Tricyclic ligands that degrade IKZF2 or IKZF4

Abstract

Tricyclic compounds that degrade IKZF2 and / or IKZF4 are provided for the medical treatment of abnormal cell proliferation, including cancer, inflammatory disorders, neurodegenerative disorders, or autoimmune disorders.

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims the interests of U.S. Provisional Patent Application No. 63 / 091,875, filed on 14 October 2020, which in whole constitutes part of this specification by reference for all purposes.

[0002] The present invention provides a tricyclic cereblon conjugate for the degradation of IKZF2(Helios) and / or IKZF4(Eos) via the ubiquitin-proteasome pathway, for the treatment of medical disorders mediated by the IKZF2(Helios) and / or IKZF4(Eos) transcription factors.

[0003] [References] The contents of the text file, named "16010-057WO1_SequenceListing_ST25.txt", created on October 14, 2021, and measuring 3.94KB, constitute part of this specification by quoting its entire contents. [Background technology]

[0004] Proteolysis is a highly regulated and essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved by the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of virtually all cellular processes, including antigen processing, apoptosis, organelle biosynthesis, the cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, neurodegeneration and muscle degeneration, neural network morphogenesis, regulation of cell surface receptors, ion channels and secretory pathways, responses to stress and extracellular regulators, ribosome biosynthesis, and viral infection.

[0005] The covalent bonding of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases labels proteins for proteasomal degradation, where the protein is digested into small peptides and ultimately into its constituent amino acids, which become the building blocks of new proteins. Defects in proteasomal degradation have been associated with a variety of clinical disorders, particularly Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0006] The Ikaros ("IKZF") family consists of a series of zinc finger protein transcription factors crucial for certain physiological processes, particularly lymphocyte development (see Non-Patent Literature 1). Ikaros ("IKZF1") was first discovered in 1992 (see Non-Patent Literature 2), and over the following 20 years, four additional homologs—Helios ("IKZF2"), Aiolos ("IKZF3"), Eos ("IKZF4"), and Pegasus ("IKZF5")—have been identified (see Non-Patent Literature 3). Each homolog gene can produce several protein isoforms through alternative splicing, and theoretically, a large number of protein complexes can be generated by various combinations of homologs. A set of two C-terminal Cys2His2 zinc finger motifs that mediate protein interactions between various members of this protein family is highly conserved among the members of this family. Up to four zinc finger motifs are present at the N-terminus for DNA sequence recognition, and the number of these N-terminal zinc fingers is altered by alternative splicing. Isoforms lacking these N-terminal zinc fingers exhibit a dominant-negative effect on transcriptional activation (see Non-Patent Literature 4).

[0007] The distribution of various members of the Ikaros protein family within the body varies considerably. Ikaros, Helios, and Aiolos are primarily found in lymphoid cells and their corresponding progenitor cells, with Ikaros also being detected in the brain, and both Ikaros and Helios being detected in erythroid cells. Eos and Pegasus are more widely distributed and found in skeletal muscle, liver, brain, and heart (see Non-Patent Documents 5, 6, and 7).

[0008] Regulatory T cells (Tregs) are a specialized subpopulation of T cells that suppress the immune response to maintain homeostasis, self-tolerance, and autoimmunity (Non-Patent Literature 8). Tregs can inhibit T cell proliferation and cytokine production. Numerous subsets of Tregs exist.

[0009] T-regs suppress CD4+ and CD8+ T cells by consuming IL-2, limiting IL-2 expression, and upregulating CTLA4 to suppress antigen-presenting cells (APCs). T-regs also inhibit effector T cell activation by producing cytokines (IL-10, IL-35, and TGF-β), and further destroy effector cells by secreting granzymes and / or perforins. In addition, T-regs can generate adenosine from ATP in the tumor microenvironment, hindering optimal T cell activation.

[0010] Tregs act antagonistically against other T cells that attack tumors or cancer cells. In a cancerous environment, excessive activity of Tregs can prevent the immune system from destroying cancer cells. In autoimmune diseases, excessively low levels of Tregs allow other autoimmune cells to attack the body's own tissues. The percentage of Tregs in the bloodstream of multiple myeloma patients is significantly higher than in healthy individuals, and multiple myeloma patients with high Treg levels have a shorter lifespan.

[0011] Tregs are a subset of CD4+ T cells that express the transcription factor FoxP3 (forkhead box P3), a master regulator of regulatory pathways in the development and function of regulatory T cells. FoxP3 is a marker for both innate Treg cells (nTregs) and adaptive / induced regulatory T cells (a / iTregs). Multiple studies have shown that FoxP3 plays a crucial role in cancer development.

[0012] IKZF2 and IKZF4 are selectively expressed in Treg cells but not in effector or memory cells. FoxP3 / IKZF4 / CtBP1 forms an inhibitory complex in Tregs that represses gene expression (IL-2, IFN-γ) and maintains its repressive signature. Knockdown of IKZF4 in Tregs results in loss of the cell's ability to suppress the immune response, enabling partial effector function. Mir-17 targets IKZF4 degradation, and its overexpression reduces the repressive activity of Tregs. Tregs lacking MiR-17 show increased repression. Syngeneic tumor-bearing mice treated with mouse FoxP3 antisense oligonucleotides show significantly reduced tumor growth. It is becoming increasingly clear that IKZF4 plays a crucial role in regulating many of the repressive functions of Tregs by interacting with FoxP3.

[0013] IKZF2 regulates T-reg differentiation through a different mechanism than IKZF4. IKZF2 knockout in FoxP3-expressing T-regs results in loss of inhibitory properties (with increased IL-2) and promotion of T-effector cytokine expression via STAT5 (which modulates FoxP3). Similar to IKZF4 knockout, IKZF2 knockout does not prevent autoimmune disease in inflammatory bowel disease models. IKZF2 is highly expressed in leukemia stem cells and contributes to leukemia induction. IKZF2 regulates and maintains the chromatin accessibility of the autoregenerative transcription factors HOXA9 and MYC in leukemia stem cells. IKZF2 inhibits myelogenesis by suppressing the accessibility of myelogenesis genes containing the C / EBP motif.

[0014] Unlike the IKZF1 and IKZF3, the IKZF4 is T H It has been suggested that it may function as a positive regulator of one gene. IKZF4 expression is associated with T at both the transcript and protein levels. H It has been shown to correlate with the expression of one gene. Therefore, IKZF4 is T H In the differentiation and regulation of function, IKZF4 may play a role in opposition to IKZF1 and IKZF3. Also, unlike IKZF1 and IKZF3, IKZF4 is T H It may negatively regulate the differentiation of 17 cells. Similarly, IKZF4 may also negatively regulate T FH The functions of IKZF1 and IKZF3 in cells appear to be in opposition.

[0015] IKZF2 and IKZF4 have not been selectively targeted by conventional small molecule inhibitors, and may not be selectively targeted at them.

[0016] Little research has been done, and therefore little progress has been made, in identifying and using drugs that can selectively degrade IKZF2 and / or IKZF4.

[0017] Novartis has an IKZF2 / 4 protein degrader in clinical trials. See Adcock, et.al., Novartis AG Patent Document 1; Beckwith, et.al., Novartis AG Patent Document 2; Visser, et.al., Novartis AG Patent Document 3; and Binazzi, et.al., Novartis AG Patent Document 4.

[0018] The Dana Farber Cancer Institute has also filed patent applications in this general area: Patent Document 5 of Gray, et al., Dana-Farber Cancer Institute, and Patent Documents 6 and 7 of Verano, et al., Dana-Farber Cancer Institute. Bristol-Myers Squibb Company has also filed applications for IKZF2 degraders, for example, Patent Documents 8 and 9.

[0019] Ionis Pharmaceuticals and Astra Zeneca have reported a high-affinity oligonucleotide (AZD8701) that targets FoxP3, inhibits the immunosuppressive function of regulatory T cells, and induces an antitumor effect in syngeneic mice (Non-Patent Literature 9).

[0020] Patent documents 10 and 11 filed by C4 Therapeutics, Inc. disclose cereblon binders for the degradation of Ikaros (IKZF1 / 3).

[0021] Patent document 12, filed by Calico Life Sciences LLC and AbbVie Inc., describes PTPN1 and PTPN2 ligands covalently bound to various cereblon ligands.

[0022] Despite these efforts, compounds that catalyze the selective degradation of zinc finger proteins such as IKZF2 and IKZF4 remain needed for medical treatments, including the treatment of disorders involving abnormal cell proliferation, such as tumors and cancer. [Prior art documents] [Patent Documents]

[0023] [Patent Document 1] International Publication No. 2020 / 012334 [Patent Document 2] International Publication No. 2020 / 012337 [Patent Document 3] International Publication No. 2019 / 038717 [Patent Document 4] International Publication No. 2020 / 128972 [Patent Document 5] International Publication No. 2020 / 006264 [Patent Document 6] International Publication No. 2020 / 117759 [Patent Document 7] International Publication No. 2021 / 087093 [Patent Document 8] International Publication No. 2021 / 101919 [Patent Document 9] International Publication No. 2021 / 194914 [Patent Document 10] International application PCT / US2019 / 24094 [Patent Document 11] International application PCT / US2020 / 02678 [Patent Document 12] International Publication No. 2021 / 127586 [Non-patent literature]

[0024] [Non-Patent Document 1] Fan, Y. and Lu, D., "The Ikaros family of zinc-finger proteins," Acta Pharmaceutica Sinica B, 2016, 6:513-521. [Non-Patent Document 2] Georgopoulos, K. et al., "Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment," Science, 1992, 258:802-812. [Non-Patent Document 3] John, LB, and Ward, AC. "The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity." Mol Immunol, 2011, 48:1272-1278. [Non-Patent Document 4] Winandy, S. et al., "A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma," Cell, 1995, 83:289-299. [Non-Patent Document 5] Perdomo, J. et al., "Eos and Pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities," J Biol Chem, 2000, 275:38347-38354. [Non-Patent Document 6] Schmitt, C. et al., "Aiolos and Ikaros: regulators of lymphocyte development, homeostasis and lymphoproliferation," Apoptosis, 2002, 7:277-284. [Non-Patent Document 7] Yoshida, T. and Georgopoulos, K., "Ikaros fingers on lymphocyte differentiation," Int J Hematol, 2014, 100:220-229. [Non-Patent Document 8] PMID:20672742 [Non-Patent Document 9] AACR Annual Meeting Abst 5561; April 2018 [Overview of the project]

[0025] Certain tricyclic glutarimide compounds have been found to be able to degrade IKZF2 and / or IKZF4. Furthermore, in certain embodiments, these tricyclic compounds exhibit selectivity in the degradation of IKZF2 and / or IKZF4 more than IKZF1 or IKZF3. Therefore, novel tricyclic compounds that can be administered in effective doses to a host, typically a human, are provided for the treatment of medical disorders (e.g., including abnormal cell proliferation including cancer, inflammatory disorders, neurodegenerative disorders, and autoimmune disorders) that respond to drugs that selectively degrade IKZF2 and / or IKZF4. The present invention comprises the described IKZF2 and / or IKZF4 degraders and their pharmaceutically acceptable salts, along with their use and manufacture.

[0026] In certain embodiments, the tricyclic compounds of the present invention exhibit at least about 1.5 times, 2 times, 3 times, 5 times, or even 10 times greater degradation selectivity in vitro than IKZF2 and / or IKZF4 than IKZF1 and / or IKZF3 in a standard HiBiT bioluminescence assay.

[0027] In certain embodiments, by selectively degrading IKZF2 and / or IKZF4, the tricyclic glutarimides described herein or their pharmaceutically acceptable salts can be used to treat diseases in an immunosuppressive environment resulting from the presence of T-reg cells and / or other relevant cytokines and mediators that reduce the host's normal immune response to the disease. In one non-limiting embodiment, the optimal treatment can be determined by examining the biomarker FoxP3, or the upregulation of IL-10, IL-35, or TGFβ in a host biopsy.

