WO2006128129A2

WO2006128129A2 - Method for treating cancer

Info

Publication number: WO2006128129A2
Application number: PCT/US2006/020821
Authority: WO
Inventors: John Bertin; Ethan P. Grant
Original assignee: Synta Pharmaceuticals Corp.
Priority date: 2005-05-26
Filing date: 2006-05-26
Publication date: 2006-11-30
Also published as: WO2006128129A3

Abstract

The invention relates to a method for treating cancers using compounds that modulate the activity of c-Rel.

Description

METHOD FOR TREATING CANCER

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 60/685,056, filed May 26, 2005, and U.S. Provisional Application No. 60/720,357, filed on September 23, 2005. The entire teachings of each of these applications are incorporated herein by reference.

BACKGROUND

Rel/NF-κB is a family of transcription factors that play a key role in inflammation, immunity, cell proliferation and apoptosis. Rel/NF-κB family members, including c-Rel, ReIA (also referred to as "p65"), ReIB, p50 and p52, exist mainly in the cytoplasm in an inactive form due to association with one or more members of a family of inhibitors known as IKB proteins (IκBα, IκBβ, IκBε, Bcl-3, plOO, plO5). The best characterized of the DdB proteins, IκBα, has a strong nuclear export sequence that keeps complexes of it and NF-κB proteins largely in the cytoplasm. Pro-inflammatory cytokines and other stimuli trigger phosphorylation of IκBα by IKB kinase (IKK) which marks it for subsequent ubiquitination and proteasomal degradation. Once liberated from association with IKB proteins, NF-κB proteins can accumulate in the nucleus and form homo- and heterodimers which activate the transcription of target genes, including those controlling cell proliferation and cell survival (anti-apoptotic genes). However, activation of NF-κB proteins is usually a transient process because one of the primary target genes of NF-κB is the gene encoding IκBα which can bind to NF-κB proteins and return them to their latent form in the cytoplasma.

The discovery of v-Rel, a retroviral oncogene encoded by avian Rev-T retrovirus which causes a lymphoid cell malignancy in chickens, was one of the first indictions that NF-κB proteins, and in particular c-Rel, could be involved in human cancers. v-Rel has been shown to transform and immortalize chicken hematopoietic cell types from primary spleen, bone marrow, or bursal cultures, including B- and T- lymphoid cells, myeloid cells, erythroid cells, and dendritic cells. In addition, retroviral vectors of chicken, mouse and human c-Rel have been shown to transform chicken lymphoid cells in vitro, but at a rate that is less efficient than v-Rel. v-Rel is about 50- to 100-fold more transforming than its avian progenitor c-Rel due in part to a large deletion in its C-terminal that removes its transactionation domain and to internal mutations that reduce its ability to interact with IκBα. Overexpression of other NF-kB family members, such as ρ50, p52, RELA, and RELB, cannot transform chicken lymphoid cells.

Rel/NF-kB signal transduction pathways have been shown to be misregulated in a variety of human cancers, especially ones of lymphoid cell origin, due to genetic changes (e.g., chromosomal rearrangements, amplification, mutation or deletions) or to chronic activation of the pathway by epigenetic mechanisms. Chronic activation of NF-κB has been shown to contribute to oncogenisis by driving proliferation, enhancing cell survival by subverting apoptotic mechanisms, and promoting angiogenesis and metastasis.

The REL gene which encodes c-Rel and is located at chromosomal position 2pl6.1-15, is the REL/NFKB/IKB gene that has most consistently been found to be amplified in human cancers, hi particular, the REL gene has been found to be amplified in B-cell lymphomas such as classical Hodgkin's lymphomas and non- Hodgkin's B-cell lymphomas (e.g., diffuse large B-cell lymphomas (DBCLs), follicular lymphomas, and mediastinal thymic B-cell lymphomas). It is estimated that REL amplification is present in about 10% to 20% of DBCLs, 15-20% of follicular B- cell lymphomas, and 40-50% of classical Hodgkin's lymphoma.

Several viruses have been shown to induce chronic activation of NF-κB and are thought to contribute to several types of cancer. For example, Epstein-Barr virus (EBV) preferentially infects B lymphocytes and has the ability to transform resting B cells into permanent, latently infected lymphoblastoid cells in vitro. EBV is widespread in human populations and persists in the majority of infected individuals as an asymptomatic infection that is kept in check by T-cell surveillance. However, EBV has been implicated in a variety of B-cell lymphomas, hi particular, T-cell immune compromised patients, such as transplant patients, AIDS patients, and malaria patients, are at high risk of developing B-cell lymphomas. LMPl, the primary transforming protein of EVB, strongly activates NF-kB transcription factors which regulate anti-apoptotic proteins and cytokines. Almost all lymphomas arising in transplant patients within the first year of transplantation, almost all cases of "endemic" Burkitt's lymphoma (Burkitt's lymphoma associated with malaria), about 15% of non-malaria associated Burkitt's lymphoma, about 30-40% of Burkitt's lymphoma associated with AIDS, and about 40% of cases of Hodgkin's lymphoma, are positive for EBV. In addition, EBV is associated with certain types of T-cell and NK-cell lymphomas and with nasopharyngeal carcinoma.

Another virus associated with chronic activation of NF-κB is human T-cell leukemia virus type I (HTLV-I) and type II (HTLV-II) which have been implicated in human T-cell malignancies such as adult T-cell leukemia. HTLV encodes Tax, a 40 kDa protein that is a strong transcriptional activator of c-Rel, and the levels of c-Rel protein and RNA, but not other other NF-kB family members such as p50 or p65, are consistently higher in HTLV infected cells than in control T-cells. Thus, it is believed that c-Rel overexpression may play a role in T-cell malignacies in HTLV infected individuals.

Knockout mice lacking c-Rel develop normally and have no gross irregularities in hemopoiesis. However, they have greatly reduced B-cell proliferation, reduced B-cell survival in response to mitogenic activation, and show reduced antibody production in response to an antigen. Thus, the primary role of c- ReI appears to be proliferation and survival of activated mature B-cell, and anticancer therapeutics that selectively target c-Rel activity would be expected to be safe and generally well tolerated. Since there are no known anti-cancer agents that selectively inhibit the activity of c-Rel, a need exists for such agents. In addition, a need exists for anti-cancer agents that are effective and reduce or eliminate unwanted side-effects of anti-cancer agents that are currently available.

SUMMARY

The present invention addresses this need for effective, well tolerated anticancer agents. Without wishing to be bound by any theory, it is believed that the compounds of the invention selectively inhibit the activity of c-Rel without materially inhibiting the activity of other members of the Rel/NF-κB family. In one aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I):

(I) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph or prodrug thereof, wherein:

R₁ is optionally substituted aryl, optionally substituted heteroaryl, or a group represented by the following formula:

R₂ and R₄, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, -C(O)R⁰, -OC(O)R⁰, -SC(O)R⁰, -NR^kC(O)R°, -C(S)R⁰, -OC(S)R⁰, -SC(S)R⁰, -NR^kC(S)R^c, -C(NR)R⁰, -OC(NR)R⁰, -SC(NR)R⁰, -NR^kC(NR)R°, -SO₂R⁰, -S(O)R⁰, -NR^kSO₂R°, -OS(O)₂R⁰, -OP(O)R⁰R⁰, -P(O)R⁰R⁰, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R₂ and R₄ taken together are =0, =S, or =NR;

R₃ is R^g;

R₅ and R₆ are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or Rs and R₆ taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;

X is O, S, S(O), S(O)₂, or NR^k;

Y is (CH(R^g))_m, C(O), C(NR), O, S, S(O), S(O)₂, N(R^k), or absent;

G is a bond, -C(0)NR^kNR^k-, -NR^kNR^kC(O)-, -NR^kN=CR^k-, -CR^k=NNR^k-, -NR^kNR^k-, -N(OH)-, -NR^kO-, -ONR^k-, -C(O)-, -C(NR)-, ~NR^kC(O)-, -C(O)NR^k-, -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(O)O-, -OC(O)NR^k-, -NR^kC(S)O-, -0C(S)NR^k-, -NR^k-C(NR)-NR^k-, -NR^k-C(O)-NR^k-, -NR^k-C(S)-NR^k-, -NR^k-S(O)₂-NR^k-, -P(O)(R^c)-, -P(O)(R^c)O-, -OP(O)(R^c)-, -OP(O)(R^c)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NR^k-, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(OR^k)₂-, -B(0R^k)-, -C(NR)-NR^k-, -NR^k-CR^gR^g-C(0)-, -C(O)-ONR^k-, -C(O)-NR^kO-, -C(S)-ONR^k-, -C(S)-NR^kO-, -C(NR)-ONR^k-, -C(NR)-NR^kO-, -OS(O)₂-NR^kNR^k-, -OC(O)-NR^kNR^k-, -OC(S)-NR^kNR^k-, -OC(NR)-NR^kNR^k-, -NR^kNR^kS(O)₂O-, -NR^kNR^kC(S)O-, -NR^kNR^kC(NR)O-, -OP(O)(R^c)O-, -NR^kP(O)(R^c)O-, -OP(O)(R^c)NR^k-, -NR^kP(O)(R^c)NR^k-, -P(0)(R^c)NR^k-, -NR^kP(O)(R^c)-,

-O-alkylene-heterocycloalkylene-NR^k-, -NR^k-CHR^g-C(O)-NR^k-CHR^g-C(O)-, -NR^k-CHR^g-C(O)-, -NR^k-C(0)-CHR^g-, or -C(O)-NR^k-CHR^g-C(O)-; and each of Q, U, and V are independently N or CR⁸, wherein at least one of Q, U, or V is N; and each CR⁸ may be the same or different;

R, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)R^c, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O)₂R^c; each of R^a and R^b, independently, is H, optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R^c, for each occurrence, is independently, H₅ an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;

R^g, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR^k, -SR^k, -NR^hR^J, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, -C(O)R^c, -OC(O)R^c, -SC(O)R^c, -NR^kC(0)R^c, -C(S)R^c, -OC(S)R^c, -SC(S)R^c,-NR^kC(S)R°, -C(NR)R^c, -OC(NR)R^c, -SC(NR)R^c, -NR^kC(NR)R^c, -SO₂R^c, -S(O)R^c, -NR^kSO₂R^c, -OS(O)₂R^c, -OP(O)R^cR^c, -P(O)R^cR^c, halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;

R^h and R^J, for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R^h and R^j taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;

R , for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; n is 0, 1, 2, 3, 4, 5, 6 or 7; and m is O, 1, 2, 3, or 4.

In another aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (II):

(H) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or polymorph thereof, wherein G, Q, U, V, Y, R₂, R₃, R₄, R₅, R₆, and n are defined as for formula (I); X₁ is represented by a formula selected from the group consisting of:

R and R^k are defined as for formula (I);

R₇ is an optionally substituted aryl or an optionally substituted heteroaryl.

In another aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (III) :

(III) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, prodrug or polymorph thereof, wherein G, Q, U, V, Y, R₂, R₃, R₄, R₅, R₆, and n are defined as for formula (I);

R₇ is defined as for formula (II);

X₃ is -C(R^g)=N-A-;

Ais O, S, S(O), S(O)₂, C(CR⁸)₂, or NR^k;

R^g and R^k are defined as for formula (I). In another aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (IV):

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrugs thereof, wherein:

U and V are each, independently, N or CR⁸;

Ring D is a 5 to 9-membered aryl, 3 to 9-membered cycloalkyl, 3 to 9- membered cyclyl, 5 to 9-membered heteroaryl, 3 to 9-membered heterocycloalkyl, or a 3 to 9-membered heterocyclyl, each of which may be further substituted with one or more substituents; one of A₁ and A₂ is -X₄-R' -L' -R" and the other is a group represented by the following formula:

Z is N or CH;

W is O, S, S(O), S(O)₂, NR^m, or NC(O)R^m,, wherein R^m, for each occurrence, is independently -H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkylcarbonyl; u is 0, 1, 2, 3, or 4;

X₄ is O, S, S(O), S(O)₂, N(R^k), C(O), C(S), C(S)NR^k, C(NR), C(NR)NR^k, C(O)NR^k, C(O)NR^kNR^k, C(O)ONR^k, C(O)NR^kO, C(O)O, OC(O), OC(O)O, (C(R^g)(R^g))_q, (C(R^g)(R_g))_qNR^k, (C(R^g)(R^g))_qO, (C(R^g)(R^g))_qS(O)_p, (C(R^g)(R^g))_qN=C(R^g), C(R^g)=N, C(R⁸)=N-0, C(R^g)=N-S(O)_p, C(R^g)=N-NR^k, C(R^g)=N-C(CR^g)₂, (C(R⁸)(R^g))_qC(R^g)=N, (C(R^g)(R⁸))_qN=N, (C(R^ε)(R^g))_qC(R^g)=C(R^g), C(R^g)=C(R^g), N=C(R^g), N(R^k)N=C(R^g), N(R^k)C(R^g)=N, N(R^k)C(R^g)=C(R^g), N=N, N(R^k)N=N, NR^kC(O)NR^k, NR^kC(S)NR^k, NR^kC(O), NR^kC(O)O, NR^kC(NR)NR^k, NR^kC(S)O, NR^kS(O)_pNR^k, OC(O)NR^k, OC(S)NR^k, OC(NR)NR^k, OS(O)_pNR^k, C(NR)O, S(O)_pNR^k, or S(O)_pNR^kNR^k;

R' is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or absent;

L' is O, S, S(O), S(O)₂, N(R^k), C(O), C(S), C(S)NR^k, C(NR), C(NR)NR^k, C(0)NR^k, C(0)NR^kNR^k, C(0)0NR^k, C(0)NR^kO, C(O)O, OC(O), OC(O)O, (C(R^g)(R^g))_q, (C(R^g)(R_g))_qNR^k, (C(R^g)(R^g))_qO, (C(R^g)(R^g))_qS(O)_p, (C(R^g)(R^g))_qN=C(R^g), C(R^g)=N, C(R^g)=N-0, C(R^g)=N-S(O)_p, C(R^g)=N-NR^k, C(R^g)=N-C(CR^g)₂ , (C(R^g)(R^g))_qC(R^g)=N, (C(R^g)(R^g))_qN=N, (C(R^g)(R^g))_qC(R^g)=C(R^g), C(R^g)=C(R^g), N=C(R^g), N(R^k)N=C(R^g), N(R^k)C(R^g)=N, N(R^k)C(R^g)=C(R^g), N=N, N(R^k)N=N, NR^kC(O)NR^k, NR^kC(S)NR^k, NR^kC(O), NR^kC(O)O, NR^kC(NR)NR^k, NR^kC(S)O, NR^kS(O)_pNR^k, OC(O)NR^k, OC(S)NR^k, OC(NR)NR^k, 0S(0)_pNR^k, C(NR)O, S(O)_pNR^k, S(0)_pNR^kNR^k or absent; and

R" is H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, N(R^k)(CH₂)_qR^g, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, -C(O)R^c, -C(S)R^c, -C(NR)R^c, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, -S(O)R^c, -S(O)₂R^c, -P(O)R^cR^c, -P(S)R^cR^c, or an optionally substituted alkylcarbonylalkyl; q, for each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, or 8; p, for each occurrence, is independently 0, 1, or 2; and

R, R^c, R^g, R^h, R^j, and R^k are defined as for formula (I).

In another aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (X):

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, prodrug thereof, wherein:

G, Y, R₂, R₃, R₄, and n are defined as for formula (I);

V, U, V, W, X4, Z, R', R", u, and Ring D are defined as for formula (IV); and w is 0 or 1.

In another aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (XIV):

(XIV) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein:

G, Q, U, V, Y, R₂, R₃, R₄, R₅, R₆ and n are defined as for formula (I): ring A is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyclyl, wherein the cycloalkyl, cyclyl, heterocycloalkyl, and heterocyclycl are optionally fused to an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; and

R₁₆, for each occurrence, is independently, H or a lower alkyl.

In another aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound that inhibits the accumulation of c-Rel in the nucleus of the cancer cells and does not inhibit the accumulation of other NF-kB family members in the nucleus of the cancer cells. In one embodiment, the cancer is a lymphoma or leukemia. In another embodiment, the cancer is a B-cell lymphoma or leukemia. In another embodiment, the cancer is a T-cell lymphoma or leukemia. In yet another embodiment, the cancer cells are infected with Epstein-Barr virus. In another embodiment, the compound that is administered to the subject is any compound disclosed herein.

In another aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound that alters the post-translational modification of c-Rel in the cancer cells and does not materially inhibit the post-translational phosphorylation of other NF -KB family members in the cancer cells. In one embodiment, the post-translational phosphorylation of c-Rel is modified. In another embodiment, post-translational phosphorylation of c-Rel is decreased. In another embodiment, the the cancer is a lymphoma or leukemia. In another embodiment, the cancer is a B-cell lymphoma or leukemia. In another embodiment, the cancer is a T-cell lymphoma or leukemia. In yet another embodiment, the cancer cells are infected with Epstein-Barr virus, hi another embodiment, the compound that is administered to the subject is any compound disclosed herein.

In another aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound that inhibits DNA binding of c-Rel to a KB site in the cancer cells and does not inhibit the DNA binding of other NF-κB family members in the cancer cells. In one embodiment, the cancer is a lymphoma or leukemia. In another embodiment, the cancer is a B-cell lymphoma or leukemia. In another embodiment, the cancer is a T- cell lymphoma or leukemia, hi yet another embodiment, the cancer cells are infected with Epstein-Barr virus. In another embodiment, the compound that is administered to the subject is any compound disclosed herein.

In another aspect, the invention provides a method of inhibiting the proliferation of and/or inducing apoptosis in B-cells, comprising contacting the B- cells with a compound that inhibits the accumulation of c-Rel in the nucleus of the cells and does not materially inhibit the accumulation of other NF -kB family members in the nucleus of the cells, hi one embodiment, the B-cells are a B-cell lymphoma or B-cell leukemia. In another embodiment, the B-cells are infected with Epstein-Barr virus, hi another embodiment, the compound is any compound disclosed herein.

In another aspect, the invention provides a method of inhibiting the proliferation of and/or inducing apoptosis in B-cells, comprising contacting the B- cells with a compound that alters the post-translational modification of c-Rel and does not materially inhibit the post-translational phosphorylation of other NF-κB family members. In one embodiment, the compound inhibits the post-translational phosphorylation of c-Rel. hi another embodiment, the compound inhibits the post- translational acetylation of c-Rel. In another embodiment, the B-cells are a B-cell lymphoma or B-cell leukemia. In another embodiment, the B-cells are infected with Epstein-Barr virus. In another embodiment, the compound is any compound disclosed herein.

In another aspect, the invention provides a method of inhibiting the proliferation of and/or inducing apoptosis in B-cells, comprising contacting B-cells with a compound that inhibits DNA binding of c-Rel to a KB site and does not inhibit the DNA binding of other NF-κB family members, hi one embodiment, the B-cells are a B-cell lymphoma or B-cell leukemia. In another embodiment, the B-cells are infected with Epstein-Barr virus. In another embodiment, the compound is any compound disclosed herein.

In another aspect, this invention features a pharmaceutical composition that includes a pharmaceutically acceptable carrier and at least one compound that inhibits the accumulation of c-Rel in the nucleus of the cancer cells and does not inhibit the accumulation of other NF-kB family members in the nucleus of the cancer cells. In one embodiment, the compound in the pharmaceutical composition that inhibits the accumulation of c-Rel is not a compound disclosed in the patents or patent applications listed in Table 2. In one embodiment, the compound in the pharmaceutical composition that inhibits the accumulation of c-Rel is not a compound disclosed in the patents or patent applications listed in Table 3.

In another aspect, this invention features a pharmaceutical composition that includes a pharmaceutically acceptable carrier and at least one compound that alters the post-translational modification of c-Rel and does not materially inhibit the post- translational phosphorylation of other NF -KB family members, hi one embodiment, the compound in the pharmaceutical composition that alters the post-translational modification of c-Rel is not a compound disclosed in the patents and patent applications listed in Table 2. hi one embodiment, the compound in the pharmaceutical composition that alters the post-translational modification of c-Rel is not a compound disclosed in the patents and patent applications listed in Table 3.

In another aspect, this invention features a pharmaceutical composition that includes a pharmaceutically acceptable carrier and at least one compound that inhibits DNA binding of c-Rel to a KB site and does not inhibit the DNA binding of other NF- KB family members. In one embodiment, the compound in the pharmaceutical composition that inhibits DNA binding of c-Rel to a KB site is not a compound disclosed in the patents and patent applications listed in Table 2. In one embodiment, the compound in the pharmaceutical composition that inhibits DNA binding of c-Rel to a KB site is not a compound disclosed in the patents and patent applications listed in Table 3.

Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a western blot analysis of THP-I nuclear extracts in stimulated and non-stimulated cells with regard to the presence of NFKB family members c-Rel, p65 or p50; α-tubulin is an internal control.

Figure 2 is an irnmunofluorescent study indicating that compound 50 can block the accumulation of c-Rel in the nucleus of cells induced by LPS. Figure 3 is an inimunofluorescent study indicating that compound 50 does not block the accumulation of p65 in the nucleus of cells induced by LPS.

Figure 4 is an immunoblot that shows the effect of a test molecule on NF-kB ρ50 nuclear translocation.

Figure 5 graphically presents the results of a densitometry showing the effect of a test molecule on p50 nuclear translocation.

Figure 6 depicts an immunoblot demonstrating the effect of a test molecule on NF-kB p65 nuclear translocation.

Figure 7 graphically presents the results of a densitometry showing the effect of a test molecule on ρ65 nuclear translocation.

Figure 8 depicts an immunoblot demonstrating the effect of a test molecule on nuclear translocation of NF-kB members, including c rel.

Figure 9 is an immunoblot showing the amount of phosphorylation of IKKβ in cells treated with Compound 50 and untreated cells 0 min., 5 min., 15 min., and 60 min. after stimulation with IFNγ/LPS.

Figure 10 is is an immunoblot showing the amount of phosphorylation of p65 in cells treated with Compound 50 and untreated cells 0 min., 30 min., 1 hour, and 6 hours after stimulation with IFNγ/LPS.

Figure 11 is is an immunoblot showing the amount of phosphorylation of p50 in cells treated with Compound 50 and untreated cells 0 min., 30 min., 1 hour, and 6 hours after stimulation with IFNγ/LPS.

Figure 12 is an immunoblot showing that Compound 50 reduces the accumulation of c-Rel in the nucleus of Jurkat T cells after stimulation with PMA + ionomycin but does not significantly reduce the nuclear accumulation of p65 or p50.

Figure 13 is a graph showing the DNA binding activity of c-Rel after stimulation with LPS/IFNγ in treated and untreated cells.

Figure 14 is an immunoblot showing the levels of c-Rel in nuclear extracts and cytosolic extracts in treated and untreated cells after stimulation with LPS/INFγ.

Figure 15 is a graph showing the densitometry measurement of the immunoblot in Figure 14.

Figure 16 is a graph showing the effects of compound 50 on the survival of B cells in the presence of BAFF. Figure 17 is a graph showing the effects of compound 50 on the survival of B cells in the presence of anti-CD40.

Figure 18 is a graph showing the effects of compound 50 on the survival of B cells in the presence of LPS.

Figure 19 are graphs showing the effect of Compound 50 on the viability of four non-B cell human tumor cell lines.

Figure 20 is a graph showing the effect of Compound 50 on apoptosis of several B-cell lymphoma cell lines.

Figure 21 A is a table summarizing the results of treatment with Compound 50 on the proliferation and survival of several B-cell tumor cell lines.

Figure 21B is a table summarizing the results of treatment with Compound 50 on the proliferation and survival of several non-B-cell tumor cell lines.

Figure 22 is a graph of the results of a SCID mouse xenograft study to determine the effect of Compound 50 on the in vivo growth rate of the human Daudi Burkitt's lymphoma tumor cell line. Tumor bearing animals (8 mice/group) were p.o. dosed with vehicle or Compound 50 7 times per week for a total of 11 doses (hatched bar) or i.v. dosed with paclitaxel 3 times per week for a total of 5 doses (hatched bar), and the average tumor volumes for each group (+ SEM) were determined every 3-5 days. Treatment with doses of 50, 100 and 150 mg/kg body weight of Compound 50 inhibited tumor growth, whereas a dose of 10 mg/kg body weight of paclitaxel did not.

Figure 23 is a graph showing that treatment with Compound 50 did not cause overt toxicity in a SCID mouse xenograft model using the human Daudi Burkitt's lymphoma tumor cell line (data derived from the same study presented in Figure 22). Tumor bearing animals (8 mice/group) were p.o. dosed with vehicle or Compound 50 seven times per week for a total of 11 doses (hatched bar) or i.v. dosed with paclitaxel 3 times per week for a total of 5 doses (hatched bar), and the cumulative average percent changes in body weights for each group relative to the start of dosing (+ SEM) were determined every day. Treatment with doses of 50, 100 and 150 mg/kg body weight of Compound 50 was not overtly toxic, as indicated by the modest effects on the animal body weights in the test article-treated versus vehicle-treated groups. 006/020821

DETAILED DESCRIPTION

In one aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I):

(I) or a pharmaceutically acceptable salt, solvate, clatlirate, hydrate, polymorph or prodrug thereof, wherein:

R₂ and R₄, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, -C(O)R^c, -OC(O)R^c, -SC(O)R^c, -NR^kC(O)R°, -C(S)R^c, -OC(S)R^c, -SC(S)R^c, -NR^kC(S)R°, -C(NR)R^c, -OC(NR)R^c, -SC(NR)R^c, -NR^kC(NR)R^c, -SO₂R^c, -S(O)R^c, -NR^kSO₂R^c, -OS(O)₂R^c, -OP(O)R^cR^c, -P(O)R^cR^c, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R₂ and R₄ taken together are =O, =S, or =NR;

R₃ is R^g;

R₅ and R₆ are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R₅ and R₆ taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;

X is O, S, S(O), S(O)₂, or NR^k;

Y is (CH(R^g))_m, C(O), C(NR), O, S, S(O), S(O)₂, N(R^k), or absent;

G is a bond, -C(0)NR^kNR^k-, -NR^kNR^kC(O)-, -NR^kN=CR^k-, -CR^k=NNR^k- -NR^kNR^k-, -N(OH)-, -NR^kO-, -0NR^k~, -C(O)-, -C(NR)-, -NR^kC(O)-, -C(O)NR^k- -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(0)0-, -OC(O)NR^k-, -NR^kC(S)O-, -OC(S)NR^k-, -NR^k-C(NR)-NR^k-, -NR^k-C(0)-NR^k-, -NR^k-C(S)-NR^k-, -NR^k-S(0)₂-NR^k-, -P(O)(R^c)-, -P(O)(R^c)O-, -OP(O)(R^c)-, -OP(O)(Rc)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NR -, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(OR^k)₂-, -B(0R^k)-, -C(NR)-NR^k-, -NR^k-CR^gR^g-C(O)-, -C(O)-ONR^k-, -C(O)-NR^kO-, -C(S)-ONR^k-, -C(S)-NR^kO-, -C(NR)-0NR^k-, -C(NR)-NR^kO-, -OS(O)₂-NR^kNR^k-, -OC(O)-NR^kNR^k-, -OC(S)-NR^kNR^k-, -OC(NR)-NR^kNR^k-, -NR^kNR^kS(O)₂O-, -NR^kNR^kC(S)O-, -NR^kNR^kC(NR)0-, -OP(O)(Rc)O-, -NR^kP(O)(R^c)O-, -OP(O)(R°)NR^k-, -NR^kP(O)(R^c)NR^k-, -P(O)(R^c)NR^k-, -NR^kP(O)(R^c)-,

-O-alkylene-heterocycloalkylene-NR^k-, -NR^k-CHR^g-C(O)-NR^k-CHR^g-C(O)-, -NR^k-CHR^g-C(0)-, -NR^k-C(0)-CHR^g-, or -C(O)-NR^k-CHR^g-C(O)-; and each of Q, U, and V are independently N or CR^g, wherein at least one of Q, U, or V is N; and each CR⁸ may be the same or different;

R°, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;

R^g, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, -C(O)R^C, -OC(O)R⁰, -SC(O)R⁰, -NR^kC(O)R°, -C(S)R⁰, -OC(S)R⁰, -SC(S)R°,-NR^kC(S)R°, -C(NR)R⁰, -OC(NR)R⁰, -SC(NR)R⁰, -NR^kC(NR)R°, -SO₂R⁰, -S(O)R⁰, -NR^kSO₂R°, -OS(O)₂R⁰, -OP(O)R⁰R⁰, -P(O)R⁰R⁰, halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;

R , for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; n is O, 1, 2, 3, 4, 5, 6 or 7; and m is O, 1, 2, 3, or 4.

