[0001] This application claims priority to U.S. Provisional Patent Application No. 63/399,480, filed August 19, 2022, the entire content of which is hereby incorporated by reference.

BACKGROUND

[0002] The 3 -phosphoinositide-dependent protein kinase-1 (PDK1, also known as PDPK1) is a master kinase that activates other kinases important in cell growth and survival including members of the Akt (protein kinase B, PKB), protein kinase C (PKC), p90 ribosomal S6 kinase RSK (S6K), and SGK families. PDK1 activates substrate kinases via activation T-loop phosphorylation.

[0003] PDK1 is a 556-amino acid protein that consists of an N-terminal kinase (catalytic) domain, and a C-terminal pleckstrin homology (PH) domain. The PH domain interacts with phosphatidylinositol (PI) (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate, contributing to localization and activation of certain PDK1 substrates, notably including Akt. The activation of Akt is believed to require a proper orientation of the kinase and PH domains of PDK1 and Akt at the membrane. Akt is itself known to be associated with cancers, and is frequently mutated or hyperactivated in human cancers.

[0004] However, while PDK1 can interact with certain of its substrates through this PI- dependent (PH-mediated) mechanism, it can interact with other substrates through a distinct Pl-independent mechanism. The N-terminal kinase domain has three ligand binding sites; a substrate binding site, an ATP binding site, and a docking site (also known as PIF pocket) for interaction with substrates. This docking site is known as the “PIF pocket,” referring to its binding to a region of protein kinase C-related kinase-2 (PRK2), termed the PDK1 -interacting fragment (PIF). Several PDK1 substrates, including S6K and PKC, require binding at this PIF pocket docking site. As noted, PDK1 is important in regulating the activity of other kinases. Of the several known PDK1 substrates, much attention has focused on AKT. Development of potent and selective AKT inhibitors has been challenging. Studies have revealed, surprisingly, that many tumor types are not sensitive to AKT inhibition or express no or little activated AKT. [0005] PDK1 is the only kinase known to phosphorylate Thr308 in the activation loop of AKT that is critical for activation of AKT kinase. Thus, PDK1 plays a critical role in AKT activation. Efforts to develop potent and selective PDK1 inhibitors with suitable drug like properties have been unsuccessful and no compounds have entered clinical development. Reported pre-clinical studies with PDK1 inhibitors GSK2334470 and BX-320/-795 have shown moderate efficacy and thus, it has been proposed that PDK1 may not be rate limiting in promoting cancer cell growth. Alternatively, these inhibitors may simply have poor pharmacological properties, failing to achieve sufficient inhibition to produce an effect, or the type of cancers cells used did not depend on PDK1 for growth.

[0006] Accordingly, it is an object of the present disclosure to provide pharmaceutical compositions comprising dual -mechanism inhibitor compounds that are stable and can be administered, for example in combination with a second therapeutic, for the treatment of diseases and disorders wherein PDK1 is implicated. Furthermore, it is believed that the efficacy of these compounds correlates with drug exposure. Accordingly, it is desirable to be able to administer such compounds at the highest possible dose, i.e., the highest possible dose at which the side-effect profile is acceptable. A dosing regimen that achieves a higher exposure to the compounds thereby would provide a meaningful benefit in the treatment of patients suffering from cancer.

[0007] Consequently, there is a need for a pharmaceutical combination for treating a disease or disorder wherein PDK1 is implicated (e.g., cancer). The present disclosure addresses these needs.

SUMMARY

[0008] In one aspect, the present disclosure provides a pharmaceutical combination comprising a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0009] In one aspect, the present disclosure provides a pharmaceutical combination comprising Compound 1 or a pharmaceutically acceptable salt thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0010] In one aspect, the present disclosure provides a kit comprising a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0011] In one aspect, the present disclosure provides a kit comprising Compound 1 or a pharmaceutically acceptable salt thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0012] In one aspect, the present disclosure provides a pharmaceutical package comprising a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0013] In one aspect, the present disclosure provides a pharmaceutical package comprising Compound 1 or a pharmaceutically acceptable salt thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0014] In one aspect, the present disclosure provides a method of treating or preventing a disease or disorder, comprising administering to a subject in need thereof a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. [0015] In one aspect, the present disclosure provides a method of treating or preventing a cancer, comprising administering to a subject in need thereof a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0016] In one aspect, the present disclosure provides a method of treating or preventing a disease or disorder, comprising administering to a subject in need thereof Compound 1, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0017] In one aspect, the present disclosure provides a method of treating or preventing a cancer, comprising administering to a subject in need thereof Compound 1, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the peptides disclosed herein, the chemical structures will control. [0019] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 depicts the insulin concentrations in serum of Compound 1, alpelisib, and vehicle, as a monotherapy and Compound 1 and alpelisib in combination.

[0021] FIG. 2 depicts the mean tumor volume in mouse after treatment with Compound 1, alpelisib, and vehicle, as a monotherapy and Compound 1 and alpelisib in combination.

DETAILED DESCRIPTION

[0022] The present disclosure relates to combinations, which may modulate PDK1 activity and are accordingly useful in methods of treatment of the human or animal body. The present disclosure also relates to their use in the treatment of disorders wherein PDK1 is implicated, such as cancer.

Definitions

[0023] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0024] Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options.

[0025] It is to be understood that a compound of the present disclosure may be depicted in a neutral form, a cationic form (e.g., carrying one or more positive charges), or an anionic form (e.g., carrying one or more negative charges), all of which are intended to be included in the scope of the present disclosure. For example, when a compound of the present disclosure is depicted in an anionic form, such depiction also refers to the various neutral forms, cationic forms, and anionic forms of the compound. For another example, when a compound the present disclosure is depicted in an anionic form, such depiction also refers to various salts (e.g., sodium salt) of the anionic form of the compound.

[0026] A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0027] As used herein, “alkyl”, “Ci, C2, C3, C4, C5 or Ce alkyl” or “Ci-C 6 alkyl” is intended to include Ci, C2, C3, C4, C5 or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or Ce branched saturated aliphatic hydrocarbon groups. For example, C _r C ₆ alkyl is intends to include C C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., Ci-Ce for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

[0028] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0029] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g. , C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms.

[0030] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0031] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3- Ce” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6 alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C2, C3, C4, C5 or Ce chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C ₂ - C ₆ alkenylene linker is intended to include C2, C3, C4, C5 and Ce alkenylene linker groups.

[0032] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0033] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl- piperidinyl and 2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridinyl.

[0034] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or Cs-Cs). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be nonaromatic.

[0035] As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. , 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2. l]heptanyl, 2,5-diazabicyclo[2.2. l]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, l,4-dioxa-8-azaspiro[4.5]decanyl, l,4-dioxaspiro[4.5]decanyl, 1- oxaspiro[4.5]decanyl, l-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-l,l'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-l,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-l,l'-furo[3,4- c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1, 4,5,6- tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4, 5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2- azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa- azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of multi cyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic.

[0036] As used herein, the term “aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. Conveniently, an aryl is phenyl.

[0037] As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. _s 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur. The nitrogen atom may be substituted or unsubstituted ( . e. , N or NR wherein R is H or other substituents, as defined). The nitrogen and sulphur heteroatoms may optionally be oxidised ( . e. , N^O and S(O) _P , where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multi cyclic system (e.g., 4, 5,6,7- tetrahydrobenzo[c]isoxazolyl).

[0038] Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodi oxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, indolizine.

[0039] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][l,3]dioxole-5-yl). As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (z.e., =0), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0040] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

[0041] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

[0042] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O'. [0043] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0044] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0045] As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0046] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, aryl carbonyl amino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and tri chi or om ethoxy .

[0047] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

[0048] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated those compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0049] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 ^th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3 ^rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser ’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the art

[0050] One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognise that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3 ^rd edition, John Wiley & Sons: New York, 1999.

[0051] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[0052] As used herein, the term “subject” is interchangeable with the term “subject in need thereof’, both of which refer to a subject having a disease or having an increased risk of developing the disease. A “subject” includes a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In one embodiment, the mammal is a human. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who has (e.g., is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (z.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that doesn't respond or hasn’t yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.

[0053] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model.

[0054] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition, or disorder, or used to identify suitable candidates for such purposes.

[0055] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0056] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3 ^rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18 ^th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

[0057] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any combination or compound described herein with at least one pharmaceutically acceptable excipient or carrier.

[0058] As used herein, the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0059] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0060] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

[0061] It is to be understood that a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulphite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0062] It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

[0063] As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0064] It is to be understood that, for any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0065] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0066] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilising processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

[0067] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0068] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0069] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0070] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebuliser.

[0071] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0072] The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. [0073] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0074] In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression.

[0075] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0076] It is to be understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure.

[0077] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulphonic, acetic, ascorbic, benzene sulphonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulphonic, 1,2-ethane sulphonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulphonic, maleic, malic, mandelic, methane sulphonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulphamic, sulphanilic, sulphuric, tannic, tartaric, toluene sulphonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0078] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0079] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulphonic acid, 2-naphthalenesulphonic acid, 4- toluenesulphonic acid, camphorsulphonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l- carboxylic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1 : 1, or any ratio other than 1 : 1, e.g., 3: 1, 2: 1, 1 :2, or 1 :3.

[0080] It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0081] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognise the advantages of certain routes of administration.

[0082] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19 ^th edition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

[0083] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0084] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

[0085] As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein, both generically and specifically.

[0086] Treating cancer can result in a reduction in size of a tumor. A reduction in size of a tumor may also be referred to as “tumor regression”. In some embodiments, after treatment, tumor size is reduced by 5% or greater, 10% or greater, 20% or greater, 30% or greater, 40% or greater, 50% or greater, or 75% or greater relative to its size prior to treatment. In some embodiments, after treatment, tumor size is reduced by 5% or greater relative to its size prior to treatment. In some embodiments, after treatment, tumor size is reduced by 10% or greater relative to its size prior to treatment. In some embodiments, after treatment, tumor size is reduced by 20% or greater relative to its size prior to treatment. In some embodiments, after treatment, tumor size is reduced by 30% or greater relative to its size prior to treatment. In some embodiments, after treatment, tumor size is reduced by 40% or greater relative to its size prior to treatment. In some embodiments, after treatment, tumor size is reduced by 50% or greater relative to its size prior to treatment. In some embodiments, after treatment, tumor size is reduced by 75% or greater relative to its size prior to treatment. Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor.

[0087] Treating cancer can result in a reduction in tumor volume. In some embodiments, after treatment, tumor volume is reduced by 5% or greater, 10% or greater, 20% or greater, 30% or greater, 40% or greater, 50% or greater, or 75% or greater relative to its volume prior to treatment. In some embodiments, after treatment, tumor volume is reduced by 5% or greater relative to its volume prior to treatment. In some embodiments, after treatment, tumor volume is reduced by 10% or greater relative to its volume prior to treatment. In some embodiments, after treatment, tumor volume is reduced by 20% or greater relative to its volume prior to treatment. In some embodiments, after treatment, tumor volume is reduced by 30% or greater relative to its volume prior to treatment. In some embodiments, after treatment, tumor volume is reduced by 40% or greater relative to its volume prior to treatment. In some embodiments, after treatment, tumor volume is reduced by 50% or greater relative to its volume prior to treatment. In some embodiments, after treatment, tumor volume is reduced by 75% or greater relative to its volume prior to treatment. Tumor volume may be measured by any reproducible means of measurement.

[0088] Treating cancer results in a decrease in number of tumors. In some embodiments, after treatment, tumor number is reduced by 5% or greater, 10% or greater, 20% or greater, 30% or greater, 40% or greater, 50% or greater, or 75% or greater relative to its number prior to treatment. In some embodiments, after treatment, tumor number is reduced by 5% or greater relative to its number prior to treatment. In some embodiments, after treatment, tumor number is reduced by 10% or greater relative to its number prior to treatment. In some embodiments, after treatment, tumor number is reduced by 20% or greater relative to its number prior to treatment. In some embodiments, after treatment, tumor number is reduced by 30% or greater relative to its number prior to treatment. In some embodiments, after treatment, tumor number is reduced by 40% or greater relative to its number prior to treatment. In some embodiments, after treatment, tumor number is reduced by 50% or greater relative to its number prior to treatment. In some embodiments, after treatment, tumor number is reduced by 75% or greater relative to its number prior to treatment. Number of tumors may be measured by any reproducible means of measurement. The number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification. Preferably, the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.

[0089] Treating cancer can result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site. In some embodiments, after treatment, number of metastatic lesions is reduced by 5% or greater, 10% or greater, 20% or greater, 30% or greater, 40% or greater, 50% or greater, or 75% or greater relative to its number of metastatic lesions prior to treatment. In some embodiments, after treatment, number of metastatic lesions is reduced by 5% or greater relative to its number of metastatic lesions prior to treatment. In some embodiments, after treatment, number of metastatic lesions is reduced by 10% or greater relative to its number of metastatic lesions prior to treatment. In some embodiments, after treatment, number of metastatic lesions is reduced by 20% or greater relative to its number of metastatic lesions prior to treatment. In some embodiments, after treatment, number of metastatic lesions is reduced by 30% or greater relative to its number of metastatic lesions prior to treatment. In some embodiments, after treatment, number of metastatic lesions is reduced by 40% or greater relative to its number of metastatic lesions prior to treatment. In some embodiments, after treatment, number of metastatic lesions is reduced by 50% or greater relative to its number of metastatic lesions prior to treatment. In some embodiments, after treatment, number of metastatic lesions is reduced by 75% or greater relative to its number of metastatic lesions prior to treatment. The number of metastatic lesions may be measured by any reproducible means of measurement. The number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. In some embodiments, the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.

[0090] Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone. In some embodiments, the average survival time is increased by more than 30 days, more than 60 days, more than 90 days, more than 120 days. In some embodiments, the average survival time is increased by more than 30 days. In some embodiments, the average survival time is increased by more than 60 days. In some embodiments, the average survival time is increased by more than 90 days. In some embodiments, the average survival time is increased by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

[0091] Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects. In some embodiments, the average survival time is increased by more than 30 days, more than 60 days, more than 90 days, or more than 120 days. In some embodiments, the average survival time is increased by more than 30 days. In some embodiments, the average survival time is increased by more than 60 days. In some embodiments, the average survival time is increased by more than 90 days. In some embodiments, the average survival time is increased by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

[0092] Treating cancer can result in increase in average survival time of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the average survival time is increased by more than 30 days, more than 60 days, more than 90 days, or more than 120 days. In some embodiments, the average survival time is increased by more than 30 days. In some embodiments, the average survival time is increased by more than 60 days. In some embodiments, the average survival time is increased by more than 90 days. In some embodiments, the average survival time is increased by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

[0093] Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving carrier alone. Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the mortality rate is decreased by more than 2%, more than 5%, more than 10%, or more than 25%. In some embodiments, the mortality rate is decreased by more than 2%. In some embodiments, the mortality rate is decreased by more than 5%. In some embodiments, the mortality rate is decreased by more than 10%. In some embodiments, the mortality rate is decreased by more than 25%. A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means. A decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound.