[0028] Selected compounds disclosed herein, their pharmaceutically acceptable salts, or their pharmaceutically acceptable compositions can be used to treat disorders mediated by IKZF2 or IKZF4, such as solid tumors including lung cancer (e.g., PD-1 or PD-L1 resistant), including small cell lung cancer or non-small cell lung cancer, melanoma (e.g., PD-1 or PD-L1 resistant), breast cancer (including triple-negative breast cancer), or hematopoietic malignancies such as multiple myeloma, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myelodysplastic syndrome, or other targeted indications. In certain embodiments, the cancer is CLL associated with FoxP3CD4+ cell proliferation. Jarcutt cells (T-ALL) are known to express IKZF2 and IKZF4, and therefore these compounds can be used to treat T-ALL. Further examples of cancers mediated by IKZF2 or IKZF4 include T-cell leukemia, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloid leukemia, nasopharyngeal carcinoma, microsatellite-stable colorectal cancer, thymoma, and carcinoid cancer.

[0029] In certain embodiments, the selective degrader of IKZF2 and / or IKZF4 is administered to a host that needs it in combination with another activator, such as a checkpoint inhibitor, CAR-T therapy, a target antibody, an antibody-drug conjugate, or other standard therapeutic therapies for the cancer or abnormal cell proliferation being treated. In certain embodiments, the patient has cancer that has progressed on immune checkpoint inhibitor therapy, has a high tumor burden, is over about 60 or 65 years of age, or has an increased number of Treg markers. When used in combination with another compound or biologic that treats immunosuppression, it may lead to the activation and enhanced effector function of CD4+ T cells, CD8+ T cells, B cells, NK cells, macrophages, or dendritic cells.

[0030] The present invention relates to a compound of formula I:

Chemical Formula

Chemical Formula

[0031] All combinations of compounds resulting from variables, substituents, embodiments, and combinations thereof are deemed to be disclosed specifically and individually, for such descriptions are for the convenience of space only and are not intended to describe only genera or even subgenera of compounds, as is known to those skilled in the art, but rather to provide the various compounds herein that are stable compounds with a desired shelf life of, for example, at least about two, three, four, five, or six months or more under ambient conditions of use.

[0032] In certain embodiments, the compounds described herein bind to cereblon, increasing the interaction between cereblon and IKZF2 or IKZF4, leading to subsequent ubiquitination and proteasome protein degradation.

[0033] Accordingly, in several embodiments, based on this discovery, compounds and methods are provided for the treatment of patients having disorders mediated by IKZF2 or IKZF4, which in certain embodiments are lymphatic disorders. In certain embodiments, the disorder is leukemia. In certain embodiments, the disorder is lymphocytic leukemia. In certain embodiments, the disorder is lymphoblastic leukemia. In several embodiments, the disorder is hematological malignancies, such as multiple myeloma, myelodysplastic syndromes such as 5q-deletion syndrome, acute lymphoblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloid leukemia, acute myeloid leukemia, chronic myeloid leukemia, or chronic lymphocytic leukemia. In another embodiment, selected compounds of the present invention are administered to achieve immunomodulation and reduce angiogenesis.

[0034] In other embodiments, but not limited to them, compounds and methods for the treatment of disorders including benign tumors, neoplasms, tumors, cancer, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid-based proteinopathy, proteinopathy, or fibrous disorders are presented. Furthermore, other disorders that can be treated with an effective amount of the compounds described herein are listed below.

[0035] In certain embodiments, any compound described herein has the substitution of at least one desired atom in an amount approximately equal to the natural abundance of the isotope, i.e., an enriched amount.

[0036] Other features and advantages of the present invention will become apparent from the following detailed description and claims.

[0037] Therefore, the present invention includes at least the following features: (a) Compounds of formula I as described herein, or pharmaceutically acceptable salts, isotopic derivatives (including deuterated derivatives), or prodrugs thereof (b) For the treatment of disorders mediated by IKZF2 or IKZF4, a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof (c) A method of treating a patient in need of treatment, typically a human, comprising administering an effective amount of a compound of formula I described herein, or a pharmaceutically acceptable salt thereof, wherein the patient has a disorder described herein, for example, a disorder mediated by IKZF2 or IKZF4, (d) A method of treating a patient in need of treatment, typically a human, comprising administering an effective amount of a compound of formula I described herein, or a pharmaceutically acceptable salt thereof, wherein the patient has a hematological malignancy such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma, (e) A method of treating a patient in need of treatment, typically a human, comprising administering an effective amount of a compound of formula I described herein, or a pharmaceutically acceptable salt thereof, wherein the patient has a solid malignancy such as non-small cell lung cancer, small cell lung cancer, breast cancer, melanoma, prostate cancer, colon cancer, pancreatic cancer, or cancer generally exhibiting an immunosuppressive environment, (f) A method of treating a patient in need of treatment, typically a human, comprising administering an effective amount of a compound of formula I described herein, or a pharmaceutically acceptable salt thereof, wherein the patient has a solid malignancy such as non-small cell lung cancer, small cell lung cancer, breast cancer, melanoma, prostate cancer, colon cancer, pancreatic cancer, or cancer generally exhibiting an immunosuppressive environment, and the patient is also being administered an anti-PD-1 agent or an anti-PD-L1 agent, (g) Patients having any one of the disorders described herein, including disorders mediated by IKZF2 or IKZF4, typically using a compound of formula I described herein in an effective dose for human treatment, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof. (h) Use of a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof, in the manufacture of a pharmaceutical for the treatment of a medical disorder to which the person is sensitive, as further described herein. (i) A method for producing a pharmaceutical for the treatment of a disorder described herein in a host, characterized by using a compound of formula I in the production. (j) For the treatment of cancer in a host containing any of the cancers described herein, a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof. (k) Use of a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof, in the manufacture of a pharmaceutical product for the treatment of any cancer described herein, including any cancer described herein. (l) A method for producing a pharmaceutical for the treatment of cancer in a host containing any of the cancers described herein, characterized by using a compound of formula I in the production. (m) For the treatment of tumors in a host containing any of the tumors described herein, a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof. (n) Use of a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof, in the manufacture of a pharmaceutical product for the treatment of any tumor described herein, (o) A method for producing a pharmaceutical for the treatment of a tumor in a host containing any of the tumors described herein, characterized by using a compound of formula I in the production. (p) For the treatment of immune disorders, autoimmune disorders, inflammatory disorders, neurodegenerative disorders or fibrous disorders in a host, a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof. (q) Use of compounds of formula I described herein, or pharmaceutically acceptable salts, isotope derivatives, or prodrugs thereof, in the manufacture of pharmaceuticals for the treatment of immunodeficiency, autoimmune disorder, inflammatory disorder, neurodegenerative disorder, or fibrous disorder. (r) A method for producing a pharmaceutical product for the treatment of immune disorders, autoimmune disorders, inflammatory disorders, neurodegenerative disorders, or fibrous disorders in a host, characterized by using a compound of formula I in the production process. (s) Compounds of formula I as described herein, or pharmaceutically acceptable salts, isotope derivatives, or prodrugs thereof, for the treatment of hematological malignancies such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma. (t) For the treatment of solid malignancies such as non-small cell lung cancer, small cell lung cancer, breast cancer, melanoma, prostate cancer, colon cancer, pancreatic cancer, or cancers that generally exhibit an immunosuppressive environment, a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof. (u) Use of compounds of formula I described herein, or pharmaceutically acceptable salts, isotope derivatives, or prodrugs thereof, in the manufacture of pharmaceuticals for the treatment of hematological malignancies such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma. (v) Method for manufacturing pharmaceuticals for the treatment of hematological malignancies such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma. (w) A pharmaceutical composition comprising an effective host therapeutic dose of a compound of formula I described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent. (x) A mixture of the compounds described herein as an enantiomer or diastereomer (if applicable) including a racemic mixture. (y) The compounds described herein in concentrated form (if applicable) as an enantiomer or diastereomer, comprising isolated enantiomers or diastereomers (i.e., of greater than 85%, 90%, 95%, 97%, or 99% purity), and (z) A manufacturing process for a therapeutic product containing an effective amount of the compound of formula I described herein. [Brief explanation of the drawing]

[0038] [Figure 1] This figure shows a synthetic scheme illustrating a non-limiting example of synthesis, in which the intermediate 3-(5-bromo-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione can be used to add a series of R1 groups. [Figure 2] This figure shows a synthetic scheme illustrating a non-limiting example of synthesis that can be used with the intermediate 1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-5-carbaldehyde derivative to functionalize a series of R1 groups. [Figure 3] This figure shows a representative formula of the IKZF2 / 4 decomposition compound of the present invention. [Modes for carrying out the invention]

[0039] I. Definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this application pertains. In this specification, singular nouns also include plural nouns unless the context clearly indicates otherwise. Methods and materials similar to or equivalent to those described herein may be used in the implementation and testing of this application, but preferred methods and materials are described below. All publications, patent applications, patents and other references referenced herein constitute part of this specification by reference. References cited herein are not considered prior art to this application. In case of conflict, this specification, including definitions, shall prevail. In addition, materials, methods and examples are illustrative and not intended to be limiting.

[0040] Compounds are described using their formal names. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this invention pertains.

[0041] In certain embodiments of each compound described herein, the compounds may be in the form of isomers such as racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, or rotational isomers, as each is specifically described, unless otherwise explicitly excluded by the context.

[0042] The terms "a" and "an" do not indicate a limitation of quantity, but rather indicate the presence of at least one of the items mentioned. The term "or" means "and / or". Unless otherwise specified herein, the enumeration of value ranges is intended merely as a simple way to refer individually to each distinct value contained within that range, and each distinct value constitutes part of this specification by reference as if they were individually enumerated herein. The endpoints of all ranges are contained within that range and can be combined independently. All methods described herein can be performed in a preferred order unless otherwise specified herein or clearly rejected by the context. The use of example or illustrative words (e.g., "such as") is intended merely to better illustrate the invention and does not indicate a limitation of the scope of the invention unless otherwise asserted.

[0043] The present invention includes compounds described herein that have isotopic substitution of at least one desired atom in an amount exceeding the natural abundance of the isotope, i.e., enriched. Isotopes are atoms that have the same atomic number but different mass numbers, i.e., the same number of protons but different number of neutrons. When isotopic substitution is used, substitution of hydrogen with at least one deuterium is common.

[0044] More generally, examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, for example. 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 35 S, and 36 Examples include each of Cl. In one non-limiting embodiment, isotope-labeled compounds are used in metabolic studies (e.g., 14 (using C), reaction dynamics studies (for example) 2 H or 3It can be used in detection or imaging techniques, including drug or substrate tissue distribution assays or radiotherapy for patients, such as positron emission tomography (PET) or single-photon emission tomography (SPECT), using H. Additionally, any hydrogen atom present in the compound of the present invention 18 Substitution with a fluorine atom is also possible, and this substitution may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds of the present invention and their prodrugs can generally be prepared by replacing the non-isotope-labeled reagent with a readily available isotope-labeled reagent, by following the procedures disclosed in the scheme or in the following examples and preparations.

[0045] As a general example, though not limited to them, hydrogen isotopes, for example, deuterium ( 2 H) and tritium ( 3 H) can be used in any part of the described structure in which the desired result is achieved. Alternatively or additionally, carbon isotopes, for example 13 C and 14 You can use C.

[0046] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen atom is replaced by deuterium. In certain embodiments, isotopes are enriched to 90%, 95%, 99%, or more at any position of interest. In one non-limiting embodiment, deuterium is enriched to 90%, 95%, or 99% at a desired position.

[0047] In one non-limiting embodiment, the substitution of a hydrogen atom with a deuterium atom can occur in any of the compounds described herein. For example, if any of the groups are methyl, ethyl, or methoxy, or contain these by substitution, for example, an alkyl residue may be deuterated (e.g., CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 in a non-limiting embodiment). In certain other embodiments, if two substituents combine to form a ring, an unsubstituted carbon may be deuterated. In certain embodiments, at least one deuterium atom is located on an atom having a bond that is cleaved during the metabolism of the compound in vivo, or on an atom one, two, or three atoms away from the bond that is metabolized (for example, sometimes referred to as the α-isotope effect, β-isotope effect, or γ-isotope effect, or the primary isotope effect, secondary isotope effect, or tertiary isotope effect).

