PI4-kinase inhibitors and methods of using the same

Abstract

To provide compounds and methods for inhibiting a PI4-kinase.SOLUTION: There are also provided methods of treating a pathogen infection and methods of treating cancer. The PI4-kinase inhibitor can be a compound that is a 5-aryl or heteroaryl-thiazole, e.g., as described herein. In certain embodiments, the PI4-kinase inhibitor is a substituted 2-amino-5-phenylthiazole or substituted 2-amino-5-pyridylthiazole compound. In some embodiments, the compounds have broad spectrum anti-infective activity against a variety of infective diseases, where the diseases are caused by pathogens containing a basic amino acid PIP-2 pincer (BAAPP) domain that interacts with phosphatidylinositol 4,5-bisphosphate (PIP-2) to mediate pathogen replication. There are also provided methods of treating a subject for cancer using a PI4-kinase inhibitor. Aspects of the methods include inhibiting PI4-kinase in a cancer cell to reduce cellular proliferation.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS Pursuant to 35 U.S.C. §119(e), this application claims priority to the filing date of U.S. Provisional Patent Application No. 62 / 821,853, filed March 21, 2019, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Government Rights This invention was made with government support under contract (AI109662) awarded by the National Institute of Allergy and Infectious Diseases. The government has certain rights in this invention.

[0003] Introduction There are no adequate treatments for many infectious diseases. The rapid increase in the number of emerging pathogens in the world's population represents a serious global health problem, highlighting the need to develop broad-spectrum anti-infective drugs that target common components of large classes of pathogens. Human rhinoviruses (HRVs) cause more than half of all cold-like illnesses, costing billions of dollars annually in hospital visits and absenteeism. Hepatitis C virus (HCV), a member of the Flaviviridae family, is responsible for C-type pneumonia and several cancers, including liver cancer (hepatocellular carcinoma, or HCC) and lymphomas in humans. It is estimated that more than 2% of the world's population is currently infected with HCV. Enteroviruses belong to the Picornaviridae family, a large and diverse group of small RNA viruses. Enterovirus infections vary in symptoms and severity, ranging from rashes in young children to summer colds, encephalitis, blurred vision, and pericarditis. Non-polioenteroviruses are responsible for 10 to 15 million infections and tens of thousands of hospitalizations in the United States.

[0004] Many cancers depend on PI4-kinase for growth and metastasis. In many cases, this is reflected in tumors' "addiction" to PI4-kinase activity. Among the methods by which this can be readily identified is the presence of increased PI4-kinase activity in target cancer cells. This increased activity can be measured directly or reliably predicted by the presence of increased levels of factors known to enhance PI4-kinase activity (e.g., eukaryotic protein translation elongation factor 1 alpha 2 (eEF1A2)) or chromosomal amplifications that increase the gene copy number for PI4-kinase. For example, elevated levels of eEF1A2 protein and mRNA can be detected in 30-60% of tumors, particularly those of the ovary, breast, and lung. Similarly, PI4-kinase amplification is readily detected in a significant proportion of most human tumor types (see The Cancer Genome Atlas (TCGA), available at cbioportal.org). Other cancer cells are also more sensitive to selective PI4-kinase inhibition compared to normal cells. Therefore, pharmacological inhibitors of PI-4-kinase useful in the treatment of human cancers, including cancers and / or their metastases, are of interest. Summary of the Invention

[0005] Compounds and methods for inhibiting PI4-kinase are provided. Methods for treating pathogen infections and methods for treating cancer are also provided. PI4-kinase inhibitors can be compounds that are certain 5-aryl or heteroaryl thiazoles, for example, as described herein. In certain embodiments, the PI4-kinase inhibitor is a substituted 2-amino-5-phenylthiazole or substituted 2-amino-5-pyridylthiazole compound.

[0006] Embodiments of the method include treating pathogen infections, including, but not limited to, viruses and other pathogens that utilize intracellular replication mechanisms, such as hepatitis C virus (HCV), Plasmodium falciparum, rhinovirus, etc. The anti-infectious compound has broad-spectrum activity against a variety of infectious diseases caused by pathogens that contain a basic amino acid PIP2 pincer (BAAPP) domain that interacts with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) to mediate replication, or that are otherwise dependent on PI4-phosphate.

[0007] Embodiments of the method include inhibiting PI4-kinase and inhibiting viral infection in a subject. The subject compounds may be formulated or provided to a subject in combination with one or more additional anti-infective agents (e.g., interferon, ribavirin). The subject compounds have been used to treat a variety of viruses, such as those from the Picornaviridae, Flaviviridae, Caliciviridae, Filoviridae, Hepeviridae, or Coronaviridae families. For the treatment of viruses such as HCV, the compounds may be formulated as prodrugs designed to specifically target the liver, for example, by conjugation with polyarginine or bile acids, or to be activated by enzymes present in the liver.

[0008] Also provided are methods for treating cancer in a subject using a PI4-kinase inhibitor. Aspects of the method include inhibiting PI4-kinase in cancer cells to suppress cell proliferation. The subject compounds may be formulated or provided to a subject in combination with one or more additional anti-cancer agents. The use of PI4-kinase inhibitors in methods of suppressing cell proliferation and treatment methods is provided for a variety of cancer cells and subjects suffering from cancer.

[0009] These and further advantages and features of the present disclosure will become apparent to those skilled in the art upon reading the details of the compositions and methods of use set forth below. [Brief explanation of the drawings]

[0010] [Figure 1A]Intracellular PI4P concentrations in H2122 lung cancer cells treated with Compound B (a PI4-kinase inhibitor) or vehicle DMSO. [Figure 1B] Left panel: Relative density of PI4KIIIβ-amplified (red) and -diploid (black) human lung adenocarcinoma cell lines by WST-1 assay after 5 days of Compound B treatment. Results are expressed relative to the lowest dose, which was set at 100%. Right panel: Half-maximal inhibitory (IC50) concentration of Compound B determined from the left panel data. [Figure 1C] Migrating and invading H23 human lung cancer cells in transwell chambers were photographed (images) and counted (bar graphs) after treatment with compound B. Results were expressed as relative values ​​to DMSO-treated cells, which was set at 1.0. [Figure 1D] Colonies formed by H2122 human lung cancer cells in soft agar (Figure 1D) and on plastic (Figure 1E) were photographed (images) and counted (bar graphs) 7 days after treatment with the indicated doses of Compound B or vehicle DMSO (0 μM). Results were expressed relative to the DMSO control, which was set at 1.0. [Figure 1E] Colonies formed by H2122 human lung cancer cells in soft agar (Figure 1D) and on plastic (Figure 1E) were photographed (images) and counted (bar graphs) 7 days after treatment with the indicated doses of Compound B or vehicle DMSO (0 μM). Results were expressed relative to the DMSO control, which was set at 1.0. [Figure 1F] Summary of Compound B treatment: Day 0, H2122 human lung cancer cell injection; Days 7-27, Compound B treatment; Day 26 tumor imaging and Day 27 necropsy. (Fig. 1F) Mice were subjected to micro-computed tomography 19 days after treatment to determine tumor area (left dot plot). Tumor diameter determined at necropsy (right dot plot). (Fig. 1G) Mice grouped based on lung tumor measurements determined at necropsy showed a shift toward smaller tumor diameters in Compound B-treated mice. [Figure 1G]Summary of Compound B treatment: Day 0, H2122 human lung cancer cell injection; Days 7-27, Compound B treatment; Day 26 tumor imaging and Day 27 necropsy. (Fig. 1F) Mice were subjected to micro-computed tomography 19 days after treatment to determine tumor area (left dot plot). Tumor diameter determined at necropsy (right dot plot). (Fig. 1G) Mice grouped based on lung tumor measurements determined at necropsy showed a shift toward smaller tumor diameters in Compound B-treated mice. [Figure 2A] Summary of Compound A treatment: Day 0, H2122 human lung cancer cell injection; Days 7-15, Compound A treatment; Day 14, tumor imaging, and Day 15, necropsy. (Figure 2A) Body weight change of mice after 8 days of treatment with vehicle (left panel) or vehicle plus 100 mg / kg / bid IP Compound A (right panel). (Figure 2B) Mice were subjected to micro-computed tomography (MCT) scans before and after treatment to determine tumor area after 7 days of treatment with vehicle or vehicle plus 100 mg / kg / bid IP Compound A. Left panel: Tumor area measured before and after treatment. Right panel: Tumor area expressed as a percentage of baseline measurement. (Figure 2C) Tumor diameter (left panel) and number of tumor metastases (right panel) determined at necropsy. [Figure 2B] Summary of Compound A treatment: Day 0, H2122 human lung cancer cell injection; Days 7-15, Compound A treatment; Day 14, tumor imaging, and Day 15, necropsy. (Figure 2A) Body weight change of mice after 8 days of treatment with vehicle (left panel) or vehicle plus 100 mg / kg / bid IP Compound A (right panel). (Figure 2B) Mice were subjected to micro-computed tomography (MCT) scans before and after treatment to determine tumor area after 7 days of treatment with vehicle or vehicle plus 100 mg / kg / bid IP Compound A. Left panel: Tumor area measured before and after treatment. Right panel: Tumor area expressed as a percentage of baseline measurement. (Figure 2C) Tumor diameter (left panel) and number of tumor metastases (right panel) determined at necropsy. [Figure 2C]Summary of Compound A treatment: Day 0, H2122 human lung cancer cell injection; Days 7-15, Compound A treatment; Day 14, tumor imaging, and Day 15, necropsy. (Figure 2A) Body weight change of mice after 8 days of treatment with vehicle (left panel) or vehicle plus 100 mg / kg / bid IP Compound A (right panel). (Figure 2B) Mice were subjected to micro-computed tomography (MCT) scans before and after treatment to determine tumor area after 7 days of treatment with vehicle or vehicle plus 100 mg / kg / bid IP Compound A. Left panel: Tumor area measured before and after treatment. Right panel: Tumor area expressed as a percentage of baseline measurement. (Figure 2C) Tumor diameter (left panel) and number of tumor metastases (right panel) determined at necropsy. [Figure 3] Breast tumors were formed by injecting human MDA-MB-468 cells into the mammary fat pads of nude mice. After tumor formation, the mice were treated with an exemplary 5-arylthiazole compound (Compound A). [Figure 4] Figure 1 shows the survival of 4-week-old AG129 mice exposed to EV-71 virus and treated with exemplary Compound B. Groups of eight AG129 mice were exposed to EV-71 virus at 10 CCID / mouse via the i.p. route. Mice were treated with the indicated dose of Compound B orally twice daily (bid) for 5 days, starting 4 hours post-infection. Mice in the placebo-treated group received vehicle control on the same schedule. As a positive control, mice treated with IVIg received a single dose of 100 mg / kg via the i.p. route 4 hours post-infection. A dose-response was observed in survival after treatment with Compound B. Kaplan-Meier survival curves were generated and compared by log-rank (Mantel-Cox) test followed by pairwise comparisons using the Gehan-Breslow-Wilcoxon test in Prism 7.0c (GraphPad Software Inc., La Jolla, CA). (*P<0.05, **P<0.01). DETAILED DESCRIPTION OF THE INVENTION

[0011] As summarized above, compounds and methods are provided for inhibiting PI4-kinase. Methods for treating pathogen infections and methods for treating cancer are also provided. The PI4-kinase inhibitor can be a compound that is a 5-aryl or heteroaryl thiazole, for example, as described herein. In certain embodiments, the PI4-kinase inhibitor is a substituted 2-amino-5-phenylthiazole or substituted 2-amino-5-pyridylthiazole compound.

[0012] In some embodiments, the PI4-kinase inhibitor compounds have broad-spectrum activity against a variety of infectious diseases caused by pathogens that contain a basic amino acid PIP-2 pincer (BAAPP) domain that interacts with phosphatidylinositol 4,5-bisphosphate (PIP-2) to mediate replication, or that are otherwise dependent on PIP4 and thus sensitive to PI4-kinase. In certain instances, the compounds have activity against one or more viruses selected from the Picornaviridae, Flaviviridae, Caliciviridae, Filoviridae, Hepeviridae, Togaviridae, Papovaviridae, Papillomaviridae, Polyomaviridae, Retroviridae, and Coronaviridae families.

[0013] In some embodiments, a PI4-kinase inhibitor compound that inhibits PI4-kinase is contacted with a pathogen at a dose and for a duration sufficient to inhibit replication. Contacting can be performed in vitro or in vivo. Such a PI4-kinase inhibitor compound can inhibit pathogen replication by inhibiting the production of PIP-2.

[0014] In some embodiments, the PI4-kinase inhibitor compounds have broad-spectrum activity against a variety of cancers. In some embodiments, the compounds inhibit PI4-kinase in cancer cells to inhibit cell proliferation. The subject compounds may be formulated or provided to a subject in combination with one or more additional anti-cancer agents. Use of PI4-kinase inhibitors in methods of inhibiting cell proliferation and in methods of treatment is provided for a variety of cancer cells and subjects with cancer.

[0015] In some embodiments, methods are provided for inhibiting PI4-kinases, including but not limited to Class III PI4-kinases, wherein a compound of the present invention is contacted with a PI4-kinase at a dosage and for a duration sufficient to inhibit the activity of the enzyme.

[0016] Also provided are pharmaceutical compositions comprising the subject compounds of the present disclosure, which can be formulated with a pharmaceutically acceptable excipient. The formulations can be provided in unit doses, where the dose provides an effective amount of the compound to achieve the desired result, including but not limited to, inhibiting pathogen replication. These compounds and methods find use in a variety of applications in which inhibition of PI-kinases is desired. [Compound]

[0017] Aspects of the present disclosure include certain PI4-kinase inhibitor compounds. Generally, the compounds comprise a 5-aryl or 5-heteroaryl thiazole core structure. The 5-aryl or 5-heteroaryl ring can be a 6-membered heteroaryl (e.g., pyridyl) or phenyl ring containing at least one additional meta-substituent on the thiazole ring substituent. The thiazole ring of the core structure can contain additional substituents at the 2- and / or 4-positions of the ring. In some embodiments, the PI4-kinase inhibitor compound is a 2-amino-5-phenylthiazole compound containing a thiazole ring bearing an amino substituent at the 2-position of the ring and a phenyl substituent at the 5-position of the ring. In some embodiments, the PI4-kinase inhibitor compound is a 2-amino-5-pyridyl-thiazole compound containing a thiazole ring bearing an amino substituent at the 2-position of the ring and a pyridyl substituent at the 5-position of the ring. In some embodiments, the amino substituent at the 2-position of the ring can be further substituted with any convenient substituent, including, but not limited to, —C(CH3)2R, —CyR. wherein R is alkyl, heteroalkyl, heterocycle, or aryl; and Cy is a cyclic group such as cycloalkyl, heterocycle, aryl, or heteroaryl; and either group R or Cy can be optionally substituted. In some embodiments, the compounds include additional substituents, such as a substituent at either the 4- or 5-position of the thiazole ring. The aryl ring of the core structure (e.g., a 5-phenyl or pyridyl ring) can be further substituted with any convenient substituent, including, but not limited to, alkyl, acyloxy, aminoalkoxy, cyano, halogen, hydroxyl, nitro, —NHCOR, —SONHR, —CONHR, or NHSOR. Wherein R is alkyl, heteroalkyl, heterocycle, or aryl. Exemplary compounds are shown in the following structures and formulas:

[0018] In some cases, the subject compounds are described by the structure of formula (Ia): [ka] where: Z 1 is a covalent bond or linking functional group. R is H, alkyl, or alkyl (e.g., lower alkyl such as methyl). Y 1 is CR 22 Or N. Y 2 is S, O or NR 19 where R is selected from 19 is selected from hydrogen, alkyl, and substituted alkyl. R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle. R 3 is selected from hydrogen, lower alkyl and substituted lower alkyl. R 4 and R 5 are each independently selected from lower alkyl and substituted lower alkyl; or R 4 and R 5 together with the carbons to which they are attached form a cyclic group selected from cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. R 6 is selected from substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; or R 4 , R 5 and R 6 together with the carbons to which they are attached, provide a bridged cyclic group selected from a bridged cycloalkyl, a substituted bridged cycloalkyl, a bridged heterocycle, and a substituted bridged heterocycle. R 20 , R 21 and R 22 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, hydroxy, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heterocycle, substituted heterocycle, cyano, halogen, amino, substituted amino, acyl, acyloxy, amido, and nitro.

[0019] In some cases, the subject compounds are described by the structure of formula (Ib): [ka] where: Z 1 is a covalent bond or linking functional group. R is H, alkyl, or alkyl (e.g., lower alkyl such as methyl). Y 1’ and Y 1 are each independently CR 20 Or N. Y 2 is S, O or NR 19 where R is selected from 19 is selected from hydrogen, alkyl, and substituted alkyl. R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle. R 3 is selected from hydrogen, lower alkyl and substituted lower alkyl. R 4 and R 5 are each independently selected from lower alkyl and substituted lower alkyl; or R 4 and R 5 together with the carbons to which they are attached form a cyclic group selected from cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. R 6 is selected from substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; or R 4 , R 5 and R 6together with the carbons to which they are attached, provide a bridged cyclic group selected from a bridged cycloalkyl, a substituted bridged cycloalkyl, a bridged heterocycle, and a substituted bridged heterocycle. R 20 , R 21 and R 22 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, hydroxy, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, heterocycle, substituted heterocycle, cyano, halogen, amino, substituted amino, acyl, acyloxy, amido, and nitro. In certain embodiments, in formula (Ia) or (Ib), R, R 1 , R 3 , R 4 , R 5 , R 6 , R 19 , R 20 , R 21 , R 22 are independently selected from the corresponding groups as shown in any of the structures in Tables 1, 2, or 3.

[0020] In some embodiments, in Formula (Ib), the compound may be a compound having Y 1’ is CH and Y 1” is CR 20 is. [ka] where: Z 1 is a covalent bond or linking functional group. R is H, alkyl, or alkyl (e.g., lower alkyl such as methyl). Y 2 is S, O or NR 19 where R is selected from 19 is selected from hydrogen, alkyl, and substituted alkyl. R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle. R 20 is selected from hydrogen, halogen, alkyl, substituted alkyl, alkoxy, and substituted alkoxy. R 3 is selected from hydrogen and alkyl. R 4 and R 5 are each independently selected from lower alkyl and substituted lower alkyl; or R 4 and R 5 together with the carbons to which they are attached form a cyclic group selected from cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. R 6 is selected from substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; or R 4 , R 5 and R 6 together with the carbons to which they are attached, provide a bridged cyclic group selected from a bridged cycloalkyl, a substituted bridged cycloalkyl, a bridged heterocycle, and a substituted bridged heterocycle. R 21 and R 22 are independently selected from hydrogen, alkyl, aryl, hydroxy, alkoxy, aryloxy, heterocycle, cyano, halogen, amino, acyl, acyloxy, amido, and nitro. In certain embodiments, R 20 is selected from hydrogen, halogen, and alkoxy. 2 is selected from hydrogen, halogen, alkyl, substituted alkyl, and alkoxy. 2 is selected from lower alkyl, halogen, substituted lower alkyl, and lower alkoxy. In certain embodiments, R 2 is selected from Me, Cl, Br, CHF2, CF3, CH2F and OMe. In some embodiments, R 3 and R 22is selected to form a six-membered ring as part of the fused tricyclic arylthiazole core structure.

[0021] In some embodiments, the subject compounds are described by the structure of formula (Id): [ka] where: W 1 is a covalent bond or linking functional group. Y 2 is S, O or NR 19 where R is selected from 19 is selected from hydrogen, alkyl, and substituted alkyl. R 1 is selected from substituted alkyl (e.g., halogenated alkyl, or heterocycle-substituted lower alkyl), aryl (e.g., phenyl), substituted aryl, heteroaryl (e.g., pyridine), substituted heteroaryl, heterocycle (e.g., pyridyl, pyrimidinyl), and substituted heterocycle. R 20 is selected from hydrogen, halogen, alkyl, substituted alkyl, alkoxy, and substituted alkoxy. R 3 and each R is independently selected from hydrogen and alkyl (e.g., lower alkyl such as methyl). R 4 and R 5 are each independently selected from lower alkyl and substituted lower alkyl; or R 4 and R 5 together with the carbons to which they are attached form a cyclic group selected from cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. R 6 is selected from substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; or R 4 , R 5 and R 6together with the carbons to which they are attached, provide a bridged cyclic group selected from a bridged cycloalkyl, a substituted bridged cycloalkyl, a bridged heterocycle, and a substituted bridged heterocycle. R 21 and R 22 are independently selected from hydrogen, alkyl, aryl, hydroxy, alkoxy, aryloxy, heterocycle, cyano, halogen, amino, acyl, acyloxy, amido, and nitro. In certain embodiments of any one of formulas (Ia), (Ib), (Ic), or (Id), Y 2 is S. In certain embodiments, Y 2 is O. In certain embodiments, Y 2 is NR 19 where R 19 is selected from hydrogen, alkyl, and substituted alkyl. In certain cases, R 19 is hydrogen.

[0022] In certain embodiments, the subject compounds are described by the structure of formula (Ie): [ka] where: W 1 is a covalent bond or linking functional group. R 1 is selected from substituted alkyl (e.g., halogenated alkyl, or heterocycle-substituted lower alkyl), aryl (e.g., phenyl), substituted aryl, heteroaryl (e.g., pyridine), substituted heteroaryl, heterocycle (e.g., pyridyl, pyrimidinyl), and substituted heterocycle. R 20 is selected from hydrogen, halogen, alkyl, substituted alkyl, alkoxy, and substituted alkoxy. R 3 and each R is independently selected from hydrogen and alkyl (e.g., lower alkyl such as methyl). R 4 and R 5 are each independently selected from lower alkyl and substituted lower alkyl; or R 4 and R5 together with the carbons to which they are attached form a cyclic group selected from cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. R 6 is selected from substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; or R 4 , R 5 and R 6 together with the carbons to which they are attached, provide a bridged cyclic group selected from a bridged cycloalkyl, a substituted bridged cycloalkyl, a bridged heterocycle, and a substituted bridged heterocycle. R 21 and R 22 are independently selected from hydrogen, alkyl, aryl, hydroxy, alkoxy, aryloxy, heterocycle, cyano, halogen, amino, acyl, acyloxy, amido, and nitro. In certain embodiments of any one of formulas (Ia), (Ib), (Ic), (Id), or (Ie), R 20 is selected from hydrogen, halogen, and alkoxy. In certain embodiments, R 20 is selected from hydrogen, halogen, alkyl, substituted alkyl, and alkoxy. 20 is selected from lower alkyl, halogen, substituted lower alkyl, and lower alkoxy. In certain embodiments, R 20 is selected from Me, Cl, Br, CHF2, CF3, CH2F and OMe. In certain embodiments of any one of formulas (Ia), (Ib), (Ic), (Id), or (Ie), R 20 In certain embodiments of any one of formulas (Ia), (Ib), (Ic), (Id), or (Ie), R 3 is methyl. In certain embodiments, in formula (Ia), (Ib), (Ic), (Id), or (Ie), R 1 , R 3 , R 4, R 5 , R 6 and R 20 are independently selected from the corresponding groups as shown in any of the structures in Tables 1, 2, or 3.

[0023] In any of the formulas described herein, the linking functional group can be any convenient divalent group. Linking functional groups of interest include, but are not limited to, amino, amide, ester, carbonyloxy, ether, carbamate, sulfonamide, carbonyl, sulfonyl, sulfinyl, and the like. In some embodiments, the linking functional group is described by one of the following formulas: -SONR-, -NR-, -NRC(=O)-, or NRC(=O)NR-, where each R is independently H, alkyl, cycloalkyl, heterocycle, heterocycloalkyl, aryl, or heteroaryl; -O-; -C(=O)-; -C(=O)X-, where X is NR, O, or S, and R is H or alkyl; -S(=O)- or SO-; it is understood that for each of the formulas depicted herein, both possible orientations of the functional group are included. In some embodiments, in formulas (Ia)-(Ic), Z 1 is —SO 2 NH— or CONH—. In some embodiments, in formula (Id) or (Ie), W 1 is -SO2-.

[0024] In certain embodiments, the subject compounds are described by the structure of formula (I): [ka] Here, Y 1 is selected from CH or N. Y 2 is S, O or NR 19 where R is selected from 19 is selected from hydrogen, alkyl, and substituted alkyl. R 1is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle. R 2 is selected from alkoxy and substituted alkoxy. R 3 is selected from hydrogen, lower alkyl and substituted lower alkyl. R 4 and R 5 are each independently selected from lower alkyl and substituted lower alkyl; or R 4 and R 5 together with the carbons to which they are attached form a cyclic group selected from cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. R 6 is selected from substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; or R 4 , R 5 and R 6 taken together with the carbons to which they are attached, provide a bridged cyclic group selected from a bridged cycloalkyl, a substituted bridged cycloalkyl, a bridged heterocycle, and a substituted bridged heterocycle. In certain embodiments of Formula (I), Y2 is S. In certain embodiments, Y 2 is O. In certain embodiments, Y 2 is NR 19 where R 19 is selected from hydrogen, alkyl, and substituted alkyl. In certain cases, R 19 is hydrogen.

[0025] In certain embodiments, formula (I) is of formula (If): [ka]

[0026] In certain embodiments, formula (I) is of formula (Ig): [ka] In some embodiments of formula (I), (If), or (Ig), R 2 is alkoxy. In some cases, R 2 is methoxy. In other cases, R 2 is a substituted alkoxy. In certain embodiments, in formula (I), (If), or (Ig), R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the corresponding groups as shown in any of the structures in Tables 1, 2, or 3. In certain embodiments of formula (I), (If), or (Ig), R 3 is lower alkyl, such as methyl, ethyl, propyl, pentyl, hexyl, etc. In some cases, R 3 is methyl. In other cases, R 3 is a substituted lower alkyl (e.g., a halogenated alkyl). In some embodiments, in formula (I), (If), or (Ig), R 2 In some embodiments, in Formula (Id) or (Ie), R 3 is methyl. In some embodiments, R 1 is not a hydroxy-substituted alkyl group such as -(CH2)2-OH. In some embodiments, R 1 is selected from alkyl, aryl (e.g., phenyl), alkyl heterocycle, and heterocycle (e.g., pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl, indolyl, furyl, imidazolyl, oxazolyl, thiazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidino, morpholino, piperazino, piperidino, tetrahydrofuran). In some embodiments, R 1is selected from substituted lower alkyl (eg, substituted methyl or ethyl), phenyl, cycloalkyl, pyridyl, and pyrimidinyl.

[0027] In some embodiments, none of the formulas described herein is: [ka] [ka] or [ka] If not, a bridged cyclic group selected from a bridged cycloalkyl, a substituted bridged cycloalkyl, a bridged heterocycle, and a substituted bridged heterocycle, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, is provided.

[0028] In the case of any one of formulas (I) to (Ig), R 4 and R 5 are each lower alkyl (e.g., methyl, ethyl, propyl, pentyl, hexyl). In some cases, R 4 and R 5 are each methyl. In certain cases, R 4 and R 5 together with the carbons to which they are attached form a cyclic group. In certain cases, R 4 and R 5 together with the carbon to which they are attached form a cyclopropyl group. In certain cases, R 4 , R 5 and R 6 can be expressed by the following formula: [ka] or [ka] where: R 6is selected from substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; and Ring C is selected from cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl.

[0029] In certain cases, R 4 , R 5 and R 6 can be expressed by the following formula: [ka] where: R 6 is selected from substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl. R 23 is one or more optional substituents selected from lower alkyl, halogen, substituted lower alkyl, and lower alkoxy (e.g., Me, Cl, Br, CHF, CF, CHF, and OMe); and s is 1, 2, 3 or 4. In some embodiments of formula (IA3), any carbon atom in the cycle can be replaced with a heteroatom (e.g., N, S, or O) if the structure is globally feasible. In certain cases, any number of R can be replaced if the structure is sterically practical. 23 In certain embodiments, R 23 There are no substituents. In certain cases, the cycle of formula (IA3) is a cyclopropyl group.

[0030] In one particular case of any of formulas (I) to (Ig), R 4 , R 5 and R 6together with the carbons to which they are attached provide a bridged cyclic group selected from bridged cycloalkyl, substituted bridged cycloalkyl, bridged heterocycle, and substituted bridged heterocycle. 4 , R 5 and R 6 can be expressed by the following formula: [ka]

[0031] In some cases of any one of formulas (I) to (Ig), R 6 is a substituted alkyl. In some cases, R 6 is the formula -(CH2) n -X 1 where n is 1, 2, or 3, and X 1 is hydroxyl, halogen, alkyl halide (e.g., CF), aryl (e.g., phenyl), or heterocycle (e.g., pyridyl (e.g., 3-pyridyl), pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl, indolyl, furyl, imidazolyl, oxazolyl, thiazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidino, morpholino, piperazino, piperidino, tetrahydrofuran). In some cases, R 6 is a cycloalkyl or heterocycle (e.g., a 5- or 6-membered saturated N-containing ring). 6 is selected from cyclohexyl, cyclopentyl, cyclopropyl, pyrrolidinyl, piperidinyl, tetrahydrofuran, phenyl, and pyridinyl. 6 can be represented by ring A (e.g., as described herein).

[0032] In some embodiments of any one of formulas (I) through (Ig), R 1 is the formula -(CH2) n -X 1 where n is 0, 1, 2, or 3, and X 1is lower alkyl (e.g., methyl), hydroxyl, halogen, alkyl halide, aryl (e.g., phenyl), or heterocycle (e.g., pyridyl (e.g., 3-pyridyl), pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl, indolyl, furyl, imidazolyl, oxazolyl, thiazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidino, morpholino, piperazino, piperidino, tetrahydrofuran). In some cases, R 1 can be represented by ring B (e.g., as described herein).

[0033] In some embodiments, the subject compounds are described by the structure of formula (II): [ka] Here, Ring A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle; and Ring B is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle. In certain embodiments, formula (II) is of formula (IV): [ka] In certain embodiments, formula (II) is of formula (V): [ka] In certain embodiments, in formula (II), (IV), or (V), R 2 , R 3 , R 4 , R 5 , Ring A and Ring B are independently selected from the corresponding groups as shown in any of the structures in Tables 1, 2, or 3.

[0034] In certain embodiments of formula (II), (IV), or (V), R 3is lower alkyl, such as methyl, ethyl, propyl, pentyl, or hexyl. 3 is methyl. In other cases, R 3 is a substituted lower alkyl (e.g., a halogenated alkyl). In some embodiments, in formula (II), (IV), or (V), R 2 In some embodiments, in formula (II), (IV), or (V), R 3 is methyl.

