CONSTRAINED N-SUBSTITUTED TETRAHYDROBENZOAZEPINE SULFONAMIDES AS ANTICANCER AND NEUROPROTECTIVE AGENTS

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority of US provisional application 62/964,174, 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 chemical modulators of PP2A, comprising cyclic constrained tetrabenzoazepines 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 FOXOl, FOX03a, FOX04 and FOX06 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] FOXOl 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 FOXOl is associated with 14-3-3 binding and cytosolic localization, whereas dephosphorylated FOXOl 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 FOXOl and dephosphorylates FOXOl. Inhibition of PP2A phosphatases rescues FOXOl -mediated cell death by regulating the level of the pro- apoptotic protein BIM. In addition, PP2A directly regulates FOX03a 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 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 heterocyclic constrained tricyclic arylsulfonamide derivatives has now been found that induce FOXOl 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:

W is selected from a benzene ring, a six-membered heteroaromatic ring, furan, and thiophene;

R ^a and R ^b are each selected from hydrogen; (Ci-C ₆ )alkyl; and phenyl optionally substituted with halogen, nitro, cyano, (Ci-C ₆ )alkyl, (Ci-C ₆ )haloalkyl, (Ci-C ₆ )haloalkoxy, (Ci-C ₆ )haloalkylthio, -NR ^X R ² , -OR ¹ , -C(0)R ¹ , -0C(0)R ¹ , -C(0)NR ¹ R ² , -C(0)0R ¹ , -SR ¹ , -SO2R ¹ , and -S0 NR ¹ R ² ; wherein at least one of R ^a and R ^b must be hydrogen;

X ¹ and X ² , are independently selected in each instance from hydrogen, halogen, nitro, cyano, (Ci-C ₆ )alkyl, (Ci-C ₆ )haloalkyl, (Ci-C ₆ )haloalkoxy, (Ci-C ₆ )haloalkylthio, -NR ^X R ² , - OR ¹ , -C(0)R ¹ , -0C(0)R ¹ , -C(0)NR ¹ R ² , -C(0)0R ¹ , -SR ¹ , -SO2R ¹ , and -S0 ₂ NR ¹ R ² ;

R ¹ and R ² are independently selected in each instance from hydrogen and (Ci- C ₆ )alkyl;

Q is selected from -(CH2) _n , -0-, -S(0) _n -, and -NR ^Q -; n is zero, 1 or 2;

R ^Q is selected from hydrogen, optionally substituted (Ci-C ₆ )alkyl, (C3-C7)cycloalkyl, aryl, or heteroaiyl; -SO2R ³ ; -S0 ₂ N(R ³ R ⁴ ); -C(=0)R ⁵ ; -C(=0)0R ⁵ ; or -C(=0)N(R ³ R ⁴ ); wherein said substituents on the (Ci-C ₆ )alkyl, (C3-C7)cycloalkyl, aryl, or heteroaryl are selected from hydroxy, halogen, cyano, nitro, amino, (Ci-C4)alkylamino, (Ci- C4)dialkylamino, (Ci-C4)acylamino, (Ci-C4)alkylsulfonyl, (Ci-C4)alkylthio, (Ci-C4)alkyl, (C3-C7)cycloalkyl, (Ci-C4)haloalkyl, (Ci-C4)haloalkoxy, and (Ci-C4)alkoxy;

R ³ and R ⁴ are independently selected in each instance from hydrogen, (Ci-C ₆ )alkyl, aryl, and arylalkyl, wherein said aryl or the aryl of the arylalkyl is optionally substituted with hydroxy, halogen, cyano, nitro, amino, (Ci-C4)alkylamino, (Ci-C4)dialkylamino, (Ci- C4)acylamino, (Ci-C4)alkylsulfonyl, (Ci-C4)alkylthio, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (Ci- C4)haloalkoxy, or (Ci-C4)alkoxy;

R ⁵ is selected from hydrogen, optionally substituted (Ci-C4)alkyl, or optionally substituted aryl, wherein said optional substituents are selected from (Ci-C3)alkyl, OR ¹ , NH2, NHMe, N(Me)2, and heterocycle;

Y is selected from hydrogen, hydroxyl, fluoro, or -NH2;

V is selected from a benzene ring, a six-membered heteroaromatic ring, furan, and thiophene;

Z ¹ and Z ² are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (Ci-C ₆ )alkyl, (Ci-C ₆ )hydroxy alkyl, (Ci-C ₆ )haloalkyl, (Ci-C ₆ )haloalkoxy, - (Ci-C ₆ )haloalkylthio, -NR ^X R ² , -NR ¹ C(0)R ² , -NR ¹ C(0)0R ⁶ , -OR ¹ , -C(0)R ¹ , -0C(0)R ¹ , - C(0)NR ¹ R ² , -C(0)0R ¹ , -SR ¹ , -SO2R ¹ , and -S0 ₂ NR ¹ R ² ; and

R ⁶ is (Ci-C ₈ )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.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 shows the inhibition of growth of HI 650 lung cancer cells by a compound of the invention as compared with a comparison PP2A activating compound.

DETAILED DESCRIPTION OF THE INVENTION

[0021] Substituents are generally defined when introduced and retain that definition throughout the specification and in all independent claims.

[0022] In a composition aspect, the invention relates to compounds of formula I:

I as described above. [0023] In some embodiments, the invention relates to compounds of formula II:

II.

[0024] In some embodiments, the invention relates to compounds of formula Ila or lib:

Ila lib.

[0025] In the embodiments described below, the compound may be of formula I, II, Ila, or lib, unless otherwise indicated.

[0026] In some embodiments, W is a benzene ring. In other embodiments, W is a six- membered heteroaromatic ring. In still other embodiments, W is pyridine. In yet other embodiments, W is pyrimidine. In some embodiments, W is pyridazine. In some embodiments, W is furan. In other embodiments, W is thiophene.

[0027] In some embodiments, V is a benzene ring. In other embodiments, V is a six- membered heteroaromatic ring. In other embodiments, V is pyridine. In still other embodiments, V is pyrimidine. In some embodiments, W is pyridazine. In some embodiments, V is furan. In other embodiments, V is thiophene. [0028] In some embodiments, W and V are each independently selected from a benzene ring, pyridine, pyrimidine, pyridazine, thiophene, and furan. In some embodiments, one of W and V is a benzene ring, and the other of W and V is selected from a benzene ring, pyridine, pyrimidine, and thiophene. In still other embodiments, W and V are each independently selected from a benzene ring and pyridine. In some embodiments, at least one of W and V is a benzene ring. In other embodiments, W and V are both benzene rings.

[0029] In some embodiments, Y is hydrogen. In other embodiments, Y is hydroxyl. In still other embodiments, Y is fluoro. In yet other embodiments, Y is -NH ₂ .