(II) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug, thereof, wherein G, Q, U, V, Y, R₂, R₃, R₄, R₅, R₆, and n are defined as for formula (I);

X₁ is represented by a formula selected from the group consisting of:

R and R are defined as for formula (I);

R₇ is an optionally substituted aryl or an optionally substituted heteroaryl.

In another aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (III):

R₇ is defined as for formula (II);

X₃ is -C(R^g)=N-A-;

A is O, S, S(O), S(O)₂, C(CR^g)₂, orNR^k;

R^g and R are defined as for formula (I). In another aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (IV):

U and V are each, independently, N or CR^g;

Ring D is a 5 to 9-membered aryl, 3 to 9-membered cycloalkyl, 3 to 9- membered cyclyl, 5 to 9-membered heteroaryl, 3 to 9-membered heterocycloalkyl, or a 3 to 9-membered heterocyclyl, each of which may be further substituted with one or more substituents; one OfA₁ and A₂ is -X₄-R' -L' -R" and the other is a group represented by the following formula:

Z is N or CH;

W is O, S, S(O), S(O)₂, NR^m, or NC(O)R^m , wherein R^m, for each occurrence, is independently -H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkylcarbonyl; u is O, 1, 2, 3, or 4;

X₄ is O, S, S(O), S(O)₂, N(R^k), C(O), C(S), C(S)NR^k, C(NR), C(NR)NR^k, C(0)NR^k, C(O)NR^kNR^k, C(O)ONR^k, C(O)NR^kO, C(O)O, OC(O), OC(O)O, (C(R^g)(R^g))_q, (C(R^g)(R_g))_qNR^k, (C(R^g)(R^g))_qO, (C(R^g)(R^g))_qS(O)_p, (C(R^g)(R^g))_qN=C(R^g), C(R^g)=N, C(R^g)=N-0, C(R^g)=N-S(O)_p, C(R^g)=N-NR^k, C(R^g)=N-C(CR^g)₂, (C(R^g)(R^g))_qC(R^g)=N, (C(R^g)(R^g))_qN=N, (C(R^g)(R^g))_qC(R^g)=C(R^g), C(R^g)=C(R^g), N=C(R^g), N(R^k)N=C(R^g), N(R^k)C(R^g)=N, N(R^k)C(R^g)=C(R^g), N=N, N(R^k)N=N, NR^kC(O)NR^k, NR^kC(S)NR^k, NR^kC(O), NR^kC(O)O, NR^kC(NR)NR^k, NR^kC(S)O, NR^kS(O)_pNR^k, OC(O)NR^k, OC(S)NR^k, OC(NR)NR^k, OS(O)pNR^k, C(NR)O, S(O)_pNR^k, or S(O)_pNR^kNR^k;

R¹ is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or absent;

L¹ is O, S, S(O), S(O)₂, N(R^k), C(O), C(S), C(S)NR^k, C(NR)₅ C(NR)NR^k, C(O)NR^k, C(O)NR^kNR^k, C(0)0NR^k, C(0)NR^k0, C(O)O, OC(O), OC(O)O, (C(R^g)(R^g))_q, (C(R^g)(R_g))_qNR^k, (C(R⁸)(R^g))_qO, (C(R^g)(R^g))_qS(O)_p, (C(R^g)(R^g))_qN=C(R^g), C(R^g)=N, C(R^g)=N-0, C(R^g)=N-S(0)_p, C(R^g)=N-NR^k, C(R^g)=N-C(CR^g)₂ , (C(R^g)(R^g))_qC(R^g)=N, (C(R^ε)(R^g))_qN=N, (C(R^g)(R^g))_qC(R^g)=C(R^g), C(R^ε)=C(R^g), N=C(R^g), N(R^k)N=C(R^g), N(R^k)C(R^g)=N, N(R^k)C(R^g)=C(R^g), N=N, N(R^k)N=N, NR^kC(O)NR^k, NR^kC(S)NR^k, NR^kC(0), NR^kC(O)O, NR^kC(NR)NR^k, NR^kC(S)O, NR^kS(O)_pNR^k, OC(O)NR^k, OC(S)NR^k, 0C(NR)NR^k, OS(O)_pNR^k, C(NR)O, S(0)_pNR^k, S(0)_pNR^kNR^k or absent; and

R" is H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, N(R^k)(CH₂)_qR^g, -0R^k, -SR^k, -NR^hR^j, hydroxylalkyl, -C(O)R^c, -C(S)R^c, -C(NR)R^c, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, -S(O)R^c, -S(O)₂R^c, -P(O)R^cR^c, -P(S)R^cR^c, or an optionally substituted alkylcarbonylalkyl; q, for each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, or 8; p, for each occurrence, is independently 0, 1, or 2; and

R, R^c, R^g, R^h, R^j, and R^k are defined as for formula (I).

G, Y, R₂, R₃, R₄, and n are defined as for formula (I);

R₁₆, for each occurrence, is independently, H or a lower alkyl.

In some embodiments, in the compounds represented by formula (I), (II), (III), or (XIV), Q, U, and V are N.

In some embodiments, in the compounds represented by formula (I), (II), (III), or (XIV), one of Q, U, or V is CR⁸, and the other two are N.

In some embodiments, in the compounds represented by formula (I), (II), (III), or (XIV), V is CR^g, Q and U are N.

In some embodiments, in the compounds represented by formula (I), (II), (III), or (XIV), Q is CR^g, V and U are N.

In some embodiments, in the compounds represented by formula (I), (II), (III), or (XIV), U is CR^g, V and Q are N.

In some embodiments, in the compounds represented by formula (I), (II), (III), or (XIV), one of Q, U, or V is N, and the other two are CR^g.

In some embodiments, in the compounds represented by formula (I), (II), (III), or (XIV), V is N, and Q and U are CR^ε.

In some embodiments, in the compounds represented by formula (I), (II), (III), or (XIV), Q is N, and V and U are CR^g.

In some embodiments, in the compounds represented by formula (I), (II), (III), or (XIV), U is N and Q, and V are CR^g.

In some embodiments, in the compounds represented by formula (I), (II), (III), or (XIV), -NR₅R₆ is an optionally substituted morpholino, an optionally substituted thiomorpholino, an optionally substituted 1-oxo-thiomorpholino, an optionally substituted 1,1-dioxo-thiomorpholino, an optionally substituted piperidinyl, or an optionally substituted piperazinyl.

In some embodiments, in the compounds represented by formula (I), X is -NR^k-. In a preferred embodiment, the R^k of group X is -H or a lower alkyl. In some embodiments, R₁ in the compounds represented by formula (I) or R₇ in the compounds represented by formula (II) or (III), is an optionally substituted aryl or an optionally substituted heteroaryl.

In some embodiments, R₁ in the compounds represented by formula (I) or R₇ in the compounds represented by formula (II) or (III), is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1- oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted carbazolyl, an optionally substituted 1,2,3,4- tetrahydro-carbazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

In some embodiments, R₁ in the compounds represented by formula (I) or R₇ in the compounds represented by formula (II) or (III), is an optionally substituted phenyl, an optionally substituted indolyl, an optionally substituted indanyl, an optionally substituted carbazolyl, or an optionally substituted 1,2,3,4-tetrahydro- carbazolyl. • In some embodiments, R₁ in the compounds represented by formula (I) or R₇ in the compounds represented by formula (II) or (III) is a group represented by the following formula:

wherein: the dashed line indicates a double or a single bond;

X₂ is -0-, -S(OV, -N(R^k)-, or -C(R^g)(R^g)-;

R₈ and R₉ are each, independently, R^g, -C(O)R⁰, -C(S)R^c, -C(NR)R^c, -NR^kC(O)R°, -OC(O)R^c, -SC(O)R^c, -NR^kC(S)R^c, -OC(S)R^c, -SC(S)R^c, -NR^kC(NR)R°, -OC(NR)R^c, or -SC(NR)R^c; or R₈ and R₉, taken together with the carbons to which they are attached, form a 5- to 7-membered optionally substituted cycloalkyl, a 5- to 7-membered optionally substituted cyclyl, a 5- to 7-membered optionally substituted aryl, a 5- to 7-membered optionally substituted heterocycloalkyl, a 5- to 7-membered optionally substituted heterocyclyl, a 5- to 7-membered optionally substituted heteroaryl;

R₁₀, for each occurrence, is, independently, R^g, -C(O)R^c, -C(S)R^c, -C(NR)R^c, -NR^kC(0)R°, -OC(O)R^c, -SC(O)R^c, -NR^kC(S)R°, -OC(S)R^c, -SC(S)R^c, -NR^kC(NR)R^c, -OC(NR)R^c, or -SC(NR)R^c; p is 0, 1, or 2; and t is O, 1, 2, or, 3.

In some embodiments, R₁ in the compounds represented by formula (I) or R₇ in the compounds represented by formula (II) or (III) is (2,3-dimethyl-1H -indol-5-yl), (1H-indol-5-yl), or (6,7,8,9-tetrahydro-5H-carbazol-3-yl).

In some embodiments, in the compounds represented by formula (II) or (III), R₇ is a group represented by the following formula:

wherein:

R₁₁ and R₁₂, for each occurrence, are, independently, R^g, -C(O)R^c, -C(S)R^c, -C(NR)R^c, -NR^kC(0)R°, -OC(O)R^c, -SC(O)R^c, -NR^kC(S)R°, -OC(S)R^c, -SC(S)R^c, -NR^kC(NR)R°, -OC(NR)R^c, or -SC(NR)R^c; and s is 0, 1, 2, 3, or 4.

In some embodiments, in the compounds represented by formula (I), R₁ is a group represented by the following formula:

In some embodiments, when R₁ of formula (I) is group (XVIII), one of R^a or R^b is -H or a lower alkyl, and the other is an optionally substituted aryl or an optionally substituted heteroaryl.

In some embodiments, when R₁ of formula (I) is group (XVIII), one of R^a or R^b is -H or a lower alkyl, and the other is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fiuorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted carbazolyl, an optionally substituted 1,2,3,4-tetrahydro-carbazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

In some embodiments, when R₁ of formula (I) is group (XVIII), one of R^a or R^b is — H or a lower alkyl, and the other is an optionally substituted phenyl, an optionally substituted indolyl, an optionally substituted indanyl, an optionally substituted carbazolyl, or an optionally substituted 1,2,3,4-tetrahydro-carbazolyl.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), Y is O.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), Y is a covalent bond.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), R₃ is H.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), R₃ is an optionally substituted aryl or an optionally substituted heteroaryl.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), R₃ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), R₃ is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2-oxopiperazinyl, an optionally substituted 2- oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3-dioxolanyl, an optionally substituted [l,4]dioxanyl, an optionally substituted 2-oxo-imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), R₃ is a hydroxy, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl. In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), R₃ is a hydroxy, an optionally substituted pyridinyl, an optionally substituted morpholino, or an optionally substituted oxazolidin-2-one.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), R₃ is -OR^k or -NR^hR^j, and R^f, R^h and R^j are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R^c.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), R₃ is -C(O)OR^k, -OC(O)R^k, -C(O)NR^hR^j, -NR^kC(O)R^k, -C(S)OR^k, -OC(S)R^k, -NR^kC(O)NR^hR^j, -NR^kC(S)NR^hR^j, -C(O)NRhRj, -S(O)₂R^k, -S(O)₂NR^hR^j, -OC(O)NR^hR^j, or-NR^kC(O)OR^k.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), each of R₂ and R₄ is, independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyclyl.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), n is 1, 2, or 3, and R₂ and R₄, for each occurrence are, independently, H or a lower alkyl.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), G is absent.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), G is an optionally substituted heteroaryl or an optionally substituted heterocyclyl.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), G is -C(O)NHNH-, -NHNHC(O)-, -CH=N-NH-, -NH-N=CH-,- NHNH- -NHO-, -O-NH-, -NR^k-O-, -CH=N-O-, -O-N=CH-, -O-C(S)-NH-, or -NH- C(S)-O-.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), G is -0-C(O)-NH-, -NH-C(NH)-NH-, -NR^k-C(NH)-NH-, -NR^k- C(NR^k)-NH-, -NH-C(N(CN))-NH-, -NH-C(NSO₂R^c)-NH-, -NR^k-C(NSO₂R^c)-NH-, - NH-C(NNO₂)-NH-, NH-C(NC(O)R^c)-NH-, -NH-C(O)-NH-, Or-NH-C(S)-NH-. In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), G is -NH-S(O)₂-NH-, -NR^k-S (O)₂-O-, -P(O)(R⁰)-, -P(O)(R^C)-O-, or - P(O)(R°)-NR^k-.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), G is an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl or an optionally substituted heterocyclyl.

In some embodiments, in the compounds represented by foπnula (I), (II), (III), (X) or (XIV), G is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted cyclohexyl, an optionally substituted cycloheptyl, an optionally substituted aziridinyl, an optionally substituted oxiranyl, an optionally substituted azetidinyl, an optionally substituted oxetanyl, an optionally substituted morpholinyl, an optionally substituted piperazinyl or an optionally substituted piperidinyl.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), G is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, -C(N-CN)-NH-, -Si(OH)₂-, -C(NH)-NR^k-, or- NR^k-CH₂-C(0)-.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), G is an optionally substituted imidazolyl, an optionally substituted imidazolidinone, an optionally substituted imidazolidineamine, an optionally substituted pyrrolidinyl, an optionally substituted pyrrolyl, an optionally substituted furanyl, an optionally substituted thienyl, an optionally substituted thiazolyl, an optionally substituted triazolyl, an optionally substituted oxadiazolyl, an optionally substituted thiadiazolyl, an optionally substituted pyrazolyl, an optionally substituted tetrazolyl, an optionally substituted oxazolyl, an optionally substituted isoxazolyl, an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidyl, an optionally substituted indolyl, or an optionally substituted benzothiazolyl.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), Y is O or CH₂; G is absent; and n is 0, 1, 2, 3 or 4.

In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), Y is absent, O, S, NR^k, or CH₂; and n is 0, 1, 2, 3, or 4. In some embodiments, in the compounds represented by formula (II), X₁ is one of the following formulas:

In some embodiments, in the compounds represented by formula (II), X₁ is represented by the following formula:

wherein R is — H or a lower alkyl.

wherein R^k is -H or a lower alkyl.

wherein R^k is -H or a lower alkyl. In some embodiments, in the compounds represented by formula (III), X₃ is -C(R^s)=N-NR^k-, wherein R⁸ and R^k of X₃ are each, independently, -H or a lower alkyl.

In some embodiments, in the compounds represented by formula (IV), the compound is represented by formula (V):

(V) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein:

G, Y, R₂, R₃, R₄, and n are defined as for formula I; and Ring D, A₁, A₂, U, and V are defined as for formula (IV).

In some embodiments, in the compounds represented by formula (IV) or (V), the compound is represented by one of the following structural formulas:

(VI)

(VII)

(VIII)

(IX) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, ug thereof, wherein:

G, Y, R₂, R₃, R₄, R^s, and n are defined as for formula I;

U, V, L, X₄, W, Z, R', R", and u are defined as for formula (IV);

X₅, X₆ and X₇ are each, independently, N or CR^§; X₈ is CR^gR^g, O₅ S(O)p, or NR^k, wherein R^k is defined as for formula (I).

In some embodiments, in the compounds represented by formula (VI) or formula (VII), U and V are N; and X₅, X₆ and X₇ are CR^g.

In some embodiments, in the compounds represented by formula (IV), (V), (VI), (VII), (VIII), or (IX), R' and U are absent.

In some embodiments, in the compounds represented by formula (IV), (V), (VI), (VII), (VIII), or (IX), R" is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.

In some embodiments, in the compounds represented by formula (IV), (V), (VI), (VII), (VIII), or (IX), R" is an optionally substituted aryl or an optionally substituted heteroaryl.

In some embodiments, in the compounds represented by formula (IV), (V), (VI), (VII), (VIII), or (IX), R" is substitituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH₂, a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, -S(O)_PR^C, and- C(O)R^C.

In some embodiments, in the compounds represented by formula (IV), (V), (VI), (VII), (VIII), or (IX), Z is N and W is O.

In some embodiments, in the compounds represented by formula (V), (VI), (VII), (VIII), or (IX), Y is a covalent bond, O, S, N(R^k), or CH₂, and n is 0, 1, 2, 3, or 4.

In some embodiments, in the compounds represented by formula (V), (VI), (VII), (VIII), or (IX), G is absent. hi some embodiments, in the compounds represented by formula (V), (VI), (VII), (VIII), or (IX), G is >C=N-R, -NR^kC(O)-, -C(O)NR^k-, -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(O)O-, -OC(O)NR¹S -NR^kC(S)O-, -OC(S)NR^k-, -NR^kC(NR)NR^k-, -NR^kC(0)NR^k-, -NR^kC(S)NR^k-, -NR^kS(O)₂NR^k-, -C(NR)NR¹S or -NR^kCR^gR^gC(O)-. hi some embodiments, in the compounds represented by formula (V), (VI), (VII), (VIII), or (IX), R₃ is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, OR^k, SR^k, or NR^hR^j.

In some embodiments, in the compounds represented by formula (V), (VI), (VII), (VIII), or (IX), R₃ is optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, in the compounds represented by formula (V), (VI), (VII), (VIII), or (EK), R₃ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

In some embodiments, in the compounds represented by formula (V), (VI), (VII), (VIII), or (IX), R₃ is an optionally substituted heterocycloalkyl.

In some embodiments, in the compounds represented by formula (V), (VI), (VII), (VIII), or (IX), R₃ is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2-oxopiperazinyl, an optionally substituted 2-oxopiρeridinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3- dioxolanyl, an optionally substituted [l,4]dioxanyl, an optionally substituted 2-oxo- imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.

In some embodiments, in the compounds represented by formula (V), (VI), (VII), (VIII), or (IX), R₃ is -OR^k or -NR^hR^j, and R^f, R^h and R^j are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R⁰.

In some embodiments, in the compounds represented by formula (V), (VI), (VII), (VIII), or (IX), R₃ is -C(O)OR^k, -OC(O)R^k, -C(O)NR^hR^j, -NR^kC(O)R^k, - C(S)OR^k, -OC(S)R^k, -NR^kC(O)NR^hR^j, -NR^kC(S)NR^hR^j, -C(O)NRhRj, -S(O)₂R^k, -S(O)₂NR^hR^j, -OC(O)NR¹¹R", or -NR^kC(0)0R^k.

In some embodiments, in the compounds represented by formula (IV), the compound is represented by one of the following structural formulas:

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein;

U, V, A₁, and A₂ are defined as for formula (IV);

X₉ is CR^gR^g, O, S(O)p, orNR^k; one ofR₁₃, R₁₄ and R₁₅ is a group represented by the following structural formula:

and the remainder of R₁₃, R₁₄ and R₁₅ are independently selected from H, R^g, or isothionitro; and

R₂, R₃, R₄, G, Y, R^e, R^k and n are defined as for formula (I).

In some embodiments, in the compounds represented by formula (XIX), (XX)₅ (XXI), (XXII), (XXIII), or (XXIV), U and V are N.

In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), R' and L' are absent.

In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), R" is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.

In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), R" is an optionally substituted aryl or an optionally substituted heteroaryl. In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), R" is substituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH₂, a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, -S(O)_PR°, and- C(O)R⁰.

In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), Z is N and W is O.

In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), Y is a covalent bond, O, S, N(R^k), or CH₂, and n is 0, 1, 2, 3, or 4.

In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), G is absent.

In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), G is >C=N-R, -NR^kC(O)-, -C(O)NR¹S -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(O)O-, -OC(O)NR^k-, -NR^kC(S)O-, -OC(S)NR^k-, -NR^kC(NR)NR^k-, -NR^kC(O)NR^k-, -NR^kC(S)NR^k-, -NR^kS(O)₂NR^k-, -C(NR)NR¹S or -NR^kCR^gR^gC(O>.

In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), R₃ is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, 0R^k, SR^k, orNR^hR^j.

In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), R₃ is optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), R₃ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally suDstituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), R₃ is an optionally substituted heterocycloalkyl.

In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), R₃ is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2-oxopiperazinyl, an optionally substituted 2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3- dioxolanyl, an optionally substituted [l,4]dioxanyl, an optionally substituted 2-oxo- imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.

In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), R₃ is -OR^k or -NR^hR^j, and R^f, R^h and R^j are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R^C.

In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI)₅ (XXII), (XXIII), or (XXIV), R₃ is -C(O)OR^k, -OC(O)R^k, -C(O)NR^hR^j, -NR^kC(O)R^k, -C(S)OR^k, -OC(S)R^k, -NR^kC(O)NR^hR^j, -NR^kC(S)NR^hR^j, -C(O)NRhRj, -S(O)₂R^k, -S(O)₂NR^hR^j, -OC(O)NR^hR^j, or -NR^kC(O)OR^k.

In some embodiments, in the compounds represented by formula (X), the compound is represented by one of the following structural formulas:

(XI)

(XII)

(XIII) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein:

G, Y, R₂, R₃, R₄, R^g and n are defined as for formula (I);

R', R", L', X₄, U, V, W, Z, and u are defined as for formula (IV); w is defined as for formula (X);

X₅, X₆ and X₇ are each, independently, N or CR^g; and

X₈, X₁₀, and X₁₁ are each, independently, CR^gR^g, O, S(0)_p, or NR^k, wherein R^k is defined as for formula (I).

In some embodiments, in the compounds represented by formula (XI), U and

V are N; and X₅ and X₆ are CR^g.

In some embodiments, in the compounds represented by formula (XI), U and

V are N; X₅ and X₆ are CR^g; and X₇ is N.

In some embodiments, in the compounds represented by formula (XI), U and

V are N; X₅ and X₆ are CR^g; and X₇ is CR^g.

In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), w is O, and R' and L' are absent.

In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), R" is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.

In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), R" is an optionally substituted aryl or an optionally substituted heteroaryl. In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), R" is substituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH₂, a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, -S(O)_PR^C, and -C(O)R⁰.

In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), Z is N and W is O.

In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), Y is a covalent bond, O, S, N(R^k), or CH₂, and n is O, 1, 2, 3, or 4.

In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), G is absent.

In some embodiments, in ^"the compounds represented by formula (XI), (XII), or (XIII), G is >C=N-R, -NR^kC(O)-, -C(O)NR^k-, -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(O)O-, -OC(O)NR¹S -NR^kC(S)O-, -OC(S)NR^k-, -NR^kC(NR)NR^k-, -NR^kC(O)NR^k-, -NR^kC(S)NR^k-, -NR^kS(O)₂NR^k-, -C(NR)NR^k-, or -NR^kCR^εR^gC(O)-.

In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), R₃ is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, 0R^k, SR^k, orNR^hR^J.

In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), R₃ is optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, in the compounds represented by formula (XI), (XU), or (XIII), R₃ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetraliydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), R₃ is an optionally substituted heterocycloalkyl.

In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), R₃ is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2-oxopiperazinyl, an optionally substituted 2- oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3-dioxolanyl, an optionally substituted [l,4]dioxanyl, an optionally substituted 2-oxo-imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.

In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), R₃ is -OR^k or -NR^hR^j, and R^f, R^h and R^j are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R⁰.

In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), R₃ is -C(O)OR^k, -OC(O)R^k, -C(O)NR^hR^j, -NR^kC(O)R^k, -C(S)OR^k, -OC(S)R^k, -NR^kC(O)NR^hR^j, -NR^kC(S)NR^hR^j, -C(O)NRhRj, -S(O)₂R^k, -S(O)₂NR^hR^j, -OC(O)NR^hR^j, or-NR^kC(O)OR^k. In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), w is 1; X₄ is O, S, or NR_k; and R' and L' are absent.

In some embodiments, in the compounds represented by formula (XIV), the compound is represented by formula (XV):

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein:

Q, U, and V are defined as for formula (I);

R₁₆ is defined as for formula (XIV); ring E is optionally substituted with one to four substituents selected from a lower alkyl, a halo, an amino, a lower alkyl amino, a lower dialkyl amino, a cyano, a nitro, a lower haloalkyl, a hydroxyl, and a lower hydroxyalkyl;

X₁₂ is O, S, S(O), S(O)₂, or CR^gR^g;

X₁₃ is O, S, S(O), S(O)₂, or CH₂;

Y₁ is O, S, NR^k, or CH₂;

R₁₇ and R₁₈, for each occurrence, are independently, H or a lower alkyl; or R₁₇ and R₁₈ taken together with the carbon to which they are attached form a cycloalkyl; and f is O, 1, 2, or 3.

hi some embodiments, in the compounds represented by formula (XIV)₅ the compound is represented by formula (XVI):

Q, U, and V are defined as for formula (I);

R₁₆ is defined as for formula (XIV);

Y₁, R₁₇, R₁₈, X₁₃, and f are defined as for formula (XV); ring F is optionally substituted with one or two substituents selected from a lower alkyl, a halo, an amino, a lower alkyl amino, a lower dialkyl amino, a cyano, a nitro, a lower haloalkyl, a hydroxyl, and a lower hydroxyalkyl; and

Xi₄ is O, NR^k, or CR^gR^g.

In some embodiments, in the compounds represented by formula (XIV), the compound is represented by formula (XVII):

(XVII) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein:

Q, U, and V are defined as for formula (I);

R₁₆ is defined as for formula (XIV);

Y₁, R₁₇, R₁₈, X₁₃, and fare defined as for formula (XV); and

X₁₅ is -OH, -NH₂ or -SH.

In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII)₅ Q, U, and V are N.

In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), one of Q, U, or V is CR^g, and the other two are N.

In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), V is CR^ε, Q and U are N.

In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), Q is CR^g, V and U are N.

In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), U is CR^g, V and Q are N.

In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), one of Q, U, or V is N, and the other two are CR^S.

In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), V is N, and Q and U are CR^g.

In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), Q is N, and V and U are CR^ε. In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), U is N and Q, and V are CR^g.

In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), -NR₅R₆ is an optionally substituted morpholino, an optionally substituted thiomorpholino, an optionally substituted l-oxo-thiomorpholino, an optionally substituted 1,1-dioxo-thiomorpholino, an optionally substituted piperidinyl, or an optionally substituted piperazinyl.

In some embodiments, in the compounds represented by formula (XIV), (XV), (XVI), or (XVII), ring A is a ring system selected from the group consisting of:

wherein:

epresents the point of attachment;

rings G, H, I, and J are each, independently, an aryl or a heteroaryl; and each ring system is optionally substituted with one or more substituents.

wherein: each ring system is optionally substituted with one or more substituents;

represents the point of attachment; and R₁₉ is H, an alkyl, an aralkyl, or an alkylcarbonyl.

wherein: each ring system is optionally substituted with one or more substituents.

