Described herein are methods for treating T-cell lymphoma in a subject in need thereof, comprising administering to the subject in need thereof, an ETP compound. Also described herein are pharmaceutical compositions and compositions for use that include such ETP compound.

BACKGROUND

Malignant cancerous growths, due to their unique characteristics, pose serious challenges for modern medicine. Their characteristics include uncontrollable cell proliferation resulting in unregulated growth of malignant tissue, an ability to invade local and even remote tissues, lack of differentiation, lack of detectable symptoms and, most significantly, lack of effective therapies. There is a need in the art for treating T-cell lymphomas. Provided here are solutions for these and other needs in the art.

BRIEF SUMMARY

Described herein, inter alia, are methods for treating T-cell lymphoma in a subject in need thereof, comprising administering to the subject in need thereof, an ETP compound. Further provided herein are methods for treating T-cell lymphoma in a subject in need thereof, comprising administering to the subject in need thereof, a bridged ETP compound or a non-bridged ETP compound. Also described herein are pharmaceutical compositions and compositions for use that include such ETP compound.

In an aspect, the compound (ETP compound) has the structure of formula (1):

or a pharmaceutically acceptable salt thereof.

R28is —SR25and R29is —SR26, wherein R28and R29are optionally joined to form *—Sp—* wherein p is an integer from 2 to 4 and each * represents the point of attachment to the remainder of the compound.

In an aspect, the compound has the structure of formula (I):

In an aspect, the compound has the structure of formula (XXI):

DETAILED DESCRIPTION

T-cell lymphoma represents a subset of non-Hodgkin's lymphoma (NHL). In Europe and North America, T-cell lymphoma accounts for 5-10% of all cases of NHL while in Asia, this percentage is as high as 24%. T-cell lymphomas, as a group, carry a poorer prognosis compared to their B cell counterpart. In the subgroup of patients with a low international prognostic index (IPI) score of 1-2, 5-year overall survival (OS) was 55% in those with T-cell lymphomas and 71% in those with B-cell lymphomas, and this difference in survival was also reflected in patients with higher IPI scores. T-cell lymphomas, however, represent a heterogeneous group of diseases with variations in clinical characteristics, prognosis, and response to treatment.

Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large-cell lymphoma (ALCL) are the most common subtypes and account for up to 74% of all T-cell lymphomas. AITL tends to occur in elderly patients, and patients often present with disseminated lymphadenopathy, hepatosplenomegaly, and autoimmune phenomena. ALCL ALK+ typically occurs in young men and presentation can be nodal or extranodal, involving the skin, bone, soft tissues, lung, and liver. On the other hand, ALCL ALK− tends to occur in an older population of patients, the presentation is usually nodal, and the disease runs a more aggressive clinical course. PTCL-NOS, represents a heterogeneous category of nodal and extranodal T cell lymphomas that cannot be grouped into defined entities. Most present with peripheral lymph-node enlargement, B symptoms and, at diagnosis, the disease is advanced.

Other uncommon T-cell lymphomas include enteropathy-associated T-cell lymphoma (EATL), adult T-cell leukemia/lymphoma (ATLL), hepatosplenic T-cell lymphoma (HSTL), and subcutaneous panniculitis-like T-cell lymphoma (SPTCL). It is recognized that EATL lymphoma consists of two distinct forms: classical or type I EATL and type II EATL. Type I EATL is associated with coeliac disease while type II EATL occurs in Asia and is not associated with coeliac disease. ATLL is caused by infection with the human T-cell-lymphotropic virus type 1 (HTLV-1), and is rare outside HTLV-I-endemic areas such as the Caribbean, Japan, and parts of central Africa. HSTL is rare; patients present with hepatosplenomegaly and systemic symptoms, and in 20% of cases it occurs in the context of chronic immune suppression. SPTCL occurs more commonly in women, and is associated with autoimmune conditions such as systemic lupus erythematosus.

Cutaneous T-cell lymphoma (CTCL) is caused by an expansion of malignant T-cell lymphocytes (involved in cell-mediated immunity) normally programmed to migrate to the skin. These skin-trafficking malignant T-cells migrate to the skin, causing various lesions to appear that may change shape as the disease progresses, typically beginning as a rash and eventually forming plaques and tumors. The disease generally presents with skin involvement only, manifested as scaly, erythematous patches. However, in advanced stages the disease is diffused to the lymph nodes and visceral organs.

CTCL constitutes a rare group of NHLs, occurring in about 4% of the approximate 500,000 individuals living with the disease. It is estimated, that CTCL affects about 40,000 individuals in the US, with approximately 2,800 new cases seen annually. CTCL mortality is related to the stage of the disease and median survival generally ranging from about 12 years in the early stages to only 2.5 years when the disease has advanced.

CTCL describes many different disorders with various symptoms and outcomes. The two most common types are mycosis fungoides (MF) and Sezary syndrome.

Mycosis fungoides is the most common type of CTCL, with approximately 16,000 to 20,000 cases across the United States, accounting for half of all CTCLs. The disease looks different in each patient, with skin symptoms that can appear as patches, plaques, or tumors. Patches are usually flat, possibly scaly, and look like a rash; plaques are thicker, raised, usually itchy lesions that are often mistaken for eczema, psoriasis, or dermatitis; and tumors are raised bumps, which may or may not ulcerate. It is possible to have more than one type of lesion.

A medical history, physical exam, and skin biopsy may be necessary for diagnosis. A physician may examine lymph nodes, order various blood tests, and may conduct other screening tests, such as a chest x-ray or a computed axial tomography (CAT) scan. Scans are usually not needed for those with the earliest stages of the disease. Mycosis fungoides is difficult to diagnose in its early stages because the symptoms and skin biopsy findings are similar to those of other skin conditions.

Sezary syndrome is an advanced, variant form of mycosis fungoides, which is characterized by the presence of lymphoma cells in the blood. Extensive thin, red, itchy rashes usually cover over 80 percent of the body. In certain patients, patches and tumors appear. Patients may also experience changes in the nails, hair, or eyelids, or have enlarged lymph nodes.

Many of the same procedures used to diagnose and stage other types of cutaneous T-cell lymphomas are used in Sezary syndrome. In addition, a series of imaging tests may be needed to determine if the cancer has spread to the lymph nodes or other organs (although that uncommonly occurs). These tests may include a CAT scan, a positron emission tomography (PET) scan, and/or a magnetic resonance imaging (MRI) scan. A bone marrow biopsy may also be done, but is usually not necessary.

Certain Terminology

The term “bridged” ETP compound or derivative as used herein, means a compound having a sulfide bridge having p sulfurs, i.e. “Sp” in a core structure, (e.g. S2is —S—S—, S3is —S—S—S—, S4is —S—S—S—S—). In contrast, the term “non-bridged” ETP compound or derivative as used herein, means a compound not having sulfide bridge (“Sp”) anywhere in its formula.

A “fused ring aryl-heterocycloalkyl” is an aryl fused to a heterocycloalkyl. A “fused ring heteroaryl-heterocycloalkyl” is a heteroaryl fused to a heterocycloalkyl. A “fused ring heterocycloalkyl-cycloalkyl” is a heterocycloalkyl fused to a cycloalkyl. A “fused ring heterocycloalkyl-heterocycloalkyl” is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring aryl-heterocycloalkyl, fused ring heteroaryl-heterocycloalkyl, fused ring heterocycloalkyl-cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substituents described herein. Fused ring aryl-heterocycloalkyl, fused ring heteroaryl-heterocycloalkyl, fused ring heterocycloalkyl-cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be named according to the size of each of the fused rings. Thus, for example, 6,5 aryl-heterocycloalkyl fused ring describes a 6 membered aryl moiety fused to a 5 membered heterocycloalkyl. Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkyl rings). Spirocyclic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.

The term “thio,” as used herein, means a sulfur that is single bonded to carbon or to another sulfur.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), Boron (B), Arsenic (As), and silicon (Si).

A “substituent group,” as used herein, means a group selected from the following moieties:

In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.

In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.

In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8cycloalkyl, and/or each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8cycloalkylene, and/or each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene.

In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7cycloalkyl, and/or each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7cycloalkylene, and/or each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene.

Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

Certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

The terms “a” or “an,” as used in herein means one or more. In addition, the phrase “substituted with a[n],” as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C1-C20alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.

Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13substituents are present, each R13substituent may be distinguished as R13A, R13B, R13C, R13D, etc., wherein each of R13A, R13B, R13C, R13D, etc. is defined within the scope of the definition of R13and optionally differently.

Description of compounds of the present disclosure is limited by principles of chemical bonding.

Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (−)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid.

As used herein, the term “salt” refers to acid or base salts of the compounds used in the methods of the present disclosure. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, and quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.

A “therapeutically effective amount” or “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman,Pharmaceutical Dosage Forms(vols. 1-3, 1992); Lloyd,The Art, Science and Technology of Pharmaceutical Compounding(1999); Pickar,Dosage Calculations(1999); andRemington: The Science and Practice of Pharmacy,20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

The term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway.

“Patient,” “subject,” “patient in need thereof,” and “subject in need thereof” are herein used interchangeably and refer to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human.

“Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. In particular, “disease” or “condition” refer to T-cell lymphoma.