[0030] In some embodiments, Q is -(Cfh , and n is selected from 0, 1, or 2. In some embodiments, Q is -(Cfh and is absent. In other embodiments, Q is -(CH ₂ )-. In still other embodiments, Q is -(CH ₂ ) ₂ -. In some embodiments, Q is -0-. In some embodiments, Q is -S(0) _n -, and n is selected from 0, 1, or 2. In other embodiments, Q is -S-. In other embodiments, Q is -S(O)-. In other embodiments, Q is -S(0)2-. In still other embodiments, Q is -NR ^q -.

[0031] In some embodiments, R ^Q is hydrogen. In other embodiments, R ^Q is optionally substituted (Ci-C ₆ )alkyl. In still other embodiments, R ^Q is optionally substituted (C ₃ - C ₇ )cycloalkyl. In yet other embodiments, R ^Q is optionally substituted aryl. In further embodiments, R ^Q is optionally substituted heteroaryl. In these instances, the optional substituents available for the (Ci-C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, aryl or heteroaryl may be one or more of hydroxy, halogen, cyano, nitro, amino, (Ci-C ₄ )alkylamino, (Ci-C ₄ )dialkylamino, (Ci-C ₄ )acylamino, (Ci-C ₄ )alkylsulfonyl, (Ci-C ₄ )alkylthio, (Ci-C ₄ )alkyl, (C ₃ -C ₇ )cycloalkyl, (Ci-C ₄ )haloalkyl, (Ci-C ₄ )haloalkoxy, and (Ci-C ₄ )alkoxy. In some embodiments, R ^Q is (Ci- C ₆ )alkyl optionally substituted with one or more of hydroxy, fluoro, or (C ₃ -C ₇ )cycloalkyl.

In still other embodiments, R ^Q is (Ci-C3)alkyl optionally substituted with one or more of hydroxy, methoxy, fluoro, or phenyl. In other embodiments, R ^Q is (Ci-C ₃ )alkyl optionally substituted with one or more of hydroxy or fluoro. In yet other embodiments, R ^Q is (C ₃ - C7)cycloalkyl optionally substituted with one or more of hydroxy, methyl, or fluoro. In still other embodiments, R ^Q is aryl optionally substituted with one or more of hydroxy, methoxy, halogen, (Ci-C ₃ )haloalkyl, nitro, amino, or methyl. In further embodiments, R ^Q is phenyl optionally substituted with one or more of hydroxy, chloro, fluoro, methoxy, nitro, amino, trifluoromethyl, or methyl. In yet other embodiments, R ^Q is heteroaryl optionally substituted with one or more of hydroxy, methoxy, halogen, (Ci-C ₃ )haloalkyl, nitro, amino, or methyl. In some embodiments, R ^Q is a nitrogen-containing heteroaryl optionally substituted with one or two methyl groups. In some embodiments, R ^Q is -SO2R ³ . In other embodiments, R ^Q is -SC>2NR ³ R ⁴ . In still other embodiments, R ^Q is -C(=0)R ⁵ . In some embodiments, R° is -C(=0)0R ⁵ . In yet other embodiments, R° is -C(=0)NR ³ R ⁴ .

[0032] In some embodiments, R ³ and R ⁴ are independently selected in each instance from hydrogen, (Ci-C ₆ )alkyl, aryl, and arylalkyl. In some embodiments, the aryl or the aryl of the arylalkyl may be optionally substituted with hydroxy, halogen, cyano, nitro, amino, (Ci- C4)alkylamino, (Ci-C4)dialkylamino, (Ci-C4)acylamino, (Ci-C4)alkylsulfonyl, (Ci- C4)alkylthio, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (Ci-C4)haloalkoxy, or (Ci-C4)alkoxy. In some embodiments, R ⁴ is selected from hydrogen and methyl. In other embodiments, R ³ is selected from hydrogen, (Ci-Ce)alkyl, (Ci-C ₆ )haloalkyl, aryl, and arylalkyl. In some of these embodiments, the aryl or the aryl of the arylalkyl is optionally substituted with one or more of hydroxy, halogen, cyano, nitro, amino, (Ci-C4)alkylamino, (Ci-C4)dialkylamino, (Ci-C4)acylamino, (Ci-C4)alkylsulfonyl, (Ci-C4)alkylthio, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (Ci-C4)haloalkoxy, and (Ci-C4)alkoxy.

[0033] In some embodiments, R ⁵ is selected from hydrogen, optionally substituted (Ci- C4)alkyl, or optionally substituted aryl. In some embodiments, the optional substituents are selected from (Ci-C3)alkyl, OR ¹ , NH2, NHMe, N(Me)2, and heterocycle. In other embodiments, R ⁵ is selected from optionally substituted (Ci-C4)alkyl or optionally substituted aryl, and the optional substituents are selected from one or more of OH, OMe, NH2, NHMe, N(Me)2, or heterocycle.

[0034] In some embodiments, R ^Q is -C(=0)R ⁵ and R ⁵ is selected from methyl, optionally substituted with OR ¹ , N¾, NHMe, N(Me)2, and heterocycle. In other embodiments, R ^Q is - C(=0)OR ⁵ and R ⁵ is selected from phenyl and (Ci-C4)alkyl, each of which may be substituted with OR ¹ ; in some of these embodiments, R ¹ is hydrogen, while in other of these embodiments, R ¹ is (Ci-C ₆ )alkyl. In still other embodiments, R ^Q is -SO2R ³ and R ³ is selected from hydrogen, (Ci-C ₆ )alkyl, and aryl. In some of these embodiments, the aryl may be substituted with hydroxy, halogen, cyano, amino, or (Ci-C4)alkoxy. In yet other embodiments, R ^Q is S0 ₂ NR ³ R ⁴ ; R ³ is selected from hydrogen, (Ci-C3)alkyl, and optionally substituted aryl; and R ⁴ is hydrogen or methyl. In further embodiments, R ^Q is - C(=0)NR ³ R ⁴ ; R ³ is selected from hydrogen, (Ci-C3)alkyl, and aryl optionally substituted with hydroxy, halogen, cyano, amino, or methoxy; and R ⁴ is hydrogen or methyl.

[0035] In some embodiments, R ^a and R ^b are each selected independently from hydrogen; (Ci-C ₆ )alkyl; and phenyl optionally substituted with halogen, nitro, cyano, (Ci-C ₆ )alkyl, (Ci-C ₆ )haloalkyl, (Ci-C ₆ )haloalkoxy, (Ci-C ₆ )haloalkylthio, -NR ^X R ² , -OR ¹ , -C(0)R ¹ , - 0C(0)R ¹ , -C(0)NR ¹ R ² , -C(0)0R ¹ , -SR ¹ , -SO2R ¹ , and -S0 ₂ NR ¹ R ² . At least one of R ^a and R ^b must be hydrogen. In still other embodiments, both of R ^a and R ^b are hydrogen.

