Therapeutic compounds and related methods of use

BACKGROUND OF INVENTION

Histone acetyl transferases, also known as HATsn are enzymes that acetylate histone proteins by transferring an acetyl group from acetyl CoA. Histone acetylation is generally linked to transcriptional activation. Acetylation and other posttranslational modifications of histones generate binding sites for specific protein-protein interaction domains, such as the acetyl-lysine binding bromodomain. Inhibition of HAT can be useful in the treatment of various diseases or disorders. Examplary HAT inhibitors include curcumin, garcinol, and anacardic acid.

SUMMARY OF INVENTION

The inventors have discovered that certain compounds are modulators of histone acetyl transferase (HAT) (e.g., inhibitors of HAT). Modulators of HAT (e.g., inhibitors of HAT) can be used to treat various disorders. Exemplary HATs include the following: CBP (CREB-binding protein), p300, pCAF, hGCN5, and ATF2 (activating transcription factor 2).

The inventors have discovered that, surprisingly, compounds described herein are modulators, generally inhibitors, of a HAT. This discovery allows optimization of a variety of methods related to these compounds. Of particular importance the discovery allows implementation and/or optimization of methods related to the clinical use of the compounds. E.g., the discovery allows more informed patient selection, instruction, treatment, selection of treatment regimes and monitoring and evaluation of patients. The discovery also allows optimization of making, testing, evaluating, and developing the compounds as well as optimized compositions, preparations and reactions, assay mixtures and reference standards which include these compounds.

The invention allows the selection of patients for treatment with a compound described herein, based on an appreciated need, of the patient, of inhibition of a HAT.

Accordingly, in one aspect, the invention features, a method of selecting or treating a patient for a condition, e.g., cancer, diabetes, or obesity. The method includes:

selecting a patient on the basis of that patient being in need of the inhibition of a HAT for the treatment of the condition; and

selecting, and preferably administering to the subject, a compound of described herein.

The selection step involves selecting the patient on the basis of the appreciation of the patient's need of inhibition of a HAT, as opposed to merely selecting a patient in need of inhibition of a HAT or even selecting a HAT inhibitor based on some basis other than being in need of inhibition of a HAT.

Conditions treatable with methods described herein include chronic and acute conditions and disorders. In embodiments the can be conditions characterized by unwanted HAT activity or unwanted levels of acetylation of a HAT substrate.

The invention also allows optimized evaluation of compounds described herein based on the HAT inhibitory activity of the compounds.

Accordingly, in another aspect, the invention includes a method of evaluating a compound described herein. The method includes:

providing a compound described herein;

providing a value related to the ability of the compound to inhibit a HAT; and

optionally, comparing the value with a reference value, thereby evaluating the compound.

In an embodiment the method further includes selecting the compound, or a batch from which the compound is taken, e.g., for release as an approved drug.

The invention allows optimal characterization and transmittal of information about the characteristics of the compounds described herein.

Accordingly, in another aspect, the invention features a method of identifying characterizing, describing, or providing information on a compound described herein.

The method includes:

identifying, characterizing, describing, or providing information that the drug is a HAT inhibitor, and

identifying the drug as a compound described herein.

In an embodiment of this or any other method herein, the compound is an approved drug.

In another aspect, the invention features, a method of instructing an entity (e.g., a care provider), on the use of a drug of a compound described herein, or of selecting a patient. The method includes:

instructing the entity to select a patient on the basis of that patient being in need of the inhibition of a HAT for the treatment of the condition; and

instructing the entity to provide, e.g., administer a compound described herein, to the patient.

Methods of the invention allow administration of a compound described herein to a patient for treatment of a condition described herein while taking steps to minimize unwanted effects or contraindicated situations.

In another aspect, the invention provides, a method of providing an entity other than the patient, e.g., caregiver, instructions on treating a condition described herein, e.g., cancer, diabetes, or obesity with a compound described herein. The method includes:

instructing the entity to provide or administer a compound described herein; and

instructing the entity to monitor for a side effect that is associated with inhibition of a HAT.

In some embodiments, the side effect is not associated with an HDAC (e.g., a SIRT such as SIRT1).

In another aspect, the invention provides, a method of providing a patient instructions on treating a condition described herein, e.g., cancer, diabetes, or obesity with a compound described herein. The method includes:

instructing the patient to accept or self administer a compound described herein; and

instructing the patient to monitor for a side effect that is associated with inhibition of a HAT, and optionally report any side effect to a caregiver.

In some embodiments, the side effect is not associated with an HDAC (e.g., a SIRT such as SIRT1).

In another aspect, the invention provides, a method of providing an entity other than the patient, e.g., a caregiver, instructions on treating a condition described herein with a compound described herein. The method includes:

instructing the entity to provide or administer a compound described herein; and

instructing the patient or a caregiver to avoid compounds known to interact adversely with an inhibitor of a HAT.

In another aspect, the invention features, a method of treating a patient with a compound described herein for a condition described herein. The method includes:

administering to the patient a compound described herein for the treatment of a condition described herein; and

instructing the patient or a caregiver to avoid compounds known to interact adversely with an inhibitor of a HAT.

A method of treating a patient, the method comprising administering a compound described herein and an activator of an HDAC (e.g., an activator of SIRT, such as SIRT1).

In another aspect, the invention includes a method of approving transfer of payment. The method includes: communicating to the reimburser that the subject is in need of a compound that inhibits a HAT, and instructing or requesting the reimburser to approve or transfer of payment for the treatment of the subject with compound described herein for a disorder described herein.

In another aspect, the invention features, a method of analyzing a preparation of a compound described herein, the method comprising providing the compound described herein and determining whether the compound described herein inhibits HAT, thereby analyzing the drug.

In another aspect, the invention features, a preparation or pharmaceutical preparation of a drug disclosed herein, the preparation comprising at least one carrier, preservative, or excipient, which is suitable for or has been selected for being suitable for an inhibitor of HAT. In an embodiment the preparation excludes CoA co-enzyme, e.g., acetyl-CoA. In an embodiment the preparation excludes a component which would antagonize, interfere with, neutralize, or substantially reduce the effectiveness of a HAT inhibitor but optimally would not antagonize, interfere with, neutralize, or substantially reduce the effectiveness of a sirtuin activator.

In another aspect, the invention features, a reaction mixture for evaluating ability of a composition described herein for inhibiting a HAT. In an embodiment it includes a compound described herein and HAT, or a purified HAT. In an embodiment, the mixture is substantially free of an activator of a sirtuin.

A cell culture comprising a compound described herein and a recombinantly produced HAT.

A method of instructing or facilitating a first party, e.g., a caregiver, a patient, a retailer, or wholesaler, on a use of a drug, the method comprising, instructing the first party that the drug is a HAT inhibitor and instructing the first party that the drug is a compound described herein.

In one aspect, the invention features a method for monitoring the progress of therapeutic treatment with a compound described herein. The method includes determining the level of acetylation of one or more HAT substrates in a biological sample from a subject being greated with a compound described herein, wherein a change in the level of acetylation of the HAT substrate relative to a control is indicative of therapeutic modulation of HAT in the subject. Exemplary HAT substrates include p53 (368-386), which is a cubstrate of CBP and p300 or histone H3 peptide, which is a substrate for pCAF and hGCN5.

In one aspect, the invention features a method for detecting modulation of a HAT in a mammal. The method includes: obtaining a biological sample from a subject that has received a compound described herein, and determining the level of acetylation of one or more HAT substrates in the sample, wherein a change in the level of acetylation of the one or more HAT substrates as compared to a control is indicative of HAT modulation in the mammal. Exemplary HAT substrates include p53 (368-386), which is a cubstrate of CBP and p300 or histone H3 peptide, which is a substrate for pCAF and hGCN5.

In one aspect, the invention features a method of identifying a subject in need of treatment with a HAT inhibiting compound. The method includes determining the level of acetylation of one or more HAT substrates in a biological sample from the subject, wherein a higher level of acetylation in a HAT substrate as compared to a control is indicative of a subject in need of treatment with a HAT inhibiting compound. Exemplary HAT substrates include p53 (368-386), which is a cubstrate of CBP and p300 or histone H3 peptide, which is a substrate for pCAF and hGCN5.

Provided herein are novel modulating compounds and methods of use thereof.

In one aspect, the invention provides modulating compounds of Formula (I):

or a salt thereof; where:

Ring A is optionally substituted, fused to another ring or both; and

Ring B is substituted with at least one carboxy, substituted or unsubstituted arylcarboxamine, substituted or unsubstituted aralkylcarboxamine, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclylcarbonylethenyl, or polycyclic aryl group or is fused to an aryl ring and is optionally substituted by one or more additional groups.

In another aspect, the invention provides sirtuin-modulating compounds of Formula (II):

or a salt thereof, where:

Ring A is optionally substituted;

R₁, R₂, R₃and R₄are independently selected from the group consisting of —H, halogen, —OR₅, —CN, —CO₂R₅, —OCOR₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)R₅, —S(O)_nOR₅, —S(O)_nNR₅R₆, —NR₅R₄, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group; and

n is 1 or 2.

In yet another aspect, the invention provides modulating compounds of Formula (III):

or a salt thereof, where:

Ring A is optionally substituted;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

R₇, R₉, R₁₀and R₁₁are independently selected from the group consisting of —H, halogen, —R₅, —OR₅, —CN, —CO₂R₅, —OCOR₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)_nR₅, —S(O)_nOR₅, —S(O)_nNR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₈is a polycyclic aryl group; and

n is 1 or 2.

In another aspect, the invention provides modulating compounds of Formula (IV):

Ar-L-J-M-K-Ar′ (IV)

or a salt thereof, wherein:

each Ar and Ar′ is independently an optionally substituted carbocyclic or heterocyclic aryl group;

L is an optionally substituted carbocyclic or heterocyclic arylene group;

each J and K is independently NR₁′, O, S, or is optionally independently absent; or when J is NR₁′, R₁′ is a C1-C4 alkylene or C2-C4 alkenylene attached to Ar′ to form a ring fused to Ar′; or when K is NR₁′, R₁′ is a C1-C4 alkylene or C2-C4 alkenylene attached to L to form a ring fused to L;

each M is C(O), S(O), S(O)₂, or CR₁′R₁′;

each R₁′ is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₅′; halo; haloalkyl; CF₃; SR₂′; OR₂′; NR₂′R₂′; NR₂′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)C(O)R₂′; C(O)NR₂′R₂′; OC(O)R₂′; S(O)₂R₂′; S(O)₂NR₂′R₂; NR₂′C(O)NR₂′R₂; NR₂′C(O)C(O)R₂′; NR₂′C(O)R₂′; NR₂′(COOR₂′); NR₂′C(O)R₅′; NR₂S(O)₂NR₂′R₂′; NR₂′S(O)₂R₂′, NR₂′S(O)₂R₅′; NR₂C(O)C(O)NR₂′R₂′; NR₂′C(O)C(O)NR₂′R₃′; C1-C10 alkyl substituted with aryl, R₄′ or R₅′; or C2-C10 alkenyl substituted with aryl, R₄′ or R₅′;

each R₂′ is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl R₆′; C1-C10 alkyl substituted with 1-3 independent aryl, R₄′ or R₆′ groups; C3-C10 cycloalkyl substituted with 1-3 independent aryl, R₄′ or R₆′ groups; or C2-C10 alkenyl substituted with 1-3 independent aryl, R₄′ or R₆′;

each R₃′ is independently C(O)R₂′, COOR₂′, or S(O)₂R₂′;

each R₄′ is independently halo, CF₃, SR₇′, OR₇′, OC(O)R₇′, NR₇′R₇′, NR₇′R₈′, NR₈′R₉′, COOR₇′, NO₂, CN, C(O)R₇′, or C(O)NR₇′R₇′;

each R₅′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₆′; halo; sulfur, oxygen; CF₃; haloalkyl; SR₂′; OR₂′; OC(O)R₂′; NR₂′R₂′; NR₂′R₃′; NR₃′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)NR₂′R₂′; C1-C10 alkyl substituted with 1-3 independent R₄′, R₆′, or aryl; or C2-C10 alkenyl substituted with 1-3 independent R₄′, R₆′, or aryl;

each R₆′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur, oxygen; CF₃; haloalkyl; SR₇′; OR₇′; NR₇′R₇′; NR₇′R₈′; NR₈′R₈′; COOR₇; NO₂; CN; C(O)R₇′; or C(O)NR₇′R₇′;

each R₇′ is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀; NR₁₀′OR₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′;

each R₈′ is independently C(O)R₇′, COOR₇′, or S(O)₂R₇′;

each R₉′ is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′;

each R₁₀′ is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; C1-C10 alkyl optionally substituted with halo, CF₃, OR₁₁′, SR₁₁′, NR₁₁′R₁₁′, COOR₁₁′, NO₂, CN; or phenyl optionally substituted with halo, CF₃, OR₁₁′, SR₁₁′, NR₁₁′R₁₁′, COOR₁₁′, NO₂, CN;

each R₁₁′ is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl; each haloalkyl is independently a C1-C10 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group; and

each aryl is independently optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R₆′; halo; haloalkyl; CF₃; OR₉′; SR₉′; NR₉′R₉′; COOR₉′; NO₂; CN; C(O)R₉′; C(O)C(O)R₉′; C(O)NR₉′R₉′; S(O)₂R₉′; N(R₉′)C(O)R₉′; N(R₉′)(COOR₉′); N(R₉′)S(O)₂R₉′; S(O)₂NR₉′R₉′; OC(O)R₉′; NR₉′C(O)NR₉′R₉′; NR₉′C(O)C(O)R₉′; NR₉′C(O)R₆′; NR₉′S(O)₂NR₉′R₉′; NR₉′S(O)₂R₆′; NR₉′C(O)C(O)NR₉′R₉′; C1-C10 alkyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; C2-C10 alkenyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉, SR₉′, NR₉′R₉, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′; NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; or R₉′.

In a further aspect, the invention provide -modulating compounds of Formula (IVa):

Het-L-Q-Ar′ (IVa)

or a salt thereof, where:

Het is an optionally substituted heterocyclic aryl group;

L is an optionally substituted carbocyclic or heterocyclic arylene group;

Ar′ is an optionally substituted carbocyclic or heterocyclic aryl group; and

Q is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(—NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′—CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—CR₁′R₁′—C(O)—NR₁′, —NR₁′—C(O)—CR₁′—CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—,

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl, wherein:

when Het is a polycyclic heteroaryl, L is an optionally substituted phenylene, Q and Het are attached to L in a meta orientation, and Ar′ is optionally substituted phenyl; then Q is not —NH—C(O)—.

In still yet another aspect, the invention provides modulating compounds of Formula (V):

or a salt thereof wherein:

Ring A is optionally substituted with at least one R₁′ group;

Y₁, Y₂, Y₃, Y₄, and Y₅are independently R₁′;

each R₁′ is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₅′; halo; haloalkyl; CF₃; SR₂′; OR₂′; NR₂′R₂′; NR₂′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)C(O)R₂′; C(O)NR₂′R₂; OC(O)R₂′; S(O)₂R₂′; S(O)₂NR₂′R₂; NR₂′C(O)NR₂′R₂′; NR₂′C(O)C(O)R₂′; NR₂′C(O)R₂′; NR₂′(COOR₂′); NR₂′C(O)R₅′; NR₂′S(O)₂NR₂′R₂′; NR₂′S(O)₂R₂′; NR₂′S(O)₂R₅′; NR₂′C(O)C(O)NR₂′R₂′; NR₂′ C(O)C(O)NR₂′R₃′; C1-C10 alkyl substituted with aryl, R₄′ or R₅′; or C2-C10 alkenyl substituted with aryl, R₄′ or R₅′;

each R₂′ is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₆′; C1-C10 alkyl substituted with 1-3 independent aryl, R₄′ or R₆′ groups; C3-C10 cycloalkyl substituted with 1-3 independent aryl, R₄′ or R₆′ groups; or C2-C10 alkenyl substituted with 1-3 independent aryl, R₄′ or R₆′;

each R₃′ is independently C(O)R₂′, COOR₂′, or S(O)₂R₂′;

each R₄′ is independently halo, CF₃, SR₇, OR₇′, OC(O)R₇′, NR₇′R₇, NR₇′R₅′, NR₈′R₉′, COOR₇′, NO₂, CN, C(O)R₇′, or C(O)NR₇′R₇′;

each R₅′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₆′; halo; sulfur, oxygen; CF₃; haloalkyl; SR₂′ OR₂′; OC(O)R₂′; NR₂′R₂′; NR₂′R₃′; NR₃′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)NR₂′R₂′; C1-C10 alkyl substituted with 1-3 independent R₄′, R₆′, or aryl; or C2-C10 alkenyl substituted with 1-3 independent R₄′, R₆′, or aryl;

each R₆′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF₃; haloalkyl; SR₇′; OR₇′; NR₇′R₇′; NR₇′R₈′; NR₈′R₈′; COOR₇′; NO₂; CN; C(O)R₇′; or C(O)NR₇′R₇′;

each R₇′ is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′;

each R₈′ is independently C(O)R₇′, COOR₇′, or S(O)₂R₇′;

each R₉′ is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′;

each R₁₁′ is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;

each aryl is independently a 5- to 7-membered monocyclic ring system or a 9- to 12-membered bicyclic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R₆′; halo; haloalkyl; CF₃; OR₉′; SR₉′; NR₉′R₉′; COOR₉′; NO₂; CN; C(O)R₉′; C(O)C(O)R₉′; C(O)NR₉′R₉′; S(O)₂R₉′; N(R₉′)C(O)R₉′; N(R₉′)(COOR₉′); N(R₉′)S(O)₂R₉′; S(O)₂NR₉′R₉′; OC(O)R₉′; NR₉′C(O)NR₉′R₉′; NR₉′C(O)C(O)R₉′; NR₉′C(O)R₉′; NR₉′S(O)₂NR₉′R₉′; NR₉′S(O)₂R₆′; NR₉′C(O)C(O)NR₉′R₉′; C1-C10 alkyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; C2-C10 alkenyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; or R₉′.

In one aspect, the invention provides modulating compounds of Structural Formula (VI):

or a salt thereof, wherein:

Het is an optionally substituted heterocyclic aryl group; and

Ar′ is an optionally substituted carbocyclic or heterocyclic aryl group.

The invention also includes prodrugs and metabolites of the compounds disclosed herein.

In another aspect, the invention provides -modulating compounds of Structural Formula (VII):

or a salt thereof, wherein:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′═CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that said compound is not:

that when R¹⁹is

and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In certain embodiments, compounds of Structural Formula (VII) have the following values:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR², or CR₁′, wherein:

each R²⁰is independently selected from H or a solubilizing group;

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and

zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

said compound is not:

when X₉and X₉are each independently selected from CR²⁰or CR₁′, R¹⁹is

and each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰, or CR₁′, then:

- a) at least one of X₈and X₉is not CH; or
- b) at least one of Z₁₀, Z₁₁, Z₁₂and Z₁₃is CR²⁰, wherein R²⁰is a solubilizing group.

In yet another embodiment, the invention provides modulating compounds of Structural Formula (VIII):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R₁′ is methyl, and R²¹is —NH—C(O)—, R³¹is not

1-methoxynaphthyl; 2-methoxynaphthyl; or unsubstituted 2-thienyl;

when R₁′ is methyl and R²¹is —NH—C(O)—CH═CH—, R³¹is not

when R₁′ is methyl, and R²¹is —NH—C(O)—CH—O—, R³¹is not unsubstituted naphthyl; 2-methoxy, 4-nitrophenyl; 4-chloro, 2-methylphenyl; or 4-t-butylphenyl; and

when R²¹is —NH—C(O)—, R³¹is not optionally substituted phenyl.

In a further embodiment, the invention provides -modulating compounds of Structural Formula (IX):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R⁵⁰is selected from 2,3-dimethoxyphenyl, phenoxyphenyl, 2-methyl-3-methoxyphenyl, 2-methoxy-4-methylphenyl, or phenyl substituted with 1 to 3 substituents, wherein one of said substituents is a solubilizing group; with the provisos that R⁵⁰is not substituted simultaneously with a solubilizing group and a nitro group, and R⁵⁰is not singly substituted at the 4-position with cyclic solubilizing group or at the 2-position with a morpholino group.

In one aspect, the invention provides modulating compounds of Structural Formula (X):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R⁵¹is selected from an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, or an optionally substituted naphthyl, wherein R⁵¹is not chloro-benzo[b]thienyl, unsubstituted benzodioxolyl, unsubstituted benzofuranyl, methyl-benzofuranyl, unsubstituted furanyl, phenyl-, bromo-, or nitro-furyl, chlorophenyl-isoxazolyl, oxobenzopyranyl, unsubstituted naphthyl, methoxy-, methyl-, or halo-naphthyl, unsubstituted thienyl, unsubstituted pyridinyl, or chloropyridinyl.

In another aspect, the invention provide modulating compounds of Structural Formula (XI):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²²is selected from —NR²³—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₇′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O— or —NR₁′—C(O)—CR₁′R₁′—, wherein R²³is an optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²²is —NH—C(O)—CH═CH—, R³¹is not unsubstituted furyl, 5-(2-methyl-3-chlorophenyl)-furanyl, 2,4-dichlorophenyl, 3,5-dichloro-2-methoxyphenyl, 3-nitrophenyl, 4-chlorophenyl, 4-chloro-3-nitrophenyl, 4-isopropylphenyl, 4-methoxyphenyl, 2-methoxy-5-bromophenyl, or unsubstituted phenyl;

when R²²is —NH—C(O)—CH₂—, R³¹is not 3,4-dimethoxyphenyl, 4-chlorophenyl, or unsubstituted phenyl;

when R²²is —NH—C(O)—CH₂—O—, R³¹is not 2,4-dimethyl-6-nitrophenyl, 2- or 4-nitrophenyl, 4-cyclohexylphenyl, 4-methoxyphenyl, unsubstituted naphthyl, or unsubstituted phenyl, or phenyl monosubstituted, disubstituted or trisubstituted solely with substituents selected from straight- or branched-chain alkyl or halo;

when R²²is —NH—C(O)—CH(CH₃)—O—, R³¹is not 2,4-dichlorophenyl, 4-chlorophenyl, or unsubstituted phenyl; and

when R²²is —NH—S(O)₂—, R³¹is not unsubstituted phenyl.

In yet another aspect, the invention provides modulating compounds of Structural Formula (XII):

or a salt thereof, wherein:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—, —NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂O—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that when R¹⁹is

Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In certain embodiments, the compounds of Structural Formula (XI) have the following values:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′—CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O— or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that:

when X₇is N, R¹⁹is

and each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰, or CR₁′, then:

- a) at least one of X, X₉or X₁₀is C—(C₁-C₃straight or branched alkyl) or C-(solubilizing group); or
- b) at least one of Z₁₀, Z₁₁, Z₁₂and Z₁₃is CR²⁰, wherein R²⁰is a solubilizing group.

In a further aspect, the invention provides compounds of Structural Formula (XIII).

or a s thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—; —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′—CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—, R³¹is not unsubstituted furyl, 5-bromofuryl, unsubstituted phenyl, phenyl monosubstituted with halo or methyl, 3- or 4-methoxyphenyl, 4-butoxyphenyl, 4-t-butylphenyl, 3-trifluoromethylphenyl, 2-benzoylphenyl, 2- or 4-ethoxyphenyl, 2,3-, 2,4-, 3,4-, or 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,4- or 2-6 difluorophenyl, 3,4-dioxymethylene phenyl, 3,4- or 3,5-dimethylphenyl, 2-chloro-5-bromophenyl, 2-methoxy-5-chlorophenyl, unsubstituted quinolinyl, thiazolyl substituted simultaneously with methyl and phenyl, or ethoxy-substituted pyridinyl;

when R²¹is —NH—C(O)—CH(CH₂—CH₃)—, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH₂—, R³¹is not unsubstituted phenyl, 3-methylphenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl or 4-methoxyphenyl;

when R²¹is —NH—C(O)—CH₂—O—, R³¹is not unsubstituted phenyl or 4-chlorophenyl; and

when R²¹is —NH—S(O)₂—, R³¹is not 3,4-dioxymethylene phenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2,4- or 3,4-dimethylphenyl, 2,5-difluorophenyl, 2,5- or 3,4-dimethoxyphenyl, fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-ethylphenyl, 4-methylphenyl, 3-methyl-4-methoxyphenyl, unsubstituted phenyl, unsubstituted pyridinyl, unsubstituted thienyl, chloro-substituted thienyl, or methyl-substituted benzothiazolyl.

In one aspect, the invention provides -modulating compounds of Structural Formula (XIV):

or a salt thereof; wherein:

each of R²³and R²⁴is independently selected from H, —CH₃or a solubilizing group;

R²⁵is selected from H, or a solubilizing group; and

R¹⁹is selected from:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group; and
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;
- each R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′, —CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic hetero r

- wherein when R¹⁹is

R²¹is —NH—C(O)— and R²⁵is —H, R³¹is not an optionally substituted phenyl group, and wherein said compound is not 2-chloro-N-[3-[3-(cyclohexylamino)imidazo[1,2-a]pyridin-2-yl]phenyl]-4-nitrobenzamide.

In another aspect, the invention provides modulating compounds of Structural Formula (XV):

or a salt thereof; wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₃′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′R₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is selected from an optionally substituted bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein:

when R²¹is —NH—C(O)—, R³²is not unsubstituted 2-furyl, 2-(3-bromofuryl), unsubstituted 2-thienyl, unsubstituted 3-pyridyl, unsubstituted 4-pyridyl,

and

when R²¹is —NR₁′—S(O)₂—, R³²is not unsubstituted 2-thienyl or unsubstituted naphthyl.

In yet another aspect, the invention provides modulating compounds of Structural Formula (XVI):

or a salt thereof, wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is an optionally substituted phenyl, wherein:

when R²¹is —NH—C(O)—, R³³is a substituted phenyl other than phenyl singly substituted with halo, methyl, nitro or methoxy; 2-carboxyphenyl; 4-n-pentylphenyl; 4-ethoxyphenyl; 2-carboxy-3-nitrophenyl; 2-chloro-4-nitrophenyl; 2-methoxy-5-ethylphenyl; 2,4-dimethoxyphenyl; 3,4,5-trimethoxyphenyl; 2,4 dichlorophenyl; 2,6-difluorophenyl; 3,5-dinitrophenyl; or 3,4-dimethylphenyl;

when R²¹is —NR₁′—C(O)—CR₁′R₁′— or —NH—C(O)—CH(CH₃)—O, R³³is a substituted phenyl;

when R²¹is —NH—C(O)—CH₂, R³³is not unsubstituted phenyl, 4-methoxyphenyl; 3,4-dimethoxyphenyl or 4-chlorophenyl;

when R²¹is —NH—C(O)—CH₂—O, R³³is not 2,4-bis(1,1-dimethylpropyl)phenyl;

when R²¹is —NH—C(O)—NH—, R³³is not 4-methoxyphenyl; and

when R²¹is —NH—S(O)₂—, R³³is a substituted phenyl other than 3-methylphenyl, 3-trifluoromethylphenyl, 2,4,5- or 2,4,6-trimethylphenyl, 2,4- or 3,4-dimethylphenyl, 2,5- or 3,4-dimethoxyphenyl, 2,5-dimethoxy-4-chlorophenyl, 3,6-dimethoxy, 4-methylphenyl, 2,5- or 3,4-dichlorophenyl, 2,5-diethoxyphenyl, 2-methyl-5-nitrophenyl, 2-ethoxy-5-bromophenyl, 2-methoxy-5-bromophenyl, 2-methoxy-3,4-dichlorophenyl, 2-methoxy-4-methyl-5-bromophenyl, 3,5-dinitro-4-methylphenyl, 3-methyl-4-methoxyphenyl, 3-nitro-4-methylphenyl, 3-methoxy-4-halophenyl, 3-methoxy-5-chlorophenyl, 4-n-butoxyphenyl, 4-halophenyl, 4-ethylphenyl, 4-methylphenyl, 4-nitrophenyl, 4-ethoxyphenyl, 4-acetylaminophenyl, 4-methoxyphenyl, 4-t-butylphenyl, or para-biphenyl.

In a further aspect, the invention provides -modulating compounds of Structural Formula (XVII):

or a salt thereof, wherein:

each of R²³and R²⁴is independently selected from H or —CH₃, wherein at least one of R²³and R²⁴is H; and

R²⁹is phenyl substituted with:

a) two —O—CH₃groups;

b) three —O—CH₃groups located at the 2, 3 and 4 positions; or

c) one —N(CH₃)₂group; and;

d) when R²³is CH₃, one —O—CH₃group at the 2 or 3 position, wherein R²⁹is optionally additionally substituted with a solubilizing group.

In one aspect, the invention provides modulating compounds of Structural Formula (XVIII):

or a salt thereof, wherein

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′,

wherein:

zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group; and

zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;

each R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₂′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁₁—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein each R₁′ is independently selected from H optionally substituted C₁-C₃straight or branched alkyl; and

- R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that when R¹⁹is

Z₁₀, Z₁₁, Z₁₁, Z₁₂and Z₁₃are each CH, R²⁰is H, and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In another aspect, the invention provides -modulating compounds of Structural Formula (XX):

or a salt thereof, rein

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′,

wherein:

- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group; and
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;

each R²⁰is independently selected from H or a solubilizing group;

R^20ais independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂O—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁₁—CR₁′R₁₁—, —NR₁′—C(O)—O—,

wherein

- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein when R¹⁹is

and Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, R^20ais a solubilizing group.

In yet another aspect, the invention provides modulating compounds of Structural Formula (XXI):

or a salt thereof, wherein

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₂′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—

wherein

- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is an optionally substituted monocyclic or bicyclic heteroaryl, or an optionally substituted bicyclic aryl, wherein:

when R²¹is —NH—C(O)—CH₂—, R³²is not unsubstituted thien-2-yl;

when R²¹is —NH—C(O)—, R³²is not furan-2-yl, 5-bromofuran-2-yl, or 2-phenyl-4-methylthiazol-5-yl;

when R²¹is —NH—S(O)₂—, R³²is not unsubstituted naphthyl or 5-chlorothien-2-yl.

In a further aspect, the invention provides modulating compounds of Structural Formula (XXII):

or a salt thereof, wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—R₁′—CR₁′R₁′—CR₁′R₁′, —NR₁′—C(O)—O—,

wherein each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is an optionally substituted phenyl, wherein:

when R²¹is —NR₁′—C(O)—, R₁′ is not H;

when R²¹is —NH—C(O)—CH₂or —NH—C(O)—CH₂—O—, R³³is not unsubstituted phenyl or 4-halophenyl; and

when R²¹is —NH—S(O)₂—, R³³is not unsubstituted phenyl, 2,4- or 3,4-dimethylphenyl, 2,4-dimethyl-5-methoxyphenyl, 2-methoxy-3,4-dichlorophenyl, 2-methoxy, 5-bromophenyl-3,4-dioxyethylenephenyl, 3,4-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-dimethylphenyl, 3- or 4-methylphenyl, 4-alkoxyphenyl, 4-phenoxyphenyl, 4-halophenyl, 4-biphenyl, or 4-acetylaminophenyl.

In one aspect, the invention provides -modulating compounds of Structural Formula (XXII):

or a salt thereof wherein:

R²¹is selected from —NH—C(O)—, or —NH—C(O)—CH₂—; and

R³³is phenyl substituted with

a) one —N(CH₃)₂group;

b) one CN group at the 3 position;

c) one —S(CH₃) group; or

bridging the 3 and 4 positions.

In another aspect, the invention provides modulating compounds of Structural Formula (XXIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′═CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—, R³¹is not is not 3,5-dinitrophenyl, 4-butoxyphenyl

when R²¹is —NH—C(O)— and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not

unsubstituted phenyl, 2- or 4-nitrophenyl, 2,4-dinitrophenyl, 2- or 4-chlorophenyl, 2-bromophenyl, 4-fluorophenyl, 2,4-dichlorophenyl, 2-carboxyphenyl, 2-azidophenyl, 2- or 4-aminophenyl, 2-acetamidophenyl, 4-methylphenyl, or 4-methoxyphenyl;

when R²¹is —NH—C(O)—, R₁″ is methyl; and each of R²⁰, R^20a, R₁′ and R₁′″ is hydrogen, R³¹is not 2-methylaminophenyl,

when R²¹is —NH—C(O)—CH₂— or NH—C(S)—NH—, and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—S(O)₂—, R₁″ is hydrogen or methyl, and each of R²⁰, R^20a, R₁′ and R₁′″ is hydrogen, R³¹is not 4-methylphenyl; and

when R²¹is —NH—S(O)₂—, R^20ais hydrogen or —CH₂—N(CH₂CH₃)₂, and each of R²⁰, R¹′, R₁″ and R₁′″ is hydrogen, R³¹is not

In a particular aspect, the invention provides modulating compounds of Structural Formula (XXIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)_z—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

wherein:

i) at least one R²⁰is a solubilizing group or at least one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl or both; or
ii) R^20ais a solubilizing group other than CH₂—N(CH₂CH₃)₂.

In yet another aspect, the invention provides modulating compounds of Structural Formula (XXIV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR²³—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′═CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—CH₂—, R³¹is not 2-methylphenyl, or 3,4-dimethoxyphenyl;

when R²¹is —NH—C(O)—CH═CH—, R³¹is not 2-chlorophenyl;

when R²¹is —NH—C(O)—NH—, R³¹is not unsubstituted benzimidazolyl;

when R²¹is —NH—S(O)₂—, and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl, 4-chlorophenyl, 4-methylphenyl, or 4-acetoamidophenyl;

when R²¹is —NH—S(O)₂—, each of R₁′ and R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, and R₁″ is hydrogen, R³¹is not 4-nitrophenyl;

when R²¹is —NH—C(O)—CH₂O—, R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, R₁′, and R₁″ is hydrogen, R³¹is not 2,3-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,4-dichloromethyl, 2,4-dimethyl-6-bromophenyl, 2- or 4-chlorophenyl, 2-(1-methylpropyl)phenyl, 5-methyl-2-(1-methylethyl)phenyl, 2- or 4-methylphenyl, 2,4-dichloro-6-methylphenyl, nitrophenyl, 2,4-dimethyl-6-nitrophenyl, 2- or 4-methoxyphenyl, 4-acetyl-2-methoxyphenyl, 4-chloro-3,5-dimethylphenyl, 3-ethylphenyl, 4-bromophenyl, 4-cyclohexyphenyl, 4-(1-methylpropyl)phenyl, 4-(1-methylethyl)phenyl, 4-(1,1-dimethylethyl)phenyl, or unsubstituted phenyl;

when R²¹is —NH—C(O)—CH₂—, R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, R₁′, and R₁″ is hydrogen, R³¹is not unsubstituted naphthyl, 4-chlorophenyl, 4-nitrophenyl, 4-methoxyphenyl, unsubstituted phenyl, unsubstituted thienyl

when R²¹is —NH—C(O)—CH₂—, R₁′ is methyl, and each of R²⁰, R^20a, R₁″, and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH═CH, R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, R₁′, and R₁″ is hydrogen, R³¹is not unsubstituted furyl, nitrophenyl-substituted furyl, 2,4-dichlorophenyl, 3,5-dichloro-2-methoxyphenyl, 3- or 4-nitrophenyl, 4-methoxyphenyl, unsubstituted phenyl, or nitro-substituted thienyl;

when R²¹is —NH—C(O)—CH(CH₂CH₃)—, and each of R²⁰, R^20a, R₁′, R₁″, and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH(CH₃)—O—, R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, R₁′, and R₁″ is hydrogen, R³¹is not 2,4-dichlorophenyl.

In a particular aspect, the invention provides -modulating compounds of Structural Formula (XXIV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group and at least one of R²⁰and R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR²¹—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—, wherein R²³is an optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.

In a further aspect, the invention sirtuin-modulating compounds of Structural Formula (XXV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group, wherein at least one of R²⁰and R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is an optionally substituted phenyl.

