PI4-Kinase Inhibitors and Methods of Use Thereof

Abstract

Compounds and methods for inhibiting PI4-kinase are provided. Methods for treating pathogen infections and methods for treating cancer are also provided. The PI4-kinase inhibitor can be a 5-aryl or heteroaryl thiazole compound, 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. In some embodiments, the compound has broad-spectrum activity against a variety of infectious diseases 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. Methods for treating cancer in a subject using a PI4-kinase inhibitor are also provided. Aspects of the method include inhibiting PI4-kinase in cancer cells to suppress cell proliferation.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to the filing date of U.S. Provisional Patent Application No. 62 / 821,853, filed on March 21, 2019, under 35 U.S.C. § 119(e), and the disclosure of that application is hereby incorporated by reference in its entirety.

[0002] Rights of the Government 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 appropriate treatments for many infectious diseases. The rapid increase in the number of new 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 rhinovirus (HRV) is responsible for more than half of cold - like illnesses and incurs billions of dollars in annual costs in terms of hospitalizations and work absences. Hepatitis C virus (HCV) belongs to the Flaviviridae family and is the cause of several cancers such as type C pneumonia and liver cancer (hepatocellular carcinoma, abbreviated: HCC) and lymphoma that develop in humans. Currently, it is estimated that more than 2% of the world's population is infected with hepatitis C virus (HCV). Enteroviruses belong to the Picornaviridae family, a large and diverse group of small RNA viruses. Enterovirus infections vary in symptoms and severity and can cause a variety of symptoms, from rash in young children to summer colds, encephalitis, meningitis, etc. Non - polio enteroviruses are responsible for 10 - 15 million infections and tens of thousands of hospitalizations in the United States.

[0004] Many cancers are dependent on PI4-kinase for growth and metastasis. Often, this reflects a tumor "addiction" to PI4-kinase activity. Among the ways this can be readily identified is the presence of increased PI4-kinase activity in the target cancer cells. This increased activity can be measured directly, or predicted reliably 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 by chromosomal amplifications that increase the gene copy number of PI4-kinase. For example, high levels of eEF1A2 protein and mRNA can be detected in 30-60% of tumors, particularly ovarian, breast, and lung tumors. Similarly, amplification of PI4-kinase is readily detected in a substantial proportion of most human tumor types (see Cancer Genome Atlas (TCGA) available from cbioportal.org). Other cancer cells are also more sensitive to selective PI-4 kinase inhibition compared to normal cells. Thus, pharmacological inhibitors of PI-4-kinase that are useful for treating human cancers and / or cancers including their metastases are of interest. SUMMARY OF THE INVENTION

[0005] Compounds and methods for inhibiting PI4-kinase are provided. Methods for treating infectious diseases of pathogens and methods for treating cancer are also provided. The PI4-kinase inhibitor can be a compound that is a particular 5-aryl or heteroaryl thiazole, as described herein, for example. In certain embodiments, the PI4-kinase inhibitor is a substituted 2-amino-5-phenylthiazole or a substituted 2-amino-5-pyridylthiazole compound.

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

[0007] Aspects of the method include inhibiting PI4-kinase and methods of inhibiting viral infection in a subject. The subject compound can be formulated or provided to the subject in combination with one or more additional anti-infective agents (e.g., interferon, ribavirin). The subject compound has been used in the treatment of various viruses, such as viruses from the family Picornaviridae, Flaviviridae, Caliciviridae, Filoviridae, Hepeviridae, or Coronaviridae. For the treatment of viruses such as HCV, the compound can be formulated as a prodrug designed to specifically target the liver, for example, by binding to polyarginine or bile acids, or to be activated by an enzyme present in the liver.

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

[0009] These and other advantages, further advantages, and features of the present disclosure will become apparent to those of ordinary skill in the art upon reading the detailed description of the compositions and methods of use described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0010]

Figure 1A

Figure 1B

Figure 1C

Figure 1D

Figure 1E

Figure 1F

Figure 1G

Figure 2A

Figure 2B

Figure 2C

Figure 3

Figure 4

Mode for Carrying Out the Invention

[0011] As outlined 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 a substituted 2-amino-5-pyridylthiazole compound.

[0012] In some embodiments, the PI4-kinase inhibitor compound has broad-spectrum activity against various infections where the disease is caused by a pathogen that interacts with phosphatidylinositol 4,5-bisphosphate (PIP-2) to mediate replication and contains a basic amino acid PIP-2 pincer (BAAPP) domain, or otherwise is PIP4-dependent and thus sensitive to PI4-kinase. In certain cases, the compound is active against one or more viruses selected from the families Picornaviridae, Flaviviridae, Caliciviridae, Filoviridae, Hepeviridae, Togaviridae, Papovaviridae, Papillomaviridae, Polyomaviridae, Retroviridae, and Coronaviridae.

[0013] In some embodiments, the PI4-kinase inhibitor compound, which is a compound that inhibits PI4-kinase, contacts the pathogen in a dosage and for a period sufficient to inhibit replication. The contact can be carried out in vitro or in vivo. Such a PI4-kinase inhibitory 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 various cancers. In some embodiments, the compounds are compounds that inhibit PI4-kinase in cancer cells to suppress cell proliferation. The subject compounds can 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 methods of treatment is provided for various cancer cells and subjects suffering from cancer.

[0015] In some embodiments, a method is provided for inhibiting PI4-kinases, including but not limited to class III PI4-kinases, wherein the compounds of the invention are contacted with the PI4-kinases for a dosage and period sufficient to inhibit the activity of the enzyme.

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

[0017] Aspects of the present disclosure include certain PI4-kinase inhibitor compounds. Generally, the compounds include 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 that includes at least a further substituent meta to the thiazole ring substituent. The thiazole ring of the core structure can include further 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 that includes a thiazole ring having 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 that includes a thiazole ring having 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. Here, R is alkyl, heteroalkyl, heterocycle, or aryl, Cy is a cyclic group such as cycloalkyl, heterocycle, aryl, heteroaryl, etc., and either group R or Cy can be optionally substituted. In some embodiments, the compound includes further substituents such as a substituent at either the 4- or 5-position of the thiazole ring. The aryl ring (e.g., 5-phenyl or pyridyl ring) of the core structure can be further substituted with any convenient substituent including, but not limited to, alkyl, acyloxy, aminoalkoxy, cyano, halogen, hydroxyl, nitro, -NHCOR, -SO2NHR, -CONHR or NHSO2R, where R is alkyl, heteroalkyl, heterocycle or aryl. Exemplary compounds are shown in the following structures and formulas.

[0018] In some cases, the subject compound is described by the structure of formula (Ia).

Chemical formula

[0019] In some cases, the target compound is described by the structure of formula (Ib).

Chemical formula

[0020] In some embodiments, in formula (Ib), as the compound is described by formula (Ic), Y 1’ is CH, and Y 1” is CR 20 .

Chemical formula

[0021] In some embodiments, the subject compound is described by the structure of formula (Id).

Chemical formula

[0022] In certain embodiments, the subject compound is described by the structure of formula (Ie).

Chemical formula

[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, etc. In some embodiments, the linking functional group is described by one of the following formulas: -SO2NR-, -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 SO2-; 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 -SO2NH- or CONH-. In some embodiments, in formula (Id) or (Ie), W 1 is -SO2-.

[0024] In certain embodiments, the subject compound is described by the structure of formula (I).

Chemical formula

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

Chemical formula

[0026] In certain embodiments, formula (I) is of formula (Ig). [Chemical formula] 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 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 the structures of any of 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 substituted lower alkyl (e.g., alkyl halide). In some embodiments, in formula (I), (If), or (Ig), R 2 is methoxy. 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 heterocyclic ring and heterocyclic ring (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 (e.g., substituted methyl or ethyl), phenyl, cycloalkyl, pyridyl, and pyrimidinyl.

[0027] In some embodiments, none of the formulas described herein are the following.

Chemical Formula

Chemical Formula

Chemical Formula

[0028] When it is 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 carbon 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 represented by the following formula.

Chemical Formula

Chemical Formula

[0029] In certain cases, R 4 , R 5 and R 6 can be represented by the following formula. [Chemical formula] Here, 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 arbitrary substituents selected from lower alkyl, halogen, substituted lower alkyl, and lower alkoxy (e.g., Me, Cl, Br, CHF2, CF3, CH2F and OMe). And s is 1, 2, 3 or 4. In some embodiments of formula (IA3), when the structure is overall realizable, any carbon atom in the cycle can be replaced with a heteroatom (e.g., N, S, or O). In certain cases, when the structure is sterically practical, any number of R 23 alternatives can be included. In certain embodiments, there is no R 23 substituent. In certain cases, the cycle of formula (IA3) is a cyclopropyl group.

[0030] In a specific case of any one of formulas (I) to (Ig), R 4 , R 5 and R 6provides a crosslinked cyclic group selected from crosslinked cycloalkyl, substituted crosslinked cycloalkyl, crosslinked heterocycle and substituted crosslinked heterocycle, together with the carbon to which they are attached. In certain cases, R 4 , R 5 and R 6 can be represented by the following formulae. [Chemical Formula]

[0031] In some cases of any one of formulae (I) to (Ig), R 6 is substituted alkyl. In some cases, R 6 can be represented by the formula -(CH2) n -X 1 , where n is 1, 2, or 3, and X 1 is hydroxyl, halogen, haloalkyl (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 certain cases, R 6 is cycloalkyl or heterocycle (e.g., 5- or 6-membered saturated N-containing ring). In certain cases, R 6 is selected from cyclohexyl, cyclopentyl, cyclopropyl, pyrrolidinyl, piperidinyl, tetrahydrofuran, phenyl and pyridinyl. In certain cases, R 6 can be represented by ring A (e.g., as described herein).

[0032] In some embodiments of any one of formulae (I) to (Ig), R 1 can be represented by the formula -(CH2) n -X 1 , where n is 0, 1, 2, or 3, and X 1is lower alkyl (e.g., methyl), hydroxyl, halogen, haloalkyl, 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 target compound is described by the structure of formula (II).

Chemical formula

Chemical formula

Chemical formula

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

Chemical formula

Chemical formula

Chemical formula

[0036] In some embodiments of formula (IIIC3), any carbon atom within the cycle can be replaced with a heteroatom (e.g., N, S, or O) if the structure is overall feasible. In certain cases, if the structure is sterically practical, any number of R 23 alternatives can be included. In certain embodiments, R 23 substituents are absent. In certain cases, the cycle of formula (IIIC3) is a cyclopropyl group.

[0037] In some embodiments, ring A is selected from aryl (e.g., phenyl), optionally containing one or more substituents. In some embodiments, ring A 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, piperidinyl, tetrahydrofuran), optionally containing one or more substituents. In some embodiments, ring A is selected from cycloalkyl (e.g., cyclohexane, cyclopentane), optionally containing one or more substituents. In some embodiments, ring A 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, ring A is described by formula (A1).

Chemical formula

[0039] In some embodiments, the A ring is described by formula (B2).

Chemical formula

[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).

Chemical formula

Chemical formula

[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, ring A is described by formula (B4).

Chemical formula

[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 a 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 a monosubstituted pyridyl, and the substituent is selected from lower alkyl (e.g., methyl) and trifluoromethyl.

[0045] In some embodiments, the A ring is described by formula (B5).

Chemical formula

[0046] In certain cases 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 a substituted pyridyl. In some cases, the pyridyl is a monosubstituted pyridyl. In other cases, the pyridyl is a disubstituted pyridyl. In other cases, the pyridyl is a trisubstituted pyridyl. In other cases, the pyridyl is a tetrasubstituted pyridyl. In certain cases, Y 3is N, and B5 is pyrimidyl. In some cases, B5 is a 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).

Chemical formula

[0048] In certain cases, p is 0 and B6 is pyridyl. In certain cases, B6 is a 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 formula (B4a), (B6a), (B5a), or (B5b).

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

[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, such as 1, 2, 3, 4, 5, 6, 7, or 8, q is greater than 0. In some cases, B7 contains one R 10 group. In some cases, B7 contains two R 10 groups. In some cases, B7 contains three R 10 groups. In some cases, B7 contains four R 10It includes a base. In certain embodiments, the substituent is 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, Ring A has any one of the formulas (B7a) or (B7b).

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0052] In certain cases, B8 is 2-oxopiperidine or substituted 2-oxopiperadine. In certain cases, B8 is 2-oxopiperazine or substituted 2-oxopiperazine. In certain cases, B8 is cyclohexanone or substituted cyclohexanone. In some cases, B8 is a lactone or substituted lactone. In some cases, B8 is morpholine-2-one or substituted morpholine-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 contains one R 10 group. In some cases, B8 contains two R10 groups. In some cases, B8 contains three B 7 groups. In some cases, B8 contains four R 10 groups. In certain embodiments, the substituent is 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, ring B is selected from aryl (e.g., phenyl), optionally containing one or more substituents. In some embodiments, ring B 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, ring B 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 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, ring B is described by formula (B1).

Chemical formula

[0055] In some embodiments, the B ring is described by formula (B2).

Chemical formula

[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).

Chemical formula

[0058] In some embodiments, the B ring is described by formula (B3).

Chemical formula

[0059] In certain cases, B3 is pyridyl. In certain cases, B3 is substituted pyridyl. In some cases, pyridyl is monosubstituted pyridyl. In other cases, pyridyl is disubstituted pyridyl. In other cases, pyridyl is trisubstituted pyridyl. In other cases, 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, pyrimidyl is monosubstituted. In some cases, pyrimidyl is disubstituted. In other cases, 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).

Chemical formula

[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, pyrimidyl is monosubstituted. In some cases, pyrimidyl is disubstituted. In other cases, 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 pyrimidyl 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 is selected from, where R 11 is hydrogen, R 10It is selected from acyl, substituted acyl, carboxy, carboxamide, substituted carboxamide, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. and m is an integer from 0 to 3.