In some embodiments, in the compounds represented by formula (XIV), (XV), (XVI), or (XVII), ring A is optionally substituted with one or more substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkyl sulfanyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted heterocyclo alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, halo, cyano, nitro, haloalkoxy, =O, =S, =NR, -OR^k, -NR^hR^j, -SR^k, -C(O)R^k, -C(O)NR^hR^j, -NR^kC(O)R^k, -C(O)OR^k, -OC(O)R^k, -NR^kC(O)NR^hR>, -OC(O)NR^hR^j, -NR^kC(O)OR^k, -C(NR)R^k, -C(NR)NR^hR^j, -NR^kC(NR)R^k, -C(NR)OR^k, -OC(NR)R^k, -NR^kC(NR)NR^hR^j, -OC(NR)NR^hR^j, -NR^kC(NR)0R^k, -C(S)R^k, -C(S)NR^hR^j, -NR^kC(S)R^k, -C(S)OR^k, -OC(S)R^k, -NR^kC(S)NR^hR^j, -OC(S)NR^hR^j, -NR^kC(S)OR^k, -C(O)SR^k, -SC(O)R^k, -S(O)_pR^k, -S(O)_pNR^hR^j, -OS(O)_pR^k, -S(O)_pOR^k, -OS(O)_pOR^k, -P(O)(OR^k)₂, ~OP(O)(OR^k)₂, -P(S)(OR^k)₂, -SP(O)(OR^k)₂, -P(O)(SR^k)(OR^k), -OP(O)(SR^k)(OR^k), -P(O)(SR^k)₂, or -OP(O)(SR^k)₂, wherein p is 1 or 2.

In some embodiments, in the compounds represented by formula (XIV)₅ (XV), (XVI), or (XVII), ring A is optionally substituted with from one to three substituents selected from the group consisting of a lower alkyl, a lower alkoxy, =0, nitro, cyano, hydroxy, amino, lower alkyl amino, lower dialkyl amino, mercapto, lower alkyl sulfanyl, halo, or haloalkyl.

In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), Y₁ is O.

In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), Y₁ is a covalent bond.

In some embodiments, in the compounds represented by formula (XIV), Y is O or CH₂; G is absent; and n is O, 1 , 2, 3 or 4.

In some embodiments, in the compounds represented by formula (XIV), Y is absent, O, S, NR^k, or CH₂; and n is 0, 1, 2, 3, or 4.

In some embodiments, in the compounds represented by formula (XV), X₁₂, X₁₃, Y₁ is O; and R₁₇ and R_1S are each, independently, H or a lower alkyl.

In some embodiments, in the compounds represented by formula (XVI), X₁₃, X₁₄, and Yi are O; and R₁₇ and R₁₈ are each, independently, H or a lower alkyl.

In some embodiments, in the compounds represented by formula (XVII), Xi₃ and Yi are O; X₁₅ is -OH; and R₁₇ and R₁₈ are each, independently, H or a lower alkyl. Specific examples of compounds of the invention are set forth below in Table :

Table 1

2006/020821

1

-

ill

TUS2006/020821

-

020821

20821

All of the features, specific embodiments and particular substituents disclosed herein may be combined in any combination. Each feature, embodiment or substituent disclosed in this specification may be replaced by an alternative feature, embodiment or substituent serving the same, equivalent, or similar purpose. In the case of chemical compounds, specific values can be combined in any combination resulting in a stable structure. Furthermore, specific values (whether preferred or not) for substituents in one type of chemical structure may be combined with values for other substituents (whether preferred or not) in the same or different type of chemical structure. Thus, unless expressly stated otherwise, each feature, embodiment or substituent disclosed is only an example of a generic series of equivalent or similar features feature, embodiments or substituents.

Examples of cancers that can be treated by administering one or more compound of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug, include leukemia, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, or retinoblastoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, esophogeal cancer, gastric cancer, hepatocellular cancer, colorectal cancer, anal carcinoma, genitourinary cancer, testicular cancer, bladder cancer, renal cell cancer, ovarian cancer, endometrial cancer, cervical cancer, breast cancer, neoplasms of endocrine organs, including the thyroid, parathyroid, tumors of adrenal medulla, pheochromocytoma, neuroblastoma, multiple endocrine neoplasia, hematologic cancers, leukemia, multiple myeloma, Hodgkins disease, non- Hodgkins lymphoma, brain cancers, craniopharyngeoma, pituitary neoplasms, astrocytomas, meningiomas, spinal cord tumors, peripheral nervous system cancers, schwannomas neuroma, acoustic neuroma, skin cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, cardiac tumors, atrial myxomas, kidney cancer, bone cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma bile duct carcinoma, choriocarcinoma, seminoma embryonal carcinoma, uterine cancer, testicular cancer, bladder carcinoma, epithelial carcinoma, glioma glioblastoma, multiforme astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, retinoblastoma, blood-borne cancers, acute lymphoblastic leukemia "ALL", acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia "AML", acute promyelocyte leukemia "APL", acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia "CML", chronic lymphocytic leukemia "CLL", hairy cell leukemia, multiple myeloma, acute lymphoblastic leukemia, acute myelogenous leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, Hodgkin's disease, non-Hodgkin's Lymphoma, Multiple myeloma, Waldenstrom's macroglobulinemia, Heavy chain disease, or Polycythemia vera.

NF-κB transcription factors transcribe genes that are involved in the inflammatory response and thus play a key role in cell proliferation and apoptosis. NF-κB has been shown to be constitutively active in many tumors. Without wishing to be bound by any theory, because the experimental evidence appears to indicates that the compounds of the invention inhibit the activity of c-Rel, an NF-κB family member, it is believed that compounds of the invention are useful in treating cancers in which NF-κB is constituatively activated. Cancers in which NF-κB is constituatively activated include Hodgkin's lymphoma, Non-Hodgkin's lymphoma, squamous cell carcinoma, breast cancer, chromic myelogenous leukemia, melanoma, colorectal cancer, squamous intraepithelial lesions, adenocarcinoma, ovarian cancer, bladder cancer, lung cancer, esophageal cancer, gastric cancer, prostate cancer, vulvar carcinoma, heptacellular carcinoma, thyroid carcinoma, thyroid carcinoma, endometrial carcinoma, oral carcinoma, renal carcinoma, familial cylindromatosis, hilar cholangiocarcinoma, astrocytoma, neuroblastoma, acute lymphoblastic leukemia, acute myelogenous leukemia, acute T-cell leukemia (HTLV-I), chromic lymphocytic leukemia (CLL), Burkitts lymphoma, primary effusion lymphoma, mantle cell lymphoma, multiple myeloma, diffuse large B-cell lymphoma, follicular B-cell lymphoma, or mediastinal B-cell lymphoma. c-Rel has been shown to play a role in the proliferation and survival of B-cells. The c-Rel protein is expressed at all stages of B-cell development, but is expressed at the highest levels in mature B-cells. c-Rel knockout mice develop normally and have no gross defects in hemopoiesis. However, they show immuno-defϊciencies which primarily stem from defects in B-cells proliferation and survival in response to mitogenic activation, such as LPS, anti-IgM, antigens, and CD40. In addition, they show reduced antibody production in response to an antigen. Without wishing to be bound by any theory, because the experimental evidence appears to indicate that the compounds of the invention inhibit the activity of c-Rel which has been shown to be necessary for B-cell proliferation and survival, it is believed that compounds of the invention are useful in treating B-cell lymphomas or leukemias. B-cell lymphomas or leukemias include B-cell chronic lymphocytic leukemia (B-CLL), small lymphocytic lymphoma (SLL), lymphoplamacytoid lymphoma, follicle center lymphoma, follicular mixed cell (FM), marginal zone B-cell lymphoma, hairy cell leukemia, plasmacytoma, B-cell prolymphocytic leukemia (B-PLL), mantle cell lymphoma, B-cell large B-cell lymphoma, precursor B-lymphoblastic leukemia, precursor B-lymphoblastic lymphoma, Burkitt's lymphoma, and high-grade B-cell lymphoma. In one embodiment, the the cancers that can be treated by administering a compound of the invention include Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular B-cell lymphoma, mediastinal B-cell lympohoma, anaplastic large cell lymphoma, and extranodal marginal zone lymphoma.

REL gene rearrangements, mutations, deletions, amplifications, and combination thereof have been shown to be present in some cancers and in a high percentage of B-cell lymphomas causing a misregulation of c-Rel and activating proliferative and anti-apoptotic genes. Therefore, without wishing to be bound by any theory, because the experimental evidence appears to indicate that the compounds of the invention inhibit the activity of c-Rel, it is believed that compounds of the invention are useful in treating cancers in which REL gene rearrangements, mutations, deletions, amplifications, and combination thereof are present. In addition, since c-Rel has been shown to activate proliferative and anti-apoptotic genes, it is believed that compounds of the invention are useful in treating cancers in which c-Rel is over expressed in comparison to non-cancerous cells.

A "mutation" includes any change of the DNA sequence within a gene or chromosome. In some instances, a mutation will alter a characteristic or trait (phenotype), but this is not always the case. Types of mutations include base substitution point mutations (e.g., transitions or transversions), deletions, and insertions. Missense mutations are those that introduce a different amino acid into the sequence of the encoded protein; nonsense mutations are those that introduce a new stop codon. In the case of insertions or deletions, mutations can be in-frame (not changing the frame of the overall sequence) or frame shift mutations, which may result in the misreading of a large number of codons (and often leads to abnormal termination of the encoded product due to the presence of a stop codon in the alternative frame). The term "mutation" specifically encompasses variations that arise through somatic mutation, for instance those that are found only in disease cells, but not constitutionally in a given individual. Examples of such somatically-acquired variations include the point mutations that frequently result in altered function of various genes that are involved in development of cancers. This term also encompasses DNA alterations that are present constitutionally, that alter the function of the encoded protein in a readily demonstrable manner, and that can be inherited by the children of an affected individual, hi particular embodiments, the term is directed to those constitutional alterations that have major impact on the health of affected individuals, such as those resulting in onset of a disease such as a hematological cancer.

An insertion or deletion of a single nucleotide, or of more than one nucleotide, resulting in a frame shift; the change of at least one nucleotide, resulting in a change in the encoded amino acid; the change of at least one nucleotide, resulting in the generation of a premature stop codon; the deletion of several nucleotides, resulting in a deletion of one or more amino acids encoded by the nucleotides; the insertion of one or several nucleotides, such as by unequal recombination or gene conversion, resulting in an interruption of the coding sequence of the gene; duplication of all or a part of the gene; transposition of all or a part of the gene; or rearrangement of all or a part of the gene. More than one such change may be present in a single gene.

EBV has the ability to transform resting B-cells into proliferating lymphoblastoid cell lines (LCLs) and has been shown to be implicated in a variety of human cancers (Thompson and Kurzrock, Clinical Cancer Research (2004), 10:803- 821). It has been shown that EBV virus latent membrane protein 1 (LMPl) causes activation of NF-KB and that this is essential for EBV transformed lymphoblastoid cell line survival (Cahir-McFarland, et al, Proc. Natl. Acad. Sd. USA (2000), 97:6055-6060). Therefore, it is believed that NK-kB activation is involved in cancers that are associated with EBV infection. Without wishing to be bound by any theory, because the experimental evidence appears to indicates that the compounds of the invention inhibit the activity of c-Rel, an NF-κB family member, it is believed that compounds of the invention are useful in treating cancers associated with EBV infection. Cancers associated with EBV infection include Burkitt's lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, nasopharyngeal carcinoma (e.g., anaplastic), breast cancer (e.g., medullary carcinoma, adenocarcinoma), gastric cancer (e.g., lymphoepithelioma-like, adenocarcinoma), post-transplant lymphoproliferative disorders, AIDS-associated lymphomas, and leiomyosarcomas. In addition, EBV infection has been associated with T-cell and NK-cell lymphomas (Young and Rickinson, Nature Reviews (2004), 4:757-767). The compounds of the invention can be used to treat EBV associated T-cell and NK-cell disorders.

Human T-cell leukemia virus type I (HTLV-I) and type II (HTLV-II) have been shown to cause adult T-cell leukemia. HTLV encodes Tax, a 40 kDa protein that is a strong transcriptional activator of c-Rel, and the levels of c-Rel protein and RNA, but not other other NF-kB family members such as p50 or p65, are consistently higher in HTLV infected cells than in control T-cells. Thus, it is believed that c-Rel overexpression may play a role in T-cell malignacies in HTLV infected individuals. Without wishing to be bound by any theory, because the experimental evidence appears to indicates that the compounds of the invention inhibit the activity of c-Rel, it is believed that compounds of the invention are useful in treating T-cell lymphomas or leukemias. T-cell lymphoma or leukemia include large granular lymphocyte leukemia, adult T-cell leukemia, adult T-cell lymphoma, mycosis fungoides, T-cell chronic lymphocytic leukemia, prolymphocytic leukemia, angiocentric lymphoma, angioimmunoblastic lymphoma, precursor T-lymphblastic leukemia, or precursor T- lymphblastic lymphoma.

NF-κB family members, including c-Rel, ReIA (also referred to as "p65"), ReIB, p50 and p52, exist mainly in the cytoplasm in an inactive form due to association with one or more members of a family of inhibitors known as IKB proteins (IκBα, IκBβ, IκBε, Bcl-3, pi 00, pi 05). The best characterized of the IkB proteins, IκBα, has a strong nuclear export sequence that keeps complexes of it and NF-κB proteins largely in the cytoplasm. Pro-inflammatory cytokines and other stimuli trigger phosphorylation of IκBα by IKB kinase (IKK) which marks it for subsequent ubiquitination and proteasomal degradation. Once liberated from association with IKB proteins, NF-κB proteins can accumulate in the nucleus and form homo- and heterodimers which activate the transcription of target genes, including those controlling cell proliferation and cell survival (anti-apoptotic genes). In normal cells, activation of NF-κB proteins is usually a transient process because one of the primary target genes of NF-κB is the gene encoding IκBα which can bind to NF-κB proteins and return them to their latent form in the cytoplasma. In many types of cancer cells, NF-kB, and in particular c-Rel, is misregulated and has become constitutively activated.

Without wishing to be bound by any theory, the compounds of the invention are believed to inhibit the accumulation of c-Rel in the nucleus, thereby down- regulating proliferative and anti-apoptotic genes associated with c-Rel activity. Therefore, in one aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound that inhibits the accumulation of c-Rel in the nucleus of the cancer cells and does not inhibit the accumulation of other NF-kB family members in the nucleus of the cancer cells. In one embodiment, the cancer is a lymphoma or leukemia. In another embodiment, the cancer is a B-cell lymphoma or leukemia. In another embodiment, the cancer is a T-cell lymphoma or leukemia. In yet another embodiment, the cancer cells are infected with Epstein-Barr virus. In another embodiment, the compound that is administered to the subject is any compound disclosed herein.

Without wishing to be bound by any theory, the compounds of the invention are believed to alter the post-translational modification (e.g., phosphorylation and acetylation) of c-Rel which inhibits the accumulation of c-Rel in the nucleus, thereby down-regulating proliferative and anti-apoptotic genes associated with c-Rel activity. In one embodiment, the compounds of the invention inhibit the post-translational phosphorylation of c-Rel. Li another embodiment, the compounds of the invention inhibit the post-translational acetylation of c-Rel. In addition, the compounds of the invention do not materially alter the accumulation of other NF-kB family members in the nucleus. In addition, the compounds of the invention do not materially alter post- translational phosphorylation of other NF-κB family members, nor do they materially alter the expression or phosphorylation of IKB. In one embodiment, the compounds of the invention inhibit the post-translational phosphorylation of c-Rel without materially inhibiting the expression of NF-kB family members other than c-Rel. hi another embodiment, the compounds of the invention inhibit the post-translational phosphorylation of c-Rel without materially inhibiting the post-translational phosphorylation of NF-kB family members other than c-Rel. In another embodiment, the compounds of the invention inhibit the post-translational phosphorylation of c-Rel without materially altering the expression of IKB. In another embodiment, the compounds of the invention inhibit the post-translational phosphorylation of c-Rel without materially inhibiting the phosphorylation of IKB. In another embodiment, the compounds of the invention inhibit the post-translational acetylation of c-Rel without materially inhibiting the expression of NF-kB family members other than c-Rel. In another embodiment, the compounds of the invention inhibit the post-translational acetylation of c-Rel without materially inhibiting the post-translational phosphorylation of NF-kB family members other than c-Rel. In another embodiment, the compounds of the invention inhibit the post-translational acetylation of c-Rel without materially altering the expression of IKB. hi another embodiment, the compounds of the invention inhibit the post-translational acetylation of c-Rel without materially inhibiting the phosphorylation of IKB.

Without wishing to be bound by any theory, the compounds of the invention are believed to inhibit the DNA binding of c-Rel to a KB site, thereby down- regulating the transcription of proliferative and anti-apoptotic genes associated with c- ReI activity. Therefore, in one aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound that inhibits DNA binding of c-Rel to a KB site in the cancer cells and does not inhibit the DNA binding of other NF-κB family members in the cancer cells. In one embodiment, the cancer is a lymphoma or leukemia. In another embodiment, the cancer is a B-cell lymphoma or leukemia. In another embodiment, the cancer is a T- cell lymphoma or leukemia. In yet another embodiment, the cancer cells are infected with Epstein-Barr virus. In another embodiment, the compound that is administered to the subject is any compound disclosed herein.

Without wishing to be bound by any theory, it is believed that the compounds of the invention can be used to inhibit proliferation and/or induce apoptosis in B-cells since it has been shown that c-Rel is necessary for proliferation and survival of B- cells. Therefore, in one aspect, the invention provides a method of inhibiting the proliferation of and/or inducing apoptosis in B-cells, comprising contacting the B- cells with a compound that inhibits the accumulation of c-Rel in the nucleus of the cells and does not materially inhibit the accumulation of other NF-kB family members in the nucleus of the cells, hi one embodiment, the B-cells are a B-cell lymphoma or B-cell leukemia. In another embodiment, the B-cells are infected with Epstein-Barr virus. In another embodiment, the B-cells are a B-cell lymphoma or B-cell leukemia infected with Epstein-Barr virus. In another embodiment, the compound is any compound disclosed herein. In another embodiment, the compound inhibits post- translational phosphorylation of c-Rel. In another embodiment, the compound inhibits the post-translational acetylation of c-Rel.

In another aspect, the invention provides a method of inhibiting the proliferation of and/or inducing apoptosis in B-cells, comprising contacting the B- cells with a compound that alters the post-translational modification of c-Rel and does not materially inhibit the post-translational phosphorylation of other NF-κB family members. In one embodiment, the compound inhibits the post-translational phosphorylation of c-Rel. Li another embodiment, the compound inhibits the post- translational acetylation of c-Rel. In another embodiment, the B-cells are a B-cell lymphoma or B-cell leukemia. In another embodiment, the B-cells are infected with Epstein-Barr virus. In another embodiment, the B-cells are a B-cell lymphoma or B- cell leukemia infected with Epstein-Barr virus. In another embodiment, the compound is any compound disclosed herein.

In another aspect, the invention provides a method of inhibiting the proliferation of and/or inducing apoptosis in B-cells, comprising contacting B-cells with a compound that inhibits DNA binding of c-Rel to a KB site and does not inhibit the DNA binding of other NF-κB family members. In one embodiment, the B-cells are a B-cell lymphoma or B-cell leukemia. In another embodiment, the B-cells are infected with Epstein-Barr virus. In one embodiment, the B-cells are a B-cell lymphoma or B-cell leukemia infected with Epstein-Barr virus. In another embodiment, the compound is any compound disclosed herein.

As used interchangeably herein, "c-rel activity," "biological activity of c-rel," or "activity of c-rel," include an activity exerted by c-rel protein on a c-rel responsive cell or tissue, e.g., a T cell, dendritic cells, NK cells, or on a c-rel target molecule, e.g., a nucleic acid molecule or protein target molecule, as determined in vivo, or in vitro, according to standard techniques. In one embodiment, c-rel activity is a direct activity, such as an association with a c-rel-target molecule. Alternatively, a c-rel activity is an indirect activity, such as a downstream biological event mediated by interaction of the c-rel protein with a c-rel target molecule.

As used herein, the term "contacting" (i.e., contacting a cell e.g. a cell, with a compound) includes incubating the compound and the cell together in vitro (e.g., adding the compound to cells in culture) as well as administering the compound to a subject such that the compound and cells of the subject are contacted in vivo. The term "contacting" does not include exposure of cells to a c-rel modulator that may occur naturally in a subject (i.e., exposure that may occur as a result of a natural physiological process).

As used herein, the term "modulate" with respect to c-rel includes changing the expression, activity or function of c-rel in such a manner that it differs from the naturally-occurring expression, function or activity of c-rel under the same conditions. For example, the expression, function or activity can be greater or less than that of naturally occurring c-rel, e.g., owing to a change in binding specificity, etc. As used herein, the various forms of the term "modulate" include stimulation (e.g., increasing or upregulating a particular response or activity) and inhibition (e.g., decreasing or downregulating a particular response or activity).

In the context of NF-κB and/or IKB (including IκBα and IκBβ) expression and/or amount, the term "without materially inhibiting" as used herein means a smaller than 40%, preferably smaller than 30%, 20%, 10%, 5%, 4%, 3%, 2%, 1%, or 0% change in the level of expression of NFKB and/or amount of IKB.

In the context of alterations in the post-translational modification state or phosphorylation state of Nf-κB family members, the term "without materially altering" as used herein means that there is a quantitative difference of no more than 30-fold, preferably 15-fold, more preferably 10-fold, more preferably two-fold, and most preferably not detectably altered. The alteration can either be increased or decreased as compared to wild-type (e.g. state in an unstimulated cell) or control/reference samples.

As used herein, the term "post-translational modification" means any type of protein or polypeptide modifications that can be made to the native polypeptide sequence after its initial translation, enzyme-catalyzed or not, such as e.g. a acylation, phosphorylation, dephosphorylation, SUMOylation, ubiquitinylation, carboxymethylation, formylation, acetylation, deacetylation, gamma carboxyglutamic acid, norleucine, amidation, deamidation, carboxylation, carboxyamylation, sulfation, methylation, demethylation, hydroxylation, ADP-ribosylation, maturation, adenylation, O-linked glycosylation, N-linked glycosyl.ation, methonine oxidation, myristoylation, formation of disulphide bonds, changes in oxidation/reduction, and addition of lipid (prenylation). As used herein, the term "stimulus" means a growth factor, a cytokine, a hormone, a steroid, a lipid, an antigen, a small molecule (e.g., Ca²⁺, cAMP, cGMP), an osmotic shock, a heat or cold shock, a pH change, a change in ionic strength, a mechanical force, a viral or bacterial infection, or an attachment or detachment from a neighboring cell or a surface with or without a coated protein.

As used herein, the term "Nf-κB family members" refers to ReIA (or p65), ReIB, NF-κBl (or plO5/p5O), NF-κB2 (or pl00/p52), and cRel.

In another aspect, this invention features a pharmaceutical composition that includes a pharmaceutically acceptable carrier and at least one compound that alters the post-translational modification of c-Rel and does not materially inhibit the post- translational phosphorylation of other NF -KB family members. In one embodiment, the compound in the pharmaceutical composition that alters the post-translational modification of c-Rel is not a compound disclosed in the patents and patent applications listed in Table 2. hi one embodiment, the compound in the pharmaceutical composition that alters the post-translational modification of c-Rel is not a compound disclosed in the patents and patent applications listed in Table 3.

In another aspect, this invention features a pharmaceutical composition that includes a pharmaceutically acceptable carrier and at least one compound that inhibits DNA binding of c-Rel to a KB site and does not inhibit the DNA binding of other NF- KB family members. In one embodiment, the compound in the pharmaceutical composition that inhibits DNA binding of c-Rel to a KB site is not a compound disclosed in the patents and patent applications listed in Table 2. hi one embodiment, the compound in the pharmaceutical composition that inhibits DNA binding of c-Rel to a KB site is not a compound disclosed in the patents and patent applications listed in Table 3.

Table 2

Table 3

Methods for making the compounds of the invention have been disclosed in the U.S. patents and patent applications listed in Table 3. The entire teachings of these patents and patent applications are incorporated herein by reference.

As used herein, the term "alkyl" refers to a straight-chained or branched hydrocarbon group containing 1 to 12 carbon atoms. The term "lower alkyl" refers to a C1-C6 alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl. Alkyl groups maybe optionally substituted with one or more substituents.

The term "alkenyl" refers to an unsaturated hydrocarbon chain that may be a straight chain or branched chain, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Alkenyl groups may be optionally substituted with one or more substituents.

The term "alkynyl" refers to an unsaturated hydrocarbon chain that may be a straight chain or branched chain, containing the 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups may be optionally substituted with one or more substituents.

The sp or sp carbons of an alkenyl group and an alkynyl group, respectively, may optionally be the point of attachment of the alkenyl or alkynyl groups.

191 The term "alkoxy," as used herein, refers to an alkyl or a cycloalkyl group which is linked to another moiety though an oxygen atom. Alkoxy groups can be optionally substituted with one or more substituents.

The term "mercapto" refers to a -SH group.

The term "alkyl sulfanyl," as used herein, refers to an alkyl or a cycloalkyl group which is linked to another moiety though a divalent sulfer atom. Alkyl sulfanyl groups can be optionally substituted with one or more substituents.

As used herein, the term "halogen" or "halo" means -F, -Cl, -Br or -I.

As used herein, the term "haloalkyl" means and alkyl group in which one or more (including all) the hydrogen radicals are replaced by a halo group, wherein each halo group is independently selected from -F, -Cl, -Br, and -I. The term "halomethyl" means a methyl in which one to three hydrogen radical(s) have been replaced by a halo group. Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.

The term "cycloalkyl" refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic ring system which is completely saturated ring. Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group maybe substituted by a substituent. Representative examples of cycloalkyl group include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and bicyclo[2.1.1 ]hexyl.

The term "cyclyl" refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic ring system having at least one non-aromatic ring, wherein the non-aromatic ring has some degree of unsaturation. Cyclyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cyclyl group may be substituted by a substituent. Examples of cyclyl groups include cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, dihydronaphthalenyl, benzocyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyelodecenyl, cyclodecadienyl and the like.

The term "aryl" refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. Aryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

As used herein, the term "aralkyl" means an aryl group that is attached to another group by a (C₁-C₆)alkylene group. Aralkyl groups may be optionally substituted, either on the aryl portion of the aralkyl group or on the alkylene portion of the aralkyl group, with one or more substituent. Representative aralkyl groups include benzyl, 2-phenyl-ethyl, naphth-3-yl-methyl and the like.

As used herein, the term "alkylene" refers to an alkyl group that has two points of attachment. The term "(Q-C^alkylene" refers to an alkylene group that has from one to six carbon atoms. Non-limiting examples of alkylene groups include methylene (-CH₂-), ethylene (-CH₂CH₂-), n-propylene (-CH₂CH₂CH₂-), isopropylene (-CH₂CH(CH₃)-), and the like. Alkylene groups may be optionally substituted.

As used herein, the term "cycloalkylene" refers to a cycloalkyl group that has two points of attachment. Cycloalkylene groups may be optionally substituted.

As used herein, the term "cyclylene" refers to a cyclyl group that has two points of attachment. Cyclylene groups may be optionally substituted.

As used herein, the term "arylene" refers to an aryl group that has two points of attachment. Arylene groups may be optionally substituted.

As used herein, the term "aralkylene" refers to an aralkyl group that has two points of attachment. Aralkylene groups may be optionally substituted.

The term "arylalkoxy" refers to an alkoxy substituted with an aryl.