[0036] In some embodiments, X ¹ and X ² are independently selected in each instance from hydrogen, halogen, nitro, cyano, (Ci-C ₆ )alkyl, (Ci-C ₆ )haloalkyl, (Ci-C ₆ )haloalkoxy, (Ci- C ₆ )haloalkylthio, -NR ^X R ² , -OR ¹ , -C(0)R ¹ , -OC(0)R ¹ , -C(0)NR ¹ R ² , -C(0)OR ¹ , -SR ¹ , - SO2R ¹ , and -S02NR ¹ R ² . In other embodiments, at least one of X ¹ and X ² is hydrogen. In still other embodiments, both of X ¹ and X ² are hydrogen.

[0037] In some embodiments, R ¹ is hydrogen. In other embodiments, R ¹ is (Ci-C ₆ )alkyl. In some embodiments, R ² is hydrogen. In other embodiments, R ² is (Ci-C ₆ )alkyl.

[0038] In some embodiments, zero, one or two of X ¹ , X ² , R ^a , and R ^b are independently selected in each instance from halogen, cyano, (C i-CV,)alkyl. and halo(Ci-C ₆ )alkyl, and the remainder are hydrogen. In other embodiments, one or two of X ¹ , X ² , R ^a , and R ^b are independently selected in each instance from F, Cl, cyano, and CF ₃ , and the remainder are hydrogen. In still other embodiments, at least three of X ¹ , X ² , R ^a , and R ^b are hydrogen. In yet other embodiments, all of X ¹ , X ² , R ^a , and R ^b are hydrogen.

[0039] In some embodiments, Z ¹ is selected from hydrogen, halogen, nitro, cyano, azide, (Ci-Ce)alkyl, (Ci-C ₆ )hydroxyalkyl, (Ci-C ₆ )haloalkyl, (Ci-Ce)haloalkoxy, -(Ci- C ₆ )haloalkylthio, -NR ^X R ² , -NR ¹ C(0)R ² , -NR ¹ C(0)OR ⁶ , -OR ¹ , -C(0)R ¹ , -OC(0)R ¹ , - C(0)NR ¹ R ² , -C(0)OR ¹ , -SR ¹ , -SO2R ¹ , and -S0 ₂ NR ¹ R ² . In some embodiments, Z ² is selected from hydrogen, halogen, nitro, cyano, azide, (C i-C7,)alkyl. (Ci-C ₆ )hydroxyalkyl, (Ci-C ₆ )haloalkyl, (Ci-C ₆ )haloalkoxy, -(Ci-C ₆ )haloalkylthio, -NR'R ² . -NR ¹ C(0)R ² , - NR ¹ C(0)OR ⁶ , -OR ¹ , -C(0)R ¹ , -OC(0)R ¹ , -C(0)NR ¹ R ² , -C(0)OR ¹ , -SR ¹ , -SO2R ¹ , and - S0 ₂ NR ¹ R ² . In other embodiments, Z ¹ and Z ² are independently selected in each instance from hydrogen, halogen, (Ci-C ₆ )haloalkyl, -NR ¹ C(0)OR ⁶ , (Ci-C ₆ )alkoxy, and (Ci- C ₆ )haloalkoxy. In still other embodiments, Z ¹ and Z ² are independently selected in each instance from hydrogen, fluoro, chloro, trifluoromethyl, -NHBoc, methoxy, and trifluoromethoxy. In some embodiments, Z ¹ is hydrogen and Z ² is selected from hydrogen, halogen, (Ci-C ₆ )haloalkyl, (Ci-C ₆ )alkoxy, (Ci-C ₆ )haloalkoxy, and NHBoc. In some embodiments, Z ¹ is hydrogen and Z ² is hydrogen, fluoro, chloro, trifluoromethyl, methoxy, trifluoromethoxy, or NHBoc. In still other embodiments, Z ¹ is hydrogen and Z ² is trifluoromethoxy. In some of these embodiments, Z ² is para to the attachment of ring V to the sulfonyl. [0040] In some embodiments, R ⁶ is (Ci-C8)hydrocarbon. In other embodiments, R ⁶ is (Ci- C ₆ )alkyl. In some embodiments, R ⁶ is t-butyl. In still other embodiments, R ⁶ is allyl. In yet other embodiments, R ⁶ is benzyl.

[0041] The person of skill will understand that, in some instances, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ may not be hydrogen. For instance, when Q is -NR ^Q -, R ^Q is -SO2R ³ , and R ³ is hydrogen, the resulting moiety will be unstable. The circumstances under which a hydrogen atom would be inappropriate will be clear to the person of skill in the art.

[0042] In some embodiments, W is a benzene ring; V is a benzene ring; Q is -(CH2) _n -; and at least three of X ¹ , X ² , R ^a , and R ^b are hydrogen, as shown below:

In some of these embodiments, X ¹ , X ² , R ^a , and R ^b are all hydrogen. In some of these embodiments, Y is -OH. In other embodiments, Y is hydrogen. In some of these embodiments, Z ¹ is hydrogen, and Z ² is hydrogen, fluoro, chloro, trifluoromethyl, -NHBoc, methoxy, or trifluoromethoxy. In some of these embodiments, Z ² is in the para position.

[0043] In some embodiments of the foregoing subgenera, the relative configurations are such that the amine and the tricycle are both trans to the substituent Y, as shown above in, for instance, formula II. In this trans: trans subgroup, compounds can be either single enantiomers, like in formulae Ila and 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.

[0044] The compounds described herein contain three or more 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 olefmic 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.

[0045] 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 representation indicates either, or both, of the two trans:trans enantiomers: in any ratio, from pure enantiomers to racemates. The graphic representation: indicates a single enantiomer of unknown absolute stereochemistry, i.e., it could be either of the two preceding structures, as a substantially pure single enantiomer. And, finally, the representation: indicates a pure (li?,2i?,65 -2-amino-6-(C-attached tricycle)heterocyclyl-4-ol. 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. Similarly, a “pure” or “substantially pure” diastereomer is intended to mean that the diastereomer is at least 95% of the relative configuration shown and 5% or less of other diastereomers. In the text describing the stereochemistry of the examples, the convention of Chemical Abstracts is used. Thus “(li?,2i?,6S)-re/-“ indicates that the three chiral centers are in that relative relationship, which would be depicted in a structural diagram by solid bold and dashed lines, whereas ( 1 R.IR. S) without the “re/” indicates a single enantiomer of that absolute configuration, which would be depicted in a structural diagram by solid and broken wedges.

