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WO2018222975A1 - Méthodes pour le traitement du cancer - Google Patents

Méthodes pour le traitement du cancer Download PDF

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Publication number
WO2018222975A1
WO2018222975A1 PCT/US2018/035575 US2018035575W WO2018222975A1 WO 2018222975 A1 WO2018222975 A1 WO 2018222975A1 US 2018035575 W US2018035575 W US 2018035575W WO 2018222975 A1 WO2018222975 A1 WO 2018222975A1
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cancer
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Masoud Fakhr TAVAZOIE
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Inspirna Inc
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Rgenix Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • GITR modulators have been shown to amplify the antitumor immune responses by multiple mechanisms. For example, activation of the GITR receptor increases proliferation and function of effector T-cells and lower the suppressive function of regulatory T-cells on tumor specific effector T-cells, thereby increasing the antitumor response. Accordingly, combinations of GITR modulators with other immunotherapies may result in synergistic effects that provide efficacious treatments for patients. Summary of the Invention
  • the invention features methods of treating cancer by administering a combination of an LXR ⁇ agonist and a GITR modulator.
  • LXR ⁇ agonists are capable of lowering MDSC levels in subjects, e.g., subjects with elevated levels such as subjects with cancer, and increasing T-cell activation. The lowering of MDSC levels and increased T-cell activation may allow the subjects immune system to more effectively work against the cancer.
  • GITR expression is increased in patients treated with LXR ⁇ agonists. Increased GITR expression has been shown to modulate T-cell activity by suppressing T-regulatory cells and extending the survival of T-effector cells.
  • a combination of an LXR ⁇ agonist to increase T-cell activation and a GITR modulator to increase the anticancer activity of the T-cells may result in a synergistic effect in the treatment of cancer by increasing T-cell levels and their anticancer activity.
  • the invention features a method of treating cancer in a subject in need thereof.
  • This method includes administering an effective amount of an LXR ⁇ agonist and an effective amount of a GITR modulator (e.g., an antibody or antigen binding fragment thereof which specifically binds to GITR) to the subject.
  • a GITR modulator e.g., an antibody or antigen binding fragment thereof which specifically binds to GITR
  • the LXR ⁇ agonist and GITR modulator are administered concurrently.
  • the GITR modulator is administered subsequently to the LXR ⁇ agonist.
  • the GITR modulator is administered prior to the LXR ⁇ agonist.
  • the GITR modulator and LXR agonist are administered within 28 days of each other (e.g., within 21, 14, 10, 7, 5, 4, 3, 2, or 1 days) or within 24 hours (e.g., 12, 6, 3, 2, or 1 hours; or concomitantly) each in an amount that together are effective to treat the subject.
  • administering comprises contacting a cell with an effective amount of an LXR ⁇ agonist and/or GITR modulator.
  • the GITR modulator is TRX518, MK- 4166, MK1248, AMG228, BMS-986156, INCAGN01876, MEDI1873, or GWN323.
  • the method includes (a) determining the level of myeloid derived suppressor cells (e.g., monocytic and/or granulocytic myeloid derived suppressor cells), the level of activated T-cells in the subject, and/or the level of GITR expression in the subject (e.g., on the T-cells in the subject or in the tumor microenvironment of the subject); and (b) administering an effective amount of an LXR ⁇ agonist to the subject if the level of myeloid derived suppressor cells are greater than a predetermined level (e.g., the level in a sample from a subject that does not have cancer), the level of activated T-cells is lower than a predetermined level (e.g., the level in a sample from a subject that does not have cancer), and/or the level of GITR expression is greater than a pre-determined level (e.g., the level in a sample from a subject that does not have cancer).
  • a predetermined level e.g.
  • the level of myeloid derived suppressor cells, the level of activated T-cells, and/or the level of GITR expression is determined in the tumor microenviroment (e.g., by determining the level in a tumor sample such as a tumor sample from a biopsy). In some embodiments of any of the methods of the invention, the level of myeloid derived suppressor cells, the level of activated T-cells, and/or the level of GITR expression is determined systemically (e.g., by determining the level in a plasma sample).
  • the myeloid derived suppressor cells are monocytic myeloid derived suppressor cells (e.g., circulating monocytic myeloid derived suppressor cells). In some embodiments of any of the methods of the invention, the myeloid derived suppressor cells are granulocytic myeloid derived suppressor cells. In some embodiments of any of the methods of the invention, the myeloid derived suppressor cells express CD11b(+), Lin(-), HLA-DR(low/-), and/or CD14(+) on their surface.
  • the myeloid derived suppressor cells express CD11b(+), Lin(-), HLA-DR(low/-), and CD14(+) on their surface. In some embodiments of any of the methods of the invention, the myeloid derived suppressor cells express CD11b(+), Lin(-), HLA-DR(low/-), and/or CD15(+) on their surface. In some embodiments of any of the methods of the invention, the myeloid derived suppressor cells express CD11b(+), Lin(-), HLA-DR(low/-), and CD15(+) on their surface.
  • the myeloid derived suppressor cells express CD33(+), HLA-DR(low/-), and CD15(+).
  • the myeloid derived suppressor cells are any known in the art, for example, those described in Talmadge et al. Nat. Rev. Cancer 2013 13(10):739-752.
  • the invention features a method for classifying a subject.
  • classification includes predicting the response to an anticancer therapy, selecting a subject that may benefit from an anticancer therapy (e.g., a GITR modulator) other than, or in addition to, an LXR ⁇ agonist, or predicting the responsiveness of a subject to an LXR ⁇ agonist.
  • the method includes: determining the level of GITR in a biological sample of the subject (e.g., the level of GITR expression on the T-cells of the subject).
  • a subject is classified based on having an increased GITR level (e.g., an increase by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, 500%, or more; or an increase by more than 1.2-fold, 1.4-fold, 1.5-fold, 1.8-fold, 2.0-fold, 3.0-fold, 3.5-fold, 4.5-fold, 5.0-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold, 1000-fold, or more), as compared to a reference (e.g., a control, such as, a predetermined control value, or a sample from a subject that does not have cancer, a subject that has cancer and responded positively to an LXR ⁇ agonist, or a sample from the subject prior to treatment with an LXR ⁇ agonist).
  • the invention features a method for treating cancer.
  • the method includes: (a) determining the level of GITR in a biological sample obtained from the subject; and (b) administering an anticancer therapy to the subject if the level of GITR is indicative that the subject may benefit from an anticancer therapy (e.g., administration of an LXR ⁇ agonist and/or one or more immunotherapies such as a GITR modulator).
  • an anticancer therapy e.g., administration of an LXR ⁇ agonist and/or one or more immunotherapies such as a GITR modulator.
  • an increased level e.g., an increase by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, 500%, or more; or an increase by more than 1.2-fold, 1.4-fold, 1.5-fold, 1.8-fold, 2.0-fold, 3.0-fold, 3.5-fold, 4.5-fold, 5.0-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold, 1000-fold, or more) of GITR, as compared to a reference (e.g., a control, such as, a predetermined control value, or a sample from a subject that does not have cancer, a subject that has cancer and responded positively to an LXR ⁇ agonist, or a sample from the subject prior to treatment with an LXR ⁇ agonist), is indicative that the subject may benefit from a reference
  • the invention features a method for treating cancer.
  • the method includes: (a) determining the level of GITR in a biological sample obtained from a subject that has been previously treated with an LXR ⁇ agonist; and (b) administering an anticancer therapy other than, or in addition to, an LXR ⁇ agonist (e.g., an immunotherapy such a GITR modulator) to the subject if the level of GITR is indicative that the subject may benefit from an anticancer therapy other than, or in addition to, an LXR ⁇ agonist.
  • an LXR ⁇ agonist e.g., an immunotherapy such a GITR modulator
  • an increased level e.g., an increase by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, 500%, or more; or an increase by more than 1.2-fold, 1.4-fold, 1.5-fold, 1.8-fold, 2.0-fold, 3.0-fold, 3.5- fold, 4.5-fold, 5.0-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold, 1000-fold, or more) of GITR as compared to a reference (e.g., a predetermined control value, or a sample from a subject that does not have cancer, a subject that has cancer and responded positively to an LXR ⁇ agonist, or a sample from the subject prior to treatment with an LXR ⁇ agonist), is indicative that the subject may benefit from an anticancer therapy other than,
  • the invention features a method for treating cancer.
  • the method includes (a) providing a subject that has been identified as likely to benefit from an anticancer therapy (e.g., a GITR modulator) other than, or in addition to, an LXR ⁇ agonist; and (b) administering an anticancer therapy (e.g., a GITR modulator) other than, or in addition to, an LXR ⁇ agonist to the subject.
  • an anticancer therapy e.g., a GITR modulator
  • an anticancer therapy e.g., a GITR modulator
  • the method further includes, prior to the determining step, the step of selecting a subject having cancer and/or the step of obtaining a biological sample from the subject.
  • the method further includes, between step (a) and step (b), the step of comparing the level of GITR to a reference (e.g., a predetermined control value, or a sample from a subject that does not have cancer, a subject that has cancer and responded positively to an LXR ⁇ agonist, or a sample from the subject prior to treatment with an LXR ⁇ agonist).
  • a reference e.g., a predetermined control value, or a sample from a subject that does not have cancer, a subject that has cancer and responded positively to an LXR ⁇ agonist, or a sample from the subject prior to treatment with an LXR ⁇ agonist.
  • the biological sample is obtained from the subject prior to the commencement of administration of an LXR ⁇ agonist. In other embodiments of any of the foregoing methods, the biological sample is obtained from the subject after commencement of administration of an LXR ⁇ agonist. In certain embodiments of any of the foregoing methods, the biological sample is obtained from the subject with 24 hours after commencement of administration of an LXR ⁇ agonist. In some embodiments of any of the foregoing methods, the biological sample is a tissue sample, whole blood, plasma, urine, saliva, pancreatic juice, bile, or serum sample. In certain embodiments of any of the foregoing methods, the biological sample is a plasma sample.
  • the level of GITR is determined prior to treatment with an LXR ⁇ agonist. In some embodiments, the level of GITR is determined subsequent to treatment with an LXR ⁇ agonist. In some embodiments, the level of GITR is determined prior to treatment with an LXR ⁇ agonist and subsequent to treatment with an LXR ⁇ agonist.
  • the method further includes the step of recording the result in a print or computer readable media.
  • the method further includes the step of informing (e.g., providing the results of the determining step on printable media) the subject that he or she may benefit from an anticancer therapy, may benefit from administration of an LXR ⁇ agonist, or may benefit from a therapy other than, or in addition to, an LXR ⁇ agonist.
  • kits for monitoring a subject with cancer can be used to determine an optimal treatment plan for a subject or to determine the efficacy of a treatment plan for a subject.
  • the subject can be treated for cancer and the prognosis of the disease can be determined by the diagnostic methods disclosed herein.
  • a diagnostic method is used to determine if a subject is responding to treatment.
  • a diagnostic method can include a screen for GITR levels by any useful detection method (e.g., unlabeled, fluorescence, radiation, or chemiluminescence).
  • a diagnostic test can further include one or more binding agents (e.g., one or more of probes, primers, peptides, small molecules, aptamers, or antibodies) to detect the level of these proteins or mRNAs encoding these proteins.
  • the subject has a compromised immune system (e.g., the subject has been determined to have decreased levels of activated T-cells or increased levels of MDSCs (e.g., monocytic and/or granulocytic MDSCs), or the subject is likely to have a decreased immune response based on the subject’s medical history such as prior treatment history), the method including
  • the subject has decreased levels of ApoE, LRP1, LRP8, and/or LXR ⁇ (e.g., in the tumor microenvironment or systemically, including immune cells) compared to a predetermined reference value (e.g., a value in a sample from a healthy subject).
  • a predetermined reference value e.g., a value in a sample from a healthy subject
  • the subject has an elevated level (e.g., the subject has a level about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, greater as compared to a reference such as the level in a sample from a healthy subject or a level that indicates an increased likelihood of response to an immunotherapy) of myeloid derived suppressor cells such as monocytic and/or granulocytic myeloid dervired suppressor cells (e.g., in the tumor microenvironment or systemically).
  • myeloid derived suppressor cells such as monocytic and/or granulocytic
  • the method further includes administering an additional immunotherapy (e.g., an antibody such as an anti-CTLA-4 antibody, anti-PD1, or anti-PDL1 antibody or adoptive T-cell transfer therapy) to the subject.
  • an additional immunotherapy e.g., an antibody such as an anti-CTLA-4 antibody, anti-PD1, or anti-PDL1 antibody or adoptive T-cell transfer therapy
  • the additional immunotherapy when present, is a CTLA-4 inhibitor, a PD1 inhibitor, a PDL1 inhibitor, or adoptive T-cell transfer therapy.
  • the additional immunotherapy is a PD-1 inhibitor such as a PD-1 antibody, a PD-L1 inhibitor such as a PD-L1 antibody, a CTLA-4 inhibitor such as a CTLA-4 antibody, a CSF-1R inhibitor, an IDO inhibitor, an A1 adenosine inhibitor, an A2A adenosine inhibitor, an A2B adenosine inhibitor, an A3A adenosine inhibitor, an arginase inhibitor, or an HDAC inhibitor.
  • a PD-1 inhibitor such as a PD-1 antibody
  • a PD-L1 inhibitor such as a PD-L1 antibody
  • CTLA-4 inhibitor such as a CTLA-4 antibody
  • CSF-1R inhibitor such as a CSF-1R inhibitor
  • IDO inhibitor an A1 adenosine inhibitor
  • an A2A adenosine inhibitor an A2B adenosine inhibitor
  • an A3A adenosine inhibitor an arginase inhibitor
  • the additional immunotherapy is a PD-1 inhibitor (e.g., nivolumab, pembrolizumab, pidilizumab, BMS 936559, BGB- A317, and/or MPDL328OA).
  • the additional immunotherapy is a PD-L1 inhibitor (e.g., atezolizumab, avelumab, and/or durvalumab (MEDI4736)).
  • the additional immunotherapy is a CTLA-4 inhibitor (e.g., ipilimumab and/or tremelimumab).
  • the additional immunotherapy is a CSF-1R inhibitor (e.g., pexidartinib and AZD6495).
  • the additional immunotherapy is an IDO inhibitor (e.g., norharmane, rosmarinic acid, epacadostat, GDC- 0919, a COX-2 inhibitor, and/or alpha-methyl-tryptophan).
  • the additional immunotherapy is an A1 adenosine inhibitor (e.g., 8-cyclopentyl-1,3-dimethylxanthine, 8-cyclopentyl-1,3- dipropylxanthine, 8-phenyl-1,3-dipropylxanthine, bamifylline, BG-9719, BG-9928, FK-453, FK-838, rolofylline, or N-0861).
  • A1 adenosine inhibitor e.g., 8-cyclopentyl-1,3-dimethylxanthine, 8-cyclopentyl-1,3- dipropylxanthine, 8-phenyl-1,3-dipropylxanthine, bamifylline, BG-9719, BG-9928, FK-453, FK-838, rolofylline, or N-0861.
  • the additional immunotherapy is an A2A adenosine inhibitor (e.g., ATL-4444, istradefylline, MSX-3, preladenant, SCH-58261, SCH-412,348, SCH-442,416, ST-1535, VER-6623, VER-6947, VER-7835, viadenant, or ZM-241,385).
  • the additional immunotherapy is an A2B adenosine inhibitor (e.g., ATL-801, CVT-6883, MRS-1706, MRS- 1754, OSIP-339,391, PSB-603, PSB-0788, or PSB-1115).
  • the additional immunotherapy is an A3A adenosine inhibitor (e.g., KF-26777, MRS-545, MRS-1191, MRS-1220, MRS- 1334, MRS-1523, MRS-3777, MRE-3005-F20, MRE-3008-F20, PSB-11, OT-7999, VUF-5574, and SSR161421).
  • A3A adenosine inhibitor e.g., KF-26777, MRS-545, MRS-1191, MRS-1220, MRS- 1334, MRS-1523, MRS-3777, MRE-3005-F20, MRE-3008-F20, PSB-11, OT-7999, VUF-5574, and SSR161421.
  • the additional immunotherapy is an arginase inhibitor (e.g., an arginase antibody, (2s)-(+)-amino-5-iodoacetamidopentanoic acid, NG-hydroxy-L-arginine, (2S)-(+)- amino-6-iodoacetamidohexanoic acid, or (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid.
  • the additional immunotherapy is an HDAC inhibitor (e.g., valproic acid, SAHA, romidepsin, or entinostat).
  • the GITR modulator, LXR agonist, and additional immunotherapy are administered within 28 days of each other (e.g., within 21, 14, 10, 7, 5, 4, 3, 2, or 1 days) or within 24 hours (e.g., 12, 6, 3, 2, or 1 hours; or concomitantly) each in an amount that together are effective to treat the subject.
  • the subject has not been previously administered an immunotherapy.
  • the subject has a cancer that has failed to respond to a previously administered an immunotherapy (e.g., the cancer of the subject has progressed despite treatment with the
  • the cancer is resistant to an immunotherapy (e.g., the cancer has been determined to be resistant to immunotherapies such as by genetic markers or the level of MDSCs (e.g., monocytic and/or granulocytic MDSCs) in a sample, or is likely to be resistant, to immunotherapies such as a cancer that has failed to respond to an immunotherapy).
  • an immunotherapy e.g., the cancer has been determined to be resistant to immunotherapies such as by genetic markers or the level of MDSCs (e.g., monocytic and/or granulocytic MDSCs) in a sample, or is likely to be resistant, to immunotherapies such as a cancer that has failed to respond to an immunotherapy.
  • the method further includes
  • an additional anticancer therapy e.g., an antiproliferative
  • the additional anticancer therapy is any one of the antiproliferatives listed in Table 4.
  • the antiproliferative is: a chemotherapeutic or cytotoxic agent, a differentiation-inducing agent (e.g. retinoic acid, vitamin D, cytokines), a hormonal agent, an chemotherapeutic or cytotoxic agent, a differentiation-inducing agent (e.g. retinoic acid, vitamin D, cytokines), a hormonal agent, an chemotherapeutic or cytotoxic agent, a differentiation-inducing agent (e.g. retinoic acid, vitamin D, cytokines), a hormonal agent, an chemotherapeutic or cytotoxic agent, a differentiation-inducing agent (e.g. retinoic acid, vitamin D, cytokines), a hormonal agent, an chemotherapeutic or cytotoxic agent, a differentiation-inducing agent (e.g. retinoic acid, vitamin D, cytokines), a hormonal agent, an chemotherapeutic or cytotoxic agent, a differentiation-inducing agent (e.g.
  • Chemotherapeutic and cytotoxic agents include, but are not limited to, alkylating agents, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposides, and others (e.g., paclitaxel, taxol, docetaxel, taxotere, cis-platinum).
  • alkylating agents include, but are not limited to, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposides, and others (e.g., paclitaxel, taxol, docetaxel, taxotere, cis-platinum).
  • paclitaxel paclitaxel
  • taxol docetaxel
  • taxotere cis-platinum
  • a list of additional compounds having antiproliferative activity can be found in L. Brunton, B. Chabner and B. Knollman (eds). Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition, 2011, McGraw
  • the antiproliferative is a PD1 inhibitor, a VEGF inhibitor, a VEGFR2 inhibitor, a PDL1 inhibitor, a BRAF inhibitor, a CTLA-4 inhibitor, a MEK inhibitor, an ERK inhibitor, vemurafenib, dacarbazine, trametinib, dabrafenib, MEDI-4736, an mTOR inhibitor, a CAR-T therapy, abiraterone, enzalutamine, ARN-509, 5-FU, FOLFOX, FOLFIRI, herceptin, xeloda, a PD1 antibody (e.g., pembrolizumab or nivolumab), a PDL-1 antibody, a CTLA-4 antibody (e.g, ipilimumab), ramucirumab, rindopepimut, glembatumumab, vedotin, ANG1005, and/or ANG404
  • the LXR ⁇ agonist is selective for LXR ⁇ over LXR ⁇ .
  • the LXR ⁇ agonist is administered in an amount sufficient to increase the expression level or activity level of ApoE to a level sufficient to suppress metastatic progression of the cancer. In certain embodiments, the LXR agonist increases the expression level of ApoE at least 2.5-fold in vitro. In some embodiments, the LXR ⁇ agonist is selective for LXR ⁇ over LXR ⁇ . In other embodiments, the LXR ⁇ agonist has activity for LXR ⁇ that is at least 2.5-fold greater than the activity of the agonist for LXR ⁇ . In some embodiments, the LXR ⁇ agonist has activity for LXR ⁇ that is at least 10-fold greater than the activity of the agonist for LXR ⁇ .
  • the LXR ⁇ agonist has activity for LXR ⁇ that is at least 100-fold greater than the activity of the agonist for LXR ⁇ . In some embodiments, the LXR agonist has activity for LXR ⁇ that is at least within 2.5-fold of the activity of the agonist for LXR ⁇ .
  • the LXR ⁇ agonist is any compound described herein (e.g., any compound having the structure of any one of Formula I-XXXVI or any one of compounds 1-826).
  • the LXR ⁇ agonist has the structure of Formula IV:
  • X is selected from hydrogen, C1-C8 alkyl, halo, -OR 10 , -NR 10 R 11 , nitro, cyano, -COOR 10 , or - COR 10 .