In one aspect, the invention provides -modulating compounds of Structural Formula (XXVI):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is selected from an optionally substituted heteroaryl or an optionally substituted bicyclic aryl, with the provisos that:

when each of R₁′ and R₁′″ is hydrogen or methyl and each of R₁″, R₂₀and R_20ais hydrogen, R³³is not 5,6,7,8-tetrahydronaphthyl, unsubstituted benzofuryl, unsubstituted benzothiazolyl, chloro- or nitro-substituted benzothienyl, unsubstituted furyl, phenyl-, bromo- or nitro-substituted furyl, dimethyl-substituted isoxazolyl, unsubstituted naphthyl, 5-bromonaphthyl, 4-methylnaphthyl, 1- or 3-methoxynaphthyl, azo-substituted naphthyl, unsubstituted pyrazinyl, S-methyl-substituted pyridyl, unsubstituted pyridyl, thienyl- or phenyl-substituted quinolinyl, chloro-, bromo- or nitro-substituted thienyl, unsubstituted thienyl, or

In a particular aspect, the invention provides modulating compounds of Structural Formula (XXVI):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group wherein at least one of R²⁰or R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is selected from an optionally substituted heteroaryl or an optionally substituted bicyclic aryl.

In another aspect, the invention provides modulating compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

- each R²⁰and R^20ais independently selected from H or a solubilizing group;
- each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and
- R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′—CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R₃₁is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

- provided that when R²¹is —NH—C(O)— and R¹⁹is

R³¹is not unsubstituted pyridyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl or unsubstituted furyl.

In a particular aspect, the invention provides modulating compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

- each R²⁰and R^20ais independently selected from H or a solubilizing group;
- each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is s

wherein:

each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and

each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:

zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group;

zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁ R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

when R^20ais a solubilizing group, R¹⁹is thienyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl;

when R^20ais a solubilizing group, R¹⁹is methylimidazolyl and R²¹is —NH—C(O)—, R³¹is not 1-methyl-4-(1,1-dimethylethyloxycarbonylamino)pyrrol-2-yl or phenyl singly substituted with a solubilizing group;

when R²¹is —NH— and R¹⁹is pyridyl, oxadiazolyl or thiadiazolyl, R³¹is not unsubstituted phenyl, 3-methoxyphenyl or 4-methoxyphenyl;

when R²¹is —NH—C(O)— and R¹⁹is thiazolyl or pyrimidinyl, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)— and R¹⁹is

R³¹is not unsubstituted pyridyl, unsubstituted thienyl, unsubstituted phenyl, 2-methylphenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, 3,4-dioxyethylenephenyl, 3-acetylamino-4-methylphenyl, 3-[(6-amino-1-oxohexyl)amino]-4-methylphenyl, 3-amino-4-methylphenyl, 2,6-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3-halo-4-methoxyphenyl, 3-nitro-4-methylphenyl, 4-propoxyphenyl, 3,4,5-trimethoxyphenyl or unsubstituted furyl;

when R²¹is —NH—C(O)— and R¹⁹is

R³¹is not 3,5-dinitrophenyl, 4-butoxyphenyl,

In a more particular embodiment, the invention provides -modulating compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and

each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:

one to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group;

zero to one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—, R¹⁹is not pyrazolyl;

when R²¹is —NH—C(O)—CH₂—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted indolyl or unsubstituted phenyl;

when R²¹is —NH—C(O)—NH—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted isoxazolyl, unsubstituted naphthyl, unsubstituted phenyl, 2,6-difluorophenyl; 2,5-dimethylphenyl; 3,4-dichlorophenyl; or 4-chlorophenyl;

when R^20ais a solubilizing group, R¹⁹is 1-methylpyrrolyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl; unsubstituted furyl; unsubstituted pyrrolyl; unsubstituted pyrazolyl; unsubstituted isoquinolinyl; unsubstituted benzothienyl; chloro-substituted benzothienyl; 2-fluoro-4-chlorophenyl or phenyl singly substituted with a solubilizing group;

when R^20ais a solubilizing group, R¹⁹is thienyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)— and R¹⁹is thiazolyl or pyrimidinyl, R³¹is not unsubstituted phenyl.

In yet another aspect, the invention provides compounds of Structural Formula (XXVIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²⁹is selected from:

wherein:

each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′, wherein one of Z₁₀, Z₁₁, Z₁₂or Z₁₃is N; and

zero to one R²⁰is a solubilizing group;

zero to one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.

In one aspect, the invention provides -modulating compounds of Formula (I):

or a salt thereof, where:

Ring A is optionally substituted, fused to another ring or both; and

In another aspect, the invention provides -modulating compounds of Formula (II):

or a salt thereof, where:

Ring A is optionally substituted;

R₁, R₂, R₃and R₄are independently selected from the group consisting of —H, halogen, —OR₅, —CN, —CO₂R₅, —OCOR₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)_nR₅, —S(O)OR₅, —S(O)_nNR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group; and

n is 1 or 2.

In yet another aspect, the invention provides -modulating compounds of Formula (III):

or a salt thereof, where:

Ring A is optionally substituted;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

R₈is a polycyclic aryl group; and

n is 1 or 2.

In another aspect, the invention provides -modulating compounds of Formula (IV):

Ar-L-J-M-K-Ar′ (IV)

or a salt thereof, wherein:

each Ar and Ar′ is independently an optionally substituted carbocyclic or heterocyclic aryl group;

L is an optionally substituted carbocyclic or heterocyclic arylene group;

each M is C(O), S(O), S(O)₂, or CR₁′R₁′;

each R₁′ is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₅′; halo; haloalkyl; CF₃; SR₂′; OR₂′; NR₂′R₂′; NR₂′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)C(O)R₂′; C(O)NR₂′R₂′; OC(O)R₂′; S(O)₂R₂′; S(O)₂NR₂′R₂′; NR₂′C(O)NR₂′R₂′; NR₂′C(O)C(O)R₂′; NR₂′C(O)R₂; NR₂′(COOR₂′); NR₂′C(O)R₅′; NR₂′S(O)₂NR₂′R₂′; NR₂′S(O)₂R₂′; NR₂′S(O)₂R₅′; NR₂′C(O)C(O)NR₂′R₂′; NR₂′C(O)C(O)NR₂′R₃′; C1-C10 alkyl substituted with aryl, R₄′ or R₅′; or C2-C10 alkenyl substituted with aryl, R₄′ or R₅′;

each R₂′ is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₆′; C1-C10 alkyl substituted with 1-3 independent aryl, R₄′ or R₆′ groups; C3-C10 cycloalkyl-substituted with 1-3 independent aryl, R₄′ or R₆′ groups; or C2-C10 alkenyl substituted with 1-3 independent aryl, R₄′ or R₆′;

each R₃′ is independently C(O)R₂′, COOR₂′, or S(O)₂R₂′;

each R₄′ is independently halo, CF₃, SR₇′, OR₇′, OC(O)R₇′, NR₇′R₇′, NR₇′R₈′, NR₈′R₈′, COOR₇′, NO₂, CN, C(O)R₇′, or C(O)NR₇′R₇′;

each R₅′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₆′; halo; sulfur; oxygen; CF₃; haloalkyl; SR₂′; OR₂′; OC(O)R₂; NR₂′R₂′; NR₂′R₃′; NR₃′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)NR₂′R₂′; C1-C10 alkyl substituted with 1-3 independent R₄′, R₄′, or aryl; or C2-C10 alkenyl substituted with 1-3 independent R₄′, R₆′, or aryl;

each R₇′ is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′;

each R₈′ is independently C(O)R₇′, COOR₇′, or S(O)₂R₇′;

each R₁₁′ is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;

each aryl is independently optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R₆′; halo; haloalkyl; CF₃; OR₉′; SR₉′; NR₉′R₉′; COOR₉′; NO₂; CN; C(O)R₉′; C(O)C(O)R₉′; C(O)NR₉′R₉′; S(O)₂R₉′; N(R₉′)C(O)R₉′; N(R₉)(COOR₉′); N(R₉′)S(O)₂R₉′; S(O)₂NR₉′R₉′; OC(O)R₉′; NR₉′C(O)NR₉′R₉′; NR₉′C(O)C(O)R₉′; NR₉′C(O)R₆′; NR₉′S(O)₂NR₉′R₉′; NR₉′S(O)₂R₉′; NR₉′C(O)C(O)NR₉′R₉′; C1-C10 alkyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₁′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; C2-C10 alkenyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; or R₉′.

In a further aspect, the invention provides -modulating compounds of Formula (IVa):

Het-L-Q-Ar′ (IVa)

or a salt thereof, where:

Het is an optionally substituted heterocyclic aryl group;

L is an optionally substituted carbocyclic or heterocyclic arylene group;

Ar′ is an optionally substituted carbocyclic or heterocyclic aryl group; and

Q is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁₁—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—,

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl, wherein:

In still yet another aspect, the invention provides -modulating compounds of Formula (V):

or a salt thereof, wherein:

Ring A is optionally substituted with at least one R₁′ group;

Y₁, Y₂, Y₃, Y₄, and Y₅are independently R₁′;

each R₁′ is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₅′; halo; haloalkyl; CF₃; SR₂′; OR₂′; NR₂′R₂′; NR₂′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)C(O)R₂′; C(O)NR₂′R₂′; OC(O)R₂′; S(O)₂R₂′; S(O)₂NR₂′R₂′; NR₂′C(O)NR₂′R₂′; NR₂′C(O)C(O)R₂′; NR₂′C(O)R₂′; NR₂′(COOR₂); NR₂′C(O)R₅′; NR₂′S(O)₂NR₂′R₂′; NR₂′S(O)₂R₂; NR₂′S(O)₂R₅′; NR₂′C(O)C(O)NR₂′R₂′; NR₂′C(O)C(O)NR₂′ R₃′; C1-C10 alkyl substituted with aryl, R₄′ or R₅′; or C2-C10 alkenyl substituted with aryl, R₄′ or R₅′;

each R₃′ is independently C(O)R₂′, COOR₂′, or S(O)₂R₂′;

each R₄′ is independently halo, CF₃, SR₇′, OR₇′, OC(O)R₇′, NR₇′R₇′, NR₇′R₇′R₈′, NR₈′R₈′, COOR₇′, NO₂, CN, C(O)R₇′, or C(O)NR₇′R₇′;

each R₅′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₆′; halo; sulfur; oxygen; CF₃; haloalkyl; SR₂′; OR₂′; OC(O)R₂′; NR₂′R₂₁; NR₂′R₃′; NR₃′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)NR₂′R₂′; C1-C10 alkyl substituted with 1-3 independent R₄′, R₆′, or aryl; or C2-C10 alkenyl substituted with 1-3 independent R₄′, R₆′, or aryl;

each R₇′ is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀ , or OC(O)R₁₀′; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′;

each R₈′ is independently C(O)R₇′, COOR₇′, or S(O)₂R₇′;

each R₁₁′ is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;

each aryl is independently a 5- to 7-membered monocyclic ring system or a 9- to 12-membered bicyclic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R₆′; halo; haloalkyl; CF₃; OR₉′; SR₉′; NR₉′R₉′; COOR₉′; NO₂; CN; C(O)R₉′; C(O)C(O)R₉′; C(O)NR₉′R₉′; S(O)₂R₉′; N(R₉′)C(O)R₉′; N(R₉′)(COOR₉′); N(R₉)S(O)₂R₉′; S(O)₂NR₉′R₉′; OC(O)R₉′; NR₉′C(O)NR₉′R₉′; NR₉′C(O)C(O)R₉′; NR₉′C(O)R₆′; NR₉′S(O)₂NR₉′R₉′; NR₉′S(O)₂R₆′; NR₉′C(O)C(O)NR₉′R₉; C1-C 0 alkyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉, OC(O)R₉′; C2-C10 alkenyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; or R₉′.

In one aspect, the invention provides modulating compounds of Structural Formula (VI):

or a salt thereof, wherein:

Het is an optionally substituted heterocyclic aryl group; and

Ar′ is an optionally substituted carbocyclic or heterocyclic aryl group.

The invention also includes prodrugs and metabolites of the compounds disclosed herein.

In another aspect, the invention provides -modulating compounds of Structural Formula (VII):

or a salt thereof, wherein:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C1-C3 straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁₁—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that said compound is not

or

that when R¹⁹is

and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In certain embodiments, compounds of Structural Formula (VII) have the following values:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

each R²⁰is independently selected from H or a solubilizing group;

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and

zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

said compound is not:

and

when Xs and X₉are each independently selected from CR²⁰or CR₁′, R¹⁹is

and each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰, or CR₁′, then:

- a) at least one of X₈and X₉is not CH; or
- b) at least one of Z₁₀, Z₁₁, Z₁₂and Z₁₃is CR²⁰, wherein R²⁰is a solubilizing group.

In yet another embodiment, the invention provides -modulating compounds of Structural Formula (VIII):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R₁′ is methyl, and R²¹is —NH—C(O)—, R³¹is not

1-methoxynaphthyl; 2-methoxynaphthyl; or unsubstituted 2-thienyl;

when R₁′ is methyl, and R²¹is —NH—C(O)—CH═CH—, R³¹is not

when R₁′ is methyl, and R²¹is —NH—C(O)—CH—O—, R³¹is not unsubstituted naphthyl; 2-methoxy, 4-nitrophenyl; 4-chloro, 2-methylphenyl; or 4-t-butylphenyl; and

when R²¹is —NH—C(O)—, R³¹is not optionally substituted phenyl.

In a further embodiment, the invention provides -modulating compounds of Structural Formula (IX):

or a salt thereof; wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

In one aspect, the invention provides modulating compounds of Structural Formula (X):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R⁵¹is selected from an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, or an optionally substituted naphthyl, wherein R⁵¹is not chloro-benzo[b]thienyl, unsubstituted benzodioxolyl, unsubstituted benzofuranyl, methyl-benzofuranyl, unsubstituted furanyl, phenyl-, bromo-, or nitro-furyl, chlorophenyl-isoxazolyl, oxobenzopyranyl; unsubstituted naphthyl, methoxy-, methyl-, or halo-naphthyl, unsubstituted thienyl, unsubstituted pyridinyl, or chloropyridinyl.

In another aspect, the invention provides modulating compounds of Structural Formula (XI):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²²is selected from —NR²³—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—C(S)—NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O— or —NR₁′—C(O)—CR₁′R₁′—, wherein R²³is an optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²²is —NH—C(O)—CH₂—, R³¹is not 3,4-dimethoxyphenyl, 4-chlorophenyl, or unsubstituted phenyl;

when R²²is —NH—C(O)—CH(CH₃)—O—, R³¹is not 2,4-dichlorophenyl, 4-chlorophenyl, or unsubstituted phenyl; and

when R²²is —NH—S(O)₂—, R³¹is not unsubstituted phenyl.

In yet another aspect, the invention provides -modulating compounds of Structural Formula (XII):

or a salt thereof, wherein:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁—; —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that when R¹⁹is

Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In certain embodiments, the compounds of Structural Formula (XI) have the following values:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O— or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that:

when X₇is N, R¹⁹is

and each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰, or CR₁′, then:

- a) at least one of X₈, X₉or X₁₀is C—(C₁-C₃straight or branched alkyl) or C-(solubilizing group); or
- b) at least one of Z₁₀, Z₁₁, Z₁₂and Z₁₃is CR²⁰, wherein R²⁰is a solubilizing group.

In a further aspect, the invention provides compounds of Structural Formula (XIII):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—CH(CH₂—CH₃)—, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH₂—, R³¹is not unsubstituted phenyl, 3-methylphenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl or 4-methoxyphenyl;

when R²¹is —NH—C(O)—CH₂—O—, R³¹is not unsubstituted phenyl or 4-chlorophenyl; and

when R²¹is —NH—S(O)₂—, R³¹is not 3,4-dioxymethylene phenyl, 2,4,5-trimethylphenyl, 2,4,6-bimethylphenyl, 2,4- or 3,4-dimethylphenyl, 2,5-difluorophenyl, 2,5- or 3,4-dimethoxyphenyl, fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-ethylphenyl, 4-methylphenyl, 3-methyl-4-methoxyphenyl, unsubstituted phenyl, unsubstituted pyridinyl, unsubstituted thienyl, chloro-substituted thienyl, or methyl-substituted benzothiazolyl.

In one aspect, the invention provides modulating compounds of Structural Formula (XIV):

or a salt thereof, wherein:

each of R²³and R²⁴is independently selected from H, —CH₃or a solubilizing group;

R²⁵is selected from H, or a solubilizing group; and

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group; and
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;
- each R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR¹′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

- wherein when R¹⁹is

In another aspect, the invention provides modulating compounds of Structural Formula (XV):

or a salt thereof, wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is selected from an optionally substituted bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein:

when R²¹is —NH—C(O)—, R³²is not unsubstituted 2-furyl, 2-(3-bromofuryl), unsubstituted 2-thienyl, unsubstituted 3-pyridyl, unsubstituted 4-pyridyl,

and

when R²¹is —NR₁′—S(O)₂—, R₃₂is not unsubstituted 2-thienyl or unsubstituted naphthyl.

In yet another aspect, the invention provides modulating compounds of Structural Formula (XVI):

or a salt thereof, wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is an optionally substituted phenyl, wherein:

when R²¹is —NR₁′—C(O)—CR₁′R₁′— or —NH—C(O)—CH(CH₃)—O, R³³is a substituted phenyl;

when R²¹is —NH—C(O)—CH₂, R³³is not unsubstituted phenyl, 4-methoxyphenyl; 3,4-dimethoxyphenyl or 4-chlorophenyl;

when R²¹is —NH—C(O)—CH₂—O, R³³is not 2,4-bis(1,1-dimethylpropyl)phenyl;

when R²¹is —NH—C(O)—NH—, R³³is not 4-methoxyphenyl; and

In a further aspect, the invention provides modulating compounds of Structural Formula (XVII):

or a salt thereof, wherein:

each of R²³and R²⁴is independently selected from H or —CH₃, wherein at least one of R²³and R²⁴is H; and

R²⁹is phenyl substituted with:

a) two —O—CH₃groups;

b) three —O—CH₃groups located at the 2, 3 and 4 positions; or

c) one —N(CH₃)₂group; and;

d) when R²³is CH₃, one —O—CH₃group at the 2 or 3 position, wherein R²⁹is optionally additionally substituted with a solubilizing group.

In one aspect, the invention provides modulating compounds of Structural Formula (XVIII):

or a salt thereof, wherein

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′,

wherein:

zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group; and

zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;

each R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that when R¹⁹is

- Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, R²⁰is H, and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In another aspect, the invention provides -modulating compounds of Structural Formula (XX):

or a salt thereof, wherein

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′,

wherein:

- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group; and
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;

each R²⁰is independently selected from H or a solubilizing group;

R^20ais independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁₁—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein

- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R¹³is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein when R¹⁹is

and Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, R^20ais a solubilizing group.

In yet another aspect, the invention provides modulating compounds of Structural Formula (XXI):

or a salt thereof, wherein

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein

- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is an optionally substituted monocyclic or bicyclic heteroaryl, or an optionally substituted bicyclic aryl, wherein:

when R²¹is —NH—C(O)—CH₂—, R³²is not unsubstituted thien-2-yl;

when R²¹is —NH—C(O)—, R³²is not furan-2-yl, 5-bromofuran-2-yl, or 2-phenyl-4-methylthiazol-5-yl;

when R²¹is —NH—S(O)₂—, R³²is not unsubstituted naphthyl or 5-chlorothien-2-yl.

In a further aspect, the invention provides -modulating compounds of Structural Formula (XXII):

or a salt thereof, wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is an optionally substituted phenyl, wherein:

when R²¹is —NR₁′—C(O)—, R₁′ is not H;

when R²¹is —NH—C(O)—CH₂or —NH—C(O)—CH₂—O—, R³³is not unsubstituted phenyl or 4-halophenyl; and

In one aspect, the invention provides modulating compounds of Structural Formula (XXII):

or a salt thereof wherein:

R²¹is selected from —NH—C(O)—, or —NH—C(O)—CH₂—; and

R³³is phenyl substituted with

a) one —N(CH₃)₂group;

b) one CN group at the 3 position;

c) one —S(CH₃) group; or

bridging the 3 and 4 positions.

In another aspect, the invention provides modulating compounds of Structural Formula (XXIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—, R³¹is not is not 3,5-dinitrophenyl, 4-butoxyphenyl,

when R²is —NH—C(O)— and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not

when R²¹is —NH—C(O)—, R₁″ is methyl; and each of R²⁰, R^20a, R₁′ and R₁′″ is hydrogen, R³¹is not 2-methylaminophenyl,

when R²¹is —NH—C(O)—CH₂— or NH—C(S)—NH—, and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—S(O)₂—, R₁″ is hydrogen or methyl, and each of R²⁰, R^20a, R₁′ and R₁″ is hydrogen, R³¹is not 4-methylphenyl; and

when R²¹is —NH—S(O)₂—, R^20ais hydrogen or —CH₂—N(CH₂CH₃)₂, and each of R²⁰, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not

In a particular aspect, the invention provides modulating compounds of Structural Formula (XXIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein:

i) at least one R²⁰is a solubilizing group or at least one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl or both; or
ii) R^20ais a solubilizing group other than CH₂—N(CH₂CH₃)₂.

In yet another aspect, the invention provides -modulating compounds of Structural Formula (XXIV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR²³—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(—NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—CH₂—, R³¹is not 2-methylphenyl, or 3,4-dimethoxyphenyl;

when R²¹is —NH—C(O)—CH═CH—, R³¹is not 2-chlorophenyl;

when R²¹is —NH—C(O)—NH—, R³¹is not unsubstituted benzimidazolyl;

when R²¹is —NH—S(O)₂—, and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl, 4-chlorophenyl, 4-methylphenyl, or 4-acetoamidophenyl;

when R²¹is —NH—S(O)₂—, each of R₁′ and R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, and R₁″ is hydrogen, R³¹is not 4-nitrophenyl;

when R²¹is —NH—C(O)—CH₂—O—, R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, R₁′, and R₁″ is hydrogen, R³¹is not 2,3-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,4-dichloromethyl, 2,4-dimethyl-6-bromophenyl, 2- or 4-chlorophenyl, 2-(1-methylpropyl)phenyl, 5-methyl-2-(1-methylethyl)phenyl, 2- or 4-methylphenyl, 2,4-dichloro-6-methylphenyl, nitrophenyl, 2,4-dimethyl-6-nitrophenyl, 2- or 4-methoxyphenyl, 4-acetyl-2-methoxyphenyl, 4-chloro-3,5-dimethylphenyl, 3-ethylphenyl, 4-bromophenyl, 4-cyclohexyphenyl, 4-(1-methylpropyl)phenyl, 4-(1-methylethyl)phenyl, 4-(1,1-dimethylethyl)phenyl, or unsubstituted phenyl;

when R²¹is —NH—C(O)—CH₂—, R₁″ is methyl or hydrogen, and each of R²⁰, R^20a, R₁′, and R₁″ is hydrogen, R³¹is not unsubstituted naphthyl, 4-chlorophenyl, 4-nitrophenyl, 4-methoxyphenyl, unsubstituted phenyl, unsubstituted thienyl

when R²¹is —NH—C(O)—CH₂—, R₁′ is methyl, and each of R²⁰, R^20a, R₁″, and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH(CH₂CH₃)—, and each of R²⁰, R^20a, R₁′, R₁″, and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH(CH₃)—O—, R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, R₁′, and R₁″ is hydrogen, R³¹is not 2,4-dichlorophenyl.

In a particular aspect, the invention provides modulating compounds of Structural Formula (XXIV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group and at least one of R²⁰and R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR²³—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—, wherein R²³is an optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.

In a further aspect, the invention provides modulating compounds of Structural Formula (XXV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group, wherein at least one of R²⁰and R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is an optionally substituted phenyl.

In one aspect, the invention provides modulating compounds of Structural Formula (XXVI):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is selected from an optionally substituted heteroaryl or an optionally substituted bicyclic aryl, with the provisos that:

In a particular aspect, the invention provides -modulating compounds of Structural Formula (XXVI):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group, wherein at least one of R²⁰or R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is selected from an optionally substituted heteroaryl or an optionally substituted bicyclic aryl.

In another aspect, the invention provides modulating compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

- each R²⁰and R^20ais independently selected from H or a solubilizing group;
- each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and
- R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

- provided that when R²¹is —NH—C(O)— and R¹⁹is

R³¹is not unsubstituted pyridyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl or unsubstituted furyl.

In a particular aspect, the invention provides -modulating compounds of Structural Formula (XXVII):

or a salt thereof; wherein:

- each R²⁰and R^20ais independently selected from H or a solubilizing group;
- each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and

each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:

zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group;

zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that when R²¹is —NH—C(O)—, R¹⁹is not pyrazolyl;

when R²¹is —NH—, and R¹⁹is thiazolyl, R³¹is not optionally substituted phenyl or optionally substituted pyridyl;

when R²¹is —NH—C(O)—CH₂—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted indolyl or unsubstituted phenyl;

when R²¹is —NH—C(O)—CH₂—, and R¹⁹is

R³¹is not 2-methylphenyl or 3,4-dimethoxyphenyl;

when R²¹is —NH—C(O)—CH═CH—, and R¹⁹is

R³¹is not 2-chlorophenyl;

when R²¹is —NH—C(O)—NH—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted isoxazolyl, unsubstituted naphthyl, unsubstituted phenyl, 2,6-difluorophenyl, 2,5-dimethylphenyl, 3,4-dichlorophenyl, or 4-chlorophenyl;

when R²¹is —NH—C(O)—NH—, and R¹⁹is

R³¹is not unsubstituted benzimidazolyl;

when R²¹is —NH—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted pyridyl;

when R^20ais a solubilizing group, R¹⁹is 1-methylpyrrolyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl, unsubstituted furyl, unsubstituted pyrrolyl, unsubstituted pyrazolyl, unsubstituted isoquinolinyl, unsubstituted benzothienyl, chloro-substituted benzothienyl, 2-fluoro-4-chlorophenyl or phenyl singly substituted with a solubilizing group;

when R^20ais a solubilizing group, R¹⁹is thienyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl;

when R²¹is —NH— and R¹⁹is pyridyl, oxadiazolyl or thiadiazolyl, R³¹is not unsubstituted phenyl, 3-methoxyphenyl or 4-methoxyphenyl;

when R²¹is —NH—C(O)— and R¹⁹is thiazolyl or pyrimidinyl, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)— and R¹⁹is

R³¹is not 3,5-dinitrophenyl, 4-butoxyphenyl,

In a more particular embodiment, the invention provides modulating compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and

each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:

one to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group;

zero to one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—, R¹⁹is not pyrazolyl;

when R²¹is —NH—C(O)—CH₂—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted indolyl or unsubstituted phenyl;

when R²¹is —NH—C(O)—NH—, and R¹⁹is pyrazolyl; R³¹is not unsubstituted isoxazolyl, unsubstituted naphthyl, unsubstituted phenyl, 2,6-difluorophenyl; 2,5-dimethylphenyl; 3,4-dichlorophenyl; or 4-chlorophenyl;

when R^20ais a solubilizing group, R¹⁹is 1-methylpyrrolyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl; unsubstituted furyl; unsubstituted pyrrolyl; unsubstituted pyrazolyl; unsubstituted isoquinolinyl; unsubstituted benzothienyl; chloro-substituted benzothienyl; 2-fluoro-chlorophenyl or phenyl singly substituted with a solubilizing group;

when R^20ais a solubilizing group, R¹⁹is thienyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl;

when R^20ais a solubilizing group, R¹⁹ⁱmethylimidazolyl and R²¹is —NH—C(O)—, R³¹is not 1-methyl-4-(1,1-dimethylethyloxycarbonylamino)pyrrol-2-yl or phenyl singly substituted with a solubilizing group; and

when R²¹is —NH—C(O)— and R¹⁹is thiazoyl or pyrimidinyl, R³¹is not unsubstituted phenyl.

In yet another aspect, the invention provides compounds of Structural Formula (XXVIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′ and R₁″ independently selected from H or optionally substituted C₁-C₃straight or branched, alkyl;

R²⁹is selected from:

wherein:

each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′, wherein one of Z₁₀, Z₁₁, Z₁₂or Z₁₃is N; and

zero to one R²⁰is a solubilizing group;

zero to one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR¹′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.

In one aspect, the invention provides modulating compounds of Formula (I):

or a salt thereof, where:

Ring A is optionally substituted, fused to another ring or both; and

In another aspect, the invention provides -modulating compounds of Formula (II):

or a salt thereof, where:

Ring A is optionally substituted;

R₁, R₂, R₃and R₄are independently selected from the group consisting of —H, halogen, —OR₅, —CN, —CO₂R₅, —OCOR₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)_nR₅, —S(O)_nOR₅, —S(O)_nNR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group; and

n is 1 or 2.

In yet another aspect, the invention provides modulating compounds of Formula (II):

or a salt thereof where:

Ring A is optionally substituted;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

R₇, R₉, R₁₀and R₁₁are independently selected from the group consisting of —H, halogen, —R₅, —OR₅, —CN, —CO₂R₅, —OCOR₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)_nR₅, —S(O)_nOR₅, —S(O)_nNR₅R₅, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₈is a polycyclic aryl group; and

n is or 2.

In another aspect, the invention provides -modulating compounds of Formula (IV):

Ar-L-J-M-K-Ar′ (IV)

or a salt thereof, wherein:

each Ar and Ar′ is independently an optionally substituted carbocyclic or heterocyclic aryl group;

L is an optionally substituted carbocyclic or heterocyclic arylene group;

each M is C(O), S(O), S(O)₂, or CR₁′R₁′;

each R₁′ is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₅′; halo; haloalkyl; CF₃; SR₂′; OR₂′; NR₂′R₂′; NR₂′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)C(O)R₂′; C(O)NR₂′R₂′; OC(O)R₂′; S(O)₂R₂′; S(O)₂NR₂′R₂′; NR₂′C(O)NR₂′ R₂′; NR₂′C(O)C(O)R₂′; NR₂′C(O)R₂′; NR₂′(COOR₂′); NR₂′C(O)R₅′; NR₂′S(O)₂NR₂′R₂′; NR₂′S(O)₂R₂′; NR₂′S(O)₂R₅′; NR₂′C(O)C(O)NR₂′R₂′; NR₂′C(O)C(O)NR₂′R₃; C1-C10 alkyl substituted with aryl, R₄′ or R₅′; or C2-C10 alkenyl substituted with aryl, R₄′ or R₅′;

each R₃′ is independently C(O)R₂′, COOR₂′, or S(O)₂R₂′;

each R₄′ is independently halo, CF₃, SR₇′, OR₇′, OC(O)R₇′, NR₇′R₇′, NR₇′R₈′, NR₈′R₈′, COOR₇′, NO₂, CN, C(O)R₇′, or C(O)NR₇′R₇′;

each R₅′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₆′; halo; sulfur; oxygen; CF₃; haloalkyl; SR₂′; OR₂′; OC(O)R₂′; NR₂′R₂′; NR₂′R₃′; NR₃′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)NR₂′R₂′; C1-C10 alkyl substituted with 1-3 independent R₄′, R₆′, or aryl; or C2-C10 alkenyl substituted with 1-3 independent R₄′, R₆′, or aryl;

each R₆is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF₃; haloalkyl; SR₇′; OR₇′; NR₇′R₇′; NR₇′R₈′; NR₈′R₈′; COOR₇′; NO₂; CN; C(O)R₇′; or C(O)NR₇′R₇′;

each R₇′ is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′;

each R₈′ is independently C(O)R₇′, COOR₇′, or S(O)₂R₇′;

each aryl is independently optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R₆′; halo; haloalkyl; CF₃; OR₉′; SR₉′; NR₉′R₉′; COOR₉′; NO₂; CN; C(O)R₉′; C(O)C(O)R₉′; C(O)NR₉′R₉′; S(O)₂R₉′; N(R₉′)C(O)R₉′; N(R₉′)(COOR₉′); N(R₉)S(O)₂R₉′; S(O)₂NR₉′R₉′; OC(O)R₉′; NR₉′C(O)NR₉′R₉′; NR₉′C(O)C(O)R₉′; NR₉′C(O)R₆′; NR₉′S(O)₂NR₉′R₉′; NR₉′S(O)₂R₆′; NR₉′C(O)C(O)NR₉′R₉′; C1-C10 alkyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; C2-C10 alkenyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; or R₉′.

In a further aspect, the invention provides -modulating compounds of Formula (IVa):

Het-L-Q-Ar′ (IVa)

or a salt thereof; where:

- Het is an optionally substituted heterocyclic aryl group;
- L is an optionally substituted carbocyclic or heterocyclic arylene group;
- Ar′ is an optionally substituted carbocyclic or heterocyclic aryl group; and
- Q is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—,

and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl, wherein:

In still yet another aspect, the invention provides -modulating compounds of Formula (V):

or a salt thereof, wherein:

Ring A is optionally substituted with at least one R₁′ group;

Y₁, Y₂, Y₃, Y₄, and Y₅are independently R₁′;

each R₁′ is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₅′; halo; haloalkyl; CF₃; SR₂′; OR₂′; NR₂′R₂′; NR₂′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)C(O)R₂′; C(O)NR₂′R₂′; OC(O)R₂′; S(O)₂R₂′; S(O)₂NR₂′R₂′; NR₂′C(O)NR₂′R₂′; NR₂′C(O)C(O)R₂′; NR₂′C(O)R₂′; NR₂′(COOR₂); NR₂′C(O)R₅′; NR₂S(O)₂NR₂′R₂′; NR₂′S(O)₂R₂′; NR₂′S(O)₂R₅′; NR₂′C(O)C(O)NR₂′R₂′; NR₂′C(O)C(O)NR₂′R₃′; C1-C10 alkyl substituted with aryl, R₄′ or R₅′; or C2-C10 alkenyl substituted with aryl, R₄′ or R₅′;

each R₃′ is independently C(O)R₂′, COOR₂′, or S(O)₂R₂′;

each R₄′ is independently halo, CF₃, SR₇′, OR₇′, OC(O)R₇′, NR₁′R₇′, NR₇′R₈′, NR₈′R₈′, COOR₇′, NO₂, CN, C(O)R₇′, or C(O)NR₇′R₇′;

each R₅′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₆′; halo; sulfur; oxygen; CF₃; haloalkyl; SR₂′; OR₂′; OC(O)R₂′; NR₂′R₂′; NR₂′R₃′; NR₃′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)NR₂′R₂′; C1-C10 alkyl substituted with 1-3 independent R₄′, R₆′, or aryl; or C2-C10 alkenyl substituted with 1-3 independent R₄′, R₆′ or aryl;

each R₆′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF₃; haloalkyl; SR₇′, OR₇′; NR₇′R₇′; NR₇′R₇′; NR₈′R₈′; COOR₇′; NO₂; CN; C(O)R₇′; or C(O)NR₇′R₇′;

each R₇′ is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′;

each R₈′ is independently C(O)R₇′, COOR₇′, or S(O)₂R₇′;

each R₁₁′ is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;

each aryl is independently a 5- to 7-membered monocyclic ring system or a 9- to 12-membered bicyclic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R₆′; halo; haloalkyl; CF₃; OR₉′; SR₉′; NR₉′R₉′; COOR₉′; NO₂; CN; C(O)R₉′; C(O)C(O)R₉′; C(O)NR₉′R₉′; S(O)₂R₉′; N(R₉′)C(O)R₉′; N(R₉′)(COOR₉′); N(R₉′)S(O)₂R₉′; S(O)₂NR₉′R₉′; OC(O)R₉′; NR₉′C(O)NR₉′R₉′; NR₉′C(O)C(O)R₉′; NR₉′C(O)R₆′; NR₉′S(O)₂NR₉′R₉′; NR₉′S(O)₂R₉′; NR₉′C(O)C(O)NR₉′R₉′; C1-C10 alkyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′, S(O)₂NR₉′R₉′, OC(O)R₉′; C2-C10 alkenyl substituted with 1-3 independent R₆, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; or R₉′.

