Methods for producing n-(chroman-3-YL) benzamide analogs as potent antimicrobial and immunomodulating agents

Abstract

In some aspects, disclosed herein are compounds of the formula: wherein the variables are defined herein. Also provided are pharmaceutical compositions thereof. In some aspects, the compounds and compositions provided herein may be used to modulate the activity of Staphylococcus aureus. Also provided are methods of administering compounds and composition provided herein to a patient in need thereof, for example, for the treatment or prevention of diseases or disorders.

Description

METHODS FOR PRODUCING N-(CHROMAN-3-YL) BENZAMIDE ANALOGS AS POTENT ANTIMICROBIAL AND IMMUNOMODULATING AGENTS

[0001] This application claims the benefit of priority to United States Provisional Application No. 63 / 639,449 filed April 26, 2024, the entire contents of which are hereby incorporated by reference. BACKGROUND OF THE INVENTION I. Field of the Invention

[0002] The present invention relates generally to the field of chemistry, particularly organic chemistry and medicinal chemistry. More particularly, it concerns compounds, compositions, and methods for the treatment and prevention of infectious diseases such as those associated with Staphylococcus aureus. II. Description of Related Art

[0003] Widespread, infectious diseases are responsible for 15 million deaths annually, and in third world countries, these infections account for almost 60% of deaths (Dye C., 2014). Over recent years, the development of new antibiotics has not kept pace with the rate at which bacteria develop resistance to these drugs, and therefore development of novel antimicrobial agents became an urgent need for the global community.

[0004] Staphylococcus aureus is a leading cause of bacterial sepsis. Bloodstream infection caused by S. aureus (SA) carries a mortality rate of up to 30% which accounts for more deaths annually than AIDS, tuberculosis, and viral hepatitis combined. Treatment of invasive infections is particularly challenging since the bacterium has developed widespread resistance to existing antimicrobials and has evolved ways to subvert the host immune system and cause persistent infections. The inability to eradicate the bacterium despite treatment with standard antibiotic therapy occurs in one of three patients with SA bloodstream infection which ultimately increases the patients' risk for complications and death from the infection. Studies in mice with bloodstream infection due to MRSA have shown that >90% of the bacterium is sequestered within the liver and captured by liver resident macrophages, Kupffer cells. However, 10% of SA survive inside these immune cells partly due to the bacterium’s ability to evade immune cell intracellular killing thereby allowing the bacterium to establish a reservoir for persistence and later dissemination to other parts of the body.

[0005] Furthermore, intracellular survival of S. aureus within Kupffer cells (KC) has been shown to be a key mechanism contributing to persistence. Published studies have shown (-)-Epigallocatechin gallate (EGCG), an active component of green tea, to increase susceptibility of S. aureus to antibiotics via different purported mechanisms. However, EGCG has poor membrane penetration. Thus, there exists a need for identification of compounds with direct antimicrobial activity against antibiotic-resistant SA as well as immunoactivating activity to enhance immune cell killing of SA.SUMMARY

[0007] The present disclosure provides compounds, compositions, and methods for the treatment and prevention of infectious diseases such as those associated with Staphylococcus aureus. In some embodiments, the compounds are further defined as:wherein: R1 and R2 are each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X1 is hydrogen, hydroxy, amino, halo, cyano, or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −alkanediyl(C≤12)−aryl(C≤12), −alkanediyl(C≤12)−heteroaryl(C≤12), −alkanediyl(C≤12)−heterocycloalkyl(C≤12), −alkanediyl(C≤12)−cycloalkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −heteroarenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12),dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), amido(C≤12), or a substituted version of any of these groups; or −C(O)R4, wherein R4 is: hydrogen, hydroxy, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), cycloalkoxy(C≤8), alkenyloxy(C≤8), aryloxy(C≤8), aralkoxy(C≤8), heteroaryloxy(C≤8), acyloxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), heteroarylamino(C≤8), alkyl- sulfonylamino(C≤8), cycloalkylsulfonylamino(C≤8), alkoxyamino(C≤8), heterocycloalkylamino(C≤8), or a substituted version of any of these groups; or −NRaRb, wherein Raand Rbare each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), thioacyl(C≤12), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −C(Ya)R5, wherein R5 is: alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −alkanediyl(C≤12)−aryl(C≤12), −alkanediyl(C≤12)−heteroaryl(C≤12), −alkanediyl(C≤12)−heterocycloalkyl(C≤12), −alkanediyl(C≤12)−cycloalkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12),−heteroarenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; and Ya is oxo or thio; or −ORcRd, wherein Rcand Rdare each independently: hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), thioacyl(C≤12), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

[0008] In some aspects, the compound is further defined as:wherein: R1 and R2 are each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X1is hydrogen, hydroxy, amino, halo, cyano, or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −alkanediyl(C≤12)−aryl(C≤12), −alkanediyl(C≤12)−heteroaryl(C≤12),−alkanediyl(C≤12)−heterocycloalkyl(C≤12), −alkanediyl(C≤12)−cycloalkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −heteroarenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), amido(C≤12), or a substituted version of any of these groups; or −C(O)R4, wherein R4is: hydrogen, hydroxy, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), cycloalkoxy(C≤8), alkenyloxy(C≤8), aryloxy(C≤8), aralkoxy(C≤8), heteroaryloxy(C≤8), acyloxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), heteroarylamino(C≤8), alkyl- sulfonylamino(C≤8), cycloalkylsulfonylamino(C≤8), alkoxyamino(C≤8), heterocycloalkylamino(C≤8), or a substituted version of any of these groups; or −NRaRb, wherein Ra and Rb are each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), thioacyl(C≤12), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −C(Ya)R5, wherein R5 is:alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −alkanediyl(C≤12)−aryl(C≤12), −alkanediyl(C≤12)−heteroaryl(C≤12), −alkanediyl(C≤12)−heterocycloalkyl(C≤12), −alkanediyl(C≤12)−cycloalkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −hetero- arenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; and Ya is oxo or thio; or a pharmaceutically acceptable salt thereof.

[0009] In some aspects,, wherein the compound is further defined as:wherein: R1and R2are each independently hydrogen; oralkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X1is hydroxy or amino; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −heteroarenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), amido(C≤12), or a substituted version of any of these groups; or −C(O)R4, wherein R4is: hydrogen, hydroxy, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), cycloalkoxy(C≤8), alkenyloxy(C≤8), aryloxy(C≤8), aralkoxy(C≤8), heteroaryloxy(C≤8), acyloxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), heteroarylamino(C≤8), alkyl- sulfonylamino(C≤8), cycloalkylsulfonylamino(C≤8), alkoxyamino(C≤8), heterocycloalkylamino(C≤8), or a substituted version of any of these groups; or −NRaRb, wherein Ra and Rb are each independently hydrogen; oralkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), thioacyl(C≤12), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −C(Ya)R5, wherein R5is: alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −alkanediyl(C≤12)−aryl(C≤12), −alkanediyl(C≤12)−heteroaryl(C≤12), −alkanediyl(C≤12)−heterocycloalkyl(C≤12), −alkanediyl(C≤12)−cycloalkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −hetero- arenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; and Yais oxo or thio; or a pharmaceutically acceptable salt thereof.

[0010] In some aspects, the compound is further defined as:wherein: R1 and R2 are each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X1is hydroxy or amino; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −heteroarenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), amido(C≤12), or a substituted version of any of these groups; or −C(O)R4, wherein R4is: amino, or mercapto; or alkylamino(C≤8), cycloalkylamino(C≤8), dialkyl- amino(C≤8), arylamino(C≤8), heteroarylamino(C≤8), alkylsulfonylamino(C≤8), cycloalkylsulfonylamino(C≤8), alkoxyamino(C≤8),heterocycloalkylamino(C≤8), or a substituted version of any of these groups; −NRaRb, wherein Raand Rbare each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), thioacyl(C≤12), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −C(Ya)R5, wherein R5 is: alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −alkanediyl(C≤12)−aryl(C≤12), −alkanediyl(C≤12)−heteroaryl(C≤12), −alkanediyl(C≤12)−heterocycloalkyl(C≤12), −alkanediyl(C≤12)−cycloalkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −hetero- arenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; and Ya is oxo or thio; or a pharmaceutically acceptable salt thereof.

[0011] In some aspects, the compound is further defined as:wherein: R1 and R2 are each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X1is hydroxy or amino; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −heteroarenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), amido(C≤12), or a substituted version of any of these groups; or −C(O)R4, wherein R4is amino, or mercapto; or alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), heteroarylamino(C≤8), alkylsulfonyl- amino(C≤8), cycloalkylsulfonylamino(C≤8), alkoxyamino(C≤8), heterocycloalkylamino(C≤8), or a substituted version of any of these groups; or−NRaRb, wherein Raand Rbare each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), thioacyl(C≤12), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −C(Ya)R5, wherein R5 is: alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −heteroarenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), or a substituted version of any of these groups; and Y2is oxo or thio; or a pharmaceutically acceptable salt thereof.

[0012] In some aspects, the compound is further defined as:wherein: R1and R2are each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups;X2is −O−, −S−; or −NR7, wherein R7 is hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; Y is oxo or thio;is alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −alkanediyl(C≤12)−aryl(C≤12), −alkanediyl(C≤12)−heteroaryl(C≤12), −alkanediyl(C≤12)−heterocycloalkyl(C≤12), −alkanediyl(C≤12)−cyclo- alkyl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

[0013] In some aspects, the compound is further defined as:wherein: R1and R2are each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; R3 is hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups;Y is oxo or thio; X3 is −O− or −S−; or −NR8−, wherein R8 is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X4and X5are each independently −or −S−; or −NR9−, wherein R9 is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −CR10R11−, wherein R10and R11are each independently absent, hydroxy, halo, amino, cyano, mercapto, −NO2, or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

[0014] In some aspects, the compound is further defined as:wherein: R3is hydrogen; oralkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; Y is oxo or thio; X3 is −O− or −S−; or −NR8−, wherein R8 is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X4 and X5 are each independently −O− or −S−; or −NR9−, wherein R9 is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −CR10R11−, wherein R10and R11are each independently absent, hydroxy, halo, amino, cyano, mercapto, −NO2, or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

[0015] In some aspects, the compound is further defined as:wherein: R3is hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X3 is −O− or −S−; or −NR8−, wherein R8is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X4 and X5 are each independently −or −S−; or −NR9−, wherein R9 is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −CR10R11−, wherein R10 and R11 are each independently absent, hydroxy, halo, amino, cyano, mercapto, −NO2, or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups;or a pharmaceutically acceptable salt thereof.

[0016] In some aspects, the compound is further defined as:wherein: X3 is −O− or −S−; or −NR8−, wherein R8 is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X4and X5are each independently −O− or −S−; or −NR9−, wherein R9 is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −CR10R11−, wherein R10and R11are each independently absent, hydroxy, halo, amino, cyano, mercapto, −NO2, or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

[0017] In some aspects, the compound is further defined as:wherein: X6is −O− or −S−; or −NR8−, wherein R8is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; R12 is hydrogen, hydroxy, halo, amino, cyano, mercapto, or −NO2; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

[0018] In some aspects, the compound is further defined as:wherein: R12is hydrogen, hydroxy, halo, amino, cyano, mercapto, or −NO2; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12), aralkyl(C≤8),heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, R1 and R2 are each independently hydrogen, alkyl(C≤8), or substituted alkyl(C≤8). In some embodiments, R1 and R2 are each hydrogen. In other embodiments, R1 or R2 are alkyl(C≤8), such as methyl or deuterated methyl. In some embodiments, X1 is −heteroarenediyl(C≤12)−aryl(C≤12) or substituted −heteroarenediyl(C≤12)−aryl(C≤12). In certain embodiments, X1 is substituted −heteroarenediyl(C≤12)−aryl(C≤12). In some embodiments, X1is: −C(O)R4, wherein R4is amino, or mercapto; or alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), heteroarylamino(C≤8), alkylsulfonylamino(C≤8), cycloalkylsulfonylamino(C≤8), alkoxyamino(C≤8), heterocycloalkylamino(C≤8), or a substituted version of any of these groups. In some embodiments, R4is heteroarylamino(C≤8) or substituted heteroarylamino(C≤8). In certain embodiments, R4 is or substituted heteroarylamino(C≤8).

[0020] In some embodiments, Ya is oxo. In other embodiments, Ya is thio. In some embodiments, R5 is heteroaryl(C≤12) or substituted heteroaryl(C≤12). In some embodiments, R5is substituted heteroaryl(C≤12). In other embodiments, R5is −heteroarenediyl(C≤12)−cycloalkyl(C≤12). In some embodiments, R3 is hydrogen or alkyl. In some embodiments, X2 is −NR7, wherein R7 is hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups. In certain embodiments, R7 is hydrogen or alkyl(C≤8). In some embodiments, R7 is hydrogen.

