Small-molecule PI5p4k alpha / beta inhibitors and methods using same

Abstract

The present disclosure relates to the discovery of 2-amino-dihydropteridinone compounds and analogues thereof capable of inhibiting phosphatidylinositol phosphate kinases. In certain embodiments, the compounds of the disclosure can be used to treat p53-null cancer in a subject. In other embodiments, the compounds of the disclosure can be used to treat metabolic disorders in a subject, including but not limited to type 2 diabetes and / or obesity.

Description

[0001]Attorney Docket No.047162-7507WO1 (02542) TITLE Small-Molecule PI5P4K Alpha / Beta Inhibitors and Methods Using Same CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No.63 / 571,218, filed March 28, 2024, which is hereby incorporated by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under GM138722, CA196530, GM150502, and GM122473 awarded by National Institutes of Health. The government has certain rights in the invention. BACKGROUND Phosphatidylinositol 4,5-bisphosphate, or PI(4,5)P2, is a versatile lipid that is best known for its constitutive function as the major membrane binding site for a wide variety of soluble, mostly cytosolic proteins and some integral membrane proteins, and for its role in signal transduction as the precursor for classic second messengers such as inositol 1,4,5- trisphosphate (IP3), diacylglycerol (DAG), and phosphatidylinositol 3,4,5-trisphosphate (PIP3). The bulk of cellular PI(4,5)P2is found at the inner leaflet of the plasma membrane, and is synthesized from phosphatidylinositol 4-phosphate, or PI(4)P, by the type 1 phosphatidylinositol phosphate kinase PI4P5K. There is a second synthetic pathway where PI(4,5)P2 can be generated from the much rarer phosphatidylinositol 5-phosphate, or PI(5)P, through the activity of the type 2 phosphatidylinositol phosphate kinase PI5P4K. The type 2 kinase is as abundantly expressed as the type 1 kinase, but functionally less well understood. It has been proposed that PI5P4K may serve to suppress PI(5)P, a lipid second messenger often induced by stress, or is responsible for producing local pools of PI(4,5)P2 at internal membrane compartments such as Golgi and nucleus. In higher animals, there are three PI5P4K isoforms, α, β and γ, which are encoded by three different genes, PIP4K2A, B and C. The three isoforms differ, at least in vitro, quite significantly in their specific activities: PI5P4Kα is two orders of magnitude more active than PI5P4Kβ, while PI5P4Kγ has very little activity. PI5P4Ks are dimeric proteins, and the possibility that they can form heterodimers may have important functional implications, -1- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) especially for the lesser active isoforms. PI5P4Kβ is the only isoform that preferentially localizes to the nucleus. Genetics has implicated PI5P4Kβ in metabolic regulation. Mice with both PIP4K2B genes inactivated manifest hypersensitivity to insulin stimulation and adult males are also leaner. Although this is consistent with the observation that PI(5)P level, which can be manipulated by overexpressing PI5P4K, or a bacterial phosphatase that robustly produces PI(5)P from PI(4,5)P2, correlates positively with PI3K / Akt signaling, the underlying molecular mechanisms remain undefined. Both male and female PIP4K2B- / -mice are mildly growth retarded. Inactivation of the only PI5P4K isoform in Drosophila also produced small and developmentally delayed animals. These phenotypes may be related to suppressed TOR signaling, but the mechanism is unclear since TORC1 is downstream of, and positively regulated by PI3K / Akt. Knocking out the enzymatically more active PI5P4Kα, in contrast, has not been shown to produce any overt metabolic or developmental phenotypes. Metabolic reprogramming is a hallmark of cancer. Cell transformation is often accompanied by metabolic vulnerabilities imposed by underlying driver mutations. Loss of p53, a tumor suppressor that is mutated in most human cancers, renders cells susceptible to nutrient stress, and to the antidiabetic drug metformin. Although TP53- / -and PIP4K2B- / -mice are themselves viable, combining the two is lethal. Removing three copies of PI5P4K (PIP4K2A- / -PIP4K2B+ / -) greatly reduces spontaneous tumor formation and cancer-related death in TP53- / -animals. The synthetic lethal interaction between p53 and the lipid kinase in proliferating tumor cells was previously thought to be caused by suppressed glucose metabolism and increased reactive oxygen species (ROS). Given the interest in the physiological function of this alternative synthetic route for PI(4,5)P2, and the potential of PI5P4K inhibitors in treating type 2 diabetes and cancer, several attempts had been made to identify chemical probes that target various PI5P4K isoforms, but these efforts yielded compounds with limited affinity and unknown selectivity. Therefore, there remains a need in the art for novel PI5P4K inhibitors that are potent and selective. In certain embodiments, these compounds can inhibit PI5P4K^ / β and modulate energy metabolism, thereby treating, ameliorating, and / or preventing cancer and metabolic disorders in subjects in need thereof. The present disclosure meets these needs. SUMMARY In one aspect, described herein is a compound of Formula (IA) or a salt, solvate, -2- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) enantiomer, diastereoisomer, or tautomer thereof: , wherein: A is optionally substituted group consisting of 1H- benzo[d][1,2,3]triazolyl, triazolyl, thiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiodiazolyl, pyridinyl, pyrimidinyl, triazinyl, pyrazinyl, thiophenyl, benzotriazolyl, benzamidazolyl, indolyl, indazolyl, pyrrolyl, and pyrazolyl; X is selected from the group consisting of: -S(O)2NH2, -C(O)OR’, -CN, - C(O)NHS(O)2R’, and 1H-tetrazolyl, wherein each occurrence of R’ is independently C1-C6alkyl; R1is selected from the group consisting of -CH2-(C3-C8 optionally substituted heteroaryl), isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentylmethyl, cyclohexylmethyl, and , R8is selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, halogen, thiol, C1-C6 thioalkoxy, -OH, C1-C6 alkoxy, and -NR”R”; wherein R9is selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, halogen, thiol, C1-C6 thioalkoxy, -OH, C1-C6 alkoxy, and -NR”R”; and wherein each occurrence of R” is independently H or C1-C6alkyl; R2is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 heteroalkyl, C3-C8heterocycloalkyl, C2-C6alkenyl, and C2-C6alkynyl; wherein in R2each occurrence of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, or alkynyl is optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8cycloalkoxy, halogen, -OH, thiol, C1-C6thioalkoxy, phenyl, heteroaryl, heterocyclyl, and -NR’’’R’’’, wherein each occurrence of R’’’ is independently H or C1-C6alkyl or the two R’’’ bound to the N combine to form 3-7 membered heterocyclyl. In another aspect, described herein is a pharmaceutical composition comprising a compound as described herein and at least one pharmaceutically acceptable carrier. In another aspect, described herein is a method of treating a p53-null cancer in a -3- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound as described herein. In another aspect, described herein is a method of treating at least one metabolic disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound as described herein. BRIEF DESCRIPTION OF THE DRAWINGS The following detailed description of specific embodiments of the disclosure will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the disclosure, specific embodiments are shown in the drawings. It should be understood, however, that the disclosure is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings. FIG.1 shows the crystal structure of 066ATZ in complex with PIP4K2A. Fo-Fc map, contoured at 3.0 sigma, confirms the presence of the bound inhibitor. The apo PIP4K2A structure (PDB ID: 7N6Z) with solvents and ions removed, was used in rigid body refinement and phase calculation. Statistics are shown in Table 2 below. FIG.2 shows characterization of 066ATZ reveals high selectivity and good in vivo pharmacokinetics despite relatively worse affinity to PI5P4Kα / β. Concentration inhibition curves of 066ATZ against PI5P4Kα and β generated by measuring enzymatic production of 32P-labeled PI(4,5)P2 on TLC ([ATP]=20μM, Km,ATP for PI5P4Kα is 13μM, Km,ATP for PI5P4Kβ is 17μM). FIG.3A shows plasma concentration vs time profile of 066ATZ in male C57 mice with 1mg / kg IV and 10 mg / kg IP injection generates good pharmacokinetic parameters. Experiments were all performed by Jubilant Biosys LTD and experimental details can be found in Tables 2-6. FIG.3B shows the effects of 066ATZ on the body weight and blood glucose levels (15min and 30min after IP injection) were tested in female nude mice. Each dose group (10, 30, 100mg / kg) contained 5 animals. A significant drop in blood sugar was observed in the two higher dose groups 30min post injection. FIG.4 shows protein kinase profiling of 066ATZ against 396 protein kinases shows only one major off-target, CK2α, as illustrated by Kinase Mapper of the human kinome (Reaction Biology). Assay ATP was 10μM and compound concentration was 0.5μM. FIG.5 shows pharmacological inhibition of PI5P4K slows down LUAD tumor growth in vivo. Tumor growth curve of H1975 cell-derived xenografts in R2G2 mice treated -4- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) by vehicle and 100 mg / kg 066ATZ exhibit the cytostatic anti-tumor effect by 066ATZ.5 mice were studied in each group with one mouse in 066ATZ-treated group dead early due to unknown sickness on day 44. **p<0.01 with two-tailed unpaired t-test with Welch’s correction. FIG.6 shows Kaplan-Meier survival curve of tumor-bearing R2G2 mice treated by vehicle and 100 mg / kg 066ATZ shows significantly improved survival rate. (n=5) *p<0.05 with Log-rank (Mantel-Cox) test. FIG.7 shows tumor growth curve of H1975 cell-derived xenografts in R2G2 mice with unchanged level of PI5P4Kα / β and genetic knockdown of PI5P4Kα / β displays no significant difference in tumor growth rate (n=5). FIG.8 shows Western Blot analysis of PI5P4Kα and β confirms knockdown of PI5P4Kα and β in all five doxycycline-treated tumors. FIG.9 shows PI5P4Kα / β inactivation impairs tumor-promoting effects of M2 macrophages through immunomodulation. Immunohistochemical staining of F4 / 80 marker in 4 different tumor tissues that represent substantial infiltration of macrophages. FIG.10 shows a schematic illustration of co-culture cell growth assay with M2 macrophages and H1975 cells. FIG.11 shows cell number of H1975 cells with or without co-culture of M2 macrophages under treatment of DMSO or 20μM 066ATZ based on CellTiter-Glo luminescence (n=4). Both H1975 cells and macrophages were incubated with same treatment. *p<0.05 with two-tailed unpaired t-test with Welch’s correction. FIG.12 shows cell number of H1975 cells based on CellTiter-Glo luminescence with or without the co-culture of M2 macrophages which either had normal level or knocked down PI5P4Kα / β (n=4). Genetic silencing was only induced in M2 macrophages and complete knockdown of PI5P4Kα and β was confirmed by Western Blot. *p<0.05 with two-tailed unpaired t-test with Welch’s correction. FIG.13 shows cell number of H1975 cells based on CellTiter-Glo luminescence with or without the co-culture of M2 macrophages which either had normal level or knocked down PI5P4Kα (n=3). Genetic silencing was only induced in M2 macrophages. *p<0.05 with two- tailed unpaired t-test with Welch’s correction. FIG.14 shows cell number of H1975 cells based on CellTiter-Glo luminescence with the co-culture of M2 macrophages which either had normal level or knocked down PI5P4Kβ (n=4). Genetic silencing was only induced in M2 macrophages. FIG.15 shows a heat map of average fold change in detected cytokine levels from the -5- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) media supernatant cultured by M2 macrophages with 20μM 066ATZ treatment or PI5P4Kα / β knockdown compared to DMSO treatment. Cytokine profiling was performed by Eve Technologies on 75μL of cell culture supernatant for each sample with n=3 for each condition. The cytokine levels were normalized against viable cell number of M2 macrophages and total supernatant volume in each well. FIG.16 shows overlay of co-crystal structures of PI5P4Kα bound to CC259 and 422A. FIG.17 shows individual growth curves of H1975-derived tumor xenografts in R2G2 mice treated by vehicle. The curve of the mouse that’s sacrificed early due to unknown sickness is indicated. FIG.18 shows individual growth curves of H1975-derived tumor xenografts in R2G2 mice treated by 100 mg / kg 066ATZ. The curve of the mouse that’s sacrificed early due to unknown sickness is indicated. FIG.19 shows tumor growth curve of H1975 cell-derived xenografts in R2G2 mice treated by vehicle and 5 mg / kg CX-4945 shows no significant difference in tumor growth rate (n=5). FIG.20 shows Western Blot analysis of phospho-AKT1 (S129) in vehicle-treated and 066ATZ-treated tumor lysates. FIG.21 shows Western Blot analysis of phospho-AKT1 (S129) in vehicle-treated and CX-4945-treated tumor lysates. FIG.22 shows cell-titer Glo measurement of H1975DKDcell number with a titration of increasing concentration of 066ATZ without serum in the culture media (n=6). FIG.23 shows cell-titer Glo measurement of H1975DKD3-day cell growth with a titration of increasing concentration of 066ATZ with serum in the culture media. (n=6). FIG.24 shows ELISA measurement of CCL18 concentration in M0 and M2 macrophages cultured media supernatants without serum. IL-4 and IL-13 were added for M2 polarization for 3 days while M0 macrophages were incubated in normal growth medium for 