[0094] Treating cancer can result in a decrease in tumor growth rate. In some embodiments, after treatment, tumor growth rate is reduced by at least 5% at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 75% relative to number prior to treatment. Tumor growth rate may be measured by any reproducible means of measurement. Tumor growth rate can be measured according to a change in tumor diameter per unit time. [0095] Treating cancer can result in a decrease in tumor regrowth. In some embodiments, after treatment, tumor regrowth is less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, or less than 75%. Tumor regrowth may be measured by any reproducible means of measurement. Tumor regrowth is measured, for example, by measuring an increase in the diameter of a tumor after a prior tumor shrinkage that followed treatment. A decrease in tumor regrowth is indicated by failure of tumors to reoccur after treatment has stopped.

[0096] As used herein, the term “selectively” means tending to occur at a higher frequency in one population than in another population. The compared populations can be cell populations. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, acts selectively on a cancer or precancerous cell but not on a normal cell. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, acts selectively to modulate one molecular target (e.g., a target kinase) but does not significantly modulate another molecular target (e.g., a non-target kinase). The disclosure also provides a method for selectively inhibiting the activity of an enzyme, such as PDK1. In some embodiments, an event occurs selectively in population A relative to population B if it occurs greater than two times more frequently in population A as compared to population B. In some embodiments, an event occurs selectively if it occurs greater than five times more frequently in population A. In some embodiments, an event occurs selectively if it occurs greater than ten times, greater than fifty times, greater than 100 times, or greater than 1000 times more frequently in population A as compared to population B. For example, cell death would be said to occur selectively in cancer cells if it occurred greater than twice as frequently in cancer cells as compared to normal cells. [0097] A compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, can modulate the activity of a molecular target (e.g., PDK1). Modulating refers to stimulating or inhibiting an activity of a molecular target. In some embodiments, a combination of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, modulates the activity of a molecular target if it stimulates or inhibits the activity of the molecular target by at least 2-fold relative to the activity of the molecular target under the same conditions but lacking only the presence of the compound. In some embodiments, a combination of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, modulates the activity of a molecular target if it stimulates or inhibits the activity of the molecular target by at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold relative to the activity of the molecular target under the same conditions but lacking only the presence of the compound. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent modulate the activity of a molecular target if it stimulates or inhibits the activity of the molecular target by at least 2-fold relative to the activity of the molecular target under the same conditions but lacking only the presence of the compound. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent modulate the activity of a molecular target if it stimulates or inhibits the activity of the molecular target by at least 5- fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold relative to the activity of the molecular target under the same conditions but lacking only the presence of the compound. The activity of a molecular target may be measured by any reproducible means. The activity of a molecular target may be measured in vitro or in vivo.

[0098] Administering a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent to a cell or a subject in need thereof can result in modulation (i.e., stimulation or inhibition) of an activity of a kinase of interest.

[0099] A change in enzymatic activity caused by a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent can be measured in the disclosed assays.

[0100] As used herein, “combination therapy” or “co-therapy” includes the administration of at least two compounds of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these at least two compounds of the present disclosure. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of these at least two compounds of the present disclosure. Administration of these at least two compounds of the present disclosure in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). “Combination therapy” may be, but generally is not, intended to encompass the administration of two or more of these compounds of the present disclosure as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present disclosure.

[0101] “ Combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous manner as used herein is administration of the at least two therapeutic agents within 1 hour of each other. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single composition having a fixed ratio of each therapeutic agent or in separate capsules for each of the therapeutic agents. Sequential manner as used herein is administration of one of the at least two therapeutic agents more than one hour after the other of the at least two therapeutic agents. In some embodiments, for sequential administration, one of the at least two therapeutic agents is administered at least 12 hours, at least 24 hours, at least 48 hours, at least 96 hours, or at least one week after administration of the other therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered in temporal proximity. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. In some embodiments, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical.

[0102] “ Combination therapy” also embraces the administration of the at least two compounds of the present disclosure as described above in further combination with other biologically active ingredients and non-drug therapies e.g., surgery or radiation treatment). Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the coaction of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

[0103] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, may be administered with second therapeutic agent (e.g., an inhibitor of an enzyme, such as a receptor or non-receptor kinase). Receptor and non-receptor kinases of the disclosure are, for example, tyrosine kinases or serine/threonine kinases. Kinase inhibitors of the disclosure are small molecules, polynucleic acids, polypeptides, or antibodies.

[0104] In some embodiments, the second therapeutic agent is a PI3K (e.g., PI3Ka, also known as PI3Ka) inhibitor.

[0105] In some embodiments, the second therapeutic agent is a CDK4/6 inhibitor.

[0106] In some embodiments, the second therapeutic agent is a BCL2 inhibitor.

[0107] In some embodiments, exemplary kinase inhibitors include, but are not limited to, those disclosed in Table A.

Table A

[0108] In the present disclosure, the structural formula of the compound(s) represents a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like.

[0109] “Isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereoisomers”, and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture”.

[0110] A carbon atom bonded to four nonidentical substituents is termed a “chiral center”. [0111] “ Chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture”. When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0112] “ Geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0113] Furthermore, the structures and other compounds discussed in this disclosure include all atropic isomers thereof. “Atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques; it has been possible to separate mixtures of two atropic isomers in select cases.

[0114] “ Tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solid form, usually one tautomer predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism. [0115] Additionally, the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0116] “ Solvate” means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0117] The term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonimides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0118] The present disclosure is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14. [0119] “Pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable carriers and/or diluents include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds.

[0120] The pharmaceutical compositions of the present teachings optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 ^th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. The carriers, diluents and/or excipients are “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0121] The term “pharmaceutically acceptable salt” refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit/risk ratio. Pharmaceutically-acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0122] Included in the present teachings are pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic acid, benzenesulfonic, benzoic, ethanesulfonic, methanesulfonic, succinic, and tri fluoroacetic acid acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). [0123] The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g. , Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergam on; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0124] In addition, the disclosed PDK1 inhibitors can be co-administered with other therapeutic agents. As used herein, the terms “co-administration”, “administered in combination with”, and their grammatical equivalents, are meant to encompass administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times. In some embodiments the one or more compounds described herein will be co-administered with other agents. These terms encompass administration of two or more agents to the subject so that both agents and/or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present. Thus, in some embodiments, the compounds described herein and the other agent(s) are administered in a single composition. In some embodiments, the compounds described herein and the other agent(s) are admixed in the composition.

Combinations

[0125] In one aspect, the present disclosure provides, a pharmaceutical combination comprising a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0126] In one aspect, the present disclosure provides, a method of treating or preventing a disease or disorder, comprising administering to a subject in need thereof a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. [0127] In one aspect, the present disclosure provides, a method of treating a disease or disorder, comprising administering to a subject in need thereof a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. [0128] In one aspect, the present disclosure provides, a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for use in combination in treating or preventing a disease or disorder in a subject in need thereof.

[0129] In one aspect, the present disclosure provides, a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for use in combination in treating a disease or disorder in a subject in need thereof.

[0130] In one aspect, the present disclosure provides, a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination with a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof in treating or preventing a disease or disorder in a subject in need thereof. [0131] In one aspect, the present disclosure provides, a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination with a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof in treating a disease or disorder in a subject in need thereof.

[0132] In one aspect, the present disclosure provides, a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in a combinational therapy with a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof in treating or preventing a disease or disorder in a subject in need thereof.

[0133] In one aspect, the present disclosure provides, a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in a combinational therapy with a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof in treating a disease or disorder in a subject in need thereof.

[0134] In one aspect, the present disclosure provides, a composition comprising a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for use in treating or preventing a disease or disorder in a subject in need thereof. [0135] In one aspect, the present disclosure provides, a composition comprising a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for use in treating a disease or disorder in a subject in need thereof.

[0136] In one aspect, the present disclosure provides, a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof in the manufacture of a medicament for the combinatorial treatment or prevention of a disease or disorder in a subject in need thereof.

[0137] In one aspect, the present disclosure provides, a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof in the manufacture of a medicament for the combinatorial treatment of a disease or disorder in a subject in need thereof.

[0138] In one aspect, the present disclosure provides, use of a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a disease or disorder in a subject in need thereof.

[0139] In one aspect, the present disclosure provides, use of a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment of a disease or disorder in a subject in need thereof.

[0140] In one aspect, the present disclosure provides, use of a composition comprising a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof in the manufacture of a medicament for the treatment or prevention of a disease or disorder in a subject in need thereof.

[0141] In one aspect, the present disclosure provides, use of a composition comprising a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof in the manufacture of a medicament for the treatment of a disease or disorder in a subject in need thereof. [0142] In some embodiments, the PDK1 inhibitor is a compound selected from Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0143] In some embodiments, the PDK1 inhibitor is a compound selected from Table 1. [0144] In some embodiments, the second therapeutic agent comprises an PI3K inhibitor. [0145] In some embodiments, the second therapeutic agent is selected from Table A.

[0146] In some embodiments, the second therapeutic agent is alpelisib.

[0147] In some embodiments, the combination is in the same pharmaceutical composition.

[0148] In some embodiments, the disease or disorder can be ameliorated by inhibition of PDK1.

[0149] In some embodiments, the disease or disorder can be ameliorated by inhibition of PDK1 and PI3K.

[0150] In some embodiments, the PI3K is PI3Ka.

[0151] In some embodiments, the disease or disorder is a cancer.

[0152] In some embodiments, the cancer is a hematologic cancer.

[0153] In some embodiments, the hematologic cancer is selected from a leukemia, lymphoma, and myeloma.

[0154] In some embodiments, the hematologic cancer is selected from anaplastic large-cell lymphoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, histiocytic lymphoma, T-cell leukemia, chronic lymphocytic leukemia, multiple myeloma, chronic myelogenous leukemia, acute lymphocytic (lymphoblastic) leukemia, acute myelogenous leukemia, acute myeloblastic leukemia, and plasma cell leukemia.

[0155] In some embodiments, the hematologic cancer is anaplastic large-cell lymphoma.

[0156] In some embodiments, the hematologic cancer is non-Hodgkin’s lymphoma.

[0157] In some embodiments, the hematologic cancer is Hodgkin’s lymphoma.

[0158] In some embodiments, the hematologic cancer is B-cell lymphoma.

[0159] In some embodiments, the hematologic cancer is T-cell lymphoma.

[0160] In some embodiments, the hematologic cancer is mantle cell lymphoma.

[0161] In some embodiments, the hematologic cancer is histiocytic lymphoma.

[0162] In some embodiments, the hematologic cancer is T-cell leukemia.

[0163] In some embodiments, the hematologic cancer is chronic lymphocytic leukemia.

[0164] In some embodiments, the hematologic cancer is multiple myeloma.

[0165] In some embodiments, the hematologic cancer is chronic myelogenous leukemia. [0166] In some embodiments, the hematologic cancer is acute lymphocytic (lymphoblastic) leukemia.

[0167] In some embodiments, the hematologic cancer is acute myelogenous leukemia. [0168] In some embodiments, the hematologic cancer is acute myeloblastic leukemia. [0169] In some embodiments, the hematologic cancer is plasma cell leukemia.

[0170] In some embodiments, the cancer is a solid tumor.

[0171] In some embodiments, the cancer is a breast cancer.

[0172] In some embodiments, the subject is a human.

[0173] In some embodiments, the PDK1 inhibitor and second therapeutic agent are administered in temporal proximity, sequentially, in alternation, in the same formulation, or as different formulation.

[0174] In some embodiments, the PDK1 inhibitor and the second therapeutic agent are administered simultaneously. In some embodiments, the PDK1 inhibitor and the second therapeutic agent are administered consecutively. In some embodiments, the PDK1 inhibitor is administered prior to the second therapeutic agent. In some embodiments, the second therapeutic agent is administered prior to the PDK1 inhibitor. In some embodiments, the PDK1 inhibitor and the second therapeutic agent are administered on the same day. In some embodiments, the PDK1 inhibitor and the second therapeutic agent are administered on different days. In some embodiments, the PDK1 inhibitor and the second therapeutic agent are administered in temporal proximity.

[0175] In some embodiments, the PDK1 inhibitor and the second therapeutic agent are administered in the same formulation. In some embodiments, the PDK1 inhibitor and the second therapeutic agent are administered in different formulations.

[0176] In one aspect, the present disclosure provides, a kit comprising a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. [0177] In one aspect, the present disclosure provides, a pharmaceutical package comprising a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0178] In some embodiments, the kit or pharmaceutical package further comprises instructions for use.

[0179] In some embodiments, the kit or pharmaceutical package is a combinatorial product. [0180] In some embodiments, the PDK1 inhibitor is administered 1-7 times per week. In some embodiments, the second therapeutic agent is administered on consecutive days. [0181] In some embodiments, the PDK1 inhibitor is administered 2-7 times per week. In some embodiments, the PDK1 inhibitor is administered on consecutive days. In some embodiments, the PDK1 inhibitor is administered 2-6 times per week. In some embodiments, the PDK1 inhibitor is administered 2-5 times per week. In some embodiments, the PDK1 inhibitor is administered 2-4 times per week. In some embodiments, the PDK1 inhibitor is administered 2-3 times per week. In some embodiments, the PDK1 inhibitor is administered on consecutive days.

[0182] In some embodiments, the PDK1 inhibitor is administered 3-6 times per week. In some embodiments, the PDK1 inhibitor is administered 3-5 times per week. In some embodiments, the PDK1 inhibitor is administered 3-4 times per week. In some embodiments, the PDK1 inhibitor is administered on consecutive days.

[0183] In some embodiments, the PDK1 inhibitor is administered 4-6 times per week. In some embodiments, the PDK1 inhibitor is administered 4-5 times per week. In some embodiments, the PDK1 inhibitor is administered on consecutive days.

[0184] In some embodiments, the PDK1 inhibitor is administered 5-6 times per week. In some embodiments, the PDK1 inhibitor is administered on consecutive days.

[0185] In some embodiments, the PDK1 inhibitor is administered at least 2 times per week. In some embodiments, the PDK1 inhibitor is administered on consecutive days.

[0186] In some embodiments, the PDK1 inhibitor is administered at least 3 times per week. In some embodiments, the PDK1 inhibitor is administered on consecutive days.

[0187] In some embodiments, the PDK1 inhibitor is administered at least 4 times per week. In some embodiments, the PDK1 inhibitor is administered on consecutive days.

[0188] In some embodiments, the PDK1 inhibitor is administered at least 5 times per week. In some embodiments, the PDK1 inhibitor is administered on consecutive days.

[0189] In some embodiments, the PDK1 inhibitor is administered at least 6 times per week. In some embodiments, the PDK1 inhibitor is administered on consecutive days.

[0190] In some embodiments, the PDK1 inhibitor is administered 1-7 times per week, and the second therapeutic agent is administered on consecutive days.

[0191] In some embodiments, the PDK1 inhibitor is administered 2-7 times per week, and the second therapeutic agent is administered on consecutive days. In some embodiments, the PDK1 inhibitor is administered 2-6 times per week, and the second therapeutic agent is administered on consecutive days. In some embodiments, the PDK1 inhibitor is administered 2-5 times per week, and the second therapeutic agent is administered on consecutive days. In some embodiments, the PDK1 inhibitor is administered 2-4 times per week, and the second therapeutic agent is administered on consecutive days. In some embodiments, the PDK1 inhibitor is administered 2-3 times per week, and the second therapeutic agent is administered on consecutive days.

