WO2019173224A1 - Composés deutérés et chimères et leurs utilisations - Google Patents

Composés deutérés et chimères et leurs utilisations Download PDF

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WO2019173224A1
WO2019173224A1 PCT/US2019/020563 US2019020563W WO2019173224A1 WO 2019173224 A1 WO2019173224 A1 WO 2019173224A1 US 2019020563 W US2019020563 W US 2019020563W WO 2019173224 A1 WO2019173224 A1 WO 2019173224A1
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compound
cell
unsubstituted
cancer
formula
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PCT/US2019/020563
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Kyle W.H. Chan
Aparajita Hoskote Chourasia
Leah Fung
Frank Mercurio
Robert Sullivan
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Biotheryx, Inc.
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Publication of WO2019173224A1 publication Critical patent/WO2019173224A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • cytokines Aberrant protein function, and/or protein imbalance is a hallmark of many disease states.
  • 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).
  • 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.
  • GSPT1 translation termination factor
  • eRF3a the translation termination factor
  • GSPT1 mediates stop codon recognition and facilitates release of a nascent peptide from the ribosome.
  • 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.
  • GSPT1 also contributes to glial scar formation and astrogliosis after a central nervous system (CNS) injury.
  • CNS central nervous system
  • 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.
  • 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.
  • Tumor necrosis factor-alpha TNF-alpha
  • IL-l interleukin-l
  • RA rheumatoid arthritis
  • Crohn’s disease inflammatory bowel disease
  • multiple sclerosis multiple sclerosis
  • endotoxin shock osteoporosis
  • Alzheimer’s disease congestive heart failure
  • psoriasis among others.
  • 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.
  • 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).
  • 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.
  • cytokines for example, soluble TNF-alpha receptor fusion protein (etanercept) or the monoclonal TNF-alpha antibody (infliximab)
  • etanercept soluble TNF-alpha receptor fusion protein
  • infliximab monoclonal TNF-alpha antibody
  • 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.
  • 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.
  • cytokines are 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.
  • 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.
  • Aiolos 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.
  • casein kinase 1 family of proteins plays a role in the mitotic spindle formation, in DNA repair, and in RNA metabolism.
  • Knippschild, et ah Cell Signal, Vol 17, pp. 675-689 (2005).
  • 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).
  • CKla inhibits TRAIL induced apoptosis by modification of the TNF receptor or FADD at the death-inducing signaling complex (DISC).
  • DISC death-inducing signaling complex
  • downregulation of CKla leads to enhancement of TRAIL-induced cell death.
  • CKla also promotes cell survival by interacting with the retinoid X receptor (RXR).
  • RXR retinoid X receptor
  • Downregulation of CKla enhances the apoptotic effect of RXR agonists.
  • the ikaros family of proteins play a role in leukemia.
  • 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.
  • 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.
  • El ubiquitin-activating enzymes
  • E2 ubiquitin-conjugating enzymes
  • E3 ubiquitin-protein ligases
  • the compounds disclosed in the present application have been discovered to exert surprising and unexpected biological effects.
  • 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.
  • 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;
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen or deuterium;
  • 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
  • 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.
  • R 5A , R 5B , and R 5C are each independently hydrogen or deuterium.
  • 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 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 -.
  • R 6 may be absent, or independently
  • Y is derivatized to attach to L.
  • Y may be selected from the group consisting of
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • R 1 is L-Y. In some embodiments, R 2 is L-Y. In some embodiments,
  • L is -Z '- t-Z 2 -
  • L is -Z 1 -(R 6 -0-R 6 )t- Z 2 -.
  • L is-Z 1 (R 6 -NH-R 6 )t-Z 2 -.
  • L is -Z 1 -(R 6 -(CO)- R 6 ) t -Z 2 -.
  • 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.
  • 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-.
  • Z 1 and Z 2 are independently -CH 2- , -0-, -(CO)-, -C0 2- , -NH-, -NH(CO)-, -(CO)NH-, -CH 2 NH(CO)NH-,
  • each R 6 is independently an unsubstituted Ci to C6 alkyl, for example, methylene or ethylene. In some embodiments, each R 6 is absent.
  • Y is derivatized to attach to L.
  • Y is , and wherein Y is derivatized to attach to L.
  • Y is wherein Y is derivatized to attach to L.
  • the compound of Formula (II) is selected from the group consisting of:
  • Some embodiments provide a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (II) as described herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
  • 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.
  • 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.