[0048] The compounds of the present invention can form solvates with a solvent (including water). Therefore, in one non-limiting embodiment, the present invention includes compounds in the solvated forms described herein. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents include water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex containing a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent may be isotope-substituted, such as D2O, d6-acetone, and d6-DMSO. Solvates may be in liquid or solid form.

[0049] A dash ("-") without a space between two letters or symbols is used to indicate the attachment point of a substituent. For example, -(C=O)NH2 is attached via the carbon of the keto (C=O) group.

[0050] "Alkyl" refers to a branched or linear saturated aliphatic hydrocarbon group. In one non-limiting embodiment, an alkyl group contains 1 to about 12 carbon atoms, more commonly 1 to about 6 carbon atoms, or 1 to about 4 carbon atoms. In one non-limiting embodiment, an alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, an alkyl group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The designations used herein refer to alkyl groups having members in each range that are described as independent species. For example, the term C1-C6 alkyl as used herein refers to linear or branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, and is intended to mean that these are each described as independent species. For example, the term C1-C4 alkyl as used herein refers to linear or branched alkyl groups having 1, 2, 3, or 4 carbon atoms, and is intended to mean that these are each described as independent species. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.

[0051] An "alkenyl" is a linear or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur at stable points along the chain. The designated ranges used herein refer to alkenyl groups having each member in the range described above as a separate species for the alkyl moiety. In one non-limiting embodiment, an alkenyl contains 2 to about 12 carbon atoms, more generally 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In certain embodiments, the alkenyl is C2, C2-C3, C2-C4, C2-C5, or C2-C6. Examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also includes "cis" and "trans" alkenyl configurations, or alternatively, "E" and "Z" alkenyl configurations. The term "alkenyl" also encompasses cycloalkyl or carbocyclic groups having at least one unsaturated point.

[0052] An "alkynyl" is a branched or linear aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can occur at any stable point along the chain. The designations used herein refer to alkynyl groups having each member within the range described above as a separate species for the alkyl moiety. In one non-limiting embodiment, an alkynyl contains 2 to about 12 carbon atoms, more generally 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In certain embodiments, the alkynyl is C2, C2-C3, C2-C4, C2-C5, or C2-C6. Examples of alkynyls include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0053] "Halo" and "halogen" are independently fluorine, chlorine, bromine, or iodine.

[0054] A "haloalkyl" is a branched or linear alkyl group substituted with one or more of the above halo atoms up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. A "perhaloalkyl" means an alkyl group in which all hydrogen atoms are replaced with halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0055] As used herein, "aryl" refers to a radical ("C") of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and 0 heteroatoms within the aromatic ring system (e.g., 6, 10, or 14 π electrons shared in a cyclic configuration). 6~14 This refers to "aryl". In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl" (for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl," for example, anthracyl. "Aryl" also includes ring systems in which the above-defined aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the radical or attachment site is on the aryl ring, in which case the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. The one or more fused cycloalkyl or heterocyclic groups may be 4-membered to 7-membered saturated or partially unsaturated cycloalkyl or heterocyclic groups.

[0056] "Arylalkyl" refers to either an alkyl group as defined herein substituted with an aryl group as defined herein, or an aryl group as defined herein substituted with an alkyl group as defined herein.

[0057] The term "heterocyclic" refers to saturated and partially saturated heteroatom-containing ring radicals that contain one, two, three, or four heteroatoms independently selected from nitrogen, sulfur, boron, silicon, and oxygen. Heterocyclic rings may include monocyclic rings with 3 to 10 members and bicyclic ring systems with 5 to 16 members (including bridging, fusion, and spirofusion bicyclic ring systems). Heterocyclic rings do not include rings containing -OO-, -OS-, or -SS- moieties. Examples of saturated heterocyclic groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, piperazinyl), saturated 3- to 6-membered heteromonocyclic groups containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl), and saturated 3- to 6-membered heteromonocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl). Examples of partially saturated heterocyclic radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanil, chromanil, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, Examples include, but are not limited to, 1,2,3,4-tetrahydroquinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazolyl-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.

[0058] "Heterocyclic" also includes groups in which a heterocyclic radical fuses / condenses with an aryl or carbocyclic radical and the attachment site is a heterocyclic system. "Heterocyclic" also includes groups in which a heterocyclic radical is an oxo group (i.e., [ka] This also includes groups substituted with ), for example, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indoline or isoindoline; partially unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms; partially unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms; and saturated condensed heterocyclic groups containing 1 or 2 oxygen or sulfur atoms.

[0059] The term “heterocycle” also includes “bicyclic heterocycle.” The term “bicyclic heterocycle” refers to a heterocycle as defined herein that has one bridging, fusion, or spirocyclic portion of the heterocycle. The bridging, fusion, or spirocyclic portion of the heterocycle can be a carbocyclic, heterocycle, or aryl group, insofar as a stable molecule is formed. Unless otherwise excluded by context, the term “heterocycle” includes bicyclic heterocycles. A bicyclic heterocycle includes a group in which the fusion heterocycle is substituted with an oxo group. Non-restrictive examples of bicyclic heterocycles include: [ka] These are some examples.

[0060] The term "heteroaryl" refers to a stable aromatic ring system containing one, two, three, or four heteroatoms independently selected from O, N, and S, in which the ring nitrogen and sulfur atoms (or more) are optionally oxidized and the nitrogen atom (or more) is optionally quaternized. Examples include unsaturated 5- or 6-membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridadinyl, and triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl); unsaturated 5- or 6-membered heteromonocyclic groups containing an oxygen atom, such as pyranyl, 2-furyl, 3-furyl; and unsaturated 5- or 6-membered heteromonocyclic groups containing a sulfur atom, such as 2-thie. Examples include, but are not limited to, nyl, 3-thienyl; unsaturated 5- or 6-membered heteromonocyclic groups containing one or two oxygen atoms and one to three nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl); and unsaturated 5- or 6-membered heteromonocyclic groups containing one or two sulfur atoms and one to three nitrogen atoms, such as thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl). In certain embodiments, the "heteroaryl" group is an 8-, 9-, or 10-membered bicyclic ring system. Examples of 8-membered, 9-membered, or 10-membered bicyclic heteroaryl groups include benzoflazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthilidinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazolyl, and benzotriazolyl.

[0061] "Heteroarylalkyl" refers to either an alkyl group as defined herein substituted with a heteroaryl group as defined herein, or a heteroaryl group as defined herein substituted with an alkyl group as defined herein.

[0062] As used herein, "carbocyclic," "carbocyclic," or "cycloalkyl" means that the non-aromatic ring system contains all the carbocyclic atoms and 3 to 14 ring carbon atoms ("C"). 3~14 The cycloalkyl group comprises a saturated or partially unsaturated (i.e., non-aromatic) group having 3 to 10 ring carbon atoms ("C"). In some embodiments, the cycloalkyl group has 3 to 10 ring carbon atoms ("C"). 3~10 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 9 ring carbon atoms ("C"). 3~9 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C"). 3~8 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 7 ring carbon atoms ("C"). 3~7 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C"). 3~6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 4 to 6 ring carbon atoms ("C"). 4~6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has five or six ring carbon atoms ("C"). 5~6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C"). 5~10 Cycloalkyl). Exemplary C 3~6 Examples of cycloalkyl groups, though not limited to them, include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3~8The cycloalkyl group is not limited to the above C 3~6 Examples include cycloalkyl groups, and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), etc. Exemplary C 3~10 The cycloalkyl group is not limited to the above C 3~8 Cycloalkyl groups, and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 Examples include the following. As shown in the above examples, in certain embodiments, the cycloalkyl group may be saturated or contain one or more intercarbon double bonds. The term "cycloalkyl" also includes ring systems in which the cycloalkyl ring defined above is fused with one heterocycle, aryl, or heteroaryl ring, and the attachment point is on the cycloalkyl ring, in which case the carbon number continues to represent the carbon number in the carbocyclic system. The term "cycloalkyl" also includes ring systems in which the cycloalkyl ring defined above has a spirocyclic heterocycle, aryl, or heteroaryl ring, and the attachment point is on the cycloalkyl ring, in which case the carbon number continues to represent the carbon number in the carbocyclic system. The term "cycloalkyl" also includes bicyclic or polycyclic fusions, bridges, or spirocyclic systems containing 5 to 14 carbon atoms and 0 heteroatoms in the non-aromatic ring system. Typical examples of "cycloalkyl" include: [ka] These include, but are not limited to, the following:

[0063] The term "bicyclic" refers to a ring system in which two rings are fused, with each ring independently selected from carbon rings, heterocyclic rings, aryl rings, and heteroaryl rings. Non-restrictive examples of bicyclic groups include: [ka] These are some examples.

[0064] The term "double ring" is R 15 , R 16 , or R 17 When used in relation to divalent residues such as, the attachment points may be on separate rings or on the same ring. In certain embodiments, both attachment points are on the same ring. In certain embodiments, both attachment points are on different rings. Non-limiting examples of divalent bicyclic groups include, [ka] These are some examples.

[0065] "Dosage form" refers to the unit of administration of the active ingredient. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, oral forms, sublingual forms, topical forms, gels, and mucosal forms. "Dosage form" may also include implants, such as optical implants.

[0066] As used herein, “endogenous” means any substance that originates from or is produced within an organism, cell, tissue, or system.

[0067] As used herein, the term “exogenous” refers to any substance introduced from or produced outside of an organism, cell, tissue, or system.

[0068] As used herein, the term "modulate" means mediating a detectable increase or decrease in the level of response in a subject compared to the level of response in the subject in the absence of the treatment or compound, and / or otherwise identical, compared to the level of response in an untreated subject. This term encompasses mediating a beneficial therapeutic response in a subject, preferably a human, by disrupting and / or affecting an inherent signal or response.

[0069] Parenteral administration of compounds includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im), or intrasternal injection, or infusion methods.

[0070] As used herein, “pharmaceutical composition” is a composition comprising at least one activator, such as a selective active compound described herein, and at least one other substance, such as a carrier. “Pharmaceutical combinations” is a combination of at least two activators, which may be combined into a single dosage form or administered together in separate dosage forms, and which are indicated to be used in combination to treat any of the disorders described herein.

[0071] As used herein, “pharmaceutically acceptable salt” is a derivative of the disclosed compound obtained by modifying the parent compound to produce its inorganic and organic salts, acid addition salts, or base addition salts, with the loss of bioacidic toxicity. Salts of the compound can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in their free acid form with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, or bicarbonate of Na, Ca, Mg, or K) or by reacting these compounds in their free base form with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water, an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical when practical. Salts of the compound further include solvates of the compound and salts of the compound.

[0072] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, ecylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) n Examples of salts prepared from organic acids such as -COOH (where n is 0 to 4) or using different acids that produce the same counterion. A further list of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0073] The term "carrier" means a diluent, additive, or vehicle in which the activator is used or delivered.

[0074] "Pharmacologically acceptable additives" mean additives that are generally safe and not inappropriate for administration to a host (usually a human), either biologically or otherwise, and that are useful in the preparation of a pharmaceutical composition / combination. In certain embodiments, additives acceptable for veterinary use are used.

[0075] "Patient," "host," or "subject" is a human or non-human animal requiring treatment for any of the disorders specifically described herein. Typically, the host is human. "Host" may also alternatively refer to, for example, mammals, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0076] The "therapeutic effective amount" of the pharmaceutical composition / combination of the present invention means an amount that is effective in producing a therapeutic effect such as improvement of symptoms or reduction or mitigation of the disease itself when administered to a host.

[0077] In certain embodiments, a “prodrug” is a parent molecule in a form that is metabolized or chemically converted to the parent molecule in vivo, for example, in mammals or humans. Non-limiting examples of prodrugs include esters, such as amides, carbonates, carbamates, phosphates, ketals, imines, oxazolidines, and thiazolidins of primary or secondary amines. Prodrugs may be designed to release the parent molecule upon a change in pH (e.g., in the stomach or intestines) or upon the action of an enzyme (e.g., esterase or amidase).