By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies, for example alemtuzumab, bendamustine, bexarotene, bleomycin, bortezomib, brentuximab vedotin, carboplatin, carfilzomib, carmustine, cisplatin, cyclophosphamide, cytarabine, dacarbazine, dazatinib, denileukin diftitox, dexamethasone, doxorubicin, etoposide, everolimus, fludarabine, forodesine, gemcitabine, hydroxydaunorubicin, ifosfamide, imiquimod, interferons, lenalidomide, liposomal doxorubicin, mechlorethamine, methotrexate, methylprednisolone, nelfinavir, oral corticosteroids, panobinostat, pentostatin, pralatrexate, prednisone, prednisolone, psoralen, retinoids, resiquimod, rituximab, romidepsin, SGX301, temsirolimus, topical corticosteroids, vinblastine, vincristine, vinorelbine, vorinostat, or a combination thereof. The compound of the disclosure can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation).

The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease means that the disease is caused by (in whole or in part), a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function, or a side-effect of the compound (e.g. toxicity) is caused by (in whole or in part) the substance or substance activity or function.

The term “T-cell lymphoma” as used herein, means a disease that affects T-lymphocytes (T-cells). T-cell lymphoma occurs when cells of the immune system called T-lymphocytes, a type of white blood cell, grow and multiply uncontrollably. Cancerous T-cell lymphocytes travel to many parts of the body, including the lymph nodes, spleen, bone marrow, blood, or other organs, and form a mass called a tumor.

The term “cancer” as used herein, refers to T-cell lymphoma.

Cancer model organism, as used herein, is an organism exhibiting a phenotype indicative of cancer, or the activity of cancer causing elements, within the organism. The term cancer is defined above. A wide variety of organisms may serve as cancer model organisms, and include for example, cancer cells and mammalian organisms such as rodents (e.g. mouse or rat) and primates (such as humans). Cancer cell lines are understood as cells exhibiting phenotypes or genotypes similar to in vivo cancers. Cancer cell lines, as used herein, include cell lines from animals (e.g. mice) and from humans, such as HUT78.

The terms “synergy”, “synergism,” “synergistic,” and “synergistic therapeutic effect” are used herein interchangeably and refer to a measured effect of compounds administered in combination where the measured effect is greater than the sum of the individual effects of each of the compounds administered alone as a single agent.

Compounds

Described herein are compounds (ETP compounds) for use in the methods provided herein having the structure of formula (1):

or a pharmaceutically acceptable salt thereof.

In embodiments, R28and R29are joined to form —Sp— and the compound has the formula:

In embodiments, R28and R29are joined to form —S2— and the compound has the

In embodiments, R28and R29are joined to form —S3— and the compound has the formula:

In embodiments, R28and R29are joined to form —S4— and the compound has the formula:

In embodiments, R28is —SR25and R29is —SR26and the compound has the formula

Bridged Forms of Compounds

Described herein are compounds (ETP compounds) for use in the methods provided herein having the structure of formula (I):

In embodiments, p is 2. In embodiments, p is 3. In embodiments, p is 4.

In some embodiments of a compound of formula (I), R18is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments of a compound of formula (I), R16is hydrogen. In some embodiments of a compound of formula (I), R3and R4are independently hydrogen. In some embodiments of a compound of formula (I), R1is —CN, —COOR1A, —CONR1BR1C, or substituted or unsubstituted heteroalkyl. In some embodiments of a compound of formula (I), R1is —CN. In some embodiments of a compound of formula (I), R2is —CF3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. In some embodiments of a compound of formula (I), R2is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In some embodiments of a compound of formula (I), R2is methyl or methoxy. In some embodiments of a compound of formula (I), R5and R6are independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl. In some embodiments of a compound of formula (I), R5and R6are independently hydrogen, methyl, ethyl, allyl, or cyclopropyl. In some embodiments of a compound of formula (I), R5and R6are independently hydrogen or unsubstituted methyl. In some embodiments of a compound of formula (I), p is 2.

R1may be an electron withdrawing group (EWG) (e.g. halogen, —N3, —NO2, —CF3, —CCl3, —CBr3, —CI3, —CN, —CHO, —CONH2, or substituted or unsubstituted 2 to 8 membered heteroalkyl). An “electron withdrawing group” is used herein according to its common meaning in the art and refers to a chemical moiety that tends to remove electrons (electron density) from a portion of the compound to which it is attached (e.g. a deactivating group). R1may be —CN. R1may be —NO2. R1may be —CF3, —CCl3, —CBr3, or —CI3. R1may be substituted or unsubstituted 2 to 8 membered heteroalkyl. R1may be —COOCH3.

In embodiments, R2is a polar substituent and provides polarity to the compounds provided herein (e.g. where R2is a substituted or unsubstituted 2 to 8 membered heteroalkyl). A “polar substituent” is understood by one skilled in the art to be a moiety that creates a dipole moment, thereby forming a positive or negative charge on a molecule. R2may be an aqueous solubility enhancing substituent (e.g. a moiety that increases the water solubility of the compound), where germinal substitution at R2with a substituent other than methyl improves the solubility of the compound in an aqueous medium. Solubility enhancing substituents may include basic substituents or groups that add polarity.

In one embodiment, R1and R18are not joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (including fused cycloalkyl-aryl, heterocycloalkyl-aryl and aryl rings) or substituted or unsubstituted heteroaryl (including fused cycloalkyl-heteroaryl, heterocycloalkyl-heteroaryl and heteroaryl rings). In one embodiment, R1and R16are not joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (including fused cycloalkyl-aryl, heterocycloalkyl-aryl and aryl rings) or substituted or unsubstituted heteroaryl (including fused cycloalkyl-heteroaryl, heterocycloalkyl-heteroaryl and heteroaryl rings).

In one embodiment, R2and R18are not joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (including fused cycloalkyl-aryl, heterocycloalkyl-aryl and aryl rings) or substituted or unsubstituted heteroaryl (including fused cycloalkyl-heteroaryl, heterocycloalkyl-heteroaryl and heteroaryl rings). In one embodiment, R2and R16are not joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (including fused cycloalkyl-aryl, heterocycloalkyl-aryl and aryl rings) or substituted or unsubstituted heteroaryl (including fused cycloalkyl-heteroaryl, heterocycloalkyl-heteroaryl and heteroaryl rings).

In one embodiment, R1and R18are not hydrogen. In one embodiment the compound of formula (I) does not have the formula (3R,8S,8aR)-8-hydroxy-2-methyltetrahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-1,4(6H)-dione. In one embodiment, the compound of formula (I) does not have the formula (3R,8S,8aR)-2-methyl-1,4-dioxohexahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazin-8-yl acetate. In one embodiment the compound of formula (I) does not have the formula (3R,6R,8S,8aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-8-hydroxy-2-methyltetrahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-1,4(6H)-dione. In one embodiment, the compound does not have the formula 2,3-dimethyltetrahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-1,4(6H)-dione. In one embodiment, the compound does not have the formula 3-(hydroxymethyl)-2-methyltetrahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-1,4(6H)-dione.

The compound of formula (I) may have the formula:

R7and R8may be joined together to form substituted or unsubstituted cycloalkyl (e.g. 3 to 8 membered cycloalkyl). R7and R8may be joined together to form substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl). R7and R8may be joined together to form substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R7and R8may be joined together to form substituted or unsubstituted heteroaryl (e.g. 3 to 8 membered heteroaryl). R7and R8may be joined together to form R7E-substituted or unsubstituted cycloalkyl (e.g. 3 to 8 membered cycloalkyl). R7and R8may be joined together to form R7E-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl). R7and R8may be joined together to form R7E-substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R7and R8may be joined together to form R7E-substituted or unsubstituted heteroaryl (e.g. 3 to 8 membered heteroaryl).

R8and R9may be joined together to form substituted or unsubstituted cycloalkyl (e.g. 3 to 8 membered cycloalkyl). R8and R9may be joined together to form substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl). R8and R9may be joined together to form substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R8and R9may be joined together to form substituted or unsubstituted heteroaryl (e.g. 3 to 8 membered heteroaryl). R8and R9may be joined together to form R8E-substituted or unsubstituted cycloalkyl (e.g. 3 to 8 membered cycloalkyl). R8and R9may be joined together to form R8E-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl). R8and R9may be joined together to form R8E-substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R8and R9may be joined together to form R8E-substituted or unsubstituted heteroaryl (e.g. 3 to 8 membered heteroaryl).

R10and R11may be joined together to form substituted or unsubstituted cycloalkyl (e.g. 3 to 8 membered cycloalkyl). R10and R11may be joined together to form substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl). R10and R11may be joined together to form substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R10and R11may be joined together to form substituted or unsubstituted heteroaryl (e.g. 3 to 8 membered heteroaryl). R10and R11may be joined together to form R10E-substituted or unsubstituted cycloalkyl (e.g. 3 to 8 membered cycloalkyl). R10and R11may be joined together to form R10E-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl). R10and R11may be joined together to form R10E-substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R10and R11may be joined together to form R10E-substituted or unsubstituted heteroaryl (e.g. 3 to 8 membered heteroaryl).

R9and R10may be joined together to form substituted or unsubstituted cycloalkyl (e.g. 3 to 8 membered cycloalkyl). R9and R10may be joined together to form substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl). R9and R10may be joined together to form substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R9and R10may be joined together to form substituted or unsubstituted heteroaryl (e.g. 3 to 8 membered heteroaryl). R9and R10may be joined together to form R9E-substituted or unsubstituted cycloalkyl (e.g. 3 to 8 membered cycloalkyl). R9and R10may be joined together to form R9E-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl). R9and R10may be joined together to form R9E-substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R9and R10may be joined together to form R9E-substituted or unsubstituted heteroaryl (e.g. 3 to 8 membered heteroaryl).

