[0001] The present application claims the benefit of priority to U.S. Provisional Appl. No. 62/638,715, filed March 5, 2018, which is hereby incorporated by reference in its entirety.

BACKGROUND

Field

[0002] Compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases, disorders, or conditions associated with protein malfunction are provided.

Description of the Related Technology

[0003] Aberrant protein function, and/or protein imbalance is a hallmark of many disease states. For example, the functioning of the immune system is finely balanced by the activities of pro-inflammatory and anti-inflammatory mediators or cytokines. Some cytokines promote inflammation (pro-inflammatory cytokines), whereas other cytokines suppress the activity of the pro-inflammatory cytokines (anti-inflammatory cytokines). For example, IL-4, IL- 10, and IL-13 are potent activators of B lymphocytes, and also act as anti-inflammatory agents. They are anti-inflammatory cytokines by virtue of their ability to suppress genes for pro- inflammatory cytokines such as IL-l, TNF, and chemokines.

[0004] Misregulation of protein synthesis may contribute to uncontrolled cell growth, proliferation, and migration, leading to cancer. For example, the translation termination factor GSPT1 (eRF3a) mediates stop codon recognition and facilitates release of a nascent peptide from the ribosome. In addition to its role in translation termination, GSPT1 is also involved in several other critical cellular processes, such as cell cycle regulation, cytoskeleton organization and apoptosis. GSPT1 has been implicated as an oncogenic driver of several different cancer types, including breast cancer, hepatocellular carcinoma, gastric cancer, and prostate cancer. See, e.g., Brito, et ak, Carcinogenesis , Vol. 26, No. 12, pp. 2046-49 (2005); Brito, et ah, Cane. Genet. Cyto., Vol. 195, pp. 132-42 (2009); Tavassoli, et al , Med. Oncol., Vol. 29, pp. 1581-85 (2011); Wright and Lange, Rev. Urol., Vol. 9, No. 4, pp. 207-213 (2007); Hoshino, et al., Apoptosis, Vol. 17, pp. 1287-99 (2012); Liu, et. al., PLOS One, Vol. 9, No. 1, e8637l (2014); and Jean- Jean, et al., Mol. Cell. Bio., Vol. 27, No. 16, pp. 5619-29 (2007). GSPT1 also contributes to glial scar formation and astrogliosis after a central nervous system (CNS) injury. See, e.g, Ishii et al., J Biol. Chem., Vol. 292, No. 4, pp. 1240-50 (2017). [0005] Unregulated activities of these mediators can lead to the development of serious inflammatory conditions. For example, autoimmune diseases arise when immune system cells (lymphocytes, macrophages) become sensitized against the“self.” Lymphocytes, as well as macrophages, are usually under control in this system. However, a misdirection of the system toward the body’s own tissues may happen in response to still unexplained triggers. One hypothesis is that lymphocytes recognize an antigen which mimics the“self’ and a cascade of activation of different components of the immune system takes place, ultimately leading to tissue destruction. Genetic predisposition has also been postulated to be responsible for autoimmune disorders.

[0006] Tumor necrosis factor-alpha (TNF-alpha) and interleukin-l (IL-l) are pro- inflammatory cytokines that mediate inflammatory responses associated with infectious agents and other cellular stresses. Overproduction of these cytokines is believed to underlie the progression of many inflammatory diseases including rheumatoid arthritis (RA), Crohn’s disease, inflammatory bowel disease, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer’s disease, congestive heart failure, and psoriasis among others.

[0007] TNF-alpha is produced by variety of activated immune cells, particularly monocytes and macrophages. Elevated levels of TNF-alpha have been implicated in several pathological conditions including inflammation, infection, autoimmune disease, cancer development and several other disorders. Indeed, virtually all of the players in the human immune system have been report to have some level of functional relationship with TNF-alpha. See, e.g., Wallach, Cytokine, Vol. 63, 225-9 (2013). TNF is able to induce fever, apoptotic cell death, cachexia, inflammation, and to inhibit tumorigenesis and viral replication.

[0008] IL-l a and IL- l b are proinflammatory cytokines that activate cells by binding the IL-l receptor type I (IL-1RI). These proteins are the most powerful endogenous pyrogens known. IL-la is constitutively expressed as a precursor in cells forming biological barriers, such as epithelial cells, keratinocytes, and mucosal and endothelial cells, as well as other organ cells. IL-la does not require processing for activation and is released from damaged or dying cells. In contrast, IL- l b must be proteolytically cleaved into its active form. Active IL-l b is primarily generated in a subset of blood monocytes, dendritic cells, and tissue macrophages, where its activation and release are tightly regulated, although studies systematically assessing other cells capable of producing P.-1b are limited. See, e.g., Nold, et ak, Blood, Vol. 113, 2324-35 (2009).

[0009] Recent data from clinical trials support the use of protein antagonists of cytokines, for example, soluble TNF-alpha receptor fusion protein (etanercept) or the monoclonal TNF-alpha antibody (infliximab), for the treatment of rheumatoid arthritis, Crohn’s disease, juvenile chronic arthritis and psoriatic arthritis. Thus, the reduction of pro-inflammatory cytokines such as TNF-alpha and interleukin- 1 (IL-I) has become an accepted therapeutic approach for potential drug intervention in these conditions.

[0010] Moreover, IL-2 is now FDA approved for the treatment of renal cancer and melanoma patients, with durable, complete remissions achieved with IL-2 up to 148 months. However, the short half-life of IL-2 in serum requires that large amounts of IL-2 be injected to achieve therapeutic levels. Many attempts have been made to minimize side effects of systemic IL-2 treatment, for example, introducing IL-2 directly into the tumor, though this complicates treatment, and has largely been unsuccessful.

[0011] Local delivery of cytokines is appealing compared to systemic delivery for a variety of reasons. It takes advantage of the natural biology of cytokines that have evolved to act locally in a paracrine or autocrine fashion. Local expression also dramatically minimizes many of the side effects of systemic delivery of cytokines. Thus, compounds and methods to increase local expression of IL-2 would be better tolerated than high dose IL-2 treatment, which would expand therapeutic utility of strategies that increase IL-2.

[0012] Additional targets include several candidate genes involved in apoptosis and cell survival, including the zinc-finger transcription factor Aiolos. Aiolos is a transcription factor whose expression is restricted to lymphoid lineages. Aiolos binds to the Bcl-2 promoter, and also interacts with the Bcl-2 and Bcl-XL proteins to promote cell survival. Upregulation of Aiolos expression, for example, can reduce apoptosis of HIV- 1 infected cells.

[0013] Likewise, expression of Aiolos in lung and breast cancers predicts significantly reduced patient survival. Aiolos decreases expression of a large set of adhesion-related genes, disrupting cell-cell and cell-matrix interactions, facilitating metastasis. Aiolos may also function as an epigenetic driver of lymphocyte mimicry in certain metastatic epithelial cancers. Thus, down-regulation of Aiolos may reduce or eliminate metastasis.

[0014] Similarly, the casein kinase 1 family of proteins plays a role in the mitotic spindle formation, in DNA repair, and in RNA metabolism. See, e.g., Knippschild, et ah, Cell Signal, Vol 17, pp. 675-689 (2005). There are six isoforms in humans: a, gΐ, g2, g3, d and e. CKla has been shown to have an anti-apoptotic function; its inhibition increased Fas-induced apoptosis, whereas the overexpression of CKla delayed BID-mediated cell death. See, e.g, Desagher, et ak, Mol Cell., Vol. 8, pp. 601-611 (2001). In addition, CKla inhibits TRAIL induced apoptosis by modification of the TNF receptor or FADD at the death-inducing signaling complex (DISC). Thus, downregulation of CKla leads to enhancement of TRAIL-induced cell death. CKla also promotes cell survival by interacting with the retinoid X receptor (RXR). Downregulation of CKla enhances the apoptotic effect of RXR agonists. Likewise, the ikaros family of proteins play a role in leukemia. [0015] One mechanism to disrupt protein drivers of disease is to decrease the cellular concentration of these proteins. For example, proteolytic degradation of cellular proteins is essential to normal cell function. Hijacking this process, by targeting specific disease-related proteins, presents a novel mechanism for the treatment of disease. The irreversible nature of proteolysis makes it well-suited to serve as a regulatory switch for controlling unidirectional processes.

[0016] Ubiquitin-mediated proteolysis begins with ligation of one or more ubiquitin molecules to a particular protein substrate. Ubiquitination occurs through the activity of ubiquitin- activating enzymes (El), ubiquitin-conjugating enzymes (E2), and ubiquitin-protein ligases (E3), acting sequentially to attach ubiquitin to lysine residues of substrate proteins. The E3 ligases confer specificity to ubiquitination reactions by binding directly to particular substrates.

SUMMARY

[0017] The compounds disclosed in the present application have been discovered to exert surprising and unexpected biological effects. In particular, the compounds disclosed in the present application modulate protein levels to restore protein homeostasis Some embodiments provide chimeric compounds comprising a targeting group, a linker group, and an El -binding group. Some embodiments provide chimeric compounds comprising a targeting group, a linker group, and an E2 -binding group. Some embodiments provide chimeric compounds comprising a targeting group, a linker group, and an E3-binding group. Some embodiments provide chimeric compounds comprising a targeting group, a linker group, and a combination of one or more E1-, E2-, or E-3-binding groups.

[0018] Some embodiments provide a compound of Formula (II):

pharmaceutically acceptable salt or solvate thereof, wherein:

R ¹ , R ² , R ³ , and R ⁴ , are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted Ci to C6 alkoxy, optionally substituted Ci to C6 alkyl, optionally substituted C3 to Cx cycloalkyl, optionally substituted C6 to C10 aryl, optionally substituted 3 to 8 membered heterocyclyl, optionally substituted 5 to 10 membered heteroaryl, or L-Y;

wherein at least one of R ¹ , R ² , R ³ , and R ⁴ is not hydrogen; R ^5A , R ^5B , and R ^5C are each independently hydrogen or deuterium;

X is CH ₂ or C=0;

L is -Z ¹ -(R ⁶ )t-Z ² -, -Z ¹ -(R ⁶ -0-R ⁶ )t-Z ² -, -Z ¹ (R ⁶ -NH-R ⁶ )t-Z ² -, -Z ¹ -(R ⁶ -(CO)-R ⁶ )t- Z ² -, -Z ¹ -(R ⁶ -(NHCO)-R ⁶ ) _t -Z ² -, or -Z ¹ -(R ⁶ -(CONH)-R ⁶ ) _t -Z ² -;

t is 1, 2, or 3;

Z ¹ and Z ² are independently -CH2-, -0-, -(CO)-, -CO2-, -NH-, -NH(CO)-, -(CO)NH-, -R ⁶ CH _2- , -R ⁶ 0-, -R ⁶ -(CO)-, -R ⁶ C0 _2- , -R ⁶ NH- -R ⁶ NH(CO)-, -R ⁶ (CO)NH-, -R ⁶ NH(CO)NH-, -R ⁶ NH(CO)R ⁶ NH-, -CH ₂ R ⁶ -, -OR ⁶ -, -(CO)-R ⁶ -, -C0 ₂ R ⁶ -, -NHR ⁶ -, -NH(CO)R ⁶ -, -(CO)NHR ⁶ -, -NH(CO)NHR ⁶ -, or -NHR ⁶ (CO)NHR ⁶ -;

each R ⁶ is absent, or independently an unsubstituted Ci to C6 alkyl;

tized to attach to L.

[0019] In some embodiments, R ¹ , R ² , R ³ , and R ⁴ , are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-ami do, optionally substituted ester, optionally substituted Ci to C6 alkoxy, optionally substituted Ci to C6 alkyl, optionally substituted C3 to Cx cycloalkyl, optionally substituted C6 to C10 aryl, optionally substituted 3 to 8 membered heterocyclyl, optionally substituted 5 to 10 membered heteroaryl, or L-Y; wherein at least one of R ¹ , R ² , R ³ , and R ⁴ is not hydrogen.

[0020] In some embodiments, R ^5A , R ^5B , and R ^5C are each independently hydrogen or deuterium.

[0021] In some embodiments, X is CH ₂ or C=0. [0022] In some embodiments,

R ⁶ ) _t -Z ² -, -Z ¹ -(R ⁶ -(CO)-R ⁶ ) _t -Z ² -, -Z ¹ -(R ⁶ -

some embodiments, t is 1, 2, or 3.

[0023] In some embodiments, Z ¹ and Z ² are independently -CH2-, -0-, -(CO)-, -CO2-, -NH-, -NH(CO)-, -(CO)NH-, -R ⁶ CH _2- , -R ^e O-, -R ⁶ -(CO)-, -R ⁶ C0 _2- , -R ⁶ NH-, -R ⁶ NH(CO)-, -R ⁶ (CO)NH-, -R ⁶ NH(CO)NH-, -R ⁶ NH(CO)R ⁶ NH-, -CH2R ⁶ -, -OR ⁶ -, -(CO)- R ⁶ , -CO2R ⁶ -, -NHR ⁶ -, -NH(CO)R ⁶ -, -(CO)NHR ⁶ -, -NH(CO)NHR ⁶ -, or -NHR ⁶ (CO)NHR ⁶ -. In some embodiments, R ⁶ may be absent, or independently an unsubstituted Ci to C6 alkyl.

and Y is derivatized to attach to L. For example, Y may be selected from the group consisting of

wherein * represents the bond’s point of attachment to L.

[0025] In some embodiments, X is CH2. In some embodiments, X is C=0.

[0026] In some embodiments, at least one of R ^5A , R ^5B , and R ^5C is deuterium. In some embodiments, one of R ^5A , R ^5B , and R ^5C is deuterium. In some embodiments, two of R ^5A , R ^5B , and R ^5C are deuterium. In some embodiments, R ^5A , R ^5B , and R ^5C are each deuterium. In some embodiments, R ^5A , R ^5B , and R ^5C are each hydrogen. In some embodiments, at least one of R ^5A , R ^5B , and R ^5C is an unsubstituted Ci to C6 alkyl. In some embodiments, one of R ^5A , R ^5B , and R ^5C is an unsubstituted Ci to C6 alkyl. In some embodiments, two of R ^5A , R ^5B , and R ^5C are independently an unsubstituted Ci to C6 alkyl. In some embodiments, R ^5A , R ^5B , and R ^5C are each independently an unsubstituted Ci to C6 alkyl.

[0027] In some embodiments, R ¹ , R ² , R ³ , and R ⁴ , are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, unsubstituted amino, unsubstituted C-amido, unsubstituted N-amido, unsubstituted Ci to C6 alkoxy, unsubstituted Ci to C6 alkyl, unsubstituted C3 to Cs cycloalkyl, unsubstituted C6 to C10 aryl, unsubstituted 3 to 8 membered heterocyclyl, and unsubstituted 5 to 10 membered heteroaryl.