[0078] In certain embodiments, “stable” means that less than 10%, less than 5%, less than 3%, or less than 1% of the compound decomposes under ambient conditions and has a shelf life of at least 3 months, 4 months, 5 months, or 6 months. In certain embodiments, compounds stored under ambient conditions are stored at approximately room temperature and exposed to air and relative humidity of less than about 40%, less than 50%, less than 60%, or less than 70%. In certain embodiments, compounds stored under ambient conditions are stored at approximately room temperature under an inert gas (such as argon or nitrogen). Typically, the parts described herein do not have more than one or two heteroatoms directly bonded to each other, unless the part is heteroaromatic.

[0079] Throughout this disclosure, various aspects of the present invention may be presented in range form. It should be understood that range form is merely for convenience and should not be interpreted as a limitation of the scope of the invention. Range descriptions should be considered to specifically disclose all conceivable subranges and the individual numerical values ​​within those ranges. For example, a range description such as 1-6 should be considered to specifically disclose subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, and the individual numbers within those ranges, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0080] II. Compounds of the present invention "alkyl" embodiment In a particular embodiment, "alkyl" is C1-C 10 It is alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1 or C2 alkyl.

[0081] In a particular embodiment, the "alkyl" contains one carbon atom.

[0082] In a particular embodiment, the "alkyl" contains two carbon atoms.

[0083] In a particular embodiment, the "alkyl" contains three carbon atoms.

[0084] In a particular embodiment, the "alkyl" contains four carbon atoms.

[0085] In a particular embodiment, the "alkyl" contains five carbon atoms.

[0086] In a particular embodiment, the "alkyl" contains six carbon atoms.

[0087] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0088] Additional, non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0089] Additional, non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0090] Additional, non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0091] Additional, non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and active pentyl.

[0092] "Haloalkyl" embodiment In a particular embodiment, "haloalkyl" is C1-C 10 These include haloalkyl, C1-C9 haloalkyl, C1-C8 haloalkyl, C1-C7 haloalkyl, C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, and C1 or C2 haloalkyl.

[0093] In a particular embodiment, the "haloalkyl" has one carbon atom.

[0094] In a particular embodiment, the "haloalkyl" has one carbon atom and one halogen atom.

[0095] In a particular embodiment, the "haloalkyl" has one carbon atom and two halogen atoms.

[0096] In a particular embodiment, the "haloalkyl" has one carbon atom and three halogen atoms.

[0097] In a particular embodiment, the "haloalkyl" has two carbon atoms.

[0098] In a particular embodiment, the "haloalkyl" has three carbon atoms.

[0099] In a particular embodiment, the "haloalkyl" has four carbon atoms.

[0100] In a particular embodiment, the "haloalkyl" has five carbon atoms.

[0101] In a particular embodiment, the "haloalkyl" has six carbon atoms.

[0102] Non-specific examples of "haloalkyl" include: [ka] These are some examples.

[0103] Additional, non-limiting examples of "haloalkyl" include: [ka] These are some examples.

[0104] Additional, non-limiting examples of "haloalkyl" include: [ka] These are some examples.

[0105] Additional, non-limiting examples of "haloalkyl" include: [ka] These are some examples.

[0106] "Aryl" embodiment In a particular embodiment, "aryl" is a six-carbon aromatic group (phenyl).

[0107] In a particular embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[0108] In certain embodiments, "aryl" is a six-carbon aromatic group fused to a heterocycle, with an aryl ring as its attachment point. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the attachment point of each group is on an aromatic ring.

[0109] for example, [ka] This is an "aryl" group.

[0110] however, [ka] This is a "heterocyclic" group.

[0111] In certain embodiments, "aryl" is a six-carbon aromatic group condensed with a cycloalkyl group, with an aryl ring as the attachment point. Non-limiting examples of "aryl" include dihydroindene and tetrahydronaphthalene, where the attachment point of each group is on an aromatic ring.

[0112] for example, [ka] This is an "aryl" group.

[0113] however, [ka] This is a "cycloalkyl" group.

[0114] "Heteroaryl" Embodiment In a particular embodiment, the "heteroaryl" is a five-membered aromatic group containing one, two, three, or four nitrogen atoms.

[0115] Non-exclusive examples of five-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

[0116] Additional non-limiting examples of five-membered "heteroaryl" groups include: [ka] These are some examples.

[0117] In certain embodiments, the "heteroaryl" is a six-membered aromatic group containing one, two, or three nitrogen atoms (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0118] Non-limiting examples of six-membered "heteroaryl" groups having one or two nitrogen atoms include: [ka] These are some examples.

[0119] In a particular embodiment, "heteroaryl" is a nine-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0120] Non-exclusive examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzoxazole, and benzothiazole.

[0121] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[0122] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[0123] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[0124] In a particular embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0125] Non-exclusive examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0126] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[0127] "Cycloalkyl" Embodiment In a particular embodiment, "cycloalkyl" is a C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3 or C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[0128] In a particular embodiment, the "cycloalkyl" has three carbon atoms.

[0129] In a particular embodiment, the "cycloalkyl" has four carbon atoms.

[0130] In a particular embodiment, the "cycloalkyl" has five carbon atoms.

[0131] In a particular embodiment, the "cycloalkyl" has six carbon atoms.

[0132] In a particular embodiment, the "cycloalkyl" has seven carbon atoms.

[0133] In a particular embodiment, the "cycloalkyl" has eight carbon atoms.

[0134] In a particular embodiment, the "cycloalkyl" has nine carbon atoms.

[0135] In a particular embodiment, the "cycloalkyl" has 10 carbon atoms.

[0136] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0137] Additional, non-limiting examples of "cycloalkyl" include dihydroindene and tetrahydronaphthalene, where the attachment points of each group are located on the cycloalkyl ring.

[0138] for example, [ka] This is a "cycloalkyl" group.

[0139] however, [ka] This is an "aryl" group.

[0140] Additional examples of the "cycloalkyl" group include: [ka] These are some examples.

[0141] "Hybrid Algebra" Embodiment In certain embodiments, "heterocycle" refers to a cyclic ring having one nitrogen atom and three, four, five, six, seven, or eight carbon atoms.

[0142] In certain embodiments, "heterocycle" refers to a cyclic ring having one nitrogen atom, one oxygen atom, and three, four, five, six, seven, or eight carbon atoms.

[0143] In certain embodiments, “heterocycle” refers to a cyclic ring having two nitrogen atoms and three, four, five, six, seven, or eight carbon atoms.

[0144] In certain embodiments, "heterocycle" refers to a cyclic ring having one oxygen atom and three, four, five, six, seven, or eight carbon atoms.

[0145] In certain embodiments, “heterocycle” refers to a cyclic ring having one sulfur atom and three, four, five, six, seven, or eight carbon atoms.

[0146] Non-restrictive examples of "heterocyclic compounds" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thiethane.

[0147] Additional, non-restrictive examples of "heterocyclic compounds" include pyrrolidines, 3-pyrroline, 2-pyrroline, pyrazolidines, and imidazolidines.

[0148] Additional, non-restrictive examples of "heterocyclic" compounds include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0149] Additional, non-restrictive examples of "heterocyclic compounds" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0150] Additional, non-restrictive examples of "heterocyclic" structures include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the attachment points of each group lie on the heterocyclic ring.

[0151] for example, [ka] This is a "heterocyclic" group.

[0152] however, [ka] This is an "aryl" group.

[0153] An unrestricted example of a "complex algebra" is: [ka] This can also be mentioned.

[0154] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[0155] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[0156] An unrestricted example of a "complex algebra" is: [ka] This can also be mentioned.

[0157] An unrestricted example of a "complex algebra" is: [ka] This can also be mentioned.

[0158] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[0159] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[0160] Any substituent In certain embodiments, a portion described herein that may be substituted with one, two, three, or four substituents is substituted with one substituent.

[0161] In a particular embodiment, a portion described herein that may be substituted with one, two, three, or four substituents is substituted with two substituents.

[0162] In a particular embodiment, a portion described herein that may be substituted with one, two, three, or four substituents is substituted with three substituents.

[0163] In a particular embodiment, a portion described herein that may be substituted with one, two, three, or four substituents is substituted with four substituents.

[0164] R1 Embodiment In a particular embodiment, R 1 teeth, [ka] (wherein each R' is independently selected from hydrogen, alkyl, haloalkyl, aryl, heterocyclic, and heteroaryl.)

[0165] In a particular embodiment, R 1 R' is a heterocyclic group optionally substituted with one or two substituents selected from R'.

[0166] In a particular embodiment, R 1 It is a six-membered heterocyclic group having one or two nitrogen atoms.

[0167] In a particular embodiment, R 1 It is a six-membered heterocyclic group having one or two oxygen atoms.

[0168] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0169] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0170] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0171] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0172] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0173] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0174] In a particular embodiment, R 1 teeth, [ka] Selected from TIFF0007863100000043.tif106170.

[0175] In a particular embodiment, R 1 teeth, [ka] Selected from TIFF0007863100000045.tif207170 and TIFF0007863100000046.tif140170.

[0176] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0177] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0178] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0179] In a particular embodiment, R 1 teeth, Selected from.

[0180] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0181] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0182] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0183] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0184] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0185] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0186] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0187] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0188] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0189] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0190] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0191] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0192] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0193] In a particular embodiment, R 1 teeth, [ka] Selected from TIFF0007863100000064.tif97170.

[0194] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0195] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0196] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0197] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0198] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0199] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0200] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0201] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0202] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0203] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0204] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0205] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0206] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0207] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0208] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0209] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0210] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0211] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0212] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0213] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0214] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0215] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0216] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0217] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0218] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0219] In a particular embodiment, R1 teeth, [ka] Selected from.

[0220] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0221] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0222] In a particular embodiment, R 1 teeth, [ka] Selected from TIFF0007863100000094.tif246170.

[0223] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0224] In a particular embodiment, R 1 teeth, [ka] Selected from TIFF0007863100000097.tif179170.

[0225] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0226] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0227] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0228] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0229] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0230] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0231] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0232] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0233] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0234] In a particular embodiment, R 1 teeth, [ka] Selected from TIFF0007863100000108.tif142170.

[0235] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0236] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0237] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0238] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0239] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0240] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0241] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0242] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0243] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0244] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0245] In a particular embodiment, R 1 teeth, [ka] (In the formula, R 42These are hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclic, aliphatic, or heteroaliphatic. X 1 , NR 19 , O, or S, X 2 is CH2 or C(O), R 19 is alkyl, hydrogen, -C(O)NR 10 R 27 , -C(O)OR 27 , -C(O)R 27 Selected from alkenes, alkynes, haloalkyls, alkoxys, aryls, heterocyclics, aliphatic, heteroaliphatic, and heteroaryls, each is used to form a stable compound within the range of valency allowed. 40 Optionally substituted with one, two, three, or four substituents independently selected from, R 20 It is an aliphatic compound containing alkyl, R 23 (These are hydrogen, alkyl, halogen, or haloalkyl.) Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0246] In a particular embodiment, R 1 teeth, [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0247] Non-limiting embodiments of A: In a particular embodiment, A is [ka] Selected from.

[0248] In a particular embodiment, A is [ka] Selected from.

[0249] In a particular embodiment, A is [ka] Selected from.

[0250] In a particular embodiment, A is [ka] Selected from.

[0251] In a particular embodiment, A is [ka] Selected from.

[0252] In a particular embodiment, A is [ka] Selected from.