[0192] In some embodiments, the PDK1 inhibitor is administered 3-6 times per week, and the second therapeutic agent is administered on consecutive days. In some embodiments, the PDK1 inhibitor is administered 3-5 times per week, and the second therapeutic agent is administered on consecutive days. In some embodiments, the PDK1 inhibitor is administered 3-4 times per week, and the second therapeutic agent is administered on consecutive days. [0193] In some embodiments, the PDK1 inhibitor is administered 4-6 times per week, and the second therapeutic agent is administered on consecutive days. In some embodiments, the PDK1 inhibitor is administered 4-5 times per week, and the second therapeutic agent is administered on consecutive days.

[0194] In some embodiments, the PDK1 inhibitor is administered 5-6 times per week, and the second therapeutic agent is administered on consecutive days.

[0195] In some embodiments, the PDK1 inhibitor is administered 1-7 times per week, and the second therapeutic agent is administered once daily.

[0196] In some embodiments, the PDK1 inhibitor is administered 2-7 times per week, and the second therapeutic agent is administered once daily. In some embodiments, the PDK1 inhibitor is administered 2-6 times per week, and the second therapeutic agent is administered once daily. In some embodiments, the PDK1 inhibitor is administered 2-5 times per week, and the second therapeutic agent is administered once daily. In some embodiments, the PDK1 inhibitor is administered 2-4 times per week, and the second therapeutic agent is administered once daily. In some embodiments, the PDK1 inhibitor is administered 2-3 times per week, and the second therapeutic agent is administered once daily.

[0197] In some embodiments, the PDK1 inhibitor is administered 3-6 times per week, and the second therapeutic agent is administered once daily. In some embodiments, the PDK1 inhibitor is administered 3-5 times per week, and the second therapeutic agent is administered once daily. In some embodiments, the PDK1 inhibitor is administered 3-4 times per week, and the second therapeutic agent is administered once daily.

[0198] In some embodiments, the PDK1 inhibitor is administered 4-6 times per week, and the second therapeutic agent is administered once daily. In some embodiments, the PDK1 inhibitor is administered 4-5 times per week, and the second therapeutic agent is administered once daily. [0199] In some embodiments, the PDK1 inhibitor is administered 5-6 times per week, and the second therapeutic agent is administered once daily.

[0200] In some embodiments, the PDK1 inhibitor is administered 1-7 times per week, and the second therapeutic agent is administered once or twice weekly.

[0201] In some embodiments, the PDK1 inhibitor is administered 2-7 times per week, and the second therapeutic agent is administered once or twice weekly. In some embodiments, the PDK1 inhibitor is administered 2-6 times per week, and the second therapeutic agent is administered once or twice weekly. In some embodiments, the PDK1 inhibitor is administered 2-5 times per week, and the second therapeutic agent is administered once or twice weekly. In some embodiments, the PDK1 inhibitor is administered 2-4 times per week, and the second therapeutic agent is administered once or twice weekly. In some embodiments, the PDK1 inhibitor is administered 2-3 times per week, and the second therapeutic agent is administered once or twice weekly.

[0202] In some embodiments, the PDK1 inhibitor is administered 3-6 times per week, and the second therapeutic agent is administered once or twice weekly. In some embodiments, the PDK1 inhibitor is administered 3-5 times per week, and the second therapeutic agent is administered once or twice weekly. In some embodiments, the PDK1 inhibitor is administered 3-4 times per week, and the second therapeutic agent is administered once or twice weekly.

[0203] In some embodiments, the PDK1 inhibitor is administered 4-6 times per week, and the second therapeutic agent is administered once or twice weekly. In some embodiments, the PDK1 inhibitor is administered 4-5 times per week, and the second therapeutic agent is administered once or twice weekly.

[0204] In some embodiments, the PDK1 inhibitor is administered 5-6 times per week, and the second therapeutic agent is administered once or twice weekly.

[0205] In some embodiments, the PDK1 inhibitor and a second therapeutic agent are administered once daily.

[0206] In some embodiments, the PDK1 inhibitor and a second therapeutic agent are administered once daily for one day per week.

[0207] In some embodiments, the PDK1 inhibitor and a second therapeutic agent are administered once daily for two days per week.

[0208] In some embodiments, the PDK1 inhibitor and a second therapeutic agent are administered once daily for three days per week. [0209] In some embodiments, the PDK1 inhibitor and a second therapeutic agent are administered once daily for four days per week.

[0210] In some embodiments, the PDK1 inhibitor and a second therapeutic agent are administered once daily for five days per week.

[0211] In some embodiments, the PDK1 inhibitor and a second therapeutic agent are administered once daily for six days per week.

[0212] In some embodiments, the PDK1 inhibitor and a second therapeutic agent are administered once daily for seven days per week.

[0213] In some embodiment, the PDK1 inhibitor and a second therapeutic agent are administered without a dosing holiday.

[0214] In some embodiment, the PDK1 inhibitor and a second therapeutic agent are administered with a dosing holiday.

[0215] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof and the second therapeutic agent are administered simultaneously. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof and the second therapeutic agent are administered consecutively. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered prior to the second therapeutic agent. In some embodiments, the second therapeutic agent is administered prior to Compound 1 or the pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof and the second therapeutic agent are administered on the same day. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof and the second therapeutic agent are administered on different days.

[0216] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 1-7 times per week. In some embodiments, the second therapeutic agent is administered on consecutive days.

[0217] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-7 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered on consecutive days.

[0218] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-6 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-5 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2- 4 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-3 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered on consecutive days.

[0219] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 3-6 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 3-5 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 3- 4 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered on consecutive days.

[0220] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 4-6 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 4-5 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered on consecutive days.

[0221] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 5-6 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered on consecutive days.

[0222] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered at least 2 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered on consecutive days.

[0223] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered at least 3 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered on consecutive days.

[0224] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered at least 4 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered on consecutive days.

[0225] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered at least 5 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered on consecutive days.

[0226] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered at least 6 times per week. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered on consecutive days.

[0227] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 1-7 times per week, and the second therapeutic agent is administered on consecutive days.

[0228] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-7 times per week, and the second therapeutic agent is administered on consecutive days.

[0229] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-6 times per week, and the second therapeutic agent is administered on consecutive days. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-5 times per week, and the second therapeutic agent is administered on consecutive days. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-4 times per week, and the second therapeutic agent is administered on consecutive days. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-3 times per week, and the second therapeutic agent is administered on consecutive days.

[0230] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 3-6 times per week, and the second therapeutic agent is administered on consecutive days. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 3-5 times per week, and the second therapeutic agent is administered on consecutive days. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 3-4 times per week, and the second therapeutic agent is administered on consecutive days.

[0231] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 4-6 times per week, and the second therapeutic agent is administered on consecutive days. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 4-5 times per week, and the second therapeutic agent is administered on consecutive days.

[0232] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 5-6 times per week, and the second therapeutic agent is administered on consecutive days.

[0233] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 1-7 times per week, and the second therapeutic agent is administered once daily. [0234] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-7 times per week, and the second therapeutic agent is administered once daily. [0235] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-6 times per week, and the second therapeutic agent is administered once daily. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-5 times per week, and the second therapeutic agent is administered once daily. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-4 times per week, and the second therapeutic agent is administered once daily. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-3 times per week, and the second therapeutic agent is administered once daily. [0236] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 3-6 times per week, and the second therapeutic agent is administered once daily. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 3-5 times per week, and the second therapeutic agent is administered once daily. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 3-4 times per week, and the second therapeutic agent is administered once daily. [0237] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 4-6 times per week, and the second therapeutic agent is administered once daily. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 4-5 times per week, and the second therapeutic agent is administered once daily. [0238] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 5-6 times per week, and the second therapeutic agent is administered once daily. [0239] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 1-7 times per week, and the second therapeutic agent is administered once or twice weekly.

[0240] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-7 times per week, and the second therapeutic agent is administered once or twice weekly.

[0241] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-6 times per week, and the second therapeutic agent is administered once or twice weekly. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-5 times per week, and the second therapeutic agent is administered once or twice weekly. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-4 times per week, and the second therapeutic agent is administered once or twice weekly. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 2-3 times per week, and the second therapeutic agent is administered once or twice weekly.

[0242] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 3-6 times per week, and the second therapeutic agent is administered once or twice weekly. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 3-5 times per week, and the second therapeutic agent is administered once or twice weekly. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 3-4 times per week, and the second therapeutic agent is administered once or twice weekly.

[0243] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 4-6 times per week, and the second therapeutic agent is administered once or twice weekly. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 4-5 times per week, and the second therapeutic agent is administered once or twice weekly.

[0244] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered 5-6 times per week, and the second therapeutic agent is administered once or twice weekly.

[0245] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof and a second therapeutic agent are administered once daily for one day per week.

[0246] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof and a second therapeutic agent are administered once daily for two days per week.

[0247] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof and a second therapeutic agent are administered once daily for three days per week.

[0248] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof and a second therapeutic agent are administered once daily for four days per week.

[0249] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof and a second therapeutic agent are administered once daily for five days per week.

[0250] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof and a second therapeutic agent are administered once daily for six days per week.

[0251] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof and a second therapeutic agent are administered once daily for seven days per week.

[0252] In some embodiment, Compound 1 or the pharmaceutically acceptable salt thereof and a second therapeutic agent are administered without a dosing holiday.

[0253] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof and a second therapeutic agent are administered followed by a dosing holiday.

[0254] In some embodiments, the daily doses described herein are administered via one administration, two administrations, or three administrations. In some embodiments, the daily doses described herein are administered via one administration. In some embodiments, the daily doses described herein are administered via two administrations. In some embodiments, the daily doses described herein are administered via three administrations.

[0255] In some embodiments, the dosage regimen can include administration, for example, at the dosing regimen disclosed herein, for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least ten weeks, at least twelve weeks, at least sixteen weeks, at least six months, at least eight months, at least twelve months, at least eighteen months, at least two years, at least five years, or at least ten years.

[0256] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 200 mg/m ² .

[0257] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 5 mg/m ² to about 200 mg/m ² .

[0258] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/m ² to about 200 mg/m ² .

[0259] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 15 mg/m ² to about 200 mg/m ² .

[0260] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 20 mg/m ² to about 200 mg/m ² .

[0261] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 25 mg/m ² to about 200 mg/m ² .

[0262] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 30 mg/m ² to about 200 mg/m ² .

[0263] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 35 mg/m ² to about 200 mg/m ² .

[0264] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 40 mg/m ² to about 200 mg/m ² .

[0265] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 45 mg/m ² to about 200 mg/m ² .

[0266] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 50 mg/m ² to about 200 mg/m ² .

[0267] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 55 mg/m ² to about 200 mg/m ² .

[0268] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 60 mg/m ² to about 200 mg/m ² . [0269] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 65 mg/m ² to about 200 mg/m ² .

[0270] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 70 mg/m ² to about 200 mg/m ² .

[0271] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 75 mg/m ² to about 200 mg/m ² .

[0272] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 80 mg/m ² to about 200 mg/m ² .

[0273] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 85 mg/m ² to about 200 mg/m ² .

[0274] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 90 mg/m ² to about 200 mg/m ² .

[0275] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 95 mg/m ² to about 200 mg/m ² .

[0276] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 100 mg/m ² to about 200 mg/m ² .

[0277] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 110 mg/m ² to about 200 mg/m ² .

[0278] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 120 mg/m ² to about 200 mg/m ² .

[0279] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 130 mg/m ² to about 200 mg/m ² .

[0280] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 140 mg/m ² to about 200 mg/m ² .

[0281] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 150 mg/m ² to about 200 mg/m ² .

[0282] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 160 mg/m ² to about 200 mg/m ² .

[0283] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 170 mg/m ² to about 200 mg/m ² .

[0284] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 180 mg/m ² to about 200 mg/m ² .

[0285] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 190 mg/m ² to about 200 mg/m ² . [0286] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 190 mg/m ² .

[0287] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 180 mg/m ² .

[0288] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 170 mg/m ² .

[0289] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 160 mg/m ² .

[0290] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 150 mg/m ² .

[0291] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 140 mg/m ² .

[0292] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 130 mg/m ² .

[0293] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 120 mg/m ² .

[0294] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 110 mg/m ² .

[0295] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 100 mg/m ² .

[0296] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 95 mg/m ² .

[0297] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 90 mg/m ² .

[0298] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 85 mg/m ² .

[0299] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 80 mg/m ² .

[0300] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 75 mg/m ² .

[0301] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 70 mg/m ² .

[0302] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 65 mg/m ² . [0303] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 60 mg/m ² .

[0304] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 55 mg/m ² .

[0305] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 50 mg/m ² .

[0306] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 45 mg/m ² .

[0307] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 40 mg/m ² .

[0308] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 35 mg/m ² .

[0309] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 30 mg/m ² .

[0310] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 25 mg/m ² .

[0311] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 20 mg/m ² .

[0312] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 15 mg/m ² .

[0313] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 10 mg/m ² .

[0314] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 5 mg/m ² .

[0315] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 1 mg/m ² .

[0316] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 5 mg/m ² .

[0317] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 10 mg/m ² .

[0318] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 15 mg/m ² .

[0319] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 20 mg/m ² . [0320] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 25 mg/m ² .

[0321] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 30 mg/m ² .

[0322] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 35 mg/m ² .

[0323] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 40 mg/m ² .

[0324] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 45 mg/m ² .

[0325] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 50 mg/m ² .

[0326] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 55 mg/m ² .

[0327] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 60 mg/m ² .

[0328] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 65 mg/m ² .

[0329] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 70 mg/m ² .

[0330] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 75 mg/m ² .

[0331] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 80 mg/m ² .

[0332] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 85 mg/m ² .

[0333] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 90 mg/m ² .

[0334] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 95 mg/m ² .

[0335] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 110 mg/m ² .

[0336] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 120 mg/m ² . [0337] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 130 mg/m ² .

[0338] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 140 mg/m ² .

[0339] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 150 mg/m ² .

[0340] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 160 mg/m ² .

[0341] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 170 mg/m ² .

[0342] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 180 mg/m ² .

[0343] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 190 mg/m ² .

[0344] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 200 mg/m ² .

[0345] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 5.1 mg/m ² .

[0346] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 25.8 mg/m ² .

[0347] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 51.6 mg/m ² .

[0348] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 200 mg/m ² .

[0349] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 5 mg/m ² to about 200 mg/m ² .

[0350] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/m ² to about 200 mg/m ² .

[0351] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 15 mg/m ² to about 200 mg/m ² .

[0352] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 20 mg/m ² to about 200 mg/m ² .

[0353] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 25 mg/m ² to about 200 mg/m ² . [0354] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 30 mg/m ² to about 200 mg/m ² .

[0355] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 35 mg/m ² to about 200 mg/m ² .

[0356] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 40 mg/m ² to about 200 mg/m ² .

[0357] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 45 mg/m ² to about 200 mg/m ² .

[0358] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 50 mg/m ² to about 200 mg/m ² .

[0359] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 55 mg/m ² to about 200 mg/m ² .

[0360] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 60 mg/m ² to about 200 mg/m ² .

[0361] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 65 mg/m ² to about 200 mg/m ² .

[0362] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 70 mg/m ² to about 200 mg/m ² .

[0363] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 75 mg/m ² to about 200 mg/m ² .

[0364] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 80 mg/m ² to about 200 mg/m ² .

[0365] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 85 mg/m ² to about 200 mg/m ² .

[0366] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 90 mg/m ² to about 200 mg/m ² .

[0367] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 95 mg/m ² to about 200 mg/m ² .

[0368] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 100 mg/m ² to about 200 mg/m ² .