The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-4 ring heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon. Heteroaryl groups may be optionally substituted with one or more substituents. Li one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent. Examples of heteroaryl groups include pyridyl, 1-oxo-pyridyl, furanyl, benzo[l,3]dioxolyl, benzo[l,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, and benzo(b)thienyl, 3H- thiazolo[2,3-c][l,2,4]thiadiazolyl, imidazo[l,2-d]-l₃2,4-thiadiazolyl, imidazo[2,l-b]- 1,3,4-thiadiazolyl, lH,2H-furo[3,4-d]-l,2,3-thiadiazolyl, lH-pyrazolo[5,l-c]-l,2,4- triazolyl, pyrrolo[3,4-d]-l,2,3-triazolyl, cyclopentatriazolyl, 3H-pyrrolo[3,4- c]isoxazolyl, lH,3H-pyrrolo[l,2-c]oxazolyl, pyrrolo[2,lb]oxazolyl, and the like.

As used herein, the term "heteroaralkyl" or "heteroarylalkyl" means a heteroaryl group that is attached to another group by a (Q-C^alkylene. Heteroaralkyl groups maybe optionally substituted, either on the heteroaryl portion of the heteroaralkyl group or on the alkylene portion of the heteroaralkyl group, with one or more substiruent. Representative heteroaralkyl groupss include 2-(pyridm-4-yi)- propyl, 2-(thien-3-yl)-ethyl, imidazol-4-yl-methyl and the like.

As used herein, the term "heteroarylene" refers to a heteroaryl group that has two points of attachment. Heteroarylene groups may be optionally substituted.

As used herein, the term "heteroaralkylene" refers to a heteroaralkyl group that has two points of attachment. Heteroaralkylene groups may be optionally substituted.

The term "heterocycloalkyl" refers to a nonaromatic, completely saturated 3-8 membered monocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, S, B, P or Si. Heterocycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocycloalkyl group may be substituted by a substiruent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4- piperidonyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, an thiirene.

The term "heterocyclyl" refers to a nonaromatic 5-8 membered monocyclic, 7- 12 membered bicyclic, or 10-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, S, B, P or Si, wherein the nonaromatic ring system has some degree of unsaturation. Heterocyclyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocyclyl group may be substituted by a substiruent. Examples of these groups include thϋrenyl, thiadiazirinyl, dioxazolyl, 1,3-oxathiolyl, 1,3-dioxolyl, 1,3-dithiolyl, oxathiazinyl, dioxazinyl, dithiazinyl, oxadiazinyl, thiadiazinyl, oxazinyl, thiazinyl, l,4-oxathiin,l,4-dioxin, 1,4-dithiin, lH-pyranyl, oxathiepinyl, 5H-1,4- dioxepinyl, 5H-l,4-dithiepinyl, 6H-isoxazolo[2,3-d]l,2,4-oxadiazolyl, 7H- oxazolo[3,2-d]l,2,4-oxadiazolyl, and the like.

As used herein, the term "heterocycloalkylene" refers to a heterocycloalkyl group that has two points of attachment. Heterocycloalkylene groups may be optionally substituted.

As used herein, the term "heterocyclylene" refers to a heterocyclyl group that has two points of attachment. Heterocyclylene groups maybe optionally substituted.

When a cycloalkyl, cyclyl, heterocycloalkyl, or heterocyclyl is fused to another ring (e.g., a cycloalkyl, cyclyl, heterocycloalkyl, heterocyclyl, aryl, heteroaryl), it shares two or more ring atoms, preferably two to four ring atoms, with the other ring.

The term "amino" refers to -NH₂. The term "alkylamino" refers to an amino in which one hydrogen is replaced by an alkyl group. The term "dialkylamino" refers to an amino in which each of the hydrogens is replaced by an independently selected alkyl group. The term "aminoalkyl" refers to an alkyl substituent which is further substituted with one or more amino groups.

The term "mercaptoalkyl" refers to an alkyl substituent which is further substituted with one or more mercapto groups.

The term "hydroxyalkyl" or "hydroxylalkyl" refers to an alkyl substituent which is further substituted with one or more hydroxy groups.

The term "sulfonylalkyl" refers to an alkyl substituent which is further substituted with one or more sulfonyl groups.

The term "sulfonylaryl" refers to an aryl substituent which is further substituted with one or more sulfonyl groups.

The term alkylcarbonyl refers to an -C(O)-alkyl.

The term "mercaptoalkoxy" refers to an alkoxy substituent which is further substituted with one or more mercapto groups.

The term "alkylcarbonylalkyl" refers to an alkyl substituent which is further substituted with -C(O)-alkyl. The alkyl or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.

Suitable substituents for an alkyl, alkoxy, alkyl sulfanyl, alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cyclyl, heterocycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkylene, cyclylene, heterocycloalkylene, heterocyclylene, arylene, aralkylene, heteroalkylene and heteroaryalkylene groups include any substituent which will form a stable compound of the invention. Examples of substituents for an alkyl, alkoxy, alkylsulfanyl, alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cyclyl, heterocycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkylene, cyclylene, heterocycloalkylene, heterocyclylene, arylene, aralkylene, heteroalkylene and heteroaryalkylene include an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkyl sulfanyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, halo, cyano, nitro, haloalkoxy, =O, =S, =NR, -OR^k, -NR^hR^j, -SR^k, -C(O)R^k, -C(O)NR^hR^j, -NR^kC(O)R^k, -C(O)OR^k, -OC(O)R^k, -NR^kC(O)NR^hR^j, -OC(O)NR^hR^j, -NR^kC(O)OR^k, -C(NR)R^k, -C(NR)NR^hR^j, -NR^kC(NR)R^k, -C(NR)OR^k, -OC(NR)R^k, -NR^kC(NR)NR^hR^j, -0C(NR)NR^hR^j, -NR^kC(NR)OR^k, -C(S)R^k, -C(S)NR^hR^j, -NR^kC(S)R^k, -C(S)OR^k, -OC(S)R^k, -NR^kC(S)NR^hR^j, -OC(S)NR^hR^j, -NR^kC(S)OR^k, -C(O)SR^k, -SC(O)R^k, -S(O)_pR^k, -S(O)_pNR^hR^j, -OS(O)_pR^k, -S(O)_pOR^k, -OS(O)_pOR^k, -P(O)(OR^k)₂, -OP(O)(OR^k)₂, -P(S)(OR^k)₂, -SP(O)(OR^k)₂, -P(O)(SR^k)(OR^k), -OP(O)(SR^k)(OR^k), -P(O)(SR^k)₂, or -OP(O)(SR^k)₂, wherein p is 1 or 2.

In addition, alkyl, cycloalkyl, alkylene, a heterocycloalkyl, a and any saturated portion of a alkenyl, a cyclyl, alkynyl, heterocyclyl, aralkyl, and heteroaralkyl groups, may also be substituted with =0, =S, or =NR.

When a heterocyclyl, heteroaryl, or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When a nitrogen atom in the aromatic ring of a heteroaryl group has a substituent the nitrogen may be a quaternary nitrogen.

Choices and combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject). Typically, such compounds are stable at a temperature of 40°C or less, in the absence of excessive moisture, for at least one week. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation.

As used herein, the term "lower" refers to a group having up to six atoms. For example, a "lower alkyl" refers to an alkyl radical having from 1 to 6 carbon atoms, and a "lower alkenyl" or "lower alkynyl" refers to an alkenyl or alkynyl radical having from 2 to 6 carbon atoms, respectively. A "lower alkoxy" or "lower alkyl sulfanyl" group refers to an alkoxy or alkyl sulfanyl group that has from 1 to 6 carbon atoms.

The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

The compounds of this invention include the compounds themselves, as well as their salts, solvate, clathrate, hydrate, polymorph, or prodrugs, if applicable. As used herein, the term "pharmaceutically acceptable salt," is a salt formed from, for example, an acid and a basic group of a compound of any one of the formulae disclosed herein. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, /?-toluenesulfonate, and pamoate (i.e., 1,1'- methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of any one of the formulae disclosed herein having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-metliyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris- (hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N- methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of any one of the formulae disclosed herein having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid. Suitable acids include hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid, lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p -toluenesulfonic acid.

As used herein, the term "polymorph" means solid crystalline forms of a compound of the present invention or complex thereof. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to stability (e.g., to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rates (which can affect bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Different physical properties of polymorphs can affect their processing. For example, one polymorph might be more likely to form solvates or might be more difficult to filter or wash free of impurities than another due to, for example, the shape or size distribution of particles of it. As used herein, the term "hydrate" means a compound of the present invention or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

As used herein, the term "clathrate" means a compound of the present invention or a salt thereof in the form of a crystal lattice that contains spaces {e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.

As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may only become active upon such reaction under biological conditions, or they may have activity in their unreacted forms. Examples of prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of any one of the formulae disclosed herein that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of compounds of any one of the formulae disclosed herein that comprise -NO, -NO₂, -ONO, or -ONO₂ moieties. Prodrugs can typically be prepared using well-known methods, such as those described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-

178, 949-982 (Manfred E. Wolff ed., 5^th ed).

As used herein and unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide" and "biohydrolyzable phosphate analogue" mean an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

In addition, some of the compounds of this invention have one or more double bonds, or one or more asymmetric centers. Such compounds can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z- double isomeric forms. All such isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein (e.g., alkylation of a ring system may result in alkylation at multiple sites, the invention expressly includes all such reaction products). AU such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.

Further, the aforementioned compounds also include their iV-oxides. The term "JV-oxides" refers to one or more nitrogen atoms, when present in a heterocyclic or heteroaryl compound, are in N-oxide form, i.e., N-→O. For example, in compounds of any one of the formula d or Table 1 when one of Q, U, or V is N, also included are compounds in which Q, U, or V, respectively, is N— >O.

As used herein, the term "pharmaceutically acceptable solvate," is a solvate formed from the association of one or more solvent molecules to one of the compounds of any of the formulae disclosed herein. The term solvate includes hydrates (e.g., hemi-hydrate, mono-hydrate, dihydrate, trihydrate, tetrahydrate, and the like).

A cancer, such as a lymphoma or leukemia, is infected with EB V if the presence of EBV genome or viral gene products can be detected within at least 10%, more preferably at least 20%, more preferably at least 30%, more preferably at least 40%, more preferably at least 50%, more preferably at least 60%, more preferably at least 70%, more preferably at least 80%, and more preferably at least 90% of the tumour-cell population. Viral gene products of EBV include EBNAl, EBN A2, EBNA3A, EBNA3B, EBNA3C, EBNA-LP, LMPl, LMP2A, LMP2B, EBERl, EBER2, CSTs and BARTs (Thompson and Kurzrock, Clinical Cancer Research (2004), 10:803-821). Detection of EBERs (non-polyadenylated RNAs produced by EBV infection) by in situ hybridization is the standard method of detecting EBV infection in the routine processing of tumor tissues.

The method can also include the step of identifying that the subject is in need of treatment for cancer. The identification can be in the judgment of a subject or a health professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or a diagnostic method).

As noted above, one embodiment of the present invention is directed to treating subjects with a cancer. "Treating a subject with a cancer" includes achieving, partially or substantially, one or more of the following: arresting the growth or spread of a cancer, reducing the extent of a cancer (e.g., reducing size of a tumor or reducing the number of affected sites), inhibiting the growth rate of a cancer, and ameliorating or improving a clinical symptom or indicator associated with a cancer (such as tissue or serum components).

An "effective amount" is the quantity of compound in which a beneficial clinical outcome is achieved when the compound is administered to a subject with a cancer. A "beneficial clinical outcome" includes a reduction in tumor mass, a reduction in metastasis, a reduction in the severity of the symptoms associated with the cancer and/or an increase in the longevity of the subject compared with the absence of the treatment. The precise amount of compound administered to a subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of cancer. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Effective amounts of the disclosed compounds typically range between about 1 mg/mm" per day and about 10 grams/mm² per day, and preferably between 10 mg/mm² per day and about 5 grams/mm². When co-administered with another anticancer agent, an "effective amount" of the second anti-cancer agent will depend on the type of drug used. Suitable dosages are known for approved anti-cancer agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of cancer being treated and the amount of the compound of the invention being used.

To practice a method of the present invention, a compound of the invention, alone, or as a component of a pharmaceutical composition, can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

A sterile injectable composition, for example, a sterile injectable aqueous or oleaginous suspension, can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides). Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.

A composition for oral administration can be any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added. A nasal aerosol or inhalation composition can be prepared according to techniques well- known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. A compound of this invention can also be administered in the form of suppositories for rectal administration.

The carrier in the pharmaceutical composition must be "acceptable" in the sense of being compatible with the active ingredient of the formulation (and preferably, capable of stabilizing it) and not deleterious to the subject to be treated. For example, solubilizing agents such as cyclodextrins, which form specific, more soluble complexes with the compounds of this invention, or one or more solubilizing agents, can be utilized as pharmaceutical excipients for delivery of the compounds of the invention. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow # 10.

As used herein, the terms "animal", "subject," "mammal" and "patient", include, but are not limited to, a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig and human (preferably, a human).

The methods for treating cancer in a patient in need thereof can further comprise administering to the patient being administered a compound of this invention, an effective amount of one or more other therapeutic agents. Such therapeutic agents may include other therapeutic agents such as those conventionally used to treat cancer. For example, the compounds of the invention can be coadministered with Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefϊngol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl ; interferon alfa-n3; interferon beta-I a; interferon gamma-Ib; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

Other anti-cancer drugs include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morpho genetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP- DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1 ; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemninB; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5- azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1 ; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfmosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfm; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. Preferred additional anti-cancer drugs are 5- fluorouracil and leucovorin.

Examples of therapeutic antibodies that can be used include but are not limited to HERCEPTIN® (Trastuzumab) (Genentech, CA) which is a humanized anti-HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer; REOPRO® (abciximab) (Centocor) which is an anti-glycoprotein Ilb/IIIa receptor on the platelets for the prevention of clot formation; ZENAP AX® (daclizumab) (Roche Pharmaceuticals, Switzerland) which is an immunosuppressive, humanized anti-CD25 monoclonal antibody for the prevention of acute renal allograft rejection; PANOREX™ which is a murine anti-17-IA cell surface antigen IgG2a antibody (Glaxo Wellcome/Centocor); BEC2 which is a murine anti-idiotype (GD3 epitope) IgG antibody (ImClone System); IMC-C225 which is a chimeric anti-EGFR IgG antibody (ImClone System); VITAXIN™ which is a humanized anti-αVβ3 integrin antibody (Applied Molecular Evolution/Medlmmune); Campath 1H/LDP-03 which is a humanized anti CD52 IgGl antibody (Leukosite); Smart Ml 95 which is a humanized anti-CD33 IgG antibody (Protein Design Lab/Kanebo); RITUXAN™ which is a chimeric anti-CD20 IgGl antibody (IDEC Pharm/Genentech, Roche/Zettyaku); LYMPHOCIDE™ which is a humanized anti-CD22 IgG antibody (Immunomedics); LYMPHOCIDE™ Y-90 (Immunomedics); Lymphoscan (Tc-99m- labeled; radioimaging; Immunomedics); Nuvion (against CD3; Protein Design Labs); CM3 is a humanized anti-ICAM3 antibody (ICOS Pharm); IDEC-114 is a primatied anti-CD80 antibody (IDEC Pharm/Mitsubishi); ZEVALIN™ is a radiolabelled murine anti-CD20 antibody (IDEC/Schering AG); IDEC-131 is a humanized anti- CD40L antibody (IDEC/Eisai); IDEC-151 is a primatized anti-CD4 antibody (IDEC); IDEC-152 is a primatized anti-CD23 antibody (IDEC/Seikagaku); SMART anti-CD3 is a humanized anti-CD3 IgG (Protein Design Lab); 5Gl.1 is a humanized anti- complement factor 5 (C5) antibody (Alexion Pharm); D2E7 is a humanized anti-TNF- α antibody (CAT/BASF); CDP870 is a humanized anti-TNF-α Fab fragment (Celltech); IDEC-151 is a primatized anti-CD4 IgGl antibody (IDEC Pharm/SmithKline Beecham); MDX-CD4 is a human anti-CD4 IgG antibody (Medarex/Eisai/Genmab); CD20-sreptdavidin (+biotin-yttrium 90; NeoPvx); CDP571 is a humanized anti-TNF-α IgG4 antibody (Celltech); LDP-02 is a humanized anti- α4β7 antibody (LeukoSite/Genentech); OrthoClone OKT4A is a humanized anti-CD4 IgG antibody (Ortho Biotech); ANTOV A™ is a humanized anti-CD40L IgG antibody (Biogen); ANTEGREN™ is a humanized anti-VLA-4 IgG antibody (Elan); and CAT- 152 is a human anti-TGF-β₂ antibody (Cambridge Ab Tech). It is believed that the combination of a compound of the invention and RITUXAN™ will be particularly useful for treating cancer, such as B-cell lymphomas and B-cell leukemias.

Chemotherapeutic agents that can be used in the methods and compositions of the invention include but are not limited to alkylating agents, antimetabolites, natural products, or hormones. Examples of alkylating agents useful for the treatment or prevention of T-cell malignancies in the methods and compositions of the invention include but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites useful for the treatment or prevention of T-cell malignancies in the methods and compositions of the invention include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples of natural products useful for the treatment or prevention of T-cell malignancies in the methods and compositions of the invention include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha). Examples of alkylating agents useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to, nitrogen mustards {e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples of natural products useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide, teniposide), antibiotics (e.g., actinomycin D, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha). Examples of hormones and antagonists useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fmoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide). Other agents that can be used in the methods and with the compositions of the invention for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide).

The compounds of the invention can also be co-administered with anti-cancer agents which act by arresting cells in the G2-M phases due to stabilization of microtubules. Examples of anti-cancer agents which act by arresting cells in the G2- M phases due to stabilization of microtubules include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP- XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C)₅ Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known as LU- 103793 and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B ), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21- aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS- 164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF- 223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM- 132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HC1), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39- L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-I (Parker Hughes Institute, also known as DDE-261 and WHI-261), HlO (Kansas State University), H16 (Kansas State University), Oncocidin Al (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA- 1 (Parker Hughes Institute, also known as SPIKET-P), 3 -IAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC- 5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3- BAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tularik, also known as T- 900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as NSCL- 96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-IlO₅ trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), SSR-250411 (Sanofi), and Hsp90 inhibitors such as geldanamycin, radicicol, herbimycin A, macbecin I and II, novobiocin, 17- Allylamino-17-demethoxygeldanamycm (17AAG), 17-Demethoxy-17-[2- (dimethylamino)ethylamino]geldanamycin (17DMAG), CNF-1010, purine-based Hsp90 inhibitors such as PU3, PU24FC1, and PU29FC1, and oxime derivatives of radicicol such as KF25706 and KF58333.

The compounds of the invention can be administered with Taxol, also referred to as "Paclitaxel", or a Taxol derivative. Many analogs of taxol are known, including taxotere. Taxotere is also referred to as "Docetaxol". These compounds have the basic taxane skeleton as a common structure feature and have also been shown to have the ability to arrest cells in the G2-M phases due to stabilization of microtubules.

The foregoing and other useful combination therapies will be understood and appreciated by those of skill in the art. Potential advantages of such combination therapies include the ability to use less of each of the individual active ingredients to minimize toxic side effects, synergistic improvements in efficacy, improved ease of administration or use and/or reduced overall expense of compound preparation or formulation.

Without further elaboration, it is believed that the above description has adequately enabled the present invention. The following specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All of the references and publications cited herein are hereby incorporated by reference in their entirety.

EXAMPLES

General Experimental Procedures:

Cell lines and culture conditions: The THP-I cell, Jurkat cell and RAW264.7 cell line were obtained from American Type Culture Collection (Manassas, VA). The THP-I Jurkat cells were cultured in RPMI 1640 (ATCC, Manassas, VA), supplemented with 10 % FCS (ATCC, Manassas, VA), and 1% penicillin/Streptomycin (Gibco-BRL, New York, N. Y. ). The RAW264.7 cells were cultured in DMEM (ATCC, Manassas, VA) supplemented with 10 % FCS (ATCC, Manassas, VA), and 1% penicillin/Streptomycin (Gibco-BRL, New York, N.Y.). The cells were stimulated with human or murine recombinant IFNγ (100 ng/ml) for 10 h followed by LPS (1 μg/ml) or SAC (0.025 %) CpG (ImM) in the presence or absence of Compound 50 at different concentrations for an additional incubation.

Isolation of Nuclear extracts:

THP-I cells were suspended in 20 volumes of buffer A containing 10 mM KCl, 10 mM HEPES (pH 7.9), I mM MgCl₂, 1 mM dithiothreitol (DTT), 0.1 % Nonidet ρ40 (NP-40), and 0.5 mM phenylmethylsulfonyl fluoride (PMSF) and homogenized and centrifuged at 10,000 rpm at 4C afor 5 min. Nuclear pellets were then suspended in buffer C containing 400 mM NaCl, 20 mM HEPES 9, pH 7.9), 15 mM MgCl₂, 0.2 mM EDTA, 1 mM DTT, 25 % glycerol, 1 mM PMSF, and 10 ug of leupeptin, 20 ug of pepstatin, and 10 ug/ml antipain, incubated for 30 min at 4C, and centrifuged at 14,000 rpm for 20 min.. The supernatants were dialyzed against buffer D containing 100 mM NaCl, 20 mM HEPES (pH 7.9), 20% glycerol, 1 mM PMSF, and 1 mM DTT.

Isolation of whole cell extracts:

The whole cell extracts were prepared using Cell Lysis Buffer (Cell Signaling, Beverly, MA, USA) according to the manufacture's instruction.

Western blot:

The 10 % SDS Polyacrylamide gels (Inveitrogen) were transferred to Pure Nitrocellulose membrane (BioRed, Hercules, CA). The membranes were blocked with 5% milk in TBST buffer and incubated with anti-c-Rel, anti-p65, anti-p50, anti- ICSBP or anti-PU-1 antibody (all the antibodies were purchased from Santa Cruz) at a dilution of 1 :500 for 1 h at room temperature or overnight at 4C. The membranes were washed and incubated with Horseradish Peroxidase-conjugated anti-rabbit IgG or anti-mouse IgG (Amersham, England) at a dilution of 1 :2000 at room temperature for 1 h.

Immunoprecipitation:

Five hundred mg of the precleared whole cell protein was incubated with 20 ul of the agarose conjugated anti-c-Rel antibody (sc-6955) for overnight at 4C. Immunoprecipitated proteins were washed 3 times with PBS, and eluted with electrophoreses sample buffer. Western blotting of immunoprecipitated protein was performed as described above.

Example 1 : Effect of Compound 50 on c-Rel and ICSBP (measuring the level of both in the nucleus)

Of the transcription factors that have been analyzed, two factors, ICSBP and c- ReI, seem to be affected by Compound 4/Compound 50 treatment. ICSBP binds indirectly to the Ets-2 site. The primary NF-κB trans-activator for IL- 12 is the c- Rel/p50 heterodimer. Other dimers (p65/p50 and p50/p50) either lack activity or have inhibitory functions. Thus, c-Rel plays a role in IL-12 transcription as a result of both activation through NF-κB and its interaction with ICSBP. Both Western blot analysis and DNA binding studies showed a decrease in nuclear c-Rel levels following Compound 50 treatment. As seen in Figure 1, a western blot assay of THPl nuclear c-Rel, p50 and p65 proteins was carried out by the following method: 10% SDS polyacrylamide gels (Invitrogen) were transferred to a Pure nitrocellulose membrane (BioRed, Hercules, CA). The membranes were blocked with 5% milk in TBST buffer and then incubated with anti-c-Rel, anti-p65, anti-p50, anti-ICSBP or anti-PU-1 antibody (all the antibodies were purchased from Santa Cruz) at a dilution of 1:500 for 1 h at room temperature or overnight at 4°C. The membranes were washed and incubated with Horseradish Peroxidase-conjugated anti-rabbit IgG or anti-mouse IgG (Amersham, England) at a dilution of 1 :2000 at room temperature for 1 h.

Both IFN-γ plus LPS and IFN-γ plus SAC treatment strongly increased the amount of nuclear c-Rel, p65 and p50. Compound 50 treatment significantly reduced the levels of c-Rel, with the post-treatment nuclear c-Rel level being equal to or below the non-stimulated level. In contrast, nuclear p65 protein increased following Compound 50 treatment. p50 levels decreased slightly following Compound 50 treatment, but remained above the non-stimulated levels. Thus, it is shown that Compound 50 treatment causes a reduction in the amount of nuclear c-Rel/p50, the primary IL- 12 activating NFKB dimer.

ICSBP, whose expression was reduced by Compound 50, was over-expressed using co-transfection with the IL-12 promoter-Luc report system. The over- expression construct of ICSBP was generated by PCR from cDNA of human PBMC using primers as follow: ICSBP-exp-F: 5'-

CCGGAATTCAGGATGTGTGACCGGAATGG-3' (SEQ ID NO:1) and ICSBP- exp-R: 5'-ATATCTAGAATGGATGCAGGACGCAGAC-S' (SEQ ID NO:2), the resulting PCR products was ligated to pCI vector (Promega). ICSBP over-expression increased the level of p40 expression and decreased the inhibition by Compound 50.

Example 2: Compound 50 Blocks accumulation of c-Rel, but not p65, in the nucleus of LPS stimulated cells.

We next examined whether compound 50 can block the accumulation of c-Rel in the nucleus of cells induced by LPS (Fig. 2). RAW264.7 cells cultured in DMEM with 10% BCS were split and seeded into 4-well chambered slides at 80,000 cells/well density. The cells were then treated with DMSO, Compound 50 (10OnM), LPS (Sigma, 5μg/mL), LPS (5μg/mL) + Compound 50 (10OnM) for 4 hours and fixed with 3% paraformaldehyde solution (1 x PBS) after 1 X quick rinse with 1 x PBS. Fixed cells were permeablized with 0.2% TXlOO and immunostained with anti-cRel antibody (SC70, Santa Cruz, 1:200 dilution) or anti-NF-κB ρ65 antibody (SCl 09, Santa Cruz, 1:100 dilution), and subsequently stained with Alexa Fluor 488 Goat-anti- Rabbit secondary antibody and DAPI (Molecular Probes, 1.1 μM). Images were obtained with CoolSNAP monochrome CCD camera on a Nikon inverted microscope TE300 using identical imaging parameters and were processed identically with Photoshop CS software. As observed previously, c-Rel localized to the cytoplasm in DMSO-treated cells and to the nucleus in LPS-treated cells. In the absence of LPS, Compound 50 treatment (4h) did not alter the nuclear/cytoplasmic distribution of c- ReI; Treatment of LPS-stimulated cells with Compound 50 inhibited the accumulation of c-Rel in the nucleus resulting in a striking reduction of nuclear c-Rel staining. These data demonstrate that Compound 50 blocks LPS-induced nuclear accumulation of c-Rel. We also examined whether Compound 50 blocks the nuclear accumulation of another NF-κB/Rel family member, p65, in LPS-stimulated RAW cells (Fig. 3). As observed for c-Rel, p65 was localized to the cytoplasm in DMSO and Compound 50-treated cells and to the nucleus in LPS-stimulated cells. However, in contrast to c- ReI, p65 nuclear accumulation induced by LPS was not blocked by Compound 50. These data demonstrate the Compound 50 blocks c-Rel but not p65 nuclear translocation in LPS-stimulated cells.

Example 3: Effect of Compound 50 on IKB

IKB degradation is one of the steps in the signaling pathway of NF-κB dependent genes. The activity of Compound 50 in inducible degradation of IκBq and IκBβ was investigated in THP-I cells using Western blot and FACS analysis. The amount of IκBα and IκBβ in the cytoplasm of THP-I and RAW267.4 cells was significantly reduced at 30 min in response to induction by IFN-γ/LPS or IFN-γ/SAC. However, there was no significant difference observed between the samples which were treated with or without Compound 50 (50OnM) at 30 min and 2 hrs. Similar results were observed from the Compound 50 pre-treatment samples in which Compound 50 was added 30 min before stimulation. These results show that Compound 50 does not induce the degradation of IκBα and IκBβ to allow free NF-κB to translocate into the nucleus where it can act as a transcription factor.