  • Z is CH, CR 3 or N, wherein when Z is CH or CR 3 , k is 0-4 and t is 0 or 1, and when Z is N, k is 0-3 and t is 0;
  • Y is selected from -O-, -S-, -N(R 12 )-, and -C(R 4 )(R 5 )- ;
  • W 1 is selected from C1-C6 alkyl, C0-C6 alkyl, C3-C6 cycloalkyl, aryl and Het, wherein said C1-C8 alkyl, C3-C8 cycloalkyl, Ar and Het are optionally unsubstituted or substituted with one or more groups independently selected from halo, cyano, nitro, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl,-C 0 -C 6 alkyl- CO2R 12 , -C0-C6alkyl-C(O)SR 12 , -C0-C6alkyl-CONR 13 R 14 , -C0-C6 alkyl-COR 15 , -C0-C6 alkyl-NR 13 R 14 , -C0-C6 alkyl-SR 12 , -C0-C6alkyl-OR 12 , -C0-C6alkyl
  • W 2 is selected from H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, -C0-C6 alkyl-NR 13 R 14 , -C0-C6 alkyl-SR 12 , -C0-C6 alkyl-OR 12 , -C0-C6 alkylCO2R 12 , -C0-C6 alkyl-C(O)SR 12 , -C0-C6 alkylCONR 13 R 14 , -C0- C6alkyl-COR 15 , -C0-C6 alkylOCOR 15 , -C0-C6alkyl-OCONR 13 R 14 , -C0-C6alkyl-NR 13 CONR 13 R 14 , -C0-C6 alkyl- NR 13 COR 15 , -C0-C6alkyl-Het, -C0-C6alkyl-Ar, and–C0-C6alkyl-C3
  • W 3 is selected from the group consisting of: H, halo, C1-C6 alkyl, -C0-C6 alkyl-NR 13 R 14 ,-C0-C6 alkylSR 12 , -C0-C6 alkyl-OR 12 , -C0-C6 alkyl-CO2R 12 , -C0-C6 alkyl-C(O)SR 12 , -C0-C6 alkyl-CONR 13 R 14 ,
  • -C0-C6 alkyl-NR 13 COR 15 -C0-C6 alkyl-Het, -C1-C6 alkyl-Ar and–C1-C6 alkyl-C3-C7 cycloalkyl, wherein said C1-C6 alkyl is optionally unsubstituted or substituted by one or more halo substituents;
  • Q is selected from C3-C8 cycloalkyl, Ar, and Het; wherein said C3-C8 cycloalkyl, Ar, and Het are optionally unsubstituted or substituted with one or more groups independently selected from halo, cyano, nitro, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl,-C0-C6 alkylCO2R 12 , -C0-C6 alkyl-C(O)SR 12 , -C0-C6 alkylCONR 13 R 14 , -C0-C6 alkyl-COR 15 , -C0-C6 alkylNR 13 R 14 , -C0-C6 alkyl-SR 12 , -C0-C6 alkyl-OR 12 , -C0-C6 alkyl-SO3H, -C0-C6 alkyl-SO2NR 13 R 14 , -C0-C6 alkyl-SO2R
  • p 0-8;
  • n 2-8;
  • n 0 or 1
  • q is 0 or 1
  • t is 0 or 1;
  • each R 1 and R 2 are independently selected from H, halo, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, -C0-C6 alkyl-NR 13 R 14 , -C0-C6 alkyl-OR 12 , -C0-C6 alkyl-SR 12 , -C1-C6 alkyl-Het, -C1-C6 alkyl-Ar, and–C1-C6 alkyl-C3-C7 cycloalkyl, or R 1 and R 2 together with the carbon to which they are attached form a 3-5 membered carbocyclic or heterocyclic ring, wherein said heterocyclic ring contains one, or more heteroatoms selected from N, O, and S, where any of said C1-C6 alkyl is optionally unsubstituted or substituted by one or more halo substituents; each R 3 is the same or different and is independently selected from halo, cyan
  • R 6 and R 7 are each independently selected from H, halo, C1-C6 alkyl, -C0-C6 alkyl-Het, -C0-C6 alkyl-Ar and–C0-C6 alkyl-C3-C7 cycloalkyl;
  • R 8 and R 9 are each independently selected from H, halo, C1-C6 alkyl, -C0-C6 alkyl-Het, -C0-C6 alkyl-Ar and–C0-C6 alkyl-C3-C7 cycloalkyl;
  • R 10 and R 11 are each independently selected from H, C1-C12 alkyl, C3-C12 alkenyl, C3-C12 alkynyl, -C0-C8 alkyl-Ar, -C0-C8 alkyl-Het, -C0-C8 alkyl-C3-C7 cycloalkyl, -C0-C8 alkyl-O-Ar, -C0-C8 alkyl-O- Het,
  • R 12 is selected from H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, -C0-C6 alkyl-Ar, -C0-C6 alkyl-Het and–C0-C6 alkyl-C3-C7 cycloalkyl;
  • each R 13 and each R 14 are independently selected from H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, -C0-C6 alkyl-Ar, -C0-C6 alkyl-Het, and-C0-C6 alkyl-C3-C7 cycloalkyl, or R 13 and R 14 together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring which optionally contains one or more additional heteroatoms selected from N, O, and S;
  • R 15 is selected from C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, -C0-C6 alkyl-Ar, -C0-C6 alkyl- Het, and–C0-C6 alkyl-C3-C7 cycloalkyl;
  • the LXR ⁇ agonist has the structure of Formula V:
  • R 00 is G 1 , G 21 , or R N ;
  • R 200 is G 1 , G 21 , or R C ;
  • R 300 and R 400 are independently R C or Q, provided one and only one of R 300 , R 400 , and R 500 is Q;
  • G 1 is–L 10 -R, wherein L 10 is a bond, L 50 , L 60 , -L 50 -L 60 -L 50 -, or -L 60 -L 50 -L 50 -, wherein
  • each L 50 is independently -[C(R 150 )2]m-;
  • R is aryl, heterocyclyl, heteroaryl or -(C3-C6) cycloalkyl, wherein R is optionally substituted with 1 to 4 R A , wherein each R A is independently halogen, nitro, heterocyclyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl)-C1-C6 alkyl-, (C3-C8 cycloalkenyl)-C1-C6 alkyl-, (C3-C8 cycloalkyl)-C1-C6 alkenyl-, arylalkyl, aryloxy, aryl-C1-6 alkoxy, C1-C6 haloalkyl, SO2R 110 , OR 110 , SR 110 , N3, SOR 110 , COR 110 , SO2N(R 110 )2,
  • each R A is optionally substituted with 1 to 4 groups which
  • L 31 is C2-6 alidiyl chain wherein the alidiyl chain is optionally interrupted by -C(R 110 )2-,
  • R 60 is C1-C6 alkyl, C1-C6 halo alkyl, aryl, C3-C8 cycloalkyl, heteroaryl, heterocyclyl, -CN,
  • each R 60a is independently -Z, -Y’-Z, or-X-Y-Z;
  • each R C is independently–L 30 -R 70 , wherein
  • each L 30 is independently a bond or-(CH2) m -V 10 -(CH2) n -, wherein
  • each L 30 is independently C2-C6 alidiyl, wherein the alidiyl chain is optionally interrupted by–C(R 110 )2-, - C(R 110 )2C(R 110 )2-, -C(R 110 )C(R 110 )-, -C(R 110 )2O-, -C(R 110 )2NR 110 -, -C ⁇ C-, -O-, -S-, -N(R 100 )CO-,
  • each R 70 is independently hydrogen, halogen, nitro, aryl, heteroaryl, heterocyclyl, -Z, -Y-Z, or-X- Y-Z,
  • aryl, heteroaryl, and heterocyclyl are each optionally substituted with 1 to 4 R 70a , wherein each R 70a is independently aryloxy, aralkyloxy, aryloxyalkyl, aryl-C0-C6 alkylcarboxy,
  • each R 70a is optionally substituted with 1 to 4 R 80 , and wherein each R 80 is independently halogen, C1 -C6 alkyl, C1-C6 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkyl(OR 110 ), C0-C6 alkylOR 110 , C0-C6 alkylCON(R 110 )2, C0-C6 alkylCOR 110 , C0-C6 alkylCOOR 110 , or C0- C6 alkylSO2R 110 ;
  • each R 130 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
  • each R 140 is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C0-C6
  • each R 150 is independently hydrogen, halogen, OR 130 , (C1- C6) alkyl or (C1-C6) haloalkyl, wherein each alkyl is optionally substituted with at least one group which are each independently halogen, cyano, nitro, azido, OR 130 , C(O)R 130 , C(O)OR 13 C(O)N(R 130 )2, N(R 130 )2, N(R 130 )C(O)R 130 , N(R 130 )S(O)2R 130 , -OC(O)OR 130 , OC(O)N(R 130 )2, N(R 130 )C(O)OR 130 , N(R 130 )C(O)N(R 130 ), SR 130 , S(O)R 130 , S(O)2R', or S(O)2N(R 130 )2; or two R 150 (bonded to same or different atoms) can be taken together to form a C3-C6 cycl
  • each X is independently -O-, -S-, or -N(R 100 )-;
  • each Y is independently -[C(R 150 )2] p -, or-C2-C6 alkenyl, wherein p is 1, 2, 3, 4, 5, or 6;
  • each Y' is independently -[C(R 150 )2]p -, -C2-C6 alkenyl C3-C8 cycloalkyl, or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with 1 to 3 Z groups;
  • each m and n is independently 0, 1, 2, 3, 4, 5, or 6.
  • LXR ⁇ agonist is any compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments of any of the foregoing methds, the LXR ⁇ agonist is a compound of any one of Formula I-XXXVI or a pharmaceutically acceptable salt thereof. In some embodiments of any of the foregoing methods, LXR ⁇ agonist is any one of compounds 1-826 or a pharmaceutically acceptable salt thereof. In some embodiments of any of the foregoing methods, the LXR ⁇ agonist is compound 682, compound 692, compound 705, compound 718, or compound 719, or a pharmaceutically acceptable salt thereof.
  • the cancer is a drug resistant cancer or has failed to respond to a prior therapy (e.g., a cancer resistant to, or a cancer that has failed to respond to prior treatment with, vemurafenib, dacarbazine, a CTLA4 inhibitor, a PD1 inhibitor, interferon therapy, a BRAF inhibitor, a MEK inhibitor, radiotherapy, temozolimide, irinotecan, a CAR-T therapy, herceptin, perjeta, tamoxifen, xeloda, docetaxol, platinum agents such as carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inihibitors, alimta, abraxane, adriamycin, gemcitabine, avastin, halaven, neratinib, a PARP inhibitor, ARN810, an mTOR inhibitor, topote
  • a prior therapy e.g.,
  • the cancer is metastatic.
  • the cancer can include cells exhibiting migration and/or invasion of migrating cells and/or include cells exhibiting endothelial recruitment and/or angiogenesis.
  • the cancer is a cell migration cancer.
  • the cell migration cancer is a non-metastatic cell migration cancer.
  • the cancer can be a cancer spread via seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces.
  • the cancer can be a cancer spread via the lymphatic system, or a cancer spread hematogenously.
  • the cancer is a cell migration cancer that is a non-metastatic cell migration cancer, such as ovarian cancer, mesothelioma, or primary lung cancer.
  • the cancer is ovarian cancer, breast cancer, lung cancer, glioblastoma, melanoma, bladder cancer, head and neck cancer, renal cell cancer, colorectal cancer, lymphoma, leukemia, multiple myeloma, or hepatocellular carcinoma.
  • the cancer is breast cancer such as triple negative breast cancer, colon cancer, renal cell cancer, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, ovarian cancer, pancreatic cancer, esophageal cancer, prostate cancer, sarcoma, glioblastoma, diffuse large B-cell lymphoma, leukemia (e.g., acute myeloid leukemia), or melanoma.
  • the cancer is melanoma.
  • the cancer is breast cancer.
  • the cancer is renal cell cancer.
  • the cancer is pancreatic cancer. In some embodiments of any of the foregoing methods, the cancer is non-small cell lung cancer. In some embodiments of any of the foregoing methods, the cancer is colon cancer. In some embodiments of any of the foregoing methods, the cancer is ovarian cancer. In some embodiments of any of the foregoing methods, the cancer is glioblastoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some
  • the cancer is diffuse large B-cell lymphoma.
  • the cancer is leukemia (e.g., acute myeloid leukemia).
  • the cancer is melanoma (e.g., metastatic melanoma) that is resistant to, or has failed to respond to prior treatment with, vemurafenib, dacarbazine, interferon therapy, a CTLA- 4 inhibitor, a BRAF inhibitor, a MEK inhibitor, a PD1 inhibitor, a PDL-1 inhibitor, and/or a CAR-T therapy.
  • the cancer is glioblastoma that is resistant to, or has failed to respond to prior treatment with, temozolimide, radiotherapy, avastin, irinotecan, a VEGFR2 inhibitor, a CAR-T therapy, and/or an mTOR inhibitor.
  • the cancer is non-small cell lung cancer such as metastatic non-small cell lung cancer (e.g., EGFR-wild type non-small cell lung cancer and/or squamous non-small cell lung cancer) that is resistant to, or has failed to respond to prior treatment with, an EGFR inhibitor, platinum agents (e.g., carboplatin), avastin, an ALK inhibitor, a MET inhibitor, a taxane (e.g., paclitaxel and/or doceltaxel), gemzar, alimta, radiotherapy, a PD1 inhibitor, a PDL1 ihibitor, and/or a CAR-T therapy.
  • metastatic non-small cell lung cancer e.g., EGFR-wild type non-small cell lung cancer and/or squamous non-small cell lung cancer
  • platinum agents e.g., carboplatin
  • avastin e.g., carboplatin
  • an ALK inhibitor e.g.,
  • the cancer is a breast cancer (e.g., triple negative breast cancer) that is resistant to, or has failed to respond to prior treatment with, herceptin, perjeta, tamoxifen, xeloda, docetaxel, carboplatin, paclitaxel, abraxane, adriamycin, gemcitabine, avastin, halaven, neratinib, a PARP inhibitor, a PD1 inhibitor, a PDL1 inhibitor, a CAR-T therapy, ARN810, and/or an mTOR inhibitor.
  • a breast cancer e.g., triple negative breast cancer
  • the cancer is ovarian cancer (e.g., metastatic ovarian cancer) that is resistant to, or has failed to respond to prior treatment with, a PARP inhibitor, avastin, platinum agents such as carboplatin, paclitaxel, docetaxel, topotecan, gemzar, a VEGR2 inhibitor, a folate receptor antagonist, a PD1 inhibitor, a PDL1 inhibitor, a CAR-T therapy, demcizumab, and/or fosbretabulin.
  • a PARP inhibitor e.g., metastatic ovarian cancer
  • platinum agents such as carboplatin, paclitaxel, docetaxel, topotecan, gemzar
  • a VEGR2 inhibitor a folate receptor antagonist
  • PD1 inhibitor a PD1 inhibitor
  • PDL1 inhibitor a PDL1 inhibitor
  • demcizumab demcizumab
  • fosbretabulin e.g., metastatic ovarian cancer
  • the cancer has increased expression of LRP1 compared to a predetermined level (e.g., a level determined to correlate with efficacy and/or the level in sample from a subject that does not respond to LXR ⁇ agonist treatment.
  • a predetermined level e.g., a level determined to correlate with efficacy and/or the level in sample from a subject that does not respond to LXR ⁇ agonist treatment.
  • the term“compound,” is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched forms of the structures depicted.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Examples prototropic tautomers include ketone– enol pairs, amide– imidic acid pairs, lactam– lactim pairs, amide– imidic acid pairs, enamine– imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds.“Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei.
  • isotopes of hydrogen include tritium and deuterium.
  • the compounds and salts of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods.
  • substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges.
  • the term“C1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
  • a phrase of the form“optionally substituted X” e.g., optionally substituted alkyl
  • X optionally substituted alkyl
  • the alkyl is optionally substituted
  • acyl represents a hydrogen or an alkyl group (e.g., a haloalkyl group), as defined herein, that is attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl.
  • exemplary unsubstituted acyl groups include from 1 to 7, from 1 to 11, or from 1 to 21 carbons.
  • the alkyl group is further substituted with 1, 2, 3, or 4 substituents as described herein.
  • Non-limiting examples of optionally substituted acyl groups include, alkoxycarbonyl,
  • alkoxycarbonylacyl arylalkoxycarbonyl, aryloyl, carbamoyl, carboxyaldehyde, (heterocyclyl) imino, and (heterocyclyl)oyl:
  • alkoxycarbonyl which as used herein, represents an alkoxy, as defined herein, attached to the parent molecular group through a carbonyl atom (e.g., -C(O)-OR, where R is H or an optionally substituted C1-6, C1-10, or C1-20 alkyl group).
  • exemplary unsubstituted alkoxycarbonyl include from 1 to 21 carbons (e.g., from 1 to 11 or from 1 to 7 carbons).
  • the alkoxy group is further substituted with 1, 2, 3, or 4 substituents as described herein.
  • alkoxycarbonylacyl represents an acyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -C(O) -alkyl-C(O)-OR, where R is an optionally substituted C1-6, C1-10, or C1-20 alkyl group).
  • R is an optionally substituted C1-6, C1-10, or C1-20 alkyl group.
  • alkoxycarbonylacyl include from 3 to 41 carbons (e.g., from 3 to 10, from 3 to 13, from 3 to 17, from 3 to 21, or from 3 to 31 carbons, such as C1-6 alkoxycarbonyl-C1-6 acyl, C1-10 alkoxycarbonyl-C1-10 acyl, or C1-20 alkoxycarbonyl-C1-20 acyl).
  • each alkoxy and alkyl group is further independently substituted with 1, 2, 3, or 4 substituents, as described herein (e.g., a hydroxy group) for each group.
  • The“arylalkoxycarbonyl” group which as used herein, represents an arylalkoxy group, as defined herein, attached to the parent molecular group through a carbonyl (e.g., -C(O)-O-alkyl-aryl).
  • exemplary unsubstituted arylalkoxy groups include from 8 to 31 carbons (e.g., from 8 to 17 or from 8 to 21 carbons, such as C6-10 aryl-C1-6 alkoxy-carbonyl, C6-10 aryl-C1-10 alkoxy-carbonyl, or C6-10 aryl-C1-20 alkoxy-carbonyl).
  • the arylalkoxycarbonyl group can be substituted with 1, 2, 3, or 4 substituents as defined herein.
  • The“aryloyl” group which as used herein, represents an aryl group, as defined herein, that is attached to the parent molecular group through a carbonyl group.
  • exemplary unsubstituted aryloyl groups are of 7 to 11 carbons.
  • the aryl group can be substituted with 1, 2, 3, or 4 substituents as defined herein.
  • The“carbamoyl” group which as used herein, represents–C(O)-N(R N1 )2, where the meaning of each R N1 is found in the definition of“amino” provided herein.
  • The“carboxyaldehyde” group which as used herein, represents an acyl group having the structure–CHO.
  • The“(heterocyclyl) imino” group which as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through an imino group.
  • the heterocyclyl group can be substituted with 1, 2, 3, or 4 substituent groups as defined herein.
  • The“(heterocyclyl)oyl” group which as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through a carbonyl group.
  • the heterocyclyl group can be substituted with 1, 2, 3, or 4 substituent groups as defined herein.
  • alkyl is inclusive of both straight chain and branched chain saturated groups from 1 to 20 carbons (e.g., from 1 to 10 or from 1 to 6), unless otherwise specified.
  • Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, and neopentyl, and may be optionally substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four substituents independently selected from the group consisting of: (1) C1-6 alkoxy; (2) C1-6 alkylsulfinyl; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(R N1 )2, where R N1 is as defined for amino); (4) C6-10 aryl-C1-6 alkoxy; (5) azi
  • alkylene and the prefix“alk-,” as used herein, represent a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, and isopropylene.
  • the term“Cx-y alkylene” and the prefix“Cx-y alk-” represent alkylene groups having between x and y carbons. Exemplary values for x are 1, 2, 3, 4, 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-6, C1-10, C2-20, C2-6, C2-10, or C2-20 alkylene).
  • the alkylene can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for an alkyl group.
  • Non-limiting examples of optionally substituted alkyl and alkylene groups include acylaminoalkyl, acyloxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkylsulfinyl, alkylsulfinylalkyl, aminoalkyl, carbamoylalkyl, carboxyalkyl, carboxyaminoalkyl, haloalkyl, hydroxyalkyl, perfluoroalkyl, and sulfoalkyl:
  • The“acylaminoalkyl” group which as used herein, represents an acyl group, as defined herein, attached to an amino group that is in turn attached to the parent molecular group through an alkylene group, as defined herein (i.e.,–alkyl-N(R N1 )-C(O)-R, where R is H or an optionally substituted C1-6, C1-10, or C1-20 alkyl group (e.g., haloalkyl) and R N1 is as defined herein).
  • alkylene group as defined herein (i.e.,–alkyl-N(R N1 )-C(O)-R, where R is H or an optionally substituted C1-6, C1-10, or C1-20 alkyl group (e.g., haloalkyl) and R N1 is as defined herein).
  • acylaminoalkyl groups include from 1 to 41 carbons (e.g., from 1 to 7, from 1 to 13, from 1 to 21, from 2 to 7, from 2 to 13, from 2 to 21, or from 2 to 41 carbons).
  • the alkylene group is further substituted with 1, 2, 3, or 4 substituents as described herein, and/or the amino group is–NH2 or– NHR N1 , wherein R N1 is, independently, OH, NO2, NH2, NR N2 2, SO2OR N2 , SO2R N2 , SOR N2 , alkyl, aryl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), or alkoxycarbonylalkyl, and each R N2 can be H, alkyl, or aryl.
  • The“acyloxyalkyl” group which as used herein, represents an acyl group, as defined herein, attached to an oxygen atom that in turn is attached to the parent molecular group though an alkylene group (i.e.,–alkyl-O-C(O)-R, where R is H or an optionally substituted C1-6, C1-10, or C1-20 alkyl group).
  • alkylene group i.e.,–alkyl-O-C(O)-R, where R is H or an optionally substituted C1-6, C1-10, or C1-20 alkyl group.
  • exemplary unsubstituted acyloxyalkyl groups include from 1 to 21 carbons (e.g., from 1 to 7 or from 1 to 11 carbons).
  • the alkylene group is, independently, further substituted with 1, 2, 3, or 4 substituents as described herein.
  • The“alkoxyalkyl” group which as used herein, represents an alkyl group that is substituted with an alkoxy group.
  • exemplary unsubstituted alkoxyalkyl groups include between 2 to 40 carbons (e.g., from 2 to 12 or from 2 to 20 carbons, such as C1-6 alkoxy-C1-6 alkyl, C1-10 alkoxy-C1-10 alkyl, or C1-20 alkoxy- C1-20 alkyl).
  • the alkyl and the alkoxy each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group.
  • alkoxycarbonylalkyl represents an alkyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -alkyl-C(O)-OR, where R is an optionally substituted C1-20, C1-10, or C1-6 alkyl group).
  • Exemplary unsubstituted alkoxycarbonylalkyl include from 3 to 41 carbons (e.g., from 3 to 10, from 3 to 13, from 3 to 17, from 3 to 21, or from 3 to 31 carbons, such as C1-6 alkoxycarbonyl-C1-6 alkyl, C1-10 alkoxycarbonyl-C1-10 alkyl, or C1-20 alkoxycarbonyl- C1-20 alkyl).
  • each alkyl and alkoxy group is further independently substituted with 1, 2, 3, or 4 substituents as described herein (e.g., a hydroxy group).
  • The“alkylsulfinylalkyl” group which as used herein, represents an alkyl group, as defined herein, substituted with an alkylsulfinyl group.
  • exemplary unsubstituted alkylsulfinylalkyl groups are from 2 to 12, from 2 to 20, or from 2 to 40 carbons.
  • each alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.
  • The“aminoalkyl” group which as used herein, represents an alkyl group, as defined herein, substituted with an amino group, as defined herein.
  • the alkyl and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group (e.g., CO2R A’ , where R A’ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) hydrogen, and (d) C1-6 alk-C6-10 aryl, e.g., carboxy, and/or an N-protecting group).
  • The“carbamoylalkyl” group which as used herein, represents an alkyl group, as defined herein, substituted with a carbamoyl group, as defined herein.
  • the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.
  • The“carboxyalkyl” group which as used herein, represents an alkyl group, as defined herein, substituted with a carboxy group, as defined herein.
  • the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein, and the carboxy group can be optionally substituted with one or more O-protecting groups.
  • The“carboxyaminoalkyl” group which as used herein, represents an aminoalkyl group, as defined herein, substituted with a carboxy, as defined herein.
  • the carboxy, alkyl, and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group (e.g., CO2R A’ , where R A’ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) hydrogen, and (d) C1-6 alk-C6-10 aryl, e.g., carboxy, and/or an N-protecting group, and/or an O-protecting group).