[0021] In some embodiments, Y is oxo. In other embodiments, Y is thio. In some embodiments, X3is −O− or −S−. In some embodiments, X3is. In other embodiments, X3 is −S−. In some embodiments, Z is substituted alkyl(C≤8). In some embodiments, X3 is −CR10R11−, wherein R10 and R11 are each independently absent,hydroxy, halo, amino, cyano, mercapto, −NO2, or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups. In certain embodiments, R10 is hydrogen. In certain embodiments, R11 is −NO2. In other embodiments, R11 is absent. In still other embodiments, R11 is cyano. In yet other embodiments, R11is acyl. In still other embodiments, R11is heterocycloalkyl(C≤8)or substituted heterocycloalkyl(C≤8). In some embodiments, R11is heterocycloalkyl(C≤8).

[0022] In some embodiments, X3is −NR8−, wherein R8is absent. In some embodiments, X4 is −NR9−, wherein R9 is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups. In some embodiments, R9is hydrogen. In some embodiments, X5is −CR10R11−, wherein R10 and R11 are each independently absent, hydroxy, halo, amino, cyano, mercapto, −NO2, or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups. In some embodiments, R10is hydrogen and R11is absent. In some embodiments, X5is −NR9−, wherein R9is absent, hydrogen, or alkyl(C≤8).

[0023] In some aspects, the compound is further defined as:

[0024] In some aspects, the present disclosure provides a pharmaceutical composition comprising: (a) a compound according to any one of claims 1-51; and (b) an excipient

[0025] In some embodiments, the pharmaceutical composition is formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in crèmes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion. In some embodiments, the pharmaceutical composition is formulated as a unit dose.

[0026] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder in a patient in need thereof comprising administering to the patient a pharmaceutically effective amount of a compound or composition described herein. In some embodiments, the disease or disorder is a disease or disorder associated with Staphylococcus aureus infection. In some embodiments, the patient is a mammal. In certain embodiments, the patient is a human.

[0001] Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. Note that simply because a particular compound is ascribed to one particular generic formula doesn’t mean that it cannot also belong to another generic formula.BRIEF DESCRIPTION OF THE FIGURES

[0003] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description.

[0004] FIG. 1 shows methods for identifying the effects of candidate compounds with immunomodulating potential on macrophage polarization markers and gene expression.

[0005] FIG. 2 shows a comparison of the inhibitory effects of M1 vs. M2.

[0006] FIGS. 3A-3D show methods of synthesizing and analyzing EGCG analogs. FIG. 3A shows methods of synthesizing EGCG analogs. FIG. 3B shows the results of a microbroth dilution MIC assay. FIG.3C shows a synergy checkerboard assay. Antibiotic tested + / - EGCG or MCC-1 (N-(5,7-dimethoxychroman-3-yl)-5-nitrofuran-2-carboxamide) were Vancomycin, Cefazolin, Oxacillin, Ceftaroline and Doxycycline. FIG. 3D shows the intracellular time kill assay.

[0007] FIG. 4 shows a comparison of M1 and M2 macrophage marker expression across treatment with Vancomycin + / - adjunctive compounds in murine Kupffer cells infected with S. aureus.

[0008] FIG. 5 shows a comparison of intracellular CFU counts across treatment with vancomycin + / - adjunctive compounds.

[0009] FIG. 6 shows the chemical properties of MCC-1 (N-(5,7-dimethoxychroman- 3-yl)-5-nitrofuran-2-carboxamide) compared to EGCG. LogD is a measure of lipophilicity, molecular weight (MW) refers to the size of the compound, polar surface area (PSA) and is generally referenced for membrane penetration, and CLogP is a measure of hydrophilicity and hydrophobicity.

[0010] FIG. 7 shows the MIC of MCC-1 (N-(5,7-dimethoxychroman-3-yl)-5- nitrofuran-2-carboxamide) against clinical S.aureus strains. USA300 and clinical bacterial strains isolated from patients were added to a 96 well plate at a concentration of 1.5x105CFUs / well. Half serial dilutions of MCC-1 (N-(5,7-dimethoxychroman-3-yl)-5-nitrofuran-2- carboxamide) were added to the bacteria. Plates were incubated for 20 hours according to CLSI guidelines.

[0011] FIG. 8 shows a comparison of MICs of EGCG and MCC-1 (N-(5,7- dimethoxychroman-3-yl)-5-nitrofuran-2-carboxamide) alone and in combination withoxacillin and cefazolin. USA 300 MRSA was added to a 96 well plate at a concentration of 1.5x105 CFUs / well. Half serial dilutions of EGCG, MCC-1 (N-(5,7-dimethoxychroman-3-yl)- 5-nitrofuran-2-carboxamide), oxacillin, cefazolin, or combinations of EGCG or Precursor 1 and oxacillin or cefazolin, were added to the bacteria. Plates were incubated for 20 hours. FIC is used to determine if two compounds in combination show a synergistic, additive, indifferent, or antagonistic effect.

[0012] FIGS. 9A and 9B show a comparison of intracellular CFU counts across treatment with EGCG, MCC-1 (N-(5,7-dimethoxychroman-3-yl)-5-nitrofuran-2-carboxamide) and no treatment (NT) + / - Vancomycin. Murine Kupffer cells (Kup5s) were seeded in 48 well plates at a concentration of 150,000 cells / well and incubated to confluency overnight. Kup5s were infected with USA300 GFP SA at an MOI of 5 for 1.5hrs. Infected Kup5s were incubated with 100ug / ml of gentamicin for 2hrs to kill extracellular bacteria. After the gentamicin treatment, infected Kup5s were treated with either high 2x MIC concentrations of EGCG, 1 / 2x MIC concentrations of EGCG and MCC-1 (N-(5,7-dimethoxychroman-3-yl)-5-nitrofuran-2- carboxamide) + / - vancomycin, or vancomycin alone. When assessed in combination with vancomycin, treatments were re-added to cells at T10. FIG.9A shows the intracellular survival: EGCG and analog alone. FIG.9B shows the intracellular survival: Vancomycin+ / - EGCG and analog.DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0013] Disclosed herein are new compounds and compositions that may be used to restore macrophage intracellular killing and decrease SA intracellular survival and may thus be useful in the treatment of SA infection. In some embodiments, these compounds may exhibit direct antimicrobial activity against antibiotic-resistant S. aureus (SA) as well as immunoactivating activity to enhance immune cell killing of SA. In some embodiments, the present disclosure provides N-(chroman-3-yl) benzamide compounds for the treatment of antibiotic-resistant S. aureus (SA). In certain embodiments, the present disclosure provides N- (chroman-3-yl) benzamide compounds with antimicrobial activity against SA, anti-virulence activity to reduce SA virulence and / or immunoactivating activity to enhance immune cell killing of SA. III. Compounds of the Present Invention

[0014] The compounds of the present invention (also referred to as “compounds of the present disclosure”) are shown, for example in the summary of the invention section, in the examples section, and in the claims. They may be made using the synthetic methods outlined in the Examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry. Such principles and techniques are taught, for example, in Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (2013), which is incorporated by reference herein. In addition, the synthetic methods may be further modified and optimized for preparative, pilot- or large-scale production, either batch or continuous, using the principles and techniques of process chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Anderson, Practical Process Research & Development – A Guide for Organic Chemists (2012), which is incorporated by reference herein.

[0015] All the compounds of the present invention may in some embodiments be used for the prevention and treatment of one or more diseases or disorders discussed herein or otherwise. In some embodiments, one or more of the compounds characterized or exemplified herein as an intermediate, a metabolite, and / or prodrug, may nevertheless also be useful for the prevention and treatment of one or more diseases or disorders. As such unless explicitly stated to the contrary, all the compounds of the present invention are deemed “active compounds” and “therapeutic compounds” that are contemplated for use as active pharmaceuticalingredients (APIs). Actual suitability for human or veterinary use is typically determined using a combination of clinical trial protocols and regulatory procedures, such as those administered by the Food and Drug Administration (FDA). In the United States, the FDA is responsible for protecting the public health by assuring the safety, effectiveness, quality, and security of human and veterinary drugs, vaccines and other biological products, and medical devices.

[0016] In some embodiments, the compounds of the present invention have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, more metabolically stable than, more lipophilic than, more hydrophilic than, and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance) than, and / or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the indications stated herein or otherwise.

[0017] Compounds of the present invention may contain one or more asymmetrically- substituted carbon, nitrogen, sulfur, or phosphorus atom and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present invention can have the S or the R configuration. In some embodiments, the present compounds may contain two or more atoms which have a defined stereochemical orientation.

[0018] Chemical formulas used to represent compounds of the present invention will typically only show one of possibly several different tautomers. For example, many types of ketone groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and regardless of which one is most prevalent, all tautomers of a given chemical formula are intended.

[0019] In addition, atoms making up the compounds of the present invention are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0020] In some embodiments, compounds of the present invention function as prodrugs or can be derivatized to function as prodrugs. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compounds employed in some methods of the invention may, if desired, be delivered in prodrug form. Thus, the invention contemplates prodrugs of compounds of the present invention as well as methods of delivering prodrugs. Prodrugs of the compounds employed in the invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Accordingly, prodrugs include, for example, compounds described herein in which a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a patient, cleaves to form a hydroxy, amino, or carboxylic acid, respectively.

[0021] In some embodiments, compounds of the present invention exist in salt or non- salt form. With regard to the salt form(s), in some embodiments the particular anion or cation forming a part of any salt form of a compound provided herein is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.

[0022] It will be appreciated that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates.” Where the solvent is water, the complex is known as a “hydrate.” It will also be appreciated that many organic compounds can exist in more than one solid form, including crystalline and amorphous forms. All solid forms of the compounds provided herein, including any solvates thereof are within the scope of the present invention. IV. Pharmaceutical Formulations and Routes of Administration

[0023] In another aspect, for administration to a patient in need of such treatment, pharmaceutical formulations (also referred to as a pharmaceutical preparations, pharmaceutical compositions, pharmaceutical products, medicinal products, medicines, medications, or medicaments) comprise a therapeutically effective amount of a compound disclosed herein formulated with one or more excipients and / or drug carriers appropriate to the indicated route of administration. In some embodiments, the compounds disclosed herein are formulated in a manner amenable for the treatment of human and / or veterinary patients. In some embodiments, formulation comprises admixing or combining one or more of the compounds disclosed hereinwith one or more of the following excipients: lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol. In some embodiments, e.g., for oral administration, the pharmaceutical formulation may be tableted or encapsulated. In some embodiments, the compounds may be dissolved or slurried in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffers. In some embodiments, the pharmaceutical formulations may be subjected to pharmaceutical operations, such as sterilization, and / or may contain drug carriers and / or excipients such as preservatives, stabilizers, wetting agents, emulsifiers, encapsulating agents such as lipids, dendrimers, polymers, proteins such as albumin, nucleic acids, and buffers.

[0024] Pharmaceutical formulations may be administered by a variety of methods, e.g., orally or by injection (e.g. subcutaneous, intravenous, and intraperitoneal). Depending on the route of administration, the compounds disclosed herein may be coated in a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound. To administer the active compound by other than parenteral administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. In some embodiments, the active compound may be administered to a patient in an appropriate carrier, for example, liposomes, or a diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in- oil-in-water CGF emulsions as well as conventional liposomes.

[0025] The compounds disclosed herein may also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally. Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

[0026] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by theuse of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

[0027] The compounds disclosed herein can be administered orally, for example, with an inert diluent or an assimilable edible carrier. The compounds and other ingredients may also be enclosed in a hard or soft-shell gelatin capsule, compressed into tablets, or incorporated directly into the patient’s diet. For oral therapeutic administration, the compounds disclosed herein may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The percentage of the therapeutic compound in the compositions and preparations may, of course, be varied. The amount of the therapeutic compound in such pharmaceutical formulations is such that a suitable dosage will be obtained.

[0028] The therapeutic compound may also be administered topically to the skin, eye, ear, or mucosal membranes. Administration of the therapeutic compound topically may include formulations of the compounds as a topical solution, lotion, cream, ointment, gel, foam, transdermal patch, or tincture. When the therapeutic compound is formulated for topical administration, the compound may be combined with one or more agents that increase the permeability of the compound through the tissue to which it is administered. In other embodiments, it is contemplated that the topical administration is administered to the eye. Such administration may be applied to the surface of the cornea, conjunctiva, or sclera. Without wishing to be bound by any theory, it is believed that administration to the surface of the eye allows the therapeutic compound to reach the posterior portion of the eye. Ophthalmic topical administration can be formulated as a solution, suspension, ointment, gel, or emulsion. Finally, topical administration may also include administration to the mucosa membranes such as the inside of the mouth. Such administration can be directly to a particular location within the mucosal membrane such as a tooth, a sore, or an ulcer. Alternatively, if local delivery to the lungs is desired the therapeutic compound may be administered by inhalation in a dry-powder or aerosol formulation.

