WO2017044571A1 - Tricyclic sultam sulfonamides as anticancer and neuroprotective agents - Google Patents

Abstract

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

Description

TRICYCLIC SULTAM SULFONAMIDES AS ANTICANCER AND

NEUROPROTECTIVE AGENTS

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority of US provisional application 62/216, 161, filed September 9, 2015, the entire disclosure of which is hereby incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The invention relates to the use of tricyclic chemical modulators of PP2A, comprising heterocyclic constrained tricyclic sulfonamides 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] PP2 A interacts directly with FOXOl and dephosphorylates FOXOl . Inhibition of PP2 A phosphatases rescues FOXOl -mediated cell death by regulating the level of the pro- apoptotic protein BIM. In addition, PP2 A 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 Mycl) target proliferative and apoptotic pathways vital for progression in cancer and they are 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:

I

wherein:

B is chosen from a direct bond, O, S, SO2 and NR^B;

R^B is selected from hydrogen and (Ci-C6)alkyl;

T is a benzene ring or a five- or six-membered heteroaromatic ring;

U is a benzene ring or a five- or six-membered heteroaromatic ring;

X¹, X², X³, and X⁴ are independently selected in each instance from hydrogen, halogen, nitro, cyano, (Ci-C₆)alkyl, (Ci-C₆)haloalkyl, (Ci-C₆)haloalkoxy, -NR¾², -OR¹, C(0)R^!, -0C(0)R¹, -C(0)NR¹R², -C(0)0R¹, -SR¹, -SO2R¹, and -SCh ^R²;

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

is chosen from

and or, when B is a direct bond, ^L^^J may be additionally chosen from:

wherein a is the point of attachment to ring T, b is the point of attachment to ring U, and c is the point of attachment to R⁵;

is -(CR¹⁵R¹⁶)p-D_q-(CR¹⁵R¹⁶)„-p

D is chosen from -0-, -NR¹⁴- and

R¹⁴ is H or (Ci-C₃)alkyl;

R¹⁵ and R¹⁶ in each occurrence are chosen independently from H, OH, cyano, amino, (Ci-C₃)alkylamino, (Ci-C₃)dialkylamino, (Ci-C₃)alkyl, (Ci-C₃)haloalkyl, (Ci- C )haloalkoxy, and (Ci-C )alkoxy, or, taken together, two of R¹⁴, R¹⁵ and R¹⁶ may form a three to seven membered carbocycle or heterocycle wherein said three to seven membered carbocycle or heterocycle may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (Ci-C )alkylamino, (Ci-C )dialkylamino, (Ci-C )alkyl, (Ci-C )haloalkyl, (Ci-C )haloalkoxy, and (Ci-C )alkoxy;

n is an integer from 2 to 4;

p is zero, 1 or 2;

q is zero or 1;

t is zero, 1 or 2;

v is 1, 2 or 3;

Z is selected from the group consisting of: -NHSO2R¹⁷, -NHC(0)NR⁸R⁹, - NHC(0)OR⁸, -S(0)₂NR⁸R⁹, substituted or unsubstituted cyclic carbamate; substituted or unsubstituted cyclic urea, cyclic imide, cyanoguanidine;

R⁸ and R⁹ are independently selected from H, substituted or unsubstituted (Ci- C₆)alkyl, and substituted or unsubstituted (C₃-C₇) cycloalkyl; and

R¹⁷ is chosen from phenyl and monocyclic heteroaryl, said phenyl and monocyclic heteroaryl optionally substituted with one or two substituents chosen from hydrogen, halogen, nitro, cyano, azide, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, -NR^R², - NR¹C(0)R², -NR¹C(0)OR²⁰, -OR¹, -C(0)R¹, -OC(0)R¹, -C(0)NR¹R², -C(0)OR¹, -SR¹, -SO2R¹, and

and R²⁰ is (Ci-C₈)hydrocarbon.

[0014] In a second 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; (e) mood disorder; (f) acne vulgaris; (g) solid organ transplant rejection; (h) graft vs. host disease; i) cardiac hypertrophy; j) viral infection; and (k) parasitic infection. These methods include administering to a patient a therapeutically effective amount of a compound described herein.

[0015] In a third 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.

[0016] In a fourth 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.

[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 a Myc dependent signaling pathway. 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 pharmaceutical compositions comprising the compounds described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0019] Substituents are generally defined when introduced and retain that definition throughout the specification and in all independent claims.

[0020] In a composition aspect, the invention relates to compounds of formula I:

as described above.

[0021] In some embodiments of (CR¹⁵R¹⁶)_n-p-Z. In other

embodiments of formula I, R is

[0022] In some embodiments, Z is selected from - HSO2R¹⁷, - HC(0) R⁸R⁹, and - HC(0)OR⁸. In some embodiments, Z is -NHSO2R¹⁷.

[0023] In some embodiments, the invention relates to compounds of formula II:

II.

[0024] In some embodiments of formula II, q is 0. In other embodiments, q is 1. In some embodiments, q is 1 and Y is hydroxyl. In other embodiments, q is 1 and Y is hydrogen.

[0025] In some embodiments of formula II, R⁶ is hydrogen. In other embodiments, R⁶ is (Ci-C6)alkyl. In some embodiments of formula II, R⁷ is hydrogen. In other embodiments, R⁷ is (Ci-C6)alkyl. In some embodiments of formula II, q is 1, and R⁶ and R⁷, together with the carbons to which they are attached, form an optionally substituted carbocyclic ring. In other embodiments, q is 1, and R⁶ and R⁷, together with the carbons to which they are attached, form an optionally substituted heterocyclic ring. In some embodiments, both R⁶ and R⁷ are hydrogen.

[0026] In some embodiments, the invention relates to compounds of formula III:

III; wherein Q is selected from -(CH2)t-, -0-, S(0)_p-, and - R^Q-, and R^Q is selected from hydrogen; optionally substituted (Ci-C6)alkyl, (C3-C?)cycloalkyl, aryl, or heteroaryl; - S0₂R³; -S0₂N(R R⁴); -C(=0)R⁵; -C(=0)OR⁵; or -C(=0)N(R R⁴); wherein said substituents on the (Ci-Ce)alkyl, (C3-C?)cycloalkyl, aryl, or heteroaryl are selected from the group consisting of hydroxy, halogen, cyano, nitro, amino, (Ci-C4)alkylamino, (Ci- C4)dialkylamino, (Ci-C4)acylamino, (Ci-C4)alkylsulfonyl, (Ci-C4)alkylthio, (Ci-C4)alkyl, (C3-C?)cycloalkyl, (Ci-C4)haloalkyl, (Ci-C4)haloalkoxy, and (Ci-C4)alkoxy.

[0027] In some embodiments of formula III, the relative stereochemistry is of formula IV:

IV.

[0028] In some embodiments of formula IV, the relative stereochemistry is of formula IVa or IVb:

IVa IVb.

[0029] In the embodiments described below, the compound may be of formula I, II, III, IV, IVa or IVb, unless otherwise indicated.

[0030] In some embodiments, B is a direct bond. In other embodiments, B is -0-. In other embodiments, B is -S-. In still other embodiments, B is -SO2-. In yet other embodiments, B is R^B-.

[0031] In some embodiments, R^B is hydrogen. In other embodiments, R^B is (Ci-C6)alkyl.

[0032] In some embodiments,

In other embodiments,

c . In some embodiments, B is a direct bond and ^l-^ilJ is

In other embodiments, B is a direct bond and is

. In still other embodiments, B is a direct bond and [XL IS

. In yet other embodiments, B

is a direct bond and [XL IS

In all of these embodiments, a is the point of attachment to ring T, b is the point of attachment to ring U, and c is the point of attachment to R⁵.

[0033] In some embodiments, T is a benzene ring. In other embodiments, T is a five- membered heteroaromatic ring. In still other embodiments, T is a six-membered heteroaromatic ring.

[0034] In some embodiments, U is a benzene ring. In other embodiments, U is a five- membered heteroaromatic ring. In still other embodiments, U is a six-membered heteroaromatic ring.

[0035] In some embodiments, T and U are each independently selected from the group consisting of a benzene ring, furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiadiazole, thiazine, thiazole, thiophene, triazine, and triazole. In some embodiments, T and U are each independently selected from a benzene ring, pyridine, pyrimidine, pyridazine, thiophene, thiazole, oxazole, imidazole, pyrrole, and furan. In some embodiments, one of T and U is a benzene ring, and the other of T and U is selected from a benzene ring, pyridine, pyrimidine, and thiophene. In still other embodiments, T and U are each independently selected from a benzene ring and pyridine. In some embodiments, at least one of T and U is a benzene ring. In other embodiments, T and U are both benzene rings.

[0036] In some embodiments, Y is hydroxyl. In other embodiments, Y is hydrogen.

[0037] In some embodiments of formula II, III, IV, IVa, and IVb, Ar is an optionally substituted aromatic ring. In other embodiments, Ar is an optionally substituted heteroaromatic ring. In some embodiments, Ar is an aromatic ring substituted with hydrogen, halogen, nitro, cyano, azide, (Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci- C₆)haloalkoxy, - R¾², - ^C^R², -OR¹, -C(0)R¹, -OC(0)R¹, -C(0) R¹R², - C(0)OR¹, -SR¹, -SO2R¹, and/or -SC NR^R². In some embodiments, Ar is a heteroaromatic ring substituted with hydrogen, halogen, nitro, cyano, azide, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (Ci-C₆)haloalkoxy, - R¾², - R^!C(0)R², -OR¹, -C(0)R¹, -OC(0)R¹, -C(0) R¹R², - C(0)OR¹, -SR¹, -SO2R¹, and/or

In some embodiments, Ar is phenyl substituted with Z¹ and Z².

[0038] In some embodiments, Z¹ is selected from hydrogen, halogen, nitro, cyano, azide, (Ci-C₆)alkyl, (Ci-C₆)haloalkyl, (Ci-C₆)haloalkoxy, - R¾², - R¹C(0)R², - R¹C(0)OR²⁰, -OR¹, -C(0)R¹, -OC(0)R¹, -C(0) R¹R², -C(0)OR¹, -SR¹, -SO2R¹, and

In some embodiments, Z² is selected from hydrogen, halogen, nitro, cyano, azide, (Ci- C₆)alkyl, (Ci-C₆)haloalkyl, (Ci-C₆)haloalkoxy, - R¾², - R¹C(0)R², - R¹C(0)OR²⁰, - OR¹, -C(0)R¹, -OC(0)R¹, -C(0) R¹R², -C(0)OR¹, -SR¹, -SO2R¹, and -S0₂ R¹R². In other embodiments, Z¹ and Z² are independently selected in each instance from hydrogen, halogen, (Ci-C₆)haloalkyl, (Ci-Ce)alkoxy, - R¹C(0)OR²⁰, and (Ci-C₆)haloalkoxy. In some embodiments, Z¹ is hydrogen and Z² is selected from hydrogen, halogen, (Ci-Ce)haloalkyl, (Ci-Ce)alkoxy, and (Ci-Ce)haloalkoxy. In some embodiments, Z¹ is hydrogen and Z² is hydrogen, fluoro, chloro, trifluoromethyl, - HBoc, methoxy, or trifluoromethoxy. In other embodiments, Z² is para to the attachment of the phenyl ring to the sulfonyl.

[0039] In some embodiments, R²⁰ is (Ci-Cs)hydrocarbon. In other embodiments, R²⁰ is (Ci- C6)alkyl. In some embodiments, R²⁰ is t-butyl. In still other embodiments, R²⁰ is allyl. In yet other embodiments, R²⁰ is benzyl.

[0040] In some embodiments of formula III, IV, IVa, and IVb, Q is -(CH2)t-, and t is 0, making Q a direct bond and the ring a cyclopentyl ring. In other embodiments, Q is -CH2-, making the ring a cyclohexyl ring. In still other embodiments, Q is -(CH2)2-, making the ring a cycloheptyl ring. In some embodiments, Q is -0-. In other embodiments, Q is - S(O)-. In still other embodiments, Q is -S(O)-. In some embodiments, Q is -S(0)2-. In yet other embodiments, Q is- R^Q-.

[0041] In some embodiments, R^Q is hydrogen. In other embodiments, R^Q is optionally substituted (Ci-Ce)alkyl. In still other embodiments, R^Q is optionally substituted (C3- C7)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-C6)alkyl, (C₃-C₇)cycloalkyl, aryl or heteroaryl may be 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, (C₃-C₇)cycloalkyl, (Ci-C₄)haloalkyl, (Ci-C₄)haloalkoxy, and (Ci-C₄)alkoxy. In some embodiments, R^Q is (Ci- C₆)alkyl optionally substituted with one or more of hydroxy, fluoro, or (C₃-C₇)cycloalkyl. In other embodiments, R^Q is (Ci-C₃)alkyl optionally substituted with one or more of hydroxy or fluoro. In yet other embodiments, R^Q is (C₃-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-C₃)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-C₃)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 -SO2R³. In other embodiments, R^Q is - S0₂ R R⁴. In still other embodiments, R^Q is -C(=0)R⁵. In some embodiments, R^Q is - C(=0)OR⁵. In yet other embodiments, R^Q is -C(=0) R R⁴.

[0042] In some embodiments, R³ and R⁴ are independently selected in each instance from hydrogen, (Ci-Ce)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, R⁴ is selected from hydrogen and methyl. In other embodiments, R³ is selected from hydrogen, (Ci-Ce)alkyl, (Ci-Ce)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.

[0043] In some embodiments, R⁵ 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, OR¹, H₂, HMe, N(Me)₂, and heterocycle. In other embodiments, R⁵ 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, H₂, HMe, N(Me)₂, or heterocycle.

[0044] In some embodiments, R¹ is hydrogen. In other embodiments, R¹ is (Ci-C6)alkyl.

[0045] In some embodiments, R^Q is -C(=0)R⁵ and R⁵ is selected from (Ci-C₄)alkyl, optionally substituted with OR¹, H2, NHMe, N(Me)₂, and heterocycle. In other embodiments, R^Q is -C(=0)OR⁵ and R⁵ is selected from the group consisting of phenyl and (Ci-C4)alkyl, each of which may be substituted with OR¹; in some of these embodiments, R¹ is hydrogen, while in other of these embodiments, R¹ is (Ci-C6)alkyl. In still other embodiments, R^Q is -SO2R³ and R³ is selected from hydrogen, (Ci-Ce)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 S0₂NR R⁴; R³ is selected from hydrogen, (Ci-C )alkyl, and optionally substituted aryl; and R⁴ is hydrogen or methyl. In further embodiments, R^Q is -C(=0)NR R⁴; R³ is selected from hydrogen, (Ci-C )alkyl, and aryl optionally substituted with hydroxy, halogen, cyano, amino, or methoxy; and R⁴ is hydrogen or methyl.

[0046] In some embodiments, X¹, X², X³, and X⁴ are independently selected in each instance from hydrogen, halogen, nitro, cyano, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (Ci- C₆)haloalkoxy, (Ci-C₆)haloalkylthio, -NR¾², -OR¹, -C(0)R¹, -OC(0)R¹, -C(0)NR¹R², - C(0)OR¹, -SR¹, -SO2R¹, and -S0₂NR¹R². In some embodiments, zero, one or two of X¹, X², X³, and X⁴ are independently selected in each instance from halogen, (Ci-Ce)alkyl, and (Ci-Ce)haloalkyl, and the remainder are hydrogen. In other embodiments, zero, one or two of X¹, X², X³, and X⁴ are independently selected in each instance from (Ci-C )alkyl, chloro, fluoro, and (Ci-C )fluoroalkyl, and the remainder are hydrogen.

[0047] In some embodiments, R¹ is hydrogen. In other embodiments, R¹ is (Ci-C6)alkyl. In some embodiments, R² is hydrogen. In other embodiments, R² is (Ci-C6)alkyl.

[0048] The person of skill will understand that, in some instances, R¹, R², R³, R⁴, and R⁵ may not be hydrogen. For instance, when Q is NR^Q, R^Q is -SO2R³, and R³ 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.