  • 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.
  • the protein is IL- 1 b.
  • the protein is IL-2.
  • the protein is IL-6.
  • 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.
  • 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.
  • 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.
  • 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.
  • the cell is a cancer cell.
  • 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.
  • a small cell lung cancer cell a non small
  • 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.
  • the immune disorder is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis.
  • 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.
  • the inflammatory disorder is fibromyalgia or osteoarthritis.
  • “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.
  • 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:
  • Y is derivatized to attached to L, Y can be:
  • Y is derivatized to attach to L, Y can be:
  • Y when derivatized to attach to L, Y can be:
  • Y may be selected from the group comprising
  • 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
  • Some embodiments provide a compound of Formula (I):
  • 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 C
  • 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 C
  • 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.
  • 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.
  • each Rs is independently H, deuterium, or unsubstituted Ci to G, alkyl.
  • each Rs is independently H or deuterium.
  • n is 1 or 2.
  • 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 -
  • t is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, t is 1 or 2.
  • 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-..
  • 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.
  • 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.
  • 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.
  • Y is derivatized to attach to L
  • the compound of Formula (I) is present in a form of a racemic mixture.
  • the compound of Formula (I) has an S-configuration.
  • the compound of Formula (I) has an R-configuration.
  • 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.
  • 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.
  • 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
  • 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 Ci to C6 alky
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 -.
  • L is -Z'-(R ) t -Z 2 -
  • L is -Z 1 -(R 6 -0-R 6 ) t -Z 2 -.
  • L is -Z 1 (R 6 -NH-R 6 ) t -Z 2 -.
  • 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.
  • 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-.
  • 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-
  • Z 1 and Z 2 are independently -CH2-, -0-, -NH-, -NH(CO)-, -(CO)NH-.
  • 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 -,
  • R 6 is an unsubstituted Ci to C6 alkyl, for example, methylene, or ethylene.
  • 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.
  • Y is wherein Y is derivatized to attach to L
  • R 1 , R 2 , R 3 , and R 4 is L-Y.
  • R 1 is L-Y.
  • R 2 is L-Y.
  • R 1 is L-Y; L is -Z ⁇ R ⁇ t -Z 2 -; and t is 1 or 2.
  • R 1 is L-Y; L is -Z 1 -(R 6 -0-R 6 ) t -Z 2 -; and t is 1 or 2.
  • R 1 is L-Y; L is -Z 1 (R 6 -NH-R 6 ) t -Z 2 -; and t is 1 or 2.
  • R 1 is L-Y; L is
  • R 1 is L-Y; L is
  • R 2 is L-Y; L is -Z 1 -(R 6 -0-R 6 )t-Z 2 -; and t is 1 or 2.
  • R 2 is L-Y; L is -Z 1 (R 6 -NH-R 6 ) t -Z 2 -; and t is 1 or 2.
  • R 2 is L-Y; L is -Y; L is -Z 1 (R 6 -NH-R 6 ) t -Z 2 -; and t is 1 or 2.
  • R 2 is L-Y; L is
  • R 2 is L-Y; L is
  • R 2 is L-Y; L is -Z 1 -(R 6 -(CONH)-R 6 ) t -Z 2 -; and t is 1 or 2.
  • 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.
  • the compound of Formula (II) is selected from the group consisting of:
  • 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.
  • 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.
  • the compound of Formula (II) is selected from:
  • the compound of Formula (II) is selected from:
  • 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.
  • the compound of Formula (II) is selected from:
  • 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.
  • the compound of Formula (II) is selected from:
  • 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.
  • the compound of Formula (II) is selected from:
  • 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.
  • the compound of Formula (II) is selected from:
  • 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.
  • Y is a compound or a portion of a compound that targets a particular protein, proteins, and/or protein complex.
  • Y is an HSP90 inhibitor.
  • Y is a kinase inhibitor.
  • Y is a phosphatase inhibitor.
  • Y is a compound targeting the estrogen receptor.
  • Y is a compound targeting the androgen receptor.
  • Y is an inhibitor of HDM2/MDM2.
  • Y is an HD AC inhibitor.
  • Y is an inhibitor of lysine methyltransf erase.
  • Y is an inhibitor of one or more core-binding factor(s).
  • 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).
  • 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.
  • 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.
  • 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).
  • 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); paz
  • Y is azacitidine ((derivatized where a linker group L is attached, for example, via the hydroxy or amino groups).