[0035] In any one of formulas (II), (IV) or (V), R 4 and R 5 are each lower alkyl (e.g., methyl, ethyl, propyl, pentyl, hexyl). In some cases, R 4 and R 5 are each methyl. In certain cases, R4 and R5, together with the carbon to which they are attached, form a cyclic group. In certain cases, R4 and R5, together with the carbon to which they are attached, form a cyclopropyl group. In certain cases, R 4 , R 5 and R 6 can be expressed by the following formula: [ka] or [ka] where: Ring C is selected from cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl. In certain cases, R 4 and R 5 can be expressed by the following formula: [ka] where: R 23is one or more optional substituents selected from lower alkyl, halogen, substituted lower alkyl, and lower alkoxy (e.g., Me, Cl, Br, CHF, CF, CHF, and OMe); and s is 1, 2, 3 or 4.

[0036] In some embodiments of formula (IIIC3), any carbon atom in the cycle can be replaced with a heteroatom (e.g., N, S, or O) if the structure is globally feasible. In certain cases, any number of R can be replaced if the structure is sterically practical. 23 In certain embodiments, R 23 There are no substituents. In certain cases, the cycle of formula (IIIC3) is a cyclopropyl group.

[0037] In some embodiments, the A ring is selected from aryl (e.g., phenyl), optionally containing one or more substituents. In some embodiments, the A ring is selected from heteroaryl or heterocycle (e.g., pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl, indolyl, furyl, imidazolyl, oxazolyl, thiazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidino, molforno, piperazino, piperidino, tetrahydrofuran), optionally containing one or more substituents. In some embodiments, the A ring is selected from cycloalkyl (e.g., cyclohexane, cyclopentane), optionally containing one or more substituents. In some embodiments, the A ring is selected from phenyl, substituted phenyl, pyridyl, substituted pyridyl, 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, substituted 6-pyrimidinyl, piperidine, substituted piperidine, piperazine, substituted piperidine, 2-oxopiperidine, 2-oxopiperazine, imidazole, substituted imidazole, thiazole, substituted thiazole, oxazole, substituted oxazole, tetrahydropyran, substituted tetrahydropyran, morpholine, substituted morpholine, cyclic sulfone, substituted cyclic sulfone, cycloalkyl, and substituted cycloalkyl.

[0038] In other embodiments, the A ring is described by formula (A1). [ka] where A1 is a 6-membered aryl, heteroaryl, heterocyclyl, or cycloalkyl; Z 1 -Z 6 are N, O, CR 11 , N.R. 11 , C.R. 11 2, SO2, and CO, and R is selected independently from the group consisting of 2, SO2, and CO, and R is selected ... 11 are each independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, halogen, acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamido, and substituted sulfonamido. 2 and Z 3 , or Z 3 and Z 4 , or Z 4 and Z 11 , or Z 11 and Z 6 is CR 11 where each R 11

[0023] Together with the carbons to which they are attached, form a 5- or 6-membered cyclic group selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, and substituted cycloalkyl. In certain cases, A1 is indole or substituted indole. In some cases, A1 is phenyl or substituted phenyl. In some cases, A1 is cycloalkyl or substituted cycloalkyl. In some cases, A1 is pyridyl or substituted pyridyl. In some cases, A1 is pyrimidinyl, such as 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, or substituted 6-pyrimidinyl. In some cases, A1 is pyridazine or substituted pyridazine. In some cases, A1 is triazine or substituted triazine. In some cases, A1 is piperidine or substituted piperidine. In some cases, A1 is piperazine or substituted piperazine. In some cases, A1 is 2-oxopiperidine or a substituted 2-oxopiperidine. In some cases, A1 is 2-oxopiperazine or a substituted 2-oxopiperazine. In some cases, A1 is tetrahydropyran or a substituted tetrahydropyran. In some cases, A1 is pyran or a substituted pyran. In some cases, A1 is morpholine or a substituted morpholine. In some cases, A1 is a cyclic sulfone or a substituted cyclic sulfone.

[0039] In some embodiments, the A ring is described by formula (B2). [ka] where: R10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. n is an integer from 0 to 5.

[0040] In certain cases, B2 is phenyl. In certain cases, B2 is monosubstituted phenyl. In certain cases, B2 is disubstituted phenyl. In certain cases, B2 is trisubstituted phenyl. In certain cases, B2 is tetrasubstituted phenyl. In certain cases, B2 is pentasubstituted aryl. In certain cases, the substituents are selected from lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl) and halogen (e.g., F, Cl, I, or Br). In certain embodiments, B2 is 2,6-disubstituted phenyl, and the substituents are independently selected from halogen and lower alkyl.

[0041] In some embodiments of the A ring, the B2 ring is described by formula (B2a). [ka] In some embodiments, the A ring is described by formula (B3). [ka] where: R 10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. Y 3 N and CR 11 where R is selected from 11 is hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. and m is an integer from 0 to 3.

[0042] In certain cases, B3 is pyridyl. In certain cases, B3 is substituted pyridyl. In some cases, the pyridyl is monosubstituted pyridyl. In other cases, the pyridyl is disubstituted pyridyl. In other cases, the pyridyl is trisubstituted pyridyl. In other cases, the pyridyl is tetrasubstituted pyridyl. In certain cases, Y 3 is N and B3 is pyrimidyl. In some cases, B3 is substituted pyrimidyl. In some cases, the pyrimidyl is monosubstituted. In some cases, the pyrimidyl is disubstituted. In other cases, the pyrimidyl is trisubstituted. In certain embodiments of B3, the substituents are selected from lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl) and halogen (e.g., F, Cl, I, or Br).

[0043] In some embodiments, the A ring is described by formula (B4). [ka] where: R 10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. Y 3 N and CR 11 where R is selected from 11 is hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. and m is an integer from 0 to 3.

[0044] In certain cases, B4 is pyridyl. In certain cases, B4 is substituted pyridyl. In some cases, the pyridyl is monosubstituted pyridyl. In other cases, the pyridyl is disubstituted pyridyl. In other cases, the pyridyl is trisubstituted pyridyl. In other cases, the pyridyl is tetrasubstituted pyridyl. In certain cases, Y 3is N and B4 is pyrimidyl. In some cases, B4 is substituted pyrimidyl. In some cases, the pyrimidyl is monosubstituted. In some cases, the pyrimidyl is disubstituted. In other cases, the pyrimidyl is trisubstituted. In certain embodiments of B4, the substituents are selected from lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl), trifluoromethyl, and halogen (e.g., F, Cl, I, or Br). In some cases, B4 is monosubstituted pyridyl and the substituents are selected from lower alkyl (e.g., methyl) and trifluoromethyl.

[0045] In some embodiments, the A ring is described by formula (B5). [ka] where: R 10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. Y 3 N and CR 11 where R is selected from 11 is hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. and m is an integer from 0 to 3.

[0046] In the particular case of formula B5, Y3 is CR 11 and formula B5 may be equivalent to B3. In certain cases, B5 is pyridyl. In certain cases, B5 is substituted pyridyl. In some cases, the pyridyl is monosubstituted pyridyl. In other cases, the pyridyl is disubstituted pyridyl. In other cases, the pyridyl is trisubstituted pyridyl. In other cases, the pyridyl is tetrasubstituted pyridyl. In certain cases, Y 3is N and B5 is pyrimidyl. In some cases, B5 is substituted pyrimidyl. In some cases, the pyrimidyl is monosubstituted. In some cases, the pyrimidyl is disubstituted. In other cases, the pyrimidyl is trisubstituted. In certain embodiments of B5, the substituents are selected from lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl), trifluoromethyl, and halogen (e.g., F, Cl, I, or Br).

[0047] In some embodiments, the A ring is described by formula (B6). [ka] where: R10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. p is an integer from 0 to 4.

[0048] In certain cases, p is 0 and B6 is pyridyl. In certain cases, B6 is substituted pyridyl. In some cases, the pyridyl is monosubstituted pyridyl. In other cases, the pyridyl is disubstituted pyridyl. In other cases, the pyridyl is trisubstituted pyridyl. In other cases, the pyridyl is tetrasubstituted pyridyl. In certain embodiments of B6, the substituents are selected from lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl), trifluoromethyl, and halogen (e.g., F, Cl, I, or Br).

[0049] In certain embodiments, the A ring has any one of formulae (B4a), (B6a), (B5a) or (B5b). [ka] or [ka] [ka] or [ka] In some embodiments, the A ring is described by formula (B7). [ka] where: R 10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. Y 3 N and CR 11 where R is selected from 11 is hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. Y 4 is CR 11 2.NR 11 , SO2 and O; and q is an integer between 0 and 8.

[0050] In certain cases, B7 is piperidine or substituted piperidine. In certain cases, B7 is piperazine or substituted piperazine. In certain cases, B7 is cycloalkyl or substituted cycloalkyl. In some cases, B7 is tetrahydropyran or substituted tetrahydropyran. In some cases, B7 is morpholine or substituted morpholine. In some cases, B7 is cyclic sulfone or substituted cyclic sulfone. In certain embodiments of B7, q is greater than 0, such as 1, 2, 3, 4, 5, 6, 7, or 8. In some cases, B7 is one R 10 In some cases, B7 contains two R 10 In some cases, B7 contains three R groups. 10 In some cases, B7 contains four R groups. 10In certain embodiments, the substituents are selected from lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl), trifluoromethyl, and halogen (e.g., F, Cl, I, or Br).

[0051] In certain embodiments, the A ring has any one of formulas (B7a) or (B7b). [ka] [ka] In some embodiments of Formula (B7a), R 11 is hydrogen. In some embodiments of Formula (B7a), R 11 is an acyl group. In some embodiments, formula (B7a) has the relative configuration of formula (B7ai) or (B7aii). [ka] or [ka] In some embodiments, the A ring is described by formula (B8). [ka] where: R 10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. Y 3 N and CR 11 where R is selected from 11 is hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. Y 4 is CR 11 2.NR11 , SO2 and O; and q 1 is an integer between 0 and 6.

[0052] In certain cases, B8 is 2-oxopiperidine or a substituted 2-oxopiperazine. In certain cases, B8 is 2-oxopiperazine or a substituted 2-oxopiperazine. In certain cases, B8 is cyclohexanone or a substituted cyclohexanone. In some cases, B8 is a lactone or a substituted lactone. In some cases, B8 is morpholin-2-one or a substituted morpholin-2-one. In certain embodiments of B8, q is greater than 0, such as 1, 2, 3, 4, 5, or 6. In some cases, B8 is one R 10 In some cases, B8 contains two R groups. In some cases, B8 contains three B 7 In some cases, B8 contains four R groups. 10 In certain embodiments, the substituents are selected from lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl), trifluoromethyl, and halogen (e.g., F, Cl, I, or Br).

[0053] In some embodiments, the B ring is selected from aryl (e.g., phenyl), optionally containing one or more substituents. In some embodiments, the B ring is selected from heteroaryl or heterocycle (e.g., pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl, indolyl, furyl, imidazolyl, oxazolyl, thiazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidino, morpholino, piperazino, piperidino, tetrahydrofuran), optionally containing one or more substituents. In some embodiments, the B ring is selected from phenyl, substituted phenyl, pyridyl, substituted pyridyl, 2-piperidyl, 2-pyrid ... pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, substituted 6-pyrimidinyl, piperidine, substituted piperidine, piperazine, substituted piperazine, 2-oxopiperidine, 2-oxopiperazine, imidazole, substituted imidazole, thiazole, substituted thiazole, oxazole, substituted oxazole, tetrahydropyran, substituted tetrahydropyran, morpholine, substituted morpholine, cyclic sulfone, substituted cyclic sulfone.

[0054] In other embodiments, the B ring is described by formula (B1). [ka] wherein B1 is a 6-membered aryl, heteroaryl, heterocyclyl, or cycloalkyl; Z 7 -Z 12 are N, O, CR 11 , N.R. 11 , C.R. 11 2, SO2, and CO, and R is selected independently from the group consisting of 2, SO2, and CO, and R is selected ... 11 are each independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, halogen, acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamido, and substituted sulfonamido. 8 and Z 9 , or Z 9 and Z 10 , or Z10 and Z 11 , or Z 11 and Z 12 is CR 11 where each R 11

[0023] Together with the carbons to which they are attached, B1 forms a 5- or 6-membered cyclic group selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, and substituted cycloalkyl. In certain cases, B1 is indole or substituted indole. In some cases, B1 is phenyl or substituted phenyl. In some cases, B1 is cycloalkyl or substituted cycloalkyl. In some cases, B1 is pyridyl or substituted pyridyl. In some cases, B1 is pyrimidinyl, such as 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, or substituted 6-pyrimidinyl. In some cases, B1 is pyridazine or substituted pyridazine. In some cases, B1 is triazine or substituted triazine. In some cases, B1 is piperidine or substituted piperidine. In some cases, B1 is pyridyl or substituted pyridazine. 1 is piperazine or substituted piperazine. In some cases, B1 is 2-oxopiperidine or substituted 2-oxopiperidine. In some cases, B1 is 2-oxopiperazine or substituted 2-oxopiperazine. In some cases, B1 is tetrahydropyran or substituted tetrahydropyran. In some cases, B1 is pyran or substituted pyran. In some cases, B1 is pyridyl or substituted pyridyl. In some cases, B1 is cyclic sulfone or substituted cyclic sulfone.

[0055] In some embodiments, the B ring is described by formula (B2). [ka] where: R10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen; and n is an integer from 0 to 5.

[0056] In certain cases, B2 is phenyl. In certain cases, B2 is disubstituted phenyl. In certain cases, B2 is trisubstituted phenyl. In certain cases, B2 is tetrasubstituted phenyl. In certain cases, B2 is pentasubstituted aryl. In certain cases, the substituents are selected from lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl) and halogen (e.g., F, Cl, I, or Br). In certain embodiments, B2 is 2,6-disubstituted phenyl, and the substituents are independently selected from halogen and lower alkyl.

[0057] In some embodiments, the B2 ring is described by formula (B2b). [ka] where: R 12 and R 13 are each independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. 12 and R13 are each independently selected from alkyl, substituted alkyl, trifluoromethyl, and halogen. In some embodiments, R 12 is a halogen (e.g., fluoro, chloro, bromo, iodo), and R 13 is lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl).

[0058] In some embodiments, the B ring is described by formula (B3). [ka] where: R 10is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. Y 3 N and CR 11 where R is selected from 11 is hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. and m is an integer from 0 to 3.

[0059] In certain cases, B3 is pyridyl. In certain cases, B3 is substituted pyridyl. In some cases, the pyridyl is monosubstituted pyridyl. In other cases, the pyridyl is disubstituted pyridyl. In other cases, the pyridyl is trisubstituted pyridyl. In other cases, the pyridyl is tetrasubstituted pyridyl. In certain cases, Y 3 is N and B3 is pyrimidyl. In some cases, B3 is substituted pyrimidyl. In some cases, the pyrimidyl is monosubstituted. In some cases, the pyrimidyl is disubstituted. In other cases, the pyrimidyl is trisubstituted. In certain embodiments of B3, the substituents are selected from lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl) and halogen (e.g., F, Cl, I, or Br).

[0060] In some embodiments, the B ring is described by formula (B4). [ka] where: R 10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. Y 3 N and CR 11 where R is selected from 11 is hydrogen, R10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. and m is an integer from 0 to 3.

[0061] In certain cases, B4 is pyridyl. In certain cases, B4 is substituted pyridyl. In some cases, the pyridyl is monosubstituted pyridyl. In other cases, the pyridyl is disubstituted pyridyl. In other cases, the pyridyl is trisubstituted pyridyl. In other cases, the pyridyl is tetrasubstituted pyridyl. In certain cases, Y 3 is N and B4 is pyrimidyl. In some cases, B4 is substituted pyrimidyl. In some cases, the pyrimidyl is monosubstituted. In some cases, the pyrimidyl is disubstituted. In other cases, the pyrimidyl is trisubstituted. In certain embodiments of B4, the substituents are selected from lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl), trifluoromethyl, and halogen (e.g., F, Cl, I, or Br). In some cases, B4 is monosubstituted pyridyl and the substituents are selected from lower alkyl (e.g., methyl) and trifluoromethyl.

[0062] In some embodiments, the B ring is described by formula (B5). [ka] where: R 10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. Y 3 N and CR 11 where R is selected from 11 is hydrogen, R 10, acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. and m is an integer from 0 to 3.

[0063] In the particular case of formula B5, Y3 is CR 11 and formula B5 may be equivalent to B3. In certain cases, B5 is pyridyl. In certain cases, B5 is substituted pyridyl. In some cases, the pyridyl is monosubstituted pyridyl. In other cases, the pyridyl is disubstituted pyridyl. In other cases, the pyridyl is trisubstituted pyridyl. In other cases, the pyridyl is tetrasubstituted pyridyl. In certain cases, Y 3 is N and B5 is pyrimidyl. In some cases, B5 is substituted pyrimidyl. In some cases, the pyrimidyl is monosubstituted. In some cases, the pyrimidyl is disubstituted. In other cases, the pyrimidyl is trisubstituted. In certain embodiments of B5, the substituents are selected from lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl), trifluoromethyl, and halogen (e.g., F, Cl, I, or Br).

[0064] In some embodiments, the B ring is described by formula (B6). [ka] where: R10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. p is an integer from 0 to 4.

[0065] In certain cases, p is 0 and B6 is pyridyl. In certain cases, B6 is substituted pyridyl. In some cases, the pyridyl is monosubstituted pyridyl. In other cases, the pyridyl is disubstituted pyridyl. In other cases, the pyridyl is trisubstituted pyridyl. In other cases, the pyridyl is tetrasubstituted pyridyl. In certain embodiments of B6, the substituents are selected from lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl), trifluoromethyl, and halogen (e.g., F, Cl, I, or Br).

[0066] In certain embodiments, the B ring has the formula (B4b) or (B6b). [ka] or [ka] where: R 14 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. In some embodiments, R is selected from alkyl, substituted alkyl, trifluoromethyl, and halogen. In some embodiments, R is lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl) or trifluoromethyl.

[0067] In some embodiments, the B ring is described by formula (B7). [ka] where: R 10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. Y 3 N and CR 11 where R is selected from 11 is hydrogen, R 10, acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. Y 4 is CR 11 2.NR 11 , SO2 and O; and q is an integer between 0 and 8.

[0068] In certain cases, B7 is piperidine or substituted piperidine. In certain cases, B7 is piperazine or substituted piperazine. In certain cases, B7 is cycloalkyl or substituted cycloalkyl. In some cases, B7 is tetrahydropyran or substituted tetrahydropyran. In some cases, B7 is morpholine or substituted morpholine. In some cases, B7 is cyclic sulfone or substituted cyclic sulfone. In certain embodiments of B7, q is greater than 0, such as 1, 2, 3, 4, 5, 6, 7, or 8. In some cases, B7 is one R 10 In some cases, B7 contains two R groups. In some cases, B7 contains three R groups. In some cases, B7 contains four R groups. 10 In certain embodiments, the substituents are selected from lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl), trifluoromethyl, and halogen (e.g., F, Cl, I, or Br).

[0069] In some embodiments, the B ring is described by formula (B8). [ka] where: R 10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. Y 3 N and CR 11 where R is selected from 11 is hydrogen, R 10, acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. Y 4 is CR 11 2.NR 11 , SO2 and O; and q 1 is an integer between 0 and 6.

[0070] In certain cases, B8 is 2-oxopiperidine or a substituted 2-oxopiperazine. In certain cases, B8 is 2-oxopiperazine or a substituted 2-oxopiperazine. In certain cases, B8 is cyclohexanone or a substituted cyclohexanone. In some cases, B8 is a lactone or a substituted lactone. In some cases, B8 is morpholin-2-one or a substituted morpholin-2-one. In certain embodiments of B8, q is greater than 0, such as 1, 2, 3, 4, 5, or 6. In some cases, B8 is one R 10 In some cases, B8 contains two R groups. In some cases, B8 contains three R groups. In some cases, B8 contains four R groups. 10 In certain embodiments, the substituents are selected from lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl), trifluoromethyl, and halogen (e.g., F, Cl, I, or Br).

[0071] In some embodiments, the B ring has the formula (B7b) or (B8a). [ka] [ka] where: R 15 , R 16 , R 17 and R 18 are each independently selected from hydrogen, alkyl, and substituted alkyl. In some cases, R 15 , R16 , R 17 and R 18 are each hydrogen. In some cases, R 15 is lower alkyl, and R 16 , R 17 and R 18 are each hydrogen. In some cases, R 15 and R 16 are each lower alkyl, and R 17 and R 18 are each hydrogen. In some cases, R 15 and R 17 are each lower alkyl, and R 16 and R 18 are hydrogen atoms.

[0072] In some embodiments, formula (B7b) has the relative configuration of formula (B7bi) or (B7bii). [ka] or [ka] In some embodiments, formula (B8a) has the relative configuration of formula (B8ai) or (B8aii). [ka] or [ka] In some embodiments, the B ring is described by formula (B10). [ka] wherein B10 is a 5-membered aryl, heteroaryl, heterocyclyl, or cycloalkyl; Z 13 -Z 17 are N, O, CR 11 , N.R. 11 , C.R. 112, SO2, and CO, and R is independently selected from the group consisting of ... 11 are each independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, halogen, acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamido, and substituted sulfonamido. 14 and Z 15 , or Z 15 and Z 16 , or Z 16 and Z 17 is CR 11 where each R 11 together with the carbons to which they are attached form a 5- or 6-membered cyclic group selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, and substituted cycloalkyl. In certain cases, B10 is imidazole or substituted imidazole. In certain cases, B10 is thiazole or substituted thiazole. In some cases, B10 is oxazole or substituted oxazole. In some cases, B10 is pyrazole or substituted pyrazole. In some cases, B10 is isoxazole or substituted isoxazole. In some cases, B10 is isothiazole or substituted isothiazole. In some cases, B10 is furan or substituted furan. In some cases, B10 is thiophene or substituted thiophene. In some cases, B10 is cyclopentane or substituted cyclopentane. In some cases, B10 is cyclopentane or substituted cyclopentane. In some cases, B10 is a cyclopentadiene or a substituted cyclopentadiene. In some cases, B10 is a cyclic sulfone or a substituted cyclic sulfone.

[0073] In some embodiments, the B ring is described by formula (B9). [ka] where: R 10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. Y 5 N and CR 11 where R is selected from 11 is hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. Y 6 is CR 11 2 and NR 11 and r is an integer between 0 and 2.

[0074] In certain cases, B9 is imidazole or substituted imidazole. In certain cases, B9 is pyrrole or substituted pyrrole. In certain cases, pyrrole is 1H-pyrrole or substituted 1H-pyrrole. In other cases, pyrrole is 3H-pyrrole or substituted 3H-pyrrole. In certain cases, B9 is cyclopentadiene or substituted cyclopentadiene. In certain embodiments of B9, r is greater than 0, such as 1 or 2. In some cases, B9 is one R 10 In some cases, B9 includes two R10 groups. In certain embodiments, the substituents are selected from lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl), trifluoromethyl, and halogen (e.g., F, Cl, I, or Br).

[0075] In certain embodiments of formula (II), the compound is described by formula (IIA): [ka] In certain embodiments, formula (IIA) is of formula (IIA1) or (IIA2): [ka] or [ka] In certain embodiments, formula (IIA) is of formula (IIAa), (IIA1j) or (IIA2j). [ka] [ka] or [ka] In certain embodiments, formula (IIA) is of formula (IIAb), (IIA1k) or (IIA2k). [ka] or [ka] [ka]

[0076] In some embodiments of Formula (IIA) through (IIA2k), the A ring is selected from aryl (e.g., phenyl), optionally containing one or more substituents. In some embodiments, the A ring is selected from heteroaryl or heterocycle (e.g., pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl, indolyl, furyl, imidazolyl, oxazolyl, thiazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidino, molforno, piperazino, piperidino, tetrahydrofuran), optionally containing one or more substituents. In some embodiments, the A ring is selected from cycloalkyl (e.g., cyclohexane), optionally containing one or more substituents. In some embodiments, the A ring is selected from phenyl, substituted phenyl, pyridyl, substituted pyridyl, 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, substituted 6-pyrimidinyl, piperidine, substituted piperidine, piperazine, substituted piperidine, 2-oxopiperidine, 2-oxopiperazine, imidazole, substituted imidazole, thiazole, substituted thiazole, oxazole, substituted oxazole, tetrahydropyran, substituted tetrahydropyran, morpholine, substituted morpholine, cyclic sulfone, substituted cyclic sulfone, cycloalkyl, and substituted cycloalkyl.

[0077] In other embodiments, the A ring is described by formula (A1). [ka] where A1 is a 6-membered aryl, heteroaryl, heterocyclyl, or cycloalkyl; Z 1 -Z 6 are N, O, CR 11 , N.R. 11 , C.R. 11 2, SO2, and CO, and R is selected independently from the group consisting of 2, SO2, and CO, and R is selected ... 11are each independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, halogen, acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamido, and substituted sulfonamido. 2 and Z 3 , or Z 3 and Z 4 , or Z 4 and Z 11 , or Z 11 and Z 6 is CR 11 where each R 11

[0023] Together with the carbons to which they are attached, form a 5- or 6-membered cyclic group selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, and substituted cycloalkyl. In certain cases, A1 is indole or substituted indole. In some cases, A1 is phenyl or substituted phenyl. In some cases, A1 is cycloalkyl or substituted cycloalkyl. In some cases, A1 is pyridyl or substituted pyridyl. In some cases, A1 is pyrimidinyl, such as 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, or substituted 6-pyrimidinyl. In some cases, A1 is pyridazine or substituted pyridazine. In some cases, A1 is triazine or substituted triazine. In some cases, A1 is piperidine or substituted piperidine. In some cases, A1 is piperazine or substituted piperazine. In some cases, A1 is 2-oxopiperidine or a substituted 2-oxopiperidine. In some cases, A1 is 2-oxopiperazine or a substituted 2-oxopiperazine. In some cases, A1 is tetrahydropyran or a substituted tetrahydropyran. In some cases, A1 is pyran or a substituted pyran. In some cases, A1 is pyridyl or a substituted pyridyl. In some cases, A1 is a cyclic sulfone or a substituted cyclic sulfone.

[0078] In certain embodiments of Formulas (IIA) through (IIA2k), the A ring is selected from any one of Formulas (B2) through (B8), for example, as described herein. In certain embodiments of Formulas (IIA) through (IIA2k), the A ring is selected from the following structures: [ka] In some embodiments, formula (IIA1) is any one of formulas (IIA1a) to (IIA1i). [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0079] In some embodiments of any one of formulas (IIA1a) through (IIA1i), Y 2 is S. In some embodiments of any one of formulas (IIA1a) through (IIA1i), Y 1 is CH. In some embodiments of any one of formulas (IIA1a) through (IIA1i), Y 2 is S and Y 1is CH. In some embodiments of any one of formulas (IIA1a) through (IIA1i), Y 2 is S and Y 1 is N. In some embodiments of any one of formulas (IIA1a) through (IIA1i), Y 2 is O. In some embodiments of any one of formulas (IIA1a) through (IIA1i), Y 2 is NR 19 In some embodiments of any one of formulas (IIA1a) to (IIA1i), Y 2 In some embodiments of any one of formulas (IIA1a) through (IIA1i), Y 2 is O and Y 1 is CH. In some embodiments of any one of formulas (IIA1a) through (IIA1i), Y 2 is NR 19 and Y 1 is CH. In some embodiments of any one of formulas (IIA1a) through (IIA1i), Y 2 is NH and Y 1 is CH. In some embodiments of any one of Formulas (IIA1a) through (IIA1i), Y2 is O and Y1 is N. In some embodiments of any one of Formulas (IIA1a) through (IIA1i), Y2 is NR19 and Y1 is N. In some embodiments of any one of Formulas (IIA1a) through (IIA1i), Y2 is NH and Y1 is N.

[0080] In certain embodiments of any one of formulas (IIA1a) through (IIA1k), R 12 is selected from alkyl, substituted alkyl, trifluoromethyl, and halogen. 12 is a lower alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl). In certain cases, the lower alkyl group is methyl. In certain cases, R 12 is a halogen. In certain cases, the halogen is chloride. In certain cases, the halogen is fluoride. In certain cases, R 12is trifluoromethyl.

[0081] In certain embodiments of any one of formulas (IIA1a) through (IIA1k), R 13 is selected from alkyl, substituted alkyl, trifluoromethyl, and halogen. 13 is a lower alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl). In certain cases, the lower alkyl group is methyl. In certain cases, R 13 is a halogen. In certain cases, the halogen is chloride. In certain cases, the halogen is fluoride.

[0082] In certain embodiments of any one of formulas (IIA1a) through (IIA1k), R 12 is a halogen and R 13 is lower alkyl. In some embodiments, R is fluoride and R 13 is methyl.

[0083] In certain embodiments of any one of formulas (IIA) through (IIA1k), R 4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 In some cases of any one of formulas (IIK) to (IIA1k), R 4 and R 5 together with the carbon to which they are attached form a cycloalkyl group.

[0084] In certain embodiments of any one of formulas (IIA) through (IIA1k), R 2 In certain embodiments of any one of formulas (IIA) through (IIA1k), R 3 is methyl.

[0085] In certain embodiments of any one of formulas (IIA) through (IIA1k), R 2 , R 3 , R 4, R 5 , R 10 and R 14 are independently selected from the corresponding groups as shown in any of the structures in Tables 1, 2, or 3.

[0086] In some embodiments, the compound is described by any of the following structures: [ka] [ka] [ka] [ka] [ka] In some embodiments, the compound is described by any of the following structures: [ka] [ka] In some embodiments, the compound is described by any of the following structures: [ka] [ka] [ka] In some embodiments, formula (IIA1) is any one of formulas (IIA2a) through (IIA2i). [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0087] In some embodiments of any one of formulas (IIA2a) through (IIA2i), Y 2 is S. In some embodiments of any one of formulas (IIA2a) through (IIA2i), Y 1 is CH. In some embodiments of any one of formulas (IIA2a) through (IIA2i), Y 2 is S and Y 1 is CH. In some embodiments of any one of formulas (IIA2a) through (IIA2i), Y 2 is S and Y 1 is N. In some embodiments of any one of formulas (IIA2a) through (IIA2i), Y 2 is O. In some embodiments of any one of formulas (IIA2a) through (IIA2i), Y 2 is NR 19 In some embodiments of any one of formulas (IIA2a) through (IIA2i), Y 2 In some embodiments of any one of formulas (IIA2a) through (IIA2i), Y 2 is O and Y 1is CH. In some embodiments of any one of formulas (IIA2a) through (IIA2i), Y 2 is NR 19 and Y 1 is CH. In some embodiments of any one of formulas (IIA2a) through (IIA2i), Y 2 is NH and Y 1 is CH. In some embodiments of any one of formulas (IIA2a) through (IIA2i), Y 2 is O and Y is N. In some embodiments of any one of formulas (IIA2a) through (IIA2i), Y 2 is NR19 and Y1 is N. In some embodiments of any one of formulas (IIA2a) through (IIA2i), Y 2 is NH and Y1 is N.