  • The“haloalkyl” group which as used herein, represents an alkyl group, as defined herein, substituted with a halogen group (i.e., F, Cl, Br, or I).
  • a haloalkyl may be substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four halogens.
  • Haloalkyl groups include perfluoroalkyls (e.g., -CF3), -CHF2, -CH2F, -CCl3, -CH2CH2Br, -CH2CH(CH2CH2Br)CH3, and -CHICH3.
  • the haloalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • The“hydroxyalkyl” group which as used herein, represents an alkyl group, as defined herein, substituted with one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group, and is exemplified by hydroxymethyl and dihydroxypropyl.
  • the hydroxyalkyl group can be substituted with 1, 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.
  • The“perfluoroalkyl” group which as used herein, represents an alkyl group, as defined herein, where each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical.
  • Perfluoroalkyl groups are exemplified by trifluoromethyl.
  • The“sulfoalkyl” group which as used herein, represents an alkyl group, as defined herein, substituted with a sulfo group of–SO3H.
  • the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein, and the sulfo group can be further substituted with one or more O-protecting groups (e.g., as described herein).
  • alkenyl represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1- propenyl, 1-butenyl, and 2-butenyl.
  • Alkenyls include both cis and trans isomers.
  • Alkenyl groups may be optionally substituted with 1, 2, 3, or 4 substituent groups that are selected, independently, from amino, aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.
  • Non-limiting examples of optionally substituted alkenyl groups include, alkoxycarbonylalkenyl, aminoalkenyl, and hydroxyalkenyl:
  • alkoxycarbonylalkenyl represents an alkenyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -alkenyl-C(O)- OR, where R is an optionally substituted C1-20, C1-10, or C1-6 alkyl group).
  • Exemplary unsubstituted alkoxycarbonylalkenyl include from 4 to 41 carbons (e.g., from 4 to 10, from 4 to 13, from 4 to 17, from 4 to 21, or from 4 to 31 carbons, such as C1-6 alkoxycarbonyl-C2-6 alkenyl, C1-10 alkoxycarbonyl-C2-10 alkenyl, or C1-20 alkoxycarbonyl-C2-20 alkenyl).
  • each alkyl, alkenyl, and alkoxy group is further independently substituted with 1, 2, 3, or 4 substituents as described herein (e.g., a hydroxy group).
  • The“aminoalkenyl” group which as used herein, represents an alkenyl group, as defined herein, substituted with an amino group, as defined herein.
  • the alkenyl and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group (e.g., CO2R A’ , where R A’ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) hydrogen, and (d) C1-6 alk-C6-10 aryl, e.g., carboxy, and/or an N-protecting group).
  • The“hydroxyalkenyl” group which as used herein, represents an alkenyl group, as defined herein, substituted with one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group, and is exemplified by
  • the hydroxyalkenyl group can be substituted with 1, 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.
  • alkynyl represents monovalent straight or branched chain groups from 2 to 20 carbon atoms (e.g., from 2 to 4, from 2 to 6, or from 2 to 10 carbons) containing a carbon- carbon triple bond and is exemplified by ethynyl, and 1-propynyl.
  • Alkynyl groups may be optionally substituted with 1, 2, 3, or 4 substituent groups that are selected, independently, from aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.
  • Non-limiting examples of optionally substituted alkynyl groups include alkoxycarbonylalkynyl, aminoalkynyl, and hydroxyalkynyl:
  • alkoxycarbonylalkynyl represents an alkynyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -alkynyl-C(O)-OR, where R is an optionally substituted C1-20, C1-10, or C1-6 alkyl group).
  • R is an optionally substituted C1-20, C1-10, or C1-6 alkyl group.
  • alkoxycarbonylalkynyl include from 4 to 41 carbons (e.g., from 4 to 10, from 4 to 13, from 4 to 17, from 4 to 21, or from 4 to 31 carbons, such as C1-6 alkoxycarbonyl-C2-6 alkynyl, C1-10 alkoxycarbonyl-C2-10 alkynyl, or C1-20 alkoxycarbonyl-C2-20 alkynyl).
  • each alkyl, alkynyl, and alkoxy group is further independently substituted with 1, 2, 3, or 4 substituents as described herein (e.g., a hydroxy group).
  • The“aminoalkynyl” group which as used herein, represents an alkynyl group, as defined herein, substituted with an amino group, as defined herein.
  • the alkynyl and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group (e.g., CO2R A’ , where R A’ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) hydrogen, and (d) C1-6 alk-C6-10 aryl, e.g., carboxy, and/or an N-protecting group).
  • The“hydroxyalkynyl” group which as used herein, represents an alkynyl group, as defined herein, substituted with one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group.
  • the hydroxyalkynyl group can be substituted with 1, 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.
  • each R N1 is, independently, H, OH, NO2, N(R N2 )2, SO2OR N2 , SO2R N2 , SOR N2 , an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkcycloalkyl, carboxyalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl groups or any described herein), sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., optionally substituted with an O- protecting group, such as optionally substituted arylalkoxycarbonyl groups or any described herein), heterocyclyl (e.
  • amino groups of the invention can be an unsubstituted amino (i.e.,–NH2) or a substituted amino (i.e.,– N(R N1 )2).
  • amino is–NH2 or–NHR N1 , wherein R N1 is, independently, OH, NO2, NH2, NR N2 2, SO2OR N2 , SO2R N2 , SOR N2 , alkyl, carboxyalkyl, sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., t-butoxycarbonylalkyl) or aryl, and each R N2 can be H, C1-20 alkyl (e.g., C1-6 alkyl), or C6-10 aryl.
  • Non-limiting examples of optionally substituted amino groups include acylamino and carbamyl:
  • The“acylamino” group which as used herein, represents an acyl group, as defined herein, attached to the parent molecular group though an amino group, as defined herein (i.e.,–N(R N1 )-C(O)-R, where R is H or an optionally substituted C1-6, C1-10, or C1-20 alkyl group (e.g., haloalkyl) and R N1 is as defined herein).
  • acylamino groups include from 1 to 41 carbons (e.g., from 1 to 7, from 1 to 13, from 1 to 21, from 2 to 7, from 2 to 13, from 2 to 21, or from 2 to 41 carbons).
  • the alkyl group is further substituted with 1, 2, 3, or 4 substituents as described herein, and/or the amino group is–NH2 or–NHR N1 , wherein R N1 is, independently, OH, NO2, NH2, NR N2 2, SO2OR N2 , SO2R N2 , SOR N2 , alkyl, aryl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), or alkoxycarbonylalkyl, and each R N2 can be H, alkyl, or aryl.
  • amino acid refers to a molecule having a side chain, an amino group, and an acid group (e.g., a carboxy group of–CO2H or a sulfo group of–SO3H), wherein the amino acid is attached to the parent molecular group by the side chain, amino group, or acid group (e.g., the side chain).
  • the amino acid is attached to the parent molecular group by a carbonyl group, where the side chain or amino group is attached to the carbonyl group.
  • Exemplary side chains include an optionally substituted alkyl, aryl, heterocyclyl, alkaryl, alkheterocyclyl, aminoalkyl, carbamoylalkyl, and carboxyalkyl.
  • Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, hydroxynorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.
  • Amino acid groups may be optionally substituted with one, two, three, or, in the case of amino acid groups of two carbons or more, four substituents independently selected from the group consisting of: (1) C1-6 alkoxy; (2) C1-6 alkylsulfinyl; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(R N1 )2, where R N1 is as defined for amino); (4) C6-10 aryl-C1-6 alkoxy; (5) azido; (6) halo; (7) (C2-9 heterocyclyl)oxy; (8) hydroxy; (9) nitro; (10) oxo (e.g., carboxyaldehyde or acyl); (11) C1-7 spirocyclyl; (12) thioalkoxy; (13) thiol; (14) -CO2R A’ , where R A’ is selected from the group consisting
  • aryl represents a mono-, bicyclic, or multicyclic carbocyclic ring system having one or two aromatic rings and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, phenanthrenyl, fluorenyl, indanyl, and indenyl, and may be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: (1) C1-7 acyl (e.g., carboxyaldehyde); (2) C1-20 alkyl (e.g., C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkylsulfinyl-C1-6 alkyl, amino-C1-6 alkyl, azido-C1-6 alkyl, (carboxyaldehyde)-C1-6 alkyl, halo-C1-6
  • (CH2)qCONR B’ R C’ where q is an integer from zero to four and where R B’ and R C’ are independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6-10 aryl, and (d) C1-6 alk-C6-10 aryl; (19)–(CH2)qSO2R D’ , where q is an integer from zero to four and where R D’ is selected from the group consisting of (a) alkyl, (b) C6-10 aryl, and (c) alk-C6-10 aryl; (20)–(CH2)qSO2NR E’ R F’ , where q is an integer from zero to four and where each of R E’ and R F’ is, independently, selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6-10 aryl, and (d) C1-6 alk-C6-10 aryl; (21) thiol; (22) C6-10 aryloxy;
  • each of these groups can be further substituted as described herein.
  • the alkylene group of a C1-alkaryl or a C1-alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.
  • The“arylalkyl” group which as used herein, represents an aryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein.
  • exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-6 alk-C6-10 aryl, C1-10 alk-C6-10 aryl, or C1-20 alk-C6-10 aryl).
  • the alkylene and the aryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups.
  • Other groups preceded by the prefix“alk-” are defined in the same manner, where“alk” refers to a C1-6 alkylene, unless otherwise noted, and the attached chemical structure is as defined herein.
  • bicyclic refers to a structure having two rings, which may be aromatic or non-aromatic.
  • Bicyclic structures include spirocyclyl groups, as defined herein, and two rings that share one or more bridges, where such bridges can include one atom or a chain including two, three, or more atoms.
  • Exemplary bicyclic groups include a bicyclic carbocyclyl group, where the first and second rings are carbocyclyl groups, as defined herein; a bicyclic aryl groups, where the first and second rings are aryl groups, as defined herein; bicyclic heterocyclyl groups, where the first ring is a heterocyclyl group and the second ring is a carbocyclyl (e.g., aryl) or heterocyclyl (e.g., heteroaryl) group; and bicyclic heteroaryl groups, where the first ring is a heteroaryl group and the second ring is a carbocyclyl (e.g., aryl) or heterocyclyl (e.g., heteroaryl) group.
  • the bicyclic group can be substituted with 1, 2, 3, or 4 substituents as defined herein for cycloalkyl, heterocyclyl, and aryl groups.
  • boranyl represents–B(R B1 )3, where each R B1 is, independently, selected from the group consisting of H and optionally substituted alkyl.
  • the boranyl group can be substituted with 1, 2, 3, or 4 substituents as defined herein for alkyl.
  • Carbocyclic and“carbocyclyl,” as used herein, refer to an optionally substituted C3-12 monocyclic, bicyclic, or tricyclic structure in which the rings, which may be aromatic or non-aromatic, are formed by carbon atoms.
  • Carbocyclic structures include cycloalkyl, cycloalkenyl, and aryl groups.
  • cyano represents an–CN group.
  • cycloalkyl represents a monovalent saturated or unsaturated non- aromatic cyclic hydrocarbon group from three to eight carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and bicycle heptyl.
  • the cycloalkyl group can be referred to as a “cycloalkenyl” group.
  • Exemplary cycloalkenyl groups include cyclopentenyl, and cyclohexenyl.
  • the cycloalkyl groups of this invention can be optionally substituted with: (1) C1-7 acyl (e.g.,
  • C1-20 alkyl e.g., C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkylsulfinyl-C1-6 alkyl, amino- C1-6 alkyl, azido-C1-6 alkyl, (carboxyaldehyde)-C1-6 alkyl, halo-C1-6 alkyl (e.g., perfluoroalkyl), hydroxy-C1-6 alkyl, nitro-C1-6 alkyl, or C1-6 thioalkoxy-C1-6 alkyl); (3) C1-20 alkoxy (e.g., C1-6 alkoxy, such as
  • each of these groups can be further substituted as described herein.
  • the alkylene group of a C1-alkaryl or a C1-alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.
  • The“cycloalkylalkyl” group which as used herein, represents a cycloalkyl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein (e.g., an alkylene group of from 1 to 4, from 1 to 6, from 1 to 10, or form 1 to 20 carbons).
  • an alkylene group as defined herein (e.g., an alkylene group of from 1 to 4, from 1 to 6, from 1 to 10, or form 1 to 20 carbons).
  • the alkylene and the cycloalkyl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group.
  • diastereomer as used herein means stereoisomers that are not mirror images of one another and are non-superimposable on one another.
  • enantiomer means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.
  • halo represents a halogen selected from bromine, chlorine, iodine, or fluorine.
  • heteroalkyl refers to an alkyl group, as defined herein, in which one or two of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • heteroalkenyl and heteroalkynyl refer to alkenyl and alkynyl groups, as defined herein, respectively, in which one or two of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkenyl and heteroalkynyl groups can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • Non-limiting examples of optionally substituted heteroalkyl, heteroalkenyl, and heteroalkynyl groups include acyloxy, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonylalkoxy, alkynyloxy, aminoalkoxy, arylalkoxy, carboxyalkoxy, cycloalkoxy, haloalkoxy, (heterocyclyl)oxy, perfluoroalkoxy, thioalkoxy, and thioheterocyclylalkyl:
  • The“acyloxy” group which as used herein, represents an acyl group, as defined herein, attached to the parent molecular group though an oxygen atom (i.e.,–O-C(O)-R, where R is H or an optionally substituted C1-6, C1-10, or C1-20 alkyl group).
  • exemplary unsubstituted acyloxy groups include from 1 to 21 carbons (e.g., from 1 to 7 or from 1 to 11 carbons).
  • the alkyl group is further substituted with 1, 2, 3, or 4 substituents as described herein.
  • alkenyloxy represents a chemical substituent of formula–OR, where R is a C2-20 alkenyl group (e.g., C2-6 or C2-10 alkenyl), unless otherwise specified.
  • alkenyloxy groups include ethenyloxy, and propenyloxy.
  • the alkenyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein (e.g., a hydroxy group).
  • alkoxy group which as used herein, represents a chemical substituent of formula–OR, where R is a C1-20 alkyl group (e.g., C1-6 or C1-10 alkyl), unless otherwise specified.
  • exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy.
  • the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein (e.g., hydroxy or alkoxy).
  • The“alkoxyalkoxy” group which as used herein, represents an alkoxy group that is substituted with an alkoxy group.
  • exemplary unsubstituted alkoxyalkoxy groups include between 2 to 40 carbons (e.g., from 2 to 12 or from 2 to 20 carbons, such as C1-6 alkoxy-C1-6 alkoxy, C1-10 alkoxy-C1-10 alkoxy, or C1-20 alkoxy-C1-20 alkoxy).
  • the each alkoxy group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.
  • alkoxycarbonylalkoxy represents an alkoxy group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -O-alkyl-C(O)-OR, where R is an optionally substituted C1-6, C1-10, or C1-20 alkyl group).
  • R is an optionally substituted C1-6, C1-10, or C1-20 alkyl group.
  • alkoxycarbonylalkoxy include from 3 to 41 carbons (e.g., from 3 to 10, from 3 to 13, from 3 to 17, from 3 to 21, or from 3 to 31 carbons, such as C1-6 alkoxycarbonyl-C1-6 alkoxy, C1-10 alkoxycarbonyl-C1-10 alkoxy, or C1-20 alkoxycarbonyl-C1-20 alkoxy).
  • each alkoxy group is further independently substituted with 1, 2, 3, or 4 substituents, as described herein (e.g., a hydroxy group).
  • alkynyloxy represents a chemical substituent of formula–OR, where R is a C2-20 alkynyl group (e.g., C2-6 or C2-10 alkynyl), unless otherwise specified.
  • exemplary alkynyloxy groups include ethynyloxy, and propynyloxy.
  • the alkynyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein (e.g., a hydroxy group).
  • The“aminoalkoxy” group which as used herein, represents an alkoxy group, as defined herein, substituted with an amino group, as defined herein.
  • the alkyl and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group (e.g., CO2R A’ , where R A’ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) hydrogen, and (d) C1-6 alk-C6-10 aryl, e.g., carboxy).
  • The“arylalkoxy” group which as used herein, represents an alkaryl group, as defined herein, attached to the parent molecular group through an oxygen atom.
  • Exemplary unsubstituted arylalkoxy groups include from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C6-10 aryl-C1-6 alkoxy, C6-10 aryl-C1-10 alkoxy, or C6-10 aryl-C1-20 alkoxy).
  • the arylalkoxy group can be substituted with 1, 2, 3, or 4 substituents as defined herein.
  • The“aryloxy” group which as used herein, represents a chemical substituent of formula–OR′, where R′ is an aryl group of 6 to 18 carbons, unless otherwise specified.
  • the aryl group can be substituted with 1, 2, 3, or 4 substituents as defined herein.
  • The“carboxyalkoxy” group which as used herein, represents an alkoxy group, as defined herein, substituted with a carboxy group, as defined herein.
  • the alkoxy group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the alkyl group, and the carboxy group can be optionally substituted with one or more O-protecting groups.
  • The“cycloalkoxy” group which as used herein, represents a chemical substituent of formula– OR, where R is a C3-8 cycloalkyl group, as defined herein, unless otherwise specified.
  • the cycloalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.
  • Exemplary unsubstituted cycloalkoxy groups are from 3 to 8 carbons.
  • the cycloalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.
  • The“haloalkoxy” group which as used herein, represents an alkoxy group, as defined herein, substituted with a halogen group (i.e., F, Cl, Br, or I).
  • a haloalkoxy may be substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four halogens.
  • Haloalkoxy groups include perfluoroalkoxys (e.g., -OCF3), -OCHF2, -OCH2F, -OCCl3, -OCH2CH2Br, -OCH2CH(CH2CH2Br)CH3, and - OCHICH3.
  • the haloalkoxy group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • The“(heterocyclyl)oxy” group which as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through an oxygen atom.
  • the heterocyclyl group can be substituted with 1, 2, 3, or 4 substituent groups as defined herein.
  • The“perfluoroalkoxy” group which as used herein, represents an alkoxy group, as defined herein, where each hydrogen radical bound to the alkoxy group has been replaced by a fluoride radical.
  • Perfluoroalkoxy groups are exemplified by trifluoromethoxy.
  • alkylsulfinyl which as used herein, represents an alkyl group attached to the parent molecular group through an -S(O)- group.
  • exemplary unsubstituted alkylsulfinyl groups are from 1 to 6, from 1 to 10, or from 1 to 20 carbons.
  • the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.
  • The“thioarylalkyl” group which as used herein, represents a chemical substituent of formula– SR, where R is an arylalkyl group.
  • R is an arylalkyl group.
  • the arylalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.
  • The“thioalkoxy” group as used herein represents a chemical substituent of formula–SR, where R is an alkyl group, as defined herein. In some embodiments, the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.
  • The“thioheterocyclylalkyl” group, which as used herein, represents a chemical substituent of formula–SR, where R is an heterocyclylalkyl group. In some embodiments, the heterocyclylalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.
  • heteroaryl represents that subset of heterocyclyls, as defined herein, which are aromatic: i.e., they contain 4n+2 pi electrons within the mono- or multicyclic ring system.
  • exemplary unsubstituted heteroaryl groups are of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons.
  • the heteroaryl is substituted with 1, 2, 3, or 4 substituents groups as defined for a heterocyclyl group.
  • heteroarylalkyl refers to a heteroaryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein.
  • exemplary unsubstituted heteroarylalkyl groups are from 2 to 32 carbons (e.g., from 2 to 22, from 2 to 18, from 2 to 17, from 2 to 16, from 3 to 15, from 2 to 14, from 2 to 13, or from 2 to 12 carbons, such as C1-6 alk-C1-12 heteroaryl, C1-10 alk-C1-12 heteroaryl, or C1-20 alk-C1-12 heteroaryl).
  • the alkylene and the heteroaryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group.
  • Heteroarylalkyl groups are a subset of heterocyclylalkyl groups.
  • heterocyclyl represents a 5-, 6- or 7-membered ring, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the 5-membered ring has zero to two double bonds, and the 6- and 7-membered rings have zero to three double bonds.
  • Exemplary unsubstituted heterocyclyl groups are of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons.
  • heterocyclyl also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and/or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group.
  • heterocyclyl includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, and benzothienyl.
  • carbocyclic rings e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl,
  • fused heterocyclyls include tropanes and 1,2,3,5,8,8a-hexahydroindolizine.
  • Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, indazolyl, quinolyl, isoquinolyl,
  • Still other exemplary heterocyclyls include: 2,3,4,5-tetrahydro-2-oxo-oxazolyl; 2,3-dihydro-2-oxo-1H- imidazolyl; 2,3,4,5-tetrahydro-5-oxo-1H-pyrazolyl (e.g., 2,3,4,5-tetrahydro-2-phenyl-5-oxo-1H-pyrazolyl); 2,3,4,5-tetrahydro-2,4-dioxo-1H-imidazolyl (e.g., 2,3,4,5-tetrahydro-2,4-dioxo-5-methyl-5-phenyl-1H- imidazolyl); 2,3-dihydro-2-thioxo-1,3,4-oxadiazolyl (e.g., 2,3-dihydro-2-thioxo-5-phenyl-1,3,4-oxadiazolyl); 4,5-dihydro-5-oxo-1H-triazolyl (
  • heterocyclics include 3,3a,4,5,6,6a- hexahydro-pyrrolo[3,4-b]pyrrol-(2H)-yl, and 2,5-diazabicyclo[2.2.1]heptan-2-yl, homopiperazinyl (or diazepanyl), tetrahydropyranyl, dithiazolyl, benzofuranyl, benzothienyl, oxepanyl, thiepanyl, azocanyl, oxecanyl n hi n l.
  • Heterocyclic groups also include groups of the formula , where
  • E′ is selected from the group consisting of -N- and -CH-;
  • G′ is selected from the group consisting of -CH- and -N-.
  • any of the heterocyclyl groups mentioned herein may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: (1) C1-7 acyl (e.g., carboxyaldehyde ); (2) C 1-20 alkyl (e.g., C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkylsulfinyl-C 1-6 alkyl, amino-C 1-6 alkyl, azido-C 1-6 alkyl, (carboxyaldehyde)-C1-6 alkyl, halo-C1-6 alkyl (e.g., perfluoroalkyl), hydroxy-C1-6 alkyl, nitro-C1-6 alkyl, or C1-6 thioalkoxy-C1-6 alkyl); (3) C1-20 alkoxy (e.g., C1-6 alkoxy, such as perfluoroalkoxy); (4) C1-6 alkylsulfinyl; (5)
  • each of these groups can be further substituted as described herein.
  • the alkylene group of a C1-alkaryl or a C1-alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.
  • heterocyclylalkyl which as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein.
  • exemplary unsubstituted heterocyclylalkyl groups are from 2 to 32 carbons (e.g., from 2 to 22, from 2 to 18, from 2 to 17, from 2 to 16, from 3 to 15, from 2 to 14, from 2 to 13, or from 2 to 12 carbons, such as C1-6 alk-C1-12 heterocyclyl, C1-10 alk-C1-12 heterocyclyl, or C1-20 alk-C1-12 heterocyclyl).