[0369] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 110 mg/m ² to about 200 mg/m ² .

[0370] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 120 mg/m ² to about 200 mg/m ² . [0371] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 130 mg/m ² to about 200 mg/m ² .

[0372] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 140 mg/m ² to about 200 mg/m ² .

[0373] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 150 mg/m ² to about 200 mg/m ² .

[0374] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 160 mg/m ² to about 200 mg/m ² .

[0375] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 170 mg/m ² to about 200 mg/m ² .

[0376] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 180 mg/m ² to about 200 mg/m ² .

[0377] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 190 mg/m ² to about 200 mg/m ² .

[0378] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 190 mg/m ² .

[0379] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 180 mg/m ² .

[0380] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 170 mg/m ² .

[0381] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 160 mg/m ² .

[0382] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 150 mg/m ² .

[0383] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 140 mg/m ² .

[0384] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 130 mg/m ² .

[0385] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 120 mg/m ² .

[0386] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 110 mg/m ² .

[0387] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 100 mg/m ² . [0388] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 95 mg/m ² .

[0389] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 90 mg/m ² .

[0390] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 85 mg/m ² .

[0391] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 80 mg/m ² .

[0392] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 75 mg/m ² .

[0393] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 70 mg/m ² .

[0394] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 65 mg/m ² .

[0395] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 60 mg/m ² .

[0396] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 55 mg/m ² .

[0397] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 50 mg/m ² .

[0398] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 45 mg/m ² .

[0399] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 40 mg/m ² .

[0400] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 35 mg/m ² .

[0401] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 30 mg/m ² .

[0402] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 25 mg/m ² .

[0403] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 20 mg/m ² .

[0404] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 15 mg/m ² . [0405] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 10 mg/m ² .

[0406] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 5 mg/m ² .

[0407] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 1 mg/m ² .

[0408] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 5 mg/m ² .

[0409] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 10 mg/m ² .

[0410] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 15 mg/m ² .

[0411] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 20 mg/m ² .

[0412] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 25 mg/m ² .

[0413] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 30 mg/m ² .

[0414] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 35 mg/m ² .

[0415] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 40 mg/m ² .

[0416] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 45 mg/m ² .

[0417] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 50 mg/m ² .

[0418] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 55 mg/m ² .

[0419] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 60 mg/m ² .

[0420] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 65 mg/m ² .

[0421] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 70 mg/m ² . [0422] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 75 mg/m ² .

[0423] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 80 mg/m ² .

[0424] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 85 mg/m ² .

[0425] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 90 mg/m ² .

[0426] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 95 mg/m ² .

[0427] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 110 mg/m ² .

[0428] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 120 mg/m ² .

[0429] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 130 mg/m ² .

[0430] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 140 mg/m ² .

[0431] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 150 mg/m ² .

[0432] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 160 mg/m ² .

[0433] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 170 mg/m ² .

[0434] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 180 mg/m ² .

[0435] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 190 mg/m ² .

[0436] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 200 mg/m ² .

[0437] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 5.1 mg/m ² .

[0438] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 25.8 mg/m ² . [0439] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 51.6 mg/m ² .

[0440] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg.

[0441] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 20 mg/kg to about 300 mg/kg.

[0442] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 30 mg/kg to about 300 mg/kg.

[0443] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 40 mg/kg to about 300 mg/kg.

[0444] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 50 mg/kg to about 300 mg/kg.

[0445] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 60 mg/kg to about 300 mg/kg.

[0446] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 70 mg/kg to about 300 mg/kg.

[0447] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 80 mg/kg to about 300 mg/kg.

[0448] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 90 mg/kg to about 300 mg/kg.

[0449] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 100 mg/kg to about 300 mg/kg.

[0450] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 110 mg/kg to about 300 mg/kg.

[0451] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 120 mg/kg to about 300 mg/kg.

[0452] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 130 mg/kg to about 300 mg/kg.

[0453] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 140 mg/kg to about 300 mg/kg.

[0454] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 150 mg/kg to about 300 mg/kg.

[0455] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 160 mg/kg to about 300 mg/kg. [0456] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 170 mg/kg to about 300 mg/kg.

[0457] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 180 mg/kg to about 300 mg/kg.

[0458] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 190 mg/kg to about 300 mg/kg.

[0459] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 200 mg/kg to about 300 mg/kg.

[0460] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 210 mg/kg to about 300 mg/kg.

[0461] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 220 mg/kg to about 300 mg/kg.

[0462] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 230 mg/kg to about 300 mg/kg.

[0463] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 240 mg/kg to about 300 mg/kg.

[0464] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 250 mg/kg to about 300 mg/kg.

[0465] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 260 mg/kg to about 300 mg/kg.

[0466] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 270 mg/kg to about 300 mg/kg.

[0467] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 280 mg/kg to about 300 mg/kg.

[0468] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 290 mg/kg to about 300 mg/kg.

[0469] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 290 mg/kg.

[0470] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 280 mg/kg.

[0471] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 270 mg/kg.

[0472] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 260 mg/kg. [0473] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 250 mg/kg.

[0474] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 240 mg/kg.

[0475] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 230 mg/kg.

[0476] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 220 mg/kg.

[0477] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 210 mg/kg.

[0478] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 200 mg/kg.

[0479] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 190 mg/kg.

[0480] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 180 mg/kg.

[0481] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 170 mg/kg.

[0482] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 160 mg/kg.

[0483] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 150 mg/kg.

[0484] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 140 mg/kg.

[0485] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 130 mg/kg.

[0486] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 120 mg/kg.

[0487] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 110 mg/kg.

[0488] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 100 mg/kg.

[0489] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 90 mg/kg. [0490] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 80 mg/kg.

[0491] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 70 mg/kg.

[0492] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 60 mg/kg.

[0493] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 50 mg/kg.

[0494] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 40 mg/kg.

[0495] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 30 mg/kg.

[0496] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 20 mg/kg.

[0497] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 10 mg/kg.

[0498] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 20 mg/kg.

[0499] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 30 mg/kg.

[0500] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 40 mg/kg.

[0501] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 50 mg/kg.

[0502] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 60 mg/kg.

[0503] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 70 mg/kg.

[0504] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 80 mg/kg.

[0505] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 90 mg/kg.

[0506] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 100 mg/kg. [0507] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 110 mg/kg.

[0508] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 120 mg/kg.

[0509] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 130 mg/kg.

[0510] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 140 mg/kg.

[0511] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 150 mg/kg.

[0512] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 160 mg/kg.

[0513] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 170 mg/kg.

[0514] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 180 mg/kg.

[0515] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 190 mg/kg.

[0516] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 200 mg/kg.

[0517] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 210 mg/kg.

[0518] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 220 mg/kg.

[0519] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 230 mg/kg.

[0520] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 240 mg/kg.

[0521] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 250 mg/kg.

[0522] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 260 mg/kg.

[0523] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 270 mg/kg. [0524] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 280 mg/kg.

[0525] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 290 mg/kg.

[0526] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 300 mg/kg.

[0527] In some embodiments, PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 21.2 mg/kg.

[0528] In some embodiments, PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 107.5 mg/kg.

[0529] In some embodiments, PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 215 mg/kg.

[0530] In some embodiments, PDK1 inhibitor is administered at a dosage of about 1.7 mg/kg, about 8.6 mg/kg, or about 17.2 mg/kg.

[0531] In some embodiments, PDK1 inhibitor is orally administered at a dosage of about 1.7 mg/kg, about 8.6 mg/kg, or about 17.2 mg/kg.

[0532] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg.

[0533] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 20 mg/kg to about 300 mg/kg.

[0534] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 30 mg/kg to about 300 mg/kg.

[0535] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 40 mg/kg to about 300 mg/kg.

[0536] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 50 mg/kg to about 300 mg/kg.

[0537] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 60 mg/kg to about 300 mg/kg.

[0538] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 70 mg/kg to about 300 mg/kg.

[0539] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 80 mg/kg to about 300 mg/kg.

[0540] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 90 mg/kg to about 300 mg/kg. [0541] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 100 mg/kg to about 300 mg/kg.

[0542] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 110 mg/kg to about 300 mg/kg.

[0543] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 120 mg/kg to about 300 mg/kg.

[0544] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 130 mg/kg to about 300 mg/kg.

[0545] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 140 mg/kg to about 300 mg/kg.

[0546] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 150 mg/kg to about 300 mg/kg.

[0547] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 160 mg/kg to about 300 mg/kg.

[0548] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 170 mg/kg to about 300 mg/kg.

[0549] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 180 mg/kg to about 300 mg/kg.

[0550] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 190 mg/kg to about 300 mg/kg.

[0551] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 200 mg/kg to about 300 mg/kg.

[0552] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 210 mg/kg to about 300 mg/kg.

[0553] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 220 mg/kg to about 300 mg/kg.

[0554] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 230 mg/kg to about 300 mg/kg.

[0555] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 240 mg/kg to about 300 mg/kg.

[0556] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 250 mg/kg to about 300 mg/kg.

[0557] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 260 mg/kg to about 300 mg/kg. [0558] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 270 mg/kg to about 300 mg/kg.

[0559] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 280 mg/kg to about 300 mg/kg.

[0560] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 290 mg/kg to about 300 mg/kg.

[0561] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 290 mg/kg.

[0562] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 280 mg/kg.

[0563] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 270 mg/kg.

[0564] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 260 mg/kg.

[0565] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 250 mg/kg.

[0566] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 240 mg/kg.

[0567] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 230 mg/kg.

[0568] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 220 mg/kg.

[0569] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 210 mg/kg.

[0570] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 200 mg/kg.

[0571] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 190 mg/kg.

[0572] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 180 mg/kg.

[0573] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 170 mg/kg.

[0574] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 160 mg/kg. [0575] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 150 mg/kg.

[0576] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 140 mg/kg.

[0577] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 130 mg/kg.

[0578] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 120 mg/kg.

[0579] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 110 mg/kg.

[0580] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 100 mg/kg.

[0581] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 90 mg/kg.

[0582] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 80 mg/kg.

[0583] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 70 mg/kg.

[0584] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 60 mg/kg.

[0585] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 50 mg/kg.

[0586] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 40 mg/kg.

[0587] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 30 mg/kg.

[0588] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 20 mg/kg.

[0589] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 10 mg/kg.

[0590] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 20 mg/kg.

[0591] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 30 mg/kg. [0592] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 40 mg/kg.

[0593] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 50 mg/kg.

[0594] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 60 mg/kg.

[0595] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 70 mg/kg.

[0596] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 80 mg/kg.

[0597] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 90 mg/kg.

[0598] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 100 mg/kg.

[0599] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 110 mg/kg.

[0600] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 120 mg/kg.

[0601] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 130 mg/kg.

[0602] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 140 mg/kg.

[0603] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 150 mg/kg.

[0604] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 160 mg/kg.

[0605] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 170 mg/kg.

[0606] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 180 mg/kg.

[0607] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 190 mg/kg.

[0608] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 200 mg/kg. [0609] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 210 mg/kg.

[0610] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 220 mg/kg.

[0611] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 230 mg/kg.

[0612] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 240 mg/kg.

[0613] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 250 mg/kg.

[0614] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 260 mg/kg.

[0615] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 270 mg/kg.

[0616] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 280 mg/kg.

[0617] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 290 mg/kg.

[0618] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 300 mg/kg.

[0619] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 21.2 mg/kg.

[0620] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 107.5 mg/kg.

[0621] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 215 mg/kg.

[0622] In some embodiments, Compound 1 is administered at a dosage of about 1.7 mg/kg, about 8.6 mg/kg, or about 17.2 mg/kg.

[0623] In some embodiments, Compound 1 is orally administered at a dosage of about 1.7 mg/kg, about 8.6 mg/kg, or about 17.2 mg/kg.

[0624] In some embodiments, alpelisib is administered at a dosage (e.g., human dosage) range from about 50 mg/m ² to about 150 mg/m ² .

[0625] In some embodiments, alpelisib is administered at a dosage (e.g., human dosage) of about 75 mg/m ² . [0626] In some embodiments, alpelisib is administered at a dosage (e.g., human dosage) range from about 150 mg/kg to about 400 mg/kg.

[0627] In some embodiments, alpelisib is administered at a dosage (e.g., human dosage) of about 312.5 mg/kg.

[0628] In some embodiments, alpelisib is administered at a dosage range from about 1 mg/kg to about 400 mg/kg.

[0629] In some embodiments, alpelisib is administered at a dosage of about 25 mg/kg.

[0630] In some embodiments, alpelisib is orally administered at a dosage of about 25 mg/kg.

[0631] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 200 mg/m ² and alpelisib is administered at a dosage (e.g., human dosage) range from about 50 mg/m ² to about 150 mg/m ² .

[0632] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg and alpelisib is administered at a dosage (e.g., human dosage) range from about 150 mg/kg to about 400 mg/kg.

[0633] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg and alpelisib is administered at a dosage (e.g., human dosage) range from about 1 mg/kg to about 400 mg/kg.

[0634] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 200 mg/m ² and alpelisib is administered at a dosage (e.g., human dosage) range from about 50 mg/m ² to about 150 mg/m ² .

[0635] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg and alpelisib is administered at a dosage (e.g., human dosage) range from about 150 mg/kg to about 400 mg/kg.

[0636] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg and alpelisib is administered at a dosage (e.g., human dosage) range from about 1 mg/kg to about 400 mg/kg.

[0637] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 5.1 mg/m ² and alpelisib is administered at a dosage (e.g., human dosage) of about 75 mg/m ² .

[0638] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 25.8 mg/m ² and alpelisib is administered at a dosage (e.g., human dosage) of about 75 mg/m ² . [0639] In some embodiments, the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 51.6 mg/m ² and alpelisib is administered at a dosage (e.g., human dosage) of about 75 mg/m ² .

[0640] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 5.1 mg/m ² and alpelisib is administered at a dosage (e.g., human dosage) of about 75 mg/m ² .

[0641] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 25.8 mg/m ² and alpelisib is administered at a dosage (e.g., human dosage) of about 75 mg/m ² .

[0642] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 51.6 mg/m ² and alpelisib is administered at a dosage (e.g., human dosage) of about 75 mg/m ² .

[0643] In some embodiments, PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 21.2 mg/kg and alpelisib is administered at a dosage (e.g., human dosage) of about 312.5 mg/kg.

[0644] In some embodiments, PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 107.5 mg/kg and alpelisib is administered at a dosage (e.g., human dosage) of about 312.5 mg/kg.

[0645] In some embodiments, PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 215 mg/kg and alpelisib is administered at a dosage (e.g., human dosage) of about 312.5 mg/kg.

[0646] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 21.2 mg/kg and alpelisib is administered at a dosage (e.g., human dosage) of about

312.5 mg/kg.

[0647] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 107.5 mg/kg and alpelisib is administered at a dosage (e.g., human dosage) of about

312.5 mg/kg.

[0648] In some embodiments, Compound 1 is administered at a dosage (e.g., human dosage) of about 215 mg/kg and alpelisib is administered at a dosage (e.g., human dosage) of about

312.5 mg/kg.

[0649] In some embodiments, PDK1 inhibitor is administered at a dosage of about 1.7 mg/kg and alpelisib is administered at a dosage of about 25 mg/kg.

[0650] In some embodiments, PDK1 inhibitor is administered at a dosage of about 8.6 mg/kg and alpelisib is administered at a dosage of about 25 mg/kg. [0651] In some embodiments, PDK1 inhibitor is administered at a dosage of about 17.2 mg/kg and alpelisib is administered at a dosage of about 25 mg/kg.