R10and R11may be joined together to form substituted or unsubstituted cycloalkyl (e.g. 3 to 8 membered cycloalkyl). R10and R11may be joined together to form substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl). R10and R11may be joined together to form substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R10and R11may be joined together to form substituted or unsubstituted heteroaryl (e.g. 3 to 8 membered heteroaryl). R10and R11may be joined together to form R11E-substituted or unsubstituted cycloalkyl (e.g. 3 to 8 membered cycloalkyl). R10and R11may be joined together to form R10E-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl). R10and R11may be joined together to form R10E-substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R10and R11may be joined together to form R10E-substituted or unsubstituted heteroaryl (e.g. 3 to 8 membered heteroaryl).

The compound of formula (II) may have the formula:

The compound of formula (II) may have the formula:

The compound of formula (II) may have the formula:

The compound of formula (II) may have the formula:

The compound of formula (II1) may have the formula:

The compound of formula (II) may have the formula:

The compound of formula (II2) may have the formula:

The compound of formula (II) may have the formula:

The compound of formula (II3) may have the formula:

The compound of formula (II) may have the formula:

p is as described herein.

The compound of formula (I) may have the formula:

The compound of formula (III) may have the formula:

The compound of formula (III) may have the formula:

The compound of formula (III1) may have the formula:

The compound of formula (III) may have the formula:

The compound of formula (I) may have the formula:

The compound of formula (IV) may have the formula:

The compound of formula (IV) may have the formula:

The compound of formula (IV1) may have the formula:

The compound of formula (IV1) may have the formula:

The compound of formula (IV2) may have the formula:

The compound of formula (IV2) may have the formula:

In some embodiments, the compound of formula (V) has the structure of formula (V(S)):

In some embodiments of a compound of formula (V (S)), X1and X2are independently O or S. In some embodiments of a compound of formula (V (S)), p is 2. In some embodiments of a compound of formula (V (S)), p is 3.

In some embodiments, the compound of formula (V) has the structure of formula (V(R)):

In some embodiments of a compound of formula (V(R)), X1and X2are independently O or S. In some embodiments of a compound of formula (V(R)), p is 2. In some embodiments of a compound of formula (V(R)), p is 3.

In some embodiments, the compound of formula (V) has the structure of formula (V1):

In some embodiments, the compound of formula (VI) has the structure of formula (V-1(S)):

In some embodiments, the compound of formula (VI) has the structure of formula (V-1(R)):

In some embodiments, the compound of formula (VI) has the structure of formula (V2):

In some embodiments of a method of treating T-cell lymphoma, the compound of formula (V2(S)) has the structure of formula (V2(S)):

In some embodiments of a compound of formula (V2(S)), R1is —CN, —OR1A, —COOR1A, or —CONR1BR1C, wherein R1A, R1B, and R1Care independently hydrogen, or substituted or unsubstituted alkyl. In some embodiments of a compound of formula (V2(S)), R1is —CN. In some embodiments of a compound of formula (V2(S)), R2is —CF3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. In some embodiments of a compound of formula (V2(S)), R2is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In some embodiments of a compound of formula (V2(S)), R2is methyl. In some embodiments of a compound of formula (V2(S)), R3and R4are independently hydrogen. In some embodiments of a compound of formula (V2(S)), R12and R11are independently hydrogen. In some embodiments of a compound of formula (V2(S)), R10and R11are independently hydrogen.

In some embodiments, the compound of formula (V1(R)) has the structure of formula (V2(R)):

In some embodiments of a compound of formula (V2(R)), R1is —CN, —OR1A, —COOR1A, or —CONR1BR1C, wherein R1A, R1B, and R1Care independently hydrogen, or substituted or unsubstituted alkyl. In some embodiments of a compound of formula (V2(R)), R1is —CN. In some embodiments of a compound of formula (V2(R)), R2is —CF3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. In some embodiments of a compound of formula (V2(R)), R2is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In some embodiments of a compound of formula (V2(R)), R2is methyl. In some embodiments of a compound of formula (V2(R)), R3and R4are independently hydrogen. In some embodiments of a compound of formula (V2(R)), R12and R11are independently hydrogen. In some embodiments of a compound of formula (V2(R)), R10and R11are independently hydrogen.

In some embodiments, the compound of formula (V) may have the structure of formula:

In some embodiments, the compound of formula (V) may have the structure of formula:

In some embodiments, the compound of formula (V) has the structure of formula (V3):

In some embodiments, the compound of formula (V3) may have the structure of formula (V3(S)):

In some embodiments, the compound of formula (V3) may have the structure of formula (IV(R)):

The compound of formula (VI) may have the formula:

The compound of formula (V4) may have the formula:

In some embodiments, the compound of formula (V4) may have the structure of formula:

The compound of formula (I) may have the formula:

The compound of formula (VI) may have the formula:

The compound formula (VI) may have the formula:

The compound of formula (VI1) may have the formula:

The compound of formula (VI) may have the formula:

Non-Bridged Forms of Compounds

In an aspect is provided a compound (ETP compound) for use in the methods provided herein having the formula (XXI):

In embodiments, the compound has the formula:

In embodiments, Ring A is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, Ring A is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, or substituted or unsubstituted thienyl. In embodiments, Ring A is substituted or unsubstituted phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

In embodiments, Ring A is a R35-substituted or unsubstituted cycloalkyl, R35-substituted or unsubstituted heterocycloalkyl, R35-substituted or unsubstituted aryl, or R35-substituted or unsubstituted heteroaryl. In embodiments, Ring A is a R35-substituted cycloalkyl, R35-substituted heterocycloalkyl, R35-substituted aryl, or R35-substituted heteroaryl. In embodiments, Ring A is a unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, Ring A is R35-substituted or unsubstituted phenyl, R35-substituted or unsubstituted pyridyl, R35-substituted or unsubstituted pyrazolyl, R35-substituted or unsubstituted imidazolyl, R35-substituted or unsubstituted oxazolyl, R35-substituted or unsubstituted isoxazolyl, R35-substituted or unsubstituted thiazolyl, R35-substituted or unsubstituted furanyl, R35-substituted or unsubstituted pyrrolyl, or R35-substituted or unsubstituted thienyl. In embodiments, Ring A is R35-substituted or unsubstituted pyridinyl. In embodiments, Ring A is R35-substituted or unsubstituted pyridazinyl. In embodiments, Ring A is R35-substituted or unsubstituted pyrimidinyl. In embodiments, Ring A is R35-substituted or unsubstituted pyrazinyl. In embodiments, Ring A is R35-substituted or unsubstituted triazinyl. In embodiments, Ring A is R35-substituted phenyl, R35-substituted pyridyl, R35-substituted pyrazolyl, R35-substituted imidazolyl, R35-substituted oxazolyl, R35-substituted isoxazolyl, R35-substituted thiazolyl, R35-substituted furanyl, R35-substituted pyrrolyl, or R35-substituted thienyl. In embodiments, Ring A is R35-substituted pyridinyl. In embodiments, Ring A is R35-substituted pyridazinyl. In embodiments, Ring A is R35-substituted pyrimidinyl. In embodiments, Ring A is R35-substituted pyrazinyl. In embodiments, Ring A is R35-substituted triazinyl. In embodiments, Ring A is unsubstituted phenyl, unsubstituted pyridyl, unsubstituted pyrazolyl, unsubstituted imidazolyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted thiazolyl, unsubstituted furanyl, unsubstituted pyrrolyl, or unsubstituted thienyl. In embodiments, Ring A is unsubstituted pyridinyl. In embodiments, Ring A is unsubstituted pyridazinyl. In embodiments, Ring A is unsubstituted pyrimidinyl. In embodiments, Ring A is unsubstituted pyrazinyl. In embodiments, Ring A is unsubstituted triazinyl.

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the formula:

In embodiments, R7and R8may optionally be joined to forma substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl. In embodiments, R8and R9may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl.

In embodiments, R7Band R7C, R8Band R8C, R9Band R9C, R10Band R10C, and R11Band R11C, substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

As described above, the symbols n6, n7, n8, n9, n10 and n11 are independently an integer from 1 to 4. Each occurrence of v6, v7, v8, v9, v10 and v11 is independently 1 or 2.

In embodiments, the compound or the pharmaceutically acceptable salt thereof has the formula:

In embodiments, R7and R8or R8and R9are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In embodiments, R7and R8are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In embodiments, R8and R9are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In embodiments, R7and R8or R8and R9are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In embodiments, R7and R8are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In embodiments, R8and R9are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In embodiments, X1is —O—, —NR21C—, or S. In embodiments, X2is —O—, —NR22C—, or S. In embodiments, m is 1 and z5 is an integer from 0 to 6. In embodiments, m is 2 and z5 is an integer from 0 to 8. In embodiments, z5 is 0.