[0063] In a specific 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, pyridyl is monosubstituted pyridyl. In other cases, pyridyl is disubstituted pyridyl. In other cases, pyridyl is trisubstituted pyridyl. In other cases, 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, pyrimidyl is monosubstituted. In some cases, pyrimidyl is disubstituted. In other cases, pyrimidyl is trisubstituted. In a specific embodiment of B5, the substituent is 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).

Chemical formula

[0065] In certain cases, p is 0 and B6 is pyridyl. In certain cases, B6 is a substituted pyridyl. In some cases, the pyridyl is a monosubstituted pyridyl. In other cases, the pyridyl is a disubstituted pyridyl. In other cases, the pyridyl is a trisubstituted pyridyl. In other cases, the pyridyl is a 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, ring B has the formula (B4b) or (B6b).

Chemical formula

Chemical formula

[0067] In some embodiments, ring B is described by formula (B7).

Chemical formula

[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 contains one R 10 group. In some cases, B7 contains two R10 groups. In some cases, B7 contains three R10 groups. In some cases, B7 contains four R 10 groups. In certain embodiments, the substituent is 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).

Chemical formula

[0070] In certain cases, B8 is 2-oxopiperidine or substituted 2-oxopiperazine. In certain cases, B8 is 2-oxopiperazine or substituted 2-oxopiperazine. In certain cases, B8 is cyclohexanone or substituted cyclohexanone. In some cases, B8 is lactone or substituted lactone. In some cases, B8 is morpholin-2-one or 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 contains one R 10 group. In some cases, B8 contains two R10 groups. In some cases, B8 contains three R10 groups. In some cases, B8 contains four R 10 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).

[0071] In some embodiments, the B ring has the formula (B7b) or (B8a).

Chemical formula

Chemical formula

[0072] In some embodiments, formula (B7b) has the relative configuration of formula (B7bi) or (B7bii).

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0073] In some embodiments, the B ring is described by formula (B9).

Chemical formula

[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 contains one R 10 group. In some cases, B9 contains 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).

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0076] In some embodiments of Formulas (IIA) through (IIA2k), Ring A is selected from aryl (e.g., phenyl), optionally including one or more substituents. In some embodiments, Ring A 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, piperidinyl, tetrahydrofuran), optionally including one or more substituents. In some embodiments, Ring A is selected from cycloalkyl (e.g., cyclohexane), optionally including one or more substituents. In some embodiments, Ring A 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, Ring A is described by Formula (A1).

Chemical formula

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

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

[0080] In a particular embodiment of any one of formulas (IIA1a) to (IIA1k), R 12 is selected from alkyl, substituted alkyl, trifluoromethyl and halogen. In certain cases, R 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 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) to (IIA1k), R 13 is selected from alkyl, substituted alkyl, trifluoromethyl, and halogen. In certain cases, R 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 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) to (IIA1k), R 12 is halogen and R 13 is lower alkyl. In some embodiments, R12 is fluoride and R 13 is methyl.

[0083] In certain embodiments of any one of formulas (IIA) to (IIA1k), R 4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 are both methyl. 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) to (IIA1k), R 2 is methoxy. In certain embodiments of any one of formulas (IIA) to (IIA1k), R 3 is methyl.

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

[0086] In some embodiments, the compound is described by any of the following structures.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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

[0088] In some embodiments of any one of formulas (IIA2) to (IIA2k), R 12 is selected from alkyl, substituted alkyl, trifluoromethyl and halogen. In certain cases, R 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 halogen. In certain cases, when Y 2 is not S and the A ring is not unsubstituted tetrahydropyran, the halogen is chloride. In certain cases, R 12 is trifluoromethyl.

[0089] In some embodiments of any one of formulas (IIA2) to (IIA2k), R 4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 are both methyl. 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 one specific embodiment of any one of formulas (IIA2) to (IIA2k), R 2 is methoxy. In one specific embodiment of any one of formulas (IIA2) to (IIA2k), R 3 is methyl.

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

[0092] In a specific embodiment, the compound is described by any one of the following structures.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0093] In a specific embodiment of formula (II), the compound is described by formula (IIB), (IIC) or (IID):

Chemical formula

[0094] In some embodiments of any one of formulas (IIB), (IIC), or (IID), ring A is selected from aryl (e.g., phenyl), optionally containing one or more substituents. In some embodiments, ring A 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, ring A is selected from cycloalkyl (e.g., cyclohexane), optionally containing one or more substituents. In some embodiments, ring A 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, ring A is described by formula (A1).

Chemical formula

[0096] In some embodiments of any one of formulas (IIB), (IIC) or (IID), the A ring is selected from any of formulas (B2) to (B8), for example as described herein. In a particular embodiment of any one of formulas (IIB), (IIC) or (IID), the A ring is selected from the following structures.

Chemical formula

[0097] In some embodiments of formula (IIB), Y 2 is S. In some embodiments of formula (IIB), Y 1 is CH. In some embodiments of formula (IIB), Y 2 is S and Y 1 is CH. 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 is NH. In some embodiments of formula (IIB), Y 2 is O and Y 1 is CH. In some embodiments of formula (IIB), Y 2 is NR 19 . and Y 1 is CH. In some embodiments of formula (IIB), Y 2 is NH and Y 1 is CH. 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 any one of the specific embodiments from (IIB) to (IIB2), R 4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 are both methyl. In some cases of any one of the formulas (IIB) to (IIB2), R 4 and R 5 together with the carbon to which they are attached form a cycloalkyl group.

[0099] In any one of the specific embodiments from (IIB) to (IIB2), R 2 is methoxy. In any one of the specific embodiments from (IIB) to (IIB2), R 3 is methyl.

[0100] In any one of the specific embodiments from (IIB) to (IIB2), R 2 , R 3 , R 4 , R 5 and R 10 are independently selected from the corresponding groups as shown in the structures of Table 1, 2, or 3. In certain embodiments, the compound is described by any of the following structures.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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

[0102] In a particular embodiment of any one of formulas (IIC1) to (IIC3), R 14 is selected from alkyl, substituted alkyl, trifluoromethyl and halogen. In certain cases, R 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 a particular embodiment 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 are both methyl. In some embodiments of any one of formulas (IIC) to (IIC3), R 4 and R 5 together with the carbon to which they are attached form a cycloalkyl group.

[0104] In a particular embodiment of any one of formulas (IIC) to (IIC3), R 2 is methoxy. In a particular embodiment of any one of formulas (IIC) to (IIC3), R 3 is methyl.

[0105] In a particular embodiment of any one of formulas (IIC) to (IIC3), R 2 , R 3 , R 4 , R 5 , R 10 and R 14It is selected independently from the corresponding groups, as shown in the structure of any one of Tables 1, 2, or 3.

[0106] In certain embodiments, the compound is described by any of the following structures.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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

[0108] In a particular embodiment of any one of formulas (IID1) to (IID3), R 14 is selected from alkyl, substituted alkyl, trifluoromethyl and halogen. In certain cases, R 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 a particular embodiment of any one of (IID) to (IID3), R4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 are both methyl. In some embodiments of any one of formulas (IID) to (IID3), R 4 and R 5 together with the carbon to which they are attached form a cycloalkyl group.

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

[0111] In certain embodiments, the compound is described by any one of the following structures.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0112] In some embodiments from formula (IIE) to (IIF), Y 2 is S. In some embodiments of any one of formula (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 is NH. 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 Y1 is N. In embodiments 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). [Chemistry] or [Chemistry] In certain embodiments of formula (II), the compound is described by formula (IIE2) or (IIF2). [Chemistry] or [Chemistry]

[0114] In some embodiments of any one of (IIE) to (IIE2) or (IIF) to (IIF2), ring A is selected from aryl (e.g., phenyl) optionally containing one or more substituents. In some embodiments, ring A 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, ring A is selected from cycloalkyl (e.g., cyclohexane) optionally containing one or more substituents. In some embodiments, ring A 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, Ring A is described by formula (A1).

Chemical formula

[0116] In one particular embodiment of any one of formula (IIE) to (IIE2) or (IIF) to (IIF2), the A ring is selected from any of formula (B2) to (B8) as described herein, for example. In one particular embodiment of any one of formula (IIE) to (IIE2) or (IIF) to (IIF2), the A ring is selected from the following structures.

Chemical formula

[0117] In certain embodiments of any one of formula (IIE) to (IIE2) or formula (IIF) to (IIF2), R 4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 are both methyl. In some cases of any one of formula (IIE) to (IIE2) or formula (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 formula (IIE) to (IIE2) or formula (IIF) to (IIF2), R 2 is methoxy. In certain embodiments of any one of formula (IIE) to (IIE2) or formula (IIF) to (IIF2), R 3 is methyl.

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

[0120] In certain embodiments, the compound is described by any one of the following structures.

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0121] In some embodiments of any one of (IIG) to (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, morpholino, 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).

Chemical formula

[0123] In some embodiments of any of formulas (IIG) to (IIG3a), the A ring is selected from any of formulas (B2) to (B8), as described herein, for example. In certain embodiments of any of formulas (IIG) to (IIG3a), the A ring is selected from the following structures.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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

[0125] In a specific embodiment of any one of (IIG) to (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 a specific embodiment of any one of (IIG1), (IIG1a) to (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 each 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 each 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 are hydrogen, and R 17 and R 18are each lower alkyl.

[0127] In one particular embodiment of any one of (IIG) to (IIG3), R 4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 are both methyl. 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 one particular embodiment of any one of formulas (IIG) to (IIG3), R 2 is methoxy. In one particular embodiment of any one of formulas (IIG) to (IIG3), R 3 is methyl.

[0129] In a particular embodiment, 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 selected independently from the corresponding groups as shown in the structures of any one of Tables 1, 2, or 3.

[0130] In a particular embodiment, the compound is described by any one of the following structures.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0131] In some embodiments of any one of formulas (IIH) to (IIH1a), ring A is selected from aryl (e.g., phenyl) optionally containing one or more substituents. In some embodiments, ring A 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, ring A is selected from cycloalkyl (e.g., cyclohexane) optionally containing one or more substituents. In some embodiments, ring A 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, ring A is described by formula (A1).

Chemical formula

[0133] In some embodiments of any of formulas (IIH) to (IIH1a), the A ring is selected from any of formulas (B2) to (B8), as described herein, for example. In one particular embodiment of any of formulas (IIH) to (IIH1a), the A ring is selected from the following structures. [Chemical formula] In one particular embodiment of any of formulas (IIH), (IIH1) or (IIH1a), q is 0, so R 10 There is no substituent. In certain embodiments of formula (IIH), the compound is described by any one of formulas (IIH1b) to (IIH1j).

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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

[0135] In a specific embodiment of any one of (IIH) to (IIH1j), R 4 and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 are both methyl. 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 a specific embodiment of any one of formulas (IIH) to (IIH1j), R 2 is methoxy. In a specific embodiment of any one of formulas (IIH) to (IIH1j), R 3 is methyl.

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

[0138] In a particular embodiment of formula (II), the compound is described by formula (IIJ).

Chemical formula

Chemical formula

Chemical formula

[0139] In any one particular embodiment of formula (IIJ), (IIJ1), or (IIJ1a), q is 0, so there is no 10 R substituent.

[0140] In some embodiments of any one of formulae (IIJ), (IIJ1) or (IIJ1a), ring A is selected from aryl (e.g., phenyl), optionally containing one or more substituents. In some embodiments, ring A 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, ring A is selected from cycloalkyl (e.g., cyclohexane), optionally containing one or more substituents. In some embodiments, ring A 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, ring A is described by formula (A1).

Chemical formula

[0142] In some embodiments of any one of formula (IIJ), (IIJ1) or (IIJ1a), ring A is selected from any one of formulas (B2) to (B8), as described herein for example. In certain embodiments of any one of formula (IIJ), (IIJ1) or (IIJ1a), ring A is selected from the following structures.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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

[0144] (In a specific embodiment 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 are both methyl. In some cases of any one of formulas (IIJ) to (IIJ1j), R 4 and R 5Together with the carbon to which they are attached, they form a cycloalkyl group.

[0145] In any one specific embodiment from formula (IIJ) to (IIJ1j), R 2 is methoxy. In any one specific embodiment from formula (IIJ) to (IIJ1j), R 3 is methyl.

[0146] In any one specific embodiment from (IIJ) to (IIJ1j), R 2 , R 3 , R 4 , R 5 and R 10 are independently selected from the corresponding groups as shown in the structures of any of Tables 1, 2, or 3. In a specific embodiment, the compound is described by any of the following structures.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0147] In some embodiments of any one of formulas (IIK) to (IIK3), ring A is selected from aryl (e.g., phenyl), optionally containing one or more substituents. In some embodiments, ring A 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, ring A is selected from cycloalkyl (e.g., cyclohexane), optionally containing one or more substituents. In some embodiments, ring A 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, ring A is described by formula (A1).

Chemical formula

[0149] In some embodiments of any one of formulas (IIK) to (IIK3), the A ring is selected from any of formulas (B2) to (B8), for example, as described herein. In a particular embodiment of any one of formulas (IIK) to (IIK3), the A ring is selected from the following structures.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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

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

[0152] In a particular embodiment of any one of formulas (IIK) to (IIK3a), R 11 is methoxy. In a particular embodiment of any one of (IIK1), (IIK1a) to (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 each 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 each 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 are hydrogen, and R 17 and R 18 are each lower alkyl.

[0153] (In a particular embodiment of any one of (IIK) to (IIK3a), R 4and R 5 are each independently lower alkyl. In certain cases, R 4 and R 5 are both methyl. 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 a particular embodiment of any one of formulas (IIK) to (IIK3a), R 2 is methoxy. In a particular embodiment of any one of formulas (IIK) to (IIK3a), R 3 is methyl.

[0155] In a particular embodiment, 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 the structures of any of Tables 1, 2, or 3.