[0029] In some embodiments, it may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosageunit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. In some embodiments, the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of a selected condition in a patient. In some embodiments, active compounds are administered at a therapeutically effective dosage sufficient to treat a condition associated with a condition in a patient. For example, the efficacy of a compound can be evaluated in an animal model system that may be predictive of efficacy in treating the disease in a human or another animal.

[0030] In some embodiments, the effective dose range for the therapeutic compound can be extrapolated from effective doses determined in animal studies for a variety of different animals. In some embodiments, the human equivalent dose (HED) in mg / kg can be calculated in accordance with the following formula (see, e.g., Reagan-Shaw et al., FASEB J., 22(3):659- 661, 2008, which is incorporated herein by reference): HED (mg / kg) = Animal dose (mg / kg) × (Animal Km / Human Km)

[0031] Use of the Kmfactors in conversion results in HED values based on body surface area (BSA) rather than only on body mass. Km values for humans and various animals are well known. For example, the Kmfor an average 60 kg human (with a BSA of 1.6 m2) is 37, whereas a 20 kg child (BSA 0.8 m2) would have a Kmof 25. Kmfor some relevant animal models are also well known, including: mice Km of 3 (given a weight of 0.02 kg and BSA of 0.007); hamster Km of 5 (given a weight of 0.08 kg and BSA of 0.02); rat Km of 6 (given a weight of 0.15 kg and BSA of 0.025) and monkey Kmof 12 (given a weight of 3 kg and BSA of 0.24).

[0032] Precise amounts of the therapeutic composition depend on the judgment of the practitioner and are specific to each individual. Nonetheless, a calculated HED dose provides a general guide. Other factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment and the potency, stability and toxicity of the particular therapeutic formulation.

[0033] The actual dosage amount of a compound of the present disclosure or composition comprising a compound of the present disclosure administered to a patient may be determined by physical and physiological factors such as type of animal treated, age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. Thesefactors may be determined by a skilled artisan. The practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual patient. The dosage may be adjusted by the individual physician in the event of any complication.

[0034] In some embodiments, the therapeutically effective amount typically will vary from about 0.001 mg / kg to about 1000 mg / kg, from about 0.01 mg / kg to about 750 mg / kg, from about 100 mg / kg to about 500 mg / kg, from about 1 mg / kg to about 250 mg / kg, from about 10 mg / kg to about 150 mg / kg in one or more dose administrations daily, for one or several days (depending of course of the mode of administration and the factors discussed above). Other suitable dose ranges include 1 mg to 10,000 mg per day, 100 mg to 10,000 mg per day, 500 mg to 10,000 mg per day, and 500 mg to 1,000 mg per day. In some embodiments, the amount is less than 10,000 mg per day with a range of 750 mg to 9,000 mg per day.

[0035] In some embodiments, the amount of the active compound in the pharmaceutical formulation is from about 2 to about 75 weight percent. In some of these embodiments, the amount if from about 25 to about 60 weight percent.

[0036] Single or multiple doses of the agents are contemplated. Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation. As an example, patients may be administered two doses daily at approximately 12-hour intervals. In some embodiments, the agent is administered once a day.

[0037] The agent(s) may be administered on a routine schedule. As used herein a routine schedule refers to a predetermined designated period of time. The routine schedule may encompass periods of time which are identical, or which differ in length, as long as the schedule is predetermined. For instance, the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks there-between. Alternatively, the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc. In other embodiments, the invention provides that the agent(s) may be taken orally and that the timing of which is or is not dependent upon food intake. Thus, for example, the agent can be taken every morning and / or every evening, regardless of when the patient has eaten or will eat.V. Chemical Definitions

[0038] When used in the context of a chemical group: “hydrogen” means −H; “hydroxy” means −OH; “oxo” means =O; “carbonyl” means −C(=O)−; “carboxy” means −C(=O)OH (also written as −COOH or −CO2H); “halo” means independently −F, −Cl, −Br or −I; “amino” means −NH2; “hydroxyamino” means −NHOH; “nitro” means −NO2; imino means =NH; “cyano” means −CN; “isocyanyl” means −N=C=O; “azido” means −N3; in a monovalent context “phosphate” means −OP(O)(OH)2 or a deprotonated form thereof; in a divalent context “phosphate” means −OP(O)(OH)O− or a deprotonated form thereof; “mercapto” means −SH; and “thio” means =S; “thiocarbonyl” means −C(=S)−; “sulfonyl” means −S(O)2−; and “sulfinyl” means −S(O)−.

[0039] In the context of chemical formulas, the symbol “−” means a single bond, “=”means a double bond, and “≡” means triple bond. The symbolrepresents an optionalbond, which if present is either single or double. The symbolrepresents a single bondor a double bond. Thus, the formulavers, for example,andAnd it is understood that no one such ring atom forms part of more than one double bond. Furthermore, it is noted that the covalent bond symbol “−”, when connecting one or two stereogenic atoms, does not indicate any preferred stereochemistry. Instead, it covers allstereoisomers as well as mixtures thereof. The symbol “”, when drawn perpendicularlyacross a bond (e.g. for methyl) indicates a point of attachment of the group. It is notedthat the point of attachment is typically only identified in this manner for larger groups in orderto assist the reader in unambiguously identifying a point of attachment. The symbolmeans a single bond where the group attached to the thick end of the wedge is “out of thepage.” The symbolmeans a single bond where the group attached to the thick end ofthe wedge is “into the page”. The symbolmeans a single bond where the geometryaround a double bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended. Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper.

[0040] When a variable is depicted as a “floating group” on a ring system, for example, the group “R” in the formula:,

[0041] then the variable may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed. When a variable is depicted as a “floating group” on a fused ring system, as for example the group “R” in the formula:,

[0042] then the variable may replace any hydrogen attached to any of the ring atoms of either of the fused rings unless specified otherwise. Replaceable hydrogens include depicted hydrogens (e.g., the hydrogen attached to the nitrogen in the formula above), implied hydrogens (e.g., a hydrogen of the formula above that is not shown but understood to be present), expressly defined hydrogens, and optional hydrogens whose presence depends on the identity of a ring atom (e.g., a hydrogen attached to group X, when X equals −CH−), so long as a stable structure is formed. In the example depicted, R may reside on either the 5-membered or the 6-membered ring of the fused ring system. In the formula above, the subscript letter “y” immediately following the R enclosed in parentheses, represents a numeric variable. Unless specified otherwise, this variable can be 0, 1, 2, or any integer greater than 2, only limited by the maximum number of replaceable hydrogen atoms of the ring or ring system.

[0043] For the chemical groups and compound classes, the number of carbon atoms in the group or class is as indicated as follows: “Cn” or “C=n” defines the exact number (n) of carbon atoms in the group / class. “C£n” defines the maximum number (n) of carbon atoms that can be in the group / class, with the minimum number as small as possible for the group / class in question. For example, it is understood that the minimum number of carbon atoms in the groups “alkyl(C≤8)”, “alkanediyl(C≤8)”, “heteroaryl(C≤8)”, and “acyl(C≤8)” is one, the minimum number of carbon atoms in the groups “alkenyl(C≤8)”, “alkynyl(C≤8)”, and “heterocycloalkyl(C≤8)” is two, the minimum number of carbon atoms in the group “cycloalkyl(C£8)” is three, and the minimum number of carbon atoms in the groups “aryl(C≤8)” and “arenediyl(C≤8)” is six. “Cn-n′” defines both the minimum (n) and maximum number (n′) of carbon atoms in the group. Thus, “alkyl(C2-10)” designates those alkyl groups having from 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical groups or class it modifies and it mayor may not be enclosed in parenthesis, without signifying any change in meaning. Thus, the terms “C1-4-alkyl”, “C1-4-alkyl”, “alkyl(C1-4)”, and “alkyl(C≤4)” are all synonymous. Except as noted below, every carbon atom is counted to determine whether the group or compound falls with the specified number of carbon atoms. For example, the group dihexylamino is an example of a dialkylamino(C12)group; however, it is not an example of a dialkylamino(C6)group. Likewise, phenylethyl is an example of an aralkyl(C=8) group. When any of the chemical groups or compound classes defined herein is modified by the term “substituted”, any carbon atom in the moiety replacing the hydrogen atom is not counted. Thus methoxyhexyl, which has a total of seven carbon atoms, is an example of a substituted alkyl(C1-6). Unless specified otherwise, any chemical group or compound class listed in a claim set without a carbon atom limit has a carbon atom limit of less than or equal to twelve.

[0044] The term “saturated” when used to modify a compound or chemical group means the compound or chemical group has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of substituted versions of saturated groups, one or more carbon oxygen double bond or a carbon nitrogen double bond may be present in the group replacing the hydrogen atom, as discussed below. And when such a bond is present, then carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine / enamine tautomerism are not precluded. When the term “saturated” is used to modify a solution of a substance, it means that no more of that substance can dissolve in that solution.

[0045] The term “aliphatic” signifies that the compound or chemical group so modified is an acyclic or cyclic, but non-aromatic compound or group. In aliphatic compounds / groups, the carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds / groups can be saturated, that is joined by single carbon- carbon bonds (alkanes / alkyl), or unsaturated, with one or more carbon-carbon double bonds (alkenes / alkenyl) or with one or more carbon-carbon triple bonds (alkynes / alkynyl).

[0046] The term “aromatic” signifies that the compound or chemical group so modified has a planar unsaturated ring of atoms with 4n +2 electrons in a fully conjugated cyclic π system. An aromatic compound or chemical group may be depicted as a single resonance structure; however, depiction of one resonance structure is taken to also refer to any other resonance structure. For example: is also taken to refer to

[0047] Aromatic compounds may also be depicted using a circle to represent the delocalized nature of the electrons in the fully conjugated cyclic π system, two non-limiting examples of which are shown below:.

[0048] The term “alkyl” refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen. The groups −CH3(Me), −CH2CH3(Et), −CH2CH2CH3(n-Pr or propyl), −CH(CH3)2 (i-Pr,iPr or isopropyl), −CH2CH2CH2CH3 (n-Bu), −CH(CH3)CH2CH3 (sec-butyl), −CH2CH(CH3)2 (isobutyl), −C(CH3)3 (tert-butyl, t-butyl, t-Bu ortBu), and −CH2C(CH3)3 (neo- pentyl) are non-limiting examples of alkyl groups. The term “alkanediyl” refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups −CH2− (methylene), −CH2CH2−, −CH2C(CH3)2CH2−, and −CH2CH2CH2− are non-limiting examples of alkanediyl groups. The term “alkylidene” refers to the divalent group =CRR′ in which R and R′ are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include: =CH2, =CH(CH2CH3), and =C(CH3)2. An “alkane” refers to the class of compounds having the formula H−R, wherein R is alkyl as this term is defined above.

[0049] The term “cycloalkyl” refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, said carbon atom forming part of one or more non- aromatic ring structures, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused, bridged, or spirocyclic. Non-limiting examples include: −CH(CH2)2(cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to a carbon atom of the non-aromatic ring structure. The term “cycloalkanediyl” refers to a divalent saturated aliphatic group with two carbon atoms as points of attachment, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The group is a non-limiting example of cycloalkanediyl group. A “cycloalkane” refers to the class of compounds having the formula H−R, wherein R is cycloalkyl as this term is defined above.

[0050] The term “alkenyl” refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, acyclic structure, at least onenonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: −CH=CH2 (vinyl), −CH=CHCH3, −CH=CHCH2CH3, −CH2CH=CH2 (allyl), −CH2CH=CHCH3, and −CH=CHCH=CH2. The term “alkenediyl” refers to a divalent unsaturated aliphatic group, with two carbon atoms as points of attachment, a linear or branched acyclic structure, at least one nonaromatic carbon- carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. The groups −CH=CH−, −CH=C(CH3)CH2−, −CH=CHCH2−, and −CH2CH=CHCH2− are non-limiting examples of alkenediyl groups. It is noted that while the alkenediyl group is aliphatic, once connected at both ends, this group is not precluded from forming part of an aromatic structure. The terms “alkene” and “olefin” are synonymous and refer to the class of compounds having the formula H−R, wherein R is alkenyl as this term is defined above. Similarly, the terms “terminal alkene” and “α-olefin” are synonymous and refer to an alkene having just one carbon-carbon double bond, wherein that bond is part of a vinyl group at an end of the molecule.