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the formula:

In embodiments, the compound or the pharmaceutically acceptable salt thereof has the formula:

In embodiments, the compound or the pharmaceutically acceptable salt thereof has the formula:

In embodiments, the compound or the pharmaceutically acceptable salt thereof has the formula:

In embodiments, the compound or the pharmaceutically acceptable salt thereof has the

In embodiments, the compound or the pharmaceutically acceptable salt thereof has the formula:

In embodiments, the compound or the pharmaceutically acceptable salt thereof has the formula:

In embodiments, the compound or the pharmaceutically acceptable salt thereof has the formula:

In embodiments, the compound or the pharmaceutically acceptable salt thereof has the formula:

In embodiments, the compound or the pharmaceutically acceptable salt thereof has the formula:

In embodiments, the compound or the pharmaceutically acceptable salt thereof has the

In embodiments, the compound or the pharmaceutically acceptable salt thereof has the formula:

In embodiments, the compound or the pharmaceutically acceptable salt thereof has the formula:

In embodiments, the compound or the pharmaceutically acceptable salt thereof has the formula:

In embodiments, the compound or the pharmaceutically acceptable salt thereof has the formula:

In some embodiments, R18is Ring A. In embodiments, Ring A is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, Ring A is R18E-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, Ring A is R18E-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, Ring A is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, Ring A is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, or substituted or unsubstituted thienyl. In embodiments, Ring A is substituted or unsubstituted phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the formula:

In embodiments, R7and R8are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

The symbols R27and z5 are as described herein. z4 may be an integer from 0 to 6.
In embodiments, R7and R8are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In embodiments, R7and R8are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In embodiments, R8and R9are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

The symbols R27and z5 are as described herein. In embodiments, R8and R9are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In embodiments, R8and R9are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural

In embodiments, R7and R8are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

The symbols R27z4 and z5 are as described herein. In embodiments, R7and R8are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In embodiments, R7and R8are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In embodiments, R8and R9are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In embodiments, R8and R9are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In embodiments, R8and R9are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In embodiments, the compound or pharmaceutically acceptable salt has the formula having the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the formula:

In some embodiments, R7and R8or R8and R9are optionally joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In some embodiments, R7and R8or R8and R9are optionally joined to forma substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

In embodiments, X1is —O—, —NR21C—, or —S—. In embodiments, X2is —O—, —NR22C—, or —S—. In embodiments, z5 is an integer from 0 to 8. In embodiments, m is 1 or 2.

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the formula:

In embodiments the compound or pharmaceutically acceptable salt thereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable salt thereof, has the formula:

In some embodiments, L1and L2are independently a bond.

In some embodiments, L1is -L1A-L1B, wherein L1Ais bonded to —C(O)— or —C(S)—; and L2is -L2A-L2B-, wherein L2Ais bonded to —C(O)— or —C(S)—; L1Ais a bond or —(CH2)z1—; L1Bis a bond, —O— or —NR30B—. L2Ais a bond or —(CH2)z2—; L2Bis a bond, —O— or —NR31B—; z1 and z2 are independently an integer from 1 to 10; and R30and R31are independently hydrogen or substituted or unsubstituted alkyl.

In some embodiments, R25and R26are joined together to form:

In some embodiments, the compound or pharmaceutically acceptable salt thereof, has the structure:

In embodiments, the compound has the structure

In embodiments, the compound has the structure:

In embodiments, the compound has the structure:

Further Forms of Compounds

The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by the forming diastereomeric and separation by recrystallization, or chromatography, or a combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

In some situations, compounds may exist as tautomers. All tautomers are included within the formula described herein.

Labelled Compounds

The compounds described herein may be labeled isotopically (e.g. with a radioisotope) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or photoactivatable or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example,2H,3H,13C,14C,15N,18O,17O,35S,18F,3DI, respectively. Certain isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Further, substitution with isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

Salts

Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein is accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary.

In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in FIESER ANDFIESER'SREAGENTS FORORGANICSYNTHESIS, Volumes 1-17 (John Wiley and Sons, 1991); RODD'SCHEMISTRY OFCARBONCOMPOUNDS, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989); March, ADVANCEDORGANICCHEMISTRY4thEd., (Wiley 1992); Carey and Sundberg, ADVANCEDORGANICCHEMISTRY4thEd., Vols. A and B (Plenum 2000, 2001); and Green and Wuts, PROTECTIVEGROUPS INORGANICSYNTHESIS3rdEd., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compounds as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. As a guide, the following synthetic methods may be utilized as described in International Patent Application PCT/US2013/066252, which is herein incorporated by reference for this disclosure.

In certain embodiments, the compound is a compound as set forth in Table 1.

TABLE 1Exemplary embodiments of compounds provided herein.StructureReferenceETP6ETP8ETP12ETP14ETP27ETP49ETP56ETP69ETP95ETP100ETP120ETP125ETP128ETP130ETP154ETP167ETP178ETP195ETP204ETP206ETP214ETP218ETP223ETP229ETP303ETP309ETP313ETP328ETP331ETP341ETP344ETP356ETP359ETP365ETP382ETP384ETP390ETP406ETP417ETP422ETP425ETP442ETP450ETP452ETP469ETP484ETP493
Pharmaceutical Composition

The pharmaceutical compositions described herein are administered to a subject by multiple administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, inhalation, buccal, topical, rectal, or transdermal administration routes. In some embodiments, pharmaceutical compositions described herein, which include a bridged ETP compound described herein, are formulated into any suitable dosage form, including, but not limited to, emulsions suitable for injection, nanosuspensions suitable for injection, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulates formulations, and mixed immediate release and controlled release formulations.

Pharmaceutical compositions may include compositions wherein the active ingredient (e.g. compounds described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application may depend, inter alia, on the condition being treated. When administered in methods to treat a disease, such compositions may contain an amount of active ingredient effective to achieve the desired result, e.g., modulating the activity of a target molecule, and/or reducing, eliminating, or slowing the progression of disease symptoms.

Generally, the ETP compound described herein is administered in an amount effective for amelioration of the symptoms of the disease or disorder (i.e., a therapeutically effective amount). In some embodiments, the therapeutically effective amount is an amount that is capable of at least partially preventing or reversing a disease or disorder. In some embodiments, the dose required to obtain an effective amount varies depending on the agent, formulation, disease or disorder, and individual to whom the ETP compound described herein is administered.

In some embodiments, the determination of the effective amount involves in vitro assays in which varying doses of the ETP compound described herein are administered to cells in culture and the concentration of agent effective for ameliorating some or all symptoms is determined in order to calculate the concentration required in vivo. In some embodiments, the effective amounts are based on in vivo animal studies.

In some embodiments, the ETP compound described herein is administered prior to, concurrently with, and subsequent to the appearance of symptoms of a disease or disorder. In some embodiments, the ETP compound described herein is administered to a subject with a family history of the disease or disorder, or who has a phenotype that may indicate a predisposition to a disease or disorder, or who has a genotype which predisposes the subject to the disease or disorder.

Methods

In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is cutaneous T-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the cutaneous T-cell lymphoma is Sezary syndrome. In some embodiments of a method of treating T-cell lymphoma, the cutaneous T-cell lymphoma is mycosis fungoides. In some embodiments of a method of treating T-cell lymphoma, the cutaneous T-cell lymphoma is folliculotropic mycosis fungoides. In some embodiments of a method of treating T-cell lymphoma, the cutaneous T-cell lymphoma is pagetoid reticulosis. In some embodiments of a method of treating T-cell lymphoma, the cutaneous T-cell lymphoma is granulomatous slack skin. In some embodiments of a method of treating T-cell lymphoma, the cutaneous T-cell lymphoma is primary cutaneous CD30+ T-cell lymphoproliferative disorder. In some embodiments of a method of treating T-cell lymphoma, the cutaneous T-cell lymphoma is lymphomatoid papulosis. In some embodiments of a method of treating T-cell lymphoma, the cutaneous T-cell lymphoma is primary cutaneous anaplastic large-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the cutaneous T-cell lymphoma is primary cutaneous γδ T-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the cutaneous T-cell lymphoma is primary cutaneous CD8+ aggressive epidermotropic lymphoma. In some embodiments of a method of treating T-cell lymphoma, the cutaneous T-cell lymphoma is primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the cutaneous T-cell lymphoma is primary cutaneous CD4+ small/medium T-cell lymphoma.

In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is nodal T-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the nodal T-cell lymphoma is follicular T-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the nodal T-cell lymphoma is angioimmunoblastic T-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the nodal T-cell lymphoma is nodal peripheral T-cell lymphoma with TFH phenotype. In some embodiments of a method of treating T-cell lymphoma, the nodal T-cell lymphoma is anaplastic large cell lymphoma ALK+. In some embodiments of a method of treating T-cell lymphoma, the nodal T-cell lymphoma is anaplastic large cell lymphoma ALK−. In some embodiments of a method of treating T-cell lymphoma, the nodal T-cell lymphoma is breast implant-associated anaplastic large-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the nodal T-cell lymphoma is peripheral T-cell lymphoma not otherwise specified (PTCL-NOS).

In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is extranodal T-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the extranodal T-cell lymphoma is systemic EBV+ T-cell lymphoma of childhood. In some embodiments of a method of treating T-cell lymphoma, the extranodal T-cell lymphoma is hydroa vacciniforme-like lymphoproliferative disorder. In some embodiments of a method of treating T-cell lymphoma, the extranodal T-cell lymphoma is extranodal NK/T-cell lymphoma nasal type. In some embodiments of a method of treating T-cell lymphoma, the extranodal T-cell lymphoma is enteropathy-associated T-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the extranodal T-cell lymphoma is hepatosplenic T-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the extranodal T-cell lymphoma is subcutaneous panniculitis-like T-cell lymphoma.

In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is leukemic T-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the leukemic T-cell lymphoma is T-cell prolymphocytic leukemia. In some embodiments of a method of treating T-cell lymphoma, the leukemic T-cell lymphoma is T-cell large-granular lymphocytic leukemia. In some embodiments of a method of treating T-cell lymphoma, the leukemic T-cell lymphoma is adult T-cell leukemia/lymphoma.

In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is monomorphic epitheliotropic intestinal T-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is indolent T-cell lymphoproliferative disorder of the gastrointestinal tract.