Example 4: Kinetics of the members of NF-kB nuclear translocation in Compound 50-treated cells

Compound 50 impairs nuclear accumulation of c-Rel and and slightly reduces nucleur accumulation of p50. We examined the nuclear translocation kinetics of NF- kB family members in LPS stimulated cells treated with Compound 50. THPl cells were stimulated with LPS in either the presence or absence of 100 nM Compound 50, and the distribution of the NF-κB ReI family members was determined by immunoblotting nuclear (n.p.) extracts collected at 5 min, 15 min, 30 min, Ih, 3h and 6h post-treatment. In response to LPS stimulation, p50 translocated into the nucleus as early as 5 minutes post-stimulation and accumulates as time goes on (Figure 4, immunoblots and Figure 5 densitometry). Treatment of LPS-stimulated cells with Compound 50 had no effect on the kinetics of p50 nuclear entry at 5 minutes to 1 Im^¬ post-stimulation, and showed a small decrease in nuclear protein levels at 3 hours. The experiment examining p65 nuclear translocation is shown in Figure 6 (immunoblots) and Figure 7 (densitometry). In LPS stimulated cells, p65 translocated into the nucleus as early as 5 minutes post-stimulation and accumulated to maximum levels at 15-30 minutes post-stimulation. Treatment of LPS-stimulated cells with Compound 50 had no effect on the kinetics of p65 nuclear entry. The level of nuclear p65 at later times (6 hours) showed a small increase in Compound 50 treated cells relative to untreated cells.

Without wishing to be bound by theory, Compound 50 does not affect the kinetics of p50 and p65 nuclear accumulation in response to LPS stimulation. At later times, Compound 50 impairs nuclear translocation of p50 (at 3 h time point), and enhances nuclear translocation of p65 (at 6 h time point), indicating a selective effect on the NF-κB family.

Example 5: The effects of Compound 50 on nuclear translocation of p52 and ReI-B

ReI B and p52 are two members of ReI family, which are preferentially complexed with each other. To determine the effect of Compound 50 on p52 and ReI- B nuclear translocation, THPl cells were stimulated with IFNγ+LPS in either the presence or absence of 100 nM Compound 50, and the distribution of p52 and ReI-B was determined by immunoblotting of nuclear at 6h post-treatment. As shown in Figure 8, the nuclear ReI-B was slightly increased in the presence of Compound 50. No significant difference was found in p52. This result indicates that Compound 50 specifically inhibits c-Rel and p50 nuclear translocation, but not other NF-kB p52 and ReI-B nuclear translocation.

Example 6: Compound 50 does not block phosphorylation of IKKβ

The phosphorylation of IKK is an early step in NF -KB activation. To determine whether Compound 50 inhibits the activation of the IKK complex, the level of phosphorylated IKKβ was investigated in drug-treated, LPS-stimulated cells. Whole cell extracts were prepared from THP-I cells that had been stimulated with IFNγ/LPS for 5min, 15 min 30 min and lhr in the either the absence or presence of 50OnM Compound 50. Phosphorylated IKKβ was determined by immunoblot analysis using an anti-phospho IKKβ antibody. As shown in Fig 9, the amount of phosphorylated IKKβ accumulated with time in response to IFNγ/LPS stimulation. Compound 50 treatment had no effect on the induction of phosphorylated IKKβ. These data demonstrate the Compound 50 does not block activation of the IKK complex.

Example 7: Compound 50 does not block LPS-induced phosphorylation of p65 or pl05/p50 NF-κB family members

In this study, we examined the effect of Compound 50 on LPS-induced phosphorylation of the NF-κB members p65 and pl05/p50. THPl monocytic cells were stimulated with IFNγ plus LPS in the presence or absence of 100 nM Compound 50 (30 min, Ih and 3h) and whole-cell extracts were immunoblotted using anti- phospho p65 and pl05/p50 antibodies to detect the phosphorylated forms of these proteins. Figure 10 shows the effect of Compound 50 on p65 phosphorylation. LPS/IFNγ induced phosphorylation of p65 as early as 30 minutes on residues Ser-276, Ser-468 and Ser-927. Compound 50 had no effect on LPS/IFNγ induced phosphorylation at these sites. Figure 11 shows the effect of Compound 50 on pi 05 (the precursor of p50) phosphorylation. LPS/IFNγ induced phosphorylation of pi 05 as early as 30 minutes on residues Ser-927 and Ser-933. Compound 50 had no effect on LPS/IFNγ induced phosphorylation at these sites. We conclude that Compound 50 does not interfere with signaling pathways that phosphorylate p65 and pl05/p50 in response to LPS/IFNγ stimulation.

Example 8: Compound 50 inhibits the accumulation of nuclear c-Rel in PMA plus ionomycin stimulated Jurkat T cells

We previously showed that Compound 50 impairs the induction of the c-Rel dependent cytokine IL-2 in PMA+ionomycin stimulated Jurkat T cells. We therefore examined the accumulation of nuclear c-Rel in these cells by immunoblot analysis. As shown in Figure 12, the levels of nuclear c-Rel were reduced at a concentration of 100 nM Compound 50. As observed previously with other cell types, the nuclear levels of p50 were slightly reduced whereas nuclear p65 levels remained unchanged. These data demonstrate that Compound 50 is able to reduce nuclear c-Rel accumulation in T cells stimulated with PMA+ionomycin.

Example 9: Compound 50 reduces the DNA binding activity of nuclear c-Rel.

Previous work has demonstrated that Compound 50 blocks c-Rel translocation into the nucleus. In this study, we examined the effect of Compound 50 on the DNA- binding activity of nuclear c-Rel. The BD transfactor assay (a non-radioactive version of a super-shift assay) was used to measure the DNA-binding activity of c- ReI. hi this assay, nuclear extracts are added to biotinylated double-stranded oligonucleotides containing the NF-κB binding site bound to a streptavidin 96-well plate. Detection of the transcription factor-DNA complex is performed' with a specific primary antibody for c-Rel. The 96-well format allows for simultaneous measurement of multiple conditions and proteins using HRP-conjugated secondary antibodies whose enzymatic product can be measured using a luminometer. The level of c-Rel DNA-binding activity increased 40-fold (relative to DMSO control) in nuclear extracts from RAW cells stimulated with LPS/IFNγ. Compound 50 (1000 nM) treatment resulted in a 40% reduction in the level of c-Rel DNA-binding activity induced by stimulation with LPS/ IFNγ (Figure 13).

Methods: 2O x IO⁶ Raw 264.7 cells were treated with either DMSO, LPS/ IFNγ, or LPS/IFNγ/ Compound 50.(LPS cone. 1 ug/ml f.c. ; mouse IFNγ mouse lOOU/ml f.c, Compound 50 1 uM f.c). (LPS: Sigma Cat # L2654. Mouse IFNγ; Cat # R+D 485-MICF). Cells were pre-treated with Compound 50 for 30 min, then LPS/ IFNγ was added. After 3 hrs, nuclear and cytoplasmic extracts were prepared according to the BD™ TransF actor Extraction Kit and user manual. Briefly, cells were washed in PBS, harvested and lysed in hypotonic lysis buffer on ice. Cells were then disrupted by drawing the cell suspension through a No.27 gauge needle 10 times. Next, the cell suspension was centrifuged, and the cytoplasmic extract (supernatant) was collected. The nuclear pellet was then disrupted by resuspension in high salt extraction buffer and was drawn through the needle 10 times. The suspension was centrifuged at high speed, and the nuclear extract was collected. After measurement of protein concentration using BioRad assay, the nuclear extract was used in a Chemiluminescent NF-κB TransF actor Kit (BD) according to the user manual. Briefly, 2 ug of nuclear extract from either DMSO, LPS/ IFNγ or LPS/ IFNγ/ Compound 50 treated cells was incubated in the wells of a 96 well plate that was coated with biotin labeled NF-κB consensus ds oligos. After washing, kit provided c-Rel specific primary antibody at a 1 :500 dilution was incubated in each well. After further washing, kit provided rabbit polyclonal secondary antibody was incubated in each well at a 1 : 10,000 dilution. Finally, amount of bound antibody to the plate was detected by incubation with chemiluminescent substrate and subsequent detection with a luminometer. The experiment was performed in duplicate.

Western Blot Method:

After treatment with Compound 50, nuclear extract and cytoplasmic extract were prepared from 2OxIO⁶ Raw264.7 cells by using Extraction kits from BD Biosciences (Cat.631921), and above for experimental details. 20 ug of each extract was dissolved with 4x sample buffer and run on a 4-12% gradient SDS-PAGE gel, and blotted onto a nitrocellulose membrane by using semi-dry transfer. Non-specific binding to nitrocellulose was blocked with 5% skim milk in TBS with 0.5% Tween at room temperature for 1 hour, then probed with anti-c-Rel(C) niAb (rabbit IgG, SC-71) and anti-beta Actin(I- 19) (goat IgG, sc-1616) as a control. HRP-conjugated goat anti- rabbit IgG (H+L) (#7074, Cell Signaling) and HRP-conjugated bovine anti-goat IgG (H+L) (sc-2350) were used as secondary Abs. LumiGLO reagent, 2Ox Peroxide (#7003, Cell Signaling) was used for visualization. Densitometry analysis was performed using Quantity One software from BioRad.

The reduction in c-Rel DNA-binding activity correlated with a 40-50% reduction in the levels of nuclear c-Rel as detected by immunoblot analysis (see immunoblot Figure 14 and densitometry Figure 15). We therefore conclude that Compound 50 reduces the accumulation of c-Rel in the nucleus resulting in a concomitant decrease in c-Rel DNA-binding activity.

Example 10: Compound 50 interferes with primary mouse B cell survival.

The analysis of c-Rel knockout mice has revealed a defect in B cell proliferation. Therefore, the effect of Compound 50 on the activation and survival of homogeneous populations of primary B and T lymphocytes has been explored. As a first step in this process, we evaluated the effect of Compound 50 on the survival of purified mouse splenic (CD19⁺) B cells. When cultured ex vivo, primary B cells undergo spontaneous apoptosis within 24-48 h in the absence of any survival signals. Examples of such stimuli include those mediated by anti-CD40 (or CD40L), BAFF, or B cell receptor signals provided by either anti-IgM or LPS. Murine primary B cells were isolated from mouse spleen using anti-CD 19 coated magnetic beads (Miltenyi Biotec) according to the manufacturer's recommendations. Purified CD 19 B cells were cultured at 100,000 cells/well in 96-well microtiter plates in culture medium (RPMI 1640 supplemented with 10% fetal bovine serum, 2mM L-glutamine, 1 mM sodium pyruvate, 20 mM HEPES, and 55 μM β-mercaptoethanol) in the presence of 10 μg/ml anti-CD40, 5 μg/ml LPS or 100 ng/ml BAFF in the presence or absence of Compound 50 for 24 h and measured the frequency of viable and apoptotic cells using Annexin V/propidum iodide flow cytometric analysis. To perform this analysis, cells were washed with PBS and labeled with Annexin V-FITC and propidium iodide (Bio Vision) according to the manufacturer's instructions. Apoptotic cell (Annexin V- positive) and live cell (Annexin V-negative/propidium iodide-negative) percentages were determined using a flow cytometer. The data are shown in Figures 16, 17, and 18. These results are summarized in Table 4.

Each of the survival factors tested increased the proportion of viable cells recovered after the 24 hour culture period. Whereas 60% of B cells cultured in medium alone were apoptotic at this time point, the proportion of apoptotic cells was reduced to 34-44% when cells were cultured with either anti-CD40, LPS or BAFF. Dramatically, 80-90% of B cells cultured in the presence of Compound 50 at concentrations >100 nM were apoptotic, indicating that at these concentrations of Compound 50 apoptosis is enhanced beyond what occurs spontaneously. Moreover, this induction of cell death overcame any cell survival signals induced by anti-CD40, LPS, or BAFF. This result indicates that Compound 50 may interfere directly with the anti-apoptotic signals induced by these survival factors or it may induces apoptosis via an independent mechanism.

Example 11 : Compound 50 does not reduce the viability of various non-B cell human tumor cell lines.

We believe that the compounds of the invention can be used to treat cancers that are dependent on c-Rel activity, such as B cell lymphomas and cancers that are associated with Epstein-Barr virus. We tested whether Compound 50 affects cell viability of four other human tumor cell lines that were not believed to be dependent on c-Rel activity during a 24-h incubation period (see Figure 19). Cells were cultured at 100,000-200,000 cells/well in 96-well microtiter plates in culture medium (RPMI 1640 or DMEM supplemented with 10% fetal bovine serum, 2mM L-glutamine, and 20 niM HEPES) for 24h in the presence of Compound 50 or DMSO vehicle control. To measure cell viability, metabolic activity was determined using an MTS assay (Promega) according to the manufacturer's instructions. At concentrations up to 1000 nM, Compound 50 had no effect on the viability of the monocytic line, THP-I and the epithelial line HeLa. There was a slight reduction in cell viability of the monocytic cell line U937 and the astrocytic cell line U373 following the 24-h culture period, but this reduction was not dose-dependent.

Example 12: Compound 50 inhibits the proliferation and survival of select human B cell tumor cell lines.

An elevation in c-Rel expression and/or activation has been associated with normal primary human B cells and with a subset of human B cell tumor lines. To identify the effects of the compounds of the invention on the growth and survival of human B cells, we screened a panel of tumor cell lines of different origin and classification. Two types of experiments were performed. To assess effects on B cell proliferation, cells were cultured for 48 h in the presence of Compound 50, at which time incorporation of BrdU into the cellular DNA was determined as a measure of proliferation. To assess effects on apoptosis and cell survival, cells were cultured for 48 h in the presence of Compound 50, at which time cells were stained with annexin V and propidium iodide to measure apoptotic cell numbers. Our initial findings are summarized in Figure 20 and Table shown in Figures 21 A and 2 IB.

Of the various B cell tumor lines screened (Figure 21 A), we observed enhanced apoptosis of two Burkitt's lymphoma cell lines, DAUDI and RAJI. Compound 50 also reduced proliferation of these two cell lines with potencies very similar to the effects seen on apoptosis of these two cell lines. A third Burkitt's lymphoma cell line, RAMOS, was not significantly affected by Compound 50. Interestingly, DAUDI and RAJI cells are positive for Epstein Barr virus (in contract to RAMOS cells which are negative for the presence of this virus). Two Hodgkin lymphoma cell lines, L540 and HD-MyZ, were modestly affected by Compound 50 exposure.

The proliferation of a diffuse large B cell lymphoma cell (DLBCL) line, RC- K8, was potently inhibited by Compound 50 (IC₅₀ = 7 nM). Interestingly, we found that Compound 50 did not induce apoptosis in this cell line at concentrations up to 300 nM suggesting that drug exposure leads to growth arrest but not cell death.

Example 13 : Compound 50 Displays Anti-tumor Activity Against Human B Lymphoma Tumor Cells in a SCID Mouse Xenograft Model

The human Burkitt's lymphoma tumor cell line, Daudi (ATCC #CCL-213; E. Klein, et al., Cancer Res. 28:1300-1310, 1968), was obtained from the American Type Culture Collection (ATCC; Manassas, Virginia, USA). The cells were cultured in growth media prepared with RPMI Media 1640 (high glucose), 10% fetal bovine serum (FBS), 1% IOOX Penicillin-Streptomycin, 1% IOOX sodium pyruvate and 1% IOOX MEM non-essential amino acids. FBS was obtained from ATCC and all other reagents were obtained from Invitrogen Corp. (Carlsbad, California, USA). Cells that had been cryopreserved in liquid nitrogen were rapidly thawed at 37⁰C and transferred to a tissue culture flask containing growth media and then incubated at 37⁰C in a 5% CO₂ incubator. To expand the cell line, cultures were passaged 1 :2 to a density of 5 x 10(6) cells/ml every three days by adding an equal volume of fresh growth media. When the flasks reached a density of approximately 10 x 10(6) cells/ml, the above passaging process was repeated until sufficient cells had been obtained for implantation into mice.

Seven to eight week old, female CB\7/lcr-Prkdc^scid/Cή (SCID) mice were obtained from Charles River Laboratories (Wilmington, Massachusetts, USA). Animals were housed 4-5/cage in micro-isolators, with a 12hr/12hr light/dark cycle, acclimated for at least 1 week prior to use and fed normal laboratory chow ad libitum. Studies were conducted on animals that were between 8 and 12 weeks of age at the time of tumor cell implantation. To implant Daudi tumor cells into SCID mice, cell cultures were centrifuged to pellet the cells, the supernatant was aspirated and the cell pellet was resuspended in 10 ml of growth media and the cell number determined using a hemocytometer, washed in PBS and resusupended at a concentration concentration of 50 x 10(6) cells/ml in 50% non-supplemented RPMI Media 1640 and 50% Matrigel Basement Membrane Matrix (#354234; BD Biosciences; Bedford, Massachusetts, USA). Using a 27 gauge needle and 1 cc syringe, 0.1 ml of the cell suspension was injected subcutaneously into the shaved flanks of SCID mice.

Tumors were then permitted to develop in vivo until they reached approximately 100-200 mm³ in volume, which typically required 1-2 weeks following implantation. Tumor volumes (V) were calculated by caliper measurement of the width (W), length (L) and thickness (T) of tumors using the following formula: V = 0.5236 x (L x W x T). Animals were randomized into treatment groups so that the average tumor volumes of each group were similar at the start of dosing.

Animals were dosed with vehicle alone or test articles either by oral gavage (p.o.) or intravenously (i.v.) at 10 ml/kg body weight. For p.o. dosing, test articles were formulated as suspensions or fully dissolved in 0.5% methylcellulose (400 cps) in water and stored in the dark at 4°C overnight for a maximum of 1 week, and then warmed to room temperature and vortexed vigorously prior to dosing. For i.v. dosing, stock solutions of test articles were prepared by dissolving the appropriate amounts of each compound in dimethyl sulfoxide (DMSO) by soni cation in an ultrasonic water bath. Stock solutions were prepared at the start of the study, stored at -2O⁰C and diluted fresh each day for dosing. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenated castor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 80% D5W (5% dextrose in water; Abbott Laboratories, North Chicago, Illinois, USA) was also prepared by first heating 100% Cremophore RH40 at 50-60⁰C until liquefied and clear, diluting 1:5 with 100% D5W, reheating again until clear and then mixing well. This solution was stored at room temperature for up to 3 months prior to use. To prepare i.v. formulations for daily dosing, DMSO stock solutions were diluted 1:10 with 20% Cremophore RH40. The final i.v. formulation for dosing contained 10% DMSO, 18% Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amount of test article.

As shown in Figure 22, p.o. treatment with 50, 100 and 150 mg/kg body weight of Compound 50 decreased the growth rate of Daudi lymphoma cells in SCID mice. This effect was not associated with overt toxicity, as shown by the minimal effect on body weights (Figure 23). In contrast, i.v. treatment with 10 mg/kg of paclitaxel (an unrelated drug that is used to treat cancer in humans) had little effect on tumor growth. OTHER EMBODIMENTS

From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. For example, compounds structurally analogous to a heterocyclic compound described in the specification also can be made, screened for their inhibiting c-Rel activities, and used to practice this invention. Thus, other embodiments are also within the claims.

Claims

WHAT IS CLAIMED IS:

1. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph or prodrug thereof, wherein:

R₂ and R₄, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, -C(O)R^C, -OC(O)R⁰, -SC(O)R⁰, -NR^kC(0)R°, -C(S)R⁰, -OC(S)R⁰, -SC(S)R⁰, -NR^kC(S)R°, -C(NR)R⁰, -OC(NR)R⁰, -SC(NR)R⁰, -NR^kC(NR)R°, -SO₂R⁰, -S(O)R⁰, -NR^kSO₂R°, -OS(O)₂R⁰, -OP(O)R⁰R⁰, -P(O)R⁰R⁰, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R₂ and R₄ taken together are =0, =S, or =NR; R₃ is R^g;

Rs and R₆ are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R₅ and R₆ taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;

X is O, S, S(O), S(O)₂, or NR^k;

Y is (CH(R^g))_m, C(O), C(NR), O, S, S(O), S(O)₂, N(R^k), or absent;

G is a bond, -C(0)NR^kNR^k-, -NR^kNR^kC(O)-, -NR^kN=CR^k-, - CR^k=NNR^k-, -NR^kNR^k-, -N(OH)-, -NR^kO-, -ONR^k-, -C(O)-, -C(NR)-, -NR^kC(O)-, -C(O)NR^k-, -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(O)O-, -OC(O)NR^k-, -NR^kC(S)O-, -OC(S)NR^k-, -NR^k-C(NR)-NR^k-, - NR^k-C(O)-NR^k-, -NR^k-C(S)-NR^k-, -NR^k-S(O)₂-NR^k-, -P(O)(R^c)-, -P(O)(R^c)O-, -OP(O)(R^c)-, -OP(O)(R^c)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NR^k-, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(OR )₂-, -B(OR^k)-, -C(NR)-NR^k-, -NR^k-CR^gR^g-C(0)-, -C(O)-ONR^k-, -C(O)-NR^kO-, -C(S)-ONR^k-, -C(S)-NR^kO-, -C(NR)-0NR^k-, -C(NR)-NR^kO-, -OS(O)₂-NR^kNR^k-, -OC(O)-NR^kNR^k-, -OC(S)-NR^kNR^k-, -OC(NR)-NR^kNR^k-, -NR^kNR^kS (O)₂O-, -NR^kNR^kC(S)O-, -NR^kNR^kC(NR)O-, -OP(O)(R^c)O-, -NR^kP(0)(R^c)O-, -OP(O)(R^c)NR^k-, -NR^kP(O)(R^c)NR^k-, -P(O)(R^c)NR^k-, -NR^kP(O)(R^c)-,

-O-alkylene-heterocycloalkylene-NR^k-, -NR^k-CHR^g-C(O)-NR^k-CHR^g-C(O)-, -NR^k-CHR^g-C(O)-, -NR^k-C(O)-CHR^g-, or -C(O)-NR^k-CHR^g-C(O)-; and each of Q, U, and V are independently N or CR^g, wherein at least one of Q, U, or V is N; and each CR^g may be the same or different; R, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)R^c, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O)₂R^c; each of R^a and R^b, independently, is H, optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R^s, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, -C(O)R^c, -OC(O)R^c, -SC(O)R⁰, -NR^kC(0)R^c, -C(S)R^c, -OC(S)R^c, -SC(S)R°,-NR^kC(S)R°, -C(NR)R^c, -OC(NR)R^c, -SC(NR)R^c, -NR^kC(NR)R^c, -SO₂R^c, -S(O)R^c, -NR^kSO₂R^c, -OS(O)₂R^c, -OP(O)R^cR^c, -P(O)R^cR^c, halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;

R and R^j, for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R^h and R^J taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;

R^k, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; n is 0, 1, 2, 3, 4, 5, 6 or 7; and m is 0, 1, 2, 3, or 4.

2. The method of Claim 1 , wherein Q, U, and V are N.

3. The method of Claim 1 , wherein one of Q, U, or V is CR^g, and the other two are N.

4. The method of Claim 3, wherein V is CR^g, Q and U are N.

5. The method of Claim 3, wherein Q is CR^g, V and U are N.

6. The method of Claim 3, wherein U is CR^g, V and Q are N.

7. The method of Claim 1 , wherein one of Q, U, or V is N, and the other two are CR^g.

8. The method of Claim 7, wherein V is N, and Q and U are CR^g.

9. The method of Claim 7, wherein Q is N, and V and U are CR^g.

10. The method of Claim 7, wherein U is N and Q, and V are CR^g.

11. The method of Claim 2, 3, or 7 wherein -NR₅R₆ is an optionally substituted morpholino, an optionally substituted thiomorpholino, an optionally substituted 1-oxo-thiomorpholino, an optionally substituted 1,1-dioxo- thiomorpholino, an optionally substituted piperidinyl, or an optionally substituted piperazinyl.

12. The method of Claim 11 , wherein X is -NR^k-.

13. The method of Claim 12, wherein the R^k of group X is -H or a lower alkyl.

14. The method of Claim 13, wherein R₁ is an optionally substituted aryl or an optionally substituted heteroaryl.

15. The method of claim 14, wherein R₁ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benziniidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted carbazolyl, an optionally substituted 1,2,3,4-tetrahydro-carbazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyriniidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

16. The method of Claim 15, wherein R₁ is an optionally substituted phenyl, an optionally substituted indolyl, an optionally substituted indanyl, an optionally substituted carbazolyl, or an optionally substituted 1,2,3,4-tetrahydro- carbazolyl.

17. The method of Claim 13, wherein R₁ is a group represented by the following formula:

18. The method of claim 17, wherein one of R^a or R^b is — H or a lower alkyl, and the other is an optionally substituted aryl or an optionally substituted heteroaryl.

19. The method of claim 18, wherein one of R^a or R is -H or a lower alkyl, and the other is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted carbazolyl, an optionally substituted 1,2,3,4-tetrahydro-carbazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

20. The method of claim 18, wherein one of R^a or R is — H or a lower alkyl, and the other is an optionally substituted phenyl, an optionally substituted indolyl, an optionally substituted indanyl, an optionally substituted carbazolyl, or an optionally substituted 1,2,3,4-tetrahydro-carbazolyl.

21. The method of Claim 11 , wherein Y is O.

22. The method of Claim 11 , wherein Y is a covalent bond.

23. The method of Claim 11 , wherein R₃ is H.

24. The method of Claim 11 , wherein R₃ is an optionally substituted aryl or an optionally substituted heteroaryl.

25. The method of Claim 24, wherein R₃ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-ρyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted p'urinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

26. The method of claim 11, wherein R₃ is a hydroxy, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.

27. The method of Claim 26, wherein R₃ is a hydroxy, an optionally substituted pyridinyl, an optionally substituted morpholino, or an optionally substituted oxazolidin-2-one.

28. The method of Claim 11 , wherein each OfR₂ and R₄ is, independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyclyl.

29. The method of Claim 28, wherein n is 1 , 2, or 3, and R₂ and R₄, for each occurrence are, independently, H or a lower alkyl.

30. The method of Claim 11 , wherein G is absent.

31. The method of Claim 11 , wherein G is an optionally substituted heteroaryl or an optionally substituted heterocyclyl.

32. The method of Claim 11 , wherein G is -C(O)NHNH-, -NHNHC(O)-, -CH=N- N NHH--,, --NNHH--NN==CCHH--,,--NNHHNNHH-- --NNHHOO--,, --O0--NH-, -NR^k-O-, -CH=N-O-, -O- N=CH-, -0-C(S)-NH-, or -NH-C(S)-O-.

33. The method of Claim 11 , wherein G is -0-C(O)-NH-, -NH-C(NH)-NH-, -NR^k-C(NH)-NH-, -NR^k-C(NR^k)-NH-, -NH-C(N(CN))-NH-, -NH- C(NSO₂R^c)-NH-, -NR^k-C(NSO₂R^c)-NH-, -NH-C(NN0₂)-NH-, NH- C(NC(O)R^c)-NH-, -NH-C(O)-NH-, Or-NH-C(S)-NH-.

34. The method of Claim 11 , wherein G is -NH-S(O)₂-NH-, -NR^k-S(O)₂-O-, -P(O)(R^c)-, -P(O)(R^c)-O-, or -P(O)(R^c)-NR^k-.

35. The method of Claim 11, wherein G is an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl or an optionally substituted heterocyclyl.

36. The method of Claim 35, wherein G is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted cyclohexyl, an optionally substituted cycloheptyl, an optionally substituted aziridinyl, an optionally substituted oxiranyl, an optionally substituted azetidinyl, an optionally substituted oxetanyl, an optionally substituted morpholinyl, an optionally substituted piperazinyl or an optionally substituted piperidinyl.

