WO2021150700A1 - N-substituted-3-tricyclyl piperidine derivatives as anticancer and neuroprotective agents - Google Patents

Abstract

A genus of N-substituted-3-tricyclyl piperidine derivatives is disclosed. The compounds are of the following genus: The compounds induce FOXO1 transcription factor translocation to the nucleus by modulating PP2A and, as a consequence, exhibit anti-proliferative effects. They are useful in the treatment of a variety of disorders, including as a monotherapy in cancer treatment, or used in combination with other drugs to restore sensitivity to chemotherapy where resistance has developed.

Description

N-SUBSTITUTED-3-TRICYCLYL PIPERIDINE DERIVATIVES AS ANTICANCER AND NEUROPROTECTIVE AGENTS

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority of US provisional application 62/964,188, filed January 22, 2020, the entire disclosure of which is hereby incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The invention relates to the use of tricyclic chemical modulators of PP2A, comprising N-substituted-3-tricyclic piperidine derivatives to treat diseases such as cancer, neurodegenerative disease and other disorders.

BACKGROUND

[0003] The FOXO (Forkhead transcription factors, Class O) proteins are a group of transcription factors involved in control of a variety of physiological, metabolic and developmental pathways. They are downstream effectors in a number of signaling pathways including insulin and growth factor signaling; they are also regulated by oxidative stress and nutrient deprivation. Cellular processes affected by FOXO activity include cell cycle control, differentiation, proliferation and apoptosis. Disregulation of FOXO mediated processes has been implicated in a number of pathologies including tumorigenesis, inflammation, diabetes and neurodegenerative conditions amongst others. Activity of FOXO transcription factors are controlled in part by their sub-cellular localization, in particular their localization to the nucleus from the cytosol, and their subsequent transcriptional activation.

[0004] Four FOXO proteins designated FOXO1, FOXO3a, FOXO4 and FOXO6 are present in human cells and their activity is controlled by a variety of mechanisms including stability (proteolytic cleavage), sub-cellular localization and transcriptional activation. Activity of the first three members of the family is controlled by cytosolic-nuclear translocation.

[0005] FOXO1 regulates expression of a number of genes that play critical roles in cell cycle and apoptosis. A pivotal regulatory mechanism of FOXO is reversible phosphorylation, catalyzed by kinases and phosphatases. Phosphorylation of FOXO1 is associated with 14-3-3 binding and cytosolic localization, whereas dephosphorylated FOXO1 translocates to the nucleus and is transcriptionally active.

[0006] Protein phosphatase 2A is one of the four major serine threonine phosphatases and is implicated in the negative control of cell growth and division. Protein phosphatase 2A holoenzymes are heterotrimeric proteins composed of a structural subunit A, a catalytic subunit C, and a regulatory subunit B. The PP2A heterotrimeric protein phosphatase is a ubiquitous and conserved phosphatase with broad substrate specificity and diverse cellular functions. Among the targets of PP2A are proteins of oncogenic signaling cascades, such as Raf, MEK, and AKT.

[0007] PP2A interacts directly with FOXO1 and dephosphorylates FOXO1. Inhibition of PP2A phosphatases rescues FOXO1 -mediated cell death by regulating the level of the pro- apoptotic protein BIM. In addition, PP2A directly regulates FOXO3a subcellular localization and transcriptional activation. Without wishing to be held to any particular theory, it may be that the compounds described herein promote apoptosis by acting on FOXO transcription factors via activation of PP2A.

[0008] Myc proteins (c-myc, Mycn and My cl) target proliferative and apoptotic pathways vital for progression in cancer and it is overexpressed and deregulated in many human cancers. The control of Myc abundance through protein degradation has attracted considerable interest and Ser-62 phosphorylation by a number of kinases has been shown to stabilize the protein. PP2A is responsible for Ser-62 dephosphorylation which primes the protein for ubiquitylation and degredation, thus PP2A functions as a negative regulator of Myc.

[0009] Prostate cancer is the second leading cause of cancer death in men in America, behind lung cancer. According to the American Cancer Society, approximately 1 man in 36 will die of prostate cancer. Male hormones, specifically testosterone, fuel the growth of prostate cancer. By reducing the amount and activity of testosterone, the growth of advanced prostate cancer is slowed. Endocrine therapy, known as androgen ablation, is the first line of treatment for metastatic prostate cancer. Androgen deprivation therapy for metastatic prostate cancer results in tumor regression and symptomatic improvement in the majority of patients. However, metastatic prostate cancer inevitably progresses despite castrate levels of serum testosterone. Several new therapies have been approved for patients with castration-resistant prostate cancer (CRPC); however, none are curative and tumors ultimately develop resistance. To combat CRPC new approaches and novel therapies are required.

[0010] Breast cancer can affect both men and women. Breast cancer is the most prevalent cancer in women, after skin cancers, with about 1 in every 8 women expected to develop invasive breast cancer at some point. One subset of breast cancer expresses the androgen receptor (AR), which has been implicated as a therapeutic target in that subset. About 10- 20% of breast cancers — more than one out of every 10 — are found to be triple-negative. "Triple negative breast cancer" refers to a breast cancer that does not contain estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2 (HER2). This means that the growth of the cancer is not supported by the hormones estrogen and progesterone, nor by the presence of too many HER2 receptors. Therefore, triple-negative breast cancer does not respond to hormonal therapy (such as tamoxifen or aromatase inhibitors) or therapies that target HER2 receptors, such as Herceptin (chemical name: trastuzumab). While these tumors are often treatable, the chemotherapy is not targeted, and response durations are short. For doctors and researchers, there is intense interest in finding new medications that can treat breast cancer.

[0011] The compounds described herein, which are based on a N-substituted-3-tri cyclic piperidine scaffold, exhibit anti-proliferative effects and are useful as monotherapy in cancer treatment. Additionally, they can be used in combination with other drugs to restore sensitivity to chemotherapy where resistance has developed.

SUMMARY OF THE INVENTION

[0012] A genus of tricyclic piperidine heteroaryl derivatives has now been found that induce FOXO1 transcription factor translocation to the nucleus by modulating PP2A. The compounds described herein exhibit anti-proliferative effects, and are useful in the treatment of a variety of disorders, including as a monotherapy in cancer treatment, or used in combination with other drugs to restore sensitivity to chemotherapy where resistance has developed.

[0013] In a first aspect the invention relates to compounds of formula (I):

wherein:

W1 is selected from a benzene ring, pyridine, pyrimidine, and thiophene;

W2 is selected from a benzene ring, pyridine, pyrimidine, and thiophene;

B is absent or is selected from a direct bond, -O-, -S-, -CH₂CH₂-, -CH=CH-, -OCH₂-, -CH₂O-, -C(O)NR^B-, and -NR^BC(O)-;

R^B is H or (C₁-C₆)alkyl;

Het-H is a heteroaryl ring selected from:

R^H is selected in each instance from hydrogen and (C₁-C₆)alkyl;

X¹, X², X³, and X⁴ are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C₁-C₆)alkyl optionally substituted with -OH, (C₁-C₆)haloalkyl, (C₁- C₆)haloalkoxy, (C₁-C₆)haloalkylthio, -NR¹R², -OR¹, -C(O)R¹, -OC(O)R¹, -C(O)NR¹R², - CCOXIR¹, -SR¹, -SO₂R¹, and -SO₂NR¹R²;

R¹ and R² are independently selected in each instance from hydrogen and (C₁- C₆)alkyl;

R³-R⁴ is selected from

m is zero, 1 or 2; n is 1 or 2; wherein m + n equals 1, 2 or 3; and wherein when m is zero and n is 1, R³-R⁴ is either

or

V is selected from phenyl, a six-membered heteroaromatic ring, furan, and thiophene; Z¹ and Z² are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, (C₁- C₆)haloalkylthio, -NR¹R², -NR¹C(O)R², -NR¹C(O)OR⁶, -OR¹, -C(O)R¹, -OC(O)R¹, - C(O)NR¹R², -C(O)OR¹, -SR¹, -SO₂R¹, and -SO₂NR¹R²; and R⁶ is (C₁-C₈)hydrocarbon.

[0014] In a second aspect, the invention relates to pharmaceutical compositions comprising the compounds described herein.

[0015] In a third aspect, the invention relates to methods and uses of the above-described compounds in medicine, particularly for the treatment of a disease chosen from (a) cancer; (b) diabetes; (c) autoimmune disease; (d) age onset proteotoxic disease (particularly neurodegenerative disease); (e) mood disorder; (f) acne vulgaris; (g) solid organ transplant rejection (graft vs. host disease); (h) pulmonary disease (such as COPD); (i) cardiac hypertrophy and heart failure; j) viral or parasitic infection; and (k) inflammatory conditions (such as asthma). These methods include administering to a patient a therapeutically effective amount of a compound described herein.

[0016] In a fourth aspect, the invention relates to a method for restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer. The method includes administering an effective amount of a compound described herein.

[0017] In a fifth aspect, the invention relates to a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of PP2A influenced signaling cascades such as the PI3K-AKT, MAP kinase and mTOR pathways. These methods include administering to a patient a therapeutically effective amount of a compound described herein.

[0018] In a sixth aspect, the invention relates to a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway. These methods include administering to a patient a therapeutically effective amount of a compound described herein.

[0019] In a seventh aspect, the invention relates to a method for treating a metabolic disease or disorder in a patient where the disease or disorder involves the dysregulation of the mTOR-PP2A signaling axis. The method includes administering an effective amount of a compound described herein. DETAILED DESCRIPTION OF THE INVENTION

[0020] Substituents are generally defined when introduced and retain that definition throughout the specification and in all independent claims.

[0021] In a composition aspect, the invention relates to compounds of formula (I):

as described above.

[0022] In some embodiments, the invention relates to compounds of formula Ila or lib:

[0023] In the embodiments described herein, the compound may be of formula I, Ila, or lib, unless otherwise indicated.

[0024] In some embodiments, m is zero. In other embodiments, m is 1. In still other embodiments, m is 2.

[0025] In some embodiments, n is 1. In other embodiments, n is 2. [0026] In some embodiments, m + n equals 1. In other embodiments, m + n equals 2. In still other embodiments, m + n equals 3.

[0027] In some embodiments, m is 1 and n is 1 (V is shown in the following examples as phenyl, but any option for V is allowed):

[0028] In some embodiments, m is 2 and n is 1 :

[0029] In some embodiments, m is 1 and n is 2:

[0030] In some embodiments, m is 0 and n is 1 :

[0031] In some embodiments, W1 is a benzene ring. In other embodiments, W1 is pyridine. In still other embodiments, W1 is pyrimidine. In yet other embodiments, W1 is thiophene.

[0032] In some embodiments, W2 is a benzene ring. In other embodiments, W2 is pyridine. In still other embodiments, W2 is pyrimidine. In yet other embodiments, W2 is thiophene.

[0033] In some embodiments, at least one of W1 and W2 is benzene. In other embodiments, both of W1 and W2 are benzene. In still other embodiments, one of W1 and W2 is benzene and the other of W1 and W2 is selected from pyridine and pyrimidine.

[0034] In some embodiments, B is absent. In these embodiments, diarylamino compounds are formed (wherein both W1 and W2 are aryl or heteroaryl, as indicated above):

In other embodiments, B is a direct bond. In still other embodiments, B is -O-. In other embodiments, B is -S-. In yet other embodiments, B is -CH₂CH₂-. In some embodiments, B is -CH=CH-. In further embodiments, B is -OCH₂-. In other embodiments, B is -CH₂O-. In still other embodiments, B is -C(O)NR^B-. In yet other embodiments, B is -NR^BC(O)-.