[0156] In a particular embodiment, the compound is described by any of the following structures.

Chemical formula

Chemical formula

[0157] In certain embodiments of formula (III), the compound is described by formula (IIIA) or (IIIB).

Chemical formula

Chemical formula

[0158] In a particular embodiment of any one of (III) to (IIIB), R 7 and R 8 are each independently lower alkyl. In certain cases, R 9 is trifluoromethyl. In some cases of any one of formulas (III) to (IIIB), R 9 can be represented by the formula -(CH2) n -X 1 where n is 0, 1, 2, or 3, and X 1 is hydroxyl, halogen, haloalkyl (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 cycloalkyl or heterocycle (e.g., 5- or 6-membered saturated N-containing ring). In certain cases, X 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 a particular embodiment of any one of formulas (III) to (IIIB), R 2 is methoxy. In a particular embodiment of any one of formulas (III) to (IIIB), R 3 is methyl.

[0160] In some embodiments of any one of formulas (III) to (IIIB), R 1 is represented by 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, haloalkyl, 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 (for example, as described herein).

[0161] In a particular embodiment of any one of formulas (III) to (IIIB), R 1 , R 2 , R 3 , R 7 , R 8 and R 9 are independently selected from the corresponding groups as shown in the structures of Table 1, 2, or 3. In some embodiments, the subject compound is described by the structure of formula (VI).

Chemical formula

Chemical formula

Chemical formula

[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 is NH. 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) to (VI) (for example, any of the formulas described herein), R 2 is methoxy. In some embodiments of any one of formulas (I) to (VI), R3 is methyl. In some embodiments of any of formulas (I) to (VI), Y 2 is S and R 3is methyl. In some embodiments of any one of formulas (I) to (VI), R2 is halogen (e.g., Cl or Br). In some embodiments of any one of formulas (I) to (VI), R 2 is substituted lower alkyl. In some embodiments of any one of formulas (I) to (VI), R 2 is CF3. In some embodiments of any one of formulas (I) to (VI), R 2 is CHF2. In some embodiments of any one of formulas (I) to (VI), R 2 is CH2F. In some embodiments of any one of formulas (I) to (VI), R 2 is lower alkyl. In some embodiments of any one of formulas (I) to (VI), R2 is methyl.

[0164] In certain embodiments, the compound is described by the structure of one of the compounds in Table 1, 2, or 3. It is understood that any of the compounds shown in Table 1, 2, or 3 may exist in the form of a salt, such as a trifluoroacetate salt (e.g., 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

Table 3

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

[0166] Aspects of the present disclosure include PI-kinase inhibitory compounds, their salts (e.g., pharmaceutically acceptable salts), and / or their solvates, hydrates, and / or prodrug forms. Further, in any of the compounds described herein that have one or more chiral centers, if the absolute stereochemistry is not explicitly shown, each center can independently be in the R configuration or the S configuration or a mixture thereof. Of course, all permutations of salts, solvates, hydrates, prodrugs, and stereoisomers are evaluated as being included in the present disclosure.

[0167] In some embodiments, the subject compound or its prodrug form is provided in the form of a pharmaceutically acceptable salt. Compounds containing an amine or nitrogen-containing heteroaryl group can be essentially basic and can thus react with any number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. The acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphates, and organic acids such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid, parabromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and salts formed from related inorganic and organic acids generally used to form salts. Thus, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, hippurates, gluconates, lactobionates, and similar salts. In certain embodiments, the pharmaceutically acceptable acid addition salts include those formed from mineral acids such as hydrochloric acid and hydrobromic acid, and those formed from organic acids such as fumaric acid and maleic acid.

[0168] In some embodiments, the subject compound is provided in prodrug form. A "prodrug" refers to a derivative of an active agent that requires conversion in the body to release the active agent. In certain embodiments, the conversion is enzymatic conversion. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the active agent. A "pro-component" refers to a form of a protecting group that, when used to mask a functional group within the active agent, converts the active agent to a prodrug. In some cases, the pro-component will be attached to the drug via a bond that is cleaved by enzymatic or non-enzymatic means in vivo. 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 pro-component is attached to a hydroxy or carboxylic acid group of the subject compound. In certain cases, the pro-component is an acyl or substituted acyl group. In certain cases, the pro-component is an alkyl or substituted alkyl group that forms an ester functional group, for example, when attached to a carboxylic acid group of the subject compound.

[0169] In some embodiments, the subject compound, prodrug, stereoisomer, or a 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 a solute (e.g., a prodrug or a pharmaceutically acceptable salt thereof, and one or more molecules of a 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 compound is provided by oral administration and is absorbed into the bloodstream. In some embodiments, the oral bioavailability of the subject compound is 30% or more. Any convenient method can be used to modify the subject compound or its formulation to enhance absorption throughout the intestinal lumen or their bioavailability. In some embodiments, the subject compound is metabolically stable (e.g., remains substantially intact in vivo during the half-life of the compound). In certain embodiments, the half-life of the compound (e.g., in vivo half-life) is 5 minutes or more, such as 10 minutes or more, 12 minutes or more, 15 minutes or more, 20 minutes or more, 30 minutes or more, 60 minutes or more, 2 hours or more, 6 hours or more, 12 hours or more, 24 hours or more, or more. [Method]

[0171] As summarized above, aspects of the present invention include PI4-kinase inhibitory compounds and methods of inhibition using the same. A PI4-kinase inhibitory compound is a compound that inhibits the activity of PI4-kinase in a cell upon contact with the cell or its components. In one embodiment, a method of treating a pathogen infection is provided. In one embodiment, a method of treating cancer is also provided. PI4-kinase inhibition in cells infected with a pathogen

[0172] In some cases, the type of cell in which the subject compound exhibits activity is one infected with a pathogen, as described herein. Inhibiting PI4-kinase means 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 certain cases, the PI4-III-kinase is PI4-IIIIα. In certain 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 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 subject compound specifically inhibits PI4-kinase without unwanted inhibition of protein kinases. In some embodiments, the subject compound specifically inhibits PI4-kinase without unwanted inhibition of PI3-kinase. In some embodiments, the subject compound specifically inhibits PI4-kinase and / or a particular PI3-kinase subclass without unwanted inhibition of other PI3-kinase subclasses or protein kinases.

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

[0175] In some embodiments, the subject compound is determined by an inhibition assay (e.g., IC 50 or EC 50By measuring the values, inhibit PI4-kinase as determined by an assay that determines the level of enzyme activity in either a cell-free system or in cells after treatment with a test compound relative to a control. In certain embodiments, the test compound has an IC 50 value (or an EC 50 value) 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.

[0176] In some embodiments, the test compound inhibits PI4-kinase as determined by a kinase activity assay (e.g., by measuring the rate of beta particle emission using a scintillation counter or phosphoimaging to determine the level of incorporation of radiolabeled phosphate from [γ- 32 P]-ATP into substrate molecules after treatment with the test compound relative to a control). In certain embodiments, the test compound has an IC 50has a value. In certain embodiments, the subject compound has an IC50 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. In certain further embodiments, the subject compound has an IC50 value for PI4K-IIIβ of 50 μM or less [etc.], 10 nM or less, 6 nM or less, or less, as set forth in Table 2-3. In certain further embodiments, the subject compound has an IC50 value for the PI3-kinase p110α-p85 complex between about 8 and about 10 nM, between about 8 μM and about 10 μM, or more. In certain further embodiments, the subject compound has an IC50 value for the PI3-kinase p110γ-p85 complex from about 2 to about 4 nM, from about 4 μM to 5 μM, or more, as described herein. In certain further embodiments, the subject compound has an IC50 value for class II PI3-kinase beta of less than about 1 μM, less than about 150 nM, less than about 30 nM, or even less, as described herein. In certain embodiments, the subject compound has an IC50 value for class II PI3-kinase alpha of less than 10 μM. In certain further embodiments, a plurality of the above criteria are independently met by a particular compound.

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

[0178] In certain embodiments, the subject compound does not significantly affect the viability of mammalian cells, as determined, for example, by a cytotoxicity assay in which the subject compound is administered to HeLa cells and the number of viable cells present is determined. The subject compound can exhibit a cell viability of 15% or more, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 120% or more, or more, compared to a control (e.g., DMSO control). The subject compound can have a CC 50 value of 1 nM or more, such as 100 nM or more, 300 nM or more, 1 μM or more, 3 μM or more, 5 μM or more, 10 μM or more, 20 μM or more, 30 μM or more, 50 μM or more, or more.

[0179] In certain embodiments, the compound has a therapeutic index (e.g., the ratio of the cytotoxicity of the compound (e.g., cytotoxicity, CC50)) against a 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). The subject compound (e.g., as described herein) can inhibit the activity of at least one of the PI-kinases in the range of 10% to 100%, such as 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 a particular assay, the subject compound can inhibit its target with an IC -6 of 1 x 10 -6 M or less (e.g., 1 x 10 -7 M or less, 1 x 10 -8 M or less, 1 x 10 -9 M or less, 1 x 10 -10 M or less, or 1 x 10 -11 M or less). 50 There is a possibility of inhibiting its target.

[0180] There are numerous protocols used to determine PI-kinase activity, including, but not limited to, binding assays; assays using purified enzyme, cell assays in which PI4P levels are measured, or cell assays in which cell phenotypes are measured, such as gene expression assays, and cell-free assays such as in vivo assays involving specific animals (which, in certain embodiments, can be animal models of conditions associated with a target pathogen).

[0181] In some embodiments, the subject method is an in vitro method that includes 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 includes evaluating whether the compound inhibits the PI-kinase. In certain embodiments, the PI-kinase is PI4-kinase or 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 in the sample, if present, using, for example, light detection.

[0183] In certain embodiments, the compound is modified with an affinity group that binds to a support or support (e.g., biotin), such that samples that do not bind to the compound can be removed (e.g., by washing). Next, if specifically bound target PI-kinase is present, it can be detected using any convenient means, such as using the 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] Method for treating a pathogen infection In contrast to the classical paradigm of anti-infective therapy, the present disclosure provides methods for treating pathogen infections by targeting host functions and / or molecules upon which the pathogen depends, thereby reducing the ability of the pathogen to evade therapeutic agents by mutation. Further, by utilizing such targets, the methods of the present disclosure enable combination therapies that address multiple targets, thereby enhancing the ability to eliminate infectious pathogens. The methods also provide a broad platform for anti-infective therapy by targeting host functions. Further, when the pathogen encodes its own PI-kinase, the present disclosure provides methods 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,” WO2009 / 148541, which is hereby incorporated by reference in its entirety. Pathogens of interest include, but are not limited to, viral pathogens of the Picornaviridae, Flaviviridae, Retroviridae, Filoviridae, Togaviridae, Papovaviridae, Papillomaviridae, Polyomaviridae, Caliciviridae, Coronaviridae, Hepaviridae, Bunyaviridae, Poxviridae, and Orthomyxoviridae families. In some embodiments, the pathogen is a hepatitis virus (e.g., HCV), norovirus, hepavirus (e.g., HEV), beta coronavirus (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., A-D), 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, selected from.

[0187] In some embodiments, when the pathogen is HCV, useful compounds include those that target the liver, have a high first-pass effect, which is usually discarded in early drug development, and as a result have low systemic bioavailability. 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, Coccidioides, Histoplasma, etc. Accordingly, symptoms of fungal diseases in which the subject method is used for treatment include, but are not limited to, candidiasis, aspergillosis, coccidioidomycosis, Cryptococcus gattii infection, histoplasmosis, etc.

[0189] In some cases, the method is a method of inhibiting PI4-kinase in a sample. Accordingly, aspects of the method include contacting the sample with the subject compound (e.g., as described above) under conditions in which the compound inhibits PI4-kinase. Any convenient protocol for contacting the compound with the sample may be used. The particular protocol used may vary, for example, depending on whether the sample is in vitro or in vivo. In the case of an in vitro protocol, contact between the sample and the compound may be achieved using any convenient protocol. In some cases, the sample contains cells maintained in an appropriate medium and the complex is introduced into the medium. In the case of an in vivo protocol, any convenient administration protocol may be used. Depending on the potency of the compound, various protocols may be used for the cells of interest, the method of administration, the number of cells present.

[0190] As used herein, the term "sample" generally refers to (but is not necessarily) a material or mixture of materials in fluid form containing one or more components of interest.

[0191] In some embodiments, the subject method is a method for treating an infectious disease that the subject suffers from. In some embodiments, the subject method comprises administering to the subject an effective amount (e.g., as described herein) of the subject compound or a pharmaceutically acceptable salt thereof. The subject compound can be administered as part of a pharmaceutical composition (e.g., as described herein). In certain cases of the method, the compound administered is a compound of one of formulas (I) to (VI). In certain cases of the method, the compound administered is described by one of the compounds in Tables 1, 2 or 3.

[0192] In some embodiments, an "effective amount" means, when administered to an individual in one or more doses in monotherapy or combination therapy, 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) reduction in the amount of virus in the individual compared to the burden of the individual in the absence of treatment with the compound, or compared to the bacterial burden of the individual before or after treatment with the compound.

[0193] In some embodiments, an "effective amount" of a compound means an amount 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 in the virus in the serum of an individual when administered one or more times to an individual infected with the virus.

[0194] In some embodiments, the effective amount of the compound is an amount in the range 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, from about 70 ng / ml to about 300 ng / ml, from about 60 ng / ml to about 100 ng / ml, from about 65 ng / ml to about 85 ng / ml, from about 70 ng / ml to about 90 ng / ml, from about 200 ng / ml to about 900 ng / ml, from about 200 ng / ml to about 800 ng / ml, from about 200 ng / ml to about 700 ng / ml, from about 200 ng / ml to about 600 ng / ml, from about 200 ng / ml to about 500 ng / ml, from about 200 ng / ml to about 400 ng / ml, or from about 200 ng / ml to about 300 ng / ml).