In one aspect, the invention provides -modulating compounds of Structural Formula (VI):

or a salt thereof, wherein.

Het is an optionally substituted heterocyclic aryl group; and

Ar′ is an optionally substituted carbocyclic or heterocyclic aryl group.

The invention also includes prodrugs and metabolites of the compounds disclosed herein.

In another aspect, the invention provides modulating compounds of Structural Formula (VII):

or a salt thereof, wherein:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R₁′ is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′, —CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that said compound is not:

or that when R¹⁹is

and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In certain embodiments, compounds of Structural Formula (VII) have the following values:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

each R²⁰is independently selected from H or a solubilizing group;

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and

zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹s selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′, —C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

said compound is not:

and

when X₈and X₉are each independently selected from CR²⁰or CR₁′, R¹⁹is

and each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰, or CR₁′, then:

- a) at least one of X₈and X₉is not CH; or
- b) at least one of Z₁₀, Z₁₁, Z₁₂and Z₁₃is CR²⁰, wherein R²⁰is a solubilizing group.

In yet another embodiment, the invention provides modulating compounds of Structural Formula (VIII):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)_z—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R₁′ is methyl, and R²¹is —NH—C(O)—, R³¹is not

1-methoxynaphthyl; 2-methoxynaphthyl; or unsubstituted 2-thienyl;

when R₁′ is methyl, and R²¹is —NH—C(O)—CH═CH—, R³¹is not

when R₁′ is methyl, and R²¹is —NH—C(O)—CH—O—, R³¹is not unsubstituted naphthyl; 2-methoxy, 4-nitrophenyl; 4-chloro, 2-methylphenyl; or 4-t-butylphenyl; and

when R²¹is —NH—C(O)—, R³¹is not optionally substituted phenyl.

In a further embodiment, the invention provides modulating compounds of Structural Formula (IX):

or a salt thereof wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

In one aspect, the invention provides -modulating compounds of Structural Formula (X):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

In another aspect, the invention provides modulating compounds of Structural Formula (XI):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR²³—C(O—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—N₁′R₁′—S(O)₂—, —NR₁—CR₁′R₁′—, —NR₁′—C(O)—CR₁═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O— or —NR₁′—C(O)—CR₁′R₁′—, wherein R²³is an optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that

when R²²is —NH—C(O)—CH₂—, R³¹is not 3,4-dimethoxyphenyl, 4-chlorophenyl, or unsubstituted phenyl;

when R²²is —NH—C(O)—CH(CH₃)—O—, R³¹is not 2,4-dichlorophenyl, 44 chlorophenyl, or unsubstituted phenyl; and

when R²²is —NH—S(O)₂—, R³¹is not unsubstituted phenyl.

In yet another aspect, the invention provides -modulating compounds of Structural Formula (XII):

or a salt thereof, wherein:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR², or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′, —NR₁′—C(O)—O—,

and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that when R¹⁹is

Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In certain embodiments, the compounds of Structural Formula (XI) have the following values:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁—, —NR₁′—C(O)—CR₁′R₁′, —CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O— or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that:

when X₇is N, R¹⁹is

and each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰, or CR₁′, then:

- a) at least one of X₈, X₉or X₁₀is C—(C₁-C₃straight or branched alkyl) or C-(solubilizing group); or
- b) at least one of Z₁₀, Z₁₁, Z₁₂and Z₁₃is CR²⁰, wherein R²⁰is a solubilizing group.

In a further aspect, the invention provides compounds of Structural Formula (XIII):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that

when R²¹is —NH—C(O)—CH(CH₂—CH₃)—, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH₂—, R³¹is not unsubstituted phenyl, 3-methylphenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl or 4-methoxyphenyl;

when R²¹is —NH—C(O)—CH₂—O—, R³¹is not unsubstituted phenyl or 4-chlorophenyl; and

In one aspect, the invention provides modulating compounds of Structural Formula (XIV):

or a salt thereof wherein:

each of R²²and R²⁴is independently selected from H, —CH₃or a solubilizing group;

R²⁵is selected from H, or a solubilizing group; and

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group; and
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;
- each R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR¹′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—, —CR₁′R₁′—, —NR₁′—C(S)—NR₁—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

- wherein when R¹⁹is

In another aspect, the invention provides modulating compounds of Structural Formula (XV):

or a salt thereof wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is selected from an Optionally substituted bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein:

when R²¹is —NH—C(O)—, R³²is not unsubstituted 2-furyl, 2-(3-bromofuryl), unsubstituted 2-thienyl, unsubstituted 3-pyridyl, unsubstituted 4-pyridyl,

and

when R²¹is —NR₁′—S(O)₂—, R³²is not unsubstituted 2-thienyl or unsubstituted naphthyl.

In yet another aspect, the invention provides -modulating compounds of Structural Formula (XVI):

or a salt thereof wherein:

R²¹is selected from —NR₁′—C(O)—, —N₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′, —C(O)—NR₁′—S(O)₂—, —NR₁′, —CR₁′R₁′, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(—N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is an optionally substituted phenyl, wherein:

when R²¹is —NR₁′—C(O)—CR₁′R₁′— or —NH—C(O)—CH(CH₃)—O, R³³is a substituted phenyl;

when R²¹is —NH—C(O)—CH₂, R³³is not unsubstituted phenyl, 4-methoxyphenyl; 3,4-dimethoxyphenyl or 4-chlorophenyl;

when R²¹is —NH—C(O)—CH₂—O, R³³is not 2,4-bis(1,1-dimethylpropyl)phenyl;

when R²¹is —NH—C(O)—NH—, R³³is not 4-methoxyphenyl; and

In a further aspect, the invention provides modulating compounds of Structural Formula (XVII):

a salt thereof, wherein:

each of R²³and R²⁴is independently selected from H or —CH₃, wherein at least one of R²³and R²⁴is H; and

R²⁹is phenyl substituted with:

a) two —O—CH₃groups;

b) three —O—CH₃groups located at the 2, 3 and 4 positions; or

c) one —N(CH₃)₂group; and

d) when R²³is CH₃, one —O—CH₃group at the 2 or 3 position, wherein R²⁹is optionally additionally substituted with a solubilizing group.

In one aspect, the invention provides modulating compounds of Structural Formula (XVIII):

or a salt thereof, wherein

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₁and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′,

wherein:

zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group; and

zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;

each R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that when R¹⁹is

Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, R²⁰is H, and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In another aspect, the invention provides modulating compounds of Structural Formula (XX):

or a salt thereof, wherein

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′,

wherein:

- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′,
- zero to one R²⁰is a solubilizing group; and
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;

each R²⁰is independently selected from H or a solubilizing group;

R^20ais independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein

- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched allyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein when R¹⁹is

and Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, R^20ais a solubilizing group.

In yet another aspect, the invention provides modulating compounds of Structural Formula (XXI):

or a salt thereof, wherein

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, NR₁′—C(O)—O—,

wherein

- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is an optionally substituted monocyclic or bicyclic heteroaryl, or an optionally substituted bicyclic aryl, wherein:

when R²¹is —NH—C(O)—CH₂—, R³²is not unsubstituted thien-2-yl;

when R²¹is —NH—C(O)—, R³²is not furan-2-yl, 5-bromofuran-2-yl, or 2-phenyl-4-methylthiazol-5-yl;

when R²¹is —NH—S(O)₂—, R³²is not unsubstituted naphthyl or 5-chlorothien-2-yl.

In a further aspect, the invention provides modulating compounds of Structural Formula (XXII):

or a salt thereof; wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′C(O)—,

wherein each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is an optionally substituted phenyl, wherein:

when R²¹is —NR₁′—C(O)—, R₁′ is not H;

when R²¹is —NH—C(O)—CH₂or —NH—C(O)—CH₂—O—, R³³is not unsubstituted phenyl or 4-halophenyl; and

In one aspect, the invention provides -modulating compounds of Structural Formula (XXII):

or a salt thereof wherein:

R²¹is selected from —NH—C(O)—; or —NH—C(O)—CH₂—; and

R³³is phenyl substituted with

a) one-N(CH₃)₂group;

b) one CN group at the 3 position;

c) one —S(CH₃) group; or

bridging the 3 and 4 positions.

In another aspect, the invention provides modulating compounds of Structural Formula (XXIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—, R³¹is not is not 3,5-dinitrophenyl, 4-butoxyphenyl,

when R²¹is —NH—C(O)— and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not

when R²¹is —NH—C(O)—, R₁″ is methyl; and each of R²⁰, R^20a, R₁′ and R₁″ is hydrogen, R³¹is not 2-methylaminophenyl,

when R²¹is —NH—C(O)—CH₂— or NH—C(S)—NH—, and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—S(O)₂—, R₁″ is hydrogen or methyl, and each of R²⁰, R^20a, R₁′ and R₁′″ is hydrogen, R³¹is not 4-methylphenyl; and

when R²¹is —NH—S(O)₂—, R^20ais hydrogen or —CH₂—N(CH₂CH₃)₂, and each of R²⁰, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not

In a particular aspect, the invention provides modulating compounds of Structural Formula (XXIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—; —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

wherein:

i) at least one R²⁰is a solubilizing group or at least one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl or both; or
ii) R^20ais a solubilizing group other than CH₂—N(CH₂CH₃)₂.

In yet another aspect, the invention provides -modulating compounds of Structural Formula (XXIV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR²³—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—CH₂—, R³¹is not 2-methylphenyl, or 3,4-dimethoxyphenyl;

when R²¹is —NH—C(O)—CH═CH—, R³¹is not 2-chlorophenyl;

when R²¹is —NH—C(O)—NH—, R³¹is not unsubstituted benzimidazolyl;

when R²¹is —NH—S(O)₂—, and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl, 4-chlorophenyl, 4-methylphenyl, or 4-acetoamidophenyl;

when R²¹is —NH—S(O)₂—, each of R₁′ and R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, and R₁″ is hydrogen, R³¹is not 4-nitrophenyl;

when R²¹is —NH—C(O)—CH₂—, R₁′ is methyl, and each of R²⁰, R^20a, R₁″, and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH(CH₂CH₃)—, and each of R²⁰, R^20a, R₁′, R₁″, and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH(CH₃)—O—, R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, R₁′, and R₁″ is hydrogen, R³¹is not 2,4-dichlorophenyl.

In a particular aspect, the invention provides -modulating compounds of Structural Formula (XXIV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group and at least one of R²⁰and R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR²³—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—, —NR₁′—C(O)—CR₁′—CR₁′═—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—, wherein R²³is an optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.

In a further aspect, the invention provides modulating compounds of Structural Formula (XXV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group, wherein at least one of R²⁰and R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is an optionally substituted phenyl.

In one aspect, the invention provides modulating compounds of Structural Formula (XXVI):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is selected from an optionally substituted heteroaryl or an optionally substituted bicyclic aryl, with the provisos that:

In a particular aspect, the invention provides modulating compounds of Structural Formula (XXVI):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group, wherein at least one of R²⁰or R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is selected from an optionally substituted heteroaryl or an optionally substituted bicyclic aryl.

In another aspect, the invention provides modulating compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

- each R²⁰and R^20ais independently selected from H or a solubilizing group;
- each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and
- R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR—CR₁′R₁′—, —NR₁′—(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(—N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

- provided that when R²¹is —NH—C(O)— and R¹⁹is

R³¹is not unsubstituted pyridyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl or unsubstituted furyl.

In a particular aspect, the invention provides -modulating compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

- each R²⁰and R^20ais independently selected from H or a solubilizing group;
- each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and

each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:

zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group;

zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′, —CR₁′R₁′, —C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—, R¹⁹is not pyrazolyl;

when R²¹is —NH—, and R¹⁹is thiazolyl, R³¹is not optionally substituted phenyl or optionally substituted pyridyl;

when R²¹is —NH—C(O)—CH₂—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted indolyl or unsubstituted phenyl;

when R²¹is —NH—C(O)—CH₂—, and R¹⁹is

R³¹is not 2-methylphenyl or 3,4-dimethoxyphenyl;

when R²¹is —NH—C(O)—CH═CH—, and R¹⁹is

R³¹is not 2-chlorophenyl;

when R²¹is —NH—C(O)—NH—, and R¹⁹is

R³¹is not unsubstituted benzimidazolyl;

when R²¹is —NH—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted pyridyl;

when R^20ais a solubilizing group, R¹⁹is thienyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl;

when R²¹is —NH— and R¹⁹is pyridyl, oxadiazolyl or thiadiazolyl, R³¹is not unsubstituted phenyl, 3-methoxyphenyl or 4-methoxyphenyl;

when R²¹is —NH—C(O)— and R¹⁹is thiazolyl or pyrimidinyl, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)— and R¹⁹is

R³¹is not 3,5-dinitrophenyl, 4-butoxyphenyl,

In a more particular embodiment, the invention provides modulating compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and

each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:

one to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group;

zero to one R₁″ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that

when R²¹is —NH—C(O)—, R¹⁹is not pyrazolyl;

when R²¹is —NH—C(O)—CH₂—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted indolyl or unsubstituted phenyl;

when R^20ais a solubilizing group, R¹⁹is thienyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)— and R¹⁹is thiazolyl or pyrimidinyl, R³¹is not unsubstituted phenyl.

In yet another aspect, the invention provides compounds of Structural Formula (XXVIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²⁹is selected from:

Wherein:

each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′, wherein one of Z₁₀, Z₁₁, Z₁₂or Z₁₃is N; and

zero to one R²⁰is a solubilizing group;

zero to one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁₁—, —NR₁′—S(O)₂—CR₁′R₁—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.

In one aspect, the invention provides modulating compounds of Formula (I):

or a salt thereof where:

Ring A is optionally substituted, fused to another ring or both; and

In another aspect, the invention provides modulating compounds of Formula (II):

or a salt thereof, where:

Ring A is optionally substituted;

R₁, R₂, R₃and R₄are independently selected from the group consisting of —H, halogen, —OR₅, —CN, —CO₂R₅, —OCOR₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)_nR₅, —S(O)_nOR₅, —S(O)_nNR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group; and

n is 1 or 2.

In yet another aspect, the invention provides -modulating compounds of Formula (III):

or a salt thereof, where:

Ring A is optionally substituted;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

R₇, R₉, R₁₀and R₁₁are independently selected from the group consisting of —H, halogen, —R₅, —OR₅, —CN, —CO₂R₅, —OCOR₅, —OCO₂R₅, —C(O)NR₅R₄, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)_nR₅, —S(O)_nOR₅, —S(O)_nNR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₈is a polycyclic aryl group; and

n is 1 or 2.

In another aspect, the invention provides -modulating compounds of Formula (IV):

Ar-L-J-M-K-Ar′ (IV)

or a salt thereof, wherein:

each Ar and Ar′ is independently an optionally substituted carbocyclic or heterocyclic aryl group;

L is an optionally substituted carbocyclic or heterocyclic arylene group;

each M is C(O), S(O), S(O)₂, or CR₁′R₁′;

each R₁′ is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₅′; halo; haloalkyl; CF₃; SR₂′; OR₂′; NR₂′R₂′; NR₂′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)C(O)R₂′; C(O)NR₂′R₂′; OC(O)R₂′; S(O)₂R₂′; S(O)₂NR₂′R₂′; NR₂′C(O)NR₂′R₂′; NR₂′C(O)C(O)R₂′; NR₂′C(O)R₂′; NR₂′(COOR₂′); NR₂′C(O)R₅′; NR₂′S(O)₂NR₂′R₂′; NR₂′S(O)R₂′; NR₂′S(O)₂R₅′; NR₂′C(O)C(O)NR₂′R₂′; NR₂′C(O)C(O)NR₂′R₃′; C1-C10 alkyl substituted with aryl, R₄′ or R₅′; or C2-C10 alkenyl substituted with aryl, R₄′ or R₅′;

each R₃′ is independently C(O)R₂′, COOR₂′, or S(O)₂R₂′;

each R₄′ is independently halo, CF₃, SR₇′, OR₇′, OC(O)R₇′, NR₇′R₇′, NR₇′R₈′, NR₈′R₈′, COOR₇′, NO₂, CN, C(O)R₇′, or C(O)NR₇′R₇′;

each R₅′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₆′; halo; sulfur; oxygen; CF₃; haloalkyl; SR₂′; OR₂′; OC(O)R₂′; NR₂′R₂′; NR₂′R₃; NR₃′R₃′; COOR₂; NO₂; CN; C(O)R₂′; C(O)NR₂′R₂′; C1-C10 alkyl substituted with 1-3 independent R₄′, R₆′, or aryl; or C2-C10 alkenyl substituted with 1-3 independent R₄′, R₆′, or aryl;

each R₇′ is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′;

each R₈′ is independently C(O)R₇′, COOR₇′, or S(O)₂R₇′;

each R₁₁′ is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;

each aryl is independently optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R₆′; halo; haloalkyl; CF₃; OR₉′; SR₉′; NR₉′R₉′; COOR₉′; NO₂; CN; C(O)R₉′; C(O)C(O)R₉′; C(O)NR₉′R₉′; S(O)₂R₉′; N(R₉′)C(O)R₉′; N(R₉′)(COOR₉′); N(R₉′)S(O)₂R₉′; S(O)₂NR₉′R₉′; OC(O)R₉′; NR₉′C(O)NR₉′R₉′; NR₉′C(O)C(O)R₉′; NR₉′C(O)R₆′; NR₉′S(O)₂NR₉′R₉′; NR₉′S(O)₂R₉′; NR₉′C(O)C(O)NR₉′R₉′; C1-C10 alkyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; C2-C10 alkenyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; or R₉′.

In a further aspect, the invention provides -modulating compounds of Formula (IVa):

Het-L-Q-Ar′ (IVa)

or a salt thereof, where:

Het is an optionally substituted heterocyclic aryl group;

L is an optionally substituted carbocyclic or heterocyclic arylene group;

Ar′ is an optionally substituted carbocyclic or heterocyclic aryl group; and

Q is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—,

and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl, wherein:

In still yet another aspect, the invention provides -modulating compounds of Formula (V):

or a salt thereof, wherein:

Ring A is optionally substituted with at least one R₁′ group;

Y₁, Y₂, Y₃, Y₄, and Ys are independently R₁′;

each R₁′ is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₅′; halo; haloalkyl; CF₃; SR₂′; OR₂′; NR₂R₂′; NR₂′R₃; COOR₂′; NO₂; CN; C(O)R₂′; C(O)C(O)R₂′; C(O)NR₂R₂′; OC(O)R₂′; S(O)₂R₂′; S(O)₂NR₂′R₂, NR₂′C(O)NR₂R₂′; NR₂′C(O)C(O)R₂′; NR₂′C(O)R₂; NR₂′(COOR₂); NR₂′C(O)R₅′; NR₂′S(O)₂NR₂′R₂′; NR₂′S(O)₂R₂′; NR₂S(O)₂R₅′; NR₂′C(O)C(O)NR₂′R₂′; NR₂′C(O)C(O)NR₂′R₃′; C1-C10 alkyl substituted with aryl, R₄′ or R₅′; or C2-C10 alkenyl substituted with aryl, R₄′ or R₅′;

each R₃′ is independently C(O)R₂′, COOR₂′, or S(O)₂R₂′;

each R₄′ is independently halo, CF₃, SR₇′, OR₇′, OC(O)R₇′, NR₇′R₇′, NR₇′R₈′, NR₈′R₈′, COOR₇′, NO₂, CN, C(O)R₇′, or C(O)NR₇′R₇′;

each R₅′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₆′; halo; sulfur; oxygen; CF₃; haloalkyl; SR₂′; OR₂′; OC(O)R₂′; NR₂′R₂′; NR₂′R₃′; NR₃′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)NR₂′R₂′; C1-C10 alkyl substituted with 1-3 independent R₄′, R₆′, or aryl; or C2-C10 alkenyl substituted with 1-3 independent R₄′, R₆′, or aryl;

each R₆′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF₃; haloalkyl; SR₇′; OR₇′; NR₇′R₇′; NR₇′R₈′; NR₈′R₈′; COOR₇′; NO₂; CN; C(O)R₇′; or C(O)NR₇′R₇′;

each R₇′ is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′;

each R₈′ is independently C(O)R₇, COOR₇′, or S(O)₂R₇;

each R₁₁′ is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;

each aryl is independently a 5- to 7-membered monocyclic ring system or a 9- to 12-membered bicyclic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R₆; halo; haloalkyl; CF₃; OR₉′; SR₉′; NR₉′R₉; COOR₉′; NO₂; CN; C(O)R₉′; C(O)C(O)R₉′; C(O)NR₉′R₉′; S(O)₂R₉′; N(R₉)C(O)R₉′; N(R₉′)(COOR₉′); N(R₉′)S(O)₂R₉′; S(O)₂NR₉′R₉′; OC(O)R₉′; NR₉′C(O)NR₉′R₉′; NR₉′C(O)C(O)R₉′; NR₉′C(O)R₆; NR₉′S(O)₂NR₉′R₉′; NR₉′S(O)₂R₆′; NR₉′C(O)C(O)NR₉′R₉′; C1-C10 alkyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; C2-C10 alkenyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; or R₉′.

In one aspect, the invention provides -modulating compounds of Structural Formula (VI):

or a salt thereof, wherein:

Het is an optionally substituted heterocyclic aryl group; and

Ar′ is an optionally substituted carbocyclic or heterocyclic aryl group.

The invention also includes prodrugs and metabolites of the compounds disclosed herein.

In another aspect, the invention provides -modulating compounds of Structural Formula (VII):

or a salt thereof, wherein:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁₁—, —NR₁′—C(O)—O—,

and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that said compound is not:

or that when R¹⁹is

and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In certain embodiments, compounds of Structural Formula (VII) have the following values:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

each R²⁰is independently selected from H or a solubilizing group;

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and

zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

said compound is not:

and

when X₈and X₉are each independently selected from CR²⁰or CR₁′, R¹⁹is

and each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰, or CR₁′, then:

- a) at least one of X₈and X₉is not CH; or
- b) at least one of Z₁₀, Z₁₁, Z₁₂and Z₁₃is CR²⁰, wherein R²⁰is a solubilizing group.

In yet another embodiment, the invention provides modulating compounds of Structural Formula (VIII):

a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R₁′ is methyl, and R₂′ is —NH—C(O)—, R³¹is not

1-methoxynaphthyl; 2-methoxynaphthyl; or unsubstituted 2-thienyl;

when R₁′ is methyl, and R²¹is —NH—C(O)—CH═CH—, R³¹is not

when R₁′ is methyl, and R²¹is —NH—C(O)—CH—O—, R³¹is not unsubstituted naphthyl; 2-methoxy, 4-nitrophenyl; 4-chloro, 2-methylphenyl; or 4-t-butylphenyl; and

when R²¹is —NH—C(O)—, R³¹is not optionally substituted phenyl.

In a further embodiment, the invention provides -modulating compounds of Structural Formula (X):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

In one aspect, the invention provides -modulating compounds of Structural Formula (X):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

In another aspect, the invention provides -modulating compounds of Structural Formula (XI):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²²is selected from —NR²³—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁—═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁₁—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—NR₁′—C(O)—O— or —NR₁′—C(O)—CR₁′R₁′—, wherein R²³is an optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²²is —NH—C(O)—CH₂—, R³¹is not 3,4-dimethoxyphenyl, 4-chlorophenyl, or unsubstituted phenyl;

when R²²is —NH—C(O)—CH(CH₃)—O—, R³¹is not 2,4-dichlorophenyl, 4-chlorophenyl, or unsubstituted phenyl; and

when R²²is —NH—S(O)₂—, R³¹is not unsubstituted phenyl.

In yet another aspect, the invention provides -modulating compounds of Structural Formula (XII):

or a salt thereof, wherein:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR₂, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that when R¹⁹is

Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In certain embodiments, the compounds of Structural Formula (XI) have the following values:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₆and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O— or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that

when X₇is N, R¹⁹is

and each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰, or CR₁′, then:

- a) at least one of Xs, X₉or X₁₀is C—(C₁-C₃straight or branched alkyl) or C-(solubilizing group); or
- b) at least one of Z₁₀, Z₁₁, Z₁₂and Z₁₃is CR²⁰, wherein R²⁰is a solubilizing group.

In a further aspect, the invention provides compounds of Structural Formula (XIII):

or a salt thereof; wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁₁—CR₁′R₁′—, —NR₁′—(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—CH(CH₂—CH₃)—, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH₂—, R³¹is not unsubstituted phenyl, 3-methylphenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl or 4-methoxyphenyl;

when R²¹is —NH—C(O)—CH₂—O—, R³¹is not unsubstituted phenyl or 4-chlorophenyl; and

when R²¹is —NH—S(O)₂—, R³¹is not 3,4-dioxymethylene phenyl; 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2,4- or 3,4-dimethylphenyl, 2,5-difluorophenyl, 2,5- or 3,4-dimethoxyphenyl, fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-ethylphenyl, 4-methylphenyl, 3-methyl-4-methoxyphenyl, unsubstituted phenyl, unsubstituted pyridinyl, unsubstituted thienyl, chloro-substituted thienyl, or methyl-substituted benzothiazolyl.

In one aspect, the invention provides modulating compounds of Structural Formula (XIV):

or a salt thereof, wherein:

each of R²³and R²⁴is independently selected from H, —CH₃or a solubilizing group;

R²⁵is selected from H, or a solubilizing group; and

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group; and
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;
- each R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR¹═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR¹′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

- wherein when R¹⁹is

In another aspect, the invention provides -modulating compounds of Structural Formula (XV):

or a salt thereof, wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is selected from an optionally substituted bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein:

when R²¹is —NH—C(O)—, R³²is not unsubstituted 2-furyl, 2-(3-bromofuryl), unsubstituted 2-thienyl, unsubstituted 3-pyridyl, unsubstituted 4-pyridyl,

and

when R²¹is —NR₁′—S(O)₂—, R³²is not unsubstituted 2-thienyl or unsubstituted naphthyl.

In yet another aspect, the invention provides -modulating compounds of Structural Formula (XVI):

or a salt thereof, wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁—CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C—NR—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is an optionally substituted phenyl, wherein:

when R²¹is —NR₁′—C(O)—CR₁′R₁′— or —NH—C(O)—CH(CH₃)—O, R³³is a substituted phenyl;

when R²¹is —NH—C(O)—CH₂, R³³is not unsubstituted phenyl, 4-methoxyphenyl; 3,4-dimethoxyphenyl or 4-chlorophenyl;

when R²¹is —NH—C(O)—CH₂—O, R³³is not 2,4-bis(1,1-dimethylpropyl)phenyl;

when R²¹is —NH—C(O)—NH—, R³³is not 4-methoxyphenyl; and

when R²¹is —NH—S(O)₂—, R³³is a substituted phenyl other than 3-methylphenyl, 3-trifluoromethylphenyl, 2,4,5- or 2,4,6-trimethylphenyl, 2,4- or 3,4-dimethylphenyl, 2,5- or 3,4-dimethoxyphenyl, 2,5-dimethoxy-4-chlorophenyl, 3,6-dimethoxy, 4-methylphenyl, 2,5- or 3,4-dichlorophenyl, 2,5-diethoxyphenyl; 2-methyl-5-nitrophenyl, 2-ethoxy-5-bromophenyl, 2-methoxy-5-bromophenyl, 2-methoxy-3,4-dichlorophenyl, 2-methoxy-4-methyl-5-bromophenyl, 3,5-dinitro-4-methylphenyl, 3-methyl-4-methoxyphenyl, 3-nitro-4-methylphenyl, 3-methoxy-4-halophenyl, 3-methoxy-5-chlorophenyl, 4-n-butoxyphenyl, 4-halophenyl, 4-ethylphenyl, 4-methylphenyl, 4-nitrophenyl, 4-ethoxyphenyl, 4-acetylaminophenyl, 4-methoxyphenyl, 4-t-butylphenyl, or para-biphenyl.

In a further aspect, the invention provides -modulating compounds of Structural Formula (XVII):

or a salt thereof; wherein:

each of R²³and R²⁴is independently selected from H or —CH₃, wherein at least one of R²³and R²⁴is H; and

R²⁹is phenyl substituted with:

a) two —O—CH₃groups;

b) three —O—CH₃groups located at the 2, 3 and 4 positions; or

c) one —N(CH₃)₂group; and;

d) when R²³is CH₃, one —O—CH₃group at the 2 or 3 position, wherein R²⁹is optionally additionally substituted with a solubilizing group.

In one aspect, the invention provides modulating compounds of Structural Formula (XVIII):

or a salt thereof, wherein

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′,

wherein:

zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group; and

zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;

each R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

- R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that when R¹⁹is

Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, R²⁰is H, and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In another aspect, the invention provides -modulating compounds of Structural Formula (XX):

or a salt thereof wherein

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′,

wherein:

- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group; and
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;

each R²⁰is independently selected from H or a solubilizing group;

R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein

- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein when R¹⁹is

and Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, R^20ais a solubilizing group.

In yet another aspect, the invention provides -modulating compounds of Structural Formula (XXI):

or a salt thereof, wherein

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′, —CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein

- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is an optionally substituted monocyclic or bicyclic heteroaryl, or an optionally substituted bicyclic aryl, wherein:

when R²¹is —NH—C(O)—CH₂—, R³²is not unsubstituted thien-2-yl;

when R²¹is —NH—C(O)—, R³²is not furan-2-yl, 5-bromofuran-2-yl, or 2-phenyl-4-methylthiazol-5-yl;

when R²¹is —NH—S(O)₂—, R³²is not unsubstituted naphthyl or 5-chlorothien-2-yl.

In a further aspect, the invention provides modulating compounds of Structural Formula (XXII):

or a salt thereof, wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is an optionally substituted phenyl, wherein:

when R²¹is —NR₁′—C(O)—, R₁′ is not H;

when R²¹is —NH—C(O)—CH₂or —NH—C(O)—CH₂—O—, R³³is not unsubstituted phenyl or 4-halophenyl; and

In one aspect, the invention provides modulating compounds of Structural Formula (XXII):

or a salt thereof wherein:

R²¹is selected from —NH—C(O)—, or —NH—C(O)—CH₂—; and

R³³is phenyl substituted with

a) one —N(CH₃)₂group;

b) one CN group at the 3 position;

c) one —S(CH₃) group; or

bridging the 3 and 4 positions.

In another aspect, the invention provides -modulating compounds of Structural Formula (XXIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—, R³¹is not 3,5-nitrophenyl, 4-butoxyphenyl,

when R²¹is —NH—C(O)— and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not

when R²¹is —NH—C(O)—, R₁″ is methyl; and each R²⁰, R^20a, R₁′ and R₁′″ is hydrogen, R³¹is not 2-methylaminophenyl,

when R²¹is —NH—C(O)—CH₂— or NH—C(S)—NH—, and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—S(O)₂—, R₁″ is hydrogen or methyl, and each of R²⁰, R^20a, R₁′ and R₁′″ is hydrogen, R³¹is not 4-methylphenyl; and

when R²¹is —NH—S(O)₂—, R²⁰is hydrogen or —CH₂—N(CH₂CH₃)₂, and each of R²⁰, R₁′, R₁″ and R₁′″ is hydro en, R³¹is not

In a particular aspect, the invention provides: -modulating compounds of Structural Formula (XXIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

wherein:

i) at least one R²⁰is a solubilizing group or at least one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl or both; or
ii) R^20ais a solubilizing group other than CH₂—N(CH₂CH₃)₂.

In yet another aspect, the invention provides modulating compounds of Structural Formula (XXIV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR²³—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—CH₂—, R³¹is not 2-methylphenyl, or 3,4-dimethoxyphenyl;

when R²¹is —NH—C(O)—CH═CH—, R³¹is not 2-chlorophenyl;

when R²¹is —NH—C(O)—NH—, R³¹is not unsubstituted benzimidazolyl;

when R²¹is —NH—S(O)₂—, and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl, 4-chlorophenyl, 4-methylphenyl, or 4-acetoamidophenyl;

when R²¹is —NH—S(O)₂—, each of R₁′ and R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, and R₁″ is hydrogen, R³¹is not 4-nitrophenyl;

when R²¹is —NH—C(O)—CH₂—, R₁′ is methyl, and each of R²⁰, R^20a, R₁″, and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH(CH₂CH₃)—, and each of R²⁰, R^20a, R₁′, R₁″, and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH(CH₃)—O—, R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, R₁′, and R₁″ is hydrogen, R³¹is not 2,4-dichlorophenyl.

In a particular aspect, the invention provides -modulating compounds of Structural Formula (XXIV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group and at least one of R²⁰and R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR²³—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—, wherein R²³is an optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.

In a further aspect, the invention provides -modulating compounds of Structural Formula (XXV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group, wherein at least one of R²⁰and R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is an optionally substituted phenyl.

In one aspect, the invention provides modulating compounds of Structural Formula (XXVI):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is selected from an optionally substituted heteroaryl or an optionally substituted bicyclic aryl, with the provisos that:

In a particular aspect, the invention provides: -modulating compounds of Structural Formula (XXVI):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group, wherein at least one of R²⁰or R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is selected from an optionally substituted heteroaryl or an optionally substituted bicyclic aryl.

In another aspect, the invention provides modulating compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

- each R²⁰and R^20ais independently selected from H or a solubilizing group;
- each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and
- R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

- provided that when R²¹is —NH—C(O)— and R¹⁹is

R³¹is not unsubstituted pyridyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl or unsubstituted furyl.

In a particular aspect, the invention provides -modulating compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

- each R²⁰and R^20ais independently selected from H or a solubilizing group;
- each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and

each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:

zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group;

zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)_z—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—, R¹⁹is not pyrazolyl;

when R²¹is —NH—, and R¹⁹is thiazolyl, R³¹is not optionally substituted phenyl or optionally substituted pyridyl;

when R²¹is —NH—C(O)—CH₂—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted indolyl or unsubstituted phenyl;

when R²¹is —NH—C(O)—CH₂—, and R¹⁹is

R³¹is not 2-methylphenyl or 3,4-dimethoxyphenyl;

when R²¹is —NH—C(O)—CH═CH—, and R¹⁹is

R³¹is not 2-chlorophenyl;

when R²¹is —NH—C(O)—NH—, and R¹⁹is

R³¹is not unsubstituted benzimidazolyl;

when R²¹is —NH—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted pyridyl;

when R^20ais a solubilizing group, R¹⁹is thienyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl;

when R²¹is —NH— and R¹⁹is pyridyl, oxadiazolyl or thiadiazolyl, R³¹is not unsubstituted phenyl, 3-methoxyphenyl or 4-methoxyphenyl;

when R²¹is —NH—C(O)— and R¹⁹is thiazolyl or pyrimidinyl, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)— and R¹⁹is

R³¹is not 3,5-dinitrophenyl, 4-butoxyphenyl,

In a more particular embodiment, the invention provides -modulating compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and

each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:

one to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group;

zero to one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that

when R²¹is —NH—C(O)—, R¹⁹is not pyrazolyl;

when R²¹is —NH—C(O)—CH₂—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted indolyl or unsubstituted phenyl;

when R^20ais a solubilizing group, R¹⁹is thienyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl;

when R²⁰is a solubilizing group, R¹⁹is methylimidazolyl and R²¹is —NH—C(O)—, R³¹is not 1-methyl-4-(1,1-dimethylethyloxycarbonylamino)pyrrol-2-yl or phenyl singly substituted with a solubilizing group; and

when R²¹is —NH—C(O)— and R¹⁹is thiazolyl or pyrimidinyl, R³¹is not unsubstituted phenyl.

In yet another aspect, the invention provides compounds of Structural Formula (XXVII):

or a salt thereof wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²⁹is selected from:

wherein:

each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′, wherein one of Z₁₀, Z₁₁, Z₁₂or Z₁₃is N; and

zero to one R²⁰is a solubilizing group;

zero to one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.

In one aspect, the invention provides modulating compounds of Formula (I):

or a salt thereof, where:

Ring A is optionally substituted, fused to another ring or both; and

In another aspect, the invention provides -modulating compounds of Formula (II):

or a salt thereof, where:

Ring A is optionally substituted;

R₁, R₂, R₃and R₄are independently selected from the group consisting of —H, halogen, —OR₅, —CN, —CO₂R₅, —OCOR₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)_nR₅, —S(O)_nOR₅, —S(O)_nNR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group; and

n is 1 or 2.