[0051] The term “alkynyl” refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not preclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups −C≡CH, −C≡CCH3, and −CH2C≡CCH3 are non-limiting examples of alkynyl groups. An “alkyne” refers to the class of compounds having the formula H−R, wherein R is alkynyl.

[0052] The term “aryl” refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more aromatic ring structures, each with six ring atoms that are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. As used herein, the term aryl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, −C6H4CH2CH3(ethylphenyl), naphthyl, and a monovalent group derived from biphenyl (e.g., 4-phenylphenyl). The term “arenediyl” refers to a divalent aromatic group with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structures, each with six ring atoms that are all carbon, and wherein the divalent group consists of no atoms other than carbon and hydrogen. As usedherein, the term arenediyl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. Non-limiting examples of arenediyl groups include:

[0053] An “arene” refers to the class of compounds having the formula H−R, wherein R is aryl as that term is defined above. Benzene and toluene are non-limiting examples of arenes.

[0054] The term “aralkyl” refers to the monovalent group −alkanediyl−aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.

[0055] The term “heteroaryl” refers to a monovalent aromatic group with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the heteroaryl group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings are fused; however, the term heteroaryl does not preclude the presence of one or more alkyl or aryl groups (carbon number limitation permitting) attached to one or more ring atoms. Non-limiting examples of heteroaryl groups include benzoxazolyl, benzimidazolyl, furanyl, imidazolyl (Im), indolyl, indazolyl, isoxazolyl, methylpyridinyl, oxazolyl, oxadiazolyl, phenylpyridinyl, pyridinyl (pyridyl), pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term “N-heteroaryl” refers to a heteroaryl group with a nitrogen atom as the point of attachment. A “heteroarene” refers to the class of compounds having the formula H−R, wherein R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes.

[0056] The term “heterocycloalkyl” refers to a monovalent non-aromatic group with a carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more non-aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the non-aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the heterocycloalkyl group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings may be fused,bridged, or spirocyclic. As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to one or more ring atoms. Also, the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, tetrahydropyridinyl, pyranyl, oxiranyl, and oxetanyl. The term “N-heterocycloalkyl” refers to a heterocycloalkyl group with a nitrogen atom as the point of attachment. N-pyrrolidinyl is an example of such a group.

[0057] The term “acyl” refers to the group −C(O)R, in which R is a hydrogen, alkyl, cycloalkyl, or aryl as those terms are defined above. The groups, −CHO, −C(O)CH3(acetyl, Ac), −C(O)CH2CH3, −C(O)CH(CH3)2, −C(O)CH(CH2)2, −C(O)C6H5, and −C(O)C6H4CH3 are non-limiting examples of acyl groups. A “thioacyl” is defined in an analogous manner, except that the oxygen atom of the group −C(O)R has been replaced with a sulfur atom, −C(S)R. The term “aldehyde” corresponds to an alkyl group, as defined above, attached to a −CHO group.

[0058] The term “alkoxy” refers to the group −OR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: −OCH3(methoxy), −OCH2CH3(ethoxy), −OCH2CH2CH3, −OCH(CH3)2(isopropoxy), or −OC(CH3)3(tert-butoxy). The terms “cycloalkoxy”, “alkenyloxy”, “alkynyloxy”, “aryloxy”, “aralkoxy”, “heteroaryloxy”, “heterocycloalkoxy”, and “acyloxy”, when used without the “substituted” modifier, refers to groups, defined as −OR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. The term “alkylthio” and “acylthio” refers to the group −SR, in which R is an alkyl and acyl, respectively. The term “alcohol” corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group. The term “ether” corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with an alkoxy group.

[0059] The term “alkylamino” refers to the group −NHR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: −NHCH3 and −NHCH2CH3. The term “dialkylamino” refers to the group −NRR′, in which R and R′ can be the same or different alkyl groups. Non-limiting examples of dialkylamino groups include: −N(CH3)2and −N(CH3)(CH2CH3). The term “amido” (acylamino), when used without the “substituted” modifier, refers to the group −NHR, in which R is acyl, as that term is defined above. A non- limiting example of an amido group is −NHC(O)CH3.

[0060] When a chemical group is used with the “substituted” modifier, one or more hydrogen atom has been replaced, independently at each instance, by −OH, −F, −Cl, −Br, −I, −NH2, −NO2, −CO2H, −CO2CH3, −CO2CH2CH3, −CN, −SH, −OCH3, −OCH2CH3, −C(O)CH3, −NHCH3, −NHCH2CH3, −N(CH3)2, −C(O)NH2, −C(O)NHCH3, −C(O)N(CH3)2, −OC(O)CH3, −NHC(O)CH3, −S(O)2OH, or −S(O)2NH2. For example, the following groups are non-limiting examples of substituted alkyl groups: −CH2OH, −CH2Cl, −CF3, −CH2CN, −CH2C(O)OH, −CH2C(O)OCH3, −CH2C(O)NH2, −CH2C(O)CH3, −CH2OCH3, −CH2OC(O)CH3, −CH2NH2, −CH2N(CH3)2, and −CH2CH2Cl. The term “haloalkyl” is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to halo (i.e. −F, −Cl, −Br, or −I) such that no other atoms aside from carbon, hydrogen and halogen are present. The group, −CH2Cl is a non- limiting example of a haloalkyl. The term “fluoroalkyl” is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to fluoro such that no other atoms aside from carbon, hydrogen and fluorine are present. The groups −CH2F, −CF3, and −CH2CF3 are non- limiting examples of fluoroalkyl groups. Non-limiting examples of substituted aralkyls are: (3-chlorophenyl)-methyl, and 2-chloro-2-phenyl-eth-1-yl. The groups, −C(O)CH2CF3, −CO2H (carboxyl), −CO2CH3 (methylcarboxyl), −CO2CH2CH3, −C(O)NH2 (carbamoyl), and −CON(CH3)2, are non-limiting examples of substituted acyl groups. The groups −NHC(O)OCH3and −NHC(O)NHCH3are non-limiting examples of substituted amido groups.

[0061] The use of the word “a” or “an,” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0062] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects or patients.

[0063] An “active ingredient” (AI) or active pharmaceutical ingredient (API) (also referred to as an active compound, active substance, active agent, pharmaceutical agent, agent, biologically active molecule, or a therapeutic compound) is the ingredient in a pharmaceutical drug that is biologically active.

[0064] The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps.

[0065] The term “effective,” as that term is used in the specification and / or claims, means adequate to accomplish a desired, expected, or intended result. “Effective amount,” “Therapeutically effective amount” or “pharmaceutically effective amount” when used in the context of treating a patient or subject with a compound means that amount of the compound which, when administered to the patient or subject, is sufficient to effect such treatment or prevention of the disease as those terms are defined below.

[0066] An “excipient” is a pharmaceutically acceptable substance formulated along with the active ingredient(s) of a medication, pharmaceutical composition, formulation, or drug delivery system. Excipients may be used, for example, to stabilize the composition, to bulk up the composition (thus often referred to as “bulking agents,” “fillers,” or “diluents” when used for this purpose), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility. Excipients include pharmaceutically acceptable versions of antiadherents, binders, coatings, colors, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, and vehicles. The main excipient that serves as a medium for conveying the active ingredient is usually called the vehicle. Excipients may also be used in the manufacturing process, for example, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life. The suitability of an excipient will typically vary depending on the route of administration, the dosage form, the active ingredient, as well as other factors.

[0067] The term “hydrate” when used as a modifier to a compound means that the compound has less than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) water molecules associated with each compound molecule, such as in solid forms of the compound.

[0068] As used herein, the term “IC50” refers to an inhibitory dose which is 50% of the maximum response obtained. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological, biochemical or chemical process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half.

[0069] An “isomer” of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs.

[0070] As used herein, the term “patient” or “subject” refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non- limiting examples of human patients are adults, juveniles, infants and fetuses.

[0071] As generally used herein “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and / or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0072] “Pharmaceutically acceptable salts” means salts of compounds disclosed herein which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4′-methylenebis(3-hydroxy-2-ene- 1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

[0073] A “pharmaceutically acceptable carrier,” “drug carrier,” or simply “carrier” is a pharmaceutically acceptable substance formulated along with the active ingredient medication that is involved in carrying, delivering and / or transporting a chemical agent. Drug carriers may be used to improve the delivery and the effectiveness of drugs, including for example, controlled-release technology to modulate drug bioavailability, decrease drug metabolism, and / or reduce drug toxicity. Some drug carriers may increase the effectiveness of drug delivery to the specific target sites. Examples of carriers include: liposomes, microspheres (e.g., made of poly(lactic-co-glycolic) acid), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, erythrocytes, virosomes, and dendrimers.

[0074] A “pharmaceutical drug” (also referred to as a pharmaceutical, pharmaceutical preparation, pharmaceutical composition, pharmaceutical formulation, pharmaceutical product, medicinal product, medicine, medication, medicament, or simply a drug, agent, or preparation) is a composition used to diagnose, cure, treat, or prevent disease, which comprises an active pharmaceutical ingredient (API) (defined above) and optionally contains one or more inactive ingredients, which are also referred to as excipients (defined above).

[0075] “Prevention” or “preventing” includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and / or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and / or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and / or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease.

[0076] “Prodrug” means a compound that is convertible in vivo metabolically into an active pharmaceutical ingredient of the present invention. The prodrug itself may or may not have activity in its prodrug form. For example, a compound comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound. Non-limiting examples of suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoate, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, and esters of amino acids. Similarly, a compound comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.

[0077] A “stereoisomer” or “optical isomer” is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs. “Enantiomers” are stereoisomers of a given compound that are mirror images of each other, like left and right hands. “Diastereomers” are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral carbon), the total number of hypothetically possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, S form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures. As used herein, the phrase “substantially free from other stereoisomers” means that the composition contains ≤ 15%, more preferably ≤ 10%, even more preferably ≤ 5%, or most preferably ≤ 1% of another stereoisomer(s).

[0078] “Treatment” or “treating” includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and / or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and / or symptomatology), and / or (3) effecting any measurable decrease in a disease or symptom thereof in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.

[0079] The term “unit dose” refers to a formulation of the compound or composition such that the formulation is prepared in a manner sufficient to provide a single therapeutically effective dose of the active ingredient to a patient in a single administration. Such unit doseformulations that may be used include but are not limited to a single tablet, capsule, or other oral formulations, or a single vial with a syringeable liquid or other injectable formulations.

[0080] The above definitions supersede any conflicting definition in any reference that is incorporated by reference herein. The fact that certain terms are defined, however, should not be considered as indicative that any term that is undefined is indefinite. Rather, all terms used are believed to describe the invention in terms such that one of ordinary skill can appreciate the scope and practice the present invention.

[0081] The term “heteroaralkyl” refers to the monovalent group −alkanediyl−heteroaryl, in which the terms alkanediyl and heteroaryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: pyridinylmethyl and 2-quinolinyl-ethyl.

[0082] The term “heteroarenediyl” refers to a divalent aromatic group, with two aromatic carbon atoms, two aromatic nitrogen atoms, or one aromatic carbon atom and one aromatic nitrogen atom as the two points of attachment, said atoms forming part of one or more aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the divalent group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings are fused; however, the term heteroarenediyl does not preclude the presence of one or more alkyl or aryl groups (carbon number limitation permitting) attached to one or more ring atoms. Non-limiting examples of heteroarenediyl groups include:

[0083] The term “heterocycloalkanediyl” refers to a divalent cyclic group, with two carbon atoms, two nitrogen atoms, or one carbon atom and one nitrogen atom as the two points of attachment, said atoms forming part of one or more ring structure(s) wherein at least one of the ring atoms of the non-aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the divalent group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings may be fused, bridged, or spirocyclic. As used herein, the term heterocycloalkanediyl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to one or more ring atoms. Also, the term does not preclude the presence of one or more double bonds in the ring or ring system,provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkanediyl groups include:.

[0084] The terms “alkylsulfonyl” and “alkylsulfinyl” refers to the groups −S(O)2R and −S(O)R, respectively, in which R is an alkyl, as that term is defined above. The terms “cycloalkylsulfonyl”, “alkenylsulfonyl”, “alkynylsulfonyl”, “arylsulfonyl”, “aralkylsulfonyl”, “heteroarylsulfonyl”, and “heterocycloalkylsulfonyl” are defined in an analogous manner.