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

[0196] In some embodiments, a single administration of the compound is performed. In other embodiments, multiple administrations are performed. When multiple administrations are performed over a certain period, the compound can be administered twice a day (qid), once a day (qd), every other day (qod), every three days, three times a week (tiw), twice a week (biw), or once a week (qw) over a certain period. For example, the compound can be administered qid, qd, qod, qw, tiw, or biw over a period of from one day to about two years or more. For example, the compound can be administered for one week, two weeks, one month, two months, six months, one year, or two years, or more, at any of the aforementioned frequencies depending on various factors.

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

[0198] In some embodiments of the treatment method, the symptoms of the infectious disease are due to infection with a positive-strand RNA virus, a negative-strand RNA virus, or a DNA virus. In some embodiments, the symptoms of the infectious disease are due to infection by a pathogen selected from the group of virus families consisting of Picornaviridae, Flaviviridae, Retroviridae, Filoviridae, Togaviridae, Papovaviridae, Papillomaviridae, Polyomaviridae, Caliciviridae, Coronaviridae, Hepadnaviridae, Bunyaviridae, Poxviridae, and Orthomyxoviridae. In some embodiments, the symptoms of the infectious disease are due to infection by a pathogen selected from the phylum Apicomplexa or the order Kinetoplastida. In some embodiments, the symptoms of the infectious disease are due to a bacterial infection. In some embodiments, the symptoms of the infectious disease are due to a fungal infection. In some embodiments, the symptoms of the infectious disease are due to infection by 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., A - D), 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 rhinovirus or Plasmodium falciparum. In some embodiments, the pathogen is hepatitis A virus. In a particular embodiment of the treatment method, the pathogen is a virus selected from EV71, EV68, human rhinovirus, HAV, HCV, norovirus, coxsackievirus, 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 polio. In certain cases, the virus is an Ebola virus. Any of the compounds described herein can be used in a method for treating a subject. In certain cases, the compound is one of any 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 compound used in the subject method has broad-spectrum activity against some of the pathogens (e.g., viruses) described herein. In certain cases, the compound has antiviral activity against a specific virus, including one or more of the above viruses. In certain cases, the compound has antifungal activity against a specific fungus.

[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 the NS5A or NS4B protein. In some embodiments, the symptoms of the infection are due to infection by 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 prevents the interaction between the BAAPP domain of the pathogen and PIP-2. In some embodiments, the compound blocks the replication of the pathogen.

[0200] In some embodiments, the subject method is a method of treating a subject's high levels of VLDL or LDL cholesterol. In some embodiments, the subject method comprises administering to the subject an effective amount of a 2-aminophenylthiazole compound (such as those 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; 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 of viral infection. In some cases, the subject method comprises diagnosing a viral infection comprising 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 of inhibiting a viral infection and comprises contacting a virus-infected cell with an effective amount of a 2-aminophenylthiazole compound (such as those described above) to inhibit viral replication. In some embodiments, the method further comprises contacting the cell 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 comprising a label, and the method further comprises detecting the label within a subject. The choice of label varies depending on the detection means. Any convenient label and detection system may be used in the methods described herein. See, e.g., Baker, “The whole picture,” Nature, 463, 2010, p977-980. In certain embodiments, the compound comprises a fluorescent label suitable for optical detection. In certain embodiments, the compound comprises a radiolabel for detection using positron emission tomography (PET) or single photon emission computed tomography (SPECT). In some cases, the compound comprises a paramagnetic label suitable for tomographic detection. The compounds described herein may be labeled as described above, but in some methods, the compound is not labeled and a secondary labeling agent is used for imaging.

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

[0205] The methods of the present disclosure can target cancer cells. Target cancer cells and their metastases can be considered to be "dependent" on an increase in PI4-kinase activity. The latter may be due to amplification of a chromosomal segment harboring a PI4-kinase gene 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. IRES is 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, especially under abnormal cellular states. Target cancer cells may have the above chromosomal amplification or increased expression of eEF1A2 without chromosomal amplification, both of which may lead to an increase in PI4 kinase activity. The inventors have found that antiviral PI4 kinase inhibitors that strongly target IRES-containing viruses are also effective in reducing cancer cell proliferation and can find use in the treatment of cancer. In some embodiments, the 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 according to the subject methods include a wide variety of cancer cells. In some cases, the cancer cells are selected from cancer cells of the bladder, breast, colon, endometrium, cervix, testis, liver, lung, non-small cell lung cancer (NSCLC), ovary, prostate, pancreas, brain, thyroid, stomach, kidney, melanoma, sarcoma.

[0207] Accordingly, aspects of the present disclosure include evaluating 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 evaluating 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 "increased expression level," "overexpression," and "overexpressed" are used synonymously and refer to an expression level in a target cell that is 20% or more, 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, higher than the natural or basal level of expression in a control cell, as compared to the natural or basal level of expression in the 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 cells from a plurality of subjects. In some cases, the subject cells are normal cells.

[0208] There are numerous methods that can be used to measure or determine the expression level within a cell, including but not limited to cell assays (e.g., gene expression assays) in which the 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 a gene of interest within 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 a 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 a high level of PI4-kinase activity. The term "elevated activity level" refers to an activity level in a target cell that is 20% or more greater than the natural 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 or more, 5-fold or more, 10-fold or more, 30-fold or more, 100-fold or more, or 1000-fold or more greater than the natural 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 cells from a plurality of subjects. In some cases, the subject cell is a normal cell.

[0210] There are numerous methods that can be used to determine PI4-kinase activity, such as binding assays; assays using purified enzymes, measurement of PI4-P levels, cell assays in which cell phenotypes are measured, such as gene expression assays; and cell-free assays including in vivo assays involving specific animals (which may be animal models of conditions dependent on PI-kinase activity) and the like, but are not limited thereto. In some cases, 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-inhibitory sensitive cells do not exhibit high levels of expression or activity of PI4KIIIβ. In some embodiments, the PI4-kinase inhibitor is an inhibitor of 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-kinase without unwanted inhibition of other protein kinases. In some embodiments, the PI4-kinase inhibitor specifically inhibits PI4-kinase without unwanted inhibition of PI3-kinase. In some embodiments, the PI4-kinase inhibitor specifically inhibits PI4-kinase and / or a specific PI3-kinase subclass without unwanted 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. US2011 / 0262565 and US9,926,309. For example, the subject compound may act by directly or indirectly reducing the level of PIP2 that specifically binds to the BAAPP domain.

[0212] The PI4-kinase inhibitor can be determined by an inhibition assay (e.g., by measuring the IC 50 or EC 50 value, respectively, in an assay that determines the level of enzyme activity in either a cell-free system or cells after treatment with the subject compound relative to a control). In certain embodiments, the subject compound has an IC 50 value (or EC 50 value) 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.

[0213] PI4-kinase inhibition can be determined by a kinase activity assay (e.g., by measuring the incorporation level of radiolabeled phosphate from [γ- 32 P]-ATP into substrate molecules using a scintillation counter or phosphoimaging to determine the level relative to a control after treatment with the subject compound). In certain embodiments, the inhibitor has an IC 50 value 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. In certain embodiments, the inhibitor has an IC 50has a value. In certain further embodiments, the inhibitor has an IC50 value of PI4K-IIIβ of 50 μM or less, such as 10 nM or less, 6 nM or less, or less, as described in Table 2-3. In certain embodiments, the inhibitor has an IC50 value of type II PI3-kinase alpha of less than 10 μM. In certain embodiments, the inhibitor has an IC50 value of 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 satisfied by a particular compound.

[0214] In some embodiments, the anti-cancer effect of the PI4-kinase inhibitor tracks anti-infective (e.g., antiviral) activity. In some cases, the enzyme activity and anti-cancer activity of the subject compound are different. In some embodiments, the anti-cancer activity of the subject compound depends on a combination of inhibition of both PI4KIIIIα and PI4KIIIβ, or a combination of inhibition of class III PI4-kinase and / or class II PI3-kinase (particularly class II PI3-kinase beta). The subject compound 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 the viability of mammalian cells, as determined by, for example, a cytotoxicity assay in which the compound is administered to primary human hepatocytes and the number of viable cells present is determined. The compound may exhibit a cell viability of 15% or more, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 120% or more, or more, compared to a control (e.g., DMSO control). The subject compound may exhibit a CC 50 value (the concentration at which 50% of the cells continue to survive) of 1 nM or more, such as 100 nM or more, 300 nm or more, 1 M or more, 3 M or more, 5 μM or more, 10 μM or more, 20 μM or more, 30 μM or more, 50 μM or more, or more.

[0216] In certain embodiments, the PI4-kinase inhibitor has a therapeutic index 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, i.e., the ratio of the cytotoxicity of the compound to its biological activity (e.g., anti-cancer activity, EC50 - the concentration at which 50% of cancer cells are inhibited) (e.g., normal cytotoxicity, CC50).

[0217] As summarized above, aspects of the present disclosure include methods of inhibiting PI4-kinase (e.g., PI4-IIIα, and / or PI4-IIIβ kinase) in cells of interest. The compounds (e.g., as described herein) can inhibit at least one activity of PI4-kinase in the range of 10% to 100%, such as 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, the PI4-kinase inhibitor can inhibit its target at an IC -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), which is the concentration required to inhibit 50% of the kinase activity. 50

[0218] There are numerous protocols for determining PI-kinase activity, including, but not limited to, binding assays; assays using purified enzymes, cell assays in which PI4P levels are measured, or cell assays in which cell phenotypes are measured, such as gene expression assays; and cell-free assays such as in vivo assays involving specific animals (which, in certain embodiments, can be animal models of conditions that are dependent on PI-kinase activity).

[0219] ​In some embodiments, the subject method is an in vitro method that includes 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 includes 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 PI4-IIIβ kinase). In another embodiment of the subject method, the sample is known to contain the target PI-kinase.

[0220] Method for treating cancer In some embodiments, the subject method is an in vivo method that includes administering to a subject an effective amount of a compound that specifically inhibits a PI4-kinase. "Effective amount" means an amount of a compound that is effective to inhibit a PI4-kinase 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 PI4-kinase activity of the subject in the absence of treatment with the compound, or compared to the PI4-kinase activity of the subject before or after treatment with the compound, when administered to the subject in one or more doses in monotherapy or combination therapy.

[0221] The subject can be a person suffering from cancer as described herein. Cancers of interest that can be treated according to the subject methods 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, stomach cancer, and kidney cancer. In some cases, the cancer is lung cancer. In certain cases, the lung cancer is lung adenocarcinoma. In some cases, the cancer is breast cancer. In certain cases, 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 in a monotherapy or combination therapy, is effective to reduce the tumor mass of 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%, such as at least about 20%, compared to the tumor mass of the individual in the absence of treatment with the compound or compared to the tumor mass in the subject prior to treatment with the compound. As used herein, the term "tumor mass" refers to the total mass of tumor tissue carried by a subject suffering from cancer.

[0223] In some embodiments, a "therapeutically effective amount" is an amount of a compound of interest that, when administered to an individual in one or more doses in a monotherapy or combination therapy, is effective to reduce the radiation dose 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 radiation dose 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 in a monotherapy or combination therapy, reduces the amount of metastasis in the individual 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 amount of metastasis in the individual in the absence of treatment with the compound or compared to the amount of metastasis in the subject prior to treatment with the compound. As used herein, the term "amount of metastasis" refers to the total mass or number of metastatic tissues carried by a subject suffering from cancer.

[0225] In some embodiments, an effective amount of the compound is an amount in the range 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, from about 70 ng / ml to about 300 ng / ml, from about 60 ng / ml to about 100 ng / ml, from about 65 ng / ml to about 85 ng / ml, from about 70 ng / ml to about 90 ng / ml, from about 200 ng / ml to about 900 ng / ml, from about 200 ng / ml to about 800 ng / ml, from about 200 ng / ml to about 700 ng / ml, from about 200 ng / ml to about 600 ng / ml, from about 200 ng / ml to about 500 ng / ml, from about 200 ng / ml to about 400 ng / ml, or from about 200 ng / ml to about 300 ng / ml).

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

[0227] In some embodiments, a single administration of the compound is performed. In other embodiments, multiple administrations are performed. When administered multiple times over a period of time, the compound can be administered twice a day (bid), once a day (qd), every other day (qod), every three days, once a week (qw), three times a week (tiw), or twice a week (biw) over a period of time. For example, the compound can be administered bid, qd, qod, tiw, or biw over a period of from 1 day to about 2 years or more. For example, the compound can be administered at any of the aforementioned frequencies for 1 week, 2 weeks, 1 month, 2 months, 6 months, 1 year, or 2 years, or more, depending on various factors. In some embodiments, the compound can 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 compound can be administered in a course that permits a "drug holiday" that can last from 1 day to 7 days.

[0228] When a therapeutically effective amount of a subject compound is administered to an individual suffering from cancer, one or more of the following may occur: 1) a decrease in tumor mass, 2) a decrease 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 morbidity or mortality in the clinical outcome, 5) a shortening of the total treatment period when combined with other anti-cancer agents, 6) a decrease in the size or number of metastases, and 7) an improvement in the indicators of disease response (e.g., alleviation of one or more symptoms of cancer). Various methods can be used to determine whether a treatment method is effective. For example, biological samples obtained from individuals treated with the subject method can be measured, or imaging studies may be performed.

