WO2025101867A1

WO2025101867A1 - Cell-impermeable akt inhibitors and pdpk1 inhibitors

Info

Publication number: WO2025101867A1
Application number: PCT/US2024/055077
Authority: WO
Inventors: Seiya KITAMURA; Betsy C. Herold; Steven C. Almo; Lucas DADA; Natalia Cheshenko; Jeffrey BONANNO
Original assignee: Albert Einstein College of Medicine
Current assignee: Albert Einstein College of Medicine
Priority date: 2023-11-10
Filing date: 2024-11-08
Publication date: 2025-05-15
Anticipated expiration: 2026-05-10

Abstract

The disclosure describes cell membrane-impermeable Akt inhibitors and PDPK1 inhibitors that are selective for Akt or PDPK1 over other kinases. Inhibition of Akt and PDPK1 by the compounds of the disclosure extracellularly reduces potential side effects. The compounds are useful for treating medical conditions involving externalization and activation of Akt or PDPK1 on the cell surface, on the outer leaflet of the plasma membrane or extracellularly, such as tumors/cancers and viral infections. In addition to therapeutic uses, the cell-impermeable Akt inhibitors and PDPK1 inhibitors can be used as research tools in molecular biology.

Description

Cell-Impermeable Akt Inhibitors and PDPK1 Inhibitors Cross-Reference To Related Applications [0001] This application claims benefit of priority from U.S. Provisional Application No. 63/548,020, filed on November 10, 2023, the entire contents of which are incorporated herein by reference for all purposes. Background of the Disclosure [0002] Protein kinase B (PKB), also known as Akt, is a set of three serine/threonine protein kinases that are key nodes in various signaling pathways including the PI3K/Akt/mTOR pathway, and regulate important cellular processes including apoptosis, cell survival, transcription, cell growth, cell proliferation, cell migration and glucose metabolism. The three isoforms of PKB/Akt are designated PKB-α/Akt1, PKB-β/Akt2 and PKB-γ/Akt3. Activated phosphoinositide 3-kinase (PI3K) phosphorylates phosphatidylinositol (3,4)-bisphosphate (PIP₂) to form phosphatidylinositol (3,4,5)-trisphosphate (PIP₃). The pleckstrin homology (PH) domain of the Akt isoforms binds to PIP3 at the inner leaflet of the plasma membrane, which causes conformational changes and exposure of phosphorylation sites Thr308 or Thr309 in the kinase domain and Ser473 or Ser474 in the C-terminal domain of Akt. The Akt isoforms are activated by phosphorylation of T308 (Akt1) or T309 (Akt2) by phosphoinositide-dependent (protein) kinase 1 (PDK1 or PDPK1) and phosphorylation of S473 (Akt1) or S474 (Akt2) by multiple kinases, including phosphoinositide-dependent (protein) kinase 2 (PDK2 or PDPK2), mechanistic target of rapamycin complex 2 (mTORC2), integrin-linked kinase (ILK), DNA- dependent protein kinase (DNA-PK), and mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2). Through their kinase activity, the activated Akt isoforms act as “master kinases” by activating or inactivating their myriad substrates, including mTOR, the Bcl-2 family of proteins regulating apoptosis, the transcription factor NF-κB, glycogen synthase kinase 3 (GSK3), and the master regulator of lysosomal biogenesis transcription factor EB (TFEB). The tumor suppressor phosphatase and tensin homolog (PTEN) is a critical negative regulator of the Akt isoforms by dephosphorylating PIP3 back to PIP2 and hence preventing membrane localization required for PI3K-dependent Akt activation, the major mode of Akt activation. The Akt isoforms can also be activated in PI3K-independent ways. [0003] Akt1 promotes cell survival by inhibiting apoptosis via phosphorylation of BAD, a member of the Bcl-2 family, and by activating NF-κB, which results in transcription of pro- survival genes. Akt1 stimulates protein synthesis pathways and hence promotes cell and tissue growth. In addition, Akt1 promotes cell cycle progression and thus cell proliferation by phosphorylating and activating mTOR and by phosphorylating and inactivating GSK3. Akt hyperactivity also promotes epithelial-to-mesenchymal transition (EMT) and hence cell migration. Furthermore, activation of Akt in endothelial cells in the lining of blood vessels promotes their survival, growth and migration and thus angiogenesis. Moreover, Akt1 phosphorylation of TFEB leads to exclusion of TFEB from the nucleus, resulting in reduced lysosomal biogenesis and autophagy. [0004] Hyperactivity of Akt is one of the most common aberrations in human tumor/cancer cells, and tumor/cancer cells frequently have constantly active Akt. Hyperactivity of Akt in human tumor/cancer cells frequently result from overactivation of PI3K, loss of PTEN function and overexpression of Akt. The Akt isoforms are overexpressed in many types of human cancers, including breast cancer, ovarian cancer, gastric cancer, pancreatic cancer, prostate cancer, glioblastoma and skin cancer. Hyperactivated Akt kinases promote tumor/cancer cell survival, proliferation, invasiveness, metastasis and energy production by glycolysis, and angiogenesis. [0005] In addition to its key role in various cellular processes, Akt (primarily Akt1) plays a critical role in cell entry by viruses, including herpes simplex virus 1 and 2 (HSV-1 and HSV-2). HSV cell entry is initiated by binding of HSV-1 glycoprotein C (gC) or HSV-2 glycoprotein B (gB) to heparan sulfate moieties on syndecan proteoglycans, followed by engagement of a glycoprotein D (gD) co-receptor, typically nectin-1 on epithelial cells [Cheshenko et al., FASEB J., 27(7):2584-2599 (2013)]. These events trigger the release of an intracellular Ca²⁺ store near the plasma membrane (PM), which activates calcium-responsive phospholipid scramblase-1 (PLSCR1) and initiates a signaling cascade at the outer leaflet of the PM and fusion of the HSV lipid-bilayer envelope with the PM. Activated PLSCR1 “flips” phosphatidylserines from the inner leaflet to the outer leaflet of the PM, which results in proteins associated with the inner leaflet of the PM becoming accessible at the outer leaflet (exofacial surface), including Akt, PDPK1 and phospholipase C-gamma (PLCγ). Once on the exofacial surface, Akt is phosphorylated at, e.g., Thr308 (presumably by externalized PDPK1) and Ser473 for Akt1. Phosphorylation of externalized Akt requires the presence of viral glycoprotein B, which co- immunoprecipitates with Akt, possibly within lipid rafts. Activation of Akt (e.g., Akt1) and downstream signaling pathways leads to the release of inositol-triphosphate receptor (IP3R)- regulated Ca²⁺ stores in the endoplasmic reticulum, culminating in intracellular delivery of viral capsids. Binding of the virus responsible for COVID-19, SARS-CoV-2, to target cells via its spike protein also activates PLSCR1, which results in externalization of inner leaflet-associated proteins such as Akt, PDPK1 and PLCγ to the outer leaflet of the PM, and ultimately viral cell entry by direct fusion [Cheshenko et al., Commun. Biol., 5:1096 (2022)]. [0006] Other viruses that require phosphatidylserine scrambling to the surface of target cells for efficient infectivity include HIV and Ebola virus, although the mechanism may differ. In addition to promoting cell entry by viruses, externalized phosphatidylserines suppress an immune response, which facilitates infection and can establish infection latency [Birge et al., Cell Death Differentiation, 23:962-978 (2016)]. [0007] Cancer cells also externalize phosphatidylserines (PS). In healthy cells, PS are asymmetrically distributed and primarily located at the inner leaflet of the plasma membrane (PM). However, externalization of PS on tumor cells is induced in the tumor microenvironment in response to cellular stress (e.g., oxidative stress), cytokines, chemotherapy, radiation and targeted therapies (Birge et al., supra). During apoptosis, PS translocate to the outer leaflet of the PM because PS serve as an “eat me” signal for phagocytosis by phagocytes such as dendritic cells and macrophages that bear PS receptors. Instead of inducing phagocytosis, however, interaction between the PS-exposing cancer cells and phagocytes induces profound immunosuppression and promotes tumor growth and metastasis. In effect, PS on the surface of cancer cells function as an immune checkpoint. Blocking PS externalization by silencing the PS scramblase Xkr8 in vivo with a short hairpin RNA (shRNA) or a small interfering RNA (siRNA) induces a strong anti-tumor immune response [Wang et al., Cell Reports, 41:111582 (2022)]. Flipping of PS by phospholipid scramblases from the inner leaflet to the outer leaflet of the PM of cancer cells is a way by which inner leaflet-associated proteins such as Akt and PDPK1 can be externalized to the surface of cancer cells. [0008] Like the Akt kinases, PDPK1 is considered a “master kinase” because it phosphorylates highly conserved serine or threonine residues in the T-loop (or activation loop) of numerous AGC kinases, including Akt (PKB), protein kinase C (PKC), p70S6 kinase (p70S6K) and serine/threonine protein kinases SGK, and thereby activates or inactivates the kinases. Akt is the main effector of PDPK1. PDPK1 has a PH domain that binds to PIP3 at the inner leaflet of the plasma membrane, allowing PDPK1 to phosphorylate and activate the Akt isoforms. PDPK1 plays a key role in signaling pathways activated by certain growth factors and hormones including insulin. Summary of the Disclosure [0009] Described herein are cell membrane-impermeable Akt inhibitors and PDPK1 inhibitors. The Akt inhibitors and PDPK1 inhibitors contain one or more moieties that impart cell impermeability. In some embodiments, the cell-impermeable moieties have one or more polar or/and ionizable functional groups. In some embodiments, the cell-impermeable moieties are - (CH₂)_n-Y, where Y is -CO₂H, -S(=O)₂OH or -P(=O)(OH)₂, or a salt thereof, and n is 1, 2, 3 or 4. [0010] Akt and PDPK1 play key roles in signaling pathways that regulate important cellular processes by phosphorylating, and thereby activating or inhibiting, many substrates intracellularly. Inhibition of Akt and PDPK1 by the compounds disclosed herein extracellularly reduces potential side effects. In addition, the compounds are selective for Akt or PDPK1 over other kinases, further reducing potential side effects. The compounds are useful for treating medical conditions involving externalization and activation of Akt or PDPK1 on the cell surface, on the outer leaflet of the plasma membrane or extracellularly. [0011] In some embodiments, the cell-impermeable Akt inhibitors and PDPK1 inhibitors are used to inhibit or treat medical conditions characterized by abnormally elevated activity of the PI3K/Akt/mTOR signaling pathway. In further embodiments, the Akt inhibitors and PDPK1 inhibitors are used to inhibit or treat tumors and cancers. In other embodiments, the Akt inhibitors and PDPK1 inhibitors are used to inhibit or treat viral infections. In addition to therapeutic uses, the Akt inhibitors and PDPK1 inhibitors can be used as molecular biology research tools. Brief Description of the Drawings [0012] A better understanding of features and advantages of the present disclosure will be obtained by reference to the following detailed description, which sets forth illustrative embodiments of the disclosure, and the accompanying drawings. [0013] Fig. 1 shows that exposure of HaCat cells (human keratinocytes) to herpes simplex virus 2 (HSV-2) in the presence of the cell-impermeable Akt inhibitor LD2-3 (“HSV + Cl”) blocked the phosphorylation of extracellular phospholipase C-gamma (PLCγ), which is a substrate of Akt kinase activity. [0014] Figs.2A and 2B show that the cell-impermeable Akt inhibitors LD2-2 and LD2-3, respectively, dose-dependently inhibited the entry of HSV-2 into HaCat cells. [0015] Figs.3A and 3B show that the cell-impermeable Akt inhibitors LD2-2 and LD2-3, respectively, were not significantly more toxic to Vero cells than DMSO as control. [0016] Figs.4A and 4B show that LD2-2 and LD2-3 significantly reduce HSV induced phosphorylation of PLC γ1. LD2-3 does not inhibit insulin–induced phosphorylation of Akt. Detailed Description of the Disclosure General Disclosure [0017] While various embodiments of the present disclosure are described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous modifications and changes to, and variations and substitutions of, the embodiments described herein will be apparent to those skilled in the art without departing from the disclosure. It is understood that various alternatives to the embodiments described herein can be employed in practicing the disclosure. It is also understood that every embodiment of the disclosure can optionally be combined with any one or more of the other embodiments described herein which are consistent with that embodiment. [0018] Where a combination is disclosed, it is understood that each possible subcombination of the elements of that combination is also disclosed. Conversely, where different elements or groups of elements are individually disclosed, combinations thereof are also disclosed. [0019] Where elements are presented in list format or as alternative members of a group (e.g., a Markush group), it is understood that each possible subgroup of the elements is also disclosed, and any one or more elements can be removed from the list or group. [0020] Where a range of numerical values is recited, it is understood that the endpoints and each intervening integer value and each fraction thereof, as well as each subrange, between the recited endpoints (upper and lower limits) of that range are specifically disclosed. The endpoints of all ranges are included within the range and are independently combinable. Where a value has an inherent limit, that inherent limit is specifically disclosed. Where a value is explicitly recited, it is understood that values which are about the same as the recited value are specifically disclosed. [0021] It is also understood that, unless clearly indicated to the contrary, in any method described or claimed herein that includes more than one act or step, the order of the acts or steps of the method is not necessarily limited to the order in which the acts or steps of the method are recited, but the disclosure encompasses embodiments in which the order is so limited. [0022] It is further understood that, in general, where an embodiment in the description or the claims is referred to as comprising one or more features, the disclosure also encompasses embodiments that consist of, or consist essentially of, such feature(s). [0023] It is also understood that any embodiment of the disclosure, e.g., any embodiment or compound found within the prior art, can be explicitly excluded from the claims, regardless of whether or not the specific exclusion is recited in the specification. [0024] In addition, it is understood that any functional language used in any claims shall not be construed as “means-plus-function” language under 35 U.S.C. §112(f), unless specifically expressed as such by use of the term “means for” or “step(s) for” in a claim. [0025] It is further understood that the present disclosure encompasses analogs, derivatives, prodrugs, metabolites, salts, solvates, hydrates, clathrates and polymorphs of all the compounds/substances disclosed herein, as appropriate. The specific recitation of “analogs”, “derivatives”, “prodrugs”, “metabolites”, “salts”, “solvates”, “hydrates”, “clathrates” or “polymorphs” with respect to a compound/substance or a group of compounds/substances in certain instances of the disclosure shall not be interpreted as an intended omission of any of these forms in other instances of the disclosure where the compound/substance or the group of compounds/substances is mentioned or shown without recitation of any of these forms, unless stated otherwise or the context clearly indicates otherwise. [0026] It is also understood that the present disclosure encompasses all possible tautomers, all possible regioisomers, and all possible stereoisomers, including both enantiomers and all possible diastereomers in substantially pure form and mixtures of both enantiomers in any ratio (including a racemic mixture of enantiomers) and mixtures of two or more diastereomers in any ratio, of the compounds/substances described herein as appropriate, and not only the specific tautomers, regioisomers and stereoisomers as indicated by drawn structure or nomenclature. Some embodiments of the disclosure relate to the specific tautomers, regioisomers and stereoisomers indicated by drawn structure or nomenclature. The specific recitation of the phrase “or tautomers thereof”, “or regioisomers thereof”, “or stereoisomers thereof” or the like with respect to a compound/substance or a group of compounds/substances in certain instances of the disclosure shall not be interpreted as an intended omission of any of the other possible tautomers, regioisomers and stereoisomers of the compound/substance or the group of compounds/substances in other instances of the disclosure where the term “compound” or the like is used, or where the compound/substance or the group of compounds/substances is mentioned or shown, without recitation of the phrase “or tautomers thereof”, “or regioisomers thereof”, “or stereoisomers thereof” or the like, unless stated otherwise or the context clearly indicates otherwise. [0027] Headings are included herein for reference and to aid in locating certain sections. Headings are not intended to limit the scope of the embodiments and concepts described in the sections under those headings, and those embodiments and concepts may have applicability in other sections throughout the entire disclosure. [0028] All patent literature and all non-patent literature cited herein are incorporated herein by reference in their entirety to the same extent as if each patent literature or non-patent literature were specifically and individually indicated to be incorporated herein by reference in its entirety. Definitions [0029] Unless defined otherwise or clearly indicated otherwise by their use herein, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this application belongs. [0030] As used in the specification and the claims, the indefinite articles “a” and “an” and the definite article “the” can include plural referents as well as singular referents unless specifically stated otherwise or the context clearly indicates otherwise. [0031] The terms “or/and” and “and/or” mean “either … or …, or both … and …” when referring to two elements, and mean “either …, … or …, or any combination or all thereof” when referring to three or more elements. As an example, the phrase “A or/and B” means “either A or B, or both A and B”, and the phrase “A, B or/and C” means “either A, B or C, or any combination or all thereof”. [0032] As used in the specification and the claims, all transitional terms such as “comprising”, “containing”, “having”, “including”, “possessing”, “holding”, “carrying”, “bearing”, “composed of”, “characterized by” and the like are open-ended and inclusive, that is, mean including but not limited to and do not exclude additional, unrecited element(s) or method step(s). Only the transitional term “consisting of” is closed, that is, excludes any additional, unrecited element or method step, and the transitional term “consisting essentially of” is semi-closed, that is, only allows inclusion of additional, unrecited element(s) or method step(s) that do not materially affect the basic and novel characteristic(s) of that particular embodiment. [0033] The term “exemplary” as used herein means “serving as an example, instance or illustration”. Any embodiment or feature characterized herein as “exemplary” should not be construed as preferred or advantageous over other embodiments or features. [0034] The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within one standard deviation. In some embodiments, when no particular margin of error (e.g., a standard deviation to a mean value given in a chart or table of data) is recited, the term "about" or “approximately” means that range which would encompass the recited value and the range which would be included by rounding up or down to the recited value as well, taking into account significant figures. In certain embodiments, the term “about” or “approximately” means within ± 10% or 5% of the specified value. Whenever the term “about” or “approximately” precedes the first numerical value in a series of two or more numerical values or in a series of two or more ranges of numerical values, the term “about” or “approximately” applies to each one of the numerical values in that series of numerical values or in that series of ranges of numerical values. [0035] In some embodiments, the term “substantially all” means at least about 90%, 95%, 96%, 97%, 98% or 99%. In some embodiments, the term “substantially free” means no more than about 10%, 5%, 4%, 3%, 2% or 1% by weight or molarity, or no more than about 1000 ppm, 500 ppm, 400 ppm, 300 ppm, 200 ppm or 100 ppm. [0036] In some embodiments, the term “substantially pure” means at least about 90%, 95%, 96%, 97%, 98% or 99% pure. In some embodiments, the term “substantially stereochemically pure” means at least about 80% enantiomeric excess (90% of one enantiomer – 10% of the other enantiomer) or 90% enantiomeric excess (95% of one enantiomer – 5% of the other enantiomer), or at least about 80% diastereomeric excess (90% of one diastereomer – 10% of all the other diastereomers) or at least about 90% diastereomeric excess (95% of one diastereomer – 5% of all the other diastereomers). [0037] Whenever the term “at least” or “greater than” precedes the first numerical value in a series of two or more numerical values, the term “at least” or “greater than” applies to each one of the numerical values in that series of numerical values. [0038] Whenever the term “no more than” or “less than” precedes the first numerical value in a series of two or more numerical values, the term “no more than” or “less than” applies to each one of the numerical values in that series of numerical values. [0039] The term “cell-impermeable” or the like means low cell permeability. In some embodiments, cell permeability is measured in a Caco-2 assay. In some embodiments, a “cell- impermeable” compound has cell permeability of about 1 x 10^-7 cm/s or less in the apical to basolateral direction and the basolateral to apical direction in a Caco-2 assay. In other embodiments, no more than about 10%, 5%, 4%, 3%, 2% or 1% of a “cell-impermeable” compound enters into a cell. [0040] The term “pharmaceutically acceptable” means that a substance (e.g., an active ingredient or an excipient) is generally safe, non-toxic and suitable for use in contact with the cells, tissues and organs of a subject without excessive irritation, allergic response, immunogenicity and other adverse reaction. A “pharmaceutically acceptable” excipient or carrier of a pharmaceutical composition is also compatible with the other ingredients of the composition. [0041] The term “therapeutically effective amount” refers to an amount of a compound that, when administered to a subject or used ex vivo, is sufficient to prevent, reduce the risk of developing, delay the onset of, slow the progression of or cause regression of the medical condition being treated, or to alleviate or ameliorate to some extent the medical condition or one or more symptoms or complications of that condition, at least in some fraction of the subjects taking that compound or undergoing ex vivo treatment with that compound. The term “therapeutically effective amount” also refers to an amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, organ, system, animal or human which is sought by a researcher, veterinarian, medical doctor or clinician. [0042] The terms “treat”, “treating” and “treatment” include alleviating, ameliorating, reducing the incidence, frequency or severity of, slowing or stopping the progress of, reversing or abrogating a medical condition or one or more symptoms or complications associated with the condition, and alleviating, ameliorating or eradicating one or more causes of the condition. Reference to “treatment” of a medical condition includes prevention of the condition. The terms “prevent”, “preventing” and “prevention” include precluding, reducing the risk or likelihood of developing, and delaying the onset of a medical condition or one or more symptoms or complications associated with the condition. [0043] The term “medical conditions” (or “conditions” for brevity) includes diseases and disorders. The terms “diseases” and “disorders” are used interchangeably herein. [0044] The term “subject” refers to an animal, including but not limited to a mammal, such as a primate (e.g., a human, a chimpanzee or a monkey), a rodent (e.g., a rat, a mouse, a guinea pig, a gerbil or a hamster), a lagomorph (e.g., a rabbit), a bovine (e.g., a cattle), a suid (e.g., a pig), a caprine (e.g., a sheep), an equine (e.g., a horse), a canine (e.g., a dog) or a feline (e.g., a cat). The terms “subject” and “patient” may be used interchangeably herein in reference to a subject/patient (e.g., a mammalian subject/patient such as a human subject/patient) having a medical condition. [0045] A “modulator” of, e.g., a receptor or enzyme can be an activator or inhibitor of that receptor or enzyme, and can increase or reduce the activity or/and the level of that receptor or enzyme. [0046] The term “compound” or the like (e.g., “molecule”) encompasses salts, solvates, hydrates, clathrates and polymorphs of that compound or a salt of that compound. A “solvate” of a compound comprises a stoichiometric or non-stoichiometric amount of a solvent molecule (e.g., water, acetone or an alcohol [e.g., ethanol]) bound non-covalently to the compound. A “hydrate” of a compound comprises a stoichiometric or non-stoichiometric amount of water molecule bound non-covalently to the compound. A “clathrate” of a compound contains molecules of a substance (e.g., a solvent) enclosed in a crystal structure of the compound. A “polymorph” of a compound is a crystalline form of the compound. The specific recitation of “salt”, “solvate”, “hydrate”, “clathrate” or “polymorph” with respect to a compound or a group of compounds in certain instances of the disclosure shall not be interpreted as an intended omission of any of these forms in other instances of the disclosure where the term “compound” or the like (e.g., “molecule”), or where the compound or the group of compounds is mentioned or shown, without recitation of any of these forms, unless stated otherwise or the context clearly indicates otherwise. [0047] The terms “halogen”, “halide” and “halo” refer to fluoride, chloride, bromide and iodide. [0048] The term “alkyl” refers to a linear or branched, saturated monovalent hydrocarbon radical, wherein the alkyl group can optionally be substituted with one or more substituents as described herein. In certain embodiments, an alkyl group is a linear saturated monovalent hydrocarbon radical that has 1 to 10 (C_1-10) or 1 to 6 (C_1-6) carbon atoms, or is a branched saturated monovalent hydrocarbon radical that has 3 to 10 (C_3-10) or 3 to 6 (C_3-6) carbon atoms. As an example, the term “C_1-6 alkyl” refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. Linear C_1-6 and branchedC_3-6 alkyl groups may also be referred to as “lower alkyl”. Non-limiting examples of alkyl groups include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including all isomeric forms, such as n-butyl, isobutyl, sec-butyl and tert- butyl), pentyl (including all isomeric forms, such as n-pentyl and isopentyl), and hexyl (including all isomeric forms, such as n-hexyl). [0049] The terms “alkylene” and “-alkyl-” refer to a divalent alkyl group, which can optionally be substituted with one or more substituents as described herein. [0050] The term “heteroalkyl” refers to a linear or branched, saturated monovalent hydrocarbon group containing one or more heteroatoms independently selected from O, N and S. In some embodiments, one or more heteroatoms are in the main chain of the linear or branched hydrocarbon group. The terms “heteroalkylene” and “-heteroalkyl-” refer to a divalent heteroalkyl group. A heteroalkyl group and a -heteroalkyl- group can optionally be substituted with one or more substituents as described herein. Examples of heteroalkyl and -heteroalkyl- groups include without limitation -(CH₂)_m-(O or S)-(CH₂)_nCH₃ and -(CH₂)_m-(O or S)-(CH₂)_p-, wherein m is 1, 2 or 3, n is 0, 1 or 2, and p is 1, 2 or 3. [0051] The term “alkoxy” refers to an -O-alkyl group, which can optionally be substituted with one or more substituents as described herein. [0052] Examples of -O-heteroalkyl and -O-heteroalkyl- groups include without limitation ethylene glycol groups and polyethylene glycol (PEG) groups, including but not limited to - (OCH₂CH₂)_n-OR and -(OCH₂CH₂)_n-O-, wherein R is hydrogen or alkyl and n is 1, 2 or 3. An - O-heteroalkyl group and an -O-heteroalkyl- group can optionally be substituted with one or more substituents as described herein. [0053] The term “haloalkyl” refers to an alkyl group that is substituted with one or more halide atoms. A haloalkyl group can optionally be substituted with one or more additional substituents as described herein. Examples of haloalkyl groups include without limitation fluoroalkyl groups such as -CH₂F, -CHF₂ and -(CH₂)_nCF₃, and perfluoroalkyl groups such as -CF₃ and -(CF₂)_nCF₃, wherein n is 1, 2, 3, 4 or 5. [0054] The term “cycloalkyl” refers to a cyclic saturated or partially unsaturated, bridged or non-bridged monovalent hydrocarbon radical, which can optionally be substituted with one or more substituents as described herein. In certain embodiments, a cycloalkyl group has from 3 to 10 (C3-10), or from 3 to 8 (C_3-8), or from 3 to 6 (C_3-6) carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, decalinyl and adamantyl. The term “-cycloalkyl-” refers to a divalent cycloalkyl group, which can optionally be substituted with one or more substituents as described herein. [0055] The terms “heterocyclyl” and “heterocyclic” refer to a monocyclic non-aromatic group or a multicyclic group that contains at least one non-aromatic ring, wherein at least one non- aromatic ring contains one or more heteroatoms independently selected from O, N and S. The non-aromatic ring containing one or more heteroatoms may be attached or fused to one or more saturated, partially unsaturated or aromatic rings. In certain embodiments, a heterocyclyl or heterocyclic group has from 3 to 15, or 3 to 12, or 3 to 10, or 3 to 8, or 3 to 6 ring atoms. In some embodiments, a heterocyclyl or heterocyclic group is a monocyclic, bicyclic or tricyclic ring system, which may include a fused or bridged ring system, and in which nitrogen or sulfur atoms can optionally be oxidized, nitrogen atoms can optionally be quaternized, and one or more rings may be fully or partially saturated, or aromatic. A heterocyclyl or heterocyclic group may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of heterocyclyl or heterocyclic groups include without limitation azepanyl, azepinyl, azetidinyl, aziridinyl, azocanyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, β-carbolinyl, chromanyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydropyranyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl,