[0085] The terms “cycloalkylamino”, “alkenylamino”, “alkynylamino”, “arylamino”, “aralkylamino”, “heteroarylamino”, “heterocycloalkylamino”, and “alkoxyamino” when used without the “substituted” modifier, refers to groups, defined as −NHR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkoxy, respectively. A non- limiting example of an arylamino group is −NHC6H5. The terms “dicycloalkylamino”, “dialkenylamino”, “dialkynylamino”, “diarylamino”, “diaralkylamino”, “diheteroarylamino”, “diheterocycloalkylamino”, and “dialkoxyamino”, refers to groups, defined as −NRR′, in which R and R′ are both cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkoxy, respectively. Similarly, the term alkyl(cycloalkyl)amino refers to a group defined as −NRR′, in which R is alkyl and R′ is cycloalkyl.

[0086] The term “alkylimino” refers to the divalent group =NR, in which R is an alkyl, as that term is defined above.

[0087] The terms “phosphine” and “phosphane” are used synonymously herein. these terms refer to a compound of the formula PR3, wherein each R is independently hydrogen, alkyl, cycloalkyl, alkenyl, aryl, or aralkyl, as those terms are defined above. Non-limiting examples include PMe3, PPh3, and PCy3 (tricyclohexylphosphine). The terms “trialkylphosphine” and “trialkylphosphane” are also synonymous. Such groups are a subset of phosphine, wherein each R is an alkyl group. The term “diphosphine” refers to a compound of the formula R2−P−L−P−R2, wherein each R is independently hydrogen, alkyl, cycloalkyl, alkenyl, aryl, or aralkyl, and wherein L is alkanediyl, cycloalkanediyl, alkenediyl, or arenediyl.

[0088] The term “phosphine oxide” refers to a compound of the formula O=PR3, wherein each R is independently hydrogen, alkyl, cycloalkyl, alkenyl, aryl, or aralkyl, as those terms are defined above. Non-limiting examples include OPMe3 (trimethylphosphine oxide) and PPh3O (triphenylphosphine oxide).

[0089] An “amine protecting group” or “amino protecting group” is well understood in the art. An amine protecting group is a group which modulates the reactivity of the amine group during a reaction which modifies some other portion of the molecule. Amine protecting groups can be found at least in Greene and Wuts, 1999, which is incorporated herein by reference. Some non-limiting examples of amino protecting groups include formyl, acetyl, propionyl, pivaloyl, t–butylacetyl, 2–chloroacetyl, 2–bromoacetyl, trifluoroacetyl, trichloroacetyl, o–nitrophenoxyacetyl, α–chlorobutyryl, benzoyl, 4–chlorobenzoyl, 4– bromobenzoyl, 4–nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p– toluenesulfonyl and the like; alkoxy- or aryloxycarbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p- methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5- dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxy- benzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkylaminocarbonyl groups (which form ureas with the protect amine) such as ethylaminocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Additionally, the “amine protecting group” can be a divalent protecting group such that both hydrogen atoms on a primary amine are replaced with a single protecting group. In such a situation the amine protecting group can be phthalimide (phth) or a substituted derivative thereof wherein the term “substituted” is as defined above. In some embodiments, the halogenated phthalimide derivative may be tetrachlorophthalimide (TCphth). When used herein, a “protected amino group”, is a group of the formula PGMANH− or PGDAN− wherein PGMAis a monovalent amine protecting group, which may also be described as a “monovalently protected amino group” and PGDAis a divalent amine protecting group as described above, which may also be described as a “divalently protected amino group”.

[0090] The term “alkylphosphate” refers to the group −OP(O)(OH)(OR), in which R is an alkyl, as that term is defined above. Non-limiting examples of alkylphosphate groupsinclude: −OP(O)(OH)(OMe) and −OP(O)(OH)(OEt). The term “dialkylphosphate” refers to the group −OP(O)(OR)(OR′), in which R and R′ can be the same or different alkyl groups, or R and R′ can be taken together to represent an alkanediyl. Non-limiting examples of dialkylphosphate groups include: −OP(O)(OMe)2, −OP(O)(OEt)(OMe) and −OP(O)(OEt)2.

[0091] The term “epoxide” refers to a class of compounds of the formula:,

[0092] wherein R1, R2, and R3are each independently hydrogen, alkyl, and R4is hydrogen, alkyl, or aryl.

[0093] As used herein, a “chiral auxiliary” refers to a removable chiral group that is capable of influencing the stereoselectivity of a reaction. Persons of skill in the art are familiar with such compounds, and many are commercially available.

[0094] “Substituent convertible to hydrogen in vivo” means any group that is convertible to a hydrogen atom by enzymological or chemical means including, but not limited to, hydrolysis and hydrogenolysis. Non-limiting examples include hydrolyzable groups, such as acyl groups, groups having an oxycarbonyl group, amino acid residues, peptide residues, o- nitrophenylsulfenyl, trimethylsilyl, tetrahydropyranyl, and diphenylphosphinyl. Non-limiting examples of acyl groups include formyl, acetyl, and trifluoroacetyl. Non-limiting examples of groups having an oxycarbonyl group include ethoxycarbonyl, tert-butoxycarbonyl (−C(O)OC(CH3)3), benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl, and β-(p-toluenesulfonyl)ethoxycarbonyl. Suitable amino acid residues include, but are not limited to, residues of Gly (glycine), Ala (alanine), Arg (arginine), Asn (asparagine), Asp (aspartic acid), Cys (cysteine), Glu (glutamic acid), His (histidine), Ile (isoleucine), Leu (leucine), Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser (serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val (valine), Nva (norvaline), Hse (homoserine), 4-Hyp (4- hydroxyproline), 5-Hyl (5-hydroxylysine), Orn (ornithine) and β-Ala. Examples of suitable amino acid residues also include amino acid residues that are protected with a protecting group. Non-limiting examples of suitable protecting groups include those typically employed in peptide synthesis, including acyl groups (such as formyl and acetyl), arylmethoxycarbonyl groups (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), and tert-butoxycarbonyl groups (−C(O)OC(CH3)3). Suitable peptide residues include peptide residues comprising two to five amino acid residues. The residues of these amino acids or peptides can be present instereochemical configurations of the D-form, the L-form or mixtures thereof. In addition, the amino acid or peptide residue may have an asymmetric carbon atom. Examples of suitable amino acid residues having an asymmetric carbon atom include residues of Ala, Leu, Phe, Trp, Nva, Val, Met, Ser, Lys, Thr and Tyr. Peptide residues having an asymmetric carbon atom include peptide residues having one or more constituent amino acid residues having an asymmetric carbon atom. Non-limiting examples of suitable amino acid protecting groups include those typically employed in peptide synthesis, including acyl groups (such as formyl and acetyl), arylmethoxycarbonyl groups (such as benzyloxycarbonyl and p- nitrobenzyloxycarbonyl), and tert-butoxycarbonyl groups (−C(O)OC(CH3)3). Other examples of substituents “convertible to hydrogen in vivo” include reductively eliminable hydrogenolyzable groups. Examples of suitable reductively eliminable hydrogenolyzable groups include, but are not limited to, arylsulfonyl groups (such as o-toluenesulfonyl); methyl groups substituted with phenyl or benzyloxy (such as benzyl, trityl and benzyloxymethyl); arylmethoxycarbonyl groups (such as benzyloxycarbonyl and o-methoxy-benzyloxycarbonyl); and haloethoxycarbonyl groups (such as β,β,β-trichloroethoxycarbonyl and β-iodoethoxycarbonyl). VI. Examples

[0095] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the example which follows represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. Example 1: Utilising non-antibiotic compounds to increase intracellular killing of Staphylococcus aureus through immunomodulation

[0096] When tested against the antibiotic-resistant S. aureus (MRSA) strain in vitro, it has been shown that N-(chroman-3-yl) benzamide analogs (for example the N-(chroman-3-yl) benzamide analogs listed in Table 1) exhibit potent antimicrobial activity with a four-fold reduction in concentration needed to inhibit the growth of the bacterium. In addition, when tested in combination with standard antibiotic agent to which MRSA has developed resistance,the compounds worked synergistically with the antibiotic and restored the antibiotic’s activity against the bacterium. Four compounds previously shown to alter immune cell function were screened: metformin (MET), simvastatin (SIM) and (-)-Epigallocatechin gallate (EGCG), as well as a N-(chroman-3-yl) benzamide analog. It was found that the N-(chroman-3-yl) benzamide analog exhibits the greatest intracellular bacterial killing of SA which correlated with unique alterations of liver macrophage function when treated with the compound. Table 1. N-(chroman-3-yl) Benzamide Analogs

[0097] Murine KCs (Kup5) were treated with 1ug / ml MET, 1ug / ml SIM, 25ug / ml EGCG or 6.25ug / ml N-(5,7-dimethoxychroman-3-yl)-5-nitrofuran-2-carboxamide and incubated for 24h. RNA was extracted to measure TNF and IL6 gene expression by quantitative RT-PCR. To assess intracellular killing, Kup5 were infected with USA300 methicillin-resistant SA at an MOI 5, incubated for 1.5h then treated with 100ug / ml gentamicin for 2h to kill extracellular bacteria. Infected cells were treated with 25ug / ml EGCG or 6.25ug / ml N-(5,7- dimethoxychroman-3-yl)-5-nitrofuran-2-carboxamide and incubated for 10h before lysing with 0.1% Triton X. Lysate was streaked on TSA and CFUs were enumerated the next day.

[0098] Compared to no treatment, Kup5s exposed to 1ug / ml MET showed a 1.5X increase in expression of IL-6 but no change in TNF while the opposite was observed with 1ug / ml SIM (4X increase in TNF, no change in IL-6). Interestingly, Kup5s exposed to 25ug / ml EGCG showed no change in either IL-6 or TNF but when exposed to the EGCG analog at 6.25ug / ml, gene expression increased for both IL-6 (1.5x) and TNF (3X) likely due to improved cellular penetration. Treatment of infected Kup5 with 6.25ug / ml of N-(5,7-dimethoxychroman-3-yl)-5-nitrofuran-2-carboxamide reduced 10h intracellular SA growth by 4-fold compared to EGCG and no treatment (2.3 and 2.2 log CFU increase from baseline respectively). MET and SIM exerted effects on IL-6 or TNF expression while N-(5,7-dimethoxychroman-3-yl)-5- nitrofuran-2-carboxamide increased expression of both pro-inflammatory mediators which correlated with enhanced intracellular killing of SA in KCs.

[0099] Differential expression of M1 markers was observed with minimal alteration of M2 markers when comparing the addition of different immunomodulatory compounds to vancomycin. Intracellular killing of SA by Kupffer cells does not appear to correlate with M1 / M2 phenotype expression when using markers such as CD38 and TNF-a Egr2, and Arg1. EGCG increased surface marker stimulation (CD38) for M1 phenotype but did not correlate with intracellular killing likely attributable to its poor intracellular penetration. MCC-1 (N-(5,7- dimethoxychroman-3-yl)-5-nitrofuran-2-carboxamide) showed greatest potentiation of vancomycin in intracellular killing, suggesting that reducing M2 phenotype expression may be more important than increasing M1 marker expression along with other mechanisms including intrinsic antimicrobial activity. Example 2: Novel synthetic EGCG analogs potentiate intracellular killing of Staphylococcus aureus within liver-resident macrophages

[0100] Three novel (-)-Epigallocatechin gallate (EGCG) analogs with improved lipophilicity and reduced polar surface area predictive of superior membrane penetration were synthesized and the in vitro activity of the EGCG analogs against S. aureus intracellular killing was assessed. Broth microdilution assays were performed following CLSI standardized methodology to determine MICs (minimum inhibitory concentration) for the analogs alone or in combination with cefazolin or oxacillin against GFP USA300 methicillin- resistant S. aureus (GFP SA). The analogs were tested at a concentration range of 1.56- 200ug / ml and cefazolin and oxacillin at 0.5-128ug / ml. MICs were read visually and GFP fluorescence was used to confirm the MIC as EGCG and some analogs have color. Murine Kupffer cells (Kup5) were infected with GFP SA at an MOI 5, incubated for 1.5h, then treated with 100ug / ml gentamicin for 2h to kill extracellular bacteria. Sub-MICs of the analogs were added to the cells and incubated for 10h before lysing with 0.1% Triton X. Lysate was streaked on TSA and CFUs were enumerated the next day to assess intracellular killing.

[0101] The MICs for all 3 EGCG analogs were significantly lower than EGCG (12.5 vs 50ug / ml). The addition of EGCG analogs at sub-MIC(6.25ug / ml) concentrations potentiated the activity of cefazolin and oxacillin, reducing their MICs from 64ug / ml to 2ug / ml.Treatment of infected Kup5 with 6.25ug / ml of our lead analog reduced 10h intracellular SA growth by at least 4-fold compared to EGCG and no treatment (2.3 and 2.2 log CFU increase from baseline respectively).