In yet another aspect, the invention provides: -modulating compounds of Formula (III):

or a salt thereof, where:

Ring A is optionally substituted;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

R₈is a polycyclic aryl-group; and

n is 1 or 2.

In another aspect, the invention provides -modulating compounds of Formula (IV):

Ar-L-J-M-K-Ar′ (IV)

or a salt thereof, wherein:

each Ar and Ar′ is independently an optionally substituted carbocyclic or heterocyclic aryl group;

L is an optionally substituted carbocyclic or heterocyclic arylene group;

each M is C(O), S(O), S(O)₂, or CR₁′R₁′;

each R₁′ is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₅′; halo; haloalkyl; CF₃; SR₂′; OR₂′; NR₂′R₂′; NR₂′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)C(O)R₂′; C(O)NR₂′R₂′; OC(O)R₂; S(O)₂R₂′; S(O)₂NR₂′R₂; NR₂′C(O)NR₂′R₂′; NR₂′C(O)C(O)R₂′; NR₂′C(O)R₂′; NR₂′(COOR₂′); NR₂′C(O)R₅′; NR₂′S(O)₂NR₂′R₂′; NR₂′S(O)₂R₂′; NR₂′S(O)₂R₅′; NR₂′C(O)C(O)NR₂′R₂′; NR₂′C(O)C(O)NR₂′R₃′; C1-C10 alkyl substituted with aryl, R₄′ or R₅′; or C2-C10 alkenyl substituted with aryl, R₄′ or R₅′;

each R₃′ is independently C(O)R₂′, COOR₂′, or S(O)₂R₂′;

each R₄′ is independently halo, CF₃, SR₇′, OR₇′, OC(O)R₇′, NR₇′R₇′, NR₇′R₈′, NR₈′R₈′, COOR₇′, NO₂, CN, C(O)R₇′, or C(O)NR₇′R₇′;

each R₅′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₆′; halo; sulfur, oxygen; CF₃; haloalkyl; SR₂′, OR₂′; OC(O)R₂′; NR₂′R₂′; NR₂′R₃′; NR₃′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)NR₂′R₂′; C1-C10 alkyl substituted with 1-3 independent R₄′, R₆′, or aryl; or C2-C10 alkenyl substituted with 1-3 independent R₄′, R₆′ or aryl;

each R₆′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF₃; haloalkyl; SR₇′; OR₇′; NR₇′R₇′; NR₇′R₈′; NR₈′R₈′; COOR₇′; NO₂; CN; C(O)R₇′; or C(O)NR₇′R₇′;

each R₇′ is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′;

each R₈′ is independently C(O)R₇′, COOR₇′, or S(O)₂R₇′;

each aryl is independently optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R₆′; halo; haloalkyl; CF₃; OR₉′; SR₉′; NR₉′R₉′; COOR₉′; NO₂; CN; C(O)R₉′; C(O)C(O)R₉′; C(O)NR₉′R₉′; S(O)₂R₉′; N(R₉′)C(O)R₉′; N(R₉′)(COOR₉′); N(R₉′)S(O)₂R₉′; S(O)₂NR₉′R₉′; OC(O)R₉′; NR₉′C(O)NR₉′R₉′; NR₉′C(O)C(O)R₉′; NR₉′C(O)R₆′; NR₉′S(O)₂NR₉′R₉′; NR₉′S(O)₂R₆′; NR₉′C(O)C(O)NR₉′R₉′; C1-C10 alkyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; C2-C10 alkenyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; or R₉′.

In a further aspect, the invention provides -modulating compounds of Formula (IVa):

Het-L-Q-Ar′ (IVa)

or a salt thereof, where:

Het is an optionally substituted heterocyclic aryl group;

L is an optionally substituted carbocyclic or heterocyclic arylene group;

Ar′ is an optionally substituted carbocyclic or heterocyclic aryl group; and

Q is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁₁—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—,

and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl, wherein:

when Het is a polycyclic heteroaryl, L is an optionally substituted phenylene, Q and Het are attached to L in a meta orientation; and Ar′ is optionally substituted phenyl; then Q is not —NH—C(O)—.

In still yet another aspect, the invention provides modulating compounds of Formula (V):

or a salt thereof, wherein:

Ring A is optionally substituted with at least one R₁′ group;

Y₁, Y₂, Y₃, Y₄, and Y₅are independently R₁′;

each R₁′ is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₅′; halo; haloalkyl; CF₃; SR₂; OR₂′; NR₂′R₂′; NR₂′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)C(O)R₂′; C(O)NR₂′R₂′; OC(O)R₂′; S(O)₂R₂′; S(O)₂NR₂′R₂; NR₂′C(O)NR₂′R₂′; —NR₂′C(O)C(O)C(O)R₂′; NR₂′C(O)R₂′; NR₂′(COOR₂′); NR₂′C(O)R₅′; NR₂′S(O)₂NR₂′R₂′; NR₂S(O)₂R₂′; NR₂′S(O)₂R₅′; NR₂′C(O)C(O)NR₂′R₂′; NR₂′C(O)C(O)NR₂′R₃′; C1-C10 alkyl substituted with aryl, R₄′ or R₅′; or C2-C10 alkenyl substituted with aryl, R₄′ or R₅′;

each R₃′ is independently C(O)R₂′, COOR₂′, or S(O)₂R₂′;

each R₄′ is independently halo, CF₃, SR₇′, OR₇′, OC(O)R₇′, NR₇′R₇′, NR₇′R₈′, NR₈′R₈′, COOR₇′, NO₂, CN, C(O)R₇′, or C(O)NR₇′R₇′;

each R₅′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₆′; halo; sulfur; oxygen; CF₃; haloalkyl; SR₂′; OR₂′; OC(O)R₂′; NR₂′R₂′; NR₂′R₃′; NR₃′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)NR₂′R₂′; C1-C10 alkyl substituted with 1-3 independent R₄′, R₆′, or aryl; or C2-C10 alkenyl substituted with 1-3 independent R₄′, R₆′, or aryl;

each R₆′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF₃; haloalkyl; SR₇′; OR₇′; NR₇′R₇′; NR₇′R₈′; NR₈′R₈′; COOR₇′; NO₂; CN; C(O)R₇′; or C(O)NR₇′R₇′;

each R₇′ is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′;

each R₈′ is independently C(O)R₇′, COOR₇′, or S(O)₂R₇′;

each R₁₁′ is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; C1-C10 alkyl optionally substituted with halo, CF₃, OR₁₁′, SR₁₁′, NR₁₁′R₁₁′, COOR₁₁′, NO₂, CN; or phenyl optionally substituted with halo, CF₃, OR₁₁′, SR₁₁′, NR₁₁′R₁₁′, COOR₁₁′, NO₂, CN;

each R₁₁′ is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;

each haloalkyl is independently a C1-C10 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group; and each aryl is independently a 5- to 7=membered monocyclic ring system or a 9- to 12-membered bicyclic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R₆′; halo; haloalkyl; CF₃; OR₉′; SR₉′; NR₉′R₉′; COOR₉′; NO₂; CN; C(O)R₉′; C(O)C(O)R₉′; C(O)NR₉′R₉′; S(O)₂R₉′; N(R₉′)C(O)R₉′; N(R₉′)(COOR₉′); N(R₉′)S(O)₂R₉′; S(O)₂NR₉′R₉′; OC(O)R₉′; NR₉′C(O)NR₉′R₉′; NR₉′C(O)C(O)R₉′; NR₉′C(O)R₆′; NR₉′S(O)₂NR₉′R₉′; NR₉′S(O)₂R₆′; NR₉′C(O)C(O)NR₉′R₉′; C1-C10 alkyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; C2-C10 alkenyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; or R₉′.

In one aspect, the invention provides -modulating compounds of Structural Formula (VI):

or a salt thereof, wherein:

Het is an optionally substituted heterocyclic aryl group; and

Ar′ is an optionally substituted carbocyclic or heterocyclic aryl group.

The invention also includes prodrugs and metabolites of the compounds disclosed herein.

In another aspect, the invention provides -modulating compounds of Structural Formula (VII):

or a salt thereof, wherein:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —CR₁′R₁′—, —NR₁′—C(O)—O—,

and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that said compound is not.

that when R¹⁹is

and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In certain embodiments, compounds of Structural Formula (VII) have the following values:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

each R²⁰is independently selected from H or a solubilizing group;

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and

zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂, or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁—)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

said compound is not:

and

when X₈and X₉are each independently selected from CR²⁰or CR₁′, R¹⁹is

and each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰, or CR₁′, then:

- a) at least one of X₈and X₉is not CH; or
- b) at least one of Z₁₀, Z₁₁, Z₁₂and Z₁₃is CR²⁰, wherein R²⁰is a solubilizing group.

In yet another embodiment, the invention provides modulating compounds of Structural Formula (VIII):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R₁′ is methyl, and R²¹is —NH—C(O)—, R³¹is not

1-methoxynaphthyl; 2-methoxynaphthyl; or unsubstituted 2-thienyl;

when R₁′ is methyl, and R²¹is —NH—C(O)—CH═CH—, R³¹is not

when R₁′ is methyl, and R²¹is —NH—C(O)—CH—O—, R³¹is not unsubstituted naphthyl; 2-methoxy, 4-nitrophenyl; 4-chloro, 2-methylphenyl; or 4-t-butylphenyl; and

when R²¹is —NH—C(O)—, R³¹is not optionally substituted phenyl.

In a further embodiment, the invention provides -modulating compounds of Structural Formula (IX):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

In one aspect, the invention provides -modulating compounds of Structural Formula (X):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

In another aspect, the invention provides modulating compounds of Structural Formula (XI):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R₂₂is selected from —NR²³—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—; —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O— or —NR₁′—C(O)—CR₁′R₁′—, wherein R²³is an optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²²is —NH—C(O)—CH₂—, R³¹is not 3,4-dimethoxyphenyl, 4-chlorophenyl, or unsubstituted phenyl;

when R²²is —NH—C(O)—CH(CH₃)—O—, R³¹is not 2,4-dichlorophenyl, 4-chlorophenyl, or unsubstituted phenyl; and

when R²²is —NH—S(O)₂—, R³¹is not unsubstituted phenyl.

In yet another aspect, the invention provides -modulating compounds of Structural Formula (XII):

or a salt thereof, herein:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that when R¹⁹is

Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In certain embodiments, the compounds of Structural Formula (XI) have the following values:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O— or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that:

when X₇is N, R¹⁹is

and each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰, or CR₁′, then:

- a) at least one of X₈, X₉or X_fo is C—(C₁-C₃straight or branched alkyl) or C-(solubilizing group); or
- b) at least one of Z₁₀, Z₁₁, Z₁₂and Z₁₃is CR²⁰, wherein R²⁰is a solubilizing group.

In a further aspect, the invention provides compounds of Structural Formula (XIII):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

R³¹is selected form an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—CH(CH₂—CH₃)—, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH₂—, R³¹is not unsubstituted phenyl, 3-methylphenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl or 4-methoxyphenyl;

when R²¹is —NH—C(O)—CH₂—O—, R³¹is not unsubstituted phenyl or 4-chlorophenyl; and

In one aspect, the invention provides -modulating compounds of Structural Formula (XIV):

or a salt thereof, wherein:

each of R²³and R²⁴is independently selected from H, —CH₃or a solubilizing group;

R²⁵is selected from H, or a solubilizing group; and

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, ZS and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group; and
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;
- each R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

- wherein when R¹⁹is

In another aspect, the invention provides -modulating compounds of Structural Formula (XV):

or a salt thereof, wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′R₁′—, —NR₁′—C(O)—O—,

and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is selected from an optionally substituted bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein:

when R²¹is —NH—C(O)—, R³²is not unsubstituted 2-furyl, 2-(3-bromofuryl), unsubstituted 2-thienyl, unsubstituted 3-pyridyl, unsubstituted 4-pyridyl,

when R²¹is —NR₁′—S(O)₂—, R³²is not unsubstituted 2-thienyl or unsubstituted naphthyl.

In yet another aspect, the invention provides modulating compounds of Structural Formula (XVI):

or a salt thereof, wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is an optionally substituted phenyl, wherein:

when R²¹is —NR₁′—C(O)—CR₁′R₁′— or —NH—C(O)—CH(CH₃)—O, R³³is a substituted phenyl;

when R²¹is —NH—C(O)—CH₂, R³³is not unsubstituted phenyl, 4-methoxyphenyl; 3,4-dimethoxyphenyl or 4-chlorophenyl;

when R²¹is —NH—C(O)—CH₂—O, R³³is not 2,4-bis(1,1-dimethylpropyl)phenyl;

when R²¹is —NH—C(O)—NH—, R³³is not 4-methoxyphenyl; and

In a further aspect, the invention provides -modulating compounds of Structural Formula (XVII):

or a salt thereof, wherein:

each of R²³and R²⁴is independently selected from H or —CH₃, wherein at least one of R²³and R²⁴is H; and

R²⁹is phenyl substituted with:

a) two —O—CH₃groups;

b) three —O—CH₃groups located at the 2, 3 and 4 positions; or

c) one —N(CH₃)₂group; and;

d) when R²³is CH₃, one —O—CH₃group at the 2 or 3 position, wherein R²⁹is optionally additionally substituted with a solubilizing group.

In one aspect, the invention provides -modulating compounds of Structural Formula (XVIII):

or a salt thereof, wherein

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′,

wherein:

zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group; and

zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;

each R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁₁—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that when R¹⁹is

Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, R²⁰is H, and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In another aspect, the invention provides -modulating compounds of Structural Formula (XX):

or a salt thereof, wherein

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′,

wherein:

- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group; and
- zero to one R₁′ is an optionally substituted C1-C3 straight or branched alkyl;

each R²⁰is independently selected from H or a solubilizing group;

R^20ais independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′-C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁—CR₁′R₁—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein

- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein when R¹⁹is

and Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, R^20ais a solubilizing group.

In yet another aspect, the invention provides modulating compounds of Structural Formula (XXI):

or a salt thereof, wherein

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein

- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is an optionally substituted monocyclic or bicyclic heteroaryl, or an optionally substituted bicyclic aryl, wherein:

when R²¹is —NH—C(O)—CH₂—, R³²is not unsubstituted thien-2-yl;

when R²¹is —NH—C(O)—, R³²is not furan-2-yl, 5-bromofuran-2-yl, or 2-phenyl-4-methylthiazol-5-yl;

when R²¹is —NH—S(O)₂—, R³²is not unsubstituted naphthyl or 5-chlorothien-2-yl.

In a further aspect, the invention provides -modulating compounds of Structural Formula (XXII):

or a salt thereof, wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is an optionally substituted phenyl, wherein:

when R²¹is —NR₁′—C(O)—, R₁′ is not H;

when R²¹is —NH—C(O)—CH₂or —NH—C(O)—CH₂—O—, R³³is not unsubstituted phenyl or 4-halophenyl; and

In one aspect, the invention provides modulating compounds of Structural Formula (XXII):

or a salt thereof wherein:

R²¹is selected from —NH—C(O)—, or —NH—C(O)—CH₂—; and

R³³is phenyl substituted with

a) one —N(CH₃)₂group;

b) one CN group at the 3 position;

c) one —S(CH₃) group; or

bridging the 3 and 4 positions.

In another aspect, the invention provides— modulating compounds of Structural Formula (XXIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—, R³¹is not is not 3,5-dinitrophenyl, 4-butoxyphenyl

when R²¹is —NH—C(O)— and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not

when R²¹is —NH—C(O)—, R₁″ is methyl; and each of R²⁰, R^20a, R₁′ and R₁′″ is hydrogen, R³¹is not 2-methylaminophenyl,

when R²¹is —NH—C(O)—CH₂— or NH—C(S)—NH—, and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—S(O)₂—, R₁″ is hydrogen or methyl, and each of R²⁰, R^20a, R₁′ and R₁′″ is hydrogen, R³¹is not 4-methylphenyl; and

when R²¹is —NH—S(O)₂—, R^20ais hydrogen or —CH₂—N(CH₂CH₃)₂, and each of R²⁰, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not

In a particular aspect, the invention provides -modulating compounds of Structural Formula (XXIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein:

i) at least one R²⁰is a solubilizing group or at least one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl or both; or
ii) R^20ais a solubilizing group other than CH₂—N(CH₂CH₃)₂.

In yet another aspect, the invention provides modulating compounds of Structural Formula (XXIV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R¹″ and R¹′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR²³—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—CH₂—, R³¹is not 2-methylphenyl, or 3,4-dimethoxyphenyl;

when R²¹is —NH—C(O)—CH═CH—, R³¹is not 2-chlorophenyl;

when R²¹is —NH—C(O)—NH—, R³¹is not unsubstituted benzimidazolyl;

when R²¹is —NH—S(O)₂—, and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl, 4-chlorophenyl, 4-methylphenyl, or 4-acetoamidophenyl;

when R²¹is —NH—S(O)₂—, each of R₁′ and R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, and R₁″ is hydrogen, R³¹is not 4-nitrophenyl;

when R²¹is —NH—C(O)—CH₂—O—, R₁′″ is methyl or hydrogen; and each of R²⁰, R^20a, R₁′, and R₁″ is hydrogen, R³¹is not 2,3-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,4-dichloromethyl, 2,4-dimethyl-6-bromophenyl, 2- or 4-chlorophenyl, 2-(1-methylpropyl)phenyl, 5-methyl-2-(1-methylethyl)phenyl, 2- or 4-methylphenyl, 2,4-dichloro-6-methylphenyl, nitrophenyl, 2,4-dimethyl-6-nitrophenyl, 2- or 4-methoxyphenyl, 4-acetyl-2-methoxyphenyl, 4-chloro-3,5-dimethylphenyl, 3-ethylphenyl, 4-bromophenyl, 4-cyclohexyphenyl, 4-(1-methylpropyl)phenyl, 4-(1-methylethyl)phenyl, 4-(1,1-dimethylethyl)phenyl, or unsubstituted phenyl;

when R²¹is —NH—C(O)—CH₂—, R₁′ is methyl, and each of R²⁰, R^20a, R₁″, and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH(CH₂CH₃)—, and each of R²⁰, R^20a, R₁′, R₁″, and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH(CH₃)—O—, R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, R₁′, and R₁″ is hydrogen, R³¹is not 2,4-dichlorophenyl.

In a particular aspect, the invention provides -modulating compounds of Structural Formula (XXIV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group and at least one of R²⁰and R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR²³—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—, wherein R²³is an optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.

In a further aspect, the invention provides modulating compounds of Structural Formula (XXV):

or a salt hereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group, wherein at least one of R²⁰and R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is an optionally substituted phenyl.

In one aspect, the invention provides modulating compounds of Structural Formula (XXVI):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is selected from an optionally substituted heteroaryl or an optionally substituted bicyclic aryl, with the provisos that:

In a particular aspect, the invention provides modulating compounds of Structural Formula (XXVI):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group, wherein at least one of R²⁰or R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is selected from an optionally substituted heteroaryl or an optionally substituted bicyclic aryl.

In another aspect, the invention provides modulating compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

- each R²⁰and R^20ais independently selected from H or a solubilizing group;
- each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and
- R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR¹′R₁′—NR₁′—, —NR₁′—C(═NR₁′—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

- provided that when R²¹is —NH—C(O)— and R¹⁹is

R³¹is not unsubstituted pyridyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl or unsubstituted furyl.

In a particular aspect, the invention provides -modulating compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

- each R²⁰and R^20ais independently selected from H or a solubilizing group;
- each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and

each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:

zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group;

zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—, R¹⁹is not pyrazolyl;

when R²¹is —NH—, and R¹⁹is thiazolyl, R³¹is not optionally substituted phenyl or optionally substituted pyridyl;

when R²¹is —NH—C(O)—CH₂—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted indolyl or unsubstituted phenyl;

when R²¹is —NH—C(O)—CH₂—, and R¹⁹is

R³¹is not 2-methylphenyl or 3,4-dimethoxyphenyl;

when R²¹is —NH—C(O)—CH═CH—, and R¹⁹is

R³¹is not 2-chlorophenyl;

when R²¹is —NH—C(O)—NH—, and R¹⁹is

R³¹is not unsubstituted benzimidazolyl;

when R²¹is —NH—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted pyridyl;

when R^20ais a solubilizing group, R¹⁹is thienyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl;

when R²¹is —NH— and R¹⁹is pyridyl, oxadiazolyl or thiadiazolyl, R³¹is not unsubstituted phenyl, 3-methoxyphenyl or 4-methoxyphenyl;

when R²¹is —NH—C(O)— and R¹⁹is thiazolyl or pyrimidinyl, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)— and R¹⁹is

R³¹is not 3,5-dinitrophenyl, 4-butoxyphenyl,

In a more particular embodiment, the invention provides: -modulating compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and

each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:

one to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group;

zero to one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—, R¹⁹is not pyrazolyl;

when R²¹is —NH—C(O)—CH₂—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted indolyl or unsubstituted phenyl;

when R^20ais a solubilizing group, R¹⁹is thienyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)— and R¹⁹is thiazolyl of pyrimidinyl, R³¹is not unsubstituted phenyl.

In yet another aspect, the invention provides compounds of Structural Formula (XXVIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²⁹is selected from:

wherein:

each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′, wherein one of Z₁₀, Z₁₁, Z₁₂or Z₁₃is N; and

zero to one R²⁰is a solubilizing group;

zero to one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′—CR₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.

In one aspect, the invention provides novel -modulating compounds of Formula (I):

or a salt thereof, where:

Ring A is an optionally substituted, aliphatic, carbocyclic or heterocyclic ring;

R₁and R₂are independently halogen, —OR₄, CN, —CO₂R₄, —OCOR₄, —OCO₂R₄, —C(O)NR₄R₅, —OC(O)NR₄R₅, —C(O)R₄, —COR₄, —SR₄, —OSO₃H, —S(O)_nR₄, —S(O)_nOR₄, —S(O)_nNR₄R₅, —NR₄R₅, —NR₄C(O)OR₅, —NR₄C(O)R₅and —NO₂, or R₁and R₂taken together are ═O, ═S or ═N;

R₄and R₅are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

Cy₁and Cy₂are independently cyclic groups optionally fused to Ring A;

Y and Z are independently CH, N, O or S, provided that O and S are not adjacent to another O or S;

n is 1 or 2; and

x is 0 or 1.

In another aspect, the invention provides novel -modulating compounds of Formula (III):

or a salt thereof, here:

R₄and R₅are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

R₇is —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

R₈is —H;

R₉is a substituted or unsubstituted aryl group;

R₁₀is a substituted or unsubstituted aryl group;

R₁₁is —H;

R₁₂is a substituted or unsubstituted aryl group;

R₁₃and R₁₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR₄, —CN, —CO₂R₄, —OCOR₄, —OCO₂R₄, —C(O)NR₄R₅, —OC(O)NR₄R₅, —C(O)R₄, —COR₄, —SR₄, —OSO₃H, —S(O)R₄, —S(O)OR₄, —S(O)NR₄R₅, —NR₄R₅, —NR₄C(O)OR₅, —NR₄C(O)R₅and —NO₂; and

n is 1 or 2.

The invention also includes salts, prodrugs and metabolites of the compounds disclosed herein.

Also provided are pharmaceutical compositions comprising one or more compounds of Formulas (I)-(IV) or a salt, prodrug or metabolite thereof.

In another aspect, the invention provides methods for using -modulating compounds, or compostions comprising modulating compounds.

In one aspect, the invention provides novel -modulating compounds of Formula (I):

or a salt thereof, where:

Ring A is optionally substituted with one or more substituents in addition to the substituent indicated in Structural Formula (I)

Ar is a substituted or unsubstituted aryl group;

R₁is —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group, typically —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

R₂and R₃are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR₄, —CN, —CO₂R₄, —OCOR₄, —OCO₂R₄, —C(O)NR₄R₅, —OC(O)NR₄R₅, —C(O)R₄, —COR⁴, —SR₄, —OSO₃H, —S(O)_nR₄, —S(O)_nOR₄, —S(O)NR₄R₅, —NR₄R₅, —NR₄C(O)OR₅, —NR₄C(O)R₅and —NO₂;

R₄and R₅are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

Z is CH or N; and

n is 1 or 2.

In another aspect, the invention provides novel modulating compounds of Formula (II):

or a salt thereof, where:

Rings A and B are optionally substituted with one or more substituents in addition to the substituents indicated in Structural Formula (II)

Ar₁and Ar₂are independently a substituted or unsubstituted aryl group;

R₁, R₆and R₈are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

R₄and R₅are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

R₇is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR₄, —CN, —CO₂R₄, —OCOR₄, —OCO₂R₄, —C(O)NR₄R₅, —OC(O)NR₄R₅, —C(O)R₄, —COR₄, —SR₄, —OSO₃H, —S(O)_nR₄, —S(O)_nOR₄, —S(O)_nNR₄R₅, —NR₄R₅, —NR₄C(O)OR₅, —NR₄C(O)R₅and —NO₂; and

n is 1 or 2.

In yet another aspect, the invention provides novel -modulating compounds of Structural Formula (IVa):

or a salt thereof, wherein:

Ring C is a substituted or unsubstituted 5-, 6- or 7-membered ring;

Ar₁is a substituted or unsubstituted aryl group;

R₁, R₆and R₁₀are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

R₄and R₅are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

R₇is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR₄, —CN, —CO₂R₄; —OCOR₄, —OCO₂₄, —C(O)NR₄R₅, —OC(O)NR₄R₅, —C(O)R₄, —COR₄, —SR₄, —OSO₃H, —S(O)_nR₄, —S(O)_nOR₄, —S(O)NR₄R₅, —NR₄R₅, —NR₄C(O)OR₅, —NR₄C(O)R₅and —NO₂;

R₉is —H, a substituted or unsubstituted acyl group, a substituted or unsubstituted aminocarbonyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

R₁₁is —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X and Y are independently CH or N; and

n is 1 or 2.

A particular group of compounds represented by Structural Formula (IVa) are represented by Structural Formula (IVb)

or a salt thereof, where:

Ar₁is a substituted or unsubstituted aryl group;

R₁, R₆and R₁₀are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

R₄and R₅are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

R₇is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR₄, —CN, —CO₂R₄, —OCOR₄, —OCO₂R₄, —C(O)NR₄R₅, —OC(O)NR₄R₅, —C(O)R₄, —COR₄, —SR₄, —OSO₃H, —S(O)_nR₄, —S(O)_nOR₄, —S(O)_nN₄R₅, —NR₄R₅, —NR₄C(O)OR₅, —NR₄C(O)R₅and —NO₂;

R₁₁is —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X and Y are independently CH or N; and

n is 1 or 2.

The invention also includes salts, prodrugs and metabolites of the compounds disclosed herein.

In one aspect, the invention provides novel -modulating compounds of Formula (I):

or a salt thereof, where, as valence permits:

Ring A is optionally substituted;

R₁and R₂are independently selected from —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR₄, —CN, —CO₂R₄, —OCOR₄, —OCO₂R₄, —C(O)NR₄R₅, —OC(O)NR₄R₅, —C(O)R₄, —COR₄, —SR₄, —OSO₂H, —S(O)_nR₄, —S(O)_nOR₄, —S(O)_nNR₄R₅, —NR₄R₅, —NR₄C(O)ORS, —NR₄C(O)R₅and —NO₂, or R₁and R₂taken together with the atoms to which they are attached form an optionally substituted ring;

L is selected from —CH═CH—C(O)—, —CH₂—N(R₄)—C(O)—, —C(O)—CH₂—, —C(O)NR₄—, —C(O)—N(R₄)—C(O)—, —C(O)—N(R₄)—N(R₅)—, —C(O)—N(R₄)—N(R₅)—C(O)—, —CH₂—N(R₄)—N(R₅)—, —N(R₄)—S(O)₂—, S(O)₂—N(R₄)—, —N(R₅)—C(O)—, —N(R₄—N(R₅)—CH₂, —N(R₄)—N(R₅)— or

R₃, R₄and R₅are, independently for each occurrence, —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

Y is selected from O, S, or NR₄;

each of X₆, X₇, X₈and X₉is independently selected from CR₇, C, or N, wherein at least two of X₆, X₇, X₈or X₉are not N;

each R₇is independently selected from H or (C₁-C₃)-straight or branched alkyl; and

n is 1 or 2.

In another aspect, the invention provides novel modulating compounds of Formula (II):

or a salt thereof, where:

Rings B and C are independently optionally substituted;

L is —NR₄R₅—, —C(O)O—, —C(O)NR₄—, —NR₄C(O)—, —NR₄—NR₅—C(O)—, —C(O)—NR₄—NR₅— or —CHR₄═CHR₅—; and

R₃, R₄and R₅are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group.

In yet another aspect, the invention provides novel: modulating compounds of Formula (III):

or a salt thereof, where, as valence permits:

Ring D is optionally substituted;

Ar is a substituted or unsubstituted aryl group;

R₂is selected from —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR₄, —CN, —CO₂R₄, —OCOR₄, —OCO₂R₄, —C(O)NR₄R₅, —OC(O)NR₄, —C(O)R₄, —COR₄, —SR₄, —OSO₃H, —S(O)_nR₄, —S(O)_nOR₄, —S(O)_nNR₄R₅, —NR₄R₅, —NR₄C(O)OR₅, —NR₄C(O)R₅and —NO₂;

L is —C(O)NR₄—, —NR₄C(O)—, —NR₄—NR₅—C(O)—, —C(O)—NR₄—NR₅— or —CHR₄═CHR₅—;

R₃, R₄and R₅are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group; and

n is 1 or 2.

Prodrugs and metabolites of the preceding compounds are also included in the invention.

In a further aspect, the invention provides sirtuin- modulating compounds represented by Structural Formula (V):

wherein, as valence permits:

each of X₁, X₂, X₃, X₄and X₅is independently selected from N or CR₆, wherein no more than two of X₁, X₂, X₃, X₄or Xs are N;

each R₆is independently selected from H, —OCH₃, —CH₃, or —CF₃;

L is selected from —CH═CH—C(O)—, —CH₂—N(R₄)—C(O)—, —C(O)—CH₂—, —C(O)—N(R₄)—, —C(O)—N(R₄)—CH₂—, —C(O)—N(R₄)—CH₂—CH₂—, —C(O)—N(R₄)—C(O)—, —C(O)—N(R₄)—N(R₅)—, —CH₂—N(R₄)—N(R₅)—, —N(R₄)—S(O)₂—, —S(O)₂—N(R₄)—, —N(R₄)—N(R₅)—C(O)—, —C(O)—N(R₄)—N(R₅)—C(O)—, —N(R₄)—N(R₅)—CH₂, —N(R₄)—N(R₅)—,

each of R₄and R₅is independently selected from H or CH₃;

Y is selected from O, S, or NR₄;

each of X₆, X₇, X₈and X₉is independently selected from CR₇, C, or N, wherein at least two of X₆, X₇, X₈or X₉are not N;

each R₇is independently selected from H or (C₁-C₃)-straight or branched alkyl; and

the hashed bonds are either simultaneously present or simultaneously absent.

In one aspect, the invention provides novel -modulating compounds of Formula (I):

or a salt thereof, where:

Ring A is optionally substituted; and

Ring B is substituted with at least one carboxy or polycyclic aryl group.

In another aspect, the invention provides novel -modulating compounds of Formula (II):

or a salt thereof, where:

Ring A is optionally substituted;

R₁, R₂, R₃and R₄are independently selected from the group consisting of —H, halogen, —OR₅, —CN, —CO₂R₅, —OCOR₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)_nR₅, —S(O)OR₅, —S(O)NR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group; and

n is 1 or 2.

In yet another aspect, the invention provides novel -modulating compounds of Formula (III):

or a salt thereof, where:

Ring A is optionally substituted;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

R₇, R₉, R₁₀and R₁₁are independently selected from the group consisting of —H, halogen, —R₅; —OR₅, —CN, —CO₂R₅, —OCOR₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)R_s, —S(O)_nOR₅, —S(O)NR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₈is a polycyclic aryl group; and

n is 1 or 2.

In one aspect, the invention provides novel -modulating compounds of Formula (I):

or a salt thereof, where, as valence permits:

Ring A is optionally substituted;

L is absent, substituted or unsubstituted phenylene, substituted or unsubstituted —O-phenylene, substituted or unsubstituted thienylene, substituted or unsubstituted pyrazolylene, substituted or unsubstituted benzothiazolylene, —NR₄—, —C(O)O—, —C(O)NR₄—, —NR₄C(O)—, —NR₄—C(O)—NR₅—, —S—, —CHR₆═CHR₇— or —CHR₆—C(O)—;

L′ is absent, substituted or unsubstituted phenylene, substituted or unsubstituted —O-phenylene, substituted or unsubstituted thienylene, substituted or unsubstituted pyrazolylene, substituted or unsubstituted benzothiazolylene, substituted or unsubstituted indenedionylene, —C(O)O—, —C(O)NR₄—, —NR₄C(O)—, —NR₄—C(O)—NR₅—, —S—, —CHR₆═CHR₇or —CHR₈—C(O)—, provided that at least one of L and L′ is substituted or unsubstituted phenylene, substituted or unsubstituted —O-phenylene, substituted or unsubstituted thienylene, substituted or unsubstituted pyrazolylene, substituted or unsubstituted benzothiazolylene, substituted or unsubstituted indenedionylene, —NR₄—, —C(O)O—, —C(O)NR₄—, —NR₄C(O)—, —NR₄—C(O)—NR₅—, —S—, —CHR₆═CHR₇— or —CHR₈—C(O)—;

R₁is absent, —H, —NR₄R₅, —N₄C(O)R₅, —OR₅, naphthyl or a heterocyclic group, provided that L and R₁are not both absent unless X is N;

R₂is —H, unsubstituted alkyl, —NR₄R₅, —NR₄C(O)R₅, —OR₅, substituted or unsubstituted phenyl, naphthyl or a heterocyclic group;

R₃is —H, —NR₄R₅, —N₄C(O)R₅, —OR₅or a substituted or unsubstituted heterocyclic group, or R₂and R₃, taken together with the atoms to which they are attached, form an optionally substituted heterocyclic group, or R₃is absent when Z is O or S;

R₄and R₅are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

R₆, R₇and R₈are independently selected from the group consisting of halogen, —R₄, —CN, —CO₂R₄, —OCOR₄, —C(O)NR₂R₄, —C(O)NR₄R₅, —OC(O)NR₄R₅, —C(O)R₄, —COR₄, —SR₄, —OSO₃H, —S(O)_nR₄, —S(O)_nOR₄, —S(O)NR₄R₅, —NR₄R₅, —NR₄C(O)OR₅, —NR₄C(O)R₅and —NO₂;

W is C or N;

X is C or N;

Y is C or N;

Z is C, N, O or S, provided that at least two of W, X, Y and Z are C; and

n is 1 or 2.

In a second aspect, the invention provides novel -modulating compounds represented by Structural Formula (Ia):

wherein:

R₁₀is selected from —H, —C(O)—N(R₄₀)(R₅₀), —S(O)₂N(R₄₀)(R₅₀), or —CH—N(R₄₀)(R₅₀); wherein each of R₄₀and R₅₀is independently selected from —H, —C₁-C₃straight or branched alkyl, —(C₁-C₃straight or branched alkyl)-N(CH₃)₂, —(C₁-C₃straight or branched alkyl)-heterocyclyl, —(C₁-C₃straight or branched alkyl)-alkylheterocyclyl, or wherein R₄₀and R₅₀taken together with the N atom to which they are bound form a 5-6 membered heterocyclic ring that is optionally substituted with —(C₁-C₃straight or branched alkyl), and wherein at least one of R₄₀or R₅₀is not H;

R₁₁is selected from —C₁-C₃straight or branched alkylene or —C(O)—; and

each of ring K and ring E is independently substituted with up to three substituents independently selected from halo, —CF₃, —O—(C₁-C₃straight or branched alkyl), —S—(C₁-C₃straight or branched alkyl), —N(R₄₀)(R₅₀), —S(O)—N(R₄₀)(R₅₀), heterocyclyl, (C₁-C₃straight or branched alkyl)-heterocyclyl, —O—(C₁-C₃straight or branched alkyl)-heterocyclyl, —S—(C₁-C₃straight or branched alkyl)-heterocyclyl, or is optionally fused to a 5-6 membered heterocyclyl or heteroaryl, wherein any heterocyclcyl or heteroaryl is optionally substituted with —C₁-C₃straight or branched alkyl.