[0046] 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. [0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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 ² H, ³ H,

¹³ C, ¹⁴ C, ¹⁵ N, ³⁵ S, ¹⁸ F, and ³⁶ C1, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. ³ H, and carbon-14, i.e., ¹⁴ C, radioisotopes are particularly preferred for their ease in preparation and detectability. Compounds that contain isotopes ⁿ C, ¹³ N, ¹⁵ 0 and ¹⁸ F 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue.

[0059] 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.

[0060] 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.

[0061] 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 FOXOl and FOX03. Thus activation of FOXO proteins in naive T- cells promotes and directs differentiation to maintain a population of Treg cells. [0062] 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.

[0063] 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)].

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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 fingolimod (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 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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 [0078] 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.

[0079] 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 dibenzybdeneacetone

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 [0080] Throughout this specification the terms and substituents retain their definitions.

[0081] 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’.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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. [0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] “Hydrocarbon” (e.g., (Ci-C ₈ )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.

[0094] 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.

[0095] 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.

[0096] 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 attached 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. [0097] The term "halogen" means fluorine, chlorine, bromine or iodine atoms. In one embodiment, halogen may be a fluorine or chlorine atom.

[0098] The terms "haloalkyl," "haloalkoxy," or “haloalkylthio” mean alkyl, alkoxy, or alkylthio, respectively, substituted with one or more halogen atoms.

[0099] 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.

[00100] 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. Example

[00101] 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.

[00102] Compounds of formula I can be synthesized using the methods described in STEREOSPECIFIC PROCESS FOR HETEROCYCLYLCYCLOALIPHATIC-l,2-DIOLS, International Patent Publication No. WO 2017/024229, HETEROCYCLIC CONSTRAINED TRICYCLIC SULFONAMIDES AS ANTI-CANCER AGENTS, International Patent Publication No. WO 2017/044569, and International Patent Publication No. WO 2015/138500, SULFONAMIDES DERIVED FROM TRICYCLYL-2- AMINOCYCLOALKANOLS AS ANTI-CANCER AGENTS, all of which are incorporated herein by reference.

The genus is exemplified by Example 1. SCHEME 1 shows a synthesis for Example 1, and the corresponding experimental procedure follows. The person of skill will understand that other options for various substituents can be expanded upon by this synthesis. For instance, ring V and its substituents (Z ¹ and Z ² ), shown below as 4-trifluoromethoxy phenyl, could be interchanged with other options by replacing the 4-trifluoromethoxybenzenesulfonyl chloride with another corresponding reactant.

[00103] Experimental Procedure

[00104] INTERMEDIATE 1: l-(cyclohex-2-en-l-yl)-2,3,4,5-tetrahydro-lH- benzo[b]azepine. A solution of 2,3,4, 5-tetrahydro-lH-benzo[b]azepine (1.50 g, 10.2 mmol) in CH2CI2 (10.0 mL) was treated with triethylamine (4.23 mL, 30.6 mmol), and 3- bromocyclohexene (0.58 mL, 12.0 mmol). The mixture was warmed to 60 °C, stirred for 14 h, then poured over a solution of saturated aqueous ammonium chloride (100 mL). The organic layer was separated and the aqueous layer was extracted with CH2CI2 (3 x 100 mL). The organic layers were combined, washed with saturated aqueous NaCl (3 x 100 mL), dried (Na2S04), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH2CI2 and purified by flash chromatography (S1O2, 0-5% ethyl acetate- hexanes) to afford the title compound as a clear oil (1.28 g, 55%). 'H NMR (600 MHz, CDCh) d 7.11-7.14 (2H, m), 7.00 (1H, d, J= 8.4 Hz), 6.83 (1H, d, J= 7.2 Hz), 5.91-5.93 (1H, m), 5.84-5.86 (1H, m), 4.13 (1H, br s), 3.13 (1H, br s), 2.77-2.81 (3H, m), 2.07-2.11 (2H, m), 2.00-2.02 (1H, m), 1.84-1.90 (1H, m), 1.60-1.74 (5H, m), 1.43-1.54 (1H, m); ¹³ C NMR (150 MHz, CDCh) d 153.3, 135.6, 131.0, 130.9, 130.8, 126.7, 120.3, 118.0, 58.6, 48.7, 36.3, 31.8, 29.1, 26.3, 25.4, 22.4; LCMS m/z 228.2 ([M + H ⁺ ], C _I6 H _I N requires 228.2).

[00105] INTERMEDIATE 2: (lR,2S,3R)-3-(2,3,4,5-tetrahydro-lH- benzo[b]azepin-l-yl)cyclohexane-l,2-diol. A solution of l-(cy clohex-2-en-l-yl)-2, 3,4,5- tetrahydro-lH-benzo[b]azepine (1.28 g, 5.63 mmol) in t-BuOH-H ₂ 05:1 (6.0 mL) at 25 °C was treated with OsCL (2.5 wt.% solution in t-BuOH, 0.71 mL, 0.0563 mmol) and N- methyl morpholine N-oxide (0.726 g, 6.19 mmol). The mixture was stirred for 14 h at 25 °C, treated with a saturated aqueous solution of sodium hydrosulfite (5 mL) and stirred for an additional 1 h. The mixture was concentrated in vacuo and the residue was taken up in a minimal amount of CH2CI2 and purified by flash chromatography (S1O2, 0-50% ethyl acetate-hexanes) to afford the title compound as a white solid (0.890 g, 60%). 'H NMR (600 MHz, CDCh) d 7.15-7.18 (2H, m), 7.04 (1H, dd, J= 7.8), 6.93 (1H, t, J = 7.2 Hz), 4.26 (1H, s), 3.63 (1H, d, J= 10.2, 2.4 Hz), 3.56 (1H, s), 3.50 (1H, dd, J= 9.6, 1.8 Hz),

3.41 (1H, br d, J= 13.8 Hz), 2.84 (1H, dd, J= 13.8, 5.4 Hz), 2.73 (1H, t, J= 12.6 Hz), 2.54 (1H, s), 2.51 (1H, t, J= 12.6 Hz), 2.14 (1H, br d, J= 13.2 Hz), 2.01 (1H, d, J= 13.8 Hz), 1.91-1.98 (2H, m), 1.84-1.90 (2H, m), 1.61-1.64 (1H, m), 1.57 (1H, qd, J= 12.6, 3.0 Hz), 1.48 (1H, t, J= 13.8 Hz), 1.33 (1H, q, J= 12.0 Hz); ¹³ C NMR (150 MHz, CDCh) d 153.1, 136.6, 130.8, 127.2, 122.2, 119.2, 72.5, 68.7, 61.5, 47.4, 36.6, 31.8, 30.0, 26.5, 26.3, 19.5; LCMS m/z 262.1808 ([M + H ⁺ ], C19H23NO2 requires 262.1802).