3 days. Then supernatants were collected after media was changed to serum free RPMI-1640 media for 1 day. The results are normalized against cell numbers of M0 and M2 macrophages measured by Cell-titer Glo (n=3). FIG.25 shows cell-titer Glo measurements of M2 macrophage cell number from the transwell inserts used in co-culture assays treated by 20 μM 066ATZ and PI5P4Kα / β knockdown (n=4). FIG.26 shows ELISA measurement of CCL18 concentration in M2 macrophages -6- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) cultured media supernatants. The supernatants were collected after 3-day treatment with 20 μM 066ATZ and 200 ng / ml doxycycline in serum-free RPMI-1640 media. To ensure genetic knockdown, M2 macrophages were subjected to doxycycline pre-treatment for 2-day in normal growth media during the 3-day polarization, making the total doxycycline treatment 5 days. The results are normalized against cell numbers of M0 and M2 macrophages measured by Cell-titer Glo (n=3). FIG.27A is a schematic diagram illustrating the time course of macrophage (MP) differentiation and polarization in vitro. THP-1* cells were treated with 200nM PMA for 3 days to induce differentiation. The adherent cells were collected and replated (~2,000,000 cells per well) on day 2. In the knockdown experiment, DOX (200ng / ml) was added on day 4 and maintained throughout the experiment. In the compound treatment experiment, 066ATZ (20mM) was added to the macrophage culture on day 5. The following reagents were added on day 6 to induce macrophage polarization (only M2a polarization was shown in the diagram): M1, IFNg (100 units / ml) and LPS (100 ng / ml); M2a, IL-4 (10 units / ml) and LPS (100 ng / ml); M2b, IgG-OVA complex and LPS (100 ng / ml); M2c, IL-10 (10 ng / ml); M2d, NECA (5 mM) and LPS (100 ng / ml). After removing polarization solutions on day 7, serum- free DMEM / F12 medium was added, and culture supernatant was collected after 24h. The WB shown below the time course diagram confirms DOX-inducible knockdown of PIP4K2A and PIP4K2B in THP-1* cells. M2a polarization caused an increase of CCL18 secretion, which was detected by ELISA. FIG.27B shows that the conditioned media from unpolarized macrophages (M0) and differently polarized macrophages (M1, M2a-d) promoted H1975 cell growth (n=6). The cell numbers were determined by CellTiter-Glo®. The control medium was collected from a well without any macrophages. During the 3d growth period, H1975 cell number doubled in the control medium. To account for this residual growth, the difference in final cell numbers was used to quantify the growth promoting effect of macrophage conditioned medium. FIG.27C shows knockdown of PIP4K2A / 2B in M2a polarized macrophage eliminated its growth promoting activity (n=6; ***, p<0.0001). FIG.27D shows the effect of PIP4K2A / 2B knockdown in other macrophages did not reach statistical significance, although in M1 polarized macrophages the knockdown appeared to produce a small reduction (n=6). FIG.27E shows that treatment with 066ATZ (20mM), or with a more potent PIP4K inhibitor, BAY-091 (2mM), reduced M2a macrophage’s growth promoting activity (n=6; **, p<0.001; ***, p<0.0001). CK2a / a’ inhibitor CX-4945 (0.5mM) had no effect on the -7- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) conditioned medium of M2a macrophages. FIG.27F shows that M2a conditioned medium promoted the growth of other cell lines: Calu-3 (lung cancer), MIA PaCa-2 (pancreatic cancer), HCT-116 (colon cancer), 22Rv1 (prostate cancer), and U-87MG (glioblastoma). Knockdown of PIP4K2A / 2B in the M2a macrophage reduced these growth promoting activities (n=6; *, p<0.01; **, p<0.001; ***, p<0.0001). DETAILED DESCRIPTION The present disclosure relates to the discovery of certain 2-amino-dihydropteridinone compounds, and analogues thereof, that are capable of inhibiting PI5P4Kα and PI5P4Kβ. In certain embodiments, the compounds of the disclosure can be used to treat p53-null cancer in a subject. In other embodiments, the compounds of the disclosure selectively kill p53-null cancer cells over non-p53-null cancer cells. In yet other embodiments, the compounds of the disclosure can be used to treat metabolic disorders in a subject, including but not limited to type 2 diabetes and / or obesity. Compounds In one aspect, the disclosure provides a 2-amino-dihydropteridinone compound, or a salt, solvate, enantiomer, diastereoisomer, or tautomer thereof, which is capable of inhibiting PI5P4Kα and PI5P4Kβ. In some aspects, provided herein is compound of Formula (IA) or a salt, solvate, enantiomer, diastereoisomer, or tautomer thereof: , wherein: A is optionally substituted heteroaryl selected from the group consisting of 1H- benzo[d][1,2,3]triazolyl, triazolyl, thiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiodiazolyl, pyridinyl, pyrimidinyl, triazinyl, pyrazinyl, thiophenyl, benzotriazolyl, benzamidazolyl, indolyl, indazolyl, pyrrolyl, and pyrazolyl; X is selected from the group consisting of -S(O)2NH2, -C(O)OR’, -CN, -C(O)NHS(O)2R’, and 1H-tetrazolyl, wherein each occurrence of R’ is independently C1-C6 alkyl; R1is selected from the group consisting of -CH2-(optionally substituted C3-C8heteroaryl), -8- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentylmethyl, cyclohexylmethyl, and , wherein: R8is selected from the group consisting of C1-C6 alkyl, C3-C8 halogen, thiol, C1-C6thioalkoxy, -OH, C1-C6alkoxy, and -NR”R”; R9is selected consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, halogen, thiol, C1-C6 thioalkoxy, -OH, C1-C6alkoxy, and -NR”R”, wherein each occurrence of R” is independently H or C1-C6 alkyl; R2is selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C3-C8 heterocycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; wherein in R2each occurrence of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, or alkynyl is optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6alkoxy, C3-C8cycloalkoxy, halogen, -OH, thiol, C1-C6thioalkoxy, phenyl, heteroaryl, heterocyclyl, and -NR’’’R’’’, wherein each occurrence of R’’’ is independently H or C1-C6alkyl or the two R’’’ bound to the N combine to form 3-7 membered heterocyclyl. In some embodiments, the compound is: , wherein R3is selected C6 alkyl, and C3-C8 cycloalkyl. In some embodiments, A is optionally substituted heteroaryl selected from the group consisting of 1H-benzo[d][1,2,3]triazolyl, triazolyl, thiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiodiazolyl, pyridinyl, pyrimidinyl, triazinyl, pyrazinyl, thiophenyl, benzotriazolyl, benzamidazolyl, indolyl, indazolyl, pyrrolyl, pyrazolyl. In some embodiments, R1is -CH2-(optionally substituted pyridyl). In some embodiments, R1is -CH2-(2-pyridyl). In some embodiments, R2is cyclopentyl. -9- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) In some embodiments, the , wherein: R1a, R1b, R1c, R1d, R2a, R2b, R2c, R2d, R2e, selected from H, C1-C6alkyl, halogen -NH2, -OH, -C(=O)OH, -C(=O)OC1-C6alkyl, - C(=O)OC3-C8 cycloalkyl -C(=O)C1-C6 alkyl, and -C(=O)C3-C8 cycloalkyl; and R3is independently selected from the group consisting of H, F, Cl, Br, I, and C1-C6alkyl. In some embodiments, the compound . In some embodiments, X is selected (O)2NH2, - C(O)NHS(O)2CH3, and 1H-tetrazolyl. In some embodiments, the compound is selected from the group consisting of: amino)-8-cyclopentyl-5-methyl-7-(pyridin-2- ylmethyl)-7,8-dihydropteridin-6(5H)-one, (pyridin-2-ylmethyl)-5,6,7,8-tetrahydropteridin-2- yl)amino)-N-(methylsulfonyl)thiazole-5-carboxamide, -10- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) N O N N 7-(pyridin-2-ylmethyl)-5,6,7,8-tetrahydropteridin-2- 7-(pyridin-2-ylmethyl)-5,6,7,8-tetrahydropteridin-2- In some embodiments, provided herein is a pharmaceutical composition comprising a compound provided herein. In certain embodiments, the compound of the disclosure, such as for example Formula (IA) or (IB), is capable of binding at least one phosphatidylinositol phosphate kinase. In other embodiments, the compound is capable of binding at least one type 2 phosphatidylinositol phosphate kinase. In yet other embodiments, the compound is capable of binding at least one selected from the group consisting of PI5P4Kα and PI5P4Kβ. In yet other embodiments, the compound is capable of inhibiting the activity of at least one phosphatidylinositol phosphate kinase. In yet other embodiments, the compound is capable of inhibiting the activity of at least one type 2 phosphatidylinositol phosphate kinase. In yet other embodiments, the compound is capable of inhibiting the activity of at least one selected from the group consisting of PI5P4Kα and PI5P4Kβ. In certain embodiments, the compound of the disclosure, such as for example Formula (IA) or (IB), is useful in the treatment of at least one disease or disorder related to activity of at least one selected from the group consisting of PI5P4Kα and PI5P4Kβ. In other embodiments, the compound is useful in treating a p53-null cancer in a subject. In yet other embodiments, the compound is useful in treating metabolic disorders in a subject. In certain embodiments, the subject is a mammal. In other embodiments, the subject is a human. In certain embodiments, the compound of the disclosure is formulated as part of a -11- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) pharmaceutical composition, further comprising at least one pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent. In other embodiments, the at least one additional therapeutic agent is a chemotherapeutic agent. The compounds of the disclosure may possess one or more stereocenters, and each stereocenter may exist independently in either the (R) or (S) configuration. In one embodiment, compounds described herein are present in optically active or racemic forms. The compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In one embodiment, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In another embodiment, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography. The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound of the disclosure, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert- butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In one embodiment, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In another embodiment, the compounds described herein exist in unsolvated form. In one embodiment, the compounds of the disclosure exist as tautomers. All tautomers are included within the scope of the compounds recited herein. In one embodiment, compounds described herein are prepared as prodrugs. A “prodrug” is an agent converted into the parent drug in vivo. In one embodiment, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or -12- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) therapeutically active form of the compound. In another embodiment, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. In one embodiment, sites on, for example, the aromatic ring portion of compounds of the disclosure are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In one embodiment, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group. Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to2H,3H,11C,13C,14C,36Cl,18F,123I,125I,13N,15N,15O,17O,18O,32P, and35S. In one embodiment, isotopically-labeled compounds are useful in drug and / or substrate tissue distribution studies. In another embodiment, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet another embodiment, substitution with positron emitting isotopes, such as11C,18F,15O and13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. In one embodiment, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are -13- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein. Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein. The disclosure further includes a pharmaceutical composition comprising the compound of the disclosure and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition further comprises at least one additional agent that is useful to treat the diseases or disorders contemplated herein. In certain embodiments, the compound of the disclosure and the additional agent are coformulated in the composition. Salts The compounds described herein may form salts with acids or bases, and such salts are included in the present disclosure. In one embodiment, the salts are pharmaceutically acceptable salts. The term “salts” embraces addition salts of free acids or bases that are useful within the methods of the disclosure. The term “pharmaceutically acceptable salt” refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present disclosure, such as for example utility in process of synthesis, purification or formulation of compounds useful within the methods of the disclosure. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. -14- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) Suitable pharmaceutically acceptable base addition salts of compounds of the disclosure include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. Methods The disclosure includes a method of treating and / or preventing p-53 null cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, such as for example Formula (IA) or (IB), or a salt, solvate, enantiomer, diastereoisomer, or tautomer thereof. In certain embodiments, the cancer is at least one selected from the group consisting of Esophageal / Stomach Cancer, Bladder / Urinary Tract Cancer, Small Cell Lung Cancer, CNS / Brain Cancer, Skin Cancer (Non-Melanoma), Head and Neck Cancer, Ampullary Carcinoma, Burkitt's lymphoma, Esophagogastric Cancer, Colorectal Cancer, Ovarian Cancer, Non-Small Cell Lung Cancer, Small Bowel Cancer, Cancer of Unknown Primary, High-grade glioma K27Mmut, Pancreatic Cancer, Uterine Sarcoma, Bladder Cancer, High- grade glioma K27Mwt, Appendiceal Cancer, Breast Cancer, Soft Tissue Sarcoma, B-cell acute lymphoblastic leukemia (hypodiploid), Endometrial Cancer, Penile Cancer, Glioma, Breast Sarcoma, Hepatobiliary Cancer, Vaginal Cancer, Gastrointestinal Neuroendocrine Tumor, Adrenocortical Carcinoma, Prostate Cancer, Sellar Tumor, Hodgkin Lymphoma, Upper Tract Urothelial Carcinoma, Non-Hodgkin Lymphoma, Melanoma, Bone Cancer, Cutaneous Melanoma, Mesothelioma, Adrenocortical carcinoma, Invasive Breast Carcinoma, Salivary Gland Cancer, B-cell acute lymphoblastic leukemia (non-hypodiploid), Anal Cancer, Embryonal tumor with multilayered rosettes, Ewing's sarcoma, Nerve Sheath Tumor, Wilms' tumors, Germ Cell Tumor, Multiple Myeloma, Cervical Cancer, Gastrointestinal Stromal Tumor, Renal Cell Carcinoma, Mature B-Cell Neoplasms, Myelodysplasia, Thymic Tumor, Sex Cord Stromal Tumor, Atypial teratoid / rhabdoid tumor, Miscellaneous Neuroepithelial Tumor, Medulloblastoma WNT, Medulloblastoma SHH, Rhabdomyosarcoma, Leukemia, Thyroid Cancer, Embryonal Tumor, Wilms Tumor, Osteosarcoma, CNS Cancer, Neuroblastoma, Medulloblastoma Group3, Pheochromocytoma, B-Lymphoblastic -15- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) Leukemia / Lymphoma. In other embodiments, the cancer is selected from the group consisting of breast cancer, prostate cancer, and lung cancer. P-53 null cancers are described in Gao, et al. Sci Signal.2013, 6 (269), pl 1, which is incorporated herein in its entirety by reference. The disclosure further includes a method of treating or preventing at least one metabolic disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, such as for example Formula (IA) or (IB), or a salt, solvate, enantiomer, diastereoisomer, or tautomer thereof. In certain embodiments, the at least one metabolic disorder is selected from the group consisting of type 2 diabetes, obesity, liver disease, and heart disease. Without being limited to any particular theory, the methods of the disclosure allow for inhibition of at least one phosphatidylinositol phosphate kinase. In certain embodiments, the at least one phosphatidylinositol phosphate kinase is a type 2 phosphatidylinositol phosphate kinase. In other embodiments, the at least one phosphatidylinositol phosphate kinase is at least one of PI5P4Kα and PI5P4Kβ. In certain embodiments, the therapeutically effective amount of a compound of Formula (IA) or (IB) is formulated as part of a pharmaceutical composition. In certain embodiments, the therapeutically effective amount of a compound of Formula (IA) or (IB), is administered to the subject by a route selected from the group consisting of parenteral and / or oral. In certain embodiments, the subject is a mammal. In other embodiments, the subject is a human. Kits The disclosure includes a kit comprising a compound of the disclosure, an applicator, and an instructional material for use thereof. The instructional material included in the kit comprises instructions for preventing or treating a disorder or disease contemplated within the disclosure in a subject. The instructional material recites the amount of, and frequency with which, the compound of the disclosure should be administered to the subject. In certain embodiments, the kit further comprises at least one additional agent useful to treat or prevent a disease or disorder contemplated within the disclosure. Combination Therapies -16- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) In certain embodiments, the compounds of the disclosure are useful in the methods of the disclosure in combination with at least one additional compound or treatment useful for treating or preventing a disease or disorder contemplated within the disclosure. This additional compound may comprise compounds identified herein or compounds, e.g., commercially available compounds, known to treat, prevent or reduce the symptoms of cancer or a metabolic disease or disorder contemplated herein. Non-limiting examples of agents useful to treat p53-null cancer are chemotherapeutic agents and immunotherapeutic agents. In other embodiments, the compounds of the disclosure are useful in treating cancer in combination with one or more cancer treating radiation therapies. Non-limiting examples of agents useful for treating type 2 diabetes include insulin, blood thinners, statins, and anti-diabetic medications. Non-limiting examples of anti-diabetic medications can include drugs such as metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors. A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emax equation (Holford & Scheiner, 19981, Clin. Pharmacokinet.6: 429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol.114: 313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul.22:27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively. Administration / Dosage / Formulations The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset of a disease or disorder contemplated in the disclosure. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. Administration of the compositions of the present disclosure to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease or disorder contemplated in the disclosure. -17- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a disease or disorder contemplated in the disclosure. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the disclosure is from about 1 and 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In particular embodiments, it is especially advantageous to formulate the compound 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 patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the disclosure are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be -18- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound for the treatment of a disease or disorder contemplated in the disclosure. In one embodiment, the compositions of the disclosure are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions of the disclosure comprise a therapeutically effective amount of a compound of the disclosure and a pharmaceutically acceptable carrier. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. In one embodiment, the compositions of the disclosure are administered to the patient in dosages that range from one to five times per day or more. In another embodiment, the compositions of the disclosure are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the disclosure varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the disclosure should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physical taking all other factors about the patient into account. Compounds of the disclosure for administration may be in the range of from about 1 ^g to about 10,000 mg, about 20 ^g to about 9,500 mg, about 40 ^g to about 9,000 mg, about 75 ^g to about 8,500 mg, about 150 ^g to about 7,500 mg, about 200 ^g to about 7,000 mg, about 3050 ^g to about 6,000 mg, about 500 ^g to about 5,000 mg, about 750 ^g to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween. In one embodiment, the present disclosure is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the disclosure, alone or in combination with a second pharmaceutical agent; and -19- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder contemplated in the disclosure. Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., anti-cancer agents, anti-diabetic agents. Routes of administration of any of the compositions of the disclosure include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the disclosure may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present disclosure are not limited to the particular formulations and compositions that are described herein. Oral Administration For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. -20- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. Parenteral Administration As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques. Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multidose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition. Additional Administration Forms Additional dosage forms of this disclosure include dosage forms as described in U.S. Patents Nos.6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms of this disclosure also include dosage forms as described in U.S. Patent Applications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms of this disclosure also include dosage forms as described in PCT Applications Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO -21- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757. Controlled Release Formulations and Drug Delivery Systems In one embodiment, the formulations of the present disclosure may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations. The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form. In one embodiment of the disclosure, the compounds of the disclosure are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that may, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours. The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration. The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration. As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration. As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration. Dosing The therapeutically effective amount or dose of a compound of the present disclosure depends on the age, sex and weight of the patient, the current medical condition of the patient -22- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) and the progression of a disease or disorder contemplated in the disclosure. The skilled artisan is able to determine appropriate dosages depending on these and other factors. A suitable dose of a compound of the present disclosure may be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses. It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the inhibitor of the disclosure is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized. -23- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) Definitions As used herein, each of the following terms has the meaning associated with it in this section. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Generally, the nomenclature used herein and the laboratory procedures in pharmacology, pharmaceutical science, separation science and organic chemistry are those well-known and commonly employed in the art. It should be understood that the order of steps or order for performing certain actions is immaterial, so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously or not. As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. As used herein, the term “about” is understood by persons of ordinary skill in the art and varies to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound useful within the disclosure with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, nasal, pulmonary and topical administration. A “disease” as used herein is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate. The terms “patient,” “subject” or “individual” are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human. In other embodiments, the patient is a non-human mammal including, for example, livestock -24- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. In yet other embodiments, the patient is an avian animal or bird. Preferably, the patient, individual or subject is human. As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the disclosure, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the disclosure. Other additional ingredients that can be included in the pharmaceutical compositions used in -25- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) the practice of the disclosure are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. The term “prevent,” “preventing” or “prevention,” as used herein, means avoiding or delaying the onset of symptoms associated with a disease or condition in a subject that has not developed such symptoms at the time the administering of an agent or compound commences. A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs. As used herein, the term “therapeutically effective amount” refers to an amount that is sufficient or effective to prevent or treat (delay or prevent the onset of, prevent the progression of, inhibit, decrease or reverse) a disease or condition described or contemplated herein, including alleviating symptoms of such disease or condition. As used herein, the term “treatment” or “treating” is defined as the application or administration of a therapeutic agent, i.e., a compound of the disclosure (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a condition contemplated herein, a symptom of a condition contemplated herein or the potential to develop a condition contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a condition contemplated herein, the symptoms of a condition contemplated herein or the potential to develop a condition contemplated herein. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics. As used herein, the term “alkenyl,” employed alone or in combination with other terms, means, unless otherwise stated, a stable monounsaturated or di-unsaturated straight chain or branched chain hydrocarbon group having the stated number of carbon atoms. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and the higher homologs and isomers. A functional group representing an alkene is exemplified by -CH2-CH=CH2. As used herein, the term “alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon -26- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) atoms, as defined elsewhere herein, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (or isopropoxy) and the higher homologs and isomers. A specific example is (C1-C3)alkoxy, such as, but not limited to, ethoxy and methoxy. As used herein, the term “alkyl” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbon atoms) and includes straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. A specific embodiment is (C1-C6)alkyl, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl and cyclopropylmethyl. As used herein, the term “alkynyl,” employed alone or in combination with other terms, means, unless otherwise stated, a stable straight chain or branched chain hydrocarbon group with a triple carbon-carbon bond, having the stated number of carbon atoms. Non- limiting examples include ethynyl and propynyl, and the higher homologs and isomers. The term “propargylic” refers to a group exemplified by -CH2-C≡CH. The term “homopropargylic” refers to a group exemplified by -CH2CH2-C≡CH. The term “substituted propargylic” refers to a group exemplified by -CR2-C≡CR’, wherein each occurrence of R’ is independently H, alkyl, substituted alkyl, alkenyl or substituted alkenyl, with the proviso that at least one R’ group is not hydrogen. The term “substituted homopropargylic” refers to a group exemplified by -CR’2CR’2-C≡CR’, wherein each occurrence of R’ is independently H, alkyl, substituted alkyl, alkenyl or substituted alkenyl, with the proviso that at least one R’ group is not hydrogen. As used herein, the term “aromatic” refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. having (4n+2) delocalized π (pi) electrons, where n is an integer. As used herein, the term “cycloalkyl” by itself or as part of another substituent refers to, unless otherwise stated, a cyclic chain hydrocarbon having the number of carbon atoms designated (i.e., C3-C6refers to a cyclic group comprising a ring group consisting of three to six carbon atoms) and includes straight, branched chain or cyclic substituent groups. Examples of (C3-C6)cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl rings can be optionally substituted. Non-limiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, -27- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5- dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1H- fluorenyl. The term “cycloalkyl” also includes bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1] heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl. As used herein, the term “halide” refers to a halogen atom bearing a negative charge. The halide anions are fluoride (F−), chloride (Cl−), bromide (Br−), and iodide (I−). As used herein, the term “halo” or “halogen” alone or as part of another substituent refers to, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. As used herein, the term “heteroalkyl” by itself or in combination with another term refers to, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -O-CH2-CH2-CH3, -CH2- CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, and -CH2CH2-S(=O)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3, or -CH2-CH2-S-S- CH3. As used herein, the term “heterocycle” or “heterocyclyl” or “heterocyclic” by itself or as part of another substituent refers to, unless otherwise stated, an unsubstituted or substituted, stable, mono- or multi-cyclic heterocyclic ring system that consists of carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure. A heterocycle may be aromatic or non-aromatic in nature. In certain embodiments, the heterocycle is a heteroaryl. As used herein, the term “heteroaryl” or “heteroaromatic” refers to a heterocycle having aromatic character. A polycyclic heteroaryl may include one or more rings that are -28- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) partially saturated. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuryl. Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3- dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin and hexamethyleneoxide. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl. Examples of polycyclic heterocycles include indolyl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (such as, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, but not limited to, 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl. The aforementioned listing of heterocyclic and heteroaryl moieties is intended to be representative and not limiting. As used herein, the term “substituted” refers to that an atom or group of atoms has replaced hydrogen as the substituent attached to another group. As used herein, the term “substituted alkyl,” “substituted cycloalkyl,” “substituted alkenyl” or “substituted alkynyl” refers to alkyl, cycloalkyl, alkenyl or alkynyl, as defined above, substituted by one, two or three substituents selected from the group consisting of halogen, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH2, -N(CH3)2, (1-methyl-imidazol-2-yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(=O)OH, trifluoromethyl, -C≡N, -C(=O)O(C1- C4)alkyl, -C(=O)NH2, -C(=O)NH(C1-C4)alkyl, -C(=O)N((C1-C4)alkyl)2, -SO2NH2, - C(=NH)NH2, and -NO2, preferably containing one or two substituents selected from halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2, and -C(=O)OH, more preferably selected -29- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) from halogen, alkoxy and -OH. Examples of substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl and 3-chloropropyl. For aryl, aryl-(C1-C3)alkyl and heterocyclyl groups, the term “substituted” as applied to the rings of these groups refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. In certain embodiments, the substituents vary in number between one and four. In another embodiment, the substituents vary in number between one and three. In yet another embodiment, the substituents vary in number between one and two. In yet another embodiment, the substituents are independently selected from the group consisting of C1-6alkyl, -OH, C1-6alkoxy, halo, amino, acetamido and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic. Unless otherwise noted, when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R2and R3taken together with the nitrogen to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen, oxygen, or sulfur. The ring can be saturated or partially saturated, and can be optionally substituted. Whenever a term or either of their prefix roots appear in a name of a substituent the name is to be interpreted as including those limitations provided herein. For example, whenever the term “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) the name is to be interpreted as including those limitations given elsewhere herein for “alkyl” and “aryl” respectively. In certain embodiments, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6 alkyl” is specifically intended to individually disclose C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6alkyl. Ranges: throughout this disclosure, various aspects of the disclosure can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values -30- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual and partial numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. The following abbreviations are used herein: 2-DG: 2-deoxyglucose; ADP: Adenosine diphosphate; AMP: Adenosine monophosphate; AMPK: 5' AMP-activated protein kinase; AMP-PNP: Adenylyl-imidodiphosphate; ATP: Adenosine triphosphate; BCA: bicinchoninic acid; BSA: bovine serum albumin; CHAPS: 3-[(3- Cholamidopropyl)dimethylammonio]-1-propanesulfonate; DAG: diacylglycerol; DCFDA: 2’,7’– dichlorofluorescin diacetate; DMSO: dimethylsulfoxide; DPBS: Dulbecco's phosphate-buffered saline; DTT: dithiothreitol; HEPES: 4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid; IP3: inositol 1,4,5-trisphosphate; kDa: kiloDalton; KRH: Krebs-Ringer-HEPES-bicarbonate buffer; LC-MS: liquid chromatography-mass spectrometry; NAC: N-acetyl cysteine; PBS: phosphate buffered saline; PIP3: phosphatidylinositol 3,4,5-trisphosphate; ROS: reactive oxygen species; RT: room temperature; TLC: thin layer chromatography; TNP-ATP: 2,4,6-trinitrophenol-adenosine triphosphate. As used herein, the phrase “CC259” refers to the compound: Cl HO N O cyclopentyl-2-((3,5-dichloro-4- 7,8-dihydropteridin-6(5H)-one, or a salt or solvate thereof. As used herein, the phrase “CC260” refers to the compound: cyclopentyl-7-(cyclopentylmethyl)-2-((3,5- 7,8-dihydropteridin-6(5H)-one, or a salt or solvate thereof. -31- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) As used herein, the phrase “422A” refers to the compound: 4- 6(5H)-one, or a As used herein, the phrase “066A” refers to the compound N O N N (carboxyl)thiazol-2-yl)amino)-8-cyclopentyl- 6(5H)-one, or a salt or solvate thereof, or a or As used herein, the phrase “ATZ066A” refers to the compound tetrazol-5-yl)thiazol-2-yl)amino)-8- 6(5H)-one, or a salt or solvate thereof. As used herein, the phrase “CX-4945” refers to the compound chlorophenyl)amino)benzo[c][2,6]naphthyridine-8- As used herein, the phrase “BAY-091” refers to the compound: -32- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) cyano-2-[4-(2-fluoro-3- butanoic acid, or a salt or solvate thereof. be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, with art- recognized alternatives and using no more than routine experimentation, are within the scope of the present application. It is to be understood that, wherever values and ranges are provided herein, the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, all values and ranges encompassed by these values and ranges are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. The description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range and, when appropriate, partial integers of the numerical values within ranges. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings or disclosure of the present disclosure as set forth herein. -33- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) EXAMPLES The disclosure is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only, and the disclosure is not limited to these Examples, but rather encompasses all variations that are evident as a result of the teachings provided herein. Materials and Methods Chemicals, reagents and cell cultures. Protein purification and crystallization used the following chemicals and reagents: 1M Tris-HCl pH 8.0 (bioWORLD), NaCl (americanBio), Imidazole (Sigma-Aldrich), 2-mercaptoethanol (Sigma-Aldrich), Lysozyme (AMERSCO, 0663-10G), Li2SO4 (Sigma-Aldrich), 1.0M HEPES pH 7.5 (Hampton Research), 50% PEG 3,350 (Hampton Research). The primary antibodies of PI5P4Kα and β were purchased from Cell Signaling Technology. All cell cultures were incubated in a 37°C incubator with 5% CO2. Example 1: Biological data Structural biology of a novel PIP4K inhibitor with improved selectivity and pharmacokinetics PI5P4Kα and β can be eliminated in all cells of an animal through germline knockout, raising the possibilities of direct and indirect anti-cancer effects caused by PI5P4K inactivation. Since small molecule can access both the animal host cells and tumor cells once injected into the animal model, a pharmacological approach was used to test both possibilities. Despite high potency against both PI5P4Kα and β, the small molecule PI5P4K inhibitor, CC260, exhibited poor pharmacokinetics (PK) in animal with low microsomal stability, Cmax, and half-life. In order to target PI5P4Kα / β in vivo, modifications were made based on the 2-amino dihydropteridinone pharmacophore of CC260 to improve the molecule’s metabolic stability while maintaining its potency and selectivity. Side chains were introduced to replace the C7-cyclopentyl and 2-amino-dichlorophenyl through synthetic effort. The C7-cyclopentyl is an useful side chain that takes advantage of the hydrophobic pocket at PI5P4Kα / β’s active site by forming hydrophobic interactions, limiting options of isosteres. The co-crystal structure also revealed a network of hydrogen bonding events among 4 water molecules, backbone amides, and the 6-carbonyl of CC260, where the non-polar C7- cyclopentyl cannot participate. Thus, with both the ability to form hydrophobic interactions -34- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) and a hydrogen bond acceptor, pyridine expectedly improves the molecule’s potency against both isoforms of PI5P4K after replacing the cyclopentyl). The new compound is named 422A. However, the co-crystal structure of PI5P4Kα bound by 422A solved at 2.67Å demonstrates the absence of hydrogen bonding between the pyridine nitrogen and the water molecule due to incorrect bond angle and bond distance between the two moieties. The slightly bulkier size of the pyridine ring compared to the cyclopentyl helps the side chain fit deeper into the hydrophobic pocket, possibly contributing to the higher potency from 422A. The substitution however failed to address the metabolic instability of the molecule as the microsomal clearance remains at a level similar to CC260). Since dehalogenation is one of the classic reactions within phase 1 drug metabolism which phenyl ring is also susceptible to, the 2-amino-dichlorophenyl potentially play a huge role in CC260 and 422A’s metabolic instability. The data show that replacing the dichlorophenol of 422A with a thiazole-5-carboxylic acid side chain substantially improves the microsomal clearance rate of the molecule, which is named 066A. However, 066A’s affinity to the β isoform of PI5P4K becomes much weaker due to the substitution, making further optimization necessary. The 3.0Å co-crystal structure with PI5P4Kα bound by 066A reveals that 066A slightly translates away from the active site relative to 422A’s position when overlayed with co-crystal structures bound to 422A (FIG. 1). Similar movement is observed again when overlaying the co-crystal structure of 066A on top of a previously solved co-crystal structure with CC259, which is a CC260 analog with C7-isopropyl being the only distinction to CC260. However, minimal movement is observed when overlaying 422A and CC259 (FIG.16), suggesting the translation of 066A is caused by the introduction of thiazole-5-carboxylic acid. Both 422A’s dichlorophenol and 066A’s thiazole-5-carboxylic