[0088] In some embodiments of any one of Formulas (IIA2) through (IIA2k), R 12 is selected from alkyl, substituted alkyl, trifluoromethyl, and halogen. 12 is a lower alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl). In certain cases, the lower alkyl group is methyl. In certain cases, R 12 is a halogen. In certain cases, Y 2 is not S and the A ring is not an unsubstituted tetrahydropyran, the halogen is chloride. 12 is trifluoromethyl.

[0089] In some embodiments of any one of Formulas (IIA2) through (IIA2k), R 4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 In some cases of any one of formulas (IIK) to (IIA2k), R 4 and R 5 together with the carbon to which they are attached form a cycloalkyl group.

[0090] In certain embodiments of any one of formulas (IIA2) through (IIA2k), R 2 In certain embodiments of any one of formulas (IIA2) through (IIA2k), R 3 is methyl.

[0091] In certain embodiments of any one of formulas (IIA2) through (IIA2k), R 2 , R 3 , R 4 , R 5 , R 10 and R 14 are independently selected from the corresponding groups as shown in any of the structures in Tables 1, 2, or 3.

[0092] In certain embodiments, the compound is described by any one of the following structures: [ka] [ka] In certain embodiments, the compound of formula (IIA2) is not one of the following structures: [ka] [ka] or [ka] If not, a bridged cyclic group selected from a bridged cycloalkyl, a substituted bridged cycloalkyl, a bridged heterocycle, and a substituted bridged heterocycle, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, is provided.

[0093] In certain embodiments of Formula (II), the compound is described by Formula (IIB), (IIC), or (IID): [ka] [ka] or [ka] In certain embodiments, the compound of formula is (IIC1) or (IID1). [ka] or [ka] In certain embodiments, the compound is described by any one of formulas (IIB1), (IIC2), or (IID2). [ka] [ka] [ka] In certain embodiments, the compound is described by any one of formulas (IIB2), (IIC3), or (IID3). [ka] [ka] [ka]

[0094] In some embodiments of any one of Formulas (IIB), (IIC), or (IID), the A ring is selected from aryl (e.g., phenyl), optionally containing one or more substituents. In some embodiments, the A ring is selected from heteroaryl or heterocycle (e.g., pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl, indolyl, furyl, imidazolyl, oxazolyl, thiazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidino, molforno, piperazino, piperidino, tetrahydrofuran), optionally containing one or more substituents. In some embodiments, the A ring is selected from cycloalkyl (e.g., cyclohexane), optionally containing one or more substituents. In some embodiments, the A ring is selected from phenyl, substituted phenyl, pyridyl, substituted pyridyl, 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, substituted 6-pyrimidinyl, piperidine, substituted piperidine, piperazine, substituted piperidine, 2-oxopiperidine, 2-oxopiperazine, imidazole, substituted imidazole, thiazole, substituted thiazole, oxazole, substituted oxazole, tetrahydropyran, substituted tetrahydropyran, morpholine, substituted morpholine, cyclic sulfone, substituted cyclic sulfone, cycloalkyl, and substituted cycloalkyl.

[0095] In other embodiments, the A ring is described by formula (A1). [ka] where A1 is a 6-membered aryl, heteroaryl, heterocyclyl, or cycloalkyl; Z 1 -Z 6 are N, O, CR 11 , N.R. 11 , C.R. 11 2, SO2, and CO, and R is selected independently from the group consisting of 2, SO2, and CO, and R is selected ... 11are each independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, halogen, acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamido, and substituted sulfonamido. 2 and Z 3 , or Z 3 and Z 4 , or Z 4 and Z 11 , or Z 11 and Z 6 is CR 11 where each R 11

[0023] Together with the carbons to which they are attached, form a 5- or 6-membered cyclic group selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, and substituted cycloalkyl. In certain cases, A1 is indole or substituted indole. In some cases, A1 is phenyl or substituted phenyl. In some cases, A1 is cycloalkyl or substituted cycloalkyl. In some cases, A1 is pyridyl or substituted pyridyl. In some cases, A1 is pyrimidinyl, such as 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, or substituted 6-pyrimidinyl. In some cases, A1 is pyridazine or substituted pyridazine. In some cases, A1 is triazine or substituted triazine. In some cases, A1 is piperidine or substituted piperidine. In some cases, A1 is piperazine or substituted piperazine. In some cases, A1 is 2-oxopiperidine or a substituted 2-oxopiperidine. In some cases, A1 is 2-oxopiperazine or a substituted 2-oxopiperazine. In some cases, A1 is tetrahydropyran or a substituted tetrahydropyran. In some cases, A1 is pyran or a substituted pyran. In some cases, A1 is pyridyl or a substituted pyridyl. In some cases, A1 is a cyclic sulfone or a substituted cyclic sulfone.

[0096] In some embodiments of any one of Formulas (IIB), (IIC), or (IID), the A ring is selected from any of Formulas (B2) through (B8), e.g., as described herein. In particular embodiments of any one of Formulas (IIB), (IIC), or (IID), the A ring is selected from the following structures: [ka]

[0097] In some embodiments of Formula (IIB), Y 2 is S. In some embodiments of Formula (IIB), Y 1 In some embodiments of Formula (IIB), Y 2 is S and Y 1 In some embodiments of Formula (IIB), Y 2 is S and Y 1 is N. In some embodiments of Formula (IIB), Y 2 is O. In some embodiments of Formula (IIB), Y 2 is NR 19 In some embodiments of Formula (IIB), Y 2 In some embodiments of Formula (IIB), Y 2 is O and Y 1 In some embodiments of Formula (IIB), Y 2 is NR 19 .Yes, Y 1 In some embodiments of Formula (IIB), Y 2 is NH and Y 1 In some embodiments of Formula (IIB), Y 2 is O and Y 1 is N. In some embodiments of Formula (IIB), Y 2 is NR 19 and Y 1 is N. In some embodiments of Formula (IIB), Y 2 is NH and Y 1 is N.

[0098] In certain embodiments of any one of (IIB) through (IIB2), R 4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 In some cases of any one of formulas (IIB) to (IIB2), R 4 and R 5 together with the carbon to which they are attached form a cycloalkyl group.

[0099] In certain embodiments of any one of formulas (IIB) through (IIB2), R 2 In certain embodiments of any one of formulas (IIB) through (IIB2), R 3 is methyl.

[0100] In certain embodiments of any one of (IIB) through (IIB2), R 2 , R 3 , R 4 , R 5 and R 10 are independently selected from the corresponding groups as shown in any of the structures in Tables 1, 2, or 3. In certain embodiments, the compound is described by any of the following structures: [ka] In some embodiments, formula (IIC1) is any one of formulas (IIC1a) through (IIC1i). [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0101] In some embodiments of any one of Formulas (IIC1a) through (IIC1i), Y 2 is S. In some embodiments of any one of formulas (IIC1a) through (IIC1i), Y 1 In some embodiments of any one of formulas (IIC1a) through (IIC1i), Y 2 is S and Y 1 In some embodiments of any one of formulas (IIC1a) through (IIC1i), Y 2 is S and Y 1 is N. In some embodiments of any one of formulas (IIC1a) through (IIC1i), Y 2 is O. In some embodiments of any one of formulas (IIC1a) through (IIC1i), Y 2 is NR 19 In some embodiments of any one of Formulas (IIC1a) through (IIC1i), Y 2 In some embodiments of any one of formulas (IIC1a) through (IIC1i), Y 2 is O and Y 1 In some embodiments of any one of Formulas (IIC1a) through (IIC1i), Y is CH 2 is NR 19 and Y 1 In some embodiments of any one of Formulas (IIC1a) through (IIC1i), Y is CH 2 is NH and Y 1is CH. In some embodiments of any one of Formulas (IIC1a) through (IIC1i), Y2 is O and Y1 is N. In some embodiments of any one of Formulas (IIC1a) through (IIC1i), Y2 is NR19 and Y1 is N. In some embodiments of any one of Formulas (IIC1a) through (IIC1i), Y2 is NH and Y1 is N.

[0102] In certain embodiments of any one of formulas (IIC1) through (IIC3), R 14 is selected from alkyl, substituted alkyl, trifluoromethyl, and halogen. 14 is a lower alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl). In certain cases, the lower alkyl group is methyl. In certain cases, R 14 is trifluoromethyl.

[0103] In certain embodiments of any one of (IIC) to (IIC3), R 4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 and are both methyl. In some embodiments of any one of Formulas (IIC) through (IIC3), R 4 and R 5 together with the carbon to which they are attached form a cycloalkyl group.

[0104] In certain embodiments of any one of formulas (IIC) through (IIC3), R 2 In certain embodiments of any one of formulas (IIC) through (IIC3), R 3 is methyl.

[0105] In certain embodiments of any one of formulas (IIC) through (IIC3), R 2 , R 3 , R 4 , R 5 , R 10 and R 14are independently selected from the corresponding groups as shown in any of the structures in Tables 1, 2, or 3.

[0106] In certain embodiments, the compound is described by any of the following structures: [ka] In some embodiments, formula (IID1) is any one of formulas (IID1a) to (IID1i). [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0107] In some embodiments of any one of formulas (IID1a) through (IID1i), Y 2 is S. In some embodiments of any one of formulas (IID1a) through (IID1i), Y 1 In some embodiments of any one of formulas (IID1a) through (IID1i), Y 2 is S and Y 1In some embodiments of any one of formulas (IID1a) through (IID1i), Y 2 is S and Y 1 is N. In some embodiments of any one of formulas (IID1a) through (IID1i), Y 2 is O. In some embodiments of any one of formulas (IID1a) through (IID1i), Y 2 is NR 19 In some embodiments of any one of formulas (IID1a) through (IID1i), Y 2 In some embodiments of any one of formulas (IID1a) through (IID1i), Y 2 is O and Y 1 In some embodiments of any one of formulas (IID1a) through (IID1i), Y 2 is NR 19 and Y 1 In some embodiments of any one of formulas (IID1a) through (IID1i), Y 2 is NH and Y 1 is CH. In some embodiments of any one of Formulas (IID1a) through (IID1i), Y2 is O and Y1 is N. In some embodiments of any one of Formulas (IID1a) through (IID1i), Y2 is NR19 and Y1 is N. In some embodiments of any one of Formulas (IID1a) through (IID1i), Y2 is NH and Y1 is N.

[0108] In certain embodiments of any one of formulas (IID1) through (IID3), R 14 is selected from alkyl, substituted alkyl, trifluoromethyl, and halogen. 14 is a lower alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl). In certain cases, the lower alkyl group is methyl. In certain cases, R 14 is trifluoromethyl.

[0109] In certain embodiments of any one of (IID) to (IID3), R4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 and are both methyl. In some embodiments of any one of Formulas (IID) through (IID3), R 4 and R 5 together with the carbon to which they are attached form a cycloalkyl group.

[0110] In certain embodiments of any one of formulas (IID) through (IID3), R 2 In certain embodiments of any one of formulas (IID) through (IID3), R 3 is methyl. In certain embodiments of any one of formulas (IID) through (IID3), R 2 , R 3 , R 4 , R 5 , R 10 and R 14 are independently selected from the corresponding groups as shown in any of the structures in Tables 1, 2, or 3.

[0111] In certain embodiments, the compound is described by any one of the following structures: [ka] [ka] or [ka] In certain embodiments, the compound is described by any of the following structures: [ka] In certain embodiments of formula (II), the compound is described by formula (IIE) or (IIF). [ka] or [ka]

[0112] In some embodiments of formulas (IIE) to (IIF), Y 2 is S. In some embodiments of any one of formulas (IIE) to (IIF), Y 1 is CH. In some embodiments of formula (IIE) or (IIF), Y 2 is S and Y 1 is CH. In some embodiments of formula (IIE) or (IIF), Y 2 is S and Y 1 is N. In some embodiments of formula (IIE) or (IIF), Y 2 is O. In some embodiments of formula (IIE) or (IIF), Y 2 is NR 19 In some embodiments of formula (IIE) or (IIF), Y 2 In some embodiments of formula (IIE) or (IIF), Y 2 is O and Y 1 is CH. In some embodiments of formula (IIE) or (IIF), Y 2 is NR 19 and Y 1 is CH. In some embodiments of formula (IIE) or (IIF), Y 2 is NH and Y 1 is CH. In some embodiments of formula (IIE) or (IIF), Y 2 is O and Y 1 is N. In some embodiments of formula (IIE) or (IIF), Y 2 is NR 19 and Y is N. In an embodiment of formula (IIE) or (IIF), Y 2 is NH and Y 1 is N.

[0113] In certain embodiments of formula (II), the compound is described by formula (IIE1) or (IIF1). [ka] or [ka] In certain embodiments of formula (II), the compound is described by formula (IIE2) or (IIF2). [ka] or [ka]

[0114] In some embodiments of any one of Formulas (IIE) through (IIE2) or (IIF) through (IIF2), the A ring is selected from aryl (e.g., phenyl), optionally containing one or more substituents. In some embodiments, the A ring is selected from heteroaryl or heterocycle (e.g., pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl, indolyl, furyl, imidazolyl, oxazolyl, thiazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidino, molforno, piperazino, piperidino, tetrahydrofuran), optionally containing one or more substituents. In some embodiments, the A ring is selected from cycloalkyl (e.g., cyclohexane), optionally containing one or more substituents. In some embodiments, the A ring is selected from phenyl, substituted phenyl, pyridyl, substituted pyridyl, 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, substituted 6-pyrimidinyl, piperidine, substituted piperidine, piperazine, substituted piperidine, 2-oxopiperidine, 2-oxopiperazine, imidazole, substituted imidazole, thiazole, substituted thiazole, oxazole, substituted oxazole, tetrahydropyran, substituted tetrahydropyran, morpholine, substituted morpholine, cyclic sulfone, substituted cyclic sulfone, cycloalkyl, and substituted cycloalkyl.

[0115] In other embodiments, the A ring is described by formula (A1). [ka] where A1 is a 6-membered aryl, heteroaryl, heterocyclyl, or cycloalkyl; Z 1 -Z 6 are N, O, CR 11 , N.R. 11 , C.R. 11 2, SO2, and CO, and R is selected independently from the group consisting of 2, SO2, and CO, and R is selected ... 11 are each independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, halogen, acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamido, and substituted sulfonamido. 2 and Z 3 , or Z 3 and Z 4 , or Z 4 and Z 11 , or Z 11 and Z 6 is CR 11 where each R 11

[0023] Together with the carbons to which they are attached, form a 5- or 6-membered cyclic group selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, and substituted cycloalkyl. In certain cases, A1 is indole or substituted indole. In some cases, A1 is phenyl or substituted phenyl. In some cases, A1 is cycloalkyl or substituted cycloalkyl. In some cases, A1 is pyridyl or substituted pyridyl. In some cases, A1 is pyrimidinyl, such as 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, or substituted 6-pyrimidinyl. In some cases, A1 is pyridazine or substituted pyridazine. In some cases, A1 is triazine or substituted triazine. In some cases, A1 is piperidine or substituted piperidine. In some cases, A1 is piperazine or substituted piperazine. In some cases, A1 is 2-oxopiperidine or a substituted 2-oxopiperidine. In some cases, A1 is 2-oxopiperazine or a substituted 2-oxopiperazine. In some cases, A1 is tetrahydropyran or a substituted tetrahydropyran. In some cases, A1 is pyran or a substituted pyran. In some cases, A1 is pyridyl or a substituted pyridyl. In some cases, A1 is a cyclic sulfone or a substituted cyclic sulfone.

[0116] In certain embodiments of any one of Formulas (IIE) to (IIE2) or (IIF) to (IIF2), the A ring is selected from any one of Formulas (B2) to (B8), e.g., as described herein. In certain embodiments of any one of Formulas (IIE) to (IIE2) or (IIF) to (IIF2), the A ring is selected from the following structures: [ka] If not, a bridged cyclic group selected from a bridged cycloalkyl, a substituted bridged cycloalkyl, a bridged heterocycle, and a substituted bridged heterocycle, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, is provided.

[0117] In certain embodiments of any one of formulas (IIE) to (IIE2) or (IIF) to (IIF2), R 4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 In some cases of any one of formulas (IIE) to (IIE2) or (IIF) to (IIF2), R 4 and R 5 together with the carbon to which they are attached form a cycloalkyl group.

[0118] In certain embodiments of any one of formulas (IIE) to (IIE2) or (IIF) to (IIF2), R 2 In certain embodiments of any one of formulas (IIE) through (IIE2) or (IIF) through (IIF2), R 3 is methyl.

[0119] In certain embodiments of any one of formulas (IIE) to (IIE2) or (IIF) to (IIF2), R 2 , R 3 , R 4 , R 5 and R 10 are independently selected from the corresponding groups as shown in any of the structures in Tables 1, 2, or 3.

[0120] In certain embodiments, the compound is described by any one of the following structures: [ka] [ka] In certain embodiments of formula (II), the compound is described by formula (IIG): [ka] In certain embodiments of formula (IIG), the compound is described by formula (IIG1): [ka] Here, R 11 is R 10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, and substituted sulfonyl; and R 15 , R 16 , R 17 and R 18 are each independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. In certain embodiments of formula (IIG), the compound is described by formula (IIG2) or (IIG3). [ka] or [ka] In certain embodiments of formula (IIG), the compound is described by formula (IIG2a) or (IIG3a). [ka] or [ka] In certain embodiments, formula (IIG1) has the relative configuration of formula (IIG1ii) or (IIG1iii). [ka] [ka]

[0121] In some embodiments of any one of Formulas (IIG) through (IIG3a), the A ring is selected from aryl (e.g., phenyl), optionally containing one or more substituents. In some embodiments, the A ring is selected from heteroaryl or heterocycle (e.g., pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl, indolyl, furyl, imidazolyl, oxazolyl, thiazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidino, molforno, piperazino, piperidino, tetrahydrofuran), optionally containing one or more substituents. In some embodiments, the A ring is selected from cycloalkyl (e.g., cyclohexane), optionally containing one or more substituents. In some embodiments, the A ring is selected from phenyl, substituted phenyl, pyridyl, substituted pyridyl, 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, substituted 6-pyrimidinyl, piperidine, substituted piperidine, piperazine, substituted piperidine, 2-oxopiperidine, 2-oxopiperazine, imidazole, substituted imidazole, thiazole, substituted thiazole, oxazole, substituted oxazole, tetrahydropyran, substituted tetrahydropyran, morpholine, substituted morpholine, cyclic sulfone, substituted cyclic sulfone, cycloalkyl, and substituted cycloalkyl.

[0122] In other embodiments, the A ring is described by formula (A1). [ka] where A1 is a 6-membered aryl, heteroaryl, heterocyclyl, or cycloalkyl; Z 1 -Z 6 are N, O, CR 11 , N.R. 11 , C.R. 11 2, SO2, and CO, and R is selected independently from the group consisting of 2, SO2, and CO, and R is selected ... 11are each independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, halogen, acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamido, and substituted sulfonamido. 2 and Z 3 , or Z 3 and Z 4 , or Z 4 and Z 11 , or Z 11 and Z 6 is CR 11 where each R 11

[0023] Together with the carbons to which they are attached, form a 5- or 6-membered cyclic group selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, and substituted cycloalkyl. In certain cases, A1 is indole or substituted indole. In some cases, A1 is phenyl or substituted phenyl. In some cases, A1 is cycloalkyl or substituted cycloalkyl. In some cases, A1 is pyridyl or substituted pyridyl. In some cases, A1 is pyrimidinyl, such as 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, or substituted 6-pyrimidinyl. In some cases, A1 is pyridazine or substituted pyridazine. In some cases, A1 is triazine or substituted triazine. In some cases, A1 is piperidine or substituted piperidine. In some cases, A1 is piperazine or substituted piperazine. In some cases, A1 is 2-oxopiperidine or a substituted 2-oxopiperidine. In some cases, A1 is 2-oxopiperazine or a substituted 2-oxopiperazine. In some cases, A1 is tetrahydropyran or a substituted tetrahydropyran. In some cases, A1 is pyran or a substituted pyran. In some cases, A1 is pyridyl or a substituted pyridyl. In some cases, A1 is a cyclic sulfone or a substituted cyclic sulfone.

[0123] In some embodiments of any of Formulas (IIG) through (IIG3a), the A ring is selected from any of Formulas (B2) through (B8), e.g., as described herein. In particular embodiments of any of Formulas (IIG) through (IIG3a), the A ring is selected from the following structures: [ka] In certain embodiments of formula (IIG1), the compound is described by any one of formulas (IIG1a) through (IIG1i). [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0124] In certain embodiments, any one of formulas (IIG1a) through (IIG1i) has the relative configuration as described by formula (IIG1ii). In certain embodiments, any one of formulas (IIG1a) through (IIG1i) has the relative configuration as described by formula (IIG1iii). In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 2 is S. In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 1 In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 2 is S and Y 1 In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 2 is S and Y 1 is N. In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 2 is O. In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 2 is NR 19 In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 2 In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 2 is O and Y 1 In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 2 is NR 19 and Y 1 In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 2 is NH and Y 1 In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii), or (IIG1iii), Y2 is O and Y 1is N. In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 2 is NR 19 and Y 1 is N. In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y2 is NH and Y 1 is N.

[0125] In certain embodiments of any one of (IIG) through (IIG3), R 11 is an acyl group. In certain cases, the acyl group is —C(O)CH3. In certain cases, R 11 is hydrogen. In certain cases, R 11 is a sulfonyl group. In certain cases, the sulfonyl group is —SO2CH3.

[0126] In certain embodiments of any one of (IIG1), (IIG1a) through (IIG1i), (IIG1ii), (IIG1iii), (IIG3), or (IIG3a), R 15 , R 16 , R 17 and R 18 are each independently selected from hydrogen, alkyl, and substituted alkyl. In certain cases, R 15 , R 16 , R 17 and R 18 are hydrogen. In certain cases, R 15 is lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl), and R 16 , R 17 and R 18 are hydrogen. In certain cases, R 15 and R 17 are each lower alkyl, and R 16 and R 18 are each hydrogen. In some cases, R 15 and R 16 is hydrogen and R 17 and R 18are each lower alkyl.

[0127] In certain embodiments of any one of (IIG) through (IIG3), R 4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 In some cases of any one of formulas (IIG) to (IIG3), R 4 and R 5 together with the carbon to which they are attached form a cycloalkyl group.

[0128] In certain embodiments of any one of formulas (IIG) through (IIG3), R 2 In certain embodiments of any one of formulas (IIG) through (IIG3), R 3 is methyl.

[0129] In certain embodiments, in formulas (IIG) to (IIG3), R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 15 , R 16 , R 17 and R 18 are independently selected from the corresponding groups as shown in any of the structures in Tables 1, 2, or 3.

[0130] In certain embodiments, the compound is described by any one of the following structures: [ka] [ka] In certain embodiments, the compound is described by any one of the following structures: [ka] [ka] In certain embodiments of formula (II), the compound is described by formula (IIH): [ka] In certain embodiments of formula (IIH), the compound is described by formula (IIH1): [ka] In certain embodiments of formula (IIH), the compound is described by formula (IIH1a): [ka]

[0131] In some embodiments of any one of Formulas (IIH) through (IIH1a), the A ring is selected from aryl (e.g., phenyl), optionally containing one or more substituents. In some embodiments, the A ring is selected from heteroaryl or heterocycle (e.g., pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl, indolyl, furyl, imidazolyl, oxazolyl, thiazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidino, molforno, piperazino, piperidino, tetrahydrofuran), optionally containing one or more substituents. In some embodiments, the A ring is selected from cycloalkyl (e.g., cyclohexane), optionally containing one or more substituents. In some embodiments, the A ring is selected from phenyl, substituted phenyl, pyridyl, substituted pyridyl, 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, substituted 6-pyrimidinyl, piperidine, substituted piperidine, piperazine, substituted piperidine, 2-oxopiperidine, 2-oxopiperazine, imidazole, substituted imidazole, thiazole, substituted thiazole, oxazole, substituted oxazole, tetrahydropyran, substituted tetrahydropyran, morpholine, substituted morpholine, cyclic sulfone, substituted cyclic sulfone, cycloalkyl, and substituted cycloalkyl.

[0132] In other embodiments, the A ring is described by formula (A1). [ka] where A1 is a 6-membered aryl, heteroaryl, heterocyclyl, or cycloalkyl; Z 1 -Z 6 are N, O, CR 11 , N.R. 11 , C.R. 11 2, SO2, and CO, and R is selected independently from the group consisting of 2, SO2, and CO, and R is selected ... 11 are each independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, halogen, acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamido, and substituted sulfonamido. 2 and Z 3 , or Z 3 and Z 4 , or Z 4 and Z 11 , or Z 11 and Z 6 is CR 11 where each R 11

[0023] Together with the carbons to which they are attached, form a 5- or 6-membered cyclic group selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, and substituted cycloalkyl. In certain cases, A1 is indole or substituted indole. In some cases, A1 is phenyl or substituted phenyl. In some cases, A1 is cycloalkyl or substituted cycloalkyl. In some cases, A1 is pyridyl or substituted pyridyl. In some cases, A1 is pyrimidinyl, such as 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, or substituted 6-pyrimidinyl. In some cases, A1 is pyridazine or substituted pyridazine. In some cases, A1 is triazine or substituted triazine. In some cases, A1 is piperidine or substituted piperidine. In some cases, A1 is piperazine or substituted piperazine. In some cases, A1 is 2-oxopiperidine or a substituted 2-oxopiperidine. In some cases, A1 is 2-oxopiperazine or a substituted 2-oxopiperazine. In some cases, A1 is tetrahydropyran or a substituted tetrahydropyran. In some cases, A1 is pyran or a substituted pyran. In some cases, A1 is pyridyl or a substituted pyridyl. In some cases, A1 is a cyclic sulfone or a substituted cyclic sulfone.

[0133] In some embodiments of any of Formulas (IIH) through (IIH1a), the A ring is selected from any of Formulas (B2) through (B8), for example, as described herein. In one particular embodiment of any of Formulas (IIH) through (IIH1a), the A ring is selected from the following structures: [ka] In certain embodiments of any one of Formulas (IIH), (IIH1), or (IIH1a), q is 0, and thus R 10 There are no substituents. In certain embodiments of formula (IIH), the compound is described by any one of formulas (IIH1b) through (IIH1j). [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0134] In some embodiments of any one of formulas (IIH1b) through (IIH1j), Y 2 is S. In some embodiments of any one of formulas (IIH1b) through (IIH1j), Y 1 is CH. In some embodiments of any one of formulas (IIH1b) through (IIH1j), Y 2 is S and Y 1 is CH. In some embodiments of any one of formulas (IIH1b) through (IIH1j), Y 2 is S and Y 1 is N. In some embodiments of any one of formulas (IIH1b) through (IIH1j), Y 2 is O. In some embodiments of any one of formulas (IIH1b) through (IIH1j), Y 2 is NR19 In some embodiments of any one of formulas (IIH1b) through (IIH1j), Y 2 In some embodiments of any one of formulas (IIH1b) through (IIH1j), Y 2 is O and Y 1 is CH. In some embodiments of any one of formulas (IIH1b) through (IIH1j), Y 2 is NR 19 and Y 1 is CH. In some embodiments of any one of formulas (IIH1b) through (IIH1j), Y 2 is NH and Y 1 is CH. In some embodiments of any one of formulas (IIH1b) through (IIH1j), Y 2 is O and Y 1 is N. In some embodiments of any one of formulas (IIH1b) through (IIH1j), Y 2 is NR 19 and Y 1 is N. In some embodiments of any one of formulas (IIH1b) through (IIH1j), Y 2 is NH and Y 1 is N.

[0135] In certain embodiments of any one of (IIH) through (IIH1j), R 4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 In some cases of any one of formulas (IIH) to (IIH1j), R 4 and R 5 together with the carbon to which they are attached form a cycloalkyl group.

[0136] In certain embodiments of any one of formulas (IIH) through (IIH1j), R 2 In certain embodiments of any one of formulas (IIH) through (IIH1j), R 3 is methyl.

[0137] In certain embodiments of any one of (IIH) through (IIH1j), R 2 , R 3 , R 4 , R 5 and R 10 are independently selected from the corresponding groups as shown in any of the structures in Tables 1, 2, or 3.

[0138] In certain embodiments of formula (II), the compound is described by formula (IIJ): [ka] In certain embodiments of formula (IIJ), the compound is described by formula (IIJ1): [ka] In certain embodiments of formula (IIJ), the compound is described by formula (IIJ1a). [ka]

[0139] In certain embodiments of any one of formulas (IIJ), (IIJ1), or (IIJ1a), q is 0, so that R 10 There are no substituents.

[0140] In some embodiments of any one of Formulas (IIJ), (IIJ1), or (IIJ1a), the A ring is selected from aryl (e.g., phenyl), optionally containing one or more substituents. In some embodiments, the A ring is selected from heteroaryl or heterocycle (e.g., pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl, indolyl, furyl, imidazolyl, oxazolyl, thiazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidino, molforno, piperazino, piperidino, tetrahydrofuran), optionally containing one or more substituents. In some embodiments, the A ring is selected from cycloalkyl (e.g., cyclohexane), optionally containing one or more substituents. In some embodiments, the A ring is selected from phenyl, substituted phenyl, pyridyl, substituted pyridyl, 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, substituted 6-pyrimidinyl, piperidine, substituted piperidine, piperazine, substituted piperidine, 2-oxopiperidine, 2-oxopiperazine, imidazole, substituted imidazole, thiazole, substituted thiazole, oxazole, substituted oxazole, tetrahydropyran, substituted tetrahydropyran, morpholine, substituted morpholine, cyclic sulfone, substituted cyclic sulfone, cycloalkyl, and substituted cycloalkyl.