dioxolanyl, dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, indolizinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxepanyl, oxetanyl, oxiranyl, oxocanyl, piperazinyl, piperidinyl, 4- piperidonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydrofuranyl (oxolanyl), tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl (tetrahydrothiophenyl or thiolanyl), thiamorpholinyl (thiomorpholinyl), thiazolidinyl and 1,3,5-trithianyl. The term “-heterocyclyl-” refers to a divalent heterocyclyl group. A heterocyclyl or heterocyclic group, and a - heterocyclyl- group, can optionally be substituted with one or more substituents as described herein. [0056] The term “aryl” refers to a monocyclic aromatic hydrocarbon group or a multicyclic group that contains at least one aromatic hydrocarbon ring. In certain embodiments, an aryl group has from 6 to 15, or 6 to 12, or 6 to 10 ring atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, biphenyl and terphenyl. The aromatic hydrocarbon ring of an aryl group may be attached or fused to one or more saturated, partially unsaturated or aromatic rings – e.g., dihydronaphthyl, indenyl, indanyl and tetrahydronaphthyl (tetralinyl). The term “-aryl-” refers to a divalent aryl group. An aryl group and an -aryl- group can optionally be substituted with one or more substituents as described herein. [0057] The term “heteroaryl” refers to a monocyclic aromatic group or a multicyclic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, N and S. The heteroaromatic ring may be attached or fused to one or more saturated, partially unsaturated or aromatic rings that may contain only carbon atoms or that may contain one or more heteroatoms. A heteroaryl group may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. In certain embodiments, a heteroaryl group has from 5 to 15, or 5 to 12, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include without limitation pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl (thiophenyl), oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridonyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridazinonyl and triazinyl. Non-limiting examples of bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl (benzofurazanyl), benzothienyl (benzothiophenyl), quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzotriazolyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinazolinyl, quinoxalinyl, indazolyl, naphthyridinyl, phthalazinyl, quinazolinyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include without limitation carbazolyl, benzindolyl, dibenzofuranyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and phenothiazinyl. The term “-heteroaryl-” refers to a divalent heteroaryl group. A heteroaryl group and a -heteroaryl- group can optionally be substituted with one or more substituents as described herein. [0058] The terms “-alkylcycloalkyl”, “-alkylheterocyclyl”, “-alkylaryl” and “-alkylheteroaryl” refer to an alkyl group that is substituted with one or more cycloalkyl groups, one or more heterocyclyl groups, one or more aryl groups, or one or more heteroaryl groups, respectively. An -alkylcycloalkyl, -alkylheterocyclyl, -alkylaryl or -alkylheteroaryl group can optionally be substituted with one or more additional substituents as described herein. [0059] Each group described herein (including without limitation monovalent and divalent alkyl, monovalent and divalent heteroalkyl, -O-alkyl, -O-heteroalkyl, haloalkyl, monovalent and divalent cycloalkyl, monovalent and divalent heterocyclyl, monovalent and divalent aryl, monovalent and divalent heteroaryl, -alkylcycloalkyl, -alkylheterocyclyl, -alkylaryl and - alkylheteroaryl), whether as a primary group or as a substituent group, can optionally be substituted with one or more substituents. In certain embodiments, each group described herein can optionally be substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from halide, cyano (-CN), nitro (-NO₂), hydroxyl (-OH), sulfhydryl (-SH), amino (-NH₂), -OR¹¹, - SR¹¹, -NR¹²R¹³, -C(=O)R¹¹, -C(=O)OR¹¹, -OC(=O)R¹¹, -C(=O)NR¹²R¹³, -NR¹²C(=O)R¹¹, - OC(=O)OR¹¹, -OC(=O)NR¹²R¹³, -NR¹²C(=O)OR¹¹, -NR¹¹C(=O)NR¹²R¹³, alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein: R¹¹ in each occurrence independently is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -alkylcycloalkyl, -alkylheterocyclyl, -alkylaryl or -alkylheteroaryl; and R¹² and R¹³ in each occurrence independently are hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -alkylcycloalkyl, -alkylheterocyclyl, -alkylaryl or -alkylheteroaryl, or R¹² and R¹³ and the nitrogen atom to which they are connected form a heterocyclic or heteroaryl ring. Cell-Impermeable Akt Inhibitors of Formula [0060] In some embodiments, cell membrane-impermeable Akt inhibitors have Formula I or are pharmaceutically acceptable salts, solvates, hydrates, clathrates or polymorphs thereof:

wherein: R¹ is -OH, -NH₂, -NHR⁵ or -NHC(=O)R⁵; R² is hydrogen, C_1-4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), or cyclopropyl; R³ and R⁴ independently are hydrogen or methyl, or R³ and R⁴ and the carbon atom to which they are attached form a cyclopropyl ring; R⁵ at each occurrence independently is C_1-4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl or tert-butyl) or cyclopropyl; R⁶ is C_1-6 alkyl, -(C_1-3 alkyl)-(C_3-6 cycloalkyl), -(C_1-3 alkyl)-(3-6-membered heterocyclyl), - (C_1-3 alkyl)-(5- or 6-membered heteroaryl), or -(C_1-3 alkyl)-phenyl, wherein the C_1-6 alkyl, C_1-3 alkyl, cycloalkyl, heterocyclyl, heteroaryl and phenyl independently can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, - CF₃ and -OCF₃; R⁷ is C_1-6 alkyl, -(C_0-3 alkyl)-(C_3-6 cycloalkyl), -(C_0-3 alkyl)-(3-6-membered heterocyclyl), - (C_0-3 alkyl)-(5- or 6-membered heteroaryl), or -(C_0-3 alkyl)-phenyl, wherein the C_1-6 alkyl, C_0-3 alkyl, cycloalkyl, heterocyclyl, heteroaryl and phenyl independently can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, - CF₃ and -OCF₃; X is -CH₂-, -O-, -S-, -NH- or -NR⁵-;

denotes the site of attachment to X and the amine nitrogen atom is attached to one or two -L²-Y moieties, and wherein each stereocenter independently can have the (R)-stereochemistry or the (S)- stereochemistry or can be racemic; -L²- at each occurrence independently is -(CH₂)q-; Y at each occurrence independently is -CO₂H, -S(=O)₂OH or -P(=O)(OH)₂, or a salt thereof; m is 2, 3, 4 or 5; n is 1, 2, 3 or 4; p is 1 or 2; and q is 1, 2, 3 or 4. [0061] In some embodiments, R¹ is -OH, -NH₂, -NHCH₃ or -NHC(=O)CH₃. In certain embodiments, R¹ is -NH₂. [0062] In some embodiments, R² is methyl or ethyl. [0063] In some embodiments of compounds of Formula I: (a) R³ is hydrogen and R⁴ is methyl; (b) R³ is methyl and R⁴ is hydrogen; (c) both R³ and R⁴ are hydrogen; or (d) both R³ and R⁴ are methyl. In certain embodiments, both R³ and R⁴ are hydrogen, or both R³ and R⁴ are methyl. [0064] In certain embodiments, X is O. [0065] In some embodiments, -L¹-NH/NR⁶/N- is -(CH₂)_m-NH/N- and m is 2, 3 or 4. [0066] In some embodiments, -L²- is -CH₂CH₂- or -CH₂CH₂CH₂-. In further embodiments, Y is -S(=O)₂OH or a salt (e.g., sodium salt or inner salt) thereof. [0067] In certain embodiments, p is 1. In other embodiments, p is 2 and -L²-Y is the same at both occurrences. [0068] In some embodiments, the Akt inhibitors have Formula Ia or are pharmaceutically acceptable salts, solvates, hydrates, clathrates or polymorphs thereof:

wherein: both R³ and R⁴ are hydrogen, or both R³ and R⁴ are methyl; -L²-Y is -CH₂CH₂S(=O)₂OH or -CH₂CH₂CH₂S(=O)₂OH, or a salt (sodium salt or inner salt) thereof; m is 2, 3 or 4; and p is 1 or 2. [0069] Non-limiting examples of Akt inhibitors of Formula I include:

and pharmaceutically acceptable salts, solvates, hydrates, clathrates and polymorphs thereof, wherein a stereocenter marked by an asterisk * in the compounds above can have the (S)- stereochemistry or the (R)-stereochemistry or can be racemic. [0070] Some Akt inhibitors of Formula I may have substantially comparable potency (e.g., IC₅₀) in inhibiting Akt1, Akt2 and Akt3. Other Akt inhibitors of Formula I may have substantially comparable potency (e.g., IC₅₀) in inhibiting Akt1 and Akt2 which is substantially stronger than the potency in inhibiting Akt3. Yet other Akt inhibitors of Formula I may have the strongest potency (e.g., lowest IC₅₀) in inhibiting Akt1 relative to Akt2 and Akt3. [0071] Akt inhibitors of Formula I can selectively inhibit Akt over other kinases. Cell-Impermeable Akt Inhibitors of Formula