  • the alkylene and the heterocyclyl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group.
  • hydrocarbon represents a group consisting only of carbon and hydrogen atoms.
  • hydroxy represents an–OH group.
  • the hydroxy group can be substituted with 1, 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.
  • isomer means any tautomer, stereoisomer, enantiomer, or diastereomer of any compound of the invention. It is recognized that the compounds of the invention can have one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
  • stereoisomers such as double-bond isomers (i.e., geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
  • the chemical structures depicted herein, and therefore the compounds of the invention encompass all of the corresponding stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates.
  • Enantiomeric and stereoisomeric mixtures of compounds of the invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and stereoisomers can also be obtained from stereomerically or
  • N-protected amino refers to an amino group, as defined herein, to which is attached one or two N-protecting groups, as defined herein.
  • N-protecting group represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene,“Protective Groups in Organic Synthesis,” 3 rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference.
  • N-protecting groups include acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4- chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl, and p-toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl, p- chlor
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t- butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
  • nitro represents an–NO2 group.
  • O-protecting group represents those groups intended to protect an oxygen containing (e.g., phenol, hydroxyl, or carbonyl) group against undesirable reactions during synthetic procedures. Commonly used O-protecting groups are disclosed in Greene,“Protective Groups in Organic Synthesis,” 3 rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference.
  • O-protecting groups include acyl, aryloyl, or carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t- butyldimethylsilyl, tri-iso-propylsilyloxymethyl, 4,4'-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4- isopropylpehenoxyacetyl, dimethylformamidino, and 4-nitrobenzoyl; alkylcarbonyl groups, such as acyl, acetyl, propionyl, and pi
  • alkoxycarbonyls such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, n-isopropoxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, sec- butyloxycarbonyl, t-butyloxycarbonyl, 2-ethylhexyloxycarbonyl, cyclohexyloxycarbonyl, and
  • ethoxymethoxycarbonyl 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl, 2-butoxyethoxycarbonyl, 2- methoxyethoxymethoxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, 2-butenoxycarbonyl, and 3- methyl-2-butenoxycarbonyl; haloalkoxycarbonyls, such as 2-chloroethoxycarbonyl, 2- chloroethoxycarbonyl, and 2,2,2-trichloroethoxycarbonyl; optionally substituted arylalkoxycarbonyl groups, such as benzyloxycarbonyl, p-methylbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2,4-dinitrobenzyloxycarbonyl, 3,5-dimethylbenzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-bromo
  • perfluoro represents anyl group, as defined herein, where each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical.
  • perfluoroalkyl groups are exemplified by trifluoromethyl.
  • protected hydroxyl refers to an oxygen atom bound to an O-protecting group.
  • spirocyclyl represents a C2-7 alkylene diradical, both ends of which are bonded to the same carbon atom of the parent group to form a spirocyclic group, and also a C1-6 heteroalkylene diradical, both ends of which are bonded to the same atom.
  • the heteroalkylene radical forming the spirocyclyl group can containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the spirocyclyl group includes one to seven carbons, excluding the carbon atom to which the diradical is attached.
  • the spirocyclyl groups of the invention may be optionally substituted with 1, 2, 3, or 4 substituents provided herein as optional substituents for cycloalkyl and/or heterocyclyl groups.
  • stereoisomer refers to all possible different isomeric as well as conformational forms which a compound may possess (e.g., a compound of any formula described herein), in particular all possible stereochemically and conformationally isomeric forms, all diastereomers, enantiomers and/or conformers of the basic molecular structure. Some compounds of the present invention may exist in different tautomeric forms, all of the latter being included within the scope of the present invention.
  • sulfonyl represents an -S(O)2- group.
  • the term“a” may be understood to mean“at least one”;
  • the term“or” may be understood to mean“and/or”;
  • the terms“comprising” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; and
  • the terms“about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (v) where ranges are provided, endpoints are included.
  • administration refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system.
  • Administration to an animal subject may be by any appropriate route.
  • administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal,
  • biological sample or“sample” is meant a fluid or solid sample from a subject.
  • Biological samples may include cells; nucleic acid, protein, or membrane extracts of cells; or blood or biological fluids including (e.g., plasma, serum, saliva, urine, bile).
  • Solid biological samples include samples taken from feces, the rectum, central nervous system, bone, breast tissue, renal tissue, the uterine cervix, the endometrium, the head or neck, the gallbladder, parotid tissue, the prostate, the brain, the pituitary gland, kidney tissue, muscle, the esophagus, the stomach, the small intestine, the colon, the liver, the spleen, the pancreas, thyroid tissue, heart tissue, lung tissue, the bladder, adipose tissue, lymph node tissue, the uterus, ovarian tissue, adrenal tissue, testis tissue, the tonsils, and the thymus.
  • Fluid biological samples include samples taken from the blood, serum, plasma, pancreatic fluid, CSF, semen, prostate fluid, seminal fluid, urine, saliva, sputum, mucus, bone marrow, lymph, and tears. Samples may be obtained by standard methods including, e.g., venous puncture and surgical biopsy.
  • the biological sample is a blood, plasma, or serum sample.
  • the biological sample is a tumor sample from a biopsy.
  • cancer refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukimias, and lymphomas.
  • Cell migration involves the invasion by the cancer cells into the surrounding tissue and the crossing of the vessel wall to exit the vasculature in distal organs of the cancer cell.
  • cell migration cancers is meant cancers that migrate by invasion by the cancer cells into the surrounding tissue and the crossing of the vessel wall to exit the vasculature in distal organs of the cancer cell.
  • classifying a subject is meant predicting a response to an anticancer therapy by a subject; selecting a subject that may benefit from an anticancer therapy; selecting a subject who may benefit from an LXR ⁇ agonist; predicting the responsiveness of a subject to an LXR ⁇ agonist; or selecting a subject that may benefit from an anticancer therapy other than, or in addition to, an LXR ⁇ agonist.
  • a“combination therapy” or“administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition.
  • the treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap.
  • the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated.
  • the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen.
  • administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other.
  • the effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic).
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally.
  • determining the level of a cell type is meant the detection of a cell type by methods known in the art either directly or indirectly.
  • Directly determining means performing a process (e.g., performing an assay or test on a sample or“analyzing a sample” as that term is defined herein) to obtain the physical entity or value.
  • Indirectly determining refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value).
  • Methods to measure cell levels generally include, but are not limited to, flow cytometry and immunohistochemistry. Exemplary methods are provided herein.
  • the level of MDSCs and/or activated T-cells may be determined as described in Iclozan et al. Cancer Immunol. Immunother.2013, 62(5): 909-918. In some embodiments of any of the foregong methods, the level of MDSCs and/or activated T-cells may be determined as described in Kitano et al. Cancer Immunol. Res.2014, 2(8); 812-821.
  • determining the level of a protein or mRNA is meant the detection of a protein or mRNA by methods known in the art either directly or indirectly.
  • Directly determining means performing a process (e.g., performing an assay or test on a sample or“analyzing a sample” as that term is defined herein) to obtain the physical entity or value.
  • Indirectly determining refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value).
  • Methods to measure protein level generally include, but are not limited to, western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA),
  • MALDI-TOF desorption/ionization time-of-flight
  • LC liquid chromatography
  • FACS fluorescence activated cell sorting
  • flow cytometry as well as assays based on a property of a protein including, but not limited to, enzymatic activity or interaction with other protein partners.
  • a cancer“determined to be drug resistant,” as used herein, refers to a cancer that is drug resistant, based on unresponsiveness or decreased responsiveness to a chemotherapeutic agent, or is predicted to be drug resistant based on a prognostic assay (e.g., a gene expression assay).
  • a prognostic assay e.g., a gene expression assay
  • diagnosis is meant identifying a molecular or pathological state, disease or condition, such as the identification of cancer, or to refer to identification of a subject having cancer who may benefit from a particular treatment regimen.
  • a“drug resistant” cancer is meant a cancer that does not respond, or exhibits a decreased response to, one or more chemotherapeutic agents (e.g., any agent described herein such as any compound of Table 3).
  • an effective amount means an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, and/or condition in accordance with a therapeutic dosing regimen, to treat the disease, disorder, and/or condition.
  • a therapeutically effective amount is one that reduces the incidence and/or severity of, and/or delays onset of, one or more symptoms of the disease, disorder, and/or condition.
  • an effective amount does not in fact require successful treatment be achieved in a particular individual. Rather, an effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment.
  • reference to an effective amount may be a reference to an amount as measured in one or more specific tissues (e.g., a tissue affected by the disease, disorder or condition) or fluids (e.g., blood, saliva, serum, sweart, tears, urine, etc).
  • tissue e.g., a tissue affected by the disease, disorder or condition
  • fluids e.g., blood, saliva, serum, sweart, tears, urine, etc.
  • an effective amount may be formulated and/or administered in a single dose.
  • an effective amount may be formulated and/or administered in a plurality of doses, for example, as part of a dosing regimen.
  • the term“failed to respond to a prior therapy” or“refractory to a prior therapy,” refers to a cancer that progressed despite treatment with the therapy.
  • a“decreased level” or an“increased level” of a cell type is meant a decrease or increase in cell level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as compared to a reference; a decrease or an increase by less than about 0.01-fold, about 0.02-fold, about 0.1-fold, about 0.3-fold,
  • a level of a cell type may be expressed in mass/vol (e.g., g/dL, mg/mL, ⁇ g/mL, ng/mL) or percentage relative to total cells in a sample.
  • the reference is a sample from a healthy subject such as a subject that does not have cancer.
  • the reference is an artificial sample with a level (e.g., a level of MDSCs such as monocytic and/or granulocytic MDSCs or activated T-cells) shown beneficial in the treatment of a disorder.
  • metastatic nodule refers to an aggregation of tumor cells in the body at a site other than the site of the original tumor.
  • metastatic tumor refers to a tumor or cancer in which the cancer cells forming the tumor have a high potential to or have begun to, metastasize, or spread from one location to another location or locations within a subject, via the lymphatic system or via haematogenous spread, for example, creating secondary tumors within the subject. Such metastatic behavior may be indicative of malignant tumors. In some cases, metastatic behavior may be associated with an increase in cell migration and/or invasion behavior of the tumor cells.
  • cancers that can be defined as metastatic include but are not limited to non-small cell lung cancer, breast cancer, ovarian cancer, colorectal cancer, biliary tract cancer, bladder cancer, brain cancer including glioblastomas and medullablastomas, cervical cancer, choriocarcinoma, endometrial cancer, esophageal cancer, gastric cancer, hematological neoplasms, multiple myeloma, leukemia, intraepithelial neoplasms, livercancer, lymphomas, neuroblastomas, oral cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer including melanoma, basocellular cancer, squamous cell cancer, testicular cancer, stromal tumors, germ cell tumors, thyroid cancer, and renal cancer.
  • “migrating cancer” refers to a cancer in which the cancer cells forming the tumor migrate and subsequently grow as malignant implants at a site other than the site of the original tumor.
  • the cancer cells migrate via seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces to spread into the body cavities; via invasion of the lymphatic system through invasion of lymphatic cells and transport to regional and distant lymph nodes and then to other parts of the body; via haematogenous spread through invasion of blood cells; or via invasion of the surrounding tissue.
  • Migrating cancers include metastatic tumors and cell migration cancers, such as ovarian cancer, mesothelioma, and primary lung cancer, each of which is characterized by cellular migration.
  • Non-metastatic cell migration cancer refers to cancers that do not migrate via the lymphatic system or via haematogenous spread.
  • the term“pharmaceutical composition” refers to an active compound, formulated together with one or more pharmaceutically acceptable carriers.
  • active compound is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam;
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses
  • A“pharmaceutically acceptable excipient,” as used herein, refers any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) having the properties of being nontoxic and non-inflammatory in a subject.
  • Typical excipients include, for example:
  • antiadherents antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration.
  • Excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine,
  • BHT butylated hydroxytoluene
  • BHT butylated hydroxytoluene
  • calcium carbonate calcium phosphate (dibasic)
  • calcium stearate calcium stearate
  • croscarmellose crosslinked polyvinyl pyrrolidone
  • citric acid crospovidone
  • cysteine ethylcellulose
  • gelatin hydroxypropyl cellulose, hydroxypropyl methylcellulose
  • Those of ordinary skill in the art are familiar with a variety of agents and materials useful as excipients.
  • pharmaceutically acceptable salt refers to those salts of the compounds described here that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.
  • the compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases.
  • the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
  • Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulphuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like for forming basic salts. Methods for preparation of the appropriate salts are well-established in the art.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
  • Predetermined level refers to a pre-specified particular level of one or more particular cell type, e.g., MDSCs such as monocytic and/or granulocytic MDSCs or activated T-cells.
  • a predetermined level is an absolute value or range.
  • a predetermined level is a relative value.
  • a predetermined level is the same as or different (e.g., higher or lower than) a level of one or more particular cell type in a reference, e.g., a reference tumor sample, or a level specified in a reference document such as a pharmaceutical specification.
  • a predetermined level is an absolute level or range of one or more cell type in a sample. In some embodiments, a predetermined level is a level or range of one or more cell types in a sample relative to total level of cells in the sample. In some embodiments, a predetermined level is a level or range of one or more cell types in a sample relative to total level of cells in the sample. In some embodiments, a predetermined level is expressed as a percent.
  • Treatment-free survival refers to the length of time during and after medication or treatment during which the disease being treated (e.g., cancer) does not get worse.
  • “Proliferation” as used in this application involves reproduction or multiplication of similar forms (cells) due to constituting (cellular) elements.
  • a“reference” is meant any useful reference used to compare protein or mRNA levels related to cancer.
  • the reference can be any sample, standard, standard curve, or level that is used for comparison purposes.
  • the reference can be a normal reference sample or a reference standard or level.
  • A“reference sample” can be, for example, a control, e.g., a predetermined negative control value such as a“normal control” or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having cancer; a sample from a subject that has been treated for cancer (e.g., with an LXR ⁇ agonist); or a sample of a purified protein (e.g., any described herein) at a known normal concentration.
  • reference standard or level is meant a value or number derived from a reference sample.
  • A“normal control value” is a pre- determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”).
  • a subject having a measured value within the normal control value for a particular biomarker is typically referred to as“within normal limits” for that biomarker.
  • a normal reference standard or level can be a value or number derived from a normal subject not having cancer; or a subject that has been treated for cancer.
  • the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health.
  • a standard curve of levels of a purified protein, e.g., any described herein, within the normal reference range can also be used as a reference.
  • selecting a subject is meant to choose a subject directly or indirectly in preference to others based on an analysis, e.g., analysis of results of the methods of the invention or clinical evaluation.
  • Directly selecting means performing a process (e.g., performing an analysis) to choose a subject.
  • Indirectly selecting refers to receiving the results of an analysis from another party or source (e.g., a third party laboratory that directly performed the analysis).
  • another party or source e.g., a third party laboratory that directly performed the analysis.
  • slowing the spread of metastasis refers to reducing or stopping the formation of new loci; or reducing, stopping, or reversing the tumor load.
  • “slowing the spread of migrating cancer” refers to reducing or stopping the formation of new loci; or reducing, stopping, or reversing the tumor load.
  • the term“subject,” as used herein, refers to a human or non-human animal (e.g., a mammal such as a non-human primate, horse, cow, or dog).
  • the term“substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • the term“substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
  • A“therapeutic regimen” refers to a dosing regimen whose administration across a relevant population is correlated with a desired or beneficial therapeutic outcome.
  • treatment refers to any administration of a substance (e.g., provided compositions) that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition .
  • a substance e.g., provided compositions
  • such treatment may be administered to a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition.
  • treatment may be administered to a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
  • treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and/or condition.
  • tumor seeding refers to the spillage of tumor cell clusters and their subsequent growth as malignant implants at a site other than the site of the original tumor.
  • PD-1 inhibitor refers to a compound such as an antibody capable of inhibiting the activity of the protein that in humans is encoded by the PDCD1 gene.
  • PD-1 inhibitors include nivolumab, pembrolizumab, pidilizumab, BMS 936559, BGB-A317, and MPDL328OA.
  • PD-L1 inhibitor refers to a compound such as an antibody capable of inhibiting the activity of the protein that in humans is encoded by the CD274 gene.
  • Known PD-L1 inhibitors include atezolizumab, avelumab, and durvalumab (MEDI4736).
  • CTLA-4 inhibitor refers to a compound such as an antibody capable of inhibiting the activity of the protein that in humans is encoded by the CTLA4 gene.
  • CTLA-4 inhibitors include ipilimumab and tremelimumab.
  • CSF-1R inhibitors refers to a compound such as an antibody capable of inhibiting the activity of the protein that in humans is encoded by the CSF1R gene.
  • Known CSF-1R inhibitors include pexidartinib and AZD6495.
  • IDO inhibitor refers to a compound such as an antibody capable of inhibiting the activity of the protein that in humans is encoded by the IDO1 gene.
  • IDO inhibitors include norharmane, rosmarinic acid, COX-2 inhibitors, epacadostat, GDC-0919, and alpha-methyl- tryptophan.
  • A1 adenosine inhibitor refers to a compound such as an antibody capable of inhibiting the activity of the protein that in humans is encoded by the ADORA1 gene.
  • Known A1 adenosine inhibitors include 8-cyclopentyl-1,3-dimethylxanthine, 8-cyclopentyl-1,3-dipropylxanthine, 8- phenyl-1,3-dipropylxanthine, bamifylline, BG-9719, BG-9928, FK-453, FK-838, rolofylline, and N-0861.
  • A2A adenosine inhibitor refers to a compound such as an antibody capable of inhibiting the activity of the protein that in humans is encoded by the ADORA2A gene.
  • Known A2A adenosine inhibitors include ATL-4444, istradefylline, MSX-3, preladenant, SCH-58261, SCH- 412,348, SCH-442,416, ST-1535, VER-6623, VER-6947, VER-7835, viadenant, and ZM-241,385.
  • A2B adenosine inhibitor refers to a compound such as an antibody capable of inhibiting the activity of the protein that in humans is encoded by the ADORA2B gene.
  • Known A2B adenosine inhibitors include ATL-801, CVT-6883, MRS-1706, MRS-1754, OSIP-339,391, PSB-603, PSB-0788, and PSB-1115.
  • A3A adenosine inhibitor refers to a compound such as an antibody capable of inhibiting the activity of the protein that in humans is encoded by the ADORA3 gene.
  • Known A3A adenosine inhibitors include KF-26777, MRS-545, MRS-1191, MRS-1220, MRS-1334, MRS-1523, MRS-3777, MRE-3005-F20, MRE-3008-F20, PSB-11, OT-7999, VUF-5574, and SSR161421.
  • arginase inhibitor refers to a compound capable of inhibiting the activity of a protein that in humans is encoded by the ARG1 or ARG2 genes.
  • arginase inhibitors include (2s)-(+)-amino-5-iodoacetamidopentanoic acid, NG-hydroxy-L-arginine, (2S)-(+)-amino-6- iodoacetamidohexanoic acid, and (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid.
  • HDAC inhibitor refers to a compound such as an antibody that is capable of inhibiting the activity of the protein that is a member of the histone deacetylase class of enzymes, e.g., HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, HDAC11, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7.
  • HDAC inhibitors include valproic acid, SAHA, romidepsin, and entinostat.
  • FIG.1A is an image of a flow cytometry plot illustrating the population of MDSCs (Gr1+ CD11b+ cells) in a control treated sample compared to a sample treated with compound 682.
  • FIG.1B is a graph illustrating the quantification of MDSCs (Gr1+ CD11b+ cells) in a control treated sample compared to a sample treated with compound 682.
  • FIG.1C is an image from a confocal microscope of tumors immunohistochemically stained for the MDSC marker Gr1.
  • FIG.1D is a graph illustrating quantification of the number of Gr1+ cells in a control treated sample compared to a sample treated with compound 682 per microscopic low-power field.
  • FIG.1E is a graph illustrating the correlation between tumor size and the number of MDSCs (Gr1+ CD11b+ cells) in B16F10 tumor bearing mice treated with compound 682.
  • FIG.2A is an image of a flow cytometry plot illustrating the population of activated CD8+ cells in control treated B16F10 tumor-bearing mice compared to B16F10 tumor-bearing mice treated with compound 682.
  • FIG.2B is a graph illustrating quantification of activated CD8+ cells in control treated B16F10 tumor-bearing mice compared to B16F10 tumor-bearing mice treated with compound 682.
  • FIG.2C is a graph illustrating the correlation between tumor size and the number of activated CD8+ cells in B16F10 tumor bearing mice treated with compound 682.
  • FIG.3A is an image of a flow cytometry plot illustrating the population of G-MDSCs (Ly6-G+) and M-MDSCs (Ly6-C+) in control treated B16F10 tumor-bearing mice compared to B16F10 tumor-bearing mice treated with compound 705. (gated on total CD11b+ cells)
  • FIG.3B is a graph illustrating quantification of G-MDSCs (Ly6-G+) and M-MDSCs (Ly6-C+)in control treated B16F10 tumor-bearing mice compared to B16F10 tumor-bearing mice treated with compound 705 as a percentage of total tumor-infiltrating CD45+ TILs.
  • FIG.3C is a graph illustrating quantification of circulating MDSCs (CD11b+ Ly6G+ cells) in control treated or compound 705 treated B16F10 tumor-bearing mice as a total percentage of circulating CD45+ lymphocytes.
  • FIG.4A is an image illustrating quantification of MDSC abundance in vitro after 3 hours of treatment with 1 ⁇ M compound 705 or control (DMSO).
  • FIG.4B is an image illustrating quantification of CD8+ cell activation (percentage of CD8+ IFN ⁇ + BV- cells of the total CD8+ population) after 24 hours of co-culture with MDSCs isolated from control- treated or compound 705 treated tumor-bearing mice.
  • FIG.5A is a graph illustrating tumor growth by B16F10 cells subcutaneously injected into pmel mice. Following tumor cell injection, animals were injected once every 3 days with 250 ⁇ g of anti-PD1 antibody I.P. and either fed a control chow or a chow supplemented with compound 705 (50 mg/kg) once tumor growth reached 5-10 mm 3 in volume.
  • FIG.5B is an image of flow-cytometry plots showing the population of activated CD8+ cells (CD8+ IFN ⁇ + Granzyme-B+ cells) in mice treated with either anti-PD-1 antibody alone or anti-PD-1 antibody in combination with compound 705.
  • FIG.5C is graph illustrating quantification of activated CD8+ cells (CD8+ IFN ⁇ + Granzyme-B+ cells) in mice treated with either anti-PD-1 antibody alone or anti-PD-1 antibody in combination with compound 705.
  • FIG.6 is a Kaplan-Meier survival curve showing the survival of mice injected subcutaneously with B16F10 and treated with either control chow, control chow plus intravenous adoptive transfer of 2 x 10 ⁇ 6 CD8+ T-cells from pmel mice, or chow supplemented with compound 705 (50 mg/kg) plus intravenous adoptive transfer of 2 x 10 ⁇ 6 CD8+ T-cells from pmel mice.