  • Y is decitabine (derivatized) (4-amino-l-(2-deoxy-b-D-erythro-pentofuranosyl)-l,3,5-triazin-2(lH)-one)
  • 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).
  • 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).
  • 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.
  • glucocorticoid including, but not limited to hydrocortisone, prednisone, prednisolone, and methylprednisolone
  • methotrexate methotrexate
  • cyclosporine including, but not limited to tacrolimus (FK-506), rapamycin, apigenin, or an actinomycin, each derivatized where a linker group L is bound.
  • Y is
  • 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.
  • 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.
  • 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.
  • 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.
  • the protein is IL- 1 b.
  • the protein is IL-2.
  • 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.
  • 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.
  • 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.
  • 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.
  • the cell is a cancer cell.
  • 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.
  • a small cell lung cancer cell a non
  • 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.
  • the immune disorder is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis.
  • 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).
  • the inflammatory disorder is fibromyalgia or osteoarthritis.
  • 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.
  • 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.
  • FGFR fibroblast growth factor receptor
  • Y targets JAK Janus kinase, e.g., JAK2
  • JAK Janus kinase
  • 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.
  • 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.
  • 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.
  • FGFR fibroblast growth factor receptor
  • 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.
  • 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.
  • the cytokine is IL-l -alpha, IL-l-beta, IL-2, IL-4, IL-6, IL-10, or a combination thereof.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the cytokine is IL-l-alpha, IL-l-beta, IL-2, IL-4, IL-6, IL-10, or a combination thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions of preferred embodiments can further comprise one or more additional therapeutically active agents other than a compound of the preferred embodiments.
  • additional therapeutically active agents can include, but are not limited to, anti-inflammatory agents, anti-cancer agents, immunostimulatory agents, and immunosuppressive agents.
  • deuterium source 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.
  • 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.
  • an“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.
  • 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.
  • 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.
  • 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.
  • 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.
  • cocktail therapy e.g., the administration of three or more active ingredients.
  • 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.
  • 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:
  • 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-carbox
  • “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.
  • 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.
  • 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-.
  • “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.
  • “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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • “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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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, pyrid
  • 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.
  • 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-triazin
  • “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
  • 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.”
  • 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.
  • heteroaryl 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • a halogen e.g ., mono-haloalkyl, di-haloalkyl, and tri- haloalkyl.
  • 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.
  • 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).
  • a halogen e.g., mono-haloalkoxy, di-haloalkoxy and tri- haloalkoxy.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • An ester and C-carboxy may be substituted or unsubstituted.
  • a thiocarbonyl may be substituted or unsubstituted.
  • A“trihalomethanesulfonyl” group refers to an“X 3 CS02-“ group wherein X is a halogen.
  • 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.
  • amino refers to a -NH2 group.
  • A“cyano” group refers to a“-CN” group.
  • An“isocyanato” group refers to a“-NCO” group.
  • A“thiocyanato” group refers to a“-CNS” group.
  • An“isothiocyanato” group refers to an“-NCS” group.
  • A“mercapto” group refers to an“-SH” group.
  • 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.
  • 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.
  • 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.
  • An O-carbamyl may be substituted or unsubstituted.
  • An N-carbamyl may be substituted or unsubstituted.
  • An O-thiocarbamyl may be substituted or unsubstituted.
  • An N-thiocarbamyl may be substituted or unsubstituted.
  • a C-amido may be substituted or unsubstituted.
  • An N-amido may be substituted or unsubstituted.
  • a urea group may be substituted or unsubstituted.
  • a thiourea group may be substituted or unsubstituted.
  • 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.
  • substituents e.g ., haloalkyl
  • substituents there may be one or more substituents present.
  • “haloalkyl” may include one or more of the same or different halogens.
  • “C1-C3 alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two, or three atoms.
  • 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
  • leaving group 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.
  • salt 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.
  • 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-
  • 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.
  • a salt of organic bases such as dicyclohexylamine, N-methyl-D- glucamine, tris(
  • 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.
  • 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.
  • 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.
  • a prodrug upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.
  • each center may independently be of R-configuration or S-configuration or a mixture thereof.
  • the compounds provided herein may be enantiomerically pure, enantiomerically enriched, or may be stereoisomeric mixtures, and include all diastereomeric, and enantiomeric forms.
  • 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.
  • 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.
  • 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.
  • a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium).
  • hydrogen- 1 protium
  • hydrogen-2 deuterium
  • tritium tritium
  • 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.