Also described herein are methods for treating T-cell lymphoma in a subject in need thereof, comprising administering to the subject in need thereof, a bridged ETP compound described herein, thereby reducing, ameliorating or eliminating a symptom or manifestation of T-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the subject in need thereof is predisposed to T-cell lymphoma, but does not yet manifest a symptom of T-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the administration of a bridged ETP compound described herein effectively prevents or delays development of symptoms associated with T-cell lymphoma. In some embodiments of a method of treating T-cell lymphoma, the symptoms of T-cell lymphoma comprise at least one of the following symptoms: chest pain, coughing, difficulty breathing, fatigue, loss of appetite, weight loss, alopecia, follicular cysts, comedolike lesions, nail dystrophy, fever, night sweats, itchy skin, swollen lymph nodes, lymphadenopathy, hepatosplenomegaly, autoimmune phenomena, swollen abdomen, painful abdomen, edematous skin, atopic dermatitis, nonspecific dermatitis, nonspecific chronic dermatitis, parapsoriasis, patches on lower trunk, patches on buttocks, palmar hyperkeratosis, plantar hyperkeratosis, minimal/absent pruritus, and intensely pruritic plaques.

In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with at least one of the following conditions: smoking, obesity, infection, HIV, Epstein-Barr virus, human T-lymphotropic virus,Helicobacter pyroliinfection, chronicHelicobacter pyroliinfection, exposure to chemicals, exposure to insecticides, exposure to pesticides, use of immunosuppressant drugs, weakened immune system, genetic disorders, previous chemotherapy, and previous radiation therapy. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with smoking. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with obesity. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with infection. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with HIV. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with Epstein-Barr virus. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with human T-lymphotropic virus. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated withHelicobacter pyroliinfection. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with chronicHelicobacter pyroliinfection. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with exposure to chemicals. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with exposure to insecticides. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with exposure to pesticides. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with use of immunosuppressant drugs. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with weakened immune system. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with genetic disorders. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with previous chemotherapy. In some embodiments of a method of treating T-cell lymphoma, the T-cell lymphoma is associated with previous radiation therapy.

In some embodiments of a method of treating T-cell lymphoma, the treatment of T-cell lymphoma in a subject in need thereof comprises the steps of: (a) identifying a subject in need of treatment of T-cell lymphoma, and (b) administering a therapeutically effective amount of a bridged ETP compound to said subject, thereby treating the T-cell lymphoma.

In some embodiments of a method of treating T-cell lymphoma, the treatment of T-cell lymphoma in a subject in need thereof results in reduction or minimization of undesired side effects in the subject associated with chemotherapy, chemotherapy, radiotherapy, or cancer therapy. In some embodiments, the undesired side effects in the subject associated with chemotherapy, chemotherapy, radiotherapy, or cancer therapy comprise fatigue, anemia, appetite changes, bleeding problems, diarrhea, constipation, hair loss, nausea, vomiting, pain, peripheral neuropathy, swelling, skin and nail changes, urinary and bladder changes, and trouble swallowing.

Embodiments P

Embodiment P1. A method for treating T-cell lymphoma in a subject in need thereof, comprising administering to the subject, a compound having the structure of formula (I):

Embodiment P2. The method of Embodiment P1, wherein R18is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Embodiment P3. The method of anyone of Embodiments P1-P2, wherein R16is hydrogen.

Embodiment P4. The method of anyone of Embodiments P1-P3, wherein R3and R4are independently hydrogen or methyl.

Embodiment P5. The method of anyone of Embodiments P1-P4, wherein R1is —CN, —COOR1A, —CONR1BR1C, or substituted or unsubstituted heteroalkyl.

Embodiment P6. The method of anyone of Embodiments P1-P5, wherein R1is —CN.

Embodiment P7. The method of anyone of Embodiments P1-P6, wherein R2is —CF3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

Embodiment P8. The method of anyone of Embodiments P1-P7, wherein R2is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl

Embodiment P9. The method of any one of Embodiments P1-P8, wherein R2is methyl or methoxy.

Embodiment P10. The method of anyone of Embodiments P1-P9, wherein R5and R6are independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl.

Embodiment P12. The method of anyone of Embodiments P1-P11, wherein R5and R6are independently hydrogen or methyl.

Embodiment P13. The method of anyone of Embodiments P1-P12, wherein p is 2.

Embodiment P14. The method of Embodiment P1, wherein the compound of formula (I) has the structure of formula (II):

Embodiment P15. The method of Embodiment P14, wherein the compound of formula (II) has the structure of formula:

Embodiment P16. The method of Embodiment P15, wherein X1and X2are independently —O— or —S—.

Embodiment P17. The method of Embodiment P15, wherein p is 2.

Embodiment P18. The method of Embodiment P15, wherein the compound of formula (II(S)) has the structure of formula (III(S)):

Embodiment P20. The method of Embodiment P18 or P19, wherein R1is —CN.

Embodiment P21. The method of anyone of Embodiments P18-P20, wherein R2is —CF3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

Embodiment P22. The method of anyone of Embodiments P18-P21, wherein R2is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.

Embodiment P23. The method of anyone of Embodiments P18-P22, wherein R2is methyl.

Embodiment P24. The method of anyone of Embodiments 19-24, wherein R3and R4are hydrogen.

Embodiment P25. The method of anyone of Embodiments P18-P24, wherein R12and R13are independently hydrogen or methyl.

Embodiment P26. The method of anyone of Embodiments P18-P25, wherein R10and R11are hydrogen.

Embodiment P27. The method of any one of Embodiments P1-P14, wherein the compound has the structure of formula:

Embodiment P28. The method of Embodiment P18, wherein the compound has the structure of formula:

Embodiment P31. The method of anyone of Embodiments P1-P30, wherein the T-cell lymphoma is associated with at least one of the following conditions: smoking, obesity, infection, HIV, Epstein-Barr virus, human T-lymphotropic virus,Helicobacter pyroliinfection, chronicHelicobacter pyroliinfection, exposure to chemicals, exposure to insecticides, exposure to pesticides, use of immunosuppressant drugs, weakened immune system, genetic disorders, previous chemotherapy, and previous radiation therapy.

Embodiment P32. The method of any one of Embodiments P1-P31, further comprising administering to the subject an additional therapeutic agent used in the treatment of T-cell lymphoma.

Embodiment P34. A pharmaceutical composition for treating T-cell lymphoma comprising an ETP derivative, at least one additional therapeutic agent used in the treatment of T-cell lymphoma, and at least one pharmaceutically acceptable excipient.

Embodiment P35. The pharmaceutical composition of Embodiment P34, wherein the ETP derivative is a compound having the structure of formula (I):

Embodiments Q

Embodiment Q1. A method for treating T-cell lymphoma in a subject in need thereof, comprising administering to the subject, a compound having the structure of formula (XXI):

Embodiment Q2. The method of Embodiment Q1, wherein R18is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Embodiment Q3. The method of Embodiment Q1 or Q2, wherein R16is hydrogen.

Embodiment Q4. The method of Embodiment Q1, wherein the compound has the formula:

Embodiment Q5. The method of any one of Embodiments Q2 to Q4, wherein R7and R8or R8and R9are joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

Embodiment Q6. The method of any one of Embodiments Q1-Q5, wherein the compound has the formula:

Embodiment Q7. The method of any one of Embodiments Q1-Q5, wherein the compound has the formula:

Embodiment Q8. The method of any one of Embodiments Q1-Q6, wherein the compound has the formula:

Embodiment Q9. The method of any one of Embodiments Q1-Q5, wherein the compound has the formula:

Embodiment Q10. The method of any one of Embodiments Q1-Q9, wherein the compound is

Embodiment Q11. The method of any one of Embodiments Q1-Q5, wherein the compound has the formula:

Embodiment Q12. The method of any one of Embodiments Q1-Q11, wherein the compound has the formula:

Embodiment Q13. The method of any one of Embodiments Q1-Q5, wherein the compound has the formula:

Embodiment Q14. The method of any one of Embodiments Q1-Q13, wherein the compound has the formula:

Embodiment Q15. The method of anyone of Embodiments Q1-Q12, wherein R10and R11are independently hydrogen.

Embodiment Q16. The method of anyone of Embodiments Q2-Q6, wherein X4is —N═.

Embodiment Q17. The method of anyone of Embodiments Q2-Q6, wherein R9is —OCH3.

Embodiment Q18. The method of anyone of Embodiments Q1-Q17, wherein R2is substituted or unsubstituted alkyl.

Embodiment Q19. The method of anyone of Embodiments Q1-Q18, wherein R2is substituted or unsubstituted C1-C3alkyl.

Embodiment Q20. The method of anyone of Embodiments Q1-Q19, wherein R2is methyl.

Embodiment Q21. The method of anyone of Embodiments Q1-Q17, wherein R2is substituted or unsubstituted alkyl.

Embodiment Q22. The method of anyone of Embodiments Q1-Q21, wherein R1is —CN.

Embodiment Q24. The method of any one of Embodiments Q1-Q23, wherein L and L2are independently a bond, —O—, or —NH—.

Embodiment Q25. The method of any one of Embodiments Q1-Q23, wherein:L1is -L1A-L1B, wherein L1Ais bonded to —C(O)— or —C(S)—; andL2is -L2A-L2B-, wherein L2Ais bonded to —C(O)— or —C(S)—;L1Ais a bond or —(CH2)z1—;L1Bis a bond, —O— or —NR30B—;L2Ais a bond or —(CH2)z2—;L2Bis a bond, —O— or —NR31B—;z1 and z2 are independently an integer from 1 to 10; andR30Band R31Bare independently hydrogen or substituted or unsubstituted alkyl.

Embodiment Q28. The method of anyone of Embodiments Q1-Q27, wherein R32and R33are independently unsubstituted C1-C3alkyl or unsubstituted aryl.