  • FIG.7A is a graph illustrating tumor growth by B16F10 cells subcutaneously injected into C57BL/6 mice. Following tumor growth to 5–10 mm 3 in volume, mice were fed a control chow or a chow supplemented with compound 682 (100 mg/kg).
  • FIG.7B is graph illustrating tumor growth by B16F10 cells depleted of ApoE by shRNA subcutaneously injected into ApoE deficient mice. Following tumor growth to 5–10 mm 3 in volume, mice were fed a control chow or a chow supplemented with compound 682 (100 mg/kg).
  • FIG.7C is a graph illustrating quantification of MDSCs isolated from ApoE depleted B16F10 treated tumors grown in ApoE deficient mice treated with control or compound 682.
  • FIG.8A is an image of flow-cytometry plots showing the populations of splenic G-MDSCs (Gr1 high) and M-MDSCs (Gr1 int) in wild type and ApoE deficient mice.
  • FIG.8B is a graph illustrating quantification of splenic G-MDSCs and M-MDSCs in wild type and ApoE deficient mice.
  • FIG.8C is an image of flow-cytometry plots showing the populations of splenic G-MDSCs (Gr1 high) and M-MDSCs (Gr1 int) in wild type and LRP8 deficient mice.
  • FIG.8D is a graph illustrating quantification of splenic G-MDSCs and M-MDSCs in wild type and LRP8 deficient mice.
  • FIG.8E is an image of flow-cytometry plots showing the populations of splenic G-MDSCs (Gr1 high) and M-MDSCs (Gr1 int) in wild type and LRP8 deficient mice.
  • FIG.8F is a graph illustrating quantification of splenic M-MDSCs in wild type and LXR ⁇ / ⁇ deficient mice.
  • FIG.9 is a graph illustrating quantification of CD8+ T-cell activation (percentage of CD8+ IFN ⁇ + BV- cells of the total CD8+ population) after 24 hours of co-culture in vitro with MDSCs isolated from ApoE deficient mice, in either 1:3 or 1:1 ratio of MDSC to CD8+ T-cells.
  • FIG.10A is a graph illustrating quantification of MDSC abundance in vitro 18 hours after isolation from either wild-type mice or ApoE deficient mice.
  • FIG.10B is a graph illustrating quantification of abundance of wild-type and ApoE deficient MDSCs 4 hours after treatment with compound 705 or control (DMSO).
  • FIG.11A is a graph illustrating tumor growth by B16F10 cells subcutaneously injected into C57BL/6 mice or B16F10 cells depleted of ApoE with shRNA injected in ApoE deficient mice.
  • FIG.11B is an image of flow-cytometry plots showing the populations of circulating G-MDSCs (Gr1 high) and M-MDSCs (Gr1 int) in wild-type mice bearing B16F10 tumors or from ApoE deficient mice bearing ApoE depleted B16F10 tumors.
  • FIG.11C is a graph illustrating quantification of circulating MDSCs from wild-type mice bearing B16F10 tumors and from ApoE deficient mice bearing ApoE depleted B16F10 tumors.
  • FIG.12 is a graph illustrating correlation analysis of tumor growth inhibition in vivo after administration of LXR agonist compound 682 (Y-axis) versus baseline gene-expression of LRP1 in tumor cells (X-axis) measured by real-time quantitative PCR.
  • FIG.13 is a graph depicting the peak change in the percentage of circulating CD8+ T-cells that express GITR after treatment with Compound 705 in cancer patients.
  • the present invention features methods for the treatment of cancer with a combination of an LXR ⁇ agonist and a GITR modulator.
  • LXR ⁇ agonists described herein may be used to reduce the levels of MDSCs (e.g., monocytic and/or granulocytic MDSCs) and increase T-cell activation in a subject in combination with a GITR modulator to increase the anticancer effect of the T-cells to treat cancer.
  • the LXR ⁇ agonists and GITR modulators may be used in combination with additional immunotherapies to treat cancer, e.g., cancer that is resistant to, or failed to respond to, an immunotherapy.
  • the LXR ⁇ agonist is a compound of Formula I:
  • e, f, g, h, and i are independently 0, 1, 2, 3, or 4;
  • j 0, 1, 2, or 3;
  • k 0, 1, 2, 3, 4, 5, 6, 7, or 8;
  • l is 01, or 2;
  • R A ,R C , R I , R L , R M , and R T are independently hydrogen, hydroxyl, optionally substituted C1-C6 acyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C12 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C 2 -C 9 heteroaryl C1-C6 alkyl
  • R D , R E , R G , R O , R P , R Q , and R R are independently hydrogen, hydroxy, optionally substituted amino, azido, halo, thiol, optionally substituted amino acid, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C12 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optional
  • each R B , R F , R H , R K , R N , and R S are independently hydroxyl, optionally substituted amino, halo, thiol, optionally substituted amino acid, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C8-C12 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 hetero
  • R J is hydrogen, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C12 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2- C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C6 alkyl; or
  • R U is hydroxyl, oxo, optionally substituted amino, halo, thiol, optionally substituted amino acid, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C8-C12 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C
  • L is absent, -O-, -S-, -N(R 12 )-, or -C(R 4 )(R 5 )-;
  • a is 2, 3, 4, 5, 6, 7, or 8;
  • b, c, and d are independently 0 or 1;
  • each R 1 , R 2 , R 6 , R 7 , R 8 , and R 9 are independently hydrogen, hydroxyl, halo, optionally substituted amino, thiol, optionally substituted amino acid, optionally substituted C1-C6 acyl, optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C
  • R 3 is hydrogen, hydroxyl, optionally substituted amino, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, or optionally substituted C2-C9 heterocyclyl;
  • R 4 and R 5 are independently hydrogen, hydroxyl, halo, optionally substituted amino, thiol, optionally substituted amino acid, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-
  • B is optionally substituted C3-C10 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, or optionally substituted C2-C9 heterocyclyl;
  • c is 0.
  • R 4 is hydrogen. In certain embodiments, R 4 is fluorine.
  • R 5 is hydrogen. In some embodiments, R 5 is fluorine.
  • b is 1. In some embodiments, b is 0.
  • each R 6 is hydrogen. In other embodiments, each R 7 is hydrogen. In certain embodiments, d is 1. In some embodiments, each R 8 is hydrogen. In other embodiments, each R 9 is hydrogen.
  • R 3 is optionally substituted C6-C10 aryl (e.g., phenyl or 4-fluoro-phenyl).
  • R 5 is optionally substituted C6-C10 aryl (e.g., phenyl). In some embodiments, R 5 is optionally substituted C3-C10 cycloalkyl (e.g., cyclohexyl). In some embodiments, R 4 is optionally substituted C1-C6 alkyl (e.g., methyl). In certain embodiments, R 5 is optionally substituted C1-C6 alkyl (e.g., methyl). In some embodiments, R 4 and R 5 are both optionally substituted C1-C6 alkyl (e.g., methyl). In some embodiments, R 5 is hydrogen, methyl, or phenyl. In other embodiments, a is 3. In certain embodiments, each R 1 is hydrogen. In some embodiments, each R 2 is hydrogen. In other embodiments, at least one R 2 is optionally substituted C1-C6
  • alkyl e.g., methyl
  • -(CR 1 R 2 )3- has the structure: .
  • -(CR 1 R 2 )3- has the structure: . In some embodiments, -(CR 1 R 2 )3- has the structure: In some embodiments, -(CR 1 R 2 )3- has the structure: In certain embodiments, L is–O-. In certain embodiments, L is absent.
  • B is optionally substituted C6-C10 aryl (e.g., 2-chloro-3-trifluoromethyl-phenyl, 2-fluoro-3-trifluoromethyl-phenyl, 3- (1,1,2,2-tetrafluoroethoxy)-phenyl, 3-trifluoromethyl-phenyl, 3-trifluoromethyl-4-fluoro-phenyl, 3- trifluoromethoxy-phenyl, or 2,2-difluoro-1,3-benzodioxole).
  • C6-C10 aryl e.g., 2-chloro-3-trifluoromethyl-phenyl, 2-fluoro-3-trifluoromethyl-phenyl, 3- (1,1,2,2-tetrafluoroethoxy)-phenyl, 3-trifluoromethyl-phenyl, 3-trifluoromethyl-4-fluoro-phenyl, 3- trifluoromethoxy-phenyl, or 2,2-difluoro-1,3-benz
  • A is:
  • e 0, 1, 2, 3, or 4;
  • R A is hydrogen, hydroxyl, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C12 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C6 al
  • each R B is independently hydroxyl, optionally substituted amino, halo, thiol, optionally substituted amino acid, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2- C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C8-C12 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C9 heterocycl
  • R A is optionally substituted C1-C6 alkyl (e.g., methyl). In certain embodiments, e is 0. In some embodiments, e is 1 or 2. In other embodiments, each R B is halo (e.g., fluoro), optionally substituted C1-C6 alkyl (e.g.,–CH2OH, -CD2OH, -CH2CH2OH, -C(CH3)2OH, - CH(CH3)OH, -C(CF3)2OH, -CH(CF3)OH,–CH2OP(O)(OH)2, -CH2NH2, or–CH2NHC(O)CH3), or optionally substituted C1-C6 acyl (e.g., -C(O)OH, -C(O)OCH3, -C(O)CH3, -C(O)NH2, -C(O)N(CH3)2, - C(O)CF3, or -C
  • A is:
  • A is:
  • f 0, 1, 2, 3, or 4;
  • R C is hydrogen, hydroxyl, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C12 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C6 al
  • R D and R E are independently hydrogen, hydroxy, optionally substituted amino, azido, halo, thiol, optionally substituted amino acid, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C12 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substitute
  • each R F is independently hydroxyl, optionally substituted amino, halo, thiol, optionally substituted amino acid, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2- C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C8-C12 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C9 heterocycl
  • R D is hydroxyl or optionally substituted C1- C6 heteroalkyl (e.g., -SO2-CH3).
  • R E is hydrogen, halo, or optionally substituted C1- C6 alkyl (e.g., methyl).
  • R F is hydrogen, halo, or optionally substituted C1-C6 alkyl (e.g., methyl).
  • A is:
  • A is:
  • g 0, 1, 2, 3, or 4;
  • R G is hydrogen, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C12 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2- C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C6 alkyl; and
  • each R H is independently hydroxyl, optionally substituted amino, halo, thiol, optionally substituted amino acid, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2- C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C8-C12 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C9 heterocycl
  • g is 0.
  • R H is hydrogen
  • A is:
  • A is:
  • h 0, 1, 2, 3, or 4;
  • R I is hydrogen, hydroxyl, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C12 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C6 al
  • R J is independently hydrogen, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C12 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C6 alkyl;
  • each R K is independently hydroxyl, optionally substituted amino, halo, thiol, optionally substituted amino acid, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2- C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C8-C12 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C9 heterocycl
  • R J is hydrogen or R J and R K combine to form an optionally substituted C2- C9 heterocyclyl.
  • R I is optionally substituted C1-C6 alkyl (e.g., methyl).
  • h is 0.
  • h is 1.
  • R K is optionally substituted C1-C6 alkyl (e.g.,–CH2OH) or R J and R K combine to form an optionally substituted C2-C9 heterocyclyl
  • A is:
  • i 0, 1, 2, 3, or 4;
  • R L and R M are independently hydrogen, hydroxyl, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C12 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1
  • i is 0.
  • R L is hydrogen or optionally substituted C1- C6 alkyl (e.g., methyl or trifluoromethyl).
  • R M is hydrogen or optionally substituted C1-C6 alkyl (e.g., methyl or trifluoromethyl).
  • A is:
  • A is:
  • j 0, 1, 2, or 3;
  • R O , R P , R Q , and R R are independently hydrogen, hydroxyl, optionally substituted amino, azido, halo, thiol, optionally substituted amino acid,optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C12 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C
  • each R S is independently hydroxyl, optionally substituted amino, halo, thiol, optionally substituted amino acid, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2- C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C8-C12 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C9 heterocycl
  • R O is hydrogen, halo, or optionally substituted C1-C6 alkyl.
  • R P is hydrogen, halo, or optionally substituted C1-C6 alkyl.
  • R Q is hydrogen. In certain embodiments, R R is hydrogen.
  • A is:
  • A is:
  • k 0, 1, 2, 3, 4, 5, 6, 7, or 8;
  • l 0, 1, or 2;
  • R T is hydrogen, hydroxyl, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C12 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclyl C1-C6 al
  • each R U is independently hydroxyl, oxo, optionally substituted amino, halo, thiol, optionally substituted amino acid, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C8-C12 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C
  • k is 0. In certain embodiments, l is 0. In some embodiments, l is 1. In certain embodiments, l is 2. In other embodiments, R T is optionally substituted C1-C6 alkyl
  • C1-C6 heteroalkyl e.g., -SO2-CH3
  • k is 0. In certain embodiments, k is 1. In some embodiments, R U is optionally substituted C1-C6 acyl (e.g., -CO2H) or optionally substituted C1-C6 alkyl (e.g.,–CH2OH). In some embodiments, l is 0. In other embodiments, l is 1. In certain embodiments, l is 2.
  • A is:
  • the compound is a prodrug, or a pharmaceutically acceptable salt of a prodrug (e.g., A includes an -OR V group, wherein R V is:
  • each R’ and R” is independently hydrogen, optionally substituted C1-C6 alkyl, such as methyl or t-butyl, or optionally substituted C6-C10 aryl C1-C6 alkyl, such as benzyl).
  • the compound has the structure: In some embodiments, the compound has the structure: . In certain embodiments, the compound has the structure: . In certain embodiments, the compound has the structure: . In some embodiments, the compound has the structure: A
  • the compound has the structure:
  • the compound has the structure: . In some embodiments, the compound has the structure:
  • the compound has the structure:
  • the LXR ⁇ agonist is any one of compounds 1 to 97 of Table 1: Table 1: Exemplary Compounds of the Invention
  • the LXR ⁇ agonist is any one of compounds 98-680 in Table 2. Table 2. LXR ⁇ agonists
  • the LXR ⁇ agonist has the structure of Formula II:
  • Ar is an aryl group
  • R 1 is a member selected from the group consisting of
  • R 2 is a member selected from the group consisting of
  • X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently a member selected from the group consisting of:
  • Y is a divalent linking group selected from the group consisting of:
  • R 12 and R 13 are each independently selected from the group consisting of:
  • R 12 forms a five- or six-membered ring fused to Ar or to R 2 through covalent attachment to Ar or to R 2 , respectively; and the subscript m is an integer of from 1 to 2;
  • R 1 is OH
  • R 2 is -N(R 12 )S(O)m-R 2 or -N(R 12 )C(O)N(R 13 )-R 2 and is attached to a position para to the quaternary carbon attached to Ar
  • R 2 is phenyl, benzyl, or benzoyl
  • at least one of R 12 or R 13 is other than hydrogen and contains an electron-withdrawing substituent
  • R 2 is substituted with a moiety other than amino, acetamido, di(C 1 -C 7 )alkylamino, (C 1 - C7)alkylamino, halogen, hydroxy, nitro, or (C1-C7)alkyl
  • the benzene ring portion of R 2 is substituted with at least three independently selected groups in addition to the Y group or point of attachment to Y.
  • Y is–N(R 12 )S(O)2- and R 1 is OH.
  • the compounds of Formula I include but are not limited the compound with the structure shown below:
  • the LXR ⁇ agonist has the structure of Formula III:
  • R 1 is-H
  • R 2 is H, C1 to C6alkyl, C2to C6alkenyl, C2to C6alkynyl, C3 to C6 cycloalkyl, -CH2OH, C7 to C11 arylalkyl, phenyl, naphthyl, C1 to C3 perfluoroalkyl, CN, C(O)NH2, CO2R 12 or phenyl substituted independently by one or more of the groups independently selected from C1 to C3 alkyl, C2to C4 alkenyl, C2 to C4 alkynyl, C1 to C3 alkoxy, C1 to C3 perfluoroalkyl, halogen, -NO2, -NR 8 R 9 , -CN, -OH, and C1 to C3alkyl substituted with 1 to 5 fluorines, or R 2 is a heterocycle selected from the group consisting of pyridine, thiophene, benzisoxazole, benzothiophene
  • X 2 is a bond or -CH2-
  • R 3 is a heterocycle selected from pyrimidine, thiophene, furan, benzothiophene, indole, benzofuran, benzimidazole, benzothiazole, benzoxazole, and quinoline, each of which may be optionally substituted with one to three groups independently selected from C1 to C3alkyl, C1 to C3 alkoxy, hydroxy, phenyl, acyl, halogen, -NH2, -CN, - NO2, C1 to C3 perfluoroalkyl, C1 to C3 alkyl substituted with
  • W is a bond, -O-, -S-, -S(O)-, -S(O)2-, -NR 11 -, or -N(COR 12 )-;
  • Y is -CO-, -S(O) 2 -, -CONR 13 ,-CONR 13 CO-,-CONR 13 SO2-, -C(NCN)-, -CSNR 13 , -C(NH)NR 13 , or - C(O)O-;
  • j 0 to 3;
  • k 0 to 3;
  • t 0 to 2;
  • p 0 to 3;
  • Z is -CO2R 11 , -CONR 10 R 11 , -C(NR 10 )NR 11 R 12 , -CONH2NH2,-CN, -CH2OH, -NR 16 R 17 , phenyl, CONHCH(R 20 )COR 12 , phthalimide, pyrrolidine-2,5dione, thiazolidine-2,4-dione, tetrazolyl, pyrrole, indole, oxazole, 2-thioxo-l,3-thiazolinin-4-one, C1 to C7 amines, C3 to C7 cyclic amines, or C1 to C3 alkyl substituted with one to two OH groups; wherein said pyrrole is optionally substituted with one or two substituents independently selected from the group consisting of-CO2CH3,-CO2H,-COCH3,-CONH2, and -CN;
  • C1 to C7amines are optionally substituted with one to two substituents independently selected from the group consisting of -OH, halogen, -OCH3,and -C ⁇ CH;
  • phenyl is optionally substituted with CO2R 11
  • said C3 to C7 cyclic amines are optionally substituted with one or two substituents independently selected from the group consisting of -OH -CH2OH, C1 to C3 alkyl, -CH2OCH3,-CO2CH3, and -CONH2, and wherein said oxazole is optionally substituted with CH2CO2R 11 ;
  • A is phenyl, naphthyl, tetrahydronaphthyl, indan or biphenyl, each of which may be optionally substituted by one to four groups independently selected from halogen, C1 to C3 alkyl, C2 to C4 alkenyl, C2 to C4 alkynyl, acyl, hydroxy, halogen, -CN, -NO2, -CO2R 11 , -CH2CO2R 11 , phenyl, C1 to C3perfluoroalkoxy, C1 to C3 perfluoroalkyl, -NR 10 R 11 , -CH2NR 10 R 11 , -SR 11 , C1 to C6 alkyl substituted with 1 to 5 fluorines, C1 to C3alkyl substituted with 1 to 2-OH groups, C1 to C6 alkoxy optionally substituted with 1to 5 fluorines, or phenoxy optionally substituted with 1 to 2 CF3 groups; or
  • A is a heterocycle selected from pyrrole, pyridine, pyridine-N-oxide, pyrimidine, pyrazole, thiophene, furan, quinoline, oxazole, thiazole, imidazole, isoxazole, indole, benzo[1,3]-dioxole, benzo[1,2,5]-oxadiazole, isochromen-l-one, benzothiophene, benzofuran,2,3-di- 5 hydrobenzo[1,4]- dioxine, bitheinyl, quinazolin-2,4-9[3H]dione, and 3-H-isobenzofuran-l-one, each of which may be optionally substituted by one to three groups independently selected from halogen, C1 to C3 alkyl, acyl, hydroxy, -CN,-NO2,C1 to C3perfluoroalkyl, -NR 10 R 11 , -CH2NR 10
  • R 4 , R 5 , and R 6 are each, independently, -H or -F;
  • R 7 is C1 to C4 alkyl, C1 to C4 perfluoroalkyl, halogen, -NO2, -CN, phenyl or phenyl substituted with one or two groups independently selected from halogen, C1 to C2alkyl and OH;
  • R 3 is selected from:
  • phenyl moiety is further optionally substituted with one or two groups independently selected from C1 to C2 alkyl, C1 to C2perfluoroalkyl, halogen, and CN; and
  • -CH CHA(CH2)kD(CH2)pZ, -C ⁇ CA(CH2)kD(CH2)pZ, or -W(CH2)jC ⁇ CA(CH2)kD(CH2)pZ;
  • each R 8 is independently-H, or C1 to C3alkyl
  • each R 9 is independently-H, or C1 to C3alkyl
  • each R 10 is independently-H, -CH, C1 to C3alkoxy, C1 to C7 alkyl, C3 to C7 alkenyl, C3 to C7 alkynyl, C3 to C7 cycloalkyl, -CH2CH2OCH3, 2-methyl-tetrahydro-furan, 2-methyl-tetrahydro-pyran, 4-methyl- piperidine, morpholine, pyrrolidine, or phenyl optionally substituted with one or two C1 to C3alkoxy groups, wherein said C1 to C7 alkyl is optionally substituted with 1, 2 or 3 groups independently selected from C1 to C3 alkoxy, C1 to C3thioalkoxy, and CN;
  • each R 11 is independently-H, C1 to C3alkyl or R 22 ; or R 10 and R 11 , when attached to the same atom, together with said atom form:
  • a 5 to 7 membered saturated ring optionally substituted by 1 to 2 groups independently selected from C1 to C3 alkyl, OH and C1-C3alkoxy; or a 5 to 7 membered ring containing 1 or 2 heteroatoms,
  • 1 to 2 groups independently selected from C1 to C3alkyl, OH and C1-C3 alkoxy;
  • each R 12 is independently-H, or C1 to C3alkyl
  • each R 13 is independently-H, or C1 to C3alkyl
  • each R 14 and R 15 is, independently, C1 toC7 alkyl, C3 to C8 cycloalkyl, C2 to C7 alkenyl, C2 to C7 alkynyl,-CH, -F, C7 to C14arylalkyl, where said arylalkyl is optionally substituted with 1 to 3 groups independently selected from NO2, C1 to C6 alkyl, C1 toC3perhaloalkyl, halogen, CH2CO2R 11 , phenyl and C1 to C3 alkoxy, or R 12 and R 15 together with the atom to which they are attached can form a 3 to 7 membered saturated ring;
  • each R 16 and R 17 is, independently, hydrogen, C1 to C3 alkyl, C1 to C3alkenyl, C1 to C3 alkynyl, phenyl, benzyl or C3 to C8 cycloalkyl, wherein said C1 to C3 alkyl is optionally substituted with one OH group, and wherein said benzyl is optionally substituted with 1 to 3 groups selected from C1 to C3alkyl and C1 to C3alkoxy; or R 16 and R 17 , together with the atom to which they are attached, can form a 3 to 8 membered heterocycle which is optionally substituted with one or two substituents independently selected from the group consisting of C1 to C3alkyl,-OH, CH2OH, -CH2OCH3,-CO2CH3, and-CONH2;
  • each R 18 and R 19 is, independently, C1 to C3alkyl; each R 20 is independently H, phenyl, or the side chain of a naturally occurring alpha amino acid; each R 22 is independently arylalkyl optionally substituted with CH2COOH; and
  • each R23 is phenyl
  • Compounds of Formula II can be synthesized as described in US patent No.7,576,215, incorporated herein by reference.