[0253] In a particular embodiment, the compound of formula I is: [ka] (In the formula, R 2 teeth, [ka] And, X 4 These are alkyl, aliphatic, aryl, heteroaryl, bicyclic, and -NR 27 -, -NR 10 -, -CR 40 R 41 -, -O-, -C(O)-, -C(NR 27Selected from -, -C(S)-, -S(O)-, -S(O)2-, -S-, piperidines bonded to the tricyclic ring via N within the piperidine ring, 6-membered heterocycles having 2, 3 or 4 heteroatoms, and 4-membered, 5-membered, or 7-membered heterocycles having 1, 2, 3 or 4 heteroatoms, each having non-hydrogen R to the extent that the valency allows to form a stable compound. 40 (Optionally substituted with one, two, three, or four substituents independently selected from the original molecule.) or a pharmaceutically acceptable salt thereof.

[0254] In a particular embodiment, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0255] In a particular embodiment, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0256] In a particular embodiment, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0257] Embodiment X In a particular embodiment, X is a bond.

[0258] In a particular embodiment, X is oxygen.

[0259] In a particular embodiment, X is sulfur.

[0260] In a particular embodiment, X is -NR 27 - is

[0261] In a particular embodiment, X is -NR 10 - is

[0262] In a particular embodiment, X is -CR 40 R 41 - is

[0263] In a particular embodiment, X is -C(O)-.

[0264] In a particular embodiment, X is -C(NR 27 )-is.

[0265] In a particular embodiment, X is -C(S)-.

[0266] In a particular embodiment, X is -S(O)2-.

[0267] In a particular embodiment, X is -C(S)-.

[0268] In a particular embodiment, X is -C(S)-.

[0269] In a particular embodiment, X is -C(S)-.

[0270] In a particular embodiment, X is a five-membered aromatic heterocycle having attachment points in 1,3 directions.

[0271] In a particular embodiment, X is a five-membered aromatic heterocycle having attachment points in 1,2 directions.

[0272] In a particular embodiment, X is a six-membered aromatic heterocycle having attachment points in 1,2 directions.

[0273] In a particular embodiment, X is a six-membered aromatic heterocycle having attachment points in 1,3 directions.

[0274] In a particular embodiment, X is a six-membered aromatic heteroring having attachment points in 1,4 directions.

[0275] In a particular embodiment, X is a six-membered aromatic heterocycle having attachment points in 1,3 directions.

[0276] In a particular embodiment, X is a five-membered complex ring having mounting points in 1 and 2 directions.

[0277] In a particular embodiment, X is a five-membered complex ring having mounting points in 1,3 directions.

[0278] In a particular embodiment, X is a six-membered complex ring having mounting points in 1 and 2 directions.

[0279] In a particular embodiment, X is a six-membered complex ring having mounting points in 1,3 directions.

[0280] In a particular embodiment, X is a six-membered complex ring having mounting points in 1,4 directions.

[0281] In a particular embodiment, X is a bicyclic heterocycle having one heteroatom.

[0282] In a particular embodiment, X is a bicyclic heterocycle having two heteroatoms.

[0283] In a particular embodiment, X is a bicyclic heterocycle having one heteroatom, with one bond to nitrogen and the other to carbon.

[0284] In a particular embodiment, X is a bicyclic heterocycle having one heteroatom, with both attachment points bonded to carbon.

[0285] In a particular embodiment, X is a bicyclic heterocycle having two heteroatoms, with both attachment points bonded to nitrogen.

[0286] In a particular embodiment, X is a bicyclic heterocycle having two heteroatoms.

[0287] In a particular embodiment, X is a condensed bicyclic alkane.

[0288] In a particular embodiment, X is a spironicyclic alkane.

[0289] In a particular embodiment, X is [ka] Selected from.

[0290] R 4 and R 5 Embodiment: In a particular embodiment, R 4 It is hydrogen.

[0291] In a particular embodiment, R 4 It is alkyl.

[0292] In a particular embodiment, R 4 It is fluorine.

[0293] In a particular embodiment, R 4 It is chlorine.

[0294] In a particular embodiment, R 4 It is bromine.

[0295] In a particular embodiment, R 4 It is a haloalkyl.

[0296] In a particular embodiment, R 4 は-OR 10 That is the case.

[0297] In a particular embodiment, R 4 Ha-SR10 That is the case.

[0298] In a particular embodiment, R 4 -S(O)R 12 That is the case.

[0299] In a particular embodiment, R 4 ha-SO2R 12 That is the case.

[0300] In a particular embodiment, R 4 -NR 10 R 11 That is the case.

[0301] In a particular embodiment, R 5 It is hydrogen.

[0302] In a particular embodiment, R 5 It is alkyl.

[0303] In a particular embodiment, R 5 It is a haloalkyl.

[0304] In a particular embodiment, R 5 は-OR 10 That is the case.

[0305] In a particular embodiment, R 5 Ha-SR 10 That is the case.

[0306] In a particular embodiment, R 5 -S(O)R 12 That is the case.

[0307] In a particular embodiment, R 5 ha-SO2R 12 That is the case.

[0308] In a particular embodiment, R 5 -NR 10 R 11 That is the case.

[0309] In a particular embodiment, R 4 and R 5 teeth, [ka] Selected from.

[0310] R 6 and R 7 Embodiment: In a particular embodiment, R 6 It is hydrogen.

[0311] In a particular embodiment, R 6 It is alkyl.

[0312] In a particular embodiment, R 6 It is fluorine.

[0313] In a particular embodiment, R 6 It is chlorine.

[0314] In a particular embodiment, R 6 It is bromine.

[0315] In a particular embodiment, R 6 It is a haloalkyl.

[0316] In a particular embodiment, R 6 は-OR 10 That is the case.

[0317] In a particular embodiment, R 6 Ha-SR 10 That is the case.

[0318] In a particular embodiment, R 6 -S(O)R 12 That is the case.

[0319] In a particular embodiment, R 6 ha-SO2R 12That is the case.

[0320] In a particular embodiment, R 6 -NR 10 R 11 That is the case.

[0321] In a particular embodiment, R 7 It is hydrogen.

[0322] In a particular embodiment, R 7 It is alkyl.

[0323] In a particular embodiment, R 7 It is fluorine.

[0324] In a particular embodiment, R 7 It is chlorine.

[0325] In a particular embodiment, R 7 It is bromine.

[0326] In a particular embodiment, R 7 It is a haloalkyl.

[0327] In a particular embodiment, R 7 は-OR 10 That is the case.

[0328] In a particular embodiment, R 7 Ha-SR 10 That is the case.

[0329] In a particular embodiment, R 7 -S(O)R 12 That is the case.

[0330] In a particular embodiment, R 7 ha-SO2R 12 That is the case.

[0331] In a particular embodiment, R 7 -NR 10 R11 That is the case.

[0332] In a particular embodiment, R 6 and R 7 teeth, [ka] Selected from.

[0333] R 10 and R 11 Embodiment In a particular embodiment, R 10 and R 11 It is hydrogen.

[0334] In a particular embodiment, R 10 It is hydrogen.

[0335] In a particular embodiment, R 11 It is hydrogen.

[0336] In a particular embodiment, R 10 It is alkyl.

[0337] In a particular embodiment, R 10 It is methyl.

[0338] In a particular embodiment, R 10 It is an aliphatic.

[0339] In a particular embodiment, R 10 It is a haloalkyl.

[0340] In a particular embodiment, R 10 It is a complex algebra.

[0341] In a particular embodiment, R 10 It is Ariel.

[0342] In a particular embodiment, R 10 It is a heteroaryl compound.

[0343] In a particular embodiment, R 10 -C(O)R 12 That is the case.

[0344] In a particular embodiment, R 10 -S(O)R 12 That is the case.

[0345] In a particular embodiment, R 10 ha-SO2R 12 That is the case.

[0346] In a particular embodiment, R 11 It is alkyl.

[0347] In a particular embodiment, R 11 It is methyl.

[0348] In a particular embodiment, R 11 It is an aliphatic.

[0349] In a particular embodiment, R 11 It is a haloalkyl.

[0350] In a particular embodiment, R 11 It is a complex algebra.

[0351] In a particular embodiment, R 11 It is Ariel.

[0352] In a particular embodiment, R 11 It is a heteroaryl compound.

[0353] In a particular embodiment, R 11 -C(O)R 12 That is the case.

[0354] In a particular embodiment, R 11 -S(O)R 12 That is the case.

[0355] In a particular embodiment, R 11 ha-SO2R 12 That is the case.

[0356] R 12 Embodiment: In a particular embodiment, R 12 It is hydrogen.

[0357] In a particular embodiment, R 12 It is alkyl.

[0358] In a particular embodiment, R 12 It is a haloalkyl.

[0359] In a particular embodiment, R 12 It is a complex algebra.

[0360] In a particular embodiment, R 12 It is Ariel.

[0361] In a particular embodiment, R 12 It is a heteroaryl compound.

[0362] In a particular embodiment, R 12 -NR 13 R 14 That is the case.

[0363] In a particular embodiment, R 12 is OR 13 That is the case.

[0364] Embodiment R 15 , R 16 , and R 17 In a particular embodiment, R 15 It is a combination.

[0365] In a particular embodiment, R 15 It is alkyl.

[0366] In a particular embodiment, R 15 It is an aliphatic.

[0367] In a particular embodiment, R 15 It is Ariel.

[0368] In a particular embodiment, R 15 It is a double ring.

[0369] In a particular embodiment, R 15 It is an alkene.

[0370] In a particular embodiment, R 15 It is an alkyne.

[0371] In a particular embodiment, R 15 It is a haloalkyl.

[0372] In a particular embodiment, R 15 It is an alkoxy.

[0373] In a particular embodiment, R 15 It is a heteroaryl compound.

[0374] In a particular embodiment, R 15 It is a complex algebra.

[0375] In a particular embodiment, R 15 It is a cycloalkyl group.

[0376] In a particular embodiment, R 15 It is heterolipid.

[0377] In a particular embodiment, R 15 -NR 27 - is

[0378] In a particular embodiment, R 15 -NR 10 That is the case.

[0379] In a particular embodiment, R 15 -CR 40 R 41 - is

[0380] In a particular embodiment, R 15 It is oxygen.

[0381] In a particular embodiment, R 15 It is -C(O)-.

[0382] In a particular embodiment, R 15 is -C(S)-.

[0383] In a particular embodiment, R 15 It is sulfur.

[0384] In a particular embodiment, R 15 is -C(S)-.

[0385] In a particular embodiment, R 15 It is -OC(O)-.

[0386] In a particular embodiment, R 15 It is --C(O)O-.

[0387] In a particular embodiment, R 15 -C(O)NR 27 - is

[0388] In a particular embodiment, R 15 -NR 27 It is C(O)-.

[0389] In a particular embodiment, R 15 -NR 10 - is

[0390] In a particular embodiment, R 15It is a 6-membered aryl group having mounting points in 1 and 2 directions.

[0391] In a particular embodiment, R 15 It is a 6-membered aryl group having mounting points in 1 and 3 directions.

[0392] In a particular embodiment, R 15 It is a 6-membered aryl group having mounting points in 1 and 4 directions.

[0393] In a particular embodiment, R 15 It is a 6-membered aryl group having mounting points in 1 and 2 directions.

[0394] In a particular embodiment, R 15 This is a heteroaryl group having attachment points in 1 and 2 directions.

[0395] In a particular embodiment, R 15 This is a heteroaryl group having attachment points in 1 and 2 directions.

[0396] In a particular embodiment, R 15 This is an aryl group having attachment points in 1 and 2 directions.

[0397] In a particular embodiment, R 16 It is a combination.

[0398] In a particular embodiment, R 16 It is alkyl.

[0399] In a particular embodiment, R 16 It is an aliphatic.

[0400] In a particular embodiment, R 16 It is Ariel.

[0401] In a particular embodiment, R 16 It is a double ring.

[0402] In a particular embodiment, R 16 It is an alkene.

[0403] In a particular embodiment, R 16 It is an alkyne.

[0404] In a particular embodiment, R 16 It is a haloalkyl.

[0405] In a particular embodiment, R 16 It is an alkoxy.

[0406] In a particular embodiment, R 16 It is a heteroaryl compound.

[0407] In a particular embodiment, R 16 It is a complex algebra.

[0408] In a particular embodiment, R 16 It is a cycloalkyl group.

[0409] In a particular embodiment, R 16 It is heterolipid.