[0049] In some embodiments of formula III, the compound is of formula V:

[0050] In some embodiments of formula II, the compound is of formula VI:

[0052] In some embodiments of formula II the compound is of formula VIII:

VIII.

[0053] In some embodiments of formula III, the compound is of formula IX:

IX.

[0054] In some embodiments formula II, the compound is of formula X:

X.

[0055] In some embodiments of formula V, VI, VII, VIII, IX, and X, Z¹ is hydrogen and Z² is selected from hydrogen, halogen, (Ci-C₆)haloalkyl, -NR^QC OR²⁰, (Ci-Ce)alkoxy, or (Ci-C6)haloalkoxy. In other embodiments, Z¹ is hydrogen and Z² is hydrogen, fluoro, chloro, trifluoromethyl, HBoc, methoxy, or trifluoromethoxy. In still other embodiments, Z¹ is hydrogen and Z² is trifluoromethoxy.

[0056] In some embodiments of formula V, VI, VII, VIII, IX, and X, zero, one or two of X¹, X², X³, and X⁴ are independently selected in each instance from halogen, (Ci-C6)alkyl, and (Ci-C6)haloalkyl, and the remainder are hydrogen. In other embodiments, zero, one or two of X¹, X², X³, and X⁴ are independently selected in each instance from (Ci-C )alkyl, chloro, fluoro, and (Ci-C )fluoroalkyl, and the remainder are hydrogen.

[0057] In some embodiments of formula VI, VIII, and X, R⁶ and R⁷ are each hydrogen.

[0058] In some embodiments of the foregoing subgenera, the relative configurations are such that the amine and the tricycle are both trans to the alcohol (Y), as shown above in Formula IV. In this trans: trans subgroup, compounds can be either single enantiomers IVa and IVb 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.

[0059] In summary, the invention relates to:

[0060] [1]· A compound of formula I, II, III, IV, IVa or IVb.

[0061] [2]. A compound according to [1] above wherein B is a direct bond

[0062] [3]· A compound according to [1] above wherein B is -0-.

[0063] [4]. A compound according to [1] above wherein B is -S-.

[0064] [5]· A compound according to [1] above wherein B is -S02-.

[0065] [6]. A compound according to [1] above wherein B is - R^B-.

[0066] [7]. A com ound according to any of [1] through [7] above wherein

[0067] [8]. A compound according to any of [1] through [7] above wherein ^ is

[0068] [9]. A compound according to one of [1] or [2] above wherein ^ is

[0069] [10]. A compound according to one of [1] or [2] above wherein is ,

[0070] [11]. A compound according to one of [1] or [2] above wherein ¹— ¹ is xr ar

[0071] [12]. A compound according to one of [1] or [2] above wherein ¹— ¹ is

[0072] [13]. A compound according to any of [1] through [12] above wherein T and U are each independently selected from the group consisting of a benzene ring and pyridine.

[0073] [14]. A compound according to any of [1] through [12] above wherein at least one of T and U is a benzene ring.

[0074] [15]. A compound according to any of [1] through [12] above wherein both T and U are benzene rings.

[0075] [16]. A compound according to any of [1] through [15] above wherein Y is hydroxyl.

[0076] [17]. A compound according to any of [1] through [15] above wherein Y is hydrogen.

[0077] [18]. A compound according to any of [1] through [17] above wherein Q is a direct bond.

[0078] [19]. A compound according to any of [1] through [17] above wherein Q is -(CH₂)t- and t is 1.

[0079] [20]. A compound according to any of [1] through [17] above wherein Q is -(CH₂)t- and t is 2.

[0080] [21]. A compound according to any of [1] through [17] above wherein Q is -0-.

[0081] [22]. A compound according to any of [1] through [17] above wherein Q is -S-.

[0082] [23]. A compound according to any of [1] through [17] above wherein Q is -S(O)-.

[0083] [24]. A compound according to any of [1] through [17] above wherein Q is -S(0)₂-.

[0084] [25]. A compound according to any of [1] through [17] above wherein Q is - R^Q-.

[0085] [26]. A compound according to any of [1] through [15] above wherein q is 0.

[0086] [27]. A compound according to any of [1] through [15] above wherein q is 1.

[0087] [28]. A compound according to any of [1], [2], [11], and [13] through [25] above, wherein the compound is of formula V. [0088] [29]. A compound according to any of [1], [2], [11], [13] through [17], [26], and [27] above, wherein the compound is of formula VI.

[0089] [30]. A compound according to any of [1], [2], [7], and [13] through [25] above, wherein the compound is of formula VII.

[0090] [31]. A compound according to any of [1], [2], [7], [13] through [17], [26], and [27] above, wherein the compound is of formula VIII.

[0091] [32]. A compound according to any of [1], [3], [7], and [13] through [25] above, wherein the compound is of formula IX.

[0092] [33]. A compound according to any of [1], [3], [7], [13] through [17], [26], and [27] above, wherein the compound is of formula X.

[0093] [34]. A compound according to any of [1] through [33] above, wherein zero, one or two of X¹, X², X³, and X⁴ are independently selected in each instance from halogen, (Ci- Ce)alkyl, and (Ci-C6)haloalkyl, and the remainder are hydrogen.

[0094] [35]. A compound according to any of [1] through [34] above, wherein zero, one or two of X¹, X², X³, and X⁴ are independently selected in each instance from (Ci-C3)alkyl, chloro, fluoro, and fluoro(Ci-C3)alkyl, and the remainder are hydrogen.

[0095] [36]. A compound according to any of [1] through [35] above, wherein Ar is an optionally substituted aromatic or heteroaromatic ring, wherein said substituents are selected from hydrogen, halogen, nitro, cyano, azide, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (Ci- C₆)haloalkoxy, - R¾², - R^C R², - R¹C(0)OR²⁰, -OR¹, -C(0)R¹, -OC(0)R¹, - C(0) R^!R², -C(0)0R¹, -SR¹, -SO2R¹, and -SCh ^R².

[0096] [37]. A compound according to any of [1] through [36] above wherein Ar is phenyl substituted with Z¹ and Z².

[0097] [38]. A compound according to any of [1] through [37] above, wherein Z¹ and Z² are independently selected in each instance from hydrogen, halogen, (Ci-Ce)haloalkyl, - R¹C(0)OR²⁰, (Ci-C₆)alkoxy, and (Ci-C₆)haloalkoxy. [0098] [39]. A compound according to any of [1] through [38] above, wherein Z¹ is hydrogen and Z² is selected from hydrogen, halogen, (Ci-C6)haloalkyl, -NR^QC OR²⁰, (Ci-Ce)alkoxy, and (Ci-Ce)haloalkoxy.

[0099] [40]. A compound according to any of [1] through [39] above, wherein Z¹ is hydrogen and Z² is hydrogen, fluoro, chloro, trifluoromethyl, HBoc, methoxy, or trifluoromethoxy.

[00100] [41]. A compound according to any of [1] through [40] above, wherein Z² is para to the attachment of the phenyl ring to the sulfonyl.

[00101] 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 olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both (£)- and {∑)- geometric isomers. Likewise, all tautomeric forms are intended to be included.

[00102] 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, 1 14-120 (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 (lR,2R,6,S)-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 "(lR,2R,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 "(1R,2R,6S)" without the "re/" indicates a single enantiomer of that absolute configuration, which would be depicted in a structural diagram by solid and broken wedges.

[00103] 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.

[00104] 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.

[00105] 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, Ν,Ν'-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.

[00106] 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.

[00107] 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.

[00108] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal 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.

[00109] 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.

[00110] 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.

[00111] 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.

[00112] It will be recognized that the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and chlorine include ²H, H, ¹ C, ¹⁴C, ¹⁵N, ⁵S, ¹⁸F, and ⁶C1, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. H, and carbon- 14, i.e., ¹⁴C, radioisotopes are particularly preferred for their ease in preparation and detectability. Compounds that contain isotopes ^UC, ¹ N, ¹⁵0 and ¹⁸F are well suited for positron emission tomography. Radiolabeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.

[00113] 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.

[00114] 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.

[00115] 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.

[00116] 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 Leydig 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.

[00117] Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue.

[00118] 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.

[00119] 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.

[00120] 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.

[00121] 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.

[00122] 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)].

[00123] 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

[00124] 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.

[00125] 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.

[00126] 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.

[00127] 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.

[00128] 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, and valvular heart disease.

[00129] 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.

[00130] 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.

[00131] 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. [00132] 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.

[00133] 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.

Abbreviations and Definitions

[00134] 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.

[00135] The following abbreviations and terms have the indicated meanings throughout:

Ac = acetyl

Aq = aqueous

Boc = t-butyloxy carbonyl

Bu = butyl

c- = cyclo

DBA = dibenzylideneacetone

DCM = dichloromethane = methylene chloride = CH2CI2 DMF = N,N-dimethylformamide

eq. or equiv. = equivalent(s)

Et = ethyl

GC = gas chromatography

h = hour(s)

KHMDS = Potassium bis(trirnethylsilyl)arnide

mCPBA = /weto-Chloroperoxybenzoic acid

Me = methyl

mesyl = methanesulfonyl

min. = minute(s)

MO or MMO = N-methylmorpholine oxide

Pg = protecting group

Ph = phenyl

RT = room temperature

sat'd or sat. = saturated

t- or tert = tertiary

TFA = trifluoroacetic acid

THF = tetrahydrofuran

tosyl = p-toluenesulfonyl

[00136] As used herein, 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. This term encompasses the terms "consisting of and "consisting essentially of.

[00137] 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.

[00138] 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.

[00139] 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.

[00140] 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.

[00141] 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.

[00142] 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.

[00143] Throughout this specification the terms and substituents retain their definitions. [00144] Ci to C20 hydrocarbon includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl,

cyclohexylmethyl, adamantyl, camphoryl and naphthylethyl. Hydrocarbyl 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, norbornyl, etc. Aromatic hydrocarbons include benzene (phenyl), naphthalene (naphthyl), anthracene, etc.

[00145] 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.

[00146] 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, norbornyl and the like.

[00147] Unless otherwise specified, the term "carbocycle" is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state. Thus (C3-C10) carbocycle refers to both non-aromatic and aromatic systems, including such systems as cyclopropane, benzene and cyclohexene; (C8-C12) carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene. Carbocycle, if not otherwise limited, refers to monocycles, bicycles and polycycles.

[00148] 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 quaternized. 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.

[00149] 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.

[00150] The term "halogen" means fluorine, chlorine, bromine or iodine atoms. In one embodiment, halogen may be a fluorine or chlorine atom.

[00151] Unless otherwise specified, acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. Examples include acetyl, benzoyl, propionyl, isobutyryl and the like. Lower- acyl refers to groups containing one to four carbons. The double bonded oxygen, when referred to as a substituent itself is called "oxo".

[00152] 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. For example, substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein one or more H atoms in each residue are replaced with halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxy lower alkyl, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, lower alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl [- C(=0)0-alkyl], alkoxycarbonylamino [ FINC(=0)0-alkyl], aminocarbonyl (also known as carboxamido) [-C(=0)NH₂], alkylaminocarbonyl [-C(=0) H-alkyl], cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl (including cycloalkylaminoalkyl), dialkylaminoalkyl, dialkylaminoalkoxy, heterocyclylalkoxy, mercapto, alkylthio, sulfoxide, sulfone, sulfonylamino, alkylsulfinyl, alkylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, hydroxyimino, alkoxyimino, oxaalkyl, amino sulfonyl, trityl, amidino, guanidino, ureido, benzyloxyphenyl, and benzyloxy. "Oxo" is also 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. In preferred embodiments, substituents are halogen, haloalkyl, alkyl, acyl, hydroxyalkyl, hydroxy, alkoxy, haloalkoxy, aminocarbonyl oxaalkyl, carboxy, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl,

alkylsulfonylamino arylsulfonyl, arylsulfonylamino, and benzyloxy.

[00153] Substituents Rⁿ are generally defined when introduced and retain that definition throughout the specification and in all independent claims.

[00154] Examples

[00155] 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.

[00156] Many compounds of formula I may be prepared by the schemes shown in U. S. Provisional Application US 62/201,819, which is incorporated herein by reference. In general, compounds described herein can be prepared as shown in the schemes below. Compounds of the present invention maybe accessed by alkylation of known tricyclic sultams, 6H-dibenzo[c,e][l,2]thiazine 5,5-dioxide, 6H-dibenzo[^ |[l,4,5]oxathiazepine 5,5-dioxide, 6H-dibenzo[c |[l,5,2]dithiazepine 5,5-dioxide, 6H- dibenzo[c |[l,5,2]dithiazepine 5,5, 11, 11-tetraoxide, 6H-dibenzo[c |[l,2,5]thiadiazepine 5,5-dioxide and 6,7-dihydrodibenzo[<i |[l,2]thiazepine 5,5-dioxide; as shown below:

6H-dibenzo[c,e][1 ,2]th^' 6/-/-dibenzo[Jb,/][1 ,4,5]oxathiazepine- 5,5-dioxide 5,5-dioxide

6/-/-dibenzo[c,/][1 ,5,2]dithiazepine- 6H-dibenzo[c,/][1 ,5,2]dithiazepine- 5,5-dioxide 5, 5, 1 1 , 1 1 -tetraoxide

6H-dibenzo[c,/][1 ,2,5]thiadiazepine- 6,7-dihydrodibenzo[cf,/][1 ,2]thiazepine- 5,5-dioxide 5,5-dioxide

[00157] Syntheses of tricyclic sultams and substituted variants are described in Laha et al, J. Org. Chem. 2014, 79, pages 8010 - 8019; Altamura et al, New J. Chem, 2009, 33, pages 2219 - 2231 and Majumdar et al, Synthesis 2009, No. 18, pages 3127 - 3135

[00158] Procedure A: Exemplary procedure for synthesis of 3-(Nitrogen bearing nucleophile)cycloalkane-l,2-diol:

[00159] Procedure A.l: To an oven-dried microwave vial equipped with a magnetic stir bar was added Pd₂.dba . CHC1 (5 mol%), and Ligand (15 mol%). The system was evacuated and filled with argon (3x), and dry, degassed DCM (0.40 M) was added. This vial was stirred at rt for 60 min. Electrophile was added. The nitrogen containing nucleophile was added in dry, degassed DCM (0.33 M). The reaction mixture was stirred at room temperature for the specified time. After completion of reaction time, the mixture was evaporated onto silica gel and subjected to column chromatography (Si0₂; ethyl acetate in hexanes) to afford Cycloalkenyl-N-nucleophile.

[00160] Procedure A.2: A solution of Cycloalkenyl-N-nucleophile (1.00 Eq), 4- methylmorpholine N-oxide monohydrate (2.20 Eq), and osmium tetroxide (0.02 Eq, 2.5% in tert-butanol) in tert-butanol (0.50 M) and water (2.5 M), was stirred at RT for 36 h. The reaction mixture was treated with solid sodium bisulfite solution, stirred for 1 h, evaporated on to silica gel and subjected to column chromatography (S1O2, 0%-70% ethyl acetate in hexanes) to afford 3 -(Nitrogen bearing nucleophile)cycloalkane-l,2-diol.

[00161] Trost ligands used in synthesis:

(f?,f?)-L1 (S,S)-L1

[00162] Procedure B: Exemplary procedure for synthesis of 3-azido-5-(Nitrogen bearing nucleophile)tetrahydro-cycloalkane-4-ol:

[00163] Procedure B.l: A solution of 3 -(Nitrogen bearing nucleophile)cycloalkane- 1,2-diol in dichloromethane under argon was cooled to -78 °C, and treated with

triethylamine. Following this thionyl chloride was added very slowly over 5 min. The reaction mixture was warmed to 0 °C/RT, and stirred for 30 min/1 h/2 h. The reaction mixture was partitioned between dichloromethane and water, concentrated to obtain a residue which was purified by flash chromatography (SiC ; ethyl acetate in hexanes) to afford 7-(Nitrogen bearing nucleophile)tetrahydro-3aH-[l,3,2]dioxathiolo[4,5- cjcycloalkane 2-oxide.