[0102] Chemical modifications to EGCG (FIGS.2 and 6-9) exhibited improved drug-like properties with enhancements of the following: (1) Demonstrated direct antibacterial activity leading to a 4x decrease in MIC value when tested against MRSA; (2) Exhibited synergy with beta-lactam agents and restored activity against MRSA; (3) Improved cell penetrating potential compared to EGCG resulting in enhanced intracellular killing of SA in Kupffer cells. Overall, MCC-1 (N-(5,7-dimethoxychroman-3-yl)-5-nitrofuran-2-carboxamide) displayed a favorable pharmacologic profile (see, for example, FIGS. 5-9). Example 3: Synthesis of N-(chroman-3-yl) benzamide analogs

[0103] General Experimental Methods: The reactions were performed under a dry argon atmosphere, and reaction temperatures were measured externally. Anhydrous solvents over molecular sieves were purchased from Sigma-Aldrich and used as such in reactions. Reactions were performed in a CEM Discover Labmate System with Intelligent Technology for Focused Microwave Synthesizer (Biotage®Initiator+). The reactions were monitored by thin-layer chromatography (TLC) on pre-coated silica gel (60F254) aluminum plates (0.25 mm) from E. Merck and visualized using UV light (254 nm). Purification of compounds was performed on an Isco Teledyne Combiflash Rf200 with a single channel to carry out purifications. Universal RediSep solid sample loading pre-packed cartridges (5.0 g silica) were used to absorb crude product and purified on 12 g silica RediSep Rf Gold Silica (20−40 μm spherical silica) columns using appropriate solvent gradients. Pure samples were dried overnight under high vacuum over P2O5 at 78 °C before analyses. The HR-LCMS spectral data were obtained on an Agilent LC-MS TOF by electrospray ionization (ESI).1H NMR spectra were recorded at 400 MHz on an Agilent / Varian MR-400 spectrometer with DMSO- d6 (OR) CDCl3 (OR) CD3OD as solvents. The chemical shifts (δ) were in ppm downfield from standard tetramethylsilane (TMS). Purity of final compounds was checked by Agilent 1260 Infinity II LC equipped with a diode array UV detector and were monitored at multiple wavelengths on ZORBAX Extend-C18 Analytical 4.6 x 150mm 5-Micron, P.N.773450-902 column using Solvent A: H2O; Solvent B: ACN, 1.0 mL / min; 25 min linear gradient from 5 to 95% B (both solvents containing 0.1% formic acid).

[0104] All final compounds were ≥95% pure, and their retention time (RT) is reported.Scheme 1. Synthesis of N-(Chroman-3-yl) benzamide analogs

[0105] General Experimental Procedure for EDC.HCl mediated amide coupling reactions: To a solution of 5,7-dimethoxychroman-3-amine (la) (1 mmol), respective organic carboxylic acid (2.1 mmol) and 1 -ethyl -3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCI) (2.5 mmol) in anhydrous dichloromethane (DCM) (15 mL) under nitrogen atmosphere at rt, was added a solution of N.N -diisopropylethylamine (6 mmol) dropwise. After completion of the addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with CH2CI2(2x100 mL). The combined organic layer was washed with aqueous saturated solutions NaHCO3, and brine (100 mL). The combined organic layer was dried over Na2SCO4, filtered, and evaporated to dryness under reduced pressure to give a residue, which was purified using a pre-packed Silica gel column on ISCO to give pure product.

[0106] N-(5, 7-dimethoxychroman-3-yl)-5-nitrofuran-2-carboxamide (MCC-1): Purification on pre-packed Silica gel column on ISCO using 0-40% EtOAc in Hexanes (20min). Yield bright yellow solid: 48 mg (56%).1H NMR (400 MHz, CDCh) δ 7.34 (d, J =3.8 Hz, 1H), 7.26 - 7.25 (m, 1H), 6.74 (d, J= 7.8 Hz, 1H), 6.11- 6.09 (m, 2H), 4.62 (dtq, J= 7.8, 3.9, 1.9 Hz, 1H), 4.23 (ddd, J= 11.0, 4.1, 2.0 Hz, 1H), 4.17 - 4.07 (m, 1H), 3.78 (d, J =2.8 Hz, 6H), 2.93 (dd, J= 17.2, 5.8 Hz, 1H), 2.77 (ddd, J= 17.2, 3.6, 2.0 Hz, 1H).13C NMR (101 MHz, CDCh) δ 159.61, 158.78, 156.66, 155.26, 151.94, 148.34, 116.42, 113.85, 101.60, 93.86, 91.99, 67.11, 55.90, 55.59, 43.36, 24.83. HR-ESIMS: m / z 349.1030 [M+H]+calcd. forC16H17N2O7found 349.1028. HPLC purity: 97.8% (Retention Time=l 2.405 min). Melting point: 169.5-172.2 ’C.

[0107] N-(5, 7-dimethoxychroman-3-yl)-5-nitrothiophene-2-carboxamide(MCC-2): Purification on pre-packed Silica gel column on ISCO using 0-40% EtOAc in Hexanes (20min). Yield bright orange solid: 34 mg (65%).1H NMR (400 MHz, CDCh) δ 7.80 (d, J= 4.3 Hz, 1H), 7.29 (d, J = 4.3 Hz, 1H), 6.34 (d, J = 8.0 Hz, 1H), 6.10 - 6.07 (m, 2H), 4.69-4.60 (m, 1H), 4.28-4.24 (ddd, . / = 11.0, 3.5, 2.2 Hz, 1H), 4.10 (dd, J= 11.0, 1.7 Hz, 1H), 3.77 (d, J= 1.9 Hz, 6H), 2.93-2.87 (dd, J = 17.3, 5.6 Hz, 1H), 2.77 (dt, J= 17.4, 2.6 Hz, 1H).13C NMR (101 MHz, CDCh) δ 159.85, 159.69, 159.17, 154.92, 144.51, 127.99, 126.06, 100.22, 93.38, 92.18, 77.21, 67.65, 55.45, 55.39, 42.98, 25.19. HR-ESIMS: m / z 365.0802 [M+H]+calcd. for C16H17N2O6S found 365.0765. HPLC purity: 98.21% (Retention Time=13.877 min). Melting point: 163.5-164.8 "C.

[0108] N-(5, 7-dimethoxychroman-3-yl)-5-nitro-lH-pyrazole-3-carboxamide(MCC-3): Purification on pre-packed Silica gel column on ISCO using 0-1% MeOH in DCM (30min). Yield dark yellow solid: 83 mg (84%). *H NMR (400 MHz, CDCh) 8 7.16 (s, 1H), 6.64 (d, J= 8.0 Hz, 1H), 6.13 - 6.06 (m, 2H), 4.71 (s, 1H), 4.34 - 4.25 (m, 1H), 4.15 - 4.07 (m, 1H), 3.78 (s, 6H), 2.92 (dd, J= 17.4, 5.6 Hz, 1H), 2.79 (d, J= 17.3 Hz, 1H).13C NMR (101 MHz, CDCh) 8 160.41, 159.61, 158.65, 156.10, 140.26, 103.15, 102.30, 94.70, 92.78, 67.94, 56.71, 56.40, 49.85, 44.05, 25.62. HR-ESIMS: m / z 347.0997 [M-H]' calcd. for C15H15N4O6 found 347.1002. HPLC purity: 95.66% (Retention Time=11.70 min). Melting point: 137.8.- 139.2’C.

[0109] N-(5, 7-dimethoxychroman-3-yl)-5-nitro-lH-imidazole-2-carboxamide (MCC-4): Purification on pre-packed Silica gel column on ISCO using 0-1% MeOH in DCM (30min). Yield white sticky solid: 18.9 mg (18%).1H NMR (400 MHz, CDCh) 8 8.00 (s, 1H), 6.14 - 6.06 (m, 2H), 4.53 - 4.48 (m, 1H), 4.18 - 4.15 (m, 2H), 3.79 (d, J = 8.3 Hz, 6H), 2.97 (dd, J= 17.0, 5.9 Hz, 1H), 2.73 (dd, J= 16.9, 5.2 Hz, 1H). HR-ESIMS: m / z 347.0997 [M-H]" calcd. for C15H15N4O6 found 347.1002. HPLC purity: 100% (Retention Time=11.01 min).

[0110] 5-cyano-N-(5,7-dimethoxychroman-3-yl)furan-2-carboxamide (MCC- 5): Purification on pre-packed Silica gel column on ISCO using 0-45% EtOAc in Hexanes (20min). Yield creamy white solid: 68 mg (63%). 'H NMR (400 MHz, CDCh) 8 7.18 - 7.11 (m, 2H), 6.64 (d, J= 8.0 Hz, 1H), 6.11 (q, J= 2.4 Hz, 2H), 4.67 - 4.59 (m, 1H), 4.23 (ddd, J= 11.0, 3.8, 2.2 Hz, 1H), 4.11 (dd, J= 11.0, 1.8 Hz, 1H), 3.78 (d, J= 0.8 Hz, 6H), 2.97 - 2.70 (m, 2H).13C NMR (101 MHz, CDCh) 8 159.85, 159.10, 156.09, 154.95, 151.09, 126.55,123.26, 114.86, 110.50, 100.23, 93.39, 92.19, 67.58, 55.43, 55.38, 42.28, 25.19. HR-ESIMS: m / z 327.0986 [M-H]' calcd. for C17H15N2O5 found 327.1059. HPLC purity: 100% (Retention Time=12.447 min). Melting point: 179.9-184.8‘C.

[0111] N-(5,7-dimethoxychroman-3-yl)-5-formylfuran-2-carboxamide (MCC- 6): Purification on pre-packed Silica gel column on ISCO using 0-45% EtOAc in Hexanes (20min). Yield sticky white solid: 31.1 mg (64%).1HNMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 7.29 - 7.21 (m, 2H), 6.80 (d, J= 7.9 Hz, 1H), 6.16 - 6.04 (m, 2H), 4.62 (ddtd, . / = 7.9, 5.9, 3.9, 2.0 Hz, 1H), 4.22 (ddd, J= 10.9, 4.2, 2.0 Hz, 1H), 4.15 - 4.10 (m, 1H), 3.77 (d, J = 3.1 Hz, 6H), 2.93 (dd, J= 17.2, 5.8 Hz, 1H), 2.75 (ddd, . / = 17.3, 3.8, 1.9 Hz, 1H).13CNMR(101 MHz, CDCl3) δ 178.12, 159.79, 159.05, 157.15, 155.02, 152.33, 151.05, 121.84, 115.83, 100.45, 93.40, 92.13, 67.55, 55.42, 55.37, 42.45, 25.17. HR-ESIMS: m / z 330.0983 [M-H]' calcd. for C17H16NO6found 330.0976. HPLC purity: 100% (Retention Time=10.9min).

[0112] N-(5,7-dimethoxychroman-3-yl)-3-nitropropanamide (MCC-7). Purification on pre-packed Silica thin layer chromatography plate using 0-20% EtOAc in Hexanes (60min). Yield off white sticky solid: 9.7 mg (12%).1H NMR (400 MHz, CDCh) 8 6.09 - 6.06 (m, 2H), 5.90 (d, J= 8.0 Hz, 1H), 4.70 (t, J= 6.2 Hz, 2H), 4.50 (d, J= 6.9 Hz, 1H), 4.15 (ddd, J= 10.8, 3.5, 2.2 Hz, 1H), 4.02 (dd, J= 11.0, 1.7 Hz, 1H), 3.77 (d, J= 2.7 Hz, 6H), 2.87 - 2.71 (m, 3H), 2.65 (dt, . / = 17.1, 2.6 Hz, 1H).13C NMR (101 MHz, CDCh) 8 167.69, 159.78, 159.18, 154.97, 100.44, 93.28, 92.00, 69.98, 67.79, 55.44, 55.38, 42.19, 32.60, 25.15. HR-ESIMS: m / z 311.1238 [M+H]+calcd. for C14H19N2O6 found 311.1235. HPLC purity: 100% (Retention Time=10.298).