[0028] In some embodiments, R ¹ , R ² , R ³ , and R ⁴ , are each independently hydrogen, deuterium, halogen, cyano, nitro, unsubstituted Ci to C6 alkoxy, unsubstituted Ci to C6 alkyl, or unsubstituted C3 to Cs cycloalkyl.

[0029] In some embodiments, R ¹ , R ² , R ³ , and R ⁴ , are each independently hydrogen, deuterium, halogen, cyano, nitro, unsubstituted Ci to C3 alkoxy, unsubstituted Ci to C3 alkyl, or unsubstituted C3 to C6 cycloalkyl. [0030] In some embodiments, R ¹ , R ² , R ³ , and R ⁴ , are each independently hydrogen, deuterium, chloro, fluoro, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0031] In some embodiments, one of R ¹ , R ² , R ³ , and R ⁴ is hydrogen. In some embodiments, two of R ¹ , R ² , R ³ , and R ⁴ are hydrogen. In some embodiments, three of R ¹ , R ² , R ³ , and R ⁴ are hydrogen. In some embodiments, R ² , R ³ , and R ⁴ are hydrogen. In some embodiments, one of R ¹ , R ² , R ³ , and R ⁴ is L-Y.

[0032] In some embodiments, R ¹ is L-Y. In some embodiments, R ² is L-Y. In some embodiments,

R ⁶ )t-Z ² -. In some embodiments, L is -Z '- t-Z ² - In some embodiments, L is -Z ¹ -(R ⁶ -0-R ⁶ )t- Z ² -. In some embodiments, L is-Z ¹ (R ⁶ -NH-R ⁶ )t-Z ² -. In some embodiments, L is -Z ¹ -(R ⁶ -(CO)- R ⁶ ) _t -Z ² -. In some embodiments,

some embodiments, L is -Z ¹ -(R ⁶ -(NHCO)-R ⁶ )t-Z ² -. In some embodiments, L is -Z ¹ -^ ⁶ - (CONH)-R ⁶ )t-Z ² -. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3.

[0033] In some embodiments, Z ¹ and Z ² are independently -R ⁶ CH _2- , -R ⁶ 0- -R ⁶ -(CO)-, -R ⁶ C0 _2- -R ⁶ NH-, -R ⁶ NH(CO)-, -R ⁶ (CO)NH-, -CH ₂ R ⁶ -, -OR ⁶ -, -(CO)-R ⁶ , -C0 ₂ R ⁶ -, -NHR ⁶ -, -NH(CO)R ⁶ -, -(CO)NHR ⁶ -, -NH(CO)NHR ⁶ -, -NHR ⁶ (CO)NHR ⁶ -, -R ⁶ NH(CO)NH-, or -R ⁶ NH(CO)R ⁶ NH-. In some embodiments, Z ¹ and Z ² are independently -CH _2- , -0-, -(CO)-, -C0 _2- , -NH-, -NH(CO)-, -(CO)NH-, -CH ₂ NH(CO)NH-,

-CH ₂ NH(CO)CH ₂ NH-, -NH(CO)NHCH _2- or -NHCH ₂ (CO)NHCH _2- . In some embodiments, Z ¹ and Z ² are each -CLL-, -0-, -NH-, -NH(CO)-, or -(CO)NH-. In some embodiments, each R ⁶ is independently an unsubstituted Ci to C6 alkyl, for example, methylene or ethylene. In some embodiments, each R ⁶ is absent.

[0034] embodiments, wherein Y is derivatized to attach to L. [0035] In some embodiments, Y is , and wherein Y is derivatized to attach to L.

[0036] In some embodiments, Y is wherein Y is derivatized to attach to L.

[0037] In some embodiments, the compound of Formula (II) is selected from the group

or a pharmaceutically acceptable salt of any of the foregoing.

[0038] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (II) as described herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0039] Some embodiments provide a method of modulating the activity of a protein, comprising contacting a cell with an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In some such embodiments, the method inhibits the activity of the protein.

[0040] Some embodiments provide a method of modulating the activity of a protein, comprising administering an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the protein is selected from the group consisting of P.-1b, IL-2, IL-6, TNFa, aiolos, ikaros, helios, CK-la, and a combination of any of the foregoing. In some embodiments, the protein is IL- 1 b. In some embodiments, the protein is IL-2. In some embodiments, the protein is IL-6. In some embodiments, the protein is TNFa. In some embodiments, the protein is aiolos. In some embodiments, the protein is ikaros. In some embodiments, the protein is helios. In some embodiments, the protein is CKla. In some embodiments, the protein is overexpressed. In some embodiments, the protein is wild-type. In some embodiments, the protein is a mutant form of the protein. In some embodiments, the method inhibits the activity of the protein.

[0041] Some embodiments provide a method of treating cancer, comprising administering an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the cancer is selected from the group consisting of: small cell lung cancer, non-small cell lung cancer, breast cancer, prostate cancer, head and neck cancer, pancreatic cancer, colon cancer, rectal cancer, teratoma, ovarian cancer, endometrial cancer, brain cancer, retinoblastoma, leukemia, skin cancer, melanoma, squamous cell carcinoma, liposarcoma, lymphoma, multiple myeloma, testicular cancer, liver cancer, esophageal cancer, kidney carcinoma, astrogliosis, relapsed/refractory multiple myeloma, and neuroblastoma.

[0042] Some embodiments provide a method of inhibiting the growth of a cell, comprising contacting a cell with an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is selected from the group consisting of: a small cell lung cancer cell, a non small cell lung cancer cell, a breast cancer cell, a prostate cancer cell, a head and neck cancer cell, a pancreatic cancer cell, a colon cancer cell, a rectal cancer cell, a teratoma cell, an ovarian cancer cell, an endometrial cancer cell, a brain cancer cell, a retinoblastoma cell, a leukemia cell, a skin cancer cell, a melanoma cell, a squamous cell carcinoma cell, a liposarcoma cell, a lymphoma cell, a multiple myeloma cell, a testicular cancer cell, a liver cancer cell, an esophageal cancer cell, a kidney carcinoma cell, an astrogliosis cell, a relapsed/refractory multiple myeloma cell, and a neuroblastoma cell.

[0043] Some embodiments provide a method of treating an immune disorder, comprising administering an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the immune disorder is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis.

[0044] Some embodiments provide a method of treating an inflammatory disorder, comprising administering an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the inflammatory disorder is fibromyalgia or osteoarthritis.

[0045] As used herein,“derivatized” to connect with L refers to the Y moiety forming a new bond (or a new functional group) with the linker moiety L. This new bond can be, but is not limited to, a C-amide, a N-amide, a C-carboxy, an O-carboxy, an ether, an substituted amine, a sulfmyl, a sulfenyl, a sulfonyl, a N-sulfonamido, a S-sulfonamido, a carbon-carbon bond (i.e., an alkyl, alkenyl, or alkynyl), an O-carbamyl, a N-carbamyl, a thiocarbonyl, a carbonyl, an O- thiocarbamyl, and a N-thiocarbamyl. Exemplary point of derivitazation include, but are not limited to those shown below with an arrow. In some embodiments, derivitaztion can include removing a functional group to expose (for example) an amino, hydroxy, or carboxy group. The necessary derivitization to the groups shown below is within the ability of one skilled in the art:

and Y is derivatized to attached to L, Y can be:

or wherein * represents the bond’s point of attachment to the L group.

[0047] As another example, when Y is

and Y is derivatized to attach to L, Y can be:

, wherein * represents the bond’s point of attachment to the L group.

[0048] As yet another example, when derivatized to attach to L, Y can be:

wherein * represents the bond’s point of attachment to the L group.

[0049] In some other embodiments, Y may be selected from the group comprising

, and, where * represents the bond’s point of attachment to the linker moiety L.

[0050] Any of the features of an embodiment is applicable to all embodiments identified herein. Moreover, any of the features of an embodiment is independently combinable, partly or wholly with other embodiments described herein in any way, e.g., one, two, or three or more embodiments may be combinable in whole or in part. Further, any of the features of an embodiment may be made optional to other embodiments. Any embodiment of a method can comprise another embodiment of a compound, and any embodiment of a compound can be configured to perform a method of another embodiment. DETAILED DESCRIPTION

[0051] Some embodiments provide a compound of Formula (I):

or a pharmaceutically acceptable salt or solvate thereof.

[0052] In some embodiments, Ri, R2, R3, and R ₄ , are each independently H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted thiourea, optionally substituted Ci to C6 alkoxy, optionally substituted Ci to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to Cx cycloalkyl, optionally substituted C6 to C10 aryl, optionally substituted C3 to Cx heterocyclyl, optionally substituted C6 to C10 heteroaryl, or L-Y.

[0053] In some embodiments, Ri, R2, R3, and R ₄ , are each independently H, deuterium, hydroxyl, halogen, cyano, nitro, unsubstituted amino, unsubstituted C-amido, unsubstituted N- amido, unsubstituted ester, unsubstituted sulfonyl, unsubstituted S-sulfonamido, unsubstituted N-sulfonamido, unsubstituted sulfonate, unsubstituted O-thiocarbamyl, unsubstituted N-thiocarbamyl, unsubstituted N-carbamyl, unsubstituted O-carbamyl, unsubstituted urea, unsubstituted thiourea, unsubstituted Ci to G alkoxy, unsubstituted Ci to G, alkyl, unsubstituted C2 to Ce alkenyl, unsubstituted C2 to G, alkynyl, unsubstituted C3 to Cx cycloalkyl, unsubstituted Ce to C10 aryl, unsubstituted C3 to Cx heterocyclyl, unsubstituted G, to C10 heteroaryl, or L-Y.

[0054] In some embodiments, three of Ri, R2, R3, and R ₄ , are H or deuterium. In some embodiments, two of Ri, R2, R3, and R ₄ , are H or deuterium. In some embodiments, one of Ri, R2, R3, and R ₄ , is H or deuterium. In some embodiments, none of Ri, R2, R3, and R ₄ , are H or deuterium. In some embodiments, at least one of Ri, R2, R3, and R ₄ is not H. In some embodiments, Ri or R2 is L-Y.

[0055] In some embodiments, each Rs is independently H, deuterium, optionally substituted Ci to G, alkyl, optionally substituted C2 to G, alkenyl, optionally substituted C2 to G, alkynyl, or optionally substituted C3 to Cx cycloalkyl. In some embodiments, each Rs is independently H, deuterium, or unsubstituted Ci to G, alkyl. In some embodiments, each Rs is independently H or deuterium. [0056] In some embodiments, X is C(R ₅ )2, CH(Rs), CH ₂ , CF ₂ , C=0, or C=S. In some embodiments, X is CH ₂ , CF ₂ , or C=0. In some embodiments, Q is C=0, C=S; S=0, or S0 _2. In some embodiments, Q is C=0. In some embodiments, n is 1 or 2.

[0057] In some embodiments, L is -Z ¹ -(Rs) _t -Z ² -, -Zi-(R6-0-R6) _t -Z _2- , -ZI(R ₆ -NH- Re) _t -Z _2- , -Zi-(R6-S-R ₆ ) _t -Z _{2- -} Zi-(R6-(CO)-R ₆ ) _t -Z _{2- -} Zi-(R6-(C0 ₂ )-R6) _t -Z _2- , -ZI-(R ₆ -(NHCO)- R ₆ ) _t -Z _{2- -} Zi-(R6-(CONH)-R ₆ ) _t -Z ₂ , -Zi-(R6-S-R ₆ ) _t -Z _{2- -} Zi-(R6-(SO)-R ₆ ) _t -Z _{2- -} Zi-(R ₆ -(S0 ₂ )- R ₆ ) _t -Z _{2- -} Zi-(R6-(NHS0 ₂ )-R6) _t -Z _2- , -Zi-(R6-(S0 ₂ NH)-R6) _t -Z _2- , or -Zi-(R6-R7-R ₆ ) _t -Z _2- .

[0058] In some embodiments, t is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, t is 1 or 2.

[0059] In some embodiments, Zi and Z ₂ are independently -CFh-, -0-, -S-, S=0, -S0 _2- , C=0, -C0 _2- , -NH-, -NH(CO)-, -(CO)NH-, -NH-S0 _2- , -S0 ₂ -NH-, -ReCH _2- , -ReO-,

-R ₆ NH(CO)R ₆ NH-, -CH ₂ R _6- , -OR/,-, -SRe-, -(SO)-Re-, -(S0 ₂ )R _6- , -(CO)-Re-, -(C0 ₂ )R _6- , -NHR _6- , -NH(CO)R _6- , -(C0)NHR _6- , -NH-S0 ₂ R _6- , or-S0 ₂ -NHR _6-. In some embodiments, Zi and Z ₂ are independently -CH _2- , -0-, -(CO)-, -C0 _2- , -NH-, -NH(CO)-, -(CO)NH- -NH(CO)NH-, -CH ₂ NH(CO)NH-, -CH ₂ NH(CO)CH ₂ NH-, -NH(CO)NHCH _2- or -NHCH ₂ (CO)NHCH _2-..

[0060] In some embodiments, each R ₆ is absent, or independently Ci to C6 alkyl, C ₂ to C6 alkenyl, C ₂ to C6 alkynyl, C6 to Cio aryl, C3 to Cs heterocyclyl, or C6 to C10 heteroaryl. In some embodiments, each R ₆ is absent. In some embodiments, each R ₆ is independently Ci to C6 alkyl, for example, methylene, or ethylene.

[0061] In some embodiments, R7 is optionally substituted Ci to C6 alkyl, optionally substituted C3 to Cx cycloalkyl, optionally substituted C6 to Cio aryl, optionally substituted C3 to Os heterocyclyl, or optionally substituted C6 to Cio heteroaryl. In some embodiments, R7 is unsubstituted Ci to C6 alkyl, unsubstituted C3 to Cx cycloalkyl, unsubstituted C6 to Cio aryl, unsubstituted C3 to Cx heterocyclyl, or unsubstituted C6 to Cio heteroaryl. wherein Y is derivatized to attach to L

[0063] In some embodiments, the compound of Formula (I) is present in a form of a racemic mixture. In some embodiments, the compound of Formula (I) has an S-configuration. In some embodiments, the compound of Formula (I) has an R-configuration. In some embodiments, the compound of Formula (I) is enriched in one enantiomer over another enantiomer, for example, enriched by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%, or any value in between. In some embodiments, the compound of Formula (I) is enriched in one diastereomer over another diastereomer for example, enriched by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%, or any value in between.

[0064] Some embodiments provide a compound of Formula (II):

or a pharmaceutically acceptable salt or solvate thereof.