[0229] Any of the PI4-kinases described herein can be utilized in the treatment methods of a subject. In certain cases, the PI4-kinase inhibitor is one of any 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, including elevated expression of PI4-kinase, or factors involved in IRES-mediated translation that stimulate PI4-kinase activity (e.g., eEF1A2), or Golgi-mediated secretion. In some cases, cancer cells include chromosomal amplification of the PI4-kinase gene (such as PI4IIIβ or PI4IIIα), chromosomal amplification of the eEF1A2 gene, or chromosomal 1q amplification (i.e., 1q amplified cancer cells containing PI4IIIβ-kinase in the amplified segment). In some embodiments, 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 certain 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 such as for animal models of disease), and non-human primates (e.g., chimpanzees, monkeys). The subject may be in need of cancer treatment. In some cases, the subject method includes a diagnosis of 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 comprising a label, and the method further includes 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 comprises a fluorescent label suitable for light detection. In certain embodiments, the compound includes a radiolabel for detection using positron emission tomography (PET) or single photon emission computed tomography (SPECT). In some cases, the compound includes a paramagnetic label suitable for tomographic detection. The subject compound can be labeled as described above, but in some methods, the compound is not labeled and a secondary labeling agent is used for imaging.

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

[0234] Metabolic enzyme inhibitors of interest 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 potent inhibitor of CYP3A4 and itself has found use as a therapeutic HIV protease inhibitor. In some cases, the metabolic enzyme inhibitor is co-administered at a dose effective to inhibit the metabolic enzyme action on the PI4-kinase inhibitor. However, this is a sub-therapeutic dose compared to its therapeutic use, for example, in the treatment of HIV.

[0235] The terms "co-administration" and "combination" include administering two or more agents simultaneously, concurrently, or sequentially without a specific time limit. In one embodiment, the agents are present in the cell or subject's body simultaneously 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 can be administered before (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 before), concomitantly with, or after (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 can be different, and representative routes of administration are described in detail below. One of ordinary skill in the art will be able to readily determine the appropriate timing, sequence, and dosage of administration of the PI4-kinase inhibitor and the additional agent.

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

[0237] The terms "co-administration" and "combination" include the administration of two or more therapeutic agents simultaneously, concurrently, or sequentially without a specific time limit. In one embodiment, the agents are present in the cell or subject's body simultaneously 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 before (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 before), concomitantly with, or after (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] "Combined administration" of a known therapeutic agent or additional therapy with the pharmaceutical compositions of the present disclosure means the administration or additional therapy of the compound and the second agent at a point in time such that both the known drug and the composition of the invention have a therapeutic effect. Such co-administration can include simultaneous (i.e., at the same time), prior, or subsequent administration of the drug with respect to the administration of the compound of interest. The routes of administration of the two agents can be different, but representative routes of administration are described in detail below. One of ordinary skill in the art will be able to readily determine the appropriate timing, sequence, and dosage of administration of the particular drugs or therapies and compounds 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 the subject within 24 hours of each other, 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 substantially simultaneously. Administered substantially simultaneously means that the compounds are administered to the subject within about 10 minutes of each other, such as within 5 minutes of each other or within 1 minute of each other.

[0240] Also provided are pharmaceutical products of PI4-kinase inhibitors and second activators. In pharmaceutical dosage forms, the compounds can be administered in the form of their pharmaceutically acceptable salts, or they can also be used alone, or in suitable combinations, and in combination with other pharmaceutically active compounds.

[0241] In combination with any of the subject methods, a PI4-kinase inhibitor (or a pharmaceutical composition containing such a compound, e.g., as described herein) can 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 can be administered before, simultaneously with, or after the administration of the other drug. In certain cases, the cancer is selected from adrenal, liver, kidney, bladder, breast, colon, stomach, ovary, cervical, uterine, esophageal, colorectal, prostate, pancreas, lung (both small cell and non-small cell), thyroid, carcinoma, sarcoma, glioma, glioblastoma, melanoma, and various head and neck tumors.

[0242] In the case of treating cancer, the PI4-kinase inhibitor can be administered in combination with a chemotherapeutic agent selected from the group consisting of alkylating agents, nitrosoureas, metabolites, anticancer antibiotics, plant (vinca) alkaloids, steroid hormones, taxanes, nucleoside analogs, steroids, anthracyclines, thyroid hormone replacement drugs, thymidylate targeting 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 tyrosine kinases such as Oncept®), and other cell therapies.

[0243] Certain 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, folfirinox, cisplatin, carboplatin, 5-fluorouracil, teysmo, paclitaxel, prednisone, levothyroxine, pemetrexed, navitoclax, and ABT-199. Peptide compounds may also be used. Chemotherapeutic agents of interest include, but are not limited to, dolastatin and its active analogs and derivatives; and auristatin and their active analogs and derivatives (e.g., monomethyl auristatin D (MMAD), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), etc.). See, e.g., WO96 / 33212, WO96 / 14856, and U.S. 6,323,315. Suitable chemotherapeutic agents also include maytansinoid and its active analogs and derivatives (see, e.g., EP1391213; and Liu et al (1996) Proc. Natl. Acad. Sci. USA 93:8618-8623, etc.), duocarmycin and its active analogs and derivatives (e.g., including synthetic analogs, KW-2189 and CB1-TM1), and benzodiazepine and its active analogs and derivatives (e.g., pyrrolobenzodiazepine (PBD)).

[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 cancer), the PI4-kinase inhibitor can be administered in combination with an immunotherapeutic agent. An immunotherapeutic agent is a convenient agent that can be used for the treatment of a disease by inducing, enhancing, or suppressing an immune response. In some cases, the immunotherapeutic agent is an immune checkpoint inhibitor. Any convenient checkpoint inhibitor can be utilized, including but not limited to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors, programmed death 1 (PD-1) inhibitors, and PD-L1 inhibitors. In certain cases, the checkpoint inhibitor is selected from cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors, programmed death 1 (PD-1) inhibitors, and PD-L1 inhibitors. 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 an inflammatory disease, the immunomodulatory polypeptide can be administered in combination with a colony-stimulating factor 1 receptor (CSF1R) inhibitor. Exemplary CSF1R inhibitors of interest include, but are not limited to, emactuzumab.

[0246] Any convenient cancer vaccination therapy and agent can be used in combination with the PI4-kinase inhibitor, composition, and method. For the treatment of cancer (e.g., ovarian cancer), the PI4-kinase inhibitor can be administered in combination with a vaccination therapy (e.g., a dendritic cell (DC) vaccine that promotes Th1 / Th17 immunity). Infiltration of Th17 cells correlates with a significant extension of the overall survival period of ovarian cancer patients. In some cases, the ENPP1 inhibitor compound can find use as an adjuvant therapy in combination with Th17-inducing vaccination.

[0247] Also, the drugs of interest include, but are not limited to, CARP-1 / CCAR1 (Cell Division Cycle and Apoptosis Regulator 1) inhibitors as described in 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, this combination results in an improved effect compared to either component alone. In some cases, the combination provides a supra-additive or synergistic effect compared to the combined or additive effect of the components. Various combinations of the subject compound and the chemotherapeutic agent can be used and can be administered sequentially or simultaneously. For multiple dosages, the two drugs can, for example, be directly alternated, or it is possible to alternate two or more dosages of one drug with a single dosage of the other drug. The simultaneous administration of both drugs can also be alternated, or otherwise interspersed with the dosages of the individual drugs. In some cases, the time between administrations can be a period of 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 more after the start of treatment. [Utility]

[0249] The compounds and methods of the present invention find use in a variety of applications, as described herein, for example. Applications of interest include, but are not limited to, research 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 the compounds.

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

[0252] In some embodiments, the subject compounds and methods find use in therapeutic applications where enterovirus infection is involved. Enteroviruses (EVs) are one of the most frequently infecting pathogens of humans worldwide and are a major cause of upper respiratory tract infections. EV infections associated with lung deterioration are relevant to patients with cystic fibrosis (CF). In certain cases, the subject methods and compounds (e.g., as described herein) find use in treating patients with cystic fibrosis (CF), for example, to alleviate symptoms or conditions associated with EV infection. In certain cases, the subject compounds and methods can be used to target the misfolding of the F508del-cystic fibrosis transmembrane conductance regulator (CFTR).

[0253] In some embodiments, the subject compounds and methods find use in therapeutic applications where rhinovirus infection is involved. Rhinoviruses are pathogens that frequently infect humans worldwide and are an important cause of asthma exacerbations. In certain cases, the subject methods and compounds (e.g., as described herein) find use in treating patients with asthma, for example, 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 the inhibition of cancer in a host and / or the treatment of a variety of different conditions where treatment 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 in this specification can be formulated using any convenient excipients, reagents, and methods. The compositions are provided as 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 in, for example, 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) A.H. Kibbe et al., eds., 3 rd ed. Amer. Pharmaceutical Assoc. and are well described in various publications.

[0256] Pharmaceutically acceptable excipients such as vehicles, adjuvants, carriers or diluents are generally readily available. Further, pharmaceutically acceptable auxiliary substances such as pH adjusters and buffers, isotonic agents, stabilizers, wetting agents, etc. are generally readily available.

[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 that vary in strength from 5 mM to 100 mM. In some embodiments, the aqueous buffer includes a reagent that provides an isotonic solution. Such reagents include sodium chloride and sugars such as, for example, mannitol, dextrose, and sucrose. In some embodiments, the aqueous buffer further includes a nonionic surfactant such as polysorbate 20 or 80. Optionally, the formulation may further include 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. The formulations can also be lyophilized, in which case they generally include cryoprotectants such as sucrose, trehalose, lactose, maltose, mannitol, and the like. Lyophilized formulations can be stored for extended periods at ambient temperature. In some embodiments, the subject compound is formulated for sustained release. In some embodiments, the subject compound is formulated for depot release.

[0258] Formulated pharmaceutical composition for treating a pathogen infection In some embodiments, the target compound and antiviral agents (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-benzimidazol-2-yl)methyl)); arildone; pre-conazole (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]decane-1-amine hydrochloride); rimantadine (alpha-methyltricyclo[3.3.1.1.3,7]decane-1-methanamine hydrochloride); acyclovir (acycloguanosine); valacyclovir; penciclovir (9-(4-hydroxy-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); didanosine (2’,3’-dideoxyinosine); zalcitabine (2’,3’-dideoxycytidine); stavudine (2’,3’-didehydro-2’,3’-dideoxythymidine); lamivudine ((-)-β-L-3’-thia-2’,3’-dideoxycytidine); abacavir ((1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-methanol succinate); emtricitabine ((-)-β-L-3’-thia-2’,3’-dideoxy-5-fluorocytidine));Tenofovir disoproxil fumarate ((R)-9-(2-phosphonylmethoxypropyl)adenine bis(isopropoxycarbonyloxymethyl)ester fumarate); Bromovinyl deoxyuridine (Brivudin); 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 (Sodium phosphonoformate); Ribavirin (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide); Raltegravir (N-[(4-fluorophenyl)methyl]-1,6-dihydro-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); Nepranosin A; Homobrevins; 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; Bebrimat; Indinavir; Relenza; Zanamivir; Oseltamivir;Trobicin etc.) is administered to an individual in a formulation (e.g., the same or a separate formulation) containing a pharmaceutically acceptable excipient.

[0259] In another aspect of the invention, the medical composition provides, 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 can be utilized in the subject method in combination with the subject compound. In some cases, the additional agent is an HCV NS3 protease inhibitor, an HCV NS5B RNA-dependent RNA polymerase inhibitor, a thiazolidide, a sustained-release thiazolidide, a nucleoside analogue, 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, a clemizole or a clemizole analogue (such as the benzimidazole and indazole analogues described in U.S. Patent Applications Nos. 12 / 383,071 and 12 / 383,030), or another NS4B inhibitor including an NS4B amphipathic helix inhibitor, an anti-HCV therapeutic agent selected from. The subject compound and the second antiviral agent, as well as the additional therapeutic agents described herein for combination therapy, can be administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or by other routes. The subject compound and the second antiviral agent can be administered by the same route of administration or by different routes of administration. The therapeutic agent can be administered by appropriate means including, for example, orally, rectally, nasally, topically (including transdermal, aerosol, buccal and sublingual), vaginally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), intravesically or by injection into the affected organ, but not limited to these. In certain cases, the therapeutic agent can be administered intranasally.

[0260] In some embodiments, the subject compound and an 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., the same or a separate formulation) containing a pharmaceutically acceptable excipient. The subject compound and a second antimalarial agent, as well as additional therapeutic agents described herein for combination therapy, can be administered orally, subcutaneously, intramuscularly, parenterally, or by other routes. The subject compound and the second antimalarial agent can be administered by the same route of administration or by different routes of administration. The therapeutic agent can be administered by suitable means including, for example, oral, rectal, nasal, topical (including transdermal, aerosol, buccal, and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous, and intradermal), intravesical, or injection into the affected organ, but not limited thereto.

[0261] The subject compound can be administered in unit dosage form and can be prepared by any method known in the art. Such methods include combining the subject compound with a pharmaceutically acceptable carrier or diluent that constitutes one or more accessory ingredients. The pharmaceutically acceptable carrier is 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 injurious to the subject. This 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, alcohols, or other organic solvents (including esters, emulsions, syrups or elixirs, suspensions, solutions, and / or suspensions, and solutions and / or suspensions reconstituted from non-foaming granules and foaming preparations reconstituted from foaming granules). Such liquid carriers can include, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickening agents, and melting agents. Preferred carriers are edible oils, for example, corn oil or canola oil. Polyethylene glycol (e.g., PEG) is also an excellent carrier.

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

[0264] Although such a need may not exist, the compounds and agents described herein can optionally target 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 the compounds to hepatocytes. Such liver-targeting compounds include, but are not limited to, asialopeptides; basic polyamino acids conjugated to 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 "targeting the liver" and "targeting hepatocytes" refer to the targeting of compounds to hepatocytes, particularly virus-infected hepatocytes, 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 the subject enters the liver via the portal vein and associates with hepatocytes (e.g., is taken up by hepatocytes).

[0266] HCV infection is associated with liver fibrosis and, in certain embodiments, an inhibitor may be useful for the treatment of liver fibrosis (particularly prevention, delay of progression, etc.). The method includes administering a compound of the disclosure, as described above, in an amount effective to reduce the viral load, thereby treating liver fibrosis in a subject. Treatment of liver fibrosis includes reducing the risk of developing liver fibrosis, reducing symptoms associated with liver fibrosis, and improving liver function.