  • the compound of formula II can be any of compounds 26-32, or a pharmaceutically acceptable salt thereof.
  • the LXR ⁇ agonist has the structure of Formula IV: wherein:
  • X is selected from hydrogen, C1-C8 alkyl, halo, -OR 10 , -NR 10 R 11 , nitro, cyano, -COOR 10 , or - COR 10 .
  • Z is CH, CR 3 or N, wherein when Z is CH or CR 3 , k is 0-4 and t is 0 or 1, and when Z is N, k is 0-3 and t is 0;
  • Y is selected from -O-, -S-, -N(R 12 )-, and -C(R 4 )(R 5 )- ;
  • W 1 is selected from C1-C6 alkyl, C0-C6 alkyl, C3-C6 cycloalkyl, aryl and Het, wherein said C1-C8 alkyl, C 3 -C 8 cycloalkyl, Ar and Het are optionally unsubstituted or substituted with one or more groups independently selected from halo, cyano, nitro, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl,-C0-C6 alkyl- CO2R 12 , -C0-C6alkyl-C(O)SR 12 , -C0-C6alkyl-CONR 13 R 14 , -C0-C6 alkyl-COR 15 , -C0-C6 alkyl-NR 13 R 14 , -C0-C6 alkyl-SR 12 , -C0-C6alkyl-OR 12 , -C0-C6alkyl-SO3H,
  • W 2 is selected from H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, -C0-C6 alkyl-NR 13 R 14 , -C0-- C 6 alkyl-SR 12 , -C 0 -C 6 alkyl-OR 12 , -C 0 -C 6 alkylCO 2 R 12 , -C 0 -C 6 alkyl-C(O)SR 12 , -C 0 -C 6 alkylCONR 13 R 14 , -C 0 - C6alkyl-COR 15 , -C0-C6 alkylOCOR 15 , -C0-C6alkyl-OCONR 13 R 14 , -C0-C6alkyl-NR 13 CONR 13 R 14 , -C0-C6 alkyl- NR 13 COR 15 , -C0-C6alkyl-Het, -C0-C6alkyl
  • W 3 is selected from the group consisting of: H, halo, C 1 -C 6 alkyl, -C 0 -C 6 alkyl-NR 13 R 14 ,-C 0 - C6alkylSR 12 , -C0-C6alkyl-OR 12 , -C0-C6alkyl-CO2R 12 , -C0-C6alkyl-C(O)SR 12 , -C0-C6alkyl-CONR 13 R 14 , -C0-C6alkyl-COR 15 , -C0-C6alkyl-OCOR 15 , -C0-C6 alkyl-OCONR 13 R 14 , -C0-C6alkylNR 13 CONR 13 R 14 , -C0-C6alkyl-NR 13 COR 15 , -C0-C6alkyl-Het, -C1-C6alkyl-Ar and–C1-C6alkyl-C3-C7cycloal
  • Q is selected from C3-C8cycloalkyl, Ar and Het; wherein said C3-C8cycloalkyl, Ar and Het are optionally unsubstituted or substituted with one or more groups independently selected from halo, cyano, nitro, C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl,-C0-C6alkylCO2R 12 , -C0-C6 alkyl-C(O)SR 12 , -C0- C6alkylCONR 13 R 14 , -C0-C6 alkyl-COR 15 , -C0-C6alkylNR 13 R 14 , -C0-C6alkyl-SR 12 , -C0-C6alkyl-OR 12 , -C0-C6 alkyl-SO3H, -C0-C6 alkyl-SO2NR 13 R 14 , -C0-C6alkyl-SO2R 12 ,
  • p 0-8;
  • n 2-8;
  • n 0 or 1
  • q is 0 or 1
  • t is 0 or 1;
  • each R 1 and R 2 are independently selected from H, halo, C1-C6alkyl, C3-C6alkenyl, C3-C6 alkynyl, -C0-C6alkyl-NR 13 R 14 , -C0-C6alkyl-OR 12 , -C0-C6 alkyl-SR 12 , -C1-C6alkyl-Het, -C1-C6alkyl-Ar and–C1-C6alkyl- C3-C7cycloalkyl, or R 1 and R 2 together with the carbon to which they are attached form a 3-5 membered carbocyclic or heterocyclic ring, wherein said heterocyclic ring contains one, or more heteroatoms selected from N, O, and S, where any of said C1-C6 alkyl is optionally unsubstituted or substituted by one or more halo substituents;
  • each R 3 is the same or different and is independently selected from halo, cyano, nitro, C1-C6 alkyl, C3-C6alkenyl, C3-C6alkynyl, -C0-C6alkyl-Ar, -C0-C6alkyl-Het, -C0-C6alkyl-C3-C7cycloalkyl, -C0-C6alkyl- CO2R 12 , -C0-C6alkyl-C(O)SR 12 , -C0-C6alkyl-CONR 13 R 14 , -C0-C6alkyl-COR 15 , -C0-C6alkyl-NR 13 R 14 , -C0- C6alkyl-SR 12 , -C0-C6alkyl-OR 12 , -C0-C6alkyl-SO3H, -C0-C6alkylSO2NR 13 R 14 ,-C0-C6 alkyl-SO2R
  • each R 4 and R 5 is independently selected from H, halo, C1-C6alkyl, -C0-C6alkyl-Het, -C0-C6alkyl-Ar and–C0-C6alkyl-C3-C7cycloalkyl;
  • R 6 and R 7 are each independently selected from H, halo, C1-C6 alkyl, -C0-C6alkyl-Het, -C0-C6 alkyl-Ar and–C0-C6alkyl-C3-C7cycloalkyl;
  • R 8 and R 9 are each independently selected from H, halo, C1-C6 alkyl, -C0-C6alkyl-Het, -C0-C6 alkyl-Ar and–C0-C6alkyl-C3-C7 cycloalkyl;
  • R 10 and R 11 are each independently selected from H, C1-C12 alkyl, C3-C12alkenyl, C3-C12alkynyl, -C0-C8alkyl-Ar, -C0-C8 alkyl-Het, -C0-C8 alkyl-C3-C7 cycloalkyl, -C0-C8 alkyl-O-Ar, -C0-C8alkyl-O-Het, -C0-C8 alkyl-O-C3-C7cycloalkyl, -C0-C8alkyl-S(O)x-C0-C6alkyl, -C0-C8alkyl-S(O)x-Ar, -C0-C8 alkyl-S(O)x-Het, -C0-C8 alkyl-S(O)x-C3-C7cycloalkyl, -C0-C8alkyl-NH-Ar, -C0-C8al
  • R 12 is selected from H, C1-C6 alkyl, C3-C6alkenyl, C3-C6alkynyl, -C0-C6alkyl-Ar, -C0-C6alkyl-Het and–C0-C6alkyl-C3-C7cycloalkyl;
  • each R 13 and each R 14 are independently selected from H, C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, -C0-C6alkyl-Ar, -C0-C6alkyl-Het and-C0-C6alkyl-C3-C7cycloalkyl, or R 13 and R 14 together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring which optionally contains one or more additional heteroatoms selected from N, O, and S;
  • R 15 is selected from C1-C6alkyl, C3-C6 alkenyl, C3-C6alkynyl, -C0-C6alkyl-Ar, -C0-C6 alkyl-Het and–C0- C6 alkyl-C3-C7 cycloalkyl;
  • X is hydrogen
  • X is hydrogen
  • X is hydrogen
  • the compounds of Formula IV include but are not limited the compounds with structures shown below GW3965682 and SB742881705:
  • the LXR ⁇ agonist has the structure of Formula V:
  • R 00 is G l , G 21 , or R N ;
  • R 200 is G 1 , G 21 , or R C ;
  • R 300 and R 400 are independently R C or Q, provided one and only one of R 300 , R 400 , and R 500 is Q;
  • G l is–L 10 -R, wherein L 10 is a bond, L 50 , L 60 , -L 50 -L 60 -L 50 -, or -L 60 -L 50 -L 50 -, wherein
  • each L 50 is independently -[C(R 150 )2]m-;
  • R is aryl, heterocyclyl, heteroaryl or -(C3-C6)cycloalkyl, wherein R is optionally substituted with 1 to 4 R A , wherein each R A is independently halogen, nitro, heterocyclyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl)-C1-C6 alkyl-, (C3-C8 cycloalkenyl)-C1-C6 alkyl-, (C3-C8 cycloalkyl)-C1C6 alkenyl-, arylalkyl, aryloxy, arylCl-6 alkoxy, C1-C6 haloalkyl, SO2R 110 , OR 110 , SR 110 , N3, SOR 110 , COR 110 , SO2N(R 110 )2, SO2NR 110 COR 110
  • L 31 is C2-6 alidiyl chain wherein the alidiyl chain is optionally interrupted by -C(R 110 )2-,
  • R 60 is C1-C6 alkyl, C1-C6 halo alkyl, aryl, C3-C8 cycloalkyl, heteroaryl, heterocyclyl, -CN,
  • each R 60a is independently -Z, -Y’-Z, or-X-Y-Z;
  • each R C is independently–L 30 -R 70 , wherein
  • each L 30 is independently a bond or-(CH2)m-V 10 -(CH2)n-, wherein
  • each L 30 is independently C2-C6 alidiyl, wherein the alidiyl chain is optionally interrupted by–C(R 110 )2-, -C(R 110 )2C(R 110 )2-, - C(R 110 )C(R 110 )-, -C(R 110 )2O-, -C(R 110 )2NR 110 -, -C ⁇ C-, -O-, -S-, -N(R 100 )CO-,
  • each R 110 is independently -hydrogen, -C1-C6 alkyl, C2-C6 alkenyl, Cl-C6 alkynyl, -C1-C6 haloalkyl, or -N(R 12 )2, wherein any of R 110 is optionally substituted with 1 to 4 radicals of R 120 ;
  • each R 130 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
  • each R 140 is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C0-C6 alkylCON(R 110 ) o , C0-C6 alkylCONR 110 R 10 , C0-C6 alkylOR 110 , or C0-C6 alkylCOOR 110 ; and
  • each R 150 is independently hydrogen, halogen, OR 130 , (C1- C6)alkyl or (C1-C6)haloalkyl, wherein each alkyl is optionally substituted with at least one group which are each independently halogen, cyano, nitro, azido, OR 130 , C(O)R 130 , C(O)OR 13 C(O)N(R 130 )2, N(R 130 )2, N(R 130 )C(O)R 130 , N(R 130 )S(O)2R 130 , -OC(O)OR 130 , OC(O)N(R 130 )2, N(R 130 )C(O)OR 130 , N(R 130 )C(O)N(R 130 ), SR 130 , S(O)R 130 , S(O)2R', or S(O)2N(R 130 )2; or two R 150 (bonded to same or different atoms) can be taken together to form a C3-C6 cyclo
  • each X is independently -O-, -S-, or -N(R 100 )-;
  • each Y is independently -[C(R 150 )2] p -, or-C2-C6 alkenyl, wherein p is 1, 2, 3, 4, 5, or 6; each Y' is independently -[C(R 150 )2] p -, -C2-C6 alkenyl C3-C8 cycloalkyl, or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with 1 to 3 Z groups;
  • each m and n is independently 0, 1,2,3,4,5, or 6.
  • the compounds of Formula V which can be useful in the methods of the invention include, but are not limited to, compounds having the structures are shown below, and pharmaceutically acceptable salts thereof:
  • the LXR agonist that can be used for the treatment and/or prevention of metastasis can be compound 704, or a pharmaceutically acceptable salt thereof.
  • WO2009/086130 WO2009/086129, WO2007/002559, WO2007/002563, WO2007/081335, WO2006/017055, WO2006/102067, WO2009/024550, US2006/0074115, US2006/0135601, WO2009/021868, WO2009/040289, WO2007/047991, WO2007/050425, WO2006/073363,
  • WO2008/065754 JP2008/179562, WO2007/092065, US2010/0069367, US7998995, US7247748, WO2010/138598, US7365085, US75776215, US63136503, US2004/0072868, US2005/0107444, US2005/0113580, US2005/0131014, US2005/0282908, US2009/0286780, incorporated herein by reference.
  • the LXR agonist is a compound of Formula XI:
  • X is N or CR c ;
  • R 1 is alkyl or -NR a R b b
  • R 3 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, monocyclic nonaromatic heterocycle, monocyclic heteroaromatic or phenyl, wherein the phenyl, monocyclic non-aromatic heterocycle and monocyclic heteroaromatic group represented by R 3 are optionally substituted with one or more groups selected from alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, nitro and -CN;
  • R 4 is halogen, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -OC(O)O(alkyl), -C(O)O(haloalkyl)- OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -NRC(O)R,-NRC(O)O(alkyl), -S(O)R -SO2R, -SO2N(R)2, - NRS(O)R, -NRSO2R,-NRC(O)N(R)2, -NRSO2N(R)2, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkyl, monocyclic non-aromatic heterocycle, monocyclic heteroaromatic or alkyl, wherein the monocyclic non- aromatic heterocycle, monocyclic heteroaromatic and alkyl group represented
  • each R is, independently, H or alkyl
  • R a and R b are, independently, H, alkyl or R a and R b can be taken together with the nitrogen to which they are attached to form a monocyclic non-aromatic heterocycle;
  • R c is H, alkyl, or halogen.
  • the compound of Formula XI has the structure of any one of Formulae XII- XVI:
  • R 3 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl or phenyl, wherein the phenyl represented by R 3 is optionally substituted with one or more groups selected from alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, nitro and -CN; and R 4 is halogen, -CN, -OR,SR, -N(R)2, -C(O)R, -C(O)OR, -OC(O)O(alkyl), -C(O)O(haloalkyl), -OC(O)R, - C(O)N(R)2, -OC(O)N(R)2, -NRC(O)R, -NRC(O)O(alkyl), -S(O)R, -SO2R, -SO2N(R)2, -
  • R 1 is methyl or -NH2;
  • R 3 is methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, iso-butyl
  • R 1 is methyl; R 2 is -CH2OH; and R 3 is isopropyl.
  • R 4 is halogen, hydroxy, alkyl, cycloalkyl, cycloalkoxy, alkoxy, haloalkoxy, haloalkyl, -N(R)2, -C(O)OH, -C(O)O(alkyl), -C(O)O(haloalkyl), - C(O)(alkyl), -C(O)N(R)2, -NRC(O)R, -SO2N(R)2, -OC(O)N(R)2, -CN, hydroxyalkyl, or dihydroxyalkyl.
  • R 4 is alkyl, haloalkyl, cycloalkyl, alkoxy, or haloalkoxy.
  • R 4 is methyl, ethyl, hydroxy, -CF3, isopropyl, cyclopropyl, -CH2OH, -CH(OH)(CH2)(OH), -C(OH)(CH3)2, -CH(OH)(CH3) , - CH(OH)(CH2)(CH3), -CH(OH)(CH2)2(CH3), -C(O)NH2, -C(O)N(CH3)2, -C(O)OH, -C(O)NH(CH3), -C(O)CH3, -C(O)CH2CH3, -C(O)O(CH2)(CH3), -C(O)O(tert-butyl), -C(O)O(C)
  • R 4 is methyl, halogenated methyl, cyclopropyl, -OCHF2, or -OCH3, preferably, R 4 is CF3.
  • the LXR agonist is any one of compounds 720-726:
  • LXR agonist is a compound disclosed in U.S. Publication No.2015/0246924, U.S. Publication No. 2015/0051214, U.S. Publication No.2015/0065515, U.S. Publication No.2015/0080406, or U.S. Publication No.2015/033693, the compounds of which are herein incorporated by reference.
  • the LXR agonist is a compound of Formula XVII:
  • X is N or CR c ;
  • R 1 is alkyl or -NR a R b
  • R 3 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, monocyclic nonaromatic heterocycle, monocyclic heteroaromatic, or phenyl, wherein the phenyl, monocyclic non-aromatic heterocycle and monocyclic heteroaromatic group represented by R 3 are optionally substituted with one or more groups selected from alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, nitro, and–CN;
  • R 4 and R 5 are, independently, is halogen, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, - OC(O)O(alkyl), -C(O)O(haloalkyl), -OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -NRC(O)R, -NRC(O)O(alkyl), - S(O)R, -SO2R, -SO2N(R)2, -NRS(O)R, -NRSO2R, -NRC(O)N(R)2, -NRSO2N(R)2, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkyl, monocyclic non-aromatic heterocycle, monocyclic heteroaromatic, or alkyl, wherein the alkyl, monocyclic non-ar
  • R 6 is H, halogen, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -OC(O)O(alkyl), - C(O)O(haloalkyl), -OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -NRC(O)R, -NRC(O)O(alkyl), -S(O)R, -SO2R, - SO2N(R)2, -NRS(O)R, -NRSO2R, -NRC(O)N(R)2, -NRSO2N(R)2, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkyl, or alkyl, wherein the alkyl group represented by R 6 is optionally substituted with one or more groups selected from -CN, -OR, -SR, -N
  • each R is, independently, H or alkyl
  • R a and R b are, independently, H, alkyl, or R a and R b can be taken together with the nitrogen to which they are attached to form a monocyclic non-aromatic heterocycle;
  • R c is H, alkyl, or halogen.
  • the compound of Formula XVII has the structure of Formula XVIII-XXIII:
  • R 3 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, or phenyl, wherein the phenyl group represented by R 3 is optionally substituted with one or more groups selected from alkyl, halogen, halo alkyl, alkoxy, haloalkoxy, nitro, and -CN;
  • R 4 and R 5 independently are halogen, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -OC(O)O(alkyl), - C(O)O(haloalkyl), -OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -NRC(O)R, -NRC(O)O(alkyl), -S(O)R, -SO2R,
  • R 1 is methyl or–NH2;
  • R 3 is methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, iso-buty
  • R 4 and R 5 independently are halogen, hydroxy, alkyl, cycloalkyl, cycloalkoxy, alkoxy, haloalkoxy, haloalkyl, -N(R)2, -C(O)OH, - C(O)O(alkyl), -C(O)O(haloalkyl), -C(O)(alkyl), -C(O)N(R)2, -NRC(O)R, -SO2N(R)2, -OC(O)N(R)2, -CN, hydroxyalkyl, or dihydroxyalkyl.
  • R 4 is alkyl, halo alkyl, cycloalkyl, alkoxy, or haloalkoxy.
  • R 4 and R 5 independently are methyl, ethyl, hydroxy, -CF3, isopropyl, cyclopropyl, -CH2OH, -CH(OH)(CH2)(OH), -C(OH)(CH3)2, - CH(OH)(CH3), -CH(OH)(CH2)(CH3), -CH(OH)(CH2)2(CH3), -C(O)NH2, -C(O)N(CH3)2, -C(O)OH, - C(O)NH(CH3), -C(O)CH3, -C(O)CH2CH3, -C(O)O(CH2)(CH3), -C(O)O(tert-butyl), -C(O)O(C)(CH3)2(CF3), - NHC(O)CH3, -OCHF2, -OCF3, -OCH2CH3, -OCH(CH3)
  • R 4 is methyl, halogenated methyl, cyclopropyl, -OCHF2, or -OCH3, preferably, R 4 is CF3.
  • the LXR agonist is any one of compounds
  • Compounds of Formula VII may be synthesized by methods known in the art, e.g., methods described in International Patent Publication No. WO2013/138568.
  • the LXR agonist is a compound of Formula XXIV:
  • a and B are each nitrogen, wherein A and B are bonded together to form a five-membered heteroaryl ring;
  • L 1 and L 2 are each independently a bond, C1-C6 alkyl, or C1-C6 heteroalkyl;
  • R 3 is hydrogen, halogen, C1-C6 alkyl, or C1-C6haloalkyl
  • R 4 is aryl or heteroaryl; wherein aryl or heteroaryl is substituted with at least one R 11 ;
  • each R 8 , each R 9 , and each R 10 are each, independently, hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkyl-aryl, aryl, or heteroaryl;
  • the LXR agonist is a compound of Formula XXV:
  • a and B are each nitrogen, wherein A and B are bonded together to form a five-membered heteroaryl ring;
  • L 1 and L 2 are each independently a bond, C1-C6 alkyl, or C1-C6 heteroalkyl;
  • R 3 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl
  • R 4 is aryl or heteroaryl; wherein aryl or heteroaryl is substituted with at least one R 11 ;
  • each R 8 , each R 9 , and each R 10 are each, independently, hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkyl-aryl, aryl, or heteroaryl;
  • the LXR agonist is a compound of Formula XXVI:
  • a and B are each nitrogen, wherein A and B are bonded together to form a five-membered heteroaryl ring;
  • L 1 and L 2 are each independently a bond, C1-C6 alkyl, or C1-C6 heteroalkyl;
  • R 3 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl
  • R 4 is aryl or heteroaryl; wherein aryl or heteroaryl is substituted with at least one R 11 ;
  • each R 8 , each R 9 , and each R 10 are each, independently, hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkyl-aryl, aryl, or heteroaryl;
  • the LXR agonist is a compound of Formula XXVII:
  • X is -N(R 12 )- , or -O-;
  • a and B are each nitrogen, wherein A and B are bonded together to form a five-membered heteroaryl ring;
  • L 1 is a bond, C1-C6 alkyl, or C1-C6 heteroalkyl
  • L 2 is C1-C6 alkyl or C1-C6 heteroalkyl
  • R 3 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl
  • R 4 is aryl or heteroaryl; wherein aryl or heteroaryl is substituted with at least one R 11 ;
  • each R 8 , each R 9 , and each R 10 are each, independently, hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, -C1-C6 alkyl-aryl, aryl, or heteroaryl;
  • R 12 is hydrogen or C1-C6 alkyl.
  • the LXR agonist is a compound of Formula XXVIII:
  • a and B are each nitrogen, wherein A and B are bonded together to form a five- membered heteroaryl ring;
  • L 1 and L 2 are each independently a bond, C1-C6 alkyl, or C1-C6 heteroalkyl;
  • R 3 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl
  • R 4 is aryl or heteroaryl; wherein aryl or heteroaryl is substituted with at least one R 11 ;
  • each R 8 , each R 9 , and each R 10 are each, independently, hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkyl-aryl, aryl, or heteroaryl;
  • the LXR agonist is a compound of Formula XXVII:
  • a and B are each nitrogen, wherein A and B are bonded together to form a five-membered heteroaryl ring;
  • L 1 is a bond, C1-C6 alkyl, or C1-C6 heteroalkyl
  • L 2 is C1-C6 alkyl or C1-C6 heteroalkyl
  • R 1 is hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CF3, -OR 8 , -N(R 8 )2,
  • R 3 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl
  • R 4 is aryl or heteroaryl; wherein aryl or heteroaryl is substituted with at least one R 11 ;
  • each R 8 , each R 9 , and each R 10 are each, independently, hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, -C1-C6 alkyl-aryl, aryl, or heteroaryl;
  • R 13 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, -C1-C6 alkyl-aryl, aryl, or heteroaryl;
  • R 14 is C1-C6 alkyl, C1-C6 heteroalkyl, -C1-C6 alkyl-aryl, aryl, or heteroaryl;
  • R 15 is C1-C6 alkyl.