[0065] In some embodiments, R ¹ , R ² , R ³ , and R ⁴ , are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-ami do, optionally substituted ester, optionally substituted Ci to C6 alkoxy (for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, t- butoxy, pentoxy (straight chain or branched), or hexoxy (straight chain or branched)), optionally substituted Ci to C6 alkyl (for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t- butyl, pentyl (straight chain or branched), or hexyl (straight chain or branched)), optionally substituted C3 to Cx cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl), optionally substituted C6 to C10 aryl (for example, phenyl or naphthyl), optionally substituted 3 to 8 membered heterocyclyl (for example, aziridine, oxirane, azetidine, oxetane, pyrrolidine, tetrahydrofuran, imidazoline, pyrazoline, piperidine, tetrahydropyran, or morpholine), optionally substituted 5 to 10 membered heteroaryl (for example, pyrrole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, or quinoline), or L-Y; wherein at least one of R ¹ , R ² , R ³ , and R ⁴ is not hydrogen.

[0066] In some embodiments, R ¹ , R ² , R ³ , and R ⁴ , are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, unsubstituted amino, unsubstituted C-amido, unsubstituted N-amido, unsubstituted Ci to C6 alkoxy (for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, t-butoxy, pentoxy (straight chain or branched), or hexoxy (straight chain or branched)), unsubstituted Ci to C6 alkyl (for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, pentyl (straight chain or branched), or hexyl (straight chain or branched)), unsubstituted C3 to Cx cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl), unsubstituted C6 to C10 aryl (for example, phenyl or naphthyl), unsubstituted 3 to 8 membered heterocyclyl (for example, aziridine, oxirane, azetidine, oxtetane, pyrrolidine, tetrahydrofuran, imidazoline, pyrazoline, piperidine, tetrahydropyran, or morpholine), and unsubstituted 5 to 10 membered heteroaryl (for example, pyrrole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, or quinoline).

[0067] In some embodiments, R ¹ , R ² , R ³ , and R ⁴ , are each independently hydrogen, deuterium, halogen, cyano, nitro, unsubstituted Ci to C6 alkoxy, unsubstituted Ci to C6 alkyl, or unsubstituted C3 to Cx cycloalkyl.

[0068] In some embodiments, R ¹ , R ² , R ³ , and R ⁴ , are each independently hydrogen, deuterium, halogen, cyano, nitro, unsubstituted Ci to C3 alkoxy, unsubstituted Ci to C3 alkyl, or unsubstituted C3 to C6 cycloalkyl.

[0069] In some embodiments, R ¹ , R ² , R ³ , and R ⁴ , are each independently hydrogen, deuterium, chloro, fluoro, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0070] In some embodiments, one of R ¹ , R ² , R ³ , and R ⁴ is hydrogen. In some embodiments, two of R ¹ , R ² , R ³ , and R ⁴ are hydrogen. In some embodiments, three of R ¹ , R ² , R ³ , and R ⁴ are hydrogen. In some embodiments, R ² , R ³ , and R ⁴ are hydrogen.

[0071] In some embodiments, R ^5A , R ^5B , and R ^5C are each independently hydrogen or deuterium. In some embodiments, at least one of R ^5A , R ^5B , and R ^5C is deuterium. In some embodiments, R ^5A is H; one of R ^5B and R ^5C is deuterium; and the other of R ^5B and R ^5C is H. In some embodiments, R ^5A is H and R ^5B and R ^5C are each deuterium. In some embodiments, one of R ⁵ A R ^SB _anc j ^S C J _S deuterium. In some embodiments, two of R ^5A , R ^5B , and R ^5C are deuterium. In some embodiments, R ^5A , R ^5B , and R ^5C are each deuterium. In some embodiments, R ^5A , R ^5B , and R ^5C are each hydrogen. In some embodiments, at least one of R ^5A , R ^5B , and R ^5C is an unsubstituted Ci to C6 alkyl. In some embodiments, one of R ^5A , R ^5B , and R ^5C is an unsubstituted Ci to C6 alkyl. In some embodiments, two of R ^5A , R ^5B , and R ^5C are independently an unsubstituted Ci to C6 alkyl. In some embodiments, R ^5A , R ^5B , and R ^5C are each independently an unsubstituted Ci to C6 alkyl.

[0072] In some embodiments, X is CH2 or C=0. In some embodiments, X is CH2. In some embodiments, X is C=0.

[0073] In some embodiments, L is -Zk^ _t -Z ² -, -Z '-(R -0-R ),-Z ² -, -Z ¹ (R ⁶ -NH- R ⁶ )t-Z ² -, or -Z ¹ -(R ⁶ -(CO)-R ⁶ )t-Z ² -. In some embodiments, L is -Z'-(R ) _t -Z ² - In some embodiments, L is -Z ¹ -(R ⁶ -0-R ⁶ ) _t -Z ² -. In some embodiments, L is -Z ¹ (R ⁶ -NH-R ⁶ ) _t -Z ² -. In some embodiments, L is -Z ¹ -(R ⁶ -(CO)-R ⁶ ) _t -Z ² -. In some embodiments, L is -Z ¹ -(R -(NHCO)-R ) _t -Z ² - or -Z ¹ -(R ⁶ -(CONH)-R ⁶ ) _t -Z ² -. In some embodiments, L is -Z ¹ -(R -(NHCO)-R ) _t -Z ² -. In some embodiments, L is -Z ¹ -(R ⁶ -(CONH)-R ⁶ ) _t -Z ² -. [0074] In some embodiments, t is 1, 2, or 3. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3.

[0075] In some embodiments, Z ¹ and Z ² are independently -CH2-, -0-, -(CO)-, -CO2-, -NH-, -NH(CO)-, -(CO)NH-, -R ⁶ CH _2- , -R ^e O-, -R ⁶ -(CO)-, -R ⁶ C0 _2- , -R ⁶ NH-, -R ⁶ NH(CO)-, -R ⁶ (CO)NH-, -CH2R ⁶ -, -OR ⁶ -, -(CO)-R ⁶ , -CO2R ⁶ -, -NHR ⁶ -, -NH(CO)R ⁶ -, -(CO)NHR ⁶ -, -NH(CO)NHR ⁶ -, -NHR ⁶ (CO)NHR ⁶ -, R ⁶ NH(CO)NH-, or -R ⁶ NH(CO)R ⁶ NH-. In some embodiments, Z ¹ and Z ² are independently -CH2-, -0-, -(CO)-, -CO2-, -NH- -NH(CO)-, -(CO)NH-, -CH ₂ NH(CO)NH-, -CH ₂ NH(CO)CH ₂ NH-, -NH(CO)NHCH _2- or -NHCH2(CO)NHCH2- In some embodiments, Z ¹ and Z ² are independently -CH2-, -0-, -NH-, -NH(CO)-, -(CO)NH-. In some embodiments, Z ¹ and Z ² are independently -R ⁶ CH2-, -R ⁶ 0- -R ⁶ -(CO)-, -R ⁶ C0 _2- , -R ⁶ NH-, -R ⁶ NH(CO)-, -R ⁶ (CO)NH-, -CH2R ⁶ -, -OR ⁶ -, -(CO)-R ⁶ -,

-CH ₂ NH(CO)CH ₂ NH-, -NH(CO)NHCH _2- or-NHCH ₂ (CO)NHCH _2- , and the other Z ¹ and Z ² is -CH2-, -0-, -NH-; and R ⁶ is an unsubstituted Ci to C6 alkyl, for example, methylene, or ethylene.

[0076] In some embodiments, each R ⁶ is absent, or independently an unsubstituted Ci to C6 alkyl, for example, methylene, or ethylene. In some embodiments, each R ⁶ is absent.

derivatized to attach to L. [0078] In some embodiments, wherein Y is

derivatized to attach to L. In some such embodiments,

wherein * represents the bond’s point of attachment to L. and wherein Y is

derivatized to attach to L In some such embodiments, and wherein * represents the bond’s point off attachment to L.

[0080] In some embodiments, Y is wherein Y is derivatized to attach to L

and wherein * represents the bond’s point of attachment to L.

[0081] In some embodiments, one of R ¹ , R ² , R ³ , and R ⁴ is L-Y. In some embodiments, R ¹ is L-Y. In some embodiments, R ² is L-Y. In some embodiments, R ¹ is L-Y; L is -Z^R^ _t -Z ² -; and t is 1 or 2. In some embodiments, R ¹ is L-Y; L is -Z ¹ -(R ⁶ -0-R ⁶ ) _t -Z ² -; and t is 1 or 2. In some embodiments, R ¹ is L-Y; L is -Z ¹ (R ⁶ -NH-R ⁶ ) _t -Z ² -; and t is 1 or 2. In some embodiments, R ¹ is L-Y; L is

-Z ¹ -(R ⁶ -(CO)-R ⁶ ) _t -Z ² -; and t is 1 or 2. In some embodiments, R ¹ is L-Y; L is

-Z ¹ -(R ⁶ -(CONH)-R ⁶ ) _t -Z ² -; and t is 1 or 2. In some embodiments, R ² is L-Y; L is -Z ¹ -(R ⁶ -0-R ⁶ )t-Z ² -; and t is 1 or 2. In some embodiments, R ² is L-Y; L is -Z ¹ (R ⁶ -NH-R ⁶ ) _t -Z ² -; and t is 1 or 2. In some embodiments, R ² is L-Y; L is

-Z ¹ -(R ⁶ -(CO)-R ⁶ ) _t -Z ² -; and t is 1 or 2. In some embodiments, R ² is L-Y; L is

-Z ¹ -(R ⁶ -(NHCO)-R ⁶ ) _t -Z ² -; and t is 1 or 2. In some embodiments, R ² is L-Y; L is -Z ¹ -(R ⁶ -(CONH)-R ⁶ ) _t -Z ² -; and t is 1 or 2. In some such embodiments, each R ⁶ is absent, or independently an unsubstituted Ci to C6 alkyl, for example, methylene, or ethylene. In some other embodiments, each R ⁶ is absent.

[0082] In some embodiments, the compound of Formula (II) is selected from the group

pharmaceutically acceptable salt of any of the foregoing.

[0083] In some embodiments, the compound of Formula (II) is racemic. In some embodiments, the compound of Formula (II) has an S-configuration. In some embodiments, the compound of Formula (II) has an R-configuration. In some embodiments, the compound of Formula (II) is enriched in one enantiomer over another enantiomer, for example, enriched by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%, or any value in between.

In some embodiments, the compound of Formula (II) is enriched in one diastereomer over another diastereomer for example, enriched by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%, or any value in between.

[0084] In some embodiments, the compound of Formula (II) is selected from:

In some embodiments of this paragraph, Ri is unsubstituted Ci to C6 alkyl. In some embodiments of this paragraph, Ri is substituted Ci to C6 alkyl. In some embodiments of this paragraph, Ri is unsubstituted C3 to Cs cycloalkyl. In some embodiments of this paragraph, Ri is substituted C3 to Cs cycloalkyl. In some embodiments of this paragraph, Ri is halogen. In some embodiments of this paragraph, R2 is halogen. In some embodiments of this paragraph, R2 is H. In some embodiments of this paragraph, R2 is deuterium.

[0085] In some embodiments, the compound of Formula (II) is selected from:

In some embodiments of this paragraph, Ri is unsubstituted Ci to C6 alkyl. In some embodiments of this paragraph, Ri is substituted Ci to C6 alkyl. In some embodiments of this paragraph, Ri is unsubstituted C3 to Cx cycloalkyl. In some embodiments of this paragraph, Ri is substituted C3 to Cs cycloalkyl. In some embodiments of this paragraph, Ri is halogen. In some embodiments of this paragraph, R3 is halogen. In some embodiments of this paragraph, R3 is H. In some embodiments of this paragraph, R3 is deuterium.

[0086] In some embodiments, the compound of Formula (II) is selected from:

In some embodiments of this paragraph, Ri is unsubstituted Ci to C6 alkyl. In some embodiments of this paragraph, Ri is substituted Ci to C6 alkyl. In some embodiments of this paragraph, Ri is unsubstituted C3 to Cx cycloalkyl. In some embodiments of this paragraph, Ri is substituted C3 to Cs cycloalkyl. In some embodiments of this paragraph, Ri is halogen. In some embodiments of this paragraph, R2 is halogen. In some embodiments of this paragraph, R2 is H. In some embodiments of this paragraph, R2 is deuterium.

[0087] In some embodiments, the compound of Formula (II) is selected from:

In some embodiments of this paragraph, Ri is unsubstituted Ci to C6 alkyl. In some embodiments of this paragraph, Ri is substituted Ci to C6 alkyl. In some embodiments of this paragraph, Ri is unsubstituted C3 to Cs cycloalkyl. In some embodiments of this paragraph, Ri is substituted C3 to Cs cycloalkyl. In some embodiments of this paragraph, Ri is halogen. In some embodiments of this paragraph, R3 is halogen. In some embodiments of this paragraph, R3 is H. In some embodiments of this paragraph, R3 is deuterium.

[0088] In some embodiments, the compound of Formula (II) is selected from:

In some embodiments of this paragraph, Ri is unsubstituted Ci to C6 alkyl. In some embodiments of this paragraph, Ri is substituted Ci to C6 alkyl. In some embodiments of this paragraph, Ri is unsubstituted C3 to Cs cycloalkyl. In some embodiments of this paragraph, Ri is substituted C3 to Cs cycloalkyl. In some embodiments of this paragraph, Ri is halogen. In some embodiments of this paragraph, R2 is halogen. In some embodiments of this paragraph, R2 is H. In some embodiments of this paragraph, R2 is deuterium.

[0089] In some embodiments, the compound of Formula (II) is selected from:

In some embodiments of this paragraph, Ri is unsubstituted Ci to C6 alkyl. In some embodiments of this paragraph, Ri is substituted Ci to C6 alkyl. In some embodiments of this paragraph, Ri is unsubstituted C3 to Cx cycloalkyl. In some embodiments of this paragraph, Ri is substituted C3 to Cs cycloalkyl. In some embodiments of this paragraph, Ri is halogen. In some embodiments of this paragraph, R3 is halogen. In some embodiments of this paragraph, R3 is H. In some embodiments of this paragraph, R3 is deuterium.

[0090] In some embodiments, Y is a compound or a portion of a compound that targets a particular protein, proteins, and/or protein complex. In some embodiments, Y is an HSP90 inhibitor. In some embodiments, Y is a kinase inhibitor. In some embodiments, Y is a phosphatase inhibitor. In some embodiments, Y is a compound targeting the estrogen receptor. In some embodiments, Y is a compound targeting the androgen receptor. In some embodiments, Y is an inhibitor of HDM2/MDM2. In some embodiments, Y is an HD AC inhibitor. In some embodiments, Y is an inhibitor of lysine methyltransf erase. In some embodiments, Y is an inhibitor of one or more core-binding factor(s).