[0652] In some embodiments, Compound 1 is administered at a dosage of about 1.7 mg/kg and alpelisib is administered at a dosage of about 25 mg/kg.

[0653] In some embodiments, Compound 1 is administered at a dosage of about 8.6 mg/kg and alpelisib is administered at a dosage of about 25 mg/kg.

[0654] In some embodiments, Compound 1 is administered at a dosage of about 17.2 mg/kg and alpelisib is administered at a dosage of about 25 mg/kg.

[0655] In some embodiments, the PDK1 inhibitor is orally administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 200 mg/m ² and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 50 mg/m ² to about 150 mg/m ² .

[0656] In some embodiments, the PDK1 inhibitor is orally administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 150 mg/kg to about 400 mg/kg.

[0657] In some embodiments, the PDK1 inhibitor is orally administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 1 mg/kg to about 400 mg/kg.

[0658] In some embodiments, Compound 1 is orally administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 200 mg/m ² and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 50 mg/m ² to about 150 mg/m ² .

[0659] In some embodiments, Compound 1 is orally administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 150 mg/kg to about 400 mg/kg.

[0660] In some embodiments, Compound 1 is orally administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 1 mg/kg to about 400 mg/kg.

[0661] In some embodiments, the PDK1 inhibitor is orally administered at a dosage (e.g., human dosage) of about 5.1 mg/m ² and alpelisib is orally administered at a dosage (e.g., human dosage) of about 75 mg/m ² . [0662] In some embodiments, the PDK1 inhibitor is orally administered at a dosage (e.g., human dosage) of about 25.8 mg/m ² and alpelisib is orally administered at a dosage (e.g., human dosage) of about 75 mg/m ² .

[0663] In some embodiments, the PDK1 inhibitor is orally administered at a dosage (e.g., human dosage) of about 51.6 mg/m ² and alpelisib is orally administered at a dosage (e.g., human dosage) of about 75 mg/m ² .

[0664] In some embodiments, Compound 1 is orally administered at a dosage (e.g., human dosage) of about 5.1 mg/m ² and alpelisib is orally administered at a dosage (e.g., human dosage) of about 75 mg/m ² .

[0665] In some embodiments, Compound 1 is orally administered at a dosage (e.g., human dosage) of about 25.8 mg/m ² and alpelisib is orally administered at a dosage (e.g., human dosage) of about 75 mg/m ² .

[0666] In some embodiments, Compound 1 is orally administered at a dosage (e.g., human dosage) of about 51.6 mg/m ² and alpelisib is orally administered at a dosage (e.g., human dosage) of about 75 mg/m ² .

[0667] In some embodiments, PDK1 inhibitor is orally administered at a dosage (e.g., human dosage) of about 21.2 mg/kg and alpelisib is orally administered at a dosage (e.g., human dosage) of about 312.5 mg/kg.

[0668] In some embodiments, PDK1 inhibitor is orally administered at a dosage (e.g., human dosage) of about 107.5 mg/kg and alpelisib is orally administered at a dosage (e.g., human dosage) of about 312.5 mg/kg.

[0669] In some embodiments, PDK1 inhibitor is orally administered at a dosage (e.g., human dosage) of about 215 mg/kg and alpelisib is orally administered at a dosage (e.g., human dosage) of about 312.5 mg/kg.

[0670] In some embodiments, Compound 1 is orally administered at a dosage (e.g., human dosage) of about 21.2 mg/kg and alpelisib is orally administered at a dosage (e.g., human dosage) of about 312.5 mg/kg.

[0671] In some embodiments, Compound 1 is orally administered at a dosage (e.g., human dosage) of about 107.5 mg/kg and alpelisib is orally administered at a dosage (e.g., human dosage) of about 312.5 mg/kg.

[0672] In some embodiments, Compound 1 is orally administered at a dosage (e.g., human dosage) of about 215 mg/kg and alpelisib is orally administered at a dosage (e.g., human dosage) of about 312.5 mg/kg. [0673] In some embodiments, PDK1 inhibitor is orally administered at a dosage of about 1.7 mg/kg and alpelisib is orally administered at a dosage of about 25 mg/kg.

[0674] In some embodiments, PDK1 inhibitor is orally administered at a dosage of about 8.6 mg/kg and alpelisib is orally administered at a dosage of about 25 mg/kg.

[0675] In some embodiments, PDK1 inhibitor is orally administered at a dosage of about 17.2 mg/kg and alpelisib is orally administered at a dosage of about 25 mg/kg.

[0676] In some embodiments, Compound 1 is orally administered at a dosage of about 1.7 mg/kg and alpelisib is orally administered at a dosage of about 25 mg/kg.

[0677] In some embodiments, Compound 1 is orally administered at a dosage of about 8.6 mg/kg and alpelisib is orally administered at a dosage of about 25 mg/kg.

[0678] In some embodiments, Compound 1 is orally administered at a dosage of about 17.2 mg/kg and alpelisib is orally administered at a dosage of about 25 mg/kg.

[0679] In some embodiments, the PDK1 inhibitor is orally administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 200 mg/m ² every three days for a dosing cycle of 28 days and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 50 mg/m ² to about 150 mg/m ² every day for a dosing cycle of 28 days. [0680] In some embodiments, the PDK1 inhibitor is orally administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg every three days for a dosing cycle of 28 days and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 150 mg/kg to about 400 mg/kg every day for a dosing cycle of 28 days.

[0681] In some embodiments, the PDK1 inhibitor is orally administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg every three days for a dosing cycle of 28 days and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 1 mg/kg to about 400 mg/kg every day for a dosing cycle of 28 days.

[0682] In some embodiments, Compound 1 is orally administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 200 mg/m ² every three days for a dosing cycle of 28 days and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 50 mg/m ² to about 150 mg/m ² every day for a dosing cycle of 28 days.

[0683] In some embodiments, Compound 1 is orally administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg every three days for a dosing cycle of 28 days and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 150 mg/kg to about 400 mg/kg every day for a dosing cycle of 28 days.

[0684] In some embodiments, Compound 1 is orally administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg every three days for a dosing cycle of 28 days and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 1 mg/kg to about 400 mg/kg every day for a dosing cycle of 28 days.

[0685] In some embodiments, PDK1 inhibitor is orally administered at a dosage of about 1.7 mg/kg every three days for a dosing cycle of 28 days and alpelisib is orally administered at a dosage of about 25 mg/kg every day for a dosing cycle of 28 days.

[0686] In some embodiments, PDK1 inhibitor is orally administered at a dosage (of about 8.6 mg/kg every three days for a dosing cycle of 28 days and alpelisib is orally administered at a dosage of about 25 mg/kg every day for a dosing cycle of 28 days.

[0687] In some embodiments, PDK1 inhibitor is orally administered at a dosage of about 17.2 mg/kg every three days for a dosing cycle of 28 days and alpelisib is orally administered at a dosage of about 25 mg/kg every day for a dosing cycle of 28 days.

[0688] In some embodiments, Compound 1 is orally administered at a dosage of about 1.7 mg/kg every three days for a dosing cycle of 28 days and alpelisib is orally administered at a dosage of about 25 mg/kg every day for a dosing cycle of 28 days.

[0689] In some embodiments, Compound 1 is orally administered at a dosage of about 8.6 mg/kg every three days for a dosing cycle of 28 days and alpelisib is orally administered at a dosage of about 25 mg/kg every day for a dosing cycle of 28 days.

[0690] In some embodiments, Compound 1 is orally administered at a dosage of about 17.2 mg/kg every three days for a dosing cycle of 28 days and alpelisib is orally administered at a dosage of about 25 mg/kg every day for a dosing cycle of 28 days. In some embodiments, the PDK1 inhibitor is orally administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 200 mg/m ² every day for a dosing cycle of 28 days and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 50 mg/m ² to about 150 mg/m ² every day for a dosing cycle of 28 days.

[0691] In some embodiments, the PDK1 inhibitor is orally administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg every day for a dosing cycle of 28 days and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 150 mg/kg to about 400 mg/kg every day for a dosing cycle of 28 days.

[0692] In some embodiments, the PDK1 inhibitor is orally administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg every day for a dosing cycle of 28 days and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 1 mg/kg to about 400 mg/kg every day for a dosing cycle of 28 days.

[0693] In some embodiments, Compound 1 is orally administered at a dosage (e.g., human dosage) ranging from about 1 mg/m ² to about 200 mg/m ² every day for a dosing cycle of 28 days and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 50 mg/m ² to about 150 mg/m ² every day for a dosing cycle of 28 days.

[0694] In some embodiments, Compound 1 is orally administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg every day for a dosing cycle of 28 days and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 150 mg/kg to about 400 mg/kg every day for a dosing cycle of 28 days.

[0695] In some embodiments, Compound 1 is orally administered at a dosage (e.g., human dosage) ranging from about 10 mg/kg to about 300 mg/kg every day for a dosing cycle of 28 days and alpelisib is orally administered at a dosage (e.g., human dosage) range from about 1 mg/kg to about 400 mg/kg every day for a dosing cycle of 28 days.

[0696] In some embodiments, PDK1 inhibitor is orally administered at a dosage of about 1.7 mg/kg every day for a dosing cycle of 28 days and alpelisib is orally administered at a dosage of about 25 mg/kg every day for a dosing cycle of 28 days.

[0697] In some embodiments, PDK1 inhibitor is orally administered at a dosage of about 8.6 mg/kg every day for a dosing cycle of 28 days and alpelisib is orally administered at a dosage of about 25 mg/kg every day for a dosing cycle of 28 days.

[0698] In some embodiments, PDK1 inhibitor is orally administered at a dosage of about 17.2 mg/kg every day for a dosing cycle of 28 days and alpelisib is orally administered at a dosage of about 25 mg/kg every day for a dosing cycle of 28 days.

[0699] In some embodiments, Compound 1 is orally administered at a dosage of about 1.7 mg/kg every day for a dosing cycle of 28 days and alpelisib is orally administered at a dosage of about 25 mg/kg every day for a dosing cycle of 28 days.

[0700] In some embodiments, Compound 1 is orally administered at a dosage of about 8.6 mg/kg every day for a dosing cycle of 28 days and alpelisib is orally administered at a dosage of about 25 mg/kg every day for a dosing cycle of 28 days.

In some embodiments, Compound 1 is orally administered at a dosage of about 17.2 mg/kg every day for a dosing cycle of 28 days and alpelisib is orally administered at a dosage of about 25 mg/kg every day for a dosing cycle of 28 days.

PDK1 Inhibitors

[0701] In some embodiments, the PDK1 inhibitor is a compound of Formula I: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:

R ¹ is hydrogen or optionally substituted Ci-6 aliphatic, or:

R ¹ and a substituent on Ring A4 are taken together with their intervening atoms to form an optionally substituted 5-7 membered partially unsaturated or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

X is -C(O)- or -S(O) ₂ -,

L ¹ is a covalent bond or an optionally substituted bivalent group selected from C1.4 alkylene, C2-4 alkenylene, or C2-4 alkynylene wherein one or more methylene units of L ¹ are optionally and independently replaced by -Cy ¹ -, -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C( 0)0-, -0C(0)N(R ² )-, -S(0) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -0C(0)-, or -C(0)0-;

Cy ¹ is an optionally substituted bivalent ring selected from a phenyl ring, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ² is hydrogen or optionally substituted Ci-6 aliphatic;

Ai is a covalent bond or an optionally substituted bivalent ring selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclylene, 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, 4-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L ² is a covalent bond, alkylidenylene, or an optionally substituted alkylene chain in which one or more methylene units of L ² are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O)O-, - OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A ₂ is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A ₂ is optionally substituted with 1-4 R ^x groups; each R ^x is independently -R, optionally substituted alkylidenyl, oxo, halo, - -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S( O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , -N(R')OR, -N(R') C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -N(R')S(O) ₂ N(R')2, -N(R')S( O) ₂ R, or -OC(O)N(R') ₂ ; each R is independently hydrogen or an optionally substituted group selected from Cl- 6 aliphatic, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently -R, or two R' groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ³ is a covalent bond or an optionally substituted Ci-4 alkylene chain in which one or more methylene units of L ³ are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O)O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A3 is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 810 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A4 is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein any substitutable carbon on Ring A4 is optionally substituted with R ³ , R ⁴ , or R ⁵ , and any substitutable nitrogen on Ring A4 is optionally substituted with R ⁶ ; each of R ³ , R ⁴ , and R ⁵ is independently -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O) CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N( R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -N(R' )S(O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or:

R ³ and R ⁴ or R ⁴ and R ⁵ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently -R, -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N (R') ₂ , or -S(O) ₂ N(R') ₂ ; or:

R ³ and R ⁶ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; provided that: when Ai is a bivalent monocyclic ring and L ¹ is a covalent bond, L ² is not -O-; when Ai is a bivalent monocyclic or bicyclic ring, L ¹ and L ² are not simultaneously a covalent bond; and

L ¹ , Ai, and L ² are not simultaneously a covalent bond.

[0702] In some embodiments, the PDK1 inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is hydrogen or optionally substituted Ci-6 aliphatic;

X is -C(O)- or -S(O) ₂ -;

L ¹ is a covalent bond or an optionally substituted C1.4 alkylene;

Ai is an optionally substituted bivalent ring selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclylene, 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, 4-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ² is a covalent bond, or an optionally substituted alkylene chain;

Ring A ₂ is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A2 is optionally substituted with 1-4 R ^x groups; each R ^x is independently -R, optionally substituted alkylidenyl, oxo, -halo, -NO2, -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -N(R')S(O) ₂ N(R')2, -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4- 7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently -R, or two R' groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ³ is a covalent bond or an optionally substituted C1.4 alkylene chain; or L ³ is unsubstituted methylene or methylene substituted with methyl or ethyl;

Ring A3 is an optionally substituted ring selected from a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, -or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring

R ³ is -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R,

-CO2R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , -N(R')OR,

-N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ ,

-N(R')S(O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ;

R ⁴ is -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , -N(R ^, )OR,-N(R ^, )C(=NR ^, )N(R') ₂ ,

-C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -NHS(O)Ci- ₆ alkyl, -N(R')S(O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or:

R ³ and R ⁴ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0703] In some embodiments, the PDK1 inhibitor is a compound disclosed in WO 2011/044157 Al, the entire contents of which is incorporated herein by reference, including their methods of their preparation.

[0704] In some embodiments, the PDK1 inhibitor is a compound of Formula I, wherein Ring A3 is phenyl, substituted by one or two fluorines at the meta position or ortho position.

[0705] In some embodiments, the PDK1 inhibitor is a compound of Formula Is: Is, or a pharmaceutically acceptable salt thereof, wherein each of Ai, A2, L ¹ and L ² is as defined for Formula I, and any substitutable carbon on Ring A4 is optionally substituted with R ³ , R ⁴ , or R ⁵ , and any substitutable nitrogen on Ring A4 is optionally substituted with R ⁶ ; each of R ³ , R ⁴ , and R ⁵ is independently -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C (O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N (R')N(R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N( R') ₂ , -N(R')S(O) ₂ N(R')2, -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or:

R ³ and R ⁴ or R ⁴ and R ⁵ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently -R, -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , or -S(O) ₂ N(R') ₂ ; or:

R ³ and R ⁶ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R ⁷ is hydrogen or methyl; and each R ⁸ is independently hydrogen or halo.