[00164] Procedure B.2: A solution of 7-(Nitrogen bearing nucleophile)tetrahydro- 3a/J-[l,3,2]dioxathiolo[4,5-c]cycloalkane 2-oxide in DMF was treated with sodium azide and heated to 100°C/110 °C in a Biotage Initiator^® microwave reactor for the specified time. Sat. aq. NH4CI was added, mixture was extracted with ethylacetate, washed with brine (100 mL x 4), concentrated, and purified by flash chromatography (S1O2; ethyl acetate in hexanes) to afford 3 -azido-5 -(Nitrogen bearing nucleophile)tetrahydro-cycloalkane-4-ol.

[00165] Procedure C: Exemplary procedure for synthesis of N-(4-hydroxy-5- (Nitrogen bearing nucleophile)tetrahydro-cycloalkane-3-yl)-aryl sulfonamide:

[00166] Procedure C.l: A solution of 3-azido-5-(Nitrogen bearing

nucleophile)tetrahydro-cycloalkane-4-ol in THF was cooled to 0 °C, treated with triphenylphosphine, water, and stirred for 14 h at RT. The solution was concentrated to dryness, dissolved in a minimal amount of CH2CI2 and purified by flash chromatography (S1O2, ethyl acetate in hexanes, dichloromethane:methanol:35% ammonium hydroxide) to afford 3-amino-5-(Nitrogen bearing nucleophile)tetrahydro-cycloalkane-4-ol.

[00167] Procedure C.2: A solution of 3-amino-5-(Nitrogen bearing

nucleophile)tetrahydro-cycloalkane-4-ol in DMF was cooled to 0 °C, treated with triethylamine, and aryl sulfonyl chloride. The mixture was warmed to RT, and stirred for 16 h. The mixture was partitioned between water (10 mL) and CH2CI2 (10 mL). The organic layer was washed with saturated aqueous NaCl (30 mL x 5), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH2CI2 and purified by chromatography (S1O2, ethylacetate-hexanes/SiC , acetone-hexanes/HPLC) to afford N-(4-hydroxy-5- (Nitrogen bearing nucleophile)tetrahydro-cycloalkane-3-yl)-aryl sulfonamide.

[00168] Procedure D: Exemplary procedure for synthesis of N-4-hydroxy-5- (Nitrogen bearing nucleophile)piperidin-3-yl)-4aryl sulfonamide: A solution of tert- butyl 4-hydroxy-3 -(Nitrogen bearing nucleophile)-5-(arylsulfonamido)piperidine-l- carboxylate in dichloromethane was cooled to 0 °C, treated with trifluoroacetic acid, and stirred at RT for the specified time. Mixture was quenched with sat. aq. NaHC0₃ solution and extracted with dichloromethane. The dichloromethane layer along with silica was concentrated to make a dry plug which was purified by flash chromatography (S1O2, ethyl acetate-hexanes, dichloromethane:methanol:35% ammonium hydroxide) to afford N-4- hydroxy- 5 -(Nitrogen bearing nucleophile)piperidin-3-yl)-4aryl sulfonamide.

[00169] Example 1 : Synthesis of N-((lR,2^,3^)-3-(5,5-dioxido-6H- dibenzo[^ |[l,4,5]oxathiazepin-6-yl)-2-hydroxycyclohexyl)-4-

(trifluoromethoxy)benzenesulfonamide: Scheme 1

[00170] Experimental procedure for synthesis of Example 1 :

[00171] 6-(cyclohex-2-en-l-yl)-6H-dibenzo[b,f] [l,4,5]oxathiazepine 5,5-dioxide. A solution of 6H-dibenzo[b,f][l,4,5]oxathiazepine 5,5-dioxide (ref. WO2009/137462 A2) (1.00 g, 4.04 mmol) in DMF (5.0 mL) was cooled to 0 °C, treated with sodium hydride (60% wt. suspension in mineral oil, 0.200 g, 4.85 mmol), stirred for 15 minutes, then treated with 3-bromocyclohexene (0.57 mL, 4.44 mmol). The mixture was warmed to 25 °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, 10% ethyl acetate-hexanes) to afford the title compound as a white solid (1.25 g, 94%). ¾ NMR (600 MHz, CDCI3) δ 7.88 (1H, dd, J= 7.8, 1.2 Hz), 7.50 (1H, td, J= 8.4, 1.8 Hz), 7.40 (1H, dd, J= 7.8, 1.2 Hz), 7.37 (1H, dd, J= 7.2, 1.8 Hz), 7.31 (1H, d, J= 8.4 Hz), 7.27-7.29 (1H, m), 7.24 (1H, t, J= 7.8 Hz), 7.22 (1H, t, J= 7.8 Hz), 5.75-5.81 (2H, m), 4.86-4.89 (1H, m), 1.95-2.00 (lH, m), 1.85-1.89 (2H, m), 1.72 (1H, qt, J= 12.0, 3.0 Hz), 1.62-1.68 (1H, m), 1.54-1.61 (lH, m); ¹ C MR (150 MHz, CDCI3) δ 156.2, 152.4, 133.8, 133.2, 132.5, 132.3, 130.4, 128.6, 128.5, 127.5, 126.2, 124.0, 122.4, 122.0, 58.2, 28.9, 24.4, 20.9; LCMS m/z 328.1012 ([M + H⁺], Ci₈Hi₇N0₃S requires 328.1002).

[00172] 6-((lR,2S,3R)-2,3-dihydroxycyclohexyl)-6H- dibenzo[b,f] [l,4,5]oxathiazepine 5,5-dioxide. A solution of 6-(cyclohex-2-en-l-yl)-6H- dibenzo[b,fJ[l,4,5]oxathiazepine 5,5-dioxide (1.25 g, 3.82 mmol) in t-BuOH-H₂0 5: 1 (6.0 mL) at 25 °C was treated with Os0₄ (2.5 wt.% solution in t-BuOH, 0.48 mL, 0.038 mmol) and N-methyl morpholine N-oxide (0.492 g, 4.20 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 (1.11 g, 80%). ¾ MR (600 MHz, CDC1₃) δ 7.88 (1H, dd, J= 7.8, 1.2 Hz), 7.52 (1H, td, J= 8.4, 1.8 Hz), 7.48 (1H, dd, J= 7.8, 1.8 Hz), 7.42 (1H, td, J= 8.4, 1.8 Hz), 7.29-7.34 (3H, m), 7.24 (1H, td, J= 7.2, 1.2 Hz), 4.38 (1H, ddd, J= 11.4, 10.8, 4.2 Hz), 4.16 (1H, d, J= 1.2 Hz), 3.48 (1H, d, J= 10.2 Hz), 3.20 (1H, br s), 2.54 (1H, br s), 1.94-1.97 (1H, m), 1.85-1.88 (1H, m), 1.71 (1H, qt, J= 13.8, 3.6 Hz), 1.41-1.44 (1H, m), 1.24-1.29 (2H, m); ¹ C NMR (150 MHz, CDC1₃) 6 156.2, 152.2, 134.1, 132.9, 132.1, 130.9, 128.4, 127.5, 126.7, 124.3, 122.8, 122.0, 72.8, 69.9, 62.3, 29.9, 29.3, 19.0; LCMS m/z 362.1062 ([M + H⁺], Ci₈Hi₉N0₅S requires 362.1057).

[00173] 6-((3aS,4R,7aR)-2-oxidohexahydrobenzo [d] [1 ,3,2] dioxathiol-4-yl)-6H- dibenzo[b,f] [l,4,5]oxathiazepine 5,5-dioxide. A solution of 6-((lR,2S,3R)-2,3- dihydroxycyclohexyl)-6H-dibenzo[b,f][l,4,5]oxathiazepine 5,5-dioxide (1.11 g, 3.07 mmol) in CH2CI2 (10.0 mL) at 0 °C was treated dropwise with triethylamine (3.41 mL, 24.57 mmol), and SOCI2 (0.67 mL, 9.21 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 (Na2SC"4), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH2CI2 and purified by flash chromatography (S1O2, 0-20% ethyl acetate-hexanes to afford the title compound as a white solid solid (1.14 g, 91%). ¾ NMR (600 MHz, CDCI3) δ (as a mixture of sulfite

diastereomers) 7.84 (1H, dd, J= 7.8, 1.2 Hz), 7.50 (1H, td, J= 7.2, 1.2 Hz), 7.42-7.47 (2H, m), 7.34 (1H, dd, J= 8.4, 1.2 Hz), 7.30-7.33 (2H, m), 7.24 (1H, t, J= 7.2 Hz), 5.08 (1H, br s), 4.65 (lH, dd, J= 9.6, 4.8 Hz), 4.11 (1H, ddd, J= 13.2, 9.6, 4.2 Hz), 2.28-2.31 (1H, m), 2.12-2.15 (lH, m), 1.61-1.77 (3H, m), 1.40 (1H, qd, J= 12.6, 3.6 Hz).

[00174] 6-((lR,2R,3S)-3-azido-2-hydroxycyclohexyl)-6H- dibenzo[b,f] [l,4,5]oxathiazepine 5,5-dioxide. A solution of 6-((3aS,4R,7aR)-2- oxidohexahydrobenzo [d] [ 1 , 3 ,2] dioxathiol-4-yl)-6H-dibenzo [b, f] [ 1 ,4, 5 joxathiazepine 5,5- dioxide (1.12 g, 2.00 mmol) in DMF (8.0 ml) was treated with sodium azide (0.390 g, 6.00 mmol), and heated to 110 °C under microwave irradiation for 14 h. The mixture was diluted with CH2CI2 (200 mL) and this organic layer was washed with saturated aqueous NaCl (3 x 100 mL), dried (Na2SC"4), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH2CI2 and purified by flash chromatography (S1O2, 0-20% ethyl acetate-hexanes) to afford the title compound as a white solid (0.542 g, 70%). ¾ NMR (600 MHz, CDCI3) δ 7.87 (1H, dd, J= 7.8, 1.2 Hz), 7.49-7.53 (2H, m), 7.44 (1H, td, J = 8.4, 1.8 Hz), 7.31-7.36 (3H, m), 7.23-7.27 (1H, m), 4.11-4.15 (1H, m), 3.32-3.39 (2H, m), 2.98 (1H, d, J= 3.6 Hz), 2.02-2.06 (1H, m), 1.93-1.95 (1H, m), 1.71-1.75 (1H, m), 1.26- 1.44 (1H, m), 1.12-1.19 (1H, m); LCMS m/z 387.1104 ([M + H⁺], C18H18N4O4S requires 387.1122).

[00175] 6-((lR,2R,3S)-3-amino-2-hydroxycyclohexyl)-6H- dibenzo[b,f] [l,4,5]oxathiazepine 5,5-dioxide. A solution of 6-((lR,2R,3S)-3-azido-2- hydroxycyclohexyl)-6H-dibenzo[b,fJ[l,4,5]oxathiazepine 5,5-dioxide (0.522 g, 1.35 mmol) in THF (8.0 mL) was cooled to 0 °C, treated with PPh₃ (0.460 g, 1.75 mmol), H₂0 (1.0 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-CH₂Cl2 to remove triphenylphosphine oxide and 17:2: 1 CH₂Cl2:MeOH: H₄OH to elute the product). The combined fractions of pure product were concentrated, dried azeotropically with toluene to afford the title compound as a white solid (0.344 g, 71%). ¾ NMR (600 MHz, CDC1₃) δ 7.87 (1H, dt, J= 7.8, 1.2 Hz), 7.54 (1H, dd, J= 7.8, 1.8 Hz), 7.49 (1H, tt, J= 9.6, 1.8 Hz), 7.40 (1H, tt, J= 7.8, 1.8 Hz), 7.27-7.32 (3H, m), 7.23 (1H, t, J= 7.2 Hz), 4.07 (1H, ddd, J = 12.0, 10.2, 4.2 Hz), 3.11 (1H, t, J= 9.0 Hz), 2.66-2.70 (1H, m), 2.29 (3H, br s), 1.98-2.02 (1H, m), 1.77-1.80 (1H, m), 1.63-1.65 (1H, m), 1.30-1.36 (2H, m), 1.02 (1H, qd, J= 13.2, 4.2 Hz); ¹ C NMR (150 MHz, CDC1₃) 156.5, 152.4, 133.8, 133.2, 132.7, 130.8, 128.3, 127.7, 126.8, 124.3, 122.7, 122.0, 76.7, 65.4, 56.3, 33.2, 29.8, 22.7; LCMS m/z 361.1209 ([M + H⁺], C18H20N2O4S requires 361.1217).

[00176] N-((l S,2R,3R)-3-(5,5-dioxido-6H-dibenzo[b,f][l,4,5]oxathiazepin-6-yl)-2- hydroxycyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide. A solution of 6-

(( 1 R,2R, 3 S)-3 -amino-2-hydroxycyclohexyl)-6H-dibenzo [b, f] [ 1 ,4, 5 Joxathiazepine 5,5- dioxide (0.0500 g, 0.139 mmol) in CH₂C1₂ (1.0 mL) was cooled to 0 °C, treated with Et₃N (20.2 \L, 0.146 mmol), and 4-trifluoromethoxybenzenesulfonyl chloride (24.7 \L, 0.146 mmol). The mixture was warmed to 25 °C, and stirred for 2 h. The mixture was partitioned between saturated aqueous NaCl (50 mL) and CH₂C1₂ (100 mL). The 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 CH₂C1₂ and purified by flash chromatography (Si0₂, 0-35% ethyl acetate-hexanes) to afford the title compound as a beige film (0.0738 g, 91%). ¾ NMR (600 MHz, CDC1₃) δ 7.94 (2H, d, J= 6.6 Hz), 7.81 (1H, dd, J= 7.8, 1.8 Hz), 7.49 (1H, td, J= 7.8, 1.2 Hz), 7.40 (1H, td, J= 7.8, 1.2 Hz), 7.28- 7.31 (4H, m), 7.26 (1H, td, J= 7.8, 1.2 Hz), 7.22 (1H, td, J= 8.4, 1.2 Hz), 5.42 (1H, d, J = 4.8 Hz), 4.01 (1H, ddd, J= 12.0, 10.2, 4.2 Hz), 3.30 (1H, t, J= 9.0 Hz), 3.23 (1H, br s), 3.00-3.05 (lH, m), 1.91-1.98 (2H, m), 1.58-1.61 (1H, m), 1.26-1.30 (2H, m), 1.09 (1H, qd, J= 13.2, 3.6 Hz); ¹ C NMR (600 MHz, CDC1₃) δ 156.5, 152.3, 152.2, 138.7, 133.9, 133.0, 132.4, 131.1, 129.5, 128.2, 127.5, 127.0, 124.4, 122.7, 122.0, 121.2, 121.0, 73.7, 65.1, 58.9, 31.1, 28.9, 22.1; LCMS m/z 585.0980 ([M + H⁺], C₂₅H₂₃F₃N₂0₇S₂ requires 585.0972).