[0141] In other embodiments, the A ring is described by formula (A1). [ka] where A1 is a 6-membered aryl, heteroaryl, heterocyclyl, or cycloalkyl; Z 1 -Z 6 are N, O, CR 11 , N.R. 11 , C.R. 11 2, SO2, and CO, and R is selected independently from the group consisting of 2, SO2, and CO, and R is selected ... 11are each independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, halogen, acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamido, and substituted sulfonamido. 2 and Z 3 , or Z 3 and Z 4 , or Z 4 and Z 11 , or Z 11 and Z 6 is CR 11 where each R 11

[0023] Together with the carbons to which they are attached, form a 5- or 6-membered cyclic group selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, and substituted cycloalkyl. In certain cases, A1 is indole or substituted indole. In some cases, A1 is phenyl or substituted phenyl. In some cases, A1 is cycloalkyl or substituted cycloalkyl. In some cases, A1 is pyridyl or substituted pyridyl. In some cases, A1 is pyrimidinyl, such as 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, or substituted 6-pyrimidinyl. In some cases, A1 is pyridazine or substituted pyridazine. In some cases, A1 is triazine or substituted triazine. In some cases, A1 is piperidine or substituted piperidine. In some cases, A1 is piperazine or substituted piperazine. In some cases, A1 is 2-oxopiperidine or a substituted 2-oxopiperidine. In some cases, A1 is 2-oxopiperazine or a substituted 2-oxopiperazine. In some cases, A1 is tetrahydropyran or a substituted tetrahydropyran. In some cases, A1 is pyran or a substituted pyran. In some cases, A1 is pyridyl or a substituted pyridyl. In some cases, A1 is a cyclic sulfone or a substituted cyclic sulfone.

[0142] In some embodiments of any one of Formulas (IIJ), (IIJ1), or (IIJ1a), the A ring is selected from any of Formulas (B2) through (B8), e.g., as described herein. In particular embodiments of any one of Formulas (IIJ), (IIJ1), or (IIJ1a), the A ring is selected from the following structures: [ka] In certain embodiments of formula (IIJ), the compound is described by any one of formulas (IIJ1b) through (IIJ1j). [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0143] In some embodiments of any one of formulas (IIJ1b) through (IIJ1j), Y 2 is S. In some embodiments of any one of formulas (IIJ1b) through (IIJ1j), Y 1 In some embodiments of any one of formulas (IIJ1b) through (IIJ1j), Y 2is S and Y 1 In some embodiments of any one of formulas (IIJ1b) through (IIJ1j), Y 2 is S and Y 1 is N. In some embodiments of any one of formulas (IIJ1b) through (IIJ1j), Y 2 is O. In some embodiments of any one of formulas (IIJ1b) through (IIJ1j), Y 2 is NR 19 In some embodiments of any one of formulas (IIJ1b) through (IIJ1j), Y 2 In some embodiments of any one of formulas (IIJ1b) through (IIJ1j), Y 2 is O and Y 1 In some embodiments of any one of formulas (IIJ1b) through (IIJ1j), Y 2 is NR 19 and Y 1 In some embodiments of any one of formulas (IIJ1b) through (IIJ1j), Y 2 is NH and Y 1 In some embodiments of any one of formulas (IIJ1b) through (IIJ1j), Y2 is O and Y 1 is N. In some embodiments of any one of formulas (IIJ1b) through (IIJ1j), Y2 is NR 19 and Y 1 is N. In some embodiments of any one of formulas (IIJ1b) through (IIJ1j), Y2 is NH and Y 1 is N.

[0144] In certain embodiments of any one of (IIJ) to (IIJ1j), R 4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 In some cases of any one of formulas (IIJ) to (IIJ1j), R 4 and R 5together with the carbon to which they are attached form a cycloalkyl group.

[0145] In certain embodiments of any one of formulas (IIJ) through (IIJ1j), R 2 In certain embodiments of any one of formulas (IIJ) through (IIJ1j), R 3 is methyl.

[0146] In certain embodiments of any one of (IIJ) to (IIJ1j), R 2 , R 3 , R 4 , R 5 and R 10 are independently selected from the corresponding groups as shown in any of the structures in Tables 1, 2, or 3. In certain embodiments, the compound is described by any of the following structures: [ka] In certain embodiments of formula (II), the compound is described by formula (IIK): [ka] In certain embodiments of formula (IIK), the compound is described by formula (IIK1): [ka] Here, R 11 is R 10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, and substituted sulfonyl; and R 15 , R 16 , R 17 and R 18 are each independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. In certain embodiments of formula (IIK), the compound is described by formula (IIK2) or (IIK3). [ka] or [ka] In certain embodiments of formula (IIK), the compound is described by formula (IIK2a) or (IIK3a). [ka] or [ka] In certain embodiments, formula (IIK1) has the relative configuration of formula (IIK1ii) or (IIK1iii). [ka] [ka]

[0147] In some embodiments of any one of Formulas (IIK) through (IIK3), the A ring is selected from aryl (e.g., phenyl), optionally containing one or more substituents. In some embodiments, the A ring is selected from heteroaryl or heterocycle (e.g., pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl, indolyl, furyl, imidazolyl, oxazolyl, thiazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidino, molforno, piperazino, piperidino, tetrahydrofuran), optionally containing one or more substituents. In some embodiments, the A ring is selected from cycloalkyl (e.g., cyclohexane), optionally containing one or more substituents. In some embodiments, the A ring is selected from phenyl, substituted phenyl, pyridyl, substituted pyridyl, 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, substituted 6-pyrimidinyl, piperidine, substituted piperidine, piperazine, substituted piperidine, 2-oxopiperidine, 2-oxopiperazine, imidazole, substituted imidazole, thiazole, substituted thiazole, oxazole, substituted oxazole, tetrahydropyran, substituted tetrahydropyran, morpholine, substituted morpholine, cyclic sulfone, substituted cyclic sulfone, cycloalkyl, and substituted cycloalkyl.

[0148] In other embodiments, the A ring is described by formula (A1). [ka] where A1 is a 6-membered aryl, heteroaryl, heterocyclyl, or cycloalkyl; Z 1 -Z 6 are N, O, CR 11 , N.R. 11 , C.R. 11 2, SO2, and CO, and R is selected independently from the group consisting of 2, SO2, and CO, and R is selected ... 11are each independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, halogen, acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamido, and substituted sulfonamido. 2 and Z 3 , or Z 3 and Z 4 , or Z 4 and Z 11 , or Z 11 and Z 6 is CR 11 where each R 11

[0023] Together with the carbons to which they are attached, form a 5- or 6-membered cyclic group selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, and substituted cycloalkyl. In certain cases, A1 is indole or substituted indole. In some cases, A1 is phenyl or substituted phenyl. In some cases, A1 is cycloalkyl or substituted cycloalkyl. In some cases, A1 is pyridyl or substituted pyridyl. In some cases, A1 is pyrimidinyl, such as 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 6-pyrimidinyl, or substituted 6-pyrimidinyl. In some cases, A1 is pyridazine or substituted pyridazine. In some cases, A1 is triazine or substituted triazine. In some cases, A1 is piperidine or substituted piperidine. In some cases, A1 is piperazine or substituted piperazine. In some cases, A1 is 2-oxopiperidine or a substituted 2-oxopiperidine. In some cases, A1 is 2-oxopiperazine or a substituted 2-oxopiperazine. In some cases, A1 is tetrahydropyran or a substituted tetrahydropyran. In some cases, A1 is pyran or a substituted pyran. In some cases, A1 is pyridyl or a substituted pyridyl. In some cases, A1 is a cyclic sulfone or a substituted cyclic sulfone.

[0149] In some embodiments of any one of Formulas (IIK) through (IIK3), the A ring is selected from any of Formulas (B2) through (B8), e.g., as described herein. In particular embodiments of any one of Formulas (IIK) through (IIK3), the A ring is selected from the following structures: [ka] In certain embodiments of formula (IIK1), the compound is described by any one of formulas (IIK1a) through (IIK1i). [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0150] In certain embodiments, any one of formulas (IIK1a) through (IIK1i) has a relative configuration as described by formula (IIK1ii). In certain embodiments, any one of formulas (IIK1a) through (IIK1i) has a relative configuration as described by formula (IIK1iii).

[0151] In some embodiments of any one of formulas (IIK1a) through (IIK1i), (IIK1ii) or (IIK1iii), Y 2 is S. In some embodiments of any one of formulas (IIK1a) through (IIK1i), (IIK1ii) or (IIK1iii), Y 1 In some embodiments of any one of formulas (IIK1a) through (IIK1i), (IIK1ii) or (IIK1iii), Y 2 is S and Y 1 In some embodiments of any one of formulas (IIK1a) through (IIK1i), (IIK1ii) or (IIK1iii), Y 2 is S and Y 1 is N. In some embodiments of any one of formulas (IIK1a) through (IIK1i), (IIK1ii) or (IIK1iii), Y 2 is O. In some embodiments of any one of formulas (IIK1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 2 is NR 19 In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 2 In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 2 is O and Y 1 In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 2 is NR 19 and Y 1 In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y 2 is NH and Y 1is CH. In some embodiments of any one of Formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y2 is O and Y1 is N. In some embodiments of any one of Formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y2 is NR 19 and Y 1 is N. In some embodiments of any one of formulas (IIG1a) through (IIG1i), (IIG1ii) or (IIG1iii), Y2 is NH and Y 1 is N.

[0152] In certain embodiments of any one of formulas (IIK) through (IIK3a), R 11 In particular embodiments of any one of (IIK1), (IIK1a) through (IIK1i), (IIK1ii), (IIK1iii), (IIK3) or (IIK3a), R 15 , R 16 , R 17 and R 18 are each independently selected from hydrogen, alkyl, and substituted alkyl. In certain cases, R 15 , R 16 , R 17 and R 18 are hydrogen. In certain cases, R 15 is lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl), and R 16 , R 17 and R 18 are hydrogen. In certain cases, R 15 and R 17 are each lower alkyl, and R 16 and R 18 are each hydrogen. In some cases, R 15 and R 16 is hydrogen and R 17 and R 18 are each lower alkyl.

[0153] In certain embodiments of any one of (IIK) through (IIK3a), R 4and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 In some cases of any one of formulas (IIK) to (IIK3a), R 4 and R 5 together with the carbon to which they are attached form a cycloalkyl group.

[0154] In certain embodiments of any one of formulas (IIK) through (IIK3a), R 2 In certain embodiments of any one of formulas (IIK) through (IIK3a), R 3 is methyl.

[0155] In certain embodiments, in formulas (IIK) to (IIK3a), R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 15 , R 16 , R 17 and R 18 are independently selected from the corresponding groups as shown in any of the structures in Tables 1, 2, or 3.

[0156] In certain embodiments, the compound is described by any of the following structures: [ka] In some embodiments, the compound is described by the structure of formula (III): [ka] Here, --- is absent or a bond. R 7 and R 8 are each independently selected from H, halogen, alkyl, and substituted lower alkyl; and R 9is substituted with substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl and substituted heteroaryl.

[0157] In certain embodiments of formula (III), the compound is described by formula (IIIA) or (IIIB). [ka] or [ka] In some embodiments of any one of formulas (III) through (IIIB), Y 2 is S. In some embodiments of any one of formulas (III) through (IIIB), Y 1 is CH. In some embodiments of any one of formulas (III) through (IIIB), Y 2 is S and Y 1 is CH. In some embodiments of any one of formulas (III) through (IIIB), Y 2 is S and Y 1 is N. In some embodiments of any one of formulas (III) through (IIIB), Y 2 is O. In some embodiments of any one of formulas (III) through (IIIB), Y 2 is NR 19 In some embodiments of any one of formulas (III) through (IIIB), Y 2 In some embodiments of any one of formulas (III) through (IIIB), Y 2 is O and Y 1 is CH. In some embodiments of any one of formulas (III) through (IIIB), Y 2 is NR 19 and Y 1 is CH. In some embodiments of any one of formulas (III) through (IIIB), Y 2 is NH and Y 1is CH. In some embodiments of any one of Formulas (III) through (IIIB), Y2 is O and Y1 is N. In some embodiments of any one of Formulas (III) through (IIIB), Y2 is NR 19 and Y1 is N. In some embodiments of any one of formulas (III) through (IIIB), Y2 is NH and Y1 is N.

[0158] In certain embodiments of any one of (III) through (IIIB), R 7 and R 8 are each independently lower alkyl. In certain cases, R 9 In some cases of any one of formulas (III) to (IIIB), R 9 is the formula -(CH2) n -X 1 where n is 0, 1, 2, or 3, and X 1 is hydroxyl, halogen, alkyl halide (e.g., CF3), aryl (e.g., phenyl), or heterocycle (e.g., pyridyl (e.g., 3-pyridyl), pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl, indolyl, furyl, imidazolyl, oxazolyl, thiazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidino, morpholino, piperazino, piperidino, tetrahydrofuran). In some cases, X 1 is a cycloalkyl or heterocycle (e.g., a 5- or 6-membered saturated N-containing ring). 1 is selected from cyclohexyl, cyclopentyl, cyclopropyl, pyrrolidinyl, piperidinyl, tetrahydrofuran, phenyl, and pyridinyl. In certain cases, X1 can be represented by Ring A (e.g., as described herein).

[0159] In certain embodiments of any one of formulas (III) through (IIIB), R 2 is methoxy. In certain embodiments of any one of formulas (III) through (IIIB), R 3 is methyl.

[0160] In some embodiments of any one of formulas (III) through (IIIB), R 1 is the formula -(CH2) n -X 1 where n is 0, 1, 2, or 3, and X 1 is lower alkyl (e.g., methyl), hydroxyl, halogen, alkyl halide, aryl (e.g., phenyl), or heterocycle (e.g., pyridyl (e.g., 3-pyridyl), pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl, indolyl, furyl, imidazolyl, oxazolyl, thiazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidino, morpholino, piperazino, piperidino, tetrahydrofuran). In some cases, R 1 or X 1 can be represented by ring B (e.g., as described herein).

[0161] In certain embodiments of any one of formulas (III) through (IIIB), R 1 , R 2 , R 3 , R 7 , R 8 and R 9 are independently selected from the corresponding groups as shown in any of the structures in Tables 1, 2, or 3. In some embodiments, the subject compounds are described by the structure of formula (VI): [ka] wherein X and Y are independently selected from the substituents shown below. [ka] Here, R a is selected from hydrogen, methyl, OMe, OtBu, OCF3. R b is selected from methyl or hydrogen. R c is selected from halogen or CF3. [ka]

[0162] In some embodiments of Formula (VI), Y 2 is S. In some embodiments of formula (VI), Y 1 is CH. In some embodiments of Formula (VI), Y 2 is S and Y 1 is CH. In some embodiments of Formula (VI), Y 2 is S and Y 1 is N. In some embodiments of formula (VI), Y 2 is O. In some embodiments of Formula (VI), Y 2 is NR 19 In some embodiments of formula (VI), Y 2 In some embodiments of formula (VI), Y 2 is O and Y 1 is CH. In some embodiments of Formula (VI), Y 2 is NR 19 and Y 1 is CH. In some embodiments of Formula (VI), Y 2 is NH and Y 1 is CH. In some embodiments of Formula (VI), Y 2 is O and Y 1 is N. In some embodiments of formula (VI), Y 2 is NR 19 and Y 1 is N. In some embodiments of Formula (IIB), Y 2 is NH and Y 1 is N.

[0163] In some embodiments of any one of Formulas (I) through (VI) (e.g., any of the formulas described herein), R 2 In some embodiments of any one of Formulas (I) through (VI), R3 is methyl. In some embodiments of any one of Formulas (I) through (VI), Y 2 is S and R 3is methyl. In some embodiments of any one of Formulas (I) through (VI), R2 is halogen (e.g., Cl or Br). In some embodiments of any one of Formulas (I) through (VI), R 2 is substituted lower alkyl. In some embodiments of any one of formulas (I) through (VI), R 2 is CF3. In some embodiments of any one of formulas (I) through (VI), R 2 is CHF2. In some embodiments of any one of formulas (I) through (VI), R 2 is CHF. In some embodiments of any one of formulas (I) through (VI), R 2 is lower alkyl. In some embodiments of any one of formulas (I) through (VI), R2 is methyl.

[0164] In certain embodiments, the compound is described by the structure of one of the compounds in Tables 1, 2, or 3. It is understood that any of the compounds shown in Tables 1, 2, or 3 can exist in the form of a salt, such as a trifluoroacetate salt (e.g., a CF3COOH salt). In some cases, the salt form of the compound is a pharmaceutically acceptable salt. Table 1: Compounds [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] Table 2: Compounds [Table 2] Table 3: Compounds [Table 3]

[0165] In certain embodiments, the compound is described by the structure of one of the compounds in Table 1. In certain embodiments, the compound is described by the structure of one of the compounds in Table 2. In certain embodiments, the compound is described by the structure of one of the compounds in Table 3. It is understood that any of the compounds shown in Tables 1, 2, or 3 can exist in the form of a salt, such as a trifluoroacetate salt (e.g., a CF3COOH salt). In some cases, the salt form of the compound is a pharmaceutically acceptable salt.

[0166] Aspects of the present disclosure include PI-kinase inhibitor compounds, their salts (e.g., pharmaceutically acceptable salts), and / or solvates, hydrates, and / or prodrug forms thereof. Furthermore, in any compound described herein possessing one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may independently be in the R or S configuration or a mixture thereof. It is understood that all permutations of salts, solvates, hydrates, prodrugs, and stereoisomers are intended to be encompassed by the present disclosure.

[0167] In some embodiments, the subject compounds or their prodrug forms are provided in the form of pharmaceutically acceptable salts. Compounds containing amine or nitrogen-containing heteroaryl groups may be basic in nature and therefore may react with any number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Acids commonly used to form salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and organic acids such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid, parabromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, and the like. benzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, hippurate, gluconate, lactobionate, and similar salts. In certain embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as fumaric acid and maleic acid.

[0168] In some embodiments, the subject compound is provided in a prodrug form. "Prodrug" refers to a derivative of an active agent that requires conversion within the body to release the active agent. In certain embodiments, the conversion is enzymatic. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the active agent. "Promoiety" refers to a form of protecting group that, when used to mask a functional group within an active agent, converts the active agent into a prodrug. In some cases, the promoiety will be attached to the drug via a bond that is cleaved in vivo by enzymatic or non-enzymatic means. Any convenient prodrug form of the subject compound can be prepared, for example, according to the strategies and methods described by Rautio et al. ("Prodrugs: design and clinical applications," Nature Reviews Drug Discovery 7, 255-270 (February 2008)). In some cases, the promoiety is attached to a hydroxy or carboxylic acid group of the subject compound. In certain cases, the promoiety is an acyl or substituted acyl group. In certain cases, the promoiety is, for example, an alkyl or substituted alkyl group that forms an ester functionality when attached to a carboxylic acid group of the compound of interest.

[0169] In some embodiments, the subject compound, prodrug, stereoisomer, or salt thereof is provided in the form of a solvate (e.g., hydrate). As used herein, the term "solvate" refers to a complex or aggregate formed by one or more molecules of solute (e.g., a prodrug or a pharmaceutically acceptable salt thereof, and one or more molecules of solvent). Such solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent. Representative solvates include water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is water, the solvate formed is a hydrate.

[0170] In some embodiments, the subject compounds are provided by oral administration and absorbed into the bloodstream. In some embodiments, the oral bioavailability of the subject compounds is 30% or greater. The subject compounds or their formulations can be modified using any convenient method to enhance absorption throughout the intestinal lumen or their bioavailability. In some embodiments, the subject compounds are metabolically stable (e.g., remain substantially intact in vivo for the half-life of the compound). In certain embodiments, the half-life (e.g., in vivo half-life) of the compound is 5 minutes or longer, such as 10 minutes or longer, 12 minutes or longer, 15 minutes or longer, 20 minutes or longer, 30 minutes or longer, 60 minutes or longer, 2 hours or longer, 6 hours or longer, 12 hours or longer, 24 hours or longer, or longer. [method]

[0171] As summarized above, aspects of the present invention include PI4-kinase inhibitor compounds and methods of inhibition using the same. PI4-kinase inhibitor compounds are compounds that inhibit the activity of PI4-kinase in cells upon contact with the cells or components thereof. In one embodiment, methods of treating pathogen infections are provided. In one embodiment, methods of treating cancer are also provided. PI4-kinase inhibition in pathogen-infected cells

[0172] In some cases, the cell types in which the subject compounds are active are those infected with a pathogen, as described herein. By inhibiting PI4-kinase, it is meant that the activity of the enzyme is reduced by 2-fold or more, such as 3-fold or more, 5-fold or more, 10-fold or more, 100-fold or more, or 1000-fold or more, compared to its normal activity (e.g., compared to a positive control).

[0173] In some embodiments, the subject compound is an inhibitor of PI3-kinase. In some embodiments, the subject compound is an inhibitor of PI4-kinase, such as PI4-III-kinase (e.g., PI4-IIIα or PI4-IIIβ). In some cases, the PI4-III-kinase is PI4-IIIα. In some cases, the PI4-III-kinase is PI4-IIIβ. In some embodiments, the subject compound has a PI-kinase inhibition profile that reflects activity against two or more PI-kinases. In some embodiments, the subject compound specifically inhibits both a type II PI3-kinase, such as PI3-kinase IIβ, and a type III PI4-kinase, such as PI4K-IIIα and / or PI4K-IIIβ. In some embodiments, the subject compound specifically inhibits PI4-kinase without undesired inhibition of protein kinases. In some embodiments, the subject compound specifically inhibits PI4-kinase without undesired inhibition of PI3-kinases. In some embodiments, the subject compounds specifically inhibit PI4-kinase and / or a particular PI3-kinase subclass without undesirable inhibition of other PI3-kinase subclasses or protein kinases.

[0174] In some embodiments, compounds of the present disclosure interfere with the interaction between a BAAPP domain and PIP2 in a pathogen (e.g., HCV). For example, a subject compound may act by directly or indirectly reducing the level of PIP2 that specifically binds to the BAAPP domain of the pathogen. Generally, pathogens that contain a BAAPP domain are amenable to inhibition by a subject compound. Similarly, pathogens that depend on PI4-kinase activity are amenable to inhibition by a subject compound.

[0175] In some embodiments, compounds of interest can be assayed by inhibition assays (e.g., IC 50 or EC 50In certain embodiments, the subject compounds inhibit PI4-kinase as determined by an assay that determines the level of activity of the enzyme in either a cell-free system or in cells after treatment with the subject compound, relative to a control, by measuring an IC value of 3 μM or less, 1 μM or less, 500 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 50 nM or less, 30 nM or less, 10 nM or less, 5 nM or less, 3 nM or less, 1 nM or less, or even less. 50 value (or EC 50 value).

[0176] In some embodiments, the subject compounds are assayed for kinase activity (e.g., by measuring beta particle emission rates using a scintillation counter or phosphorimaging) to determine whether the [γ- 32 In certain embodiments, the subject compounds inhibit PI4K-IIIβ with an IC50 of less than about 1 μM, less than about 0.2 μM, less than about 0.1 μM, less than about 10 nM, less than about 1 nM, or less, as set forth in Table 2-3. 50In certain embodiments, the subject compounds have an IC50 value with PI4K-IIIα of less than about 50 μM, less than about 10 μM, less than about 1 μM, less than about 0.1 μM, less than about 10 nM, less than about 1 nM, or less, as described in Table 2-3. In certain further embodiments, the subject compounds have an IC50 value with PI4K-IIIβ of less than [such as] 50 μM, less than 10 nM, less than 6 nM, or less, as described in Table 2-3. In certain further embodiments, the subject compounds have an IC50 value with PI3-kinase p110α-p85 complex of between about 8 and about 10 nM, between about 8 μM and about 10 μM, or more. In certain further embodiments, the subject compounds have an IC50 value with PI3-kinase p110γ-p85 complex of about 2 to about 4 nM, about 4 μM to 5 μM, or more, as described herein. In certain further embodiments, the subject compounds have an IC50 value for type II PI3-kinase beta, as described herein, of less than about 1 μM, less than about 150 nM, less than about 30 nM, or even less. In certain further embodiments, the subject compounds have an IC50 value for type II PI3-kinase alpha of less than 10 μM. In certain further embodiments, more than one of the above criteria is independently met by a particular compound.

[0177] In some embodiments, the potency of a PI4-kinase inhibitor compound tracks its anti-infective (e.g., antiviral) activity. In some cases, the enzymatic activity and anti-infective activity of a subject compound are distinct. In some embodiments, the anti-infective activity of a subject compound depends on the combined inhibition of both PI4KIIIα and PI4KIIIβ, or the combined inhibition of Class III PI4-kinase and Class II PI3-kinase (particularly Class II PI3-kinase beta). A subject compound may have increased specificity for one isoform of these PI-kinase family members.

[0178] In certain embodiments, the subject compounds do not significantly affect mammalian cell viability, as determined by a cytotoxicity assay, e.g., by administering the subject compound to HeLa cells and determining the number of viable cells present. The subject compounds may exhibit cell viability of 15% or greater, such as 20% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 70% or greater, 80% or greater, 90% or greater, 100% or greater, 120% or greater, or greater, compared to a control (e.g., a DMSO control). The subject compounds may exhibit a CC of 1 nM or greater, such as 100 nM or greater, 300 nM or greater, 1 μM or greater, 3 μM or greater, 5 μM or greater, 10 μM or greater, 20 μM or greater, 30 μM or greater, 50 μM or greater, or greater. 50 The value may be indicated.

[0179] In certain embodiments, the compound has a therapeutic index (e.g., the ratio of the compound's cytotoxicity (e.g., cytotoxicity, CC50) to biological activity (e.g., antiviral activity, EC50) of 20 or more, such as 50 or more, 100 or more, 200 or more, 300 or more, 400 or more, 500 or more, or more. As summarized above, aspects of the present disclosure include methods of inhibiting PI-kinases (e.g., PI3, PI4-IIIα, or PI4-IIIβ kinases). A subject compound (e.g., as described herein) may inhibit the activity of at least one PI-kinase in the range of 10% to 100%, e.g., 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more. In certain assays, a subject compound may be present in a concentration of 1x10 -6 M or less (e.g. 1x10 -6 M or less, 1x10 -7 M or less, 1x10 -8 M or less, 1x10 -9 M or less, 1x10 -10 M or less, or 1x10 -11 M or less) IC 50 may inhibit its target.

[0180] Protocols used to determine PI-kinase activity are numerous and include, but are not limited to, binding assays; assays using purified enzymes; cellular assays in which PI4P levels are measured, or cellular assays in which cellular phenotype is measured, e.g., gene expression assays; and cell-free assays, such as in vivo assays involving specific animals, which in certain embodiments may be animal models of a condition associated with the target pathogen.

[0181] In some embodiments, a subject method is an in vitro method comprising contacting a sample with a subject compound that specifically inhibits a target PI-kinase. In certain embodiments, the sample is suspected of containing a PI-kinase, and the subject method further comprises assessing whether the compound inhibits the PI-kinase. In certain embodiments, the PI-kinase is a PI4-kinase or a PI-3 kinase.

[0182] In certain embodiments, the subject compound is a modified compound that includes a label (e.g., a fluorescent label), and the subject method further includes detecting the label, if present, in the sample, e.g., using optical detection.

[0183] In certain embodiments, the compound is modified with an affinity group that binds to a support or a support (e.g., biotin), so that sample that does not bind to the compound can be removed (e.g., by washing). Specifically bound target PI-kinase, if present, can then be detected using any convenient means, such as using binding of a labeled target-specific probe or using a fluorescent protein-reactive reagent.

[0184] In another embodiment of the subject method, the sample is known to contain the target PI-kinase.

[0185] Treatment of pathogenic infections In contrast to the classical paradigm of anti-infective therapy, the present disclosure provides a method for treating pathogen infections by targeting host functions and / or molecules on which the pathogen depends, thereby reducing the pathogen's ability to evade therapeutic agents through mutation. Furthermore, by utilizing such targets, the disclosed method enables combination therapies that address multiple targets, thereby enhancing the ability to eliminate infectious pathogens. The method also provides a broad platform for anti-infective therapy by targeting host functions. Furthermore, in cases where a pathogen encodes its own PI-kinase, the present disclosure provides a method for treating pathogen infections by targeting the pathogen PI-kinase.

[0186] Pathogens of interest include those described in Glenn et al., "PIP-2 Inhibition-Based Antiviral and Anti-Hyperlipidemic Therapies," WO 2009 / 148541, the disclosure of which is incorporated herein by reference in its entirety. Pathogens of interest include, but are not limited to, viral pathogens from the families Picornaviridae, Flaviviridae, Retroviridae, Filoviridae, Togaviridae, Papovaviridae, Papillomaviridae, Polyomaviridae, Caliciviridae, Coronaviridae, Hepeviridae, Bunyaviridae, Poxviridae, and Orthomyxoviridae. In some embodiments, the pathogen is selected from hepacivirus (e.g., HCV), norovirus, hepevirus (e.g., HEV), betacolonvirus (e.g., SARS virus, MERS virus, or SARS-CoV-2 virus), rhinovirus (e.g., B or C), Plasmodium (e.g., Plasmodium falciparum), Toxoplasma, Ebola virus, Francisella tularensis, hantavirus, vaccinia, smallpox, Japanese encephalitis virus, hepatitis A virus, influenza virus, norovirus, poliovirus, enterovirus (e.g., AD), EV71, EV68, human rhinovirus, human poliovirus, hepatovirus (e.g., HAV), West Nile virus, and dengue virus (e.g., 1-4), coxsackievirus, BK virus, JC virus, human papillomavirus, HIV, rubella, cytomegalovirus, and Pseudomonas aeruginosa.

[0187] In some embodiments, when the pathogen is HCV, useful compounds include compounds that target the liver and have a high first-pass effect and consequently low systemic bioavailability, which are typically discarded in early drug development. In other embodiments for the treatment of HCV, the compound or formulation is modified to specifically target the liver.

[0188] Pathogens of interest also include pathogenic fungi. Fungal pathogens of interest that may be targeted using the subject compounds include, but are not limited to, Candida, Aspergillus, Cryptococcus, coccidiosis, histoplasmosis, and the like. Accordingly, fungal disease conditions that the subject methods are used to treat include, but are not limited to, candidiasis, aspergillosis, coccidioidomycosis, Cryptococcus gattii infections, histoplasmosis, and the like.

[0189] In some cases, the method is a method for inhibiting PI4-kinase in a sample. Thus, an embodiment of the method includes contacting a sample with a target compound (for example, as described above) under conditions in which the compound inhibits PI4-kinase. Any convenient protocol can be used for contacting a compound with a sample. The specific protocol used can vary, for example, depending on whether the sample is in vitro or in vivo. For in vitro protocols, the contact between the sample and the compound can be achieved using any convenient protocol. In some cases, the sample includes cells maintained in an appropriate medium, and the complex is introduced into the medium. For in vivo protocols, any convenient administration protocol can be used. Depending on the efficacy of the compound, the cells of interest, the administration method, and the number of cells present, various protocols can be used.

[0190] The term "sample" as used herein generally (but not necessarily) relates to a material or mixture of materials in fluid form that contains one or more components of interest.