[0072] In other embodiments, cell membrane-impermeable Akt inhibitors have Formula II or are pharmaceutically acceptable salts, solvates, hydrates, clathrates or polymorphs thereof:

wherein: X is -NR⁴-L-Y or -NR⁴-(CH₂)_m-NH/N-(L-Y)_n; R¹ and R² independently are hydrogen, halide, cyano, -CH₃, -CH₂CH₃, -CF₃, -OCH₃ or - OCF₃, wherein at least one of R¹ and R² is not hydrogen; R³ is hydrogen, or R³ and -NR⁴- and the carbon atom to which they are attached form a 5- or 6-membered heterocyclic ring (e.g., pyrrolidine, piperidine, piperazine or morpholine) which can optionally be substituted with -F, -Cl, -CH₃, -OH or -OCH₃; R⁴ is hydrogen, -L-Y, C_1-4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), C_3-6 cycloalkyl or 3-6-membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, -OH, C_1-4 alkyl, C_1-4 alkoxy, C_3-6 cycloalkyl and 3-6-membered heterocyclyl, or -NR⁴- and R³ and the carbon atom to which they are attached form a 5- or 6-membered heterocyclic ring which can optionally be substituted with -F, -Cl, -CH₃, -OH or -OCH₃; -L- at each occurrence independently is -(CH₂)_q-; Y at each occurrence independently is -CO₂H, -S(=O)₂OH or -P(=O)(OH)₂, or a salt thereof; m is 2, 3 or 4; n is 1 or 2; and q is 1, 2, 3 or 4. [0073] In some embodiments, the phenyl (Ph) ring is 3-F-Ph, 3-Cl-Ph, 3-CF₃-Ph, 4-F-Ph, 4-Cl- Ph, 4-CF₃-Ph, 3,4-F₂-Ph, 3,4-Cl₂-Ph, 3,4-(CF₃)₂-Ph, 3-F-4-Cl-Ph, 3-F-4-CF₃-Ph, 3-Cl-4-F-Ph, 3- Cl-4-CF₃-Ph, 3-CF₃-4-F-Ph or 3-CF₃-4-Cl-Ph. [0074] In certain embodiments, R³ is hydrogen. [0075] In some embodiments, R⁴ is hydrogen, -CH₂CH₂S(=O)₂OH or -CH₂CH₂CH₂S(=O)₂OH or a salt thereof, isopropyl, isobutyl, sec-butyl, tert-butyl, -CH₂CH₂F, -CH₂CH₂Cl, -CH₂CH₂OH, -CH₂CH₂-OCH₃, -CH(CH₃)CH₂OH, -CH(CH₃)CH₂OCH₃, -C(CH₃)₂CH₂OH, - C(CH₃)₂CH₂OCH₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl-OH (e.g., trans 1,3-N-cyclopentyl-OH), cyclopentyl-OCH₃ (e.g., trans 1,3-N-cyclopentyl-OCH₃), cyclohexyl-OH (e.g., trans 1,4-N-cyclohexyl-OH), cyclohexyl-OCH₃ (e.g., trans 1,4-N- cyclohexyl-OCH₃), tetrahydrofuranyl (e.g., 3-tetrahydrofuranyl), tetrahydropyranyl (e.g., 4- tetrahydropyranyl), -CH₂-cyclopropyl, -CH₂-cyclobutyl, -CH₂-cyclopentyl, -CH₂-cyclohexyl, - CH₂-tetrahydrofuranyl (e.g., -CH₂-3-tetrahydrofuranyl), or -CH₂-tetrahydropyranyl (e.g., -CH₂- 4-tetrahydropyranyl), or -NR⁴- and R³ and the carbon atom to which they are attached form a pyrrolidine, piperidine, piperazine [with, e.g., -N(CH₃)- or -N(acetyl)-] or morpholine ring which can optionally be substituted with -F, -Cl, -CH₃, -OH or -OCH₃, wherein if a ring has a stereocenter, the stereocenter can have the (S)-stereochemistry or the (R)-stereochemistry or can be racemic. [0076] In some embodiments, L is -CH₂CH₂- or -CH₂CH₂CH₂-. In further embodiments, Y is -S(=O)₂OH or a salt (e.g., sodium salt or inner salt) thereof. In some embodiments, if -L-Y occurs more than once, -L-Y is the same at all occurrences. [0077] In certain embodiments, m is 2. [0078] In some embodiments, the Akt inhibitors have Formula IIa or are pharmaceutically acceptable salts, solvates, hydrates, clathrates or polymorphs thereof:

wherein: X is -NR⁴-L-Y or -NR⁴-(CH₂)₂-NH/N-(L-Y)_n; R³ is hydrogen, or R³ and -NR⁴- and the carbon atom to which they are attached form a pyrrolidine, piperidine, piperazine [with, e.g., -N(CH₃)- or -N(acetyl)-] or morpholine ring which can optionally be substituted with -F, -Cl, -CH₃, -OH or -OCH₃; R⁴ is hydrogen, -CH₂CH₂S(=O)₂OH or -CH₂CH₂CH₂S(=O)₂OH or a salt thereof, isopropyl, isobutyl, sec-butyl, tert-butyl, -CH₂CH₂F, -CH₂CH₂Cl, -CH₂CH₂OH, -CH₂CH₂-OCH₃, - CH(CH₃)CH₂OH, -CH(CH₃)CH₂OCH₃, -C(CH₃)₂CH₂OH, -C(CH₃)₂CH₂OCH₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl-OH (e.g., trans 1,3-N-cyclopentyl-OH), cyclopentyl-OCH₃ (e.g., trans 1,3-N-cyclopentyl-OCH₃), cyclohexyl-OH (e.g., trans 1,4-N- cyclohexyl-OH), cyclohexyl-OCH₃ (e.g., trans 1,4-N-cyclohexyl-OCH₃), tetrahydrofuranyl (e.g., 3- tetrahydrofuranyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), -CH₂-cyclopropyl, -CH₂- cyclobutyl, -CH₂-cyclopentyl, -CH₂-cyclohexyl, -CH₂-tetrahydrofuranyl (e.g., -CH₂-3- tetrahydrofuranyl), or -CH₂-tetrahydropyranyl (e.g., -CH₂-4-tetrahydropyranyl), or -NR⁴- and R³ and the carbon atom to which they are attached form a pyrrolidine, piperidine, piperazine [with, e.g., - N(CH₃)- or -N(acetyl)-] or morpholine ring which can optionally be substituted with -F, -Cl, -CH₃, - OH or -OCH₃, wherein if a ring has a stereocenter, the stereocenter can have the (S)-stereochemistry or the (R)-stereochemistry or can be racemic; -L-Y is -CH₂CH₂S(=O)₂OH or -CH₂CH₂CH₂S(=O)₂OH, or a salt (e.g., sodium salt or inner salt) thereof; and n is 1 or 2. [

and pharmaceutically acceptable salts, solvates, hydrates, clathrates and polymorphs thereof, wherein a stereocenter marked by an asterisk * in the compounds above can have the (S)- stereochemistry or the (R)-stereochemistry or can be racemic. [0080] Some Akt inhibitors of Formula II may have substantially comparable potency (e.g., IC₅₀) in inhibiting Akt1, Akt2 and Akt3. Other Akt inhibitors of Formula II may have substantially comparable potency (e.g., IC₅₀) in inhibiting Akt1 and Akt2 which is substantially stronger than the potency in inhibiting Akt3. Yet other Akt inhibitors of Formula II may have the strongest potency (e.g., lowest IC₅₀) in inhibiting Akt1 relative to Akt2 and Akt3. [0081] Akt inhibitors of Formula II can selectively inhibit Akt over other kinases. Cell-Impermeable PDPK1 Inhibitors of Formula III [0082] In some embodiments, cell membrane-impermeable PDPK1 inhibitors have Formula III or are pharmaceutically acceptable salts, solvates, hydrates, clathrates or polymorphs thereof:

wherein: R¹ and R² independently are hydrogen, halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, -CF₃ or -OCF₃; R³ is hydrogen, C_1-6 alkyl (e.g., methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl), C_3-6 cycloalkyl, -(C_1-3 alkyl)-(C_3-6 cycloalkyl), -(C_1-3 alkyl)-phenyl or -C(=O)R⁴, wherein the phenyl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, -CF₃ and -OCF₃; R⁴ is C_1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n-pentyl or n-hexyl), C_3-6 cycloalkyl or phenyl, wherein the phenyl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, -CF₃ and -OCF₃; R⁵ is C_1-4 alkyl (e.g., methyl, ethyl, n-propyl or n-butyl); R⁶ is hydrogen, C_1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl or n-hexyl), cycloalkyl (e.g., C_3-6 cycloalkyl), heterocyclyl (e.g., 3-6- membered heterocyclyl), aryl (e.g., 6-10-membered aryl), heteroaryl (e.g., 5-10-membered heteroaryl), -(C_1-3 alkyl)-(C_3-6 cycloalkyl), -(C_1-3 alkyl)-(3-6-membered heterocyclyl), -(C_1-3 alkyl)- phenyl, or -(C_1-3 alkyl)-(5-9-membered heteroaryl), wherein the aryl, heteroaryl and phenyl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, -CF₃ and -OCF₃; X is -CH₂-, -O-, -S-, -NH- or -NR⁵-; -L- at each occurrence independently is -(CH₂)_q-; Y at each occurrence independently is -CO₂H, -S(=O)₂OH or -P(=O)(OH)₂, or a salt thereof; m is 1, 2 or 3; n is 1 or 2; q is 1, 2, 3 or 4; and the stereocenter marked by an asterisk * in Formula III can have the (S)-stereochemistry or the (R)-stereochemistry or can be racemic. [0083] In some embodiments, both R¹ and R² are -OCH₃. [0084] In some embodiments, R³ is hydrogen, -CH₃ or -C(=O)CH₃. In certain embodiments, R³ is hydrogen. [0085] In certain embodiments, X is O. In further embodiments, m is 1. [0086] In some embodiments, R⁶ is hydrogen, methyl, ethyl, n-propyl, n-butyl, isobutyl, -CH₂- phenyl, -CH₂-2-pyridyl, -CH₂-3-pyridyl, -CH₂-4-pyridyl, or -CH₂-3-indolyl, wherein the phenyl, pyridyl and indolyl can optionally be substituted as defined above. In further embodiments, R⁶ is -CH₂-phenyl, -CH₂-2-F-phenyl, -CH₂-3-F-phenyl, -CH₂-4-F-phenyl, -CH₂-2,3-F₂-phenyl, -CH₂- 2,4-F₂-phenyl, -CH₂-2,5-F₂-phenyl, -CH₂-2,6-F₂-phenyl, -CH₂-3,4-F₂-phenyl, -CH₂-3,5-F₂- phenyl, -CH₂-3,6-F₂-phenyl, -CH₂-2-Cl-phenyl, -CH₂-3-Cl-phenyl, -CH₂-4-Cl-phenyl, -CH₂-2,3- Cl₂-phenyl, -CH₂-2,4-Cl₂-phenyl, -CH₂-2,5-Cl₂-phenyl, -CH₂-2,6-Cl₂-phenyl, -CH₂-3,4-Cl₂- phenyl, -CH₂-3,5-Cl₂-phenyl, -CH₂-3,6-Cl₂-phenyl, -CH₂-2-CF₃-phenyl, -CH₂-3-CF₃-phenyl or - CH₂-4-CF₃-phenyl. [0087] In some embodiments, L is -CH₂CH₂- or -CH₂CH₂CH₂-. In further embodiments, Y is -S(=O)₂OH or a salt (e.g., sodium salt or inner salt) thereof. [0088] In certain embodiments, n is 1. In other embodiments, n is 2 and -L-Y is the same at both occurrences. [0089] In some embodiments, the PDPK1 inhibitors have Formula IIIa or are pharmaceutically acceptable salts, solvates, hydrates, clathrates or polymorphs thereof:

wherein: R⁶ is hydrogen, methyl, ethyl, n-propyl, n-butyl, isobutyl, -CH₂-2-pyridyl, -CH₂-3-pyridyl, - CH₂-4-pyridyl, -CH₂-3-indolyl, -CH₂-phenyl, -CH₂-2-F-phenyl, -CH₂-3-F-phenyl, -CH₂-4-F-phenyl, -CH₂-2,3-F₂-phenyl, -CH₂-2,4-F₂-phenyl, -CH₂-2,5-F₂-phenyl, -CH₂-2,6-F₂-phenyl, -CH₂-3,4-F₂- phenyl, -CH₂-3,5-F₂-phenyl, -CH₂-3,6-F₂-phenyl, -CH₂-2-Cl-phenyl, -CH₂-3-Cl-phenyl, -CH₂-4-Cl- phenyl, -CH₂-2,3-Cl₂-phenyl, -CH₂-2,4-Cl₂-phenyl, -CH₂-2,5-Cl₂-phenyl, -CH₂-2,6-Cl₂-phenyl, - CH₂-3,4-Cl₂-phenyl, -CH₂-3,5-Cl₂-phenyl, -CH₂-3,6-Cl₂-phenyl, -CH₂-2-CF₃-phenyl, -CH₂-3-CF₃- phenyl or -CH₂-4-CF₃-phenyl; -L-Y is -CH₂CH₂S(=O)₂OH or -CH₂CH₂CH₂S(=O)₂OH, or a salt (e.g., sodium salt or inner salt) thereof; n is 1 or 2; and the stereocenter marked by an asterisk * in Formula IIIa can have the (S)-stereochemistry or the (R)-stereochemistry or can be racemic. [0090] Examples of PDPK1 inhibitors of Formula III include without limitation: H