In a further aspect, the invention provides novel -modulating compounds of Formula (Ib):

wherein:

Z is selected from O or S;

R₁₀is selected from —H, C(O)—N(R₄₀)(R₅₀), —S(O)₂N(R₄₀)(R₅₀), or —CH₂—N(R₄₀)(R₅₀); wherein each of R₄₀and R₅₀is independently selected from —H, —C₁-C₃straight or branched alkyl, —(C₁-C₃straight or branched alkyl)-N(CH₃)₂, —(C₁-C₃straight or branched alkyl)-heterocyclyl, —(C₁-C₃straight or branched alkyl)-alkylheterocyclyl, or wherein R₄₀and R₅₀taken together with the N atom to which they are bound form a 5-6 membered heterocyclic ring that is optionally substituted with —(C₁-C₃straight or branched alkyl), and wherein at least one of R₄₀or R₅₀is not H.

R₁₁is selected from —C₁-C₃straight or branched alkylene or —C(O)—;

each of R₁₂and R₁₃is independently selected from —H or —(C₁-C₃straight or branched alkyl), or R₁₂and R₁₃are taken together to form a benzene ring that is substituted with up to two substituents independently selected from —(C₁-C₃straight or branched alkyl), —CF₃or halo; and

ring K is substituted with up to three substituents independently selected from halo, —CF₃, —O—(C₁-C₃straight or branched alkyl), —S—(C₁-C₃straight or branched alkyl), —N(R₄₀)(R₅₀), —S(O)_z—N(R₄₀)(R₅₀), heterocyclyl, (C₁-C₃straight or branched alkyl)-heterocyclyl, —O—(C₁-C₃straight or branched alkyl)-heterocyclyl, —S—(C₁-C₃straight or branched alkyl)-heterocyclyl, or is optionally fused to a 5-6 membered heterocyclyl or heteroaryl, wherein any heterocyclcyl or heteroaryl is optionally substituted with —C₁-C₃straight or branched alkyl.

In another aspect, the invention provides novel -modulating compounds of Formula (II):

or a salt thereof; where:

Rings C, D and E are optionally substituted; and

x is 0 or 1.

In yet another aspect, the invention provides novel -modulating compounds of Formula (VII):

or a salt thereof, where:

Ring F is optionally substituted;

L′ is substituted or unsubstituted phenylene, substituted or unsubstituted thienylene, —C(O)O—, —S—, —CHR₆═CHR₇— or —CHR₈—C(O)—;

R₂is —H, unsubstituted alkyl, —NR₄R₅, —NR₄C(O)R₅, —OR₅or a heterocyclic group;

R₃is —H, —NR₄R₅, —N₄C(O)R₅, —OR₅or a heterocyclic group, or R₂and R₃, taken together with the atoms to which they are attached, form an optionally substituted heterocyclic group, or R₃is absent when Z is O or S;

R₄and R₅are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

R₆, R₇and R₈are independently selected from the group consisting of halogen, —OR₄, —CN, —CO₂R₄, —OCOR₄, —OCO₂R₄, —C(O)NR₄R₅, —OC(O)NR₄R₅, —C(O)R₄, —COR₄, —SR₄, —OSO₃H, —S(O)_nR₄, —S(O)OR₄, —(O), NR₄R₅, —NR₄C(O)OR₅, —NR₄C(O)R₅and —NO₂;

Z is C, N, O or S; and

n is 1 or 2

In one aspect, the invention provides novel modulating compounds of Formula (I):

or a salt thereof, where:

Cy₁and Cy₂are independently a substituted or unsubstituted cyclic group; and

R₁and R₂are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group, or R₁and R₂taken together with the atoms to which they are attached from an optionally substituted heterocycle.

In another aspect, the invention provides novel -modulating compounds of Formula (II):

or a salt thereof where:

Cy₁and Cy₂are independently a substituted or unsubstituted cyclic group;

R₃and R₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NRC(O)R′, —NO₂, ═O and ═S; and

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group.

The invention also includes salts, prodrugs and metabolites of the compounds disclosed herein.

Also provided are pharmaceutical compositions comprising one or more compounds of Formulas (I)-(II) or a salt, prodrug or metabolite thereof.

In another aspect, the invention provides methods for using -modulating compounds, or compostions comprising modulating compounds. In certain embodiments, -modulating compounds that increase the level and/or activity of a

protein may be used for a variety of therapeutic applications including, for example, increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, chemotherapeutic induced neuropathy, neuropathy associated with an ischemic event, ocular diseases and/or disorders, cardiovascular disease, blood clotting disorders, inflammation, and/or flushing, etc. -modulating compounds that increase the level and/or activity of a

protein may also be used for treating a disease or disorder in a subject that would benefit from increased mitochondrial activity, for enhancing muscle performance, for increasing muscle ATP levels, or for treating or preventing muscle tissue damage associated with hypoxia or ischemia. In other embodiments, modulating compounds that decrease the level and/or activity of a protein may be used for a variety of therapeutic applications including, for example, increasing cellular sensitivity to stress, increasing apoptosis, treatment of cancer, stimulation of appetite, and/or stimulation of weight gain, etc. As described further below, the methods comprise administering to a subject in need thereof a pharmaceutically effective amount of a

-modulating compound.

In certain aspects, the -modulating compounds may be administered alone or in combination with other compounds, including other -modulating compounds, or other therapeutic agents.

In one aspect, the invention provides novel: modulating compounds of Formula (I):

or a salt thereof, wherein:

Ring A optionally has one or more substituents in addition to -L-Q;

L is —C(O)NR—, —NRC(O)—, —NR—NR′—C(O)—, —C(O)—NR—NR′— or —CHR═CHR′—;

Q is a substituted or unsubstituted alkyl group or a substituted or unsubstituted cyclic group, or Q and R taken together with the atoms to which they are attached form a heterocyclic group;

R₁is —H, a substituted or unsubstituted acyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group, or R₁and R₂taken together with the atoms to which they are attached form an optionally substituted fused ring;

R₂and R₃are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)R, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NRC(O)R, —NO₂, ═O and ═S;

R₄is —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group; and

n is 1 or 2.

In certain embodiments of the first aspect, novel compounds of the invention are represented by Structural Formula (I):

or a salt thereof, wherein:

Ring A optionally has one or more substituents in addition to -L-Cy₁;

L is —C(O)NR—, —NRC(O)—, —NR—NR′—C(O)—, —C(O)—NR—NR′— or —CHR═CHR′—;

Q is a substituted or unsubstituted alkyl group (e.g., an aminoalkyl group) or a substituted or unsubstituted cyclic group;

R₂and R₃are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NRC(O)R′, —NO₂, ═O and ═S;

R₄is —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group; and

n is 1 or 2.

In another aspect, the invention provides novel -modulating compounds of Formula (II):

or a salt thereof, wherein:

Ring A optionally has one or more substituents in addition to -L-Cy₁;

Cy₁is a substituted or unsubstituted cyclic group;

L is —C(O)NR—, —NRC(O)—, —NR—NR′—C(O)—, —C(O)—NR—NR′— or —CHR═CHR′—;

R₂and R₃are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NRC(O)R′, —NO₂, ═O and ═S;

R₄is —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group; and

n is 1 or 2.

In yet another aspect, the invention provides novel -modulating compounds of Formula (III):

or a salt thereof, wherein:

Ar is a substituted or unsubstituted aryl group;

R₅, R₆, R₇and R₈are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group.

The invention also includes salts, prodrugs and metabolites of the compounds disclosed herein.

Also provided are pharmaceutical compositions comprising one or more compounds disclosed herein, including salts, prodrugs and metabolites thereof.

In one aspect, the invention provides novel -modulating compounds of Formula (Ia):

or a salt thereof, wherein:

Ring A is optionally substituted;

R₁is —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

X is —(C—R₂)_m—NHCO—R₃, —(CHR₂)—NHCONR₄R₅, —(CH₂)—NR₁SO₂—R₃, —SR₃or -arylene-R₂;

each R₂is independently selected from the group consisting of a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, halogen, —OR₄, —CN, —CO₂R₄, —OCOR₄, —OCO₂R₄, —C(O)NR₄R₅, —OC(O)NR₄R₅, —C(O)R₄, —COR₄, —SR₄, —OSO₃H, —S(O)_nR₄, —S(O)_nOR₄, —S(O)_nNR₄R₅, —NR₄R₅, —NR₄C(O)OR₅, —NR₄C(O)R₅and —NO₂;

R₃is a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

R₄and R₅are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

m is an integer from 2 to 12;

n is 1 or 2; and

r is an integer from 0 to 12.

In another aspect, the invention provides novel modulating compounds of Formula (I):

or a salt thereof, where:

Ring A is optionally substituted;

R₁is —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

R₃is a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

R₄and R₅are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

m is an integer from 2 to 12; and

n is 1 or 2.

In yet another aspect, the invention provides novel -modulating compounds of Formula (II):

or a salt thereof, where:

R₁is —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

each R₂is independently selected from the group consisting of a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, halogen, —OR₄, —CN, —CO₂R₄, —OCOR₄, —OCO₂R₄, —C(O)NR₄R₅, —OC(O)NR₄R₅, —C(O)R₄, —COR₄, —SR₄, —OSO₃H, —S(O)_nR₄, —S(O)OR₄, —S(O)_nNR₄R₅, —NR₄R₅, —NR₄C(O)OR₅, —NR₄C(O)R₅and —NO₂;

R₃is a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

R₄and R₅are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

R₆and R₇are independently —I, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, or R₆and R₇taken together with the nitrogen atom to which they are attached form a heterocyclic ring;

m is an integer from 2 to 12; and

n is 1 or 2.

The invention also includes salts, prodrugs and metabolites of the compounds disclosed herein.

Also provided are pharmaceutical compositions comprising one or more compounds disclosed herein, or a salt, prodrug or metabolite thereof.

In one aspect, the invention provides novel activating compounds of Formula (Ia):

or a salt thereof, wherein:

- Ring A′ is a 5- to 7-membered ring optionally fused to a second 5- to 7-membered ring, which is optionally substituted with one to three functional groups selected from the group consisting of halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR, —NRC(O)R, —NO₂, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted non-aromatic heterocyclic and substituted or unsubstituted aryl;
- Ring B′ is a 5- to 7-membered ring optionally substituted with one to four functional groups selected from the group consisting of halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR, —NRC(O)R, —NO₂, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted non-aromatic heterocyclic and substituted or unsubstituted aryl;
- J is O or S;
- L is —C═C— or —NH—(CH₂)_k—;
- R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aryl group;
- a is 0 or 1;
- k is an integer from 1 to 4; and
- n is 1 or 2,

provided that Ring A′ and Ring B′ are not both phenyl and at least one is substituted with at least one hydrogen bond donating group, and provided that the compound is not 4-((E)-2-(pyridin-4-yl)vinyl)phenol.

In another aspect, the invention provides novel activating compounds of Formula (I):

or a salt thereof, wherein:

- W is CH or N;
- X is CH or N;
- Y is CH or N;
- Z is S, O or NH;
- W′ is CH or N;
- X′ is CH or N;
- Y′ is CH or N;
- Z′ is S, O or NH;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aryl group;

n is 1 or 2;

Ring A is substituted with at least one hydrogen bond donating group and is optionally substituted with one to three functional groups selected from the group consisting of halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)R, —S(O)_nOR, —S(O)NRR′, —NRR′, —NRC(O)OR, —NRC(O)R, —NO₂, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted non-aromatic heterocyclic and substituted or unsubstituted aryl; and

Ring B is optionally substituted with one to four functional groups selected from the group consisting of halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —S(O)R, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR, —NRC(O)R, —NO₂, —OSO₃H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted non-aromatic heterocyclic and substituted or unsubstituted aryl.

In another aspect, the invention provides novel: compounds of Formulas (I)-(XVIII) (including (IA)), including salts, prodrugs and metabolites thereof. Also provided are pharmaceutical compositions comprising a compounds of Formulas (I)-(XVIII) (including (IA)), or a salt prodrug or metabolites thereof.

In one embodiment, the invention is a method for promoting survival of a eukaryotic cell comprising contacting the cell with at least one compound of Structural Formula (I) or (II):

or pharmaceutically acceptable salt thereof where:

R₃₀₁and R₃₀₂are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aryl group, or R₃₀₁and R₃₀₂taken together with the atom to which they are attached form a substituted or unsubstituted non-aromatic heterocyclic group;

R₃₀₃, R₃₀₄, R₃₀₅and R₃₀₆are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR, —NO₂and —NRC(O)R′;

R₃₀₇, R₃₀₈and R₃₁₀are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C(O)R, —C(O)OR, —C(O)NHR, —C(S)R, —C(S)OR and —C(O)SR;

R₃₀₉is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)R, —S(O)OR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′ and —NRC(O)R;

R₃₁₁, R₃₁₂, R₃₁₃and R₃₁₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —OSO₃H, —S(O)_nR, —S(O)OR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X is O or S; and

n is 1 or 2.

In another embodiment, the invention is method for treating or preventing a disease or disorder associated with cell death, cell dysfunction or aging in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Structural Formula (I) or (II):

or a pharmaceutically acceptable salt thereof, where:

R₃₀₉is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′ and —NRC(O)R′;

R₃₁₁, R₃₁₂, R₃₁₃and R₃₁₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X is O or S; and

n is 1 or 2.

In yet another embodiment, the invention is a method for treating or preventing insulin resistance, a metabolic syndrome, hypercholesterolemia, artherogenic dyslipidemia, diabetes, or complications thereof, or for increasing insulin sensitivity in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Structural Formula (I) or (II):

or a pharmaceutically acceptable salt thereof, where:

R₃₀₉is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)R, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′ and —NRC(O)R′;

R₃₁₁, R₃₁₂, R₃₁₃and R₃₁₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X is O or S; and

n is 1 or 2,

provided that when X is O and R₃₀₁-R₃₀₉and R₃₁₁-R₃₁₄are —H, R₃₁₀is not —H.

In a further embodiment, the invention is method for reducing the weight of a subject, or preventing weight gain in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Structural Formula (I) or (II):

or a pharmaceutically acceptable salt thereof; wherein:

R₃₀₉is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)OR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′ and —NRC(O)R′;

R₃₁₁, R₃₁₂, R₃₁₃and R₃₁₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R and R′ are independently-H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X is O or S; and

n is 1 or 2.

In one embodiment, the invention is a method for preventing the differentiation of a pre-adipocyte, comprising contacting the pre-adipocyte with at least one compound of Structural Formula (I) or (II):

or a pharmaceutically acceptable salt thereof, where:

R₃₀₁and R₃₀₂are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aryl group, or R₃₀₁and R₃₀₂taken together with, the atom to which they are attached form a substituted or unsubstituted non-aromatic heterocyclic group;

R₃₀₃, R₃₀₄, R₃₀₅and R₃₀₆are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)NRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R₃₀₉is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′ and —NRC(O)R′;

R₃₁₁, R₃₁₂, R₃₁₃and R₃₁₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR, —NO₂and —NRC(O)R;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X is O or S; and

n is 1 or 2.

In another embodiment, the invention is a method for prolonging the lifespan of a subject comprising administering to a subject a therapeutically effective amount of at least one compound of Structural Formula (I) or (II):

or a pharmaceutically acceptable salt thereof; where:

R₃₀₃, R₃₀₄, R₃₀₅and R₃₀₆are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)OR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R₃₁₁, R₃₁₂, R₃₁₃and R₃₁₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X is O or S; and

n is 1 or 2.

In yet another embodiment, the invention is a method for treating or preventing a neurodegenerative disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Structural Formula (I) or (II):

or a pharmaceutically acceptable salt thereof where:

R₃₀₁and R₃₀₂are independently-H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aryl group, or R₃₀₁and R₃₀₂taken together with the atom to which they are attached form a substituted or unsubstituted non-aromatic heterocyclic group;

R₃₀₃, R₃₀₄, R₃₀₅and R₃₀₆are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)NRR′, —NRR′, —NRC(O)OR, —NO₂and —NRC(O)R′;

R₃₀₉is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(Oh)R, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′ and —NRC(O)R′;

R₃₁₁, R₃₁₂, R₃₁₃and R₃₁₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X is O or S; and

n is 1 or 2.

In a further embodiment, the invention is a method of for treating or preventing a blood coagulation disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Structural Formula (I) or (II):

or a pharmaceutically acceptable salt thereof, where:

R₃₀₃, R₃₀₄, R₃₀₅and R₃₀₆are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)NRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R₃₀₉is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)₁′OR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′ and —NRC(O)R′;

R₃₁₁, R₃₁₂, R₃₁₃and R₃₁₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X is O or S; and

n is 1 or 2.

In the above methods, the compound represented by Structural Formula (I) or (II) is typically represented by Structural Formula (III) or (IV):

or a pharmaceutically acceptable salt thereof, where:

R₂₀₁and R₂₀₂are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aryl group, or R₂₀₁and R₂₀₂taken together with the atom to which they are attached form a substituted or unsubstituted non-aromatic heterocyclic group;

R₂₀₃, R₂₀₄, R₂₀₅and R₂₀₆are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO_{2l R, —OCOR, —OCO}₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R₂₀₇, R₂₀₈and R₂₁₀are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C(O)R, —C(O)OR, —C(O)NHR, —C(S)R, —C(S)OR and —C(O)SR;

R₂₀₉is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′ and —NRC(O)R′;

R₂₁₁, R₂₁₂, R₂₁₃and R₂₁₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted, or unsubstituted non-aromatic heterocyclic group, halogen, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X is O or S; and

n is 1 or 2.

Another aspect of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by Structural Formula (V) or (VI):

or a pharmaceutically acceptable salt thereof, where:

R₁and R₂are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aryl group, or R₁and R₂taken together with the atom to which they are attached form a substituted or unsubstituted non-aromatic heterocyclic group, provided that when one of R₁and R₂is —H, the other is not an alkyl group substituted by —C(O)OCH₂CH₃;

R₃, R₄and R₅are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R₆is selected from the group consisting of —H, a substituted or unsubstituted alkyl group; a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R₉selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)₈OR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′ and —NRC(O)R′;

R₁₁, R₁₂, R₁₃and R₁₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X is O or S; and

n is 1 or 2,

provided that R₁-R₁₄are not each —H and that R₁-R₉and R₁-R₁₄are not each —H when R₁₀is —C(O)C₆H₅.

In one embodiment, the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by Structural Formula (VII) or (VIII):

or a pharmaceutically acceptable salt thereof wherein:

R₁₀₁and R₁₀₂are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aryl group, or R₁₁₀and R₁₀₂taken together with the atom to which they are attached form a substituted or unsubstituted non-aromatic heterocyclic group;

R₁₀₃, R₁₀₄, R₁₀₅and R₁₀₆are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)OR, —S(O)NRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R₁₀₇and R₁₀₈are selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C(O)R, —C(O)OR, —C(O)NHR, —C(S)R, —C(S)OR and —C(O)SR, wherein at least one of R₁₀₇and R₁₀₈is a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C(O)R, —C(O)OR, —C(O)NHR, —C(S)R, —C(S)OR or —C(O)SR,

R₁₀₉is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)R, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′ and —NRC(O)R′;

R₁₁₀is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C(O)R, —C(O)OR, —C(O)NHR; —C(S)R, —C(S)OR and —C(O)SR, provided that R₁₁₀is not —C(O)C₆H₅;

R₁₁₁, R₁₁₂, R₁₁₃and R₁₁₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′.

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X is O or S; and

n is 1 or 2.

In another embodiment, the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by Structural Formula (IX) or (X):

or unsubstituted aryl group, or R₁₁₀and R₁₂taken together with the atom to which they are attached form a substituted or unsubstituted non-aromatic heterocyclic group;

R₁₀₃, R₁₀₄, R₁₀₅and R₁₀₆are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)R, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R₁₀₉is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′ and —NRC(O)R′;

R₁₁₀is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C(O)R, —C(O)OR, —C(O)NHR, —C(S)R, —C(S)OR and —C(O)SR, provided that R₁₁₀is not —C(O)C₆H₅;

R₁₁₁, R₁₁₂, R₁₁₃and R₁₁₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)NRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R and R′ are independently-H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X is O or S; and

n is 1 or 2.

A further aspect of the invention is a compound represented by Structural Formula (XI) or (XII):

or a pharmaceutically acceptable salt thereof, where:

R₃and R₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)_nOR′, —NO₂and —NRC(O)R′;

R₅is selected from the group consisting of —H, a substituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R₆is selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R₉selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′ and —NRC(O)R′;

R₁₁, R₄₂, R₁₃and R₁₄are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X is O or S; and

n is 1 or 2,

provided that R₁-R₆are not each —H.

Yet another aspect of the invention is a compound represented by Structural Formula (XI) or (XII):

or a pharmaceutically acceptable salt thereof, wherein:

R₁and R₂are independently-H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aryl group, or R₁and R₂taken together with the atom to which they are attached form a substituted or unsubstituted non-aromatic heterocyclic group;

R₃, R₄, R₅and R₆are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group; halogen, —OR, —CN, —CO₂R, —OCOR; —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)NRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R₇, R₈and R₁₀are independently selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C(O)R, —C(O)OR, —C(O)NHR, —C(S)R, —C(S)OR and —C(O)SR, wherein at least one of R₇and R₈is a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C(O)R, —C(O)OR, —C(O)NHR, —C(S)R, —C(S)OR or —C(O)SR, provided that none of R₇and R₈are —C(O)C₆H₅and that R₇and R₈are not both —C(O)CH₃or —C(O)C₆H₄F;

R₉selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)NRR′, —NRR′, —NRC(O)OR′ and —NRC(O)R′;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X is O or S; and

n is 1 or 2.

A further aspect of the invention is a compound represented by Structural Formula (XI) or (XII):

or a pharmaceutically acceptable salt thereof, where:

R₃, R₄, R₅and R₆are independently selected from the group consisting of H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′, —NO₂and —NRC(O)R′;

R₇and R⁸are selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C(O)R, —C(O)OR, —C(O)NHR, —C(S)R, —C(S)OR and —C(O)SR;

R₉selected from the group consisting of —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′, —OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_nR, —S(O)_nOR, —S(O)_nNRR′, —NRR′, —NRC(O)OR′ and —NRC(O)R′;

R₁₀is selected from the group consisting of a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C(O)R, —C(O)OR, —C(O)NHR, —C(S)R, —C(S)OR and —C(O)SR, provided that R₁₀is not —C(C₆H₅)₃, —C(O)C₆H₅, —C(O)CH₃, —C(O)C₆H₄F or —C(O)CH(OC(O)CH₃)CH(CH₃)CH₂CH₃;

R and R′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group;

X is O or S; and

n is 1 or 2.

In one embodiment, sirtuin-modulating compounds of the invention are represented by Structural Formula I:

wherein:

one of R₁, R₂, R₃or R₄is selected from a 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, O or S, wherein said heteroaryl is optionally benzofused or optionally fused to a second 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, O or S and is bound to the rest of the compound via a carbon ring atom, wherein said heteroaryl is optionally substituted on a single carbon ring atom with a substituent selected from a solubilizing group, or a C₁-C₄straight or branched alkyl;

the others of R₁, R₂, R₃and R₄are independently selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl, wherein at least two of R₁, R₂, R₃or R₄are hydrogen;

X is selected from O, S or NR₆, wherein R₆is selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl; and

R₅is an optionally substituted aryl or an optionally substituted heteroaryl.

In certain embodiments, when X is NR₆, R₆is hydrogen, and R₂or R₃is 1,2,4-oxadiazole-3-yl, pyridin-4-yl, or furan-2-yl, then R₅is not phenyl substituted with an acylamino group.

In certain embodiments, when X is NR₆, R₆is H or alkoxymethyl, and R₂or R₃is substituted or unsubstituted 1H-imidazo[4,5-b]pyridin-2-yl, substituted or unsubstituted 1H-benzimidazol-2-yl, or substituted or unsubstituted oxazolo[5,4-b]pyridin-2-yl, then R₅is not phenyl monosubstituted with hydroxy or methoxy.

In certain embodiments, when X is NR₆s R₆is H or alkoxymethyl, and R₂or R₃is benzo[b]thienyl, then R₅is not 2H-indazol-3-yl.

In certain embodiments, when X is NR₆, R₆is H or alkoxymethyl and R₂or R₃is 1H-imidazo[2,1-b]thiazol-3-yl, then R₅is not unsubstituted pyridin-4-yl.

In certain embodiments, when X is NR₆and R₂or R₃is 1,2,4-oxadiazol-3-yl, then R₅is not 2-chloro-5-nitrophenyl.

In certain embodiments, when X is NR₆and R₂or R₃is thien-3-yl or furan-2-yl, then R₅is not unsubstituted 2H-indazol-3-yl.

In certain embodiments, when X is NR₆and R₂or R₃is imidazol-4-yl or thiazolyl, then R₅is not unsubstituted thiazol-4-yl.

In certain embodiments, when X is NR₆and R₂or R₃is pyridazin-3-yl, then R₅is not 4-methylphenyl or 4-methoxyphenyl.

In certain embodiments, when X is NR₆and R₂or R₃is pyridinyl, then R₅is not unsubstituted phenyl, 4-fluorophenyl, 4-methylphenyl, 4-(1,1-dimethylethyl)phenyl, or 4-trifluoromethylphenyl.

In certain embodiments, when X is S and R₂or R₃is substituted or unsubstituted benzothiazol-2-yl, then R₅is not unsubstituted phenyl, 2-methyl substituted phenyl, 4-nitrophenyl, 4-amino substituted phenyl, 3- or 4-methylaminophenyl, 4-thiophenyl, 4-hydroxyphenyl, 4-(sulfonatomethyl)aminophenyl, 2-methyl substituted benzthiazol-6-yl, 2,3-dimethylbenzthiazol-6-yl, 4-amino-3-sulfonatophenyl, 4-amino-3-iodophenyl, 4-(4-acetamidophenylsulfamoyl)phenyl, or 4-(4-dimethylaminophenyl)iminophenyl.

In certain embodiments, when X is S and R₂is substituted or unsubstituted pyrimidinyl, then R₅is not phenyl substituted with an octyloxy-, propoxypropoxy-, glycine- or hexanoic acid-containing substituent and optionally one or more additional substituents.

In certain embodiments, when X is O and R₄is substituted or unsubstituted benzoxazol-2-yl, then R₅is not phenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 2-phenylmethoxyphenyl, 2-hydroxy-3-phenylmethylphenyl, or 2-hydroxy-6-methylphenyl.

In certain embodiments, when X is O and R₄is substituted or unsubstituted 1H-benzimidazol-2-yl, then R₅is not 2-hydroxyphenyl.

In certain embodiments, when X is O and one of R₂or R₃is substituted or unsubstituted 1H-benzimidazol-2-yl, substituted or unsubstituted oxazolo[5,4-b]pyridin-2-yl or substituted or unsubstituted 1H-imidazo[4,5-b]pyridin-2-yl, then R₅is not 4-hydroxyphenyl, 4-methoxyphenyl, 4-N,N-bis-(2-chloroethyl)aminophenyl, or naphthalen-4-yl.

In certain embodiments, when X is O and R₃is 1-methyl-1H-pyrrol-2-yl, then R₅is not 3-chloro-4-(5-methoxyfuran-2-yl)ethenylphenyl or 3-chloro-4-(5-methoxythien-2-yl)ethenylphenyl.

In certain embodiments, when X is O and R₂is benzo[b]thien-2-yl, then R₅is not 2-methoxy-5-aminophenyl, 3-amino-4-methoxyphenyl, 2-propylamino-5-aminophenyl, 2-methoxy-5-nitrophenyl, 4-methoxy-3-nitrophenyl, or 5-nitro-2-propylaminophenyl.

In certain embodiments, when X is O and one of R₂or R₃is benzofuran-2-y, then R₅is not 2-methoxy-5-aminophenyl, 2-propylamino-5-aminophenyl, 2-fluoro-5-nitrophenyl, 2-methoxy-5-nitrophenyl, 4-methoxy-3-nitrophenyl, or 5-nitro-2-propylaminophenyl.

In certain embodiments, when X is O and one of R₂or R₃is substituted or unsubstituted benzoxazol-2-yl, then R₅is not 4-hydroxyphenyl, 4-styrylphenyl, 4-tert-butylphenyl, or 5-phenylthien-2-yl.

In certain embodiments, when X is O and R₁is substituted or unsubstituted benzoxazol-2-yl, then R₅is not 2-methoxyphenyl.

In certain embodiments, when X is O and one of R₂, R₃or R₄is furan-2-yl, then R₅is not substituted or unsubstituted phenyl, benzo[b]thien-2-yl, benzoxazol-2-yl, naphthalen-2-yl, benzofuran-2-yl, quinolin-6-yl, or 5-methylthien-2-yl.

In certain embodiments, when X is O and R₃is pyridin-3-yl, then R₅is not 3-methoxyphenyl.

In certain embodiments, when X is O and one of R₂or R₃is substituted or unsubstituted pyrimidin-5-yl, then R₅is not phenyl.

In certain embodiments, when X is O and R₃is thiazol-2-yl, then R₅is not thiazol-4-yl.

In certain embodiments, when X is O and one of R₂or R₃is substituted or unsubstituted thien-2-yl, then R₅is not 3-amino-4-methoxyphenyl, 2-hydroxyphenyl, 3-[5-carboxylic acid-2,3-dihydro-1,3-dioxo-1H-isoindol-1-yl]-4-methoxyphenyl or 3-nitro-4-methoxyphenyl.

In another embodiment, sirtuin-modulating compounds of the invention are represented by Structural Formula II:

wherein:

one of R₂or R₃is selected from a 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, O or S, wherein said heteroaryl is optionally benzofused or fused to a second 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, O or S and is bound to the rest of the compound via a carbon ring atom, wherein said heteroaryl is optionally substituted on a single carbon ring atom with a substituent selected from a solubilizing group, or a C₁-C₄straight or branched alkyl;

R₁, R₄, and the other of R₂or R₃are each independently selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl, wherein at least two of R₁, R₂, R₃and R₄are hydrogen;

X is selected from O, S or NR₆, wherein R₆is selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl; and

R₁₅is an optionally substituted heteroaryl or an optionally substituted naphthalenyl.

In certain embodiments, when X is NR₆, R₆is hydrogen, and R₂or R₃is 1,2,4-oxadiazole-3-yl, pyridin-4-yl, or furan-2-yl, then R₅is not phenyl substituted with an acylamino group.

In certain embodiments, when X is NR₆and R₂or R₃is benzo[b]thienyl, then R₅is not 2H-indazol-3-yl.

In certain embodiments, when X is NR₆and R₂or R₃is 1H-imidazo[2,1-b]thiazol-3-yl, then R₅is not unsubstituted pyridin-4-yl.

In certain embodiments, when X is NR₆and R₂or R₃is thien-3-yl or furan-2-yl, then R₅is not unsubstituted 2H-indazol-3-yl.

In certain embodiments, when X is NR₆and R₂or R₃is imidazol-4-yl or thiazolyl, then R₅is not unsubstituted thiazol-4-yl.

In certain embodiments, when X is S and R₂is benzothiazol-2-yl, then R₅is not 2-methyl substituted benzthiazol-6-yl.

In certain embodiments, when X is O and one of R₂or R₃is benzoxazol-2-yl, then R₅is not 5-phenylthien-2-yl.

In certain embodiments, when X is O and R₃is thiazol-2-yl, then R₅is not thiazol-4-yl.

In certain embodiments, when X is O and one of R₂or R₃is furan-2-yl, then R₅is not unsubstituted benzo[b]thien-2-yl, unsubstituted benzoxazol-2-yl, or unsubstituted naphthalen-2-yl.

In another embodiment, sirtuin-modulating compounds of the invention are represented by Structural Formula III:

wherein:

one of R₁or R₄is a 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, O or S, wherein said heteroaryl is optionally benzofused or fused to a second 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, O or S and is bound to the rest of the compound via a carbon ring atom, wherein said heteroaryl is optionally substituted on a single carbon ring atom with a substituent selected from a solubilizing group, or a C₁-C₄straight or branched alkyl;

R₂, R₃and the other of R₁or R₄are independently selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl, wherein at least two of R₁, R₂, R₃or R₄are hydrogen;

X is selected from O, S or NR₆, wherein R₆is selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl; and

R₅is an optionally substituted aryl or an optionally substituted heteroaryl.

In certain embodiments, when X is O and R₄is benzoxazol-2-yl, then R₅is not unsubstituted phenyl or, 2-hydroxy, 2-methoxy or 2-phenylmethoxy substituted phenyl.

In certain embodiments, when X is O and R₄is benzimidazole-2-yl, then R₅is not 2-hydroxyphenyl.

In certain embodiments, when X is O and R₁is benzoxazol-2-yl, then R₅is not 2-methoxyphenyl.

In certain embodiments, one of R₁-R₄is selected from:

wherein:

X₁, X₂, X₃, and X₄are each independently selected from CR₁₆or N; and

two or three occurrences of R₁₆are H and the other(s) is a substituent selected from a solubilizing group, or a C₁-C₄straight or branched alkyl.

In certain embodiments, R₅is selected from phenyl, 1H-pyrrolyl, pyridinyl, quinolinyl, quinoxalinyl, thienyl, or furanyl, wherein R₅is optionally substituted.

In certain embodiments, R₅is selected from 3,4-dimethoxyphenyl, 4-dimethylaminophenyl, 4-methoxyphenyl, 4-morpholinophenyl, or 3,4-dioxymethylenephenyl.

In another embodiment, sirtuin-modulating compounds of the invention are represented by Structural Formula IIIa:

wherein:

X is selected from S or NR₆, wherein R₆is selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl; and

R₅is an optionally substituted aryl or an optionally substituted heteroaryl.

In certain embodiments, one of R₁-R₄is selected from:

wherein:

X₁, X₂, X₃, and X₄are each independently selected from CR₁₆or N; and

two or three occurrences of R₁₆are H and the other(s) is a substituent selected from a solubilizing group, or a C₁-C₄straight or branched alkyl.

In certain embodiments, R₅is selected from phenyl, 1H-pyrrolyl, pyridinyl, quinolinyl, quinoxalinyl, thienyl, or furanyl, wherein R₅is optionally substituted.

In certain embodiments, R₅is selected from 3,4-dimethoxyphenyl, 4-dimethylaminophenyl, 4-methoxyphenyl, 4-morpholinophenyl, or 3,4-dioxymethylenephenyl.

In another embodiment, sirtuin-modulating compounds of the invention are represented by Structural Formula IIIb:

wherein:

one of R₁or R₄is a 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, O or S, wherein said heteroaryl is optionally benzofused or fused to a second 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, O or S and is bound to the rest of the compound via a carbon ring atom, wherein when said heteroaryl is benzofused, said heteroaryl comprises a S atom, and wherein said heteroaryl is optionally substituted on a single carbon ring atom with a substituent selected from a solubilizing group, or a C₁-C₄straight or branched alkyl;

X is selected from O, S or NR₆, wherein R₆is selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl; and

R₅is an optionally substituted aryl or an optionally substituted heteroaryl.

In certain embodiments, one of R₁-R₄is selected from:

wherein:

X₁, X₂, X₃, and X₄are each independently selected from CR₁₆or N; and

two or three occurrences of R₁₆are H and the other(s) is a substituent selected from a solubilizing group, or a C₁-C₄straight or branched alkyl.