[0267] Whether treatment with a compound described herein is effective for reducing liver fibrosis is determined by any of a number of established techniques for measuring liver fibrosis and liver function. The benefits of antifibrotic therapy can be measured and evaluated using the Child-Pugh scoring system, which consists of a multi-component point system based on abnormalities in serum bilirubin levels, serum albumin levels, 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, a patient can be classified into one of three categories (A, B, or C) of increasing severity of clinical disease.

[0268] Treatment of liver fibrosis (e.g., reduction of liver fibrosis) can also be determined by analyzing a liver biopsy sample. Analysis of a liver biopsy consists of the evaluation of two major elements of lesions of fibrosis and parenchymal or vascular remodeling, which are evaluated by "grade" as a measure of severity and ongoing disease activity and by "stage" as reflecting long-term disease progression. See, e.g., Brunt (2000) Hepatol. 31:241-246; and METAVIR (1994) Hepatology 20:15-20. Based on the analysis of the liver biopsy, a score is assigned. There are a number of standardized scoring systems that provide a quantitative assessment of the degree 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 biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, eosinophilic shrinkage, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); changes in bile ducts; and the Knodell index (scores for periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage of the METAVIR system are as follows. Score 0, no fibrosis; Score 1, stellate expansion of portal tracts, but no septum formation; Score 2, expansion of portal tracts with rare septum formation; Score 3, multiple septa without cirrhosis; Score 4, cirrhosis.

[0270] The Knodell scoring system, also called the hepatitis activity index, classifies specimens based on scores for the following four categories of histological features. I, periportal and / or bridging necrosis; II, intralobular degeneration and focal necrosis; III, portal inflammation; IV, fibrosis. In the Knodell staging system, the scores are as follows. Score 0, no fibrosis; Score 1, mild fibrosis (fibrosing portal expansion); Score 2, moderate fibrosis; Score 3, severe fibrosis (bridging fibrosis); Score 4, cirrhosis. The higher the score, the more severe the damage to the liver tissue. Knodell (1981) Hepatol.1:431.

[0271] In the Scheuer scoring system, the scores are as follows. Score 0, no fibrosis; Score 1, expanded fibrosing portal tracts; Score 2, periportal or portal-portal septa, but intact architecture; Score 3, fibrosis with distortion of architecture, but no obvious 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 expansion of some portal areas, regardless of the presence of short fibrous septa; Stage 2, fibrous expansion of most portal areas, regardless of the presence of short fibrous septa; Stage 3, fibrous expansion of most portal areas with portal-portal (P-P) bridging: Stage 4, marked bridging (P-P) and fibrous expansion of portal areas at the portal center (P-C); Stage 5, marked bridging (P-P and / or P-C) with occasional nodules (incomplete cirrhosis); Stage 6, cirrhosis, possible or definite.

[0273] In some embodiments, a therapeutically effective amount of a compound of the present disclosure is an amount of the compound that results in a change of 1 unit or more in the 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 the subject compound decreases hepatic fibrosis by at least 1 unit in the Child-Pugh, METAVIR, Knodell, Scheuer, Ludwig, or Ishak scoring system.

[0274] Secondary or indirect indicators of liver function can be used to evaluate the effectiveness of treatment. Morphometric computerized semi-automatic evaluation of the quantitative degree 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 the treatment method for the subject. Secondary indicators of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal vein pressure, albumin levels, and evaluation of the Child-Pugh score. The effective amount of the subject compound is 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 indicators of liver function of untreated individuals or individuals in the placebo administration group, and is an amount effective to increase the indicators of liver function. Those skilled in the art can easily measure such indicators of liver function using standard assay methods, many of which are commercially available and routinely used in the clinical setting.

[0275] Serum markers of liver fibrosis can also be measured as an indicator of the effectiveness of the treatment method for 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 the subject compound is an amount effective to lower the serum level of a marker of 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, as compared to the level of the marker in untreated individuals or individuals in a placebo-administered group. Those skilled in the art can readily measure such serum markers of liver fibrosis using standard assay methods, many of which are commercially available and routinely used in the clinical setting. Methods for measuring serum markers include immunologically based methods that use antibodies specific for a given serum marker, such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, and the like.

[0277] It is also possible to evaluate the effectiveness of treatment with a drug using qualitative or quantitative tests of functional liver reserve capacity. These include 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 as a result following the development of liver fibrosis, and includes, but is 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 rate of disorders associated with cirrhosis (e.g., the likelihood that an individual will develop the disorder) 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, as compared to untreated individuals or individuals in a placebo-administered group.

[0280] Those skilled in the art can readily determine whether treatment with the compound of interest is effective in reducing the incidence rate of diseases associated with cirrhosis.

[0281] A decrease in the amount of HCV virus and a decrease in liver fibrosis may be associated with an increase in liver function. Accordingly, the present disclosure generally provides a method for increasing liver function, including 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, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleotidase, γ-glutamyl transpeptidase, etc.), the synthesis of bilirubin, the synthesis of cholesterol, and the synthesis of bile acids; liver metabolic functions including carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; the detoxification of exogenous drugs; and hemodynamic functions including visceral and portal hemodynamics.

[0282] Whether liver function increases can be readily confirmed by one of ordinary skill in the art using well-established tests for liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, etc. can be evaluated 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 from the liver are within the normal range can be determined by measuring the levels of such proteins using standard immunological and enzymatic assays. The normal range of such serum proteins is known to the person skilled in the art. The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays. Normal bilirubin levels are usually less than about 1.2 mg / dL. Serum albumin levels are measured using standard assays. Normal serum albumin levels range from about 35 to about 55 g / L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than the control.

[0284] A therapeutically effective amount of the compound in this context is 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, and is effective in enhancing liver function. For example, a therapeutically effective amount of the compound is 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, and is an amount effective in reducing a high-level serum marker of liver function or reducing the level of a serum marker of liver function within the normal range. A therapeutically effective amount of the compound is to increase 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, and is also an amount effective in raising the level of a decreased serum marker of liver function or raising the level of a serum marker of liver function within the normal range.

[0285] HCV infection is associated with liver cancer, and in certain embodiments, the present disclosure provides compositions and methods for reducing the risk that an individual will develop liver cancer. The method includes administering the subject compound as described above, wherein the amount of virus in the individual is reduced and the risk that the individual will develop liver cancer is reduced. An effective amount of the compound is 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, and is one that reduces the risk of liver cancer. Whether the risk of liver cancer is reduced can be determined, for example, in a study group of individuals treated according to the subject method in which the incidence of liver cancer is reduced.

[0286] Formulated pharmaceutical composition for treating cancer In some embodiments, for example, PI4-kinase inhibitors and a second active agent (e.g., as described herein), such as small molecules, chemotherapeutic agents, antibodies, antibody fragments, antibody-drug conjugates, aptamers, or proteins, are administered to an individual in a formulation (e.g., the same or a separate formulation) 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, a PD-L1 inhibitor, etc.

[0287] In another aspect, a medical composition is provided that comprises, consists of, or consists essentially 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 can be utilized in the subject method in combination with the subject compound. The subject compound can be administered in unit dosage form and can be prepared by any method known in the art. Such methods include combining the subject compound with a pharmaceutically acceptable carrier or diluent that constitutes one or more accessory ingredients. The pharmaceutically acceptable carrier is 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 injurious to the subject. This carrier can 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, alcohols or other organic solvents (including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions, and solutions and / or suspensions reconstituted from non-foaming granules and foaming preparations reconstituted from foaming granules). Such liquid carriers can include, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickening agents, and melting agents. Preferred carriers are edible oils, such as corn oil or canola oil. Polyethylene glycol (e.g., PEG) is also an excellent carrier.

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

[0290] Although such need may not exist, the compounds and agents described herein can optionally target 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 the compound to the site of cancer. The terms “targeting the site of cancer” and “targeting cancer” refer to the targeting of a compound to the site of cancer, and 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 the subject enters the site of cancer.

[0291] Subjects suitable for treatment using the compounds of the present disclosure Individuals clinically diagnosed as infected with a pathogen of interest are suitable for treatment by the methods of the present disclosure. In certain specific embodiments of interest, individuals of interest for treatment according to 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 of HCV titer, or have more than 2 million genomic copies of HCV per milliliter of serum. Similar methods can be used to determine whether a subject infected with another pathogen is suitable for treatment using the subject method.

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

[0293] The amount of virus can be measured by measuring the titer or level of the virus in the serum. These methods include, but are not limited to, quantitative polymerase chain reaction (PCR) and branched DNA (bDNA) tests. 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 clinically diagnosed as having cancer are also suitable for treatment by the methods of the present disclosure. In certain embodiments of interest, the individuals to be treated according to the present disclosure have detectable cancer. Any convenient method can be used to determine whether a subject having cancer is suitable for treatment using the subject method. The effectiveness of the anti-cancer treatment can be determined using any convenient method. For example, whether the subject method is effective for treating cancer can be determined by measuring the improvement of one or more symptoms, measuring the reduction in the size of the tumor or metastasis in an imaging diagnosis, or measuring cancer cells in a biological sample of the subject to be treated. [Definitions]

[0295] Before further describing embodiments of the present disclosure, it is to be understood that the present disclosure is not limited to the specific embodiments described, as variations will naturally occur. 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 is defined only by the appended claims.

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

[0297] Certain ranges are presented in this specification with the term "about" preceding the numerical value. The term "about" is used in this specification to provide literal support for the exact number that it precedes, as well as numbers that are near to or approximately the number that the term precedes. When determining whether a number is near to or approximately specified, a non-recited number of approximation or nearness may, in the context in which it is presented, be a number that provides substantially the same as the specifically recited number.

[0298] Unless defined otherwise, 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 will now be described.

[0299] All publications and patents cited in this specification are hereby incorporated by reference as if each individual publication or patent was specifically and individually indicated to be incorporated by reference and was set forth in full herein to disclose and describe the methods and / or materials associated with the citation of the publication. The citation of a publication is for the purpose of disclosure prior to the filing date and should not be construed as an admission that the present invention has no right to antedate such publication by virtue of prior invention. Further, the provided publication dates may be different from the actual publication dates that need to be independently verified.

[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 further be noted that the claims may be drafted to exclude any element. Thus, this statement is intended to serve as a basis for using exclusive terms such as "solely", "only", etc. in connection with the recitation of claim elements, or for using "negative" limitations.

[0301] Upon reading this disclosure, it will be apparent to those skilled in the art that each of the individual embodiments described and illustrated herein has discrete components and features that can be readily separated from or combined with any of the features of some other embodiments without departing from the scope or spirit of the present invention. Any of the methods described may be performed in the order of the events described, or in any other order that is logically possible.

[0302] The apparatus and method are described, or are to be described, with functional descriptions for grammatical fluidity, but the claims should not necessarily be construed as being limited in any way by the construction of "means" or "step" limitations, unless expressly made in accordance with 35 U.S.C. § 112. However, the meaning of the definitions provided by claims based on the judicial doctrine of equivalents and the full scope of equivalents should be recognized, and when the claims are expressly made in accordance with 35 U.S.C. § 112, they become full statutory equivalents under 35 U.S.C. § 112. When describing and claiming the present invention, certain terms are used according to the definitions set forth below. The definitions provided herein are not intended to be mutually exclusive. Thus, some chemical moieties may be included in the definitions of multiple terms.

[0303] As used herein, the phrases "for example," "such as," or "including" are intended to introduce examples that further clarify a more general subject. These examples are provided only as an aid to understanding the disclosure and are not intended to limit 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" WO2009 / 148541 and incorporated herein by reference in its entirety, provides a mechanism for recognizing (including, but not limited to, binding and activation or inhibition of activity) PIP2 (phosphatidylinositol, 4,5-bisphosphate [PtdIns(4,5)P2], PI(4,5)P2). Alteration or variation of the BAAPP domain may result in recognition of other phosphatidylinositol variants.

[0305] Phosphoinositides such as phosphatidylinositol (PI)-4-phosphate (PI(4)P) and PI-4,5-bisphosphate (PI(4,5)P2, or “PIP2”) are enriched at various specific plasma membrane and intracellular locations. The steady-state location and abundance of specific intracellular PI isoform pools are regulated by families of PI-kinases and phosphatases. There are at least four human PI4-kinases, the family members PI4KIIIα and PI4KIIIβ, which are localized mainly to membranes from the endoplasmic reticulum and Golgi that contribute to these membrane-associated PI(4)P and PI(4,5)P2 pools, and the family members PI4KIIα and PI4KIIβ, which contribute mainly to other pools.

[0306] The BAAPP domain mediates specific interactions with PIP2, resulting in structural changes in the BAAPP domain that affect major pathogen regulators. In HCV, the replication complex is established at sites enriched in intracellular PIP2, and point mutations in the BAAPP domain abrogate PIP2 binding and HCV RNA replication. Such a critical dependence 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 with good tolerance by host cells.

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

[0308] The BAAPP domain has 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 the BAAPP domain, enzymes involved in PIP-2 metabolism, and molecules that inhibit or activate the BAAPP domain act to treat infectious diseases and affect host physiology or pathophysiology.

[0309] Examples of proteins having the 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 Coxsackievirus 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 have the BAAPP domain, similar to the Plasmodium falciparum PfNDH2 protein. In the Flaviviridae family, the NS5A protein of HCV with a BAAPP domain containing lysine residues conserved at residues 20 and 26 of the processed protein, for example, a peptide having the amino acid sequence SGSWLRDVWDWICTVLTDFKTWLQSKLL (SEQ ID NO: 1) containing lysine residues K20 and K26. Other BAAPP domains harbored by pathogens include HAV, Vaccinia, Ebola virus, Francisella tularensis, Influenza virus polymerase protein, Smallpox (Variola), Sin Nombre virus (Hantavirus), Pseudomonas aeruginosa, CMV.