and pharmaceutically acceptable salts, solvates, hydrates, clathrates or polymorphs thereof, wherein the stereocenter marked by an asterisk * in the compounds above can have the (S)- stereochemistry or the (R)-stereochemistry or can be racemic. [0091] In some embodiments, PDPK1 inhibitors of Formula III have the (S)-stereochemistry at the stereocenter marked by an asterisk *. [0092] PDPK1 inhibitors of Formula III can selectively inhibit PDPK1 over other kinases. Salt Forms [0093] The Akt inhibitors and PDPK1 inhibitors described herein have one or more basic nitrogen atoms and one or more acidic groups. The compounds can exist and be used in non- ionic form or in ionic form as addition salts or inner salts. A basic nitrogen atom can form an addition salt with an acid, such as a mineral acid (e.g., HCl, HBr, HI, nitric acid, phosphoric acid or sulfuric acid) or an organic acid (e.g., a carboxylic acid or a sulfonic acid). Suitable acids for use in the preparation of pharmaceutically acceptable salts include without limitation acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, alpha-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (±)-DL-lactic acid, (+)-L-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy- 2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, propionic acid, L-pyroglutamic acid, pyruvic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (±)-DL-tartaric acid, (+)-L-tartaric acid, thiocyanic acid, p- toluenesulfonic acid, undecylenic acid, and valeric acid. [0094] An acidic group can form an addition salt with a base. Pharmaceutically acceptable base addition salts can be formed with, e.g., metals (e.g., alkali metals or alkaline earth metals) or amines (e.g., organic amines). Examples of metals useful as cations include without limitation alkali metals (e.g., lithium, sodium, potassium and cesium), alkaline earth metals (e.g., magnesium, calcium and barium), aluminum and zinc. Metal cations can be provided by way of, e.g., inorganic bases such as hydroxides, carbonates and hydrogen carbonates. Non-limiting examples of organic amines useful for forming base addition salts include chloroprocaine, choline, cyclohexylamine, dibenzylamine, N,N’-dibenzylethylenediamine, dicyclohexylamine, diethanolamine, ethylenediamine, N-ethylpiperidine, histidine, isopropylamine, N- methylglucamine, procaine, pyrazine, triethylamine, trimethylamine and tromethamine. Pharmaceutically acceptable salts are discussed in detail in Handbook of Pharmaceutical Salts, Properties, Selection and Use, P. Stahl and C. Wermuth, Eds., Wiley-VCH (2011). Pharmaceutical Compositions [0095] The disclosure provides pharmaceutical compositions comprising an Akt inhibitor or PDPK1 inhibitor described herein, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof, and one or more pharmaceutically acceptable excipients or carriers. The compositions can optionally contain an additional therapeutic agent. A pharmaceutical composition contains a therapeutically effective amount, or any appropriate fraction thereof, of an Akt inhibitor or PDPK1 inhibitor, one or more pharmaceutically acceptable excipients or carriers, and optionally a therapeutically effective amount of an additional therapeutic agent, and is formulated for administration to a subject for therapeutic use. [0096] A pharmaceutical composition contains an Akt inhibitor or PDPK1 inhibitor and optionally an additional therapeutic agent in substantially pure form. In some embodiments, the purity of the Akt inhibitor or PDPK1 inhibitor and the optional additional therapeutic agent independently is at least about 95%, 96%, 97%, 98% or 99%. In addition, a pharmaceutical composition is substantially free of contaminants or impurities. In some embodiments, the level of contaminants or impurities other than residual solvent in a pharmaceutical composition is no more than about 5%, 4%, 3%, 2% or 1% relative to the combined weight of the intended active and inactive ingredients. Pharmaceutical compositions generally are prepared according to current good manufacturing practice (GMP), as recommended or required by, e.g., the Federal Food, Drug, and Cosmetic Act §501(a)(2)(B) and the International Conference on Harmonisation Q7 Guideline. [0097] Pharmaceutical compositions/formulations can be prepared in sterile form. For example, pharmaceutical compositions/formulations for parenteral administration by injection or infusion generally are sterile. Sterile pharmaceutical compositions/formulations are compounded or manufactured according to pharmaceutical-grade sterilization standards known to those of skill in the art, such as those disclosed in or required by the United States Pharmacopeia Chapters 797, 1072 and 1211, and 21 Code of Federal Regulations 211. [0098] Pharmaceutically acceptable excipients and carriers include pharmaceutically acceptable substances, materials and vehicles. Non-limiting examples of types of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersing agents, disintegration agents, emulsifying agents, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption-delaying agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweetening agents, flavoring agents, coloring agents, encapsulating materials and coating materials. The use of such excipients in pharmaceutical formulations is known in the art. For example, conventional vehicles and carriers include without limitation oils (e.g., vegetable oils such as olive oil and sesame oil), aqueous solvents {e.g., saline, buffered saline (e.g., phosphate-buffered saline [PBS]) and isotonic solutions (e.g., Ringer’s solution)}, and organic solvents (e.g., dimethyl sulfoxide [DMSO] and alcohols [e.g., ethanol, glycerol and propylene glycol]). Except insofar as any conventional excipient or carrier is incompatible with the active ingredient (for purposes of the content of a pharmaceutical composition, the term “active ingredient” encompasses a prodrug), the disclosure encompasses the use of conventional excipients and carriers in formulations containing an Akt inhibitor or PDPK1 inhibitor. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania) (2005); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Pre-formulation and Formulation, Gibson, Ed., CRC Press (Boca Raton, Florida) (2004). [0099] Appropriate formulation can depend on various factors, such as the route of administration chosen. Potential routes of administration of pharmaceutical compositions comprising an Akt inhibitor or PDPK1 inhibitor include without limitation oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intra-arterial, intraperitoneal, intracavitary, intramedullary, intrathecal and topical), and topical (including dermal/epicutaneous, transdermal, mucosal, transmucosal, intranasal [e.g., by nasal spray or drop], ocular/intraocular [e.g., by eye drop], pulmonary [e.g., by oral or nasal inhalation], buccal, sublingual, rectal [e.g., by suppository], and vaginal [e.g., by suppository]). Topical formulations can be designed to produce a local or systemic therapeutic effect. [00100] As an example, formulations of an Akt inhibitor or PDPK1 inhibitor suitable for oral administration can be presented in discrete units adapted for instant, controlled or sustained release as, e.g., boluses; capsules (including push-fit capsules and soft capsules), tablets, pills, cachets or lozenges; as powders or granules; as semisolids, electuaries, pastes or gels; as solutions or suspensions in an aqueous liquid or/and a non-aqueous liquid; or as oil-in-water liquid emulsions or water-in-oil liquid emulsions. [00101] Push-fit capsules or two-piece hard gelatin capsules can contain an Akt inhibitor or PDPK1 inhibitor in admixture with, e.g., a filler or inert solid diluent (e.g., calcium carbonate, calcium phosphate, kaolin or lactose), a binder (e.g., a starch), a glidant or lubricant (e.g., talc or magnesium stearate), and a disintegrant (e.g., crospovidone), and optionally a stabilizer or/and a preservative. For soft capsules or single-piece gelatin capsules, an Akt inhibitor or PDPK1 inhibitor can be dissolved or suspended in a suitable liquid (e.g., liquid polyethylene glycol or an oil medium, such as a fatty oil, peanut oil, olive oil or liquid paraffin), and the liquid-filled capsules can contain one or more other liquid excipients or/and semi-solid excipients, such as a stabilizer or/and an amphiphilic agent (e.g., a fatty acid ester of glycerol, propylene glycol or sorbitol). [0102] Tablets can contain an Akt inhibitor or PDPK1 inhibitor in admixture with, e.g., a filler or inert diluent (e.g., calcium carbonate, calcium phosphate, lactose, mannitol or microcrystalline cellulose), a binding agent (e.g., a starch, gelatin, acacia, alginic acid or a salt thereof, or microcrystalline cellulose), a lubricating agent (e.g., stearic acid, magnesium stearate, talc or silicon dioxide), and a disintegrating agent (e.g., crospovidone, croscarmellose sodium or colloidal silica), and optionally a surfactant (e.g., sodium lauryl sulfate). The tablets can be uncoated or can be coated with, e.g., an enteric coating that protects the active ingredient from the acidic environment of the stomach, or with a material that delays disintegration and absorption of the active ingredient in the gastrointestinal tract and thereby provides a sustained action over a longer time period. [0103] Compositions for oral administration can also be formulated as solutions or suspensions in an aqueous liquid or/and a non-aqueous liquid, or as oil-in-water liquid emulsions or water-in- oil liquid emulsions. Dispersible powder or granules of an Akt inhibitor or PDPK1 inhibitor can be mixed with any suitable combination of an aqueous liquid, an organic solvent or/and an oil and any suitable excipients (e.g., any combination of a dispersing agent, a wetting agent, a suspending agent, an emulsifying agent or/and a preservative) to form a solution, suspension or emulsion. [0104] An Akt inhibitor or PDPK1 inhibitor can also be formulated for parenteral administration by injection or infusion to circumvent gastrointestinal absorption and first-pass metabolism. An exemplary parenteral route is intravenous. Additional advantages of intravenous administration include direct administration of a therapeutic agent into systemic circulation to achieve a rapid systemic effect, and the ability to administer the agent continuously or/and in a large volume if desired. Formulations for injection or infusion can be in the form of, e.g., solutions, suspensions or emulsions in oily or aqueous vehicles, and can contain excipients such as suspending agents, dispersing agents or/and stabilizing agents. For example, aqueous or non-aqueous (e.g., oily) sterile injection solutions can contain an Akt inhibitor or PDPK1 inhibitor along with excipients such as an antioxidant, a buffer, a bacteriostat and solutes that render the formulation isotonic with the blood of the subject. Aqueous or non-aqueous sterile suspensions can contain an Akt inhibitor or PDPK1 inhibitor along with excipients such as a suspending agent and a thickening agent, and optionally a stabilizer and an agent that increases the solubility of the Akt inhibitor or PDPK1 inhibitor to allow for the preparation of a more concentrated solution or suspension. As another example, a sterile aqueous solution for injection or infusion (e.g., subcutaneously or intravenously) can contain an Akt inhibitor or PDPK1 inhibitor, an isotonic agent (e.g., sodium chloride), a buffering agent (e.g., sodium citrate), a preservative (e.g., meta-cresol), and optionally a base (e.g., NaOH) or/and an acid (e.g., HCl) to adjust pH. [0105] Topical formulations for application to the skin or mucosa can be useful for transdermal or transmucosal administration of a therapeutic agent to the local target site of action, or into the blood for systemic distribution. Advantages of topical administration can include circumvention of the gastrointestinal tract (including enzymes and acid in the gastrointestinal tract and absorption through it) and first-pass metabolism; delivery of a therapeutic agent with a short half-life, a small therapeutic index or/and low oral bioavailability; controlled, continuous and sustained release of the therapeutic agent; a more uniform plasma level or delivery profile of the therapeutic agent; lower dose and less frequent dosing of the therapeutic agent; reduction of systemic side effects (e.g., side effects caused by a temporary overdose or an overly high peak plasma drug concentration); minimal or no invasiveness; ease of self-administration; and increased patient compliance. For purposes of the content of a pharmaceutical composition, the term “therapeutic agent”, “active agent”, “drug” or the like encompasses a prodrug. [0106] Compositions suitable for topical administration include without limitation liquid or semi-liquid preparations such as sprays, gels, liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, foams, ointments and pastes, and solutions or suspensions such as drops (e.g., eye drops, nose drops and ear drops). See Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania [2005]). Various excipients can be included in a topical formulation. For example, solvents, including a suitable amount of an alcohol, can be used to solubilize the active agent. Other optional excipients include without limitation gelling agents, thickening agents, emulsifiers, surfactants, stabilizers, buffers, antioxidants, preservatives, cooling agents (e.g. menthol), opacifiers, fragrances and colorants. For an active agent having a low rate of permeation through the skin or mucosal tissue, a topical formulation can contain a chemical permeation enhancer (e.g., a fatty acid ester, a fatty acid or an alcohol) to increase the permeation of the active agent through the skin or mucosal tissue. A topical formulation can also contain an irritation-mitigating excipient that reduces any irritation to the skin or mucosa caused by the active agent, the chemical permeation enhancer or any other component of the formulation. In some embodiments, a topical composition comprises a therapeutic agent dissolved, dispersed or suspended in a carrier. The carrier can be in the form of, e.g., a solution, a suspension, an emulsion, an ointment or a gel base, and can contain, e.g., petrolatum, lanolin, a wax (e.g., bee wax), mineral oil, a long-chain alcohol, polyethylene glycol or polypropylene glycol, a diluent (e.g., water or/and an alcohol [e.g., ethanol or propylene glycol]), a gel, an emulsifier, a thickening agent, a stabilizer or a preservative, or any combination thereof. A topical formulation can be administered by means of, e.g., a transdermal or transmucosal delivery device, such as a transdermal patch, a microneedle patch or an iontophoresis device. A topical composition can deliver a drug transdermally or transmucosally via a concentration gradient (with or without the use of a chemical permeation enhancer) or an active mechanism (e.g., iontophoresis or microneedles). [0107] For topical administration, an Akt inhibitor or PDPK1 inhibitor can be formulated as, e.g., a buccal or sublingual tablet or pill. Advantages of a buccal or sublingual tablet or pill include avoidance of gastrointestinal absorption and first-pass metabolism, and rapid absorption into systemic circulation. A buccal or sublingual tablet or pill can be designed to provide faster release of the Akt inhibitor or PDPK1 inhibitor for more rapid uptake of it into systemic circulation. In addition to a therapeutically effective amount of an Akt inhibitor or PDPK1 inhibitor, the buccal or sublingual tablet or pill can contain suitable excipients, including without limitation any combination of fillers and diluents (e.g., mannitol and sorbitol), binding agents (e.g., sodium carbonate), wetting agents (e.g., sodium carbonate), disintegrants (e.g., crospovidone and croscarmellose sodium), lubricants (e.g., silicon dioxide [including colloidal silicon dioxide] and sodium stearyl fumarate), stabilizers (e.g., sodium bicarbonate), flavoring agents (e.g., spearmint flavor), sweetening agents (e.g., sucralose), and coloring agents (e.g., yellow iron oxide). [0108] For topical administration, an Akt inhibitor or PDPK1 inhibitor can also be formulated for intranasal administration, which may be advantageous for treating a medical condition involving the nasal cavity, such as a viral infection. The nasal mucosa provides a big surface area, a porous endothelium, a highly vascular subepithelial layer and a high absorption rate, and hence allows for high bioavailability. Moreover, intranasal administration avoids first-pass metabolism and can introduce a significant concentration of the active agent to the CNS. An intranasal formulation can comprise an Akt inhibitor or PDPK1 inhibitor along with excipients, such as a solubility enhancer (e.g., propylene glycol), a humectant (e.g., mannitol or sorbitol), a buffer and water, and optionally a preservative (e.g., benzalkonium chloride), a mucoadhesive agent (e.g., hydroxyethylcellulose) or/and a penetration enhancer. An intranasal solution or suspension formulation can be administered to the nasal cavity by any suitable means, including but not limited to a dropper, a pipette, or a spray using, e.g., a metering atomizing spray pump. Table 1 shows exemplary excipients of nasal-spray formulations. [0109] An additional route of topical administration of an Akt inhibitor or PDPK1 inhibitor is pulmonary, which may be advantageous for treating a medical condition involving the lungs, such as a viral infection in the lower airways. Pulmonary administration can be achieved by oral inhalation or nasal inhalation. A pulmonarily administered drug can treat a lung disorder or/and a systemic disorder, as the lungs serve as a portal to the systemic circulation. Advantages of pulmonary drug delivery include, for example: 1) avoidance of first-pass metabolism; 2) fast drug action; 3) large surface area of the alveolar region for absorption, high permeability of the lungs (thin air-blood barrier), and profuse vasculature of the airways; 4) reduced extracellular enzyme levels compared to the GI tract due to the large alveolar surface area; and 5) smaller doses to achieve equivalent therapeutic effect compared to other oral routes, and hence reduced systemic side effects. Oral inhalation can also enable more rapid action of a drug in the CNS. An advantage of oral inhalation over nasal inhalation includes deeper penetration/deposition of the drug into the lungs, although nasal inhalation can deliver the drug into systemic circulation transmucosally in the nasal cavity as well as in the lungs. Oral or nasal inhalation can be achieved by means of, e.g., a metered-dose inhaler (MDI), a dry powder inhaler (DPI) or a nebulizer, as is known in the art. In certain embodiments, a sterile aqueous solution for oral inhalation contains an Akt inhibitor or PDPK1 inhibitor, sodium chloride, a buffering agent (e.g., sodium citrate), optionally a preservative (e.g., meta-cresol), and optionally a base (e.g., NaOH) or/and an acid (e.g., HCl) to adjust pH. Table 1 shows other exemplary excipients of oral- inhalation formulations. [0110] Table 1. Exemplary excipients and carriers of pulmonary and nasal formulations