In certain embodiments, R₅is selected from phenyl, 1H-pyrrolyl, pyridinyl, quinolinyl, quinoxalinyl, thienyl, or furanyl, wherein R₅is optionally substituted.

In certain embodiments, R₅is selected from 3,4-dimethoxyphenyl, 4-dimethylaminophenyl, 4-methoxyphenyl, 4-morpholinophenyl, or 3,4-dioxymethylenephenyl.

In another embodiment, sirtuin-modulating compounds of the invention are represented by Structural Formula IV:

wherein:

one of R₁₁-R₁₄is an 8- to 10-membered bicyclic heteroaryl comprising at least one heteroatom selected from N, O or S in each ring, wherein at least one of said heteroatoms in the bicyclic heteroaryl is an S atom, wherein said heteroaryl is bound to the rest of the compound via a carbon ring atom, and wherein said heteroaryl is optionally substituted on a single carbon ring atom with a substituent selected from a solubilizing group, or a C₁-C₄straight or branched alkyl;

and the remainder of R₁₁-R₁₄are each independently selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl, wherein at least two of R₁₁, R₁₂, R₁₃or R₁₄are hydrogen;

X is selected from O, S or NR₆, wherein R₆is selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl; and

R₅is an optionally substituted aryl or heteroaryl.

In certain embodiments, when R₅is 4-pyridyl, R₅is a substituted 4-pyridyl. In certain such embodiments, the 4-pyridyl may be substituted with halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aryl, heteroaryl, cycloalkyl, or C₂-C₁₀alkyl. In certain embodiments, the 4-pyridyl may be substituted with hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aryl, heteroaryl, cycloalkyl, or C₂-C₁₀alkyl.

In certain embodiments, X is NR₆.

In another embodiment, sirtuin-modulating compounds of the invention are represented by Structural Formula IVa:

wherein:

one of R₁₂or R₁₃is an 8- to 10-membered bicyclic heteroaryl comprising at least one heteroatom selected from N, O or S in each ring, wherein at least one of said heteroatoms in the bicyclic heteroaryl is an S atom, wherein said heteroaryl is bound to the rest of the compound via a carbon ring atom, and wherein said heteroaryl is optionally substituted on a single carbon ring atom with a substituent selected from a solubilizing group, or a C₁-C₄straight or branched alkyl;

R₁₁, R₁₄and the other of R₁₂or R₁₃are each independently selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl, wherein at least two of R₁₁, R₁₂, R₁₃or R₁₄are hydrogen;

X is selected from O, S or NR₆, wherein R₆is selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl; and

R₅is an optionally substituted phenyl.

In certain embodiments, X is NR₆.

In another embodiment, sirtuin-modulating compounds of the invention are represented by Structural Formula V:

wherein:

one of R₂, or R₃or R₄is selected from

wherein:

- one of X₁, X₂, X₃or X₄is N and the others are each CR₁₆;
- Z is selected from NH, or O; and
- each R₁₆is independently selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl, wherein no more than one R₁₆is selected from a solubilizing group, or a C₁-C₄straight or branched alkyl;

R₁, R₄and the other of R₂and R₃are each independently selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl, wherein at least two of R₁, R₂, R₃or R₄are hydrogen;

X is selected from O, S or NR₆, wherein R₆is selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl; and

R₅is an optionally substituted phenyl.

In certain embodiments, when X is NR₆and R₂or R₃is 1H-imidazo[4,5-b]pyridin-2-yl, 1H-benzimidazol-2-yl, or oxazolo[5,4-b]pyridin-2-yl, and R₅is phenyl substituted with hydroxy or methoxy, then there is at least one additional substituent. In certain such embodiments, the at least one additional substituent is selected from halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aryl, heteroaryl, cycloalkyl, or C₂-C₁₀alkyl. In certain embodiments, the at least one additional substituent is selected from hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aryl, heteroaryl, cycloalkyl, or C₂-C₁₀alkyl.

In certain embodiments, when X is O and R₄is 1H-benzimidazole-2-yl, then R₅is not 2-hydroxyphenyl.

In certain embodiments, when X is O and one of R₂or R₃is 1H-benzimidazol-2-yl, oxazolo[5,4-b]pyridin-2-yl or 1H-imidazo[4,5-b]pyridin-2-yl, then R₅is not 4-hydroxyphenyl, 4-methoxyphenyl, or 4-N,N-bis(2-chloroethyl)aminophenyl.

In another embodiment, sirtuin-modulating compounds of the invention are represented by Structural Formula VI:

wherein:

one of R₂or R₃is selected from

wherein:

- one of X₁, X₂, X₃or X₄and the others are each CR₁₆;
- Z is selected from NH, S or O; and
- each R₁₆is independently selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl, wherein no more than one R₁₆is selected from a solubilizing group, or a C₁-C₄straight or branched alkyl;

R₁, R₄, and the other of R₂and R₃are each independently selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl, wherein at least two of R₁, R₂, R₃or R₄are hydrogen;

X is S; and

R₅is an optionally substituted aryl or an optionally substituted heteroaryl.

In certain embodiments, X is NR₆.

In certain embodiments, R₅is selected from phenyl, 1H-pyrrolyl, pyridinyl, quinolinyl, quinoxalinyl, thienyl, or furanyl; and wherein R₅is optionally substituted.

In certain embodiments, R₅is selected from 5-methylfuran-2-yl, unsubstituted pyridin-4-yl, or unsubstituted thien-2-yl.

In certain embodiments, R₅is selected from 1-methyl-1H-pyrrol-2-yl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 4-methoxyphenyl, 2,4,6-trimethylphenyl, 3-hydroxyphenyl, 2-fluoro-5-methylphenyl, unsubstituted phenyl, 4-dimethylaminophenyl, 3,4-dioxymethylenephenyl, 4-carboxyphenyl, unsubstituted pyridin-3-yl, unsubstituted pyridin-4-yl, unsubstituted quinolinyl, unsubstituted quinoxalinyl, or unsubstituted thien-2-yl.

In another embodiment, sirtuin-modulating compounds of the invention are represented by Structural Formula VIa:

wherein:

one of R₁-R₄is selected from

wherein:

- one of X₁, X₂, X₃or X₄is N and the others are each CR₁₆;
- Z is S; and
- each R₁₆is independently selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl, wherein no more than one R₁₆is selected from a solubilizing group, or a C₁-C₄straight or branched alkyl;

the remainder of R₁-R₄are each independently selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl, wherein at least two of R₁, R₂, R₃or R₄are hydrogen;

X is selected from O, S or NR₆, wherein R₆is selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl; and

R₅is an optionally substituted aryl or heteroaryl.

In certain embodiments, X is NR₆.

In certain embodiments, R₅is selected from phenyl, 1H-pyrrolyl, pyridinyl, quinolinyl, quinoxalinyl, thienyl, or furanyl; and wherein R₅is optionally substituted.

In certain embodiments, R₅is selected from 5-methylfuran-2-yl, unsubstituted pyridin-4-yl, or unsubstituted thien-2-yl.

In another embodiment, sirtuin-modulating compounds of the invention are represented by Structural Formula VII:

wherein:

X is selected from S or NR₆, wherein R₆is selected from hydrogen, a solubilizing group, or a C₁-C₄straight or branched alkyl; and

R₅is an optionally substituted aryl or an optionally substituted heteroaryl.

In certain embodiments, X is NR₆.

In certain embodiments, one of R₁or R₄is selected from:

In certain embodiments, R₅is selected from phenyl, 1H-pyrrolyl, pyridinyl, quinolinyl, quinoxalinyl, thienyl, or furanyl; and wherein R₅is optionally substituted.

In certain embodiments of formulae I-VII above, the solubilizing group is selected from

In certain embodiments of formulae I-VII above, R₅or R₁₅is selected from

wherein the selection is consistent with the corresponding definition of R₅or R₁₅as recited above.

Compounds of the invention, including novel compounds of the invention, can also be used in the methods described herein.

The compounds and salts thereof described herein also include their corresponding hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate) and solvates. Suitable solvents for preparation of solvates and hydrates can generally be selected by a skilled artisan.

The compounds and salts thereof can be present in amorphous or crystalline (including co-crystalline and polymorph) forms.

Also provided are pharmaceutical compositions comprising one or more compounds of the compounds described herein or a salt, prodrug or metabolite thereof. In another aspect, the invention provides methods for using a compound described herein. In certain embodiments, a compound described herein may be used for a variety of therapeutic applications including, for example, increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, chemotherapeutic induced neuropathy, neuropathy associated with an ischemic event, ocular diseases and/or disorders, cardiovascular disease, blood clotting disorders, inflammation, and/or flushing, etc. A compound described herein also be used for treating a disease or disorder in a subject that would benefit from increased mitochondrial activity, for enhancing muscle performance, for increasing muscle ATP levels, or for treating or preventing muscle tissue damage associated with hypoxia or ischemia. In other embodiments, a compound described herein may be used for a variety of therapeutic applications including, for example, increasing cellular sensitivity to stress, increasing apoptosis, treatment of cancer, stimulation of appetite, and/or stimulation of weight gain, etc. As described further below, the methods comprise administering to a subject in need thereof a pharmaceutically effective amount of a compound described herein.

In embodiments of any of the methods, preparations, compounds, compositions, reaction mixtures, the compound or compounds are selected from those described WO 2007/019346, WO 2007/019345, WO 2007/019344, WO 2007/019417, WO 2007/019416, WO 2006/094248, WO 2006/094246, WO 2006/094237, WO 2006/094236, WO 2006/094235, WO 2006/094233, WO 2006/094210, WO 2006/094209, WO 2006/078941, WO 2006/105440, and WO 2008/073451, each of which is hereby incorporated by reference. In other embodiments the compounds are selected from those described as activators of a sirtuin in WO 2007/019346, WO 2007/019345, WO 2007/019344, WO 2007/019417, WO 2007/019416, WO 2006/094248, WO 2006/094246, WO 2006/094237, WO 2006/094236, WO 2006/094235, WO 2006/094233, WO 2006/094210, WO 2006/094209, WO 2006/078941, WO 2006/105440, and WO 2008/073451.

In certain aspects, a compound described herein may be administered alone or in combination with other compounds or other therapeutic agents.

DETAILED DESCRIPTION
Definitions

The singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

The term “agent” is used herein to denote a chemical compound, a mixture of chemical compounds, a biological macromolecule (such as a nucleic acid, an antibody, a protein or portion thereof, e.g., a peptide), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. The activity of such agents may render it suitable as a “therapeutic agent” which is a biologically, physiologically, or pharmacologically active substance (or substances) that acts locally or systemically in a subject.

The term “bioavailable” when referring to a compound is art-recognized and refers to a form of a compound that allows for it, or a portion of the amount of compound administered, to be absorbed by, incorporated to, or otherwise physiologically available to a subject or patient to whom it is administered.

The term “companion animals” refers to cats and dogs. As used herein, the term “dog(s)” denotes any member of the species Canis familiaris, of which there are a large number of different breeds. The term “cat(s)” refers to a feline animal including domestic cats and other members of the family Felidae, genus Felis. The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included.

“Diabetes” refers to high blood sugar or ketoacidosis, as well as chronic, 10 general metabolic abnormalities arising from a prolonged high blood sugar status or a decrease in glucose tolerance. “Diabetes” encompasses both the type I and type II (Non Insulin Dependent Diabetes Mellitus or NIDDM) forms of the disease. The risk factors for diabetes include the following factors: waistline of more than 40 inches for men or 35 inches for women, blood pressure of 130/85 mmHg or higher, triglycerides above 150 mg/dl, fasting blood glucose greater than 100 mg/dl or high-density lipoprotein of less than 40 mg/dl in men or 50 mg/dl in women.

A “direct activator” of a HAT is a molecule that activates a HAT by binding to it. A “direct inhibitor” of a HAT is a molecule inhibits a HAT by binding to it.

The term “ED₅₀” is art-recognized. In certain embodiments, ED₅₀means the 20 dose of a drug which produces 50% of its maximum response or effect, or alternatively, the dose which produces a pre-determined response in 50% of test subjects or preparations. The term “LD₅₀” is art-recognized. In certain embodiments, LD₅₀means the dose of a drug which is lethal in 50% of test subjects. The term “therapeutic index” is an art-recognized term which refers to the therapeutic index of a drug, defined as LD₅₀/ED₅₀.

The term “hyperinsulinemia” refers to a state in an individual in which the level of insulin in the blood is higher than normal.

The term “insulin resistance” refers to a state in which a normal amount of insulin produces a subnormal biologic response relative to the biological response in a subject that does not have insulin resistance.

An “insulin resistance disorder,” as discussed herein, refers to any disease or condition that is caused by or contributed to by insulin resistance. Examples include: diabetes, obesity, metabolic syndrome, insulin-resistance syndromes, syndrome X, insulin resistance, high blood pressure, hypertension, high blood cholesterol, dyslipidemia, hyperlipidemia, dyslipidemia, atherosclerotic disease including stroke, coronary artery disease or myocardial infarction, hyperglycemia, hyperinsulinemia and/or hyperproinsulinemia, impaired glucose tolerance, delayed insulin release, diabetic complications, including coronary heart disease, angina pectoris, congestive heart failure, stroke, cognitive functions in dementia, retinopathy, peripheral neuropathy, nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis some types of cancer (such as endometrial, breast, prostate, and colon), complications of pregnancy, poor female reproductive health (such as menstrual irregularities, infertility, irregular ovulation, polycystic ovarian syndrome (PCOS)), lipodystrophy, cholesterol related disorders, such as gallstones, cholescystitis and cholelithiasis, gout, obstructive sleep apnea and respiratory problems, osteoarthritis, and prevention and treatment of bone loss, e.g. osteoporosis.

“Obese” individuals or individuals suffering from obesity are generally individuals having a body mass index (BMI) of at least 25 or greater. Obesity may or may not be associated with insulin resistance.

The terms “parenteral administration” and “administered parenterally” are art-recognized and refer to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

A “patient”, “subject”, “individual” or “host” refers to either a human or a non-human animal.

The term “pharmaceutically acceptable carrier” is art-recognized and refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof. Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

The term “protecting group” is art-recognized and refers to temporary substituents that protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed by Greene and Wuts in Protective Groups in Organic Synthesis (2<nd> ed., Wiley: New York, 1991).

“Replicative lifespan” of a cell refers to the number of daughter cells produced by an individual “mother cell.” “Chronological aging” or “chronological lifespan,” on the other hand, refers to the length of time a population of non-dividing cells remains viable when deprived of nutrients. “Increasing the lifespan of a cell” or “extending the lifespan of a cell,” as applied to cells or organisms, refers to increasing the number of daughter cells produced by one cell; increasing the ability of cells or organisms to cope with stresses and combat damage, e.g., to DNA, proteins; and/or increasing the ability of cells or organisms to survive and exist in a living state for longer under a particular condition, e.g., stress (for example, heatshock, osmotic stress, high energy radiation, chemically-induced stress, DNA damage, inadequate salt level, inadequate nitrogen level, or inadequate nutrient level). Lifespan can be increased by at least about 20%, 30%, 40%, 50%, 60% or between 20% and 70%, 30% and 60%, 40% and 60% or more using methods described herein.

“HAT-activating compound” refers to a compound that increases the level of a HAT and/or increases at least one activity of a HAT. In an exemplary embodiment, a HAT-activating compound may increase at least one biological activity of a HAT by at least about 10%, 25%, 50%, 75%, 100%, or more. Exemplary biological activities of HAT include acetylation, e.g., of histones and p53; extending lifespan; increasing genomic stability; silencing transcription; and controlling the segregation of oxidized proteins between mother and daughter cells.

“HAT-inhibiting compound” refers to a compound that decreases the level of a HAT and/or decreases at least one activity of a HAT. In an exemplary embodiment, a HAT-inhibiting compound may decrease at least one biological activity of a HAT by at least about 10%, 25%, 50%, 75%, 100%, or more. Exemplary biological activities of HATs include acetylation, e.g., of histones and p53; extending lifespan; increasing genomic stability; silencing; transcription; and controlling the segregation of oxidized proteins between mother and daughter cells.

“HAT-modulating compound” refers to a compound described herein. In exemplary embodiments, a HAT-modulating compound may either up regulate (e.g., activate or stimulate), down regulate (e.g., inhibit or suppress) or otherwise change a functional property or biological activity of a HAT. HAT-modulating compounds may act to modulate a HAT either directly or indirectly. In certain embodiments, a HAT-modulating compound may be a HAT-activating compound or a HAT-inhibiting compound.

The terms “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” are art-recognized and refer to the administration of a subject composition, therapeutic or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes.

The term “therapeutic agent” is art-recognized and refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance that acts locally or systemically in a subject. The term also means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and/or conditions in an animal or human.

The term “therapeutic effect” is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance. The phrase “therapeutically-effective amount” means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. The therapeutically effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. For example, certain compositions described herein may be administered in a sufficient amount to produce a desired effect at a reasonable benefit/risk ratio applicable to such treatment.

In one embodiment -modulating compounds of the invention are represented by Structural Formula (I):

or a salt thereof, where:

Ring A is optionally substituted; and

In certain embodiments, Ring B is substituted with at least a carboxy group.

In certain embodiments, Ring B is substituted with at least a substituted or unsubstituted arylcarboxamine, a substituted or unsubstituted aralkylcarboxamine or a polycyclic aryl group.

In certain embodiments, Ring B is substituted with at least a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted heterocyclylcarbonylethenyl group.

In another embodiment, modulating compounds of the invention are represented by Structural Formula (II):

or a salt thereof; where:

Ring A is optionally substituted;

R₁, R₂, R₃and R₄are independently selected from the group consisting of —H, halogen, —OR₅, —CN, —CO₂R₅, —OCOR₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)_nR₅, —S(O)_nOR₅, —S(O)_nNR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₄and —NO₂;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group; and

n is 1 or 2.

In a further embodiment, -modulating compounds of the invention are represented by Structural Formula (Ia):

or a salt thereof, where:

Ring A is optionally substituted;

R₁, R₂, R₃and R₄are independently selected from the group consisting of —H, halogen, —OR₅, —CN, —CO₂R₅, —OCOR₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)_nR₅, —S(O)_nOR₅, —S(O)_nNR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group; and

n is 1 or 2.

In yet another embodiment, -modulating compounds of the invention are represented by Structural Formula (II):

or a salt thereof, where:

Ring A is optionally substituted;

R₁, R₂, R₃and R₄are independently selected from the group consisting of —H, halogen, —OR₅, —CN, —CO₂R₅, —OCOR₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR_s, —OSO₃H, —S(O)R₅, —S(O)_nOR₅, —S(O)_nNR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group; and

n is 1 or 2.

In certain embodiments, R₁, R₂, R₃and R₄in Structural Formulas (II)-(IIb) are independently selected from the group consisting of —H, —OR₅and —SR₅, particularly —H and —OR₅(e.g., —H, —OH, —OCH₃).

Ring A is preferably substituted. Suitable substituents include halogens (e.g., bromine), acyloxy groups (e.g., acetoxy), aminocarbonyl groups (e.g., arylaminocarbonyl such as substituted, particularly carboxy-substituted, phenylaminocarbonyl groups) and alkoxy (e.g., methoxy, ethoxy) groups.

In yet another aspect, the invention provides novel: -modulating compounds of Formula (III):

or a salt thereof; where:

Ring A is optionally substituted;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

R₇, R₉, R₁₀and R₁₁are independently selected from the group consisting of —H, halogen, —R₅, —OR₅, —CN, —CO₂R₅, —OCOR₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)_nR₅, —S(O)OR₅, —S(O)_nNR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₈is a polycyclic aryl group; and

n is 1 or 2.

In certain embodiments, one or more of R₇, R₉, R₁₀and R₁₁are —H. In particular embodiments, R₇, R₉, R₁₀and R₁₁are each —H.

In certain embodiments, R₈is a heteroaryl group, such as an oxazolo[4,5-b]pyridyl group. In particular embodiments, R₈is a heteroaryl group and one or more of R₇, R₉, R₁₀and R₁₁are —H.

Ring A is preferably substituted. Suitable substituents include halogens (e.g., bromine), acyloxy groups (e.g., acetoxy); aminocarbonyl groups (e.g., arylaminocarbonyl, such as substituted, particularly carboxy-substituted, phenylaminocarbonyl groups) and alkoxy (e.g., methoxy, ethoxy) groups, particularly alkoxy groups. In certain embodiments, Ring A is substituted with at least one alkoxy or halo group, particularly methoxy.

In certain embodiments, Ring A is optionally substituted with up to 3 substituents independently selected from (C₁-C₃straight or branched alkyl), O—(C₁-C₃straight or branched alkyl), N(C₁-C₃straight or branched alkyl)₂, halo, or a 5 to 6-membered heterocycle.

In certain embodiments, Ring A is not substituted with a nitrile or pyrrolidyl group.

In certain embodiments, R₈is a substituted or unsubstituted bicyclic heteroaryl group, such as a bicyclic heteroaryl group that includes a ring N atom and 1 to 2 additional ring heteroatoms independently selected from N, O or S. Preferably, R₈is attached to the remainder of the compound by a carbon-carbon bond. In certain such embodiments, 2 additional ring heteroatoms are present, and typically at least one of said additional ring heteroatoms is O or S. In certain such embodiments, 2 total ring nitrogen atoms are present (with zero or one O or S present), and the nitrogen atoms are typically each in a different ring. In certain such embodiments, R₈is not substituted with a carbonyl-containing moiety, particularly when R₈is thienopyrimidyl or thienopyridinyl.

In certain such embodiments, R₈is selected from oxazolopyridyl, benzothienyl, benzofuryl, indolyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl or isoindolyl. In certain such embodiments, R₈is selected from thiazolopyridyl, imidazothiazolyl, benzoxazinonyl, or imidazopyridyl.

Particular examples of R₈, where indicates attachment to the remainder of Structural Formula (III) include:

where up to 2 ring carbons not immediately adjacent to the indicated attachment point are independently substituted with O—C₁-C₃straight or branched alkyl, C₁-C₃straight or branched alkyl or halo, particularly C₁-C₃straight or branched alkyl or halo. In certain embodiments, R₈is

In certain embodiments, R₈is

and Ring A is optionally substituted with up to 3 substituents independently selected from (C₁-C₃straight or branched alkyl), O—(C₁-C₃straight or branched alkyl), N(C₁-C₃straight or branched alkyl)₂, halo, or a 5 to 6-membered heterocycle. In certain such embodiments, Ring A is not simultaneously substituted at the 2- and 6-positions with O—(C₁-C₃straight or branched alkyl). In certain such embodiments, Ring A is not simultaneously substituted at the 2-, 4- and 6-positions with O—(C₁-C₃straight or branched alkyl). In certain such embodiments, Ring A is not simultaneously substituted at the 2-, 3-, and 4-positions with O—(C₁-C₃straight or branched alkyl). In certain such embodiments, Ring A is not substituted at the 4-position with a 5 to 6-membered heterocycle. In certain such embodiments, Ring A is not singly substituted at the 3- or 4-position (typically 4-position) with O—(C₁-C₃straight or branched alkyl). In certain such embodiments, Ring A is not substituted at the 4-position with O—(C₁-C₃straight or branched alkyl) and at the 2- or 3-position with C₁-C₃straight or branched alkyl.

In certain embodiments, R₈is

and Ring A is optionally substituted with up to 3 substituents independently selected from (C₁-C₃straight or branched alkyl), (C₁-C₃straight or branched haloalkyl, where a haloalkyl group is an alkyl group substituted with one or more halogen atoms), O—(C₁-C₃straight or branched alkyl), N(C₁-C₃straight or branched alkyl)₂, halo, or a 5 to 6-membered heterocycle. In certain such embodiments, Ring A is not singly substituted at the 3- or 4-position with O—(C₁-C₃straight or branched alkyl). In certain such embodiments, Ring A is not substituted at the 4-position with O—(C₁-C₃straight or branched alkyl) and at the 2- or 3-position with C₁-C₃straight or branched alkyl.

In certain embodiments, R₈is

(e.g., where one or both halo is chlorine) and Ring A is optionally substituted with up to 3 substituents independently selected from (C₁-C₃straight or branched alkyl), O—(C₁-C₃straight or branched alkyl), N(C₁-C₃straight or branched alkyl)₂, halo, or a 5 to 6-membered heterocycle, but not singly substituted at the 3-position with O—(C₁-C₃straight or branched alkyl).

In certain embodiments, such as when R₈has one of the values described above, Ring A is substituted with up to 3 substituents independently selected from chloro, methyl, O-methyl, N(CH₃)₂or morpholino. In certain such embodiments, R₈is selected from

where up to 2 ring carbons not immediately adjacent to the indicated attachment point are independently substituted with C₁-C₃straight or branched alkyl or halo; each of R₇, R₉, and R₁₁is —H; and R₁₀is selected from —H, —CH₂OH, —CO₂H, —CO₂CH₃, —CH₂-piperazinyl, CH₂N(CH₃)₂, —C(O)—NH—(CH₂)₂—N(CH₃)₂, or —C(O)-piperazinyl. In certain such embodiments, when R₈is

and Ring A is 3-dimethylaminophenyl, none of R₇, R₉, R₁₀and R₁₁is —CH₂—N(CH₃)₂or —C(O)—NH—(CH₂N(CH₃)₂, and/or when R₈is

and Ring A is 3,4 dimethoxyphenyl, none of R₇, R₉, R₁₀and R₁₁is C(O)OCH₃or C(O)OH.

In certain embodiments, such as when R₈has one of the values described above and/or Ring A is optionally substituted as described above, at least one of R₇, R₉, R₁₀and R₁₁is —H. In certain such embodiments, each of R₇, R₉, R₁₀and R₁₁is —H.

In certain embodiments, R₇, R₉, R₁₀or R₁₁is selected from —C(O)OH, —N(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂-piperazinyl, —CH₂-methylpiperazinyl, —CH₂-pyrrolidyl, —CH₂-piperidyl, —CH₂-morpholino, —CH₂—N(CH₃)₂, —C(O)—NH—(CH₂)_n-piperazinyl, —C(O)—NH—(CH₂)_n-methylpiperazinyl, —C(O)—NH—(CH₂)_n-pyrrolidyl, —C(O)—NH—(CH₂)_n-morpholino, —C(O)—NH—(CH₂)_n-piperidyl, or —C(O)—NH—(CH₂)_n—N(CH₃)₂, wherein n is 1 or 2. In certain such embodiments, R₁₀is selected from —C(O)OH, —N(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂-piperazinyl, —CH₂-methylpiperazinyl, —CH₂-pyrrolidyl, —CH₂-piperidyl, —CH₂-morpholino, —CH₂—N(CH₃)₂, —C(O)—NH—(CH₂)_n-piperazinyl, —C(O)—NH—(CH₂)_n-methylpiperazinyl, —C(O)—NH—(CH₂)_n-pyrrolidyl, —C(O)—NH—(CH₂)_n-morpholino, —C(O)—NH—(CH₂)_n-piperidyl, or —C(O)—NH—(CH₂)_n—N(CH₃)₂, wherein n is 1 or 2, and each of R₇, R₉, and R₁₁is H.

In certain embodiments, Ring A is substituted with a nitrile group or is substituted at the para position with a 5- or 6-membered heterocycle. Typical examples of the heterocycle include pyrrolidyl, piperidinyl and morpholinyl.

In yet another aspect, the invention provides novel -modulating compounds of Formula (IV):

Ar-L-J-M-K-Ar′ (IV)

or a salt thereof, wherein: each Ar and Ar′ is independently an optionally substituted carbocyclic or heterocyclic aryl group;

L is an optionally substituted carbocyclic or heterocyclic arylene group;

each M is C(O), S(O), S(O)₂, or CR₁′R₁′;

each R₁′ is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₅′; halo; haloalkyl; CF₃; SR₂′; OR₂′; NR₂′R₂′; NR₂′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)C(O)R₂′; C(O)NR₂′R₂′; OC(O)R₂′; S(O)₂R₂′; S(O)₂NR₂′R₂′; NR₂′C(O)NR₁′R₂′; NR₂′C(O)C(O)R₂′; NR₂′C(O)R₂′; NR₂′ (COOR₂′); NR₂′C(O)R₅′; NR₂′S(O)₂NR₂′R₂′; NR₂′S(O)₂R₂′; NR₂′S(O)₂R₅′; NR₂′C(O)C(O)NR₂′R₂′; NR₂′C(O)C(O)NR₂′R₃′; C1-C10 alkyl substituted with aryl, R₄′ or R₅′; or C2-C10 alkenyl substituted with aryl, R₄′ or R₅′;

each R₃′ is independently C(O)R₂′, COOR₂′, or S(O)₂R₂′;

each R₄′ is independently halo, CF₃, SR₇′, OR₇′, OC(O)R₇′, NR₇′R₇′, NR₇′R₈′, NR₈′R₈′, COOR₇′, NO₂, CN, C(O)R₇′, or C(O)NR₇′R₇′;

each R₅′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or 8, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₆′; halo; sulfur; oxygen; CF₃; haloalkyl; SR₂′; OR₂; OC(O)R₂; NR₂′R₂′; NR₂′R₃; NR₃′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)NR₂′R₂′; C1-C10 alkyl substituted with 1-3 independent R₄′, R₆′, or aryl; or C2-C10 alkenyl substituted with 1-3 independent R₄′, R₆′ or aryl;

each R₆′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur oxygen; CF₃; haloalkyl; SR₇′; OR₇′; NR₇′R₇′; NR₇′R₈′; NR₈′R₈′; COOR₇′; NO₂; CN; C(O)R₇′; or C(O)NR₇′R₇′;

each R₇′ is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′;

each R₈′ is independently C(O)R₇′, COOR₇′, or S(O)₂R₇′;

each R₁₁′ is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;

each aryl is independently optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R₆′; halo; haloalkyl; CF₃; OR₉′; SR₉′; NR₉′R₉′; COOR₉′; NO₂; CN; C(O)R₉′; C(O)C(O)R₉′; C(O)NR₉′R₉′; S(O)₂R₉′; N(R₉′)C(O)R₉′; N(R₉′)(COOR₉′); N(R₉′)S(O)₂R₉′; S(O)₂NR₉′R₉′; OC(O)R₉′; NR₉′C(O)NR₉′R₉′; NR₉′C(O)C(O)R₉′; NR₉′C(O)R₉′; NR₉′S(O)₂NR₉′R₉′; NR₉′S(O)₂R₆′; NR₉′C(O)C(O)NR₉′R₉′; C1-C10 alkyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; C2-C10 alkenyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; or R₉′.

In a preferred embodiment of the invention, each Ar, L, and Ar′ is independently an optionally substituted 5- to 7-membered monocyclic ring system or an optionally substituted 9- to 12-membered bicyclic ring system.

According to another preferred embodiment,

- Ar is

- X₁, X₂, X₃, X₄, and X₅are independently selected from CR₁′ and N; and
- X₆is selected from NR₁′, O, and S;

According to yet another preferred embodiment, X₁and X₂are N; X₃, X₄, and X₅are CR₁′; and X₆is O.

According to still yet another preferred embodiment, X₁and X₃are N; X₂, X₄, and X₅are CR₁′; and X₆is O.

According to still yet another preferred embodiment, X₁and X₄are N; X₂, X₃, and X₅are CR₁′; and X₆is O.

According to still yet another preferred embodiment, X₁and X₅are N; X₂, X₃, and X₄are CR₁′; and X₆is O.

In another embodiment, the compounds of the formula above are those wherein J is NR₁′, K is absent, and M is C(O).

In yet another embodiment, the compounds of the formula above are those wherein J is absent, K is NR₁′, and M is C(O).

In a further embodiment, compounds of formula (IV) are those where when J is absent and K is NR₁′, M is not C(O) and when J is NR₁′ and K is absent, M is not C(O).

In a preferred embodiment, the compounds above are those wherein L is an optionally substituted 5- to 7-membered carbocyclic or heterocyclic aryl group.

In yet another preferred embodiment, the compounds are those wherein L is an optionally substituted phenylene, pyridinylene, imidazolylene, oxazolylene, or thiazolylene.

In a particularly preferred embodiment, L is an optionally substituted phenylene.

In another particularly preferred embodiment, L is an optionally substituted pyridinylene.

In an even more preferred embodiment, L is phenylene.

In another even more preferred embodiment, L is pyridinylene.

In either of these embodiments, Ar and J may be attached to L at the ortho-, meta-, or para-positions. Particularly preferred are those embodiments where attachment is at the meta-position.

In certain embodiments, L is not phenylene when Ar′ is phenyl. Examples of such embodiments include embodiments where L is an optionally substituted heterocyclic aryl group and Ar′ is an optionally substituted carbocyclic or heterocyclic aryl group, or wherein L is an optionally substituted carbocyclic or heterocyclic aryl group and Ar′ is an optionally substituted heterocyclic aryl group.

In yet another aspect, the invention provides novel -modulating compounds of Formula (I) or a salt thereof, wherein

Ring A is substituted with at least one R₁′ group;

R₁′, R₂′, R₃′, R₄′, R₅′, R₆′, R₇′, R₈′, R₉′, R₁₀′, and R₁₁′ are as defined above;

each aryl is independently a 5- to 7-membered monocyclic ring system or a 9- to 12-membered bicyclic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R₆′; halo; haloalkyl; CF₃; OR₉′; SR₉′; NR₉′R₉′; COOR₉′; NO₂; CN; C(O)R₉′; C(O)C(O)R₉′; C(O)NR₉′R₉′; S(O)₂R₉′; N(R₉′)C(O)R₉′; N(R₉′)(COOR₉′); N(R₉′)S(O)₂R₉′; S(O)₂NR₉′R₉′; OC(O)R₉′; NR₉′C(O)NR₉′R₉′; NR₉′C(O)C(O)R₉′; NR₉′C(O)R₆′; NR₉′S(O)₂NR₉′R₉′; NR₉′S(O)₂R₆′; NR₉′C(O)C(O)NR₉′R₉′; C1-C10 alkyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉ ), S(O)₂NR₉′R₉′C(O)R₉′; C2-C10 alkenyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′—, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)NR₉′R₉′, OC(O)R₉′; or R₉′; and

Ring B is substituted with at least one

wherein

X₁, X₂, X₃, X₄, and X₅are independently selected from CR₁′ and N; and

X₆is selected from NR₁′, O, and S.

In a preferred embodiment, Ring B is phenyl or pyridinyl.

In a further aspect, the invention provides novel -modulating compounds of Formula (IVa):

Het-L-Q-Ar′ (IVa)

or a salt thereof, wherein:

Het is an optionally substituted heterocyclic aryl group;

L is an optionally substituted carbocyclic or heterocyclic arylene group;

Ar′ is an optionally substituted carbocyclic or heterocyclic aryl group; and

Q is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—CO)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—,

and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl, wherein:

In certain embodiments, when Het is a polycyclic heteroaryl, L is optionally substituted phenylene, and Ar′ is optionally substituted phenyl; then Q is not —NH—C(O)—.

In certain embodiments, Het and Q are attached to L in a 1-, 2- or 1-,3-configuration (e.g., when L is phenylene, Het and Q are attached in an ortho or a meta orientation). In certain embodiments where Het and Q are attached to L in a 1-,3-configuration, if Het is benzoxazolyl, L is pyridylene and Q is —NH—C(O)—NH, then Ar′ is not 3,4 dioxymethylene phenyl; if Het is methyl thiazolyl, L is phenylene and Q is —NH—C(O)—, then Ar′ is not 3-dimethylamino phenyl; if Het is oxazolopyridyl, L is pyridylene and Q is —NH—C(O)—NH, then Ar′ is not 4-dimethylamino phenyl; if Het is oxazolopyridyl or benzoxazolyl and L is

then Q is not —NH—(SO)₂—; and if Het is oxazolopyridyl, L is

and Q is —NH—C(O)—, then Ar′ is not 3,4 dimethoxyphenyl or pyridyl.