37. The method of Claim 11 , wherein G is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, - C(N-CN)-NH-, -Si(OH)₂-, -C(NH)-NR¹S or -NR^k-CH₂-C(O)-.

38. The method of Claim 37, wherein G is an optionally substituted imidazolyl, an optionally substituted imidazolidinone, an optionally substituted imidazolidineamine, an optionally substituted pyrrolidinyl, an optionally substituted pyrrolyl, an optionally substituted furanyl, an optionally substituted thienyl, an optionally substituted thiazolyl, an optionally substituted triazolyl, an optionally substituted oxadiazolyl, an optionally substituted thiadiazolyl, an optionally substituted pyrazolyl, an optionally substituted tetrazolyl, an optionally substituted oxazolyl, an optionally substituted isoxazolyl, an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidyl, an optionally substituted indolyl, or an optionally substituted benzothiazolyl.

39. The method of Claim 11 , wherein:

Y is O or CH₂; G is absent; and n is O, 1, 2, 3 or 4.

40. The method of Claim 11 , wherein:

Y is absent, O, S, NR^k, or CH₂; and n is O, 1, 2, 3, or 4.

41. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (H):

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or polymorph thereof, wherein:

X₁ is represented by a formula selected from the group consisting of:

R.2 and R₄, for each occurrence, are independently, H₃ an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, -C(O)R^c, -OC(O)R^c, -SC(O)R^c, -NR^kC(O)R°, -C(S)R^c, -OC(S)R^c, -SC(S)R^c, -NR^kC(S)R^c, -C(NR)R^c, -OC(NR)R^c, -SC(NR)R^c, -NR^kC(NR)R°, -SO₂R^c, -S(O)R^c, -NR^kSO₂R^c, -OS(O)₂R^c, -OP(O)R^cR^c, -P(O)R^cR^c, halo, haloalkyl, aminoalkyl, mercapto alkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R₂ and R₄ taken together are =O, =S, or =NR;

R₃ is R^g;

R₇ is an optionally substituted aryl or an optionally substituted heteroaryl;

Y is (CH(R^g))_m, C(O), C(NR)₅ O, S, S(O), S(O)₂, N(R^k), or absent;

G is a bond, -C(0)NR^kNR^k-, -NR^kNR^kC(O)-, -NR^kN=CR^k-, - CR^k=NNR^k- -NR^kNR^k-, -N(OH)-, -NR^kO-, -ONR^k-, -C(O)-, -C(NR)-, -NR^kC(0)-, -C(O)NR^k-, -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(O)O-, -OC(O)NR¹S -NR^kC(S)O-, -OC(S)NR¹S -NR^k-C(NR)-NR^k-, - NR^k-C(0)-NR^k-, -NR^k-C(S)-NR^k-, -NR^k-S(O)₂-NR^k-, -P(O)(R^c)-, -P(O)(R^c)O-, -OP(O)(R^c)-, -OP(O)(R^c)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NR^k-, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(OR^k)₂-, -B(OR^k)-₅ -C(NR)-NR^k-, -NR^k-CR^gR^g-C(O)-, -C(O)-ONR^k-, -C(O)-NR^kO-, -C(S)-ONR¹S -C(S)-NR^kO-, -C(NR)-ONR^k-, -C(NR)-NR^kO-, -OS(O)₂-NR^kNR^k-, -OC(O)-NR^kNR^k-, -OC(S)-NR^kNR^k-, -0C(NR)-NR^kNR^k-, -NR^kNR^kS(O)₂O-, -NR^kNR^kC(S)O-, -NR^kNR^kC(NR)O-, -OP(O)(R^C)O-, -NR^kP(O)(R°)O-, -OP(O)(R^c)NR^k-, -NR^kP(O)(R^c)NR^k-, -P(O)(R^c)NR^k-, -NR^kP(O)(R⁰)-, -O-alkylene-heterocycloalkylene-NR'S -NR^k-CHR^g-C(O)-NR^k-CHR^g-C(O)-, -NR^k-CHR^g-C(O)-, -NR^k-C(O)-CHR^g-, or -C(O)-NR^k-CHR^g-C(O)-; and each of Q, U, and V are independently N or CR^g, wherein at least one of Q, U, or V is N; and each CR^g may be the same or different;

R, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)R^C, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O)₂R⁰;

R^c, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;

R^g, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, -C(O)R^c, -OC(O)R^c, -SC(O)R^c, -NR^kC(O)R°, -C(S)R^c, -OC(S)R^c, -SC(S)R°,-NR^kC(S)R°, -C(NR)R^c, -OC(NR)R^c, -SC(NR)R^c, -NR^kC(NR)R°, -SO₂R^c, -S(O)R^c, -NR^kSO₂R^c, -OS(O)₂R^c, -OP(O)R^cR^c, -P(O)R^cR^c, halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;

R and R", for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocyclo alkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R^h and R^j taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;

R^k, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; n is O, 1, 2, 3, 4, 5, 6 or 7; and m is 0, 1, 2, 3, or 4.

42. The method of Claim 41 , wherein Q, U, and V are N.

43. The method of Claim 41 , wherein one of Q, U, or V is CR^g, and the other two are N.

44. The method of Claim 43, wherein V is CR^g, Q and U are N.

45. The method of Claim 43, wherein Q is CR^g, V and U are N.

46. The method of Claim 43, wherein U is CR^g, V and Q are N.

47. The method of Claim 41 , wherein one of Q, U, or V is N, and the other two are CR^g.

48. The method of Claim 47, wherein V is N, and Q and U are CR^g.

49. The method of Claim 47, wherein Q is N, and V and U are CR^g.

50. The method of Claim 47, wherein U is N and Q, and V are CR^g.

51. The method of Claim 42, 43, or 47 wherein -NR₅R₆ is an optionally substituted morpholino, an optionally substituted thiomorpholino, an optionally substituted 1-oxo-thiomorpholino, an optionally substituted 1,1- dioxo-thiomorpholino, an optionally substituted piperidinyl, or an optionally substituted piperazinyl.

52. The method of Claim 51 , wherein X₁ is one of the following formulas:

53. The method of Claim 52, wherein X₁ is represented by the following formula:

wherein R^k is -H or a lower alkyl.

54. The method of Claim 52, wherein X₁ is represented by the following formula:

wherein R^k is -H or a lower alkyl.

55. The method of Claim 52, wherein X₁ is represented by the following formula:

; wherein R^k is -H or a lower alkyl.

56. The method of claim 52, wherein R₇ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted carbazolyl, an optionally substituted 1,2,3,4-tetrahydro-carbazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrirnidinyl, or an optionally substituted benzo(b)thienyl.

57. The method of claim 56, wherein R₇ is an optionally substituted phenyl, an optionally substituted indolyl, an optionally substituted indanyl, an optionally substituted carbazolyl, or an optionally substituted 1,2,3,4-tetrahydro- carbazolyl.

58. The method of Claim 52, wherein R₇ is a group represented by the following formula:

wherein: the dashed line indicates a double or a single bond;

X₂ is -O-, -S(CO_p-, -N(R^k)-, or -C(R^g)(R^g)-;

R₈ and R₉ are each, independently, R^g, -C(O)R⁰, -C(S)R⁰, -C(NR)R⁰, -NR^kC(O)R^c, -OC(O)R⁰, -SC(O)R⁰, -NR^kC(S)R°, -OC(S)R⁰, -SC(S)R^C, -NR^kC(NR)R°, -OC(NR)R⁰, or -SC(NR)R⁰; or R₈ and R₉, taken together with the carbons to which they are attached, form a 5- to 7-membered optionally substituted cycloalkyl, a 5- to 7-membered optionally substituted cyclyl, a 5- to 7-membered optionally substituted aryl, a 5- to 7-membered optionally substituted heterocycloalkyl, a 5- to 7-membered optionally substituted heterocyclyl, a 5- to 7-membered optionally substituted heteroaryl; R_1O, for each occurrence, is, independently, R^g, -C(O)R^c, -C(S)R^c, -C(NR)R⁰, -NR^kC(O)R°, -OC(O)R^c, -SC(O)R^c, -NR^kC(S)R°, -OC(S)R⁰, -SC(S)R^c, -NR^kC(NR)R^c, -OC(NR)R^c, or -SC(NR)R^c; p is O, 1, or 2; and t is O, 1, 2, or, 3.

59. The method of claim 58, wherein R₇ is (2,3-dimethyl-lH-indol-5-yl), (IH- indol-5-yl), or (6,7,8,9-tetrahydro-5H-carbazol-3-yl).

60. The method of Claim 52, wherein R₇ is a group represented by the following formula:

wherein:

R₁₁ and R₁₂, for each occurrence, are, independently, R^g, -C(O)R^c, -C(S)R^c, -C(NR)R^c, -NR^kC(0)R°, -OC(O)R^c, -SC(O)R^c, -NR^kC(S)R°, -OC(S)R^c, -SC(S)R^c, -NR^kC(NR)R°, -OC(NR)R^c, or -SC(NR)R^c; and s is O, 1, 2, 3, or 4.

61. The method of Claim 52, wherein Y is O.

62. The method of Claim 52, wherein Y is a covalent bond.

63. The method of Claim 52, wherein R₃ is Η.

64. The method of Claim 52, wherein R₃ is an optionally substituted aryl or an optionally substituted heteroaryl.

65. The method of Claim 64, wherein R₃ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

66. The method of claim 52, wherein R₃ is a hydroxy, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.

67. The method of Claim 66, wherein R₃ is a hydroxy, an optionally substituted pyridinyl, an optionally substituted morpholino, or an optionally substituted oxazolidin-2-one.

68. The method of Claim 52, wherein each of R₂ and R₄ is, independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, an υpuonany substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted lieterocycloalkyl, or an optionally substituted heterocyclyl.

69. The method of Claim 68, wherein n is 1, 2, or 3, and R₂ and R₄, for each occurrence are, independently, H or a lower alkyl.

70. The method of Claim 52, wherein G is absent.

71. The method of Claim 52, wherein G is an optionally substituted heteroaryl or an optionally substituted heterocyclyl.

72. The method of Claim 52, wherein G is -C(O)NHNH-, -NHNHC(O)-, -CH=N- NH-, -NH-N=CH-,-NHNH- -NHO-, -0-NH-, -NR^k-0-, -CH=N-O-, -O- N=CH-, -0-C(S)-NH-, or -NH-C(S)-O-.

73. The method of Claim 52, wherein G is -0-C(O)-NH-, -NH-C(NH)-NH-, -NR^k-C(NH)-NH-, -NR^k-C(NR^k)-NH-, -NH-C(N(CN))-NH-, -NH- C(NSO₂R^C)-NH-, -NR^k-C(NSO₂R^c)-NH-, -NH-C(NN0₂)-NH-, NH- C(NC(O)R^C)-NH-, -NH-C(O)-NH-, Or -NH-C(S)-NH-.

74. The method of Claim 52, wherein G is -NH-S(O)₂-NH-, -NR^k-S(O)₂-O-, -P(O)(R⁰)-, -P(O)(R^C)-O-, or -P(O)(R^c)-NR^k-.

75. The method of Claim 52, wherein G is an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl or an optionally substituted heterocyclyl.

76. The method of Claim 75, wherein G is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted cyclohexyl, an optionally substituted cycloheptyl, an optionally substituted aziridinyl, an optionally substituted oxiranyl, an optionally substituted azetidinyl, an optionally substituted oxetanyl, an optionally substituted morpholinyl, an optionally substituted piperazinyl or an optionally substituted piperidinyl.

77. The method of Claim 52, wherein G is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, - C(N-CN)-NH-, -Si(OH)₂-, -C(NH)-NR^k-₅ or -NR^k-CH₂-C(O)-.

78. The method of Claim 77, wherein G is an optionally substituted imidazolyl, an optionally substituted imidazolidinone, an optionally substituted imidazolidineamine, an optionally substituted pyrrolidinyl, an optionally substituted pyrrolyl, an optionally substituted furanyl, an optionally substituted thienyl, an optionally substituted thiazolyl, an optionally substituted triazolyl, an optionally substituted oxadiazolyl, an optionally substituted thiadiazolyl, an optionally substituted pyrazolyl, an optionally substituted tetrazolyl, an optionally substituted oxazolyl, an optionally substituted isoxazolyl, an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidyl, an optionally substituted indolyl, or an optionally substituted benzothiazolyl.

79. The method of Claim 52, wherein:

Y is O or CH₂; G is absent; and n is O, 1, 2, 3 or 4.

80. The method of Claim 52, wherein:

Y is absent, O, S, NR^k, or CH₂; and n is O, 1, 2, 3, or 4.

81. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (HI):

(HI) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, prodrug or polymorph thereof, wherein:

X₃ is -C(R^g)=N-A-;

A is O, S, S(O), S(O)₂, C(CR^g)₂, orNR^k;

R₂ and R₄, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -0R^k, -SR^k, -NR^hR^j, hydroxylalkyl, -C(O)R^C, -0C(0)R^c, -SC(O)R⁰, -NR^kC(0)R^c, -C(S)R⁰, -OC(S)R⁰, -SC(S)R⁰, -NR^kC(S)R°, -C(NR)R⁰, -OC(NR)R⁰, -SC(NR)R⁰, -NR^kC(NR)R°, -SO₂R⁰, -S(O)R⁰, -NR^kSO₂R°, -OS(O)₂R⁰, -OP(O)R⁰R⁰, -P(O)R⁰R⁰, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R₂ and R₄ taken together are =0, =S, or =NR;

R₃ is R^g;

R₅ and R₆ are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R₅ and R₆ taken together with the N to which they are attached is an optionally substituted lieterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;

R₇ is an optionally substituted aryl or an optionally substituted heteroaryl;

Y is (CH(R^g))_m, C(O), C(NR), O, S, S(O), S(O)₂, N(R^k), or absent;

G is a bond, -C(0)NR^kNR^k-, -NR^kNR^kC(O)-, -NR^kN-CR^k-, - CR^k= NNR^k-, -NR^kNR^k-, -N(OH)-, -NR^kO-, -ONR^k-, -C(O)-, -C(NR)-, -NR^kC(O)-, -C(O)NR^k-, -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(O)O-, -OC(O)NR^k-, -NR^kC(S)O-, -OC(S)NR^k-, -NR^k-C(NR)-NR^k-, - NR^k-C(0)-NR^k-, -NR^k-C(S)-NR^k-, -NR^k-S(O)₂-NR^k-, -P(O)(R^c)-, -P(O)(R^c)O-, -OP(O)(R^c)-, -OP(O)(R^c)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NR -, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(OR^k)₂-, -B(OR^k)-, -C(NR)-NR^k-, -NR^k-CR^gR^g-C(0)-, -C(O)-ONR^k-, -C(O)-NR^kO-, -C(S)-0NR^k-, -C(S)-NR^kO-, -C(NR)-ONR^k-, -C(NR)-NR^kO-, -OS(O)₂-NR^kNR^k-, -0C(0)-NR^kNR^k-, -OC(S)-NR^kNR^k-, -0C(NR)-NR^kNR^k-, -NR^kNR^kS(O)₂O-, -NR^kNR^kC(S)O-, -NR^kNR^kC(NR)O-, -OP(O)(R°)O-, -NR^kP(O)(R^c)O-, -OP(O)(R^c)NR^k-, -NR^kP(O)(R^c)NR^k-, -P(O)(R^c)NR^k-, -NR^kP(0)(R^c)-,

-O-alkylene-heterocycloalkylene-NR^k-, -NR^k-CHR^g-C(O)-NR^k-CHR^g-C(O)-, -NR^k-CHR^g-C(0)-, -NR^k-C(0)-CHR^g-, or -C(O)-NR^k-CHR^g-C(O)-; and each of Q, U, and V are independently N or CR^g, wherein at least one of Q, U, or V is N; and each CR^g may be the same or different;

R, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)R^c, -0R^k, -SR^k, -NR^hR^j, hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O)₂R^c; R^c, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;

R^s, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, alkylcarbonylalkyl; mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, -C(O)R⁰, -OC(O)R⁰, -SC(O)R⁰, -NR^kC(O)R°, -C(S)R⁰, -OC(S)R⁰, -SC(S)R°,-NR^kC(S)R°, -C(NR)R⁰, -OC(NR)R⁰, -SC(NR)R⁰, -NR^kC(NR)R°, -SO₂R⁰, -S(O)R⁰, -NR^kS0₂R^c, -OS(O)₂R⁰, -OP(O)R⁰R⁰, -P(O)R⁰R⁰, halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;

R^k, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; n is 0, 1, 2, 3, 4, 5, 6 or 7; and m is O, 1, 2, 3, or 4.

82. The method of Claim 81 , wherein Q, U, and V are N.

83. The method of Claim 81 , wherein one of Q, U, or V is CR^S, and the other two are N.

84. The method of Claim 83, wherein V is CR^g, Q and U are N.

85. The method of Claim 83, wherein Q is CR^g, V and U are N.

86. The method of Claim 83, wherein U is CR^g, V and Q are N.

87. The method of Claim 81 , wherein one of Q, U, or V is N, and the other two are CR^g.

88. The method of Claim 87, wherein V is N, and Q and U are CR^S.

89. The method of Claim 87, wherein Q is N, and V and U are CR^g.

90. The method of Claim 87, wherein U is N and Q, and V are CR^g.

91. The method of Claim 82, 83, or 87 wherein -NR₅R₆ is an optionally substituted morpholino, an optionally substituted thiomorpholino, an optionally substituted 1-oxo-thiomorpholino, an optionally substituted 1,1- dioxo-thiomorpholino, an optionally substituted piperidinyl, or an optionally substituted piperazinyl.

92. The method of Claim 91 , wherein X₃ is -C(R^g)=N-NR^k-, wherein R^s and R^k of X₃ are each, independently, -H or a lower alkyl.

93. The method of claim 92, wherein R₇ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofiiryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted carbazolyl, an optionally substituted 1,2,3,4-tetrahydro-carbazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidmyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

94. The method of claim 93, wherein R₇ is an optionally substituted phenyl, an optionally substituted indolyl, an optionally substituted indanyl, an optionally substituted carbazolyl, or an optionally substituted 1,2,3,4-tetrahydro- carbazolyl.

95. The method of Claim 92, wherein R₇ is a group represented by the following formula:

wherein: the dashed line indicates a double or a single bond;

X₂ is -O-, -S(O)_p-_, -N(R^k)-, or -C(R^g)(R^g)-;

R₈ and R₉ are each, independently, R^g, -C(O)R^c, -C(S)R^c, -C(NR)R^c, -NR^kC( OR^c, -OC(O)R^c, -SC(O)R^c, -NR^kC(S)R^c, -OC(S)R^c, -SC(S)R^c, -NR^kC(NR)R^c, -OC(NR)R^c, or -SC(NR)R^c; or R₈ and R₉, taken together with the carbons to which they are attached, form a 5- to 7-membered optionally substituted cycloalkyl, a 5- to 7-membered optionally substituted cyclyl, a 5- to 7-membered optionally substituted aryl, a 5- to 7-membered optionally substituted heterocycloalkyl, a 5- to 7-membered optionally substituted heterocyclyl, a 5- to 7-membered optionally substituted heteroaryl;

R₁₀, for each occurrence, is, independently, R^g, -C(O)R^c, -C(S)R^c, -C(NR)R^c, -NR^kC(0)R°, -OC(O)R^c, -SC(O)R^c, -NR^kC(S)R°, -OC(S)R^c, -SC(S)R^c, -NR^kC(NR)R°, -OC(NR)R^c, or -SC(NR)R^c; p is 0, 1, or 2; and t is O, 1, 2, or, 3.

96. The method of claim 95, wherein R₇ is (2,3-dimethyl-lH-indol-5-yl), (IH- indol-5-yl), or (6,7,8,9-tetrahydro-5/f-carbazol-3-yl).

97. The method of Claim 92, wherein R₇ is a group represented by the following formula:

wherein:

R₁₁ and R₁₂, for each occurrence, are, independently, R^g, -C(O)R^c, -C(S)R^c, -C(NR)R^c, -NR^kC(O)R°, -OC(O)R^c, -SC(O)R^c, -NR^kC(S)R^c, -OC(S)R^c, -SC(S)R^c, -NR^kC(NR)R°, -OC(NR)R^c, or -SC(NR)R^c; and s is O, 1, 2, 3, or 4.

98. The method of Claim 92, wherein Y is O.

99. The method of Claim 92, wherein Y is a covalent bond.

100. The method of Claim 92, wherein R₃ is H.

101. The method of Claim 92, wherein R₃ is an optionally substituted aryl or an optionally substituted heteroaryl.

102. The method of Claim 101, wherein R₃ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

103. The method of claim 92, wherein R₃ is a hydroxy, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.

104. The method of Claim 103 , wherein R₃ is a hydroxy, an optionally substituted pyridinyl, an optionally substituted morpholino, or an optionally substituted oxazolidin-2-one.

105. The method of Claim 92, wherein each of R₂ and R₄ is, independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyclyl.

106. The method of Claim 105, wherein n is 1, 2, or 3, and R₂ and R₄, for each occurrence are, independently, H or a lower alkyl.

107. The method of Claim 92, wherein G is absent.

108. The method of Claim 92, wherein G is an optionally substituted heteroaryl or an optionally substituted heterocyclyl.

109. The method of Claim 92, wherein G is -C(O)NHNH-, -NHNHC(O)-, -CH=N- N NHH--,, --NNHH--NN==CCHH-- --NNHHNNHH-- --NNHHOO--,, --O0--NH-, -NR^k-0-, -CH=N-O-, -O- N=CH-, -0-C(S)-NH-, or -NH-C(S)-O-.

110. The method of Claim 92, wherein G is -0-C(O)-NH-, -NH-C(NH)-NH-, -NR^k-C(NH)-NH-, -NR^k-C(NR^k)-NH-, -NH-C(N(CN))-NH-, -NH- C(NSO₂R^C)-NH-, -NR^k-C(NSO₂R°)-NH-, -NH-C(NN0₂)-NH-, NH- C(NC(0)R°)-NH-, -NH-C(O)-NH-, Or-NH-C(S)-NH-.

111. The method of Claim 92, wherein G is -NH-S(O)₂-NH-, -NR^k- S (O)₂-O-, -P(O)(R⁰)-, -P(O)(R^C)-O-, or -P(0)(R^c)-NR^k-.

112. The method of Claim 92, wherein G is an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl or an optionally substituted heterocyclyl.

113. The method of Claim 112, wherein G is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted cyclohexyl, an optionally substituted cycloheptyl, an optionally substituted aziridinyl, an optionally substituted oxiranyl, an optionally substituted azetidinyl, an optionally substituted oxetanyl, an optionally substituted morpholinyl, an optionally substituted piperazinyl or an optionally substituted piperidinyl.

114. The method of Claim 92, wherein G is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, - C(N-CN)-NH-, -Si(OH)₂-, -C(NH)-NR^k-, or -NR^k-CH₂-C(0)-.

115. The method of Claim 114, wherein G is an optionally substituted imidazolyl, an optionally substituted imidazolidinone, an optionally substituted imidazolidineamine, an optionally substituted pyrrolidinyl, an optionally substituted pyrrolyl, an optionally substituted furanyl, an optionally substituted thienyl, an optionally substituted thiazolyl, an optionally substituted triazolyl, an optionally substituted oxadiazolyl, an optionally substituted thiadiazolyl, an optionally substituted pyrazolyl, an optionally substituted tetrazolyl, an optionally substituted oxazolyl, an optionally substituted isoxazolyl, an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidyl, an optionally substituted indolyl, or an optionally substituted benzothiazolyl.

116. The method of Claim 92, wherein:

Y is O or CH₂; G is absent; and n is O, 1, 2, 3 or 4.

117. The method of Claim 92, wherein:

Y is absent, O, S, NR^k, or CH₂; and n is O, 1, 2, 3, or 4.

118. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (IV)

U and V are each, independently, N or CR^g;

Ring D is a 5 to 9-membered aryl, 3 to 9-membered cycloalkyl, 3 to 9- membered cyclyl, 5 to 9-membered heteroaryl, 3 to 9-membered heterocycloalkyl, or a 3 to 9-membered heterocyclyl, each of which maybe further substituted with one or more substituents; one OfA₁ and A₂ is — X₄-R^U-R" and the other is a group represented by the following formula:

Z is N or CH;

W is O, S, S(O), S(O)₂, NR^m, or NC(O)R^m , wherein R^m, for each occurrence, is independently — H, alkyl, aryl, heteroaryl, cycloalkyl, ^■ heterocycloalkyl, or alkylcarbonyl; u is O, 1, 2, 3, or 4;

X₄ is O, S, S(O), S(O)₂, N(R^k), C(O), C(S), C(S)NR^k, C(NR), C(NR)NR^k, C(O)NR^k, C(0)NR^kNR^k, C(0)0NR^k, C(0)NR^k0, C(O)O, OC(O), OC(O)O, (C(R^g)(R^g))_q, (C(R^g)(R_g))_qNR^k, (C(R^g)(R^g))_qO, (C(R^g)(R^g))_qS(O)_p, (C(R^g)(R^g))_qN=C(R^g), C(R^g)-N, C(R^g)=N-0, C(R^g)=N-S(O)_p, C(R^g)=N-NR^k, C(R^g)=N-C(CR^g)₂ , (C(R^g)(R^g))_qC(R^g)=N, (C(R^g)(R^g))_qN=N, (C(R^g)(R^g))_qC(R^g)=C(R^g), C(R^g)=C(R^g), N=C(R^g), N(R^k)N=C(R^g), N(R^k)C(R^g)=N, N(R^k)C(R^g)=C(R^g), N=N, N(R^k)N=N, NR^kC(O)NR^k, NR^kC(S)NR^k, NR^kC(O), NR^kC(O)O, NR^kC(NR)NR^k, NR^kC(S)O, NR^kS(0)_pNR^k, OC(O)NR^k, OC(S)NR^k, OC(NR)NR^k, OS(O)_pNR^k, C(NR)O, S(O)_pNR^k, or S(0)_pNR^kNR^k;

R, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)R^c, -0R^k, -SR^k, -NR^hR^j, hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O)₂R^c;

L' is O, S, S(O), S(O)₂, N(R^k), C(O), C(S), C(S)NR^k, C(NR), C(NR)NR^k, C(O)NR^k, C(O)NR^kNR^k, C(O)ONR^k, C(0)NR^kO, C(O)O, OC(O), OC(O)O, (C(R⁸)(R⁸))_q, (C(R^g)(R_g))_qNR^k, (C(R^g)(R^g))_qO, (C(R^g)(R^g))_qS(O)_p, (C(R^g)(R^g))_qN=C(R^g), C(R^g)=N, C(R^g)=N-0, C(R^g)=N-S(O)_p, C(R^g)=N-NR^k, C(R^g)=N-C(CR^g)₂ , (C(R^g)(R^g))_qC(R^g)=N, (C(R^g)(R^g))_qN=N, (C(R^g)(R^g))_qC(R^g)=C(R^g), C(R^g)=C(R^g), N=C(R⁸), N(R^k)N=C(R^g), N(R^k)C(R^g)=N, N(R^k)C(R^g)=C(R^g), N=N, N(R^k)N=N, NR^kC(O)NR^k, NR^kC(S)NR^k, NR^kC(O), NR^kC(O)O, NR^kC(NR)NR^k, NR^kC(S)O, NR^kS(O)_pNR^k, 0C(0)NR^k, OC(S)NR^k, OC(NR)NR^k, OS(O)_pNR^k, C(NR)O, S(0)_pNR^k, S(O)_pNR^kNR^kor absent; and

R" is H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, N(R^k)(CH₂)_qR^g, -0R^k, -SR^k, -NR^hR^j, hydroxylalkyl, -C(O)R⁰, -C(S)R^C, -C(NR)R⁰, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, -S(O)R⁰, -S(O)₂R⁰, -P(O)R⁰R⁰, -P(S)R⁰R⁰, or an optionally substituted alkylcarbonylalkyl;

R°, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -0R^k, -SR^k, -NR^hR^j, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;

R^g, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, -C(O)R⁰, -OC(O)R⁰, -SC(O)R⁰, -NR^kC(O)R°, -C(S)R⁰, -OC(S)R⁰, -SC(S)R°,-NR^kC(S)R^c, -C(NR)R⁰, -OC(NR)R⁰, -SC(NR)R⁰, -NR^kC(NR)R°, -SO₂R⁰, -S(O)R⁰, -NR^kSO₂R^c, -OS(O)₂R^c, -OP(O)R^cR^c, -P(O)R^cR^c, halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;

R^k, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; q, for each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, or 8; and p, for each occurrence, is independently O, 1, or 2.