[0111] In some embodiments, an Akt inhibitor or PDPK1 inhibitor is administered transdermally. In certain embodiments, the topical composition or transdermal delivery system comprises a chemical permeation enhancer (e.g., a surfactant [e.g., sodium laureth sulfate], optionally in combination with an aromatic compound [e.g., phenylpiperazine]) that facilitates the transport of the Akt inhibitor or PDPK1 inhibitor across the skin. In further embodiments, the Akt inhibitor or PDPK1 inhibitor is administered via a transdermal patch. In certain embodiments, the transdermal patch is a reservoir-type patch comprising an impermeable backing layer/film, a liquid- or gel-based drug reservoir, a semi-permeable membrane that serves as a rate-limiting or rate-controlling diffusion barrier, and a skin-contacting adhesive layer. The semi-permeable membrane can be composed of, e.g., a suitable polymeric material such as cellulose nitrate or acetate, polyisobutene, polypropylene, polyvinyl acetate or a polycarbonate. In other embodiments, the transdermal patch is a drug-in-adhesive patch comprising an impermeable backing layer/film and a skin-contacting adhesive layer incorporating the drug in a polymeric or viscous adhesive. The adhesive of the drug-loaded, skin-contacting adhesive layer can be, e.g., a pressure-sensitive adhesive (PSA), such as a PSA composed of an acrylic polymer (e.g., polyacrylate), a polyalkylene (e.g., polyisobutylene) or a silicone-based polymer (e.g., silicone-2675 or silicone-2920). Transdermal drug-delivery systems, including patches, can be designed to provide controlled and prolonged release of a drug over a period of about 1 week, 2 weeks, 3 weeks, 1 month or longer. WO 1993/003696 and US Pat. Nos. 3,598,122; 4,144,317; 4,201,211; 4,262,003 and 4,379,454 describe various transdermal drug-delivery systems, including patches, which can deliver a controlled amount of a drug for an extended period of time ranging from several hours to several days. Such systems can be adapted for transdermal delivery of an Akt inhibitor or PDPK1 inhibitor. [0112] Topical administration of an Akt inhibitor or PDPK1 inhibitor may be particularly advantageous for treatment of a medical condition involving the skin or a mucosa. For example, a topical composition (e.g., a gel, ointment or cream) or a transdermal patch containing an Akt inhibitor or PDPK1 inhibitor can be applied to the penis, or a topical composition (e.g., a gel, ointment or cream) or a suppository containing an Akt inhibitor or PDPK1 inhibitor can be applied to the vagina, for treatment of a genital viral (e.g., HSV-1 or HSV-2) infection. [0113] In some embodiments, an Akt inhibitor or PDPK1 inhibitor is delivered from a sustained-release composition. As used herein, the term “sustained-release composition” encompasses sustained-release, prolonged-release, extended-release, delayed-release, slow- release and controlled-release compositions, systems and devices. Advantages of a sustained- release composition include without limitation a more uniform blood level of the drug (e.g., avoidance of wide peak-to-trough fluctuations), delivery of a therapeutically effective amount of the drug over a prolonged time period, reduced frequency of administration, and reduced side effects (e.g., avoidance of a drug overdose). In some embodiments, the sustained-release composition delivers the Akt inhibitor or PDPK1 inhibitor over a period of at least about 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks or 4 weeks (1 month). [0114] In some embodiments, the sustained-release composition is a drug-encapsulation system, such as nanoparticles, microparticles or a capsule made of, e.g., a biodegradable polymer or/and a hydrogel. In certain embodiments, the sustained-release composition comprises a hydrogel. Non-limiting examples of polymers of which a hydrogel can be composed include polyvinyl alcohol, acrylate polymers (e.g., sodium polyacrylate), and other homopolymers and copolymers having a relatively large number of hydrophilic groups (e.g., hydroxyl or/and carboxylate groups). In other embodiments, the sustained-release drug-encapsulation system comprises a membrane-enclosed reservoir, wherein the reservoir contains a drug and the membrane is permeable to the drug. Such a drug-delivery system can be in the form of, e.g., a transdermal patch. [0115] In certain embodiments, the sustained-release composition is formulated as polymeric nanoparticles or microparticles, wherein the polymeric particles can be delivered, e.g., by injection or from an implant. In some embodiments, the polymeric implant or polymeric nanoparticles or microparticles are composed of a biodegradable polymer. In certain embodiments, the biodegradable polymer comprises lactic acid or/and glycolic acid [e.g., an L- lactic acid-based copolymer, such as poly(L-lactide-co-glycolide) or poly(L-lactic acid-co-D,L- 2-hydroxyoctanoic acid)]. For example, biodegradable polymeric microspheres composed of polylactic acid or/and polyglycolic acid can serve as sustained-release pulmonary drug-delivery systems. The biodegradable polymer of the polymeric implant or polymeric nanoparticles or microparticles can be selected so that the polymer substantially completely degrades around the time the period of treatment is expected to end, and so that the byproducts of the polymer’s degradation, like the polymer, are biocompatible. [0116] In further embodiments, a sustained-release composition comprises a dendrimer. In certain embodiments, the dendrimer is a water-soluble dendrimer, such as a poly(amidoamine) (PAMAM) dendrimer. In some embodiments, a dendrimer encapsulates a drug through the formation of a dendrimer-drug supramolecular assembly. In other embodiments, a sustained- release composition comprises a water-soluble polymer [e.g., poly(DL-lactide)] or a liposome encapsulating a drug complexed with a dendrimer. [0117] In other embodiments, the sustained-release composition is an oral dosage form, such as a tablet or capsule. For example, a drug can be embedded in an insoluble porous matrix such that the dissolving drug must make its way out of the matrix before it can be absorbed through the gastrointestinal tract. Alternatively, a drug can be embedded in a matrix that swells to form a gel through which the drug exits. Sustained release can also be achieved by way of a single- layer or multi-layer osmotic controlled-release oral delivery system (OROS). An OROS is a tablet with a semi-permeable outer membrane and one or more small laser-drilled holes in it. As the tablet passes through the body, water is absorbed through the semi-permeable membrane via osmosis, and the resulting osmotic pressure pushes the drug out through the hole(s) in the tablet and into the gastrointestinal tract where it can be absorbed. [0118] For a delayed or sustained release of an Akt inhibitor or PDPK1 inhibitor, a composition can also be formulated as, e.g., a depot that can be implanted in or injected into a subject, e.g., intramuscularly, intracutaneously or subcutaneously. A depot formulation can be designed to deliver the Akt inhibitor or PDPK1 inhibitor over an extended period of time, e.g., over a period of at least about 1 week, 2 weeks, 3 weeks or 1 month. For example, an Akt inhibitor or PDPK1 inhibitor can be formulated with a polymeric material (e.g., polyethylene glycol [PEG], polylactic acid [PLA] or polyglycolic acid [PGA], or a copolymer thereof [e.g., PLGA or PLA-PEG]), with a hydrophobic material (e.g., as an emulsion in an oil) and/or an ion- exchange resin, as a more lipophilic derivative (e.g., as an ester of or a salt with a fatty acid such as a C8-C20 fatty acid [e.g., decanoic acid]), or as a sparingly soluble derivative (e.g., a sparingly soluble salt). As an illustrative example, an Akt inhibitor or PDPK1 inhibitor can be incorporated or embedded in sustained-release microparticles composed of PLGA and formulated as a monthly depot. [0119] An Akt inhibitor or PDPK1 inhibitor can also be contained or dispersed in a matrix material. The matrix material can comprise a polymer (e.g., ethylene-vinyl acetate) and controls the release of the compound by controlling dissolution and/or diffusion of the compound from, e.g., a reservoir, and can enhance the stability of the compound while contained in the reservoir. Such a release system can be designed as a sustained-release system, can be configured as, e.g., a transdermal or transmucosal patch, and can contain an excipient that can accelerate the compound’s release, such as a water-swellable material (e.g., a hydrogel) that aids in expelling the compound out of the reservoir. US Pat. Nos.4,144,317 and 5,797,898 describe examples of such a release system. [0120] In addition, pharmaceutical compositions comprising an Akt inhibitor or PDPK1 inhibitor can be formulated as, e.g., liposomes, micelles (e.g., those composed of biodegradable natural or/and synthetic polymers, such as lactosomes), nanoparticles (e.g., lipid nanoparticles such as solid lipid nanoparticles), microparticles or microspheres, whether or not designed for sustained release. In some embodiments, liposomes or micelles are composed of one or more phospholipids, such as phosphatidylcholines. Liposomes and micelles can provide sustained release of a drug based in part on the rate of degradation of the liposomes and micelles. For example, liposomes can be used as sustained‐release pulmonary drug-delivery systems that deliver drugs to the alveolar surface for treatment of lung disorders and systemic disorders. As another example, lipid nanoparticles containing a lipophilic drug can be delivered into the lungs by oral inhalation for treatment of a lung disorder or a systemic disorder. [0121] The pharmaceutical compositions can be manufactured in any suitable manner known in the art, such as by means of conventional mixing, dissolving, suspending, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or compressing processes, or any combination thereof. [0122] The compositions can be presented in unit dosage form as a single dose wherein all active and inactive ingredients are combined in a suitable system, and components do not need to be mixed to form the composition to be administered. A unit dosage form generally contains a therapeutically effective dose of the drug, but can contain an appropriate fraction thereof so that taking multiple unit dosage forms achieves the therapeutically effective dose. Examples of a unit dosage form include a tablet, capsule, or pill for oral uptake; a solution in a pre-filled syringe of a single-use pen or a pen with a dose counter for parenteral (e.g., intravenous, subcutaneous or intramuscular) injection; a capsule, cartridge or blister pre-loaded in or manually loaded into an inhaler; and a reservoir-type transdermal patch or a drug-in-adhesive patch. [0123] Alternatively, the compositions can be presented as a kit in which the active ingredient, excipient(s) and carrier(s) [e.g., solvent(s)] are provided in two or more separate containers (e.g., ampules, vials, tubes, bottles or syringes) and need to be combined to form the composition to be administered. The kit can contain instructions for storing, preparing and administering the composition (e.g., a solution to be injected parenterally). [0124] A kit can contain all active and inactive ingredients in unit dosage form or the active ingredient and inactive ingredients in two or more separate containers, and can contain instructions for administering or using the pharmaceutical composition to treat a medical condition. A kit can further contain a device for delivering the composition, such as a needle and a syringe, an injection pen, an inhaler or a transdermal patch. [0125] In some embodiments, a kit contains an Akt inhibitor or PDPK1 inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof, or a pharmaceutical composition comprising the same, and instructions for administering or using the Akt inhibitor or PDPK1 inhibitor or the composition to treat a medical condition. In certain embodiments, the kit further contains a device for delivering the Akt inhibitor or PDPK1 inhibitor or the composition, such as an injection pen, an inhaler or a transdermal patch. Therapeutic Uses of Cell-Impermeable Akt inhibitors and PDPK1 inhibitors [0126] The cell membrane-impermeable Akt inhibitors and PDPK1 inhibitors described herein can be used to treat medical conditions in which extracellular activated Akt or/and PDPK1 (e.g., on the cell surface or the outer leaflet of the plasma membrane) play(s) a role. In some embodiments, a cell-impermeable Akt inhibitor or/and a cell-impermeable PDPK1 inhibitor is/are used to inhibit or treat a tumor or cancer. In some embodiments, the tumor or cancer is characterized by abnormally elevated activity of the PI3K/Akt/mTOR signaling pathway. [0127] Non-limiting examples of tumors and cancers that can be treated with an Akt inhibitor or/and a PDPK1 inhibitor include solid tumors and cancers, breast cancer (e.g., breast carcinoma), cervical cancer, ovarian cancer (e.g., ovarian carcinoma and granulosa cell tumors such as juvenile granulosa cell tumors), fallopian tube cancer, peritoneal cancer (e.g., peritoneal carcinoma), gastric cancer (e.g., gastric adenocarcinoma), colorectal cancer (e.g., colorectal carcinoma), pancreatic cancer, kidney cancer (e.g., renal cell carcinoma [RCC]), liver cancer (e.g., hepatocellular carcinoma [HCC]), prostate cancer (e.g., prostate carcinoma), urothelial cancer, nasopharyngeal cancer (e.g., nasopharyngeal carcinoma), lung cancer (e.g., non-small cell lung cancer), skin cancer (e.g., melanoma), brain tumors and cancers (e.g., glioblastoma), other tumors and cancers of the nervous system (e.g., glioma, neuroblastoma and neuroendocrine tumors), tumor and cancer syndromes (e.g., Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease and Proteus syndrome), and tumors and cancers of the hematopoietic tissues/blood system and the lymphoid tissues/lymphatic system {e.g., leukemias (e.g., chronic lymphocytic leukemia/small lymphocytic lymphoma [CLL/SLL]) and lymphomas including non-Hodgkin lymphomas (e.g., diffuse large B-cell lymphoma [DLBCL] and follicular lymphoma)}. In some embodiments, the tumor or cancer is a solid tumor or cancer, breast cancer, ovarian cancer, gastric cancer, pancreatic cancer, prostate cancer, skin cancer or glioblastoma. [0128] In some embodiments, a cell-impermeable Akt inhibitor or/and a cell-impermeable PDPK1 inhibitor is/are used in combination with one or more additional anti-tumor/cancer agents to treat a tumor or cancer. In some embodiments, the one or more additional anti- tumor/cancer agents comprise a PI3K inhibitor, an mTOR inhibitor or a phospholipid scramblase inhibitor (e.g., R5421), or any combination or all thereof. Non-limiting examples of PI3K inhibitors include buparlisib, copanlisib, duvelisib, gedatolisib, idelalisib and pictilisib. Non- limiting examples of mTOR inhibitors include first-generation mTOR inhibitors (e.g., rapamycin [sirolimus], everolimus, ridaforolimus, temsirolimus, umirolimus and zotarolimus) and dual mTORC1/mTORC2 inhibitors (e.g., sapanisertib, torin-1, torin-2, vistusertib, AZD2014 and AZD8055). Non-limiting examples of dual PI3K/mTOR inhibitors include apitolisib, dactolisib, voxtalisib, BGT226, NVPBE235, PKI-587 and SF1126. [0129] In other embodiments, a cell-impermeable Akt inhibitor or/and a cell-impermeable PDPK1 inhibitor is/are used to inhibit or treat a viral infection. In some embodiments, the mechanism of cell entry by the virus involves binding of the virus to the cell surface which results in translocation of Akt, and potentially other proteins such as PDPK1, from the inner leaflet of the plasma membrane to the outer leaflet of the PM. [0130] In some embodiments, the virus is a herpesvirus, a coronavirus (e.g., SARS-CoV-1, SARS-CoV-2 or MERS-CoV), a human immunodeficiency virus (e.g., HIV-1 or HIV-2), an Ebolavirus (e.g., Zaire ebolavirus), or a Flavivirus (e.g., Dengue virus). In some embodiments, the virus is a herpesvirus. Herpesviruses that cause diseases in humans include herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), Varicella zoster virus (VZV) Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), human betaherpesvirus 6A (HHV-6A), human betaherpesvirus 6B (HHV-6B), human betaherpesvirus 7 (HHV-7), and Kaposi’s sarcoma- associated herpesvirus (KSHV). In certain embodiments, the herpesvirus is HSV-1 or HSV-2. In other embodiments, the herpesvirus is an alphaherpesvirus that causes a disease in animals, such as a pseudorabies virus (e.g., suid herpesvirus 1) or a bovine herpesvirus (e.g., bovine herpesvirus 1). [0131] In some embodiments, the subject has a latent viral (e.g., herpesvirus) infection. In further embodiments, the subject has a viral (e.g., herpesvirus) infection which is resistant to aciclovir or/and valaciclovir. Treatment with an Akt inhibitor or/and a PDPK1 inhibitor may reduce resistance to aciclovir or/and valaciclovir. [0132] In some embodiments, a cell-impermeable Akt inhibitor or/and a cell-impermeable PDPK1 inhibitor is/are used in combination with one or more additional antiviral agents to treat a viral infection. In some embodiments, the one or more additional antiviral agents comprise an inhibitor of viral DNA replication (e.g., aciclovir or valaciclovir) or viral RNA replication, or/and a phospholipid scramblase inhibitor (e.g., R5421). [0133] The therapeutically effective amount and frequency of administration of a cell- impermeable Akt inhibitor or PDPK1 inhibitor may depend on various factors, including the medical condition being treated, the severity of the condition, the potency of the compound, the route of administration, the age, body weight, general health, gender and diet of the subject, and the response of the subject to the treatment, and can be determined by the treating physician. In some embodiments, the effective dose (e.g., maintenance dose) of an Akt inhibitor or a PDPK1 inhibitor per day is about 1-200 mg, 1-50 mg, 50-100 mg, 100-150 mg or 150-200 mg, or as deemed appropriate by the treating physician, which can be administered in a single dose or in divided doses (e.g., 2, 3 or 4 times daily). In certain embodiments, the effective dose (e.g., maintenance dose) of an Akt inhibitor or a PDPK1 inhibitor per day is about 1-25 mg or 25-50 mg. The dosing frequency may depend on, e.g., the route of administration chosen. For example, dosing by intranasal administration (e.g., by nose drop or spray) or pulmonary administration (e.g., by oral inhalation) may occur more frequently (e.g., 2, 3 or 4 times daily). To more quickly establish a therapeutic level of the Akt inhibitor or the PDPK1 inhibitor, a loading dose of the inhibitor that is greater (e.g., about 2- or 3-fold greater) than the maintenance dose can be administered at the beginning (e.g., in the first three days) of treatment followed by administration of the maintenance dose. [0134] An Akt inhibitor or a PDPK1 inhibitor can be administered via any suitable route, which may depend on, e.g., the medical condition being treated and its location and the pharmacokinetics of the inhibitor. Potential routes of administration of an Akt inhibitor or a PDPK1 inhibitor include without limitation oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intra-arterial, intraperitoneal, intracavitary, intramedullary, intrathecal and topical), and topical (including dermal/epicutaneous, transdermal, mucosal, transmucosal, intranasal [e.g., by nasal spray or drop], ocular/intraocular [e.g., by eye drop], pulmonary [e.g., by oral or nasal inhalation], buccal, sublingual, rectal [e.g., by suppository], and vaginal [e.g., by suppository]). [0135] For treatment of a tumor or cancer, in some embodiments an Akt inhibitor or a PDPK1 inhibitor is administered orally. In other embodiments, an Akt inhibitor or a PDPK1 inhibitor is administered parenterally, such as intravenously, subcutaneously or intramuscularly. [0136] For treatment of a viral infection, in some embodiments an Akt inhibitor or a PDPK1 inhibitor is administered systemically, such as orally or parenterally (e.g., intravenously, subcutaneously or intramuscularly). In other embodiments, an Akt inhibitor or a PDPK1 inhibitor is administered topically to the local site(s) of infection or potential or suspected infection, such as to a mucous membrane (e.g., a mucous membrane in the oral cavity, the nasal cavity, the pharynx or the lungs) or to a surface of a genitalia (e.g., vagina or penis). [0137] The length of treatment with an Akt inhibitor or a PDPK1 inhibitor can be determined by the treating physician to achieve the desired outcome. In some embodiments, an Akt inhibitor or a PDPK1 inhibitor is administered for at least about 1 week, 2 weeks or 3 weeks or 4 weeks (1 month). In other embodiments, an Akt inhibitor or a PDPK1 inhibitor is administered for at least about 6 weeks, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years or longer. Use of Cell-Impermeable Akt Inhibitors and PDPK1 Inhibitors as Research Tools [0138] In addition to therapeutic uses, the cell-impermeable Akt inhibitors and PDPK1 inhibitors described herein can be utilized as research tools in molecular biology or a related field. Accordingly, the disclosure provides a method of inhibiting Akt or PDPK1, comprising contacting a cell with a cell-impermeable Akt inhibitor or a cell-impermeable PDPK1 inhibitor, respectively. In some embodiments, the contacting occurs in vitro. Comparison of the differences in, e.g., the levels of mRNAs, proteins or phosphorylated proteins, or in cellular characteristics and processes, resulting from treatment of the cell with the cell-impermeable Akt inhibitor or PDPK1 inhibitor and from no treatment helps to elucidate the targets of extracellular Akt or PDPK1 kinase activity and the effects of inhibition of Akt or PDPK1 on the cell surface, on the outer leaflet of the plasma membrane or extracellularly. Synthesis of Cell-Impermeable Akt inhibitors and PDPK1 inhibitors [0139] The synthesis of Akt inhibitors of Formula I without a cell-impermeable moiety -L²-Y is described in Heerding et al., J. Med. Chem., 51:5663-5679 (2008). The synthesis of Akt inhibitors of Formula II without a cell-impermeable moiety -L-Y is described in Blake et al., J. Med. Chem., 55:8110-8127 (2012). The synthesis of PDPK1 inhibitors of Formula III without a cell-impermeable moiety -L-Y is described in Nittoli et al., Eur. J. Med. Chem., 45:1379-1386 (2010). [0140] The following scheme shows a general process for adding the cell-impermeable moiety -CH₂S(=O)₂OH or a salt (e.g., sodium salt) thereof to an amine compound:

If one of R₁ and R₂ is hydrogen, the use of about 1.2-1.4 equiv. iodomethansulfonyl fluoride provides the mono-addition product, while the use of about 2.5-3.0 equiv. iodomethanesulfonyl fluoride provides the bis-addition product. [0141] The following scheme shows a general process for adding the cell-impermeable moiety -CH₂CH₂S(=O)₂OH or a salt (e.g., sodium salt) thereof to an amine compound:

If one of R₁ and R₂ is hydrogen, the use of about 1.2-1.4 equiv. ethenesulfonyl fluoride provides the mono-Michael addition product, while the use of about 2.5-3.0 equiv. ethenesulfonyl fluoride provides the bis-Michael addition product. [0142] The following scheme shows a general process for adding the cell-impermeable moiety -CH₂CH₂CH₂S(=O)₂OH or a salt (e.g., sodium salt) thereof to an amine compound:

If one of R1 and R2 is hydrogen, the use of about 1.2-1.4 equiv. methyl 3-bromopropanesulfonate provides the mono-addition product, while the use of about 2.5-3.0 equiv. methyl 3- bromopropanesulfonate provides the bis-addition product. [0143] The following scheme shows a general process for adding a -CH₂CH₂NH₂ group to an amine compound before adding one or more cell-impermeable moieties -(CH₂)_nS(=O)₂OH or a salt (e.g., sodium salt) thereof, where n is 1, 2, 3 or 4:

A -(CH₂)_nS(=O)₂OH moiety, or a salt (e.g., sodium salt) thereof, can optionally be added to the nitrogen atom attached to R¹ in the compound having two such moieties. Boc denotes tert- butyloxycarbonyl. Representative Embodiments [0144] The following embodiments of the disclosure are provided by way of illustration and example: 1. A compound of Formula I or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

wherein: R¹ is -OH, -NH₂, -NHR⁵ or -NHC(=O)R⁵; R² is hydrogen, C_1-4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl or tert-butyl), or cyclopropyl; R³ and R⁴ independently are hydrogen or methyl, or R³ and R⁴ and the carbon atom to which they are attached form a cyclopropyl ring; R⁵ at each occurrence independently is C_1-4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) or cyclopropyl; R⁶ is C_1-6 alkyl, -(C_1-3 alkyl)-(C_3-6 cycloalkyl), -(C_1-3 alkyl)-(3-6-membered heterocyclyl), -(C_1-3 alkyl)-(5- or 6-membered heteroaryl), or -(C_1-3 alkyl)-phenyl, wherein the C_1-6 alkyl, C_1-3 alkyl, cycloalkyl, heterocyclyl, heteroaryl and phenyl independently can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, -CF₃ and -OCF₃; R⁷ is C_1-6 alkyl, -(C_0-3 alkyl)-(C_3-6 cycloalkyl), -(C_0-3 alkyl)-(3-6-membered heterocyclyl), -(C_0-3 alkyl)-(5- or 6-membered heteroaryl), or -(C_0-3 alkyl)-phenyl, wherein the C_1-6 alkyl, C_0-3 alkyl, cycloalkyl, heterocyclyl, heteroaryl and phenyl independently can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, -CF₃ and -OCF₃; X is -CH₂-, -O-, -S-, -NH- or -NR⁵-;

wherein the single asterisk * denotes the site of attachment to X and the amine nitrogen atom is attached to one or two -L²-Y moieties, and wherein each stereocenter independently can have the (R)-stereochemistry or the (S)-stereochemistry or can be racemic; -L²- at each occurrence independently is -(CH₂)_q-; Y at each occurrence independently is -CO₂H, -S(=O)₂OH or -P(=O)(OH)₂, or a salt thereof; m is 2, 3, 4 or 5; n is 1, 2, 3 or 4; p is 1 or 2; and q is 1, 2, 3 or 4. 2. The compound of embodiment 1, wherein R¹ is -OH, -NH₂, -NHCH₃ or -NHC(=O)CH₃. 3. The compound of embodiment 2, wherein R¹ is -NH₂. 4. The compound of any one of the preceding embodiments, wherein R² is methyl or ethyl. 5. The compound of any one of the preceding embodiments, wherein: (a) R³ is hydrogen and R⁴ is methyl; (b) R³ is methyl and R⁴ is hydrogen; (c) both R³ and R⁴ are hydrogen; or (d) both R³ and R⁴ are methyl. 6. The compound of embodiment 5, wherein both R³ and R⁴ are hydrogen, or both R³ and R⁴ are methyl. 7. The compound of any one of the preceding embodiments, wherein X is O. 8. The compound of any one of the preceding embodiments, wherein -L¹-NH/NR⁶/N- is - (CH₂)_m-NH/N- and m is 2, 3 or 4. 9. The compound of any one of the preceding embodiments, wherein -L²- is -CH₂CH₂- or - CH₂CH₂CH₂-. 10. The compound of any one of the preceding embodiments, wherein Y is -S(=O)₂OH or a salt (e.g., sodium salt or inner salt) thereof. 11. The compound of any one of the preceding embodiments, wherein p is 1. 12. The compound of any one of embodiments 1 to 10, wherein p is 2 and -L²-Y is the same at both occurrences. 13. The compound of any one of the preceding embodiments, which has Formula Ia or is a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

wherein: both R³ and R⁴ are hydrogen, or both R³ and R⁴ are methyl; -L²-Y is -CH₂CH₂S(=O)₂OH or -CH₂CH₂CH₂S(=O)₂OH, or a salt (sodium salt or inner salt) thereof; m is 2, 3 or 4; and p is 1 or 2. 14. The compound of any one of the preceding embodiments, which is one of the following compounds or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

wherein a stereocenter marked by an asterisk * in the compounds above can have the (S)- stereochemistry or the (R)-stereochemistry or can be racemic. 15. A compound of Formula II or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

wherein: X is -NR⁴-L-Y or -NR⁴-(CH₂)_m-NH/N-(L-Y)_n; R¹ and R² independently are hydrogen, halide, cyano, -CH₃, -CH₂CH₃, -CF₃, -OCH₃ or - OCF₃, wherein at least one of R¹ and R² is not hydrogen; R³ is hydrogen, or R³ and -NR⁴- and the carbon atom to which they are attached form a 5- or 6-membered heterocyclic ring (e.g., pyrrolidine, piperidine, piperazine or morpholine) which can optionally be substituted with -F, -Cl, -CH₃, -OH or -OCH₃; R⁴ is hydrogen, -L-Y, C_1-4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), C_3-6 cycloalkyl or 3-6-membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, -OH, C_1-4 alkyl, C_1-4 alkoxy, C_3-6 cycloalkyl and 3-6- membered heterocyclyl, or -NR⁴- and R³ and the carbon atom to which they are attached form a 5- or 6-membered heterocyclic ring which can optionally be substituted with -F, -Cl, -CH₃, -OH or -OCH₃; -L- at each occurrence independently is -(CH₂)_q-; Y at each occurrence independently is -CO₂H, -S(=O)₂OH or -P(=O)(OH)₂, or a salt thereof; m is 2, 3 or 4; n is 1 or 2; and q is 1, 2, 3 or 4. 16. The compound of embodiment 15, wherein the phenyl (Ph) ring is 3-F-Ph, 3-Cl-Ph, 3- CF₃-Ph, 4-F-Ph, 4-Cl-Ph, 4-CF₃-Ph, 3,4-F₂-Ph, 3,4-Cl₂-Ph, 3,4-(CF₃)₂-Ph, 3-F-4-Cl-Ph, 3-F-4- CF₃-Ph, 3-Cl-4-F-Ph, 3-Cl-4-CF₃-Ph, 3-CF₃-4-F-Ph or 3-CF₃-4-Cl-Ph. 17. The compound of embodiment 15 or 16, wherein R³ is hydrogen. 18. The compound of any one of embodiments 15 to 17, wherein R⁴ is hydrogen, - CH₂CH₂S(=O)₂OH or -CH₂CH₂CH₂S(=O)₂OH or a salt thereof, isopropyl, isobutyl, sec-butyl, tert-butyl, -CH₂CH₂F, -CH₂CH₂Cl, -CH₂CH₂OH, -CH₂CH₂-OCH₃, -CH(CH₃)CH₂OH, - CH(CH₃)CH₂OCH₃, -C(CH₃)₂CH₂OH, -C(CH₃)₂CH₂OCH₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl-OH (e.g., trans 1,3-N-cyclopentyl-OH), cyclopentyl-OCH₃ (e.g., trans 1,3-N-cyclopentyl-OCH₃), cyclohexyl-OH (e.g., trans 1,4-N-cyclohexyl-OH), cyclohexyl-OCH₃ (e.g., trans 1,4-N-cyclohexyl-OCH₃), tetrahydrofuranyl (e.g., 3- tetrahydrofuranyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), -CH₂-cyclopropyl, -CH₂- cyclobutyl, -CH₂-cyclopentyl, -CH₂-cyclohexyl, -CH₂-tetrahydrofuranyl (e.g., -CH₂-3- tetrahydrofuranyl), or -CH₂-tetrahydropyranyl (e.g., -CH₂-4-tetrahydropyranyl), or -NR⁴- and R³ and the carbon atom to which they are attached form a pyrrolidine, piperidine, piperazine [with, e.g., -N(CH₃)- or -N(acetyl)-] or morpholine ring which can optionally be substituted with -F, - Cl, -CH₃, -OH or -OCH₃, wherein if a ring has a stereocenter, the stereocenter can have the (S)- stereochemistry or the (R)-stereochemistry or can be racemic. 19. The compound of any one of embodiments 15 to 18, wherein L is -CH₂CH₂- or - CH₂CH₂CH₂-. 20. The compound of any one of embodiments 15 to 19, wherein Y is -S(=O)₂OH or a salt (e.g., sodium salt or inner salt) thereof. 21. The compound of any one of embodiments 15 to 20, wherein if -L-Y occurs more than once, -L-Y is the same at all occurrences. 22. The compound of any one of embodiments 15 to 21, wherein m is 2. 23. The compound of any one of embodiments 15 to 22, which has Formula IIa or is a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

wherein: X is -NR⁴-L-Y or -NR⁴-(CH₂)₂-NH/N-(L-Y)_n; R³ is hydrogen, or R³ and -NR⁴- and the carbon atom to which they are attached form a pyrrolidine, piperidine, piperazine [with, e.g., -N(CH₃)- or -N(acetyl)-] or morpholine ring which can optionally be substituted with -F, -Cl, -CH₃, -OH or -OCH₃; R⁴ is hydrogen, -CH₂CH₂S(=O)₂OH or -CH₂CH₂CH₂S(=O)₂OH or a salt thereof, isopropyl, isobutyl, sec-butyl, tert-butyl, -CH₂CH₂F, -CH₂CH₂Cl, -CH₂CH₂OH, -CH₂CH₂- OCH₃, -CH(CH₃)CH₂OH, -CH(CH₃)CH₂OCH₃, -C(CH₃)₂CH₂OH, -C(CH₃)₂CH₂OCH₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl-OH (e.g., trans 1,3-N-cyclopentyl- OH), cyclopentyl-OCH₃ (e.g., trans 1,3-N-cyclopentyl-OCH₃), cyclohexyl-OH (e.g., trans 1,4- N-cyclohexyl-OH), cyclohexyl-OCH₃ (e.g., trans 1,4-N-cyclohexyl-OCH₃), tetrahydrofuranyl (e.g., 3-tetrahydrofuranyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), -CH₂-cyclopropyl, - CH₂-cyclobutyl, -CH₂-cyclopentyl, -CH₂-cyclohexyl, -CH₂-tetrahydrofuranyl (e.g., -CH₂-3- tetrahydrofuranyl), or -CH₂-tetrahydropyranyl (e.g., -CH₂-4-tetrahydropyranyl), or -NR⁴- and R³ and the carbon atom to which they are attached form a pyrrolidine, piperidine, piperazine [with, e.g., -N(CH₃)- or -N(acetyl)-] or morpholine ring which can optionally be substituted with -F, - Cl, -CH₃, -OH or -OCH₃, wherein if a ring has a stereocenter, the stereocenter can have the (S)- stereochemistry or the (R)-stereochemistry or can be racemic; -L-Y is -CH₂CH₂S(=O)₂OH or -CH₂CH₂CH₂S(=O)₂OH, or a salt (e.g., sodium salt or inner salt) thereof; and n is 1 or 2. 24. The compound of any one of embodiments 15 to 23, which is one of the following compounds or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

wherein a stereocenter marked by an asterisk * in the compounds above can have the (S)- stereochemistry or the (R)-stereochemistry or can be racemic. 25. A compound of Formula III or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

wherein: R¹ and R² independently are hydrogen, halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, - CF₃ or -OCF₃; R³ is hydrogen, C_1-6 alkyl (e.g., methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl), C_3-6 cycloalkyl, -(C_1-3 alkyl)-(C_3-6 cycloalkyl), -(C_1-3 alkyl)-phenyl or -C(=O)R⁴, wherein the phenyl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, -CF₃ and -OCF₃; R⁴ is C_1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n-pentyl or n-hexyl), C_3-6 cycloalkyl or phenyl, wherein the phenyl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, -CF₃ and -OCF₃; R⁵ is C_1-4 alkyl (e.g., methyl, ethyl, n-propyl or n-butyl); R⁶ is hydrogen, C_1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl or n-hexyl), cycloalkyl (e.g., C_3-6 cycloalkyl), heterocyclyl (e.g., 3-6- membered heterocyclyl), aryl (e.g., 6-10-membered aryl), heteroaryl (e.g., 5-10-membered heteroaryl), -(C_1-3 alkyl)-(C_3-6 cycloalkyl), -(C_1-3 alkyl)-(3-6-membered heterocyclyl), -(C_1-3 alkyl)-phenyl, or -(C_1-3 alkyl)-(5-9-membered heteroaryl), wherein the aryl, heteroaryl and phenyl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, -CF₃ and -OCF₃; X is -CH₂-, -O-, -S-, -NH- or -NR⁵-; -L- at each occurrence independently is -(CH₂)_q-; Y at each occurrence independently is -CO₂H, -S(=O)₂OH or -P(=O)(OH)₂, or a salt thereof; m is 1, 2 or 3; n is 1 or 2; q is 1, 2, 3 or 4; and the stereocenter marked by an asterisk * in Formula III can have the (S)-stereochemistry or the (R)-stereochemistry or can be racemic. 26. The compound of embodiment 25, wherein both R¹ and R² are -OCH₃. 27. The compound of embodiment 25 or 26, wherein R³ is hydrogen, -CH₃ or -C(=O)CH₃. 28. The compound of embodiment 27, wherein R³ is hydrogen. 29. The compound of any one of embodiments 25 to 28, wherein X is O. 30. The compound of any one of embodiments 25 to 29, wherein m is 1. 31. The compound of any one of embodiments 25 to 30, wherein R⁶ is hydrogen, methyl, ethyl, n-propyl, n-butyl, isobutyl, -CH₂-phenyl, -CH₂-2-pyridyl, -CH₂-3-pyridyl, -CH₂-4-pyridyl, or -CH₂-3-indolyl, wherein the phenyl, pyridyl and indolyl can optionally be substituted as defined in embodiment 25. 32. The compound of embodiment 31, wherein R⁶ is -CH₂-phenyl, -CH₂-2-F-phenyl, -CH₂-3- F-phenyl, -CH₂-4-F-phenyl, -CH₂-2,3-F₂-phenyl, -CH₂-2,4-F₂-phenyl, -CH₂-2,5-F₂-phenyl, - CH₂-2,6-F₂-phenyl, -CH₂-3,4-F₂-phenyl, -CH₂-3,5-F₂-phenyl, -CH₂-3,6-F₂-phenyl, -CH₂-2-Cl- phenyl, -CH₂-3-Cl-phenyl, -CH₂-4-Cl-phenyl, -CH₂-2,3-Cl₂-phenyl, -CH₂-2,4-Cl₂-phenyl, -CH₂- 2,5-Cl₂-phenyl, -CH₂-2,6-Cl₂-phenyl, -CH₂-3,4-Cl₂-phenyl, -CH₂-3,5-Cl₂-phenyl, -CH₂-3,6-Cl₂- phenyl, -CH₂-2-CF₃-phenyl, -CH₂-3-CF₃-phenyl or -CH₂-4-CF₃-phenyl. 33. The compound of any one of embodiments 25 to 32, wherein L is -CH₂CH₂- or - CH₂CH₂CH₂-. 34. The compound of any one of embodiments 25 to 33, wherein Y is -S(=O)₂OH or a salt (e.g., sodium salt or inner salt) thereof. 35. The compound of any one of embodiments 25 to 34, wherein n is 1. 36. The compound of any one of embodiments 25 to 34, wherein n is 2 and -L-Y is the same at both occurrences. 37. The compound of any one of embodiments 25 to 36, which has Formula IIIa or is a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

wherein: R⁶ is hydrogen, methyl, ethyl, n-propyl, n-butyl, isobutyl, -CH₂-2-pyridyl, -CH₂-3- pyridyl, -CH₂-4-pyridyl, -CH₂-3-indolyl, -CH₂-phenyl, -CH₂-2-F-phenyl, -CH₂-3-F-phenyl, - CH₂-4-F-phenyl, -CH₂-2,3-F₂-phenyl, -CH₂-2,4-F₂-phenyl, -CH₂-2,5-F₂-phenyl, -CH₂-2,6-F₂- phenyl, -CH₂-3,4-F₂-phenyl, -CH₂-3,5-F₂-phenyl, -CH₂-3,6-F₂-phenyl, -CH₂-2-Cl-phenyl, -CH₂- 3-Cl-phenyl, -CH₂-4-Cl-phenyl, -CH₂-2,3-Cl₂-phenyl, -CH₂-2,4-Cl₂-phenyl, -CH₂-2,5-Cl₂- phenyl, -CH₂-2,6-Cl₂-phenyl, -CH₂-3,4-Cl₂-phenyl, -CH₂-3,5-Cl₂-phenyl, -CH₂-3,6-Cl₂-phenyl, - CH₂-2-CF₃-phenyl, -CH₂-3-CF₃-phenyl or -CH₂-4-CF₃-phenyl; -L-Y is -CH₂CH₂S(=O)₂OH or -CH₂CH₂CH₂S(=O)₂OH, or a salt (e.g., sodium salt or inner salt) thereof; n is 1 or 2; and the stereocenter marked by an asterisk * in Formula IIIa can have the (S)-stereochemistry or the (R)-stereochemistry or can be racemic. 38. The compound of any one of embodiments 25 to 37, which is one of the following compounds or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph

wherein the stereocenter marked by an asterisk * in the compounds above can have the (S)- stereochemistry or the (R)-stereochemistry or can be racemic. 39. The compound of any one of embodiments 25 to 38, wherein the stereocenter marked by an asterisk * has the (S)-stereochemistry. 40. A pharmaceutical composition comprising a compound of any one of the preceding embodiments or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof, and a pharmaceutically acceptable excipient or carrier. 41. The pharmaceutical composition of embodiment 40, further comprising an additional therapeutic agent. 42. A method of inhibiting or treating a tumor or cancer, comprising administering to a subject an amount of a compound of any one of embodiments 1 to 39, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof, effective to inhibit or treat a tumor or cancer. 43. The method of embodiment 42, wherein the tumor or cancer is characterized by abnormally elevated activity of the PI3K/Akt/mTOR signaling pathway. 44. The method of embodiment 42 or 43, wherein the tumor or cancer is selected from solid tumors and cancers, breast cancer (e.g., breast carcinoma), cervical cancer, ovarian cancer (e.g., ovarian carcinoma and granulosa cell tumors such as juvenile granulosa cell tumors), fallopian tube cancer, peritoneal cancer (e.g., peritoneal carcinoma), gastric cancer (e.g., gastric adenocarcinoma), colorectal cancer (e.g., colorectal carcinoma), pancreatic cancer, kidney cancer (e.g., renal cell carcinoma [RCC]), liver cancer (e.g., hepatocellular carcinoma [HCC]), prostate cancer (e.g., prostate carcinoma), urothelial cancer, nasopharyngeal cancer (e.g., nasopharyngeal carcinoma), lung cancer (e.g., non-small cell lung cancer), skin cancer (e.g., melanoma), brain tumors and cancers (e.g., glioblastoma), other tumors and cancers of the nervous system (e.g., glioma, neuroblastoma and neuroendocrine tumors), tumor and cancer syndromes (e.g., Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease and Proteus syndrome), and tumors and cancers of the hematopoietic tissues/blood system and the lymphoid tissues/lymphatic system {e.g., leukemias (e.g., chronic lymphocytic leukemia/small lymphocytic lymphoma [CLL/SLL]) and lymphomas including non-Hodgkin lymphomas (e.g., diffuse large B-cell lymphoma [DLBCL] and follicular lymphoma)}. 45. The method of embodiment 44, wherein the tumor or cancer is a solid tumor or cancer, breast cancer, ovarian cancer, gastric cancer, pancreatic cancer, prostate cancer, skin cancer or glioblastoma. 46. The method of any one of embodiments 42 to 45, wherein the compound is administered orally or parenterally (e.g., intravenously, subcutaneously or intramuscularly). 47. The method of any one of embodiments 42 to 46, further comprising administering one or more additional anti-tumor/cancer agents. 48. The method of embodiment 47, wherein the one or more additional anti-tumor/cancer agents comprise a PI3K inhibitor, an mTOR inhibitor or a phospholipid scramblase inhibitor (e.g., R5421), or any combination or all thereof. 49. The method of embodiment 48, wherein the PI3K inhibitor is selected from buparlisib, copanlisib, duvelisib, gedatolisib, idelalisib and pictilisib. 50. The method of embodiment 48, wherein the mTOR inhibitor is selected from first- generation mTOR inhibitors (e.g., rapamycin [sirolimus], everolimus, ridaforolimus, temsirolimus, umirolimus and zotarolimus) and dual mTORC1/mTORC2 inhibitors (e.g., sapanisertib, torin-1, torin-2, vistusertib, AZD2014 and AZD8055). 51. The method of embodiment 48, wherein the dual PI3K/mTOR inhibitor is selected from apitolisib, dactolisib, voxtalisib, BGT226, NVPBE235, PKI-587 and SF1126. 52. A method of inhibiting or treating a viral infection, comprising administering to a subject an amount of a compound of any one of embodiments 1 to 39, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof, effective to inhibit or treat a viral infection. 53. The method of embodiment 52, wherein binding of the virus to the cell surface results in translocation of Akt to the outer leaflet of the plasma membrane. 54. The method of embodiment 52 or 53, wherein the virus is a herpesvirus, a coronavirus (e.g., SARS-CoV-1, SARS-CoV-2 or MERS-CoV), a human immunodeficiency virus (e.g., HIV-1 or HIV-2), an Ebolavirus (e.g., Zaire ebolavirus), or a Flavivirus (e.g., Dengue virus). 55. The method embodiment 54, wherein the virus is a herpesvirus. 56. The method embodiment 55, wherein the herpesvirus is herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), Varicella zoster virus (VZV) Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), human betaherpesvirus 6A (HHV-6A), human betaherpesvirus 6B (HHV-6B), human betaherpesvirus 7 (HHV-7), or Kaposi’s sarcoma-associated herpesvirus (KSHV). 57. The method of embodiment 56, wherein the herpesvirus is HSV-1 or HSV-2. 58. The method of any one of embodiments 52 to 57, wherein the subject has a latent viral (e.g., herpesvirus) infection. 59. The method of any one of embodiments 52 to 58, wherein the subject has a viral (e.g., herpesvirus) infection which is resistant to aciclovir or/and valaciclovir. 60. The method of embodiment 59, wherein treatment with the compound reduces resistance to aciclovir or/and valaciclovir. 61. The method of any one of embodiments 52 to 60, wherein the compound is administered systemically, such as orally or parenterally (e.g., intravenously, subcutaneously or intramuscularly). 62. The method of any one of embodiments 52 to 60, wherein the compound is administered topically, such as to a mucous membrane (e.g., a mucous membrane in the oral cavity, the nasal cavity, the pharynx or the lungs) or to a surface of a genitalia (e.g., vagina or penis). 63. The method of any one of embodiments 52 to 62, further comprising administering one or more additional antiviral agents. 64. The method of embodiment 63, wherein the one or more additional antiviral agents comprise an inhibitor of viral DNA replication (e.g., aciclovir or valaciclovir) or viral RNA replication, or/and a phospholipid scramblase inhibitor (e.g., R5421). 65. A method of inhibiting protein kinase B (PKB, also called Akt), comprising contacting a cell with a compound of any one of embodiments 1 to 24 or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof. 66. The method of embodiment 65, wherein the compound inhibits PKB on the cell surface, on the outer leaflet of the plasma membrane or extracellularly. 67. The method of embodiment 65 or 66, wherein the contacting occurs in the body of a subject. 68. The method of embodiment 65 or 66, wherein the contacting occurs in vitro. 69. A method of inhibiting phosphoinositide-dependent (protein) kinase 1 (PDK1 or PDPK1), comprising contacting a cell with a compound of any one of embodiments 25 to 39 or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof.