  • 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.
  • 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.
  • the compounds described herein 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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; els
  • 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;
  • 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; telimoma
  • 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.
  • 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.
  • 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.
  • 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.
  • MMC microcrystalline cellulose
  • L-HPC low- substituted hydroxypropyl cellulose
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • ophthalmic delivery units such as eye drop containers
  • 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.
  • a 0.05M phosphate buffer solution pH 4.4
  • Dosing Regimes 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing is administered each cycle of treatment.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a pharmaceutically acceptable salt of any of the foregoing is administered at least once per day.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • One enantiomer either compound 2.3 (shown above) or compound 2.2, is dissolved in an organic solvent, such as fluorobenzene or ACN.
  • an organic solvent such as fluorobenzene or ACN.
  • an oxidizing agent for example, Dess-Martin periodinane or Mn02
  • the reaction mixture heated to an elevated temperature, such as 80°C.
  • 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.
  • reaction is diluted with an organic solvent, such as ethyl acetate, and extracted with H2O.
  • 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
  • N-bromosuccinimide N-bromosuccinimide
  • AIBN 2,2’-azobis(2- methylpropionitrile)
  • 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-methylpyrimidin-4- vOaminolbenzenesulfonamide
  • MV-4-11 cells were grown in RPMI 1640 media supplemented with 10% fetal bovine serum, streptomycin and penicillin.
  • 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).
  • IKAROS activity is shown in Table 1.
  • CK-la activity is shown in Table 2.
  • GSPT1 activity is shown in 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.
  • 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.
  • AllCells PB003F, Normal Peripheral Blood MNC (Alameda, CA)
  • RPMI- 1640 10% FBS/l% Pen-Str
  • IL-2 activity is measured as fold difference from the DMSO control.
  • 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.
  • 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.
  • 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.
  • CCG CellTiterGlow
  • 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

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Abstract

La présente invention concerne des composés qui modulent la fonction des protéines et/ou rétablissent l'homéostasie des protéines. L'invention concerne des procédés de modulation de maladies, de troubles, d'états ou de réponses à médiation par des protéines. L'invention concerne également des compositions, y compris en combinaison avec d'autres agents thérapeutiques.
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WO2022061348A1 (fr) 2020-09-16 2022-03-24 Biotheryx, Inc. Agents de dégradation de protéine sos1, compositions pharmaceutiques de ceux-ci, et leurs applications thérapeutiques
WO2022087335A1 (fr) 2020-10-23 2022-04-28 Biotheryx, Inc. Agents de dégradation de protéine kras, compositions pharmaceutiques de ceux-ci, et leurs applications thérapeutiques
WO2022132603A1 (fr) 2020-12-14 2022-06-23 Biotheryx, Inc. Agents de dégradation de la pde4, compositions pharmaceutiques et applications thérapeutiques
WO2022251588A1 (fr) * 2021-05-27 2022-12-01 Halda Therapeutics Opco, Inc. Composés hétérobifonctionnels et procédés de traitement de maladie
WO2024054832A1 (fr) 2022-09-09 2024-03-14 Innovo Therapeutics, Inc. COMPOSÉS DE DÉGRADATION CK1α ET DOUBLE CK1α/GSPT1

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Publication number Priority date Publication date Assignee Title
JP2022507267A (ja) * 2018-11-13 2022-01-18 バイオセリックス， インコーポレイテッド 置換イソインドリノン
WO2022061348A1 (fr) 2020-09-16 2022-03-24 Biotheryx, Inc. Agents de dégradation de protéine sos1, compositions pharmaceutiques de ceux-ci, et leurs applications thérapeutiques
WO2022087335A1 (fr) 2020-10-23 2022-04-28 Biotheryx, Inc. Agents de dégradation de protéine kras, compositions pharmaceutiques de ceux-ci, et leurs applications thérapeutiques
WO2022132603A1 (fr) 2020-12-14 2022-06-23 Biotheryx, Inc. Agents de dégradation de la pde4, compositions pharmaceutiques et applications thérapeutiques
WO2022251588A1 (fr) * 2021-05-27 2022-12-01 Halda Therapeutics Opco, Inc. Composés hétérobifonctionnels et procédés de traitement de maladie
WO2024054832A1 (fr) 2022-09-09 2024-03-14 Innovo Therapeutics, Inc. COMPOSÉS DE DÉGRADATION CK1α ET DOUBLE CK1α/GSPT1

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