When Het is substituted, it is typically substituted at up to 2 carbon atoms with a substituent independently selected from R₁₂, N(R₁₂)₂, NH(R₁₂), OR₁₂, C(O)—NH—R₁₂, C(O)—N(R₁₂)₂, N(R₁₂)—OR₁₂, CH₂—N(R₁₂)₂, C(O)OR₁₂, C(O)OH,

where each R₁₂is independently selected from optionally substituted C₁-C₃straight or branched alkyl.

In certain embodiments, Het is selected from oxazolopyridyl, benzothienyl, benzofuryl, indolyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl or isoindolyl. In other embodiments, Het comprises one ring N heteroatom and 1 to 2 additional ring heteroatoms independently selected from N, O or S, such as thiazolyl, triazolyl, oxadiazolyl, thiazolopyridyl, imidazothiazolyl, benzoxazinonyl, or imidazopyridyl.

Particular examples of Het include:

where up to 2 ring carbons not immediately adjacent to the indicated attachment point are independently substituted with optionally substituted C₁-C₃straight or branched alkyl, phenyl, halo, N(R₁₂)₂, NH(R₁₂), OR₁₂, C(O)—NH—R₁₂, C(O)—N(R₁₂)₂, N(R₁₂)—OR₁₂, CH₂—N(R₁₂)₂, C(O)OR₁₂, C(O)OH,

wherein each R₁₂is independently selected form optionally substituted C₁-C₃straight or branched alkyl.

In certain embodiments, L is selected from

wherein:

each of Z₁, Z₂, Z₃and Z₄is independently selected from CH or N, wherein not more than three of said Z₁, Z₂, Z₃or Z₄is N;

each of Z₅and Z₆is independently selected from C, N, O or S, provided that at least one of Z₅and Z₆is N; and

L is optionally substituted at 1 to 2 carbon atoms with a substituent independently selected from R₁₂, N(R₁₂)₂, NH(R₁₂), OR₁₂, C(O)—NH—R₁₂, C(O)—N(R₁₂)₂, N(R₁₂)—OR₁₂, CH₂—N(R₁₂)₂, C(O)OR₁₂, C(O)OH,

In preferred embodiments, L is selected from phenylene or pyridylene, such as unsubstituted phenylene or phenylene substituted with a single substituent selected from C(O)OCH₃, C(O)OH, CH₂OH, N(CH)₂, or CH₂N(CH₃)₂, or unsubstituted pyridylene.

In certain embodiments, Q is selected from —NH—C(O)—, —NH—S(O)₂—, —NH—C(O)—NH—, —C(O)—NH—, —CH₂—, —N(CH₃)—C(O)—NH—, —NH—C(O)—N(CH₃)—, or —NH—S(O)₂—NH—, particularly —NH—C(O)—, —C(O)—NH—, —NH—, —NH—C(O)—NH, or —NH—S(O)₂—.

In certain embodiments, Ar′ is selected from optionally substituted phenyl, benzothiazolyl, or benzoxazolyl. When Ar′ is phenyl, typical optional substituents are 1 to 3 substituents independently selected from halo, (optionally substituted C₁-C₃straight or branched alkyl), O-(optionally substituted C₁-C₃straight or branched alkyl), S-(optionally substituted C₁-C₃straight or branched alkyl), N(CH₃)₂or optionally substituted heterocyclyl, or wherein two substituents on adjacent ring atoms are taken together to form a dioxymethylene.

In certain embodiments, Het is selected from

and wherein up to 2 ring carbons not immediately adjacent to the idcated attachment point are independently substituted with optionally substituted C₁-C₃straight or branched alkyl, phenyl or halo;

L is selected from unsubstituted phenylene, phenylene substituted with a single substituent selected from C(O)OCH₃, C(O)OH, CH₂OH, N(CH₃)₂, or CH₂N(CH₃)₂, or unsubstituted pyridylene;

Q is selected from—NH—C(O)—, —C(O)—NH—, —NH—, —NH—C(O)—NH, or —NH—S(O)₂—; and

Ar′ is selected from optionally substituted phenyl, benzothiazolyl, or benzoxazolyl, wherein said phenyl is optionally substituted with 1 to 3 substituents independently selected from chloro, methyl, O-methyl, S-methyl, N(CH₃)₂, morpholino, or 3,4 dioxymethylene.

In certain embodiments, Q is selected from —NH—C(O)—, —C(O)—NH—, —NH— or —NH—C(O)—NH.

In certain embodiments, the substituents on Ar′ are selected from chloro, methyl, O-methyl, S-methyl or N(CH₃)₂. In certain embodiments, the only substituent on Ar′ is an O-methyl group, particularly an O-methyl group ortho or meta to Q. In certain embodiments, when there are two or more O-methyl groups or Ar′, at least one is ortho or meta to Q.

In certain embodiments, L is pyridyl and Het and Q are at the 1,3- or 2,4-position with respect to the pyridyl nitrogen atom. In certain such embodiments, Q is —NH—S(O)₂—.

In certain embodiments where L is further substituted, the substituent is typically meta to both Het and Q.

In certain embodiments, Q is —NH— and Het is thiazolyl or oxazolopyridyl.

In certain embodiments, Q is —NH— and Ar is benzothiazolyl or benzoxazolyl.

In certain embodim such as when the sirtuin modulator is a sirtuin activator, L is

and Q is —NH—(SO)₂—. In certain such embodiments, Het is oxazolopyndyl. When L, Q and optionally Het have these values, Ar′ is advantageously naphthyl or phenyl, where Ar′ is optionally substituted with 1 to 3 substituents independently selected from CN, halo, (C₁-C₃straight or branched alkyl), O—(C₁-C₃straight or branched alkyl), N(C₁-C₃straight or branched alkyl)₂, or a 5 to 6-membered heterocycle.

In certain embodiments, L is

and Q is —NH—C(O)—. In certain such embodiments, Het is oxazolopyridyl. When L, Q and optionally Het have these values, Ar′ is advantageously pyridyl or phenyl optionally substituted with 1 to 3 substituents independently selected from CN, halo, (C₁-C₃straight or branched alkyl), O—(C₁-C₃straight or branched alkyl), N(C₁-C₃straight or branched alkyl)2, or a 5 to 6-membered heterocycle.

In certain embodiments,

, Het comprises one N heteroatom and 1 to 2 additional heteroatoms independently selected from N, O or S;

L is

and is optionally substituted;

Q is —NH—C(O)—; and

Ar′ is phenyl substituted with 1 to 3 substituents independently selected from CN, halo, C₁-C₃straight or branched alkyl, O—(C₁-C₃straight or branched alkyl), N(C₁-C₃straight or branched alkyl)₂, or a 5 to 6-membered heterocycle, wherein when R₈is unsubstituted

then ring A is:

- a) not simultaneously substituted at the 2- and 6-positions with O—(C₁-C₃straight or branched alkyl);
- b) not simultaneously substituted at the 2-position with C₁-C₃straight or branched alkyl or O—(C₁-C₃straight or branched alkyl) and at the 3-position with O—(C₁-C₃straight or branched alkyl);
- c) not substituted at the 4-position with O—(C₁-C₃straight or branched alkyl) unless simultaneously substituted at the 3-position with halo or O—(C₁-C₃straight or branched alkyl) and unsubstituted at all other positions;
  
  not substituted at the 4-position with N(C₁-C₃straight or branched alkyl)₂, or said 5 to 6-membered heterocycle. In certain such embodiments, L is unsubstituted and/or Het is oxazolopyridyl.

In yet another aspect, the invention provides novel -modulating compounds of Formula (V):

or a salt thereof, wherein:

Ring A is optionally substituted with at least one R₁′ group;

Y₁, Y₂, Y₃, Y₄, and Y₅are independently R₁′;

R₁′, R₂′, R₃′, R₄′, R₅′, R₆′, R₇′, R₈′, R₉′, R₁₀′, and R₁₁′ are as defined above;

each aryl is independently a 5- to 7-membered monocyclic ring system or a 9- to 12-membered bicyclic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R₆′; halo; haloalkyl; CF₃; OR₉′; SR₉′; NR₉′R₉′; COOR₉′; NO₂; CN; C(O)R₉′; C(O)C(O)R₉′; C(O)NR₉′R₉′; S(O)₂R₉′; N(R₉′C(O)R₉′; N(R₉′)(COOR₉′); N(R₉′S(O)₂R₉′; S(O)₂NR₉′R₉′; OC(O)R₉′; NR₉′C(O)NR₉′R_R′; NR₉′C(O)C(O)R₉′; NR₉′C(O)R₆′; NR₉′S(O)₂NR₉′R₉′; NR₉′S(O)₂R₉′; NR₉′C(O)C(O)NR₉′R₉′; C1-C10 alkyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′ R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; C2-C10 alkenyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′; COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; or R₉′.

In a preferred embodiment of the above compound, either Y₂or Y₃is

X₁, X₂, X₃, X₄, and X₅are independently selected from CR₁′ and N; and

X₆is selected from NR₁′, O, and S.

According to an even more preferred embodiment, X₁and X₂are N; X₃, X₄, and X₅are CR₁′; and X₆is O.

According to another even more preferred embodiment, X₁and X₃are N; X₂, X₄, and X₅are CR₁′; and X₆is O.

According to another even more preferred embodiment, X₁and X₄are N; X₂, X₃, and X₅are CR₁′; and X₆is O.

According to another even more preferred embodiment, X₁and X₅are N; X₂, X₃, and X₄are CR₁′; and Xs is O.

In another aspect, the invention provides -modulating compounds of Structural Formula (VII):

or a salt thereof, wherein:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Zo₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that said compound is not:

that when R¹⁹is

and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In certain embodiments, compounds of Structural Formula (VII) have the following values:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

each R²⁰is independently selected from H or a solubilizing group;

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and

zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅sand Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′—CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

said compound is not:

and

when X₈and X₉are each independently selected from CR²⁰or CR₁′, R¹⁹is

and each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰, or CR₁′, then:

a) at least one of X₈and X₉is not CH; or

b) at least one of Z₁₀, Z₁₁, Z₁₂and Z₁₃is CR²⁰, wherein R²⁰is a solubilizing group.

In certain embodiments, when Z₁₂is CR²⁰and R²⁰is a solubilizing group, the solubilizing group is not —C(O)OCH₂CH₃, —COOH,

In certain embodiments, when X₈and X₉are each independently selected from CR²⁰or CR₁′, R¹⁹is

and each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰, or CR₁′, then:

- a) at least one of X₈and X₉is not CH; or
- b) at least one of Z₁₀, Z₁₁and Z₁₃is CR²⁰, wherein R²⁰is a solubilizing group.

In certain embodiments, when R¹⁹is

and each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is CR²⁰, or CR₁′; X₈and X₉are CR²⁰or CR₁′; R²¹is —NHC(O)—; and R³¹is optionally substituted phenyl, then R³¹is a substituted phenyl, at least one R₁′ in a CR₁′ moiety is optionally substituted C₁-C₃straight or branched alkyl, or at least one R²⁰in a CR²⁰is a solubilizing group, or a combination thereof.

In certain embodiments, R¹⁹is selected from phenyl, pyridyl, thienyl or furyl.

In certain embodiments, R¹⁹is

wherein each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰or CR₁′; and

R²¹is —NH—C(O)—; and

R³¹is a substituted phenyl.

In certain such embodiments, when X₉is N, R³¹is not 2,4 dimethoxyphenyl and/or when X₁₀is N, R³¹is not halo substituted phenyl; 3,4-dioxoethylenephenyl; or 3,5-dimethoxyphenyl.

In preferred embodiments, R³¹is optionally substituted with 1 to 3 substituents independently selected from —OCH₃, —CH₃, —N(CH₃)₂, pyrazinoxy or a solubilizing group. Suitable examples of R³¹include 3-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl, 3-methoxy-4-morpholinomethylphenyl, 3-methoxy-4-diaminomethylphenyl, 3-methoxy-4-((pyrrolidin-1-yl)methyl)phenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, or 3,5-dimethylphenyl.

In certain embodiments, R¹⁹is selected from

wherein one of Z₁₀, Z₁₁, Z₁₂, and Z₁₃is N and the others are independently selected from CR²⁰or CR₁′;

R²¹is selected from —NH—, —NH—C(O)—, —NH—C(O)—NH, —NH—C(S)—NH— or —NH—S(O)₂—; and

R³¹is selected from an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted heteroaryl.

In certain such embodiments,

- a) when R²¹is —NH—S(O)₂—, either:
  - i) Z₁₀is N; or
  - ii) Z₁₁is N and R³¹is halophenyl or 2-methoxy-5-methylphenyl;
- b) when R¹⁹is

R³¹is not 4-dimethylaminophenyl, 2,3,4-trimethoxyphenyl, or 3,5 dimethoxyphenyl; and/or

- c) when R²¹is —NH—C(O)—NH— and Z₁₀is N, R³¹is not 4-dimethylaminophenyl.

In certain such embodiments, R³¹is selected from optionally substituted phenyl, benzothiazolyl, or benzoxazolyl.

In yet another embodiment, the invention provides: -modulating compounds of Structural Formula (VIII):

or a salt thereof wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′-S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁—CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R₁′ is methyl, and R²¹is —NH—C(O)—, R³¹is not

1-methoxynaphthyl, 2-methoxynaphthyl, or unsubstituted 2-thienyl;

when R₁′ is methyl, and R²¹is —NH—C(O)—CH═CH—, R³¹is not

when R₁′ is methyl, and R²¹is —NH—C(O)—CH—O—, R³¹is not unsubstituted naphthyl, 2-methoxy, 4-nitrophenyl, 4-chloro-2-methylphenyl, or 4-t-butylphenyl; and

when R²¹is —NH—C(O)—, R³¹is not optionally substituted phenyl.

In certain embodiments, R²¹is —NH—C(O)—; and R³¹is phenyl optionally substituted with 1 to 3 substituents independently selected from —OCH₃, —CH₃, —N(CH₃)₂, or a solubilizing group.

In certain such embodiments, R²¹is —NH—C(O)— and R³¹is selected from unsubstituted phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2,3,4-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-methyl-3-methoxyphenyl, 2-morpholinophenyl, 2-methoxy-4-methylphenyl, 2-dimethylaminophenyl, 4-dimethylaminophenyl, or

particularly phenyl; 2-methoxyphenyl; 3-methoxyphenyl; 2,3,4-trimethoxyphenyl; 3,4,5-trimethoxyphenyl; 2,4-dimethoxyphenyl; 3,5-dimethoxyphenyl; 2-methyl-3-methoxyphenyl; 2-morpholinophenyl; 2-methoxy-4-methylphenyl; 2-dimethylaminophenyl; or 4-dimethylaminophenyl.

In a further embodiment, the invention provides -modulating compounds of Structural Formula (IX):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

In one aspect, the invention provides -modulating compounds of Structural Formula (X):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

In certain embodiments, R⁵¹is selected from pyrazolyl, thiazolyl, oxazolyl, pyrimidinyl, furyl, thienyl, pyridyl, isoxazolyl, indolyl, benzopyrazolyl, benzothiazolyl, benzoxazolyl, quinoxalinyl, benzofuranyl, benzothienyl, quinolinyl, benzoisoxazolyl, benzotriazinyl, triazinyl, naphthyl, or

and wherein R⁵¹is optionally substituted. In certain such embodiments, R⁵¹is selected from pyrazolyl, thiazolyl, oxazolyl, pyrimidinyl, indolyl, pyrazinyl, triazinyl, or

and R⁵¹is optionally substituted.

In another aspect, the invention provides modulating compounds of Structural Formula (XI):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²²is selected from —NR₂₃—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′S(O)₂—NR₁′—, —NR₁′C(O)—NR₁′S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁—O—, —NR₁′—C(O)—CR₁′R₁—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—, wherein R₂₃is an optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an Optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R₂₂is —NH—C(O)—CH₂—, R³¹is not 3,4-dimethoxyphenyl, 4-chlorophenyl, or unsubstituted phenyl;

when R²²is —NH—(O)—CH₂—O—R³¹is not 2,4-dimethyl-6-nitrophenyl, 2- or 4-nitrophenyl, 4-cyclohexylphenyl, 4-methoxyphenyl unsubstituted naphthyl, or unsubstituted phenyl, or phenyl monosubstituted, disubstituted or trisubstituted solely with substituents selected from straight- or branched-chain alkyl or halo;

when R²²is —NH—C(O)—CH(CH₃)—O—, R³¹is not 2,4-dichlorophenyl, 4-chlorophenyl, or unsubstituted phenyl; and

when R²²is —NH—S(O)₂, R³¹is not unsubstituted phenyl.

In certain embodiments, R²²is selected from —C(O)—NH—, —NH—, or —CC(O)—NH—CH₃.

In certain embodiments, such as when R²²is selected from —C(O)—NH—, —NH—, or —C(O)—NH—CH₃, R³¹is selected from optionally substituted phenyl, benzothiazolyl, quinoxalinyl, or benzoxazolyl.

In yet another aspect, the invention provides -modulating compounds of Structural Formula (XII):

or a salt thereof, wherein:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z_1l, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that when R₁₉is

Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In certain embodiments, the compounds of Structural Formula (XI) have the following values:

each of X₇, X₈, X₉and X₁₀is independently selected from N, CR²⁰, or CR₁′, wherein:

- each R²⁰is independently selected from H or a solubilizing group;
- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- one of X₇, X₈, X₉and X₁₀is N and the others are selected from CR²⁰or CR₁′; and
- zero to one R²⁰is a solubilizing group;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or heteroaryl, with the proviso that:

when X₇is N, R¹⁹is

and each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰, or CR₁′, then:

- a) at least one of X₈, X₉or X₁₀is C—(C₁-C₃straight or branched alkyl) or C-(solubilizing group); or
- b) at least one of Z₁₀, Z₁₁, Z₁₂and Z₁₃is CR²⁰, wherein R²⁰is a solubilizing group.

In certain embodiments, R²¹is —NH—C(O)— and R¹⁹is selected from:

In certain embodiments, R¹⁹is selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thienyl or optionally substituted furyl.

In certain embodiments, R¹⁹is

wherein each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰or CR₁′; and

R²¹is selected from —NH—C(O)—, —NH—C(O)—CH(CH₃)—O—, —NH—C(O)—CH₂—O—, or —NH—S(O)₂—CH₂—CH₂—; and

R³¹is selected from an optionally substituted aryl, or an optionally substituted heteroaryl.

In certain such embodiments, R³¹is optionally substituted with 1 to 3 substituents independently selected from —OCH₃, —CH₃, —N(CH₃)₂, phenyl, phenoxy, 3,4-dioxymethylene, fluoro, or another solubilizing group. Suitable examples of R³¹include unsubstituted quinolinyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 3,5-dimethylphenyl, 3,5-difluorophenyl, 3-trifluoromethoxyphenyl, unsubstituted quinoxalinyl, unsubstituted benzopyrimidinyl, quinoxalinyl, unsubstituted benzopyrimidinyl,

In certain such embodiments, R³¹is not phenyl-substituted furyl.

In certain embodiments, R¹⁹is selected from

each of Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from CR²⁰, or CR₁′,

R²¹is selected from —NH—C(O)—, NH—C(O)—CH₂—CH(CH₃)—O, —NH—C(O)—NH—, —NH—C(S)—NH—, —NH—C(S)—NH—CH₂—, or —NH—S(O)₂—; and

R³¹is selected from an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted heteroaryl.

In certain such embodiments, R³¹is selected from phenyl, naphthyl, pyrazolyl, furyl, thienyl, pyridyl, isoxazolyl, benzopyrazolyl, benzofuryl, benzothienyl, quinolinyl, benzoisoxazolyl, or

and R³¹is optionally substituted (e.g., optionally substituted with up to three substituents independently selected from —OCH₃, —CH₃, —N(CH₃)₂, —O-phenyl, or another solubilizing group). Suitable examples of R³¹include unsubstituted phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3 dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-bis(trifluoromethyl)phenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2-methoxy-4-methylphenyl, 2-phenoxyphenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, unsubstituted 2-furanyl, unsubstituted 2-thienyl,

In certain embodiments, one or more of the following conditions applies:

when Xs is N, R²¹is —NH—C(S)—NH—, and R¹⁹is phenyl, R³¹is not 2-methoxy-5-nitrophenyl, 2-S-methylphenyl or 2-acetylphenyl;

when X₈is N, R²¹is —NH—S(O)₂—, and R¹⁹is phenyl, R³¹is not thiadiazole-substituted thienyl or 4-methylsulfonylphenyl;

when X₈is N, R²¹is —NH—CO—, and R¹⁹is phenyl, R³¹is not 2,4-difluorophenyl, pyridyl-substituted thienyl, 3,4-dichlorophenyl, 4-t-butylphenyl, or 3-benzyloxyphenyl;

when X₉is N, R²¹is —NH—C(O)— and R¹⁹is

R³¹is not 2,3,4-trimethoxyphenyl or 3,5-dimethoxyphenyl; and

when X₉is N, R²¹is —NH—C(O)— and R¹⁹is phenyl, R³¹is not 3,5-dimethoxyphenyl.

In a further embodiment, the invention provides compounds of Structural Formula (XIII):

or a salt thereof, wherein:

R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′↑CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—CH(CH₂—CH₃)—, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH₂—, R³¹is not unsubstituted phenyl, 3-methylphenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl or 4-methoxyphenyl;

when R²¹is —NH—C(O)—CH₂—O—, R³¹is not unsubstituted phenyl or 4-chlorophenyl; and

In certain embodiments, R₁′ is selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from a monocyclic or bicyclic aryl or a monocyclic or bicyclic heteroaryl, and comprises a solubilizing group substituent.

In certain embodiments, R³¹is selected from phenyl, naphthyl, pyrazolyl, furyl, thienyl, pyridyl, isoxazolyl, benzopyrazolyl, benzofuryl, benzothienyl, quinolinyl, benzoisoxazolyl, or

and R³¹is optionally substituted.

In certain embodiments, R²¹is selected from —NH—C(O)—, NH—C(O)—CH₂—CH(CH₃)—O, —NH—C(O)—NH—, —NH—C(S)—NH—, —NH—C(S)—NH—CH₂—, or —NH—S(O)₂—; and

R³¹is selected from an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted heteroaryl.

In certain such embodiments, particularly when R²¹is —NH—C(O)—, R³¹is selected from R³¹is selected from unsubstituted phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3 dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-bis(trifluoromethyl)phenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2-methoxy-4-methylphenyl, 2-phenoxyphenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, unsubstituted 2-furanyl, unsubstituted 2-thienyl,

In one aspect, the invention provides -modulating compounds of Structural Formula (XIV):

or a salt thereof, wherein:

each of R²³and R²⁴is independently selected from H, —CH₃or a solubilizing group;

R²⁵is selected from H or a solubilizing group; and

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group; and
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;
- each R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁₁—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O— or —NR₁′—C(O)—CR₁′R₁′—; and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

- wherein when R¹⁹is

In certain embodiments, each of R²³and R²⁴is independently selected from H, —CH₃or a solubilizing group;

R²⁵is selected from H, or a solubilizing group; and

R¹⁹is selected from:

wherein:

each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰; or CR₁′; and

- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR₂, or CR₁′,

wherein:

zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group; and
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;
- each R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁—CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O— or —NR₁′—C(O)—CR₁′R₁′— (particularly —NH—C(O)—); and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.

In certain such embodiments, R³¹is not 2,4-dimethoxyphenyl.

Typically, R²⁵is selected from H, —CH₂—N(CH₃)₂, or

Typically, R²³and R²⁴are H.

Typically, R¹⁹is selected from phenyl, pyridyl, thienyl or furyl, particularly optionally substituted phenyl. Preferably, a phenyl is optionally substituted with:

a) up to three —O—CH₃groups; or

b) one —N(CH₃)₂group.

In certain embodiments, each of R²³and R²⁴is independently selected from H, —CH₃or a solubilizing group;

R²⁵is selected from H, or a solubilizing group; and

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆is N or NR₁′;
- zero to one R²⁰is a solubilizing group; and
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;
- each R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O— or —NR₁′—C(O)—CR₁′R₁′— (particularly —NH—C(O)—); and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

wherein when R¹⁹is phenyl, at least one of R²³, R²⁴, or R²⁵is a solubilizing group and wherein said compound is not 2-chloro-N-[3-[3-(cyclohexylamino)imidazo[1,2-a]pyridin-2-yl]phenyl]-4-nitrobenzamide.

Typically, R²⁵is selected from H, —CH₂—N(CH₃)₂, or

Typically, R²³and R²⁴are H.

Typically, R¹⁹is selected from phenyl, pyridyl, thienyl or furyl, particularly optionally substituted phenyl. Preferably, a phenyl is optionally substituted with:

b) up to three —O—CH₃groups; or

b) one —N(CH₃)₂group.

In another aspect, the invention provides -modulating compounds of Structural Formula (XV):

or a salt thereof, wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′, —C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O— or —NR₁′—C(O)—CR₁′R₁′— (particularly —NH—C(O)—); and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl and

R³²is selected from an optionally substituted bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein:

when R²¹is —NH—C(O)—, R³²is not unsubstituted 2-furyl, 2-(3-bromofuryl), unsubstituted 2-thienyl, unsubstituted 3-pyridyl, unsubstituted 4-pyridyl,

and

when R²¹is —NR₁′—S(O)₂—, R³²is not unsubstituted 2-thienyl or unsubstituted naphthyl.

In yet another aspect, the invention provides -modulating compounds of Structural Formula (XVI):

or a salt thereof, wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O— or —NR₁′—C(O)—CR₁′R₁′— (particularly —NH—C(O)—); and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is an optionally substituted phenyl, wherein:

when R²¹is —NR₁′—C(O)—CR₁′R₁′— or —NH—C(O)—CH(CH₃)—O, R³³is a substituted phenyl;

when R²¹is —NH—C(O)—CH₂, R³³is not unsubstituted phenyl, 4-methoxyphenyl; 3,4-dimethoxyphenyl or 4-chlorophenyl;

when R²¹is —NH—C(O)—CH₂—O, R³³is not 2,4-bis(1,1-dimethylpropyl)phenyl;

when R²¹is —NH—C(O)—NH—, R³³is not 4-methoxyphenyl; and

In certain embodiments, R²¹is selected from —NR²²—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²²is an optionally substituted C₁-C₃straight or branched alkyl; and

R³³is phenyl comprising a solubilizing group substituent, wherein: when R²¹is —NH—S(O)₂said phenyl comprises an additional substituent.

In certain embodiments, R²¹is selected from —NR²²—C(O)—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′—CR₁′—CR₁′R₁′—, or —NR₁′—C(═N—CN)—NR₁′—,

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R²²is an optionally substituted C₁-C₃straight or branched alkyl.

In certain embodiments, R³³is optionally substituted on up to three carbon atoms with a substituent independently selected from —O—CH₃, —CH₃, —N(CH₃)₂, —S(CH₃), or CN; or substituted on adjacent carbon atoms with

bridging said adjacent carbon atoms.

In a further embodiment, the invention provides -modulating compounds of Structural Formula (XVII):

or a salt thereof wherein:

each of R²³and R²⁴is independently selected from H or —CH₃, wherein at least one of R²³and R²⁴is H; and

R²⁹is phenyl substituted with:

a) two —O—CH₃groups;

b) three —O—CH₃groups located at the 2, 3 and 4 positions; or

c) one —N(CH₃)₂group; and;

d) when R²is CH₃, one —O—CH₃group at the 2 or 3 position,

wherein R²⁹is optionally additionally substituted with a solubilizing group.

In certain embodiments, R²⁹is phenyl substituted with:

a) three —O—CH₃groups located at the 2, 3 and 4 positions; or

b) one —N(CH₃)₂group.

In one aspect, the invention provides -modulating compounds of Structural Formula (XVIII):

or a salt thereof, wherein

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′,

wherein:

zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄Z₁₅and Z₁₆is N, NR₁′, S or O;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group; and

zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;

each R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that when R¹⁹is

Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, R²⁰is H, and R²¹is —NHC(O)—, R³¹is not an optionally substituted phenyl.

In certain embodiments, R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′,

wherein:

zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;

at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;

zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;

zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;

zero to one R²⁰is a solubilizing group; and

zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;

each R²⁰is independently selected from H or a solubilizing group;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′≡CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.

In certain such embodiments, compounds of Structural Formula (XVIII) have the formula:

or a salt thereof, wherein

R²⁰is selected from H or a solubilizing group;

R²¹is selected from —NH—C(O)—; or —NH—C(O)—CH₂—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.

Typically, R¹⁹in compounds of Structural Formula (XVIII) is selected from phenyl, pyridyl, thienyl or furyl, particularly optionally substituted phenyl.

Typically, R²⁰is selected from H, —CH₂—N(CH₃)₂,

Typically, R³¹is selected from phenyl, pyrazolyl, furyl, pyridyl, pyrimidinyl, thienyl, naphthyl, benzopyrazolyl, benzofuryl, quinolinyl, quinoxalinyl, or benzothienyl and wherein R³¹is optionally substituted.

Typically, R²¹is selected from —NH—C(O)— or —NH—C(O)—CH₂—.

In certain such embodiments, when R²¹is —NR₁′—C(O)—, R³¹is not 4-cyanophenyl or

and/or when R²¹is —NR₁′—S(O)₂—, R³¹is not 4-methoxyphenyl or 4-t-butylphenyl.

In certain such embodiments, when R¹⁹is

and R²¹is —NR₁′—C(O)—, R³¹is not 4-cyanophenyl or

and/or when R¹⁹is

and R²¹is —NR₁′—S(O)₂—, R³¹is not 4-methoxyphenyl or 4-t-butylphenyl.

In another aspect, the invention provides modulating compounds of Structural Formula (XX):

or a salt thereof, wherein

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′,

wherein:

- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, O or S;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group; and
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl;

each R²⁰is independently selected from H or a solubilizing group;

R²⁰is independently selected from H or a solubilizing group;

R^20ais selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′—CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; ═NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—NR₁′—C(O)—R₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein

- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein when R¹⁹is

and Z₁₀, Z₁₁, Z₁₂and Z₁₃are each CH, R^20ais a solubilizing group.

Typically, R¹⁹in compounds of Structural Formula (XX) is selected from phenyl, pyridyl, thienyl or furyl, particularly optionally substituted phenyl.

Typically, R^20ais selected from H, —CH₂—N(CH₃)₂,

Typically, R²¹is selected from —NH—C(O)— or —NH—C(O)—CH₂—.

In yet another aspect, the invention provides -modulating compounds of Structural Formula (XXI):

or a salt thereof, wherein

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—; —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein

- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is an optionally substituted monocyclic or bicyclic heteroaryl, or an optionally substituted bicyclic aryl, wherein:

when R²¹is —NH—C(O)—CH₂—, R³²is not unsubstituted thien-2-yl;

when R²¹is —NH—C(O)—, R³²is not furan-2-yl, 5-bromofuran-2-yl, or 2-phenyl-4-methylthiazol-5-yl;

when R²¹is —NH—S(O)₂—, R³²is not unsubstituted naphthyl or 5-chlorothien-2-yl.

In certain embodiments, R³²is selected from pyrrolyl, pyrazolyl, pyrazinyl, furyl, pyridyl, pyrimidinyl, or thienyl, and R³²is optionally substituted and is optionally benzofused.

In certain embodiments, R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═—CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′-C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, CR₁′R₁′—CR₁′R₁′—, —NR₁′—C(O)—O—,

wherein

- each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is selected from benzofuryl, methylfuryl, benzothienyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, wherein said methyfuryl, pyridyl, pyrazinyl, pyrimidinyl or pyrazolyl is optionally benzofused and wherein R³²is optionally substituted or further substituted.

In a further aspect, the invention provides -modulating compounds of Structural Formula (XXII):

or a salt thereof, wherein:

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—,

wherein each R₁′ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is an optionally substituted phenyl, wherein:

when R²¹is —NR₁′—C(O)—, R₁′ is not H;

when R²¹is —NH—C(O)—CH₂or —NH—C(O)—CH—O—, R³³is not unsubstituted phenyl or 4-halophenyl; and

Preferably, R²¹is selected from —NH—C(O)— or —NH—C(O)—CH₂—.

In one aspect, the invention provides -modulating compounds of Structural Formula (XXII):

or a salt thereof, wherein:

R²¹is selected from —NH—C(O)—, or —NH—C(O)—CH₂—; and

R³³is phenyl substituted with

e) one —N(CH₃)₂group;

f) one CN group at the 3 position;

g) one —S(CH₃) group; or

bridging the 3 and 4 positions.

In another aspect, the invention provides -modulating compounds of Structural Formula (XXIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—, R³¹is not is not 3,5-dinitrophenyl, 4-butoxyphenyl,

when R²¹is —NH—C(O)— and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not

- when R²¹is —NH—C(O)—, R₁″ is methyl; and each of R²⁰, R^20a, R₁′ and R₁′″ is hydrogen, R³¹is not 2-methylaminophenyl,

- when R²¹is —NH—C(O)—CH₂— or NH—C(S)—NH—, and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;
- when R²¹is —NH—S(O)₂—, R₁″ is hydrogen or methyl, and each of R²⁰, R^20a, R₁′ and R₁′″ is hydrogen, R³¹is not 4-methylphenyl; and

when R²¹is —NH—S(O)₂—, R^20ais hydrogen or —CH₂—N(CH₂CH₃)₂, and each of R²⁰, R₁′, R₁″ and R₁′″ is hydrogen, R³¹is not

In certain embodiments, R²¹is selected from —NH—C(O)—, or —NH—C(O)—NR₁′—.

In certain embodiments, R³¹is selected from optionally substituted phenyl, quinoxalinyl or quinolinyl. For example, R³¹is optionally substituted with up to 3 substituents independently selected from —OCH₃, —N(CH₃)₂, or a solubilizing group. Suitable examples of R³¹include 4-dimethylaminophenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-methoxy-4-((piperazin-1-yl)methyl)phenyl, 3-methoxy-4-((morpholino)methyl)phenyl, 3-methoxy-4-((pyrrolidin-1-yl)methyl)phenyl, unsubstituted phenyl, unsubstituted quinoxalinyl, and unsubstituted quinolinyl.

In a particular aspect, the invention provides -modulating compounds of Structural Formula (XXIII):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

wherein:

- i) at least one R²⁰is a solubilizing group or at least one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl or both; or
- ii) R^20ais a solubilizing group other than CH₂—N(CH₂CH₃)₂.

In certain embodiments, R²¹is selected from —NH—C(O)—, or —NH—C(O)—NR₁′—.

In yet another aspect, the invention provides -modulating compounds of Structural Formula (XXIV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR²³—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—CH₂—, R³¹is not 2-methylphenyl, or 3,4-dimethoxyphenyl;

when R²¹is —NH—C(O)—CH═CH—, R³¹is not 2-chlorophenyl;

when R²¹is —NH—C(O)—NH—, R³¹is not unsubstituted benzimidazolyl;

when R²¹is —NH—S(O)₂—, and each of R²⁰, R^20a, R₁′, R₁″ and R₁′″ is hydrogen,

R³¹is not unsubstituted phenyl, 4-chlorophenyl, 4-methylphenyl, or 4-acetoamidophenyl;

when R²¹is —NH—S(O)_z—, each of R₁′ and R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, and R₁″ is hydrogen, R³¹is not 4-nitrophenyl;

when R²¹is —NH—C(O)—CH₂—, R₁′ is methyl, and each of R²⁰, R^20a, R₁″, and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH(CH₂CH₃)—, and each of R²⁰, R^20a, R₁′, R₁″, and R₁′″ is hydrogen, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)—CH(CH₃)—O—, R₁′″ is methyl or hydrogen, and each of R²⁰, R^20a, R₁′, and R₁″ is hydrogen, R³¹is not 2,4-dichlorophenyl.

In a particular, aspect, the invention provides -modulating compounds of Structural Formula (XXIV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group and at least one of R²⁰and R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R²¹is selected from —NR²³—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′—CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—, wherein R²³is an optionally substituted C₁-C₃straight or branched alkyl; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.