[0410] In a particular embodiment, R 16 -NR 27 - is

[0411] In a particular embodiment, R 16 -NR 10 That is the case.

[0412] In a particular embodiment, R 16 -CR 40 R 41 - is

[0413] In a particular embodiment, R 16 It is oxygen.

[0414] In a particular embodiment, R16 It is -C(O)-.

[0415] In a particular embodiment, R 16 is -C(S)-.

[0416] In a particular embodiment, R 16 It is sulfur.

[0417] In a particular embodiment, R 16 is -C(S)-.

[0418] In a particular embodiment, R 16 It is -OC(O)-.

[0419] In a particular embodiment, R 16 It is --C(O)O-.

[0420] In a particular embodiment, R 16 -C(O)NR 27 - is

[0421] In a particular embodiment, R 16 -NR 27 It is C(O)-.

[0422] In a particular embodiment, R 16 -NR 10 - is

[0423] In a particular embodiment, R 16 It is a 6-membered aryl group having mounting points in 1 and 2 directions.

[0424] In a particular embodiment, R 16 It is a 6-membered aryl group having mounting points in 1 and 3 directions.

[0425] In a particular embodiment, R 16 It is a 6-membered aryl group having mounting points in 1 and 4 directions.

[0426] In a particular embodiment, R 16 It is a 6-membered aryl group having mounting points in 1 and 2 directions.

[0427] In a particular embodiment, R 16 This is a heteroaryl group having attachment points in 1 and 2 directions.

[0428] In a particular embodiment, R 16 This is a heteroaryl group having attachment points in 1 and 2 directions.

[0429] In a particular embodiment, R 16 This is an aryl group having attachment points in 1 and 2 directions.

[0430] In a particular embodiment, R 17 It is a combination.

[0431] In a particular embodiment, R 17 It is alkyl.

[0432] In a particular embodiment, R 17 It is an aliphatic.

[0433] In a particular embodiment, R 17 It is Ariel.

[0434] In a particular embodiment, R 17 It is a double ring.

[0435] In a particular embodiment, R 17 It is an alkene.

[0436] In a particular embodiment, R 17 It is an alkyne.

[0437] In a particular embodiment, R 17 It is a haloalkyl.

[0438] In a particular embodiment, R 17 It is an alkoxy.

[0439] In a particular embodiment, R 17 It is a heteroaryl compound.

[0440] In a particular embodiment, R 17 It is a complex algebra.

[0441] In a particular embodiment, R 17 It is a cycloalkyl group.

[0442] In a particular embodiment, R 17 It is heterolipid.

[0443] In a particular embodiment, R 17 -NR 27 - is

[0444] In a particular embodiment, R 17 -NR 10 That is the case.

[0445] In a particular embodiment, R 17 -CR 40 R 41 - is

[0446] In a particular embodiment, R 17 It is oxygen.

[0447] In a particular embodiment, R 17 It is -C(O)-.

[0448] In a particular embodiment, R 17 is -C(S)-.

[0449] In a particular embodiment, R 17 It is sulfur.

[0450] In a particular embodiment, R 17is -C(S)-.

[0451] In a particular embodiment, R 17 It is -OC(O)-.

[0452] In a particular embodiment, R 17 It is --C(O)O-.

[0453] In a particular embodiment, R 17 -C(O)NR 27 - is

[0454] In a particular embodiment, R 17 -NR 27 It is C(O)-.

[0455] In a particular embodiment, R 17 -NR 10 - is

[0456] In a particular embodiment, R 17 It is a 6-membered aryl group having mounting points in 1 and 2 directions.

[0457] In a particular embodiment, R 17 It is a 6-membered aryl group having mounting points in 1 and 3 directions.

[0458] In a particular embodiment, R 17 It is a 6-membered aryl group having mounting points in 1 and 4 directions.

[0459] In a particular embodiment, R 17 It is a 6-membered aryl group having mounting points in 1 and 2 directions.

[0460] In a particular embodiment, R 17 This is a heteroaryl group having attachment points in 1 and 2 directions.

[0461] In a particular embodiment, R 17This is a heteroaryl group having attachment points in 1 and 2 directions.

[0462] In a particular embodiment, R 17 This is an aryl group having attachment points in 1 and 2 directions.

[0463] In a particular embodiment, R 18 It is hydrogen.

[0464] In a particular embodiment, R 18 It is a halogen.

[0465] In a particular embodiment, R 18 It is cyano.

[0466] In a particular embodiment, R 18 is -C(O)OR 27 That is the case.

[0467] In a particular embodiment, R 18 It is alkyl.

[0468] In a particular embodiment, R 18 -C(O)NR 10 R 27 That is the case.

[0469] In a particular embodiment, R 18 -NR 27 C(O)R 27 That is the case.

[0470] In a particular embodiment, R 18 -NR 10 R 27 That is the case.

[0471] In a particular embodiment, R 18 is SR 27 That is the case.

[0472] In a particular embodiment, R 18 It is a haloalkyl.

[0473] In a particular embodiment, R 18 It is an alkoxy.

[0474] In a particular embodiment, R 18 It is Ariel.

[0475] In a particular embodiment, R 18 It is a complex algebra.

[0476] In a particular embodiment, R 18 It is an aliphatic.

[0477] In a particular embodiment, R 18 It is heterolipid.

[0478] In a particular embodiment, R 18 It is a heteroaryl compound.

[0479] In a particular embodiment, R 18 は-OR 27 That is the case.

[0480] R 19 Embodiment: In a particular embodiment, R 19 It is alkyl.

[0481] In a particular embodiment, R 19 It is hydrogen.

[0482] In a particular embodiment, R 19 -C(O)NR 10 R 27 That is the case.

[0483] In a particular embodiment, R 19 is -C(O)OR 27 That is the case.

[0484] In a particular embodiment, R 19 -C(O)R27 That is the case.

[0485] In a particular embodiment, R 19 It is an alkene.

[0486] In a particular embodiment, R 19 It is an alkyne.

[0487] In a particular embodiment, R 19 It is a haloalkyl.

[0488] In a particular embodiment, R 19 It is an alkoxy.

[0489] In a particular embodiment, R 19 It is Ariel.

[0490] In a particular embodiment, R 19 It is a complex algebra.

[0491] In a particular embodiment, R 19 It is an aliphatic.

[0492] In a particular embodiment, R 19 It is heterolipid.

[0493] In a particular embodiment, R 19 It is a heteroaryl compound.

[0494] R 20 Embodiment: In a particular embodiment, R 20 It is an aliphatic.

[0495] In a particular embodiment, R 20 It is alkyl.

[0496] In a particular embodiment, R 20 teeth, [ka] Selected from.

[0497] R 23 Embodiment: In a particular embodiment, R 23 It is hydrogen.

[0498] In a particular embodiment, R 23 It is fluorine.

[0499] In a particular embodiment, R 23 It is bromine.

[0500] In a particular embodiment, R 23 It is chlorine.

[0501] In a particular embodiment, R 23 It is a haloalkyl.

[0502] In a particular embodiment, R 23 teeth, [ka] Selected from.

[0503] R 27 Embodiment: In a particular embodiment, R 27 It is hydrogen.

[0504] In a particular embodiment, R 27 It is alkyl.

[0505] In a particular embodiment, R 27 It is an arylalkyl.

[0506] In a particular embodiment, R 27 It is a heteroarylalkyl.

[0507] In a particular embodiment, R 27It is an alkene.

[0508] In a particular embodiment, R 27 It is an alkyne.

[0509] In a particular embodiment, R 27 It is Ariel.

[0510] In a particular embodiment, R 27 It is a heteroaryl compound.

[0511] In a particular embodiment, R 27 It is a complex algebra.

[0512] In a particular embodiment, R 27 It is a cycloalkyl group.

[0513] In a particular embodiment, R 27 It is an aliphatic.

[0514] In a particular embodiment, R 27 It is heterolipid.

[0515] In a particular embodiment, R 27 teeth, [ka] Selected from.

[0516] R 40 Embodiment: In a particular embodiment, R 40 It is hydrogen.

[0517] In a particular embodiment, R 40 It is an aliphatic.

[0518] In a particular embodiment, R 40 It is heterolipid.

[0519] In a particular embodiment, R 40 It is cyano.

[0520] In a particular embodiment, R 40 It is nitro.

[0521] In a particular embodiment, R 40 It is alkyl.

[0522] In a particular embodiment, R 40 It is fluorine.

[0523] In a particular embodiment, R 40 It is chlorine.

[0524] In a particular embodiment, R 40 It is bromine.

[0525] In a particular embodiment, R 40 It is a haloalkyl.

[0526] In a particular embodiment, R 40 は-OR 10 That is the case.

[0527] In a particular embodiment, R 40 Ha-SR 10 That is the case.

[0528] In a particular embodiment, R 40 -S(O)R 12 That is the case.

[0529] In a particular embodiment, R 40 ha-SO2R 12 That is the case.

[0530] In a particular embodiment, R 40 -NR 10 R 11 That is the case.

[0531] In a particular embodiment, R40 teeth, [ka] Selected from.

[0532] R 41 Embodiment: In a particular embodiment, R 41 It is an aliphatic.

[0533] In a particular embodiment, R 41 It is a heteroaryl compound.

[0534] In a particular embodiment, R 41 It is hydrogen.

[0535] In a particular embodiment, R 41 It is an aliphatic.

[0536] In a particular embodiment, R 41 It is an aliphatic.

[0537] In a particular embodiment, R 41 It is an aliphatic.

[0538] In a particular embodiment, R 41 teeth, [ka] Selected from.

[0539] R 42 Embodiment: In a particular embodiment, R 42 teeth, [ka] Selected from.

[0540] Non-restrictive examples of compounds of formula I Typical examples of compounds of formula I include: [ka] Examples include TIFF0007863100000142.tif230170, TIFF0007863100000143.tif212170, TIFF0007863100000144.tif231170, TIFF0007863100000145.tif228170, TIFF0007863100000146.tif190170, TIFF0007863100000147.tif198170, TIFF0007863100000148.tif47170, or their pharmaceutically acceptable salts.

[0541] Non-restrictive isotope embodiments In certain embodiments, the compound is isotope-labeled. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R', R 19 , R 20 , R 23 , R 27 , R 40 , R 41 or R 42 At least one R group independently selected from isotopes is isotoped with one, two, or more isotopes, if permitted by valency. In certain embodiments, the isotope label is deuterium. In certain embodiments, at least one deuterium is located on an atom having a bond that is broken during the metabolism of the compound in vivo, or is one, two, or three atoms away from the bond that is metabolized (e.g., α, β, or γ, or sometimes referred to as primary, secondary, or tertiary isotope effects). In other embodiments, the isotope label is 13It is C. In other embodiments, the isotope label is 18 It is F.

[0542] III. Treatment method Any of the tricyclic compounds described herein may be used in an effective amount for the treatment of a host, including a human, in need, in an optionally pharmaceutically acceptable carrier, to treat any of the disorders described herein. In certain embodiments, the method involves administering an effective amount of the active compound described herein or a salt thereof, in an optionally pharmaceutically acceptable additive, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), in combination with or alternately with optionally additional therapeutic agents or combinations of therapeutic agents.

[0543] In a particular embodiment, the compound of the present invention selectively degrades IKZF2 and / or IKZF4 to one or more IKZF1 and / or IKZF3 and / or IKZF5.

[0544] In certain embodiments, the disorder treated by the compounds of the present invention is an immunomodulatory disorder. In certain embodiments, the disorder treated by the compounds of the present invention is mediated by angiogenesis. In certain embodiments, the disorder treated by the compounds of the present invention is related to the lymphatic system.

[0545] In certain embodiments, the compounds of the present invention or their pharmaceutical salts in a pharmaceutical composition as optionally described herein are used to degrade IKZF2 or IKZF4, which are mediators of disorders affecting patients such as humans. The control of protein levels achieved by any of the compounds of the present invention results in the treatment of disease conditions or pathologies modulated by IKZF2 or IKZF4 by reducing the level of that protein in cells, e.g., patient cells, or by reducing the level of downstream proteins within the cells. In certain embodiments, the method comprises administering an effective amount of the compounds described herein, optionally including pharmaceutically acceptable additives, carriers, and adjuvants (i.e., a pharmaceutically acceptable composition), in combination with or alternately with an optional additional therapeutic agent or combination of therapeutic agents.