[00177] Synthesis of Example 2a (Scheme 2)

[00178] Synthesis of (R)-6-(3,6-dihydro-2H-pyran-3-yl)-6H- dibenzo[£,/][l,4,5]oxathiazepine 5,5-dioxide:

[00179] Using the typical procedure 6H-dibenzo[£/][l,4,5]oxathiazepine 5,5-dioxide 15 (0.494 g, 2.00 mmol) was reacted with tert-butyl (3,6-dihydro-2H-pyran-3-yl) carbonate 5 (0.961 g, 4.80 mmol) in presence of (R,R L1 ligand for 10 days to afford (R)-6-(3,6- dihydro-2H-pyran-3-yl)-6H-dibenzo[£ ][l,4,5]oxathiazepine 5,5-dioxide (0.525 g, 80%) obtained as a white solid. ¾ NMR (600 MHz, MeOD) δ 7.81 (1H, dd, J= 7.8, 1.2 Hz), 7.63-7.60 (lH, m), 7.48 (1H, dd, J= 7.8, 1.2 Hz), 7.43-7.38 (2H, m), 7.32-7.30 (2H, m), 7.25 (1H, td, J= 7.8, 1.2 Hz), 5.87-5.86 (1H, m), 5.73 (1H, br s), 4.56 (1H, s), 4.11-4.09 (1H, m), 3.98-3.95 (1H, m), 3.88-3.84 (2H, m); ¹ C NMR (150 MHz, MeOD) δ 134.7, 134.1, 133.4, 132.4, 130.3, 128.1, 126.2, 125.8, 125.1, 124.1, 122.5, 122.3, 121.9, 121.6, 69.3, 64.6, 54.3; Material produced in this fashion exhibited [a]²⁵D = -190.0° (c = 1.0, CH₃OH). HPLC analysis: 91% ee (CHIRALPAK IA, 70:30:0.1 hexanes-EtOH- diethylamine, 1.0 mL/min, UV: 280 nm), tR = 15.17 min (minor), 9.69 min (major); HRMS m/z 330.0796 ([M + H⁺], Ci₇Hi₆N0₄S requires 330.0795).

[00180] 6-((3S,4R,5S)-4,5-dihydroxytetrahydro-2H-pyran-3-yl)-6H- dibenzo[Z>,/] [1,4,5] oxathiazepine 5,5-dioxide: Using the typical procedure A.2 6-(3,6- dihydro-2H-pyran-3-yl)-6H-dibenzo[^ |[l,4,5]oxathiazepine 5,5-dioxide (0.460 g, 1.39 mmol) was transformed to 6-((3,S',4R,5₎S)-4,5-dihydroxytetrahydro-2H-pyran-3-yl)-6H- dibenzo[^ |[l,4,5]oxathiazepine 5,5-dioxide (0.461 g, 91%) which was obtained as a white solid. ¾ NMR (600 MHz, MeOD) δ 7.79 (1H, dd, J= 7.8, 1.2 Hz), 7.60-7.55 (2H, m), 7.46-7.43 (1H, m), 7.38-7.34 (2H, m), 7.32-7.30 (1H, m), 7.26 (1H, t, J= 7.8 Hz), 4.427- 4.421 (1H, m), 3.98 (1H, dd, J= 10.8, 4.2 Hz), 3.81 (1H, br s), 3.75 (1H, d, J= 12.0 Hz), 3.55-3.53 (1H, m), 3.35-3.26 (2H, m); ¹ C NMR (150 MHz, MeOD) δ 156.2, 152.4, 134.0, 132.9, 132.4, 130.7, 127.6, 126.0, 123.9, 122.2, 121.8, 70.4, 69.6, 69.3, 67.8, 59.4; LCMS m/z 364.3036 ([M + H⁺], CnHisNOeS requires 364.0849).

[00181] 6-((35',4^,5R)-5-azido-4-hydroxytetrahydro-2H-pyran-3-yl)-6H- dibenzo [b ] [ 1 ,4, 5]oxathiazepine 5 , 5 -dioxide :

[00182] Using the typical procedure B. l 6-((3^,4R,55)-4,5-dihydroxytetrahydro-2H- pyran-3-yl)-6H-dibenzo[£,/][l,4,5]oxathiazepine 5,5-dioxide (0.406 g, 1.12 mmol) in dichloromethane (10.0 mL) was reacted with triethylamine (1.24 mL, 8.96 mmol), and thionyl chloride (0.121 mL, 1.68 mmol). The mixture was stirred at 0 °C for 1 h. Flash chromatography (S1O2, 0%-75% ethylacetate-hexanes) afforded crude 6-((3aS,7S,7aR)-2- oxidotetrahydro-3 a/J- [ 1 , 3 ,2] dioxathiolo [4, 5 -c]pyran-7-yl)-6H- dibenzo[£,/][l,4,5]oxathiazepine 5,5-dioxide (0.348 g) which was taken to the next step without further purification.

[00183] Using the typical procedure B.2 e-^a-S'^^^aR^-oxidotetrahydro-Sa/J-

[l,3,2]dioxathiolo[4,5-c]pyran-7-yl)-6H-dibenzo[^ |[l,4,5]oxathiazepine 5,5-dioxide (0.332 g, 0.810 mmol) in DMF (2.0 mL) was reacted with sodium azide (0.157 g, 2.43 mmol) at 110 °C for 4 h, (pressure was released from the vial), then 110 °C for 12 h.

Purification by flash chromatography (S1O2, 0%-50% ethylacetate-hexanes) afforded 6- ((35',45',5R)-5-azido-4-hydroxytetrahydro-2H-pyran-3-yl)-6H- dibenzo[6 ][l,4,5]oxathiazepine 5,5-dioxide (0.197 g, 48% over two steps). ¾ NMR (600 MHz, MeOD) δ 7.80 (1H, dd, J= 7.8, 1.8 Hz), 7.60-7.56 (2H, m), 7.49-7.46 (1H, m), 7.39- 7.36 (2H, m), 7.35-7.32 (1H, m), 7.28 (1H, t, J= 7.8 Hz), 4.11-4.08 (1H, m), 4.05 (1H, d, J = 10.8, 4.8 Hz), 3.83 (1H, dd, J= 11.4, 5.4 Hz), 3.49-3.45 (1H, m), 3.37 (1H, t, J= 9.6 Hz), 3.29-3.27 (1H, m), 2.87 (1H, t, J= 10.8 Hz); ¹ C NMR (150 MHz, MeOD) δ 156.2, 152.4, 134.0, 132.8, 132.3, 130.9, 127.6, 127.3, 126.1, 123.9, 122.3, 121.9, 72.5, 68.2, 68.1, 63.8, 62.0; LCMS m/z 389.0931 ([M + H⁺], C17H17N4O5S requires 389.0915).

[00184] N-((3R,4^,5^-5 5,5-dioxido-6H-dibenzo[* ][l,4,5]oxathiazepin-6-yl)-4- hydroxytetrahydro-2H-pyran-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (Example 2a):

[00185] Using the typical procedure C.1 6-((3S,4S,5R)-5-azido-4-hydroxytetrahydro-

2H-pyran-3-yl)-6H-dibenzo[£ ][l,4,5]oxathiazepine 5,5-dioxide (0.177 g, 0.455 mmol) in THF (2.0 mL) was reacted with triphenylphosphine (0.131 g, 0.501 mmol), and water (0.001 mL, 0.055 mmol). Flash chromatography (S1O2, 100% hexanes, 50% ethyl acetate- hexanes, 5% methanol-dichloromethane, 17:2: 1 dichloromethane:methanol:35%

ammonium hydroxide) afforded crude 6-((3,S',4₎S',5R)-5-amino-4-hydroxytetrahydro-2H- pyran-3-yl)-6H-dibenzo[£ ][l,4,5]oxathiazepine 5,5-dioxide (0.130 g) which was taken to the next step without further purification.

[00186] Using the typical procedure C.2 6-((35',45',5R)-5-amino-4- hydroxytetrahydro-2H-pyran-3-yl)-6H-dibenzo[^ |[l,4,5]oxathiazepine 5,5-dioxide (0.130 g, 0.358 mmol) in DMF (3.0 mL) was reacted with triethylamine (0.199 mL, 1.43 mmol), and 4-(trifluoromethoxy)benzene-l-sulfonyl chloride (0.066 mL, 0.393 mmol). Purification by flash chromatography (S1O2, 0%-50% ethylacetate-hexanes) afforded N-((3R,4S,5S)-5- (5,5-dioxido-6H-dibenzo[^ |[l,4,5]oxathiazepin-6-yl)-4-hydroxytetrahydro-2H-pyran-3- yl)-4-(trifluoromethoxy)benzenesulfonamide Example 2a (0.074 g, 30% over two steps).

¾ NMR (600 MHz, MeOD) δ 7.97 (2H, d, J= 8.4 Hz), 7.77 (1H, dd, J = 7.8, 1.2 Hz), 7.57-7.53 (2H, m), 7.46-7.41 (3H, m), 7.36-7.35 (2H, m), 7.31 (1H, t, J= 7.8 Hz), 7.26 (1H, t, J= 7.8 Hz), 4.04-4.03 (1H, m), 3.96 (1H, dd, J= 10.8, 4.8 Hz), 3.67 (1H, dd, J = 11.4, 5.4 Hz), 3.35 (1H, t, J= 11.4 Hz), 3.19 (1H, td, J= 10.2, 4.8 Hz), 2.88 (1H, t, J= 10.8 Hz); ¹ C NMR (150 MHz, MeOD) δ 156.3, 152.4, 151.8, 140.4, 133.9, 132.9, 132.4, 130.9, 129.2, 127.5, 126.2, 124.0, 122.3, 121.9, 120.9, 70.6, 69.8, 68.0, 62.6, 56.9; Material produced in this fashion exhibited [a]²⁵D = +67.0° (c = 1.0, CH3OH). LCMS m/z 587.0 ([M + H⁺], C24H22F3N2O8S2 requires 587.0).

[00187] Alkylation of the tricyclic sulfonamides may be carried out with control of absolute stereochemistry as shown in Scheme 3 below.

[00188]

Scheme

Synthesis of Examples 3 a and 3b

[00189] To a solution of tert-butyl 5-hydroxy-5,6-dihydropyridine-l(2H)-carboxylate (10.0 g, 50.1 mmol) in THF (160 mL) was added «-butyllithium (2.5 M in hexanes, 19.8 mL, 2.50 mmol) at -78 °C. The resulting solution was warmed to 0 °C and stirred for 5 min prior to addition of di-tert-butyl dicarbonate (12.0 g, 55.1 mmol) in THF (80.0 mL). The reaction was warmed to RT, stirred for 16 h. The reaction was then quenched with water, extracted with ethyl acetate, washed with brine, concentrated, and the residue purified by flash chromatography (S1O2, 0%-3% ethyl acetate-hexanes) to afford slightly crude tert- butyl 5-((tert-butoxycarbonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate, (reagent 1 of Scheme 3) (15.3 g) as a colorless oil which was taken to the next step without further purification.

[00190] A 5 mL Biotage^® microwave reaction vial is charged with Pd2.dba₃. CHC1₃ (0.025 g, 0.024 mmol), and (R,R)-DACH-phenyl Trost ligand (0.052 g, 0.075 mmol). The vial is sealed, evacuated and backfilled with argon three times. Dry degassed

dichloromethane (1.25 mL) is added to this vial, and the mixture is stirred at room temperature for 30 min. Reagent 1 of Scheme 3 (1.20 mmol) is added to the vial and the contents were transferred to a separate 5 mL Biotage^® microwave reaction vial containing 6H-dibenzo[c,e][l,2]thiazine 5,5-dioxide (1.0 mmol) in dry degassed dichloromethane. The reaction mixture is stirred at room temperature for 10 days. At this point, the reaction mixture is evaporated onto silica gel and subjected to column chromatography to afford crude tert-butyl (R)-3-(5,5-dioxido-6H-dibenzo[c,e][l,2]thiazin-6-yl)-3,6-dihydropyridine- l(2H)-carboxylate. This material is carried forward using steps analogous to those shown in Scheme 1 to give Example 3a. Example 3a is deprotected by stirring in 30% TFA in methylene chloride to give Example 3b: N-((3R,4S,5S)-5-(5,5-dioxido-6H- dibenzo[c,e] [ 1 ,2]thiazin-6-yl)-4-hydroxypiperidin-3 -yl)-4- (trifluoromethoxy)benzenesulfonamide.

[00191] The piperidine NH in the foregoing example may be condensed with any acylating or alkylating agent needed by procedures well-known in the art. Introduction of aryl or heteroaryl moieties onto the ring nitrogen may be achieved by SNAT substitution reactions for electron deficient aromatic systems such 4-nitrophenyl or electrophilic heteroaromatic systems such as 4-pyrimidinyl systems. More generally arylation or heteroarylation of the ring nitrogen may be achieved by palladium mediated N-aryl amination: the Buchwald-Hartwig reaction, see for example N. Marion et al, in "Modified ( HC)Pd(allyl)Cl ( HC ) N-Heterocyclic Carbene) Complexes for Room-Temperature Suzuki-Miyaura and Buchwald-Hartwig Reactions" J. Am. Chem. Soc. 2006, 128, 4101 or J. P. Wolfe et al in "Rational Development of Practical Catalysts for Aromatic Carbon- Nitrogen Bond Formation.

[00192] Use of (^^-DACH-phenyl Trost ligand will give rise to the Examples 3c and 3d, enriched in the opposite enantiomer. The foregoing schemes 1, 2 and 3 produce cyclic sulfonamide products of the (l S,2S,3R)-re/ configuration. When products of other relative configurations are desired, the cycloalkene may be oxidized with reagents, such as meta- chloroperbenzoic acid and others well-known to persons of skill in the art, and the resulting epoxide opened in a trans sense.

[00193] Similarly, when compounds in which Y is hydrogen are desired, the olefin in Scheme 1 may be treated with a sterically hindered hydroborating agent such as 9-BBN or the like, followed by oxidation of the alkyboron to the alcohol with an oxidant such as N- methylmorpholine-N-oxide or aqueous hydrogen peroxide. The alchol intermediate is converted to leaving group such as the mesylate and displaced with azide. Alternatively, compounds in which Y = H maybe accessed via radical mediated deoxgenation processes on the hydroxy cycloaliphatics above, as described in, for example, W. Hartwig in "Modern Methods For The Radical Deoxgenation of Alcohols", Tetrahedron Vol. 39, No. 16, page 2609 (1983).

Scheme 4

Synthesis of Examples 4a and 4b

[00194] 8-chloro-6H-dibenzo[^ |[l,4,5]oxathiazepine 5,5-dioxide, 1 of Scheme 4, is deprotonated with a base such as sodium hydride, cesium carbonate or potassium bistrimethylsilylamide in an aprotic solvent such as THF, DMF or Toluene; the mixture is treated with a small excess of N-Phthaloyl-3-bromopropylamine and stirred at room temperature to 50 °C for one to 24 hr. The reaction mixture is diluted with an organic solvent such as ethyl acetate, or methylene choride and washed with water or dilute aqueous ammonium choride, then dried, filtered and evaporated to give crude intermediate 2, which is purified by chromatography on silica gel.

[00195] Intermediate 2 is deprotected by stirring with hydrazine in ethanol room temperature for 1 to 24 hours. The reaction mixture is evaporated and the residue taken up in an organic solvent such as ethyl acetate or methylene choride and washed with one molar sodium hydroxide, then brine, then dried, filtered and evaporated to give intermediate 3. Intermediate 3 maybe purified by chromatography or used crude.

[00196] Intermediate 3 is dissolved in a solvent such as methylene chloride, DMF or THF and treated with a small excess of a tertiary amine base such as triethyl amine or Hunigs base then with an aromatic sulfonyl chloride such as 4-

(trifluoromethoxy)benzenesulfonyl chloride. The mixture is stirred for one to 24 hours, then concentrated and diluted into ethyl acetate, and washed with dilute hydrochloric acid, brine then dried, filtered and concentrated to give crude Example 4, which is purified by chromatography on silica gel.

[00197] Use of N-Phthaloyl-2-bromoethylamine in the above procedure will give the lower homolog, Example 4b.

Scheme 5

Synthesis of Examples 5a, 5b and 5c.

[00198] 7-fluoro-2-methyl-6H-dibenzo[c,e][l,2]thiazine 5,5-dioxide 1 of Scheme 5, is deprotonated with a base such as sodium hydride, cesium carbonate or potassium

bistrimethylsilylamide in an aprotic solvent such as THF, DMF or Toluene; the mixture is treated with a small excess of epichlorohydrin and stirred at room temperature to 100 °C for one to 24 hr. The reaction mixture is diluted with an organic solvent such as ethyl acetate, or methylene choride and washed with water or dilute hydrochloric acid, then dried, filtered and evaporated to give crude intermediate 2, which is purified by chromatography on silica gel.