[00106] INTERMEDIATE 31 : (3aS,4R,7aR)-4-(2,3,4,5-tetrahydro- 1H- benzo[b]azepin-l-yl)hexahydrobenzo[d][l,3,2]dioxathiole 2-oxide. A solution of (lR,2S,3R)-3-(2,3,4,5-tetrahydro-lH-benzo[b]azepin-l-yl)cycl ohexane-l,2-diol (0.880 g, 3.36 mmol) in CH2CI2 (10.0 mL) at 0 °C was treated dropwise with triethylamine (3.73 mL, 26.9 mmol), and SOCI2 (0.73 mL, 10.1 mmol). The mixture was warmed to 25 °C, stirred for 2 h, poured over a solution of saturated aqueous sodium chloride (100 mL), and then extracted CH2CI2 (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL), saturated aqueous sodium chloride (100 mL), dried (Na ₂ SC> ₄ ), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH2CI2 and purified by flash chromatography (S1O2, 0-35% ethyl acetate-hexanes to afford the title compound as an orange solid (0.313 g, 30%). ¾ NMR (600 MHz, CDCh) d (as a mixture of sulfite diastereomers) 7.08-7.13 (2H, m), 6.86-6.91 (2H, m), 1H[5.19 (s), 4.51 (br s)], 1H[4.73- 4.76 (m), 4.08-4.16 (m)], 3.24-3.33 (2H, m), 2.83-2.89 (1H, m), 2.76-2.80 (2H, m), 2.37 (1H, br d, J= 15.6 Hz), 2.06 (1H, br d, J= 13.2 Hz), 1.84-1.95 (2H, m), 1.72-1.80 (2H, m), 1.64-1.71 (1H, m), 1.50-1.60 (2H, m), 1.41-1.49 (1H, m); LCMS m/z 308.1320 ([M + H ⁺ ], C16H21NO3S requires 308.1315).

[00107] INTERMEDIATE 4: (lS,2S,6R)-2-azido-6-(2,3,4,5-tetrahydro-lH- benzo[b]azepin-l-yl)cyclohexanol. A solution of (3aS,4R,7aR)-4-(2,3,4,5-tetrahydro-lH- benzo[b]azepin-l-yl)hexahydrobenzo[d][l,3,2]dioxathiole 2-oxide (0.313 g, 1.02 mmol) in DMF (2.0 ml) was treated with sodium azide (0.199 g, 3.06 mmol), and heated to 110 °C under microwave irradiation for 14 h. The mixture was diluted with CH2CI2 (100 mL) and this organic layer was washed with saturated aqueous NaCl (3 x 50 mL), dried (Na2SC>4), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH2CI2 and purified by flash chromatography (S1O2, 0-10% ethyl acetate-hexanes) to afford the title compound as a beige oil (0.160 g, 55%). ¾NMR (600 MHz, CDCh) d 7.13-7.18 (2H, m), 6.97 (1H, d, J= 7.8 Hz), 6.93 (1H, t, J= 7.2 Hz), 3.61 (1H, s), 3.44 (1H, t, J= 9.6 Hz), 3.33-3.49 (2H, m), 3.20 (1H, td, J= 12.0, 3.0 Hz), 2.83 (1H, dd, J= 13.8, 5.4 Hz), 2.73 (1H, t, J= 12.6 Hz), 2.55 (1H, t, J= 12.6 Hz), 2.14 (1H, br d, J= 13.2 Hz), 2.02 (1H, br d, J= 12.0 Hz), 1.91-1.94 (1H, m), 1.85-1.90 (2H, m), 1.57-1.67 (3H, m), 1.50 (1H, d, J = 13.2 Hz), 1.33-1.40 (2H, m); ¹³ C NMR (150 MHz, CDCh) d 152.7, 136.8, 130.9, 127.1, 122.5, 119.1, 74.8, 66.4, 65.5, 47.5, 36.4, 31.7, 30.2, 26.3, 26.1, 22.4; LCMS m/z 287.1877 ([M + H ⁺ ], C16H22N4O requires 287.1866).

[00108] INTERMEDIATE 5: (lR,2S,6R)-2-amino-6-(2,3,4,5-tetrahydro-lH- benzo[b]azepin-l-yl)cyclohexanol. A solution of (lS,2S,6R)-2-azido-6-(2,3,4,5- tetrahydro-lH-benzo[b]azepin-l-yl)cyclohexanol (0.140 g, 0.489 mmol) in THF (3.0 mL) was cooled to 0 °C, treated with PPh3 (0.167 g, 0.635 mmol), H2O (0.25 mL), and stirred for 14 h at 25 °C. The solution was concentrated to dryness, dissolved in a minimal amount of CH2CI2 and purified by flash chromatography (S1O2, 0-50% ethyl acetate-hexanes to remove nonpolar impurities followed by 3% MeOH-CH2Cb to remove triphenylphosphine oxide and 17:2:1 CH ₂ Cl ₂ :Me0H:NH ₄ 0H to elute the product). The combined fractions of pure product were concentrated, dried azeotropically with toluene to afford the title compound as a beige film (0.120 g, 94%). ¾ NMR (600 MHz, CDCb) d (as a mixture of retainers) 7.12-7.15 (2H, m), 6.99 (1H, d, J= 7.8 Hz), 6.90 (1H, t, J= 7.2 Hz), 1H[3.53- 3.58 (m), 3.34-3.41 (m)], 2H[3.63-3.66 (m), 3.13-3.21 (m)], 2.97 (3H, br s), 2.82 (1H, dd, J = 13.2, 5.4 Hz), 2.66-2.76 (2H, m), 2.53 (1H, t, J= 12.0 Hz), 2.11 (1H, br d, J= 13.2 Hz), 1.86-1.94 (2H, m), 1.79-1.86 (2H, m), 1.56-1.64 (2H, m), 1.44-1.52 (1H, m), 1.33 (1H, br q, J= 12.0 Hz), 1.24 (1H, br d, J= 13.2, 4.2 Hz); ¹³ C NMR (150 MHz, CDCb) d 153.0, 136.5, 130.7, 127.0, 122.0, 119.1, 76.6, 66.3, 62.5, 56.0, 47.3, 36.4, 33.0, 31.7, 26.3, 22.8; LCMS m/z 261.1985 ([M + H ⁺ ], Ci ₆ H ₂₄ N ₂ 0 requires 261.1961).