[0035] In some embodiments, R^B is H. In other embodiments, R^B is (C₁-C₆)alkyl.

[0036] In some embodiments, R³-R⁴ is

. In other embodiments, R³-R⁴ is

. In still other embodiments, R³-R⁴ is . In yet other embodiments, R³-R⁴ is

In further embodiments, R³-R⁴ is

. In some embodiments, R³-

R⁴ is . In other embodiments, R³-R⁴ is

. In still other

. In yet other embodiments, R³-R⁴ is

. In further embodiments, R³-R⁴ is . In still other

[0037] In some A compound according to any of [1] through [64] above, or according to other embodiments of the invention, wherein

[0038] In some embodiments, X¹, X², X³, and X⁴ are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C₁-C₆)alkyl optionally substituted with - OH, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, (C₁-C₆)haloalkylthio, -NR³R², -OR¹, -C(O)R¹, - OC(O)R¹, -C(O)NR¹R², -C(O)OR¹, -SR¹, -SO₂R¹, and -SO₂NR¹R². In other embodiments, X² and X⁴ are each hydrogen. In still other embodiments, X² and X⁴ are each hydrogen, and X¹ and X³ are each chosen independently from -H, -F, -Cl, -CF₃,- C(CH₃)₂OH, or -C(O)NMe₂. In further embodiments, all of X¹, X², X³ and X⁴ are each hydrogen. In yet other embodiments, at least one of X¹, X², X³ and X⁴ is located at a carbon two positions away from a bridgehead carbon.

[0039] In some embodiments, R¹ is hydrogen. In other embodiments, R¹ is (C₁-C₆)alkyl. In other embodiments, R¹ is methyl. In some embodiments, R² is hydrogen. In other embodiments, R² is (C₁-C₆)alkyl. In other embodiments, R² is methyl.

[0040] In some embodiments, V is phenyl. In other embodiments, V is a six-membered heteroaromatic ring. In still other embodiments, V is pyridine. In some embodiments, V is pyrimidine. In some embodiments, V is thiophene. In some embodiments, V is furan. [0041] In some embodiments, Z¹ and Z² are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, (C₁-C₆)haloalkylthio, -NR¹R², -NR¹C(O)R², -NR¹C(O)OR⁶, -OR¹, -C(O)R¹, -OC(O)R¹, - C(O)NR¹R², -C(O)OR¹, -SR¹, -SO₂R¹, and -SO₂NR¹R². In other embodiments, Z¹ is H. In still other embodiments, Z² is chosen from hydrogen, halogen, and (C₁-C₆)haloalkoxy. In yet other embodiments, Z² is chosen from hydrogen, F, Cl, and OCF₃. In further embodiments, Z² is in the para position.

[0042] In some embodiments, R⁶ is (C₁-C₈)hydrocarbon.

[0043] In some embodiments: both W1 and W2 are benzene, or one of W1 and W2 is benzene and the other of W1 or W2 is pyridine or pyrimidine;

B is selected from a direct bond, -O-, and -CH₂CH₂-;

R^B is H or (C₁-C₆)alkyl;

X² and X⁴ are each hydrogen, and X¹ and X³ are each chosen independently from -H, -F, -Cl, -CF₃,-C(CH₃)₂OH, -C(O)NMe₂;

R¹ and R² are independently selected in each instance from the group consisting of hydrogen and (C₁-C₆)alkyl;

V is phenyl;

Z¹ is hydrogen; and

Z² is selected in each instance from hydrogen, halogen, and (C₁-C₆)haloalkoxy..

[0044] In some of these embodiments, Z² is in the para position. In some of these embodiments, B is a direct bond. In other of these embodiments, B is O. In some of these embodiments, both W1 and W2 are benzene. In other of these embodiments, one of W1 and W2 is benzene and the other of W1 or W2 is pyridine or pyrimidine. In some of these

n is 1. In other of these embodiments, m is 2 and n is 1. In still other of these embodiments, m is 1 and n is 2. In yet other of these embodiments, m is 0 and n is 1.

[0045] The compounds described herein contain asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined in terms of absolute stereochemistry as ( R )- or (S)-. The present invention is meant to include all such possible diastereomers as well as their racemic and optically pure forms. Optically active ( R )- and (S)- isomers may be prepared using homo-chiral synthons or homo-chiral reagents, or optically resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both ( E )- and (Z)- geometric isomers. Likewise, all tautomeric forms are intended to be included.

[0046] The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are a modified version of the denotations taken from Maehr J. Chem. Ed. 62, 114-120 (1985): simple lines provide no information about stereochemistry and convey only connectivity; solid and broken wedges are used to denote the absolute configuration of a chiral element; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but not necessarily denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. For example, the graphic representations

indicate each single enantiomer of known absolute stereochemistry, i.e., each of the two structures is a substantially pure single enantiomer. For the purpose of the present disclosure, a “pure” or “substantially pure” enantiomer is intended to mean that the enantiomer is at least 95% of the configuration shown and 5% or less of other enantiomers. The graphic representation:

indicates a single enantiomer of unknown absolute stereochemistry, i.e., it could be either of the two structures shown above, as a substantially pure single enantiomer. And, finally, the structure:

conveys no information regarding stereochemistry. This structure could be a single enantiomer or a mixture of enantiomers, including a racemic micture.

[0047] In any of these possiblities, compounds can be single enantiomers of formula Ila or formula lib or a mixture of the two. If a mixture, the mixture will most commonly be racemic, but it need not be. Substantially pure single enantiomers of biologically active compounds such as those described herein often exhibit advantages over their racemic mixture. [0048] Some of the options for R³-R⁴ may also be of specific configuration. For instance, the graphic representation

indicates either, or both, of the two enantiomers:

in any ratio, from pure enantiomers to racemates.

[0049] All the members of the genus described above exhibit biological activity in screens that are predictive of utility. However, it may be found upon examination that certain species and genera are not patentable to the inventors in this application. In this case, the exclusion of species and genera in applicants' claims are to be considered artifacts of patent prosecution and not reflective of the inventors' concept or description of their invention, which encompasses all members of the genus I that are not in the public’s possession.

[0050] Also provided herein is a pharmaceutical composition comprising a compound disclosed above, or a pharmaceutically acceptable salt form thereof, and a pharmaceutically acceptable carrier or diluent.

[0051] While it may be possible for the compounds of formula I to be administered as the raw chemical, it is preferable to present them as a pharmaceutical composition. According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0052] Formulations of the compounds and compositions described herein may be administered by a variety of methods: oral (including, but not limited to, capsules, cachets, tablets, powder, granules, solutions, suspensions, emulsions, tablets, or sublingual tablets), buccal, by inhalation (by using, for instance, an inhaler, a nebulizer, an aerosol, a gas, etc.), nasal, topical (including, but not limited to, lotions, creams, ointments, patches (i.e., transdermal), gels, liniments, pastes), ophthalmic, to the ear, rectal (for instance, by using a suppository or an enema), vaginal, or parenteral, depending on the severity and type of the disease being treated. In some embodiments, the compositions are administered orally or intravenously. The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intracranial, intravenous and intraarticular), rectal, vaginal, nasal (inhalation), and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula (I) or a pharmaceutically acceptable salt thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0053] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[0054] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.

[0055] Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.

Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0056] It will be recognized that the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and chlorine include ²H, ³H,

¹³C, ¹⁴C, ¹⁵N, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. ³H, and carbon-14, i.e., ¹⁴C, radioisotopes are particularly preferred for their ease in preparation and detectability. Compounds that contain isotopes ¹¹C, ¹³N, ¹⁵0 and ¹⁸F are well suited for positron emission tomography. Radiolabeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.

[0057] The compounds provided herein can be used for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I. In some embodiments, the cancer is characterized by dysregulation of the PI3K-AKT-FOXO signaling pathway. For example, the cancer can be selected from the group consisting of: ovarian, pancreatic, renal cell, breast, prostate, lung, hepatocellular carcinoma, glioma, leukemia, lymphoma, colorectal cancers, and sarcomas. [0058] In some embodiments, the method further comprises administering one or more additional cancer chemotherapeutic agents. In some embodiments, the one or more additional cancer chemotherapeutic agents are EGFR inhibitors.

[0059] In some embodiments, the cancer is chemotherapy resistant cancer. In some embodiments, the method further comprises administering one or more cancer chemotherapeutic agents. In some embodiments, the one or more cancer chemotherapeutic agents are EGFR inhibitors.

[0060] In some embodiments, administration of a compound of formula I can restore sensitivity to one or more chemotherapeutic agents in a patient wherein the patient has developed a resistance to the one or more chemotherapeutic agents. More particularly, cancers that may be treated by the compounds, compositions and methods described herein include, but are not limited to, the following: cardiac cancers, including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma; lung cancers, including, for example, bronchogenic carcinoma, e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma; gastrointestinal cancer, including, for example, cancers of the esophagus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma, lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; cancers of the large bowel, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma; genitourinary tract cancers, including, for example, cancers of the kidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia; cancers of the bladder and urethra, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancers of the prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma; liver cancers, including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma; bone cancers, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; nervous system cancers, including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma; gynecological cancers, including, for example, cancers of the uterus, e.g., endometrial carcinoma; cancers of the cervix, e.g., cervical carcinoma, and pre tumor cervical dysplasia; cancers of the ovaries, e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa thecal cell tumors, Sertoli Ley dig cell tumors, dysgerminoma, and malignant teratoma; cancers of the vulva, e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of the vagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopian tubes, e.g., carcinoma; hematologic cancers, including, for example, cancers of the blood, e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin's lymphoma, non Hodgkin's lymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia; skin cancers, including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and adrenal gland cancers, including, for example, neuroblastoma.

[0061] Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue.

[0062] The compounds described herein can also be administered in combination with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery. Thus, there is further provided a method of treating cancer comprising administering an effective amount of a compound according to formula I to a patient, wherein a therapeutically effective amount of one or more additional cancer chemotherapeutic agents are administered to the patient.

[0063] Also provided herein is a method for treating diabetes in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I.

[0064] Further provided herein is a method for treating an autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I. The autoimmune disease can be, for example, inflammatory bowel disease (IBD). Immune responses are constantly and tightly regulated and one important cellular component in maintaining self tolerance (i.e., prevention of autoimmunity) and tolerance of benign commensal gut flora are regulatory T cells (Treg). Treg can be subdivided into multiple phenotypes, but the most common are CD4+CD25+ T cells that express the transcription factor Foxp3. Foxp3 is a direct transcriptional target of FOXO proteins, particularly FOXO1 and FOXO3. Thus activation of FOXO proteins in naive T- cells promotes and directs differentiation to maintain a population of Treg cells.

[0065] Acute immune mediated rejection and chronic immune mediated rejection are key obstacles to successful solid organ transplantation. It is believed that these forms of rejection can be prevented/overcome by amplifying Treg number and or function.