Embodiment Q29. The method of any one of Embodiments Q1 to Q28, wherein R32and R33are independently halogen.

Embodiment Q30. The method of any one of Embodiments Q1 to Q21, wherein R25and R26are joined together to form:

Embodiment Q31. The method of anyone of Embodiments Q1-Q30, wherein R6is methyl.

Embodiment Q32. The method of any one of Embodiments Q1-Q31, wherein the compound has the structure:

Embodiment Q35. The method of anyone of Embodiments Q1-Q34, wherein the T-cell lymphoma is associated with at least one of the following conditions: smoking, obesity, infection, HIV, Epstein-Barr virus, human T-lymphotropic virus,Helicobacter pyroliinfection, chronicHelicobacter pyroliinfection, exposure to chemicals, exposure to insecticides, exposure to pesticides, use of immunosuppressant drugs, weakened immune system, genetic disorders, previous chemotherapy, and previous radiation therapy.

Embodiment Q36. The method of any one of Embodiments Q1-Q35, further comprising administering to the subject an additional therapeutic agent used in the treatment of T-cell lymphoma.

Embodiment Q38. A pharmaceutical composition for treating T-cell lymphoma comprising an ETP derivative, at least one additional therapeutic agent used in the treatment of T-cell lymphoma, and at least one pharmaceutically acceptable excipient.

Embodiment Q39. The pharmaceutical composition of Embodiment Q38, wherein the ETP derivative is a compound having the structure of formula (XXI):

EMBODIMENTS

Embodiment 1. A method for treating T-cell lymphoma in a subject in need thereof, comprising administering to the subject, a compound having the structure of formula (1):

Embodiment 2. The method of Embodiment 1, wherein R18is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Embodiment 3. The method of Embodiment 1, wherein R16is hydrogen.

Embodiment 4. The method of Embodiments 1-3, wherein the compound having the structure of formula (I):

Embodiment 5. The method of Embodiment 4, wherein R3and R4are independently hydrogen or unsubstituted methyl.

Embodiment 6. The method of Embodiments 4-5, wherein R is —CN, —COOR1A, —CONR1BR1C, or substituted or unsubstituted heteroalkyl.

Embodiment 7. The method of Embodiments 4-6, wherein R1is —CN.

Embodiment 8. The method of Embodiments 4-7, wherein R2is —CF3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

Embodiment 9. The method of Embodiments 4-8, wherein R2is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.

Embodiment 10. The method of Embodiments 4-9, wherein R2is methyl or methoxy.

Embodiment 11. The method of Embodiments 4-10, wherein R5and R6are independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl.

Embodiment 13. The method of Embodiments 4-12, wherein R5and R6are independently hydrogen or unsubstituted methyl.

Embodiment 14. The method of Embodiments 4-13, wherein p is 2.

Embodiment 15. The method of Embodiment 4, wherein the compound of formula (I) has the structure of formula (II):

Embodiment 16. The method of Embodiment 15, wherein the compound of formula (II) has the structure of formula:

Embodiment 17. The method of Embodiment 16, wherein X1and X2are independently —O— or —S—.

Embodiment 18. The method of Embodiments 15-17, wherein p is 2.

Embodiment 19. The method of Embodiments 16-17, wherein the compound of formula (II(S)) has the structure of formula (III(S)):

Embodiment 21. The method of Embodiments 19 or 20, wherein R1is —CN.

Embodiment 22. The method of Embodiments 19-21, wherein R2is —CF3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

Embodiment 23. The method of Embodiments 19-22, wherein R2is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.

Embodiment 24. The method of Embodiments 19-23, wherein R2is methyl.

Embodiment 26. The method of Embodiments 19-25, wherein R12and R13are independently hydrogen or unsubstituted methyl.

Embodiment 28. The method of Embodiments 4-27, wherein the compound is:

Embodiment 29. The method of Embodiment 28, wherein the compound is:

Embodiment 30. The method of Embodiments 1-3, a compound having the structure of formula (XXI):

Embodiment 31. The method of Embodiment 30, wherein the compound has the formula:

Embodiment 32. The method of Embodiment 31, wherein R7and R8or R8and R9are joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl having structural formula:

Embodiment 33. The method of Embodiments 30-32, wherein the compound has the formula:

Embodiment 34. The method of Embodiment 31, wherein the compound has the formula:

Embodiment 35. The method of Embodiment 31, wherein the compound has the formula:

Embodiment 36. The method of Embodiment 31, wherein the compound has the formula:

Embodiment 37. The method of Embodiment 36, wherein the compound is

Embodiment 38. The method of Embodiment 31, wherein the compound has the formula:

Embodiment 39. The method of Embodiment 38, wherein the compound has the

Embodiment 40. The method of Embodiment 30, wherein the compound has the formula:

Embodiment 41. The method of Embodiment 40, wherein the compound has the formula:

Embodiment 43. The method of Embodiments 30-33, wherein X4is —N═.

Embodiment 44. The method of Embodiments 30-33, wherein R9is —OCH3.

Embodiment 45. The method of Embodiments 30-44, wherein R2is substituted or unsubstituted alkyl.

Embodiment 46. The method of Embodiments 30-45, wherein R2is substituted or unsubstituted C1-C3alkyl.

Embodiment 47. The method of Embodiments 30-46, wherein R2is methyl.

Embodiment 48. The method of Embodiments 30-47, wherein R1is —CN.

Embodiment 50. The method of Embodiments 30-49, wherein L1and L2are independently a bond, —O—, or —NH—;

Embodiment 51. The method of Embodiments 30-49, wherein:L1is -L1A-L1B-, wherein L1Ais bonded to —C(O)— or —C(S)—; andL2is -L2A-L2B-, wherein L2Ais bonded to —C(O)— or —C(S)—;L1Ais a bond or —(CH2)z1—;L1Bis a bond, —O— or —NR30B—;L2Ais a bond or —(CH2)z2—;L2Bis a bond, —O— or —NR31B—;z1 and z2 are independently an integer from 30 to 10; andR30Band R31Bare independently hydrogen or substituted or unsubstituted alkyl.

Embodiment 56. The method of Embodiments 30-48, wherein R2and R26are joined together to form:

Embodiment 57. The method of Embodiments 30-56, wherein R6is methyl.

Embodiment 58. The method of Embodiments 30-57, wherein the compound has the structure:

Embodiment 61. The method of Embodiments 1-60, wherein the T-cell lymphoma is associated with at least one of the following conditions: smoking, obesity, infection, HIV, Epstein-Barr virus, human T-lymphotropic virus,Helicobacter pyroliinfection, chronicHelicobacter pyroliinfection, exposure to chemicals, exposure to insecticides, exposure to pesticides, use of immunosuppressant drugs, weakened immune system, genetic disorders, previous chemotherapy, and previous radiation therapy.

Embodiment 62. The method of Embodiments 1-61, further comprising administering to the subject an additional therapeutic agent used in the treatment of T-cell lymphoma.

Embodiment 64. A pharmaceutical composition for treating T-cell lymphoma comprising an ETP derivative, at least one additional therapeutic agent used in the treatment of T-cell lymphoma, and at least one pharmaceutically acceptable excipient.

Embodiment 65. The pharmaceutical composition of Embodiment 64, wherein the ETP derivative is a compound having the structure of formula (1):

EXAMPLES

The compounds of Formulae I-XVIII can be prepared in a number of ways well known to those skilled in the art, including both solid phase and solution phase techniques. The compounds can be synthesized, for example, by the methods described below, or variations thereof as appreciated by the skilled artisan. Although these syntheses are illustrated for preparation of ETPs having substituted aryl substituents at C6, identical sequences can be employed to prepare ETPs with substituted heteroaryl substituents at C6. See e.g. Martins, M. M.; CarvalhoTetrahedron2007, 63, 9923-9932; Borthwick, A. D.Chem Rev2012, 112, 3641-3716; Iwasa, E.; Hamashima, Y.; Sodeoka, M. Isr.J. Chem.2011, 51, 420-433; Nicolaou, K. C.; Lu, M.; Totokotsopoulos, S.; Heretsch, P.; Giguère, D.; Sun, Y.-P.; Sarlah, D.; Nguyen, T. H.; Wolf, I. C.; Smee, D. F.; Day, C. W.; Bopp, S.; Winzeler, E. A.J. Am. Chem. Soc.2012, 134, 17320-17332. All processes disclosed in association with the present invention are contemplated to be practiced on any scale, including milligram, gram, multigram, kilogram, multikilogram or commercial industrial scale.

Embodiments of Formula I may be prepared as shown in Scheme 1 above. Dehydrative condensation of an aldehyde with a glycine derivative renders an intermediate imine such as 1, which when treated with base in the presence of lithium bromide generates an azomethine ylide that subsequently undergoes a dipolar cycloaddition reaction to generate the desired pyrrolidine product such as 2. The azomethine ylide can be generated and the cycloaddition accomplished in many ways known in the art (Grigg, R. and V. Sridharan (1993). Azomethine Ylide Cycloadditions via 1,2-Prototropy and Metallo-Dipole Formation from Imines.Advances in Cycloaddition. D. P. Curran. Greenwich, CT, Jai Press Inc. 3: 161-204). For example, the cycloaddition may be carried out by simply heating the components in a solvent or by the use of other metal complexes or salts and other bases. Compounds 2 are typically generated as mixtures of diasteroisomers, the isomer exemplified by 2 can be separated from the mixture based on its reduced solubility in solvent mixtures like MeOH/DCM (1:1). If required, the diastereoisomer products can be obtained in high purity by column chromatography; the subsequent steps can be performed with the separated stereoisomers or carried out with the mixture of stereoisomers with separation being accomplished by column chromatography, crystallization or other common techniques after the polysulfur bridge is incorporated.