The method of Claim 118, wherein the compound is represented by formula (V):

(V) wherein:

Ring D is a 5- or 6-membered cycloalkyl, 5- or 6-membered cyclyl, 5- or 6-membered aryl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which optionally may be further substituted with one or more substituent; R₂ and R₄, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, -C(O)R⁰, -OC(O)R⁰, -SC(O)R⁰, -NR^kC(0)R^c, -C(S)R⁰, -OC(S)R⁰, -SC(S)R^C, -NR^kC(S)R^c, -C(NR)R⁰, -OC(NR)R⁰, -SC(NR)R⁰, -NR^kC(NR)R°, -SO₂R⁰, -S(O)R⁰, -NR^kSO₂R^c, -OS(O)₂R⁰, -OP(O)R⁰R⁰, -P(O)R⁰R⁰, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R₂ and R₄ taken together are =0, =S, or =NR;

R₃ is R^g;

Y is (CH(R^g))_m, C(O), C(NR), O, S, S(O), S(O)₂, N(R^k), or absent;

G is a bond, -C(O)NR^kNR^k-, -NR^kNR^kC(0)-, -NR^kN=CR^k-, - CR^k=NNR^k-, -NR^kNR^k-, -N(OH)-, -NR^k0-, -0NR^k-, -C(O)-, -C(NR)-, -NR^kC(0)-, -C(0)NR^k-, -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(O)O-, -OC(O)NR^k-, -NR^kC(S)O-, -OC(S)NR^k-, -NR^k-C(NR)-NR^k-, - NR^k-C(0)-NR^k-, -NR^k-C(S)-NR^k-, -NR^k-S(O)₂-NR^k-, -P(O)(R⁰)-, -P(O)(R°)O-, -OP(O)(R⁰)-, -OP(O)(R°)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NR -, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(OR )₂-, -B(OR^k)-, -C(NR)-NR^k-, -NR^k-CR^gR^g-C(0)-, -C(0)-0NR^k-, -C(O)-NR^kO-, -C(S)-ONR^k-, -C(S)-NR^kO-, -C(NR)-ONR^k-, -C(NR)-NR^kO-, -0S(0)₂-NR^kNR^k-, -OC(O)-NR^kNR^k-, -OC(S)-NR^kNR^k-, -0C(NR)-NR^kNR^k-, -NR^kNR^kS(O)₂O-, -NR^kNR^kC(S)0-, -NR^kNR^kC(NR)O-, -OP(O)(R°)O-, -NR^kP(O)(R°)O-, -OP(O)(R°)NR^k-, -NR^kP(O)(R°)NR^k-, -P(O)(R°)NR^k-, -NR^kP(O)(R^c)-,

-O-alkylene-heterocycloalkylene-NR^k-, -NR^k-CHR^g-C(O)-NR^k-CHR^g-C(O)-, -NR^k-CHR^g-C(0)-, -NR^k-C(O)-CHR^g-, or -C(O)-NR^k-CHR^g-C(O)-; and n is 0, 1, 2, 3, 4, 5, 6, or 7; and m is O, 1, 2, 3, or 4.

The method of Claim 119, wherein the compound is represented by one of the following structural formulas:

(VI)

(VII)

(VIII)

(IX) wherein:

X₅, X₆ and X₇ are each, independently, N or CR^g;

X₈ is CR^gR^g, O, S(O)_p, orNR^k.

121. The method of Claim 120, wherein the compound is represented by formula (VI) or formula (VII); and wherein:

U and V are N; and X₅, X₆ and X₇ are CR^g.

122. The method of Claim 121, wherein R' and L' are absent.

123. The method of Claim 122, wherein R" is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.

124. The method of Claim 123, wherein R" is an optionally substituted aryl or an optionally substituted heteroaryl.

125. The method of Claim 124, wherein R" is substitituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH₂, a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, -S(O)_PR^C, and-C(O)R^c.

126. The method of claim 123 , wherein Z is N and W is O.

127. The method of claim 123, wherein Y is a covalent bond, O, S, N(R^k), or CH₂, and n is O, 1, 2, 3, or 4.

128. The method of Claim 127, wherein G is absent.

129. The method of Claim 127, wherein G is >C=N-R, -NR^kC(O)-, -C(0)NR^k-, -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(0)0-, -0C(0)NR^k-, -NR^kC(S)O-, -OC(S)NR^k-, -NR^kC(NR)NR^k-, -NR^kC(0)NR^k-, -NR^kC(S)NR^k-, -NR^kS(O)₂NR^k-, -C(NR)NR^k-, or -NR^kCR^gR^gC(O)-.

130. The method of claim 128, wherein R₃ is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, 0R^k, SR^k, orNR^hR^j.

131. The method of claim 130, wherein R₃ is optionally substituted aryl or optionally substituted heteroaryl.

132. The method of claim 131, wherein R₃ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

133. The method of claim 130, wherein R₃ is an optionally substituted heterocycloalkyl.

134. The method of claim 133, wherein R₃ is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2- oxopiperazinyl, an optionally substituted 2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3-dioxolanyl, an optionally substituted [l,4]dioxanyl, an optionally substituted 2-oxo-imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.

135. The method of claim 130, wherein R₃ is -OR^k or -NR^hR^j, and R^f, R^h and R^j are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R^C.

136. The method of Claim 128, wherein R₃ is -C(O)OR^k, -OC(O)R^k, -C(O)NR^hR^j, -NR^kC(0)R^k, -C(S)OR^k, -OC(S)R^k, -NR^kC(O)NR^hR^j, -NR^kC(S)NR^hR^j, -C(O)NRhRj, -S(O)₂R^k, -S(O)₂NR^hR^j, -OC(O)NR^hR^j, or -NR^kC(O)0R^k.

137. The method of claim 118, wherein the compound is represented by one of the following structural formulas:

wherein;

and the remainder of R₁₃, R₁₄ and R₁₅ are independently selected from H, R⁸, or isothionitro;

R₂ and R₄, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -OR^k, -SR^k, -NR^hR^J, hydroxylalkyl, -C(O)R^C, -OC(O)R⁰, -SC(O)R⁰, -NR^kC(O)R°, -C(S)R⁰, -OC(S)R⁰, -SC(S)R⁰, -NR^kC(S)R°, -C(NR)R⁰, -OC(NR)R⁰, -SC(NR)R⁰, -NR^kC(NR)R°, -SO₂R⁰, -S(O)R⁰, -NR^kS0₂R°, -OS(O)₂R⁰, -OP(O)R⁰R⁰, -P(O)R⁰R⁰, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R₂ and R₄ taken together are =0, =S, or =NR;

R₃ is R^ε;

Y is (CH(R^g))_m, C(O), C(NR), O, S, S(O), S(O)₂, N(R^k), or absent;

G is a bond, -C(0)NR^kNR^k-, -NR^kNR^kC(0)-, -NR^kN=CR^k-, - CR¹^NNR^k-, -NR^kNR^k-, -N(OH)-, -NR^kO-, -0NR^k-, -C(O)-, -C(NR)-, -NR^kC(O)-, -C(O)NR^k-, -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(O)O-, -OC(O)NR^k-, -NR^kC(S)O-, -OC(S)NR^k-, -NR^k-C(NR)-NR^k-, - NR^k-C(O)-NR^k-, -NR^k-C(S)-NR^k-, -NR^k-S(O)₂-NR^k-, -P(O)(R^c)-, -P(O)(R^c)O-, -OP(O)(R^c)-, -OP(O)(R^c)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NR^k-, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(OR^k)₂-, -B(0R^k)-, -C(NR)-NR^k-, -NR^k-CR^gR^g-C(0)-, -C(O)-ONR^k-, -C(O)-NR^kO-, -C(S)-ONR^k-, -C(S)-NR^kO-, -C(NR)-0NR^k-, -C(NR)-NR^kO-, -OS(O)₂-NR^kNR^k-, -OC(O)-NR^kNR^k-, -0C(S)-NR^kNR^k-, -0C(NR)-NR^kNR^k-, -NR^kNR^kS(O)₂O-, -NR^kNR^kC(S)O-, -NR^kNR^kC(NR)O-, -OP(O)(R^c)O-, -NR^kP(O)(R^c)O-, -OP(O)(R^c)NR^k-, -NR^kP(0)(R^c)NR^k-, -P(0)(R^c)NR^k-, -NR^kP(O)(R^c)-,

-O-alkylene-heterocycloalkylene-NR^k-, -NR^k-CHR^g-C(O)-NR^k-CHR^g-C(O)-, -NR^k-CHR^g-C(O)-, -NR^k-C(0)-CHR^g-, or -C(O)-NR^k-CHR^g-C(O)-; and n is 0, 1, 2, 3, 4, 5, 6, or 7.

138. The method of Claim 137, wherein U and V are N.

139. The method of Claim 137, wherein R' and L' are absent.

140. The method of Claim 139, wherein R" is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.

141. The method of Claim 140, wherein R" is an optionally substituted aryl or an optionally substituted heteroaryl.

142. The method of Claim 141 , wherein R" is substitituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH₂, a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, -S(O)_PR^C, and-C(O)R^c.

143. The method of claim 140, wherein Z is N and W is O.

144. The method of claim 140, wherein Y is a covalent bond, O, S, N(R^k), or CH₂, and n is 0, 1, 2, 3, or 4.

145. The method of Claim 144, wherein G is absent.

146. The method of Claim 144, wherein G is >C=N-R, -NR^kC(O)-, -C(O)NR^k-, -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(O)O-, -0C(0)NR^k-, -NR^kC(S)O-, -OC(S)NR¹X -NR^kC(NR)NR^k-, -NR^kC(O)NR^k-, -NR^kC(S)NR^k-, -NR^kS(O)₂NR^k-, -C(NR)NR¹X or -NR^kCR^gR^gC(O)-.

147. The method of claim 145, wherein R₃ is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, OR^k, SR^k, orNR^hR^j.

148. The method of claim 147, wherein R₃ is optionally substituted aryl or optionally substituted heteroaryl.

149. The method of claim 148, wherein R₃ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

150. The method of claim 147, wherein R₃ is an optionally substituted heterocycloalkyl.

151. The method of claim 150, wherein R₃ is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2- oxopiperazinyl, an optionally substituted 2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3-dioxolanyl, an optionally substituted [l,4]dioxanyl, an optionally substituted 2-oxo-imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.

152. The method of claim 147, wherein R₃ is -OR^k or -NR^hR^j, and R^f, R^h and R^j are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R⁰.

153. The method of Claim 145, wherein R₃ is -C(O)OR^k, -OC(O)R^k, -C(O)NR^hR^j, -NR^kC(0)R^k, -C(S)OR^k, -OC(S)R^k, -NR^kC(O)NR^hR^j, -NR^kC(S)NR^hR^j, -C(O)NRhRj, -S(O)₂R^k, -S(O)₂NR^hR^j, -OC(O)NR^hR^j, or -NR^kC(O)OR^k.

154. A method of treating cancer in a subj ect in need thereof, comprising administering to the subject an effective amount of a compound of formula

(X):

(X)

Ring D is a 5 to 9-membered aryl, 3 to 9-membered cycloalkyl, 3 to 9- membered cyclyl, 5 to 9-membered heteroaryl, 3 to 9-membered heterocycloalkyl, or a 3 to 9-membered heterocyclyl, each of which may be further substituted with one or more substituents;

U and V are each, independently, N or CR^g;

Z is N or CH;

W is O, S, S(O), S(O)₂, NR^m, or NC(O)R^m, wherein R^m is H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkylcarbonyl; u is O, 1, 2, 3, or 4;

X₄ is O, S, S(O), S(O)₂, N(R^k), C(O), C(S), C(S)NR^k, C(NR), C(NR)NR^k, C(O)NR^k, C(0)NR^kNR^k, C(O)ONR^k, C(0)NR^k0, C(O)O, OC(O), OC(O)O, (C(R^g)(R^g))_q, (C(R^g)(R_g))_qNR^k, (C(R^g)(R^g))_qO, (C(R^g)(R^g))_qS(O)_p, (C(R^g)(R^g))_qN=C(R^g), C(R^g)=N, C(R^g)=N-O, C(R^g)=N-S(O)_p, C(R^g)=N-NR^k, C(R^g)=N-C(CR^e)₂, (C(R^g)(R^g))_qC(R^g)=N, (C(R⁸)(R^g))_qN=N, (C(R^g)(R^g))_qC(R^g)=C(R^g), C(R^g)=C(R^g), N=C(R^g), N(R^k)N=C(R^g), N(R^k)C(R^g)=N, N(R^k)C(R^g)=C(R^g), N=N, N(R^k)N=N, NR^kC(0)NR^k, NR^kC(S)NR^k, NR^kC(O), NR^kC(O)O, NR^kC(NR)NR^k, NR^kC(S)O, NR^kS(0)_pNR^k, OC(O)NR^k, 0C(S)NR^k, OC(NR)NR^k, 0S(0)_pNR^k, C(NR)O, S(O)_pNR^k, or S(0)_pNR^kNR^k; w is 0 or 1;

R, for each occurrence, is independently H₅ an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)R⁰, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O)₂R⁰;

L' is O, S, S(O), S(O)₂, N(R^k), C(O), C(S), C(S)NR^k, C(NR), C(NR)NR^k, C(O)NR^k, C(O)NR^kNR^k, C(O)ONR^k, C(0)NR^k0, C(O)O, OC(O), OC(O)O, (C(R^g)(R^g))_q, (C(R^g)(R_g))_qNR^k, (C(R^g)(R^g))_qO, (C(R^g)(R^g))_qS(O)_p, (C(R^g)(R^g))_qN=C(R^g), C(R^g)=N, C(R^g)=N-O, C(R^g)=N-S(O)_p, C(R^g)=N-NR^k, C(R^g)=N-C(CR^g)₂ , (C(R^g)(R^g))_qC(R^g)= N, (C(R^g)(R^g))_qN=N, (C(R^g)(R^g))_qC(R^g)=C(R^g), C(R^g)=C(R^g), N=C(R^g), N(R^k)N=C(R^g), N(R^k)C(R^g)=N, N(R^k)C(R^g)=C(R^g), N=N, N(R^k)N=N, NR^kC(O)NR^k, NR^kC(S)NR^k, NR^kC(0), NR^kC(O)O, NR^kC(NR)NR^k, NR^kC(S)0, NR^kS(0)_pNR^k, OC(O)NR^k, OC(S)NR^k, 0C(NR)NR^k, 0S(0)_pNR^k, C(NR)O, S(O)_pNR^k, S(O)_pNR^kNR^kor absent;

R" is H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, N(R^k)(CH₂)_qR^g, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, -C(O)R^c, -C(S)R^c, -C(NR)R^c, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, -S(O)R^c, -S(O)₂R^c, -P(O)R^cR^c, -P(S)R^cR^c, or an optionally substituted alkylcarbonylalkyl;

R₂ and R₄, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -0R^k, -SR^k, -NR^hR^j, hydroxylalkyl, -C(O)R^c, -OC(O)R^c, -SC(O)R^c, -NR^kC(O)R°, -C(S)R^c, -OC(S)R^c, -SC(S)R^c, -NR^kC(S)R°, -C(NR)R^c, -OC(NR)R^c, -SC(NR)R^c, -NR^kC(NR)R°, -SO₂R^c, -S(O)R^c, -NR^kSO₂R^c, -OS(O)₂R^c, -OP(O)R^cR^c, -P(O)R^cR^c, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R₂ and R₄ taken together are =0, =S, or =NR;

R₃ is R^g;

Y is (CH(R^g))_m, C(O), C(NR), O, S, S(O), S(O)₂, N(R^k), or absent;

G is a bond, -C(0)NR^kNR^k-, -NR^kNR^kC(0)-, -NR^kN=CR^k-, - CR¹HNNR¹S -NR^kNR^k-, -N(OH)-, -NR^kO-, -0NR^k-, -C(O)-, -C(NR)-, -NR^kC(0)-, -C(O)NR¹S -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(0)0-, -OC(O)NR¹S -NR^kC(S)O-, -OC(S)NR^k-, -NR^k-C(NR)-NR^k-, - NR^k-C(0)-NR^k-, -NR^k-C(S)-NR^k-, -NR^k-S(0)₂-NR^k-, -P(O)(R⁰)-, -P(O)(R°)O-, -OP(O)(R⁰)-, -OP(O)(R^C)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NR^k-, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(OR^k)₂-, -B(0R^k)-, -C(NR)-NR^k-, -NR^k-CR^gR^g-C(0)-, -C(O)-ONR^k-, -C(O)-NR^kO-, -C(S)-ONR^k-, -C(S)-NR^kO-, -C(NR)-ONR^k-, -C(NR)-NR^kO-, -OS(O)₂-NR^kNR^k-, -OC(O)-NR^kNR^k-, -0C(S)-NR^kNR^k-, -OC(NR)-NR^kNR^k-, -NR^kNR^kS (O)₂O-, -NR^kNR^kC(S)0-, -NR^kNR^kC(NR)0-, -OP(O)(R°)O-, -NR^kP(O)(R°)O-, -OP(O)(R°)NR^k-, -NR^kP(O)(R°)NR^k-, -P(0)(R°)NR^k-, -NR^kP(0)(R°)-,

-O-alkylene-heterocycloalkylene-NR^k-, -NR^k-CHR^g-C(O)-NR^k-CHR^g-C(O)-, -NR^k-CHR^g-C(0)-, -NR^k-C(O)-CHR^g-, or -C(0)-NR^k-CHR^g-C(0)-;

R^g, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, -C(O)R^C, -OC(O)R⁰, -SC(O)R⁰, -NR^kC(0)R^c, -C(S)R⁰, -OC(S)R⁰, -SC(S)R°,-NR^kC(S)R^c, -C(NR)R⁰, -OC(NR)R⁰, -SC(NR)R⁰, -NR^kC(NR)R°, -SO₂R⁰, -S(O)R⁰, -NR^kS0₂R^c, -OS(O)₂R⁰, -OP(O)R⁰R⁰, -P(O)R⁰R⁰, halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;

R^h and R", for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R and R^J taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;

R , for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; m, for each occurrence, is independently 1, 2, 3, or 4; n, for each occurrence, is independently O, 1, 2, 3, 4, 5, 6, or 7; p, for each occurrence, is independently O, 1, or 2; and q, for each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, or 8.

155. The method of Claim 154, wherein the compound is represented by one of the following structural formulas:

(XI)

(XII)

(XIII) wherein:

X₅, X₆ and X₇ are each, independently, N or CR^g; and X₈, X₁₀, and X₁₁ are each, independently, CR^gR^g, O, S(O)_P, or NR^k.

156. The method of Claim 155, wherein the compounds are represented by formula (XI); and wherein:

U and V are N; and X₅ and X₆ are CR^g.

157. The method of Claim 156, wherein X₇ is N.

158. The method of Claim 156, wherein X₇ is CR^g.

159. The method of Claim 156, wherein w is O₅ and R' and L' are absent.

160. The method of Claim 159, wherein R" is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.

161. The method of Claim 160, wherein R" is an optionally substituted aryl or an optionally substituted heteroaryl.

162. The method of Claim 161, wherein R" is substituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH₂, a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, -S(O)_PR^c, and -C(O)R^c.

163. The method of claim 160, wherein Z is N and W is O.

164. The method of claim 160, wherein Y is a covalent bond, O, S, N(R^k), or CH₂, and n is 0, 1, 2, 3, or 4.

165. The method of Claim 164, wherein G is absent.

166. The method of Claim 164, wherein G is >C=N-R, -NR^kC(O)-, -C(O)NR^k-, -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(O)O-, -OC(O)NR^k- -NR^kC(S)O-, -OC(S)NR¹S -NR^kC(NR)NR^k-, -NR^kC(0)NR^k-, -NR^kC(S)NR^k-, -NR^kS(O)₂NR^k-, -C(NR)NR¹S or -NR^kCR^gR^gC(O)-.

167. The method of claim 165, wherein R₃ is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, OR^k, SR^k, orNR^hR^j.

168. The method of claim 167, wherein R₃ is optionally substituted aryl or optionally substituted heteroaryl.

169. The method of claim 168, wherein R₃ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl., an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

170. The method of claim 167, wherein R₃ is an optionally substituted heterocycloalkyl.

171. The method of claim 170, wherein R₃ is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2- oxopiperazinyl, an optionally substituted 2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3-dioxolanyl, an optionally substituted [l,4]dioxanyl, an optionally substituted 2-oxo-imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.

172. The method of claim 167, wherein R₃ is -OR^k or -NR^hR^j, and R^f, R^h and R^j are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R⁰.

173. The method of Claim 165, wherein R₃ is -C(O)OR^k, -OC(O)R^k, -C(0)NR^hR^j, -NR^kC(0)R^k, -C(S)OR^k, -OC(S)R^k, -NR^kC(0)NR^hR^j, -NR^kC(S)NR^hR^j, -C(O)NRhRj, -S(O)₂R^k, -S(O)₂NR^hR^j, -OC(O)NR^hR^j, or -NR^kC(0)0R^k.

174. The method of Claim 156, wherein: w is 1;

X₄ is O, S, or NR_k; and

R' and U are absent.

175. The method of Claim 174, wherein R" is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.

176. The method of Claim 175, wherein R" is an optionally substituted aryl or an optionally substituted heteroaryl.

177. The method of Claim 176, wherein R" is substitituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH₂, a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, or -C(O)R^y, wherein R^y is a lower alkyl.

178. The method of claim 175, wherein Z is N and W is O.

179. The method of claim 175, wherein Y is a covalent bond, O, S, N(R^k), or CH₂, and n is O, 1, 2, 3, or 4.

180. The method of Claim 179, wherein G is absent.

181. The method of Claim 179, wherein G is >C=N-R, -NR^kC(O)-, -C(O)NR^k-, -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(0)0-, -OC(O)NR¹S -NR^kC(S)O-, -OC(S)NR¹S -NR^kC(NR)NR^k-, -NR^kC(0)NR^k-, -NR^kC(S)NR^k-, -NR^kS(0)₂NR^k-, -C(NR)NR^k-, or -NR^kCR^εR^gC(0)-.

182. The method of claim 180, wherein R₃ is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, 0R^k, SR^k, orNR^hR^j.

183. The method of claim 182, wherein R₃ is optionally substituted aryl or optionally substituted heteroaryl.

184. The method of claim 183, wherein R₃ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

185. The method of claim 182, wherein R₃ is an optionally substituted heterocycloalkyl.

186. The method of claim 185, wherein R₃ is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2- oxopiperazinyl, an optionally substituted 2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3-dioxolanyl, an optionally substituted [l,4]dioxanyl, an optionally substituted 2-oxo-imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.

187. The method of claim 182, wherein R₃ is -OR^k or -NR^hR^j, and R^f, R^h and R^j are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R^C.

188. The method of Claim 180, wherein R₃ is -C(O)OR^k, -OC(O)R^k, -C(O)NR^hR^j, -NR^kC(O)R^k, -C(S)OR^k, -OC(S)R^k, -NR^kC(O)NR^hR^j, -NR^kC(S)NR^hR^j, -C(O)NRhRj, -S(O)₂R^k, -S(O)₂NR^hR^j, -OC(O)NR^hR^j, or -NR^kC(O)OR^k. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (XIV):

(XIV) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein: ring A is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyclyl, wherein the cycloalkyl, cyclyl, heterocycloalkyl, and heterocyclycl are optionally fused to an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; each of Q, U₅ and V are independently N or CR^g, wherein at least one of Q, U, or V is N; and each CR^g may be the same or different;

Y is a covalent bond, (CH(R^g))_m, C(O), C(NR), O, S, S(O), S(O)₂, NR^k, or absent;

G is a bond, -C(0)NR^kNR^k-, -NR^kNR^kC(O)-, -NR^kN=CR^k-, -

-NR^kNR -, -N(OH)-, -NRO-, -ONR -, -C(O)-, -C(NR)-, -NR^kC(O)-, -C(O)NR^k-, -OC(O)-, -C(O)O-, -OC(O)O-, -NR^kC(0)0-, -OC(O)NR^k-, -NR^kC(S)O-, -OC(S)NR^k-, -NR^k-C(NR)-NR^k-, - NR^k-C(O)-NR^k-, -NR^k-C(S)-NR^k-, -NR^k-S(O)₂-NR^k-, -P(O)(R^c)-, -P(O)(R^c)O-, -OP(O)(R^c)-, -OP(O)(R^c)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted lieteroarylene-NR^k-, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-0-, -Si(OR^k)₂-, -B(OR^k)-, -C(NR)-NR^k-, -NR^k-CR^gR^g-C(O)-, -C(O)-ONR^k-, -C(O)-NR^kO-, -C(S)-ONR^k-, -C(S)-NR^kO-, -C(NR)-ONR^k-, -C(NR)-NR^kO, -OS(O)₂-NR^kNR^k-, -OC(O)-NR^kNR^k-, -OC(S)-NR^kNR^k-, -OC(NR)-NR^kNR^k-, -NR^kNR^kS(O)₂O-, -NR^kNR^kC(S)O-, -NR^kNR^kC(NR)O-, -OP(O)(R^C)O-, -NR^kP(O)(R^c)O-, -OP(O)(R°)NR^k-, -NR^kP(O)(R^c)NR^k-, -P(O)(R^c)NR^k-, -NR^kP(O)(R°)-,

-O-alkylene-heterocycloalkylene-NR^k-, -NR^k-CHR^s-C(O)-NR^k-CHR^g-C(O)-, -NR^k-CHR^g-C(O)-, -NR^k-C(O)-CHR^g-, or -C(O)-NR^k-CHR^g-C(O)-, provided that G is not -NR^kN=CR^k- or -CR^k=NNR^kS when n is 0 and Y is a covalent bond;

R, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)R^c, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O)₂R^c;

R₁₆, for each occurrence, is independently, H or a lower alkyl;

R₂ and R₄, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, -C(O)R^c, -OC(O)R^c, -SC(O)R^c, -NR^kC(O)R^c, -C(S)R^c, -OC(S)R^c, -SC(S)R^c, -NR^kC(S)R^c, -C(NR)R^c, -OC(NR)R^c, -SC(NR)R^c, -NR^kC(NR)R^c, -SO₂R^c, -S(O)R^c, -NR^kSO₂R^c, -OS(O)₂R^c, -OP(O)R^cR^c, -P(O)R^cR^c, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R₂ and R₄ taken together are =O, =S, or =NR;

R₃ is R^g; heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R^h and R^J taken together with the nitrogen to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;

R^k, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; m is O, 1, 2, 3, or 4; and n is O, 1, 2, 3, 4, 5, 6, or 7.