  • the LXR agonist is any one of compounds 774-780:
  • the LXR agonist is a compound disclosed in U.S. Publication No.
  • the LXR agonist is a compound of Formula XXVIII:
  • L is a bond, -[C(R 1 )2]m-, -cyclopropyl-, or -CO-;
  • n 1 or 2;
  • n 0, 1, 2, 3, or 4;
  • R 1 is independently selected from H, C1-3 alkyl, -OH, or halo;
  • A is phenyl, cyclohexyl, a 5 or 6 membered heterocyclyl, or a 5 or 6 membered heteroaryl, wherein the phenyl is optionally fused to a 5 or 6 membered heterocyclyl or 5 or 6 membered heteroaryl, wherein A is optionally substituted with 1, 2, or 3 R A groups, wherein each R A is independently R A1 , -C1-C6 alkyl-R A1 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or heterocyclyl, wherein the cycloalkyl or heterocyclyl are each optionally substituted with 1, 2, 3, or 4 groups that are independently R A1 , C1-C6 alkyl, or–C1-C6 alkyl-R A1 , wherein each R A1 is independently halogen, cyan
  • ring C is a 5 membered heterocyclic ring selected from triazolyl, imidazolyl, pyrrazolyl, oxazolyl; wherein when ring C is pyrrazolyl, imidazolyl, or oxazolyl, then ring C is optionally substituted with C1-C4 alkyl, C2-C3 alkenyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, CF3, C1-C4 alkyl-OH, C1-C4 alkyl-O-C1-C3 alkyl, C1- C3 alkyl-NR2; C1-C3 alkyl-CO2H, C1-C3 alkyl-NHSO2-C1-C3 alkyl, -NH-C1-C3alkyl-OR, C1-C3 alkyl- pyrrolidinyl;
  • R B1 is hydrogen, CI-C3 alkyl, halo, or C1-C3haloalkyl
  • R B2 is hydrogen, C1-C3 alkyl, halo, or C I-C3 haloalkyl
  • R B3 is hydrogen, C1-C4 alkyl, halo, CN, C1-C4 haloalkyl, -C(O)-C1-C3 alkyl , -CO-NH2, -CO-NR2, or -C1-C3 alkyl-OH;
  • each R D1 and R D2 are independently R D3 , C1-C6 alkyl, -C1-C6 alkyl-R D3 , C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or heterocyclyl, wherein the cycloalkyl and heterocyclyl are each optionally substituted with 1, 2, 3, or 4 groups that are independently R D3 , C1-C6 alkyl, C3-C8 cycloalkyl, or -C1-C6 alkyl-R D3 , wherein each R D3 is independently halogen, cyano, -OR, -NR2, -SR, -C(O)R, - C(O)OR, -C(O)NR2, -S(O)R, -S(O)2R, -S(O)NR2, -S(O)2NR2, -OC(O)
  • R C is hydrogen, halogen, cyano, or C1-C6 alkyl
  • each R group is independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-R 2 , C1-C6 haloalkyl, -C1-C6 haloalkyl-R 2 , C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl, wherein each R 2 is independently cyano, - OR 3 , -N(R 3 )2, -N(R 3 )S(O)2R 3 , -N(R 3 )S(O)2OR 3 , or -N(R 3 )S(O)2N(R 3 )2, wherein each R 3 is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl.
  • the LXR agonist is a compound of Formula XXIX:
  • L is a bond, -[C(R 1 )2]m-, -cyclopropyl-, or -CO-;
  • n 1 or 2;
  • R 1 is independently selected from H, C1-C3 alkyl, -OH, or halo;
  • A is phenyl, cyclohexyl, benzofuranyl, 2,3-dihydro-lH-indenyl, pyridyl, pyrazinyl, pyrimidinyl, dihydrobenzofuranyl, pyridin-2(1 H)-one, imidazo[1,2-a]pyridinyl, or piperidinyl, wherein A is optionally substituted with 1, 2, or 3 R A groups, wherein each R A is independently halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, -O-R, NR2, -O-C1-C6 alkyl, -O-C1-C6 alkyl-C3-C6 cycloalkyl, -S-R, -CO-R, -C(O)OR, -C1-C6 alkyl- CO-NR2, pyrrolidinone, or pyrrolidinyl, alternatively, 2
  • ring C is a 5 membered heterocyclic ring selected from triazolyl, imidazolyl, pyrrazolyl, oxazolyl; wherein when ring C is pyrrazolyl, imidazolyl, or oxazolyl, then ring C is optionally substituted with C1-C4 alkyl, C2-C3 alkenyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, -CF3, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C3 alkyl, -C1-C3 alkyl-NR2, -C1-C3 alkyl-CO2H, -C1-C3 alkyl-NHSO2-C1-C3 alkyl, -NH-C1-C3 alkyl-OR, or–C1- C3 alkyl-pyrrolidinyl;
  • R B1 is hydrogen, C1-C3 alkyl, halo, or C1-C3 haloalkyl
  • R B2 is hydrogen, methyl or halo
  • R B3 is hydrogen, C1-C4 alkyl, halo, CN, C1-C4 haloalkyl, cyclopropyl, -CO-NH2, -CONR2, or–C1-C3 alkyl-OH,
  • R C is hydrogen, halogen, or cyano
  • n 0,1, 2, 3, or 4;
  • R D1 is -SO2-C1-C6 alkyl, -SO2-C1-C6 haloalkyl, -SO2-C3-C6 cycloalkyl, -SO2-C1-C6 alkyl-OH, -SO2- C1-C6 alkyl-O-C1-C6 alkyl, -C(Me)2-COOH, C(Me)2-CONR2, cyclopropyl-CONR2, -SO2NR2, -SO2NR-C1-C6 alkyl-OH, -SO2-pyrrolidinyl, or CONR2;
  • R D2 is independently C1-C6 haloalkyl, -C1-C6 alkyl-OH, halo, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-NHSO2-C1-C6 alkyl, C1-C6 haloalkyl, or -O-C1-C6 alkyl-O-C1-C6 haloalkyl,
  • each R group is independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-R 2 , C1-C6 haloalkyl, -C1-C6 haloalkyl-R 2 , C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 cycloalkyl;
  • each R 2 is independently -OR 3 , wherein each R 3 is independently hydrogen; and C1-C6 alkyl, or C1-C6 haloalkyl.
  • the LXR agonist is a compound of Formula XXX:
  • L is a bond, -[C(R 1 )2]m-, -cyclopropyl-, or -CO-;
  • n 1 or 2;
  • n 0, 1, 2, 3, or 4;
  • R 1 is independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, -OH, and halo;
  • A is phenyl, cyclohexyl, a 5 or 6 membered heterocycle, or a 5 or 6 membered heteroaryl, wherein the phenyl is optionally fused to a 5 or 6 membered heterocycle or 5 or 6 membered heteroaryl, wherein A is optionally substituted with 1, 2, or 3 R A groups, wherein each R A is independently R A1 , -C1-C6 alkyl-R A1 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or heterocyclyl, wherein the cycloalkyl or heterocyclyl are each optionally substituted with 1, 2, 3, or 4 groups that are independently R A1 , C1-C6 alkyl, or–C1-C6 alkyl-R A1 , wherein each R A1 is independently halogen, cyano, nitro
  • ring C is a 5 membered heterocyclic ring selected from triazolyl, imidazolyl, pyrrazolyl, and oxazolyl; wherein when ring C is pyrrazolyl, imidazolyl, or oxazolyl, then ring C is optionally substituted with C1-C4 alkyl, C2-C3 alkenyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, -CF3, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1- C3 alkyl, -C1-C3 alkyl-NR2, -C1-C3 alkyl-CO2H, -C1-C3 alkyl-NHSO2-C1-C3alkyl, -NH-C1-C3 alkyl-OR, or– C1-C3 alkyl-pyrrolidinyl;
  • R B1 is hydrogen, C1-C3 alkyl, halo, or C1-C3 haloalkyl
  • R B2 is hydrogen or halo
  • R B3 is hydrogen, C1-C3 alkyl, halo, CN, C1-C3 haloalkyl, -C(O)-C1-C3 alkyl , -CO-NH2, -CO-N(R)2, or–C1-C3 alkyl-OH;
  • R D1 and R D2 are each independently R D3 , C1-C6 alkyl, -C1-C6 alkyl-R D3 , C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl, or heterocyclyl, wherein the cycloalkyl or heterocyclyl are each optionally substituted with 1, 2, 3, or 4 groups that are independently R D3 , C1-C6 alkyl, C3-C6 cycloalkyl, or -C1-C6 alkyl-R D3 , wherein each R D3 is independently halogen, cyano, -OR, -NR2, -SR, -C(O)R, - C(O)OR, -C(O)NR2, -S(O)R, -S(O)2R, -S(O)NR2, -S(O)2NR2, -OC(O
  • R C is hydrogen, halogen, C1-C6 alkyl, cyano, or nitro
  • each R group is independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-R 2 , C1-C6 haloalkyl, -C1-C6 haloalkyl-R 2 , C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or–C1-C6 alkyl-C3-C8 cycloalkyl, wherein each R 2 is independently cyano, -OR 3 , -N(R 3 )2, -N(R 3 )S(O)2R 3 , -N(R 3 )S(O)2OR 3 , or -N(R 3 )S(O)2N(R 3 )2, wherein each R 3 is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl.
  • the LXR agonist is a compound of Formula XX
  • L is a bond, -[C(R 1 )2]m-, -cyclopropyl-, or -CO-;
  • n 1 or 2;
  • R 1 is independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, -OH, and halo;
  • A is phenyl, cyclohexyl, naphthalenyl, benzofuranyl, 2,3-dihydro-1H-indenyl, 1H-indolyl, pyridyl, pyrazinyl, pyrimidinyl, dihydrobenzofuranyl, pyridin-2(1H)-one, imidazo[1,2-a]pyridinyl, or piperidinyl, wherein A is optionally substituted with 1, 2, or 3 R A groups; wherein each R A is independently halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, -O-R, -NR2, -O-C1-C6 alkyl, -O-C1-C6 alkyl-C3-C6 cycloalkyl, -S-R, -CO- R, -C(O)O-R, -C1-C6 alkyl-CO-NR2,
  • ring C is a 5 membered heterocyclic ring selected from triazolyl, imidazolyl, pyrrazolyl, and oxazolyl; wherein when ring C is pyrrazolyl, imidazolyl, or oxazolyl, then ring C is optionally substituted with C1-C4 alkyl, C2-C3 alkenyl, C1-3 haloalkyl, C3-C6 cycloalkyl, -CF3, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1- C3 alkyl, -C1-C3 alkyl-NR2; -C1-C3 alkyl-CO2H, -C1-C3 alkyl-NHSO2-C1-C3 alkyl, -NH-C1-C3 alkyl-OR, or– C1-C3 alkyl-pyrrolidinyl;
  • R B1 is hydrogen, C1-C3 alkyl, halo, or C1-C3 haloalkyl
  • R B2 is hydrogen or halo
  • R B3 is hydrogen, C1-C3 alkyl, halo, CN, C1-C4 haloalkyl, cyclopropyl, -CO-NH2, -CONR2, or–C1-C3 alkyl-OH;
  • R C is hydrogen, halogen, or cyano
  • n 0, 1, 2, 3, or 4;
  • R D1 is -SO2-C1-C6 alkyl, -SO2-C1-C6 haloalkyl, -SO2-C3-C6 cycloalkyl, -SO2-C1-C6 alkylOH, -SO2- C1-C6 alkyl-O-C1-C6 alkyl, -C(Me)2-COOH, -C(Me)2-CONR2, -cyclopropyl-CONR2-, -SO2NR2, -SO2NR-C1- C6 alkyl-OH, -SO2-pyrrolidinyl, or -CONR2;
  • R D2 is independently–C1-C6 haloalkyl-C1-C6 alkyl-OH, halo, -C1-C6 alkyl-O-C1-C6 alkyl, -C1- C6alkyl-NHSO2-C1-C6 alkyl, C1-C6 haloalkyl, or -O-C1-C6 alkyl-O-C1-C6 haloalkyl, each R group is independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-R 2 , C1-C6 haloalkyl, -C1-C6 haloalkyl-R 2 , C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl; and
  • each R 2 is independently -OR 3 , wherein each R 3 is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl.
  • the LXR agonist is a compound of Formula XXXII:
  • R 1 and R 1 ' are independently selected from -H, OR, or -OR a , wherein R a is a hydroxyl protecting group or COR b , or R 1 and R 1’ taken together form a keto function;
  • R 2 and R 2' are independently selected from the group consisting of -H, -C1-C6 alkyl, phenyl, or substituted phenyl, -OH, -OR a , or R 2 and R 2' taken together to form a keto function;
  • R 3 and R 3' are independently selected from the group consisting of -H, -C1-C6 alkyl, phenyl, or substituted phenyl, -OH, -OR a ; or R 3 and R 3' taken together form a keto function;
  • R b is selected from the group consisting of -C1-C6 alkyl, -C3-C7 cycloalkyl, phenyl, aryl, alkylaryl, and alkylheterocyclic;
  • R 4 is selected from the group consisting of -H, -OH, -OR a , -C1-C6 alkyl, phenyl, or substituted phenyl; R 4 ' is -H;
  • R 5 is a group selected from hydrogen, -C1-C6 alkyl, phenyl, or substituted phenyl;
  • R 6 and R 7 are each independently selected from the group consisting of -H, -C1-C6 alkyl, -C2-C8 alkenyl, phenyl, or substituted phenyl;
  • R 8 and R 9 are each independently selected from -H, -C1-C6 alkyl, phenyl, or substituted phenyl, halo, -NO2, -NR 12 R 13 , -CONR 14 R 15 , and -COOR 16 ;
  • R 10 is -H, OH, OR a , COR a , -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or substituted phenyl, CH2OR a , -CHO , -CONR 14 R 15 , or -COOR 16 ;
  • R 11 is -H, -C1-C6 alkyl, -C2-C8 alkenyl, phenyl or substituted phenyl, aryl, alkylaryl, or
  • R 12 and R 13 are independently selected from -H, -C1-C6 alkyl, -C3-C7 cycloalkyl, phenyl, aryl, alkylaryl, or R 12 taken together with R 13 forms a 4, 5, 6, or 7-membered heterocyclic ring containing a nitrogen atom;
  • R 14 and R 15 are each independently selected from H, -C1-C6 alkyl, -C3-C7 cycloalkyl, phenyl, aryl, alkylaryl, or taken together form a 4, 5, 6, or 7-membered heterocyclic ring containing a nitrogen atom; and
  • R 16 is -H, -C1-C6 alkyl, phenyl, substituted phenyl, or benzyl;
  • R 9 when R 9 is pyrolidine, R 5 is methyl, and R 10 is carboxyethyl ester group, and R 1 is in a trans relationship to R 5' then R 1 is not -OH; and if R 1 and R 1' are -OH and H respectively, or taken together to form a ketone, then R 9 is not pyrolidinyl and R 10 is not methyl, or hydroxylmethyl.
  • the LXR agonist is:
  • the LXR agonist is a compound of Formula XXXIII:
  • R 3 is hydrogen, amino, carboxyl, oxo, halo, sulfonic acid, -O-sulfonic acid, or .
  • alkyl that is optionally inserted with -NH-, -N(alkyl)-, -O-, -S-, -SO-, -SO2-, -OSO2-, -SO2-O-, -O-SO3- , -SO3-O-, -CO-, -CO-O-, -O-CO-, -CO-NH-, -CON(alkyl)-, -NH-CO-, or -N(alkyl)-CO-, and further optionally substituted with hydroxy, halo, amino, carboxyl, sulfonic acid, or -O-sulfonic acid.
  • R 1 , R 2 , R 4 , R 4' , R 6 , R 7 , R 11 , R 12 , R 15 , R 16 , and R 17’ is, independently, hydrogen, hydroxy, amino, carboxyl, oxo, halo, sulfonic acid, -O-sulfonic acid, or alkyl that is optionally inserted with -NH-, -N(alkyl)-, -O-, -S-, -SO-, -SO2-, -O-SO2-, -SO2O-, -O-SO3-, -SO3-O-, -CO-, -CO-O-, -O-CO-, -CO-NH-, -CO-N(alkyl)-, -NH-CO-, or - N(alkyl)-CO-, and further optionally substituted with hydroxy, halo, amino, carboxyl, sulfonic acid, or -O-CO-
  • R 5 , R 8 , R 9 , R 10 , R 13 , and R 14 independently, is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxy, or amino.
  • R 17 is -X-Y-Z.
  • X is a bond, or alkyl or alkenyl, optionally inserted with -NH-, -N(alkyl)-, -O-, or -S-, and further optionally forming a cyclic moiety with R 16 and the 2 ring carbon atoms to which R 16 and R 17 are bonded.
  • Y is -CO-, -SO-, -SO2-, -O-SO2-, -SO2-O-, -O-SO3-, - SO3-O-, -CO-O-, -O-CO-, -CONH-,-CO-N(alkyl)-, -NH-CO-, -N(alkyl)-CO-, or a bond.
  • Z is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, and is optionally substituted with hydroxy, alkoxy, amino, halo, sulfonic acid, -O-sulfonic acid, carboxyl, oxo, alkyloxycarbonyl, alkylcarbonyloxy, alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, or alkylthio; or is -CH(A)-B.
  • B is hydrogen, -NR a R b , or -COOR c wherein each of R a , R b , and R c , independently, is hydrogen or alkyl.
  • n is 0, 1, or 2.
  • Y is a bond and either X or Z contains at least one double bond, and that when Y is a bond, either X is -NH-alkyl-, -NH- alkenyl-, -N(alkyl)-alkyl-, -N(alkyl)-alkenyl-, -O-alkyl-, -O-alkenyl-, -S-alkyl-, or -S-alkenyl-; or Z is substituted with halo, sulfonic acid, -O-sulfonic acid, alkylsulfinyl, or alkylsulfonyl, or is alkenyl, or a pharmaceutically acceptable salt thereof.
  • the LXR agonist is any one of compounds 781-806:
  • the LXR agonist is a compound of Formula XXXIV:
  • n 0, 1, or 2;
  • A is alkylene, alkenylene, or alkynylene
  • each of R' and R’’ independently, is hydrogen, alkyl, or halo alkyl
  • the LXR agonist is any one of compounds 807-812:
  • the LXR agonist is a compound of Formula XXXV:
  • each of A and D, independently, is deleted or alkylene;
  • X and Y, independently, is alkyl;
  • the LXR agonist is any one of compounds 813-816:
  • Compounds of Formula XXXV may be synthesized by methods known in the art, e.g., methods described in International Patent Publication No. WO2011/014661.
  • the LXR agonist is a compound of Formula XXXVI:
  • A is selected from the group consisting of hydrogen, hydroxy, or oxygen
  • RI is selected from the group consisting of:
  • Z is nitrogen that can be anywhere in the ring
  • X 1 can be bonded to any position on the ring and is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine, and
  • X 2 is selected from the group consisting of fluorine, chlorine, bromine, and iodine
  • X 3 can be bonded to any position on the ring and is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine
  • the LXR agonist is any one of compounds 817-826: or pharmaceutically acceptable salts thereof.
  • Compounds of Formula XXXVI may be synthesized by methods known in the art, e.g., methods described in International Patent Publication No. WO2011/103175.
  • the LXR agonist is hyodeoxycholic acid (also known as 4-[(5R,8S,10R,13R,17R)-3,6-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17- tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid) or a pharmaceutically acceptable salt thereof.