[0706] In some embodiments, the PDK1 inhibitor is a compound of Formula Iw: or a pharmaceutically acceptable salt thereof, wherein each of Ai, A2, L ¹ and L ² is as defined for Formula I, and any substitutable carbon on Ring A4 is optionally substituted with R ³ , R ⁴ , or R ⁵ , and any substitutable nitrogen on Ring A4 is optionally substituted with R ⁶ ; each of R ³ , R ⁴ , and R ⁵ is independently -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C (O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N (R')N(R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N( R') ₂ , -N(R')S(O) ₂ N(R')2, -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or:

R ³ and R ⁴ or R ⁴ and R ⁵ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently -R, -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , or -S(O) ₂ N(R') ₂ ; or:

R ³ and R ⁶ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0707] In some embodiments, the PDK1 inhibitor is a compound of Formula lx: or a pharmaceutically acceptable salt thereof, wherein each of Ai, A2, L ¹ and L ² is as defined for Formula I, and each of R ³ and R ⁴ is independently -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C (O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N (R')N(R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N( R') ₂ , -N(R')S(O) ₂ N(R')2, -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or:

R ³ and R ⁴ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0708] In some embodiments, the PDK1 inhibitor is a compound of Formula ly: or a pharmaceutically acceptable salt thereof, wherein each of Ai, A2, L ¹ and L ² is as defined for Formula I, and R ³ is -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O) R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , - N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -N(R')S( O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ .

[0709] In some embodiments, the PDK1 inhibitor is a compound of Formula Iz: or a pharmaceutically acceptable salt thereof, in which Ai, A2, L ¹ and L ² are as defined for Formula I.

In some embodiments, the PDK1 inhibitor is compound disclosed in Table 1, or a pharmaceutically acceptable salt there. [0710] In some embodiments, the PDK1 inhibitor is compound disclosed in Table 1.

[0711] In some embodiments, the PDK1 inhibitor is Compound 1 in Table 1, or a pharmaceutically acceptable salt thereof.

[0712] In some embodiments, the PDK1 inhibitor is Compound 1 in Table 1.

Table 1

Biological Assays

[0713] Combinations designed, selected and/or optimised by methods described above, once produced, can be characterised using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the combination can be characterised by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.

[0714] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the combinations described herein for activity, using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

[0715] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the combinations of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

EXEMPLARY EMBODIMENTS

[0716] Exemplary Embodiment 1. A pharmaceutical combination comprising a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. [0717] Exemplary Embodiment 2. The pharmaceutical combination of Exemplary

Embodiment 1, wherein the PDK1 inhibitor is a compound of Formula I: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:

R ¹ is hydrogen or optionally substituted Ci-6 aliphatic, or:

R ¹ and a substituent on Ring A4 are taken together with their intervening atoms to form an optionally substituted 5-7 membered partially unsaturated or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

X is -C(O)- or -S(O) ₂ -,

L ¹ is a covalent bond or an optionally substituted bivalent group selected from C1.4 alkylene, C2-4 alkenylene, or C2-4 alkynylene wherein one or more methylene units of L ¹ are optionally and independently replaced by -Cy ¹ -, -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O)O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Cy ¹ is an optionally substituted bivalent ring selected from a phenyl ring, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ² is hydrogen or optionally substituted Ci-6 aliphatic;

Ai is a covalent bond or an optionally substituted bivalent ring selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclylene, 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, 4-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ² is a covalent bond, alkylidenylene, or an optionally substituted alkylene chain in which one or more methylene units of L ² are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A ₂ is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A ₂ is optionally substituted with 1-4 R ^x groups; each R ^x is independently -R, optionally substituted alkylidenyl, oxo, halo, - -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , -N(R')OR, - N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -N(R')S(O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; each R is independently hydrogen or an optionally substituted group selected from Cl-6 aliphatic, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently -R, or two R' groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ³ is a covalent bond or an optionally substituted Ci-4 alkylene chain in which one or more methylene units of L ³ are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A3 is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 810 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A4 is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein any substitutable carbon on Ring A4 is optionally substituted with R ³ , R ⁴ , or R ⁵ , and any substitutable nitrogen on Ring A4 is optionally substituted with R ⁶ ; each of R ³ , R ⁴ , and R ⁵ is independently -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C (O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, - N(R')N(R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N (R') ₂ , -N(R')S(O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or:

R ³ and R ⁴ or R ⁴ and R ⁵ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently -R, -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C( O)N(R') ₂ , or -S(O) ₂ N(R') ₂ ; or:

R ³ and R ⁶ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; provided that: when Ai is a bivalent monocyclic ring and L ¹ is a covalent bond, L ² is not -O-; when Ai is a bivalent monocyclic or bicyclic ring, L ¹ and L ² are not simultaneously a covalent bond; and

L ¹ , Ai, and L ² are not simultaneously a covalent bond.

[0718] Exemplary Embodiment 3. The pharmaceutical combination of Exemplary Embodiment 1 or Exemplary Embodiment 2, wherein the PDK1 inhibitor is Compound 1 : or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0719] Exemplary Embodiment 4. The pharmaceutical combination of any one of Exemplary Embodiments 1-3, wherein the PDK1 inhibitor is a compound selected from Table 1.

[0720] Exemplary Embodiment 5. The pharmaceutical combination of any one of Exemplary Embodiments 1-4, wherein the second therapeutic agent comprises an PI3K inhibitor.

[0721] Exemplary Embodiment 6. The pharmaceutical combination of any one of Exemplary Embodiments 1-5, wherein the second therapeutic agent is selected from Table A.

[0722] Exemplary Embodiment 7. The pharmaceutical combination of any one of Exemplary Embodiments 1-6, wherein the second therapeutic agent is alpelisib. [0723] Exemplary Embodiment 8. The pharmaceutical combination of any one of Exemplary Embodiments 1-7, wherein the combination is in the same pharmaceutical composition.

[0724] Exemplary Embodiment 9. A method of treating or preventing a disease or disorder, comprising administering to a subject in need thereof a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0725] Exemplary Embodiment 10. The method of Exemplary Embodiment 9, wherein the disease or disorder can be ameliorated by inhibition of PDK1.

[0726] Exemplary Embodiment 11. The method of Exemplary Embodiment 9 or Exemplary Embodiment 10, wherein the disease or disorder can be ameliorated by inhibition ofPDKl and PI3K.

[0727] Exemplary Embodiment 12. The method of Exemplary Embodiment 11, wherein the PI3K is PI3Ka.

[0728] Exemplary Embodiment 13. The method of any one of Exemplary Embodiments 9- 12, wherein the disease or disorder is a cancer.

[0729] Exemplary Embodiment 14. The method of Exemplary Embodiment 13, wherein the cancer is a hematologic cancer.

[0730] Exemplary Embodiment 15. The method of Exemplary Embodiment 14, wherein the hematologic cancer selected from the group consisting of leukemias, lymphomas, and myelomas.

[0731] Exemplary Embodiment 16. The method of Exemplary Embodiment 14, wherein the hematologic cancer is selected from anaplastic large-cell lymphoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, histiocytic lymphoma, T-cell leukemia, chronic lymphocytic leukemia, multiple myeloma, chronic myelogenous leukemia, acute lymphocytic (lymphoblastic) leukemia, acute myelogenous leukemia, acute myeloblastic leukemia, and plasma cell leukemia.

[0732] Exemplary Embodiment 17. The method of Exemplary Embodiment 13, wherein the cancer is breast cancer.

[0733] Exemplary Embodiment 18. The method of any one of Exemplary Embodiments 9- 17, wherein the PDK1 inhibitor is a compound of Formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:

R ¹ is hydrogen or optionally substituted Ci-6 aliphatic, or:

R ¹ and a substituent on Ring A4 are taken together with their intervening atoms to form an optionally substituted 5-7 membered partially unsaturated or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

X is -C(O)- or -S(O) ₂ -,

L ¹ is a covalent bond or an optionally substituted bivalent group selected from C1.4 alkylene, C2-4 alkenylene, or C2-4 alkynylene wherein one or more methylene units of L ¹ are optionally and independently replaced by -Cy ¹ -, -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O)O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Cy ¹ is an optionally substituted bivalent ring selected from a phenyl ring, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ² is hydrogen or optionally substituted Ci-6 aliphatic;

Ai is a covalent bond or an optionally substituted bivalent ring selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclylene, 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, 4-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L ² is a covalent bond, alkylidenylene, or an optionally substituted alkylene chain in which one or more methylene units of L ² are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A ₂ is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A ₂ is optionally substituted with 1-4 R ^x groups; each R ^x is independently -R, optionally substituted alkylidenyl, oxo, halo, - -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , -N(R')OR, - N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -N(R')S(O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; each R is independently hydrogen or an optionally substituted group selected from Cl-6 aliphatic, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently -R, or two R' groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ³ is a covalent bond or an optionally substituted Ci-4 alkylene chain in which one or more methylene units of L ³ are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A3 is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 810 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A4 is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein any substitutable carbon on Ring A4 is optionally substituted with R ³ , R ⁴ , or R ⁵ , and any substitutable nitrogen on Ring A4 is optionally substituted with R ⁶ ; each of R ³ , R ⁴ , and R ⁵ is independently -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C (O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, - N(R')N(R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N (R') ₂ , -N(R')S(O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or:

R ³ and R ⁴ or R ⁴ and R ⁵ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently -R, -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C( O)N(R') ₂ , or -S(O) ₂ N(R') ₂ ; or:

R ³ and R ⁶ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; provided that: when Ai is a bivalent monocyclic ring and L ¹ is a covalent bond, L ² is not -O-; when Ai is a bivalent monocyclic or bicyclic ring, L ¹ and L ² are not simultaneously a covalent bond; and

L ¹ , Ai, and L ² are not simultaneously a covalent bond.

[0734] Exemplary Embodiment 19. The method of any one of Exemplary Embodiments 9- 18, wherein the PDK1 inhibitor is Compound 1 : or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0735] Exemplary Embodiment 20. The method of any one of Exemplary Embodiments 9- 18, wherein the PDK1 inhibitor is a compound selected from Table 1.

[0736] Exemplary Embodiment 21. The method of any one of Exemplary Embodiments 9- 20, wherein the second therapeutic agent comprises a PI3K inhibitor.

[0737] Exemplary Embodiment 22. The method of Exemplary Embodiment 21, wherein the PI3K inhibitor is selected from Table 2.

[0738] Exemplary Embodiment 23. The method of Exemplary Embodiment 21 or Exemplary Embodiment 22, wherein the PI3K inhibitor is alpelisib.

[0739] Exemplary Embodiment 24. The method of any one of Exemplary Embodiments 9- 23, wherein the subject is a human.

[0740] Exemplary Embodiment 25. The method of Exemplary Embodiment 24, wherein the PDK1 inhibitor and second therapeutic agent are administered in temporal proximity, sequentially, in alternation, in the same formulation, or as different formulation. [0741] Exemplary Embodiment 26. A PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for use in combination in treating or preventing a disease or disorder in a subject in need thereof.

[0742] Exemplary Embodiment 27. The PDK1 inhibitor of Exemplary Embodiment 26 being a compound of Formula I: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:

R ¹ is hydrogen or optionally substituted Ci-6 aliphatic, or:

R ¹ and a substituent on Ring A4 are taken together with their intervening atoms to form an optionally substituted 5-7 membered partially unsaturated or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

X is -C(O)- or -S(O) ₂ -,

L ¹ is a covalent bond or an optionally substituted bivalent group selected from C1.4 alkylene, C2-4 alkenylene, or C2-4 alkynylene wherein one or more methylene units of L ¹ are optionally and independently replaced by -Cy ¹ -, -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O)O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Cy ¹ is an optionally substituted bivalent ring selected from a phenyl ring, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ² is hydrogen or optionally substituted Ci-6 aliphatic;

Ai is a covalent bond or an optionally substituted bivalent ring selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclylene, 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, 4-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ² is a covalent bond, alkylidenylene, or an optionally substituted alkylene chain in which one or more methylene units of L ² are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A ₂ is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A ₂ is optionally substituted with 1-4 R ^x groups; each R ^x is independently -R, optionally substituted alkylidenyl, oxo, halo, - -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , -N(R')OR, - N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -N(R')S(O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; each R is independently hydrogen or an optionally substituted group selected from Cl-6 aliphatic, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently -R, or two R' groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ³ is a covalent bond or an optionally substituted Ci-4 alkylene chain in which one or more methylene units of L ³ are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A3 is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 810 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A4 is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein any substitutable carbon on Ring A4 is optionally substituted with R ³ , R ⁴ , or R ⁵ , and any substitutable nitrogen on Ring A4 is optionally substituted with R ⁶ ; each of R ³ , R ⁴ , and R ⁵ is independently -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C (O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, - N(R')N(R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N (R') ₂ , -N(R')S(O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or: R ³ and R ⁴ or R ⁴ and R ⁵ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently -R, -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C( O)N(R') ₂ , or -S(O) ₂ N(R') ₂ ; or:

R ³ and R ⁶ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; provided that: when Ai is a bivalent monocyclic ring and L ¹ is a covalent bond, L ² is not -O-; when Ai is a bivalent monocyclic or bicyclic ring, L ¹ and L ² are not simultaneously a covalent bond; and

L ¹ , Ai, and L ² are not simultaneously a covalent bond.

[0743] Exemplary Embodiment 28. The PDK1 inhibitor of Exemplary Embodiment 26 being Compound 1 : (Compound 1); or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0744] Exemplary Embodiment 29. A PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination with a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof in treating or preventing a disease or disorder in a subject in need thereof.

[0745] Exemplary Embodiment 30. The PDK1 inhibitor of Exemplary Embodiment 29 being a compound of Formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:

R ¹ is hydrogen or optionally substituted Ci-6 aliphatic, or:

R ¹ and a substituent on Ring A4 are taken together with their intervening atoms to form an optionally substituted 5-7 membered partially unsaturated or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

X is -C(O)- or -S(O) ₂ -,

L ¹ is a covalent bond or an optionally substituted bivalent group selected from C1.4 alkylene, C2-4 alkenylene, or C2-4 alkynylene wherein one or more methylene units of L ¹ are optionally and independently replaced by -Cy ¹ -, -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O)O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Cy ¹ is an optionally substituted bivalent ring selected from a phenyl ring, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ² is hydrogen or optionally substituted Ci-6 aliphatic;

Ai is a covalent bond or an optionally substituted bivalent ring selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclylene, 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, 4-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L ² is a covalent bond, alkylidenylene, or an optionally substituted alkylene chain in which one or more methylene units of L ² are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A ₂ is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A ₂ is optionally substituted with 1-4 R ^x groups; each R ^x is independently -R, optionally substituted alkylidenyl, oxo, halo, - -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , -N(R')OR, - N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -N(R')S(O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; each R is independently hydrogen or an optionally substituted group selected from Cl-6 aliphatic, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently -R, or two R' groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ³ is a covalent bond or an optionally substituted Ci-4 alkylene chain in which one or more methylene units of L ³ are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A3 is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 810 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A4 is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein any substitutable carbon on Ring A4 is optionally substituted with R ³ , R ⁴ , or R ⁵ , and any substitutable nitrogen on Ring A4 is optionally substituted with R ⁶ ; each of R ³ , R ⁴ , and R ⁵ is independently -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C (O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, - N(R')N(R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N (R') ₂ , -N(R')S(O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or:

R ³ and R ⁴ or R ⁴ and R ⁵ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently -R, -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(

O)N(R') ₂ , or -S(O) ₂ N(R') ₂ ; or:

R ³ and R ⁶ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; provided that: when Ai is a bivalent monocyclic ring and L ¹ is a covalent bond, L ² is not -O-; when Ai is a bivalent monocyclic or bicyclic ring, L ¹ and L ² are not simultaneously a covalent bond; and

L ¹ , Ai, and L ² are not simultaneously a covalent bond.