[0546] In certain embodiments, the compounds of the present invention may be used to treat disorders including, but are not limited to, benign tumors, neoplasms, tumors, cancer, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid protein disorders, protein disorders, or fibrous disorders.

[0547] The terms “disease state” or “pathological condition,” when used in relation to any compound, are intended to refer to any disease state or pathological condition mediated by IKZF2 or IKZF4, such as cell proliferation, or any disease state or pathological condition mediated by downstream proteins of IKZF2 or IKZF4, the degradation of such proteins in a patient may provide beneficial therapy or symptom relief to the patient in need. In some cases, the disease state or pathological condition may be cured.

[0548] In certain embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in effective amounts to treat a host, such as a human, with lymphoma or lymphocytic or myeloid proliferative disorders or abnormalities. For example, the compounds described herein can be administered to a host suffering from Hodgkin lymphoma or non-Hodgkin lymphoma. For example, the host may include, but is not limited to, AIDS-associated lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK cell lymphoma; Burkitt lymphoma; Burkitt-like lymphoma (small non-incisional nuclear cell lymphoma); small incisional nuclear cell diffuse lymphoma (DSCCL); chronic lymphocytic leukemia / small lymphocytic lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathy type T-cell lymphoma; follicular lymphoma; hepatosplenic γ-δ T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; pediatric lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transforming lymphoma; treatment-related T-cell lymphoma; and non-Hodgkin lymphoma such as Langerhans cell histiocytosis or Waldenström macroglobulinemia.

[0549] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in effective amounts to treat a host, such as a human, having Hodgkin lymphoma, including but not limited to tuberous sclerosis classical Hodgkin lymphoma (CHL), mixed cell type CHL, lymphopenic CHL, lymphocyte-rich CHL, lymphocyte-dominant Hodgkin lymphoma, or nodular lymphocyte-dominant HL.

[0550] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in effective amounts to treat a host having an immunomodulatory condition, such as a human. Non-limiting examples of immunomodulatory conditions include arthritis, lupus, celiac disease, Sjögren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes mellitus, alopecia areata, vasculitis, and temporal arteritis.

[0551] In certain embodiments, the conditions treated with the compounds of the present invention are disorders associated with abnormal cell proliferation. Abnormal cell proliferation, particularly hyperproliferation, can result from a wide range of factors, including gene mutations, infections, exposure to toxins, autoimmune disorders, and the induction of benign or malignant tumors.

[0552] Abnormal proliferation of B cells, T cells, and / or NK cells can lead to a wide range of diseases, including cancer, proliferative disorders, and inflammatory / immune diseases. A host suffering from any of these disorders, such as a human, can be treated with an effective amount of one of the compounds described herein to achieve a reduction in symptoms (palliative agent) or a reduction in the underlying disease (disease modifying agent).

[0553] In certain embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, are not limited to, multiple myeloma; diffuse large B-cell lymphoma; follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT); small cell lymphocytic lymphoma; diffuse poorly differentiated lymphocytic lymphoma; mediastinal large B-cell lymphoma B-cell lymphoma; nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary exudative lymphoma; or lymphomatoid granulomatosis; B-cell prelymphocytic leukemia; hairy cell leukemia; unclassifiable splenic lymphoma / leukemia; diffuse red pulp small B-cell lymphoma; hairy cell leukemia - subtype; lymphoplasmacytic lymphoma; heavy chain disease, e.g., α-heavy chain disease, γ-heavy chain disease, μ-heavy chain disease; form It can be used in effective doses to treat specific B-cell lymphomas or proliferative disorders in hosts, such as humans, including: plasmacytomyeloma; solitary plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicular lymphoma; T-cell / histiocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL lower extremity type; ALK + large B-cell lymphoma; plasmablastic lymphoma; large B-cell lymphoma occurring in HHV8-associated multicentric Castleman disease; unclassifiable B-cell lymphoma with intermediate features between diffuse large B-cell lymphoma and classical Hodgkin lymphoma; or unclassifiable B-cell lymphoma with intermediate features between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0554] In certain embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, are not limited to, anaplastic lymphoma kinase (ALK)-positive, ALK-negative, anaplastic large cell lymphoma or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphomas, e.g., mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous progressive epidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous γ-δ T-cell lymphoma; primary cutaneous small / medium cell CD4+ T-cell lymphoma and lymphomatoid papulosis; adult T-cell leukemia / lymphoma (ATLL); bud It can be used in effective doses to treat hosts, such as humans, who have T-cell or NK-cell lymphomas, including: cytoplasmic NK-cell lymphoma; enteropathy-type T-cell lymphoma; hepatosplenic γ-δ T-cell lymphoma; lymphoblastic lymphoma; nasal NK / T-cell lymphoma; treatment-associated T-cell lymphoma; lymphoma occurring after, for example, solid organ or bone marrow transplantation; pre-T-cell lymphocytic leukemia; T-cell macrogranular lymphocytic leukemia; chronic lymphoproliferative disorder of NK cells; rapidly progressive NK-cell leukemia; systemic EBV+ T-cell lymphoproliferative disorder in children (associated with chronic active EBV infection); vaccinia-like varicella-like lymphoma; adult T-cell leukemia / lymphoma; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; or subcutaneous panniculitis-like T-cell lymphoma.

[0555] In certain embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used to treat a host having leukemia, such as a human. For example, the host may have, but is not limited to, acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); macrogranular lymphocytic leukemia; or acute or chronic leukemia of lymphocyte or myeloid origin, such as adult T-cell chronic leukemia. In certain embodiments, the patient suffers from acute myeloid leukemia, such as undifferentiated AML (M0); myeloblastic leukemia (M1; with / without minimal cellular maturation); myeloblastic leukemia (M2; with cellular maturation); promyelocytic leukemia (M3 or subtype M3 (M3V)); myelomonocytic leukemia (M4 or subtype M4 with eosinophilia (M4E)); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7).

[0556] Numerous skin disorders are associated with cell overgrowth. For example, psoriasis is a benign disease of human skin generally characterized by plaques covered with thickened scales. This disease is caused by an increase in the proliferation of epidermal cells of unknown origin. Chronic eczema is also associated with marked epidermal overgrowth. Other diseases caused by excessive proliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

[0557] Other hyperproliferative cell disorders include vascular disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancers.

[0558] Vascular proliferative disorders include neovascularization and vascular disorders. The proliferation of smooth muscle cells during plaque formation in vascular tissue leads to conditions such as restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[0559] Fibrotic disorders are often caused by abnormal formation of the extracellular matrix. Examples of fibrotic disorders include cirrhosis and mesangial proliferative cytotoxicity. Cirrhosis is characterized by an increase in extracellular matrix components that lead to the formation of liver scars. Cirrhosis can lead to diseases such as liver cirrhosis. The increase in extracellular matrix that leads to liver scars may also be due to viral infections such as hepatitis. Lipid cells appear to play an important role in liver cirrhosis.

[0560] Mesangial disorders are caused by the abnormal proliferation of mesangial cells. Mesangial hyperproliferative cytotoxicity includes various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, graft rejection, and glomerulopathy.

[0561] Another disease caused by proliferative components is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease associated with the activity of autoreactive T cells and caused by autoantibodies produced against collagen and IgE.

[0562] Other disorders that may contain abnormal cell proliferation components include Behçet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and general inflammation.

[0563] The compounds described herein, or their pharmaceutically acceptable salts, isotope analogs, or prodrugs, can be used in effective amounts to treat hosts, such as humans, that have proliferative conditions including myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myelometaplastic myelopathy with myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), eosinophilic syndrome (HES), and systemic mastocytosis (SMCD). In another embodiment, the compounds provided herein are useful for the treatment of primary myelofibrosis, post-polycythemia myelofibrosis, post-essential thrombocythemia myelofibrosis, and secondary acute myeloid leukemia.

[0564] In certain embodiments, the compounds described herein, or their pharmaceutically acceptable salts, isotopic analogs, or prodrugs, can be used in effective amounts to treat hosts, such as humans, who have myelodysplastic syndromes (MDS), including but not limited to refractory cytopenia with monocytic lineage dysplasia, refractory anemia with ring sideroblasts (RARS), refractory anemia-thrombocytosis with ring sideroblasts (RARS-t), refractory cytopenia with polycytic lineage dysplasia (RCMD), including RCMD-RS, refractory anemia I (RAEB-I) and II (RAEB-II), 5q syndrome, and childhood refractory cytopenia.

[0565] In certain embodiments, the compounds of the present invention can induce therapeutic effects by directly degrading Helios or Eos, which can alter the transcriptional regulation of downstream proteins of Helios or Eos.

[0566] The terms “neoplasia” or “cancer” are used to refer to the pathological process that results in the formation and growth of malignant or cancerous neoplasms, which are abnormal tissues that grow more rapidly than normal through cell proliferation and continue to grow even after the stimulus that initiated the new growth has ceased. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissue, most invade surrounding tissues, metastasize to several sites, and may recur even after attempts to remove them, leading to patient death if not properly treated. As used herein, the term neoplasia is used to describe all cancerous disease conditions and includes or encompasses pathological processes associated with malignant hematological malignancies, ascites tumors, and solid tumors. Exemplary cancers that can be treated with this compound alone or in combination with at least one additional anticancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancers of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovaries, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's positivity. Sarcomas including sarcomas, liposarcomas, myosarcomas, peripheral neuroepitheliomas, synovial sarcomas, gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, gangliocytomas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas, and Schwann cell tumors; intestinal cancers, breast cancers, prostate cancers, cervical cancers, uterine cancers, lung cancers, ovarian cancers, testicular cancers, thyroid cancers, astrocytomas, esophageal cancers, pancreatic cancers, gastric cancers, liver cancers, colon cancers, melanomas; carcinosarcomas, Hodgkin's disease, Wilms' tumors, and teratomas. Additional cancers that can be treated with the compounds according to the present invention include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[0567] Additional cancers that can be treated with the compounds disclosed according to the present invention include, for example, acute granulocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal carcinoma, anaplastic astrocytoma, angiosarcoma, appendiceal carcinoma, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder cancer, bone cancer, bone marrow cancer, intestinal cancer, brain cancer, brainstem glioma, breast cancer, triple (estrogen, progesterone, and HER-2) negative breast cancer, double negative breast cancer (estrogen, progesterone, and HER-2) (negative for both progesterone and HER-2), single-negative (negative for one of estrogen, progesterone, and HER-2), estrogen receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CL) L), chronic myeloid leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic cholangiocarcinoma, ocular cancer, fallopian tubes Cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumor (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasion Lobular carcinoma (ILC), inflammatory breast cancer (IBC), colon cancer, intrahepatic cholangiocarcinoma, invasive breast cancer, islet cell carcinoma, jaw cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leukemia, lip cancer, liposarcoma, liver cancer, non-invasive lobular carcinoma, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous cell carcinoma of the neck, mixed glioma, monodermal teratoma, mouth cancerCancer), mucinous carcinoma, mucosal melanoma, multiple bone marrow abscess, fungal polyposis, osteomyelopathy syndrome, nasal cavity cancer, nasopharyngeal carcinoma, neck cancer, neuroblastoma, neuroendocrine tumor (NET), non-homologous lymphadenopathy, non-small cell lung cancer (NSCLC), oat cell carcinoma, ocular cancer, intraocular melanoma, follicular colloid tumor, oral cancer, oral cavity cancer, oral and pharyngeal cancer, osteosarcoma, osteosarcoma, ovarian carcinoma, epithelial ovarian carcinoma, ovarian germ cell tumor, ovarian Primary peritoneal carcinoma, ovarian cord-stromal tumor, pethopathy, lipoma, papillary carcinoma, paranasal cavity carcinoma, parathyroid carcinoma, pelvic carcinoma, penile cancer, peripheral nerve carcinoma, peritoneal carcinoma, pharyngeal carcinoma, brown cell tumor, trichomeal stellate tumor, pineal gland tumor, pineal bud, pituitary carcinoma, primary central nervous system (CNS) lipoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma. Sarcoma, sarcoma, paranasal cavity cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal cord cancer, spinal marrow cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell leukemia, seminal vesicle cancer, pharyngeal cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, cancer of unknown diagnosis, ureteral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell acute leukemia (T-ALL), T-cell leukemia (T-LL), peripheral T-cell leukemia, adult T-cell leukemia, Pre-BALL, Pre-B lymphoma, Large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, Juvenile myelomonocytic leukemia (JMML), Acute promyelocytic leukemia (a subtype of AML), Large granular lymphocytic leukemia, Adult T-cell chronic leukemia, Diffuse large B-cell lymphoma, Follicular lymphoma; Mucosa-associated lymphoid tissue lymphoma (MALT), Small cell lymphocytic lymphoma, Mediastinal large B-cell lymphoma, Nodal marginal zone B-cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary exudative lymphoma; or Lymphomatoid granulomatosis; B-cell prelymphocytic leukemia; Unclassifiable splenic lymphoma / leukemia, Diffuse red pulp small B-cell lymphoma; Lymphoid Plasma cell lymphoma; heavy chain disease, e.g., α-heavy chain disease, γ-heavy chain disease, μ-heavy chain disease; plasma cell myeloma; solitary plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicular lymphoma; T-cell / histiocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL lower extremity type; ALK + large B-cell lymphoma; plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease; unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma; or unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. In certain embodiments, the lesion is adenoid cystic carcinoma. In certain embodiments, the lesion is NUT midline carcinoma.