acid side chain interact with three hydrophobic residues, F134, F200, and L277, which collectively form a hydrophobic cleft that sandwiches the compounds’ side chains (FIG.16). The non-polar phenyl ring fits snugly within the cleft as appropriate distances are observed between the three residue side chains and the phenol ring (FIG.16). However, the nitrogen and the sulfur atoms within the thiazole ring appear to be at greater distances from the F200 and L277 side chains possibly due to being more electronegative and bulkier than the corresponding carbon in the phenyl ring. Therefore, without wishing to be limited by any theory, steric clash between the thiazole ring and the two hydrophobic residues is responsible for pushing the thiazole-5-carboxylic acid slightly out of the hydrophobic cleft to then displace 066A’s core -35- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) away from the binding pocket. Since pyridine forms hydrophobic interactions with the hydrophobic pocket of the kinase, moving the pyridine away from the pocket can undermine the binding affinity of 066A which might explain its lower affinity against both isoforms. As the exposed acidic group of 066A is also highly susceptible to phase 2 drug metabolism and the negative charge might make it difficult for 066A to cross cellular membrane, various isosteres of carboxylic acid have been introduced to preclude the potential liabilities. Tetrazole emerges as a preferred substitute for carboxylic acid with relatively high potency against the α isoform (173 nM), some potency against β (873 nM) and low microsomal clearance rate as shown in Table 1. Table 1. Structure Ki (α) Ki (β) Microsomal clearance -36- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) 500 >1,000 2,213.6 further characterized. The low affinity to PI5P4Kβ makes it challenging for 066ATZ to achieve sufficient inhibition on PI5P4Kβ in cells or animals. However, in animal studies the β isoform is not completely eliminated either as the knockout of both α alleles and only one β allele was sufficient to prevent late onset tumorigenesis among TP53- / -miceR. Thus, 066ATZ can confer anti-tumor efficacy by fully inhibiting PI5P4Kα activity despite incomplete suppression of PI5P4Kβ activity. Similar to the chemical synthesis of CC260, the replacement of C7-cyclopentyl to C7-pyridine inevitably generated a racemic mixture of 066ATZ with R and S stereochemistry at the C7 bond. The co-crystal structure of PI5P4Kα clearly shows the R-form of 066ATZ as the dominant specie that binds to the protein. Thus, further chiral purification was performed to obtain only the R-form of 066ATZ to exclude the potential side effects caused by the S-form counterpart. All experiments using and testing 066ATZ reported herein will hence refer only to the pure R-form of the compound. Table 2. Crystallographic statistics for PIP4K2A in complex with 066ATZ (space group: P6122). Data Collection -37- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) <I / σ> 12.8 a,bRmerge 0.064 (0.959) bRmerge = ∑ │ Ii - │ / ∑ IicRwork = ∑ Fo – Fc / ∑ Fo. Rfree is the cross-validation R factor for the test set of reflections model refinement. Consistent with the microsomal stability study result, the t1 / 2at 0.49h and Cmaxat 2,484 ng / ml (about 5μM) of 066ATZ are also significantly improved with IP injection at 10 mg / kg dosage compared to CC260’s PK profile (FIG.3A). Toxicity study also shows no weight loss among 066ATZ-treated mice at 100 mg / kg dosage (IP), indicating the compound’s high tolerance. While investigating the maximum tolerated dose (MTD), we observed a transient 14% blood sugar drop 30min after IP injection in the 30mg / kg and 100mg / kg groups, but not in the 10mg / kg group (FIG.3B). This response appears consistent with the genetic studies showing that PIP4K2A / 2B knockout alters whole body metabolism. Table 3. Summary of study details IAEC protocol # IAEC / JDC / 2021-246R -38- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) Total groups 3 Mice / group 5 % Change in Body wt (Individual Animals) SNo Groups Dose Gr Animal 1 2 3 4 5 5 7 .1 .4 9 8 .0 4 4 4 4 1 2 5 5 Table 5. Average body weight change over dose study. Body weight Change -39- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) Body weight Average body weight (g) on days .5 .8 .6 , , Grou Treatmen % Change in Body weight on days Vs Day 1 # t Table 7. Blood glucose concentration measured on the fifth day of dosing. Blood Glucose mg / dl on day 5 -40- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) SEM 6.0 6.5 3 066ATZ 100 mg / Kg Mean 116.6 104.8 ction at 100 mg / kg dosage can theoretically raise the Cmaxto approximately 50 μM, which allows sufficient suppression of both PI5P4Kα with a frequent dosing scheme. Selectivity profiling results exhibit 066ATZ’s strong selectivity at 0.5μM against 396 protein kinases and 17 lipid kinases with only one major off target, the casein kinase 2 alpha CK2α and CK2α2 (FIG.4). At 066ATZ’s IC50 of inhibiting PI5P4Kα in the presence of 2 mM cellular ATP (26.8 μM), only CK2α2 is inhibited to a greater extent with about 90% inhibition, while proto-oncogene serine / threonine-protein kinase (Pim-1) is similarly inhibited to about 50% by 066ATZ (Table 8). Protein kinases are sorted based on simulated percent of inhibition on protein kinase activity in the presence of 2 mM ATP and 26.79 μM 066ATZ (IC50for PI5P4Kα based on Ki) from highest to lowest. Kinases with top 30 highest percent of inhibition are shown below in Table 8. Table 8. Protein kinase percent inhibition by 066ATZ in binding study. -41- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) The results showe the targeted protein kinase. Lipid kinases were also screened to assess selectivity of 066-ATZ. The results are shown in Table 9. Lipid kinases are sorted based on simulated percent of inhibition on protein kinase activity in the presence of 2 mM ATP and 26.79 μM 066ATZ (IC50for PI5P4Kα based on Ki) from highest to lowest. All 17 lipid kinases tested in the profiling assay are shown in Table 8. Table 9. -42- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) These ed small molecule that can be used in animal study to target PI5P4Kα and β. The co-crystal structure of PI5P4Kα bound by 066ATZ was also solved at 2.35Å, and for the first time the electron density of K209’s flexible side chain was located and confirmed electrostatic interaction between the K209 amine and tetrazole’s partial negative charge with a 3.33Å distance. Similar to 066A, the thiazole side chain of 066ATZ also generated a dramatic positional shift relative to CC259’s location. Combined, a highly selective and relatively bioavailable inhibitor of PI5P4Kα / β, 066ATZ was developed, with decent potency against α and some inhibition against β through optimization. Pharmacological inhibition of PIP4K suppresses H1975 tumor xenograft growth 066ATZ’s efficacy against LUAD tumor was first tested in an in vivo cell line- derived xenograft model. Lab-cultured H1975 cells, a commonly studied LUAD cell line, were subcutaneously injected into Rag2 / IL2RG double knockout mice (R2G2) to form xenograft tumors.100 mg / kg body weight of 066ATZ compound was administered through IP injection into the animals 5 days per week. All mice were sacrificed only when the -43- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) xenografts reached over 1,000 mm3, as such design of endpoint would not only demonstrate differences in the growth curves but also allow us to compare the survival rate in two groups. 29 days post implantation marked the first time a mouse from the vehicle group has reached endpoint, and at this point, 066ATZ was observed to significantly suppress the growth of H1975 xenograft tumors (FIG.5). The tumors treated by 066ATZ however did not remain static as 4 of the 5 mice in this group eventually reached endpoint. In certain embodiments, 066ATZ confers cytostatic instead of cytotoxic antitumor effects against LUAD. One of the 066ATZ-treated mice had to be sacrificed due to unknown sickness on day 44 post implantation (FIG.17, 18). Since this specific xenograft was growing slowly with a size of only 550 mm3on day 44, 066ATZ treatment in theory could have slowed down the tumor growth to an even larger extent if all five mice reached endpoint. Overall, the Kaplan-Myer Survival Plot also shows that 066ATZ treatment has significantly improved the mice’s survival rate (FIG.17, 18). To rule out the possibility that the observed anti-tumor effects were caused by inhibiting 066ATZ’s off-target CK2α, the in vivo experiment was repeated with 5 mg / kg body weight of CX-4945, a well-studied CK2α inhibitor already in clinical trials. Since CX- 4945 (Ki < 0.40nM) is about 100 times more potent at targeting CK2α than 066ATZ, dosing at 5 mg / kg CX-4945 through IP injection (po Cmax=0.9 μM) is expected to suppress CK2α at an even higher level than the 100 mg / kg dosage of 066ATZ. However, the data demonstrate that CX-4945 dosed 5 days per week at 5 mg / kg did not significantly alter the growth curve of H1975 tumor xenografts (FIG.19). Additionally, the western blot analysis on the phosphorylation status of CK2’s direct substrate, AKT1 at S129, revealed no significant difference between vehicle-treated and 066ATZ-treated tumor lysates (FIG.20), indicating 066ATZ’s suppression of CK2 activity conferred limited pharmacodynamic effects. On the contrary, 4 out of 5 tumor lysates that were treated by CX-4945 exhibited inhibition of AKT1 phosphorylation at S129 with one sample showing almost complete inhibition (FIG.21). Such observation indicates that 066ATZ slows down LUAD tumor growth through on-target inactivation of PI5P4Kα and β. Surprisingly, there was no replication of the in vivo results in the in vitro cell-based survival and proliferation assays.066ATZ was shown to minimally alter the number of H1975 cells that survived serum starvation treatment (FIG.22), which can be interpreted as the compound being cytostatic rather than cytotoxic. However, in experiments that probed proliferation, H1975 cells that grew in the presence of 066ATZ for 3 days did not exhibit significant reduction in growth rate (FIG.23). Without wishing to be limited by any theory, -44- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) instead of directly perturbing the tumor cells, 066ATZ treatment modulated certain external factors that are essential to LUAD tumor growth to then externally delay the growth of H1975 xenografts. To test this hypothesis, tetracycline-inducible shRNA knockdown was used as an alternative approach to only target PI5P4Kα and β within the H1975 tumor cells. As the plasmid tightly controlling the shRNA expression was transduced only into H1975 cells, the in vivo knockdown of PI5P4Kα and β cannot occur in the animal host and can only be induced in the H1975-derived xenografts. Thus, this technique distinguishes from the pharmacological approach to directly address whether 066ATZ’s anti-cancer effects were direct or indirect. Another advantage of the tet-on inducible knockdown system is that it mimics drug action when compared to the traditional shRNA method or CRISPR-Cas9 knockout. All mice in both groups started with the same tumor cells, and only after the xenografts were formed, shRNA knockdown was induced in one group of mice through drinking water containing doxycycline (more stable derivative of tetracycline). Although complete removal of both PI5P4Kα and β were reported by western blots on tumor lysates, the genetic inactivation of the lipid kinases did not significantly reduce the growth rate of H1975 xenografts (FIG.7). Combined with the lack of in vitro effects shown by 066ATZ, this result from the genetic study confirms that shutting down PI5P4Ks in the animal host rather than in the H1975 cells caused the tumor growth to slow down. PI5P4Kα and β do not seem to play essential roles in the viability and growth of H1975 cells, but inactivating the lipid kinases in certain cells from the host dramatically disrupts how these cells modulate the tumor growth to then externally induce anti-cancer effects. Since H1975 cell line harbors TP53 loss-of- function mutation, the genetic study shows that loss of PI5P4Ks is not synthetically lethal with loss of p53 at least in the model presently studied. It does not, however, rule out the possibility that initiation of tumors is susceptible to the proposed synthetic lethality. Herein, it has been shown that in vivo pharmacological inhibition of PI5P4Kα / β indirectly slows down LUAD tumor growth via alterations on tumor-associated external factors. A variety of external factors from the animal host could be essential to the xenograft growth including the energy metabolism in the muscle and liver cells, the host immune system and vasculature in the tumor microenvironment, and so forth. As R2G2 mice were used in the in vivo studies, the lack of T cells, B cells, and Natural Killer cells in this animal model rules out the possibility of adaptive immunity being the external factor that links PI5P4K inhibition to its anti-cancer effects. The immunohistochemistry (IHC) staining on -45- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) CD31 showed no significant difference in vasculature between vehicle and 066ATZ treated tissues. However, the IHC staining on F4 / 80, a specific marker of macrophages, revealed substantial infiltration of tumor-associated macrophages (TAM) (FIG.9), which indicates the possibility of 066ATZ inducing the cytostatic effects through TAM. Elevated level of macrophage infiltration in tumor is strongly correlated with poor prognosis of cancer or enhanced progression of tumor. Over 50% of immune cells that infiltrate into tumors are macrophages comprising both macrophages differentiated from recruited blood