70. The method of embodiment 69, wherein the compound inhibits PDPK1 on the cell surface, on the outer leaflet of the plasma membrane or extracellularly. 71. The method of embodiment 69 or 70, wherein the contacting occurs in the body of a subject. 72. The method of embodiment 69 or 70, wherein the contacting occurs in vitro. Examples [0145] The following examples are intended only to illustrate the disclosure. Other assays, studies, protocols, procedures, methodologies, techniques, reagents and conditions may alternatively be used as appropriate. Example 1. Synthesis of Cell-Impermeable Akt Inhibitors LD2-2 and LD2-3

[0146] All reagents and solvents were obtained from commercial suppliers and were used without further purification. The cell-permeable Akt inhibitor compound A was obtained from MedChemExpress (USA). ¹H-, ¹³C-, ¹⁹F- and 2D-NMR spectra were recorded on a Bruker 300 -70- or 600 MHz spectrometer. ¹H and ¹³C chemical shifts (δ) were reported relative to tetramethylsilane as the internal standard or relative to residual solvent signals, while trichlorofluoromethane was used as the internal standard for ¹⁹F-NMR. Reactions were monitored on reverse phase LC-MS. The purity of compounds LD2-2 and LD2-3 was > 95% based on ¹H-NMR and reverse phase HPLC-UV on monitoring absorption at 254 nm. Abbreviations: DABCO = 1,4-Diazabicyclo[2.2.2]octane DMF = N,N-Dimethylformamide DMSO = Dimethyl sulfoxide HPLC = High-performance liquid chromatography LCMS or LC-MS = Liquid chromatography-mass spectrometry MS ESI = Mass spectrometry electrospray ionization NMR = Nuclear magnetic resonance Tf = Trifluoromethanesulfonate or triflate UV = Ultraviolet 2-((3-((2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxyprop-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7-yl)oxy)propyl)amino)ethane-1-sulfonyl fluoride (LD2-1): [0147] Compound A (9.36 mg, 26.2 μmol) was dissolved in a mixture of DMF/water (1:10, 50 mM), and ethenesulfonyl fluoride (3.00 μL, 36.2 μmol, 1.4 eq) was added in three portions over 20 min at room temperature. After 30 min of stirring, reverse-phase LCMS analysis showed almost complete conversion of the starting material. The solvent was removed under high vacuum, and the crude product was dissolved in DMSO/MeCN and purified by preparative reverse-phase HPLC to give compound LD2-1 (5.52 mg, 45%). ¹H-NMR (600 MHz, MeOH-d₄): δ 8.60 (s, 1H), 5.36 (t, 2H, J=6.5 Hz), 4.97 (q, 2H, J=7.0 Hz), 4.63 (s, 2H), 4.54 (q, 2H, J=6.2 Hz), 4.48 (t, 2H, J=5.8 Hz), 3.15 (t, 2H, 7.6 Hz), 2.31-2.26 (m, 2H), 1.51 (t, 3H, J=7.1 Hz).¹³C-NMR (125 MHz, MeOH-d₄): δ 158.0, 149.7, 145.7, 143.5, 138.3, 135.5, 128.0, 125.0, 72.6, 69.7, 54.0, 51.5, 50.3, 50.2, 45.7, 37.8, 28.0, 16.3. ¹⁹F-NMR (57 MHz, MeOH-d₄): δ -74.94 (s, 1F). Rt 1.10 min. Identified as [M+H]⁺ 468.2. 2,2'-((3-((2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxyprop-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7-yl)oxy)propyl)azanediyl)bis(ethane-1-sulfonyl fluoride) (LD2-1bis): [0148] Compound A (4.6 mg, 13.0 μmol) was dissolved in a mixture of DMF/water (1:10, 100 mM), and ethenesulfonyl fluoride (2.7 μL, 32 μmol, 2.5 eq) was added at room temperature. After 3 hr of stirring, reverse-phase LCMS analysis showed almost complete conversion of the starting material. The solvent was removed under high vacuum, and the crude product was dissolved in DMSO/MeCN and purified by preparative reverse-phase HPLC to give compound LD2-1bis (3.3 mg, 40%). ¹H-NMR (600 MHz, MeCN-d₃): δ 8.16 (s, 1H), 6.15 (s, 2H), 4.95 (q, 2H, J=7.1 Hz), 4.52 (s, 2H), 4.37 (t, 2H, J=6.1 Hz), 3.77 (td, 4H, J=4.2, 6.7 Hz), 3.15 (t, 2H, J=6.7Hz), 2.80 (t, 2H, J=7.0 Hz), 2.12-2.07 (m, 2H), 1.51 (t, 3H, J=7.1 Hz).¹³C-NMR (125 MHz, MeCN-d₃): δ 157.6, 145.2, 142.6, 139.0, 132.1, 127.8, 124.9, 78.8, 69.0, 51.3, 50.5, 49.6, 49.5, 48.0, 44.7, 27.5, 16.6.¹⁹F- NMR (57 MHz, MeCN-d₄): δ -74.94 (s, 1F). Rt 2.62 min. Identified as [M+H]⁺ 578.2. General procedure for sulfonyl fluoride hydrolysis: [0149] To a solution of the sulfonyl fluoride (4.3 µmol, 21 mM) in THF/water (1:1) were added Ca(NTf₂)₂ (3 eq) and DABCO (5 eq), and the reaction mixture was stirred overnight at room temperature. Reverse-phase LCMS analysis showed complete hydrolysis of the sulfonyl fluoride group. The crude reaction product was purified by preparative reverse-phase HPLC to give the sulfonic acid. 2-((3-((2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxyprop-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7-yl)oxy)propyl)amino)ethane-1-sulfonic acid (LD2-2): ¹H-NMR (600 MHz, DMSO-d₆): δ 8.18 (s, 1H), 4.83 (q, 2H, J=7.1 Hz), 4.42 (s, 2H), 4.39 (t, 2H, J=6.0 Hz), 3.02 (t, 2H, 6.6 Hz), 2.97 (t, 2H, J=7.0 Hz), 2.70 (t, 2H, J=6.6 Hz) 2.11-2.05 (m, 2H), 1.46 (t, 3H, J=7.1 Hz). ¹³C-NMR (125 MHz, DMSO-d₆): δ 156.3, 142.7, 141.9, 141.1, 137.7, 128.8, 128.4, 126.7, 92.6, 80.4, 66.9, 49.5, 48.7, 44.8, 42.9, 40.4, 27.3, 16.1. Rt 1.33 min. Identified as [M+H]⁺ 466.1, [M-H]^– 464.3. 2,2'-((3-((2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxyprop-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7-yl)oxy)propyl)azanediyl)bis(ethane-1-sulfonic acid) (LD2-3): ¹H-NMR (600 MHz, D₂O): δ 7.87 (s, 1H), 4.67 (q, 2H, J=7.0 Hz), 4.51 (s, 2H), 4.32 (t, 2H, J=5.7 Hz), 3.53 (m, 4H), 3.38-3.28 (m, 4H), 3.31 (t, 2H, J=7.5 Hz), 2.36-2.29 (m, 2H), 1.40 (t, 3H, J=7.1 Hz).¹³C-NMR (125 MHz, D₂O): δ 156.0, 143.2, 142.4, 140.9, 137.6, 129.4, 127.2, 125.5, 92.3, 79.8, 66.6, 50.8, 49.9, 49.3, 45.4, 43.3, 38.7, 24.0, 15.6. Rt 1.22 min. Identified as [M+H]⁺ 574.3, [M-H]^– 572.4. Determination of the purity of compounds LD2-2 and LD2-3: [0150] Reverse-phase LCMS analysis was performed using an Agilent InfinityLab Poroshell 120 EC-C18 column, 2.1 x 50 mm, 1.9 µm at 25 °C . The table below describes the gradient employed. Solvent A: acetonitrile with 0.1% formic acid. Solvent B: water with 0.1% formic acid. Purity was determined at 254 nm. The identity of the compounds was verified by MS ESI.

Example 2. Inhibition of Extracellular Akt by Cell-Impermeable Akt Inhibitor [0151] HaCat cells (human keratinocytes) were serum-starved for 24 hr and then exposed to herpes simplex virus 2 [HSV-2(G)] (MOI = 10 PFU/cell) in the presence of control buffer (0.1% DMSO) or a cell-impermeable Akt inhibitor (10 µM). At different times post-viral exposure, the cells were harvested and lysed in a buffer containing 20 mM Tris, pH 7.5, 50 mM NaCl, 1% NP- 40, 0.05% sodium deoxycholate (DOC), supplemented with fresh protease and phosphatase inhibitors (118735, Roche Diagnostics, and P0044, P5726, Sigma-Aldrich, respectively). Proteins were separated by SDS-PAGE and transferred to membranes for immunoblotting with antibodies specific for the particular proteins. Blots were visualized using ChemiDoc imaging system equipped with GelDoc2000 software (RRID:SCR_014210, Bio-Rad). [0152] Fig. 1 shows that the cell-impermeable Akt inhibitor LD2-3 (“HSV + Cl”) did not prevent the phosphorylation of extracellular Akt (which is mediated by PDPK1 and a second kinase), but blocked the phosphorylation of extracellular phospholipase C-gamma (PLCγ), which is a substrate of Akt kinase activity. For the three test groups, “30” means 30 min after viral exposure and “120” means 120 min after viral exposure. Example 3. Inhibition of HSV-2 Cell Entry by Cell-Impermeable Akt Inhibitors [0153] For plaque assays, HaCat cells were exposed to 400-500 PFU of HSV-2(G) virus per well in a 6-well plate for 1 hr at 37 °C in the presence of control (DMSO) or varying concentrations of a cell-impermeable Akt inhibitor. The cells were washed once with a low pH buffer to inactivate extracellular/bound virus that has not yet penetrated cells, and then were washed three times with phosphate-buffered saline (PBS, pH 7.4), before overlaying with methyl cellulose 0.5%. After 48 hr of incubation, plaques were counted using crystal violet staining. [0154] Figs.2A and 2B show that the cell-impermeable Akt inhibitors LD2-2 and LD2-3, respectively, dose-dependently inhibited the entry of HSV-2 into HaCat cells. LD2-2 and LD2-3 inhibited HSV-2 cell entry with an EC₅₀ of about 10 nM, which is surprisingly about 50-100x more potent than that of another cell-impermeable Akt inhibitor, cell-impermeable staurosporine (CIMSS). Example 4. Cell-Impermeable Akt Inhibitors Were Not Cytotoxic [0155] To assess the effects of cell-impermeable Akt inhibitors on cell growth and viability, Vero cells were plated on 96-well plates, allowed to adhere overnight to 90-100% confluence (cytotoxicity), and then cultured for 6 days in culture media alone, media containing increasing concentrations of a cell-impermeable Akt inhibitor, or media containing an equivalent concentration of DMSO as control (0.1% DMSO for 10 μM Akt inhibitor, 0.5% DMSO for 50 μM Akt inhibitor, and 1% DMSO for 100 μM Akt inhibitor). Cell proliferation and viability were determined using the Cell Titer 96 Aqueous One Solution, and optical density was determined using a SpectraMax M5e Molecular Devices multidetection microplate reader. [0156] Figs.3A and 3B show that the cell-impermeable Akt inhibitors LD2-2 and LD2-3, respectively, were not significantly more toxic to Vero cells than DMSO as control. [0157] Example 5. Inhibition of herpes simplex virus (HSV) cell entry by cell- impermeable LD2-2 and LD2-3

[0158] Figs.4B shows that LD2-2 and LD2-3 significantly reduces HSV induced phosphorylation of PLC γ, which is required for HSV cell entry. For the three test groups, “30” means 30 min after viral exposure and “120” means 120 min after HSV viral exposure. [0159] It is understood that, while particular embodiments have been illustrated and described, various modifications can be made thereto and are contemplated herein. It is also understood that the disclosure is not limited by the specific examples provided herein. The description and illustration of embodiments and examples of the disclosure herein are not intended to be construed in a limiting sense. It is further understood that all aspects of the disclosure are not limited to the specific depictions, configurations or relative proportions set forth herein, which may depend upon a variety of conditions and variables. Various modifications and variations in form and detail of the embodiments and examples of the disclosure will be apparent to a person skilled in the art. It is therefore contemplated that the disclosure also covers any and all such modifications, variations and equivalents.

Claims

What Is Claimed Is: 1. A compound of Formula I or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

denotes the site of attachment to X and the amine nitrogen atom is attached to one or two -L²-Y moieties, and wherein each stereocenter independently can have the (R)-stereochemistry or the (S)-stereochemistry or can be racemic; -L²- at each occurrence independently is -(CH₂)_q-; Y at each occurrence independently is -CO₂H, -S(=O)₂OH or -P(=O)(OH)₂, or a salt thereof; m is 2, 3, 4 or 5; n is 1, 2, 3 or 4; p is 1 or 2; and q is 1, 2, 3 or 4.

2. The compound of claim 1, wherein R¹ is -OH, -NH₂, -NHCH₃ or -NHC(=O)CH₃.

3. The compound of claim 2, wherein R¹ is -NH₂.

4. The compound of any one of the preceding claims, wherein R² is methyl or ethyl.

5. The compound of any one of the preceding claims, wherein: (a) R³ is hydrogen and R⁴ is methyl; (b) R³ is methyl and R⁴ is hydrogen; (c) both R³ and R⁴ are hydrogen; or (d) both R³ and R⁴ are methyl.

6. The compound of claim 5, wherein both R³ and R⁴ are hydrogen, or both R³ and R⁴ are methyl.

7. The compound of any one of the preceding claims, wherein X is O.

8. The compound of any one of the preceding claims, wherein -L¹-NH/NR⁶/N- is -(CH₂)_m- NH/N- and m is 2, 3 or 4.

9. The compound of any one of the preceding claims, wherein -L²- is -CH₂CH₂- or - CH₂CH₂CH₂-.

10. The compound of any one of the preceding claims, wherein Y is -S(=O)₂OH or a salt (e.g., sodium salt or inner salt) thereof.

11. The compound of any one of the preceding claims, wherein p is 1.

12. The compound of any one of claims 1 to 10, wherein p is 2 and -L²-Y is the same at both occurrences.

13. The compound of any one of the preceding claims, which has Formula Ia or is a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

wherein: both R³ and R⁴ are hydrogen, or both R³ and R⁴ are methyl; -L²-Y is -CH₂CH₂S(=O)₂OH or -CH₂CH₂CH₂S(=O)₂OH, or a salt (sodium salt or inner salt) thereof; m is 2, 3 or 4; and p is 1 or 2.

14. The compound of any one of the preceding claims, which is one of the following compounds or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

wherein a stereocenter marked by an asterisk * in the compounds above can have the (S)- stereochemistry or the (R)-stereochemistry or can be racemic.

15. A compound of Formula II or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

wherein: X is -NR⁴-L-Y or -NR⁴-(CH₂)_m-NH/N-(L-Y)_n; R¹ and R² independently are hydrogen, halide, cyano, -CH₃, -CH₂CH₃, -CF₃, -OCH₃ or - OCF₃, wherein at least one of R¹ and R² is not hydrogen; R³ is hydrogen, or R³ and -NR⁴- and the carbon atom to which they are attached form a 5- or 6-membered heterocyclic ring (e.g., pyrrolidine, piperidine, piperazine or morpholine) which can optionally be substituted with -F, -Cl, -CH₃, -OH or -OCH₃; R⁴ is hydrogen, -L-Y, C_1-4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), C_3-6 cycloalkyl or 3-6-membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, -OH, C_1-4 alkyl, C_1-4 alkoxy, C_3-6 cycloalkyl and 3-6- membered heterocyclyl, or -NR⁴- and R³ and the carbon atom to which they are attached form a 5- or 6-membered heterocyclic ring which can optionally be substituted with -F, -Cl, -CH₃, -OH or -OCH₃; -L- at each occurrence independently is -(CH₂)_q-; Y at each occurrence independently is -CO₂H, -S(=O)₂OH or -P(=O)(OH)₂, or a salt thereof; m is 2, 3 or 4; n is 1 or 2; and q is 1, 2, 3 or 4.