[0091] In some embodiments, Y is a compound or a portion of a compound targeting the BET bromodomain. In some embodiments, Y is a compound targeting FKBP. In some embodiments, Y is a compound targeting the RAF receptor. In some embodiments, Y is a compound targeting the aryl hydrocarbon receptor. In some embodiments, Y is an immunosuppressive compound. In some embodiments, Y is an angiogenesis inhibitor. In some embodiments, Y is a compound targeting HIV protease. In some embodiments, Y is a compound targeting the thyroid hormone receptor. In some embodiments, Y is a compound targeting one or more ligase(s).

[0092] In some embodiments, Y is a compound or a portion of a compound targeting HIV integrase. In some embodiments, Y is a compound targeting HCV protease. In some embodiments, Y is a compound targeting acyl-protein thioesterase 1. In some embodiments, Y is a compound targeting acyl-protein thioesterase 2. In some embodiments, Y is a compound that is derivatized where L is attached.

[0093] In some embodiments, Y can be selected from:

s attached, for example, via an ether, an amide, a carbon or nitrogen atom in a heterocyclyl group, a carbon atom in an alkyl group, or other functional group.

[0094] In some embodiments, Y is geldanamycin ((4E,6Z,8S,9S,l0E,l2S, l3R, 14S, l6R)-l3-hy droxy-8, 14,19-trimethoxy-4, 10, 12,-16-tetram ethyl-3, 20, 22-trioxo-2- azabicyclo[l6.3. l], or a derivative thereof (e.g. l7-alkylamino-l7-desmethoxygeldanamycin (“17-AAG”) or l7-(2-dimethylaminoethyl)amino-l7-desmethoxygeldanamycin (“17-DMAG”)) (derivatized where a linker group L is attached, for example, via the amide group).

[0095] In some embodiments, Y is afatinib (derivatized where a linker group L is attached, for example, via the aliphatic amine); fostamatinib (derivatized where a linker group L is attached, for example, via a methoxy); gefitinib (derivatized where a linker group L is attached, for example, via a methoxy or ether group); lenvatinib (derivatized where a linker group L is attached, for example, via the cyclopropyl); vandetanib (derivatized where a linker group L is attached, for example, via the methoxy or hydroxyl); vemurafenib (derivatized where a linker group L is attached, for example, via the sulfonyl propyl group); Gleevec (derivatized where R is a linker group L is attached, for example, via the amide or via the aniline amine); pazopanib (derivatized where R is a linker group L attached, for example, to the phenyl or via the aniline amine). [0096] In some embodiments, Y is azacitidine ((derivatized where a linker group L is attached, for example, via the hydroxy or amino groups). In some embodiments, Y is decitabine (derivatized) (4-amino-l-(2-deoxy-b-D-erythro-pentofuranosyl)-l,3,5-triazi n-2(lH)-one)

(Derivatized where a linker group L is attached, for example, via either of the hydroxy or amino).

[0097] In some embodiments, Y is GA-l (derivatized) and derivatives and analogs thereof, having the structure(s) and binding to linkers as described in Sakamoto, et ah, Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, Mol Cell Proteomics, 2(12): 1350-58 (2003).

[0098] In some embodiments, Y is estradiol or testosterone, and related derivatives (including, but not limited to, DHT) which may be bound to a linker group L as is generally described in Rodriguez-Gonzalez, et ah, Oncogene , 27, 7201-7211 (2008) and/or Sakamoto, et al. , Mol Cell Proteomics, 2(12): 1350-58 (2003).

[0099] In some embodiments, Y is ovalicin, fumagillin, a glucocorticoid (including, but not limited to hydrocortisone, prednisone, prednisolone, and methylprednisolone), methotrexate, cyclosporine, tacrolimus (FK-506), rapamycin, apigenin, or an actinomycin, each derivatized where a linker group L is bound.

[0100] In some embodiments, Y is

derivatized wherein“R” represents the attachment of linker group L via, for example, an ether, an amide, a carbon or nitrogen atom in a heterocyclyl group, or other functional group. [0101] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing; and a pharmaceutically acceptable excipient.

[0102] Some embodiments provide a method of modulating the activity of a protein, comprising contacting a cell with an effective amount of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. In some such embodiments, the method inhibits the activity of the protein.

[0103] Some embodiments provide a method of modulating the activity of a protein, comprising administering an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing, to a subject in need thereof. In some embodiments, the protein is selected from the group consisting of IL- 1 b, IL-2, IL-6, TNFa, aiolos, ikaros, helios, CK-la, and a combination of any of the foregoing. In some embodiments, the protein is IL- 1 b. In some embodiments, the protein is IL-2. In some embodiments, the protein is IL-6. In some embodiments, the protein is TNFa. In some embodiments, the protein is aiolos. In some embodiments, the protein is ikaros. In some embodiments, the protein is helios. In some embodiments, the protein is CKla. In some embodiments, the protein is overexpressed. In some embodiments, the protein is wild-type. In some embodiments, the protein is a mutant form of the protein. In some embodiments of any of the method described herein, the method inhibits the activity of the protein.

[0104] Some embodiments provide a method of treating cancer, comprising administering an effective amount of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing, (or a pharmaceutical composition comprising a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing) to a subject in need thereof. In some embodiments, the cancer is selected from the group consisting of: small cell lung cancer, non-small cell lung cancer, breast cancer, prostate cancer, head and neck cancer, pancreatic cancer, colon cancer, rectal cancer, teratoma, ovarian cancer, endometrial cancer, brain cancer, retinoblastoma, leukemia, skin cancer, melanoma, squamous cell carcinoma, liposarcoma, lymphoma, multiple myeloma, testicular cancer, liver cancer, esophageal cancer, kidney carcinoma, astrogliosis, relapsed/refractory multiple myeloma, and neuroblastoma.

[0105] Some embodiments provide a method of inhibiting the growth of a cell, comprising contacting a cell with an effective amount of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is selected from the group consisting of: a small cell lung cancer cell, a non-small cell lung cancer cell, a breast cancer cell, a prostate cancer cell, a head and neck cancer cell, a pancreatic cancer cell, a colon cancer cell, a rectal cancer cell, a teratoma cell, an ovarian cancer cell, an endometrial cancer cell, a brain cancer cell, a retinoblastoma cell, a leukemia cell, a skin cancer cell, a melanoma cell, a squamous cell carcinoma cell, a liposarcoma cell, a lymphoma cell, a multiple myeloma cell, a testicular cancer cell, a liver cancer cell, an esophageal cancer cell, a kidney carcinoma cell, an astrogliosis cell, a relapsed/refractory multiple myeloma cell, and a neuroblastoma cell.

[0106] Some embodiments provide a method of treating an immune disorder, comprising administering an effective amount of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing, (or a pharmaceutical composition comprising a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing) to a subject in need thereof. In some embodiments, the immune disorder is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis.

[0107] Some embodiments provide a method of treating an inflammatory disorder, comprising administering an effective amount of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing, (or a pharmaceutical composition comprising a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing). In some embodiments, the inflammatory disorder is fibromyalgia or osteoarthritis.

[0108] Some embodiments provide methods of treating, ameliorating, or preventing a disease, disorder, or condition associated with protein misregulation, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing, wherein the protein is the target of Y. For example, if Y targets the fibroblast growth factor receptor (FGFR), then the embodiments provides methods of treating, ameliorating, or preventing a disease, disorder, or condition associated with FGFR misregulation, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. Likewise, if Y targets JAK (Janus kinase, e.g., JAK2), then the embodiments provides methods of treating, ameliorating, or preventing a disease, disorder, or condition associated with JAK misregulation, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. The definitions for compounds of Formula (I) and Formula (II) are the same as those set forth above. [0109] Some embodiments provide methods of inhibiting protein activity, comprising contacting a cell with a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing, wherein the protein is the target of Y. For example, if Y targets the fibroblast growth factor receptor (FGFR), then the embodiments provides methods of inhibiting FGFR activity, comprising contacting a cell with a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. Likewise, if Y targets JAK, then the embodiments provides methods of inhibiting JAK activity, comprising contacting a cell with a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing.

[0110] Some embodiments provide methods of treating, ameliorating, or preventing a disease, disorder, or condition associated with cytokines, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the cytokine is IL-l -alpha, IL-l-beta, IL-2, IL-4, IL-6, IL-10, or a combination thereof.

[0111] Some embodiments provide methods of treating, ameliorating, or preventing a disease, disorder, or condition associated with TNF-alpha, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing.

[0112] Some embodiments provide methods of treating, ameliorating, or preventing a disease, disorder, or condition associated with aiolos or ikaros, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing

[0113] Some embodiments provide methods of treating, ameliorating, or preventing a disease, disorder, or condition associated with CK1 -alpha, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing.

[0114] In some embodiments, the disease, disorder, or condition selected from inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel diseases, Crohn’s disease, ulcerative colitis, uveitis, inflammatory lung diseases, chronic obstructive pulmonary disease, Alzheimer’s disease, organ transplant rejection, and cancer. In some embodiments, the compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing, is administered in combination with a second therapeutic agent.

[0115] Some embodiments provide methods of inhibiting cytokine activity, comprising contacting a cell with a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered in combination with a second therapeutic agent. In some embodiments, the cytokine is IL-l-alpha, IL-l-beta, IL-2, IL-4, IL-6, IL-10, or a combination thereof.

[0116] Some embodiments provide methods of inhibiting TNF-alpha activity, comprising contacting a cell a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered in combination with a second therapeutic agent.

[0117] Some embodiments provide methods of inhibiting aiolos activity, ikaros activity, or aiolos and ikaros activity, comprising contacting a cell a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered in combination with a second therapeutic agent.

[0118] Some embodiments provide methods of inhibiting CK1 -alpha activity, comprising contacting a cell with a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered in combination with a second therapeutic agent.

[0119] One or more of the compounds of preferred embodiments can be provided in the form of pharmaceutically acceptable salts, solvates, active metabolites, tautomers, or prodrugs thereof. Some embodiments can be provided in pharmaceutical compositions comprising a therapeutically effective amount of the compound. In some embodiments, the pharmaceutical composition also contains at least one pharmaceutically acceptable inactive ingredient. The pharmaceutical composition can be formulated for intravenous injection, subcutaneous injection, oral administration, buccal administration, inhalation, nasal administration, topical administration, transdermal administration, ophthalmic administration, or otic administration. The pharmaceutical composition can be in the form of a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop.

[0120] The pharmaceutical compositions of preferred embodiments can further comprise one or more additional therapeutically active agents other than a compound of the preferred embodiments. Such agents can include, but are not limited to, anti-inflammatory agents, anti-cancer agents, immunostimulatory agents, and immunosuppressive agents. [0121] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.

Definitions

[0122] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. As used in the specification and the appended claims, the singular forms“a,”“an” and“the” include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. The use of“or” or“and” means“and/or” unless stated otherwise. Furthermore, use of the term“including” as well as other forms, such as “include”,“includes,” and“included,” is not limiting. As used in this specification, whether in a transitional phrase or in the body of the claim, the terms“comprise(s)” and“comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases“having at least” or“including at least.” When used in the context of a process, the term“comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term“comprising” means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0123] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0124] As used herein, common organic abbreviations are defined as follows:

[0125] The term“deuterium source” as used herein refers to compound or mixture of compounds containing one or more labile deuterium atoms. These one or more labile deuterium atoms may be removed and incorporated into compounds of Formula (I), compounds of Formula (II) and pharmaceutically acceptable salts of any of the foregoing, as described herein.

[0126] The terms“co-administration” and similar terms as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0127] The terms“effective amount” and“therapeutically effective amount” are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an“effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate“effective” amount in any individual case may be determined using techniques, such as a dose escalation study. Where a drug has been approved by the U. S. Food and Drug Administration (FDA) or a counterpart foreign medicines agency, a“therapeutically effective amount” optionally refers to the dosage approved by the FDA or its counterpart foreign agency for treatment of the identified disease or condition.

[0128] The term“pharmaceutical combination” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term“fixed combination” means that the active ingredients, e.g., a compound of a preferred embodiment and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term“non- fixed combination” means that the active ingredients, e.g, a compound of a preferred embodiment and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0129] As used herein, any“R” group(s) such as, without limitation, R ₂ , R3, R4, Rs, R6, R9, and Rio represent substituents that can be attached to the indicated atom. An R group may be substituted or unsubstituted. If two“R” groups are described as being“taken together” the R groups and the atoms they are attached to can form a cycloalkyl, aryl, heteroaryl, or heterocycle. For example, without limitation, if R ² and R ³ , or R ² , R ³ , or R ⁴ , and the atom to which it is attached, are indicated to be“taken together” or“joined together” it means that they are covalently bonded to one another to form a ring:

[0130] Whenever a group is described as being“optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being“unsubstituted or substituted” if substituted, the substituent may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated“optionally substituted” or“substituted” group may be individually and independently substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfmyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino group and di-substituted amino group, and protected derivatives thereof.

[0131] As used herein,“C _a to Cb” in which“a” and“b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring of the heteroaryl or ring of the heteroalicyclyl can contain from“a” to“b”, inclusive, carbon atoms. Thus, for example, a“Ci to C ₄ alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (Cft^CH-, CH3CH2CH2CH2- , CFLCFLCFhCFb)- and (CFL^C-. If no“a” and“b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group, the broadest range described in these definitions is to be assumed. [0132] As used herein,“alkyl” refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as“1 to 20” refers to each integer in the given range; e.g.,“1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds may be designated as“Ci-C ₄ alkyl” or similar designations. By way of example only,“Ci-C ₄ alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyls. The alkyl group may be substituted or unsubstituted.

[0133] As used herein,“alkenyl” refers to an alkyl group, as defined herein, that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group may be unsubstituted or substituted.

[0134] As used herein,“alkynyl” refers to an alkyl group as defined herein, that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group may be unsubstituted or substituted.

[0135] As used herein,“cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0136] As used herein,“cycloalkenyl” refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be“aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl group may be unsubstituted or substituted.

[0137] As used herein,“cycloalkynyl” refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more triple bonds in at least one ring. If there is more than one triple bond, the triple bonds cannot form a fully delocalized pi-electron system throughout all the rings. When composed of two or more rings, the rings may be joined together in a fused fashion. A cycloalkynyl group may be unsubstituted or substituted.

[0138] As used herein,“carbocyclyl” or“cyclic hydrocarbyl” refers to all carbon ring systems. Such systems can be unsaturated, can include some unsaturation, or can contain some aromatic portion, or be all aromatic. Carbocyclyl group can contain from 3 to 30 carbon atoms. A carbocyclyl group may be unsubstituted or substituted.

[0139] As used herein,“aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including, e.g., fused, bridged, or spiro ring systems where two carbocyclic rings share a chemical bond, e.g., one or more aryl rings with one or more aryl or non aryl rings) that has a fully delocalized pi-electron system throughout at least one of the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C6-C14 aryl group, a C6-C10 aryl group, or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. An aryl group may be substituted or unsubstituted.