The product of this cycloaddition reaction is a pyrrolidine ester, which can be converted to a dioxopiperazine in many well-known ways (Martins, M. B., Ivone, C. (2007) Diketopiperazines: biological activity and synthesis.Tetrahedron63, 9923-9932). For example, the pyrrolidine ester can be acylated on the free nitrogen with an α-halo acid chloride to yield the corresponding amide. These compounds can be treated with an excess of a primary amine to undergo a cyclocondensation reaction furnishing the desired diketopiperazine ring, compounds, exemplified by 3 and 4. In general the diketopiperazine was isolated as mixture of diastereoisomers which need not be separated at this stage. Alternatively, the pyrrolidine ester can be coupled with an α-aminoester (typically protected on nitrogen) to give a dipeptide, which directly or upon removal of the nitrogen-protecting group can be cyclized to the dioxopiperazine intermediate.

The diketopiperazine then undergoes a sulfidation process, one example of which is illustrated in Scheme 1, to yield the desired ETP. Alternatively, the intermediate in this sequence, can be reduced and the dithiol product protected on the two sulfur atoms. The conversion of the diooxopiperazine intermediate to an ETP product can be accomplished in many ways well known in the art (Iwasa, E.; Hamashima, Y.; Sodeoka, M. (2011) Epipolythiodiketopiperazine Alkaloids: Total Syntheses and Biological Activities Isr.J. Chem.51, 420-433. Nicolaou, K. C., et al. (2011) Synthesis and Biological Evaluation of Epidithio-, Epitetrathio-, and bis-(Methylthio)diketopiperazines: Synthetic Methodology, Enantioselective Total Synthesis of Epicoccin G, 8,8′-epi-ent-Rostratin B, Gliotoxin, Gliotoxin G, Emethallicin E, and Haematocin and Discovery of New Antiviral and Antimalarial AgentsJ. Am. Chem. Soc.,133, 8150-8153.)

Synthetic scheme for enantioselective synthesis of ETP analogues described herein.

General Procedure for the Synthesis of Polyfunctionalized Pyrrolidine Esters.

4-Fluorobenzaldehyde (1.24 g, 10 mmol) was dissolved in 15 mL of MeCN containing triethylamine (1.5 mL, 11 mmol) and glycine methyl ester hydrochloride (1.35 g, 11 mmol). The reaction mixture was stirred for 5 h at room temperature. After removing the solvent in vacuo, the solid residue was re-dissolved in CH2Cl2and washed twice from water to give the imine intermediate as colourless oil. To a solution of this material in 20 mL of THF, solid LiBr (1.1 g, 12 mmol) and triethylamine (1.7 mL, 12 mmol) were added portionwise. After 2 min, methyl methacrylate (1.5 g, 15 mmol) was added and the resulting solution was stirred at room temperature for 8 h. After evaporation of the solvent in vacuo and extractive work-up (3 times, CH2Cl2/water), the desired product was isolated as yellow oil (2.6 g, 90% yield, as a single diastereomer). In some cases the cycloadduct was isolated as a mixture of C4 epimers, which were separated by crystallization or chromatography

General Procedure for Forming Diketopiperazines by Sequential Reaction of Pyrrolidine Esters with 2-Chloroalkanonyl Chlorides and Amines.

The corresponding pyrrolidine (1.0 equiv) was dissolved in 10 mL of CH2Cl2and cooled to 0° C. with an ice-bath. Triethylamine (1.2 equiv) was added, followed by dropwise addition of a solution of 2-chloropropionyl chloride (1.2 equiv, 50% v/v in CH2Cl2). This mixture was stirred for 1 h with cooling, followed by 1 h after removal of the ice-bath. The intermediate α-chloroimide is then directly extracted (3×CH2Cl2) and isolated as brownish foam after removal of the volatiles in vacuo. The corresponding amide was re-dissolved in 10 mL of CH2Cl2and combined with the equivalent volume of 40% aq MeNH2solution to give a biphasic mixture, which was stirred at rt for 12-16 h. Extraction of this mixture gives the crude diketopiperazine (DKP) product as yellow foam (purity 50-80%). This residue was stirred with MeOH (1 M) for 1 h, whereupon a colorless solid was obtained 70% yield. Trituration of this material from a methanolic solution in CH2Cl2(often accelerated by vigorous stirring) gave the major DKP stereoisomer as a colorless solid after filtration and drying under high vacuum. Either the pure DKP steroisomer, or the solid 5:1 mixture of DKP isomers, could be employed in the subsequent sulfidation step.

Alternate Procedure for Forming Diketopiperazines from Substituted Prolidine Esters and Protected α-Amino Acids.

To a solution of N-Boc-phenylalanine (263 mg, 1.00 mmol, 1.5 equiv) in dry CH2Cl2(2 mL) at 0° C. was added N,N-diisopropylethylamine (0.12 mL, 0.66 mmol, 1 equiv) and BOPCl (253 mg, 1.00 mmol, 1.5 equiv) and the reaction was allowed to warm to room temperature over 1 h. After recooling to 0° C. additional N,N-diisopropylethylamine (0.23 mL, 1.3 mmol, 2 equiv) was added, followed by the dropwise addition of a solution of the corresponding pyrrolidine ester (200 mg, 0.66 mmol, 1 equiv) in CH2Cl2(1.3 mL). The reaction was allowed to warm to room temperature overnight, after which time TLC analysis showed full conversion of the starting material. After an extractive work-up (CH2Cl2/water), the crude product was filtered through a silica gel plug using hexanes/ethyl acetate (1:1) as the eluent and the volatiles were removed in vacuo. The crude acylated pyrrolidine ester was dissolved in dry CH2Cl2(2.1 mL) and cooled to 0° C. Trifluoroacetic acid (0.8 mL) was added, the reaction allowed to warm to rt over 3 h, and the volatiles were removed under reduced pressure. The resulting residue was dissolved in a 4:1 mixture i-BuOH/toluene (18 mL) containing N,N-diisopropylethylamine (0.46 mL, 2.65 mmol, 4 equiv). The vial was sealed with a teflon cap and heated to 100° C. overnight. After an extractive work up (CH2Cl2/water) and concentration, two diastereomeric DKPs were separated by silica gel chromatography (eluent: hexanes/EtOAc 1:3).

Both DKP products were individually methylated in a separate reaction vessel by the following procedure: To the intermediate DKP (91 mg, 0.23 mmol, 1 equiv) in acetone (2.8 mL) was added K2CO3(620 mg, 4.5 mmol, 20 equiv) and Mel (1.4 mL, 23 mmol, 100 equiv) and the reaction was stirred for 2 d at room temperature with the exclusion of light. After an extractive work up (CH2Cl2/water), each diasteromeric DKP was obtained as amorphous solid.

General Procedure for Synthesis of Epidithiodiketopiperazines.

To a suspension of elemental sulfur (32 mg, 1.0 mmol) in dry THF (5 mL) was added a solution of NaHMDS (0.25 mL, 2 M in THE) at room temperature. After 1 min, a solution of the diketopiperazine (35 mg, 0.1 mmol, in 2 mL THF) was added, followed by a second aliquot of NaHMDS (0.25 mL, 2 M in THF) within another 2 min. The resulting orange-brown solution was stirred for 30 min at rt, cooled to 0° C. and quenched by addition of aqueous NH4Cl. After extractive work-up (CH2Cl2/water) and evaporation of the solvent, a yellow residue was obtained. This residue was re-dissolved in a mixture of MeOH/THF (5 mL) to which NaBH4(350 mg, 1 mmol) was added portionwise at 0° C. After stirring for 30 min, this mixture was quenched with aqueous NH4Cl, extracted (CH2Cl2/water) and the extract was dried over Na2SO4. After evaporation of the solvent, a yellow residue was obtained, which was subsequently dissolved in EtOAc (10 mL). A solution of KI3(0.5 M, 2 mL) in water was added and the biphasic system was stirred at rt for 15 min, after which time 3 mL of saturated aqueous Na2S2O3was added to give a pale yellow EtOAc layer. Aqueous extraction and evaporation of the organic phase gives a yellow oil, which was purified by preparative TLC (Et2O/CH2Cl2) to give the title compound as a yellow oil.

Alternate Simplified General Procedure for Synthesis of Epidithiodiketopiperazines.

To a suspension of S8(83 mg, 0.32 mmol) in dry THF (3.4 mL) was added a solution of NaHMDS (1.7 mL, 0.93 mmol, 3.3 equiv, 0.56 M in toluene) at room temperature over 40 sec. After 1 min, a solution of the diketopiperazine (100 mg, 0.28 mmol, in 2.6 mL THF) was added dropwise, followed by a second aliquot of NaHMDS (1.1 mL, 0.62 mmol, 2.2 equiv, 0.56 M in toluene) within another 30-40 sec. The resulting orange-yellow solution was stirred for 50 min at rt and quenched by addition of saturated aqueous NH4Cl. After extractive work-up (CH2Cl2/water) and evaporation of the solvent, a yellow-brown amorphous residue was obtained. This residue was evaporated onto 2.2 g SiO2and placed on top of a filter frit containing 12 g SiO2. Washing of this SiO2plug with 150 mL of hexanes removes the majority of HMDS-related material. Subsequent washing with 150 mL of MeCN elutes the sulfidated products as a mixture of epidi- and epitrisulfide products (epidi:epitri usually ˜9:1). These products were separated by preparative TLC (2-4% EtOAc/CH2Cl2). The desired epidisulfide product (Rf˜0.3) was isolated as an off-white solid (purity 95%) after removal of the volatiles in vacuo.