Similarly, a common and morbid complication of allogeneic hematopoietic cell transplants (Allo-HCT) used to treat various malignant and non-malignant conditions, is graft versus host disease, in which the transplanted immune cells from the donor damage multiple organs in the recipient (most notably skin, gut, and liver). Increasing experimental and clinical data indicate that Tregs can be harnessed to prevent and or treat this disease process. [0066] Thus compounds of the present invention are useful in treatment of autoimmune and related diseases, by activating FOXO proteins and inducing T cell differentiation to Tregs. Compounds may be administered therapeutically to subjects directly, or alternatively, T cells may be collected from a subject and differentiated ex vivo to Tregs as described by Taylor et al. [Blood 99, 3493-3499 (2002)].

[0067] Aspects of the invention include methods for treatment of autoimmune disease characterized by deficiency in Treg function comprising administering a therapeutically useful amount of compound of formula I. The method can also include extraction of naive T-cells from a patient, differentiation of T-cells to Tregs ex vivo by treatment with a compound of formula I, optionally supplemented with an HDACi, followed by administration of Tregs to patient with optional separation of compound of formula I from Tregs prior to their administration. As stated above, autoimmune diseases that can be so treated include IBD, solid organ transplant rejection, and GvHD in allo-HCT.

[0068] In some embodiments, the compounds can be administered to a patient to treat an autoimmune disorder, for example, Addison’s disease, Amyotrophic Lateral Sclerosis, celiac disease, Crohn's disease, diabetes, eosinophilic fasciitis, Guillain-Barre syndrome (GBS), Graves’ disease, Lupus erythematosus, Miller-Fisher syndrome, psoriasis, rheumatoid arthritis, ulcerative colitis, and vasculitis. In some embodiments, the compound provided herein can be used for treating a disease or disorder in a patient wherein the disease or disorder involves excessive or unregulated cellular proliferation, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I. Also provided herein is a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I.

[0069] Further provided herein is a method for treating a disease in a patient wherein the disease is characterized by proteotoxicity, including age onset proteotoxicity leading to neurodegeneration, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I. Hyperphosphorylated Tau has been implicated as the pathogenic protein in several neurodegenerative diseases and furthermore PP2A has been shown to be an important phosphatase in reversing aberrant phosphorylation of Tau; see for example Ludovic Martin et al., Tau protein phosphatases in Alzheimer’s disease: The leading role of PP2A in Ageing Research Reviews 12 (2013) 39- 49; Miguel Medina and Jesus Avila, Further understanding of tau phosphorylation: implications for therapy in Expert Rev. Neurotherapy, 15(1), 115-112 (2015) and Michael Voronkov et al., Phosphoprotein phosphatase 2A: a novel druggable target for Alzheimer’s disease in Future Med Chem. 2011 May, 3(7) 821-833. Hyperphosphorylated alpha- Synuclein is a second exemplar of a toxic protein, and again PP2A has been shown to reverse its aberrantly phosphorylated state; see for example Kang-Woo Lee et al., Enhanced Phosphatase Activity Attenuates alpha-Synucleinopathy in a Mouse Model in Neurobiology of Disease, May 11, 2011, 31(19) 6963-6971. In some embodiments, the disease is selected from the group consisting of: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and Pick’s disease.

[0070] The compounds provided herein may further be used in a method for treating a mood disorder in a patient by administering to the patient a therapeutically effective amount of a compound of formula I. In some embodiments, the mood disorder is stress- induced depression.

[0071] Also provided herein is a method for treating acne vulgaris in a patient by administering to the patient a therapeutically effective amount of a compound of formula I.

[0072] Further provided herein is a method for treating pulmonary disease such as COPD. Protein phosphatase 2A (PP2A) is a primary serine-threonine phosphatase that modulates inflammatory responses in asthma and COPD. PP2A has shown to be dysregulated in mouse models of COPD, and inhibiting PP2A activity exacerbated inflammatory responses in the lung. Conversely, increasing PP2A activity via PP2A protein transfection down regulated cytokine expression and prevented the induction of proteases following cigarette smoke extract (CSE) treatment. Thus, increasing PP2A activity by treatment with compounds of the present invention may ameliorate or reverse the pathology underlying lung diseases such as COPD.

[0073] Impaired PP2A/AKT signaling has been observed in cellular models of idiopathic pulmonary hypertension, where it causes obstructive hyperproliferation and apoptosis resistance of distal pulmonary artery smooth muscle cells. Increasing PP2A activity may reverse this, thus, treatment with compounds of the present invention may be an effective treatment for pulmonary hypertension.

[0074] Further provided herein is a method for treating cardiac hypertrophy in a patient by administering to the patient a therapeutically effective amount of a compound of formula I. In some embodiments, the cardiac hypertrophy is associated with a disease selected from hypertension, myocardial infarction, heart failure, and valvular heart disease. Cardiac physiology and hypertrophy are regulated by the phosphorylation status of many proteins, including receptors and ion channels, which is partly controlled by a PP2A-alpha4 intracellular signalling axis. Studies indicate that the type 2A protein phosphatases are differentially regulated in both the healthy and hypertrophied myocardium. The data suggest that pressure overload-induced hypertrophy is associated with (1) altered expression of type 2A protein phosphatases and their regulatory subunits and (2) an increase in expression of their non-catalytic inhibitor protein alpha4. Thus, treatment with compounds of the present invention may ameliorate cardiac hypertrophy. Also, significant reduction in endosomal PP2A activity has been observed in heart failure samples versus controls, suggesting that inhibited resensitization of beta-adrenergic receptors occurs in human heart failure. These studies suggest that resensitization of beta adrenergic receptors is inhibited in human heart failure and targeting the PP2A inhibitor SET to derepress and activate PP2A may provide preservation of receptor function and beneficial cardiac remodeling. Thus, treatment with compounds of the present invention may have a beneficial effect in heart failure.

[0075] Further provided herein is a method for treating a parasitic infection in a patient by administering to the patient a therapeutically effective amount of a compound of formula I. Examples of parasites that may cause parasitic infections to be treated include, but are not limited to, Plasmodium and Theileria.

[0076] Further provided herein is a method for treating inflammatory conditions. Reduced PP2A activity occurs in animal models of allergic airway disease and patients with severe asthma. Treatment with small molecule activators of PP2A such as fmgolimod (FTY720) or 2-amino-4-(4-(heptyloxy) phenyl)-2-methylbutan-l-ol (AAL(S)) inhibited the development of inflammation, airway hyperreactivity in mouse models of allergic airway disease. Thus, compounds of the present invention may be useful in the treatment of asthma. Dephosphorylation of tristetraprolin (TTP) functions as an “off-switch” in inflammatory responses, and can be promoted by compounds that stimulate PP2A activity. Therapeutic efficacy of protein phosphatase 2A (PP2A)-activating drugs, to target tristetraprolin (TTP), in models of rheumatoid arthritis has been demonstrated in vitro and in vivo. Thus, treatment with compounds of the present invention may be useful in chronic inflammatory conditions such as rheumatoid arthritis. [0077] PP2A enzymes are involved in the regulation of cell transcription, cell cycle, and viral transformation. Many viruses, including cytomegalovirus, parainfluenza, DNA tumor viruses, and HIV-1, utilize different approaches to exploit PPA2 in order to modify, control, or inactivate cellular activities of the host [Garcia et al., Microbes and Infection, 2, 2000, 401-407]. Therefore, the compounds provided herein may further be used in a method for treating a viral infection in a patient by administering to the patient a therapeutically effective amount of a compound of formula I. Examples of viruses that may cause viral infections to be treated include, but are not limited to: a polyomavirus, such as John Cunningham Virus (JCV), Simian virus 40 (SV40), or BK Virus (BKV); influenza, Human Immunodeficiency Virus type 1 (HIV-1), Human Papilloma Virus (HPV), adenovirus, Epstein-Barr Virus (EBV), Hepatitis C Virus (HCV), Molluscum contagiosum virus (MCV); Human T- lymphotropic virus type 1 HTLV-1), Herpes Simplex Virus type 1 (HSV-1), cytomegalovirus (CMV), hepatitis B virus, Bovine papillomavirus (BPV-1), human T-cell lymphotropic virus type 1, Japanese encephalitis virus, respiratory syncytial virus (RSV), and West Nile virus.

[0078] Serine/Threonine phosphatases, including PP2A, are involved in modulation of synaptic plasticity (D. G. Winder and J. D. Sweatt, Nature Reviews Neuroscience, vol 2,

July 2001, pages 461 - 474). Persistently decreased PP2A activity is associated with maintenance of Long Term Potentiation (LTP) of synapses, thus treatment PP2A activators such as those described here may reverse synaptic LTP. Psychostimulant drugs of abuse such as cocaine and methamphetamine are associated with deleterious synaptic LTP (L.

Mao et al, Neuron 67, September 9, 2010 and A. Stipanovich et al, Nature vol 453, 2008, pages 879 - 884), which may underlie the pathology of addiction and relapse therefore PP2A activators described here may be useful as treatments for psychostimulant abuse.

[0079] Abnormalities in synaptic structure and signaling are linked to autistic spectrum disorder, see for example, Y Chen et al., CTTNBP2, but not CTTNBP2NL, regulates dendritic spinogenesis and synaptic distribution of the striatin-PP2A complex, Molecular Biology of the Cell, 23, November 15, 2012, 4383-4392. PP2A has been shown to be important in normal development of dendritic spines, and treatment with compounds of the present invention may ameliorate or reverse autistic spectrum disorder.

[0080] Further provided herein is a method for treating a disease or disorder in which the disease or disorder involves the dysregulation of the mTOR-PP2A signaling axis.

Mammalian target of rapamycin (mTOR) is a serine/threonineprotein kinase that regulates cell growth, proliferation, and survival: mTOR is frequently activated in human cancers and is a commonly sought anticancer therapeutic target. PP2A is a key element in mTOR-AKT signaling during nutritional deprivation, and it has important implications in cell cycle progression and quiescence. Dysregulation of cellular metabolism is a feature of cancer, with nutrient transport defects, nutrient sensing defects, dysregulated autophagy and constitutive anabolism being common in tumors; aberrant activation of mTOR is implicated in all of these processes and PP2A activation has been demonstrated to modulate them in vivo. PP2A has been shown to be involved in regulatory feedback loops with mTOR, and PP2A activators of the present invention would be expected to affect these processes directly by interacting with mTOR complexes, or indirectly by counterbalancing mTOR’s effects by dephosphorylating its targets. Perturbation of the mTOR signaling cascade appears to be a common pathophysiological feature of human neurological disorders, including mental retardation syndromes and autism spectrum disorders, and neurodegenerative conditions such as Alzhiemer’s disease. Activation of PP2A has been shown to be effective in animal models of neurodegenerative disease by modulating the PP2A mTOR axis; thus, molecules of the present invention will be useful in treatment of these conditions. PP2A activators of the present invention are likely to be useful in the treatment of diseases in which mTOR signaling is dysregulated; these include cancer, diabetes and neurodegenerative conditions. Compounds of the present invention may also promote innate immunity to infection and promote healthy aging.

Abbreviations and Definitions

[0081] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. A comprehensive list of abbreviations utilized by organic chemists (i.e. persons of ordinary skill in the art) appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled “Standard List of Abbreviations” is incorporated herein by reference. In the event that there is a plurality of definitions for terms cited herein, those in this section prevail unless otherwise stated.