[00109] EXAMPLE 1: N-((lS,2S,3R)-2-hydroxy-3-(2,3,4,5-tetrahydro-lH- benzo[b]azepin-l-yl)cyclohexyl)-4-(trifluoromethoxy)benzenes ulfonamide. A solution of (lR,2S,6R)-2-amino-6-(2,3,4,5-tetrahydro-lH-benzo[b]azepin-l -yl)cyclohexanol (0.060 g, 0.230 mmol) in CH2CI2 (1.0 mL) was cooled to 0 °C, treated with Et3N (32.0 pL, 0.230 mmol), and 4-trifluoromethoxybenzenesulfonyl chloride (40.0 pL. 0.230 mmol). The mixture was warmed to 25 °C, and stirred for 2 h. The mixture was partitioned between saturated aqueous NaCl (50 mL) and CH2CI2 (100 mL). The organic layer was washed with saturated aqueous NaCl (3 x 50 mL), dried (Na ₂ SC>4), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH2CI2 and purified by flash chromatography (Si0 ₂ , 0-35% ethyl acetate-hexanes). The pure fractions were combined, concentrated, and the residue was dissolved in a minimal amount of ethyl acetate and precipitated with the addition of hexanes to afford the title compound as a white solid (0.078 g, 70%). mp. 163-164 °C (white powder, ethyl acetate-hexanes); 'HNMR (600 MHz, CDCh) d 7.96 (2H, d, J= 8.4 Hz), 7.30 (2H, d, J= 8.4 Hz), 7.13 (2H, t, J= 7.8 Hz), 6.92 (2H, t, J= 6.6 Hz), 5.14 (1H, s), 3.44 (1H, s), 3.32 (1H, d, J= 7.8 Hz), 3.26 (1H, t, J = 7.8 Hz), 3.10 (1H, t, J= 9.0 Hz), 2.94-2.99 (1H, m), 2.81 (1H, dd, J= 13.8, 5.4 Hz), 2.66 (1H, t, J= 13.2 Hz), 2.50 (1H, t, J= 12.6 Hz), 2.29 (1H, br d, J= 12.6 Hz), 2.11 (1H, t , J = 13.2 Hz), 1.89-1.97 (1H, m), 1.80-1.89 (2H, m), 1.49-1.63 (2H, m), 1.33-1.47 (2H, m); ¹³ C NMR (150 MHz, CDCh) d 152.6, 152.2, 138.7, 136.8, 130.9, 129.6, 127.2, 122.6, 121.3, 120.9, 119.1, 73.0, 66.3, 58.9, 47.4, 36.4, 32.0, 31.8, 26.23, 26.1622.3; LCMS m/z 485.1713 ([M + H ⁺ ], C23H27F3N2O4S requires 485.1716).

Cell viability assays (IC50 determination)

[00110] The genus is exemplified by Example 1, shown in Figure 1, which inhibits the growth of H1650 lung cancer cells with GI50 of approximately 15 micromolar; a well- characterized comparator PP2A activating compound, Comparison, is shown for reference: Comparison.

[00111] Cell viability assays were performed according to Denizot, F. and R. Lang, Journal of Immunological Methods, 1986. 89(22): p. 271 - 277. H1650 lung cancer cells were plated at 150,000 cells per well in a 12 well plate. Twenty-four hours after plating, cells were treated as described with increasing concentrations of drug and control. Forty- eight hours after drug treatment, cells were treated with 100 pL of 3-(4,5-Dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide (MTT) and incubated for 2 hours at 37 C. The MTT solution was subsequently replaced with 300 pL of n-propyl alcohol and re-aliquoted to a 96 well plate. Spectrophotometric analysis of each solution was performed using a 96 well plate reader at 600 nm in triplicate. Results are shown in Table 1 :

[00112] Tablel. Cell Viability Data Colony Formation Assay

[00113] Protocol for clonogenic assay follows Sangodkar et al., J Clin Invest 2012;122:2637-51.

[00114] 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 are 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 (HI 650) 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 HI 650 cells may be analyzed separately.

In vivo cancer model

[00115] To assess the in vivo effects of the compounds, subcutaneous xenograft of lung cancer cell line H441 are generated. Cells (5 ^c 10 ⁶ ) 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 100mm ³ 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.

[00116] Various embodiments of the invention can be described in the text below:

[1] A compound of formula I: wherein

W is selected from a benzene ring, a six-membered heteroaromatic ring, furan, and thiophene;

R ^a and R ^b are each selected from hydrogen; (Ci-C ₆ )alkyl; and phenyl optionally substituted with halogen, nitro, cyano, (Ci-C ₆ )alkyl, (Ci-C ₆ )haloalkyl, (Ci-C ₆ )haloalkoxy, (Ci-C ₆ )haloalkylthio, -NR ^X R ² , -OR ¹ , -C(0)R ¹ , -OC(0)R ¹ , -C(0)NR ¹ R ² , -C(0)OR ¹ , -SR ¹ , -SO2R ¹ , and -S0 NR ¹ R ² ; wherein at least one of R ^a and R ^b must be hydrogen;

X ¹ and X ² , are independently selected in each instance from hydrogen, halogen, nitro, cyano, (Ci-C ₆ )alkyl, (Ci-C ₆ )haloalkyl, (Ci-C ₆ )haloalkoxy, (Ci-C ₆ )haloalkylthio, -NR ^X R ² , - OR ¹ , -C(0)R ¹ , -OC(0)R ¹ , -C(0)NR ¹ R ² , -C(0)OR ¹ , -SR ¹ , -SO2R ¹ , and -S0 ₂ NR ¹ R ² ;

R ¹ and R ² are independently selected in each instance from hydrogen and (Ci- C ₆ )alkyl;

Q is selected from -(CH2) _n , -0-, -S(0) _n -, and -NR ^Q -; n is zero, 1 or 2; R ^Q is selected from hydrogen, optionally substituted (C i-C7,)alkyl. (C3-C?)cycloalkyl, aryl, or heteroaryl; -S0 ₂ R ³ ; -S0 ₂ N(R ³ R ⁴ ); -C(=0)R ⁵ ; -C(=0)0R ⁵ ; or -C(=0)N(R ³ R ⁴ ); wherein said substituents on the (Ci-C ₆ )alkyl, (C3-C ₆ )cycloalkyl, aryl, or heteroaryl are selected from hydroxy, halogen, cyano, nitro, amino, (Ci-C4)alkylamino, (Ci- C4)di alkyl amino, (Ci-C4)acylamino, (Ci-C4)alkylsulfonyl, (Ci-C4)alkylthio, (Ci-C4)alkyl, (C3-C7)cycloalkyl, (Ci-C4)haloalkyl, (Ci-C4)haloalkoxy, and (Ci-C4)alkoxy;

