibitory activity against several transformed cell lines including Ras-driven cells. IODVA1 decreases cell-cell and cell-extra cellular matrix interactions and reduces growth of Ras-driven tumors. Applicants also synthesized compound NIRA2 and showed in vitro and in vivo efficacy and potency against models of Ph+(BCR-ABL1) B-ALL and of colon adenocarcinoma xenografts.

A small molecule compound IODVA1 has been found to have cellular inhibitory activity against several transformed cell lines including Ras-driven cells. IODVA1 decreases cell-cell and cell-extra cellular matrix interactions and reduces growth of Ras-driven tumors. Applicants also synthesized compound NIRA2 and showed in vitro and in vivo efficacy and potency against models of Ph+(BCR-ABL1) B-ALL and of colon adenocarcinoma xenografts.

An in vitro assay was designed to measure the activity of the alphavirus non-structural protein 2 (nsP2), which is the viral protease and is required for viral replication. By taking advantage of fluorescence-resonance energy transfer between two proteins, a protease cleavage assay was generated. This was utilized for high-throughput screening of 40,000 small molecules. Inhibitors were validated using cell-based assays to measure alphavirus infection and cytotoxicity. Certain compounds were then characterized for anti-viral efficacy in various cell lines in numerous assays. Compounds were tested against Chikungunya virus, Venezuelan Equine Encephalitis virus, Rift Valley Fever virus, and Zika virus. Three compounds (compounds I, II, and III) showed pan-alphavirus anti-viral efficacy at concentrations that did not result in cell toxicity. An additional compound, structure IV, showed broad spectrum inhibition of all viruses tested. Pharmaceutical preparations and methods of treatment including these compounds are provided herein.

An in vitro assay was designed to measure the activity of the alphavirus non-structural protein 2 (nsP2), which is the viral protease and is required for viral replication. By taking advantage of fluorescence-resonance energy transfer between two proteins, a protease cleavage assay was generated. This was utilized for high-throughput screening of 40,000 small molecules. Inhibitors were validated using cell-based assays to measure alphavirus infection and cytotoxicity. Certain compounds were then characterized for anti-viral efficacy in various cell lines in numerous assays. Compounds were tested against Chikungunya virus, Venezuelan Equine Encephalitis virus, Rift Valley Fever virus, and Zika virus. Three compounds (compounds I, II, and III) showed pan-alphavirus anti-viral efficacy at concentrations that did not result in cell toxicity. An additional compound, structure IV, showed broad spectrum inhibition of all viruses tested. Pharmaceutical preparations and methods of treatment including these compounds are provided herein.

The present invention provides AHR inhibitors, formulations and unit dosage forms thereof, and methods of use thereof.