[0746] Exemplary Embodiment 31. The PDK1 inhibitor of Exemplary Embodiment 29 being Compound 1 : or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0747] Exemplary Embodiment 32. A PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in a combinational therapy with a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof in treating or preventing a disease or disorder in a subject in need thereof.

[0748] Exemplary Embodiment 33. The PDK1 inhibitor of Exemplary Embodiment 32 being a compound of Formula I: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:

R ¹ is hydrogen or optionally substituted Ci-6 aliphatic, or:

R ¹ and a substituent on Ring A4 are taken together with their intervening atoms to form an optionally substituted 5-7 membered partially unsaturated or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

X is -C(O)- or -S(O) ₂ -,

L ¹ is a covalent bond or an optionally substituted bivalent group selected from C1.4 alkylene, C2-4 alkenylene, or C2-4 alkynylene wherein one or more methylene units of L ¹ are optionally and independently replaced by -Cy ¹ -, -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O)O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Cy ¹ is an optionally substituted bivalent ring selected from a phenyl ring, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ² is hydrogen or optionally substituted Ci-6 aliphatic;

Ai is a covalent bond or an optionally substituted bivalent ring selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclylene, 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, 4-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ² is a covalent bond, alkylidenylene, or an optionally substituted alkylene chain in which one or more methylene units of L ² are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A ₂ is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A2 is optionally substituted with 1-4 R ^x groups; each R ^x is independently -R, optionally substituted alkylidenyl, oxo, halo, - -NO2, -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , -N(R')OR, - N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -N(R')S(O) ₂ N(R')2, -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; each R is independently hydrogen or an optionally substituted group selected from Cl-6 aliphatic, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently -R, or two R' groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ³ is a covalent bond or an optionally substituted C1.4 alkylene chain in which one or more methylene units of L ³ are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ill Ring A3 is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 810 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A4 is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein any substitutable carbon on Ring A4 is optionally substituted with R ³ , R ⁴ , or R ⁵ , and any substitutable nitrogen on Ring A4 is optionally substituted with R ⁶ ; each of R ³ , R ⁴ , and R ⁵ is independently -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C (O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, - N(R')N(R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N (R') ₂ , -N(R')S(O) ₂ N(R')2, -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or:

R ³ and R ⁴ or R ⁴ and R ⁵ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently -R, -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C( O)N(R') ₂ , or -S(O) ₂ N(R') ₂ ; or:

R ³ and R ⁶ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; provided that: when Ai is a bivalent monocyclic ring and L ¹ is a covalent bond, L ² is not -O-; when Ai is a bivalent monocyclic or bicyclic ring, L ¹ and L ² are not simultaneously a covalent bond; and

L ¹ , Ai, and L ² are not simultaneously a covalent bond.

[0749] Exemplary Embodiment 34. The PDK1 inhibitor of Exemplary Embodiment 32 or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0750] Exemplary Embodiment 35. A composition comprising a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for use in treating or preventing a disease or disorder in a subject in need thereof.

[0751] Exemplary Embodiment 36. The composition of Exemplary Embodiment 35, wherein the PDK1 inhibitor is a compound of Formula I: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:

R ¹ is hydrogen or optionally substituted Ci-6 aliphatic, or:

R ¹ and a substituent on Ring A4 are taken together with their intervening atoms to form an optionally substituted 5-7 membered partially unsaturated or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

X is -C(O)- or -S(O) ₂ -, L ¹ is a covalent bond or an optionally substituted bivalent group selected from Ci-4 alkylene, C2-4 alkenylene, or C2-4 alkynylene wherein one or more methylene units of L ¹ are optionally and independently replaced by -Cy ¹ -, -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O)O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Cy ¹ is an optionally substituted bivalent ring selected from a phenyl ring, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ² is hydrogen or optionally substituted Ci-6 aliphatic;

Ai is a covalent bond or an optionally substituted bivalent ring selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclylene, 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, 4-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ² is a covalent bond, alkylidenylene, or an optionally substituted alkylene chain in which one or more methylene units of L ² are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A2 is optionally substituted with 1-4 R ^x groups; each R ^x is independently -R, optionally substituted alkylidenyl, oxo, halo, - -NO2, -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , -N(R')OR, - N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -N(R')S(O) ₂ N(R')2, -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; each R is independently hydrogen or an optionally substituted group selected from Cl-6 aliphatic, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently -R, or two R' groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ³ is a covalent bond or an optionally substituted C1.4 alkylene chain in which one or more methylene units of L ³ are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A3 is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 810 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A4 is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein any substitutable carbon on Ring A4 is optionally substituted with R ³ , R ⁴ , or R ⁵ , and any substitutable nitrogen on Ring A4 is optionally substituted with R ⁶ ; each of R ³ , R ⁴ , and R ⁵ is independently -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C (O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, - N(R')N(R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N (R') ₂ , -N(R')S(O) ₂ N(R')2, -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or:

R ³ and R ⁴ or R ⁴ and R ⁵ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently -R, -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C( O)N(R') ₂ , or -S(O) ₂ N(R') ₂ ; or:

R ³ and R ⁶ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; provided that: when Ai is a bivalent monocyclic ring and L ¹ is a covalent bond, L ² is not -O-; when Ai is a bivalent monocyclic or bicyclic ring, L ¹ and L ² are not simultaneously a covalent bond; and

L ¹ , Ai, and L ² are not simultaneously a covalent bond. [0752] Exemplary Embodiment 37. The composition of Exemplary Embodiment 35, wherein the PDK1 inhibitor is Compound 1 : or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0753] Exemplary Embodiment 38. A PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof in the manufacture of a medicament for the combinatorial treatment or prevention of a disease or disorder in a subject in need thereof.

[0754] Exemplary Embodiment 39. The PDK1 inhibitor of Exemplary Embodiment 38 being a compound of Formula I: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:

R ¹ is hydrogen or optionally substituted Ci-6 aliphatic, or:

R ¹ and a substituent on Ring A4 are taken together with their intervening atoms to form an optionally substituted 5-7 membered partially unsaturated or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

X is -C(O)- or -S(O) ₂ -,

L ¹ is a covalent bond or an optionally substituted bivalent group selected from C1.4 alkylene, C2-4 alkenylene, or C2-4 alkynylene wherein one or more methylene units of L ¹ are optionally and independently replaced by -Cy ¹ -, -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O)O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Cy ¹ is an optionally substituted bivalent ring selected from a phenyl ring, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ² is hydrogen or optionally substituted Ci-6 aliphatic;

Ai is a covalent bond or an optionally substituted bivalent ring selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclylene, 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, 4-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ² is a covalent bond, alkylidenylene, or an optionally substituted alkylene chain in which one or more methylene units of L ² are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A ₂ is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A ₂ is optionally substituted with 1-4 R ^x groups; each R ^x is independently -R, optionally substituted alkylidenyl, oxo, halo, - -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , -N(R')OR, - N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -N(R')S(O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; each R is independently hydrogen or an optionally substituted group selected from Cl-6 aliphatic, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently -R, or two R' groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ³ is a covalent bond or an optionally substituted Ci-4 alkylene chain in which one or more methylene units of L ³ are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A3 is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 810 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A4 is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein any substitutable carbon on Ring A4 is optionally substituted with R ³ , R ⁴ , or R ⁵ , and any substitutable nitrogen on Ring A4 is optionally substituted with R ⁶ ; each of R ³ , R ⁴ , and R ⁵ is independently -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C (O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, - N(R')N(R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N (R') ₂ , -N(R')S(O) ₂ N(R')2, -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or:

R ³ and R ⁴ or R ⁴ and R ⁵ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently -R, -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C( O)N(R') ₂ , or -S(O) ₂ N(R') ₂ ; or:

R ³ and R ⁶ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; provided that: when Ai is a bivalent monocyclic ring and L ¹ is a covalent bond, L ² is not -O-; when Ai is a bivalent monocyclic or bicyclic ring, L ¹ and L ² are not simultaneously a covalent bond; and

L ¹ , Ai, and L ² are not simultaneously a covalent bond.

[0755] Exemplary Embodiment 40. The PDK1 inhibitor of Exemplary Embodiment 38 being Compound 1 : or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0756] Exemplary Embodiment 41. Use of a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a disease or disorder in a subject in need thereof.

[0757] Exemplary Embodiment 42. The use of a PDK1 inhibitor of Exemplary Embodiment 41, wherein the PDK1 inhibitor is a compound of Formula I: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:

R ¹ is hydrogen or optionally substituted Ci-6 aliphatic, or:

R ¹ and a substituent on Ring A4 are taken together with their intervening atoms to form an optionally substituted 5-7 membered partially unsaturated or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

X is -C(O)- or -S(O) ₂ -,

L ¹ is a covalent bond or an optionally substituted bivalent group selected from C1.4 alkylene, C2-4 alkenylene, or C2-4 alkynylene wherein one or more methylene units of L ¹ are optionally and independently replaced by -Cy ¹ -, -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O)O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Cy ¹ is an optionally substituted bivalent ring selected from a phenyl ring, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ² is hydrogen or optionally substituted Ci-6 aliphatic;

Ai is a covalent bond or an optionally substituted bivalent ring selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclylene, 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, 4-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ² is a covalent bond, alkylidenylene, or an optionally substituted alkylene chain in which one or more methylene units of L ² are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A ₂ is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A ₂ is optionally substituted with 1-4 R ^x groups; each R ^x is independently -R, optionally substituted alkylidenyl, oxo, halo, - -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , -N(R')OR, - N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -N(R')S(O) ₂ N(R')2, -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; each R is independently hydrogen or an optionally substituted group selected from Cl-6 aliphatic, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently -R, or two R' groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ³ is a covalent bond or an optionally substituted Ci-4 alkylene chain in which one or more methylene units of L ³ are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A3 is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 810 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A4 is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein any substitutable carbon on Ring A4 is optionally substituted with R ³ , R ⁴ , or R ⁵ , and any substitutable nitrogen on Ring A4 is optionally substituted with R ⁶ ; each of R ³ , R ⁴ , and R ⁵ is independently -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C (O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, - N(R')N(R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N (R') ₂ , -N(R')S(O) ₂ N(R')2, -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or:

R ³ and R ⁴ or R ⁴ and R ⁵ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently -R, -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C( O)N(R') ₂ , or -S(O) ₂ N(R') ₂ ; or:

R ³ and R ⁶ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; provided that: when Ai is a bivalent monocyclic ring and L ¹ is a covalent bond, L ² is not -O-; when Ai is a bivalent monocyclic or bicyclic ring, L ¹ and L ² are not simultaneously a covalent bond; and

L ¹ , Ai, and L ² are not simultaneously a covalent bond.

[0758] Exemplary Embodiment 43. The use of a PDK1 inhibitor of Exemplary Embodiment 41, wherein the PDK1 inhibitor is Compound 1 : or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0759] Exemplary Embodiment 44. Use of a composition comprising a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof in the manufacture of a medicament for the treatment or prevention of a disease or disorder in a subject in need thereof.

[0760] Exemplary Embodiment 45. The use of a PDK1 inhibitor of Exemplary Embodiment 44, wherein the PDK1 inhibitor is a compound of Formula I: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:

R ¹ is hydrogen or optionally substituted Ci-6 aliphatic, or:

R ¹ and a substituent on Ring A4 are taken together with their intervening atoms to form an optionally substituted 5-7 membered partially unsaturated or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

X is -C(O)- or -S(O) ₂ -,

L ¹ is a covalent bond or an optionally substituted bivalent group selected from C1.4 alkylene, C2-4 alkenylene, or C2-4 alkynylene wherein one or more methylene units of L ¹ are optionally and independently replaced by -Cy ¹ -, -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O)O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Cy ¹ is an optionally substituted bivalent ring selected from a phenyl ring, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ² is hydrogen or optionally substituted Ci-6 aliphatic;

Ai is a covalent bond or an optionally substituted bivalent ring selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclylene, 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, 4-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ² is a covalent bond, alkylidenylene, or an optionally substituted alkylene chain in which one or more methylene units of L ² are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A ₂ is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A ₂ is optionally substituted with 1-4 R ^x groups; each R ^x is independently -R, optionally substituted alkylidenyl, oxo, halo, - -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , -N(R')OR, - N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -N(R')S(O) ₂ N(R')2, -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; each R is independently hydrogen or an optionally substituted group selected from Cl-6 aliphatic, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently -R, or two R' groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ³ is a covalent bond or an optionally substituted Ci-4 alkylene chain in which one or more methylene units of L ³ are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A3 is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 810 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A4 is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein any substitutable carbon on Ring A4 is optionally substituted with R ³ , R ⁴ , or R ⁵ , and any substitutable nitrogen on Ring A4 is optionally substituted with R ⁶ ; each of R ³ , R ⁴ , and R ⁵ is independently -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C (O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, - N(R')N(R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N (R') ₂ , -N(R')S(O) ₂ N(R')2, -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or:

R ³ and R ⁴ or R ⁴ and R ⁵ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently -R, -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C( O)N(R') ₂ , or -S(O) ₂ N(R') ₂ ; or:

R ³ and R ⁶ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; provided that: when Ai is a bivalent monocyclic ring and L ¹ is a covalent bond, L ² is not -O-; when Ai is a bivalent monocyclic or bicyclic ring, L ¹ and L ² are not simultaneously a covalent bond; and

L ¹ , Ai, and L ² are not simultaneously a covalent bond.

[0761] Exemplary Embodiment 46. The use of a PDK1 inhibitor of Exemplary Embodiment 44, wherein the PDK1 inhibitor is Compound 1 : or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0762] Exemplary Embodiment 47. A kit comprising a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. [0763] Exemplary Embodiment 48. The kit of Exemplary Embodiment 47, wherein the PDK1 inhibitor is a compound of Formula I: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:

R ¹ is hydrogen or optionally substituted Ci-6 aliphatic, or:

R ¹ and a substituent on Ring A4 are taken together with their intervening atoms to form an optionally substituted 5-7 membered partially unsaturated or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

X is -C(O)- or -S(O) ₂ -,

L ¹ is a covalent bond or an optionally substituted bivalent group selected from C1.4 alkylene, C2-4 alkenylene, or C2-4 alkynylene wherein one or more methylene units of L ¹ are optionally and independently replaced by -Cy ¹ -, -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O)O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Cy ¹ is an optionally substituted bivalent ring selected from a phenyl ring, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ² is hydrogen or optionally substituted Ci-6 aliphatic;

Ai is a covalent bond or an optionally substituted bivalent ring selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclylene, 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, 4-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ² is a covalent bond, alkylidenylene, or an optionally substituted alkylene chain in which one or more methylene units of L ² are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A ₂ is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A ₂ is optionally substituted with 1-4 R ^x groups; each R ^x is independently -R, optionally substituted alkylidenyl, oxo, halo, - -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , -N(R')OR, - N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -N(R')S(O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; each R is independently hydrogen or an optionally substituted group selected from Cl-6 aliphatic, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently -R, or two R' groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ³ is a covalent bond or an optionally substituted Ci-4 alkylene chain in which one or more methylene units of L ³ are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A3 is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 810 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A4 is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein any substitutable carbon on Ring A4 is optionally substituted with R ³ , R ⁴ , or R ⁵ , and any substitutable nitrogen on Ring A4 is optionally substituted with R ⁶ ; each of R ³ , R ⁴ , and R ⁵ is independently -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C (O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, - N(R')N(R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N (R') ₂ , -N(R')S(O) ₂ N(R')2, -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or:

R ³ and R ⁴ or R ⁴ and R ⁵ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently -R, -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C( O)N(R') ₂ , or -S(O) ₂ N(R') ₂ ; or:

R ³ and R ⁶ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; provided that: when Ai is a bivalent monocyclic ring and L ¹ is a covalent bond, L ² is not -O-; when Ai is a bivalent monocyclic or bicyclic ring, L ¹ and L ² are not simultaneously a covalent bond; and

L ¹ , Ai, and L ² are not simultaneously a covalent bond.