[0082] The following abbreviations and terms have the indicated meanings throughout:

Ac acetyl

Aq aqueous

Boc t-butyloxy carbonyl

Bu butyl c-

cyclo cat catalyst

Cbz carboxy benzyl

DBA dibenzylideneacetone

DCM dichloromethane = methylene chloride = CH₂CI₂

DMF N,N-dimethylformamide eq. or equiv. equivalent(s)

Et ethyl

GC gas chromatography h hour(s)

KHMDS Potas slum bis(trimethy 1 si !y l)ami d e

LG leaving group

Ln chiral ligands mCPBA /weta-Chloroperoxy benzoic acid

Me methyl mesyl methanesulfonyl min. minute(s)

Ms mesylate

NMO orNMMO N-methylmorpholine oxide

Pg protecting group

Ph phenyl

RT room temperature sat’d or sat. saturated t- or tert tertiary

Tf triflate

TFA trifluoroacetic acid

THF tetrahydrofuran tosyl

p-toluenesulfonyl

[0083] Throughout this specification the terms and substituents retain their definitions.

[0084] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprise” (and any form of comprise, such as “comprises” and “comprising”), “have” (and any form of have, such as “has” and “having”), “include” (and any form of include, such as “includes” and “including”), and “contain” (and any form contain, such as “contains” and “containing”) are open-ended linking verbs. As a result, a method or composition that “comprises”, “has”, “includes” or “contains” one or more steps or elements possesses those one or more steps or elements, but is not limited to possessing only those one or more steps or elements. Likewise, a step of a method or an element of a composition that “comprises”, “has”, “includes” or “contains” one or more features possesses those one or more features, but is not limited to possessing only those one or more features. The terms “comprising” and “including” or grammatical variants thereof are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof. For example, "X includes a, b and c" means that X includes, but is not limited to, a, b and c. This term encompasses the terms “consisting of” and “consisting essentially of”.

[0085] The phrase “consisting essentially of” or grammatical variants thereof when used herein are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof, but only if the additional features, integers, steps, components or groups thereof do not materially alter the basic and novel characteristics of the claimed composition or method.

[0086] Unless otherwise specified, the phrase "such as" is intended to be open-ended. For example, "X can be a halogen, such as fluorine or chlorine" means that X can be, but is not limited to, fluorine or chlorine.

[0087] As used herein, and as would be understood by the person of skill in the art, the recitation of “a compound” - unless expressly further limited - is intended to include salts of that compound. In a particular embodiment, the term “compound of formula” refers to the compound or a pharmaceutically acceptable salt thereof.

[0088] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic, pamoic, pantothenic, phosphoric, pivalic, polygalacturonic, salicylic, stearic, succinic, sulfuric, tannic, tartaric acid, teoclatic, p-toluenesulfonic, and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.

[0089] The terms "subject" or "subject in need thereof or “patient” are used interchangeably herein. These terms refer to a patient who has been diagnosed with the underlying disorder to be treated. The subject may currently be experiencing symptoms associated with the disorder or may have experienced symptoms in the past. Additionally, a "subject in need thereof may be a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological systems of a disease, even though a diagnosis of this disease may not have been made. As anon-limiting example, a "subject in need thereof, for purposes of this application, may include a male who is currently diagnosed with prostate cancer or was diagnosed with prostate cancer in the past, regardless of current symptomatology.

[0090] A “patient,” as used herein, includes both humans and other animals, particularly mammals. Thus the methods are applicable to both human therapy and veterinary applications. In some embodiments, the patient is a mammal, for example, a primate. In some embodiments, the patient is a human.

[0091] As used herein, the terms “treatment” or “treating" are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit. Therapeutic benefit includes eradication or amelioration of the underlying disorder being treated; it also includes the eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.

[0092] Treatment can involve administering a compound described herein to a patient diagnosed with a disease, and may involve administering the compound to a patient who does not have active symptoms. Conversely, treatment may involve administering the compositions to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0093] The terms “administer”, “administering” or “administration” in reference to a dosage form of the invention refers to the act of introducing the dosage form into the system of subject in need of treatment. When a dosage form of the invention is given in combination with one or more other active agents (in their respective dosage forms), “administration” and its variants are each understood to include concurrent and/or sequential introduction of the dosage form and the other active agents. Administration of any of the described dosage forms includes parallel administration, co-administration or sequential administration. In some situations, the therapies are administered at approximately the same time, e.g. , within about a few seconds to a few hours of one another.

[0094] A “therapeutically effective” amount of the compounds described herein is typically one which is sufficient to achieve the desired effect and may vary according to the nature and severity of the disease condition, and the potency of the compound. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease. A therapeutic benefit is achieved with the amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.

[0095] The term “modulate” with respect to a FOXO transcription factor protein refers to activation of the FOXO transcription factor protein and its biological activities associated with the FOXO pathway. Modulation of FOXO transcription factor proteins includes up- regulation (i.e., agonizing, activation or stimulation). The mode of action of a FOXO modulator can be direct, e.g., through binding to the FOXO transcription factor protein as a ligand. The modulation can also be indirect, e.g., through binding to and/or modifying another molecule which otherwise binds to and activates the FOXO transcription factor protein.

[0096] “Hydrocarbon” (e.g., (C₁-C₈)hydrocarbon) includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, adamantyl, norbomyl, and naphthylethyl. Hydrocarbyl (or hydrocarbon) refers to any substituent comprised of hydrogen and carbon as the only elemental constituents. Aliphatic hydrocarbons are hydrocarbons that are not aromatic; they may be saturated or unsaturated, cyclic, linear or branched. Examples of aliphatic hydrocarbons include isopropyl, 2-butenyl, 2-butynyl, cyclopentyl, norbomyl, etc.

Aromatic hydrocarbons include benzene (phenyl), naphthalene (naphthyl), anthracene, etc.

[0097] Unless otherwise specified, alkyl (or alkylene) is intended to include linear or branched saturated hydrocarbon structures and combinations thereof. Alkyl refers to alkyl groups from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.

[0098] Cycloalkyl is a subset of hydrocarbon and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include cy -propyl, cy-butyl, cy- pentyl, norbomyl and the like.

[0099] Alkoxy or alkoxyl refers to groups of from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms of a straight or branched configuration atached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purpose of this application, alkoxy and lower alkoxy include methylenedioxy and ethylenedioxy.

[00100] The term "halogen" means fluorine, chlorine, bromine or iodine atoms. In one embodiment, halogen may be a fluorine or chlorine atom.

[00101] The terms "haloalkyl," "haloalkoxy," or “haloalkylthio” mean alkyl, alkoxy, or alkylthio, respectively, substituted with one or more halogen atoms.

[00102] Heterocycle means an aliphatic or aromatic carbocycle residue in which from one to four carbons is replaced by a heteroatom selected from the group consisting of N, O, and S. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized. Unless otherwise specified, a heterocycle may be non-aromatic (heteroaliphatic) or aromatic (heteroaryl). Examples of heterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like. Examples of heterocyclyl residues include piperazinyl, piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl (also historically called thiophenyl), benzothienyl, thiamorpholinyl, oxadiazolyl, triazolyl and tetrahydroquinolinyl. Examples of heteroaryls include imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole. In some embodiments, examples of heteroaryls include imidazole, pyridine, thiophene, thiazole, furan, pyrimidine, pyrazine, tetrazole and pyrazole.

[00103] As used herein, the term “optionally substituted” may be used interchangeably with “unsubstituted or substituted”. The term “substituted” refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical. “Oxo” may also be included among the substituents referred to in “optionally substituted”; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl). In one embodiment, 1, 2, or 3 hydrogen atoms are replaced with a specified radical. In the case of alkyl and cycloalkyl, more than three hydrogen atoms can be replaced by fluorine; indeed, all available hydrogen atoms could be replaced by fluorine.

Examples

[00104] Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W. Greene and P.G.M.Wuts [John Wiley & Sons, New York, 1999], in Protecting Group Chemistry, 1^st Ed., Oxford University Press, 2000; and in March ’s Advanced Organic chemistry: Reactions, Mechanisms, and Structure, 5^th Ed., Wiley-Interscience Publication, 2001.

[00105] General Synthesis

[00106] Unsaturated 3-tricyclyl piperidines may be synthesized by the methods described in STEREOSPECIFIC PROCESS FOR HETEROCYCLYLCYCLOALIPHATIC-l,2-DIOLS, International Patent Publication No. WO 2017/024229 and HETEROCYCLIC CONSTRAINED TRICYCLIC SULFONAMIDES AS ANTI-CANCER AGENTS, International Patent Publication No. WO 2017/044569, both of which are incorporated herein by reference. This is shown generically in SCHEME A.

SCHEME A. Synthesis of 3-Tricyclyl Piperidine

The unsaturated intermediate may be reacted to give N-heterocyclyl moieties with hydrogen bond donating functionality to give compounds of formula I. The ring double bond may then be optionally derivatized by, for example, hydrogenation, dihydroxylation or cyclopropanation. Alternatively, the ring double bond may be derivatized, followed by N-deprotection and H-donor heterocycle formation. These are are shown schematically in SCHEME B.

SCHEME B. Synthesis of Compounds of Formula I [00107] Exemplary syntheses are presented below: [00108] SCHEME C: Synthesis of examples wherein linking group D is a hydrogen bond donating heterocyclic are shown in Schemes C1, C2, and C3.

[00109] In SCHEME Cl, (R)-3.7-dichloro- 10-C pi peri din-3-y l )- 10H-phenoxa/ine (R)- 3.7-dichloro- 10-(piperidin-3-yl)- 1 () H-phenoxa/ine. which can be prepared by the methods referred to above, is reacted with diphosgene to give the carbamoyl cloride A which is then reacted with hydrazine to give the hydrazide B. Hydrazide B is condensed with methyl 4- (trifluoromethoxy)benzimidate (prepared by reacting 4-trifluoromethoxybenzonitrile with HC1 in dry methanol) to give the target PP2A activator, (R)-3,7-dichloro-10-(1-(3-(4- (trifluoromethoxy)phenyl)-1H-1 ,2,4-triazol-5-yl)piperidin-3-yl)-10H-phenoxazine, C.

SCHEME C1

[00110] In SCHEME C2 tert-butyl (R)-3-(9H-carbazol-9-yl)-3.6-dihydropyridine- l(2//)-carbo\ylate is prepared by the methods referred to above, then cyclopropanated using Simmons-Smith or other conditions to give Boc protected intermediate A. Deprotection, activation of the piperidine as the carbamoyl chloride and treatment with hydrazine gives the hydrazide intermediate B. Treatment with methyl 4- (trifluoromethyl)benzimidate (prepared from the appropriate benzonitrile as above) gives the target PP2A activator, 9-((5R )-3-(3-(4-(tririuoromethyl)phenyl)- 1 H- 1 ,2,4-triazol-5-yl)- 3-azabicyclo[4. 1.0] heptan-5-yl)-9H-carbazole, C.

In SCHEME C3, benzyl (R)-3-( 10, 11 -dihydro-5H-dibenzo[b,f ]azepin-5-yl)-3.6- dihydropyridine-l(2iy)-carboxylate, prepared by the methods referred to above, is subjected to osmium tetroxide mediated dihydroxylation then protected as an acetonide to give intermediate A. A is deprotected by hydrogenolysis and converted to hydrazide intermediate B as described above. Condensation with methyl 4-chlorobenzimidate and subsequent acetonide deprotection gives the target PP2A activator, (3ri',4i?,5ri)-l-(3-(4- chlorophenyl)-1H-1 ,2,4-triazol-5-yl)-5-(10, 11 -dihydro-5H-dibenzo[b,f ]azepin-5- yl)piperidine-3,4-diol, C.