  • hyodeoxycholic acid also known as 4-[(5R,8S,10R,13R,17R)-3,6-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17- tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid
  • the LXR agonist is a compound described in International Patent Publication No. WO2006/046593, e.g., any one of (4'- ⁇ [2-(tert- butoxycarbonyl)-3-hydroxy-4-(trifluoromethyl)benzyl]oxy ⁇ -1,1'-biphenyl-4-yl)acetic acid; 2-(4'- ⁇ [2-(tert- butoxycarbonyl)-3-hydroxy-4-(trifluoromethyl)benzyl]oxy ⁇ -1,1'-biphenyl-4-yl)propanoic acid; 1-(4'- ⁇ [2-(tert- butoxycarbonyl)-3-hydroxy-4-(trifluoromethyl)benzyl]oxy ⁇ -1,1'-biphenyl-4-yl)cyclopropanecarboxylic acid; 2-(4'- ⁇ [2-(tert-butoxycarbonyl)-3-hydroxy-4-(trifluoromethyl)benzyl]oxy ⁇
  • the LXR agonist is a compound described in International Patent Publication No. WO2006/073366, e.g., any one of: 2-tert-butyl-4-( ⁇ 3-[3- (hydroxymethyl)phenoxy]propyl ⁇ amino)-5-phenylisothiazol-3(2H)-one 1,1–dioxide; 2-tert-butyl-5-phenyl- 4-[(4-phenylbutyl)amino]isothiazol-3(2H)-one 1,1-dioxide; 2-tert-butyl-4- ⁇ [3-(2- methoxyphenoxy)propyl]amino ⁇ -5-phenylisothiazol-3(2H)-one 1,1-dioxide; 2-tert-butyl-4-( ⁇ 3-[4- (hydroxymethyl)phenoxy]propyl ⁇ amino)-5-phenylisothiazol-3(2H)-one 1,1-dioxide; 2-tert
  • the LXR agonist is a compound described in U.S. Patent Publication No. US2009/0247587, e.g., any one of: 5-(2H-1,3-benzodioxol-5-yl)-5-methyl- 3-(4- ⁇ [7-propyl-3,3-bis(trifluoromethyl)-2,3-dihydro-1-benzofuran-6-yl]oxy ⁇ butyl)imidazolidine-2,4-dione; 5- (3-methoxyphenyl)-5-methyl-3-(4- ⁇ [7-propyl-3,3-bis(trifluoromethyl)-2,3-dihydro-1-benzofuran-6- yl]oxy ⁇ butyl)imidazolidine-2,4-dione; 5-(3-bromo-4-fluorophenyl)-5-methyl-3-(4- ⁇ [7-propyl-3,3- bis(trifluoro
  • the LXR agonist is a compound described in International Patent Publication No. WO2009/133692, e.g., any one of: 5-(2H-1,3- benzodioxol-5-yl)-3-(6- ⁇ [3-benzyl-8-(trifluoromethyl)quinolin-4-yl]oxy ⁇ hexyl)-5-methylimidazolidine-2,4- dione; 3-(6- ⁇ [3-benzyl-8-(trifluoromethyl)quinolin-4-yl]oxy ⁇ hexyl)-5-methyl-5-(quinoxalin-6-yl)imidazolidine- 2,4-dione; 5-(2H-1,3-benzodioxol-5-yl)-3-(3- ⁇ 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenoxy ⁇ propyl)- 5-methylimidazolidine-2,4-d
  • the LXR agonist is a compound described in International Patent Publication No. WO2010/125811, e.g., any one of: 3-(2- ⁇ 4-[4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenyl]piperazin-1-yl ⁇ -2-oxoethyl)-5-methyl-5-[5- (propan-2-yloxy)pyridin-2-yl]imidazolidine-2,4-dione; 3-(2- ⁇ 4-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan- 2-yl)-2-propylphenyl]piperazin-1-yl ⁇ -2-oxoethyl)-5-methyl-5-[4-(propan-2-yloxy)phenyl]imidazolidine-2,4- dione; 5-(2H-1,3-benzodioxol
  • the LXR agonist is a compound described in International Patent Publication No. WO2009/138438, e.g., any one of: 1- (cyclopropylmethyl)-3-(4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-benzyl)piperazine-1- carbonyl)phenyl)urea; 1-butyl-3-(4-(4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine- 1-carbonyl)phenyl)urea; 1-(4-(4-(4-(4-(1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1- carbonyl)phenyl)-3-isobutylurea; 1-cyclobutyl-3-(4-(4-(4-(4-(1,1,1,1,3,3,3
  • the LXR agonist is a compound described in International Patent Publication No. WO2010/025179, e.g., any one of: N-tert-butyl-5-((4-(4- (3-cyclobutylureido)-3-fluorobenzoyl)piperazin-1-yl)methyl)furan-2-carboxamide; N-tert-butyl-5-((4-(3- fluoro-4-(3-isobutylureido)benzoyl)piperazin-1-yl)methyl)furan-2-carboxamide; N-tert-butyl-5-((4-(4-(3- (cyclopropylmethyl)ureido)-3-fluorobenzoyl)piperazin-1-yl)methyl)furan-2-carboxamide; N-tert-butyl-5-((4- (3-fluoro-4-(3-neopentylurei
  • the LXR agonist is a compound described in International Patent Publication No. WO2009/144961, e.g., any one of: 5-(2H-1,3- benzodioxol-5-yl)-3-( ⁇ 3-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy]phenyl ⁇ methyl)- 5-methylimidazolidine-2,4-dione; 5-(2,3-dihydro-1-benzofuran-5-yl)-3-( ⁇ 3-[4-(1,1,1,3,3,3-hexafluoro-2- hydroxypropan-2-yl)-2-propylphenoxy]phenyl ⁇ methyl)-5-methylimidazolidine-2,4-dione; 5-(2,3-dihydro-1- benzofuran-5-yl)-3-(1- ⁇ 3-[4-(1,1,1,3,3,3-
  • the LXR agonist is a compound described in International Patent Publication No. WO2013/076257, e.g., any one of: 5 ⁇ -hydroxy-6 ⁇ -[2- (1H-imidazol-4-yl)ethylamino]cholestan-3 ⁇ -ol (Dendrogenin A), 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4- yl)ethylamino]campestan-3 ⁇ -ol, 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]sitostan-3 ⁇ -ol, 3 ⁇ - acetoxy-5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]cholestane, 3 ⁇ -acetoxy-5 ⁇ -hydroxy-6 ⁇ -[2-(1H- imidazol-4-yl)ethylamino]campestane, 3 ⁇ -ace
  • the LXR agonist is a compound described in International Patent Publication No. WO2013/057148, e.g., acid addition salt of 5 ⁇ -hydroxy- 6 ⁇ -[2-(1H-imidazol-4yl)ethylamino]cholestan-3 ⁇ -ol such as acid addition salts formed with
  • the LXR agonist is an LXR agonist described in International Patent Publication Nos: WO2006/046593; WO2006/073366; WO2010/125811;
  • the LXR agonist is an LXR agonist described in Li et al, Expert Opin. Ther. Patents (2010) 20(4):535-562 and Tice et al., J. Med. Chem. (2014) 57:7182-7205, the compounds of which are herein incorporated by reference.
  • LXR agonists are an LXR agonist described in Li et al, Expert Opin. Ther. Patents (2010) 20(4):535-562 and Tice et al., J. Med. Chem. (2014) 57:7182-7205, the compounds of which are herein incorporated by reference.
  • LXR agonists include any compound described herein such as a compound of any one of Formula I-XXXVI and/or any one of compounds 1-826, or pharmaceutically acceptable salts thereof.
  • LXR ⁇ and LXR ⁇ are initially discovered by multiple groups at roughly the same time (Apfel et al., 1994; Willy et al., 1995; Song et al., 1994; Shinar et al., 1994; Teboul et al., 1995), belong to a family of nuclear hormone receptors that are endogenously activated by cholesterol and its oxidized derivatives to mediate transcription of genes involved in maintaining glucose, cholesterol, and fatty acid metabolism (Janowski et al., 1996; Calkin and Tontonoz, 2012).
  • LXR ⁇ an ideal therapeutic target, as exemplified by the broad-ranging responsiveness of melanoma cells to LXR ⁇ activation therapy.
  • LXR agonist As used herein, reference to the activity of an LXR agonist at LXR ⁇ and LXR ⁇ refer to the activity as measured using the ligand sensing assay (LiSA) described in Spencer et al. Journal of Medicinal Chemistry 2001, 44, 886-897, incorporated herein by reference.
  • the LXR agonist has an EC50 of less than 1 ⁇ M in the ligand sensing assay (e.g., 0.5 nm to 500 nM, 10 nM to 100 nM).
  • the methods of the invention can be performed using an LXR ⁇ agonist having activity for LXR ⁇ that is at least 3-fold greater than the activity of the agonist for LXR ⁇ , or having activity for LXR ⁇ that is at least 10-fold greater than the activity of the agonist for LXR ⁇ , or having activity for LXR ⁇ that is at least 100-fold greater than the activity of said agonist for LXR ⁇ , or having activity for LXR ⁇ that is at least within 3-fold of the activity of the agonist for LXR ⁇ .
  • the term“greater activity” in the LiSA assay assay refers to a lower EC50.
  • the term“increases the level of ApoE expression in vitro” refers to certain LXR agonists capable of increasing the level of ApoE expression 2.5-fold in a qPCR assay at a concentration of less than 5 ⁇ M (e.g., at a concentration of 100 nM to 2 ⁇ M, at a concentration of less than or equal to 1 ⁇ M).
  • the LXR agonists exhibiting this in vitro effect can be highly efficacious for use in the methods of the invention.
  • GITR modulator refers to a GITR-targeting agent, e.g., an antibody which specifically binds to GITR, which results in a change in T-cell activity, e.g., a downregulation of T- regulatory cells and/or an increase in T-effector cells or increased activity of T-effector cells.
  • a GITR modulator will increase the CD8/Treg ratio resulting in an increase in T-cell related anticancer activity.
  • GITR modulators are currently in development and/or in clinical trials including, but not limited to, TRX518, MK-4166, MK-1248, AMG228, BMS-986156, INCAGN01876, MEDI1873, and GWN323.
  • the GITR modulator is an antibody (e.g., a bivalent antibody).
  • the GITR modulator is a GITRL fusion protein.
  • the GITR modulator is an antibody drug conjugate.
  • the methods described here can be used to treat cancer.
  • Treating cancer can result in a reduction in size or volume of a tumor.
  • tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to its size prior to treatment.
  • Size of a tumor may be measured by any reproducible means of measurement.
  • the size of a tumor may be measured as a diameter of the tumor or by any reproducible means of measurement.
  • Treating cancer may further result in a decrease in number of tumors.
  • tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment.
  • Number of tumors may be measured by any reproducible means of measurement.
  • the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).
  • Treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site.
  • the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment.
  • the number of metastatic noduless may be measured by any reproducible means of measurement.
  • the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 50x).
  • Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days).
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the invention.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with the compound of the invention.
  • Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population.
  • the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%).
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with the compound of the invention.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with the compound of the invention.
  • Treating cancer can also result in an increased average progression-free survival time of a population of treated subjects in comparison to an untreated population.
  • the average progression-free survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days).
  • An increase in average progression-free survival time of a population may be measured by any reproducible means.
  • An increase in average progression-free survival time of a population may be measured, for example, by calculating for a population the average length of progression-free survival following initiation of treatment with the compound of the invention.
  • An increase in average progression- free survival time of a population may also be measured, for example, by calculating for a population the average length of progression-free survival following completion of a first round of treatment with the compound of the invention.
  • the methods described herein may be useful for the treatment of infections such as bacterial infections, parasitic infections, or fungal infections.
  • Compounds of the present invention may be administered by any appropriate route for treatment or prophylactic treatment of a disease or condition associated with an infection. These may be administered to humans, domestic pets, livestock, or other animals with a pharmaceutically acceptable diluent, carrier, or excipient.
  • Administration may be topical, parenteral, intravenous, intra-arterial, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal,
  • compositions are administered intraperitoneal, intranasal, aerosol, by suppositories, or oral administration.
  • compositions that contains a suitable carrier and one or more of the therapeutic agents described above.
  • the composition can be a pharmaceutical composition that contains a pharmaceutically acceptable carrier, a dietary composition that contains a dietarily acceptable suitable carrier, or a cosmetic composition that contains a cosmetically acceptable carrier.
  • composition refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • A“pharmaceutically acceptable carrier,” after administered to or upon a subject, does not cause undesirable physiological effects.
  • the carrier in the pharmaceutical composition must be“acceptable” also in the sense that it is compatible with the active ingredient and can be capable of stabilizing it.
  • One or more solubilizing agents can be utilized as pharmaceutical carriers for delivery of an active compound.
  • a pharmaceutically acceptable carrier include, but are not limited to, biocompatible vehicles, adjuvants, additives, and diluents to achieve a composition usable as a dosage form.
  • examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow # 10.
  • the term“pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic response, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. For example, S.M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below.
  • a free base function can be reacted with a suitable acid.
  • suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
  • suitable pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • the pharmaceutical compositions of the present invention additionally include a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired.
  • Remington s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
  • any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; natural and synthetic phospholipids, such as soybean and egg yolk phosphatides, lecithin, hydrogenated soy lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, dioleoyl lec
  • Phospholipon 90G and Phospholipon 90 NG are particularly preferred; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • buffering agents such as magnesium hydroxide and aluminum hydroxide
  • alginic acid such as pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents
  • compositions in any of the forms described above, can be used for treating melanoma, or any other disease or condition described herein.
  • An effective amount refers to the amount of an active compound/agent that is required to confer a therapeutic effect on a treated subject. Effective doses will vary, as recognized by those skilled in the art, depending on the types of diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatment.
  • a pharmaceutical composition of this invention can be administered parenterally, orally, nasally, rectally, topically, or buccally.
  • parenteral refers to subcutaneous
  • a sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • solutions include, but are not limited to, 1,3-butanediol, mannitol, water, Ringer’s solution, and isotonic sodium chloride solution.
  • fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides).
  • Fatty acid such as, but not limited to, oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as, but not limited to, olive oil or castor oil,
  • oil solutions or suspensions also can contain a long chain alcohol diluent or dispersant such as, but not limited to, carboxymethyl cellulose, or similar dispersing agents.
  • a long chain alcohol diluent or dispersant such as, but not limited to, carboxymethyl cellulose, or similar dispersing agents.
  • Other commonly used surfactants such as, but not limited to, Tweens or Spans or other similar emulsifying agents or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms also can be used for the purpose of formulation.
  • a composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions.
  • commonly used carriers include, but are not limited to, lactose and corn starch.
  • Lubricating agents such as, but not limited to, magnesium stearate, also are typically added.
  • useful diluents include, but are not limited to, lactose and dried corn starch.
  • compositions for topical administration can be formulated as solutions, ointments, creams, suspensions, lotions, powders, pastes, gels, sprays, aerosols, or oils.
  • topical formulations can be in the form of patches or dressings impregnated with active ingredient(s), which can optionally include one or more excipients or diluents.
  • the topical formulations include a material that would enhance absorption or penetration of the active agent(s) through the skin or other affected areas.
  • a topical composition contains a safe and effective amount of a dermatologically acceptable carrier suitable for application to the skin.
  • A“cosmetically acceptable” or“dermatologically-acceptable” composition or component refers a composition or component that is suitable for use in contact with human skin without undue toxicity, incompatibility, instability, or allergic response.
  • the carrier enables an active agent and optional component to be delivered to the skin at an appropriate concentration(s).
  • the carrier thus can act as a diluent, dispersant, solvent, or the like to ensure that the active materials are applied to and distributed evenly over the selected target at an appropriate concentration.
  • the carrier can be solid, semi-solid, or liquid.
  • the carrier can be in the form of a lotion, a cream, or a gel, in particular one that has a sufficient thickness or yield point to prevent the active materials from sedimenting.
  • the carrier can be inert or possess dermatological benefits. It also should be physically and chemically compatible with the active components described herein, and should not unduly impair stability, efficacy, or other use benefits associated with the composition. Combination Therapies
  • the pharmaceutical composition may further include an additional compound having antiproliferative activity.
  • the additional compound having antiproliferative activity can be selected from a group of antiproliferative agents including those shown in Table 4.
  • the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • the therapies employed may achieve a desired effect for the same disorder, or they may achieve different effects (e.g., control of any adverse effects).
  • antiproliferative agent any antiproliferative agent, including those antiproliferative agents listed in Table 4, any of which can be used in combination with a LXR agonist to treat the medical conditions recited herein.
  • Antiproliferative agents also include organo-platine derivatives, naphtoquinone and benzoquinone derivatives, chrysophanic acid and anthroquinone derivatives thereof.
  • mice were assigned to a control chow or a chow supplemented with compound 682 (Sigma-Aldrich) or compound 705 (Rgenix, Inc.) at 50, or 100 mg/kg/day, as indicated.
  • compound 682 Sigma-Aldrich
  • compound 705 Rgenix, Inc.
  • mice were fed a compound 705-supplemented diet and co-treated with anti-PD-1 antibody (clone RMP1-14 BioXcell), 10 mg/kg by i.p. injection every 3 days for 3 total doses starting on the day of tumor injection. All drug-formulated diets were prepared by Research Diets. Tumor Growth Assays
  • mice were injected with 5 x 10 4 B16F10 melanoma cells.
  • cells for all tumor growth experiments, cells (suspension in 50 ml of PBS) were mixed 1:1 with matrigel (356231, BD Biosciences, Bedford, MA) and subcutaneously injected into the lower flank of 6-8 week-old sex-matched mice.
  • mice were assigned to the following treatment groups as described below. All drug-formulated diets were prepared by Research Diets. After the indicated number of days, either peripheral blood or tumors were isolated to obtain tumor-infiltrating lymphocytes for flow-cytometry analysis as described below. Isolation of tumor-infiltrating lymphocytes for flow cytometry analysis
  • tumors were isolated from euthanized mice and minced into small ( ⁇ 1mm 2 ) pieces with a scalpel and then enzymatically dissociated. Enzymatic dissociation was achieved by incubation of minced tumor fragments in HBSS supplemented with 2% FBS, Collagenase 8, DnaseI, Hepes, and NaPyruvate for 30-45 minutes at 37 ⁇ C while shaken at 80 RPM. Following enzymatic dissociation, lymphocytes were purified using a 30/70 % Percoll gradient (GE Healthcare Life Sciences), followed by filtration through a 40uM filter (Corning Inc) to obtain a single cell suspension of lymphocytes.
  • a 30/70 % Percoll gradient GE Healthcare Life Sciences
  • spleens were isolated from euthanized mice and mechanically dissociated and treated with RBC Lysis Buffer (Sigma) followed by filtration through a 40uM filter (Corning Inc) to obtain a single cell suspension of lymphocytes.
  • Cells were then stained with the indicated antibodies: anti-CD45 (clone 104), anti-Gr1 (clone R86 ⁇ 8C5), anti-CD11b (clone M1/70), anti-Ly6G (clone 1A8), anti- Ly6C (clone AL21). After staining, cells were subsequently analyzed by flow cytometry using an LSRII flow cytometer (BD Biosciences). Data was analyzed using FlowJo software. Isolation of lymphocytes from circulating blood for flow cytometry analysis
  • CD8+ cells were purified from single cell suspensions from spleens of mice using the MACS CD8+ T-cell isolation kit (Miltenyi Biotech) according to manufacturer’s protocol. Cells were then labeled with cell tracker reagent (BV). The labeled CD8+ T cells were plated on 96-well plates coated with 1 mg/ml anti-CD3 and anti-CD28 beads (Dynabeads® Mouse T-Activator CD3/CD28 for T-Cell Expansion and Activation; Gibco). Recombinant IL-2 (Gibco) was then added to the wells according to
  • MDSC Mesenchymal cells
  • MACS Myeloid-Derived Suppressor Cell Isolation Kit
  • T-cell activation was measured by flow cytometry by assessing the percent of T-cells positive for IFN ⁇ staining with diluted BV dye.
  • MDSCs were isolated from the spleens of tumor-bearing wild-type or ApoE -/- mice, as indicated, using the MACS Myeloid-Derived Suppressor Cell Isolation Kit (Miltenyi Biotech) according to manufacturer’s protocol. MDSCs were then incubated in RPMI (Sigma) supplemented with 10% FBS and either COMPOUND 705 (dissolved in 2% DMSO at the indicated concentration) or control (2% DMSO) and subsequently incubated at 37 ⁇ C for the indicated time. Abundance was assessed by quantifying the percent of live cells using propidium Iodide staining.
  • RPMI Sigma
  • COMPOUND 705 dissolved in 2% DMSO at the indicated concentration
  • control 2% DMSO
  • mice were palpated every two days for tumor formation.
  • mice were randomly assigned to a control diet treatment or a GW3965-supplemented diet (100 mg/kg/day; Sigma-Aldrich). Tumor dimensions were measured using digital calipers, and tumor volume was calculated as (small diameter) 2 X (large diameter)/2. Tumors were isolated on day 12-14 for flow-cytometry analysis of tumor-infiltrating lymphocytes.
  • treatment with the LXR agonist compound 682 reduces the number of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) in B16F10 melanoma. Further, as shown in Figures 2A-2C, treatment with the LXR agonist compound 682 increases the number of tumor- infiltrating activated CD8+ T-cells in B16F10 melanoma.
  • Example 2 Treatment of tumors with Compound 705
  • mice were randomly assigned to receive a 100uL daily I.P. injection of either vehicle control (5% ethanol/95% corn oil) or COMPOUND 705 (2mg dissolved in vehicle control; Rgenix). Tumor dimensions were measured using digital calipers, and tumor volume was calculated as (small diameter) 2 X (large diameter)/2. Tumors were isolated on day 12-14 for flow- cytometry analysis of tumor-infiltrating lymphocytes.
  • treatment with the LXR agonist compound 705 reduces the number of both granulocytic MDSCs (G-MDSC) and monocytic MDSCs (M-MDSC) in B16F10 melanoma.
  • G-MDSC granulocytic MDSCs
  • M-MDSC monocytic MDSCs
  • treatment with compound 705 reduces abundance of MDSCs in vitro and reverses MDSC-mediated suppression of CD8+ T-cells.
  • Example 3 Treatment of tumors with Compound 705 + anti-PD1 antibody
  • mice were treated with anti-PD-1 antibody at a dose of 10mg/kg (clone RMP1-14; BioXcell), by intraperitoneal (I.P.) injection every 3 days for 3 total doses starting on the day of tumor injection.
  • mice were randomly assigned to receive a control diet treatment or an COMPOUND 705-supplemented diet (50 mg/kg/day; Rgenix). Tumor dimensions were measured using digital calipers, and tumor volume was calculated as (small diameter) 2 X (large diameter)/2. Tumors were isolated on day 12-14 for flow-cytometry analysis of tumor-infiltrating lymphocytes.
  • mice After tumor cell injection, tumor volumes were measured every two days. Upon tumors measuring 90-100 mm 3 in volume (day 6-7), mice were randomly assigned to a control diet treatment or a
  • COMPOUND 705-supplemented diet 50 mg/kg/day; Rgenix.
  • 2 x 10 6 CD8+ T-cells from Pmel mice were adoptively transferred via retro-orbital injection into both control and COMPOUND 705 treated mice.
  • CD8+ T-cells were obtained from 6-8 week old Pmel mice.
  • a single cell suspension was obtained by mechanical dissociation followed by filtration through a 70uM filter (Corning Inc).
  • CD8+ T-cells were then purified from the suspension using the MACS CD8+ T-cell isolation kit (Miltenyi Biotec) according to manufacturer’s protocol.
  • CD8+ T-cells were re- suspended in 100uL of PBS in preparation for adoptive transfer. For survival analyses, mice were euthanized when total tumor burden exceeded 1,500 mm 3 in volume.
  • treatment with compound 705 enhances the anti-tumor activity of adoptively transferred melanoma-targeting CD8+ T-cells.
  • Example 5 Treatment of tumors with compound 682 in ApoE deficient mice
  • mice deficient in ApoE, LRP8, or LXR ⁇ / ⁇ were determined using flow cytometry as described above.
  • mice that are deficient in ApoE, LRP8, or LXR ⁇ / ⁇ have higher baseline numbers of systemic MDSCs.
  • Example 7 Determination of the effect of ApoE deficient MDSCs on CD+8 T-cell activation
  • ApoE deficient MDSCs exhibit enhanced abundance in vitro and are resistant to LXR agonist-mediated cell-death.
  • LRP1 gene expression in tumors correlates with response to LXR agonists.
  • Example 11 Determining the level of GITR on CD8+ cells after treatment with LXR agonists

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Abstract

L'invention concerne des méthodes de traitement du cancer au moyen d'une combinaison d'un agoniste de LXRß et d'un modulateur GITR. L'invention concerne également des méthodes de traitement du cancer comprenant des combinaisons d'agonistes de LXRP et de modulateurs GITR avec des immunothérapies telles que des thérapies avec des inhibiteurs de PDl, avec des inhibiteurs de PDLl et des thérapies par transfert de lymphocytes T adoptifs.
PCT/US2018/035575 2017-06-02 2018-06-01 Méthodes pour le traitement du cancer Ceased WO2018222975A1 (fr)

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EP4417616A1 (fr) 2023-02-14 2024-08-21 Ospedale San Raffaele S.r.l. Antagonistes de lxr

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WO2017079112A1 (fr) * 2015-11-03 2017-05-11 Janssen Biotech, Inc. Anticorps se liant spécifiquement à pd-1 et leurs utilisations

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WO2017079112A1 (fr) * 2015-11-03 2017-05-11 Janssen Biotech, Inc. Anticorps se liant spécifiquement à pd-1 et leurs utilisations

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NOVARTIS PHARMACEUTICALS: "Phase I/lb Study of GWN323 Alone and in Combination With PDR001 in Patients With Advanced Malignancies and Lymphomas", CLINICALTRIALS NCT02740270, 21 March 2017 (2017-03-21), XP055562008, [retrieved on 20180804] *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4417616A1 (fr) 2023-02-14 2024-08-21 Ospedale San Raffaele S.r.l. Antagonistes de lxr
WO2024170646A1 (fr) 2023-02-14 2024-08-22 Ospedale San Raffaele S.R.L. Antagonistes de lxr

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