In certain embodiments, when R²¹is —NH—C(O)—CH₂—, R³¹is not 2-methylphenyl; or 3,4-dimethoxyphenyl; when R²¹is —NH—C(O)—CH═CH—, R³¹is not 2-chlorophenyl; and/or when R²¹is —NH—C(O)—NH—, R³¹is not unsubstituted benzimidazolyl.

In a further aspect, the invention provides -modulating compounds of Structural Formula (XXV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group, wherein at least one of R²⁰and R^20ais a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³²is an optionally substituted phenyl.

In certain embodiments, R³²is selected from 3,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, or 2,4-dimethoxyphenyl; wherein R³is further optionally substituted with a solubilizing group.

In certain embodiments, R³²is not unsubstituted thienyl; unsubstituted phenyl; 2-methylphenyl; 4-fluorophenyl; 4-methoxyphenyl; 4-methylphenyl; 3,4-dioxyethylenephenyl; 3-acetylamino-4-methylphenyl; 3-[(6-amino-1-oxohexyl)amino]-4-methylphenyl; 3-amino-4-methylphenyl; 3,5-dimethoxyphenyl; 3-halo-4-methoxyphenyl; 3-nitro-4-methylphenyl; or 4-propoxyphenyl.

In one aspect, the invention provides -modulating compounds of Structural Form (XXIV):

or a salt thereof, wherein:

each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is selected from an optionally substituted heteroaryl or an optionally substituted bicyclic aryl, with the provisos that:

In a particular aspect, the invention provides -modulating compounds of Structural Formula (XXVI):

or a salt thereof, wherein:

- each R²⁰and R^20ais independently selected from H or a solubilizing group, wherein at least one of R²⁰or R^20ais a solubilizing group;
- each R₁′, R₁″ and R₁′″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl; and

R³³is selected from an optionally substituted heteroaryl or an optionally substituted bicyclic aryl.

In another aspect, the invention provides -modulating compounds of Structural Formula (XXVII):

- each R²⁰and R^20ais independently selected from H or a solubilizing group;
- each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and
- R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —C(O)—NR₁′—, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

- provided that when R²¹is —NH—C(O)— and R¹⁹is

R³¹is not unsubstituted pyridyl, 2,6-ethoxyphenyl, 3,4,5-trimethoxyphenyl or unsubstituted furyl.

In a particular aspect, the invention provides: -modulating compounds of Structural Formula (XXVII):

or a salt thereof; wherein:

- each R²⁰and R^20ais independently selected from H or a solubilizing group;
- each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- zero to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′ is an optionally substituted C₁-C₃straight or branched alkyl; and
- R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, R₁′C(═NR₁′)—NR₁′, —C(O)—NR₁′, —C(O)—NR₁′—S(O)₂—, —NR₁′—, —CR₁′R₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and

R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:

when R²¹is —NH—C(O)—, R¹⁹is not pyrazolyl;

when R²¹is —NH—, and R¹⁹is thiazolyl, R³¹is not optionally substituted phenyl or optionally substituted pyridyl;

when R²¹is —NH—C(O)—CH₂—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted indolyl or unsubstituted phenyl;

when R²¹is —NH—C(O)—CH₂—, and R¹⁹is

R³¹is not 2-methylphenyl or 3,4-dimethoxyphenyl;

when R²¹is —NH—C(O)—CH═CH—, and R¹⁹is

R³¹is not 2-chlorophenyl;

when R²¹is —NH—C(O)—NH—, and R¹⁹is

R³¹is not unsubstituted benzimidazolyl;

when R²¹is —NH—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted pyridyl;

when R^20ais a solubilizing group, R¹⁹is thienyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl;

when R²¹is —NH— and R¹⁹is pyridyl, oxadiazolyl or thiadiazolyl, R³¹is not unsubstituted phenyl, 3-methoxyphenyl or 4-methoxyphenyl;

when R²¹is —NH—C(O)— and R¹⁹is thiazolyl or pyrimidinyl, R³¹is not unsubstituted phenyl;

when R²¹is —NH—C(O)— and R¹⁹is

R³¹is not 3,5-dinitrophenyl, 4-butoxyphenyl,

In certain embodiments, R²¹is selected from —NH—C(O)— or —NH—C(O)—NR₁′—, preferably —NH—C(O)—.

In certain embodiments, R³¹is selected from optionally substituted phenyl, quinoxalinyl or quinolinyl; preferably optionally substituted phenyl. For example, R³¹is optionally substituted with up to 3 substituents independently selected from —OCH₃, —N(CH₃)₂, or a solubilizing group. Suitable examples of R³¹include 4-dimethylaminophenyl; 3,4-dimethoxyphenyl; 3,5-dimethoxyphenyl; 3,4,5-trimethoxyphenyl; 3-methoxy-4-((piperazin-1-yl)methyl)phenyl; 3-methoxy-4-((morpholino)methyl)phenyl; 3-methoxy-4-((pyrrolidin-1-yl)methyl)phenyl; unsubstituted phenyl; unsubstituted quinoxalinyl; and unsubstituted quinolinyl. Preferred examples of R³¹include 3,4-dimethoxyphenyl; 2,6-dimethoxyphenyl; or 2,4-dimethoxyphenyl; wherein R³¹is further optionally substituted with a solubilizing group.

In preferred embodiments, R²¹is —NH—C(O)— and R³¹is selected from 3-methoxyphenyl; 3,4-dimethoxyphenyl; 3,4,5-trimethoxyphenyl; or 4-dimethylaminophenyl.

In certain embodiments, when R²¹is —NH—C(O)—, R¹⁹is not

In certain embodiments, when R²¹is —NH—C(O)—, R¹⁹is not optionally substituted pyrazolyl, thiazolyl, thienyl, pyrrolyl or pyrimidinyl; when R²¹is —NH—C(O)—CH2— or —NH—C(O)—NH—, R¹⁹is not pyrazolyl; and/or when R²¹is —NH—, R¹⁹is not optionally substituted pyridyl, thiazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl.

In a more particular aspect, the invention provides -modulating compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

- each R²⁰and R^20ais independently selected from H or a solubilizing group;

each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;

R¹⁹is selected from:

wherein:

- each Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′; and
- each Z₁₄, Z₁₅and Z₁₆is independently selected from N, NR₁′, S, O, CR²⁰, or CR₁′, wherein:
- one to two of Z₁₀, Z₁₁, Z₁₂or Z₁₃are N;
- at least one of Z₁₄, Z₁₅and Z₁₆is N, NR₁′, S or O;
- zero to one of Z₁₄, Z₁₅and Z₁₆is S or O;
- zero to two of Z₁₄, Z₁₅and Z₁₆are N or NR₁′;
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl; and
- R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and
- R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the provisos that:
- when R²¹is —NH—C(O)—, R¹⁹is not pyrazolyl;
- when R²¹is —NH—C(O)—CH₂—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted indolyl or unsubstituted phenyl;
- when R²¹is —NH—C(O)—NH—, and R¹⁹is pyrazolyl, R³¹is not unsubstituted isoxazolyl, unsubstituted naphthyl, unsubstituted phenyl, 2,6-difluorophenyl; 2,5-dimethylphenyl; 3,4-dichlorophenyl; or 4-chlorophenyl;
- when R^20ais a solubilizing group, R¹⁹is 1-methylpyrrolyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl; unsubstituted furyl; unsubstituted pyrrolyl; unsubstituted pyrazolyl; unsubstituted isoquinolinyl; unsubstituted benzothienyl; chloro-substituted benzothienyl; 2-fluoro-4-chlorophenyl or phenyl singly substituted with a solubilizing group;
- when R^20ais a solubilizing group, R¹⁹is thienyl and R²¹is —NH—C(O)—, R³¹is not unsubstituted phenyl;
- when R^20ais a solubilizing group, R¹⁹is methylimidazolyl and R²¹is —NH—C(O)—, R³¹is not 1-methyl-4-(1,1-dimethylethyloxycarbonylamino)pyrrol-2-yl or phenyl singly substituted with a solubilizing group; and
- when R²¹is —NH—C(O)— and R¹⁹is thiazolyl or pyrimidinyl, R³¹is not unsubstituted phenyl.

In certain embodiments, R²¹is selected from —NH—C(O)— or —NH—C(O)—NR₁′—, preferably —NH—C(O)—.

- In preferred embodiments, R²¹is —NH—C(O)— and R³¹is selected from 3-methoxyphenyl; 3,4-dimethoxyphenyl; 3,4,5-trimethoxyphenyl; or 4-dimethylaminophenyl.

In yet another aspect, the invention provides compounds of Structural Formula (XXVII):

or a salt thereof, wherein:

- each R²⁰and R^20ais independently selected from H or a solubilizing group;
- each R₁′ and R₁″ is independently selected from H or optionally substituted C₁-C₃straight or branched alkyl;
- R²⁹is selected from:

wherein:

- Z₁₀, Z₁₁, Z₁₂and Z₁₃is independently selected from N, CR²⁰, or CR₁′, wherein one of Z₁₀, Z₁₁, Z₁₂or Z₁₃is N; and
- zero to one R²⁰is a solubilizing group;
- zero to one R₁′″ is an optionally substituted C₁-C₃straight or branched alkyl; and
- R²¹is selected from —NR₁′—C(O)—, —NR₁′—S(O)₂—, —NR₁′—C(O)—NR₁′—, —NR₁′—C(S)—NR₁′—, —NR₁′—C(S)—NR₁′—CR₁′R₁′—, —NR₁′—C(O)—CR₁′R₁′—NR₁′—, —NR₁′—C(═NR₁′)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—, —NR₁′—S(O)₂—NR₁′—, —NR₁′—C(O)—NR₁′—S(O)₂—, —NR₁′—CR₁′R₁′—C(O)—NR₁′—, —NR₁′—C(O)—CR₁′═CR₁′—CR₁′R₁′—, —NR₁′—C(═N—CN)—NR₁′—, —NR₁′—C(O)—CR₁′R₁′—O—, —NR₁′—C(O)—CR₁′R₁′—CR₁′R₁′—O—, —NR₁′—S(O)₂—CR₁′R₁′—, —NR₁′—S(O)₂—CR₁′R₁′—CR₁′R₁′—, or —NR₁′—C(O)—CR₁′R₁′—; and
- R³¹is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.

In certain embodiments, R³¹is optionally substituted phenyl, such as 3-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, or 4-dimethylaminophenyl.

In certain embodiments, R²¹is —NH—C(O)—.

In preferred embodiments, R²¹is —NH—C(O)— and R³¹is an optionally substituted phenyl, such as 3-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, or 4-dimethylaminophenyl.

In a further aspect, the invention provides novel: -modulating compounds of Formula (VI):

or a salt thereof, wherein:

Het is an optionally substituted heterocyclic aryl group; and

Ar′ is an optionally substituted carbocyclic or heterocyclic aryl group.

In certain embodiments, Het comprises one N heteroatom and 1 to 2 additional heteroatoms independently selected from N, O or S, such as oxazolopyridyl.

In certain embodiments, Ar′ is selected from optionally substituted phenyl, benzothiazolyl, or benzoxazolyl. When Ar′ is substituted phenyl, typically it is substituted with 1 to 3 substituents independently selected from halo, methyl, O-methyl, S-methyl or N(CH₃)₂, morpholino, or 3,4 dioxymethylene.

Compounds of the invention, including novel compounds of the invention, can also be used in the methods described herein.

The compounds and salts thereof can be present in amorphous or crystalline (including co-crystalline and polymorph) forms.

In the compounds described above, bivalent groups disclosed as possible values for variables can have either orientation, provided that such orientation results in a stable molecule. Preferably, however, the left hand side of a bivalent group (e.g., —NR₁′—C(O)—) is attached to a bivalent arylene or heteroarylene group (e.g., R¹⁹) and the right hand side of a bivalent group is attached to a monovalent aryl group (e.g., R³¹).

- -modulating compounds of the invention having hydroxyl substituents, unless otherwise indicated, also include the related secondary metabolites, such as phosphate, sulfate, acyl (e.g., acetyl, fatty acid acyl) and sugar (e.g., glucurondate, glucose) derivatives (e.g., of hydroxyl groups), particularly the sulfate, acyl and sugar derivatives. In other words, substituent groups —OH also include —OSO₃⁻M⁺, where M⁺ is a suitable cation (preferably H⁺, NH₄⁺ or an alkali metal ion such as Na⁺ or K⁺) and sugars such as

TABLE 4

COM-

ED₅₀
ED₅₀
FOLD

POUND

FP
MS
ACT.

NO
[M + H]+
STRUCTURE
ASSAY
ASSAY
MS

1

A
NT

2

D
NT

3

B
NT

4

N/A
NT

5

B
NT

6

D
NT

7
346

A
NT

8

B
NT

9

C
NT

10

D
NT

19
409.6

D
D
C

20
401.3

D
D
C

21
399.1

D
D
C

22
414.0

D
D
C

24
359.4

D
D
C

27
376.1

D
D
C

29
385.1

D
D
C

31
360.1

D
D
C

32
400.0

D
D
C

33
376.1

D
D
C

34
406.3

D
D
C

35
346.5

D
D
C

36
376.7

D
D
C

37
316.4

D
D
C

38
401.0

D
D
C

39
399.1

D
D
C

40
414.2

D
D
C

41
414.2

D
D
C

42
359.1

A
A
B

43
359.1

A
A
B

45
341.0

D
D
C

46
376.1

D
D
C

48
406.3

D
D
C

49
360.1

D
A
B

50
400.0

NT
D

51
360.1

A
A
B

52
376.1

A
A
B

53
406.1

D
D
C

54
346.4

NT
D

55
376.1

A
A
B

56
316.0

D
A
B

57
407.1

A

58
377.1

NA

59
318.1

NA

60
413.1

A

61
413.1

NA

62
349.0

NA

63
377.1

A

64
360.1

A

65
383.0

NA

66
407

A

67
377

A

68
360

A

69
377.1

A
B

70
360.1

A
B

71
376.1

A
B

72
422.1

NT

73
377

NT

74
412

D
C

75
407.1

A
B

76
360.1

A
B

77
376.1

A
B

78
445.1

79
338

D
C

80
355

A
B

81
354.5

A
B

82
402

C

83
355

A
B

84
417

A
B

85
335.1

D
C

86
375.1

D
C

87
375.1

D
C

88
382.1

D
C

89
365.1

D
C

90
381.1

91
412.1

D
C

92
308.1

A
B

93
329.1

A
B

94
434.1

A
B

95
345.1

A′
B

96
376.1

A′
B

97
359.1

A′
B

98
408.1

D
C

99
391

A′
A

100
376

A
B

101
376

A
A

102
406

A
A

103
374

D
C

104
346.1

A′
B

105
330.1

A′
B

106
406.1

A′
B

107
488

A
B

108
324

NA

109
401

A
B

110
381

C

111
359

A
B

112
376

A
B

113
375

A
B

114
392

A′
A

115
422

A
A

116
386

C

117
388

A
A

118
410

A
A

119
375

A
B

120
391

NT

121
414

D
C

122
417

C

123
474

NT

124
391

A
B

125
433

B
B

126
374

A
B

127
355

A
A

128
388

A
B

129
418

A′
A

130
358

A
B

131
418

A
A

132
350

A
A

133
480

A′
B

134
466

A′
B

135
452

A′
B

136
434

D
C

137
420

D

138
471

A
B

139
488

A
B

141
374.1

A′
B

142
374.1

A′
A

143
410.1

D

144
427.1

D
C

145
397.1

A′
B

146
397.1

A′
B

147
392.1

D

148
405.2

D

149
359.0

A′
B

150
375.0

A′
B

151
375.0

D
C

152
392.1

D
C

153
490

A
B

154
473

C
A

155
490

A
B

156
433

A
B

157
416

D
B

158
433

A
B

159
474

A
B

160
457

B
A

161
474

A
A

162
392.1

A′
B

163
422.1

A′
B

164
488

A
B

165
416

D
A

166
457

A
B

167
373

A
B

168
388.1

NA
C

169
343.1

A′
B

174
479

B
A

175
323.1

B
B

176
354.1

B
B

177
324.1

D
B

178
437

A
A

179
467

A′
A

180
358.0

A
B

181
405.0

A′
A

182
359.0

A′
A

183
358.0

A
A

184
375.0

A′
B

185
374.9

A′
A

186
405.3

NA
C

187
358.9

A
B

188
358.9

NA
C

189
375.2

NA
C

190
375.3

A′
B

191
375.0

A′
B

192
375.0

A
B

193
358.0

NA
C

194
422.3

NA
C

195
375.9

NA
C

196
374.9

A
B

197
391.1

A′
B

198
422.4

A
B

199
375.9

A′
B

200
375.4

A′
B

201
391.9

A
B

202
392.4

A′
B

203
380

A′
B

204
410

A′
A

205
437

A
A

206
467

A
A

207
478

A
A

208
508

A
A

209
479

A
A

210
509

A
B

211

A′
B

212
362

A
B

213
392

A′
B

214
392

A
B

215
392

A′
B

216
362

A′
B

217
422

A′
A

218
405

A′
A

219
419

A
A

220
423

NA
C

221
321.4

A
B

222
366.8

A
B

223
337.4

A′
B

225
332.4

NA
C

226
412.5

227
333.4

NA
C

228
391.5

A
A

229
418.5

NA
C

230
459.5

NA
C

231
425.5

NA
C

232
423.5

NA
C

234
449.5

NA
C

235
436.3

NA
C

236
423.5

NA
C

237
450.5

NA
C

238
480.5

A′
B

239
466.5

A
B

240
392.4

NA
C

241
397.2

A′
B

244
332.4

NA
C

245
423.5

A′
B

246
391.5

A′
B

247
413.5

NA
C

248
467.4

A
B

249
395.9

NA
C

250
385.5

NA
C

251
425.5

NA
C

252
453.5

NA
C

253
373.1

NA
C

254
373

A′
B

255
403

A′
B

256
356

NA
C

257
413.1

NA
C

258
383.1

A
B

259
405.1

A′
A

260
375.1

A′
A

261
375.1

A′
A

262
374.1

A′
B

263
404

A
B

264
357

A′
B

265
374.1

A
B

266
374

A′
A

267
404

A′
B

268
357

A′
B

270
478

A
A

271
508

A′
A

272
392

A′
B

273
422

A
A

276
375.1

A′
B

280
381.5

282
386.5

NA
C

283
451.6

NA
C

284
439.5

NA
C

285
440.5

NA
C

286
390.1

NA
C

287
457.6

288
424.5

A
B

289
427.5

A
B

290
445.5

NA
C

292
420.1

D

293
404.1

A′
A

294
374

A′
B

295
252.1

A′
B

296
376

A
B

297
376

A
B

298
406

A
B

299
359

A
B

303
437.5

NA

304
336.4

A′
B

305
414.5

NA

306
424.5

A
B

307
382.4

A′
A

308
400.3

NA

309
367.4

NA

310
387.5

NA

311
359

A
B

313
418.1

A
B

314
388.1

A
B

315
388.1

NA

317
392

A′
B

318
392

A
B

319
422

A′
B

320
375

A′
B

321
375

A′
B

322
392

NA

323
392

A
B

324
422

NA

325
375

NA

326
478

A
B

327
461

A
A

328
418

B
A

329
462

A
A

330
443

A
A

331
335

A
B

332
335.1

A
B

333
365

A
B

334
340.1

A
B

335
340

A
B

336 10
370

A
B

337
443

NA

338
458

A
A

339
376

NA

340
376

NA

341
406

A′
B

342
359

NA

343
406

A
B

344
375

A′
B

345
376

NA

346
376

NA

347
406

A′
B

348
359

NA

349
375

NA

350
431.1

B
B

351
461

A
B

359
472.1

NA

362
502

B
B

364
472

D
A

367
359.1

NA

369
350.8

NA

370
437.0

NA

371
381.1

NA

372
431.1

NA

373
445.0

NA

374
421.1

NA

375
358.2

NA

376
350.0

NA

377

NA

378
412.1

NA

379
380.0

NA

380
429.9

NA

381
444.1

NA

382
420.0

NA

383
515.7

NA

384
487.8

NA

385
397.2

NA

387
366.8

NA

390
412.5

A
B

391
333.4

A
B

392
424.5

A
B

393
400.3

NA

394
457.6

NA

396
389.5

A
B

398
460.1

A
B

399
424.5

A
B

400
392

NA

401
422

A
B

402
375

A′
B

403
375

A′
B

404
376

A′
B

405
406

A′
B

406
359

A′
B

407
359

A′
B

408
359

B
B

409
422

NA

410
359

NA

411
422

A
B

412
406

NA

413
385.1

B
B

414
385

A
B

415
415

B
B

416
368

NA

419
406

NA

420
376

NA

421
406

A
B

422
382

A
B

423
382

A′
B

424
382

NA

425
412

NA

426
412

A′
B

427
365

A′
B

428
365

NA

429
376

A′
B

430
406

A
A

431
359

A
B

436
445.1

A
A

437
375.1

A
B

438
375

A′
A

439
405

A′
B

440
468

A′
A

441
470

A′
A

442
472

A′
A

443
436

A
A

444
464

A
A

445
432

A
B

446
424

A
B

447
484

NA

448
510

NA

449
376

NA

450
392

NA

451
376

A
B

452
406

A
B

453
359

A
B

454
376

A
B

455
376

A′
B

456
376

A′
B

457
406

A
B

458
359

A′
B

459
359

A′
B

460
359.4

A
B

461
367.4

NA

462
391.5

A′
B

463
375.4

A
B

465
395.9

NA

466
445.5

NA

467
427.2

NA

468
345.0

A
B

469
435.4

NA

470
365.0

NA

471
488.9

NA

472
437.5

NA

473
420.5

A′
B

474

NA

475
408.6

NA

476
410.9

NA

477
435.9

NA

478
404.8

NA

479
420.9

NA

481
428.5

A
B

482
344.1

A′
B

483
364.1

NA

484
448.6

A
B

485
363.5

A
A

486
385.9

NA

487
396.1

NA

488
435.1

NA

489
410.1

NA

490
434.9

NA

491
420.5

NA

492
404.0

NA

493

NA

494
422.9

NA

495
366.0

NA

496
349.9

NA

497
346.0

NA

498
406.5

A
B

499
362.1

NA

500

NA

501
347.1

NA

502
363.1

NA

503
443.1

A′
A

504
358

A
B

505
359

NA

506
429.1

A
A

507
388.1

A′
A

508
366.1

A′
A

510
457

A′
A

511
460

NA

512
484

A′
A

513
470

A′
A

514
466

A
B

515
398

A′
B

516
398

NA

517
428

NA

518
381

A′
B

519
381

A′
B

520
428

A′
B

521
375.0

A′
B

522
405.0

A
A

523
359.0

A
B

524
358.0

A′
B

525
375.0

A′
B

526
400.0

A′
A

527
398.0

A′
B

528
412.9

A′
B

529
399.1

A′
B

530
359.0

A′
B

531
345.0

A′
B

532
345.0

A′
B

533
315.0

A′
B

534
358.0

A′
B

535
428.1

A
A

536
442.1

A
A

537
444.0

A′
A

538
443.1

A
A

539
457.1

A′
A

540
402.1

A
A

541
443.1

A
B

542
444

A
A

543
420

A′
A

544
474

A
A

545
378.1

A
B

546
408

A
B

547
369

A′
B

548
370

A′
B

556
365.1

A′
A

557
542.1

NA

558
442.1

A′
A

559
508

NA

560
470

NA

561
382

A′
B

562
382

A′
B

563
412

A
B

565
400.8

NA

566
409.9

A
B

567
374.9

NA

568
367.0

NA

569
374.9

NA

570
361.0

NA

571
444.0

A
B

572
429.9

B
B

573
431.8

NA

574
376.2

NA

575
439.9

NA

576
376.1

NA

577
400.1

NA

578
368.1

NA

579
401.1

NA

580
374.0

NA

581
334.0

A
B

582
400.0

NA

583
374.1

NA

584
360.0

NA

585
443.1

A
B

587
427.1

A′
B

588
520

A
A

589
490

A′
A

590
474

A
B

591
458

A′
A

592
455

A′
B

593
473

A′
A

594
466

A
B

596
467.4

A′
B

597
377.2

A′
B

599
422.3

A′
B

600
422.5

D
B

601
405.5

NA

604
360.4

NA

605
377.4

NA

607
415.4

NA

608
332.4

NA

609
439.3

NA

610
418.6

NA

611
465.6

A′
B

612
402.5

NA

614
428.5

NA

615
408.6

NA

616
437.5

617
471.1

A′
A

618
469.1

A′
B

619
455

A′
B

620
493.1

A′
B

621
472

A′
A

622
482

A′
A

623
437

NA
C

624
458

A′
A

625
496

A′
A

628
574.1

A′
B

629
429.0

A
A

630
403.1

A
A

631
445.0

A′
B

632
458.1

A
A

633
423.3

NA
C

634
364.9

D
B

635
421.1

D
A

636
359.9

B
B

637
459.3

D
B

638
445.2

D
B

639
378.9

A
B

640
368.9

NA
C

641
334.9

D
B

642
446.2

D
B

643
535.1

A
B

644
434

A
A

645
469

A′
A

646
481

A
A

647
473.1

A′
A

648
402.1

A′
B

649
512.2

A′
A

650
570.2

NA

651
512.2

A′
A

655
393.0

NA
C

656
393.2

NA
C

657
423.1

NA
C

658
382.1

NA
C

659
509.2

NA
C

660
408.1

A
B

661
408.2

A′
B

662
378.2

NA
C

663
438.0

A
B

664
477.8

NA
C

665
406.1

NA
C

666
391.0

NA
C

667
448.0

A
A

668
410.0

A
B

669
392.0

NA
C

670
392.0

A
B

671
422.0

NA
C

672
415.1

NA
C

673

NA
C

674

NA
C

675
407.1

NA
C

676

A′
A

677

A′
A

678

A
B

679

A
B

680
484.2

A′
A

681
522

A
A

682
492

A′
A

683
475

A
B

684
460

A
B

685
456

A′
B

686
475

A′
A

687
467

NA
C

688
483

NA
C

689
479

A
A

690
483

A′
A

692
469

C
B

695
454

A′
A

697
596

NA
C

698
502

A′
A

699

A
A

700
512.2

A′
A

701
477

A′
A

702
534

A
A

703
468

NA
C

704
454

NA
C

705
387

706
445.1

707
386.1

A′
A

708
494.2

A′
A

709
494.1

NA
C

710
494.1

A′
A

711

A
B

714

A
B

715

A′
B

716

A′
A

717

A
B

718
444.1

NA
C

719
416

A
A

720

NA
C

721

A
A

722
449

A′
A

723
490

A
A

724
482

A′
A

725
505

A′
A

726
491

A′
A

727
458

A′
A

728
466

A
A

729
481

A′
A

730
488

A
A

731
498

A
A

732
497

A′
B

733
484.2

A′
A

735
514.2

A′
A

736
514.2

A′
A

737
500.1

A′
A

738
448.1

A
A

739
424.1

A′
A

740
377.1

A′
B

741
498.1

A′
A

742
487.1

A′
B

743
466.1

A
A

744
437.1

B
A

745
452.1

A′
A

TABLE 5

COMPOUND

IC₅₀FP
IC₅₀MS

No
[M + H]+
STRUCTURE
ASSAY
ASSAY

13

A

14

B

15

C

23
359.4

D

25
341.3

B

26
341.4

B

28
401.1

D

30
380.0

D

44
341.0

D

47
385.0

B

291

B

652

B

653

C

654

D

TABLE 6

COMPOUND No
STRUCTURE
ED₅₀

11

N/A

12

N/A

TABLE 7

COMPOUND No
STRUCTURE
IC₅₀

1

N/A

2

N/A

15

B

16

C

17

B

18

B

TABLE 8

COMPOUND

ED₅₀ATP
IC₅₀ATP

No
STRUCTURE
ASSAY
ASSAY

52

A

42

A

49

A

115

D

79

A

117

B

120

A

121

NA

123

D

85

NA

86

A

87

NA

88

NA

89

A

90

D

91

A

92

B

93

D

94

D

95

NA

97

A

98

NA

99

A

100

A

101

C

102

A

103

NA

104

A

105

A

133

NA

134

NA

135

A

106

A

In one embodiment, -modulating compounds of the invention are represented by Structural Formula (I):

or a salt thereof, where:

Ring A is optionally substituted; and

In certain embodiments, Ring B is substituted with at least a carboxy group.

In certain embodiments, Ring B is substituted with at least a substituted or unsubstituted arylcarboxamine, a substituted or unsubstituted aralkylcarboxamine or a polycyclic aryl group.

In certain embodiments, Ring B is substituted with at least a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted heterocyclylcarbonylethenyl group;

In another embodiment, modulating compounds of the invention are represented by Structural Formula (II):

or a salt thereof, where:

Ring A is optionally substituted;

R₁, R₂, R₃and R₄are independently selected from the group consisting of —H, halogen, —OR₅, —CN, —CO₂R₅, —OCO₂R₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)_nR₅, —S(O)OR₅, —S(O)NR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group; and

n is 1 or 2.

In a further embodiment, -modulating compounds of the invention are represented by Structural Formula (IIa):

or a salt thereof, where:

Ring A is optionally substituted;

R₁, R₂, R₃and R₄are independently selected from the group consisting of —H, halogen, —OR₅, —CN, —CO₂R₅, —OCO₂R₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)_nR₅, —S(O)OR₅, —S(O)_nNR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group; and

n is 1 or 2.

In yet another embodiment, -modulating compounds of the invention are represented by Structural Formula (II):

or a salt thereof, where:

Ring A is optionally substituted;

R₁, R₂, R₃and R₄are independently selected from the group consisting of —H, halogen, —OR₅, —CN, —CO₂R₅, —OCO₂R₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)R₅, —S(O)_nOR₅, —S(O)_nNR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group; and

n is 1 or 2.

In yet another aspect, the invention provides novel modulating compounds of Formula (III):

or a salt thereof, where:

Ring A is optionally substituted;

R₅and R₆are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

R₇, R₉, R₁₀and R₁₁are independently selected from the group consisting of —H, halogen, —R₅, —OR₅, —CN, —CO₂R₅, —OCO₂R₅, —OCO₂R₅, —C(O)NR₅R₆, —OC(O)NR₅R₆, —C(O)R₅, —COR₅, —SR₅, —OSO₃H, —S(O)_nR₅, —S(O)_nOR₅, —S(O)_nNR₅R₆, —NR₅R₆, —NR₅C(O)OR₆, —NR₅C(O)R₆and —NO₂;

R₈is a polycyclic aryl group; and

n is 1 or 2.

In certain embodiments, one or more of R₇, R₉, R₁₀and R₁₁are —H. In particular embodiments, R₇, R₉, R₁₀and R₁₁are each —H.

Ring A is preferably substituted. Suitable substituents include halogens (e.g., bromine), acyloxy groups (e.g., acetoxy), aminocarbonyl groups (e.g., arylaminocarbonyl, such as substituted, particularly carboxy-substituted, phenylaminocarbonyl groups) and alkoxy (e.g., methoxy, ethoxy) groups, particularly alkoxy groups. In certain embodiments, Ring A is substituted with at least one alkoxy or halo group, particularly methoxy.

In certain embodiments, Ring A is not substituted with a nitrile or pyrrolidyl group.

Particular examples of R₈, where

indicates attachment to the remainder of Structural Formula (III), include:

In certain embodiments, R₈is

and Ring A is 3-dimethylaminophenyl, none of R₇, R₉, R₁₀and R₁₁is —CH₂—N(CH₃)₂or —C(O)—NH—(CH₂)₂—N(CH₃)₂, and/or when R₈is

and Ring A is 3,4 dimethoxyphenyl, none of R₇, R₉, R₁₀and R₁₁is C(O)OCH₃or C(O)OH.

In yet another aspect, the invention provides novel -modulating compounds of Formula (IV):

Ar-L-J-M-K-Ar′ (IV)

or a salt thereof, wherein:

each Ar and Ar′ is independently an optionally substituted carbocyclic or heterocyclic aryl group;

L is an optionally substituted carbocyclic or heterocyclic arylene group;

each M is C(O), S(O), S(O)₂, or CR₁′R₁′;

each R₁′ is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₅′; halo; haloalkyl; CF₃; SR₂′; OR₂′ NR₂′R₂′; NR₂′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)C(O)R₂′; C(O)NR₂′R₂′; OC(O)R₂′; S(O)₂R₂′; S(O)₂NR₂′R₂′; NR₂′C(O)NR₂′R₂′; NR₂′C(O)C(O)R₂′; NR₂′C(O)R₂′; NR₂′(COOR₂′); NR₂′C(O)R₅′; NR₂′S(O)₂NR₂′R₂′; NR₂′S(O)₂R₂′; NR₂′S(O)₂R₅′; NR₂′C(O)C(O)NR₂′R₂′; NR₂′C(O)C(O)NR₂′R₃′; C1-C10 alkyl substituted with aryl, R₄′ or R₅′; or C2-C10 alkenyl substituted with aryl, R₄′ or R₅′;

each R₃′ is independently C(O)R₂′, COOR₂′, or S(O)₂R₂′;

each R₄′ is independently halo, CF₃, SR₇′, OR₇′, OC(O)R₇′, NR₇′R₇′, NR₇′R₈′, NR₈′R₈′, COOR₇′, NO₂, CN, C(O)R₇′, or C(O)NR₇′R₇′;

each R₅′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R₆′; halo; sulfur; oxygen; CF₃; haloalkyl; SR₂′; OR₂′; OC(O)R₂′; NR₂′R₂′; NR₂′R₃′; NR₃′R₃′; COOR₂′; NO₂; CN; C(O)R₂′; C(O)NR₂′R₂′; C1-C10 alkyl substituted with 1-3 independent R₄′, R₆′, or aryl; or C2-C10 alkenyl substituted with 1-3 independent R₄′, R₆′, or aryl;

each R₆′ is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 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, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF₃; haloalkyl; SR₇′; OR₇′; NR₇′R₇′; NR₇′R₈′; NR₈′R₈′; COOR₇′; NO₂; CN; C(O)R₇′; or C(O)NR₇′R₇′;

each R₇′ is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF₃, OR₁₀′, SR₁₀′, NR₁₀′R₁₀′, COOR₁₀′, NO₂, CN, C(O)R₁₀′, C(O)NR₁₀′R₁₀′, NHC(O)R₁₀′, or OC(O)R₁₀′;

each R₈′ is independently C(O)R₇′, COOR₇′, or S(O)₂R₇′;

each R₁₁′ is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;

each aryl is independently optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R₆′; halo; haloalkyl; CF₃; OR₉′; SR₉′; NR₉′R₉′; COOR₉′; NO₂; CN; C(O)R₉′; C(O)C(O)R₉′; C(O)NR₉′R₉′; S(O)₂R₉′; N(R₉′)C(O)R₉′; N(R₉′)(COOR₉′); N(R₉′)S(O)₂R₉′; S(O)₂NR₉′R; OC(O)R₉′; NR₉′C(O)NR₉′R₉′; NR₉′C(O)C(O)R₉′; NR₉′C(O)R₆′; NR₉′S(O)₂NR₉′R₉′; NR₉′S(O)₂R₆′; NR₉′C(O)C(O)NR₉′R₉′; C1-C10 alkyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉′, NHC(O)R₉′, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; C2-C10 alkenyl substituted with 1-3 independent R₆′, halo, CF₃, OR₉′, SR₉′, NR₉′R₉′, COOR₉′, NO₂, CN, C(O)R₉′, C(O)NR₉′R₉, NHC(O)R₉, NH(COOR₉′), S(O)₂NR₉′R₉′, OC(O)R₉′; or R₉′.

According to another preferred embodiment,

Ar is

X₁, X₂, X₃, X₄, and X₅are independently selected from CR₁′ and N; and

X₆is selected from NR₁′, O, and S;

According to yet another preferred embodiment, X₁and X₂are N; X₃, X₄, and X₅are CR₁′; and X₆is O.

According to still yet another preferred embodiment, X₁and X₃are N; X₂, X₄, and Xs are CR₁′; and X₆is O.