R ³ and R ⁴ are independently selected in each instance from hydrogen, (Ci-C ₆ )alkyl, aryl, and arylalkyl, wherein said aryl or the aryl of the arylalkyl is optionally substituted with hydroxy, halogen, cyano, nitro, amino, (Ci-C4)alkylamino, (Ci-C4)dialkylamino, (Ci- C4)acylamino, (Ci-C4)alkylsulfonyl, (Ci-C4)alkylthio, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (Ci- C4)haloalkoxy, or (Ci-C4)alkoxy;

R ⁵ is selected from hydrogen, optionally substituted (Ci-C4)alkyl, or optionally substituted aryl, wherein said optional substituents are selected from (Ci-C3)alkyl, OR ¹ , NH ₂ , NHMe, N(Me) ₂ , and heterocycle;

Y is selected from hydrogen, hydroxyl, fluoro, or -NH ₂ ;

V is selected from a benzene ring, a six-membered heteroaromatic ring, furan, and thiophene;

Z ¹ and Z ² are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (Ci-C ₆ )alkyl, (Ci-C ₆ )hydroxyalkyl, (Ci-C ₆ )haloalkyl, (Ci-C ₆ )haloalkoxy, - (Ci-C ₆ )haloalkylthio, C(0)NR ¹ R ² , -C(0)0

R ⁶ is (Ci-C ₈ )hydrocarbon.

[2] A compound of [1] above, or according to other embodiments of the invention, wherein W is a benzene ring.

[3] A compound of [1] above, or according to other embodiments of the invention, wherein W is a six-membered heteroaromatic ring, particularly pyridine, pyrimidine, or pyridazine.

[4] A compound of [1] above, or according to other embodiments of the invention, wherein W is furan.

[5] A compound of [1] above, or according to other embodiments of the invention, wherein W is thiophene. [6] A compound of any of [1] to [5] above, or according to other embodiments of the invention, wherein V is a benzene ring.

[7] A compound of any of [1] to [5] above, or according to other embodiments of the invention, wherein V is a six-membered heteroaromatic ring, particularly pyridine, pyrimidine, or pyridazine.

[8] A compound of any of [1] to [5] above, or according to other embodiments of the invention, wherein V is furan.

[9] A compound of any of [1] to [5] above, or according to other embodiments of the invention, wherein V is thiophene.

[10] A compound of [1], [2], [3], [4], [5], [6], [7], [8], or [9] above, or according to other embodiments of the invention, wherein Y is hydroxyl.

[11] A compound of [1], [2], [3], [4], [5], [6], [7], [8], or [9] above, or according to other embodiments of the invention, wherein Y is hydrogen.

[12] A compound of [1], [2], [3], [4], [5], [6], [7], [8], or [9] above, or according to other embodiments of the invention, wherein Y is fluoro.

[13] A compound of [1], [2], [3], [4], [5], [6], [7], [8], or [9] above, or according to other embodiments of the invention, wherein Y is -NH2.

[14] A compound of any of [1] to [13] above, or according to other embodiments of the invention, wherein Q is -(CH2) _n - and n is 0 (i.e., Q is absent).

[15] A compound of any of [1] to [13] above, or according to other embodiments of the invention, wherein Q is-(CH2) _n - and n is 1 (i.e., Q is -(CH2)-).

[16] A compound of any of [1] to [13] above, or according to other embodiments of the invention, wherein Q is-(CH2) _n - and n is 2 (i.e., Q is -(CH2)2).

[17] A compound of any of [1] to [13] above, or according to other embodiments of the invention, wherein Q is -S(0) _n - and n is 0 (i.e., Q is -S-).

[18] A compound of any of [1] to [13] above, or according to other embodiments of the invention, wherein Q is -S(0) _n - and n is 1 (i.e., Q is -S(O)-). [19] A compound of any of [1] to [13] above, or according to other embodiments of the invention, wherein Q is -S(0) _n - and n is 2 (i.e., Q is -S(0)2-)·

[20] A compound of any of [1] to [13] above, or according to other embodiments of the invention, wherein Q is -0-.

[21] A compound of any of [1] to [13] above, or according to other embodiments of the invention, wherein Q is -NR ⁰ -.

[22] A compound of [21] above, or according to other embodiments of the invention, wherein R ^Q is selected from hydrogen; (Ci-C ₆ )alkyl optionally substituted with one or more of OR ¹ , (C3-C7)cycloalkyl, fluoro or phenyl; (C3-C ₆ )cycloalkyl optionally substituted with one or more of hydroxy, methyl, or fluoro; aryl optionally substituted with one or more of hydroxy, methoxy, halogen, nitro, amino, or methyl; heteroaryl optionally substituted with one or more of hydroxy, methoxy, halogen, nitro, amino, or methyl; -SO2R ³ ; -SC>2NR ³ R ⁴ ; - C(=0)R ⁵ ; -C(=0)0R ⁵ ; or -C(=0)NR ³ R ⁴ ;

R ³ is selected in each instance from hydrogen, (Ci-C ₆ )alkyl, (Ci-C ₆ )haloalkyl, aryl, and arylalkyl, wherein said aryl or the aryl of the arylalkyl is optionally substituted with one or more of hydroxy, halogen, cyano, nitro, amino, (Ci-C4)alkylamino, (Ci-C4)dialkylamino, (Ci-C4)acylamino, (Ci-C4)alkylsulfonyl, (Ci-C4)alkylthio, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (Ci-C4)haloalkoxy, and (Ci-C4)alkoxy;

R ⁴ is selected in each instance from hydrogen and methyl; and R ⁵ is selected from optionally substituted (Ci-C4)alkyl or optionally substituted aryl, wherein said optional substituents are selected from one or more of OH, OMe, NH2, NHMe, N(Me)2, or heterocycle.

[23] A compound of [22] above, or according to other embodiments of the invention, wherein R ^Q is selected from hydrogen; (Ci-C3)alkyl optionally substituted with one or more of hydroxy, methoxy, fluoro, or phenyl; phenyl optionally substituted with one or more of hydroxy, fluoro, methoxy, nitro, amino, or methyl; or a nitrogen-containing heteroaryl optionally substituted with one or two methyl groups.

[24] A compound of [22] above, or according to other embodiments of the invention, wherein R° is -C(=0)R ⁵ . [25] A compound of [24] above, or according to other embodiments of the invention, wherein R ⁵ is selected from (Ci-C3)alkyl and phenyl, each of which may be optionally substituted with OR ¹ , Nth, NHMe, N(Me)2, or heterocycle.

[26] A compound of [22] above, or according to other embodiments of the invention, wherein R° is -C(=0)0R ⁵ .

[27] A compound of [26] above, or according to other embodiments of the invention, wherein R ⁵ is selected from the group consisting of phenyl and (Ci-C4)alkyl, each of which may be substituted with OR ¹ .