[00199] A solution of epoxide intermediate 2 in 4: 1 ethanoLE O is treated with sodium azide, ammonium chloride and heated from room temperature 80 °C for 1 to 14 h. The mixture was cooled to 25 °C, concentrated dissolved in a solvent such as ethyl acetate or methylene chloride. The is washed with brine, dried, filtered and concentrated in vacuo, and the crude material is purified by chromatography on silica gel to give azide intermediate 3.

[00200] Intermediate 3 is dissolved in THF, cooled to 0 °C and treated with a small excess of PPh for one to two hours. Water, one to five percent by volume is added, and stirred for 12 to 24 hours at room temperature. The solution is concentrated to dryness, dissolved in a minimal amount of methylene chloride and purified by chromatography on silica gel.

[00201] The amine intermediate 4 is dissolved in a solvent such as methylene chloride, DMF or THF and treated with a small excess of a tertiary amine base such as triethyl amine or Hunigs base then with an aromatic sulfonyl chloride such as 4- (trifluoromethoxy)benzenesulfonyl chloride. The mixture is stirred for one to 24 hours, then concentrated and diluted into ethyl acetate, and washed with dilute hydrochloric acid, brine then dried, filtered and concentrated to give crude Example 4, which is purified by chromatography on silica gel.

[00202] Use of racemic epichlorohydrin gives racemic Example 5 a, use of either enantiomer of epichlorohydrin gives the products as S or R enantiomers, Examples 5b and 5c respectively.

[00203] Use of the synthetic methods shown in Schemes 1 - 5 using the sultam, 6,7- dihydrodibenzo[<i |[l,2]thiazepine 5,5-dioxide, gives access to Examples 6 through 11, shown below:

[00204] Procedure E: Alternate Epoxidation Route

ί^" Ύ^' 1 ,

[00205] An alternative route to PP2A modulators described in the present application is outlined in Procedure E in which a heterocyclic allylic carbonate is first reacted with a protected aryl sulfonamide in the presence of a palladium catalyst. This may be carried out with control of the newly formed chiral center by using a chiral ligand such as the Trost- DACH bisphosphine. Thus reagents of type (i) are reacted with an optionally protected arylsulfonamide(ii), for example 4-trifluoromethoxybenzene sulfonamide in the presence of a chiral palladium catalyst to give enantiomerically enriched allylarylsulfonamides of type (iii). Protecting groups, Pg, include but are not limited to, benzyl and substituted benzyl groups or alkoxycarbonyl groups such as Boc or Cbz. The protected allylic sulfonamides (iii) may be epoxidized in a non-diastereoselective fashion to give a diasteromeric mixture of epoxides, (iv), which are separated by chromatographic techniques; or alternatively stero selective expoxidation will give access to one diastereoisomer preferentially.

Epoxidation reagents include peroxoic acids such as mCPBA, dioxiranes such as dimethyldioxirane, oxaziridines such as 3-phenyl-2-tosyl-l,2-oxaziridine or hydroperoxides such as t-butylhydroperoxide with transition metal ion catalysis. Either isomer of compound (iv) is converted to a PP2A activator by treatment with a tricyclic sultam moiety such as an optionally substituted 6H-dibenzo[£ ][l,4,5]oxathiazepine 5,5-dioxide (B=0 in Scheme above) or 6H-dibenzo[c,e][l,2]thiazine 5,5-dioxide (B=bond) in the presence of a base such as sodium amide, sodium hydride or potassium t-butoxide in an aprotic solvent, followed by deprotection under conditions appropriate for the original choice of Pg.

Alternatively the diastereomeric mixture of (iv) may be carried forward and isomers separated at the penultimate benzyl protected stage or the final deprotected products.

[00206] A specific example (Example 2b) of Procedure E is shown in Scheme 6:

Example 2b

[00207] Synthesis of (R)-N-benzyl-N-(3,6-dihydro-2H-pyran-3-yl)-4- (trifluoromethoxy)benzenesulfonamide (iii) :

[00208] Using the exemplary procedure, N-benzyl-4-

(trifluoromethoxy)benzenesulfonamide (0.200 g, 0.603 mmol) was reacted with tert-butyl (3,6-dihydro-2H-pyran-3-yl) carbonate (0.289 g, 1.45 mmol) in presence of (R,R)-L1 for 10 days to afford (R)-N-benzyl-N-(3,6-dihydro-2H-pyran-3-yl)-4-

(trifluoromethoxy)benzenesulfonamide (0.228 g, 92%). ¾ MR (600 MHz, MeOD) δ 7.89 (2H, d, J= 8.4 Hz), 7.43 (2H, d, J= 8.4 Hz), 7.32 (2H, d, J = 7.2 Hz), 7.26-7.20 (3H, m), 5.93 (1H, d, J= 10.2 Hz), 5.41 (1H, d, J= 10.2 Hz), 4.66-4.63 (1H, m), 4.48-4.44 (2H, m), 3.98-3.91 (2H, m), 3.70 (1H, dd, J = 12.0, 4.2 Hz), 3.55 (1H, dd, J = 12.0 3.6 Hz); ¹ C

MR (150 MHz, MeOD) δ 152.0, 140.0, 138.6, 132.0, 129.3, 127.9, 127.0, 123.0, 121.2, 1 19.6, 68.1, 64.5, 51.6, 48.3; HPLC analysis: (CHIRALPAK IA-3, 70:30 hexanes-EtOH- diethylamine, 1.0 mL/min, UV: 254 nm), tR = 2.72 min (minor), 5.10 min (major); HPLC analysis: >94%ee Material produced in this fashion exhibited [a]²⁵D = -93.0° (c = 1.0, CH₃OH); HRMS m/z 414.0989 ([M + H⁺], C19H19F3NO4S requires 414.0988).

[00209] Z ms-stereoselective epoxidation of intermediate (iii) is carried out using conditions reported in O'Brien et al, Organic Letters, vol. 5, Pages 4955-4957, 2003, to give epoxide intermediate, (iv)-isomer 2. Epoxide opening is carried out with 6H- dibenzo[£,/][l,4,5]oxathiazepine 5,5-dioxide in the presence of a base such as Na H₂ in toluene with heating for 50 - 100°C for between 1 and 24 hours. Deprotection of the benzyl group is carried out by hydrogenolysis with a catalyst such as palladium on carbon or palladium hydroxide, to give the PP2A modulator.

[00210] Synthesis of compounds with cyclic sulfone, Q = SO2

[0021 1] Synthesis of 3,6-dihydro-2H-thiopyran-3-ol is described in Evans et al, J. Am. Chem. Soc. 2000, Vol. 122, Pages 7095 - 7920. This may be converted to fert-butyl (3,6- dihydro-2H-thiopyran-3-yl) carbonate as already described and used in the synthesis of PP2A modulators in two ways. First as shown in by the example in Scheme 7, where conditions are analogous to those described for the pyran, except that additional oxidant may be employed the dihydroxylation step to effect oxidation of the ring sulfur. Extended reaction times or heating may also be used in the dihydroxylation step.

[00212] Scheme 7

[00213] A second route to the cyclic sulfone is shown in Procedure F; again additional oxidant or extended reaction times may be used in the epoxidation step to effect oxidation of the ring sulfur.

[00214] Procedure F

[00215] Synthesis of acyclic examples: Example 12 and Example 13

[00216] 2-(3-(5,5-dioxido-6H-dibenzo [b,f] [1,4,5] oxathiazepin-6- yl)propyl)isoindoline-l,3-dione. A solution of 6H-dibenzo[b,fJ[l,4,5]oxathiazepine 5,5- dioxide (0.300 g, 1.21 mmol) in DMF (1.0 mL) was cooled to 0 °C, treated with sodium hydride (60% wt. suspension in mineral oil, 0.097 g, 2.42 mmol), stirred for 15 minutes, then treated with 2-(3-bromopropyl)isoindoline-l,3-dione (0.421 g, 1.57 mmol). The mixture was warmed to 25 °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 50 mL). The organic layers were combined, washed with saturated aqueous NaCl (3 x 50 mL), dried (Na₂S04), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH2CI2 and purified by flash

chromatography (S1O2, 35% ethyl acetate-hexanes) to afford the title compound as a beige solid (0.418 g, 80%). ¾ MR (600 MHz, CDCI3) δ 7.84 (1H, dd, J = 7.8, 1.2 Hz), 7.83 (2H, dd, J= 5.4, 3.0 Hz), 7.71 (1H, dd, J = 4.8, 2.4 Hz), 7.62 (1H, dd, J = 7.8, 1.2 Hz), 7.51 (1H, td, J= 8.4, 1.2 Hz), 7.37 (1H, qd, J = 7.8, 1.2 Hz), 7.33 (1H, d, J= 7.8 Hz), 7.30 (2H, q, J = 6.6 Hz), 7.25 (1H, t, J = 7.8 Hz); 7.12-7.17 (1H, m), 3.84 (1H, t, J = 7.8 Hz), 3.76 (1H, t, J= 6.6 Hz), 1.96 (1H, quintet, J = 7.2 Hz); ¹ C MR (600 MHz, CDCI3) δ 168.4, 156.0, 152.3, 134.2, 134.0, 132.6, 132.2, 131.6, 130.8, 130.7, 129.0, 126.9, 124.7, 123.5, 122.7, 122.3, 49.1, 35.6, 27.7; LCMS m/z 435.1027 ([M + H⁺], C23H18N2O5S requires 435.1009).

[00217] 6-(3-aminopropyl)-6H-dibenzo[b,f] [l,4,5]oxathiazepine 5,5-dioxide. A solution of 2-(3 -(5 , 5-dioxido-6H-dibenzo [b, fj [ 1 ,4, 5 ] oxathiazepin-6-yl)propyl)isoindoline- 1,3-dione (0.418 g, 0.963 mmol) in ethanol (2.0 mL) was treated with hydrazine hydrate (0.093 mL, 1.93 mmol), warmed to 90 °C and stirred for 2 h. The mixture was cooled to 25 °C, filtered, and concentrated in vacuo. The residue was dissolved in a minimal amount of CH2CI2 and purified by flash chromatography (S1O2, 17:2: 1 CH₂Cl₂:MeOH: H₄OH) to afford the title compound as a clear oil (0.229 g, 78%). ¾ NMR (600 MHz, CDCI3) δ 7.85 (1H, br s), 7.50 (1H, br s), 7.43 (1H, br s), 7.17-7.36 (5H, m), 3.71 (2H, br s), 2.85 (2H, br s), 1.75 (2H, br s), 1.71 (2H, br s); ¹ C NMR (600 MHz, CDCI3) δ 155.9, 152.2, 133.9, 132.1, 131.4, 131.1, 130.5, 129.0, 126.7, 124.6, 122.7, 122.2, 49.0, 38.9, 32.1; LCMS m/z 305.0957 ([M + H⁺], Ci₅Hi₆N₂0₃S requires 305.0954).

[00218] N-(3-(5,5-dioxido-6H-dibenzo [b,f] [1,4,5] oxathiazepin-6-yl)propyl)-4- (trifluoromethoxy)benzenesulfonamide (Example 12). A solution of 6-(3-aminopropyl)- 6H-dibenzo[b,fJ[l,4,5]oxathiazepine 5,5-dioxide (0.072 g, 0.238 mmol) in CH₂C1₂ (1.5 mL) was cooled to 0 °C, treated with Et₃N (36.3 \L, 0.262 mmol), and 4- trifluoromethoxybenzenesulfonyl chloride (44.4 \L, 0.262 mmol). The mixture was warmed to 25 °C, and stirred for 2 h. The mixture was partitioned between saturated aqueous NaCl (50 mL) and CH₂C1₂ (50 mL). The organic layer was washed with saturated aqueous NaCl (20 mL), dried (Na₂SC"4), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH₂C1₂ and purified by flash chromatography (Si0₂, 0- 35% ethyl acetate-hexanes) to afford Example 12 (0.109 g, 86%). ¾ NMR (600 MHz, CDC1₃) δ 7.93 (2H, br s), 7.84 (1H, br s), 7.54 (1H, br s), 7.40 (1H, br s), 7.30-7.34 (4H, m), 7.27 (2H, br s), 5.23 (1H, s), 3.71 (2H, s), 3.25 (2H, s), 1.81 (2H, s); ¹ C NMR (150 MHz, CDC1₃) δ 155.9, 152.3, 145.5, 138.7, 134.3, 131.9, 131.3, 131.0, 130.7, 129.4, 129.1, 126.9, 124.9, 123.0, 122.8, 122.4, 121.3, 48.7, 39.9, 29.1; LCMS m/z 529.0771 ([M + H⁺], C22H19F3N2O6S2 requires 529.0709).

[00219] 6-allyl-6H-dibenzo[b,f] [l,4,5]oxathiazepine 5,5-dioxide. A solution of 6H- dibenzo[b,fJ[l,4,5]oxathiazepine 5,5-dioxide (0.300 g, 1.21 mmol) in DMF (1.0 mL) was cooled to 0 °C, treated with sodium hydride (60% wt. suspension in mineral oil, 0.097 g, 2.42 mmol), stirred for 15 minutes, then treated with allyl bromide (0.21 mL, 2.42 mmol). The mixture was warmed to 25 °C, stirred for 14 h, then poured over a solution of saturated aqueous ammonium chloride (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2CI2 (3 x 50 mL). The organic layers were combined, 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, 10% ethyl acetate-hexanes) to afford the title compound as a clear oil which solidified slowly upon standing (0.342 g, 98%). ¾ NMR (600 MHz, CDCI3) δ 7.86 (1H, dd, J= 7.8, 1.2 Hz), 7.51 (1H, td, J= 9.0, 1.8 Hz), 7.39 (1H, dd, J= 7.8, 1.8 Hz), 7.34 (1H, t, J= 8.4, 1.8 Hz), 7.33 (1H, d, J= 7.8 Hz), 7.27 (1H, dd, J= 8.4, 1.8 Hz), 7.22- 7.26 (2H, m), 5.84-5.90 (1H, m), 5.15 (1H, dd, J= 16.8, 1.2 Hz), 5.12 (1H, d, J= 10.2 Hz), 4.25 (1H, d, J= 6.6 Hz); ¹ C NMR (150 MHz, CDCI3) δ 155.5, 152.3, 134.0, 132.5, 132.1, 131.9, 130.9, 130.4, 128.9, 126.5, 124.6, 122.5, 122.3, 119.9, 54.6; LCMS m/z 288.0692 ([M + H⁺], C15H13NO3S requires 288.0689).

[00220] 6-(oxiran-2-ylmethyl)-6H-dibenzo[b,f] [1,4,5] oxathiazepine 5,5-dioxide. A solution of 6-allyl-6H-dibenzo[b,f][l,4,5]oxathiazepine 5,5-dioxide (0.337 g, 1.17 mmol) in CH2CI2 (2.0 mL) was cooled to 0 °C and treated with 3-chloroperbenzoic acid (0.404 g, 2.34 mmol). The mixture was warmed to 25 °C, stirred for 14 h, then poured over a solution of saturated aqueous NaHCC (50 mL). The mixture was extracted into CH2CI2 (3 x 50 mL), and the combined organic layers were washed with saturated aqueous NaCl (100 mL), dried (Na₂SC"4), and concentrated in vacuo. The residue was purified by flash chromatography (S1O2, 0-10% ethyl acetate-hexanes) to afford the title compound (0.352 g, 99%) as a clear film. ¾ NMR (600 MHz, CDC1₃) δ 7.87 (1H, dd, J= 7.8, 1.8 Hz), 7.56 (1H, d, J= 7.2 Hz), 7.51-7.55 (1H, m), 7.37-7.41 (1H, m), 7.35 (1H, d, J= 7.8 Hz), 7.30 (1H, d, J= 7.2 Hz), 7.23-7.27 (2H, m), 3.90 (1H, dd, J= 14.4, 4.2 Hz), 3.70 (1H, dd, J = 14.4, 6.0 Hz), 3.28 (1H, septet, J= 4.2 Hz), 2.78 (1H, t, J= 4.2 Hz), 2.78 (1H, dd, J= 4.2, 2.4 Hz); ¹ C NMR (150 MHz, CDCI3) δ 155.9, 152.2, 133.9, 132.1, 131.4, 131.1, 130.5, 129.0, 126.7, 124.6, 122.7, 122.2, 49.0, 38.9, 32.1; LCMS m/z 304.0638 ([M + H⁺], C15H13NO4S requires 304.0638).