SCHEME C3 [00111] Exemplary syntheses are shown below when m is 0 and n is 1, forming a five- membered ring (pyrrolidine). Compounds of this type may be synthesized as shown in SCHEMES D and E. In SCHEME D, N-Cbz-3-hydroxypyrrolidine, which is commercially available as a racemate or optically pure as either enantiomer, is converted to the known 3- chloro- or 3-bromo (LG = Cl or Br in Scheme 2) derivatives. Alternatively, the hydroxyl may be converted to a leaving group such as mesylate or triflate, (LG = Ms or Tf) using standard protocols. The activated pyrrolidine derivative is used as an alkylating agent for optionally substituted tricyclics such as carbazoles, phenoxazines, dibenzazepines or phenothiazines (or their heterocyclic analogs). Displacement of the leaving group is carried out in the presence of a base to deprotonate the tricyclic in an aprotic solvent with optional heating. The 3-(N-tricyclyl)-N-Cbz-pyrrolidine is deprotected by hydrogenolysis and converted to a hydrazide intermediate as described above and shown below. Condensation with an optionally substituted methyl benzimidate and subsequent acetonide deprotection gives the requisite optionally substituted compound of formula I.

SCHEME D

[00112] Compounds in which R³ is hydroxyl-substituted are synthesized as shown in SCHEME E: commercially available N-Cbz-2,5-dihydropyrrole is converted to the known epoxide with mCPBA. The epoxide is then treated with optionally substituted tricyclics such as carbazoles, phenoxazines, dibenzazepines or phenothiazines (or their heterocyclic analogs); the epoxide opening is carried out in the presence of a base to deprotonate the tricyclic in an aprotic solvent with optional heating. Alternatively N-Cbz-2,5- dihdyropyrrole may be dihydroxylated and activated as a cyclic sulfite or cyclic sulfate which is then ring opened by nucleophilic displacement with a tricyclic in an analogous manner to the epoxide. The hydroxy intermediate is deprotected by hydrogenolysis and converted to a hydrazide intermediate as described above and shown below. Condensation with an optionally substituted methyl benzimidate and subsequent acetonide deprotection gives the requisite optionally substituted compound of formula I.

SCHEME E

[00113] Compounds wherein the tricyclic moiety is a dibenzazepine, that is where B = CH₂CH₂ may be accessed as shown in Schemes 1A, 1B, 1C and ID. tert-Butyl 3-hydroxy- 3.6-dihydropyridine- 1 (2H )-carbo\ylate is converted to the corresponding allylic chloride or bromide by treatment with carbon tetrachloride or carbon tetrabromide in a solvent such as methylene chloride or acetonitrile, cooling to 0°C, then adding triphenylphosphine, the mixture is then warmed to room temperature and stirred till conversion of the starting material is complete. The reaction is concentrated and purified by chromatography on silica gel eluting with hexane - ethylacetate. The tricyclic, for example, 2,8-difluoro-10,11- dihydro-5H-dibenzo[b,f]azepine, is alkylated by treating with the allylic chloride or bromide in an solvent such as DMF in the presence of a tertiary amine base such as diisopropylethylamine or triethyl amine with optional heating. Alternatively a strong base such as sodium amide in toluene, or sodium hydride in THF, may be used to deprotonate the tricyclic, followed by treatment with the allylic chloride or bromide. The reactions are worked up by diluting with ethyl acetate, and washing the organic with aqueous ammonium chloride, saturated brine, then drying the organic layer over magnesium or sodium sulfate. The solution is concentrated and the residue purified by chromatography on silica gel, eluting with a hexane-ethyl acetate gradient to yield Intermediate 1 of Scheme 1 A.

[00114] The double bond of Intermediate 1 may be hydrogenated under mild conditions, for example by stirring under hydrogen atmosphere with 10% palladium on charcoal in methanol, filtration through celite and concentration. The hydrogenated material is boc-deprotected by treatment with acid such as trifluoroacetic acid in methylene chroride or HC1 in dioxane. The deprotection reaction is concentrated, dissolved in ethyl acetate and washed with 1M sodium hydroxide, saturated brine and dried over anhydrous sodium sulfate. The organic is concentrated and the residue purified by chromatography, to give the piperidine, Intermediate 2.

[00115] The piperidine intermediate 2 is treated excess phosgene, or a convenient phosgene equivalent such as diphosgene in a solvent such as methylene chloride or THF with a weak base such as sodium bicarbonate, and optional cooling to 0°C to form a carbamoyl chloride, which is isolated by filtration through celite, and the solution evaporated to give crude material which is used without further purification. The carbamoyl chloride is dissolved in a solvent such THF, methylene chloride or dioxane, cooled to 0°C and treated with hydrazine. Alternatively a solution of the carbamoyl chloride in THF may be added dropwise to a cooled solution of hydrazine in a solvent such as ethanol. The carbohydrazide is worked up by diluting the reaction with ethyl acetate and washing with brine, and the organic solution is dried over sodium sulfate, filtered and evaporated. The crude carbohydrazide may purified by chromatography or crystallization.

[00116] An appropriately substituted methyl bezimidate, for example methyl 4- (trifluoromethoxy)benzimidate, is prepared by dissolving the corresponding nitrile in dry methanol and bubbling in dry HCl gas with cooling at 0°C. The methyl benimidate precipitates as the hydrochloride salt and is collected by filtration.

[00117] A solution of the carbo hydrazide, for example 3-(2,8-difluoro-10, 11-dihydro- 5 H-di benzo[ b,f ]azepin-5-yl)pi peri dine- 1 -carbohydrazide shown in Scheme 1 A is treated with a substituted a methyl benzimidate in a solvent such as acetonitrile or dioxane with and the mixture is heated to effect ring closure to give the desired triazole. Alternatively the mixture may be treated with one equivalent of a dehydrating agent such as phosphorus oxychloride to effect the ring closure. The reaction is worked up by diluting into ethyl acetate washing with brine and drying the organic over sodium sulfate. The solution is filtered evaporated and the crude material purified by chromatography, to give the product, 2,8-difluoro-5-(1-(3-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-5-yl)piperidin-3-yl)- 10.1 1 -dihydro-5H-dibenzo[b,f]azepine. as shown in Scheme 1A, triazole example 1A.

[00118] Imidazole examples 1B and 1C may be obtained from piperidine intermediate 2, by the transformations shown in Scheme 1A. Thus piperidine intermediate 2 is reacted with a guanidinylating agent such as 1H-pyrazole- 1-carboximidamide to form the corresponding piperidine- 1-carboximidamide in a solvent such as DMF or THF in the presence of a base such as diisopropylethylamine and isolated by diluting with ethyl acetate washing with brine drying the organic over sodium sulfate, filtering and evaporating to give crude material. The piperidine- 1-carboximidamide is condensed with an alpha- haloacetophenone, such as 2-chloro-4-trifluoromethoxyacetophenone in a solvent such as dioxane, acetonitrile or toluene in the presence of air or an added oxidant such as DDQ, with optional heating, to give the product imidazole. Alternatively an appropriately substituted acetophenone may be oxidized to the alpha-oxo acetophenone with selenium dioxide, and then condensed with the appropriate piperidine- 1-carboximidamide to give the product imidazole, example 1B. The product is isolated by isolated by diluting the reaction with ethyl acetate, washing with brine drying the organic over sodium sulfate, filtering and evaporating to give crude material which is purified by chromatography.

[00119] The isomeric imidazole, example 1C is obtained by reacting piperidine intermediate 2 with one equivalent of chloroacetyl chloride (or bromo acetylbromide), then condensing the product with an appropriately substituted phenyl amidine, as shown in Scheme 1 A, to give the product imidazole.

SCHEME 1A

[00120] Variants of the transformations shown in the scheme above may also be employed to give other examples. Scheme 1B shows some of these: for example, intermediate 2 may be reacted with thiophosgene to give a carbothioyl chloride which is condensed with a substituted benzimidohydrazine, formed by reaction of a substituted methyl benzimidate with one equivalent of hydrazine, to give the product triazole, the example in Scheme 1B being 5-( 1 -(3-(4-chlorophenyl)- 1 H- 1 ,2,4-triazol-5-yl)piperidin-3- yl)-2,8-difluoro-10,11-dihydro-5H-dibenzo[b,f]azepine (Example 4). Where ring closure to the triazole is not spontaneous, it may be promoted by optional heating or the addition of silver(i) nitrate or mercuric acetate.

SCHEME 1B

[00121] Imidazole examples wherein R^H is lower alkyl, for example methyl, may be synthesized as shown in Scheme 1B: apiperidine-1-carboximidamide (synthesized as described above), may be reacted with a substituted alpha-halopropiphenone and the mixture heated in the presence of air, or an added oxidant such as DDQ, to give the substituted imidazole wherein R^H = Me (Example 5). Alternatively, a substituted propiophenone may be oxidized to the 1,2-dicarbonyl with selenium dioxide and condensed with the piperidine-l-carboximidamide to give the appropriate substituted imidazole (Example 6).

[00122] The isomeric imidazoles may be synthesized by reacting piperidine intermediate 2 at low temperature with 2-oxopropanoyl chloride, thus a solution of 2,8- difluoro-5-(piperidin-3-yl)-10.11 -dihydro-5H-dibenzo[b,f]azepine and one equivalent of diisopropylethylamine in THF is cooled to -78°C with stirring and 2-oxopropanoyl chloride is added dropwise and the reaction warmed to 0°C. The intermediate alpha ketoamide may be condensed directly in the same pot with a substituted benzimidamide to give the product imidiazole. Alternatively, the alpha-ketoamide may be worked-up by diluting the reaction with ethyl acetate, washing the organic with brine, and drying over sodium sulfate.

Filtering and evaporation gives the crude alpha-ketoamide, which may be used in a condensation with a substituted benzimidamide to give the products. Alternatively, piperidine intermediate 2 may be reacted with an alpha-halopropionyl halide to give the alpha-haloamide, which is condensed with a substituted benzimidamide in the presence of air or an added oxidant to give the imidazole product. Finally piperidine intermediate 2 may be reacted with an alpha-hydroxy carboxylic acid to give an alpha hydroxyl amide which is oxidized to the alpha-ketoamide using Swem conditions, pyridine-sulfurtrioxide or an oxidant such as yridinium chlorochromate. The alpha keto amide is the condensed with a substituted benzimidamide to give the product.

[00123] Various heterocyclic analogs of the dibenzazepine are known, see for example, Lam et al, J. Org. Chem. 2017, 82, 6089-6099, and the methods shown above may be used to synthesize optionally substituted heterocyclic analogs of the compounds wherein B = CH₂CH₂ and one of the aromatic rings is heterocyclic; an example is shown in Scheme 1C (Example 7).

SCHEME 1C

[00124] In the examples above the alkene present in the dehydropiperidine was hydrogenated, however other derivatives maybe formed from it, for example by cyclopropanation or difluorocyclopropanation, for example as shown in Scheme ID (Example 8).

SCHEME ID

[00125] The examples above describe dibenzoazepines, B = CH₂CH₂, and heterocyclic variants thereof. It will be readily appreciated the synthetic methods described above may be applied to other tricyclic systems, for example carbazoles or their heterocyclic analogs such as the carbolines. An example is shown in Schemes 2A, 2B, and 2C.