[0113] Methyl 5-((5, 7-dimethoxychroman-3-yl)carbamoyl)j:uran-2-carboxylate (MCC-8): Purification on pre-packed Silica gel column on ISCO using 0-45% EtOAc in Hexanes (30min). Yield off white color solid: 50 mg (54%). ’H NMR (400 MHz, CDCh) 8 7.18 (t, 2H), 6.75 (d, J= 7.9 Hz, 1H), 6.09 (q, J= 2.4 Hz, 2H), 4.61 (ddt, J= 8.0, 4.9, 2.8 Hz, 1H), 4.23 - 4.09 (m, 2H), 3.89 (s, 3H), 3.78 (d, J= 3.7 Hz, 6H), 2.93 (dd, J= 17.1, 5.9 Hz, 1H), 2.78 - 2.68 (m, 1H).13C NMR (101 MHz, CDCh) 8 159.74, 159.01, 158.58, 157.30, 155.07, 150.03, 144.85, 119.08, 115.56, 100.65, 93.37, 92.06, 67.62, 55.42, 55.36, 52.27, 42.42, 25.22. HR-ESIMS: m / z 362.1234 [M+H]+calcd. for C18H20NO7found 362.1228. HPLC purity: 100% (Retention Time=12.106 min). Melting point: 134.8-137.5 ’C.

[0114] 5 -((5, 7-dimethoxychroman-3-yl)carbamoyl)juran-2-carboxylic acid(MCC-9): Purification by precipitating using ice-cold water. Yield off-white solid: 55 mg (57%).1H NMR (400 MHz, CDCh) 8 7.22 - 7.15 (m, 2H), 6.09 (q, J= 2.3 Hz, 2H), 4.54 (s,1H), 4.20 (dd, J= 10.7, 2.4 Hz, 1H), 4.10 (dd, J= 10.8, 6.0 Hz, 1H), 3.79 (d, J= 1.2 Hz, 3H), 3.77 (s, 3H), 2.99 (dd, J= 17.0, 6.1 Hz, 1H), 2.75 -2.63 (m, 1H).13CNMR(101 MHz, CDC13) 8 159.51, 158.82, 157.85, 155.04, 118.78, 115.57, 100.96, 93.21, 91.75, 67.37, 55.29 (d, J = 5.2 Hz), 42.56, 30.80, 24.89. HR-ESIMS: m / z 348.1078 [M+H]+calcd. for CI7HI8NO7found 348.2305. HPLC purity: 96.72% (Retention Time=6.504 min). Melting point: 236.9-239.2 "C.

[0115] N-(5, 7-dimethoxychroman-3-yl)-4-nitrothiophene-2-carboxamide(MCC-11). Purification of pre-packed Silica gel column on ISCO using 0-40% EtOAc in Hexanes (20min). Yield off-white solid: 81 mg (91%).1HNMR (400 MHz, CDCh) 8 8.38 (d, J= 1.5 Hz, 1H), 8.01 (dd, J= 1.5, 0.7 Hz, 1H), 6.08 - 6.03 (m, 2H), 4.53 (d, J= 6.2 Hz, 1H), 4.19 - 4.05 (m, 2H), 3.74 (d, J= 3.8 Hz, 6H), 2.88 (dd, J = 17.1, 5.9 Hz, 1H), 2.74 - 2.64 (m, 1H).,3C NMR (101 MHz, CDCh) 8 159.74, 158.99, 154.91, 131.05, 121.71, 93.22, 92.00, 77.25, 67.54, 55.43, 55.36, 42.89, 30.88, 24.91. HR-ESIMS: m / z 363.0656 [M-H]" calcd. for C16H15N2O6S found 363.0670. HPLC purity: 97.1% (Retention Time=13.416 min). Melting point: 189.8-192.0 ’C.

[0116] N-(5, 7-dimethoxychroman-3-yl)-2-(2, 4-dioxoimidazolidin-l- yl)acetamide (MCC-12): Purification of reverse-phase on ISCO using 0-38% HPLC ACN in Water (90min). Yield white sticky solid: 19 mg (20%). *H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J= 7.4 Hz, 1H), 6.11 (d, J= 2.4 Hz, 1H), 6.03 (d, J= 2.3 Hz, 1H), 4.24 (d, J= 8.3 Hz, 1H), 4.14 (s, 2H), 4.10 - 4.04 (m, 1H), 4.01 (s, 2H), 3.95 - 3.86 (m, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 2.89 - 2.79 (m, 1H), 2.53 (dd, J= 16.5, 6.2 Hz, 1H).13C NMR (101 MHz, DMSO-d6) δ 172.32, 166.51, 159.55, 158.85, 157.61, 155.28, 101.41, 93.90, 91.91, 67.39, 55.87, 55.58, 46.47, 42.63, 25.04. HR-ESIMS: m / z 348.1201 [M-H]" calcd. for C16H18N3O6found 348.1212. HPLC purity: 100% (Retention Time=8.043 min).

[0117] N-(5, 7-dimethoxychroman-3-yl)-5-melhyl-4-nitroj:uran-2-carboxamide(MCC-14): Purification on pre-packed Silica gel column on ISCO using 0-40% EtOAc in Hexanes (20min). Yield light-yellow solid: 28 mg (50%).1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 6.54 (d, J= 8.0 Hz, 1H), 6.13 - 6.09 (m, 2H), 4.64 (s, 1H), 4.23 (dt, J= 11.2, 2.9 Hz, 1H), 4.14 - 4.07 (m, 1H), 3.78 (s, 6H), 2.90 (dd, J= 17.3, 5.7 Hz, 1H), 2.77 (s, 1H), 2.74 (s, 3H).13CNMR(101 MHz, CDCh) 8 159.75, 159.15,110.32, 100.48, 93.37, 92.04, 77.22, 67.76, 55.47, 55.41, 42.12, 30.97, 25.21, 14.48. HR-ESIMS: m / z 363.1187 [M+H]+calcd. for C17H19N2O7found 363.1178. HPLC purity: 100% (Retention Time=13.153 min). Melting point: 90.2-93.0 "C.Scheme 2. Synthesis of 1-(5,7-dimethoxychroman-3-yl)-4-(3,4,5-trimethoxyphenyl)-1H - 1,2,3-triazole

[0118] 1-(5,7-dimethoxychroman-3-yl)-4-(3,4,5-trimethoxyphenyl)-lH-1,2,3-triazoIe (MCC-10): Solution of 5-ethynyl-l,2,3-trimethoxybenzene (107.3 mg, 0.558 mmol), 3-azido-5,7-dimethoxychromane lb (131.33 mg, 0.558 mmol), sodium ascorbate (11.06 mg, 0.0558 mmol) and copper sulfate pentahydrate (1.39 mg, 0.00558 mmol) in tert- butanol (t-BuOH) and HPLC grade water (1 : 1 volume ratio) (4 mL) were stirred at run at room temperature overnight. The resulting solution was diluted with 50 mL Dl-water and then extracted by CH2CI2 (2X100 mL). The combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure, followed by the purification on a pre-packed Silica gel column on ISCO using 0-35% EtOAc in Hexanes (20 mins). Yield light brown solid: 120 mg (50%).1H NMR (400 MHz, CDCh) 5 7.68 (s, 1H), 7.01 (s, 2H), 6.14 - 6.12 (m, 2H),5.28 - 5.19 (m, 1H), 4.47 - 4.39 (m, 2H), 3.91 (s, 6H), 3.86 (s, 3H), 3.79 (d, J= 5.6 Hz, 6H),3.28 (dd, J= 17.4, 6.6 Hz, 1H), 3.10 (dd, J= 17.4, 5.1 Hz, 1H).13C NMR (101 MHz, CDCh) 8 160.06, 158.71, 154.86, 153.59, 147.72, 138.17, 126.20, 118.38, 103.13, 99.94, 93.46, 92.37, 77.33, 77.21, 77.01, 67.53, 60.95, 56.33, 55.52, 55.42, 53.20, 25.37. HR-ESIMS: m / z 428.1816 [M+H]+calcd. for C22H26N3O6 found 428.1769. HPLC purity: 98.62% (Retention Time=15.0 min). Melting point: 137.7-139.8 ’C.Scheme 3. Synthesis of N-(5-hydroxy-7-methoxychroman-3-yl)-5-nitrofuran-2- carboxamide

[0119] N-(5-hydroxy-7-methoxychroman-3-yl)-5-nitrofuran-2- carboxamide (MCC-15): In a microwave vial, IN HC1 in diethyl ether (2.87 mL, 2.87 mmol) was slowly added to pyridine (231.2 pL). The reaction was stirred at room temperature for 10 minutes. Diethyl ether was blown off using a stream of continuous nitrogen gas flow. MCC-1 (100 mg, 0.287 mmol) was then added to the vial. The reaction was heated in a microwave at 160 "C for 30 minutes. The cap of the vial was removed and recapped every 30 minutes for a total of 2 hours. The reaction was diluted with 50 mL of Dl-water and then extracted with ethyl acetate and CH3OH mixture (95:5). The ethyl acetate layer was washed with 50 mL of 1 N HC1 and brine (50 mL) and dried over anhydrous Na2SO4. Filtered and concentrated under reduced pressure, followed by purification on a preparative thin-layer chromatography plate using 0- 60% EtOAc in Hexanes (60min). Yield light yellow oil: 9 mg (9%). ’H NMR (400 MHz, CDCh) 5 7.33 (t, J = 3.7 Hz, 1H), 7.27 (d, J = 3.4 Hz, 1H), 6.87 (dd, J = 15.3, 7.8 Hz, 1H), 6.07 - 6.00 (m, 2H), 4.63 (dtt, J= 7.8, 3.9, 1.9 Hz, 1H), 4.23 (tdd, J= 11.1, 4.1, 2.0 Hz, 1H), 4.12 (td, J = 12.0, 1.9 Hz, 1H), 3.75 (d, J = 13.0 Hz, 3H), 2.94 (ddd, J= 26.4, 16.9, 5.6 Hz, 1H), 2.82 - 2.70 (m, 1H).13C NMR (101 MHz, CDCh) 5 159.56, 159.24, 156.30, 156.25, 155.79, 155.35, 155.30, 154.87, 147.67, 147.60, 116.38, 116.32, 112.42, 100.11, 99.16, 95.96, 95.67, 94.17, 92.38, 77.33, 77.01, 76.69, 67.42, 67.37, 55.46, 55.32, 42.68, 25.09, 24.95. HR- ESIMS: m / z 335.0873 [M+H]+calcd. for C15H15N2O7 found 335.0867. HPLC purity: 100% (Retention Time=9.477 min).REFERENCES

[0120] The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.Anderson, Practical Process Research & Development - A Guide for Organic Chemists, 2nded., Academic Press, New York, 2012.Handbook of Pharmaceutical Salts: Properties, and Use, Stahl and Wermuth Eds., Veriag Helvetica Chimica Acta, 2002.Reagan-Shaw etal, FASEBJ, 22(3):659-661, 2008.Smith, March *s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7thEd, Wiley, 2013.Dye C. Phil Trans R Soc B. 2014; 369(1645):20130426.Kourtis AP et al., MMWR 2019;68:214-219.Van Hal SJ, et al., Clin Microbiol Rev. 2012 Apr;25(2):362-86.Ali RA, et al., J Immunol. 2017; 198(l):344-351.Bas G.J., et al., Exp Med 2016; 213 (7): 1141-1151.Zhao WH, et al., Antimicrobial Agents Chemotherapy. 2001 Jun;45(6): 1737-42.Liu C, et al., Int Immunopharmacology. 2021 Nov; 100: 108170.Yang Y, et al., J Agric Food Chem. 2021 May 26;69(20):5638-5651.