[0191] In some embodiments, the subject method is a method for treating an infectious disease suffered by a subject. In some embodiments, the subject method includes administering to the subject an effective amount of a subject compound (e.g., as described herein) or a pharmaceutically acceptable salt thereof. The subject compound may be administered as part of a pharmaceutical composition (e.g., as described herein). In certain of the methods, the administered compound is a compound of one of Formulas (I) to (VI). In certain of the methods, the administered compound is described by one of the compounds in Table 1, 2, or 3.

[0192] In some embodiments, an "effective amount" is an amount of a subject compound that, when administered to an individual in one or more doses, either as a monotherapy or in combination therapy, is effective to reduce an individual's viral load by at least about 20% (20% inhibition), at least about 30% (30% inhibition), at least about 40% (40% inhibition), at least about 50% (50% inhibition), at least about 60% (60% inhibition), at least about 70% (70% inhibition), at least about 80% (80% inhibition), or at least about 90% (90% inhibition) compared to the individual's load in the absence of compound treatment or compared to the individual's bacterial load before or after treatment with the compound.

[0193] In some embodiments, an "effective amount" of a compound is an amount that, when administered one or more times to an individual infected with a virus, is effective to achieve a 1.5 log, 2 log, 2.5 log, 3 log, 3.5 log, 4 log, 4.5 log, or 5 log reduction of the virus in the serum of the individual.

[0194] In some embodiments, an effective amount of the compound is from about 50 ng / ml to about 50 μg / ml (e.g., from about 50 ng / ml to about 40 μg / ml, from about 30 ng / ml to about 20 μg / ml, from about 50 ng / ml to about 10 μg / ml, from about 50 ng / ml to about 1 μg / ml, from about 50 ng / ml to about 800 ng / ml, from about 50 ng / ml to about 700 ng / ml, from about 50 ng / ml to about 600 ng / ml, from about 50 ng / ml to about 500 ng / ml, from about 50 ng / ml to about 400 ng / ml, from about 60 ng / ml to about 400 ng / ml , about 70 ng / ml to about 300 ng / ml, about 60 ng / ml to about 100 ng / ml, about 65 ng / ml to about 85 ng / ml, about 70 ng / ml to about 90 ng / ml, about 200 ng / ml to about 900 ng / ml, about 200 ng / ml to about 800 ng / ml, about 200 ng / ml to about 700 ng / ml, about 200 ng / ml to about 600 ng / ml, about 200 ng / ml to about 500 ng / ml, about 200 ng / ml to about 400 ng / ml, or about 200 ng / ml to about 300 ng / ml).

[0195] In some embodiments, an effective amount of the compound is from about 10 pg to about 100 mg, e.g., from about 10 pg to about 50 pg, from about 50 pg to about 150 pg, from about 150 pg to about 250 pg, from about 250 pg to about 500 pg, from about 500 pg to about 750 pg, from about 750 pg to about 1 ng, from about 1 ng to about 10 ng, from about 10 ng to about 50 ng, from about 50 ng to about 150 ng, from about 150 ng to about 250 ng, or from about 250 ng The amount may range from about 500 ng to about 750 ng, about 750 ng to about 1 μg, about 1 μg to about 10 μg, about 10 μg to about 50 μg, about 50 μg to about 150 μg, about 150 μg to about 250 μg, about 250 μg to about 500 μg, about 500 μg to about 750 μg, about 750 μg to about 1 mg, about 1 mg to about 50 mg, about 1 mg to about 100 mg, or about 50 mg to about 100 mg. The amount may be a single dose or a total daily amount. The total daily amount may range from 10 pg to 100 mg, or from 100 mg to about 500 mg, or from 500 mg to about 1000 mg or about 3000 mg.

[0196] In some embodiments, the compound is administered in a single dose. In other embodiments, it is administered multiple times. When administered multiple times over a period of time, the compound can be administered twice a day (qid), once a day (qd), every other day (qod), every third day, three times a week (tiw), twice a week (biw), or once a week (qw) over a period of time. For example, the compound is administered qid, qd, qod, qw, tiw, or biw for a period of 1 day to about 2 years or more. For example, the compound is administered at any of the aforementioned frequencies for 1 week, 2 weeks, 1 month, 2 months, 6 months, 1 year, 2 years, or more, depending on various factors.

[0197] Administration of an effective amount of a subject compound to an individual in need thereof may result in one or more of the following: 1) a reduction in viral load, 2) a reduction in viral load in a target biological sample, 3) a reduction in viral spread from one cell to another in the individual, 4) a reduction in viral entry into cells (e.g., a reduction in viral internalization into cells), 5) a reduction in time to seroconversion, 6) an increase in the rate of durable responses to treatment, 7) a reduction in morbidity or mortality in clinical outcomes, 8) a reduction in the total duration of treatment when used in combination with other antiviral agents, and 9) an improvement in indicators of disease response (e.g., a reduction in one or more symptoms of a viral infection, such as fever). Various methods may be used to determine whether a treatment method is effective. For example, a biological sample obtained from an individual treated with a subject method may be measured.

[0198] In some embodiments of the methods of treatment, the infectious disease symptoms result from infection with a positive-strand RNA virus, a negative-strand RNA virus, or a DNA virus. In some embodiments, the infectious disease symptoms result from infection with a pathogen selected from the group of viral families consisting of Picornaviridae, Flaviviridae, Retroviridae, Filoviridae, Togaviridae, Papovaviridae, Papillomaviridae, Polyomaviridae, Caliciviridae, Coronaviridae, Hepeviridae, Bunyaviridae, Poxviridae, and Orthomyxoviridae. In some embodiments, the infectious disease symptoms result from infection with a pathogen selected from the phylum Apicomplexa or the order Kinetoplastida. In some embodiments, the infectious disease symptoms result from a bacterial infection. In some embodiments, the infectious disease symptoms result from a fungal infection. In some embodiments, the symptoms of infectious disease are due to infection with a pathogen selected from HCV, rhinovirus (e.g., A, B, C, and unclassified), Plasmodium, Plasmodium falciparum, Ebola virus, Francisella tularensis, Hantavirus, SARS virus, MERS virus, SARS-CoV-2 virus, vaccinia, smallpox, Japanese encephalitis virus, Hepatitis A virus, Influenza virus, Norovirus, Poliovirus, Enterovirus (e.g., AD), HEV, EV71, EV68, Coxsackievirus, BK virus, JC virus, Human papillomavirus, West Nile virus, and Dengue virus (e.g., 1-4). In some embodiments, the pathogen is HCV. In some embodiments, the pathogen is a rhinovirus or Plasmodium falciparum. In some embodiments, the pathogen is Hepatitis A virus. In certain embodiments of the methods of treatment, the pathogen is a virus selected from EV71, EV68, human rhinovirus, HAV, HCV, norovirus, coxsackie, BK, polio, and Ebola virus. In some embodiments, the pathogen is hepatitis A virus. In certain cases, the virus is EV71 or EV68. In certain cases, the virus is human rhinovirus. In certain cases, the virus is HAV. In certain cases, the virus is norovirus.In certain cases, the virus is a Coxsackievirus. In certain cases, the virus is a BK virus. In certain cases, the virus is a poliovirus. In certain cases, the virus is an Ebola virus. Any of the compounds described herein may be used in a subject method of treatment. In certain cases, the compound is of any one of Formulas I to VI. In certain cases, the compound is one of the compounds described in Tables 1, 2, or 3. In some cases, the compounds used in the subject methods have broad-spectrum activity against some of the pathogens (e.g., viruses) described herein. In certain cases, the compound has antiviral activity against certain viruses, including one or more of the viruses listed above. In certain cases, the compound has antifungal activity against certain fungi.

[0199] In some embodiments, the pathogen is characterized by having a BAAPP domain that interacts with PIP-2, or a protein that binds to PI(4,5)P2 or PI(4)P. In some embodiments, the pathogen is characterized by having a protein that interacts with one or more PI-4 kinases or PI phosphatases. In some embodiments, the BAAPP domain is derived from an NS5A or NS4B protein. In some embodiments, the symptoms of the infectious disease result from infection with a pathogen that is susceptible to PI4-kinase inhibition. In some embodiments, the compound specifically inhibits PI4-kinase. In some embodiments, the compound has broad-spectrum activity against two or more pathogens. In some embodiments, the compound modulates the activity of PIP-2. In some embodiments, the compound interferes with the interaction of a BAAPP domain of the pathogen with PIP-2. In some embodiments, the compound blocks replication of the pathogen.

[0200] In some embodiments, a subject method is a method of treating high levels of VLDL or LDL cholesterol in a subject. In some embodiments, a subject method includes administering to a subject an effective amount of a 2-aminophenylthiazole compound (e.g., as described above), alone or in combination with other agents known to affect LDL or VLDL levels (e.g., 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors such as lovastatin, fluvastatin, atorvastatin, pravastatin, simvastatin, rosuvastatin, etc.; microsomal triglyceride transfer protein inhibitors such as lomitapide; inhibitors of intestinal cholesterol absorption such as ezetimibe; peroxisome proliferator-activated receptor alpha activators such as fenofibrate).

[0201] In some embodiments, the subject is a human. The subject may be in need of treatment for a viral infection or may be at risk for a viral infection. In some cases, the subject method includes diagnosing a viral infection, including any one of the viruses described herein. In some embodiments, the compound is administered as a pharmaceutical.

[0202] In some embodiments, the subject method is a method for inhibiting viral infection, comprising contacting virally infected cells with an effective amount of a 2-aminophenylthiazole compound (e.g., as described above) to inhibit viral replication. In some embodiments, the method further comprises contacting the cells with a second antiviral agent.

[0203] In some embodiments, the compound is formulated to target the liver. In certain embodiments, the compound is a modified compound containing a label, and the method further comprises detecting the label in the subject. The choice of label depends on the detection means. Any convenient label and detection system can be used in the subject method. See, e.g., Baker, "The whole picture," Nature, 463, 2010, p977-980. In certain embodiments, the compound contains a fluorescent label suitable for optical detection. In certain embodiments, the compound contains a radioactive label for detection using positron emission tomography (PET) or single photon emission computed tomography (SPECT). In some cases, the compound contains a paramagnetic label suitable for tomographic detection. The subject compound can be labeled as described above, but in some methods, the compound is unlabeled, and a secondary labeling agent is used for imaging.

[0204] PI-kinase inhibition in cancer cells In some cases, the cell type in which the compound is active is a cancer cell, as described herein. By inhibiting PI4-kinase, it is meant that the activity of the enzyme is reduced by 2-fold or more, such as 3-fold or more, 5-fold or more, 10-fold or more, 100-fold or more, or 1000-fold or more, compared to its normal activity (e.g., compared to a positive control).

[0205] The disclosed method can target cancer cells. Targeted cancer cells and their metastasis can be considered "addicted" to increased PI4-kinase activity. The latter may result from amplification of chromosomal segments harboring PI4-kinase genes, such as PI4-III-kinase α or PI4-III-kinase β, or eukaryotic protein translation elongation factor 1 alpha 2 (eEF1A2). eEF1A2 is a translation factor involved in internal ribosome entry site (IRES)-mediated translation. eEF1A2 also stimulates PI4-kinase activity and is overexpressed in many cancers. IRESs are often used by viruses as a means to maintain viral translational activity when host translation is inhibited. IRES-mediated translation can contribute to the translation of specific cellular RNAs, particularly under abnormal cellular conditions. Targeted cancer cells may have increased expression of eEF1A2 with or without the above-mentioned chromosomal amplification, either of which may lead to increased PI4-kinase activity. The present inventors have discovered that antiviral PI4 kinase inhibitors that potently target IRES-containing viruses are also effective in reducing the proliferation of cancer cells, and are therefore useful in treating cancer. In some embodiments, cancer cells have normal levels of PI4-kinase activity but are more sensitive to PI4-kinase activity than normal cells.

[0206] Cancer cells of interest that can be targeted in accordance with the subject methods include a wide variety of cancer cells, in some cases, the cancer cells are selected from bladder, breast, colon, endometrial, cervical, testicular, liver, lung, non-small cell lung cancer (NSCLC), ovarian, prostate, pancreatic, brain, thyroid, stomach, kidney, melanoma, and sarcoma cancer cells.

[0207] Thus, aspects of the present disclosure include assessing or measuring the expression level of a PI4-kinase gene or a factor involved in IRES-mediated translation that stimulates PI4-kinase activity (e.g., the eEF1A2 translation factor) in a target cell. In some cases, the assessing or measuring step includes determining whether the target cell has a high level of expression of the PI4-kinase gene or the eEF1A2 translation factor. As used herein, the terms "elevated expression level," "overexpression," and "overexpressed" are used interchangeably and refer to an expression level in a target cell that is 20% or more above the native or basal level of expression in a control cell, such as 30% or more, 40% or more, 40% or more, 40% or more, 40% or more, 40% or more, 40% or more, 2-fold or more, 5-fold or more, 10-fold or more, 30-fold or more, 100-fold or more, or 1000-fold or more compared to the native or basal level of expression in a control cell. In some cases, the control cell is one or more control cells from multiple subjects. In certain cases, the control cells are one or more control cells from a plurality of cells of the same type as the target cells from a plurality of subjects. In some cases, the target cells are normal cells.

[0208] There are many methods that can be used to measure or determine the expression level in a cell, including, but not limited to, cellular assays (e.g., gene expression assays) in which a cell phenotype is measured. The method can be qualitative or quantitative. The expression level can be determined directly or indirectly. In some cases, the gene copy number of the gene of interest in the target cell is measured. In some cases, the gene copy number of PI4 is determined (e.g., PI4KIIIβ or PI4KIIIα). In certain cases, the gene copy number of eEF1A2 is determined. In some cases, the eEF1A2 transcription level is determined. In some cases, the target cancer cell has more than the diploid copy number of the PI4KIIIβ gene.

[0209] Aspects of the present disclosure include assessing or measuring the level of PI4-kinase activity in a target cell. In some cases, the assessing or measuring step includes determining whether the target cell has an elevated level of PI4-kinase activity. The term "elevated activity level" refers to an activity level in a target cell that is 20% or more than the native or basal level of activity in a control cell, such as 30% or more, 40% or more, 40% or more, 40% or more, 40% or more, 40% or more, 40% or more, 2-fold, 5-fold, 10-fold, 30-fold, 100-fold, or 1000-fold or more compared to the native or basal level of activity in a control cell. In some cases, the control cell is one or more control cells from a plurality of subjects. In certain cases, the control cell is one or more control cells from a plurality of cells of the same type as the target cell from a plurality of subjects. In some cases, the target cell is a normal cell.

[0210] Numerous methods can be used to determine PI4-kinase activity, including, but not limited to, binding assays; assays using purified enzymes; measuring PI4-P levels; cellular assays in which cellular phenotype is measured, e.g., gene expression assays; and cell-free assays, such as in vivo assays involving certain animals (which, in certain embodiments, may be animal models of conditions dependent on PI-kinase activity). In some cases, the target cancer cells have high levels of PI4KIIIβ activity. In some embodiments of the subject methods, the target cancer cells are cells sensitive to PI4KIIIβ inhibition. In certain cases, these PI4KIIIβ inhibition-sensitive cells do not exhibit high levels of PI4KIIIβ expression or activity. In some embodiments, the PI4-kinase inhibitor is an inhibitor of a PI4-III-kinase (e.g., PI4-IIIα or PI4-IIIβ). In some embodiments, the PI4-kinase inhibitor has a PI-kinase inhibition profile that reflects activity against two or more PI-kinases. In some embodiments, the PI4-kinase inhibitor specifically inhibits both type II PI3-kinases, such as PI3-kinase IIβ, and type III PI4-kinases, such as PI4K-IIIα and / or PI4K-IIIβ. In some embodiments, the PI4-kinase inhibitor specifically inhibits PI4-kinases without undesired inhibition of other protein kinases. In some embodiments, the PI4-kinase inhibitor specifically inhibits PI4-kinases without undesired inhibition of PI3-kinases. In some embodiments, the PI4-kinase inhibitor specifically inhibits PI4-kinases and / or a particular PI3-kinase subclass without undesired inhibition of other PI3-kinase subclasses or protein kinases.

[0211] In some embodiments, the PI4-kinase inhibitor interferes with the interaction of the intracellular basic amino acid PIP-2 pincer (BAAPP) domain with phosphatidylinositol-4,5-bisphosphate PIP2. See Glenn et al. US 2011 / 0262565 and US 9,926,309. For example, the subject compound may act by directly or indirectly decreasing the level of PIP2 that specifically binds to the BAAPP domain.

[0212] PI4-kinase inhibitors can be identified by inhibition assays (e.g., IC 50 or EC 50 In certain embodiments, the subject compound has an IC50 of 10 μM or less, such as 3 μM or less, 1 μM or less, 500 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 50 nM or less, 30 nM or less, 10 nM or less, 5 nM or less, 3 nM or less, 1 nM or less, or less, or less. 50 value (or EC 50 value).

[0213] PI4-kinase inhibition can be determined by a kinase activity assay (e.g., by measuring the beta particle emission rate using a scintillation counter or phosphorimaging) after treatment with a compound of interest relative to a control, as determined by [γ- 32 In certain embodiments, the inhibitor has an IC50 of PI4K-IIIβ of less than about 1 μM, less than about 0.2 μM, less than about 0.1 μM, less than about 10 nM, less than about 1 nM, or less, as set forth in Table 3. 50 In certain embodiments, the inhibitor has an IC value for PI4K-IIIα of less than about 50 μM, less than about 10 μM, less than about 1 μM, less than about 0.1 μM, less than about 10 nM, less than about 1 nM, or less, as set forth in Table 2-3. 50In certain further embodiments, the inhibitor has an IC50 value with PI4K-IIIβ of 50 μM or less, such as 10 nM or less, 6 nM or less, or less, as set forth in Table 2-3. In certain embodiments, the inhibitor has an IC50 value with type II PI3-kinase alpha of less than 10 μM. In certain embodiments, the inhibitor has an IC50 value with type II PI3-kinase alpha of 1 μM or more, such as 10 μM or more. In certain further embodiments, two or more of the above criteria are independently met by a particular compound.

[0214] In some embodiments, the anti-cancer activity of a PI4-kinase inhibitor tracks with its anti-infective (e.g., antiviral) activity. In some cases, the enzymatic activity and anti-cancer activity of the subject compounds are distinct. In some embodiments, the anti-cancer activity of the subject compounds relies on the combined inhibition of both PI4K IIIIα and PI4K IIIβ, or the combined inhibition of Class III PI4-kinases and / or Class II PI3-kinases (particularly Class II PI3-kinase beta). The subject compounds may have increased specificity for one isoform of these PI-kinase family members.

[0215] In certain embodiments, the PI4-kinase inhibitor does not significantly affect mammalian cell viability, as determined by a cytotoxicity assay, e.g., by administering the compound to primary human hepatocytes and determining the number of viable cells present. The compound may exhibit 15% or greater cell viability, such as 20% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 70% or greater, 80% or greater, 90% or greater, 100% or greater, 120% or greater, or greater, compared to a control (e.g., a DMSO control). The subject compound may exhibit a CC of 1 nM or greater, such as 100 nM or greater, 300 nM or greater, 1 M or greater, 3 M or greater, 5 μM or greater, 10 μM or greater, 20 μM or greater, 30 μM or greater, 50 μM or greater, or greater. 50 The value (the concentration at which 50% of the cells remain viable) can be shown.

[0216] In certain embodiments, the PI4-kinase inhibitor has a therapeutic index (e.g., the ratio of the cytotoxicity of the compound (e.g., normal cytotoxicity, CC50) to the biological activity (e.g., anticancer activity, EC50 - the concentration at which 50% of cancer cells are inhibited)) of two or more, such as 5 or more, 10 or more, 20 or more, 50 or more, 100 or more, 200 or more, 300 or more, 400 or more, 500 or more, or more.

[0217] As summarized above, embodiments of the present disclosure include methods of inhibiting PI4-kinase (e.g., PI4-IIIα and / or PI4-IIIβ kinase) in a cell of interest. The compounds (e.g., as described herein) may inhibit at least one activity of PI4-kinase in the range of 10% to 100%, e.g., 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more. In certain assays, PI4-kinase inhibitors are present in a concentration of 1x10 -6 M or less (e.g. 1x10 -6 M or less, 1x10 -7 M or less, 1x10 -8 M or less, 1x10 -9 M or less, 1x10 -10 M or less, or 1x10 -11 M or less) IC 50 (the concentration required to inhibit 50% of kinase activity) may inhibit its target.

[0218] There are many protocols used to determine PI-kinase activity, including, but not limited to, binding assays; assays using purified enzymes, cellular assays in which PI4P levels are measured, or cellular assays in which cellular phenotype is measured, e.g., gene expression assays; and cell-free assays, such as in vivo assays involving certain animals, which in certain embodiments may be animal models of conditions that are dependent on PI-kinase activity.

[0219] In some embodiments, a subject method is an in vitro method comprising contacting a sample with a compound that specifically inhibits a target PI-kinase. In certain embodiments, the sample is suspected of containing a PI-kinase, and the subject method further comprises assessing whether the compound inhibits the PI-kinase or a PI kinase-dependent function, such as cancer cell growth. In certain embodiments, the PI-kinase is a PI4-kinase (e.g., a PI4-III kinase, such as a PI4-IIIβ kinase). In another embodiment of the subject method, the sample is known to contain the target PI-kinase.

[0220] Cancer treatment In some embodiments, a subject method is an in vivo method comprising administering to a subject an effective amount of a compound that specifically inhibits PI4-kinase. An "effective amount" is an amount of compound that, when administered to an individual in one or more doses, either monotherapy or in combination therapy, is effective to inhibit PI4-kinase by at least about 20% (20% inhibition), e.g., at least about 30% (30% inhibition), at least about 40% (40% inhibition), at least about 50% (50% inhibition), at least about 60% (60% inhibition), at least about 70% (70% inhibition), at least about 80% (80% inhibition), or at least about 90% (90% inhibition), compared to the individual's PI4-kinase activity in the absence of compound treatment, or compared to the PI4-kinase activity in the individual before or after treatment with the compound.

[0221] The subject may be a person suffering from cancer as described herein.Cancers of interest that can be treated according to the subject method include, but are not limited to, bladder cancer, breast cancer, colon cancer, endometrial cancer, liver cancer, cervical cancer, testicular cancer, lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, pancreatic cancer, brain cancer, melanoma, sarcoma, thyroid cancer, gastric cancer, and kidney cancer.In some cases, the cancer is lung cancer.In particular, the lung cancer is lung adenocarcinoma.In some cases, the cancer is breast cancer.In particular, the breast cancer is breast adenocarcinoma.In some cases, the cancer is brain cancer.In some cases, the brain cancer is glioblastoma (GBM).

[0222] In some embodiments, a "therapeutically effective amount" is an amount of a compound that, when administered to an individual in one or more doses, either as a monotherapy or in combination therapy, is effective to reduce the subject's tumor burden by at least about 20%, such as at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, compared to the individual's tumor burden in the absence of compound treatment or compared to the tumor burden in the subject prior to treatment with the compound. As used herein, the term "tumor burden" refers to the total mass of tumor tissue carried by a subject with cancer.

[0223] In some embodiments, a "therapeutically effective amount" is an amount of a subject compound that, when administered in one or more doses to an individual ia, either in monotherapy or combination therapy, is effective to reduce the dose of radiation therapy required to observe tumor shrinkage in the subject by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, compared to the dose of radiation therapy required to observe tumor shrinkage in the individual in the absence of treatment with the compound.

[0224] In some embodiments, a "therapeutically effective amount" is an amount of a compound that, when administered to an individual in one or more doses, either as a monotherapy or in combination therapy, is effective to reduce the metastatic burden in a subject by at least about 20%, e.g., at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, compared to the metastatic burden in the individual in the absence of treatment with the compound, or compared to the metastatic burden in the subject prior to treatment with the compound. As used herein, the term "metastatic burden" refers to the total mass or number of metastatic tissues carried by a subject with cancer.

[0225] In some embodiments, an effective amount of the compound is from about 50 ng / ml to about 50 μg / ml (e.g., from about 50 ng / ml to about 40 μg / ml, from about 30 ng / ml to about 20 μg / ml, from about 50 ng / ml to about 10 μg / ml, from about 50 ng / ml to about 1 μg / ml, from about 50 ng / ml to about 800 ng / ml, from about 50 ng / ml to about 700 ng / ml, from about 50 ng / ml to about 600 ng / ml, from about 50 ng / ml to about 500 ng / ml, from about 50 ng / ml to about 400 ng / ml, from about 60 ng / ml to about 400 ng / ml , about 70 ng / ml to about 300 ng / ml, about 60 ng / ml to about 100 ng / ml, about 65 ng / ml to about 85 ng / ml, about 70 ng / ml to about 90 ng / ml, about 200 ng / ml to about 900 ng / ml, about 200 ng / ml to about 800 ng / ml, about 200 ng / ml to about 700 ng / ml, about 200 ng / ml to about 600 ng / ml, about 200 ng / ml to about 500 ng / ml, about 200 ng / ml to about 400 ng / ml, or about 200 ng / ml to about 300 ng / ml).

[0226] In some embodiments, an effective amount of the compound is from about 10 pg to about 100 mg, e.g., from about 10 pg to about 50 pg, from about 50 pg to about 150 pg, from about 150 pg to about 250 pg, from about 250 pg to about 500 pg, from about 500 pg to about 750 pg, from about 750 pg to about 1 ng, from about 1 ng to about 10 ng, from about 10 ng to about 50 ng, from about 50 ng to about 150 ng, from about 150 ng to about 250 ng, or from about 250 ng The amount may range from about 500 ng to about 750 ng, about 750 ng to about 1 μg, about 1 μg to about 10 μg, about 10 μg to about 50 μg, about 50 μg to about 150 μg, about 150 μg to about 250 μg, about 250 μg to about 500 μg, about 500 μg to about 750 μg, about 750 μg to about 1 mg, about 1 mg to about 50 mg, about 1 mg to about 100 mg, or about 50 mg to about 100 mg. The amount may be a single dose or a total daily amount. The total daily amount may range from 10 pg to 100 mg, or from 100 mg to about 500 mg, or from 500 mg to about 1000 mg or 3000 mg.

[0227] In some embodiments, a single dose of the compound is administered. In other embodiments, multiple doses are administered. When administered multiple times over a period of time, the compound may be administered twice daily (bid), once daily (qd), every other day (qod), every third day, once weekly (qw), three times weekly (tiw), or twice weekly (biw) over a period of time. For example, the compound may be administered bid, qd, qod, tiw, or biw for a period ranging from one day to about two years or more. For example, the compound may be administered at any of the aforementioned frequencies for one week, two weeks, one month, two months, six months, one year, two years, or more, depending on various factors. In some embodiments, the compound may be administered orally, intravenously, subcutaneously, intramuscularly, via inhalation, topically, or sublingually, among other routes of administration, including depot administration. In some embodiments, the compound is administered in combination with a metabolic inhibitor, such as an inhibitor of cytochrome P450 3A / 4 (e.g., ritonavir or cobicistat). In some embodiments, the compounds may be administered in courses that allow for "drug holidays" that may last from 1 to 7 days.

[0228] Administration of a therapeutically effective amount of a subject compound to an individual suffering from cancer may result in one or more of the following: 1) a decrease in tumor burden, 2) a reduction in the dose of radiation therapy required to cause tumor shrinkage, 3) a decrease in the spread of cancer from one location to another in the individual, 4) a decrease in clinical outcomes such as morbidity or mortality, 5) a decrease in the total duration of treatment when combined with other anti-cancer agents, 6) a decrease in the size or number of metastases, and 7) an improvement in indicators of disease response (e.g., a reduction in one or more symptoms of cancer). Various methods may be used to determine whether a therapeutic method is effective. For example, biological samples obtained from an individual treated with a subject method may be measured, or imaging studies may be performed.

[0229] Any of the PI4-kinase inhibitors described herein may be used in a subject method of treatment. In certain cases, the PI4-kinase inhibitor is of any one of formulas (I) through (VI). In certain cases, the compound is one of the compounds described in Tables 1, 2, or 3.

[0230] In some embodiments, the compound specifically inhibits PI4-kinase. In some embodiments, the compound specifically inhibits PI4III-kinase. In some embodiments, the compound specifically inhibits PI4IIIβ-kinase. In some embodiments, the compound specifically inhibits PI4IIIα-kinase. In some embodiments, the compound modulates the activity of cancer cells containing elevated expression of PI4-kinase, or factors involved in IRES-mediated translation (e.g., eEF1A2) that stimulate PI4-kinase activity, or Golgi-mediated secretion. In some cases, the cancer cells contain chromosomal amplification of a PI4-kinase gene (e.g., PI4IIIβ or PI4IIIα), chromosomal amplification of the eEF1A2 gene, or chromosome 1q amplification (i.e., 1q-amplified cancer cells containing PI4IIIβ-kinase in the amplified segment). In some embodiments, the cancer cells have increased expression of eEF1A2 that is not the result of chromosomal amplification of the eEF1A2 gene.

[0231] In some embodiments, the subject is a mammal. In particular cases, the subject is a human. Other subjects include household pets (e.g., dogs and cats), livestock (e.g., cows, pigs, goats, horses, etc.), rodents (e.g., mice, guinea pigs, rats, as animal models of disease), and non-human primates (e.g., chimpanzees, monkeys). The subject may be in need of treatment for cancer. In some cases, the subject method includes diagnosing cancer, including any one of the cancers described herein. In some embodiments, the compound is administered as a pharmaceutical.

[0232] In certain embodiments, the PI4-kinase inhibitor is a modified compound containing a label, and the method further comprises detecting the label in the subject. The choice of label depends on the detection means. Any convenient label and detection system can be used in the subject method. See, e.g., Baker, "The whole picture," Nature, 463, 2010, p. 977-980. In certain embodiments, the compound contains a fluorescent label suitable for optical detection. In certain embodiments, the compound contains a radioactive label for detection using positron emission tomography (PET) or single photon emission computed tomography (SPECT). In some cases, the compound contains a paramagnetic label suitable for tomographic detection. The subject compound can be labeled as described above, but in some methods, the compound is unlabeled, and a secondary labeling agent is used for imaging.

[0233] Coadministration with metabolic enzyme inhibitors In some embodiments of the subject method, the subject PI4-kinase inhibitor may be administered to the subject in combination with an additional or second agent, such as an agent that extends half-life and / or increases the plasma concentration of the co-administered PI4-kinase inhibitor. The additional agent may be a compound that can inhibit an enzyme that metabolizes the PI4-kinase inhibitor from its active form to a less active or inactive form or a derivative of the compound in situ. In some cases, the metabolic enzyme is a cytochrome P-450. Any convenient cytochrome P-450 may be targeted for inhibition by using an additional agent in the subject method. In certain cases, the cytochrome P-450 is CYP3A4.