monocytes and resident macrophages differentiated from tissue precursors. Due to the complexity of the tumor microenvironment, TAMs confer plasticity and heterogeneity in terms of phenotypes and functions. Classically activated macrophages via interferons from type 1 immune responses, often categorized as ‘M1-like’ phenotype, are proinflammatory and are reported to induce anti-cancer effects directly by causing cancer cell death or tissue damage, and indirectly by facilitating the recruitment and activation of the adaptive immune system. However in most established tumors, the dominant macrophages are reported to confer ‘M2-like’ phenotype by secreting factors such as EGF, IGF-1 to promote tumor cell proliferation, VEGF to enhance angiogenesis, and IL10, TGFβ for immunosuppression. Among NSCLC patients specifically, M2 macrophages are found to be significantly more abundant in tumor tissue and stroma than M1 macrophages and M2 infiltration is negatively correlated with the overall survival of patients. Therefore, the macrophages detected in the tumor samples are likely M2 macrophages which could have played a major role in facilitating tumor growth during the xenograft experiment. Since there was no observed significant difference in the amount of F4 / 80 signal between vehicle and compound groups, PI5P4Kα / β inhibition does not affect the migration and infiltration of macrophages but rather impairs the tumor-promoting communication between tumor cells and M2 macrophages. In the co-culture assays (FIG.10) with THP-1 derived M2 macrophages and H1975 cells, M2 macrophages were observed to promote H1975 cell proliferation, but such growth- stimulatory effect was significantly undermined by 066ATZ, as the increase in H1975 cell number by M2 co-culture became non-significant in the presence of 20μM 066ATZ (FIG. 11). For control purposes, M2 polarization is confirmed by significant increase in the secretion of one of the M2 markers, CCL18, through ELISA (FIG.24) and 066ATZ is shown to confer no toxicity to H1975 cells. To further validate this finding, stable cell lines of THP- 1 cells were generated with the tetracycline-inducible shRNA knockdown targeting PI5P4Kα and β. In a similar pattern, the complete knockdown of both isoforms of PI5PK4s -46- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) significantly diminished the growth stimulation by M2 co-culture, rendering it inconsequential to the cell growth of H1975 (FIG.12). Moreover, it was found that removing PI5P4Kα alone, but not β alone, in M2 macrophages is sufficient to replicate the results in the same co-culture setting (FIG.13), providing an explanation to why 066ATZ as a relatively weak β inhibitor could still significantly modulate the M2 macrophages. Additionally, neither 066ATZ nor PI5P4Ks knockdown induced cytotoxicity to M2 macrophages directly (FIG. 25). These results collectively indicate that PI5P4Kα / β inactivation especially α inactivation impairs the growth-promoting effects from M2 macrophages to tumor cells. Since only soluble molecules can move through the 0.4μm-pore membrane in the co- culture assays and M2 macrophages secret cytokines, chemokines or growth factors as one of the pathways of stimulating cancer cell growth, it is possible that PI5P4Kα / β inactivation in M2 could alter the production or secretion of these growth-relevant molecules. Cytokine profiling results on M2-cultured supernatant exhibits significant immunomodulatory effect of PI5P4Kα / β inactivation, as elevation in was observed for proinflammatory molecules including TNFβ, MCP-1, RANTES, GM-CSF, IL27, and Fractalkine / CX3CL1, and so forth. that were secreted by the generally anti-inflammatory M2 macrophages (FIG.15). In total, levels of 19 pro-inflammatory factors were increased by either 066ATZ treatment or PI5P4Kα / β knockdown or both. However, based on ELISA results, M2 marker CCL18 is not significantly affected by PI5P4Kα / β inactivation (FIG.26), suggesting that the observed upsurge of pro-inflammatory molecules is unlikely a result of M2 polarization being fully reversed. Although the mechanism of the observed immunomodulation is unclear, the altered levels of multiple secreted molecules by M2 macrophages correlate with anti-tumor activity. Cancer cells co-cultured with M1 macrophages display increased level of cell apoptosis accompanied by elevated expression of TNF, IL1, IP-10 / CXCL10 within the macrophages, which were also stimulated by 066ATZ in M2 macrophages based on the cytokine profiling results. Both IL-27 and CX3CL1 expression were shown to confer direct anti-tumor effects in melanoma and NSCLC animal models, and both factors were elevated by 066ATZ and PI5P4Kα / β knockdown. Moreover, EGF, which is known to stimulate cell growth by activating EGFR-PI3K-Akt-mTOR signaling, is shown to be decreased by both 066ATZ and PI5P4Kα / β knockdown. Combined, the results indicate that PI5P4Kα / β inactivation renders M2 macrophages less favorable to tumor cells by amplifying the secretion of direct anti-tumor molecules and reducing the output of growth stimulatory factors. And since the infiltration of macrophages were significant in the tumor tissues (FIG. 11), immunomodulating M2 macrophages as a potential pathway to disrupt the macrophages’ -47- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) growth-stimulatory effect could be one of the possible mechanisms for PI5P4Kα / β inhibition to slow down LUAD tumor growth in vivo (FIG.5). Building on these results, we generated a THP-1* cell line with tetracycline-inducible PIP4K2A / 2B-targeting shRNA to circumvent the antiproliferative effect associated with PIP4K2A knockdown in undifferentiated parent THP-1 cells. After differentiation, the M0 macrophages were polarized into M1, M2a, M2b, M2c and M2d states (FIG.27A). The supernatants of the macrophage cultures, especially that from M2b, stimulated the growth of H1975 cells (FIG.27B). DOX-induced knockdown of PIP4K2A / 2B most drastically reduced the ability of M2a conditioned medium to promote tumor cell growth (FIGS.27C, 27D). Treating cultured M2a macrophages with 066ATZ, or another PIP4K2A inhibitor BAY-091, which shares the same ATP-competitive mechanism but has a different pharmacophore, eliminated the growth-promoting activity of the conditioned media (FIG.27E). To further rule out the possibility that off-target inhibition of protein kinase CK2^ or CK2^’ by 066ATZ could contribute to this effect, M2a macrophages were also treated with CX-4945, a sub-nanomolar CK2^ / ^’ inhibitor. At 0.5^M, CX-4945 produced a similar degree of CK2^ / ^’ inhibition as 20^M 066ATZ but had no effect on M2a macrophage’s growth promoting activity (FIG.27E). Taken together, these results strongly suggest that inactivation of PIP4K2A / 2B could profoundly alter the function of tumor associated macrophages (TAMs), reducing their ability to support tumor cell proliferation. The effect of PIP4K2A / 2B inactivation on M2a conditioned medium is not limited to H1975 cells. We tested five other tumor cell lines, harboring different oncogenic or tumor suppressor mutations and representing lung adenocarcinoma (Calu-3), undifferentiated pancreatic carcinoma (MIA PaCa-2), colon carcinoma (HCT-116), prostate carcinoma (22Rv1) and glioblastoma (U- 87MG), and found them to respond similarly to the altered M2a conditioned medium (FIG. 27F). In this study, with the newly developed pharmacological tool 066ATZ, it has been shown that PI5P4Kα / β inhibition within the host cells instead of the tumor cells induced cytostatic effect against LUAD tumor growth in vivo. Despite the absence of intrinsic cytotoxicity against LUAD tumor cells, PI5P4Kα / β inactivation externally suppress tumor cell growth by altering one of the tumor-associated host factors in the tumor microenvironment, macrophages. Inactivating PI5P4Kα / β pharmacologically and genetically both impair the growth promoting crosstalk from M2 macrophages to the tumor cells through immunomodulating the M2 macrophages, which are -48- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) the dominant species of tumor-infiltrated macrophages in established tumors that play crucial roles in facilitating tumor progression. For the first time, anti-tumor efficacy is shown to be elicited through pharmacological inhibition of PI5P4Kα / β against another clinically important cancer model, LUAD. Moreover, the findings have broadened the perspective on PI5P4K research as critical roles of PI5P4Ks in modulating the cytokine profiles of macrophages have become implicated. With the ability to counteract pro-tumor TAMs, the strategy of targeting PI5P4Ks can be extended into other cancers sensitive to perturbations in TME immunity. Additionally, PI5P4K inhibitors can be combined with other immunotherapy therapeutics to improve anti-tumor efficacy and overcome cancers that are resistant to immunotherapies. Example 2: Preparation of compounds Chemical Synthesis Chemical synthesis of 066ATZ.066ATZ was synthesized in eight steps from commercially available (2R)-2-amino-3-(pyridin-2-yl)propanoic acid hydrochloride 1. Treatment with thionyl chloride in methanol gave quantitative conversion to methyl ester 2. Reductive amination with cyclopentanone and sodium triacetoxyborohydride gave amine 3 which was treated with 2,4-dichloro-5-nitropyrimidine to give chloropyrimidine 4. Reduction of the nitro group with iron and acetic acid gave cyclized product 5. Alkylation with methyl iodide and sodium hydride gave intermediate 6. Treatment with trimethylsilylbrodide in propionitrile at 150oC gave bromine substituted product 7. Treatment with 5-aminothiazole- 2-carbonitrile and cesium carbonate with zantphos and Pd2(dba)3in dioxane at 100oC gave thiazole 8. The formation of the tetrazole with sodium azide in DMF at 115oC gave target compound 9. -49- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) ,)xc iuild Drt.ihf-e4,nr,2 Ha o4b,rC o t)cN(,ac°5.Cg° ;I3-2-110C°H Cel,ola(02 €ozF M n H -aO 0 ;h aihD ee ,2 1loMl,to,lCC niC4z,a2l2 °rtC H C5m H 7eO,a-5 N, fS,3H)3t) )cOgNoa(Ac(asi .s Osn (A ,,hN)e0 heo (i HF 3, ;httiBn da)dCh°8y nN (S o;0 1,.c ,eC°51C°1d nnoan0 ,a2-eli0r0e sttn0 ti 1,me neepennoenhg ocaSelc otipaxRye occaropid-50- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) Experimental procedures Synthesis of tetrazole analog: Methyl (R)-2-amino-3-(pyridin-2-yl)propanoate dihydrochloride (2): solution of (2R)-2-amino-3-(pyridin-2-yl)propanoic acid g, 62.74 mmol) in MeOH (150 mL) was cooled to 0 oC and treated with thionyl chloride (2.5 eq., 18.66 g, 11.38 mL, 156.84 mmol) dropwise over 15 min. After the addition was complete, the cooling bath was removed and the reaction mixture was heated to reflux for 4 h. After cooling to room temperature, the solution was concentrated under reduced pressure and stirred with ether (150 mL) for 30 min. The precipitated product was isolated by filtration and dried under high vacuum to give methyl (2R)-2-amino-3-(pyridin-2-yl)propanoate dihydrochloride 2 (16 g, 100%) as white solid, which was used without further purification.1H NMR (400 MHz, D2O) δ 3.51-3.53 (m, 2H), 3.59 (s, 3H), 4.51 (t, J = 7.5 Hz, 1H), 7.77 (d, J = 7 Hz, 1H), 7.82 (d, J = 8 Hz, 1H), 8.33 (t, J = 8 Hz, 1H), 8.55 (d, J = 6 Hz, 1H). Methyl (R)-2-(cyclopentylamino)-3-(pyridin-2-yl)propanoate (3): methyl (2R)-2-amino-3-(pyridin-2-yl)propanoate dihydrochloride 2 (1 eq., 16 g, 63.21 mmol) and cyclopentanone (2.1 eq., 11.17 g, 11.75 mL, 132.74 mmol) in dichloromethane (160 mL) was cooled to 0 oC (ice-bath) and treated with sodium acetate (2 eq., 10.37 g, 126.42 mmol) and sodium triacetoxyborohydride (1.5 eq., 20.095 g, 94.82 mmol). After stirring for 1 h, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature with continued stirring overnight. The resulting heterogeneous solution was re-cooled in an ice-bath and quenched by careful addition of saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane (3 x 50 mL). The organic layer was dried over -51- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash column chromatography (eluent: 50 % ethyl acetate in hexanes, ethyl acetate, 1- 4 % MeOH in ethyl acetate) to give methyl (2R)-2-(cyclopentylamino)-3-(pyridin-2-yl)propanoate 3 (11.15 g, 71%) as brown oil.1H NMR (400 MHz, CDCl3) δ 1.24-2-04 (m, 8H), 3.09-3.32 (m, 3H), 3.73 (s, 3H), 3.81-3.85 (m, 1H), 7.38 – 7.02 (m, 3H), 7.59 (td, J = 7.7, 1.7 Hz, 1H), 8.51 (d, J = 4.9 Hz, 1H). Mass (m / z): calculated for: C14H20N2O2248, found 249 (M+H). Methyl (R)-2-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-3-(pyridin-2- yl)propanoate (4) an ice-cold, stirred solution of methyl (2R)-2- (cyclopentylamino)-3-(pyridin-2-yl)propanoate 3 (1 eq., 11.1 g, 44.7 mmol) in acetone (110 mL) was treated with potassium carbonate (1.1 eq., 6.8 g, 49.17 mmol) and a solution of 2,4- dichloro-5-nitropyrimidine (1.1 eq., 9.54 g, 49.17 mmol) in acetone (90 mL). Once the addition was complete, he cooling bath was removed and the reaction mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, diluted with water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (eluent: 0-25 % ethyl acetate in hexanes) to give methyl (2R)-2-[(2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino]-3- (pyridin-2-yl)propanoate 4 (8.3 g, 46 %) as light orange resin.1H NMR (400 MHz, CDCl3) δ 1.51-1.77 (m, 8H), 3.40 (dd, J = 15.6, 6.3 Hz, 1H), 3.64 (s, 3H), 3.88 (dd, J = 15.6, 6.3 Hz, 1H), 3.75-3.96 (m, 1H), 4.74 (s, 1H), 7.21 (d, J = 8 Hz, 2H), 7.67 (t, J = 7.7 Hz, 1H), 8.52 (d, J = 4.7 Hz, 1H), 9.28 (s, 1H). (R)-2-Chloro-8-cyclopentyl-7-(pyridin-2-ylmethyl)-7,8-dihydropteridin-6(5H)-one (5) -52- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) (2R)-2-[(2-chloro-5-nitropyrimidin-4- yl) - 2-yl)propanoate 4 (1 eq., 10.5 g, 25.87 mmol) in acetic acid (105 mL) was heated to 75oC and treated