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula: (I), wherein: R1and R2are each independently hydrogen; or alkyl(C£8), cycloalkyl(C£8), alkenyl(C£8), alkynyl(C£8), aryl(C£8), aralkyl(C£8), heteroaryl(C£8), heterocycloalkyl(C£8), heteroaralkyl(C£8), or a substituted version of any of these groups; X1 is hydrogen, hydroxy, amino, halo, cyano, or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −alkanediyl(C≤12)−aryl(C≤12), −alkanediyl(C≤12)−heteroaryl(C≤12), −alkanediyl(C≤12)−heterocycloalkyl(C≤12), −alkanediyl(C≤12)−cycloalkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −heteroarenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), amido(C≤12), or a substituted version of any of these groups; or −C(O)R4, wherein R4 is:hydrogen, hydroxy, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), cycloalkoxy(C≤8), alkenyloxy(C≤8), aryloxy(C≤8), aralkoxy(C≤8), heteroaryloxy(C≤8), acyloxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), heteroarylamino(C≤8), alkyl- sulfonylamino(C≤8), cycloalkylsulfonylamino(C≤8), alkoxyamino(C≤8), heterocycloalkylamino(C≤8), or a substituted version of any of these groups; or −NRaRb, wherein Raand Rbare each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), thioacyl(C≤12), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −C(Ya)R5, wherein R5 is: alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −alkanediyl(C≤12)−aryl(C≤12), −alkanediyl(C≤12)−heteroaryl(C≤12), −alkanediyl(C≤12)−heterocycloalkyl(C≤12), −alkanediyl(C≤12)−cycloalkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −heteroarenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12),−heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; and Ya is oxo or thio; or −ORcRd, wherein Rcand Rdare each independently: hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), thioacyl(C≤12), aryl(C≤8), aralkyl(C≤8), hetero- aryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is further defined as:wherein: R1and R2are each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X1 is hydrogen, hydroxy, amino, halo, cyano, or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −alkanediyl(C≤12)−aryl(C≤12), −alkanediyl(C≤12)−heteroaryl(C≤12), −alkanediyl(C≤12)−heterocycloalkyl(C≤12), −alkanediyl(C≤12)−cycloalkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12),−arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −heteroarenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), amido(C≤12), or a substituted version of any of these groups; or −C(O)R4, wherein R4 is: hydrogen, hydroxy, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), cycloalkoxy(C≤8), alkenyloxy(C≤8), aryloxy(C≤8), aralkoxy(C≤8), heteroaryloxy(C≤8), acyloxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), heteroarylamino(C≤8), alkyl- sulfonylamino(C≤8), cycloalkylsulfonylamino(C≤8), alkoxyamino(C≤8), heterocycloalkylamino(C≤8), or a substituted version of any of these groups; or −NRaRb, wherein Raand Rbare each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), thioacyl(C≤12), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −C(Ya)R5, wherein R5 is: alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12),aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −alkanediyl(C≤12)−aryl(C≤12), −alkanediyl(C≤12)−heteroaryl(C≤12), −alkanediyl(C≤12)−heterocycloalkyl(C≤12), −alkanediyl(C≤12)−cycloalkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −hetero- arenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; and Yais oxo or thio; or a pharmaceutically acceptable salt thereof.

3. The compound of either claim 1 or claim 2, wherein the compound is further defined as:wherein: R1and R2are each independently hydrogen; oralkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X1is hydroxy or amino; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −heteroarenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), amido(C≤12), or a substituted version of any of these groups; or −C(O)R4, wherein R4is: hydrogen, hydroxy, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), cycloalkoxy(C≤8), alkenyloxy(C≤8), aryloxy(C≤8), aralkoxy(C≤8), heteroaryloxy(C≤8), acyloxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), heteroarylamino(C≤8), alkyl- sulfonylamino(C≤8), cycloalkylsulfonylamino(C≤8), alkoxyamino(C≤8), heterocycloalkylamino(C≤8), or a substituted version of any of these groups; or −NRaRb, wherein Ra and Rb are each independently hydrogen; oralkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), thioacyl(C≤12), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −C(Ya)R5, wherein R5is: alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −alkanediyl(C≤12)−aryl(C≤12), −alkanediyl(C≤12)−heteroaryl(C≤12), −alkanediyl(C≤12)−heterocycloalkyl(C≤12), −alkanediyl(C≤12)−cycloalkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −hetero- arenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; and Yais oxo or thio; or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1-3, wherein the compound is further defined as:wherein: R1and R2are each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X1 is hydroxy or amino; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −heteroarenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), amido(C≤12), or a substituted version of any of these groups; or −C(O)R4, wherein R4 is: amino, or mercapto; or alkylamino(C≤8), cycloalkylamino(C≤8), dialkyl- amino(C≤8), arylamino(C≤8), heteroarylamino(C≤8), alkylsulfonylamino(C≤8),cycloalkylsulfonylamino(C≤8), alkoxyamino(C≤8), heterocycloalkylamino(C≤8), or a substituted version of any of these groups; −NRaRb, wherein Raand Rbare each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), thioacyl(C≤12), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −C(Ya)R5, wherein R5 is: alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −alkanediyl(C≤12)−aryl(C≤12), −alkanediyl(C≤12)−heteroaryl(C≤12), −alkanediyl(C≤12)−heterocycloalkyl(C≤12), −alkanediyl(C≤12)−cycloalkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −hetero- arenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; and Ya is oxo or thio; or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1-4, wherein the compound is further defined as:wherein: R1and R2are each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X1is hydroxy or amino; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −heteroarenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), amido(C≤12), or a substituted version of any of these groups; or −C(O)R4, wherein R4is amino, or mercapto; or alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), heteroarylamino(C≤8), alkylsulfonyl- amino(C≤8), cycloalkylsulfonylamino(C≤8),alkoxyamino(C≤8), heterocycloalkylamino(C≤8), or a substituted version of any of these groups; or −NRaRb, wherein Raand Rbare each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), thioacyl(C≤12), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −C(Ya)R5, wherein R5 is: alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −arenediyl(C≤12)−aryl(C≤12), −arenediyl(C≤12)−heteroaryl(C≤12), −arenediyl(C≤12)−heterocycloalkyl(C≤12), −arenediyl(C≤12)−cycloalkyl(C≤12), −heteroarenediyl(C≤12)−aryl(C≤12), −heteroarenediyl(C≤12)−heteroaryl(C≤12), −heteroarenediyl(C≤12)−heterocycloalkyl(C≤12), −heteroarenediyl(C≤12)−cycloalkyl(C≤12), −heterocycloalkanediyl(C≤12)−aryl(C≤12), −heterocycloalkanediyl(C≤12)−heteroaryl(C≤12), or a substituted version of any of these groups; and Y2 is oxo or thio; or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1-5, wherein the compound is further defined as:wherein: R1 and R2 are each independently hydrogen; oralkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X2is −O−, −S−; or −NR7, wherein R7 is hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; Y is oxo or thio; Z is alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), −alkanediyl(C≤12)−aryl(C≤12), −alkanediyl(C≤12)−heteroaryl(C≤12), −alkanediyl(C≤12)−heterocycloalkyl(C≤12), −alkanediyl(C≤12)−cyclo- alkyl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

7. The compound of either claim 1 or claim 6, wherein the compound is further defined as:wherein: R1 and R2 are each independently hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups;R3is hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; Y is oxo or thio; X3 is −O− or −S−; or −NR8−, wherein R8is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X4 and X5 are each independently −O− or −S−; or −NR9−, wherein R9is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −CR10R11−, wherein R10 and R11 are each independently absent, hydroxy, halo, amino, cyano, mercapto, −NO2, or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1-7, wherein the compound is further defined as:wherein: R3 is hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; Y is oxo or thio; X3is −O− or −S−; or −NR8−, wherein R8 is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X4and X5are each independently −O− or −S−; or −NR9−, wherein R9 is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −CR10R11−, wherein R10and R11are each independently absent, hydroxy, halo, amino, cyano, mercapto, −NO2, or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C£8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12),arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of claims 1-8, wherein the compound is further defined as:wherein: R3 is hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X3is −O− or −S−; or −NR8−, wherein R8is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X4 and X5 are each independently −O− or −S−; or −NR9−, wherein R9is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −CR10R11−, wherein R10 and R11 are each independently absent, hydroxy, halo, amino, cyano, mercapto, −NO2, or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12),aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of claims 1-9, wherein the compound is further defined as:wherein: X3 is −O− or −S−; or −NR8−, wherein R8is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; X4 and X5 are each independently −O− or −S−; or −NR9−, wherein R9 is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; or −CR10R11−, wherein R10and R11are each independently absent, hydroxy, halo, amino, cyano, mercapto, −NO2, or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8),heteroaralkyl(C≤8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

11. The compound according to any one of claims 1-10, wherein the compound is further defined as:wherein: X6 is −O− or −S−; or −NR8−, wherein R8 is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups; R12is hydrogen, hydroxy, halo, amino, cyano, mercapto, or −NO2; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of claims 1-11, wherein the compound is further defined as:wherein: R12 is hydrogen, hydroxy, halo, amino, cyano, mercapto, or −NO2; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12), aralkyl(C£8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

13. The compound according to any one of claims 1-7, wherein R1and R2are each independently hydrogen, alkyl(C≤8), or substituted alkyl(C≤8).

14. The compound according to any one of claims 1-7, wherein R1and R2are each hydrogen.

15. The compound of claim 13, wherein R1or R2are alkyl(C≤8).

16. The compound of claim 15, wherein R1or R2are methyl or deuterated methyl.

17. The compound according to any one of claims 1-5, wherein X1is −heteroarenediyl(C≤12)−aryl(C≤12) or substituted −heteroarenediyl(C≤12)−aryl(C≤12).

18. The compound according to any one of claims 1-5, wherein X1 is substituted −heteroarenediyl(C≤12)−aryl(C≤12).

19. The compound according to any one of claims 1-5, wherein X1 is: −C(O)R4, wherein R4 is amino, or mercapto; or alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), heteroarylamino(C≤8), alkylsulfonylamino(C≤8),cycloalkylsulfonylamino(C≤8), alkoxyamino(C≤8), hetero- cycloalkylamino(C≤8), or a substituted version of any of these groups.

20. The compound of claim 19, wherein R4is heteroarylamino(C≤8)or substituted heteroarylamino(C≤8).

21. The compound of claim 20, wherein R4is or substituted heteroarylamino(C≤8).

22. The compound according to any one of claims 1-5, wherein Yais oxo.

23. The compound according to any one of claims 1-5, wherein Ya is thio.

24. The compound according to any one of claims 1-5, wherein R5 is heteroaryl(C≤12) or substituted heteroaryl(C≤12).

25. The compound according to any one of claims 1-5, wherein R5is substituted heteroaryl(C≤12).

26. The compound according to any one of claims 1-5, wherein R5is −heteroarenediyl(C≤12)−cycloalkyl(C≤12).

27. The compound according to any one of claims 7-9, and 13-16, wherein R3 is hydrogen or alkyl.

28. The compound of claim 6, wherein X2is −NR7, wherein R7is hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), hetero- aryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups.

29. The compound of claim 28, wherein R7 is hydrogen or alkyl(C≤8).

30. The compound of claim 28, wherein R7 is hydrogen.

31. The compound according to any one of claims 6-8, wherein Y is oxo.

32. The compound according to any one of claims 6-8, wherein Y is thio.

33. The compound according to any one of claims 7-9, wherein X3 is −O− or −S−.

34. The compound of claim 33, wherein X3is −O−.

35. The compound of claim 33, wherein X3is −S−.

36. The compound of claim 6, wherein Z is substituted alkyl(C≤8).

37. The compound according to any one of claims 7-9, wherein X3is −CR10R11−, wherein R10 and R11 are each independently absent, hydroxy, halo, amino, cyano, mercapto, −NO2, or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups.

38. The compound of claim 37, wherein R10is hydrogen.

39. The compound of claim 37, wherein R11is −NO2.

40. The compound of claim 37, wherein R11 is absent.

41. The compound of claim 37, wherein R11is cyano.

42. The compound of claim 37, wherein R11is acyl.

43. The compound of claim 37, wherein R11 is heterocycloalkyl(C≤8) or substituted heterocycloalkyl(C≤8).

44. The compound of claim 37, wherein R11 is heterocycloalkyl(C≤8).

45. The compound according to any one of claims 7-9, wherein X3 is −NR8−, wherein R8 is absent.

46. The compound according to any one of claims 7-9, wherein X4is −NR9−, wherein R9is absent or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), hetero- aryl(C≤8), heterocycloalkyl(C≤8), heteroaralkyl(C≤8), or a substituted version of any of these groups.

47. The compound of claim 46, wherein R9is hydrogen.

48. The compound according to any one of claims 7-9, wherein X5is −CR10R11−, wherein R10 and R11 are each independently absent, hydroxy, halo, amino, cyano, mercapto, −NO2, or hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), alkoxy(C≤12), amido(C≤12), acyl(C≤12), acyloxy(C≤12), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), heteroaralkyl(C≤8), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups.

49. The compound of claim 48, wherein R10 is hydrogen and R11 is absent.

50. The compound according to any one of claims 7-9, wherein X5 is −NR9−, wherein R9 is absent, hydrogen, or alkyl(C≤8).

51. The compound according to any one of claims 1-50, wherein the compound is further defined as:.

52. A pharmaceutical composition comprising: (a) a compound according to any one of claims 1-51; and (b) an excipient.

53. The pharmaceutical composition of claim 52, wherein the pharmaceutical composition is formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally,intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in crèmes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion.

54. The pharmaceutical composition of either claim 52 or claim 53, wherein the pharmaceutical composition is formulated as a unit dose.

56. A method of treating or preventing a disease or disorder in a patient in need thereof comprising administering to the patient a pharmaceutically effective amount of a compound or composition according to any one of claims 1-52.

57. The method of claim 53, wherein the disease or disorder is a disease or disorder associated with Staphylococcus aureus infection.

58. The method of either claim 56 or claim 57, wherein the patient is a mammal.

59. The method according to any one of claims 56-58, wherein the patient is a human.

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