[0140] As used herein,“heterocyclyl” refers to mono- or polycyclic ring systems including at least one heteroatom (e.g., O, N, S). Such systems can be unsaturated, can include some unsaturation, or can contain some aromatic portion, or be all aromatic. A heterocyclyl group can contain from 3 to 30 atoms. A heterocyclyl group may be unsubstituted or substituted.

[0141] As used herein,“heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring system having a least one ring with a fully delocalized pi-electron system) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen, and sulfur, and at least one aromatic ring. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, l,2,3-oxadiazole, l,2,4-oxadiazole, thiazole, 1,2,3- thiadiazole, l,2,4-thiadiazole, benzothi azole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. A heteroaryl group may be substituted or unsubstituted.

[0142] As used herein,“heteroalicyclic” or“heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to l8-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatoms are independently selected from oxygen, sulfur, and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heteroalicyclic may be quaternized. Heteroalicyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such “heteroalicyclic” or“heteroalicyclyl” groups include but are not limited to, 1,3 -dioxin, 1,3- dioxane, l,4-dioxane, l,2-dioxolane, l,3-dioxolane, l,4-dioxolane, l,3-oxathiane, l,4-oxathiin, l,3-oxathiolane, l,3-dithiole, l,3-dithiolane, l,4-oxathiane, tetrahydro-l,4-thiazine, 2H-l,2- oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-l,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine A -oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4- piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, 3,4- methylenedioxyphenyl).

[0143] “Lower alkylene groups” are straight-chained -CEE- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Lower alkylene groups contain from 1 to 6 carbon atoms. Examples include but are not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene

(-CH2CH2CH2CH2-). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of “substituted.”

[0144] As used herein,“aralkyl” and“aryl(alkyl)” refer to an aryl group, as defined above, connected, as a substituent, via a lower alkylene group, as described above. The lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0145] As used herein,“heteroaralkyl” and“heteroaryl(alkyl)” refer to a heteroaryl group , as defined above, connected, as a substituent, via a lower alkylene group, as defined above. The lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3 -thienyl alkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and their benzo-fused analogs. [0146] A“(heteroalicyclyl)alkyl” is a heterocyclic or a heteroalicyclylic group, as defined above, connected, as a substituent, via a lower alkylene group, as defined above. The lower alkylene and heterocyclic or a heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited to tetrahydro-2H-pyran-4-yl)methyl, (piperidin-4-yl)ethyl, (piperidin-4-yl)propyl, (tetrahydro-2H-thiopyran-4-yl)methyl, and (1,3- thiazinan-4-yl)m ethyl.

[0147] As used herein,“alkoxy” refers to the formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl or a cycloalkynyl, as defined above. A non limiting list of alkoxys is methoxy, ethoxy, n-propoxy, l-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. An alkoxy may be substituted or unsubstituted.

[0148] As used herein,“acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl, as defined above, connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted.

[0149] As used herein,“hydroxy alkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxy ethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2- dihydroxy ethyl. A hydroxyalkyl may be substituted or unsubstituted.

[0150] As used herein,“haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen ( e.g ., mono-haloalkyl, di-haloalkyl, and tri- haloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and l-chloro-2-fluorom ethyl, 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.

[0151] As used herein,“haloalkoxy” refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri- haloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and l-chloro-2-fluoromethoxy, 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

[0152] As used herein,“aryloxy” and“arylthio” refers to RO- and RS-, in which R is an aryl, as defined above, such as but not limited to phenyl. Both an aryloxy and arylthio may be substituted or unsubstituted.

[0153] A“sulfenyl” group refers to an“-SR” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. A sulfenyl may be substituted or unsubstituted.

[0154] A“sulfmyl” group refers to an“-S(=0)-R” group in which R can be the same as defined with respect to sulfenyl. A sulfmyl may be substituted or unsubstituted. [0155] A“sulfonyl” group refers to an“SO2R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.

[0156] An“O-carboxy” group refers to a“RC(=0)0-” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. An O-carboxy may be substituted or unsubstituted.

[0157] The terms“ester” and“C-carboxy” refer to a“-C(=0)0R” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.

[0158] A“thiocarbonyl” group refers to a“-C(=S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.

[0159] A“trihalomethanesulfonyl” group refers to an“X ₃ CS02-“ group wherein X is a halogen.

[0160] A“trihalomethanesulfonamido” group refers to an“X3CS(0)2N(RA)-” group wherein X is a halogen and RA hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl.

[0161] The term“amino” as used herein refers to a -NH2 group.

[0162] As used herein, the term“hydroxy” refers to a -OH group.

[0163] A“cyano” group refers to a“-CN” group.

[0164] The term“azido” as used herein refers to a -N3 group.

[0165] An“isocyanato” group refers to a“-NCO” group.

[0166] A“thiocyanato” group refers to a“-CNS” group.

[0167] An“isothiocyanato” group refers to an“-NCS” group.

[0168] A“mercapto” group refers to an“-SH” group.

[0169] A“carbonyl” group refers to a C=0 group.

[0170] An“S-sulfonamido” group refers to a“-S02N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. An S-sulfonamido may be substituted or unsubstituted.

[0171] An“N-sulfonamido” group refers to a“RS02N(RA)-“ group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. An N-sulfonamido may be substituted or unsubstituted.

[0172] An“O-carbamyl” group refers to a“-OC(=0)N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. An O-carbamyl may be substituted or unsubstituted.

[0173] An“N-carbamyl” group refers to an“R0C(=0)N(RA) -“ group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. An N-carbamyl may be substituted or unsubstituted.

[0174] An“O-thiocarbamyl” group refers to a“-OC(=S)-N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. An O-thiocarbamyl may be substituted or unsubstituted.

[0175] An“N-thiocarbamyl” group refers to an“ROC(=S)N(RA)-“ group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. An N-thiocarbamyl may be substituted or unsubstituted.

[0176] A“C-amido” group refers to a“-C(=0)N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. A C-amido may be substituted or unsubstituted.

[0177] An“N-amido” group refers to a“RC(=0)N(RA)-“ group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. An N-amido may be substituted or unsubstituted.

[0178] A“urea” group refers to a“-N(RARB)-C(=0)-N(RARB)-” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. A urea group may be substituted or unsubstituted.

[0179] A“thiourea” group refers to a“-N(RARB)-C(=S)-N(RARB)-” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. A thiourea group may be substituted or unsubstituted.

[0180] The term“halogen atom” or“halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine, and iodine.

[0181] In all of the definitions described herein, the terms used to define a new term are as previously defined herein. [0182] Where the numbers of substituents is not specified ( e.g ., haloalkyl), there may be one or more substituents present. For example“haloalkyl” may include one or more of the same or different halogens. As another example,“C1-C3 alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two, or three atoms.

[0183] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 11 :942-944 (1972)).

[0184] The terms“protecting group” and“protecting groups” as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unwanted chemical reactions. Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis , 3. Ed. John Wiley & Sons, 1999, and in J.F.W. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, both of which are hereby incorporated by reference for the limited purpose of disclosing suitable protecting groups. The protecting group moiety may be chosen in such a way, that they are stable to certain reaction conditions and readily removed at a convenient stage using methodology known from the art. A non-limiting list of protecting groups include benzyl; substituted benzyl; alkylcarbonyls (e.g, t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls (e.g, benzyloxycarbonyl or benzoyl); substituted methyl ether (e.g, methoxymethyl ether); substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyl ethers (e.g, trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, or t- butyldiphenylsilyl); esters (e.g, benzoate ester); carbonates (e.g, methoxymethylcarbonate); sulfonates (e.g, tosylate or mesylate); acyclic ketal (e.g, dimethyl acetal); cyclic ketals (e.g, 1,3- dioxane or l,3-dioxolanes); acyclic acetal; cyclic acetal; acyclic hemiacetal; cyclic hemiacetal; cyclic dithioketals (e.g, l,3-dithiane or l,3-dithiolane); and triarylmethyl groups (e.g, trityl; monomethoxytrityl (MMTr); 4,4’-dimethoxytrityl (DMTr); or 4,4’,4”-trimethoxytrityl (TMTr)).

[0185] “Leaving group” as used herein refers to any atom or moiety that is capable of being displaced by another atom or moiety in a chemical reaction. More specifically, in some embodiments,“leaving group” refers to the atom or moiety that is displaced in a nucleophilic substitution reaction. In some embodiments,“leaving groups” are any atoms or moieties that are conjugate bases of strong acids. Examples of suitable leaving groups include, but are not limited to, tosylates and halogens. Non-limiting characteristics and examples of leaving groups can be found, for example in Organic Chemistry , 2d ed., Francis Carey (1992), pages 328-331; Introduction to Organic Chemistry , 2d ed., Andrew Streitwieser and Clayton Heathcock (1981), pages 169-171; and Organic Chemistry , 5 ^th ed., John McMurry (2000), pages 398 and 408; all of which are incorporated herein by reference for the limited purpose of disclosing characteristics and examples of leaving groups.

[0186] The term“pharmaceutically acceptable salt” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid ( e.g hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic acid, acetic acid (AcOH), propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid, fumaric acid, trifluoroacetic acid (TFA), benzoic acid, cinnamic acid, mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluensulfonic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, 1,2- ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2- naphthalenesulfonic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a lithium, sodium or a potassium salt, an alkaline earth metal salt, such as a calcium, magnesium or aluminum salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D- glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, and salts with amino acids such as arginine and lysine; or a salt of an inorganic base, such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, or the like.

[0187] The term“solvate” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to mean that the solvent is complexed with a compound in a reproducible molar ratio, including, but not limited to, 0.5: 1, 1 : 1, or 2: 1. Thus, the term“pharmaceutically acceptable solvate,” refers to a solvate wherein the solvent is one that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.

[0188] The term“prodrug” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a compound or a pharmaceutical composition that can be administered to a patient in a less active or inactive form, which can then be metabolized in vivo into a more active metabolite. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0189] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, or may be stereoisomeric mixtures, and include all diastereomeric, and enantiomeric forms. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.

[0190] Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.

[0191] Wherever a substituent is depicted as a di -radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated. Thus, for example, a substituent depicted as -AE- or includes the substituent being oriented such that the A is attached at the leftmost attachment point of the molecule as well as the case in which A is attached at the rightmost attachment point of the molecule.

[0192] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens and/or deuteriums.

[0193] It is understood that the compounds described herein can be labeled isotopically or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0194] It is understood that the methods and formulations described herein include the use of crystalline forms, amorphous phases, and/or pharmaceutically acceptable salts, solvates, hydrates, and conformers of compounds of preferred embodiments, as well as metabolites and active metabolites of these compounds having the same type of activity. A conformer is a structure that is a conformational isomer. Conformational isomerism is the phenomenon of molecules with the same structural formula but different conformations (conformers) of atoms about a rotating bond. In specific embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Other forms in which the compounds of preferred embodiments can be provided include amorphous forms, milled forms and nano particulate forms.

[0195] Likewise, it is understood that the compounds described herein, such as compounds of preferred embodiments, include the compound in any of the forms described herein ( e.g pharmaceutically acceptable salts, prodrugs, crystalline forms, amorphous form, solvated forms, enantiomeric forms, tautomeric forms, and the like).

Additional Therapeutic Agents

[0196] Some embodiments provide pharmaceutical compositions comprising a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing and a pharmaceutically acceptable carrier. Some embodiments provide pharmaceutical compositions comprising a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing, a pharmaceutically acceptable carrier, and a second therapeutic agent. Some embodiments provide methods of inhibiting cytokine activity, comprising contacting a cell with a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. Some embodiments provide methods of inhibiting cytokine activity, comprising contacting a cell with a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing in combination with a second therapeutic agent. Some embodiments provide methods of treating, ameliorating, or preventing a disease, disorder, or condition associated with cytokines, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. Some embodiments provide methods of treating, ameliorating, or preventing a disease, disorder, or condition associated with cytokines, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing with a second therapeutic agent.

[0197] In some embodiments, the second therapeutic agent is an anti-inflammatory agent. In some embodiments, the second therapeutic agent is a non-steroidal anti-inflammatory agent. In some embodiments, the second therapeutic agent is an anti-cancer agent. In some embodiments, the second therapeutic agent is an immunostimulatory agent. In some embodiments, the second therapeutic agent is an immunosuppressive agent. In some embodiments, the second therapeutic agent is an antibody.