SCHEME 2A (B = bond)

[00126] In Scheme 2A methyl 5H-pyrido|3.2-/)|indole-7-carbo\ylate is alkylated as described above to give a racemate or optically pure material may be obtained using the methods described in STEREOSPECIFIC PROCESS FOR

HETEROCYCLYLCYCLOALIPHATIC-1,2-DIOLS, International Patent Publication No. WO 2017/024229. The alkene is hydrogenated under mild conditions, for example with hydrogen atmosphere and 10% Pd/C catalyst. The product is dissolved in dry THF, cooled to -78°C, and a solution of methyl magnesium bromide or methyl lithium, 3 equiv, in THF is added dropwise with stirring. The reaction is warmed to 0°C and stirred for lhr - 12 hrs. The reaction is quenched with methanol then diluted with ethyl acetate. The organic is washed with brine, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The crude material is purified by chromatography eluting with ethylacetate- hexanes. Boc deprotection is carried out with by stirring in TFA-methylene chloride at 0°C - room temperature for 1 - 12 hrs, to give intermediate 1. Piperidine intermediate 1 is converted to the corresponding carbamoyl chloride by treatment with phosgene or a convenient phosgene equivalent such as diphosgene in methylene chloride with sodium bicarbonate. The carbamoyl chloride is filtered, concentrated in vacuo and used crude; it is converted to the piperidine-1 -carbohydrazide by treatment with hydrazine. The piperidine- 1-carbohydrazide is treated with a substituted methyl benzimidate and ring closure to the triazole is effected by heating with removal of water, for example by azeotropic reflux in benzene or toluene (Example 9). Alternatively intermediate 1 may be treated with thiophosgene to give a carbothioyl chloride which is treated in a second step with a substituted benzimidohydrazide; ring closure to the triazole is effected by optional heating or addition of an equivalent of a silver(i) nitrate, mercuric acetate or cuprous chloride.

[00127] Scheme 2B shows the synthesis of examples wherein the donor heterocycle is imidazole, routes and conditions are analogous to those shown in Scheme 1A (Examples 10 and 11).

SCHEME 2B

[00128] Carboxamide substituents on the carboline may be accessed as shown in Scheme 2C; here, ester substituted intermediate 1 is N-Boc deprotected and converted to the triazole via the carbothioyl chloride and condensation with a substituted benzimidohydrazide. The ester on the carboline is then hydrolyzed, for example with aqueous sodium hydroxide followed by neutralization (Example 12). The carboxylic acid may then be coupled with amines using, for example, a carbodiimide such as EDC, to give the requisite carboxamide substituted carboline (Example 13).

SCHEME 2C

[00129] Methods described in Scheme 1A and 1B may be applied to the synthesis of examples wherein the tricyclic substituent on the piperidine is a phenothiazine and this is shown in SCHEME 3 (Examples 14, 15, 16).

SCHEME 3

Cell viability assays (IC₅₀ determination)

[00130] Cell viability assays are performed according to Denizot, F. and R. Lang, Journal of Immunological Methods, 1986. 89(22): p. 271 - 277. H1650 lung cancer cells are plated at 150,000 cells per well in a 12 well plate. Twenty-four hours after plating, cells are treated as described with increasing concentrations of drug and control. Forty-eight hours after drug treatment, cells are treated with 100 μL of 3-(4,5-Dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) and incubated for 2 hours at 37 C. The MTT solution is subsequently replaced with 300 μL of n-propyl alcohol and re-aliquoted to a 96 well plate. Spectrophotometric analysis of each solution is performed using a 96 well plate reader at 600 nm in triplicate. Results are shown in IC50 (pM).

Colony Formation Assay

[00131] Protocol for clonogenic assay follows Sangodkar et al., J Clin Invest 2012;122:2637-51. [00132] Cell culture and staining: For both A5491uc and H1650 cells, 500 cells are seeded into each well of a 6-well plate and allowed to attach for 24 hours before drug treatment. The following day, cells are treated with either the appropriate dose of drug or an equivalent volume of DMSO (two replicates were treated for each condition). For each condition, depleted media is replaced with fresh media containing the equivalent drug dose four days after initial treatment. Cells are harvested either 7 (A5491uc) or 8 ( H1650) days after initial treatment. Briefly, medium is aspirated from each well and the cells are washed twice with ice-cold PBS, then plates are allowed to dry at room temperature for 4 hours. Cells are fixed for one hour in a fixing solution consisting of 10% methanol and 10% glacial acetic acid in distilled water, then stained overnight in 1% (w/v) crystal violet dissolved in methanol. The next day, staining solution is aspirated from the wells and plates are washed gently with distilled water to remove excess stain before colony counting. Colonies are imaged on a ChemiDoc XRS+ (Bio-Rad) and images are exported as 8-bit TIFF files. Colonies are counted using the Colony Counter plugin in ImageJ, with colony size defined as between 4 and 400 square pixels, and minimum circularity set at 0.6. Duplicate wells are averaged to obtain a single value for each condition. Results (number of colonies) for A5491uc cells and results (number of colonies) for H1650 cells may be analyzed separately.

In vivo cancer model

[00133] To assess the in vivo effects of the compounds, subcutaneous xenograft of lung cancer cell line H441 are generated. Cells (5 × 10⁶) are injected into the right flank of 6- to 8-week-old male BALB/c nu/nu mice (Charles River, Wilmington, MA). Tumor volume is assessed twice a week by caliper measurement. Mice are randomized to treatment groups based on initial tumor volume average of 100mm³ per group. Mice are dosed by oral gavage with 15mg/kg of a compound of formula I QD, 15mg/kg of a compound of formula I BID, or 50mg/kg of a compound of formula I QD. Mouse tumors are measured twice a week for the duration of the study. Mouse body weights are recorded weekly and percentage of mice body weights during treatment are calculated as: weight at each time point/initial weight xlOO. Animals are observed for signs of toxicity (mucous diarrhea, abdominal stiffness and weight loss) and adverse signs are observed. Mice undergo treatment for 30 days and are sacrificed 2 hours after the last dose. Tumors are then excised and cut for both formalin-fixation and snap frozen in liquid nitrogen.

Inhibition of tumor(T) growth versus vehicle control(C) is determined. [00134] Various embodiments of the invention can be described in the text below: [1]. A compound of formula (I):

wherein:

W1 is selected from a benzene ring, pyridine, pyrimidine, and thiophene;

W2 is selected from a benzene ring, pyridine, pyrimidine, and thiophene;

B is absent or is selected from a direct bond, -O-, -S-, -CH₂CH₂-, -CH=CH-, -OCH₂-, -CH₂O-, -C(O)NR^B-, and -NR^BC(O) -;

R^B is H or (C₁-C₆)alkyl;

Het-H is a heteroaryl ring selected from:

R^H is selected in each instance from hydrogen and (C₁-C₆)alkyl;

X¹, X², X³, and X⁴ are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C₁-C₆)alkyl optionally substituted with -OH, (C₁-C₆)haloalkyl, (C₁- C₆)haloalkoxy, (C₁-C₆)haloalkylthio, -NR¹R², -OR¹, -C(O)R¹, -OC(O)R¹, -C(O)NR¹R², - C(O)OR¹, -SR¹, -SO₂R¹, and -SO₂NR¹R²;

R¹ and R² are independently selected in each instance from hydrogen and (C₁- C₆)alkyl;

R³-R⁴ is selected from

m is zero, 1 or 2; n is 1 or 2; wherein m + n equals 1, 2 or 3; and wherein when m is zero and n is 1, R³-R⁴ is either

or

V is selected from phenyl, a six-membered heteroaromatic ring, furan, and thiophene; Z¹ and Z² are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, (C₁- C₆)haloalkylthio, -NR¹R², -NR¹C(O)R², -NR¹C(O)OR⁶, -OR¹, -C(O)R¹, -OC(O)R¹, - C(O)NR¹R², -C(O)OR¹, -SR¹, -SO₂R¹, and -SO₂NR¹R²; and R⁶ is (C₁-C₈)hydrocarbon.

[2]. A compound according to [1] above, or according to other embodiments of the invention, of formula Ila:

[3]. A compound according to [1] above, or according to other embodiments of the invention, of formula lib:

[4]. A compound according to any of [1] through [3] above, or according to other embodiments of the invention, wherein W1 is a benzene ring.

[5]. A compound according to any of [1] through [3] above, or according to other embodiments of the invention, wherein W1 is pyridine.

[6]. A compound according to any of [1] through [3] above, or according to other embodiments of the invention, wherein W1 is pyrimidine.

[7]. A compound according to any of [1] through [3] above, or according to other embodiments of the invention, wherein W1 is thiophene. [8]. A compound according to any of [1] through 7] above, or according to other embodiments of the invention, wherein W2 is a benzene ring.

[9]. A compound according to any of [1] through [7] above, or according to other embodiments of the invention, wherein W2 is pyridine.

[10]. A compound according to any of [1] through [7] above, or according to other embodiments of the invention, wherein W2 is pyrimidine.

[11]. A compound according to any of [1] through [7] above, or according to other embodiments of the invention, wherein W2 is thiophene.

[12]. A compound according to any of [1] through [3] above, or according to other embodiments of the invention, wherein at least one of W1 and W2 is benzene.

[13]. A compound according to any of [1] through [3] above, or according to other embodiments of the invention, wherein both of W1 and W2 are benzene.

[14]. A compound according to any of [1] through [3] above, or according to other embodiments of the invention, wherein one of W1 and W2 is benzene and the other of W1 and W2 is selected from pyridine and pyrimidine.

[15]. A compound according to any of [1] through [14] above, or according to other embodiments of the invention, wherein B is a direct bond.

[16]. A compound according to any of [1] through [14] above, or according to other embodiments of the invention, wherein B is -O-.

[17]. A compound according to any of [1] through [14] above, or according to other embodiments of the invention, wherein B is -(CH₂)₂-.

[18]. A compound according to any of [1] through [14] above, or according to other embodiments of the invention, wherein B is -CH₂O-.

[19]. A compound according to any of [1] through [14] above, or according to other embodiments of the invention, wherein B is OCH₂-.

[20]. A compound according to any of [1] through [14] above, or according to other embodiments of the invention, wherein B is -S-.

[21]. A compound according to any of [1] through [14] above, or according to other embodiments of the invention, wherein B is -CH=CH-. [22]. A compound according to any of [1] through [14] above, or according to other embodiments of the invention, wherein B is -C(O)NR^B-.

[23]. A compound according to any of [1] through [14] above, or according to other embodiments of the invention, wherein B is -NR^BC(O)-.

[24]. A compound according to any of [1] through [14] above, or according to other embodiments of the invention, wherein B is absent.

[25]. A compound according to any of [1] through [24] above, or according to other embodiments of the invention, wherein R^B is H.

[26]. A compound according to any of [1] through [24] above, or according to other embodiments of the invention, wherein R^B is (C₁-C₆)alkyl.

[27]. A compound according to [26] above, or according to other embodiments of the invention, wherein R^B is methyl.

[28]. A compound according to any of [1] through [27] above, or according to other embodiments of the invention, wherein m is 0.

[29]. A compound according to any of [1] through [27] above, or according to other embodiments of the invention, wherein m is 1.

[30]. A compound according to any of [1] through [27] above, or according to other embodiments of the invention, wherein m is 2.

[31]. A compound according to any of [1] through [30] above, or according to other embodiments of the invention, wherein n is 1.