16. The compound of claim 15, wherein the phenyl (Ph) ring is 3-F-Ph, 3-Cl-Ph, 3-CF₃-Ph, 4-F-Ph, 4-Cl-Ph, 4-CF₃-Ph, 3,4-F₂-Ph, 3,4-Cl₂-Ph, 3,4-(CF₃)₂-Ph, 3-F-4-Cl-Ph, 3-F-4-CF₃-Ph, 3- Cl-4-F-Ph, 3-Cl-4-CF₃-Ph, 3-CF₃-4-F-Ph or 3-CF₃-4-Cl-Ph.

17. The compound of claim 15 or 16, wherein R³ is hydrogen.

18. The compound of any one of claims 15 to 17, wherein R⁴ is hydrogen, - CH₂CH₂S(=O)₂OH or -CH₂CH₂CH₂S(=O)₂OH or a salt thereof, isopropyl, isobutyl, sec-butyl, tert-butyl, -CH₂CH₂F, -CH₂CH₂Cl, -CH₂CH₂OH, -CH₂CH₂-OCH₃, -CH(CH₃)CH₂OH, - CH(CH₃)CH₂OCH₃, -C(CH₃)₂CH₂OH, -C(CH₃)₂CH₂OCH₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl-OH (e.g., trans 1,3-N-cyclopentyl-OH), cyclopentyl-OCH₃ (e.g., trans 1,3-N-cyclopentyl-OCH₃), cyclohexyl-OH (e.g., trans 1,4-N-cyclohexyl-OH), cyclohexyl-OCH₃ (e.g., trans 1,4-N-cyclohexyl-OCH₃), tetrahydrofuranyl (e.g., 3- tetrahydrofuranyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), -CH₂-cyclopropyl, -CH₂- cyclobutyl, -CH₂-cyclopentyl, -CH₂-cyclohexyl, -CH₂-tetrahydrofuranyl (e.g., -CH₂-3- tetrahydrofuranyl), or -CH₂-tetrahydropyranyl (e.g., -CH₂-4-tetrahydropyranyl), or -NR⁴- and R³ and the carbon atom to which they are attached form a pyrrolidine, piperidine, piperazine [with, e.g., -N(CH₃)- or -N(acetyl)-] or morpholine ring which can optionally be substituted with -F, - Cl, -CH₃, -OH or -OCH₃, wherein if a ring has a stereocenter, the stereocenter can have the (S)- stereochemistry or the (R)-stereochemistry or can be racemic.

19. The compound of any one of claims 15 to 18, wherein L is -CH₂CH₂- or -CH₂CH₂CH₂-.

20. The compound of any one of claims 15 to 19, wherein Y is -S(=O)₂OH or a salt (e.g., sodium salt or inner salt) thereof.

21. The compound of any one of claims 15 to 20, wherein if -L-Y occurs more than once, -L- Y is the same at all occurrences.

22. The compound of any one of claims 15 to 21, wherein m is 2.

23. The compound of any one of claims 15 to 22, which has Formula IIa or is a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

wherein: X is -NR⁴-L-Y or -NR⁴-(CH₂)₂-NH/N-(L-Y)_n; R³ is hydrogen, or R³ and -NR⁴- and the carbon atom to which they are attached form a pyrrolidine, piperidine, piperazine [with, e.g., -N(CH₃)- or -N(acetyl)-] or morpholine ring which can optionally be substituted with -F, -Cl, -CH₃, -OH or -OCH₃; R⁴ is hydrogen, -CH₂CH₂S(=O)₂OH or -CH₂CH₂CH₂S(=O)₂OH or a salt thereof, isopropyl, isobutyl, sec-butyl, tert-butyl, -CH₂CH₂F, -CH₂CH₂Cl, -CH₂CH₂OH, -CH₂CH₂- OCH₃, -CH(CH₃)CH₂OH, -CH(CH₃)CH₂OCH₃, -C(CH₃)₂CH₂OH, -C(CH₃)₂CH₂OCH₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl-OH (e.g., trans 1,3-N-cyclopentyl- OH), cyclopentyl-OCH₃ (e.g., trans 1,3-N-cyclopentyl-OCH₃), cyclohexyl-OH (e.g., trans 1,4- N-cyclohexyl-OH), cyclohexyl-OCH₃ (e.g., trans 1,4-N-cyclohexyl-OCH₃), tetrahydrofuranyl (e.g., 3-tetrahydrofuranyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), -CH₂-cyclopropyl, - CH₂-cyclobutyl, -CH₂-cyclopentyl, -CH₂-cyclohexyl, -CH₂-tetrahydrofuranyl (e.g., -CH₂-3- tetrahydrofuranyl), or -CH₂-tetrahydropyranyl (e.g., -CH₂-4-tetrahydropyranyl), or -NR⁴- and R³ and the carbon atom to which they are attached form a pyrrolidine, piperidine, piperazine [with, e.g., -N(CH₃)- or -N(acetyl)-] or morpholine ring which can optionally be substituted with -F, - Cl, -CH₃, -OH or -OCH₃, wherein if a ring has a stereocenter, the stereocenter can have the (S)- stereochemistry or the (R)-stereochemistry or can be racemic; -L-Y is -CH₂CH₂S(=O)₂OH or -CH₂CH₂CH₂S(=O)₂OH, or a salt (e.g., sodium salt or inner salt) thereof; and n is 1 or 2.

24. The compound of any one of claims 15 to 23, which is one of the following compounds or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

25. A compound of Formula III or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

wherein: R¹ and R² independently are hydrogen, halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, - CF₃ or -OCF₃; R³ is hydrogen, C_1-6 alkyl (e.g., methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl), C_3-6 cycloalkyl, -(C_1-3 alkyl)-(C_3-6 cycloalkyl), -(C_1-3 alkyl)-phenyl or -C(=O)R⁴, wherein the phenyl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, -CF₃ and -OCF₃; R⁴ is C_1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n-pentyl or n-hexyl), C_3-6 cycloalkyl or phenyl, wherein the phenyl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, -CF₃ and -OCF₃; R⁵ is C_1-4 alkyl (e.g., methyl, ethyl, n-propyl or n-butyl); R⁶ is hydrogen, C_1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl or n-hexyl), cycloalkyl (e.g., C_3-6 cycloalkyl), heterocyclyl (e.g., 3-6- membered heterocyclyl), aryl (e.g., 6-10-membered aryl), heteroaryl (e.g., 5-10-membered heteroaryl), -(C_1-3 alkyl)-(C_3-6 cycloalkyl), -(C_1-3 alkyl)-(3-6-membered heterocyclyl), -(C_1-3 alkyl)-phenyl, or -(C_1-3 alkyl)-(5-9-membered heteroaryl), wherein the aryl, heteroaryl and phenyl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, -OH, C_1-4 alkyl, C_1-4 alkoxy, -CF₃ and -OCF₃; X is -CH₂-, -O-, -S-, -NH- or -NR⁵-; -L- at each occurrence independently is -(CH₂)_q-; Y at each occurrence independently is -CO₂H, -S(=O)₂OH or -P(=O)(OH)₂, or a salt thereof; m is 1, 2 or 3; n is 1 or 2; q is 1, 2, 3 or 4; and the stereocenter marked by an asterisk * in Formula III can have the (S)-stereochemistry or the (R)-stereochemistry or can be racemic.

26. The compound of claim 25, wherein both R¹ and R² are -OCH₃.

27. The compound of claim 25 or 26, wherein R³ is hydrogen, -CH₃ or -C(=O)CH₃.

28. The compound of claim 27, wherein R³ is hydrogen.

29. The compound of any one of claims 25 to 28, wherein X is O.

30. The compound of any one of claims 25 to 29, wherein m is 1.

31. The compound of any one of claims 25 to 30, wherein R⁶ is hydrogen, methyl, ethyl, n- propyl, n-butyl, isobutyl, -CH₂-phenyl, -CH₂-2-pyridyl, -CH₂-3-pyridyl, -CH₂-4-pyridyl, or - CH₂-3-indolyl, wherein the phenyl, pyridyl and indolyl can optionally be substituted as defined in claim 25.

32. The compound of claim 31, wherein R⁶ is -CH₂-phenyl, -CH₂-2-F-phenyl, -CH₂-3-F- phenyl, -CH₂-4-F-phenyl, -CH₂-2,3-F₂-phenyl, -CH₂-2,4-F₂-phenyl, -CH₂-2,5-F₂-phenyl, -CH₂- 2,6-F₂-phenyl, -CH₂-3,4-F₂-phenyl, -CH₂-3,5-F₂-phenyl, -CH₂-3,6-F₂-phenyl, -CH₂-2-Cl-phenyl, -CH₂-3-Cl-phenyl, -CH₂-4-Cl-phenyl, -CH₂-2,3-Cl₂-phenyl, -CH₂-2,4-Cl₂-phenyl, -CH₂-2,5-Cl₂- phenyl, -CH₂-2,6-Cl₂-phenyl, -CH₂-3,4-Cl₂-phenyl, -CH₂-3,5-Cl₂-phenyl, -CH₂-3,6-Cl₂-phenyl, - CH₂-2-CF₃-phenyl, -CH₂-3-CF₃-phenyl or -CH₂-4-CF₃-phenyl.

33. The compound of any one of claims 25 to 32, wherein L is -CH₂CH₂- or -CH₂CH₂CH₂-.

34. The compound of any one of claims 25 to 33, wherein Y is -S(=O)₂OH or a salt (e.g., sodium salt or inner salt) thereof.

35. The compound of any one of claims 25 to 34, wherein n is 1.

36. The compound of any one of claims 25 to 34, wherein n is 2 and -L-Y is the same at both occurrences.

37. The compound of any one of claims 25 to 36, which has Formula IIIa or is a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

wherein: R⁶ is hydrogen, methyl, ethyl, n-propyl, n-butyl, isobutyl, -CH₂-2-pyridyl, -CH₂-3- pyridyl, -CH₂-4-pyridyl, -CH₂-3-indolyl, -CH₂-phenyl, -CH₂-2-F-phenyl, -CH₂-3-F-phenyl, - CH₂-4-F-phenyl, -CH₂-2,3-F₂-phenyl, -CH₂-2,4-F₂-phenyl, -CH₂-2,5-F₂-phenyl, -CH₂-2,6-F₂- phenyl, -CH₂-3,4-F₂-phenyl, -CH₂-3,5-F₂-phenyl, -CH₂-3,6-F₂-phenyl, -CH₂-2-Cl-phenyl, -CH₂- 3-Cl-phenyl, -CH₂-4-Cl-phenyl, -CH₂-2,3-Cl₂-phenyl, -CH₂-2,4-Cl₂-phenyl, -CH₂-2,5-Cl₂- phenyl, -CH₂-2,6-Cl₂-phenyl, -CH₂-3,4-Cl₂-phenyl, -CH₂-3,5-Cl₂-phenyl, -CH₂-3,6-Cl₂-phenyl, - CH₂-2-CF₃-phenyl, -CH₂-3-CF₃-phenyl or -CH₂-4-CF₃-phenyl; -L-Y is -CH₂CH₂S(=O)₂OH or -CH₂CH₂CH₂S(=O)₂OH, or a salt (e.g., sodium salt or inner salt) thereof; n is 1 or 2; and the stereocenter marked by an asterisk * in Formula IIIa can have the (S)-stereochemistry or the (R)-stereochemistry or can be racemic.

38. The compound of any one of claims 25 to 37, which is one of the following compounds or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:

wherein the stereocenter marked by an asterisk * in the compounds above can have the (S)- stereochemistry or the (R)-stereochemistry or can be racemic.

39. The compound of any one of claims 25 to 38, wherein the stereocenter marked by an asterisk * has the (S)-stereochemistry.

40. A pharmaceutical composition comprising a compound of any one of the preceding claims or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof, and a pharmaceutically acceptable excipient or carrier.

41. The pharmaceutical composition of claim 40, further comprising an additional therapeutic agent.

42. A method of inhibiting or treating a tumor or cancer, comprising administering to a subject an amount of a compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof, effective to inhibit or treat a tumor or cancer.

43. The method of claim 42, wherein the tumor or cancer is characterized by abnormally elevated activity of the PI3K/Akt/mTOR signaling pathway.

44. The method of claim 42 or 43, wherein the tumor or cancer is selected from solid tumors and cancers, breast cancer (e.g., breast carcinoma), cervical cancer, ovarian cancer (e.g., ovarian carcinoma and granulosa cell tumors such as juvenile granulosa cell tumors), fallopian tube cancer, peritoneal cancer (e.g., peritoneal carcinoma), gastric cancer (e.g., gastric adenocarcinoma), colorectal cancer (e.g., colorectal carcinoma), pancreatic cancer, kidney cancer (e.g., renal cell carcinoma [RCC]), liver cancer (e.g., hepatocellular carcinoma [HCC]), prostate cancer (e.g., prostate carcinoma), urothelial cancer, nasopharyngeal cancer (e.g., nasopharyngeal carcinoma), lung cancer (e.g., non-small cell lung cancer), skin cancer (e.g., melanoma), brain tumors and cancers (e.g., glioblastoma), other tumors and cancers of the nervous system (e.g., glioma, neuroblastoma and neuroendocrine tumors), tumor and cancer syndromes (e.g., Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease and Proteus syndrome), and tumors and cancers of the hematopoietic tissues/blood system and the lymphoid tissues/lymphatic system {e.g., leukemias (e.g., chronic lymphocytic leukemia/small lymphocytic lymphoma [CLL/SLL]) and lymphomas including non-Hodgkin lymphomas (e.g., diffuse large B-cell lymphoma [DLBCL] and follicular lymphoma)}.

45. The method of claim 44, wherein the tumor or cancer is a solid tumor or cancer, breast cancer, ovarian cancer, gastric cancer, pancreatic cancer, prostate cancer, skin cancer or glioblastoma.

46. The method of any one of claims 42 to 45, wherein the compound is administered orally or parenterally (e.g., intravenously, subcutaneously or intramuscularly).

47. The method of any one of claims 42 to 46, further comprising administering one or more additional anti-tumor/cancer agents.

48. The method of claim 47, wherein the one or more additional anti-tumor/cancer agents comprise a PI3K inhibitor, an mTOR inhibitor or a phospholipid scramblase inhibitor (e.g., R5421), or any combination or all thereof.

49. The method of claim 48, wherein the PI3K inhibitor is selected from buparlisib, copanlisib, duvelisib, gedatolisib, idelalisib and pictilisib.

50. The method of claim 48, wherein the mTOR inhibitor is selected from first-generation mTOR inhibitors (e.g., rapamycin [sirolimus], everolimus, ridaforolimus, temsirolimus, umirolimus and zotarolimus) and dual mTORC1/mTORC2 inhibitors (e.g., sapanisertib, torin-1, torin-2, vistusertib, AZD2014 and AZD8055).

51. The method of claim 48, wherein the dual PI3K/mTOR inhibitor is selected from apitolisib, dactolisib, voxtalisib, BGT226, NVPBE235, PKI-587 and SF1126.

52. A method of inhibiting or treating a viral infection, comprising administering to a subject an amount of a compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof, effective to inhibit or treat a viral infection.

53. The method of claim 52, wherein binding of the virus to the cell surface results in translocation of Akt to the outer leaflet of the plasma membrane.

54. The method of claim 52 or 53, wherein the virus is a herpesvirus, a coronavirus (e.g., SARS-CoV-1, SARS-CoV-2 or MERS-CoV), a human immunodeficiency virus (e.g., HIV-1 or HIV-2), an Ebolavirus (e.g., Zaire ebolavirus), or a Flavivirus (e.g., Dengue virus).

55. The method claim 54, wherein the virus is a herpesvirus.

56. The method claim 55, wherein the herpesvirus is herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), Varicella zoster virus (VZV) Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), human betaherpesvirus 6A (HHV-6A), human betaherpesvirus 6B (HHV-6B), human betaherpesvirus 7 (HHV-7), or Kaposi’s sarcoma-associated herpesvirus (KSHV).

57. The method of claim 56, wherein the herpesvirus is HSV-1 or HSV-2.

58. The method of any one of claims 52 to 57, wherein the subject has a latent viral (e.g., herpesvirus) infection.

59. The method of any one of claims 52 to 58, wherein the subject has a viral (e.g., herpesvirus) infection which is resistant to aciclovir or/and valaciclovir.

60. The method of claim 59, wherein treatment with the compound reduces resistance to aciclovir or/and valaciclovir.

61. The method of any one of claims 52 to 60, wherein the compound is administered systemically, such as orally or parenterally (e.g., intravenously, subcutaneously or intramuscularly).

62. The method of any one of claims 52 to 60, wherein the compound is administered topically, such as to a mucous membrane (e.g., a mucous membrane in the oral cavity, the nasal cavity, the pharynx or the lungs) or to a surface of a genitalia (e.g., vagina or penis).

63. The method of any one of claims 52 to 62, further comprising administering one or more additional antiviral agents.

64. The method of claim 63, wherein the one or more additional antiviral agents comprise an inhibitor of viral DNA replication (e.g., aciclovir or valaciclovir) or viral RNA replication, or/and a phospholipid scramblase inhibitor (e.g., R5421).

65. A method of inhibiting protein kinase B (PKB, also called Akt), comprising contacting a cell with a compound of any one of claims 1 to 24 or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof.

66. The method of claim 65, wherein the compound inhibits PKB on the cell surface, on the outer leaflet of the plasma membrane or extracellularly.

67. The method of claim 65 or 66, wherein the contacting occurs in the body of a subject.

68. The method of claim 65 or 66, wherein the contacting occurs in vitro.

69. A method of inhibiting phosphoinositide-dependent (protein) kinase 1 (PDK1 or PDPK1), comprising contacting a cell with a compound of any one of claims 25 to 39 or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof.

70. The method of claim 69, wherein the compound inhibits PDPK1 on the cell surface, on the outer leaflet of the plasma membrane or extracellularly.

71. The method of claim 69 or 70, wherein the contacting occurs in the body of a subject.

72. The method of claim 69 or 70, wherein the contacting occurs in vitro.