[0198] In some embodiments, the second therapeutic agent is selected from aspirin; diflunisal; salsalate; acetaminophen; ibuprofen; dexibuprofen; naproxen; fenoprofen; ketoprofen; dexketoprofen; flurbiprofen; oxaprozin; loxoprofen; indomethacin; tolmetin; sulindac; etodolac; ketorolac; diclofenac; aceclofenac; nabumetone; enolic acid; piroxicam; meloxicam; tenoxicam; droxicam; lomoxicam; isoxicam; mefenamic acid; meclofenamic acid; flufenamic acid; tolfenamic acid; sulfonanilides; clonixin; licofelone; dexamethasone; and prednisone. In some embodiments, the second therapeutic agent is selected from mechlorethamine; cyclophosphamide; melphalan; chlorambucil; ifosfamide; busulfan; N-nitroso-N-methylurea (MNU); carmustine (BCNU); lomustine (CCNU); semustine (MeCCNU); fotemustine; streptozotocin; dacarbazine; mitozolomide; temozolomide; thiotepa; mytomycin; diaziquone (AZQ); cisplatin; carboplatin; and oxaliplatin. In some embodiments, the second therapeutic agent is selected from vincristine; vinblastine; vinorelbine; vindesine; vinflunine; paclitaxel; docetaxel; etoposide; teniposide; tofacitinib; ixabepilone; irinotecan; topotecan; camptothecin; doxorubicin; mitoxantrone; and teniposide. In some embodiments, the second therapeutic agent is selected from actinomycin; bleomycin; plicamycin; mitomycin; daunorubicin; epirubicin; idarubicin; pirarubicin; aclarubicin; mitoxantrone; cyclophosphamide; methotrexate; 5-fluorouracil; prednisolone; folinic acid; methotrexate; melphalan; capecitabine; mechlorethamine; uramustine; melphalan; chlorambucil; ifosfamide; bendamustine; 6-mercaptopurine; and procarbazine. In some embodiments, the second therapeutic agent is selected from cladribine; pemetrexed; fludarabine; gemcitabine; hydroxyurea; nelarabine; cladribine; clofarabine; ytarabine; decitabine; cytarabine; cytarabine liposomal; pralatrexate; floxuridine; fludarabine; colchicine; thioguanine; cabazitaxel; larotaxel; ortataxel; tesetaxel; aminopterin; pemetrexed; pralatrexate; raltitrexed; pemetrexed; carmofur; and floxuridine. In some embodiments, the second therapeutic agent is selected from azacitidine; decitabine; hydroxycarbamide; topotecan; irinotecan; belotecan; teniposide; aclarubicin; epirubicin; idarubicin; amrubicin; pirarubicin; valrubicin; zorubicin; mitoxantrone; pixantrone; mechlorethamine; chlorambucil; prednimustine; uramustine; estramustine; carmustine; lomustine; fotemustine; nimustine; ranimustine; carboquone; thioTEPA; triaziquone; and triethylenemelamine. In some embodiments, the second therapeutic agent is selected from nedaplatin; satraplatin; procarbazine; dacarbazine; temozolomide; altretamine; mitobronitol; pipobroman; actinomycin; bleomycin; plicamycin; aminolevulinic acid; methyl aminolevulinate; efaproxiral; talaporfm; temoporfm; verteporfm; alvocidib; seliciclib; palbociclib; bortezomib; carfilzomib; anagrelide; masoprocol; olaparib; belinostat; panobinostat; romidepsin; vorinosta; idelalisib; atrasentan; bexarotene; testolactone; amsacrine; trabectedin; alitretinoin; tretinoin; demecolcine; elsamitrucin; etoglucid; lonidamine; lucanthone; mitoguazone; mitotane; oblimersen; omacetaxine mepesuccinate; and eribulin. In some embodiments, the second therapeutic agent is selected from azathioprine; Mycophenolic acid; leflunomide; teriflunomide; tacrolimus; cyclosporin; pimecrolimus; abetimus; gusperimus; lenalidomide; pomalidomide; thalidomide; anakinra; sirolimus; everolimus; ridaforolimus; temsirolimus; umirolimus; zotarolimus; eculizumab; adalimumab; afelimomab; certolizumab pegol; golimumab; infliximab; nerelimomab; mepolizumab; omalizumab; faralimomab; elsilimomab; lebrikizumab; ustekinumab; etanercept; otelixizumab; teplizumab; visilizumab; clenoliximab; keliximab; zanolimumab; efalizumab; erlizumab; obinutuzumab; rituximab; and ocrelizumab. In some embodiments, the second therapeutic agent is selected from pascolizumab; gomiliximab; lumiliximab; teneliximab; toralizumab; aselizumab; galiximab; gavilimomab; ruplizumab; belimumab; blisibimod; ipilimumab; tremelimumab; bertilimumab; lerdelimumab; metelimumab; natalizumab; tocilizumab; odulimomab; basiliximab; daclizumab; inolimomab; zolimoma; atorolimumab; cedelizumab; fontolizumab; maslimomab; morolimumab; pexelizumab; reslizumab; rovelizumab; siplizumab; talizumab; telimomab; vapaliximab; vepalimomab; abatacept; belatacept; pegsunercept; aflibercept; alefacept; and rilonacept.

Pharmaceutical Compositions

Parenteral Pharmaceutical Composition

[0199] To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous, or the like), 0.1 mg to 100 mg of a water-soluble salt/soluble material itself/solubilized complex of a compound described herein is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.

Injectable Pharmaceutical Composition

[0200] To prepare an injectable formulation, 0.1 mg to 100 mg of a compound of Formula (I) or (II), 2.0 mL of sodium acetate buffer solution (0.4 M), HC1 (1 N) or NaOH (1 M) (q.s. to suitable pH), water (distilled, sterile) (q.s. to 20 mL) are mixed. All of the above ingredients, except water, are combined and stirred and if necessary, with slight heating if necessary. A sufficient quantity of water is then added.

Oral Pharmaceutical Composition

[0201] To prepare a pharmaceutical composition for oral delivery, 0.1 mg to 100 mg of a compound of Formula (I) or (II) is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, or 0.1 mg to 100 mg of compound is granulated with binder solution such as starch solution along with suitable diluents such as microcrystalline cellulose or like, disintegrants such as croscaramellose sodium, dry the resultant mixture and add lubricant and compress into tablet which is suitable for oral administration.

Sublingual (Hard Lozenge) Pharmaceutical Composition

[0202] To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, 0.1 mg to 100 mg of a compound of Formula (I) or (II) is mixed with 420 mg of powdered sugar/mannitol/xylitol or such sugars that provide negative heat of solution to the system, 1.6 mL of light com syrup, 2.4 mL distilled water, and 0.42 mL mint extract or other flavorants. The mixture is blended and poured into a mold to form a lozenge suitable for buccal administration.

Fast-Disintegrating Sublingual Tablet

[0203] A fast-disintegrating sublingual tablet is prepared by mixing 48.5% by weigh of a compound of Formula (I) or (II) 20% by weight of microcrystalline cellulose (KG-802), 24.5% by weight of either mannitol or modified dextrose or combination that help dissolve the compressed tablet faster in the mouth, 5% by weight of low- substituted hydroxypropyl cellulose (50 pm), and 2% by weight of magnesium stearate. Tablets are prepared by direct compression (AAPS PharmSciTech. 2006; 7(2):E4l). The total weight of the compressed tablets is maintained at 150 mg. The formulation is prepared by mixing the amount of the compound of a preferred embodiment with the total quantity of microcrystalline cellulose (MCC) and mannitol/modified dextrose or combination, and two-thirds of the quantity of low- substituted hydroxypropyl cellulose (L-HPC) by using a three dimensional manual mixer (Inversina®, Bioengineering AG, Switzerland) for 4.5 minutes. All of the magnesium stearate (MS) and the remaining one-third of the quantity of L-HPC are added 30 seconds before the end of mixing. Inhalation Pharmaceutical Composition

[0204] To prepare a pharmaceutical composition for inhalation delivery, 0.1 mg to 100 mg of a compound of Formula (I) or (II) is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.

Nebulizer Suspension Pharmaceutical Composition

[0205] In another embodiment, a compound of Formula (I) or (II) (0.1 mg to 100 mg) is suspended in sterile water (100 mL); Span 85 (1 g) is added followed by addition of dextrose (5.5 g) and ascorbic acid (10 mg). Benzalkonium chloride (3 mL of a 1 :750 aqueous solution) is added and the pH is adjusted to 7 with phosphate buffer. The suspension is packaged in sterile nebulizers.

Transdermal Patch Pharmaceutical Composition

[0206] To prepare a pharmaceutical composition for transdermal delivery, 0.1 mg to 100 mg of a compound of Formula (I) or (II) is embedded in, or deposited on, a patch with a single adhesive face. The resulting patch is then attached to the skin via the adhesive face for transdermal administration.

Topical Gel Pharmaceutical Composition

[0207] To prepare a pharmaceutical topical gel composition, 0.1 mg to 100 mg of a compound of Formula (I) or (II) is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.

Ophthalmic Solution

[0208] To prepare a pharmaceutical ophthalmic solution composition, 0.1 mg to 100 mg of a compound of Formula (I) or (II) is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.

Nasal Spray Solution

[0209] To prepare a pharmaceutical nasal spray solution, 0.1 mg to 100 mg of a compound of Formula (I) or (II) is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 pl of spray for each application.

Dosing Regimes [0210] In some embodiments, about 1 mg to about 5 grams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each day. In some embodiments, about 2 mg to about 2 grams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each day. In some embodiments, about 5 mg to about 1 gram of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each day. In some embodiments, about 10 mg to about 800 milligrams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each day. In some embodiments, about 20 mg to about 600 milligrams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each day. In some embodiments, about 30 mg to about 400 milligrams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each day. In some embodiments, about 40 mg to about 200 milligrams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each day. In some embodiments, about 50 mg to about 100 milligrams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each day.

[0211] In some embodiments, about 1 mg to about 5 grams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each week. In some embodiments, about 2 mg to about 2 grams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each week. In some embodiments, about 5 mg to about 1 gram of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each week. In some embodiments, about 10 mg to about 800 milligrams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each week. In some embodiments, about 20 mg to about 600 milligrams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each week. In some embodiments, about 30 mg to about 400 milligrams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each week. In some embodiments, about 40 mg to about 200 milligrams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each week. In some embodiments, about 50 mg to about 100 milligrams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each week.

[0212] In some embodiments, about 1 mg to about 5 grams of a compound of Formula

(I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each cycle of treatment. In some embodiments, about 2 mg to about 2 grams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each cycle of treatment. In some embodiments, about 5 mg to about 1 gram of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each cycle of treatment. In some embodiments, about 10 mg to about 800 milligrams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each cycle of treatment. In some embodiments, about 20 mg to about 600 milligrams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each cycle of treatment. In some embodiments, about 30 mg to about 400 milligrams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each cycle of treatment. In some embodiments, about 40 mg to about 200 milligrams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each cycle of treatment. In some embodiments, about 50 mg to about 100 milligrams of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each cycle of treatment.

[0213] In some embodiments, a compound of Formula (I), a compound of Formula

(II), or a pharmaceutically acceptable salt of any of the foregoing is administered at least once per day. In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered at least twice per day. In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered at least three times per day. In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered at least four times per day.

[0214] In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered at least once per week. In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered at least twice per week. In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered at least three times per week. In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered at least four times per week.

[0215] In some embodiments, each cycle of treatment lasts 1 day. In some embodiments, each cycle of treatment lasts 2 days. In some embodiments, each cycle of treatment lasts 3 days. In some embodiments, each cycle of treatment lasts 4 days. In some embodiments, each cycle of treatment lasts 5 days. In some embodiments, each cycle of treatment lasts 6 days. In some embodiments, each cycle of treatment lasts 7 days. In some embodiments, each cycle of treatment lasts 8 days. In some embodiments, each cycle of treatment lasts 9 days. In some embodiments, each cycle of treatment lasts 10 days. In some embodiments, each cycle of treatment lasts 11 days. In some embodiments, each cycle of treatment lasts 12 days. In some embodiments, each cycle of treatment lasts 13 days. In some embodiments, each cycle of treatment lasts 14 days.

[0216] In some embodiments, each cycle of treatment has at least one day between administrations of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, each cycle of treatment has at least two days between administrations of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, each cycle of treatment has at least three days between administrations of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, each cycle of treatment has at least four days between administrations of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, each cycle of treatment has at least five days between administrations of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, each cycle of treatment has at least six days between administrations of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, each cycle of treatment has at least seven days between administrations of a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing.

[0217] In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is provided intravenously over about 10 minutes. In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is provided intravenously over about 20 minutes. In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is provided intravenously over about 30 minutes. In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is provided intravenously over about 1 hour. In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is provided intravenously over about 1.5 hours. In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is provided intravenously over about 2 hours. In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is provided intravenously over about 2.5 hours. In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is provided intravenously over about 3 hours. In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is provided intravenously over about 3.5 hours. In some embodiments, a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is provided intravenously over about 4 hours.

EXAMPLES

[0218] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.

[0219] Characterization of the compounds disclosed herein was performed with Bruker AV-500 and Bruker DRX-500 NMR spectrometers and a Perkin Elmer PE-SCIEX API- 150 mass spectrometer.

Example 1. General Synthesis

Scheme 1

1.1a : Q = H 1.2a : Q = H

1.1 b : Q = Protecting group 1.2b : Q = Protecting group

[0220] To a solution of compound 1.1a in an organic solvent (for example, THF), at a cooled temperature, such as 0°C, is added a base (for example, NaH or nBuLi). After sufficient time for reaction, such as 20 min, a deuterium source (for example, D2O) is added. After sufficient time for reaction, such as 20 min, the reaction is diluted with an organic solvent, (for example, ethyl acetate), and extracted with H2O. The organic phase is washed with brine, dried using a drying agent, such as MgSCri, filtered and concentrated under vacuum to provide crude compound 1.2a. The crude mixture is purified by chiral HPLC to isolate R-enantiomer 1.3 and S-enantiomer 1.4

[0221] To a solution of compound 1.1b in an organic solvent (for example, THF), at a cooled temperature, such as 0°C, is added a base (for example, NaH or nBuLi). After sufficient time for reaction, such as 20 min, a deuterium source (for example, D2O) is added. After sufficient time for reaction, such as 20 min, the reaction is diluted with an organic solvent, (for example, ethyl acetate), and extracted with H2O. The organic phase is washed with brine, dried using a drying agent, such as MgSCri, filtered and concentrated under vacuum to provide crude compound 1.2b. The crude material is subjected to conditions to remove the protecting group Q (for example, a Boc, acetyl, or Fmoc group). After sufficient time for reaction, such as 60 min, the reaction is diluted with an organic solvent, (for example, ethyl acetate), and extracted with H2O. The organic phase is washed with brine, dried using a drying agent, such as MgSCri, filtered and concentrated under vacuum. The crude mixture is purified by chiral HPLC to isolate R-enantiomer 1.3 and S- enantiomer 1.4. Scheme 2

[0222] To a solution of compound 2.1 in an organic solvent, (for example, THF), at a cooled temperature, such as 0°C, is added a base (for example, NaH or nBuLi). After sufficient time for reaction, such as 20 min, a deuterium source (for example, D2O) is added. After sufficient time for reaction, such as 20 min, the reaction is diluted with an organic solvent, such as ethyl acetate, and extracted with H2O. The organic phase is washed with brine, dried using a drying agent, such as MgSCri, filtered and concentrated under vacuum. The crude mixture is purified by chiral HPLC to isolate R-enantiomer 2.2 and S-enantiomer 2.3.

[0223] One enantiomer, either compound 2.3 (shown above) or compound 2.2, is dissolved in an organic solvent, such as fluorobenzene or ACN. To this solution is added, wet DMSO, followed by an oxidizing agent (for example, Dess-Martin periodinane or Mn02), and the reaction mixture heated to an elevated temperature, such as 80°C. After sufficient time for reaction, such as 18 hours, the reaction is quenched with saturated Na2S20 ₄ and extracted with an organic solvent, such as DCM. The organic phase is washed with brine, dried using a drying agent, such as MgS0 ₄ , filtered and concentrated under vacuum. The crude mixture is purified by reverse phase HPLC to provide compound 2.4.

Scheme 3

[0224] To a solution of compound 3.1 in an organic solvent (for example, dioxane) at RT is added B0C2O, and a base, such as DMAP. After sufficient time for reaction, such as 18 hours, the reaction is diluted with an organic solvent, such as ethyl acetate, and extracted with H2O. The organic phase is washed with brine, dried using a drying agent, such as MgSCri, filtered and concentrated under vacuum to provide compound 3.2.