[32]. A compound according to any of [1] through [29] above, or according to other embodiments of the invention, wherein n is 2.

[33]. A compound according to any of [1] through [32] above, or according to other embodiments of the invention, wherein R³-R⁴ is

[34]. A compound according to any of [1] through [32] above, or according to other embodiments of the invention, wherein R³-R⁴ is

[35]. A compound according to any of [1] through [32] above, or according to other embodiments of the invention, except when m is 0 and n is 1, wherein R³-R⁴ is

[36]. A compound according to any of [1] through [32] above, or according to other embodiments of the invention, except when m is 0 and n is 1, wherein R³-R⁴ is

[37]. A compound according to any of [1] through [32] above, or according to other embodiments of the invention, except when m is 0 and n is 1, wherein R³-R⁴ is

[38]. A compound according to any of [1] through [32] above, or according to other embodiments of the invention, except when m is 0 and n is 1, wherein R³-R⁴ is

[39]. A compound according to any of [1] through [32] above, or according to other embodiments of the invention, except when m is 0 and n is 1, wherein R³-R⁴ is

[40]. A compound according to any of [1] through [32] above, or according to other embodiments of the invention, except when m is 0 and n is 1, wherein R³-R⁴ is

[41]. A compound according to any of [1] through [32] above, or according to other embodiments of the invention, except when m is 0 and n is 1, wherein R³-R⁴ i i.s

[42]. A compound according to any of [1] through [32] above, or according to other embodiments of the invention, except when m is 0 and n is 1, wherein R³-R⁴ is

[43]. A compound according to any of [1] through [32] above, or according to other embodiments of the invention, except when m is 0 and n is 1, wherein R³-R⁴ is

[44]. A compound according to any of [1] through [43] above, or according to other embodiments of the invention, wherein X¹, X², X³, and X⁴ are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C₁-C₆,)alkyl optionally substituted with -OH, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, (C₁-C₆)haloalkylthio, -NR³R², -OR¹, - C(O)R¹, -OC(O)R¹, -C(O)NR¹R², -C(O)OR¹, -SR¹, -SO₂R¹, and -SO₂NR¹R².

[45]. A compound according to any of [1] through [44] above, or according to other embodiments of the invention, wherein X² and X⁴ are each hydrogen.

[46]. A compound according to any of [1] through [45] above, or according to other embodiments of the invention, wherein X¹ and X³ are each chosen independently from hydrogen, halogen, nitro, cyano, (C₁-C₆)alkyl optionally substituted with -OH, (C₁- C₆)haloalkyl, (C₁-C₆)haloalkoxy, (C₁-C₆)haloalkylthio, -NR³R², -OR¹, -C(O)R¹, -OC(O)R¹, -C(O)NR¹R², -C(O)OR¹, -SR¹, -SO₂R¹, and -SO₂NR¹R².

[47]. A compound according to any of [1] through [46] above, or according to other embodiments of the invention, wherein X¹ and X³ are each chosen independently from -H, - F, -Cl, -CF₃,-C(CH₃)₂OH, or -C(O)NMe₂.

[48]. A compound according to any of [1] through [47] above, or according to other embodiments of the invention, wherein all of X¹, X², X³ and X⁴ are each hydrogen.

[49]. A compound according to any of [1] through [48] above, or according to other embodiments of the invention, wherein at least one of X¹, X², X³ and X⁴ is located at a carbon two positions away from a bridgehead carbon.

[50]. A compound according to any of [1] through [49] above, or according to other embodiments of the invention, wherein R¹ is hydrogen. [51]. A compound according to any of [1] through [49] above, or according to other embodiments of the invention, wherein R¹ is (C₁-C₆)alkyl.

[52]. A compound according to any of [1] through [49] above, or according to other embodiments of the invention, wherein R¹ is methyl.

[53]. A compound according to any of [1] through [52] above, or according to other embodiments of the invention, wherein R² is hydrogen.

[54]. A compound according to any of [1] through [52] above, or according to other embodiments of the invention, wherein R² is (C₁-C₆)alkyl.

[55]. A compound according to any of [1] through [52] above, or according to other embodiments of the invention, wherein R² is methyl.

[56]. A compound according to any of [1] through [55] above, or according to other embodiments of the invention, wherein Z¹ and Z² are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁- C₆)haloalkoxy, (C₁-C₆)haloalkylthio, -NR'R². -NR¹C(O)R², -NR¹C(O)OR⁶, -OR¹, - C(O)R¹, -OC(O)R¹, -C(O)NR¹R², -C(O)OR¹, -SR¹, -SO₂R¹, and -SO₂NR¹R².

[57]. A compound according to any of [1] through [56] above, or according to other embodiments of the invention, wherein Z¹ and Z² are independently selected in each instance from hydrogen, halogen, halo(C₁-C₆)alkyl. (C₁-C₆)alko\y. -NR¹C(O)OR⁶, and halo(C₁-C₆)alkoxy.

[58]. A compound according to any of [1] through [57] above, or according to other embodiments of the invention, wherein Z¹ is hydrogen.

[59]. A compound according to any of [1] through [58] above, or according to other embodiments of the invention, wherein Z² is chosen from hydrogen, halogen, and (C₁- C₆)haloalkoxy.

[60]. A compound according to any of [1] through [59] above, or according to other embodiments of the invention, wherein Z² is chosen from hydrogen, F, Cl, and trifluoromethoxy.

[61]. A compound according to any of [1] through [60] above, or according to other embodiments of the invention, wherein Z² is trifluoromethoxy. [62]. A compound according to any of [1] through [61] above, or according to other embodiments of the invention, wherein one of Z¹ and Z² is para to the attachment of ring V to the sulfonyl.

[63]. A compound according to any of [1] through [62] above, or according to other embodiments of the invention, wherein one of Z² is para to the attachment of ring V to the sulfonyl.

[64]. A compound according to any of [1] through [63] above, or according to other embodiments of the invention, wherein R⁶ is (C₁-C₈)hydrocarbon.

[65]. A compound according to any of [1] through [64] above, or according to other embodiments of the invention, wherein V is phenyl.

[66]. A compound according to any of [1] through [64] above, or according to other embodiments of the invention, wherein V is a six-membered heteroaromatic ring.

[67]. A compound according to any of [1] through [64] above, or according to other embodiments of the invention, wherein V is pyridine.

[68]. A compound according to any of [1] through [64] above, or according to other embodiments of the invention, wherein V is pyrimidine.

[69]. A compound according to any of [1] through [64] above, or according to other embodiments of the invention, wherein V is thiophene.

[70]. A compound according to any of [1] through [64] above, or according to other embodiments of the invention, wherein V is furan.

[71]. A compound according to any of [1] through [70] above, or according to other embodiments of the invention, wherein Het-H is

[72]. A compound according to any of [1] through [70] above, or according to other embodiments of the invention, wherein Het-H is

[73]. A compound according to any of [1] through [70] above, or according to other embodiments of the invention, wherein

[74]. A compound according to any of [1] through [70] above, or according to other embodiments of the invention, wherein

[75]. A compound according to any of [1] through [70] above, or according to other embodiments of the invention, wherein

[76]. A compound according to any of [1] through [70] above, or according to other embodiments of the invention, wherein

[77]. A compound according to any of [1] through [70] above, or according to other embodiments of the invention, wherein

[78]. A compound according to any of [1] through [70] above, or according to other embodiments of the invention, wherein

[79]. A compound according to any of [1] through [70] above, or according to other embodiments of the invention, wherein

[80]. A compound according to any of [1] through [70] above, or according to other embodiments of the invention, wherein

[81]. A compound according to any of [1] through [70] above, or according to other embodiments of the invention, wherein

[82]. A compound according to any of [1] through [70] above, or according to other embodiments of the invention, wherein

[83]. A compound according to any of [1] through [70] above, or according to other embodiments of the invention, wherein

[84]. A compound according to any of [1] through [70] above, or according to other embodiments of the invention, wherein

[85]. A compound according to any of [1] through [82] above, or according to other embodiments of the invention, wherein R^H is selected in each instance from hydrogen and (C₁-C₆)alkyl.

[86]. A compound according to any of [1] through [82] above, or according to other embodiments of the invention, wherein R^H is hydrogen.

[87]. A compound according to any of [1] through [82] above, or according to other embodiments of the invention, wherein R^H is (C₁-C₆)alkyl.

[88]. A compound according to any of [1] through [82] above, or according to other embodiments of the invention, wherein R^H is methyl.

[89]. A compound according to [1] above, or according to other embodiments of the invention, wherein both W1 and W2 are benzene, or one of W1 and W2 is benzene and the other of W1 or W2 is pyridine or pyrimidine; B is selected from a direct bond, -O-, and -

CH₂CH₂-; Het-H is selected from

; m is 1 and n is 1, or m is 2 and n is 1, or m is 1 and n is 2, or m is zero and n is 1; X² and X⁴ are each hydrogen, and X¹ and X³ are each chosen independently from -H, -F, -Cl, -CF₃,- C(CH₃)₂OH, -C(O)NMe₂; R¹ and R² are independently selected in each instance from the group consisting of hydrogen and (C₁-C₆)alkyl; V is phenyl; Z¹ is hydrogen; and Z² is selected in each instance from hydrogen, halogen, and (C₁-C₆)haloalkoxy.

[90]. A compound according to [89] above, or according to other embodiments of the invention, wherein Z² is in the para position.

[91]. A compound according to [89] or [90] above, or according to other embodiments of the invention, wherein B is a direct bond.

[92]. A compound according to [89] or [90] above, or according to other embodiments of the invention, wherein B is O.

[93]. A compound according to any of [89] through [92] above, or according to other embodiments of the invention, wherein both W1 and W2 are benzene. [94]. A compound according to any of [89] through [92] above, or according to other embodiments of the invention, wherein one of W1 and W2 is benzene and the other of W1 or W2 is pyridine or pyrimidine.

[95]. A compound according to any of [89] through [94] above, or according to other

[96]. A compound according to any of [89] through [95] above, or according to other embodiments of the invention, wherein m is 1 and n is 1.

[97]. A compound according to any of [89] through [95] above, or according to other embodiments of the invention, wherein m is 2 and n is 1.

[98]. A compound according to any of [89] through [95] above, or according to other embodiments of the invention, wherein m is 1 and n is 2.

[99]. A compound according to any of [89] through [95] above, or according to other embodiments of the invention, wherein m is 0 and n is 1.

[100]. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any of [1] to [99] above, or according to other embodiments of the invention.

[101]. A method for treating a disease in a patient chosen from:

(a) cancer

(b) diabetes

(c) autoimmune disease

(d) age onset proteotoxic disease, particularly neurodegenerative disease

(e) mood disorder (1) acne vulgaris

(g) solid organ transplant rejection (graft vs. host disease)

(h) pulmonary disease, such as COPD

(i) cardiac hypertrophy and heart failure

(j) viral or parasitic infection and

(k) inflammatory conditions, such as asthma; the method comprising administering to the patient a therapeutically effective amount of a compound of any of [1] to [99] above, or according to other embodiments of the invention.

[102]. A method for treating a disease in a patient chosen from:

(a) cancer

(b) diabetes

(c) autoimmune disease

(d) age onset proteotoxic disease, particularly neurodegenerative disease

(e) mood disorder

(f) acne vulgaris

(g) solid organ transplant rejection (graft vs. host disease)

(h) pulmonary disease, such as COPD

(i) cardiac hypertrophy and heart failure

(j) viral or parasitic infection and

(k) inflammatory conditions, such as asthma; the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of [100] above, or according to other embodiments of the invention.