with iron (2.5 eq., 3.61 g, 0.46 mL, 64.68 mmol) portion-wise. After stirring for 1 h, the heating bath was removed and the reaction mixture was allowed to cool to room temperature. The resulting mixture was filtered through Celite, washing the Celite thoroughly with ethyl acetate and finally with MeOH. The filtrate was concentrated and purified by silica gel flash column chromatography (eluent: ethyl acetate, 0.5- 2 % MeOH in ethyl acetate) to give (7R)-2-chloro-8-cyclopentyl-7-[(pyridin-2- yl)methyl]-5,6,7,8-tetrahydropteridin-6-one 5 (5.5 g, 62%) as light brown solid.1H NMR (400 MHz, CDCl3) δ 2.26 – 1.57 (m, 8H), 3.27 (dd, J = 13.9, 8.2 Hz, 1H), 3.50 (dd, J = 13.8, 4.3 Hz, 1H), 4.37-4.58 (m, 1H), 4.74 (dd, J = 8.2, 4.2 Hz, 1), 7.32 (d, J = 8 Hz, 1H), 7.37 (d, J =7.2 Hz, 1H), 7.54 (s, 1H), 7.81 (t, J = 7.7 Hz, 1H), 8.27 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H). (R)-2-Chloro-8-cyclopentyl-5-methyl-7-(pyridin-2-ylmethyl)-7,8-dihydropteridin-6(5H)-one (6): 2-chloro-8-cyclopentyl-7-[(pyridin-2-yl)methyl]-5,6,7,8- tetrahydropteridin-6-one 5 (1 eq., 5.5 g, 16 mmol) and iodomethane (1.3 eq., 2.95 g, 1.29 mL, 20.8 mmol) in DMF (55 mL) was cooled to -10oC and treated with sodium hydride (1.3 eq., 0.83 g, 60% in mineral oil, 20.8 mmol) portion-wise. After stirring for 30 min, the cooling bath was removed and reaction mixture was allowed to warm to room temperature. After stirring an additional 3 h at RT, the reaction mixture was cooled in an ice-bath and quenched by the careful addition of cold water (200 mL). The resulting mixture was extracted with ethyl acetate (5 x 50 mL). The combined organic layer was dried over sodium sulfate and concentrated. The crude product was purified by silica gel flash column chromatography -53- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) (eluent: ethyl acetate, 1 - 2 % MeOH in ethyl acetate) to give (7R)-2-chloro-8-cyclopentyl-5- methyl-7-[(pyridin-2-yl)methyl]-5,6,7,8-tetrahydropteridin-6-one 6 (5 g, 13.97 mmol, 87%) as cream colored solid.1H NMR (400 MHz, CDCl3) δ1.62-2.09 (m, 8H), 3.11 (dd, J = 13.9, 8 Hz, 1H), 3.19 (s, 3H), 3.38 (dd, J = 13.9, 4 Hz, 1H), 4.41-4.47 (m, 1H), 4.75 (dd, J = 6.5, 4 Hz, 1H), 6.95 (d, J = 8 Hz, 1H), 7.02 (dd, J= 8, 4 Hz, 1H), 7.31 (s, 1H), 7.43 (t, J = 8 Hz, 1H), 8.39 (d, J = 5 Hz, 1H). Mass (m / z) calculated for C18H20ClN5O 357, found 358 (M+H). (R)-2-Bromo-8-cyclopentyl-5-methyl-7-(pyridin-2-ylmethyl)-7,8-dihydropteridin-6(5H)-one (7) chloro-8-cyclopentyl-5-methyl-7-[(pyridin-2-yl)methyl]- 5,6,7,8-tetrahydropteridin-6-one 6 (1 eq., 5 g, 13.97 mmol) in propionitrile (55 mL) in a pressure flask, was treated with bromotrimethylsilane (5 eq., 10.7 g, 9.22 mL, 69.86 mmol) and the flask was capped. It was placed in an oil bath at 150oC. After stirring for 4 h the solution was cooled to room temperature, opened and treated with additional bromotrimethylsilane (1.085 eq., 2.32 g, 2 mL, 15.15 mmol) and re-heated to 150oC for 4 h. The reaction mixture was stirred overnight at room temperature, opened and treated with additional bromotrimethylsilane (1.085 eq., 2.32 g, 2 mL, 15.15 mmol). The solution was re- heated to 150oC for 4 h. After cooling to room temperature the solution was concentrated, dissolved in saturated aqueous sodium bicarbonate (100mL) and extracted with ethyl acetate (3 x 50 mL) and then with dichloromethane (3 x 25 mL). The combined organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (eluent: 0-5 % MeOH in ethyl acetate) to give (7R)-2-bromo-8- cyclopentyl-5-methyl-7-[(pyridin-2-yl)methyl]-5,6,7,8-tetrahydropteridin-6-one 7 (4.1 g, 73%) as off-white solid.1H NMR (400 MHz, CDCl3) δ 1.58-2.23 (m, 8H), 3.15 (dd, J = 13.8, 4 Hz, 1H), 3.16 (s, 3H), 3.33 (dd, J = 13.8, 4 Hz, 1H), 4.36-4.48 (m, 1H), 7.72 (dd, J = 5.8, 4.0 Hz, 1H), 6.98 (d, J = 8 Hz, 1H), 7.05 (td, J = 8, 4 Hz, 1H), 7.29 (s, 1H), 7.46 (td, J = 7.7, 2.2 Hz, 1H), 8.35 (d, J = 4.8 Hz, 1H). Mass (m / z) calculated for C18H20BrN5O 401, found 402 (M+H). -54- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) (R)-5-((8-Cyclopentyl-5-methyl-6-oxo-7-(pyridin-2-ylmethyl)-5,6,7,8-tetrahydropteridin-2- yl)amino)thiazole-2-carbonitrile (8): -2-bromo-8-cyclopentyl-5-methyl-7- [ - 6-one 7 (1 eq., 4.1 g, 10.19 mmol) and 2- amino-1,3-thiazole-5-carbonitrile (1.8 eq., 2.3 g, 18.34 mmol) in dioxane (41 mL) was degassed with nitrogen and treated with cesium carbonate (3 eq., 9.96 g, 30.57 mmol), xantphos (0.3 eq., 1.77 g, 3.057 mmol) and tris (dibenzylideneacetone) dipalladium (0) (0.1 eq., 0.93 g, 1.019 mmol). The reaction vessel was capped and heated at 100oC for 18 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Water was added to the residue and this aqueous phase was sonicated with ethyl acetate (100 mL) and the organic layer was separated. The aqueous layer was extracted 2 more times with ethyl acetate (100 mL each). The insoluble material present was separated by filtration and sonicated with dichloromethane (3 x 50 mL). The dichloromethane layer was mixed with ethyl acetate extracts. The aqueous layer was then extracted dichloromethane (3 x 50 mL). The combined organic layer was then dried over sodium sulfate and concentrated. The residue was then triturated with 1:1 mixture of ethyl acetate and MeOH (50 mL). The solid was isolated by filtration to give 2-{[(7R)-8-cyclopentyl-5-methyl-6-oxo-7-[(pyridin-2- yl)methyl]-5,6,7,8-tetrahydropteridin-2-yl]amino}-1,3-thiazole-5-carbonitrile 8 (3 g, 6.72 mmol, 66%) as beige solid.1H-NMR (400 MHz, CDCl3): ^ 1.68-2.27 (m, 8H), 3.14 (dd, J = 13.7, 6.3 Hz, 1H), 3.25 (s, 3H), 3.31 (dd, J = 13.6, 4.3 Hz, 1H), 4.62-4.81 (m, 2H), 6.99 (d, J = 7.8 Hz, 1H), 7.06 (dd, J = 7.6, 4.9 Hz, 1H), 7.46 (td, J = 7.7, 1.8 Hz, 1H), 7.64 (s, 1H), 7.99 (s, 1H), 8.37 (d, J = 4.9 Hz, 1H). Mass (m / z) calculated for C22H22N8OS 446, found 447 (M+H). (R)-2-((2-(2H-tetrazol-5-yl)thiazol-5-yl)amino)-8-cyclopentyl-5-methyl-7-(pyridin-2- ylmethyl)-7,8-dihydropteridin-6(5H)-one (9) -55- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) of 2-{[(7R)-8-cyclopentyl-5-methyl-6-oxo- 7-[ - 2-yl]amino}-1,3-thiazole-5-carbonitrile 8 (1 eq., 1.3 g, 2.91 mmol), sodium azide (10 eq., 1.89 g, 1.023 mL, 29.11 mmol), and ammonium chloride (10 eq., 1.56 g, 1.025 mL, 29.11 mmol) in DMF (13 mL) were heated to 115oC in a pressure tube for 4h. After cooling to room temperature, the reaction mixtures were combined and the solids were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was triturated with a mixture of 20 mL of ether and 10 mL of ethyl acetate. The solid was isolated by filtration. This solid was then dissolved ethyl acetate (20 mL) and MeOH (20 mL). The insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was filtered through a small silica gel column (eluent: 5 %, 10 % MeOH in dichloromethane containing a drop of AcOH, then 25 %, 50 % EtOH in dichloromethane with a drop of AcOH) to give 2.2 g of (7R)-8- cyclopentyl-5-methyl-7-[(pyridin-2-yl)methyl]-2-{[5-(2H-1,2,3,4-tetrazol-5-yl)-1,3-thiazol-2- yl]amino}-5,6,7,8-tetrahydropteridin-6-one 9 (2.28 g, 77%) as off-white solid.1H-NMR (400 MHz, DMSO-d6): ^ 1.68-1.93 (m, 8H), 3.05-3.19 (m, 2H), 3.15 (s, 3H), 4.58-4.72 (m, 1H), 4.73 (dd, J = 6.2, 4.2 Hz, 1H), 7.08 (d, J = 8 Hz, 1H), 7.12 (dd, J = 8, 4 Hz, 1H), 7.54 (t, J = 8 Hz, 1H), 7.69 (s, 1H), 7.95 (s, 1H), 8.33 (d, J = 4.9 Hz, 1H), 11.48 (brs, 1H). Mass (m / z) calculated for C22H23N11OS 489, found 490 (M+H). Enumerated Embodiments: The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance. Embodiment 1: A compound of Formula (IA) or a salt, solvate, enantiomer, diastereoisomer, or tautomer thereof: , wherein: A is optionally the group consisting of 1H- -56- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) benzo[d][1,2,3]triazolyl, triazolyl, thiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiodiazolyl, pyridinyl, pyrimidinyl, triazinyl, pyrazinyl, thiophenyl, benzotriazolyl, benzamidazolyl, indolyl, indazolyl, pyrrolyl, and pyrazolyl; X is selected from the group consisting of: -S(O)2NH2, -C(O)OR’, -CN, - C(O)NHS(O)2R’, and 1H-tetrazolyl, wherein each occurrence of R’ is independently C1-C6alkyl; R1is selected from the group consisting of -CH2-(optionally substituted C3-C8 heteroaryl), isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentylmethyl, cyclohexylmethyl, and , R8is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, halogen, thiol, C1-C6 thioalkoxy, -OH, C1-C6 alkoxy, and -NR”R”; wherein R9is selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, halogen, thiol, C1-C6 thioalkoxy, -OH, C1-C6 alkoxy, and -NR”R”; and wherein each occurrence of R” is independently H or C1-C6alkyl; R2is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 heteroalkyl, C3-C8heterocycloalkyl, C2-C6alkenyl, and C2-C6alkynyl; wherein in R2each occurrence of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, or alkynyl is optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8cycloalkoxy, halogen, -OH, thiol, C1-C6thioalkoxy, phenyl, heteroaryl, heterocyclyl, and -NR’’’R’’’, wherein each occurrence of R’’’ is independently H or C1-C6alkyl or the two R’’’ bound to the N combine to form 3-7 membered heterocyclyl. Embodiment 2: The compound of Embodiment 1, which is: , wherein R3is selected C6 alkyl, and C3-C8 cycloalkyl. Embodiment 3: The compound of any one of Embodiments 1-2, wherein A is optionally substituted heteroaryl selected from the group consisting of triazolyl, thiazolyl, -57- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) oxazolyl, isooxazolyl, oxadiazolyl, thiodiazolyl, thiophenyl, pyrrolyl, and pyrazolyl. Embodiment 4: The compound of any one of Embodiments 1-3, wherein R1is -CH2- (optionally substituted pyridyl). Embodiment 5: The compound of any one of Embodiments 1-4, wherein R1is -CH2- (2-pyridyl). Embodiment 6: The compound of any one of Embodiments 1-5, wherein R2is cyclopentyl. Embodiment 7: The compound of Embodiment 1, which is , wherein R1a, R1b, R1c, R1d, R2a, R2b, R2c, R2d, R2e, from the group selected from H, C1-C6 alkyl, halogen -NH2, -OH, -C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)OC3-C8cycloalkyl -C(=O)C1- C6 alkyl, and -C(=O)C3-C8 cycloalkyl; and R3is independently selected from the group consisting of H, F, Cl, Br, I, and C1-C6alkyl. Embodiment 8: The compound of any one of Embodiment 7, which is: . Embodiment 9: The 1-8, wherein X is selected from -CN, -S(O)2-NH2, -C(O)-NH-S(O)2-CH3, and 1H-tetrazolyl. Embodiment 10: The compound of Embodiment 1, which is selected from the group consisting of: tetrazol-5-yl)thiazol-2- yl) dihydropteridin-6(5H)-one, -58- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) (8-cyclopentyl-5-methyl-6-oxo-7- -N-(methylsulfonyl)thiazole-5- N O N N 7-(pyridin-2-ylmethyl)-5,6,7,8- or 7-(pyridin-2-ylmethyl)-5,6,7,8- tetrahydropteridin-2-yl)amino)thiazole-5-sulfonamide. Embodiment 11: A pharmaceutical composition comprising the compound of any one of Embodiments 1-10 and at least one pharmaceutically acceptable carrier. Embodiment 12: A method of treating a p53-null cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-10. Embodiment 13: The method of Embodiment 12, wherein the cancer is at least one selected from the group consisting of Esophageal / Stomach Cancer, Bladder / Urinary Tract Cancer, Small Cell Lung Cancer, CNS / Brain Cancer, Skin Cancer (Non-Melanoma), Head and Neck Cancer, Ampullary Carcinoma, Burkitt's lymphoma, Esophagogastric Cancer, Colorectal Cancer, Ovarian Cancer, Non-Small Cell Lung Cancer, Small Bowel Cancer, Cancer of Unknown Primary, High-grade glioma K27Mmut, Pancreatic Cancer, Uterine Sarcoma, Bladder Cancer, High-grade glioma K27Mwt, Appendiceal Cancer, Breast Cancer, Soft Tissue Sarcoma, B-cell acute lymphoblastic leukemia (hypodiploid), Endometrial Cancer, Penile Cancer, Glioma, Breast Sarcoma, Hepatobiliary Cancer, Vaginal Cancer, -59- 55303980.3 Attorney Docket No.047162-7507WO1 (02542) Gastrointestinal Neuroendocrine Tumor, Adrenocortical Carcinoma, Prostate Cancer, Sellar Tumor, Hodgkin Lymphoma, Upper Tract Urothelial Carcinoma, Non-Hodgkin Lymphoma, Melanoma, Bone Cancer, Cutaneous Melanoma, Mesothelioma, Adrenocortical carcinoma, Invasive Breast Carcinoma, Salivary Gland Cancer, B-cell acute lymphoblastic leukemia (non-hypodiploid), Anal Cancer, Embryonal tumor with multilayered rosettes, Ewing's sarcoma, Nerve Sheath Tumor, Wilms' tumors, Germ Cell Tumor, Multiple Myeloma, Cervical Cancer, Gastrointestinal Stromal Tumor, Renal Cell Carcinoma, Mature B-Cell Neoplasms, Myelodysplasia, Thymic Tumor, Sex Cord Stromal Tumor, Atypial teratoid / rhabdoid tumor, Miscellaneous Neuroepithelial Tumor, Medulloblastoma WNT, Medulloblastoma SHH, Rhabdomyosarcoma, Leukemia, Thyroid Cancer, Embryonal Tumor, Wilms Tumor, Osteosarcoma, CNS Cancer, Neuroblastoma, Medulloblastoma Group3, Pheochromocytoma, B-Lymphoblastic Leukemia / Lymphoma. Embodiment 14: The method of any one of Embodiments 12-13, wherein the compound is formulated as part of a pharmaceutical composition. Embodiment 15: The method of any one of Embodiments 12-14, wherein the compound is administered by a route selected from the group consisting of parenteral, intratumoral, and / or oral. Embodiment 16: A method of treating at least one metabolic disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-10. Embodiment 17: The method of Embodiment 16, wherein the at least one metabolic disorder is selected from the group consisting of type 2 diabetes, obesity, liver disease, and heart disease. The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. Whereas this disclosure has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this disclosure may be devised by others skilled in the art without departing from the true spirit and scope of the disclosure. The appended claims are intended to be construed to include all such embodiments and equivalent variations. -60- 55303980.3