[0310] The Ns5 encoding viruses include, but are not limited to, flaviviruses, pestiviruses, and hepatitis C virus (e.g., yellow fever virus (YFV); dengue virus 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; Omsk hemorrhagic fever virus).

[0311] The term "flavivirus family virus" means any virus of the flavivirus family, including viruses that infect humans and non-human animals. The polynucleotide and polypeptide sequences encoding these viruses are known in the art and can be found 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_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), and the contents of the database entries are hereby incorporated by reference in their entirety into this specification.

[0312] The term "picornavirus family virus" means a virus of the picornavirus family, including but not limited to enteroviruses, that infects humans and non-human animals. The polynucleotide and polypeptide sequences encoding these viruses are known in the art and can be found in the NCBI GenBank database.

[0313] "Caliciviridae virus" means a virus of the family Caliciviridae, including viruses that infect humans and non-human animals such as norovirus. The polynucleotide and polypeptide sequences encoding these viruses are known in the art and can be found in the NCBI GenBank database.

[0314] "Filoviridae virus" means a virus of the family Filoviridae, including viruses that infect humans and non-human animals such as Ebola virus. The polynucleotide and polypeptide sequences encoding these viruses are known in the art and can be found in the NCBI GenBank database.

[0315] "Hepeviridae virus" means a virus of the family Hepeviridae, including viruses that infect humans and non-human animals such as hepevirus (e.g., HEV). The polynucleotide and polypeptide sequences encoding these viruses are known in the art and can be found in the NCBI GenBank database.

[0316] "Polyomaviridae virus" means a virus of the family Polyomaviridae, including viruses that infect humans and non-human animals such as BK virus and JC virus. The polynucleotide and polypeptide sequences encoding these viruses are known in the art and can be found in the NCBI GenBank database.

[0317] "Papillomaviridae virus" means a virus of the family Papillomaviridae, including viruses that infect humans and non-human animals such as human papillomavirus (e.g., HPV). The polynucleotide and polypeptide sequences encoding these viruses are known in the art and can be found in the NCBI GenBank database.

[0318] The term "coronavirus family virus" means a virus of the coronavirus family, including viruses that infect humans and non-human animals, such as beta coronaviruses (SARS, MERS, SARS-CoV-2, etc.). Polynucleotide and polypeptide sequences encoding these viruses are known in the art and can be found in the NCBI GenBank database. In some embodiments, the coronavirus family 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 coronavirus family virus is SARS-CoV-2.

[0319] The terms "active agent", "antagonist", "inhibitor", "drug" and "pharmacologically active agent" are used synonymously herein and refer to a chemical substance or compound that, when administered to a living organism (human or animal), induces a desired pharmacological and / or physiological effect by local and / or systemic action.

[0320] As used herein, the terms “treatment,” “treating,” etc. refer to obtaining a desired pharmacological and / or physiological effect, such as a decrease in viral titer. The effect can be prophylactic in terms of completely or partially preventing a disease or its symptoms, and / or can be therapeutic in terms of partial or complete cure of a disease and / or adverse effects caused by the disease. “Treatment” as used herein covers any treatment of a disease in a mammal, particularly a human, and includes the following. (a) Preventing a disease or the symptoms of a disease from occurring in a subject who may have a predisposition to the disease but has not yet been diagnosed as having it (e.g., including diseases associated with or caused by a primary disease (such as liver fibrosis that may lead to a situation of chronic HCV infection)); (b) inhibiting a disease, i.e., preventing its onset; (c) reducing a disease, i.e., causing regression of the disease (e.g., a decrease in viral titer).

[0321] The term “pharmaceutically acceptable salt” means a salt that is acceptable for administration to a patient, such as a mammal (a salt that includes a counterion having 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 a pharmaceutically acceptable salt of a compound, and the salt is derived from various organic and inorganic counterions known in the art, and by way of example only, includes sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and when the molecule contains a basic function, salts of organic or inorganic acids such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, etc.

[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 such as monkeys and humans, rodents such as rats and mice, cows, horses, sheep, cats, dogs, etc. "Mammal" means one or more members of any mammalian species, and examples include dogs, cats, horses, cows, sheep, rodents, etc., as well as non-human primates and primates such as humans. For example, mammalian, such as non-human primates, mice, and other non-human animal models such as lagomorphs, can be used in experimental investigations.

[0323] As used herein, the terms "determine", "measure", "evaluate", and "analyze" are used interchangeably and include both quantitative and qualitative determinations. The terms "polypeptide" and "protein" are used interchangeably herein and refer to a polymeric form of amino acids of any length that can include encoded and non-encoded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides with modified peptide backbones. This term includes fusion proteins with heterologous amino acid sequences, fusions with heterologous and native leader sequences, immunologically tagged proteins, fusion proteins with detectable fusion partners (e.g., fluorescent proteins, β-galactosidase, luciferase, etc. as fusion partners), and fusion proteins including, but not limited to, such fusion proteins.

[0324] The terms "nucleic acid molecule" and "polynucleotide" are used synonymously and refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or any analogs thereof. A polynucleotide can have any three-dimensional structure and can 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. A nucleic acid molecule can be linear or circular.

[0325] "Therapeutically effective amount" or "effective amount" means an 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 of the disease, condition, or disorder. A "therapeutically effective amount" varies depending on the compound, the disease and its severity, and the age, weight, etc. of the subject being treated.

[0326] As used herein, "unit dosage form" refers to physically discrete units 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 produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle. The specification of the unit dosage form depends on the particular compound used, the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

[0327] The terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable diluent", "pharmaceutically acceptable carrier", and "pharmaceutically acceptable adjuvant" generally mean excipients, diluents, carriers, and adjuvants that are safe, non-toxic, not biologically undesirable, and acceptable for use in veterinary and human pharmaceuticals, and are useful in the preparation of pharmaceutical compositions containing such excipients, diluents, carriers, and adjuvants. 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, the term "pharmaceutical composition" is meant to encompass compositions suitable for administration to a subject, particularly a mammal such as a human. Generally, a "pharmaceutical composition" is sterile and preferably free of contaminants that may induce unwanted reactions within the subject (e.g., the compounds in the pharmaceutical composition are of pharmaceutical grade). A pharmaceutical composition can 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, and the like.

[0329] The terms "having a formula" or "having a structure" are not intended to be limiting and are used in the same manner as the term "comprising" is commonly used. The term "independently selected from" is used herein to indicate that the recited 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 situation described later may or may not occur. Therefore, the description includes both the case where the situation occurs and the case where it does not occur. For example, the phrase "optionally substituted" means that a non-hydrogen substituent may or may not be present on a particular atom, and thus this description includes both structures with a non-hydrogen substituent and structures without a non-hydrogen substituent.

[0331] "Acyl" refers to the group H-C(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 heteroaryl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclyl-C(O)-, where the 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 CH3C(O)-.

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

[0333] The term "substituted alkyl" means containing an alkyl group as defined herein, where one or more carbon atoms of the alkyl chain are optionally -O-,-N-,-S-,-S(O) n-(n is from 0 to 2), replaced by 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, azide, cyano, halogen, hydroxyl, oxo, thioketone, 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 having 1 to 5 substituents selected from the group consisting of, where 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] As used herein, the term "alkenyl" 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 always, the alkenyl groups herein can contain from 2 to about 18 carbon atoms, for example, they can contain from 2 to about 12 carbon atoms. The term "lower alkenyl" means 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 is replaced by a heteroatom. Unless otherwise specified, the terms "alkenyl" and "lower alkenyl" each include straight-chain, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkenyl or lower alkenyl, respectively.

[0335] As used herein, the term "alkynyl" 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 always, the alkynyl groups herein can contain from 2 to about 18 carbon atoms, for example, they can contain from 2 to about 12 carbon atoms. The term "lower alkynyl" means 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 is replaced by a heteroatom. Unless otherwise specified, the terms "alkynyl" and "lower alkynyl" each include straight-chain, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkynyl or lower alkynyl, respectively.

[0336] As used herein, the term "alkoxy" is intended to mean an alkyl group attached via 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 is intended to mean an alkoxy group containing from 1 to 6 carbon atoms and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy, and the like. Substituents identified herein as "C1-C6 alkoxy" or "lower alkoxy" can contain, for example, from 1 to 3 carbon atoms, and as a further example, such substituents can contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy).

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

[0338] As used herein, the term "aryl", unless otherwise specified, generally, but not necessarily, refers to an aromatic substituent containing from 5 to 30 carbon atoms, including a single aromatic ring or multiple aromatic rings (different aromatic rings being bonded to a common group such as a methylene or ethylene moiety) that are fused, directly bonded, or indirectly bonded. An aryl group can, for example, contain from 5 to 20 carbon atoms, and as a further example, an aryl group can contain from 5 to 12 carbon atoms. For example, an aryl group 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, diphenyl ether, 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 aryl in which at least one carbon atom is replaced by a heteroatom, as will be described in more detail below. Aryl is intended to include stable cyclic, heterocyclic, polycyclic, and polycyclic unsaturated C3-C 14 moieties, and examples include, but are not limited to, phenyl, biphenyl, naphthyl, pyridyl, furyl, thiophenyl, imidazolyl, pyrimidinyl, and oxazolyl. These can be further substituted with 1 to 5 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 having an aryl substituent, and the term "alkaryl" refers to an aryl group having an alkyl substituent, where "alkyl" and "aryl" are as defined above. Generally, the aralkyl and alkaryl groups described herein contain from 6 to 30 carbon atoms. The 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 indicated, such groups include a saturated hydrocarbon chain containing from 1 to 24 carbon atoms, which can be substituted or unsubstituted, can include one or more alicyclic groups, and can contain heteroatoms. "Lower alkylene" refers to an alkylene bond containing from 1 to 6 carbon atoms. Examples include methylene (--CH2--), ethylene (--CH2CH2--), propylene (--CH2CH2CH2--), 2-methylpropylene (-CH2--CH(CH3)--CH2--), hexylene (--(CH2)6--) and the like.

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

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

[0343] The terms "halo" and "halogen" are used in their conventional meaning to refer to chloro, bromo, fluoro or iodo substituents.

[0344] "Carboxyl", "carboxy" or "carboxylate" refers to -CO2H or its salts.

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

[0346] The term "substituted cycloalkyl" refers to a cycloalkyl group having from 1 to 5 substituents selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketone, 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, or a cycloalkyl group having from 1 to 3 substituents.

[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 are replaced by atoms 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 contains a heteroatom, the term "heterocyclic" or "heterocycle" refers to a cyclic substituent that contains a heteroatom, and the terms "heteroaryl" and "heteroaromatic" refer to "aryl" and "aromatic" substituents that contain a heteroatom and the like, 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, and 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, such as 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from groups consisting of oxygen, nitrogen, and sulfur in the ring. Such heteroaryl groups can have a single ring (such as pyridinyl, imidazolyl, furyl, etc.) or a plurality of fused rings of a ring system (for example, groups such as indolizinyl, quinolinyl, benzofuran, benzimidazolyl, benzothienyl, etc.), and when the bonding point is through an atom of the aromatic ring, at least one ring in the ring system is aromatic, and at least one ring in the ring system is aromatic. In certain embodiments, the nitrogen and / or sulfur ring atoms of the 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 restricted by the definition of the heteroaryl substituent, such heteroaryl groups can be substituted with 1 to 5 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, azide, 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, or can be optionally substituted with 1 to 3 substituents.

[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 bridges and spiro ring systems, and having from 3 to 15 ring atoms containing from 1 to 4 heteroatoms. These ring atoms are selected from groups consisting of nitrogen, sulfur, or oxygen, and in a fused ring system, when the point of attachment is through a non-aromatic ring, one or more of the 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, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, 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 restricted by the definition of the heterocyclic substituent, the heterocyclic group may be substituted with 1 to 5, or 1 to 3 substituents selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketone, 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, -SO2-heteroaryl, and fused heterocycles.

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

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

[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" means 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), urea (-(NH)-(CO)-NH2), cyano (-C≡N), isocyano (-N+≡C-), cyanato (-OC≡N), isocyanato (-O-N+≡C-), isothiocyanato (-SC≡N), azide (-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 alkylamide (-(NH)-(CO)-alkyl), C5-C20 arylamide (-(NH)-(CO)-aryl), imino (-CR=NH, where R = hydrogen, C1-C24 alkyl, C5-C20 aryl, C6-C20 alkaryl, C6-C20 aralkyl, etc.), alkylimino (-CR=N(alkyl), where R = hydrogen, alkyl, aryl, alkaryl, etc.), arylimino (-CR=N(aryl), where 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;(also referred to as "arylthio"), 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 phosphine, and other chemical groups. In addition, when permitted by a particular group, the foregoing functional groups 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", such as "linking group", "linker moiety", etc., means a divalent radical moiety that connects two groups via a covalent bond. Examples of such linking groups include, but are not limited to, alkylene, alkenylene, alkynylene, arylene, alkarylene, aralkylene, and linking moieties containing functional groups such as amide (-(NH-CO-)), ureylene (-(NH-CO-NH-)), imide (-(CO-NH-CO-)), epoxy (-(O-)), episulfide (-(S-)), epidioxide (-(O-O-)), carbonyldioxy (-(O-CO-O-)), alkyldioxy (-(O-(CH2)n-O-)), epoxyimide (-(O-NH-)), epimino (-(NH-)), carbonyl (-(CO-)). Any convenient orientation and / or connection of the linker to the linking group may be used. When the term "substituted" is shown before a list of possible substituents, the term is intended to 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] In addition to the disclosure of this specification, the term "substituted" can also mean that when used to modify a specified group or radical, one or more hydrogen atoms of a particular group or radical are independently replaced by the same or different substituents defined below.