[0225] To a solution of compound 3.2 in an organic solvent (for example, THF), at a cooled temperature, such as 0 °C, is added a base (for example, NaH or nBuLi). After sufficient time for reaction, such as 20 min, a deuterium source (for example, D2O) is added. After sufficient time for reaction, such as 20 min, the reaction is diluted with an organic solvent, such as ethyl acetate, and extracted with H2O. The organic phase is washed with brine, dried using a drying agent, such as MgSCri, filtered and concentrated under vacuum. The residue is then subjected to acidic conditions sufficient to remove the Boc group. After sufficient time for reaction, such as 60 min, the reaction is diluted with an organic solvent, such as ethyl acetate, and extracted with H2O. The organic phase is washed with brine, dried using a drying agent, such as MgSCri, filtered and concentrated under vacuum. The crude mixture is purified by chiral HPLC to isolate R- enantiomer 3.3 and S-enantiomer 3.4.

Example 2 Compound 1 : fV)-3- /-3-(4-isopropyl- l -oxoisoindolin-2-yl )azepane-2.7-dione

[0226] To a solution of methyl 3-iodo-2-methylbenzoate (5.20 g, 18.8 mmol) in CCI4 (90 mL) at RT was added N-bromosuccinimide (NBS) (4.02 g, 22.6 mmol) then the reaction flask was purged with N2. After the mixture was stirred at 85 °C for 5 m, 2,2’-azobis(2- methylpropionitrile) (AIBN) (1.62 g, 9.42 mmol) was added. The mixture was stirred overnight at 85 °C then concentrated. The residue was diluted with H2O and extracted with EtOAc. The organic phase was dried over Na2S0 ₄ , filtered, and concentrated to give the crude product, which was purified using silica gel eluting with EtOAc in petroleum ether from 0% to 1% to afford methyl 2-(bromomethyl)-3-iodobenzoate (2.64 g, 40% yield) as a solid.

[0227] To a solution of (ri)-3 -amino-3 -<i-azepan-2-one (450.6 mg, 3.493 mmol) in DMF (12 mL) at 0 °C was added TEA (803.2 mg, 7.938 mmol) and methyl 2-(bromomethyl)-3- iodobenzoate (1.13 g, 3.175 mmol). The mixture was stirred at RT overnight then concentrated, and the residue was purified using silica gel eluting with MeOH in DCM (0% to 5%) to give ( S )- 2-(3-7-2-oxoazepan-3-yl)-4-iodoisoindolin-l-one (986 mg, 84% yield) as a solid. MS (ESI) m/z = 372 [M+H] ⁺ .

[0228] To a solution of S)-2-(3-7-2-oxoazepan-3-yl)-4-iodoisoindolin-l-one (400 mg, 1.08 mmol) in toluene/EhO (10: 1) was added 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2- dioxaborolane (271.7 mg, 1.617 mmol) and K2CO3 (371.9 mg, 2.695 mmol). The reaction flask was purged with N2, and Pd(dppf)Cl2 (315.5 mg, 0.4312 mmol) was added. The suspension was heated at 100 °C overnight then concentrated. The residue was diluted with H2O and extracted with DCM. The organic phase was dried over Na2S0 ₄ , filtered, and concentrated. The crude product was purified using silica gel eluting with EtOAc in petroleum (10% to 80%) to give ( S )- 2-(3-7-2-oxoazepan-3-yl)-4-(prop-l-en-2-yl)isoindolin-l-one (191 mg, 62% yield) as a solid. MS (ESI) m/z = 286 [M+H] ⁺ .

[0229] To a solution of S)-2-(3-7-2-oxoazepan-3-yl)-4-(prop-l-en-2-yl)isoindolin-l- one (191 mg, 0.67 mmol) in MeOH (3 mL) at RT was added Pd/C (100 mg). The mixture was stirred at RT under Eb for 12 h. The mixture was filtered, and the filtrate was concentrated to give (A)-2-(3-7-2-oxoazepan-3-yl)-4-isopropylisoindolin-l-one (180 mg, yield: 94% yield) as a solid. MS (ESI) m/z = 288 [M+H] ⁺ .

[0230] To a solution of (A)-2-(3-7-2-oxoazepan-3-yl)-4-isopropylisoindolin-l-one (180 mg, 0.627 mmol) in fluorobenzene (12 mL), DMSO (2 mL), and 1 drop of H2O at 0 °C was added Dess-Martin reagent (665 mg, 1.57 mmol). The mixture was stirred at 80 °C overnight then cooled to RT. Saturated Na2S203 solution (15 mL) was added and allowed to stir for 5 m. The mixture was extracted with DCM and the organic phase was washed with 10% aq. Na2S2Ch / aq. NaElCCh (1 : 1 mixture) (20 mL) then brine. The organic layer was dried over Na2S0 ₄ , filtered, and concentrated to afford the crude product, which was purified using silica gel eluting with EtOAc in petroleum (10% to 85%) to give Compound 1 (58.3 mg, 31% yield) as a solid. ¾ NMR (400 MHz, DMSO-de) d 10.70 (s, 1 H), 7.56-7.46 (m, 3 H), 4.55 (s, 2 H), 3.12-2.99 (m, 2 H), 2.58 (d, J= 16.8 Hz, 1 H), 2.36-2.32 (m, 1 H), 2.14-2.02 (m, 2 H), 1.85-1.80 (m, 1 H), 1.26 (d, 7= 6.8 Hz, 6 H). MS (ESI) m/z = 302 [M+H] ⁺ .

Example 3 Compound 2: (y)-3-7-3-(4-cvclopentyl-l-oxoisoindolin-2-vDazepane-2.7-dio ne

[0231] To a solution of S)-2-(3-7-2-oxoazepan-3-yl)-4-iodoisoindolin-l-one (180 mg, 0.485 mmol) in toluene/H20 (5mL/0.5 mL) was added 2-(cyclopent-l-en-l-yl)-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (188.2 mg, 0.9703 mmol) and K2CO3 (200.8 mg, 1.455 mmol). The reaction flask was purged with N2, and Pd(dppf)Cl2 (142 mg, 0.194 mmol) was added. The suspension was heated at 100 °C overnight then cooled to RT and concentrated. The residue was diluted with H2O and extracted with DCM. The organic phase was dried over Na2S0 ₄ , filtered, and concentrated. The crude product was purified using silica gel eluting with EtOAc in petroleum (10% to 80%) to give fV)-2-(3-6/-2-oxoazepan-3-yl)-4-(cyclopent- 1 -en- 1 -yl)isoindolin- l-one (91 mg, 60% yield) as a solid. MS (ESI) m/z = 312 [M+H] ⁺ .

[0232] To a solution of fV)-2-(3-6/-2-oxoazepan-3-yl)-4-(cyclopent- l -en- 1 - yl)isoindolin-l-one (91 mg, 0.29 mmol) in MeOH (3 mL) at RT was added Pd/C (100 mg). The mixture was stirred under Eb at RT for 12 h. The mixture was filtered, and the filtrate was concentrated to give (ri)-2-(3-<7-2-oxoazepan-3-yl)-4-cyclopentylisoindolin-l- one (90 mg, 98% yield) as an oil-solid. MS (ESI) m/z = 314 [M+H] ⁺ .

[0233] To a solution of fV)-2-(3-6/-2-oxoazepan-3-yl)-4-cyclopentylisoindolin- l -one (90 mg, 0.29 mmol) in fluorobenzene (6 mL), DMSO (1 mL), and 1 drop of H2O at 0 °C was added Dess-Martin reagent (304.9 mg, 0.7188 mmol). The mixture was stirred at 80 °C overnight then cooled to RT. Saturated Na2S203 solution (15 mL) was added and the mixture was stirred for 5 m. The mixture was extracted with DCM and the organic phase was washed with 10% aq. Na2S20s / aq. NaElCCh (1 : 1 mixture) (20 mL) then brine. The organic layer was dried over Na2S0 ₄ , filtered, and concentrated to afford the crude product, which was purified using silica gel eluting with EtOAc in petroleum (10% to 90%) to give Compound 2 (92 mg, 55% yield) as a solid. ¾ NMR (400 MHz, DMSO-de) d 10.73 (s, 1 H), 7.56-7.53 (m, 2 H), 7.48-7.45 (m, 1 H), 4.55 (s, 2 H), 3.12-3.05 (m, 2 H), 2.58 (d, J= 16.8 Hz, 1 H), 2.33-2.32 (m, 1 H), 2.13-2.00 (m, 4 H), 1.81-1.79 (m, 3 H), 1.69-1.58 (m, 4 H). MS (ESI) m/z = 328 [M+H] ⁺ .

Example 4 Compound 3 : 6y)-3-<7-3-(4-cvclopentyl-6-fluoro-l-oxoisoindolin-2-vDaz epane-2.7- dione

[0234] To a solution of methyl 3-bromo-5-fluoro-2-methylbenzoate (3.38 g, 13.7 mmol) in CCl ₄ (40 mL) at RT was added NBS (3.18 g, 17.9 mmol) and the reaction flask was purged with N2. After heating at 85 °C for 5 m, AIBN (1.18 g, 6.87 mmol) was added, and the mixture was heated at 85 °C overnight. The mixture was concentrated, diluted with H2O, and extracted with EtOAc. The organic phase was dried over Na2S0 ₄ , filtered, and concentrated to give the crude product, which was purified using silica gel eluting with EtOAc in petroleum ether (0% to 1%) to give methyl 3-bromo-2-(bromomethyl)-5-fluorobenzoate (3.3 g, 74% yield) as an oil.

[0235] To a solution of (S)-3 -amino-3 -<7-azepan-2-one (225.2 mg, 1.746 mmol) in DMF (8 mL) at 0 °C was added TEA (401.5 mg, 3.968 mmol) and methyl 3-bromo-2- (bromomethyl)-5-fluorobenzoate (516 g, 1.59 mmol). The mixture was stirred at RT overnight then concentrated. The residue was purified using silica gel eluting with MeOH in DCM (0% to 6%) to give (A)-4-bromo-2-(3- ₆ /-2-oxoazepan-3-yl)-6-fluoroisoindolin- l -one (302 mg, 56% yield) as a solid. MS (ESI) m/z = 342 [M+H] ⁺ .

[0236] To a solution of S)-4-bromo-2-(3-<7-2-oxoazepan-3-yl)-6-fluoroisoindolin-l - one (202 mg, 0.5923 mmol) in toluene/EEO (10 mL/l mL) was added 2-(cyclopent-l-en-l-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (138 mg, 0.7108 mmol) and K2CO3 (163.5 mg, 1.185 mmol). The reaction flask was purged with N2 then Pd(dppf)Ch (86.7 mg, 0.119 mmol) was added. The suspension was stirred at 100 °C overnight. The mixture was cooled to RT and concentrated to afford a residue which was diluted with H2O and extracted with DCM. The organic phase was dried over Na2S0 ₄ , filtered, and concentrated. The crude product was purified using silica gel eluting with EtOAc in petroleum (10% to 80%) to give S)-2-(3-<7-2-oxoazepan- 3-yl)-4-(cyclopent-l-en-l-yl)-6-fluoroisoindolin-l-one (166 mg, 83% yield) as a solid. MS (ESI) m/z = 330 [M+H] ⁺ .

[0237] To a solution of (ri)-2-(3-<7-2-oxoazepan-3-yl)-4-(cyclopent-l-en-l-yl)-6- fluoroisoindolin-l-one (246 mg, 0.748 mmol) in MeOH (3 mL) at RT was added Pd/C (200 mg) then the reaction flask was purged with H2. The mixture was stirred at RT for 12 h then filtered, and the filtrate was concentrated to give (ri)-2-(3-<7-2-oxoazepan-3-yl)-4-cyclopentyl-6- fluoroisoindolin-l-one (247.4 mg, quantitative yield) as an oil-solid. MS (ESI) m/z = 332 [M+H] ⁺ .

[0238] To a solution of (ri)-2-(3-<7-2-oxoazepan-3-yl)-4-cyclopentyl-6- fluoroisoindolin-l-one (247 mg, 0.747 mmol) in fluorobenzene (15 mL), DMSO (2.5 mL), and 1 drop of H2O at 0 °C was added Dess-Martin reagent (792.8 mg, 1.869 mmol). The mixture was stirred at 80 °C overnight then cooled to RT. Saturated Na2S203 solution (15 mL) was added and the mixture was stirred for 5 m. The mixture was extracted with DCM and the organic phase was washed with 10% aq. Na.2S20 ₃ / aq. NaHC03 (1 : 1 mixture) (20 mL) then brine. The organic layer was dried over Na2S0 ₄ , filtered, and concentrated to afford the crude product, which was purified using silica gel eluting with EtOAc in petroleum (10% to 65%) to give Compound 3 (174.8 mg, 68% yield) as a solid. ¾ NMR (400 MHz, DMSO-de) d 10.72 (s, 1 H), 7.40-7.31 (m, 2 H), 4.53 (s, 2 H), 3.10-3.04 (m, 2 H), 2.58 (d, J = 16.8 Hz, 1 H), 2.35-2.30 (m, 1 H), 2.13-2.02 (m, 4 H), 1.82-1.80 (m, 3 H), 1.68-1.58 (m, 4 H). MS (ESI) m/z = 346 [M+H] ⁺ .

Example 5 Compound 4: fV)-A ^f -(7c/V-butyl )-3-(Y2-(Y4-i3-i3-(Y2-i3- /-2.7-dioxoazepan-3-yl )- 1 - oxoisoindolin-5-vDmethvDureido)piOpoxy)phenvDamino)-5-methyl pyrimidin-4- vOaminolbenzenesulfonamide

[0239] To a solution of 3-aminoazepan-2-one (10.0 g, 60.95 mmol) in H2O (25 mL) at RT was added NaOH (2.68 g, 67.04 mmol). The mixture was stirred at 0 °C for 5 m then dried by lyophilization. The resulting residue was diluted in AcOD (25 mL) and benzaldehyde (387.6 mg, 3.657 mmol) was added. The mixture was stirred at 65 °C for 10 d then concentrated to afford crude 3 -amino-3 -<7-azepan-2-one, which was used directly in the next step.

[0240] To a solution of 3 -amino-3 -<7-azepan-2-one (7.0 g, 54 mmol) in THF/H2O (80 mL:80 mL) at 0 °C was added NaHCCh (5.0 g, 59.62 mmol). After stirring at 0 °C for 10 m, di- /-butyl decarbonate (13.0 g, 59.6 mmol) was added, and the mixture was stirred at RT overnight. The mixture was concentrated then diluted with H2O and extracted with /-butyl methyl ether. The organic layer was washed with brine, dried over Na2S0 ₄ , filtrated, and concentrated. The residue was purified using silica gel eluting with EtOAc in petroleum (0% to 55%) to give tert-butyl (3- <7-2-oxoazepan-3-yl)carbamate (4.8 g, 39% yield) as a solid. 7er/-butyl (3-<7-2-oxoazepan-3- yl)carbamate was separated by chiral column to afford (ri)-/e/7-butyl (3-<7-2-oxoazepan-3- yl)carbamate (2.0 g) and (R)-ter t-butyl (3 -i/-2-oxoazepan -3 -yl (carbamate (2.1 g).