[0234] Interesting metabolic enzyme inhibitors include, but are not limited to, clarithromycin, cobicistat, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir.For example, ritonavir is a strong inhibitor of CYP3A4, and finds use as a therapeutic HIV protease inhibitor.In some cases, metabolic enzyme inhibitors are co-administered at a dose effective to inhibit metabolic enzyme action on PI4-kinase inhibitors.However, this is a subtherapeutic dose compared to its therapeutic use, for example, in the treatment of HIV.

[0235] The terms "co-administration" and "combination" include the administration of two or more agents simultaneously, in parallel, or sequentially, without specific time limitations. In one embodiment, the agents are present in a cell or subject's body at the same time, or exert their biological or therapeutic effects simultaneously. In one embodiment, the agents are in the same composition or unit dosage form. In other embodiments, the agents are in separate compositions or unit dosage forms. In certain embodiments, the first agent may be administered prior to (e.g., minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the second agent. The routes of administration of the two agents may differ, and representative routes of administration are described in detail below. One skilled in the art would readily be able to determine the appropriate timing, sequence, and dosages of administration of the PI4-kinase inhibitor and the additional agent.

[0236] Combination therapy The PI4-kinase inhibitors disclosed herein may be administered to a subject alone or in combination with an additional (i.e., second) active agent. In combination therapy, the PI4-kinase inhibitor may be used in combination with a second active agent or additional therapy (e.g., radiation therapy). The terms "agent," "compound," and "drug" are used interchangeably herein. For example, a PI4-kinase inhibitor can be administered alone or in combination with one or more other drugs, such as drugs used to treat a disease of interest, including, but not limited to, immunomodulatory diseases and conditions and cancer. In some embodiments, the subject method further includes co-administering a second agent (e.g., a small molecule, a chemotherapeutic agent, an antibody, an antibody fragment, an antibody-drug conjugate, an aptamer, a protein, or a checkpoint inhibitor), either simultaneously or sequentially. In some embodiments, the method further includes administering radiation therapy to the subject.

[0237] The terms "co-administration" and "combination" include the administration of two or more therapeutic agents simultaneously, in parallel, or sequentially, without specific time limitations. In one embodiment, the agents are present in a cell or subject's body at the same time or exert their biological or therapeutic effects simultaneously. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agents are in separate compositions or unit dosage forms. In certain embodiments, the first agent may be administered prior to (e.g., minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or following (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the second therapeutic agent.

[0238] "Co-administration" of a known therapeutic agent or additional treatment with a pharmaceutical composition of the present disclosure means administration of the compound and the second agent or additional treatment at a time such that both the known drug and the composition of the present disclosure have a therapeutic effect. Such co-administration can include administration of the drug simultaneously (i.e., at the same time), before, or after administration of the subject compound. The routes of administration of the two agents can vary, with representative routes of administration being described in detail below. One of ordinary skill in the art will be able to readily determine the appropriate timing, sequence, and dosages of administration for a particular drug or treatment and compound of the present disclosure.

[0239] In some embodiments, the compounds (e.g., a PI4-kinase inhibitor and at least one additional compound or therapy) are administered to a subject within 24 hours of each other, such as within 12 hours of each other, within 6 hours of each other, within 3 hours of each other, or within 1 hour of each other. In certain embodiments, the compounds are administered within 1 hour of each other. In certain embodiments, the compounds are administered at about the same time. By administered at about the same time, it is meant that the compounds are administered to a subject within about 10 minutes or less of each other, such as within 5 minutes or less of each other, or within 1 minute or less of each other.

[0240] Pharmaceutical preparations of PI4-kinase inhibitors and second active agents are also provided. In pharmaceutical dosage forms, the compounds may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination with other pharmaceutically active compounds.

[0241] In conjunction with any of the subject methods, a PI4-kinase inhibitor (e.g., as described herein) (or a pharmaceutical composition comprising such a compound) may be administered in combination with another agent designed to reduce or prevent inflammation, treat or prevent chronic inflammation or fibrosis, or treat cancer. In each case, the PI4-kinase inhibitor may be administered before, simultaneously with, or after the administration of the other agent. In certain cases, the cancer is selected from adrenal, liver, kidney, bladder, breast, colon, stomach, ovary, cervix, uterus, esophagus, colorectal, prostate, pancreas, lung (both small cell and non-small cell), thyroid, carcinoma, sarcoma, glioma, glioblastoma, melanoma, and various head and neck tumors.

[0242] For the treatment of cancer, PI4-kinase inhibitors may be administered in combination with chemotherapeutic agents selected from the group consisting of alkylating agents, nitrosoureas, metabolites, anticancer antibiotics, plant (vinca) alkaloids, steroid hormones, taxanes, nucleoside analogues, steroids, anthracyclines, thyroid hormone replacement drugs, thymidylate-targeted drugs, chimeric antigen receptor / T-cell therapy, chimeric antigen receptor / NK cell therapy, apoptosis regulator inhibitors (e.g., B-cell CLL / lymphoma 2 (BCL-2) BCL-2-like 1 (BCL-XL) inhibitors), CARP-1 / CCAR1 (cell division cycle and apoptosis regulator 1) inhibitors, colony-stimulating factor-1 receptor (CSF1R) inhibitors, CD47 inhibitors, cancer vaccines (e.g., Th17-inducing dendritic cell vaccines, or genetically modified tyrosinase such as Oncept®), and other cell therapies.

[0243] Specific chemotherapeutic agents of interest include, but are not limited to, gemcitabine, docetaxel, bleomycin, erlotinib, gefitinib, lapatinib, imatinib, dasatinib, nilotinib, bosutinib, crizotinib, ceritinib, trametinib, bevacizumab, sunitinib, temsirolimus, sorafenib, trastuzumab, ado-trastuzumab, doxorubicin, Abraxane, Forfirinox, cisplatin, carboplatin, 5-fluorouracil, Teismo, paclitaxel, prednisone, levothyroxine, pemetrexed, navitoclax, and ABT-199. Peptide compounds may also be used. Cancer chemotherapeutic agents of interest include, but are not limited to, dolastatins and their active analogs and derivatives; and auristatins and their active analogs and derivatives (e.g., monomethylauristatin D (MMAD), monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), etc.). See, e.g., WO96 / 33212, WO96 / 14856, and U.S. Pat. No. 6,323,315. Suitable cancer chemotherapeutic agents also include maytansinoids and their active analogues and derivatives (see, e.g., EP 1391213; and Liu et al (1996) Proc. Natl. Acad. Sci. USA 93:8618-8623), duocarmycins and their active analogues and derivatives (e.g., synthetic analogues, including KW-2189 and CB1-TM1), and benzodiazepines and their active analogues and derivatives (e.g., pyrrolobenzodiazepines (PBDs)).

[0244] In some embodiments, the PI4-kinase inhibitor may be administered in combination with a chemotherapeutic agent to treat cancer. In certain cases, the chemotherapeutic agent is gemcitabine. In some cases, the chemotherapeutic agent is docetaxel. In some cases, the chemotherapeutic agent is Abraxane.

[0245] For the treatment of cancer (e.g., solid tumors), a PI4-kinase inhibitor may be administered in combination with an immunotherapeutic agent. Immunotherapeutic agents are convenient agents that can be used to treat diseases by inducing, enhancing, or suppressing immune responses. In some cases, the immunotherapeutic agent is an immune checkpoint inhibitor. Any convenient checkpoint inhibitor may be utilized, including, but not limited to, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a programmed death 1 (PD-1) inhibitor, and a PD-L1 inhibitor. In certain cases, the checkpoint inhibitor is selected from a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a programmed death 1 (PD-1) inhibitor, and a PD-L1 inhibitor. Exemplary checkpoint inhibitors of interest include, but are not limited to, ipilimumab, pembrolizumab, and nivolumab. In certain embodiments, for the treatment of cancer and / or inflammatory diseases, an immunomodulatory polypeptide may be administered in combination with a colony-stimulating factor 1 receptor (CSF1R) inhibitor. CSF1R inhibitors of interest include, but are not limited to, emactuzumab.

[0246] Any convenient cancer vaccine therapy and agent may be used in combination with the PI4-kinase inhibitors, compositions, and methods. For the treatment of cancer (e.g., ovarian cancer), PI4-kinase inhibitors may be administered in combination with vaccination therapy (e.g., dendritic cell (DC) vaccinators that promote Th1 / Th17 immunity). Infiltration of Th17 cells correlates with significantly increased overall survival in ovarian cancer patients. In some cases, ENPP1 inhibitor compounds may find use as adjuvant therapy in combination with Th17-inducing vaccination.

[0247] Also of interest are CARP-1 / CCAR1 (cell cycle and apoptosis regulator 1) inhibitors, including but not limited to those described by Rishi et al., Journal of Biomedical Nanotechnology, Volume 11, Number 9, September 2015, pp. 1608-1627(20), ENPP1 inhibitors, including but not limited to those described by Carozza et al., and CD47 inhibitors, including but not limited to anti-CD47 antibody agents such as Hu5F9-G4.

[0248] In certain cases, the combination provides improved efficacy compared to either component alone. In some cases, the combination provides a supra-additive or synergistic effect compared to the combined or additive effects of the components. Various combinations of the subject compound and chemotherapeutic agent can be used, and can be used sequentially or simultaneously. For multiple doses, the two agents can be, for example, directly alternating, or two or more doses of one agent can be alternating with a single dose of the other agent. Simultaneous administration of both agents can also be staggered or otherwise interspersed with doses of the individual agents. In some cases, the time between administrations can be about 1 to 6 hours, about 6 to 12 hours, about 12 to 24 hours, about 1 to 2 days, about 1 to 2 weeks, or longer, after initiation of treatment. [Usefulness]

[0249] The compounds and methods of the present invention find use in a variety of applications, for example, as described herein. Applications of interest include, but are not limited to, research applications and therapeutic applications. The methods of the present invention find use in a variety of different applications, including any convenient application where inhibition of PI4-kinase is desired.

[0250] The subject compounds and methods find use in a variety of research applications: The subject compounds and methods can be used to optimize the bioavailability and metabolic stability of compounds.

[0251] The subject compounds and methods find use in a variety of therapeutic applications. Therapeutic applications of interest include those in which pathogen infection is a causative or compounding factor in disease progression. As such, the subject compounds find use in treating a variety of different conditions in which inhibition and / or treatment of viral infection in a host is desired. For example, the subject compounds and methods may find use in treating infections caused by pathogens (e.g., as described herein), such as HCV.

[0252] In some embodiments, the subject compounds and methods find use in therapeutic applications involving enterovirus infection. Enteroviruses (EVs) are among the most frequent pathogens infecting humans worldwide and are a leading cause of upper respiratory tract infections. EV infections, accompanied by pulmonary exacerbations, are associated with cystic fibrosis (CF) patients. In certain cases, the subject methods and compounds (e.g., as described herein) find use in treating cystic fibrosis (CF) patients, e.g., to alleviate symptoms or conditions associated with EV infection. In certain cases, the subject compounds and methods can be used to target misfolding of the F508del-cystic fibrosis transmembrane conductance regulator (CFTR).

[0253] In some embodiments, the subject compounds and methods find use in therapeutic applications involving rhinovirus infection. Rhinoviruses are frequent pathogens that infect humans worldwide and are a significant cause of asthma exacerbations. In certain cases, the subject methods and compounds (e.g., as described herein) find use in treating patients with asthma, e.g., to alleviate symptoms or conditions associated with rhinovirus infection.

[0254] Therapeutic applications of interest also include their use in cancer treatment. Thus, the subject compounds find use in treating a variety of different conditions in which inhibition and / or treatment of cancer in a host is desired. For example, the subject compounds and methods can find use in treating solid cancers (e.g., as described herein). [Pharmaceutical composition]

[0255] The compounds discussed herein may be formulated using any convenient excipients, reagents, and methods. The compositions are provided in formulations containing pharmaceutically acceptable excipients. A wide variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients are described, for example, in A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7 th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) AHKibbe et al., eds., 3 rd The invention is well documented in various publications, including ed. Amer. Pharmaceutical Assoc.

[0256] Pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers, or diluents, are readily available to the public. Additionally, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents, and the like, are readily available to the public.

[0257] In some embodiments, the subject compound is formulated in an aqueous buffer. Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate, and phosphate buffers ranging in strength from 5 mM to 100 mM. In some embodiments, the aqueous buffer contains an agent that provides an isotonic solution. Such agents include sodium chloride and a sugar, such as mannitol, dextrose, or sucrose. In some embodiments, the aqueous buffer further contains a non-ionic surfactant, such as polysorbate 20 or 80. If necessary, the formulation may further contain a preservative. Suitable preservatives include, but are not limited to, benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In many cases, the formulation is stored at about 4°C. Formulations can also be lyophilized, in which case they generally contain a cryoprotectant, such as sucrose, trehalose, lactose, maltose, or mannitol. Lyophilized formulations can be stored for long periods at ambient temperatures. In some embodiments, the subject compound is formulated for sustained release. In some embodiments, the subject compounds are formulated for depot release.

[0258] Combined pharmaceutical composition for treating pathogen infections In some embodiments, the subject compound and an antiviral agent (e.g., interferon, ribavirin, enfuvirtide; RFI-641 (4,4″-bis-{4,6-bis-[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]-(1,3,5)triazin-2-ylamino}-biphenyl-2,2″-disulfonic acid); BMS-433771 (2H-imidazo(4,5-c)pyridin-2-one, 1-cyclopropyl-1,3-dihydro-3-((1-(3-hydroxypropyl)-1H-benzimidazo[4,5-c] ... 2-(2-isoxazol-2-yl)methyl); Allildone; Pleconaril (3-(3,5-dimethyl-4-(3-(3-methyl-5-isoxazolyl)propoxy)phenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole); Amantadine (tricyclo[3.3.1.1.3,7]decan-1-amine hydrochloride); Rimantadine (alpha-methyltricyclo[3.3.1.1.3,7]decane-1-methanamine hydrochloride); Acyclovir (acycloguanosine); Valacyclovir; Penciclovir (9-(4-hydroxybenzoyl)phenyl)-9-methyl-2-oxazol-2-yl); oxy-3-hydroxymethyl-but-1-yl)guanine; famciclovir (diacetyl ester of 9-(4-hydroxy-3-hydroxymethyl-but-1-yl)-6-deoxyguanine); ganciclovir (9-(1,3-dihydroxy-2-propoxymethyl)guanine); Ara-A (adenosine arabinoside); zidovudine (3'-azido-2',3'-dideoxythymidine); cidofovir (1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate); dideoxyinosine lamivudine ((-)-β-L-3'-thia-2',3'-dideoxycytidine); abacavir (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol succinate; emtricitabine (-)-β-L-3'-thia-2',3'-dideoxy-5-fluorocytidine;Tenofovir disoproxil ((R)-9-(2-phosphonylmethoxypropyl)adenine bis(isopropoxycarbonyloxymethyl) ester fumarate salt); Bromovinyldeoxyuridine (Brivudine); Iodo-deoxyuridine (Idoxuridine); Trifluorothymidine (Trifluridine); Nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-f][1,4]diazepin-6-one); Delavirdine (1-(5-methanesulfonamido-1H- Indol-2-yl-carbonyl)-4-[3-(1-methylethyl-amino)pyridinyl]piperazine monomethanesulfonate; Efavirenz ((-)6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one); Foscarnet (phosphonoformate trisodium); Ribavirin (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide); Raltegravir (N-[(4-fluorophenyl)methyl]-1,6-di Hydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide monopotassium salt; Neplanocin A; Fomivirsen; Saquinavir (SQ); Ritonavir ([5S-(5R,8R,10R,11R)]-10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12 -Tetraazatridecan-13-oic acid 5-thiazolylmethyl ester; indinavir ([(1S,2R,5(S)-2,3,5-trideoxy-N-(2,3-dihydro-2-hydroxy-1H-inden-1-yl)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl-erythro)pentonamide); amprenavir; nelfinavir; lopinavir; atazanavir; Bevirimat; indinavir; Relenza; zanamivir; oseltamivir;Trobicin, etc.) are administered to an individual in a formulation (e.g., in the same or a separate formulation) that includes a pharmaceutically acceptable excipient;

[0259] In another aspect of the invention, a pharmaceutical composition is provided that comprises, or consists of, a compound of the invention, or a pharmaceutically acceptable salt, isomer, tautomer, or prodrug thereof, and further comprises one or more additional antiviral agents of interest. Any convenient antiviral agent may be utilized in the subject methods in combination with the subject compounds. In some cases, the additional agent is an anti-HCV therapeutic agent selected from an HCV NS3 protease inhibitor, an HCV NS5B RNA-dependent RNA polymerase inhibitor, a thiazolide, a sustained-release thiazolide, a nucleoside analog, interferon alpha or lambda, pegylated interferon, ribavirin, levovirin, viramidine, a TLR7 agonist, a TLR9 agonist, a cyclophilin inhibitor, an α-glucosidase inhibitor, an NS5A inhibitor, an NS3 helicase inhibitor, clemizole or a clemizole analog (such as the benzimidizole and indazole analogs described in U.S. Patent Application Nos. 12 / 383,071 and 12 / 383,030), or another NS4B inhibitor, including an NS4B amphipathic helix inhibitor. The subject compound and second antiviral agent, and the additional therapeutic agent described herein for combination therapy, may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or by other routes. The subject compound and the second antiviral agent may be administered by the same or different routes of administration. The therapeutic agents may be administered by any suitable means, including, but not limited to, oral, rectal, nasal, topical (including transdermal, aerosol, buccal, and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous, and intradermal), intravesical, or by injection into an affected organ. In certain cases, the therapeutic agent may be administered intranasally.

[0260] In some embodiments, the subject compound and the antimalarial agent (e.g., chloroquine, primaquine, mefloquine, doxycycline, atovaquone-proguanil, quinine, quinidine, artesunate, artemether, lumefantrine, etc.) are administered to an individual in a formulation (e.g., in the same or separate formulations) comprising pharmaceutically acceptable excipients. The subject compound and the second antimalarial agent, as well as any additional therapeutic agents described herein for combination therapy, may be administered orally, subcutaneously, intramuscularly, parenterally, or by other routes. The subject compound and the second antimalarial agent may be administered by the same or different routes of administration. The therapeutic agents may be administered by any suitable means, including, but not limited to, oral, rectal, nasal, topical (including transdermal, aerosol, buccal, and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous, and intradermal), intravesical, or by injection into the affected organ.

[0261] The subject compounds can be administered in unit dosage form and can be prepared by any method known in the art. Such methods include combining the subject compounds with pharmaceutically acceptable carriers or diluents, which constitute one or more accessory ingredients. Pharmaceutically acceptable carriers are selected based on the chosen route of administration and standard pharmaceutical practice. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the subject. The carrier can be solid or liquid, and the type is generally selected based on the type of administration being used.

[0262] Examples of suitable solid carriers include lactose, sucrose, gelatin, agar, and bulk powders. Examples of suitable liquid carriers include water, pharmaceutically acceptable oils and fats, alcohols, or other organic solvents (including esters, emulsions, syrups, elixirs, suspensions, solutions, and / or suspensions), and solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid carriers may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents. Preferred carriers are edible oils, such as corn oil or canola oil. Polyethylene glycols (e.g., PEG) are also excellent carriers.

[0263] Any drug delivery device or system that provides the dosing regimen of the present instant disclosure may be used. A wide variety of delivery devices and systems are known to those skilled in the art.

[0264] Although it may not be necessary, the compounds and drugs described herein can be optionally targeted to the liver using any known targeting means.The compounds of the present disclosure can be formulated with a wide variety of compounds that have been demonstrated to target compounds to hepatocytes.Such liver-targeting compounds include, but are not limited to, asialoglycopeptides; basic polyamino acids linked with galactose or lactose residues; galactosylated albumin; asialoglycoprotein-poly-L-lysine conjugates; lactosaminated albumin; lactosylated albumin-poly-L-lysine conjugates; galactosylated poly-L-lysine; galactose-PEG-poly-L-lysine conjugates; lactose-PEG-poly-L-lysine conjugates; asialofetuin; and lactosylated albumin.

[0265] The terms "targeted to the liver" and "targeted to hepatocytes" refer to targeting of a compound to hepatocytes, particularly hepatocytes infected with a virus, such that at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% or more of the compound administered to a subject enters the liver via the hepatic portal vein and becomes associated with (e.g., taken up by) hepatocytes.

[0266] HCV infection is associated with liver fibrosis, and in certain embodiments, inhibitors can be useful for treating (particularly preventing, delaying progression, etc.) liver fibrosis.The method comprises administering the disclosed compound as described above in an amount effective to reduce viral load, thereby treating liver fibrosis in a subject.Treatment of liver fibrosis includes reducing the risk of liver fibrosis, alleviating the symptoms associated with liver fibrosis, and improving liver function.

[0267] Whether treatment with the compounds described herein is effective in reducing liver fibrosis can be determined by any of the many established techniques for measuring liver fibrosis and liver function.An advantage of anti-fibrotic therapy is that it can be measured and evaluated using the Child-Pugh scoring system, which is a multi-component point system based on abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy.Based on the presence and severity of abnormalities in these parameters, patients can be classified into one of three categories (A, B, or C) of increasing clinical disease severity.

[0268] Treatment of liver fibrosis (e.g., reduction of liver fibrosis) can also be determined by analyzing liver biopsy samples. Analysis of liver biopsies consists of assessment of two major components: necroinflammation, assessed by "grade" as a measure of severity and ongoing disease activity, and fibrosis and parenchymal or vascular remodeling lesions, assessed by "stage" as a reflection of long-term disease progression. See, e.g., Brunt (2000) Hepatol. 31:241-246; and METAVIR (1994) Hepatology 20:15-20. Based on analysis of the liver biopsy, a score is assigned. Many standardized scoring systems exist that provide a quantitative assessment of the extent and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[0269] The METAVIR scoring system is based on the analysis of various features of liver biopsies, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (fragmentary and lobular necrosis, eosinophilic shrinkage, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphocytic aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (a score for periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). Each stage in the METAVIR system is defined as follows: score 0, no fibrosis; score 1, stellate dilation of portal tracts but no septum formation; score 2, dilation of portal tracts with rare septum formation; score 3, numerous septa without cirrhosis; and score 4, cirrhosis.

[0270] The Knodell scoring system, also known as the Hepatitis Activity Index, classifies specimens based on scores for four categories of histologic features: I, periportal and / or bridging necrosis; II, intralobular degeneration and focal necrosis; III, portal inflammation; and IV, fibrosis. The Knodell staging system scores are as follows: score 0, no fibrosis; score 1, mild fibrosis (fibrotic portal vein dilation); score 2, moderate fibrosis; score 3, severe fibrosis (bridging fibrosis); and score 4, cirrhosis. The higher the score, the more severe the liver tissue damage. Knodell (1981) Hepatol. 1:431.

[0271] In the Scheuer scoring system, scores are as follows: score 0, no fibrosis; score 1, enlarged fibrous portal tracts; score 2, periportal or porto-portal septa, but intact architecture; score 3, fibrosis with architectural distortion, but no overt cirrhosis; score 4, possible or definite cirrhosis. Scheuer (1991) J. Hepatol. 13:372.

[0272] The Ishak scoring system is described in Ishak (1995) J. Hepatol. 22:696-699. Stage 0, no fibrosis; Stage 1, fibrous dilation of some portal areas with or without short fibrous septa; Stage 2, fibrous dilation of most portal areas with or without short fibrous septa; Stage 3, fibrous dilation of most portal areas with portal-portal (PP) bridging; Stage 4, fibrous dilation of portal areas with marked bridging (PP) and portal centers (PC); Stage 5, marked bridging (PP and / or PC) with occasional nodules (incomplete cirrhosis); Stage 6, possible or definite cirrhosis.

[0273] In some embodiments, a therapeutically effective amount of a compound of the present disclosure is the amount of compound that results in a change of 1 unit or more in fibrosis stage based on pre- and post-treatment measurements of liver function (e.g., as determined by biopsy). In certain embodiments, a therapeutically effective amount of a subject compound results in a reduction of liver fibrosis by at least 1 unit according to the Child-Pugh, METAVIR, Knodell, Scheuer, Ludwig, or Ishak scoring system.

[0274] Secondary or indirect indicators of liver function can be used to assess the effectiveness of treatment. Morphometric computerized semi-automated assessment of the quantitative extent of liver fibrosis based on specific staining of collagen and / or serum markers of liver fibrosis can also be measured as an indicator of the effectiveness of a treatment. Secondary indicators of liver function include, but are not limited to, assessment of serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin levels, and Child-Pugh score. An effective amount of a subject compound is an amount effective to increase an indicator of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% or more compared to the indicator of liver function of untreated individuals or individuals administered a placebo. Those skilled in the art can readily measure such indicators of liver function using standard assays, many of which are commercially available and routinely used in clinical settings.

[0275] Serum markers of liver fibrosis can also be measured as an indicator of the effectiveness of treatment of the subject.Serum markers of liver fibrosis include, but are not limited to, hyaluronic acid, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide and laminin.Additional biochemical markers of liver fibrosis include α-2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A and gamma glutamyl transpeptidase.

[0276] In some cases, a therapeutically effective amount of a subject compound is an amount effective to reduce the serum level of a marker for liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% or more, compared to the level of the marker in untreated individuals or individuals administered a placebo. Those skilled in the art can easily measure such serum markers for liver fibrosis using standard assay methods, many of which are commercially available and routinely used in clinical settings. Methods for measuring serum markers include immunologically based methods, such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, etc., using antibodies specific for a given serum marker.

[0277] Qualitative or quantitative tests of functional hepatic reserve can also be used to assess the effectiveness of drug treatment, including indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.

[0278] As used herein, "complications associated with cirrhosis" refers to diseases that are sequelae of decompensated liver disease, i.e., diseases that occur subsequent to and as a result of the development of liver fibrosis, and include, but are not limited to, the development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver failure, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related death.

[0279] A therapeutically effective amount of a compound in this context can be considered an amount effective to reduce the incidence of (e.g., the likelihood that an individual will develop) a disorder associated with cirrhosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% or more compared to untreated individuals or individuals in a placebo group.

[0280] Whether treatment with the subject compounds is effective in reducing the incidence of diseases associated with cirrhosis of the liver can be readily determined by one of ordinary skill in the art.

[0281] A reduction in HCV viral load and a reduction in liver fibrosis may be associated with an increase in liver function. Therefore, the present disclosure generally provides a method for increasing liver function, comprising administering a therapeutically effective amount of a compound of the present disclosure. Liver function includes, but is not limited to, the synthesis of proteins such as serum proteins (e.g., albumin, coagulation factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, γ-glutaminyltranspeptidase, etc.), bilirubin synthesis, cholesterol synthesis, and bile acid synthesis; liver metabolic functions including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; hemodynamic functions including splanchnic and portal hemodynamics.

[0282] Whether liver function is increased can be easily confirmed by those skilled in the art using well-established tests of liver function. Thus, the synthesis of markers of liver function, such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, and bilirubin, can be assessed by measuring the levels of these markers in serum using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and / or resistance using standard methods. Metabolic function can be measured by measuring the level of ammonia in serum.

[0283] Whether serum proteins normally secreted by the liver are within the normal range can be determined by measuring the levels of such proteins using standard immunological and enzymatic assays. Normal ranges for such serum proteins are known to those skilled in the art. The following are non-limiting examples: The normal range for alanine transaminase is about 7 to about 56 units per liter of serum. The normal range for aspartate transaminase is about 5 to about 40 units per liter of serum. Bilirubin is measured using a standard assay. Normal bilirubin levels are usually less than about 1.2 mg / dL. Serum albumin levels are measured using a standard assay. Normal levels of serum albumin range from about 35 to about 55 g / L. Prolongation of prothrombin time is measured using a standard assay. A normal prothrombin time is less than about 4 seconds longer than the control.

[0284] In this context, a therapeutically effective amount of a compound is one that is effective for increasing liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, a therapeutically effective amount of a compound is an amount effective for reducing elevated levels of serum markers of liver function or for reducing the level of serum markers of liver function to within the normal range by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. A therapeutically effective amount of a compound is also an amount effective for increasing the level of a reduced serum marker of liver function or for raising the level of serum markers of liver function to within the normal range by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%, at least about 80%, or more.

[0285] HCV infection is associated with liver cancer, and in certain embodiments, the present disclosure provides compositions and methods for reducing an individual's risk of developing liver cancer. The methods include administering a subject compound as described above, which reduces the viral load in the individual and reduces the individual's risk of developing liver cancer. An effective amount of the compound reduces the risk of liver cancer by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more. Whether the risk of liver cancer is reduced can be determined, for example, in a study group in which individuals treated according to the subject method have a reduced incidence of liver cancer.

[0286] Combined pharmaceutical composition for treating cancer In some embodiments, the PI4-kinase inhibitor and a second active agent (e.g., as described herein), such as a small molecule, chemotherapeutic agent, antibody, antibody fragment, antibody-drug conjugate, aptamer, or protein, are administered to an individual in a formulation (e.g., in the same or separate formulations) comprising a pharmaceutically acceptable excipient. In some embodiments, the second active agent is a checkpoint inhibitor, such as a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a programmed death 1 (PD-1) inhibitor, or a PD-L1 inhibitor.

[0287] In another aspect, a medical composition is provided that comprises, contains, or consists of a PI4-kinase inhibitor, or a pharmaceutically acceptable salt, isomer, tautomer, or prodrug thereof, and further comprises one or more additional anti-cancer agents of interest. Any convenient anti-cancer agent may be utilized in the subject method in combination with the subject compound. The subject compound may be administered in unit dosage form and may be prepared by any method known in the art. Such methods include combining the subject compound with pharmaceutically acceptable carriers or diluents, which constitute one or more accessory ingredients. Pharmaceutically acceptable carriers are selected based on the chosen route of administration and standard pharmaceutical practice. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the subject. The carrier may be solid or liquid, and the type is generally selected based on the type of administration being used.

[0288] Examples of suitable solid carriers include lactose, sucrose, gelatin, agar, and bulk powders. Examples of suitable liquid carriers include water, pharmaceutically acceptable oils and fats, alcohols, or other organic solvents (including esters, emulsions, syrups, elixirs, suspensions, solutions, and / or suspensions), and solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid carriers may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents. Preferred carriers are edible oils, such as corn oil or canola oil. Polyethylene glycols (e.g., PEG) are also excellent carriers.