[00221 ] 6-(3-azido-2-hydroxypropyl)-6H-dibenzo [b,f] [1,4,5] oxathiazepine 5,5- dioxide. A solution of 6-(oxiran-2-ylmethyl)-6H-dibenzo[b,f][l,4,5]oxathiazepine 5,5- dioxide (0.342 g, 1.13 mmol) in 4: 1 ethanol:H₂0 (5.0 ml) was treated with sodium azide (0.096, 1.47 mmol), ammonium chloride (0.078 g, 1.47 mmol) and heated to 80 °C for 14 h. The mixture was cooled to 25 °C and concentrated in vacuo. The residue was dissolved in a minimal amount of CH₂C1₂ and purified by flash chromatography (Si0₂, 0-20% ethyl acetate-hexanes) to afford the title compound as a clear oil (0.285 g, 73%). ¾ NMR (600 MHz, CDCI3) δ 7.76-7.78 (1H, m), 7.44-7.46 (2H, m), 7.27-7.31 (2H, m), 7.19-7.24 (3H, m), 3.96 (1H, br s), 3.62-3.73 (2H, m), 3.41-3.44 (1H, m), 3.32-3.34 (1H, m), 2.67 (1H, br s); ¹ C NMR (150 MHz, CDCI3) δ 155.7, 152.3, 134.3, 132.2, 131.8, 131.0, 130.9, 129.1, 127.1, 125.0, 122.9, 122.3, 69.5, 55.3, 54.2; LCMS m/z 319.0739 ([M⁺ - N₂], C15H14N4O4S requires 319.0747).

[00222] 6-(3-amino-2-hydroxypropyl)-6H-dibenzo [b,f] [1,4,5] oxathiazepine 5,5- dioxide. A solution of 6-(3-azido-2-hydroxypropyl)-6H-dibenzo[b,f][l,4,5]oxathiazepine 5,5-dioxide (0.265 g, 0.765 mmol) in THF (1.0 mL) was cooled to 0 °C, treated with PPh₃ (0.261 g, 0.994 mmol), H₂0 (0.1 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-CH₂Cl₂ to remove triphenylphosphine oxide and 17:2: 1

CH2Cl2:MeOH: H40H 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 (0.205 g, 84%). ¾ NMR (600 MHz, CDC1₃) δ 7.85 (1H, d, J= 7.8 Hz), 7.52 (2H, d, J= 7.2 Hz), 7.38 (1H, td, 7= 7.8, 0.6 Hz), 7.35 (1H, d, 7= 8.4 Hz), 7.31 (1H, d, 7= 7.8 Hz), 7.25- 7.28 (1H, m), 7.18 (1H, d, 7= 7.2 Hz); 3.78 (1H, quintet, 7= 5.4 Hz), 3.69 (1H, dd, 7 = 13.2, 5.4 Hz), 3.64 (1H, dd, 7= 14.4, 7.2 Hz), 2.90 (1H, dd, 7= 13.2, 4.2 Hz), 2.85 (1H, dd, 7= 13.2, 6.0 Hz), 2.37 (1H, s), 2.02-2.24 (2H, br m); ¹ C NMR (150 MHz, CDC1₃) δ 155.8, 134.1, 132.2, 132.0, 130.7, 129.3, 129.1, 128.4, 126.9, 124.8, 122.8, 122.3, 69.9, 55.1, 44.2; LCMS m/z 321.0900 ([M + H⁺], C15H16N2O4S requires 321.0904).

[00223 ] N-(3-(5,5-dioxido-6H-dibenzo [b,f] [1,4,5] oxathiazepin-6-yl)-2- hydroxypropyl)-4-(trifluoromethoxy)benzenesulfonamide (Example 13). A solution of 6-(3-amino-2-hydroxypropyl)-6H-dibenzo[b,f][l,4,5]oxathiazepine 5,5-dioxide (0.075 g, 0.234 mmol) in CH2CI2 (1.5 mL) was cooled to 0 °C, treated with Et₃N (35.6 μί, 0.257 mmol), and 4-trifluoromethoxybenzenesulfonyl chloride (43.6 \L, 0.257 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 (50 mL). The organic layer was washed with saturated aqueous NaCl (20 mL), dried (Na₂S04), 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 Example 13(0.0841 g, 66%) as a clear oil. ¾ NMR (600 MHz, CDC1₃) δ 7.80 (2H, d, 7= 9.0 Hz), 7.72 (1H, dd, 7= 8.4, 1.8 Hz), 7.45 (1H, td, 7 = 7.2, 1.8 Hz), 7.38 (1H, d, J= 7.8, 1.2 Hz), 7.26-7.30 (2H, m), 7.20-7.24 (3H, m), 7.18 (1H, td, 7= 7.8, 1.2 Hz), 7.15 (1H, td, 7= 7.8, 1.2 Hz), 5.55 (1H, t, 7= 6.6 Hz), 3.85-3.90 (1H, m), 3.60 (1H, dd, 7= 14.4, 7.2 Hz), 3.56 (1H, dd, 7= 14.4, 4.8 Hz), 3.24 (1H, d, 7 = 4.8 Hz), 3.15 (1H, d of dd, 7= 7.2, 4.2 Hz), 2.98 (1H, dt, 7= 13.2, 6.0 Hz); ¹ C MR (150 MHz, CDC1₃) δ 155.7, 152.36, 152.33, 138.1, 134.4, 131.96, 131.94, 131.0, 130.8, 129.5, 129.1, 127.1, 125.0, 122.9, 122.5, 121.3, 119.6, 68.7, 54.9, 45.9; LCMS m/z 545.0681 ([M + H⁺], C22H19F3N2O7S2 requires 545.0659).

Cell viability assays (IC50 determination)

[00224] 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 μL 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 μL 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 :

Table 1. Cell Viability Data

Colony Formation Assay

[00225] Protocol for clonogenic assay follows Sangodkar et al, J Clin Invest

2012;122:2637-51.

[00226] Cell culture and staining: For both A5491uc and HI 650 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 H1650 cells may be analyzed separately.

In vivo cancer model

[00227] To assess the in vivo effects of the compounds, subcutaneous xenograft of lung cancer cell line H441 is generated. Cells (5 ^χ 10⁶) are injected into the right flank of 6- to 8-week-old male BALB/c nu/nu mice (Charles River, Wilmington, MA). Tumor volume is assessed twice a week by caliper measurement. Mice are randomized to treatment groups based on initial tumor volume average of 100mm³ per group. Mice are dosed by oral gavage with, for example, 15 mg/kg QD, 15 mg/kg BID, 50 mg/kg QD, or 50 mg/kg.

BID. 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 is calculated as: weight at each time point/initial weight xlOO. Animals are observed for signs of toxicity (mucous diarrhea, abdominal stiffness and weight loss). 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.

[00228] Various embodiments of the invention can be described in the text below:

[ 1 ] . A compound of formula I:

I

wherein:

B is chosen from a direct bond, O, S, SO2 and NR^B;

R^B is selected from hydrogen and (Ci-C6)alkyl;

T is a benzene ring or a five- or six-membered heteroaromatic ring;

U is a benzene ring or a five- or six-membered heteroaromatic ring;

X¹, X², X³, and X⁴ are independently selected in each instance from hydrogen, halogen, nitro, cyano, (Ci-C₆)alkyl, (Ci-C₆)haloalkyl, (Ci-C₆)haloalkoxy, -NR¾², -OR¹, - C(0)R^!, -0C(0)R¹, -C(0)NR¹R², -C(0)0R¹, -SR¹, -SO2R¹, and -SCh ^R²;

R¹ and R² are independently selected in each instance from the group consisting of hydro en and (Ci-Ce)alkyl;

or, when B is a direct bond, may be additionally chosen from:

wherein a is the point of attachment to ring T, b is the point of attachment to ring U, and c is the point of attachment to R⁵;

R^A is -(CR¹⁵R¹⁶)p-D_q-(CR¹⁵R¹⁶)„-p

D is chosen from -0-, -NR¹⁴- and

R¹⁴ is H or (Ci-C₃)alkyl; R¹⁵ and R¹⁶ in each occurrence are chosen independently from H, OH, cyano, amino, (Ci-C3)alkylamino, (Ci-C3)dialkylamino, (Ci-C₃)alkyl, (Ci-C₃)haloalkyl, (Ci-C₃)haloalkoxy, and (Ci-C₃)alkoxy, or, taken together, two of R¹⁴, R¹⁵ and R¹⁶ may form a three to seven membered carbocycle or heterocycle wherein said three to seven membered carbocycle or heterocycle may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (Ci-C₃)alkylamino, (Ci-C₃)dialkylamino, (Ci-C₃)alkyl, (Ci-C₃)haloalkyl, (Ci- C₃)haloalkoxy, and (Ci-C₃)alkoxy;

n is an integer from 2 to 4;

p is zero, 1 or 2;

q is zero or 1;

t is zero, 1 or 2;

v is 1, 2 or 3;

Z is selected from the group consisting of: - HSO2R¹⁷, - HC(0) R⁸R⁹, - HC(0)OR⁸, -S(0)₂ R⁸R⁹, substituted or unsubstituted cyclic carbamate; substituted or unsubstituted cyclic urea, cyclic imide, cyanoguanidine;

R⁸ and R⁹ are independently selected from H, substituted or unsubstituted (Ci- C₆)alkyl, and substituted or unsubstituted (C₃-C₇) cycloalkyl; and

R¹⁷ is chosen from phenyl and monocyclic heteroaryl, said phenyl and monocyclic heteroaryl optionally substituted with one or two substituents chosen from hydrogen, halogen, nitro, cyano, azide, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (Ci-Ce)haloalkoxy, -NR^R², - R¹C(0)R², -OR¹, -C(0)R¹, -OC(0)R¹, -C(0) R¹R², -C(0)OR¹, -SR¹, -SO2R¹, and - SOi R!R².

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

II

wherein q is 0 or 1;

Y is hydrogen or hydroxyl;

R⁶ and R⁷ are each independently selected in each instance from hydrogen and (Ci- Ce)alkyl, or, when q is 1, R⁶ and R⁷ together with the carbons to which they are attached, may form an optionally substituted carbocyclic or heterocyclic ring; and

Ar is an optionally substituted aromatic or heteroaromatic ring, wherein said substituents are selected from hydrogen, halogen, nitro, cyano, azide, (Ci-Ce)alkyl, (Ci- C₆)haloalkyl, (Ci-C₆)haloalkoxy, - R¾², - R¹C(0)R², -OR¹, -C(0)R¹, -OC(0)R¹, - C(0) R¹R², -C(0)OR¹, -SR¹, -SO2R¹, and -SCh ^R².

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

III

wherein

Q is selected from -(CH2),-, -0-, S(0)_p-, and - R^Q-;

p is zero, 1 or 2;

t is zero, 1 or 2;

R^Q is selected from hydrogen; optionally substituted (Ci-Ce)alkyl, (C₃-C₇)cycloalkyl, aryl, or heteroaryl; -SO2R³; -S0₂N(R R⁴); -C(=0)R⁵; -C(=0)OR⁵; or -C(=0)N(R R⁴); wherein said substituents on the (Ci-Ce)alkyl, (C₃-C₇)cycloalkyl, aryl, or heteroaryl are selected from the group consisting of 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;

R³ and R⁴ are independently selected in each instance from hydrogen, (Ci-Ce)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;

R⁵ is selected from hydrogen, optionally substituted (Ci-C₄)alkyl, or optionally substituted aryl, wherein said optional substituents are selected from the group consisting of (Ci-C₃)alkyl, OR¹, H₂, HMe, N(Me)₂, and heterocycle;

Y is hydrogen or hydroxyl; and

Ar is an optionally substituted aromatic or heteroaromatic ring, wherein said substituents are selected from hydrogen, halogen, nitro, cyano, azide, (Ci-Ce)alkyl, (Ci- C₆)haloalkyl, (Ci-C₆)haloalkoxy, - R¾², - R^!C(0)R², -OR¹, -C(0)R¹, -OC(0)R¹, - C(0) R¹R², -C(0)OR¹, -SR¹, -SO*¹, and -SO^^².

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

[5]. A compound of [1] above, or according to other embodiments of the invention, wherein B is -0-.

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

[7]. A compound of [1] above, or according to other embodiments of the invention, wherein B is -S0₂-.

[8]. A compound of [1] above, or according to other embodiments of the invention, wherein B is - R^B-.

[9]. A compound of [1 2], [3], or [4] above or according to other embodiments of the

invention, wherein

[10]. A compound of [1 [2], [3], or [4] above, or according to other embodiments

of the invention, wherein

[11]. A compound of [1], [2], or [3] above, or according to other embodiments of

the invention, wherein B is a direct bond and

[12]. A compound of [1], [2], or [3] above, or according to other embodiments of

the invention, wherein B is a direct bond and

[13]. A compound of [1], [2], or [3] above, or according to other embodiments of

the invention, wherein B is a direct bond and

[14]. A compound of [1], [2], or [3] above, or according to other embodiments of

the invention, wherein B is a direct bond and is

[15]. A compound of [1] above, or according to other embodiments of the invention, wherein T and U are each independently selected from the group consisting of a benzene ring and pyridine.

[16]. A compound of [15] above, or according to other embodiments of the invention, wherein at least one of T and U is a benzene ring. [17]. A compound of [16] above, or according to other embodiments of the invention, wherein both T and U are benzene rings.

[18]. A compound of [2] or [3]above, or according to other embodiments of the invention, wherein Y is hydroxyl.

[19]. A compound of [2] or [3] above, or according to other embodiments of the invention, wherein Y is hydrogen.

[20]. A compound of [3] above, or according to other embodiments of the invention, wherein Q is -(CH₂)t-.

[21]. A compound of [20] above, or according to other embodiments of the invention, wherein t is 1.

[22]. A compound of [20] above, or according to other embodiments of the invention, wherein t is 2.

[23]. A compound of [3] above, or according to other embodiments of the invention, wherein Q is -0-.

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

[25]. A compound of [24] above, or according to other embodiments of the invention, wherein R^Q is hydrogen; (Ci-C6)alkyl optionally substituted with one or more of hydroxy, fluoro, or (C3-C?)cycloalkyl; (C3-C?)cycloalkyl optionally substituted with one or more of hydroxy, methyl, or fluoro; aryl optionally substituted with one or more of hydroxy, methoxy, halogen, (Ci-C3)haloalkyl, nitro, amino, or methyl; heteroaryl optionally substituted with one or more of hydroxy, methoxy, halogen, (Ci-C3)haloalkyl, nitro, amino, or methyl; -S0₂R³; -S0₂ R R⁴; -C(=0)R⁵; -C(=0)OR⁵; or -C(=0) R R⁴;

R³ is selected in each instance from hydrogen, (Ci-Ce)alkyl, (Ci-Ce)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;

R⁴ is selected in each instance from hydrogen and methyl;

R⁵ 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, H₂,

HMe, N(Me)₂, or heterocycle. [26]. A compound of [25] 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 or fluoro; (C₃-C7)cycloalkyl optionally substituted with one or more of hydroxy, methyl, or fluoro; phenyl optionally substituted with one or more of hydroxy, chloro, fluoro, methoxy, nitro, amino, trifluoromethyl, or methyl; or a nitrogen-containing heteroaryl optionally substituted with one or two methyl groups.

[27]. A compound of [24] above, or according to other embodiments of the invention, wherein R^Q is -C(=0)R⁵.