[103]. The method of [101] or [102] above, or according to other embodiments of the invention, wherein said cancer is selected from the group consisting of: ovarian, pancreatic, renal cell, breast, prostate, lung, hepatocellular carcinoma, glioma, leukemia, lymphoma, colorectal cancers, and sarcomas.

[104]. The method of [101] or [102] above, or according to other embodiments of the invention, for treating cancer, wherein said cancer is chemotherapy resistant cancer.

[105]. The method of any of [101], [102], [103], or [104] above, or according to other embodiments of the invention, wherein the method further comprises administering one or more additional cancer chemotherapeutic agents.

[106]. The method of [101] or [102] above, or according to other embodiments of the invention, for treating an age onset proteotoxic disease, particularly neurodegenerative disease, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.

[107]. The method of [101] or [102] above, or according to other embodiments of the invention, for treating a viral infection. [108]. The method of [107] above, or according to other embodiments of the invention, wherein the viral infection is caused by a virus selected from influenza, HIV-1, HPV, adenovirus, BKV, EBV, JCV, HCV, MCV, polyomavirus, SV40, HTLV-1, HSV-1, CMV, hepatitis B, BPV-1, human T-cell lymphotropic virus type 1, Japanese encephalitis virus, RSV, and West Nile virus.

[109]. The method of [101] or [102] above, or according to other embodiments of the invention, for treating a parasitic infection.

[110]. The method of [109] above, or according to other embodiments of the invention, wherein the parasitic infection is caused by a parasite selected from Plasmodium and Theileria.

[111]. A method for restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer, the method comprising administering an effective amount of a compound of any of [1] to [99] above, or according to other embodiments of the invention.

[112]. A method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway, the method comprising administering to the patient a therapeutically effective amount of a compound of any of [1] to [99] above, or according to other embodiments of the invention.

[113]. A method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway, the method comprising administering to the patient a therapeutically effective amount of a compound of any of [1] to [99] above, or according to other embodiments of the invention.

[114]. A method for treating a metabolic disease or disorder in a patient wherein the disease or disorder involves the dysregulation of the mTOR-PP2A signaling axis, the method comprising administering to the patient a therapeutically effective amount of a compound of any of [1] to [99] above, or according to other embodiments of the invention.

[115]. A method for restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer, the method comprising administering an effective amount of a pharmaceutical composition of [100] above, or according to other embodiments of the invention.

[116]. A method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of [100] above, or according to other embodiments of the invention.

[117]. A method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of [100] above, or according to other embodiments of the invention.

[118] . A method for treating a metabolic disease or disorder in a patient wherein the disease or disorder involves the dysregulation of the mTOR-PP2A signaling axis, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of [100] above, or according to other embodiments of the invention.

[00135] While typical embodiments have been set forth for the purpose of illustration, the foregoing descriptions and examples should not be deemed to be a limitation on the scope of the invention. Accordingly, various modifications, adaptations, and alternatives may occur to one skilled in the art without departing from the spirit and scope of the present invention.

Claims

CLAIMS We claim:

1. A compound of formula (I):

wherein:

W1 is selected from a benzene ring, pyridine, pyrimidine, and thiophene;

W2 is selected from a benzene ring, pyridine, pyrimidine, and thiophene;

B is absent or is selected from a direct bond, -O-, -S-, -CH₂CH₂-, -CH=CH-, -OCH₂-, -CH₂O-, -C(O)NR^B-, and -NR^BC(O) -;

R^B is H or (C₁-C₆)alkyl;

Het-H is a heteroaryl ring selected from:

R^H is selected in each instance from hydrogen and (C₁-C₆)alkyl:

X¹, X², X³, and X⁴ are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C₁-C₆)alkyl optionally substituted with -OH, (C₁-C₆)haloalkyl, (C₁- C₆)haloalkoxy, (C₁-C₆)haloalkylthio, -NR¹R², -OR¹, -C(O)R¹, -OC(O)R¹, -C(O)NR¹R², - C(O)OR¹, -SR¹, -SO₂R¹, and -SO₂NR¹R²;

R¹ and R² are independently selected in each instance from hydrogen and (C₁- C₆)alkyl;

R³-R⁴ is selected from

m is zero, 1 or 2; n is 1 or 2; wherein m + n equals 1, 2 or 3; and wherein when m is zero and n is 1, R³-R⁴ is either

V is selected from phenyl, a six-membered heteroaromatic ring, furan, and thiophene; Z¹ and Z² are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, (C₁- C₆)haloalkylthio, -NR¹R², -NR¹C(O)R², -NR¹C(O)OR⁶, -OR¹, -C(O)R¹, -OC(O)R¹, - C(O)NR¹R², -C(O)OR¹, -SR¹, -SO₂R¹, and -SO₂NR¹R²; and R⁶ is (C₁-C₈)hydrocarbon.

2. A substantially pure single enantiomer according to claim 1 of formula Ila or lib:

3. A compound according to claim 1 or claim 2, wherein at least one of W1 and W2 is benzene.

4. A compound according to claim 3, wherein both of W1 and W2 are benzene.

5. A compound according to claim 1 or claim 2, wherein one of W1 and W2 is benzene and the other of W1 and W2 is selected from pyridine and pyrimidine.

6. A compound according to any one of claims 1-5, wherein B is a direct bond.

7. A compound according to any one of claims 1-5, wherein B is -O-.

8. A compound according to any one of claims 1-5, wherein B is -(CH₂)₂-.

9. A compound according to any one of claims 1-8, wherein m is 1 and n is 1.

10. A compound according to any one of claims 1-8, wherein m is 2 and n is 1.

11. A compound according to any one of claims 1-8, wherein m is 1 and n is 2.

12. A compound according to any one of claims 1-8, wherein m is zero and n is 1.

13. A compound according to any one of claims 1-12, wherein R³-R⁴ is

14. A compound according to any one of claims 1-11, wherein R³-R⁴ is

15. A compound according to any one of claims 1-11, wherein R³-R⁴ is

16. A compound according to any one of claims 1-11, wherein R³-R⁴ is

17. A compound according to any one of claims 1-16, wherein Het-H is

18. A compound according to any one of claims 1-16, wherein Het-H is

19. A compound according to any one of claims 1-18, wherein R is hydrogen or methyl.

20. A compound according to any one of claims 1-19, wherein R is hydrogen.

21. A compound according to any one of claims 1-20, wherein X² and X⁴ are each hydrogen, and X¹ and X³ are each chosen independently from hydrogen, halogen, nitro, cyano, (C₁-C₆)alkyl optionally substituted with -OH, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, (C₁-C₆)haloalkylthio, -NR³R², -OR¹, -C(O)R¹, -OC(O)R¹, -C(O)NR¹R², -C(O)OR¹, -SR¹, -SO₂R¹, and -SO₂NR¹R².

22. A compound according to claim 21, wherein X² and X⁴ are each hydrogen, and X¹ and X³ are each chosen independently from -H, -F, -Cl, -CF₃,-C(CH₃)₂OH, -C(O)NMe₂.

23. A compound according to claim 22, wherein all of X¹, X², X³ and X⁴ are each hydrogen.

24. A compound according to any one of claims 20-22, wherein at least one of X¹, X², X³ and X⁴ is located at a carbon two positions away from a bridgehead carbon.

25. A compound according to any one of claims 1-24, wherein V is phenyl.

26. A compound according to any one of claims 1-25, wherein Z¹ is H.

27. A compound according to any one of claims 1-26, wherein Z² is chosen from hydrogen, halogen, and (C₁-C₆)haloalkoxy.

28. A compound according to claim 27, wherein Z² is chosen from hydrogen, F, Cl, and OCF₃.

29. A compound according to any one of claims 1-28, wherein Z² is in the para position.

30. A compound according to claim 1 or 2, wherein: both W1 and W2 are benzene, or one of W1 and W2 is benzene and the other of W1 or W2 is pyridine or pyrimidine;

B is selected from a direct bond, -O-, and -CH₂CH₂-;

X² and X⁴ are each hydrogen, and X¹ and X³ are each chosen independently from -H, -F, -Cl, -CF₃,-C(CH₃)₂OH, -C(O)NMe₂;

R¹ and R² are independently selected in each instance from the group consisting of hydrogen and (C₁-C₆)alkyl;

V is phenyl;

Z¹ is hydrogen; and

Z² is selected in each instance from hydrogen, halogen, and (C₁-C₆)haloalkoxy.

31. A compound according to claim 30, wherein Z² is in the para position.

32. A compound according to claim 30 or 31, wherein B is a direct bond.

33. A compound according to claim 30 or 31, wherein B is O.

34. A compound according to any one of claims 30-33, wherein both W1 and W2 are benzene.

35. A compound according to any one of claims 30-33, wherein one of W1 and W2 is benzene and the other of W1 or W2 is pyridine or pyrimidine.

36. A compound according to any one of claims 30-35, wherein Het-H is

37. A compound according to any one of claims 30-36, wherein m is 1 and n is 1.

38. A compound according to any one of claims 30-36, wherein m is 2 and n is 1.

39. A compound according to any one of claims 30-36, wherein m is 1 and n is 2.

40. A compound according to any one of claims 30-36, wherein m is 0 and n is 1.

41. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1-40.

42. A method for treating a disease in a patient chosen from: (a) cancer

(b) diabetes

(c) autoimmune disease

(d) age onset proteotoxic disease

(e) mood disorder

(f) acne vulgaris

(g) solid organ transplant rejection (graft vs. host disease)

(h) pulmonary disease

(i) cardiac hypertrophy and heart failure

(j) viral or parasitic infection and

(k) inflammatory conditions; the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-40.

43. The method according to claim 42, wherein said cancer is selected from the group consisting of: ovarian, pancreatic, renal cell, breast, prostate, lung, hepatocellular carcinoma, glioma, leukemia, lymphoma, colorectal cancers, and sarcomas.

44. The method according to claim 42 for treating cancer, wherein said cancer is chemotherapy resistant cancer.

45. The method of claim 44, wherein the method further comprises administering one or more additional cancer chemotherapeutic agents.

46. The method according to claim 42 for treating an age onset proteotoxic disease, wherein said disease is selected from the group consisting of: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.

47. The method according to claim 42 for treating a viral infection.

48. The method according to claim 47 wherein said viral infection is caused by a virus selected from the group consisting of influenza, HIV-1, HPV, adenovirus, BKV, EBV, JCV, HCV, MCV, polyomavirus, SV40, HTLV-1, HSV-1, CMV, hepatitis B, BPV-1, human T-cell lymphotropic virus type 1, Japanese encephalitis virus, RSV, and West Nile virus.

49. The method according to claim 42 for treating a parasitic infection.

50. The method according to claim 49, wherein said parasitic infection is caused by a parasite selected from the group consisting of Plasmodium and Theileria.

51. A method for restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer, the method comprising administering an effective amount of a compound according to any one of claims 1-40.

52. A method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-40.

53. A method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway, the method comprising administering to the patient a therapeutically effective amount of compound according to any one of claims 1-40.

53. A method for treating a metabolic disease or disorder in a patient wherein the disease or disorder involves the dysregulation of the mTOR-PP2A signaling axis, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-40.