[0289] Any drug delivery device or system that provides the dosing regimen of the instant disclosure may be used. A wide variety of delivery devices and systems are known to those skilled in the art.

[0290] Although such may not be necessary, the compounds and agents described herein can be optionally targeted to the site of cancer using any known targeting means. The compounds of the present disclosure can be formulated with a wide variety of compounds that have been demonstrated to target compounds to the site of cancer. The terms "targeted to the site of cancer" and "targeting cancer" refer to targeting of a compound to the site of cancer, such that at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% or more of the compound administered to a subject enters the site of cancer.

[0291] Subjects suitable for treatment with compounds of the present disclosure Individuals who have been clinically diagnosed as infected with a pathogen of interest are suitable for treatment with the methods of the present disclosure. In particular embodiments of interest, individuals of interest for treatment with the present disclosure have a detectable pathogen titer indicative of active replication, e.g., at least about 10 4 , at least about 10 5 , at least about 5x10 5 , or at least 10 6 or greater than 2 million genome copies of HCV per milliliter of serum. Similar methods may be used to determine whether a subject infected with another pathogen is suitable for treatment using the subject method.

[0292] The effectiveness of an anti-infective treatment may be determined using any convenient method, for example, whether a subject method is effective in treating a viral infection may be determined by measuring viral load or by measuring a parameter associated with the infection.

[0293] Viral load can be measured by measuring the titer or level of virus in serum. These methods include, but are not limited to, quantitative polymerase chain reaction (PCR) and branched DNA (bDNA) testing. Many such assays are commercially available, including quantitative reverse transcription PCR (RT-PCR) (Amplicor HCV Monitor™, Roche Molecular Systems, New Jersey) and branched DNA (deoxyribonucleic acid) signal amplification assay (Quantiplex™ HCV RNA Assay (bDNA), Chiron Corp., Emeryville, California). See, e.g., Glenn et al. (1995) Ann. Intern. Med. 123:321-329.

[0294] Individuals who have been clinically diagnosed with cancer are also suitable for treatment with the methods of the present disclosure. In certain embodiments of interest, individuals who are candidates for treatment with the present disclosure have detectable cancer. Any convenient method may be used to determine whether a subject with cancer is suitable for treatment using a subject method. The effectiveness of anti-cancer treatment may be determined using any convenient method. For example, the effectiveness of a subject method for treating cancer may be determined by measuring an improvement in one or more symptoms, a reduction in the size of a tumor or metastasis by imaging, or measuring cancer cells in a biological sample from the subject. [Definition]

[0295] Before further describing the embodiments of the present disclosure, it is to be understood that this disclosure is not limited to particular embodiments described, as these may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, as the scope of the present disclosure will be limited only by the appended claims.

[0296] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of that range and any other stated or intervening value within that stated range is included in the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also included in the invention, subject to any specifically excluded proviso in the stated range. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0297] Certain ranges are presented herein with the numerical values ​​preceded by the term "about." The term "about" is used herein to provide literal support for the exact number it precedes, as well as a number that is close to or approximately the number it precedes. When determining whether a number is close to or approximately a specifically recited number, the approximately or approximating unrecited number may be a number that, in the context in which it is presented, provides a substantial equivalent to the specifically recited number.

[0298] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, and representative exemplary methods and materials are now described.

[0299] All publications and patents cited herein are incorporated by reference as if each individual publication or patent was specifically and individually indicated to be incorporated by reference to disclose and describe the methods and / or materials in connection with which the publication is cited. The citation of a publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the publication dates provided may be different from the actual publication dates which may need to be independently confirmed.

[0300] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should be further noted that the claim may be drafted to exclude any element. This statement is thus intended to serve as a predicate basis for using exclusive terminology such as "solely," "only," or "negative" limitations in connection with the recitation of claim elements.

[0301] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features which may be readily separated or combined with the features of any of the other several embodiments without departing from the scope or spirit of the invention. Any described method may be carried out in the order of events described or in any other order which is logically possible.

[0302] Although the apparatus and methods have been or will be described with functional descriptions for grammatical fluidity, the claims should not necessarily be construed as being limited in any way by the construction of "means" or "step" limitations unless illustratively formulated under 35 U.S.C. § 112. However, the full scope of meaning and equivalents of the definitions provided by the claims under the judicial principle of equivalents should be recognized, and if the claims are expressly formulated under 35 U.S.C. § 112, they constitute full statutory identification under 35 U.S.C. § 112. In describing and claiming the present invention, certain terms will be used in accordance with the definitions set forth below. It will be appreciated that the definitions provided herein are not intended to be mutually exclusive. Accordingly, some chemical moieties may be included within multiple definitions of a term.

[0303] As used herein, the phrases "for example," "such as," or "including" are intended to introduce examples that further clarify a more general subject matter. These examples are provided solely as an aid in understanding the disclosure and are not intended to be limiting in any way.

[0304] The basic amino acid PIP2 pincer (BAAPP) domain, described by Glenn et al., "PIP-2 Inhibition-Based Antiviral and Anti-Hyperlipidemic Therapies," WO 2009 / 148541, incorporated herein by reference in its entirety, provides a mechanism for recognizing (including, but not limited to, binding to, and activating or inhibiting the activity of) PIP2 (phosphatidylinositol, 4,5-diphosphate [PtdIns(4,5)P2], PI(4,5)P2). Alterations or variations in the BAAPP domain can result in the recognition of other phosphatidylinositol variants.

[0305] Phosphoinositides, such as phosphatidylinositol (PI)-4-phosphate (PI(4)P) and PI-4,5-diphosphate (PI(4,5)P2, or "PIP2"), are enriched at various specific plasma membrane and intracellular locations. The steady-state location and abundance of specific PI isoform pools within cells is regulated by families of PI kinases and phosphatases. There are at least four human PI4-kinases, with family members PI4KIIIα and PI4KIIIβ, which are primarily localized to endoplasmic reticulum- and Golgi-derived membranes, where they contribute to these membrane-associated PI(4)P and PI(4,5)P2 pools, and family members PI4KIIα and PI4KIIβ, which primarily contribute to other pools.

[0306] The BAAPP domain mediates specific interactions with PIP2, resulting in conformational changes in the BAAPP domain that affect key pathogenic regulators. In HCV, replication complexes are established at intracellular PIP2-rich sites, and point mutations in the BAAPP domain abolish PIP2 binding and HCV RNA replication. Such a critical dependency on PIP2 is widespread among pathogens. Targeting specific intracellular PIP2 pools by siRNA-mediated knockdown of enzymes involved in PIP2 production—such as PI4KIIIα and PI4KIIIβ—abrogates HCV replication while being well tolerated by host cells.

[0307] Molecules that inhibit the enzymatic pathway involved in PIP-2 production are of interest for use in the methods of the present disclosure, including, but not limited to, inhibitors of phosphatidylinositol 4-kinase III alpha (see, e.g., Berger et al. (2009) PNAS 106:7577-7582, specifically incorporated herein by reference) and inhibitors of phosphatidylinositol 4-kinase III beta.

[0308] BAAPP domains have been identified in multiple organisms, including, but not limited to, pathogens such as viruses, bacteria, fungi, and parasites, as well as hosts such as humans. BAAPP domain peptides, molecules that mimic BAAPP domains, enzymes involved in PIP-2 metabolism, and molecules that inhibit or activate BAAPP domains act to treat infectious diseases and affect host physiology or pathophysiology.

[0309] Examples of proteins containing a BAAPP domain include, but are not limited to, the 2C proteins of Picornaviridae, Rhinovirus 14, Rhinovirus B, Rhinovirus C, Poliovirus, Enterovirus A, Enterovirus B, Enterovirus C, Enterovirus D, Enterovirus 71, and Coxsackie A virus 18. The core proteins of Japanese encephalitis virus, West Nile virus, Dengue virus 1, Dengue virus 2, Dengue virus 3, and Dengue virus 4 contain a BAAPP domain, as does the PfNDH2 protein of Plasmodium falciparum. In the Flaviviridae family, the NS4B AH1 protein of HCV has a BAAPP domain containing conserved lysine residues at residues 20 and 26 of the processed protein, e.g., a peptide having the amino acid sequence SGSWLRDVWDWICTVLTDFKTWLQSKLL (SEQ ID NO: 1) containing lysine residues K20 and K26. Other BAAPP domains harboring pathogens include HAV, vaccinia, Ebola virus, Francisella tularensis, influenza virus polymerase protein, variola major (smallpox), Sin Nombre virus (hantavirus), Pseudomonas aeruginosa, and CMV.

[0310] Ns5-encoding viruses include, but are not limited to, flaviviruses, pestiviruses, and hepatitis C viruses (e.g., yellow fever virus (YFV); dengue viruses, including dengue types 1-4; Japanese encephalitis virus; Murray Valley encephalitis virus; St. Louis encephalitis virus; West Nile virus; tick-borne encephalitis virus; hepatitis C virus; Kunjin virus; Central European encephalitis virus; Russian spring-summer encephalitis virus; Powassan virus; Kyasanur Forest disease virus; and Omsk hemorrhagic fever virus).

[0311] "Flaviviridae virus" refers to any virus in the Flaviviridae family, including viruses that infect humans and non-human animals. Polynucleotide and polypeptide sequences encoding these viruses are known in the art and are available in the NCBI GenBank database (e.g., Genbank accession numbers NC_004102, AB031663, D11355, D11168, AJ238800, NC_001809, NC_001437, NC_004355, NC_004119, NC_003996, NC_004119 ... NC_003690, NC_003687, NC_003675, NC_003676, NC_003218, NC_001563, NC_000943, NC_003679, NC_003678, NC_003677, NC_002657, NC_002032, and NC_001461), the contents of the database entries are incorporated herein by reference in their entireties.

[0312] "Picornaviridae virus" refers to viruses of the Picornaviridae family, including viruses that infect humans and non-human animals, including but not limited to enteroviruses. Polynucleotide and polypeptide sequences encoding these viruses are known in the art and can be found in NCBI's GenBank database.

[0313] "Caliciviridae virus" refers to viruses of the Caliciviridae family, which includes viruses that infect humans and non-human animals, such as norovirus. Polynucleotide and polypeptide sequences encoding these viruses are known in the art and can be found in NCBI's GenBank database.

[0314] "Filoviridae virus" refers to viruses of the Filoviridae family, which includes viruses that infect humans and non-human animals, such as Ebola virus. Polynucleotide and polypeptide sequences encoding these viruses are known in the art and can be found in NCBI's GenBank database.

[0315] "Hepeviridae virus" refers to viruses of the Hepeviridae family, including viruses that infect humans and non-human animals, such as Hepevirus (e.g., HEV). Polynucleotide and polypeptide sequences encoding these viruses are known in the art and can be found in NCBI's GenBank database.

[0316] "Polyomaviridae virus" refers to viruses of the Polyomaviridae family, which includes viruses that infect humans and non-human animals, such as BK virus and JC virus. Polynucleotide and polypeptide sequences encoding these viruses are known in the art and can be found in NCBI's GenBank database.

[0317] "Papillomaviridae virus" refers to viruses of the Papillomaviridae family, including viruses that infect humans and non-human animals, such as human papillomaviruses (e.g., HPV). Polynucleotide and polypeptide sequences encoding these viruses are known in the art and can be found in NCBI's GenBank database.

[0318] "Coronavirus virus" refers to viruses of the Coronaviridae family, including viruses that infect humans and non-human animals, such as betacoronoviruses (e.g., SARS, MERS, SARS-CoV-2). Polynucleotide and polypeptide sequences encoding these viruses are known in the art and can be found in NCBI's GenBank database. In some embodiments, the Coronaviridae virus is selected from human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), SARS-CoV (the causative agent of severe acute respiratory syndrome (SARS)), human coronavirus NL63 (HCoV-NL63, New Haven coronavirus), human coronavirus HKU1, MERS-CoV ("Middle East Respiratory Syndrome coronavirus" or MERS), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or COVID-19 (coronavirus disease 2019). In some cases, the Coronaviridae virus is SARS-CoV-2.

[0319] The terms "activator," "antagonist," "inhibitor," "drug," and "pharmacologically active agent" are used interchangeably herein and refer to chemical compounds or compounds that, when administered to an organism (human or animal), induce a desired pharmacological and / or physiological effect through local and / or systemic action.

[0320] As used herein, the terms "treatment," "treating," and the like refer to obtaining a desired pharmacological and / or physiological effect, such as a reduction in viral titer. The effect can be preventative, in that a disease or its symptoms are completely or partially prevented, and / or therapeutic, in that a disease and / or adverse effects resulting from the disease are partially or completely cured. As used herein, "treatment" covers any treatment of disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptoms of the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as suffering from it (e.g., including diseases that may be associated with or caused by a primary disease, such as liver fibrosis, which may result in a state of chronic HCV infection); (b) inhibiting the disease, i.e., preventing its development; and (c) alleviating the disease, i.e., causing regression of the disease (e.g., a reduction in viral titer).

[0321] The term "pharmaceutically acceptable salt" refers to a salt that is acceptable for administration to a patient, such as a mammal (a salt that contains a counterion that has acceptable mammalian safety for a given dosing regimen). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids. "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound, derived from a variety of organic and inorganic counterions known in the art, including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and, where the molecule contains a basic function, includes salts of organic or inorganic acids such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, and the like.

[0322] The terms "individual," "host," "subject," and "patient" are used interchangeably herein and refer to animals including, but not limited to, humans and non-human primates, including monkeys and humans, rodents, including rats and mice, cattle; horses, sheep, cats, dogs, etc. "Mammal" means one or more members of any mammalian species, including, for example, primates such as dogs, cats, horses, cattle, sheep, rodents, etc., and non-human primates, and humans. For example, non-human animal models of mammals, e.g., non-human primates, murines, lagomorphs, etc., may be used in experimental investigations.

[0323] As used herein, the terms "determine," "measure," "assess," and "analyze" are used interchangeably and include both quantitative and qualitative determinations. The terms "polypeptide" and "protein," used interchangeably herein, refer to polymeric forms of amino acids of any length, which may include coded and non-coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides with modified peptide backbones. The terms also include fusion proteins, including, but not limited to, fusion proteins with heterologous amino acid sequences, fusions with heterologous and native leader sequences, with or without an N-terminal methionine residue, immunologically tagged proteins, fusion proteins with a detectable fusion partner (e.g., fluorescent proteins, β-galactosidase, luciferase, etc., as fusion partners), and the like.

[0324] The terms "nucleic acid molecule" and "polynucleotide" are used interchangeably and refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or their analogs. Polynucleotides may have any three-dimensional structure and may perform any function, known or unknown. Non-limiting examples of polynucleotides include genes, gene fragments, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, control regions, any isolated RNA sequence, nucleic acid probes, and primers. Nucleic acid molecules can be linear or circular.

[0325] "Therapeutically effective amount" or "effective amount" means the amount of a compound that, when administered to a mammal or other subject for treating a disease, condition, or disorder, is sufficient to effect such treatment for the disease, condition, or disorder. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0326] As used herein, a "unit dosage form" is a physically discrete unit suitable as a single dosage for human and animal subjects, each unit containing a predetermined quantity of a compound (e.g., an aminopyrimidine compound described herein) calculated to be sufficient to produce a desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle. The specifications for the unit dosage form depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

[0327] "Pharmaceutically acceptable excipient," "pharmaceutically acceptable diluent," "pharmaceutically acceptable carrier," and "pharmaceutically acceptable adjuvant" refer to excipients, diluents, carriers, and adjuvants useful in the preparation of pharmaceutical compositions, including excipients, diluents, carriers, and adjuvants that are generally safe, non-toxic, non-biologically undesirable, and acceptable for use in veterinary and human medicine. As used herein and in the claims, "pharmaceutically acceptable excipients, diluents, carriers, and adjuvants" includes both one or more such excipients, diluents, carriers, and adjuvants.

[0328] As used herein, "pharmaceutical composition" is meant to encompass compositions suitable for administration to a subject, such as a mammal, particularly a human. Generally, a "pharmaceutical composition" is sterile and preferably free of contaminants that may induce an undesirable reaction in the subject (e.g., the compounds in the pharmaceutical composition are pharmaceutical grade). Pharmaceutical compositions may be designed to be administered to a subject or patient in need thereof via several different routes of administration, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intratracheal, intramuscular, subcutaneous, etc.

[0329] The terms "having the formula" or "having the structure" are not intended to be limiting and are used in the same manner as the term "comprising" is generally used. The term "independently selected from" is used herein to indicate that the listed elements, R groups, or the like, can be the same or different.

[0330] As used herein, the terms "may," "optionally," "optionally," or "optionally may" mean that the subsequently described situation may or may not occur. Thus, the description includes situations where the situation may or may not occur. For example, the phrase "optionally substituted" means that a non-hydrogen substituent may or may not be present at a particular atom, and thus the description includes structures where the non-hydrogen substituent is present and structures where the non-hydrogen substituent is not present.

[0331] "Acyl" refers to the groups HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted ... " refers to heteroaryl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclyl-C(O)-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl includes the "acetyl" group CHC(O)-.

[0332] The term "alkyl," as used herein, refers to a branched or unbranched saturated hydrocarbon group (i.e., monoradical) typically (but not necessarily) containing from 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl and cyclohexyl. Generally, although not necessarily, alkyl groups herein can contain from 1 to about 18 carbon atoms, and such groups can contain from 1 to about 12 carbon atoms. The term "lower alkyl" refers to an alkyl group of 1 to 6 carbon atoms. "Substituted alkyl" refers to an alkyl group substituted with one or more substituents, including when two hydrogen atoms from the same carbon atom of the alkyl substituent are replaced, for example, in a carbonyl group (i.e., the substituted alkyl group can contain a -C(=O)- moiety). The terms "heteroatom-containing alkyl" and "heteroalkyl" refer to an alkyl substituent in which at least one carbon atom has been replaced with a heteroatom, as described in more detail below. Unless otherwise specified, the terms "alkyl" and "lower alkyl" include straight-chain, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkyl or lower alkyl, respectively.

[0333] The term "substituted alkyl" is meant to include alkyl groups, as defined herein, wherein one or more carbon atoms of the alkyl chain are optionally substituted with -O-, -N-, -S-, -S(O) n- (n is 0 to 2), substituted with a heteroatom such as -NR- (where R is hydrogen or alkyl), alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, and NR a R b wherein R' and R' may be the same or different and are selected from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocycle.

[0334] The term "alkenyl," as used herein, refers to a straight-chain, branched, or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethynyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, etc. Generally, although not necessarily, an alkenyl group herein can contain from 2 to about 18 carbon atoms, e.g., from 2 to about 12 carbon atoms. The term "lower alkenyl" refers to an alkenyl group of 2 to 6 carbon atoms. The term "substituted alkenyl" refers to an alkenyl substituted with one or more substituents, and the terms "heteroatom-containing alkenyl" and "heteroalkenyl" refer to an alkenyl in which at least one carbon atom has been replaced with a heteroatom. Unless otherwise specified, the terms "alkynyl" and "lower alkyl" include straight-chain, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkynyl or lower alkynyl, respectively.

[0335] The term "alkynyl," as used herein, refers to a straight-chain or branched hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, etc. Generally, although not necessarily, an alkynyl group herein can contain from 2 to about 18 carbon atoms, for example, from 2 to about 12 carbon atoms. The term "lower alkynyl" refers to an alkynyl group of 2 to 6 carbon atoms. The term "substituted alkynyl" refers to an alkynyl substituted with one or more substituents, and the terms "heteroatom-containing alkynyl" and "heteroalkynyl" refer to an alkynyl in which at least one carbon atom has been replaced with a heteroatom. Unless otherwise specified, the terms "alkynyl" and "lower alkynyl" include straight-chain, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkynyl or lower alkynyl, respectively.

[0336] The term "alkoxy" as used herein intends an alkyl group attached through a single, terminal ether linkage, i.e., an "alkoxy" group can be represented as -O-alkyl, where alkyl is as defined above. A "lower alkoxy" group intends an alkoxy group containing 1 to 6 carbon atoms and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy, and the like. A substituent identified herein as "C1 to C6 alkoxy" or "lower alkoxy" can contain, for example, 1 to 3 carbon atoms; as a further example, such a substituent can contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy).

[0337] The term "substituted alkoxy" refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O-, where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl, and substituted alkynyl are as defined herein.

[0338] As used herein, unless otherwise specified, the term "aryl" generally, but not necessarily, refers to an aromatic substituent containing 5 to 30 carbon atoms and including a single aromatic ring or multiple aromatic rings that are fused, directly bonded, or indirectly bonded (such that different aromatic rings are bonded to a common group, such as a methylene or ethylene moiety). Aryl groups can contain, for example, 5 to 20 carbon atoms, and as a further example, 5 to 12 carbon atoms. For example, aryl groups can contain one aromatic ring or two or more fused or linked aromatic rings (i.e., biaryl, aryl-substituted aryl, etc.). Examples include phenyl, naphtha, biphenyl, diphenylether, diphenylamine, benzophenone, etc. The term "substituted aryl" refers to an aryl moiety substituted with one or more substituents, and the terms "heteroatom-containing aryl" and "heteroaryl" refer to aryls in which at least one carbon atom has been replaced with a heteroatom, as described in more detail below. Aryl refers to stable cyclic, heterocyclic, polycyclic, and polycyclic unsaturated C3-C 14 The term "aryl" is intended to include moieties, examples of which include, but are not limited to, phenyl, biphenyl, naphthyl, pyridyl, furyl, thiophenyl, imidazolyl, pyrimidinyl, and oxazolyl, which may be further substituted with one to five members selected from the group consisting of hydroxy, C1-C8 alkoxy, C1-C8 branched or straight chain alkyl, acyloxy, carbamoyl, amino, N-acylamino, nitro, halogen, trifluoromethyl, cyano, and carboxyl (see Katritzky, Handbook of Heterocyclic Chemistry). Unless otherwise specified, the term "aryl" includes unsubstituted, substituted, and / or heteroatom-containing aromatic substituents.

[0339] The term "aralkyl" refers to an alkyl group with an aryl substituent, and the term "alkaryl" refers to an aryl group with an alkyl substituent, where "alkyl" and "aryl" are defined above. Generally, the aralkyl and alkaryl groups described herein contain from 6 to 30 carbon atoms. Aralkyl and alkaryl groups can, for example, contain from 6 to 20 carbon atoms, and as a further example, such groups can contain from 6 to 12 carbon atoms.

[0340] The term "alkylene," as used herein, refers to a diradical alkyl group. Unless otherwise specified, such groups include saturated hydrocarbon chains containing 1 to 24 carbon atoms, which may be substituted or unsubstituted, may contain one or more alicyclic groups, and may contain heteroatoms. "Lower alkylene" refers to an alkylene linkage containing 1 to 6 carbon atoms. Examples include methylene (--CH--), ethylene (--CHCH--), propylene (--CHCHCH--), 2-methylpropylene (--CH--CH(CH)--CH--), hexylene (--(CH)--), and the like.

[0341] Similarly, the terms "alkenylene," "alkynylene," "arylene," "aralkylene," and "alkylene" as used herein refer to the diradicals alkenyl, alkynyl, aryl, aralkyl, and alkaryl, respectively.

[0342] The term "amino" is used herein to refer to the group -NRR', where R and R' are independently hydrogen or non-hydrogen substituents, with non-hydrogen substituents including, for example, alkyl, aryl, alkenyl, aralkyl, and substituted and / or heteroatom-containing variants thereof.

[0343] The terms "halo" and "halogen" are used in the conventional sense to refer to a chloro, bromo, fluoro, or iodo substituent.

[0344] "Carboxyl", "carboxy" or "carboxylate" refers to -CO2H or a salt thereof.

[0345] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings, including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl.

[0346] The term "substituted cycloalkyl" refers to a cycloalkyl group having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and SO2-heteroaryl.

[0347] The term "heteroatom-containing," such as "heteroatom-containing alkyl group" (also referred to as "heteroalkyl" group) or "heteroatom-containing aryl group" (also referred to as "heteroaryl" group), refers to a molecule, bond, or substituent in which one or more carbon atoms have been replaced with an atom other than carbon, such as nitrogen, oxygen, sulfur, phosphorus, or silicon, typically nitrogen, oxygen, or sulfur. Similarly, the term "heteroalkyl" refers to an alkyl substituent that is heteroatom-containing, the terms "heterocyclic" or "heterocycle" refer to a cyclic substituent that is heteroatom-containing, and the terms "heteroaryl" and "heteroaromatic" refer to heteroatom-containing and related "aryl" and "aromatic" substituents, respectively. Examples of heteroalkyl groups include alkoxyaryl, alkylsulfanyl-substituted alkyl, N-alkylated aminoalkyl, and the like. Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, furyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, and the like; examples of heteroatom-containing alicyclic groups include pyrrolidino, morpholino, piperazino, piperidino, tetrahydrofuran, and the like.

[0348] "Heteroaryl" refers to an aromatic group of 1 to 15 carbon atoms, including 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl, imidazolyl, furyl, etc.) or multiple condensed rings in a ring system (e.g., indolizinyl, quinolinyl, benzofuran, benzimidazolyl, benzothienyl, etc.), where at least one ring in the ring system is aromatic and at least one ring in the ring system is aromatic when the point of attachment is through an aromatic ring atom. In certain embodiments, the nitrogen and / or sulfur ring atoms of a heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Examples of this term include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless otherwise constrained by the definition of the heteroaryl substituent, such heteroaryl groups may be optionally substituted with from 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and SO2-heteroaryl, and trihalomethyl.

[0349] As used herein, the terms "heterocycle," "heterocyclic," "heterocycloalkyl," and "heterocyclyl" refer to saturated or unsaturated groups having a single ring or multiple fused rings, including fused bridged and spiro ring systems, and having 3 to 15 ring atoms, including 1 to 4 heteroatoms. These ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen; in fused ring systems, when the point of attachment is through a non-aromatic ring, one or more rings can be cycloalkyl, aryl, or heteroaryl. In certain embodiments, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide an N-oxide, -S(O)-, or -SO2- moiety.

[0350] Examples of heterocycles and heteroaryls include azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, These include, but are not limited to, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydrofuran, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.

[0351] Unless otherwise constrained by the definition of the heterocyclic substituent, a heterocyclic group may be substituted with one to five, or one to three, substituents selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -O-aryl, -SO-heteroaryl, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, and fused heterocycle.

[0352] "Hydrocarbyl" refers to a monovalent hydrocarbyl radical containing 1 to about 24 carbon atoms, further containing 1 to about 18 carbon atoms, further containing about 1 to 12 carbon atoms, and containing 1 to about 30 carbon atoms, including straight-chain, branched, cyclic, saturated, and unsaturated species such as alkyl, alkenyl, and aryl groups. Hydrocarbyls can be substituted with one or more substituents. The term "heteroatom-containing hydrocarbyl" refers to a hydrocarbyl in which at least one carbon atom has been replaced with a heteroatom. Unless otherwise specified, the term "hydrocarbyl" should be interpreted to include substituted and / or heteroatom-containing hydrocarbyl moieties.

[0353] As alluded to in some of the above definitions, "substituted," as in "substituted hydrocarbyl," "substituted alkyl," "substituted aryl," etc., means that at least one hydrogen atom bonded to a carbon (or other) atom in a hydrocarbyl, alkyl, aryl, or other moiety, is replaced with one or more non-hydrogen substituents. Examples of such substituents include, but are not limited to, functional groups and hydrocarbyl moieties C1-C24 alkyl (including C1-C18 alkyl, further including C1-C12 alkyl, and further including C1-C6 alkyl), C2-C24 alkenyl (including C2-C18 alkenyl, further including C2-C12 alkenyl, and further including C2-C6 alkenyl), C2-C24 alkynyl (including C2-C18 alkynyl, further including C2-C12 alkynyl, and further including C2-C6 alkynyl), C5-C30 aryl (including C5-C20 aryl, further including C5-C12 aryl), and C6-C30 aralkyl (including C6-C20 aralkyl, and further including C6-C12 aralkyl). The above hydrocarbyl moieties may be further substituted with one or more functional groups or additional hydrocarbyl moieties such as those specifically listed. Unless otherwise stated, any group described herein should be interpreted to include substituted and / or heteroatom-containing moieties in addition to unsubstituted groups.

[0354] "Sulfonyl" refers to the groups SO2-alkyl, SO2-substituted alkyl, SO2-alkenyl, SO2-substituted alkenyl, SO2-cycloalkyl, SO2-substituted cycloalkyl, SO2-cycloalkenyl, SO2-substituted cycloalkenyl, SO2-aryl, SO2-substituted aryl, SO2-heteroaryl, SO2-substituted heteroaryl, SO2-heterocyclic, and SO2-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Examples of sulfonyl include methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.

[0355] The term "functional group" includes halo, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl (including C2-C24 alkylcarbonyl (-CO-alkyl) and C6-C20 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C20 aryloxycarbonyl (-(CO)-O-aryl), halocarbonyl (-CO)-X, where X is halo), C2 -C24 alkyl carbonate (-O-(CO)-O-alkyl), C6-C20 aryl carbonate (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO-), carbamoyl (-(CO)-NH2), monosubstituted C1-C24 alkylcarbamoyl (-(CO)-NH(C1-C24 alkyl)), disubstituted alkylcarbamoyl (-(CO)-N(C1-C24 alkyl)2), monosubstituted arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamide (-NH-(CO )-NH2), cyano (-C≡N), isocyano (-N≡C-), cyanato (-OC≡N), isocyanato (-O-N≡C-), isothiocyanato (-SC≡N), azido (-N=N+=N-), formyl (-(CO)-H), thioformyl (-(CS)-H), amino (-NH2), mono- and di-(C1-C24 alkyl)-substituted amino, mono- and di-(C5-C20 aryl)-substituted amino, C2-C24 alkylamido (-NH-(CO)-alkyl), C5-C20 arylamido (-NH-(CO)-aryl), imino (-CR=NH , R=hydrogen, C1-C24 alkyl, C5-C20 aryl, C6-C20 alkaryl, C6-C20 aralkyl, etc.), alkylimino (-CR=N(alkyl), R=hydrogen, alkyl, aryl, alkaryl, etc.), arylimino (-CR=N(aryl), R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO2), nitroso (-NO), sulfo (-SO2-OH), sulfonato (-SO2-O-), C1-C24 alkylsulfanyl (-S-alkyl; also called "alkylthio"), arylsulfanyl (-S-aryl;"arylthio" refers to chemical groups such as C1-C24 alkylsulfinyl (-(SO)-alkyl), C5-C20 arylsulfinyl (-(SO)-aryl), C1-C24 alkylsulfonyl (-SO2-alkyl), C5-C20 arylsulfonyl (-SO2-aryl), phosphono (-P(O)(OH)2), phosphonato (-P(O)(O-)2), phosphinato (-P(O)(O-)), phospho (-PO2), and phosphino (-PH2), mono- and di-(C1-C24 alkyl)-substituted phosphino, mono- and di-(C5-C20 aryl)-substituted phosphines. Additionally, the aforementioned functional groups, if permitted by the particular group, may be further substituted with one or more additional functional groups or one or more hydrocarbyl moieties, such as those specifically listed above. "Linkage" or "linker," as in "linking group," "linker moiety," refers to a divalent radical moiety that connects two groups via a covalent bond. Examples of such linking groups include alkylene, alkenylene, alkynylene, arylene, alkarylene, aralkylene, and linking moieties containing functional groups, including, but not limited to, amido (-NH-CO-), ureylene (-NH-CO-NH-), imido (-CO-NH-CO-), epoxy (-O-), epithio (-S-), epidioxy (-OO-), carbonyldioxy (-O-CO-O-), alkyldioxy (-O-(CH2)nO-), epoxyimide (-O-NH-), epimino (-NH-), carbonyl (-CO-), and the like. Any convenient orientation and / or attachment of the linker to the linking group may be used. When the term "substituted" appears before a list of possible substituents, it is intended that the term apply to all members of that group. For example, the phrase "substituted alkyl and aryl" should be interpreted as "substituted alkyl and substituted aryl."