[28]. A compound of [27] above, or according to other embodiments of the invention, wherein R⁵ is selected from (Ci-C4)alkyl, optionally substituted with OR¹, NH₂, NHMe, N(Me)₂, and heterocycle.

[29]. A compound of [24] above, or according to other embodiments of the invention, wherein R^Q is -C(=0)OR⁵.

[30]. A compound of [29] above, or according to other embodiments of the invention, wherein R⁵ is selected from the group consisting of phenyl and (Ci-C4)alkyl, each of which may be substituted with OR¹.

[31]. A compound of [24] above, or according to other embodiments of the invention, wherein R^Q is -SO2R³.

[32]. A compound of [31] above, or according to other embodiments of the invention, wherein wherein R³ is selected from the group consisting of hydrogen, (Ci-Ce)alkyl, and aryl; wherein said aryl is optionally substituted with hydroxy, halogen, cyano, amino, or (Ci-C4)alkoxy.

[33]. A compound of [24] above, or according to other embodiments of the invention, wherein R^Q is S0₂NR R⁴.

[34]. A compound of [33] above, or according to other embodiments of the invention, wherein R³ is selected from the group consisting of hydrogen, (Ci-C₃)alkyl, and optionally substituted aryl; and R⁴ is hydrogen or methyl.

[35]. A compound of [24] above, or according to other embodiments of the invention, wherein R^Q is -C(=0)NR R⁴.

[36]. A compound of [35] above, or according to other embodiments of the invention, wherein R³ is selected from the group consisting of hydrogen, (Ci-C₃)alkyl, and aryl optionally substituted with hydroxy, halogen, cyano, amino, or methoxy; and R⁴ is hydrogen or methyl.

[37]. A compound of [3] above, or according to other embodiments of the invention, wherein Q is -S(0)_p-.

[38]. A compound of [37] above, or according to other embodiments of the invention, wherein p is 2.

[39]. A compound of [37] above, or according to other embodiments of the invention, wherein p is 1.

[40]. A compound of [37] above, or according to other embodiments of the invention, wherein p is 0.

[41]. A compound of [2] above, or according to other embodiments of the invention, wherein q is 0.

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

[43]. A compound of [42] above, or according to other embodiments of the invention, wherein Y is hydrogen.

[44]. A compound of [42] above, or according to other embodiments of the invention, Y is hydroxyl.

[45]. A compound of [41], [42], [43], or [44] above, or according to other embodiments of the invention, wherein R⁶ and R⁷ are each hydrogen.

[46]. A compound of [2] or [3] above, or according to other embodiments of the invention, wherein Ar is phenyl substituted with Z¹ and Z²; and

Z¹ and Z² are independently selected in each instance from the group consisting of hydrogen, halogen, nitro, cyano, azide, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci- C₆)haloalkoxy, - R¾², - R¹C(0)R², -OR¹, -C(0)R¹, -OC(0)R¹, -C(0) R¹R², - C(0)OR¹, -SR¹, -SO2R¹, and -SCh ^R².

[47]. A compound of [46] above, or according to other embodiments of the invention, wherein Z¹ and Z² are independently selected in each instance from hydrogen, halogen, (Ci-Ce)haloalkyl, (Ci-C6)alkoxy, and (Ci-C6)haloalkoxy. [48]. A compound of [47] above, or according to other embodiments of the invention, wherein Z¹ is hydrogen and Z² is selected from hydrogen, halogen, (Ci-C6)haloalkyl, (Ci- C6)alkoxy, and (Ci-C6)haloalkoxy.

[49]. A compound of [48] above, or according to other embodiments of the invention, wherein Z² is hydrogen, fluoro, chloro, trifluoromethyl, methoxy, or trifluoromethoxy.

[50]. A compound of [49] above, or according to other embodiments of the invention, wherein Z² is para to the attachment of the phenyl ring to the sulfonyl.

[51]. A compound of [1], [2], or [3] above, or according to other embodiments of the invention, wherein zero, one or two of X¹, X², X³, and X⁴ are independently selected in each instance from halogen, (Ci-Ce)alkyl, and (Ci-Ce)haloalkyl, and the remainder are hydrogen.

[52]. A compound of [51] above, or according to other embodiments of the invention, wherein zero, one or two of X¹, X², X³, and X⁴ are independently selected in each instance from (Ci-C )alkyl, chloro, fluoro, and fluoro(Ci-C )alkyl, and the remainder are hydrogen.

[53]. A compound of [3] above, or according to other embodiments of the invention, wherein the relative stereochemistr is of formula IV:

IV.

[54]. A compound of [53] above, or according to other embodiments of the invention, of formula IVa:

IVa.

[55]. A compound of [53] above, or according to other embodiments of the invention, of formula IVb:

IVb.

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

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

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

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

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

XI.

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

X.

[62]. A compound of [56], [57], [58], [59], [60], or [61] above, or according to other embodiments of the invention, wherein Z¹ is hydrogen and Z² is selected from hydrogen, halogen, halo(Ci-C6)alkyl, (Ci-Ce)alkoxy, or halo(Ci-C6)alkoxy.

[63]. A compound of [62] above, or according to other embodiments of the invention, wherein Z² is hydrogen, fluoro, chloro, trifluoromethyl, methoxy, or trifluoromethoxy

[64]. A compound of [63] above, or according to other embodiments of the invention, wherein Z² is trifluoromethoxy.

[65]. A compound of [56], [57], [58], [59], [60], or [61] above, or according to other embodiments of the invention, wherein zero, one or two of X¹, X², X³, and X⁴ are independently selected in each instance from halogen, (Ci-Ce)alkyl, and halo(Ci-Ce)alkyl, and the remainder are hydrogen. [66]. A compound of [65] above, or according to other embodiments of the invention, wherein one or two of X¹, X², X³, and X⁴ are independently selected in each instance from (Ci-C3)alkyl, chloro, fluoro, and fluoro(Ci-C3)alkyl, and the remainder are hydrogen.

[67]. A compound of [57], [59], or [61] above, or according to other embodiments of the invention, wherein R⁶ and R⁷ are each hydrogen.

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

(a) cancer

(b) diabetes

(c) autoimmune disease

(d) age onset proteotoxic disease

(e) mood disorder

(f) acne vulgaris

(g) solid organ transplant rejection

(h) graft vs. host disease

(i) cardiac hypertrophy

(j) viral infection and

(k) parasitic infection;

the method comprising administering to the patient a therapeutically effective amount of a compound of any of [1] to [8], [15] to [17], [20] to [44], or [53] to [61] above, or according to other embodiments of the invention.

[69]. The method of [68] 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.

[70]. The method of [68] above, or according to other embodiments of the invention, for treating cancer, wherein said cancer is chemotherapy resistant cancer.

[71]. The method of [70] above, or according to other embodiments of the invention, wherein the method further comprises administering one or more additional cancer chemotherapeutic agents.

[72]. The method of [68] above, or according to other embodiments of the invention, for treating an age onset proteotoxic disease, wherein said disease is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

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

[74]. The method of [73] above, or according to other embodiments of the invention, wherein said viral infection is caused by a virus selected from the group consisting of influenza, HIV-1, HPV, adenovirus, BKV, EBV, JCV, HCV, MCV, polyomavirus, SV40, HTLV-1, HSV-1, CMV, hepatitis B, BPV-1, human T-cell lymphotropic virus type 1, Japanese encephalitis virus, RSV, and West Nile virus.

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

[76]. The method of [75] above, or according to other embodiments of the invention, wherein said parasitic infection is caused by a parasite selected from the group consisting of Plasmodium and Theileria.

[77]. 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 [8], [15] to [17], [20] to [44], or [53] to [61] above, or according to other embodiments of the invention.

[78]. 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 [8], [15] to [17], [20] to [44], or [53] to [61] above, or according to other embodiments of the invention.

[79]. 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 [8], [15] to [17], [20] to [44], or [53] to [61] above, or according to other embodiments of the invention.

[80]. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any of [1] to [8], [15] to [17], [20] to [44], or [53] to [61] above, or according to other embodiments of the invention. [00229] Various embodiments of the invention can be described in the text below:

[101]. A compound of form la I:

I

wherein:

B is chosen from a direct bond, O, S, SO2 and R^B;

R^B is selected from hydrogen and (Ci-C6)alkyl;

T is a benzene ring or a five- or six-membered heteroaromatic ring;

U is a benzene ring or a five- or six-membered heteroaromatic ring;

X¹, X², X³, and X⁴ are independently selected in each instance from hydrogen, halogen, nitro, cyano, (Ci-C₆)alkyl, (Ci-C₆)haloalkyl, (Ci-C₆)haloalkoxy, - R¾², -OR¹, C(0)R!, -0C(0)R¹, -C(0) R¹R², -C(0)0R¹, -SR¹, -SO2R¹, and -SCh ^R²;

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

> chosen from

and or, when B is a direct bond, may be additionally chosen from:

wherein a is the point of attachment to ring T, b is the point of attachment to ring U, and c is the point of attachment to R⁵; R^A is -(CR¹⁵R¹⁶)p-D_q-(CR¹⁵R¹⁶)„-p-Z

O

D is chosen from -0-, -NR¹⁴- and °> ° ;

R¹⁴ is H or (Ci-C₃)alkyl;

R¹⁵ and R¹⁶ in each occurrence are chosen independently from H, OH, cyano, amino, (Ci-C )alkylamino, (Ci-C )dialkylamino, (Ci-C )alkyl, (Ci-C )haloalkyl, (Ci-C )haloalkoxy, and (Ci-C )alkoxy, or, taken together, two of R¹⁴, R¹⁵ and R¹⁶ may form a three to seven membered carbocycle or heterocycle wherein said three to seven membered carbocycle or heterocycle may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (Ci-C )alkylamino, (Ci-C )dialkylamino, (Ci-C )alkyl, (Ci-C )haloalkyl, (Ci- C )haloalkoxy, and (Ci-C )alkoxy;

n is an integer from 2 to 4;

p is zero, 1 or 2;

q is zero or 1;

t is zero, 1 or 2;

v is 1, 2 or 3;

Z is selected from the group consisting of: -NHSO2R¹⁷, -NHC(0)NR⁸R⁹, - NHC(0)OR⁸, -S(0)₂NR⁸R⁹, substituted or unsubstituted cyclic carbamate; substituted or unsubstituted cyclic urea, cyclic imide, cyanoguanidine;

R⁸ and R⁹ are independently selected from H, substituted or unsubstituted (Ci- C₆)alkyl, and substituted or unsubstituted (C -C₇) cycloalkyl; and

R¹⁷ is chosen from phenyl and monocyclic heteroaryl, said phenyl and monocyclic heteroaryl optionally substituted with one or two substituents chosen from hydrogen, halogen, nitro, cyano, azide, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (Ci-Ce)haloalkoxy, -NR^R², - NR¹C(0)R², -NR¹C(0)OR²⁰, -OR¹, -C(0)R¹, -OC(0)R¹, -C(0)NR¹R², -C(0)OR¹, -SR.¹, - SO2R¹, and -S0₂NR¹R²; and

R²⁰ is (Ci-Cs)hydrocarbon [102]. A compound of [101] above, or according to other embodiments of the invention, of formula II:

II

wherein

q is 0 or 1 ;

Y is hydrogen or hydroxyl;

R⁶ and R⁷ are each independently selected in each instance from hydrogen and (Ci- Ce)alkyl, or, when q is 1, R⁶ and R⁷ together with the carbons to which they are attached, may form an optionally substituted carbocyclic or heterocyclic ring; and

Ar is an optionally substituted aromatic or heteroaromatic ring, wherein said substituents are selected from hydrogen, halogen, nitro, cyano, azide, (Ci-Ce)alkyl, (Ci- C₆)haloalkyl, (Ci-C₆)haloalkoxy, - R¾², - R¹C(0)R², - R¹C(0)OR²⁰, -OR¹, -C(0)R¹, OC(0)R¹, -C(0) R¹R², -C(0)OR¹, -SR¹, -SO2R¹, and -SCh ^R².

[103]. A compound of [101] above, or according to other embodiments of the invention, of formula III:

III

wherein

Q is selected from -(CH2),-, -0-, S(0)_p-, and - R^Q-;

p is zero, 1 or 2; t is zero, 1 or 2;

R^Q is selected from hydrogen; optionally substituted (Ci-C6)alkyl, (C₃-C₇)cycloalkyl, aryl, or heteroaryl; -S0₂R³; -S0₂N(R R⁴); -C(=0)R⁵; -C(=0)OR⁵; or -C(=0)N(R R⁴); wherein said substituents on the (Ci-Ce)alkyl, (C₃-C₇)cycloalkyl, aryl, or heteroaryl are selected from the group consisting of 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;

R³ and R⁴ are independently selected in each instance from hydrogen, (Ci-Ce)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;

R⁵ is selected from hydrogen, optionally substituted (Ci-C4)alkyl, or optionally substituted aryl, wherein said optional substituents are selected from the group consisting of (Ci-C₃)alkyl, OR¹, H₂, HMe, N(Me)₂, and heterocycle;

Y is hydrogen or hydroxyl; and

Ar is an optionally substituted aromatic or heteroaromatic ring, wherein said substituents are selected from hydrogen, halogen, nitro, cyano, azide, (Ci-Ce)alkyl, (Ci- C₆)haloalkyl, (Ci-C₆)haloalkoxy, - R¾², - R^!C(0)R², - R¹C(0)OR²⁰, -OR¹, -C(0)R¹, - OC(0)R¹, -C(0) R¹R², -C(0)OR¹, -SR.¹, -SO*¹, and -SO^^².

[ 104] . A compound of [ 101 ] above, or according to other embodiments of the invention, wherein B is a direct bond.

[105]. A compound of [ 101 ] above, or according to other embodiments of the invention, wherein B is -0-.

[ 106] . A compound of [ 101 ] above, or according to other embodiments of the invention, wherein B is -S-.

[ 107] . A compound of [ 101 ] above, or according to other embodiments of the invention, wherein B is -S0₂-.

[108]. A compound of [104], [105], [106], [107], or [108] above, or according to other embodiments of the invention, wherein B is - R^B-. [109]. A compound of [104], [105], [106], 107], or [108] above, or according to

other embodiments of the invention, wherein

[110]. A compound of [104], [105], [106], 107], or 108] above, or according to

other embodiments of the invention, wherein

[111]. A compound of [ 101 ] , [ 102] , or [ 103 ] above, or according to other

embodiments of the invention, wherein B is a direct bond and '-^-' is

[112]. A compound of [ 101 ] , [ 102] , or [ 103 ] above, or according to other

embodiments of the invention, wherein B is a direct bond and '-^-' is

[113]. A compound of [ 101 ] , [ 102] , or [ 103 ] above, or according to other embodiments of the invention, wherein B is a direct bond and is

[114]. A compound of [101], [102], or [103] above, or according to other embodiments of the invention, wherein B is a direct bond and is

[115]. A compound of [ 101 ] above, or according to other embodiments of the

invention, wherein T and U are each independently selected from the group consisting of a benzene ring and pyridine.

[116]. A compound of [ 115] above, or according to other embodiments of the invention, wherein at least one of T and U is a benzene ring.

[117]. A compound of [ 116] above, or according to other embodiments of the invention, wherein both T and U are benzene rings.

[118]. A compound of [102] or [103] above, or according to other embodiments of the invention, wherein Y is hydroxyl.

[119]. A compound of [ 102] or [ 103 ] above, or according to other embodiments of the invention, wherein Y is hydrogen.

[120]. A compound of [103] above, or according to other embodiments of the invention, wherein Q is -(CH₂)t-.

[121]. A compound of [120] above, or according to other embodiments of the invention, wherein t is 1. [ 122] . A compound of [ 120] above, or according to other embodiments of the invention, wherein t is 2.

[123]. A compound of [103] above, or according to other embodiments of the invention, wherein Q is -0-.

[124]. A compound of [103] above, or according to other embodiments of the invention, wherein Q is - R^Q-.