[0764] Exemplary Embodiment 49. The kit of Exemplary Embodiment 47, wherein the or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. [0765] Exemplary Embodiment 50. A pharmaceutical package comprising a PDK1 inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0766] Exemplary Embodiment 51. The pharmaceutical package of Exemplary

Embodiment 50, wherein the PDK1 inhibitor is a compound of Formula I: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:

R ¹ is hydrogen or optionally substituted Ci-6 aliphatic, or:

R ¹ and a substituent on Ring A4 are taken together with their intervening atoms to form an optionally substituted 5-7 membered partially unsaturated or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

X is -C(O)- or -S(O) ₂ -,

L ¹ is a covalent bond or an optionally substituted bivalent group selected from C1.4 alkylene, C2-4 alkenylene, or C2-4 alkynylene wherein one or more methylene units of L ¹ are optionally and independently replaced by -Cy ¹ -, -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O)O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Cy ¹ is an optionally substituted bivalent ring selected from a phenyl ring, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ² is hydrogen or optionally substituted Ci-6 aliphatic;

Ai is a covalent bond or an optionally substituted bivalent ring selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclylene, 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, 4-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ² is a covalent bond, alkylidenylene, or an optionally substituted alkylene chain in which one or more methylene units of L ² are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A ₂ is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A ₂ is optionally substituted with 1-4 R ^x groups; each R ^x is independently -R, optionally substituted alkylidenyl, oxo, halo, - -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, -N(R')N(R') ₂ , -N(R')OR, - N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N(R') ₂ , -N(R')S(O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; each R is independently hydrogen or an optionally substituted group selected from Cl-6 aliphatic, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently -R, or two R' groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L ³ is a covalent bond or an optionally substituted Ci-4 alkylene chain in which one or more methylene units of L ³ are optionally and independently replaced by -O-, -S-, -N(R ² )-, -C(O)-, -C(O)N(R ² )-, -N(R ² )C(O)N(R ² )-, -N(R ² )C(O)-, -N(R ² )C(O) O-, -OC(O)N(R ² )-, -S(O) ₂ -, -S(O) ₂ N(R ² )-, -N(R ² )S(O) ₂ -, -OC(O)-, or -C(O)O-;

Ring A3 is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 810 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A4 is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein any substitutable carbon on Ring A4 is optionally substituted with R ³ , R ⁴ , or R ⁵ , and any substitutable nitrogen on Ring A4 is optionally substituted with R ⁶ ; each of R ³ , R ⁴ , and R ⁵ is independently -R, -halo, -NO ₂ , -CN, -OR, -SR, -N(R') ₂ , -C(O)R, -CO ₂ R, -C(O)C(O)R, -C (O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C(O)N(R') ₂ , -S(O) ₂ N(R') ₂ , -OC(O)R, -N(R')C(O)R, - N(R')N(R') ₂ , -N(R')OR, -N(R')C(=NR')N(R') ₂ , -C(=NR')N(R') ₂ , -C=NOR, -N(R')C(O)N (R') ₂ , -N(R')S(O) ₂ N(R') ₂ , -N(R')S(O) ₂ R, or -OC(O)N(R') ₂ ; or: R ³ and R ⁴ or R ⁴ and R ⁵ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently -R, -C(O)R, -CO ₂ R, -C(O)C(O)R, -C(O)CH ₂ C(O)R, -S(O)R, -S(O) ₂ R, -C( O)N(R') ₂ , or -S(O) ₂ N(R') ₂ ; or:

R ³ and R ⁶ are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; provided that: when Ai is a bivalent monocyclic ring and L ¹ is a covalent bond, L ² is not -O-; when Ai is a bivalent monocyclic or bicyclic ring, L ¹ and L ² are not simultaneously a covalent bond; and

L ¹ , Ai, and L ² are not simultaneously a covalent bond.

[0767] Exemplary Embodiment 52. The pharmaceutical package of Exemplary

Embodiment 50, wherein the PDK1 inhibitor is Compound 1 : or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0768] Exemplary Embodiment 53. The kit or pharmaceutical package of any one of Exemplary Embodiments 47-52 further comprising instructions for use.

[0769] Exemplary Embodiment 54. The use, combination, PDK1 inhibitor, kit, or pharmaceutical package of any one of Exemplary Embodiments 26-53, wherein the second therapeutic agent is alpelisib.

[0770] Exemplary Embodiment 55. The pharmaceutical combination of Exemplary Embodiment 1 or Exemplary Embodiment 2, wherein the PDK1 inhibitor is a compound selected from Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0771] Exemplary Embodiment 56. The method of any one of Exemplary Embodiments 9- 18, wherein the PDK1 inhibitor is a compound selected from Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0772] Exemplary Embodiment 57. The method of Exemplary Embodiment 9, wherein the second therapeutic agent is alpelisib and wherein the PDK1 inhibitor is administered at a dosage ranging from about 10 mg/kg to about 300 mg/kg and alpelisib is administered at a dosage range from about 1 mg/kg to about 400 mg/kg.

[0773] Exemplary Embodiment 58. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 10 mg/kg.

[0774] Exemplary Embodiment 59. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 20 mg/kg.

[0775] Exemplary Embodiment 60. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 30 mg/kg.

[0776] Exemplary Embodiment 61. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 40 mg/kg.

[0777] Exemplary Embodiment 62. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 50 mg/kg.

[0778] Exemplary Embodiment 63. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 60 mg/kg.

[0779] Exemplary Embodiment 64. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 70 mg/kg.

[0780] Exemplary Embodiment 65. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 80 mg/kg.

[0781] Exemplary Embodiment 66. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 90 mg/kg.

[0782] Exemplary Embodiment 67. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 100 mg/kg.

[0783] Exemplary Embodiment 68. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 110 mg/kg.

[0784] Exemplary Embodiment 69. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 120 mg/kg. [0785] Exemplary Embodiment 70. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 130 mg/kg.

[0786] Exemplary Embodiment 71. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 140 mg/kg.

[0787] Exemplary Embodiment 72. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 150 mg/kg.

[0788] Exemplary Embodiment 73. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 160 mg/kg.

[0789] Exemplary Embodiment 74. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 170 mg/kg.

[0790] Exemplary Embodiment 75. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 180 mg/kg.

[0791] Exemplary Embodiment 76. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 190 mg/kg.

[0792] Exemplary Embodiment 77. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 200 mg/kg.

[0793] Exemplary Embodiment 78. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 210 mg/kg.

[0794] Exemplary Embodiment 79. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 220 mg/kg.

[0795] Exemplary Embodiment 80. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 230 mg/kg.

[0796] Exemplary Embodiment 81. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 240 mg/kg.

[0797] Exemplary Embodiment 82. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 250 mg/kg.

[0798] Exemplary Embodiment 83. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 260 mg/kg.

[0799] Exemplary Embodiment 84. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 270 mg/kg.

[0800] Exemplary Embodiment 85. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 280 mg/kg.

[0801] Exemplary Embodiment 86. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 290 mg/kg. [0802] Exemplary Embodiment 87. The method of Exemplary Embodiment 57, wherein the PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 300 mg/kg.

[0803] Exemplary Embodiment 88. The method of Exemplary Embodiment 57, wherein PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 21.2 mg/kg.

[0804] Exemplary Embodiment 89. The method of Exemplary Embodiment 57, wherein PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 107.5 mg/kg.

[0805] Exemplary Embodiment 90. The method of Exemplary Embodiment 57, wherein PDK1 inhibitor is administered at a dosage (e.g., human dosage) of about 215 mg/kg.

[0806] Exemplary Embodiment 91. The method of Exemplary Embodiment 57, wherein PDK1 inhibitor is administered at a dosage of about 1.7 mg/kg, about 8.6 mg/kg, or about 17.2 mg/kg.

[0807] Exemplary Embodiment 92. The method of Exemplary Embodiment 57, wherein alpelisib is administered at a dosage of about 25 mg/kg.

[0808] Exemplary Embodiment 93. The method of Exemplary Embodiment 57, wherein alpelisib is administered at a dosage (e.g., human dosage) of about 312.5 mg/kg.

EXAMPLES

Example 1. Biological Activity of the Compounds of the Present Disclosure

[0809] The biological activity of the compounds of the present disclosure was determined utilising the assay described herein.

PDK1 kinase assay

[0810] PDK1 (amino acids 51-359) and AKT2 (amino acids 140-467 fused to PIFtide, amino acids EEQEMFRDFDYIADW) were expressed as N-terminally tagged GST fusion proteins in insect cells and purified to homogeneity. Enzyme activity was determined in a coupled PDKl/AKT/FAM-crosstide assay and phosphorylation of FAM-crosstide was determined by standard IMAP protocol (Molecular Devices). For inhibition studies, compounds were titrated 4-fold in DMSO and diluted 40-fold into assay buffer (10 mM Tris HC1 pH7.2; 10 mM MgC12; 0.01% Triton X-100; 1 mM DTT) containing PDK1, AKT2, and FAM-crosstide (final concentrations: 0.75 nM PDK1, 10 nM unphosphorylated AKT2, and 100 nM crosstide substrate). The kinase reaction was initiated by adding ATP to a final concentration of 40 M of PDK1 and incubated at 25 °C for 30 min. To detect assay product, the kinase reaction was combined with Progressive Binding Solution (1 :600 Progressive Binding Reagent, 50% Buffer A, 50% Buffer B, Molecular Devices) in a 1 :3 ratio. The mixture was incubated for 2 hours at 25 °C and the plate was scanned on an Analyst AD with excitation at 485 nm and emission at 530 nm. The fluorescence polarization value “P” is defined by the equation below. The value “mP” is generated by multiplying the P value for each reaction well by a factor of 1000. The value “AmP” for each well is the mP value for that well minus the mP value for the average negative control.

Eq. : P = (Fpar - Fperp)/ (Fpar + Fperp)

[0811] Where “par” is fluorescence intensity parallel to the excitation plane; and “perp” is fluorescence intensity perpendicular to the excitation plane. AmP values were plotted as a function of compound concentration and the data were analyzed with a 4-parameter fit using GraphPad Prism software.

[0812] Determination of ECsos for the inhibition of phospho-akt (Thr308) was accomplished by treating PC-3 cells with subject inhibitors for 2 hours in no serum then using the Meso Scale Discovery (MSD) phospho-akt 308 ELISA kit to detect p-akt (Thr308) levels.

[0813] PC-3 cells were harvested by trypsin and counted. Cells were plated in coated 96-well flat bottom plates (plate 15,000 cells/well in lOOul growth media (10% FBS, IX pen-strep) an placee in an incubator overnight.

[0814] Subject inhibitors were were stocked at at 50mM, then diluted to 30mM (4.8 pl cpd plus 1.6ul DMSO) in 100% DMSO. Three-fold dilutions were performed from 30mM stock. (4 pl into 8ul 100% DMSO). Aliquots of 1.0 pl of inhibitor solution were transferred into SF Medium (using deep well block).

[0815] Control wells were prepared as follows. For DMSO high controls, 1.0 pl of 100% DMSO was added into 1.0ml SF. For low controls for PC-3 cells, 5 pM of Wortmannin (10 pl of ImM Wortmannin stock was added into 2ml SF Medium. The supernatant media was removed and the plate was blotted. lOOpl of controls/media or compound/media were added to cells and placed in incubator for 2 hours. The supernatant media was removed and the plate was blotted. 55 pl of the MSD complete lysis buffer was added (10 mis Tris Lysis buffer, 200ul protease inhibitor, lOOul phosphatase inhibitor 1, and lOOul phosphatase inhibitor II). The plate was placed on a plate shaker for 60 mins at 4 deg.

[0816] MSD plates were blocked for 1 hour by adding 150 pl of Blocking Solution (3% BSA) to each well. The MSD plates were washed 4X with TBST, and 50 pl lysates were transferred to MSD plate and place on plate shaker shake at 4 degrees O/N, light shaking (speed 3.5). The plate was washed 4X with TBST.

[0817] For detection, the following detection antibody solution was used: 1ml Blocking Solution (3% BSA stock, 1% BSA final); 2mls TBST! and 91 pl of stock (0.33uM) detection antibody (final concentration lOnM). 25 pl of Ab detection solution was added to each well. The plate was sealed and incubated Ihr RT, light shaking (speed 3.5). The plate was washed 4 times with TBST. 150 pl of Read Buffer was added (5mls 4x MSD Read Buffer + 15mls water). Finally the plate was read immediately on the MSD plate reader.

[0818] Materials: PC-3 (cultured in F12K media - Invitrogen cat# 21127-030 plus 10% FBS and IX pen-strep); Mesoscale Discovery phospho-akt (Thr 308) kit - cat# K151DYD-1 (includes MSD plate, Tris Wash Buffer, Blocking Solution A, Read buffer, Tris Lysis Buffer, protease inhibitor, phosphatase inhibitor I, phosphatase inhibitor II, and detection); Wortmannin - Calbiochem, cat# 681675 (ImM stock, aliquoted and stored at -20deg); and 96 well Poly-L-Lysine coated plates - Becton Dickinson cat# 35-4516 (stored at room temp).

Example 2. Treatment Using Compound 1

[0819] Animals were housed, maintained, and treated at Memorial Sloan Kettering Cancer Center (MSKCC) in accordance with Institutional Animal Care and Use Committee (protocol number 12-10-019). 5 3 106 cells in 1 : 1 PBS/Matrigel (Corning) were injected subcutaneously into athymic Foxnlnu nude mice. When a volume of _150mm3 was reached mice were randomized and treated, and tumors were measured twice per week for 1 month.

[0820] Compound 1 is administered to a subject in need thereof at a dosage of about 1.7 mg/kg, 8.6 mg/kg, or 17.2 mg/kg in combination with alpelisib at a dosage of 25 mg/kg.

[0821] The insulin concentrations in serum of Compound 1, alpelisib, and vehicle, as a monotherapy and Compound 1 and alpelisib in combination are shown in Fig. 1.

[0822] Mean tumor volume in mouse after treatment with Compound 1, alpelisib, and vehicle, as a monotherapy and Compound 1 and alpelisib in combination is shown in Fig. 2.

EQUIVALENTS

[0823] The details of one or more embodiments of the invention are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference.

[0824] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the invention to the precise form disclosed, but by the claims appended hereto.