[0241] To a solution of {S)-tert- butyl (3 -i/-2-oxoazepan-3-yl (carbamate (400 mg, 1.75 mmol) in DCM (3 mL) at 0 °C was added trifluoroacetic acid (TFA) (1 mL). The mixture was stirred at RT for 2.5 h then concentrated to afford (S)-3 -amino-3 -<7-azepan-2-one TFA acid salt as an oil, which was used directly in the next step.

[0242] To a solution of (ri)-3 -amino-3 -<7-azepan-2-one TFA salt (366.1 mg, 2.838 mmol) in DMF (10 mL) at 0 °C was added TEA (598.3 mg, 5.912 mmol) and methyl 2- (bromomethyl)-4-cyanobenzoate (598.3 mg, 2.365 mmol). The mixture was stirred at RT overnight then concentrated. The residue was purified using silica gel eluting with MeOH in DCM (0% to 5%) to give (ri)-2-(3-<7-2-oxoazepan-3-yl)-l-oxoisoindoline-5-carboni trile (340 mg, 53% yield) as a solid. MS (ESI) m/z = 271 [M+H] ⁺ . [0243] To a solution of fV)-2-(3-6/-2-oxoazepan-3-yl)- l -oxoisoindoline-5-carbonitrile (340 mg, 1.259 mmol) in fluorobenzene (18 mL), DMSO (3 mL), and 1 drop of H2O at 0 °C was added Dess-Martin reagent (1.33 g, 3.148 mmol). The mixture was stirred at 80 °C overnight then cooled to RT. Saturated NanS^Cb solution (15 mL) was added and the mixture was stirred for 5 m. The mixture was extracted with DCM and the organic phase was washed with 10% aq. Na2S2.Cb / aq. NaHCCb (1 : 1 mixture) (20 mL) then brine. The organic layer was dried over Na2S0 ₄ , filtered, and concentrated to afford the crude product, which was purified using silica gel eluting with EtOAc in petroleum (10% to 90%) to give fV)-2-(3 -r/-2, 7 -di oxoazepan-3 -y 1 )- 1 - oxoisoindoline-5-carbonitrile (260 mg, 73% yield) as a solid. MS (ESI) m/z = 286 [M+H] ⁺ .

[0244] To a solution of (ri)-2-(3-7-2,7-dioxoazepan-3-yl)-l-oxoisoindoline-5- carbonitrile (260 mg, 0.915 mmol) in THF (20 mL) at RT was added di-tert-butyl dicarbonate (399.1 mg, 1.831 mmol) and Raney-Ni (100 mg). The reaction flask was purged with EL and the mixture was stirred at RT for 16 h. The mixture was filtered, and the filtrate was purified using silica gel eluting with EtOAc in petroleum (10% to 85%) to give (k)-tert-butyl ((2-(3-d-2,7- dioxoazepan-3-yl)-l-oxoisoindolin-5-yl)methyl)carbamate (249 mg, 70% yield) as a solid. MS (ESI) m/z = 391 [M+H] ⁺ .

[0245] To a solution of S)-tert-butyl ((2-(3-r/-2, 7-di oxoazepan-3 -yl)- l -oxoisoindolin- 5-yl)methyl)carbamate (100 mg, 0.258 mmol) in DCM (4 mL) at 0 °C was added 2,2,2- trifluoroacetic acid (1 mL). The mixture was stirred at RT for 1.5 hours. The mixture was concentrated, and the residue was diluted with THF (4 mL), then TEA (52.2 mg, 0.5154 mmol) and 4-nitrophenoxy carbonyl chloride (62.2 mg, 0.309 mmol) was added at 0 °C. The mixture was stirred at RT for 30 m to afford a crude solution of fV)-4-nitrophenyl ((2-(3-d-2J- dioxoazepan-3-yl)-l-oxoisoindolin-5-yl)methyl)carbamate used directly in the next step.

[0246] To a solution of 3-((2-((4-(3-aminopropoxy)phenyl)amino)-5- methylpyrimidin-4-yl)amino)-N-(tert-butyl)benzenesulfonamide (124.7 mg, 0.2577 mmol) in THF (4 mL) at 0°C was dropwise added the above solution of fV)-4-nitrophenyl ((2-(3-d-2,7- dioxoazepan-3-yl)-l-oxoisoindolin-5-yl)methyl)carbamate and additional TEA (208.6 mg, 2.062 mmol). The mixture was stirred at RT for 5 h then concentrated. The residue was purified using silica gel eluting with MeOH in DCM (0% to 9%) to give Compound 4 (34.2 mg, 35% yield) as a solid. ¾ NMR (400 MHz, DMSO-de) d 10.71 (s, 1 H), 8.80 (s, 1 H), 8.55 (s, 1 H), 8.12 (s, 2 H), 7.90 (s, 1 H), 7.66 (d, J= 8.0 Hz, 1 H), 7.58-7.46 (m, 6 H), 7.38 (d, J= 7.6 Hz, 1 H), 6.79 (d, J= 8.8 Hz, 2 H), 6.51 (t, J= 5.2 Hz, 1 H), 6.14 (t, J= 5.2 Hz, 1 H), 4.52-4.42 (m, 2 H), 4.32 (d, J = 5.6 Hz, 2 H), 3.92 (t, J= 6.0 Hz, 2 H), 3.19-3.17 (m, 2 H), 3.06 (t, 7= 13.6 Hz, 1 H), 2.56 (d, J = 17.2 Hz, 1 H), 2.23-2.21 (m, 1 H), 2.11 (s, 3 H), 2.08-1.98 (m, 2 H), 1.85-1.80 (m, 3 H), 1.11 (s, 9 H). MS (ESI) m/z = 799 [M+H] ⁺ . Comparative Compound A: fV)-A ^f -(7cvV-butyl )-3-((2-((4-(3-(3-((2-(2.7-dioxoazepan-3-yl )- 1 - oxoisoindolin-5-vOmethvOureido)propoxy)phenvOamino)-5-methyl pyrimidin-4- vOaminolbenzenesulfonamide

[0247] Compound A is the non-deuterated analog of Compound 4 and included for comparative purposes.

Example 6 Bioactivitv Analysis

Western Blot Analysis

[0248] MV-4-11 cells were grown in RPMI 1640 media supplemented with 10% fetal bovine serum, streptomycin and penicillin.

[0249] Cells were seeded at approximately 3 x 10 ⁶ cells per mL and incubated in DMSO or the indicated compounds for 6-8 hours. Whole cell extracts were prepared using RIPA buffer according to manufacturer’s protocol (Pierce). Briefly, 3 x 10 ⁶ cells were washed once in PBS, the cell pellets were resuspended in RIPA buffer and allowed to incubate for 15 min on ice. Cells debris was removed by centrifugation and the cleared whole cell lysates were transferred to new tubes for further analysis.

[0250] For Western blot analysis, whole cell protein extracts were separated on 4-12% SDS-polyacrylamide gels, transferred to nitrocellulose and probed with the indicated primary antibodies. Membranes were subsequently washed and probed with the appropriate IRDye secondary antibodies (LI-COR). The signal was detected using the Odyssey Imaging System (LI- COR).

[0251] The following antibodies were used in these studies: Anti-eRF3/GSPTl : Abeam, abl26090 (Cambridge, MA); Anti-Ikaros: Abeam, abl9l394 (Cambridge, MA); Anti- CKla: Abeam, ab 108296 (Cambridge, MA); b-actin (8H10D10) mouse monoclonal antibody: Cell Signaling Technology, #3700 (Danvers, MA); IRDye 680RD Goat anti-rabbit antibody: LI- COR, 926-68071 (Lincoln, NE); IRDye 800CW Goat anti-mouse antibody: LI-COR, 926-32210 (Lincoln, NE).

[0252] IKAROS activity is shown in Table 1. CK-la activity is shown in Table 2. GSPT1 activity is shown in Table 3.

[0253] The decrease in IKAROS protein levels after exposure to Compounds 1, 2, 3, 4 and comparative Compound A is shown in Table 1. Compounds 1, 2, 3, and 4 reduced IKAROS protein levels by greater than 56% at 10 mM. Compound 4 reduced IKAROS protein levels by 58% at 1 mM whereas Compound A reduced protein levels by only 16% at the same concentration (Table 1).

[0254] The decrease in CK-la protein levels after exposure to Compounds 1, 2, 3, 4 and comparative Compound A is shown in Table 2. Compounds 1, 2, 3, and 4 reduced CK-la protein levels by greater than 87% at 10 mM. Compound 4 reduced CK-la protein levels by 71% at 1 pM whereas Compound A reduced protein levels by only 33% at the same concentration (Table 2).

[0255] The decrease in GSPT1 protein levels after exposure to Compound 4 and comparative Compound A is shown in Table 3. Compound 4 reduced GSPT1 protein levels by 81% at 1 pM whereas Compound A reduced protein levels by only 44% at the same concentration (Table 3).

Table 1 : Activity of Compounds 1-4 and comparative Compound A in IKAROS degradation assay. The compounds were tested at 10 mM and 1 pM.

Table 2: Activity of Compounds 1-4 and comparative Compound A in CKl-a degradation assay. The compounds were tested at 10 mM and 1 pM.

Table 3 : Activity of Compound 4 and comparative Compound A in GSPT1 degradation assay. The compounds were tested at 10 mM and 1 pM.

Cell-Based Assays

[0256] Either frozen primary blood mononuclear cells (PBMCs) or frozen CD14+ mobilized peripheral blood monocytes were purchased from AllCells (PB003F, Normal Peripheral Blood MNC (Alameda, CA)). Cells were quick thawed, washed l-time with RPMI- 1640 (10% FBS/l% Pen-Strep) and plated in 96 well plates at 200,000 cells per well. Cells were pretreated with DMSO only or the indicated compounds for 1 h and then induced with lOOng/mL lipopolysaccharide (LPS) for 18-24 h. The supernatant was analyzed for IL-6, IL-lp, and TNFa, using Meso Scale assay according to manufacturer’s protocol. The negative control wells were treated with DMSO.

[0257] For the IL-2 analysis, 96 well plates were precoated with 1 pg/mL anti-human CD3 antibody (OKT3, eBioscience Inc., San Diego, CA). After washing with PBS, compounds were added (50 pL/well) followed by PBMCs diluted at 3 - 4 million cells/mL (150 pL/well). Plates were incubated for 24 h and the supernatants collected for Mesoscale IL-2 analysis. IL-2 activity is measured as fold difference from the DMSO control.

[0258] IL-6 activity is shown in Table 4. IL-l-beta activity is shown in Table 5. TNF- alpha activity and IL-2 activity is shown in Table 6.

[0259] Compound 4 reduced expression of IL-6 in LPS-stimulated PBMCs by 92% at 10 pM whereas comparative Compound A reduced expression by 81% at the same concentration (Table 4). Compound 4 reduced expression of PMb in LPS-stimulated PBMCs by 64% at 10 pM whereas comparative Compound A reduced expression by 63% at the same concentration (Table 5). Compounds 1, 2, 3, and 4 each reduced expression of TNFa in LPS-stimulated PBMCs by greater than 23% at 10 pM (Table 6). Compound 4 reduced expression of TNFa by 79% at 10 pM whereas Compound A reduced expression by 69% at the same concentration. For IL-2 in LPS-stimulated PBMCs, Compounds 1, 2, 3, and 4 each demonstrated a less than 0.8-fold difference from the DMSO control (Table 6). Compound 4 shown 0.5-fold change at 10 pM whereas Compound A shown 0.8-fold change at the same concentration, indicating that each of Compounds 1-4 has better inhibitory effect on IL-2, as compared to Compound A.

Table 4: Activity of Compound 4 and comparative Compound A in IL-6 assay. The compounds were tested at 10 pM and 1 pM.

Table 5: Activity of Compound 4 and comparative Compound A in IL-lp assay. The compounds were tested at 10 pM and 1 pM.

Table 6: Activity of Compounds 1-4 and comparative Compound A in TNFa assay and in IL-2 assay. The compounds were tested at 10 mM.

Cell Viability Assays

[0260] Molm-l3 and MV-4-11 cells were cultured in RPMI 1640 media supplemented with 10% fetal bovine serum, streptomycin and penicillin, and were plated in white walled 96- well plates at 2500 cells/well. Cells were incubated in DMSO (control) or the indicated compounds for 3 days at 37°C and 5% CO2. Following the incubation period, 100 pL of CellTiterGlow (CTG) reagent (CellTiter-Glo ^® Luminescent Cell Viability Assay, Promega (Madison, WI)) was added to each well. Following a 10 min incubation with shaking, luminescence was measured using the EnVision Multimode plate reader.

[0261] Molm-l3 cellular proliferation activities are shown in Table 7. MV-4-11 cellular proliferation activities are shown in Table 8.

[0262] Compounds 1, 2, 3, and 4 each reduced cell viability of Molm-l3 at 30 and 10 pM. Compound 4 reduced cell viability of Molm-l3 to 0.03% DMSO control at 30 pM (Table 7). Compounds 1, 2, 3, and 4 each reduced cell viability of MV-4-11 at 30 and 10 pM. Compound 4 reduced cell viability of MV-4-11 to about 0% DMSO control at 30 pM (Table 8).

Table 7: Activity of Compounds 1-4 in MOLM-13 cell viability assay. The compounds were tested at 30 pM and 10 pM.

Table 8: Activity of Compounds 1-4 in MV-4-11 cell viability assay. The compounds were tested at 30 mM and 10 mM

[0263] All references cited herein are incorporated herein by reference in their entirety. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

[0264] Unless otherwise defined, all terms (including technical and scientific terms) are to be given their ordinary and customary meaning to a person of ordinary skill in the art, and are not to be limited to a special or customized meaning unless expressly so defined herein. It should be noted that the use of particular terminology when describing certain features or aspects of the disclosure should not be taken to imply that the terminology is being re-defined herein to be restricted to include any specific characteristics of the features or aspects of the disclosure with which that terminology is associated.

[0265] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

[0266] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term‘including’ should be read to mean ‘including, without limitation,’‘including but not limited to,’ or the like; the term‘comprising’ as used herein is synonymous with‘including,’‘containing,’ or‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’ the term‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; adjectives such as‘known’,‘normal’, ‘standard’, and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but instead should be read to encompass known, normal, or standard technologies that may be available or known now or at any time in the future; and use of terms like‘preferably,’‘preferred,’‘desired,’ or‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention.

[0267] It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should typically be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, typically means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to“at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g.,“a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to“at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g.,“a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.).

[0268] All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term ‘about.’ Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0269] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it is apparent to those skilled in the art that certain changes and modifications may be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention to the specific embodiments and examples described herein, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.