At the end of the concentration process, MeOH (1-2 mL) and CH2Cl2(1-2 mL) can be added and then again removed in vacuo to facilitate the formation of a colorless powder. In other cases, the epidi- and epitrisulfide products can be separated by column chromatography on silica gel using a mixtures of CH2Cl2and EtOAc as the eluent. Generally either of the two procedures described above can be used to prepare the epidithiodiketopiperazine products.

Prepared from rac-(3R,6S,7S,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxo-octahydropyrrolo[1,2-a]-pyrazine-7-carbonitrile by conventional NiCl2/NaBH4reduction of the nitrile, Eschweiler-Clarke dimethylation of the resulting primary amine and sulfidation.

Separation of Enantiomers of ETP Products.

Isolation of (3S,6S,7S,8aS)- and (3R,6R,7R,8aR)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitriles

Cell Viability Assay of Compound (1) against CTCL

Compound (1) and FK-228 (an anticancer agent used in CTCL) were tested in a cell viability assay using HUT78 cells in a CELLTITER-GLO® assay. An IC50value of 6.61 nM was determined for compound (1). See,FIG.1B. An IC50value of 6.95 nM was determined for FK-228. SeeFIG.1C. Analysis of the results demonstrates that the compound (1) has potent antitumor activities against CTCL.

Compound (1) was tested in a carboxy-fluorescein succinimidyl ester (CFSE) stained HUT78 CTCL proliferation assay. HUT78 cells were stained with CFSE dye. The CFSE stained cells were plated into 96-well plates in growth medium. The resulted cells were treated with 1.0, 10, or 100 nM solution of compound (1), and then incubated for 72 h under the growth conditions. After, optical densities were read on a multiwell scanning spectrophotometer at wavelength 488 nm. Cells cultured in the absence of compound (1) served as a control. Analysis of the results demonstrates that the compound (1) inhibits proliferation of HUT78 CTCL cells (seeFIG.2).

Effects of Compound (1) on HUT78 CTCL cells

Compound (1) was tested in a cell proliferation assay using HUT78 CTCL cells. The cells were treated with 0.3, 1, 3, 10, 30, or 100 nM concentration of compound (1), and then incubated for 48 h or 72 h under the growth conditions. An IC50value of 75.00 nM was determined when the cells were incubated in the growth media for 48 h. An IC50value of 10.04 nM was determined when the cells were incubated in the growth media for 72 h. Cells cultured in the absence of compound (1) served as a control. Analysis of the results demonstrates that the compound (1) inhibits proliferation of HUT78 CTCL cells in a dose- and time-dependent manner (seeFIG.3)

Induction of Apoptosis by Compound (1)

Compound (1) was tested in a cell apoptosis assay using HUT78 CTCL cells. The cells were treated with 1, 3, 10, or 100 nM concentration of compound (1), and then incubated for 72 h under the growth conditions. An IC50value of 19.71 nM was determined after the cells were incubated in the growth media for 72 h. Cells cultured in the absence of compound (1) served as a control. Analysis of the results demonstrates that the compound (1) induces apoptosis of HUT78 CTCL cells in a dose-dependent manner (seeFIG.4).

Tumor Volume, Size, and Weight Comparison in Compound (1) Regimen Versus FK-228 Regimen in HUT78 CTCL Mouse Xenograft Model

Compound (1) and FK-228 were tested for tumor growth inhibition in CTCL mouse xenograft models. One group of mice was treated with 20 mg/kg of compound (1) using gavage during 3 consecutive days, followed by 3 consecutive days of break. Another group of mice was treated with 2 mg/kg of FK-228 intraperitoneal, twice weekly. Mice with no treatment served as a control. The tumor volume, size, and weight were compared 12 days after the treatments started. Analysis of the results demonstrates that compound (1) regimen (squares) results in tumor growth inhibition, compared to the FK-228 regimen (triangles), and to the vehicle (circles) (FIG.5). Compound (1) regimen also results in the reduction of the tumor size (FIG.6).

Ascites and diarrhea in mice were observed in romidespin regimen, suggesting drug associated toxicity, while no toxicity was observed in compound (1) regimen. The tumor weight inhibition in a HUT78 CTCL mouse xenograft model was 89.8% in compound (1) regimen (P<0.001), suggesting compound (1) exhibited significantly more potent in vivo efficacy than romidepsin (FIG.7).

Phase 1/2 Study to Evaluate Safety of Compound 1 in Subjects with Cutaneous T-Cell Lymphoma (CTCL)

The primary objective of this study is to characterize the safety, tolerability, and dose-limiting toxicities (DLTs) of compound (1) when administered orally to patients with CTCL that has relapsed (returned after responding to previous treatment) or is refractory (has not responded to previous treatment).

Study ObjectivesThe safety and tolerability of multiple doses of compound (1);The effect of multiple doses of compound (1) on relapsed CTCL; andThe effect of multiple doses of compound (1) on refractory CTCL.

Patients: Eligible subjects will be men and women 18 years and old. Healthy volunteers are not eligible.

Inclusion Criteria:Histologically confirmed diagnosis of CTCL including:a. Mycosis fungoidesb. Sézary syndromec. Primary cutaneous anaplastic large cellStage Ib to IVb diseaseProgression of disease (PD) or relapse of disease after at least 1 previous systemic therapy, PD after last prior treatment regimen, and recovered from the toxic effects of prior therapyEastern Cooperative Oncology Group (ECOG) Performance Status ≤2Age >18 years, of either sexLife expectancy ≥3 monthsAdequate blood, liver, and kidney function as determined by laboratory testsFemale patients with childbearing potential must be using a hormonal contraceptive, intra uterine device, diaphragm with spermicide, or condom with spermicide for the duration of the study. Women of childbearing potential must have a negative serum or urinary hCG pregnancy testMale patients, who are not surgically sterile, must use a condom with spermicide for the duration of the studyHave given written informed consent, prior to any study related procedure not part of the patient's normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care

Primary Outcome Measures:The primary objective of this study is to characterize the safety, which includes the tolerability and dose-limiting toxicity (DLT), of compound (1) when administered to subjects with CTCL. Specifically, this measure will be assessed by number of subjects experiencing treatment emergent adverse events indicative of DLT [Time Frame: Assessed at the end of every even-numbered cycle (every 8 weeks) for the first 6 months, then every 4 cycles (16 weeks)]

Secondary Outcome Measures:The assessment of patient-reported changes of pruritus during treatment [Time Frame: Monthly]Responses in index lesions assessed by lesion measurements with photographic supporting documentation [Time Frame: Monthly]Duration of Response (DOR) [Time Frame: Day 1 until disease progression/recurrence, or up to 12 months (Lead-in) and Day 1 until disease progression/recurrence, or up to 30 months]Time to Response (TTR) [Time Frame: Up to 12 months (Lead-in) and up to 30 months]Objective Response Rate (ORR) [Time Frame: Day 1 until disease progression/recurrence, up to 12 months (Lead-in) and Day 1 until disease progression/recurrence, up to 30 months]

Synthesis and Characterization Data

Rel-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile (2) and Rel-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epitrithiopyrrolo[1,2-a]pyrazine-7-carbonitrile (3). A three-neck 250 mL round bottom flask was fitted with an overhead mechanical stirrer with a grease-sealed glass fitting. The flask was charged with 1 (2.07 g, 6.1 mmol) and S8(1.56 g, 6.1 mmol) and fitted with two rubber septa. The flask was evacuated under vacuum and back-filled with Ar three times. The solids were suspended in anhydrous THF (60 mL) and the suspension was cooled in an ice bath. After 5 min., a solution of NaHMDS (0.6 M in PhMe, 60 mL, 36 mmol) was added over 10 min with vigorous stirring. The reaction was maintained at 0° C. for 3 h. The reaction was quenched with sat. aq. NH4Cl (50 mL) and H2O (50 mL). The biphasic mixture was extracted with EtOAc (3×150 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (30×250 mm of SiO2, 5 to 10% EtOAc in CH2Cl2gradient elution) afforded a 2:1 mixture of 2 and 3 (880 mg, ca. 2.12 mmol, 35% yield) as an off-white solid.

Cell Viability Assay of Compound (2) against CTCL

Compound (2) (FIG.8A) was tested in a cell viability assay using HUT78 cells in a CELLTITER-GLO® assay. To determine IC50value of Compound (2) against human CTCL HUT78 cells, viability assay was performed using CELLTITER-GLO® Reagent as described by the supplier (Promega, Madison, WI). Briefly, cells (7500/well) were seeded in opaque 96-well plates and exposed to Compound (1) in a dose-dependent manner for 72 h at 37° C. in 5% CO2. After 72 h treatment with compound (1), CELLTITER-GLO® Reagent (50 L/well) was added to 96-well plates. Viable cells which are metabolically active are directly proportional to the ATP present. Luminescent signals correlate with the amount of ATP present in cells. After 10 min incubation with CELLTITER-GLO® Reagent, luminescence was measured at an integration time of 1 second/well using an automated BMG plate reader. Dimethyl sulfoxide (DMSO) was used as the vehicle control. Each experiment was conducted in triplicate. IC50values were determined using CalcuSyn software (Biosoft).

An IC50value of 2.8 nM was determined for compound (2). SeeFIG.8B. Analysis of the results demonstrates that the compound (2) exhibits in antitumor activities against CTCL.