Claims

Attorney Docket No.047162-7507WO1 (02542) CLAIMS What is claimed is:

1. A compound of Formula (IA) or a salt, solvate, enantiomer, diastereoisomer, or tautomer thereof: , wherein:A is optionally substituted group consisting of 1H- benzo[d][1,2,3]triazolyl, triazolyl, thiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiodiazolyl, pyridinyl, pyrimidinyl, triazinyl, pyrazinyl, thiophenyl, benzotriazolyl, benzamidazolyl, indolyl, indazolyl, pyrrolyl, and pyrazolyl; X is selected from the group consisting of: -S(O)2NH2, -C(O)OR’, -CN, - C(O)NHS(O)2R’, and 1H-tetrazolyl, wherein each occurrence of R’ is independently C1-C6alkyl; R1is selected from the group consisting of -CH2-(C3-C8 optionally substituted heteroaryl), isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentylmethyl, cyclohexylmethyl, and ,R8is selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, halogen, thiol, C1-C6 thioalkoxy, -OH, C1-C6 alkoxy, and -NR”R”; wherein R9is selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, halogen, thiol, C1-C6 thioalkoxy, -OH, C1-C6 alkoxy, and -NR”R”; and wherein each occurrence of R” is independently H or C1-C6alkyl; R2is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 heteroalkyl, C3-C8heterocycloalkyl, C2-C6alkenyl, and C2-C6alkynyl; wherein in R2each occurrence of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, or alkynyl is optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halogen, -OH, thiol, C1-C6 thioalkoxy, phenyl, heteroaryl, heterocyclyl, and -NR’’’R’’’, wherein each occurrence of R’’’ is independently H or C1-C6 alkyl or the two R’’’ -61- 55303980.3Attorney Docket No.047162-7507WO1 (02542) bound to the N combine to form 3-7 membered heterocyclyl.

2. The compound of claim 1, which is: , wherein R3is selected C6 alkyl, and C3-C8 cycloalkyl.

3. The compound any one of claims 1-2, wherein A is optionally substituted heteroaryl selected from the group consisting of triazolyl, thiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiodiazolyl, thiophenyl, pyrrolyl, and pyrazolyl.

4. The compound of any one of claims 1-3, wherein R1is -CH2-(optionally substituted pyridyl).

5. The compound of any one of claims 1-4, wherein R1is -CH2-(2-pyridyl).

6. The compound of any one of claims 1-5, wherein R2is cyclopentyl.

7. The compound of claim 1, which is , whereinR1a, R1b, R1c, R1d, R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2iare independently selected from the group selected from H, C1-C6 alkyl, halogen -NH2, -OH, -C(=O)OH, - C(=O)OC1-C6alkyl, -C(=O)OC3-C8cycloalkyl -C(=O)C1-C6alkyl, and -C(=O)C3-C8cycloalkyl; and R3is independently selected from the group consisting of H, F, Cl, Br, I, and C1-C6-62- 55303980.3Attorney Docket No.047162-7507WO1 (02542) alkyl.

8. The compound of claim 7, which is: .

9. The compound of any one selected from -CN, -S(O)2- NH2, -C(O)-NH-S(O)2-CH3, and 1H-tetrazolyl.

10. The compound of claim 1, which is selected from the group consisting of:amino)-8-cyclopentyl-5-methyl-7-(pyridin-2- ylmethyl)-7,8-dihydropteridin-6(5H)-one,(pyridin-2-ylmethyl)-5,6,7,8-tetrahydropteridin-2- yl)amino)-N-(methylsulfonyl)thiazole-5-carboxamide, N O7-(pyridin-2-ylmethyl)-5,6,7,8-tetrahydropteridin-2- yl)amino)thiazole-5-carbonitrile, or -63- 55303980.3Attorney Docket No.047162-7507WO1 (02542) 7-(pyridin-2-ylmethyl)-5,6,7,8-tetrahydropteridin-2-11. A pharmaceutical composition comprising the compound of any one of claims 1-10 and at least one pharmaceutically acceptable carrier.

12. A method of treating a p53-null cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-10.

13. The method of claim 12, wherein the cancer is at least one selected from the group consisting of Esophageal / Stomach Cancer, Bladder / Urinary Tract Cancer, Small Cell Lung Cancer, CNS / Brain Cancer, Skin Cancer (Non-Melanoma), Head and Neck Cancer, Ampullary Carcinoma, Burkitt's lymphoma, Esophagogastric Cancer, Colorectal Cancer, Ovarian Cancer, Non-Small Cell Lung Cancer, Small Bowel Cancer, Cancer of Unknown Primary, High-grade glioma K27Mmut, Pancreatic Cancer, Uterine Sarcoma, Bladder Cancer, High-grade glioma K27Mwt, Appendiceal Cancer, Breast Cancer, Soft Tissue Sarcoma, B-cell acute lymphoblastic leukemia (hypodiploid), Endometrial Cancer, Penile Cancer, Glioma, Breast Sarcoma, Hepatobiliary Cancer, Vaginal Cancer, Gastrointestinal Neuroendocrine Tumor, Adrenocortical Carcinoma, Prostate Cancer, Sellar Tumor, Hodgkin Lymphoma, Upper Tract Urothelial Carcinoma, Non-Hodgkin Lymphoma, Melanoma, Bone Cancer, Cutaneous Melanoma, Mesothelioma, Adrenocortical carcinoma, Invasive Breast Carcinoma, Salivary Gland Cancer, B-cell acute lymphoblastic leukemia (non-hypodiploid), Anal Cancer, Embryonal tumor with multilayered rosettes, Ewing's sarcoma, Nerve Sheath Tumor, Wilms' tumors, Germ Cell Tumor, Multiple Myeloma, Cervical Cancer, Gastrointestinal Stromal Tumor, Renal Cell Carcinoma, Mature B-Cell Neoplasms, Myelodysplasia, Thymic Tumor, Sex Cord Stromal Tumor, Atypial teratoid / rhabdoid tumor, Miscellaneous Neuroepithelial Tumor, Medulloblastoma WNT, Medulloblastoma SHH, Rhabdomyosarcoma, Leukemia, Thyroid Cancer, Embryonal Tumor, Wilms Tumor, -64- 55303980.3Attorney Docket No.047162-7507WO1 (02542) Osteosarcoma, CNS Cancer, Neuroblastoma, Medulloblastoma Group3, Pheochromocytoma, B-Lymphoblastic Leukemia / Lymphoma.

14. The method of any one of claims 12-13, wherein the compound is formulated as part of a pharmaceutical composition.

15. The method of any one of claims 12-14, wherein the compound is administered by a route selected from the group consisting of parenteral, intratumoral, and / or oral.

16. A method of treating at least one metabolic disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-10.

17. The method of claim 16, wherein the at least one metabolic disorder is selected from the group consisting of type 2 diabetes, obesity, liver disease, and heart disease. -65- 55303980.3

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