[0357] In addition to the groups disclosed for the individual terms of this specification, unless otherwise specified, substituents for replacing one or more hydrogens (any two hydrogens on a single carbon can be replaced by =O, =NR70, =N-OR70, =N2 or =S) on the saturated carbon atoms of the specified group or radical are -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 + ), -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 . Here, R 60 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each R 70 is independently hydrogen or R 60 , each R 80 is independently R 70 , or together with the nitrogen atom to which they are attached, two R 80 are selected from the group consisting of O, N and S, where N may have -H or C 1 -C3 alkyl substitution and form a 5-, 6- or 7-membered heterocycloalkyl optionally containing from 1 to 4 additional heteroatoms, the same or different, and each M+ is a counterion having a net single positive charge. Each M + is independently, for example, an alkali ion such as K + , Na + , Li + , etc., + an ammonium ion such as N(R 60 )4, or, [Ca 2+ 0.5 , [Mg 2+ 0.5 , or [Ba 2+ ​​​0.5 such as alkaline earth metal ions (the subscript 0.5 means that one of the counterions of such divalent alkaline earth metal ions can be an ionized form of the compound of the present invention, and other typical counterions such as chlorides, or two ionized compounds disclosed herein can function as counterions of such divalent alkaline earth metal ions, or the double-ionized compound of the present invention can function as a counterion of such divalent alkaline earth metal ions). As a specific example, -NR 80 R 80 means including -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl, and N-morpholinyl.

[0358] In addition to the disclosure herein, the substituents of hydrogen on the unsaturated carbon atoms of "substituted" alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, -R 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 wherein, in the case of a substituted alkene or alkyne, the substituent is -O - M + , -OR 70 , -SR 70 , or S - M + and when not, R 60 , R 70 , R 80 and M + are as previously defined.

[0359] In addition to the groups disclosed for the individual terms of this specification, the substituents of the hydrogens on the 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 - )(M + ), -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 wherein R 60 , R 70 , R 80 and M+ is as previously defined.

[0360] In addition to the disclosure of this specification, in certain embodiments, the group to be substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0361] Unless otherwise specified, the nomenclature of substituents not explicitly defined in this specification is achieved by following the adjacent function towards the point of attachment and naming the terminal part of the function. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-O-C(O)-.

[0362] With respect to any of the groups disclosed herein that contain one or more substituents, it is understood that such groups do not contain sterically non - practical and / or synthetically infeasible substitutions or substitution patterns. Further, the subject compounds include all stereochemical isomers resulting from the substitution of these compounds.

[0363] In certain embodiments, substituents may contribute to the optical and / or stereoisomerization of the compound. Salt, solvate, hydrate, and prodrug forms of the compound are also of interest. All such forms are included in this disclosure. Accordingly, the compounds described herein include their salts, solvates, hydrates, prodrugs, and isomers, including their salt, solvate, hydrate, prodrug, and isomeric forms. In certain embodiments, the compound may be metabolized into a pharmaceutically active derivative.

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

[0365] The definitions of other terms and concepts are presented throughout the detailed description. Notwithstanding the appended claims, the disclosure described herein is also described by the following clauses. [Clause 1] A compound of formula (I): [Chemical formula] Herein, Y 1 is selected from CH or N; Y 2 is selected from S, O or NR 19 wherein 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 are such that the compound of formula (I) [Chemical formula] [Chemical formula] or [Chemical formula] If not, a crosslinked cyclic group selected from crosslinked cycloalkyl, substituted crosslinked cycloalkyl, crosslinked heterocycle and substituted crosslinked 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 herein is of formula (II). [Chemical formula] Herein, A is a ring system selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle and substituted heterocycle; 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 according to Item 2, wherein the B ring system herein 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 Item 3, wherein the B ring system herein is selected from B2 to B9. [Chemical formula] [Chemical formula] [Chemical formula] [Chemistry] [Chemistry] [Chemistry] [Chemistry] and [Chemistry] Herein, Y 3 and Y 5 are each independently selected from N and CR 11 , wherein R 11 is selected from hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamide, substituted carboxamide, sulfonyl, substituted sulfonyl, sulfonamide, and substituted sulfonamide; Y 4 is selected from CR 11 2, NR 11 , SO2, and O; Y 6 is selected from CR 11 2 and NR 11 ; 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.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0371] [Item 7] The compound according to any one of Items 2 to 6, wherein the compound is any one of Formulas (IIA) to (IIF).

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0372] [Item 8] The compound according to Item 7, wherein the compound is of Formula (IIA1), (IIA2), (IIC1) or (IID1).

Chemical formula

Chemical formula

[0373] [Item 9] The compound according to any one of Items 2 to 6, wherein the compound herein is of formula (IIG), (IIH), (IIJ) or (IIK). [Chemical formula] [Chemical formula] and [Chemical formula] [Chemical formula] Herein, the 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; R 11 is selected from hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamide, substituted carboxamide, 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 herein is of formula (IIG1) or (IIK1). [Chemical formula]

Chem.

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

Chem.

Chem.

Chem.

Chem.

[0376] [Item 12] The compound according to Item 8, wherein the compound is any one of the following formulas.

Chem.

Chem.

Chem.

Chem.

Chem.

[0377] [Item 13] The compound according to Item 8 selected from the following formulas. [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] and [Chemical formula]

[0378] [Item 14] The compound according to Item 8, wherein the compound is any one of the following formulas. [Chemical formula] [Chemical formula] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] and [Chemistry]

[0379] [Item 15] The compound according to Item 8, wherein the compound is any one of the following formulas. [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] and [Chemistry]

[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] A compound according to Item 12 or 13, wherein R 12 is halogen and R 13 is lower alkyl.

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

[0383] [Item 19] A compound according to Item 10 or 11, wherein the compound is any of the following formulas. [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] and [Chemical formula]

[0384] [Item 20] The compound according to Item 10 or 11, wherein the compound is any of the following formulas. [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] and [Chemical formula]

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

[0386] [Item 22] The compound according to any one of Items 19 to 21, wherein R here 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 here 15 , R 16 , R 17 and R18 are each hydrogen.

[0388] [Item 24] The compound according to Item 22, wherein R here 15 is lower alkyl, and R 16 , R 17 and R 18 are each hydrogen.

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

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

[0391] [Item 27] Any one of the compounds according to Items 1 to 26, wherein R here 4 and R 5 are each independently lower alkyl; or R 4 and R 5 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 here 4 and R 5 are cyclopropyl together with the carbon to which they are attached.

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

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

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

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

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

[0398] [Item 34] The compound according to Item 1 or 2, wherein the compound is any one of the following structures.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0399] [Item 35] The compound according to Item 1 or 2, wherein the compound is any one of the following structures. [Chemical formula] [Chemical formula] [Chemical formula] and [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0400] [Item 36] The compound according to Item 1 or 2, wherein the compound is any one of the following structures. [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] and [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0401] [Item 37] The compound according to Claim 1, wherein the compound has the formula (III). [Chemical formula] Here, --- is absent or a covalent bond. R 7 and R 8 are each independently selected from hydrogen, halogen, alkyl, and substituted alkyl, and 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 here 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 here 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] The compound according to any one of Items 1 to 38, wherein Y here 1 is CH.

[0405] [Item 41] The compound according to any one of Items 1 to 38, wherein Y here 1 is N.

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

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

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

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

[0410] [Item 46] A pharmaceutical composition comprising any of the compounds according to 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 according to Items 1 to 45.

[0412] [Item 48] The method according to Item 47, wherein the PI4-kinase here is PI4-III kinase.

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

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

[0415] [Item 51] A method for treating a subject for an infectious condition, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the compound according to any one of Items 1 to 45 or a pharmaceutically acceptable salt thereof, wherein the infectious condition here is caused by an infection with a pathogen susceptible to PI4-kinase inhibition.

[0416] [Item 52] The method according to Item 51, wherein the infectious condition here is caused by an infection with a virus selected from the families Retroviridae, Picornaviridae, Flaviviridae, Caliciviridae, Filoviridae, Hepaviridae, Togaviridae, Polyomaviridae, Papillomaviridae, Papovaviridae, and Coronaviridae.

[0417] [Item 53] The method according to Item 51, wherein the medical condition of the infectious disease is caused by an 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, Coxsackie virus, BK virus, JC virus, human papillomavirus (HPV), HIV, rubella, West Nile virus, cytomegalovirus, Pseudomonas aeruginosa, and dengue virus.

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

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

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

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

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

[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 the metastasis of solid tumors.

[0425] [Item 61] Any one of the methods according to Items 57 to 60, wherein the cancer is derived from the bladder (e.g., urothelial), breast, colon, endometrium, cervix, testis, liver, lung (e.g., non-small cell lung cancer (NSCLC)), ovary, prostate, pancreas, brain, melanoma, sarcoma, thyroid, stomach, kidney.

[0426] [Item 62] The method according to Item 61, wherein the cancer is lung cancer.

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

[0428] [Item 64] The method according to Item 61, wherein the cancer is breast cancer.

[0429] [Item 65] The method according to Item 61, wherein the cancer is brain cancer.

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

[0431] [Item 67] Any one of the methods according to Items 57 to 67, wherein the subject's cancer cells comprise a high level of PI4K expression (e.g., as compared to the basal level of one or more normal cells or control cells).

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

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

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

[0435] [Item 71] Any one of the methods according to Items 57 to 70, wherein the target cancer cells herein contain a high level of PI4KIII activity.

[0436] [Item 72] The method according to Item 71, wherein the target cancer cells herein contain a high level of PI4KIIIβ activity.

[0437] [Item 73] Any one of the methods according to Items 57 to 72, wherein the target cancer cells herein are sensitive to PI4KIIIβ inhibition.

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

[0439] [Item 75] Any one of the methods according to Items 57 to 74, wherein the target cancer cells herein are greater than the diploid copy number of the PI4K gene.

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

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

[0442] [Item 78] Any one of the methods according to Items 57 to 74, wherein the compound herein is more selective for PI4-kinase than for PI3-kinase.

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

[0444] [Item 80] Any one of the methods according to Items 57 to 78, wherein the compound herein is a PI4KIIIα inhibitor.

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

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

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

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

[0449] [Item 85] The method according to Item 81 or Item 83, wherein the additional agent herein 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 growth of cancer cells, the method comprising: contacting the cancer cells with an effective amount of a compound according to any one of Items 1 to 45.

[0451] [Item 87] The method according to Item 86, wherein the cancer cells herein are selected from cells of 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.

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

[0453] [Item 89] Th...

Claims

1. A compound selected from formula (I), or a pharmaceutically acceptable salt thereof: 【Chemical 1】 wherein, Y 1 is selected from CH or N; Y 2 is selected from S, O or NR 19 wherein R 19 is selected from hydrogen, alkyl, and substituted alkyl; R 1 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 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 both methyl; R 6 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl.

2. The compound according to claim 1, wherein R 1 is selected from B2 to B9. [Chemical Formula 2] 【Chemical Formula 3】 【Chemical Formula 4】 [Chemical Formula 5] 【Chemical Formula 6】 【Chemical Formula 7】 wherein, Y 3 and Y 5 are each independently selected from N and CR 11 wherein R 11 is selected from hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamide, substituted carboxamide, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. Y 6 is selected from CR 11 2 and NR 11 ; 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; and r is an integer from 0 to 2.

3. The compound according to claim 2, wherein R 6 is selected from the following. [Chemical 8] 【Chemical Formula 9】 【Chemical Formula 10】 【Chemical Formula 11】 【Chemical 12】 wherein, Y 3 is selected from N and CR 11 wherein R 11 is selected from hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxamide, substituted carboxamide, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide. 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; and p is an integer from 0 to 4.

4. A compound according to claim 2 or 3, wherein the compound is any of the following formulas: 【Chemical 13】 【Chemical Formula 14】 【Chemical Formula 15】 【Chemical 16】 【Chemical 17】 【Chemical 18】 【Chemical 19】 【Chemical 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemical 24】 【Chemical 25】 【Chemical 26】 【Chemical 27】 【Chemical 28】 【Chemical Formula 29】 【Chemical Formula 30】 【Chemical 31】 【Chemical 32】 【Chemical 33】 【Chemical 34】 【Chemical 35】 and 【Chemical 36】 wherein, R 12 , R 13 and R 14 are each independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl and halogen.

5. The compound according to any one of claims 1 to 4, wherein Y 2 is S.

6. The compound according to claim 1, wherein R 1 is selected from aryl, disubstituted aryl, trisubstituted aryl, tetrasubstituted aryl, pentasubstituted aryl, heteroaryl, and substituted heteroaryl.

7. A compound according to claim 1, wherein the compound is selected from the following. 【Chemical 37】 【Chemical Formula 38】 【Chemical Formula 39】 【Chemical Formula 40】 【Chemical 41】 【Chemical 42】 【Chemical Formula 43】 【Chemical 44】 【Chemical 45】 【Chemical 46】 【Chemical 47】 【Chemical 48】 【Chemical 49】 【Chemical Formula 50】 【Chemical 51】 【Chemical 52】 【Chemical Formula 53】 【Chemical 54】 and 【Chemical 55】

8. A pharmaceutical composition comprising: A compound according to any one of claims 1 to 7, and A pharmaceutically acceptable excipient.

9. The pharmaceutical composition according to claim 8, which is for the treatment of an infectious medical condition.

10. The pharmaceutical composition according to claim 8, which is for the treatment of cancer.

11. An anti-cancer kit comprising: An effective amount of a compound according to any one of claims 1 to 7, An effective amount of an additional anti-cancer agent, and Instructions for use in the treatment of cancer.

12. A compound according to claim 1, wherein the compound has the following structure. 【Chemical 56】

13. A compound according to claim 1, wherein the compound has the following structure. 【Chemical 57】

14. A compound according to claim 1, wherein the compound has the following structure. 【Chemical 58】

15. A compound according to claim 1, wherein the compound has the following structure. 【Chemical Formula 59】

16. A compound according to claim 1, wherein the compound has the following structure. 【Chemical Formula 60】

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