[125]. A compound of [124] above, or according to other embodiments of the invention, wherein R^Q is hydrogen; (Ci-C6)alkyl optionally substituted with one or more of hydroxy, fluoro, or (C3-C?)cycloalkyl; (C3-C?)cycloalkyl optionally substituted with one or more of hydroxy, methyl, or fluoro; aryl optionally substituted with one or more of hydroxy, methoxy, halogen, (Ci-C3)haloalkyl, nitro, amino, or methyl; heteroaryl optionally substituted with one or more of hydroxy, methoxy, halogen, (Ci-C3)haloalkyl, nitro, amino, or methyl; -S0₂R³; -S0₂ R R⁴; -C(=0)R⁵; -C(=0)OR⁵; or -C(=0) R R⁴;

R³ is selected in each instance from hydrogen, (Ci-Ce)alkyl, (Ci-Ce)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;

R⁴ is selected in each instance from hydrogen and methyl;

R⁵ 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, H₂,

HMe, N(Me)₂, or heterocycle.

[126]. A compound of [125] 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 or fluoro; (C3-C?)cycloalkyl optionally substituted with one or more of hydroxy, methyl, or fluoro; phenyl optionally substituted with one or more of hydroxy, chloro, fluoro, methoxy, nitro, amino, trifluoromethyl, or methyl; or a nitrogen- containing heteroaryl optionally substituted with one or two methyl groups.

[127]. A compound of [124] above, or according to other embodiments of the invention, wherein R^Q is -C(=0)R⁵. [128]. A compound of [127] above, or according to other embodiments of the invention, wherein R⁵ is selected from (Ci-C4)alkyl, optionally substituted with OR¹, H₂, HMe, N(Me)₂, and heterocycle.

[129]. A compound of [1024above, or according to other embodiments of the invention, wherein R^Q is -C(=0)OR⁵.

[130]. A compound of [129] above, or according to other embodiments of the invention, wherein R⁵ is selected from the group consisting of phenyl and (Ci-C4)alkyl, each of which may be substituted with OR¹.

[131]. A compound of [ 124] above, or according to other embodiments of the invention, wherein R^Q is -S0₂R³.

[132]. A compound of [ 131 ] above, or according to other embodiments of the invention, wherein wherein R³ is selected from the group consisting of hydrogen, (Ci- C₆)alkyl, and aryl; wherein said aryl is optionally substituted with hydroxy, halogen, cyano, amino, or (Ci-C4)alkoxy.

[133]. A compound of [124] above, or according to other embodiments of the invention, wherein R^Q is S0₂ R R⁴.

[134]. A compound of [133] above, or according to other embodiments of the invention, wherein R³ is selected from the group consisting of hydrogen, (Ci-C )alkyl, and optionally substituted aryl; and R⁴ is hydrogen or methyl.

[135]. A compound of [124] above, or according to other embodiments of the invention, wherein R^Q is -C(=0) R R⁴.

[136]. A compound of [135] above, or according to other embodiments of the invention, wherein R³ is selected from the group consisting of hydrogen, (Ci-C )alkyl, and aryl optionally substituted with hydroxy, halogen, cyano, amino, or methoxy; and R⁴ is hydrogen or methyl.

[137]. A compound of [103] above, or according to other embodiments of the invention, wherein Q is -S(0)_p-.

[138]. A compound of [137] above, or according to other embodiments of the invention, wherein p is 2.

[139]. A compound of [137] above, or according to other embodiments of the invention, wherein p is 1. [140]. A compound of [137] above, or according to other embodiments of the invention, wherein p is 0.

[141]. A compound of [ 102] above, or according to other embodiments of the invention, wherein q is 0.

[142]. A compound of [102] above, or according to other embodiments of the invention, wherein q is 1.

[143]. A compound of [142] above, or according to other embodiments of the invention, wherein Y is hydrogen.

[144]. A compound of [142] above, or according to other embodiments of the invention, wherein Y is hydroxyl.

[145]. A compound of [141], [142], [143], or [144] above, or according to other embodiments of the invention, wherein R⁶ and R⁷ are each hydrogen.

[146]. A compound of [102] or [103] above, or according to other embodiments of the invention, wherein Ar is phenyl substituted with Z¹ and Z²; and

Z¹ and Z² are independently selected in each instance from the group consisting of hydrogen, halogen, nitro, cyano, azide, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci- C₆)haloalkoxy, - R¾², - R¹C(0)R², - R¹C(0)OR²⁰, -OR¹, -C(0)R¹, -OC(0)R¹, - C(0) R!R², -C(0)0R¹, -SR¹, -SO2R¹, and -SCh ^R².

[147]. A compound of [146] above, or according to other embodiments of the invention, wherein Z¹ and Z² are independently selected in each instance from hydrogen, halogen, (Ci-C₆)haloalkyl, - R¹C(0)OR²⁰, (Ci-C₆)alkoxy, and (Ci-C₆)haloalkoxy

[148]. A compound of [147] above, or according to other embodiments of the invention, wherein Z¹ is hydrogen and Z² is selected from hydrogen, halogen, (Ci- C₆)haloalkyl, - R¹C(0)OR²⁰, (Ci-C₆)alkoxy, and (Ci-C₆)haloalkoxy

[149]. A compound of [148] above, or according to other embodiments of the invention, wherein Z² is hydrogen, fluoro, chloro, trifluoromethyl, -NHBoc, methoxy, or trifluoromethoxy

[150]. A compound of [149] above, or according to other embodiments of the invention, wherein Z² is para to the attachment of the phenyl ring to the sulfonyl.

[151]. A compound of [ 101 ] , [ 102] , or [ 103 ] above, or according to other embodiments of the invention, wherein zero, one or two of X¹, X², X³, and X⁴ are independently selected in each instance from halogen, (Ci-C6)alkyl, and (Ci-Ce)haloalkyl, and the remainder are hydrogen.

[152]. A compound of [ 151 ] above, or according to other embodiments of the invention, wherein zero, one or two of X¹, X², X³, and X⁴ are independently selected in each instance from (Ci-C )alkyl, chloro, fluoro, and fluoro(Ci-C )alkyl, and the remainder are hydrogen.

[153]. A compound of [103] above, or according to other embodiments of the invention, wherein the relative stereochemistry is of formula IV:

IV.

[154]. A compound of [153] above, or according to other embodiments of the invention, of formula IVa:

IVa.

[155]. A compound of [153] above, or according to other embodiments of the invention, of formula IVb:

IVb.

[156]. A compound of [153] above, or according to other embodiments of the invention, of formula V:

[157]. A compound of [102] above, or according to other embodiments of the invention, of formula VI:

[158]. A compound of [103] above, or according to other embodiments of the invention, of formula VII:

VII.

[159]. A compound of [102] above, or according to other embodiments of the invention, of formula VIII:

VIII.

[160]. A compound of [103] above, or according to other embodiments of the invention, of formula XI:

XL [161]. A compound of [ 102] above, or according to other embodiments of the invention, of formula X:

X.

[162]. A compound of [156], [157], [158], [159], [160], or [161] above, or according to other embodiments of the invention, wherein Z¹ is hydrogen and Z² is selected from hydrogen, halogen, halo(Ci-C₆)alkyl, - R^C OR²⁰, (Ci-Ce)alkoxy, or halo(Ci-C₆)alkoxy

[163]. A compound of [162] above, or according to other embodiments of the invention, wherein Z² is hydrogen, fluoro, chloro, trifluoromethyl, HBoc, methoxy, or trifluoromethoxy

[164]. A compound of [163] above, or according to other embodiments of the invention, wherein Z² is trifluoromethoxy.

[165]. A compound of [156], [157], [158], [159], [160], or [161] above, or according to other embodiments of the invention, wherein zero, one or two of X¹, X², X³, and X⁴ are independently selected in each instance from halogen, (Ci-Ce)alkyl, and halo(Ci-Ce)alkyl, and the remainder are hydrogen.

[166]. A compound of [165] above, or according to other embodiments of the invention, wherein one or two of X¹, X², X³, and X⁴ are independently selected in each instance from (Ci-C )alkyl, chloro, fluoro, and fluoro(Ci-C )alkyl, and the remainder are hydrogen.

[167]. A compound of [157], [159], or [161] above, or according to other embodiments of the invention, wherein R⁶ and R⁷ are each hydrogen.

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

(a) cancer

(b) diabetes (c) autoimmune disease

(d) age onset proteotoxic disease

(e) mood disorder

(f) acne vulgaris

(g) solid organ transplant rejection

(h) graft vs. host disease

(i) cardiac hypertrophy

(j) viral infection and

(k) parasitic infection;

the method comprising administering to the patient a therapeutically effective amount of a compound of any of [101] to [167] above, or according to other embodiments of the invention.

[169]. The method of [168] 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.

[170]. The method of [168] above, or according to other embodiments of the invention, for treating cancer, wherein said cancer is chemotherapy resistant cancer.

[171]. The method of [170] above, or according to other embodiments of the invention, wherein the method further comprises administering one or more additional cancer chemotherapeutic agents.

[172]. The method of [168] above, or according to other embodiments of the invention, for treating an age onset proteotoxic disease, wherein said disease is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

[173]. The method of [168] above, or according to other embodiments of the invention, for treating a viral infection.

[174]. The method of [173] above, or according to other embodiments of the invention, wherein said viral infection is caused by a virus selected from the group consisting of influenza, HIV-1, HPV, adenovirus, BKV, EBV, JCV, HCV, MCV, polyomavirus, SV40, HTLV-1, HSV-1, CMV, hepatitis B, BPV-1, human T-cell lymphotropic virus type 1, Japanese encephalitis virus, RSV, and West Nile virus. [175]. The method of [168] above, or according to other embodiments of the invention, for treating a parasitic infection.

[176]. The method of [175] above, or according to other embodiments of the invention, wherein said parasitic infection is caused by a parasite selected from the group consisting of Plasmodium and Theileria.

[177]. 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 [101] to [167] above, or according to other embodiments of the invention.

[178]. 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 [101] to [167] above, or according to other embodiments of the invention.

[179]. 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 [101] to [167] above, or according to other embodiments of the invention.

[180]. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any of [101] to [167] above, or according to other embodiments of the invention.

[00230] While typical embodiments have been set forth for the purpose of illustration, the foregoing descriptions and examples should not be deemed to be a limitation on the scope of the invention. Accordingly, various modifications, adaptations, and alternatives may occur to one skilled in the art without departing from the spirit and scope of the present invention.

Claims

We claim:

1. A compound of formula II

II

wherein

B is chosen from a direct bond, O, S, SO2 and NR^B;

R^B is selected from hydrogen and (Ci-C6)alkyl;

T is a benzene ring or a five- or six-membered heteroaromatic ring;

U is a benzene ring or a five- or six-membered heteroaromatic ring;

X¹, X², X³, and X⁴ are independently selected in each instance from hydrogen, halogen, nitro, cyano, (Ci-C₆)alkyl, (Ci-C₆)haloalkyl, (Ci-C₆)haloalkoxy, -NR¾², -OR¹, C(0)R¹, -OC(0)R¹, -C(0)NR¹R², -C(0)OR¹, -SR¹, -SO2R¹, and -SCh ^R²;

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

> chosen from

and or, when B is a direct bond, may be additionally chosen from:

wherein a is the point of attachment to ring T, b is the point of attachment to ring U, and c is the point of attachment to CHR⁶;

q is 0 or 1;

Y is hydrogen or hydroxyl;

R⁶ and R⁷ are each independently selected in each instance from hydrogen and (Ci- Ce)alkyl, or, when q is 1, R⁶ and R⁷ together with the carbons to which they are attached, may form an optionally substituted carbocyclic or heterocyclic ring;

Ar is an optionally substituted aromatic or heteroaromatic ring, wherein said substituents are selected from hydrogen, halogen, nitro, cyano, azide, (Ci-Ce)alkyl, (Ci-

C₆)haloalkyl, (Ci-C₆)haloalkoxy, - R¾², - R¹C(0)R², - R¹C(0)OR²⁰, -OR¹, -C(0)R¹, - OC(0)R¹, -C(0) R¹R², -C(0)OR¹, -SR¹, -SO2R¹, and -SCh ^R²; and

R²⁰ is (Ci-Cs)hydrocarbon.

2. A compound according to claim 1 of formula III:

III

wherein

Q is selected from -(CH₂ -, -0-, S(0)_p-, and - R^Q-;

p is zero, 1 or 2;

t is zero, 1 or 2;

R^Q is selected from hydrogen; optionally substituted (Ci-Ce)alkyl, (C₃-C₇)cycloalkyl, aryl, or heteroaryl; -SO2R³; -S0₂N(R R⁴); -C(=0)R⁵; -C(=0)OR⁵; or -C(=0)N(R R⁴); wherein said substituents on the (Ci-Ce)alkyl, (C₃-C₇)cycloalkyl, aryl, or heteroaryl are selected from the group consisting of 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; R³ and R⁴ are independently selected in each instance from hydrogen, (Ci-C6)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;

R⁵ is selected from hydrogen, optionally substituted (Ci-C₄)alkyl, or optionally substituted aryl, wherein said optional substituents are selected from the group consisting of (Ci-C₃)alkyl, OR¹, H₂, HMe, N(Me)₂, and heterocycle;

Y is hydrogen or hydroxyl; and

Ar is an optionally substituted aromatic or heteroaromatic ring, wherein said substituents are selected from hydrogen, halogen, nitro, cyano, azide, (Ci-Ce)alkyl, (Ci- C₆)haloalkyl, (Ci-C₆)haloalkoxy, - R¾², - R^!C(0)R², - R¹C(0)OR²⁰, -OR¹, -C(0)R¹, - OC(0)R¹, -C(0) R¹R², -C(0)OR¹, -SR.¹, -SO*¹, and -SO^^².

3. A compound according to claim 1 or claim 2 wherein B is a direct bond.

4. A compound according to claim 1 or claim 2 wherein B is -O-

5. A compound according to any one of claims 1-4, wherein

6. A compound according to any one of claims 1, 2, or 3, wherein B is a direct bond and

7. A compound according to any one of the above claims wherein T and U are each independently selected from the group consisting of a benzene ring and pyridine.

8. A compound according to claim 2 wherein Q is -(CH₂)_t- and t is 1.

9. A compound according to claim 2 wherein Q is -O-

10. A compound according to claim 2 wherein Q is - R^Q-.

11. A compound according to claim 1, wherein R⁶ and R⁷ are each hydrogen.

12. A compound according to any one of the above claims, wherein Ar is phenyl substituted with Z¹ and Z²; and

Z¹ and Z² are independently selected in each instance from the group consisting of hydrogen, halogen, nitro, cyano, azide, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci- C₆)haloalkoxy, - R¾², - R¹C(0)R², - R¹C(0)OR²⁰, -OR¹, -C(0)R¹, -OC(0)R¹, - C(0) R^!R², -C(0)0R¹, -SR¹, -SO2R¹, and -SCh ^R².

13. A compound according to claim 12 wherein Z² is hydrogen, fluoro, chloro, trifluoromethyl, - HBoc, methoxy, or trifluoromethoxy.

14. A compound according to claim 12 or claim 13, wherein Z² is para to the attachment of the phenyl ring to the sulfonyl.

15. A compound according to any one of the above claims, wherein zero, one or two of X¹, X², X³, and X⁴ are independently selected in each instance from halogen, (Ci-Ce)alkyl, and (Ci-Ce)haloalkyl, and the remainder are hydrogen.

A compound according to claim 2 wherein the relative stereochemistry is of formula

IV:

IV.

A method for treating a disease in a patient chosen from:

(a) cancer

(b) diabetes

(c) autoimmune disease (d) age onset proteotoxic disease

(e) mood disorder

(f) acne vulgaris

(g) solid organ transplant rejection

(h) graft vs. host disease

(i) cardiac hypertrophy

(j) viral infection and

(k) parasitic infection;

the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-16.

18. A method for restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer, the method comprising administering an effective amount of a compound according to any one of claims 1-16.

19. A method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-16.

20. 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 according to any one of claims 1-16.

21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1-16.