190. The method of Claim 189, wherein Q, U, and V are N.

191. The method of Claim 189, wherein one of Q, U, or V is CR^S, and the other two are N.

192. The method of Claim 191, wherein V is CR^g, Q and U are N.

193. The method of Claim 191, wherein Q is CR^g, V and U are N.

194. The method of Claim 191, wherein U is CR^g, V and Q are N.

195. The method of Claim 189, wherein one of Q, U, or V is N, and the other two are CR^S.

196. The method of Claim 195, wherein V is N, and Q and U are CR^g.

197. The method of Claim 195, wherein Q is N, and V and U are CR^S.

198. The method of Claim 195, wherein U is N and Q, and V are CR^g.

285 R₅ and R₆ are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R₅ and R₆ taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;

R^c, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or mercaptoalkoxy;

R^g, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR^k, -SR^k, -NR^hR^j, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, mercaptoalkoxy, -C(O)R^c, -OC(O)R^c, -SC(O)R^c, -NR^kC(O)R^c, -C(S)R^c, -OC(S)R^c, -SC(S)R^c,-NR^kC(S)R^c, -C(NR)R^c, -OC(NR)R^c, -SC(NR)R^c, -NR^kC(NR)R°, -S(O)₂R^c, -S(O)R^c, -NR^kS(O)₂R^c, -OS(O)₂R^c, -OP(O)R^cR^c, -P(O)R^cR^c, halo, cyano, nitro, nitroso, or azide;

R¹ and R^J, for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted

284

199. The method of Claim 190, 191, or 195 wherein -NR₅R₆ is an optionally substituted morpholino, an optionally substituted thiomorpholino, an optionally substituted 1-oxo-thiomorpholino, an optionally substituted 1,1- dioxo-thiomorpholino, an optionally substituted piperidinyl, or an optionally substituted piperazinyl.

200. The method of Claim 199, wherein ring A is a ring system selected from the group consisting of:

wherein:

Il C. M

S represents the point of attachment; rings G, H, I, and J are each, independently, an aryl or a heteroaryl; and each ring system is optionally substituted with one or more substituents.

201. The method of Claim 199, wherein ring A is a ring system selected from the group consisting of:

epresents the point of attachment; and

R_1P is H, an alkyl, an aralkyl, or an alkylcarbonyl.

202. The method of Claim 201 , wherein ring A is a ring system selected from the group consisting of:

290

203. The method of Claim 202, wherein ring A is optionally substituted with one or more substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkyl sulfanyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, halo, cyano, nitro, haloalkoxy, =0, =S, =NR, -OR^k, -NR^hR^j, -SR^k, -C(O)R^k, -C(0)NR^hR^j, -NR^kC(0)R^k, -C(O)OR^k, -OC(O)R^k, -NR^kC(0)NR^hR^j, -OC(O)NR^hR^j, -NR^kC(O)OR^k, -C(NR)R^k, -C(NR)NR^hR^j, -NR^kC(NR)R^k, -C(NR)OR^k, -OC(NR)R^k, -NR^kC(NR)NR^hR^j, -OC(NR)NR^hR^j, -NR^kC(NR)0R^k, -C(S)R^k, -C(S)NR^hR^j, -NR^kC(S)R^k, -C(S)OR^k, -OC(S)R^k, -NR^kC(S)NR^hR^j ₅ -OC(S)NR^hR^j, -NR^kC(S)OR^k, -C(O)SR^k, -SC(O)R^k, -S(O)_pR^k, -S(O)_pNR^hR^j, -OS(O)_pR^k, -S(O)_pOR^k, -OS(O)_pOR^k, -P(O)(OR^k)₂, -OP(O)(OR^k)₂, -P(S)(OR^k)₂, -SP(O)(OR^k)₂, -P(O)(SR^k)(OR^k), -OP(O)(SR^k)(OR^k), -P(O)(SR^k)₂, or -OP(O)(SR^k)₂, wherein p is 1 or 2.

204. The method of Claim 203, wherein ring A is optionally substituted with from one to three substituents selected from the group consisting of a lower alkyl, a lower alkoxy, =O, nitro, cyano, hydroxy, amino, lower alkyl amino, lower dialkyl amino, mercapto, lower alkyl sulfanyl, halo, or haloalkyl.

205. The method of Claim 199, wherein Y is O.

206. The method of Claim 199, wherein Y is a covalent bond.

207. The method of Claim 199, wherein R₃ is H.

208. The method of Claim 199, wherein R₃ is an optionally substituted aryl or an optionally substituted heteroaryl.

209. The method of claim 208, wherein R₃ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzoforyl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.

210. The method of claim 199, wherein R₃ is a hydroxy, an optionally substituted heterocycloalkyl or an optionally substituted heterocyelyl.

211. The method of Claim 210, wherein R₃ is a hydroxy, an optionally substituted morpholino, or an optionally substituted oxazolidin-2-one.

212. The method of Claim 199, wherein each of R₂ and R₄ is, independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyelyl.

213. The method of Claim 212, wherein n is 1 , 2, or 3 , and R₂ and R₄, for each occurrence are, independently, H or a lower alkyl.

214. The method of Claim 199, wherein G is absent.

215. The method of Claim 199, wherein G is an optionally substituted heteroaryl or an optionally substituted heterocyclyl.

216. The method of Claim 199, wherein G is -C(O)NHNH-, -NHNHC(O)-, - C CHH==NN--NNHH--,, --NNHH--NN==CCHH-- --NNHHNNHH-- --NNHHOO-, -0-NH-, -NR^k-0-, -CH=N-O-, - 0-N=CH-, -0-C(S)-NH-, or -NH-C(S)-O-.

217. The method of Claim 199, wherein G is -0-C(O)-NH-, -NH-C(NH)-NH-, -NR^k-C(NH)-NH-, -NR^k-C(NR^k)-NH-, -NH-C(N(CN))-NH-, -NH- C(NSO₂R^C)-NH-, -NR^k-C(NSO₂R^c)-NH-, -NH-C(NN0₂)-NH-, NH- C(NC(O)R^C)-NH-, -NH-C(O)-NH-, Or-NH-C(S)-NH-.

218. The method of Claim 199, wherein G is -NH-S(O)₂-NH-, -NR^k-S(O)₂-O-, -P(O)(R⁰)-, -P(O)(R^C)-O-, or -P(O)(R^c)-NR^k-.

219. The method of Claim 199, wherein G is an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl or an optionally substituted heterocyclyl.

220. The method of Claim 219, wherein G is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted cyclohexyl, an optionally substituted cycloheptyl, an optionally substituted aziridinyl, an optionally substituted oxiranyl, an optionally substituted azetidinyl, an optionally substituted oxetanyl, an optionally substituted morpholinyl, an optionally substituted piperazinyl or an optionally substituted piperidinyl.

221. The method of Claim 199, wherein G is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, - C(N-CN)-NH-, -Si(OH)₂-, -C(NH)-NR¹S or -NR^k-CH₂-C(0)-.

222. The method of Claim 221, wherein G is an optionally substituted imidazolyl, an optionally substituted imidazolidinone, an optionally substituted imidazolidineamine, an optionally substituted pyrrolidinyl, an optionally substituted pyrrolyl, an optionally substituted furanyl, an optionally substituted thienyl, an optionally substituted thiazolyl, an optionally substituted triazolyl, an optionally substituted oxadiazolyl, an optionally substituted thiadiazolyl, an optionally substituted pyrazolyl, an optionally substituted tetrazolyl, an optionally substituted oxazolyl, an optionally substituted isoxazolyl, an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidyl, an optionally substituted indolyl, or an optionally substituted benzothiazolyl.

223. The method of Claim 199, wherein:

Y is O or CH₂; G is absent; and n is O, 1, 2, 3 or 4.

224. The method of Claim 199, wherein:

Y is absent, O, S, NR^k, or CH₂; and n is O, 1, 2, 3, or 4.

225. The method of Claim 189, wherein the compound is represented by formula (XV):

(XV) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein: ring E is optionally substituted with one to four substituents selected from a lower alkyl, a halo, an amino, a lower alkyl amino, a lower dialkyl amino, a cyano, a nitro, a lower haloalkyl, a hydroxyl, and a lower hydroxyalkyl;

X₁₂ is O, S, S(O)₅ S(O)₂, or CR^gR^s;

Xi₃ is O, S, S(O)₅ S(O)₂, or CH₂;

Y₁ is O, S, NR^k, or CH₂;

R₁₇ and R₁₈, for each occurrence, are independently, H or a lower alkyl; or R₁₇ and R₁₈ taken together with the carbon to which they are attached form a cycloalkyl; and fis O, 1, 2, or 3.

226. The method of Claim 225, wherein Q, U, and V are N.

227. The method of Claim 225, wherein one of Q, U, or V is CR^g, and the other two are N.

228. The method of Claim 227, wherein V is CR^g, Q and U are N.

229. The method of Claim 227, wherein Q is CR^g, V and U are N.

230. The method of Claim 227, wherein U is CR^g, V and Q are N.

231. The method of Claim 225, wherein one of Q, U, or V is N, and the other two are CR^g.

232. The method of Claim 231 , wherein V is N, and Q and U are CR^g.

233. The method of Claim 231, wherein Q is N, and V and U are CR^g.

234. The method of Claim 231 , wherein U is N and Q, and V are CR^g.

235. The method of Claim 226, 227, or 231 , wherein ring A is a ring system selected from the group consisting of:

wherein:

epresents the point of attachment; rings G, H, I, and J are each, independently, an aryl or a heteroaryl; and each ring system is optionally substituted with one or more substituents.

236. The method of Claim 226, 227, or 231 , wherein ring A is a ring system selected from the group consisting of:

represents the point of attachment; and

Ri ₉ is H, an alkyl, an aralkyl, or an alkylcarbonyl.

237. The method of Claim 236, wherein ring A is a ring system selected from the group consisting of:

238. The method of Claim 237, wherein ring A is optionally substituted with one or more substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkyl sulfanyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, halo, cyano, nitro, haloalkoxy, =0, =S, =NR, -OR^k, -NR^hR^j, -SR^k, -C(O)R^k, -C(O)NR^hR^j, -NR^kC(O)R^k, -C(O)OR^k, -OC(O)R^k, -NR^kC(0)NR^hR^j, -OC(O)NR^hR^j, -NR^kC(O)OR^k, -C(NR)R^k, -C(NR)NR^hR^j, -NR^kC(NR)R^k, -C(NR)OR^k, -OC(NR)R^k, -NR^kC(NR)NR^hR^j, -OC(NR)NR^hR^j, -NR^kC(NR)OR^k, -C(S)R^k, -C(S)NR^hR^j, -NR^kC(S)R^k, -C(S)OR^k, -OC(S)R^k ₅ -NR^kC(S)NR^hR^j, -OC(S)NR^hR^j, -NR^kC(S)OR^k, -C(O)SR^k, -SC(O)R^k, -S(O)_pR^k, -S(O)_pNR^hR^j, -OS(O)_pR^k, -S(O)_pOR^k, -OS(O)_pOR^k, -P(O)(OR^k)₂, -OP(O)(OR^k)₂, -P(S)(OR^k)₂, -SP(O)(OR^k)₂, -P(O)(SR^k)(OR^k), -OP(O)(SR^k)(OR^k), -P(O)(SR^k)₂, or -OP(O)(SR^k)₂, wherein p is 1 or 2.

239. The method of Claim 238, wherein ring A is optionally substituted with from one to three substituents selected from the group consisting of a lower alkyl, a lower alkoxy, =0, nitro, cyano, hydroxy, amino, lower alkyl amino, lower dialkyl amino, mercapto, lower alkyl sulfanyl, halo, or haloalkyl.

240. The method of Claim 238, wherein:

X₁₂, X₁₃, Yi is O; and

R₁₇ and R₁₈ are each, independently, H or a lower alkyl.

241. The method of Claim 189, wherein the compound is represented by formula (XVI):

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein: ring F is optionally substituted with one or two substituents selected from a lower alkyl, a halo, an amino, a lower alkyl amino, a lower dialkyl amino, a cyano, a nitro, a lower haloalkyl, a hydroxyl, and a lower hydroxyalkyl;

X₁₃ is O, S, S(O), S(O)₂, or CH₂;

X₁₄ is O, NR^k, or CR^gR^g;

Y₁ is O, S, NR^k, or CH₂; R₁₇ and R₁₈, for each occurrence, are independently, H or a lower alkyl; or R₁₇ and R₁₈ taken together with the carbon to which they are attached form a cycloalkyl; and fis O, 1, 2, or 3.

242. The method of Claim 241 , wherein Q, U, and V are N.

243. The method of Claim 241 , wherein one of Q, U, or V is CR^g, and the other two are N.

244. The method of Claim 243 , wherein V is CR^ε, Q and U are N.

245. The method of Claim 243 , wherein Q is CR^g, V and U are N.

246. The method of Claim 243, wherein U is CR^g, V and Q are N.

247. The method of Claim 241 , wherein one of Q, U, or V is N, and the other two are CR^g.

248. The method of Claim 247, wherein V is N, and Q and U are CR^S.

249. The method of Claim 247, wherein Q is N, and V and U are CR^g.

250. The method of Claim 247, wherein U is N and Q, and V are CR^g.

251. The method of Claim 242, 243, or 247, wherein ring A is a ring system selected from the group consisting of:

wherein: represents the point of attachment;

252. The method of Claim 242, 243, or 247, wherein ring A is a ring system selected from the group consisting of:

represents the point of attachment; and

R₁₉ is H, an alkyl, an aralkyl, or an alkylcarbonyl.

253. The method of Claim 252, wherein ring A is a ring system selected from the group consisting of:

254. The method of Claim 253, wherein ring A is optionally substituted with one or more substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkyl sulfanyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, halo, cyano, nitro, haloalkoxy, =0, =S, =NR, -OR^k, -NR^hR^j, -SR^k, -C(O)R^k, -C(0)NR^hR^j, -NR^kC(O)R^k, -C(O)OR^k, -OC(O)R^k, -NR^kC(0)NR^hR^j, -OC(O)NR^hR^j, -NR^kC(O)OR^k, -C(NR)R^k, -C(NR)NR^hR^j, -NR^kC(NR)R^k, -C(NR)0R^k, -OC(NR)R^k, -NR^kC(NR)NR^hR^j, -0C(NR)NR^hR^j, -NR^kC(NR)0R^k, -C(S)R^k, -C(S)NR^hR^j, -NR^kC(S)R^k, -C(S)OR^k, -OC(S)R^k, -NR^kC(S)NR^hR^j, -OC(S)NR^hR^j, -NR^kC(S)OR^k, -C(O)SR^k, -SC(O)R^k, -S(O)_pR^k, -S(O)_pNR^hR^j, -OS(O)_pR^k, -S(O)_pOR^k, -OS(O)_pOR^k, -P(O)(OR^k)₂, -OP(O)(OR^k)₂, -P(S)(OR^k)₂, -SP(O)(OR^k)₂, -P(O)(SR^k)(OR^k), -OP(O)(SR^k)(OR^k), -P(O)(SR^k)₂, or -OP(O)(SR^k)₂, wherein p is 1 or 2.

255. The method of Claim 254, wherein ring A is optionally substituted with from one to three substituents selected from the group consisting of a lower alkyl, a lower alkoxy, =0, nitro, cyano, hydroxy, amino, lower alkyl amino, lower dialkyl amino, mercapto, lower alkyl sulfanyl, halo, or haloalkyl.

256. The method of Claim 254, wherein: X₁₃, X₁₄, and Y₁ are O; R₁₇ and R₁₈ are each, independently, H or a lower alkyl.

257. The method of Claim 189, wherein the compound is represented by formula (XVII):

X₁₃ is O, S, S(O), S(O)₂, or CH₂;

X₁₅ is -OH, -NH₂ or-SH;

Yi is O, S, NR^k, or CHa;

258. The method of Claim 257, wherein Q, U, and V are N.

259. The method of Claim 257, wherein one of Q, U, or V is CR^ε, and the other two are N.

260. The method of Claim 259, wherein V is CR^g, Q and U are N.

261. The method of Claim 259, wherein Q is CR^g, V and U are N.

262. The method of Claim 259, wherein U is CR^g, V and Q are N.

263. The method of Claim 257, wherein one of Q, U, or V is N, and the other two are CR^g.

264. The method of Claim 263, wherein V is N, and Q and U are CR^g.

265. The method of Claim 263, wherein Q is N, and V and U are CR^g.

266. The method of Claim 263 , wherein U is N and Q, and V are CR^g.

267. The method of Claim 258, 259, or 263, wherein ring A is a ring system selected from the group consisting of:

wherein:

268. The method of Claim 258, 259, or 263, wherein ring A is a ring system selected from the group consisting of:

represents the point of attachment; and R_Ϊ9 is H, an alkyl, an aralkyl, or an alkylcarbonyl.

269. The method of Claim 268, wherein ring A is a ring system selected from the group consisting of:

270. The method of Claim 269, wherein ring A is optionally substituted with one or more substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkyl sulfanyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, halo, cyano, nitro, haloalkoxy, =0, =S, =NR, -OR^k, -NR^hR^j, -SR^k, -C(O)R^k, -C(O)NR^hR^j, -NR^kC(O)R^k, -C(O)OR^k, -OC(O)R^k, -NR^kC(O)NR^hR^j, -OC(O)NR^hR^j, -NR^kC(O)OR^k, -C(NR)R^k, -C(NR)NR^hR^j, -NR^kC(NR)R^k, -C(NR)0R^k, -OC(NR)R^k, -NR^kC(NR)NR^hR^j, -OC(NR)NR^hR^j, -NR^kC(NR)0R^k, -C(S)R^k, -C(S)NR^hR^j, -NR^kC(S)R^k, -C(S)OR^k, -OC(S)R^k, -NR^kC(S)NR^hR^j, -OC(S)NR^hR^j, -NR^kC(S)OR^k, -C(O)SR^k, -SC(O)R^k, -S(O)_pR^k, -S(O)_pNR^hR^j, -OS(O)_pR^k, -S(O)_pOR^k, -OS(O)_pOR^k, -P(O)(OR^k)₂, -OP(O)(OR^k)₂, -P(S)(OR^k)₂, -SP(O)(OR^k)₂, -P(O)(SR^k)(OR^k), -OP(O)(SR^k)(OR^k), -P(O)(SR^k)₂, or -OP(O)(SR^k)₂, wherein p is 1 or 2.

271. The method of Claim 270, wherein ring A is optionally substituted with from one to three substituents selected from the group consisting of a lower alkyl, a lower alkoxy, =0, nitro, cyano, hydroxy, amino, lower alkyl amino, lower dialkyl amino, mercapto, lower alkyl sulfanyl, halo, or haloalkyl.

272. The method of Claim 270, wherein:

X₁₃ and Y₁ are O;

X₁₅ is -OH; and

R₁₇ and R₁₈ are each, independently, H or a lower alkyl.

273. The method of Claim 1 , 41 , 81 , 118, 154, or 189, wherein the cancer is leukemia, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, or retinoblastoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, esophogeal cancer, gastric cancer, hepatocellular cancer, colorectal cancer, anal carcinoma, genitourinary cancer, testicular cancer, bladder cancer, renal cell cancer, ovarian cancer, endometrial cancer, cervical cancer, breast cancer, neoplasms of endocrine organs, including the thyroid, parathyroid, tumors of adrenal medulla, pheochromocytoma, neuroblastoma, multiple endocrine neoplasia, hematologic cancers, leukemia, multiple myeloma, Hodgkins disease, non-Hodgkins lymphoma, brain cancers, craniopharyngeoma, pituitary neoplasms, astrocytomas, meningiomas, spinal cord tumors, peripheral nervous system cancers, schwannomas neuroma, acoustic neuroma, skin cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, cardiac tumors, atrial myxomas, kidney cancer, bone cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma bile duct carcinoma, choriocarcinoma, seminoma embryonal carcinoma, uterine cancer, testicular cancer, bladder carcinoma, epithelial carcinoma, glioma glioblastoma, multiforme astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, retinoblastoma, blood-borne cancers, acute lymphoblastic leukemia "ALL", acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblasts leukemia "AML", acute promyelocyte leukemia "APL", acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia "CML", chronic lymphocytic leukemia "CLL", hairy cell leukemia, multiple myeloma, acute lymphoblastic leukemia, acute myelogenous leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, Hodgkin's disease, non-Hodgkin's Lymphoma, Multiple myeloma, Waldenstrom's macroglobulinemia, Heavy chain disease, or Polycythemia vera.

274. The method of Claim 1 , 41 , 81 , 118, 154, or 189, wherein the cancer is

Hodgkin's lymphoma, Non-Hodgkin's lymphoma, squamous cell carcinoma, breast cancer, chromic myelogenous leukemia, melanoma, colorectal cancer, squamous intraepithelial lesions, adenocarcinoma, ovarian cancer, bladder cancer, lung cancer, esophageal cancer, gastric cancer, prostate cancer, vulvar carcinoma, heptacellular carcinoma, thyroid carcinoma, thyroid carcinoma, endometrial carcinoma, oral carcinoma, renal carcinoma, familial cylindromatosis, hilar cholangiocarcinoma, astrocytoma, neuroblastoma, acute lymphoblastic leukemia, acute myelogenous leukemia, acute T-cell leukemia (HTLV-I), chromic lymphocytic leukemia (CLL), Burkitts lymphoma, primary effusion lymphoma, mantle cell lymphoma, multiple myeloma, diffuse large B-cell lymphoma, follicular B-cell lymphoma, or mediastinal B- cell lymphoma.

275. The method of Claim 1, 41, 81, 118, 154, or 189, wherein the cancer is a B- cell lymphoma or leukemia.

276. The method of Claim 275, wherein the B-cell lymphoma or leukemia is B-cell chronic lymphocytic leukemia (B-CLL), small lymphocytic lymphoma (SLL), lymphoplamacytoid lymphoma, follicle center lymphoma, follicular mixed cell (FM), marginal zone B-cell lymphoma, hairy cell leukemia, plasmacytoma, B-cell prolymphocytic leukemia (B-PLL), mantle cell lymphoma, B-cell large B-cell lymphoma, precursor B-lymphoblastic leukemia, precursor B-lymphoblastic lymphoma, Burkitt's lymphoma, or high-grade B-cell lymphoma.

277. The method of Claim 275, wherein the cancer is Hodgkin's lymphoma, non- Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular B-cell lymphoma, mediastinal B-cell lympohoma, anaplastic large cell lymphoma, and extranodal marginal zone lymphoma.

278. The method of Claim 275, wherein the cancer cells are infected with Epstein Barr virus.

279. The method of Claim 1, 41, 81, 118, 154, or 189, wherein the cancer is a T- cell lymphoma or leukemia.

280. The method of Claim 279, wherein the T-cells are infected with EBV or HTLV.

281. The method of Claim 279, wherein the T-cell lymphoma or leukemia is large granular lymphocyte leukemia, adult T-cell leukemia, adult T-cell lymphoma, mycosis fungoides, T-cell chronic lymphocytic leukemia, prolymphocytic leukemia, angiocentric lymphoma, angioimmunoblastic lymphoma, precursor T-lymphblastic leukemia, or precursor T-lymphblastic lymphoma.

282. The method of Claim 280, wherein the T-cell lymphoma or leukemia is adult T-cell leukemia or lymphoma.

283. The method of Claim 1 , 41 , 81 , 118, 154, or 189, wherein c-Rel is overexpressed in the cancer cells.

284. The method of Claim 1 , 41 , 81 , 118, 154, or 189, wherein the cancer cells have ReI gene rearrangements, mutations, deletions, amplifications, or a combination thereof.

285. The method of Claim 1 , 41 , 81 , 118, 154, or 189, wherein the compound inhibits the expression of c-Rel.

286. The method of Claim 285, wherein the compound does not materially inhibit the expression of NF-κB family members other than c-Rel.

287. The method of Claim 285, wherein the compound does not materially inhibit the expression of IKB.

288. The method of Claim 1, 41, 81, 118, 154, or 189, wherein the compound inhibits the accumulation of c-Rel in the nucleus of the cancer cells.

289. The method of Claim 288, wherein the compound does not inhibit the accumulation of NF-κB family members other than c-Rel in the nucleus of the cancer cells.

290. The method of Claim 1 , 41 , 81 , 118, 154, or 189, wherein the compound inhibits DNA binding of c-Rel to a KB site in the cancer cells.

291. The method of Claim 290, wherein the compound does not inhibit the DNA binding of NF-κB family members other than c-Rel to a KB site in the cancer cells.

292. A method of treating a lymphoma or leukemia in a subject in need thereof, comprising administering to the subject a compound that inhibits the accumulation of c-Rel in the nucleus of the lymphoma or leukemia cells and does not materially inhibit the accumulation of other NF-kB family members in the nucleus of the lymphoma or leukemia cells.

293. The method of Claim 292, wherein the compound is a compound of Claim 1 , 41, 81, 118, 154, or 189.

294. The method of Claim 293, wherein the subject is a human.

295. The method of Claim 293, wherein the lymphoma or leukemia is a B-cell lymphoma or leukemia.

296. The method of Claim 295, wherein the B-cells are infected with EBV.

297. The method of Claim 295, wherein the lymphoma or leukemia is Hodgkin' s lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular B-cell lymphoma, mediastinal B-cell lympohoma, anaplastic large cell lymphoma, and extranodal marginal zone lymphoma.

298. The method of Claim 293, wherein the lymphoma or leukemia is a T-cell lymphoma or leukemia.

299. The method of Claim 298, wherein the T-cells are infected with EBV or HTLV.

300. The method of Claim 299, wherein the lymphoma or leukemia is adult T-cell leukemia or lymphoma.

301. A method of treating a lymphoma or leukemia in a subject in need thereof, comprising administering to the subject a compound that inhibits DNA binding of c-Rel to a KB site in the lymphoma or leukemia cells and does not inhibit the DNA binding of other NF-κB family members in the lymphoma or leukemia cells.

302. The method of Claim 301, wherein the compound is a compound of Claim 1, 41, 81, 118, 154, or 189.

303. The method of Claim 302, wherein the subject is a human.

304. The method of Claim 302, wherein the lymphoma or leukemia is a B-cell lymphoma or leukemia.

305. The method of Claim 304, wherein the B-cells are infected with EBV.

306. The method of Claim 304, wherein the lymphoma or leukemia is Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular B-cell lymphoma, mediastinal B-cell lympohoma, anaplastic large cell lymphoma, and extranodal marginal zone lymphoma.

307. The method of Claim 302, wherein the lymphoma or leukemia is a T-cell lymphoma or leukemia.

308. The method of Claim 307, wherein the T-cells are infected with EBV and HTLV.

309. The method of Claim 307, wherein the lymphoma or leukemia is adult T-cell leukemia or lymphoma.

310. A method of inhibiting the proliferation of and/or inducing apoptosis in B- cells, comprising contacting the B-cells with a compound that inhibits the accumulation of c-Rel in the nucleus of the cells and does not materially inhibit the accumulation of other NF-kB family members in the nucleus of cells.

311. The method of Claim 310, wherein the B-cells are a B-cell lymphoma or a B- cell leukemia.

312. The method of Claim 310, wherein the B-cells are infected with EBV.

313. The method of Claim 329, wherein the compound is a compound of Claim 1 , 41, 81, 118, 154, or 189.

314. A method of inhibiting the proliferation of and/or inducing apoptosis in B- cells, comprising contacting B-cells with a compound that inhibits DNA binding of c-Rel to a KB site and does not inhibit the DNA binding of other NF-κB family members.

315. The method of Claim 314, wherein the B-cells are a B-cell lymphoma or a B- cell leukemia.

316. The method of Claim 314, wherein the B-cells are infected with EBV.

317. The method of Claim 314, wherein the compound is a compound of Claim 1 , 41, 81, 118, 154, or 189.

318. The method of Claim 1, 41, 81, 118, 154, or 189, wherein the cancer is infected with Epstein Barr virus.

319. The method of Claim 343, wherein the cancer is Burkitt's lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, breast cancer, gastric cancer, post-transplant lymphoproliferative disorder, AIDS-associated lymphoma, or Leiomyosarcoma.