[0356] Further to the disclosure herein, the term "substituted," when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are replaced, independently of each other, with the same or different substituents, as defined below.

[0357] In addition to the groups disclosed for individual terms herein, unless otherwise specified, substituents for replacing one or more hydrogens on a saturated carbon atom of a specified group or radical (any two hydrogens on a single carbon can be replaced with =O, =NR, =N-OR, =N, or =S) include -R 60 , halo, =O, -OR 70 , -SR 70 , -NR 80 R 80 , trihalomethyl, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -SO2R 70 , -SO2O - M + , -SO2OR 70 , -OSO2R 70 , -OSO2O - M + , -OSO2OR 70 , -P(O)(O - )2(M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -C(O)O - M + , -C(O)OR 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OC(O)O - M +, -OC(O)OR 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 where R 60 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; and each R 70 are independently hydrogen or R 60 and each R 80 is independently R 70 or two R together with the nitrogen atom to which they are attached 80 is selected from the group consisting of O, N, and S, wherein N is —H or C 1 Each M is a counterion with a net single positive charge. + are independently, e.g., K + , Na + , Li + Alkaline ions such as + N(R 60 )4 or ammonium ions such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ]0.5 (The subscript 0.5 means that one of the counterions to such divalent alkali rare earth ions can be the ionized form of a compound of the present invention, other typical counterions such as chloride, or a doubly ionized compound disclosed herein can serve as a counterion to such divalent alkali rare earth ion, or a doubly ionized compound of the present invention can serve as a counterion to such divalent alkali rare earth ion.) Specific examples include -NR 80 R 80 is meant to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, N-methyl-piperazin-1-yl, and N-morpholinyl.

[0358] Further to the disclosure herein, the substitution of hydrogen on an unsaturated carbon atom of a "substituted" alkene, alkyne, aryl, and heteroaryl group is represented by -R unless otherwise specified. 60 , halo, -O - M + , -OR 70 , -SR 70 , -S - M + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 , -OSO2R 70 , -OSO3 - M + , -OSO3R 70 , -PO3 -2 (M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70, -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 and NR 70 C(NR 70 )NR 80 R 80 and in the case of a substituted alkene or alkyne, the substituent is -O - M + , -OR 70 , -SR 70 , or S - M + If not, here's R 60 , R 70 , R 80 and M + is as previously defined.

[0359] In addition to the groups disclosed for individual terms herein, the substituents of hydrogens on nitrogen atoms of "substituted" heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R 60 , -O - M + , -OR 70 , -SR 70 , -S - M +, -NR 80 R 80 , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R 70 , -S(O)2O - M + , -S(O)2OR 70 , -OS(O)2R 70 , -OS(O)2O - M + , -OS(O)2OR 70 , -P(O)(O - )2(M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -C(O)OR 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OC(O)OR 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 C(O)OR 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 and NR 70 C(NR 70 )NR 80 R 80 where R 60 , R 70 , R 80 and M+ is as previously defined.

[0360] Further to the disclosure herein, in certain embodiments, a substituted group has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0361] Unless otherwise noted, the nomenclature of substituents not explicitly defined herein is arrived at by naming the terminal portion of the function followed by the adjacent function toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-OC(O)-.

[0362] With respect to any of the groups disclosed herein that contain one or more substituents, it is of course understood that such groups do not include substitutions or patterns that are sterically impractical and / or globally impractical. Furthermore, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0363] In certain embodiments, substituents may contribute to the optical isomerization and / or stereoisomerization of the compound. Salts, solvates, hydrates, and prodrug forms of the compound are also of interest. All such forms are included in the present disclosure. Thus, the compounds described herein include their salts, solvates, hydrates, prodrugs, and isomeric forms, including their pharmaceutically acceptable salts, solvates, hydrates, prodrugs, and isomers. In certain embodiments, the compound can be metabolized to a pharmaceutically active derivative.

[0364] Unless otherwise specified, a reference to an atom is meant to include isotopes of that atom. For example, a reference to H is 1 H, 2 H (i.e., D) and 3 H (i.e., T) and reference to C 12 C and all isotopes of carbon ( 13 C, etc.)

[0365] Definitions of other terms and concepts appear throughout the detailed description. Notwithstanding any appended claims, the disclosure set forth herein is also set forth by the following clauses. [Item 1] A compound of formula (I): [ka] Here, Y 1 is selected from CH or N; Y 2 is S, O or NR 19 Selected from R 19 R19 is selected from hydrogen, alkyl, and substituted alkyl; R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle; R 2 is selected from alkoxy and substituted alkoxy; R 3 is selected from hydrogen, lower alkyl and substituted lower alkyl; R 4 and R 5 are each independently selected from lower alkyl and substituted lower alkyl; or R 4 and R 5 together with the carbon to which they are attached provide a cyclic group selected from cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl and substituted heteroaryl; R 6 is selected from substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; or R 4 , R 5 and R 6 is a compound of formula (I) [ka] [ka] or [ka] If not, a bridged cyclic group selected from a bridged cycloalkyl, a substituted bridged cycloalkyl, a bridged heterocycle, and a substituted bridged heterocycle, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, is provided.

[0366] [Item 2] The compound according to item 1, wherein the compound is of formula (II). [ka] wherein A is a ring system selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle; and B is a ring system selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle.

[0367] [Item 3] The compound of item 2, wherein the B ring system is selected from phenyl, substituted phenyl, pyridyl, substituted pyridyl, 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 4-pyrimidinyl, substituted 4-pyrimidinyl, 6-pyrimidinyl, substituted 6-pyrimidinyl, piperidine, substituted piperidine, piperazine, substituted piperazine, 2-oxopiperidine, 2-oxopiperazine, imidazole, substituted imidazole, thiazole, substituted thiazole, oxazole, substituted oxazole, tetrahydropyran, substituted tetrahydropyran, morpholine, substituted morpholine, cyclic sulfone, and substituted cyclic sulfone.

[0368] [Item 4] The compound according to item 2 or 3, wherein the B ring system is selected from B2 to B9. [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka] Here, Y 3 and Y 5 are independently N and CR 11 where R is selected from 11 is hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamido, and substituted sulfonamido; Y 4 is CR 11 2.NR 11 , SO2 and O; Y 6 is CR 11 2 and NR 11 Selected; each R 10 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen; n is an integer from 0 to 5; m is an integer from 0 to 3; p is an integer from 0 to 4; q is an integer from 0 to 8; q' is an integer from 0 to 6; and r is an integer from 0 to 2.

[0369] [Item 5] The compound according to any one of items 2 to 4, wherein the B ring system is selected from phenyl, substituted phenyl, pyridyl, substituted pyridyl, 2-pyrimidinyl, substituted 2-pyrimidinyl, 3-pyrimidinyl, substituted 3-pyrimidinyl, 4-pyrimidinyl, substituted 4-pyrimidinyl, 6-pyrimidinyl, substituted 6-pyrimidinyl, piperidine, substituted piperidine, piperazine, substituted piperazine, tetrahydropyran, substituted tetrahydropyran, morpholine, and substituted morpholine.

[0370] [Item 6] The compound according to any one of items 2 to 5, wherein the A ring is selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] Here, Y 3 are independently N and CR 11 where R is selected from 11 is hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamido, and substituted sulfonamido; Y 4 is CR 11 2.NR 11 , SO2 and O; R 10is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen; n is an integer from 0 to 5; m is an integer from 0 to 3; p is an integer from 0 to 4; and q is an integer from 0 to 8.

[0371] [Item 7] A compound according to any one of items 2 to 6, wherein the compound is any one of formulas (IIA) to (IIF). [ka] [ka] [ka] [ka] [ka] and [ka] wherein A ring system is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle; each R 10 is independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen; n is an integer from 0 to 5; m is an integer from 0 to 3; and p is an integer from 0 to 4.

[0372] [Item 8] The compound according to item 7, wherein the compound is of formula (IIA1), (IIA2), (IIC1) or (IID1). [ka] [ka] [ka] or [ka] Here, R 12 , R 13 and R 14 are each independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen.

[0373] [Item 9] A compound according to any one of items 2 to 6, wherein the compound is of formula (IIG), (IIH), (IIJ) or (IIK). [ka] [ka] and [ka] [ka] wherein A ring system is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle; each R 10 are independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen; R 11 is hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, and substituted sulfonyl; and q is an integer from 0 to 8.

[0374] [Item 10] The compound according to item 9, wherein the compound is of formula (IIG1) or (IIK1). [ka] [ka] Here, R 11 is R 10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, and substituted sulfonyl; R 15 , R 16 , R 17 and R 18 are each independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen.

[0375] [Item 11] The compound according to item 10, wherein the compound is of formula (IIG1ii), (IIG1iii), (IIK1ii) or (IIKliii). [ka] [ka] [ka] [ka]

[0376] [Item 12] The compound according to item 8, wherein the compound has any one of the following formulas: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0377] [Item 13] A compound according to item 8 selected from the following formulas: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0378] [Item 14] The compound according to item 8, wherein the compound has any one of the following formulas: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0379] [Item 15] The compound according to item 8, wherein the compound has any one of the following formulas: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0380] [Item 16] Any compound according to items 12 to 15, wherein R 12 , R 13 and R 14 are each independently selected from alkyl, substituted alkyl, trifluoromethyl, and halogen.

[0381] [Item 17] The compound according to item 12 or 13, wherein R 12 is a halogen and R 13 is lower alkyl.

[0382] [Item 18] The compound according to item 14 or 15, wherein R 14 is a lower alkyl group or trifluoromethyl.

[0383] [Item 19] The compound according to item 10 or 11, wherein the compound has one of the following formulas: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0384] [Item 20] The compound according to item 10 or 11, wherein the compound has one of the following formulas: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0385] [Item 21] The compound according to item 19 or 20, wherein R 11 is an acyl group.

[0386] [Item 22] A compound according to any one of items 19 to 21, wherein R 15 , R 16 , R 17 and R 18 are each independently selected from hydrogen, alkyl, and substituted alkyl.

[0387] [Item 23] The compound according to item 22, wherein R 15 , R 16 , R 17 and R18 are hydrogen atoms.

[0388] [Item 24] The compound according to item 22, wherein R 15 is lower alkyl, and R 16 , R 17 and R 18 Each of is hydrogen.

[0389] [Item 25] The compound according to item 22, wherein R 15 and R 17 are each lower alkyl, and R 16 and R 18 are hydrogen atoms.

[0390] [Item 26] The compound according to item 22, wherein R 15 and R 16 are hydrogen, and R 17 and R 18 are each lower alkyl.

[0391] [Item 27] ​​Any compound according to items 1 to 26, wherein R 4 and R 5 are each independently lower alkyl; or R 4 and R 5 taken together with the carbon to which they are attached provide a cycloalkyl or substituted cycloalkyl cyclic group.

[0392] [Item 28] The compound according to item 27, wherein R 4 and R 5 are from the cyclopropyl along with the carbon to which they are attached.

[0393] [Item 29] A compound according to any one of items 1 to 26, wherein R 4 and R 5 are both methyl.

[0394] [Item 30] A compound according to any one of items 1 to 29, wherein Y 2 is S.

[0395] [Item 31] A compound according to any one of items 1 to 29, wherein Y 2 is O.

[0396] [Item 32] A compound according to any one of items 1 to 29, wherein Y 2 is NR 19 is.

[0397] [Item 33] The compound according to item 32, wherein R 19 is hydrogen.

[0398] [Item 34] A compound according to item 1 or 2, wherein the compound has any one of the following structures: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka] or a pharmaceutically acceptable salt thereof.

[0399] [Item 35] A compound according to item 1 or 2, wherein the compound has any one of the following structures: [ka] [ka] [ka] and [ka] or a pharmaceutically acceptable salt thereof.

[0400] [Item 36] A compound according to item 1 or 2, wherein the compound has any one of the following structures: [ka] [ka] [ka] [ka] [ka] and [ka] or a pharmaceutically acceptable salt thereof.

[0401] [Item 37] The compound of claim 1, wherein the compound is of formula (III): [ka] Here, --- is absent or a covalent bond. 7 and R 8 are each independently selected from hydrogen, halogen, alkyl, and substituted alkyl; R 9 is selected from substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl.

[0402] [Item 38] The compound according to item 1, wherein R 1 is selected from aryl, disubstituted aryl, trisubstituted aryl, tetrasubstituted aryl, pentasubstituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle.

[0403] [Item 39] The compound according to item 1, wherein the compound is selected from any one of the compounds in Table 1, Table 2, or Table 3, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0404] [Item 40] A compound according to any one of items 1 to 38, wherein Y 1 is CH.

[0405] [Item 41] A compound according to any one of items 1 to 38, wherein Y 1 is N.

[0406] [Item 42] A compound according to any one of items 1 to 38, wherein Y 2 is S.

[0407] [Item 43] A compound according to any one of items 1 to 38, wherein Y 2 is O.

[0408] [Item 44] A compound according to any one of items 1 to 38, wherein Y 2 is NR 19 is.

[0409] [Item 45] A compound according to any one of items 1 to 38, wherein Y 2 is NH.

[0410] [Item 46] A pharmaceutical composition comprising any of the compounds described in items 1 to 45 and a pharmaceutically acceptable excipient.

[0411] [Item 47] A method for inhibiting PI4-kinase, the method comprising contacting a sample containing PI4-kinase with any one of the compounds described in items 1 to 45.

[0412] [Item 48] The method of item 47, wherein the PI4-kinase is a PI4-III kinase.

[0413] [Item 49] The method according to item 47, wherein the PI4-III kinase is PI4KIIIβ-kinase.

[0414] [Item 50] The method according to item 47, wherein the PI4-III kinase is PI4KIIIα-kinase.

[0415] [Clause 51] A method of treating a subject for an infectious condition, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound described in any one of clauses 1 to 45 or a pharmaceutically acceptable salt thereof, wherein the infectious condition results from infection with a pathogen susceptible to PI4-kinase inhibition.

[0416] [Section 52] The method of section 51, wherein the infectious disease condition is caused by infection with a virus selected from the Retroviridae, Picornaviridae, Flaviviridae, Caliciviridae, Filoviridae, Hepeviridae, Togaviridae, Polyomaviridae, Papillomaviridae, Papovaviridae, and Coronaviridae families.

[0417] [Section 53] The method of section 51, wherein the infectious disease condition results from infection with a pathogen selected from HCV, rhinovirus, Plasmodium (e.g., Plasmodium falciparum), Toxoplasma, Ebola virus, Francisella tularensis, hantavirus, SARS virus, MERS virus, SARS-CoV-2 virus, vaccinia, smallpox, Japanese encephalitis virus, hepatitis A virus, influenza virus, norovirus, poliovirus, enterovirus, HEV, EV71, EV68, coxsackievirus, BK virus, JC virus, human papillomavirus (HPV), HIV, rubella, West Nile virus, cytomegalovirus, Pseudomonas aeruginosa, and dengue virus.

[0418] [Item 54] The method of item 53, wherein the pathogen is selected from EV71, EV68, human rhinovirus, hepatitis A virus, HCV, norovirus, coxsackievirus, BK virus, JC virus, HPV, poliovirus, and Ebola virus.

[0419] [Item 55] The method of item 54, wherein the compound is selected from the compounds of Tables 1, 2, and 3.

[0420] [Item 56] The method of item 51, wherein the compound has activity against two or more pathogens.

[0421] [Item 57] A method for treating cancer, the method comprising: administering to a subject suffering from cancer a therapeutically effective amount of a compound according to any one of items 1 to 45.

[0422] [Item 58] The method of item 57, wherein the cancer is a type of cancer.

[0423] [Item 59] The method according to item 57 or 58, wherein the cancer is a solid cancer.

[0424] [Item 60] The compound according to item 59, wherein the compound inhibits metastasis of solid tumors.

[0425] [Section 61] Any one of the methods of sections 57 to 60, wherein the cancer arises from the bladder (e.g., urothelium), breast, colon, endometrium, cervix, testis, liver, lung (e.g., non-small cell lung cancer (NSCLC)), ovary, prostate, pancreas, brain, melanoma, sarcoma, thyroid, stomach, or kidney.

[0426] [Item 62] The method of item 61, wherein the cancer is lung cancer.

[0427] [Item 63] The method of item 62, wherein the cancer is lung adenocarcinoma.

[0428] [Item 64] The method of item 61, wherein the cancer is breast cancer.

[0429] [Item 65] The method of item 61, wherein the cancer is brain cancer.

[0430] [Item 66] The method of item 61, wherein the cancer is glioblastoma (GBM).

[0431] [Claim 67] Any one of the methods described in paragraphs 57 to 67, wherein the subject's cancer cells contain high levels of PI4K expression (e.g., compared to basal levels in one or more normal or control cells).

[0432] [Item 68] The method of item 67, wherein the PI4K expression is PI4KIII expression.

[0433] [Item 69] The method of item 68, wherein the PI4KIII expression is PI4KIIIβ expression.

[0434] [Item 70] Any one of the methods described in items 57 to 69, wherein the subject's cancer cells contain high expression levels of a factor involved in IRES-mediated translation (e.g., eEF1A2) that stimulates PI4-kinase activity.

[0435] [Item 71] Any one of the methods described in items 57 to 70, wherein the subject's cancer cells contain high levels of PI4KIII activity.

[0436] [Item 72] The method of item 71, wherein the subject's cancer cells contain high levels of PI4KIIIβ activity.

[0437] [Item 73] Any one of the methods described in items 57 to 72, wherein the subject's cancer cells are sensitive to PI4KIIIβ inhibition.

[0438] [Section 74] Any one of the methods described in Articles 57 to 73 further includes measuring the expression or activity level of PI4KIIIβ in cancer cells of a biological sample obtained from the subject, and determining whether the expression or activity level of PI4KIIIβ in the cancer cells is elevated compared to one or more control cells.

[0439] [Item 75] Any one of the methods described in items 57 to 74, wherein the subject's cancer cells have a greater than diploid copy number of the PI4K gene.

[0440] [Item 76] The method according to item 75, wherein the PIK gene is a PI4KIII gene.

[0441] [Item 77] The method according to item 76, wherein the PIKIII gene is a PI4KIIIβ gene.

[0442] [Item 78] The method of any one of items 57 to 74, wherein the compound is selective for PI4-kinase over PI3-kinase.

[0443] [Item 79] The method according to any one of items 57 to 78, wherein the compound is a PI4KIIIβ inhibitor.

[0444] [Item 80] The method of any one of items 57 to 78, wherein the compound is a PI4KIIIα inhibitor.

[0445] [Item 81] Any one of the methods described in items 57 to 80, further comprising co-administering to the subject an effective amount of an additional agent.

[0446] [Item 82] The method of item 81, wherein the additional agent is a chemotherapeutic agent or an immunotherapeutic agent.

[0447] [Item 83] The method of item 81, wherein the additional agent is an inhibitor of a compound-metabolizing enzyme.

[0448] [Item 84] The method according to item 83, wherein the metabolic enzyme is a cytochrome P-450 (e.g., CYP3A4).

[0449] [Item 85] The method of item 81 or 83, wherein the additional agent is selected from clarithromycin, cobicistat, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir (e.g., ritonavir or cobicistat).

[0450] [Item 86] A method for inhibiting the proliferation of cancer cells, the method comprising: contacting cancer cells with an effective amount of a compound described in any one of items 1 to 45.

[0451] [Section 87] The method of Section 86, wherein the cancer cells are selected from bladder (e.g., urothelial) cancer, breast cancer, colon cancer, endometrial cancer, cervical cancer, testicular cancer, liver cancer, lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, pancreatic cancer, brain cancer, melanoma, sarcoma, thyroid cancer, gastric cancer, and kidney cancer cells.

[0452] [Item 88] Any one of the methods described in items 86 to 87, wherein the cancer cells express PI4K at high levels (e.g., compared to basal levels in one or more normal or control cells).

[0453] [Item 89] The method of item 88, wherein the PI4K expression is PI4KIII expression.

[0454] [Item 90] The method of item 89, wherein the PI4KIII expression is PI4KIIIβ expression.

[0455] [Item 91] The method of items 86 or 87, wherein the cancer cells contain high expression levels of a factor involved in IRES-mediated translation that stimulates PI4-kinase activity (e.g., eEF1A2).

[0456] [Item 92] Any one of the methods described in items 86 to 91, wherein the cancer cells contain high levels of PI4KIIIβ activity.

[0457] [Item 93] Any one of the methods described in items 86 to 92, wherein the cancer cells are sensitive to PI4KIIIβ inhibition.

[0458] [Clause 94] An anti-cancer kit comprises an effective amount of any compound described in clauses 1 through 45, an effective amount of an additional anti-cancer agent, and instructions for use in treating cancer. [Example]

[0459] The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use embodiments of the present disclosure, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature). However, some experimental error and deviation should be accounted for. Unless otherwise specified, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

[0460] General methods in molecular and cellular biochemistry are covered in Molecular Cloning: A Laboratory Manual, 3rd Ed. (Sambrook et al., Harvard Laboratory Press 2001); Short Protocols in Molecular Biology, 4th Ed. (Ausubel et al. eds., John Wiley & Sons 1999); Protein Methods (Bollag et al., John Wiley & Sons 1996); Nonviral Vectors for Gene Therapy (Wagner et al. eds., Academic Press 1999); Viral Vectors (Kaplift & Loewy eds., Academic Press 1995); Immunology Methods Manual (I. Lefkovits ed., Academic Press 1997); and Cell and Tissue Culture: Laboratory Procedures in Biotechnology (Doyle & Griffiths, John Wiley & Sons These methods are described in standard textbooks such as "The Genetic Algorithm of Cells," "The Genetic Algorithm of Cells," and "The Genetic Algorithm of Cells," the disclosures of which are incorporated herein by reference. Reagents, cloning vectors, cells, and kits for the methods referred to in or related to this disclosure are available from commercial vendors such as BioRad, Agilent Technologies, Thermo Fisher Scientific, Sigma-Aldrich, New England Biolabs (NEB), Takara Bio USA, Inc., and repositories such as ddgene, Inc., and the American Type Culture Collection (ATCC).

[0461] While the present invention has been described with reference to specific embodiments thereof, it should be understood by those skilled in the art that various modifications may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps to the objective, spirit and scope of the present disclosure. All such modifications are intended to be within the scope of the claims appended hereto.

[0462] Example 1: Synthesis The compounds may be prepared using any convenient method, for example, by a method similar to that described by Shokat et al. "A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling." Cell. 2006;125(4):733-47. Raw materials are obtained from Aldrich or Alfa Aesar. Reactions are monitored by LC / MS, and reaction products are characterized by LC / MS and 1H NMR. Intermediates and final products are purified by silica gel chromatography or reverse-phase HPLC.

[0463] An exemplary synthetic scheme 1 that can be adapted for the synthesis of compounds of interest is shown below. [ka]

[0464] Example 2: Assay PI-kinase inhibition: Compounds are tested in C.1.1. PI kinase assay as described by Shokat et al., "A membrane capture assay for lipid kinase activity." Nat. Protoc. 2007;2(10):2459-66.

[0465] Anti-HCV assay: Anti-HCV assays are performed as described by Cho et al. "Identification of a class of HCV inhibitors directed against the nonstructural protein NS4B." Sci. Transl. Med. 2011;2(15):15ra6.

[0466] Broad-Spectrum Anti-Infective Assay: Compounds are tested for activity against selected agents harboring proteins with the BAAPP domain or other PI-4 or PIP2 binding motifs (i.e., vaccine virus, Japanese encephalitis virus, hepatitis A virus, and influenza virus) in clinical studies. Activity against multiple NIAID Category A, B, and C pathogens is measured.

[0467] Vaccinia virus assay: Standard plaque assays are performed in CV-1 cells in the presence of vehicle or vehicle plus various concentrations of compound using the method described by Glenn et al., "Amphipathic helix-dependent localization of NS5A mediates hepatitis C virus RNA replication." J. Virol. 2003;77(10):6055-61.

[0468] HAV Assay: Huh7 cells containing an HAV replicon encoding a blasticidin resistance gene (Yang et al., "Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor." Proc Nat...

Claims

1. Compounds of formula (I): 【Chemical 1】 Here, Y 1 is selected from CH or N. Y 2 is S, O or NR 19 where R is selected from 19 is selected from hydrogen, alkyl, and substituted alkyl. R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle. R 2 is selected from alkoxy and substituted alkoxy. R 3 is selected from hydrogen, lower alkyl and substituted lower alkyl. R 4 and R 5 are each independently selected from lower alkyl and substituted lower alkyl. 4 and R 5 together with the carbon to which they are attached provide a cyclic group selected from cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl and substituted heteroaryl. R 6 is selected from substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; or R 4 , R 5 and R 6 together with the carbons to which they are attached provide a bridged cyclic group selected from a bridged cycloalkyl, a substituted bridged cycloalkyl, a bridged heterocycle, and a substituted bridged heterocycle; or the compound of formula (I) 【Chemistry 2】 【Chemistry 3】 or 【Chemistry 4】 If not, a bridged cyclic group selected from a bridged cycloalkyl, a substituted bridged cycloalkyl, a bridged heterocycle, and a substituted bridged heterocycle, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, is provided.

2. A compound according to claim 1, wherein the compound is of formula (II): 【Chemistry 5】 Here, A is a ring system selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle; and B is a ring system selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle.

3. The compound of claim 2, wherein the B ring system is selected from B2 to B9. 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 Here, Y 3 and Y 5 is N and CR 11 are each independently selected from 11 is hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. Y 4 is CR 11 2 , N.R. 11 , S.O. 2 and O; Y 6 is CR 11 2 and NR 11 Selected from: Each R 10 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen; n is an integer from 0 to 5; m is an integer from 0 to 3; p is an integer from 0 to 4; q is an integer from 0 to 8 q is an integer from 0 to 6; and r is an integer from 0 to 2;

4. The compound according to claim 2 or claim 3, wherein the A ring is selected from the following: 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 Here, Y 3 is N and CR 11 where R is selected from 11 is hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamido, substituted carboxamido, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. Y 4 is CR 11 2 , N.R. 11 , S.O. 2 and O; R 10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl, and halogen. n is an integer from 0 to 5; m is an integer from 0 to 3; p is an integer from 0 to 4; and q is an integer from 0 to 8;

5. Compounds according to claims 2 to 4, wherein the compounds are of any of the following formulae: 【Chemistry 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemistry 24】 【Chemistry 25】 【Chemical 26】 【Chemical 27】 【Chemical 28】 【Chemical 29】 【Chemistry 30】 【Chemical 31】 【Chemical 32】 【Chemical 33】 【Chemical 34】 【Chemistry 35】 【Chemical 36】 【Chemical 37】 【Chemical 38】 【Chemical 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemical 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 【Chemistry 50】 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemical 54】 【Chemistry 55】 【Chemical 56】 【Chemical 57】 【Chemistry 58】 【Chemical Formula 59】 【Chemistry 60】 【Hua 61】 【Hua 62】 【Chemistry 63】 【Hua 64】 【Chemistry 65】 【Hua 66】 【Chemical 67】 【Chemistry 68】 【Chemical 69】 【Chemistry 70】 【Chemical Formula 71】 【Chemical Formula 72】 and 【Chemical 73】

6. 6. The compound of claim 5, wherein the compound is of any one of formulas (IIG1a) to (IIG1i), or (IIK1a) to (IIK1i), and R 11 is an acyl group.

7. A compound according to any one of claims 1 to 6, wherein R 4 and R 5 are both methyl.

8. A compound according to any one of claims 1 to 7, wherein Y 2 is S.

9. 10. The compound of claim 1, wherein the compound is of formula (III): 【Chemical 74】 Here, --- is absent or a covalent bond. R 7 and R 8 are each independently selected from hydrogen, halogen, alkyl, and substituted lower alkyl; and R 9 is selected from substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl.

10. 10. The compound of claim 1, wherein R 1 is selected from aryl, disubstituted aryl, trisubstituted aryl, tetrasubstituted aryl, pentasubstituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle.

11. 10. The compound of claim 1, wherein the compound is selected from any one of the compounds of Table 1, Table 2, or Table 3, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising: A compound according to any one of claims 1 to 11, and Pharmaceutically acceptable excipients.

13. A method for inhibiting PI4-kinase, the method comprising contacting a sample containing PI4-kinase with a compound according to any one of claims 1 to 11.

14. The method of claim 13, wherein the PI4-kinase is a PI4-III kinase.

15. 12. A method of treating a subject for an infectious condition, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein the infectious condition is caused by infection with a pathogen susceptible to PI4-kinase inhibition.

16. A method for treating cancer, the method including:

12. A method comprising administering to a subject suffering from cancer a therapeutically effective amount of a compound of any one of claims 1 to 11.

17. The method of claim 16, further comprising: measuring the expression or activity level of PI4KIIIβ in cancer cells of a biological sample obtained from the subject; and Determining whether the expression or activity level of PI4KIIIβ is elevated in the cancer cells compared to one or more control cells.

18. The method of any one of claims 16-17, further comprising co-administering to the subject an effective amount of an additional agent.

19. 1. A method of inhibiting the proliferation of cancer cells, the method comprising:

12. Contacting cancer cells with an effective amount of a compound according to any one of claims 1 to 11.

20. The anti-cancer kit includes: an effective amount of a compound according to any one of claims 1 to 11; an effective amount of an additional anticancer agent; and Indications for use in the treatment of cancer.

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