[28] A compound of [22] above, or according to other embodiments of the invention, wherein R ^Q is -SO2R ³ .

[29] A compound of [28] above, or according to other embodiments of the invention, wherein R ³ is selected from the group consisting of (Ci-C ₆ )alkyl, CF3, and aryl; wherein said aryl is optionally substituted with hydroxy, halogen, cyano, amino, or (Ci-C4)alkoxy.

[30] A compound of [22] above, or according to other embodiments of the invention, wherein R° is SC>2NR ³ R ⁴ .

[31] A compound of [30] above, or according to other embodiments of the invention, wherein R ³ is selected from the group consisting of hydrogen, (Ci-C3)alkyl, and aryl optionally substituted with hydroxy, halogen, cyano, amino, or methoxy; and R ⁴ is hydrogen or methyl.

[32] A compound of [22] above, or according to other embodiments of the invention, wherein R° is -C(=0)NR ³ R ⁴ .

[33] A compound of [32] above, or according to other embodiments of the invention, wherein R ³ is selected from the group consisting of hydrogen, (Ci-C3)alkyl, and aryl optionally substituted with hydroxy, halogen, cyano, amino, or methoxy; and R ⁴ is hydrogen or methyl.

[34] A compound of any of [1] to [33] above, or according to other embodiments of the invention, wherein zero, one or two X ¹ , X ² , R ^a , and R ^b are independently selected in each instance from halogen, cyano, (Ci-C ₆ )alkyl, and halo(Ci-C ₆ )alkyl, and the remainder are hydrogen. [35] A compound of any of [1] to [34] above, or according to other embodiments of the invention, wherein one or two of X ¹ , X ² , R ^a , and R ^b are independently selected in each instance from F, Cl, cyano, and CF3, and the remainder are hydrogen.

[36] A compound of any of [1] to [33] above, or according to other embodiments of the invention, wherein at least three of X ¹ , X ² , R ^a , and R ^b are hydrogen.

[37] A compound of any of [1] to [33] above, or according to other embodiments of the invention, wherein all of X ¹ , X ² , R ^a , and R ^b are hydrogen.

[38] A compound of any of [1] to [37] above, or according to other embodiments of the invention, wherein Z ¹ and Z ² are independently selected in each instance from hydrogen, halogen, halo(Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, -NR ¹ C(0)0R ⁶ , and halo(Ci-C ₆ )alkoxy.

[39] A compound of any of [1] to [38] above, or according to other embodiments of the invention, wherein Z ¹ is hydrogen.

[40] A compound of any of [1] to [39] above, or according to other embodiments of the invention, wherein Z ² is selected from hydrogen, halogen, halo(Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, NHBoc, and halo(Ci-Ce)alkoxy.

[41] A compound of [40] above, or according to other embodiments of the invention, wherein Z ² is hydrogen, fluoro, chloro, trifluoromethyl, -NHBoc, methoxy, or trifluoromethoxy .

[42] A compound of any of [1] to [41] above, or according to other embodiments of the invention, wherein Z ² is trifluoromethoxy.

[43] A compound of any of [1] to [42] above, or according to other embodiments of the invention, wherein one of Z ¹ and Z ² is para to the attachment of ring V to the sulfonyl.

[44] A compound of any of [1] to [43] above, or according to other embodiments of the invention, wherein Z ² is para to the attachment of ring V to the sulfonyl.

[45] A compound of any of [1] to [44] above, or according to other embodiments of the invention, wherein R ¹ is hydrogen.

[46] A compound of any of [1] to [44] above, or according to other embodiments of the invention, wherein R ¹ is (Ci-C ₆ )alkyl. [47] A compound of any of [1] to [46] above, or according to other embodiments of the invention, wherein R ² is hydrogen.

[48] A compound of any of [1] to [46] above, or according to other embodiments of the invention, wherein R ² is (Ci-C ₆ )alkyl.

[49] A compound of any of [1] to [48] above, or according to other embodiments of the invention, wherein the relative stereochemistry is of formula II:

[50] A compound of any of [1] to [49] above, or according to other embodiments of the invention, of formula Ila:

[51] A compound of any of [1] to [49] above, or according to other embodiments of the invention, of formula lib:

lib.

[52] A compound of [1] above, or according to other embodiments of the invention, wherein W is a benzene ring; V is a benzene ring; Q is -(CH2) _n -; and at least three of X ¹ , X ² , R ^a , and R ^b are hydrogen, of formula:

[53] A compound of [1] or [52] above, or according to other embodiments of the invention, wherein X ¹ , X ² , R ^a , and R ^b are all hydrogen.

[54] A compound of [1], [52], or [53] above, or according to other embodiments of the invention, wherein Y is -OH.

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

[56] A compound of [1], [52], [53], [54], or [55] above, or according to other embodiments of the invention, wherein Z ¹ is hydrogen and Z ² is hydrogen, fluoro, chloro, trifluoromethyl, - NHBoc, methoxy, or trifluoromethoxy.

[57] A compound of [1], [52], [53], [54], [55], or [56] above, or according to other embodiments of the invention, wherein Z ² is trifluoromethoxy. [58] A compound of [1], [52], [53], [54], [55], [56], or [57] above, or according to other embodiments of the invention, wherein Z ² is in the para position.

[59] A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any of [1] to [58] above, or according to other embodiments of the invention.

[60] . 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 compound of any of [1] to [58] above, or according to other embodiments of the invention.

[61] 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 [59] above, or according to other embodiments of the invention.

[62] The method of [60] or [61] 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.

[63] The method of [60] or [61] above, or according to other embodiments of the invention, for treating cancer, wherein said cancer is chemotherapy resistant cancer.

[64] The method of any of [60], [61], [62], or [63] above, or according to other embodiments of the invention, wherein the method further comprises administering one or more additional cancer chemotherapeutic agents.

[65] The method of [60] or [61] 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.

[66] The method of [60] or [61] above, or according to other embodiments of the invention, for treating a viral infection.

[67] The method of [66] 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.

[68] The method of [60] or [61] above, or according to other embodiments of the invention, for treating a parasitic infection.

[69] The method of [68] above, or according to other embodiments of the invention, wherein the parasitic infection is caused by a parasite selected from Plasmodium and Theileria. [70] 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 [58] above, or according to other embodiments of the invention.

[71] 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 [58] above, or according to other embodiments of the invention.

[72] 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 [58] above, or according to other embodiments of the invention.

[72] 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 [58] above, or according to other embodiments of the invention.

[73] 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 [59] above, or according to other embodiments of the invention.

[74] 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 [59] above, or according to other embodiments of the invention.

[75] 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 [59] above, or according to other embodiments of the invention.

[76] 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 [59] above, or according to other embodiments of the invention.

[00117] 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.