[0568] In another embodiment, the compounds described herein, or their pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in effective amounts to treat a host with an autoimmune disorder, such as a human. Examples include acute disseminated encephalomyelitis (ADEM); Addison's disease; agammaglobulinemia; alopecia areata; amyotrophic lateral sclerosis (also known as Lou Gehrig's disease; motor neuron disease); ankylosing spondylitis; antiphospholipid antibody syndrome; antisynthetic enzyme syndrome; atopic allergy; atopic dermatitis; autoimmune aplastic anemia; autoimmune arthritis; autoimmune cardiomyopathy; autoimmune enteropathy; autoimmune granulocytopenia; autoimmune hemolytic anemia; autoimmune hepatitis; autoimmune hypoparathyroidism; autoimmune inner ear disease; autoimmune lymphoproliferative syndrome; autoimmune myocarditis; autoimmune pancreatitis; autoimmune peripheral neuropathy; autoimmune ovarian failure; polyglandular autoimmune syndrome; autoimmune progesterone dermatitis; autoimmune thrombocytopenic purpura; autoimmune thyroid disorder; autoimmune urticaria; autoimmune uveitis; autoimmune vasculitis; and Barlow's disease. (disease) / Barrow concentric sclerosis; Behçet's disease; Berger's disease; Bickerstaff's encephalitis; Blau syndrome; bullous pemphigoid; cancer; Castleman disease; celiac disease; Chagas disease; chronic inflammatory demyelinating polyneuropathy; chronic inflammatory demyelinating polyneuropathy; chronic obstructive pulmonary disease; chronic relapsing polymyelitis; Churg-Strauss syndrome; scarring pemphigoid; Cogan syndrome; cold agglutinin disease; complement component 2 deficiency; contact dermatitis; cranial arteritis; CREST syndrome; Crohn's disease; Cushing's syndrome; cutaneous leukocytoclastic vasculitis; Degos disease; Darkham's disease; herpetiform dermatitis; dermatomyositis; type 1 diabetes; diffuse dermatitis Systemic sclerosis of the skin; discoid lupus erythematosus; Dressler syndrome; drug-induced lupus; eczema; endometriosis; enthesitis-associated arthritis; eosinophilic fasciitis; eosinophilic gastroenteritis; eosinophilic pneumonia; acquired epidermolysis bullosa; erythema nodosum; erythroblastosis fetus; essential mixed cryoglobulinemia; Evans syndrome; exogenous and endogenous reactive airway disease (asthma); fibrodysplasia ossificans progressive; fibrous alveolitis (or idiopathic pulmonary fibrosis); gastritis; pemphigoid gastroenteritis; glomerulonephritis; Goodpasture syndrome; Graves' disease; Guillain-Barré syndrome (GBS); Hashimoto's encephalopathy; Hashimoto's disease; hemolytic anemia; Henoch-Schönlein purpura;Herpes zoster of pregnancy (bullous pemphigoid of pregnancy); hidradenitis suppurativa; Hughes-Stovin syndrome; hypogammaglobulinemia; idiopathic inflammatory demyelinating disease; idiopathic pulmonary fibrosis; idiopathic thrombocytopenic purpura; IgA nephropathy; immune glomerulonephritis; immune nephritis; immune pneumonia; inclusion body myositis; inflammatory bowel disease; interstitial cystitis; juvenile idiopathic arthritis, also known as juvenile rheumatoid arthritis; Kawasaki disease; Lambert-Eaton myasthenic syndrome; leukocytoclastic vasculitis; lichen planus; lichen sclerosing; linear IgA disease (LAD) ); Lupoid hepatitis, also known as autoimmune hepatitis; lupus erythematosus; Magid's syndrome; microscopic polyangiitis; Miller-Fischer syndrome; mixed connective tissue disease; focal scleroderma; Mucher-Habermann disease, also known as acute pityriasis lichenoides; multiple sclerosis; myasthenia gravis; myositis; Meniere's disease; narcolepsy; neuromyelitis optica (also known as Devic's disease); neuromyotonia; ocular pemphigoid; opsoclonus myoclonus syndrome; Ord's thyroiditis Thyroiditis; Recurrent rheumatoid arthritis; PANDAS (Pediatric autoimmune streptococcal neuropsychiatric disorder); Paraneoplastic cerebellar degeneration; Paroxysmal nocturnal hemoglobinuria (PNH); Parry-Romberg syndrome; Slamic mange; Personage-Turner syndrome; Pemphigus vulgaris; Perivenous encephalomyelitis; Pernicious anemia; POEMS syndrome; Polyarteritis nodosa; Polymyalgia rheumatica; Polymyositis; Primary biliary cirrhosis; Primary sclerosing cholangitis; Progressive inflammatory neuropathy; Psoriasis; Psoriatic arthritis; Pure red cell aplasia; Pyoderma gangrenosum; Rasmussen's encephalitis; Raynaud's phenomenon; Reiter's syndrome; Relapsing polychondritis; Restless legs syndrome Retroperitoneal fibrosis; rheumatic fever; rheumatoid arthritis; sarcoidosis; schizophrenia; Schmidt syndrome; Schnitzler syndrome; scleritis; scleroderma; sclerosing cholangitis; serum sickness; Sjögren's syndrome; spondyloarthritis; stiff person syndrome; Still's disease; subacute bacterial endocarditis (SBE); Suzak syndrome; Sweet's syndrome; Sydenham's chorea; sympathetic ophthalmitis; systemic lupus erythematosus; Takayasu's arteritis; temporal arteritis (also known as "giant cell arteritis"); thrombocytopenia; Tolosa-Hunt syndrome; transverse myelitis; ulcerative colitis; undifferentiated connective tissue disease; undifferentiated spondyloarthritis; urticarial vasculitis; vasculitis; vitiligo;Examples include, but are not limited to, viral diseases such as Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV-1, varicella-zoster virus (VZV), and human papillomavirus (HPV); or Wegener's granulomatosis. In some embodiments, autoimmune diseases are allergic conditions, including asthma, food allergies, atopic dermatitis, chronic pain, and rhinitis.

[0569] Skin contact hypersensitivity and asthma are just two examples of immune responses that may have a significant prevalence. Other examples include atopic dermatitis, eczema, Sjögren's syndrome including keratoconjunctivitis sicca secondary to Sjögren's syndrome, alopecia areata, allergic reactions to arthropod bites, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may present with one or more of the following symptoms or signs: itching, swelling, redness, blistering, crusting, ulceration, pain, desquamation, cracking, hair loss, scarring, or exudation of fluid from the skin, eyes, or mucous membranes.

[0570] In atopic dermatitis and eczema, immune-mediated leukocyte infiltration into the skin (particularly mononuclear cells, lymphocytes, neutrophils, and eosinophils) generally plays a significant role in the development of these diseases. Chronic eczema is also associated with marked epidermal hyperplasia. Immune-mediated leukocyte infiltration can occur in areas other than the skin, such as the airways in asthma and the tear-producing glands in keratoconjunctivitis sicca.

[0571] The compounds described herein, or their pharmaceutically acceptable salts, isotopic variants, or prodrugs, can be used in effective amounts to treat hosts, such as humans, who have skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, skin rashes, skin irritations, or skin sensitization (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances, including some pharmaceuticals, may cause skin sensitization when applied topically. In some embodiments, skin disorders are treated by topical administration of compounds known in the art in combination with the compounds disclosed herein. In one non-limiting embodiment, the compounds of the present invention are used as topical agents for the treatment of contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjögren's syndrome including keratoconjunctivitis sicca secondary to Sjögren's syndrome, alopecia areata, allergic responses due to arthropod bites, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. This novel method may also be useful in reducing skin infiltration by malignant leukocytes in diseases such as mycosis fungoides.

[0572] Diseases or conditions that can be treated with the compounds according to the present invention include, for example, autoimmune diseases such as asthma and multiple sclerosis, various cancers, ciliary diseases, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, intellectual disability, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease 1 (PKD1) or 2 (PKD2), Prader-Willi syndrome, sickle cell anemia, Tay-Sachs disease, and Turner syndrome.

[0573] Further disease conditions or pathological states that can be treated with the compounds according to the present invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorders, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes, type 2 diabetes, epilepsy, Guillain-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette syndrome, and vasculitis.

[0574] Further additional disease conditions or pathologies that can be treated with the compounds according to the present invention include, in particular, aceruloplasminemia, achondroplasia type II, chondrodysplasia, acrocephaly, Gaucher disease type II, acute intermittent porphyria, Canavan disease, adenomatous polyposis of the colon, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuric tissue browning, α1-antitrypsin deficiency, α-1 proteinase inhibitor deficiency, emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, amelodysplasia, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, and diffuse endokeratosis. Candidoma, retinal hemangioma (von Hippel-Lindau disease), Apert syndrome, arachnoid finger (Marfan syndrome), Stickler syndrome, congenital polyarthralgia (Ehlers-Danlos syndrome #polyarthralgia type), telangiectasia ataxia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Behle-Stevenson gyrus syndrome, familial Mediterranean fever, Benjamin syndrome, β-thalassemia, bilateral acoustic neurofibromatosis (neurofibromatosis type II), factor V Leiden embolism, Bloch-Salzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnewi-Ulrich syndrome (Turner syndrome), Brunneville disease (tubular sclerosis), prion disease, Birt-Hogg-Duvet syndrome, osteoporosis (osteogenesis imperfecta), broad thumb-toe syndrome (Broad Thumb-Hallux syndrome (Rubinstein-Taybe syndrome), Bronzed Cirrhosis (hemochromatosis), Spinal and bulbar muscular atrophy (Kennedy disease), Bürger-Grütz syndrome (lipoprotein lipase deficiency), CGD (chronic granulomatous disease), flexor limb dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cat-meow syndrome, CAVD (congenital absence of the vas deferens), Keiler's cardiac face syndrome (CBAVD), CEP (congenital erythroblastic porphyria), cystic fibrosis, congenital hypothyroidism, chondrodysplasia (chondrodysplasia), megaepiphysis of the otospinal dysplasia, Lesch-Nyhan syndrome,Galactosemia, Ehlers-Danlos syndrome, fatal dysplasia, Coffin-Lowry syndrome, Cockayne syndrome (familial adenomatous polyposis), congenital erythroblastic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, chondrodysplasia, X-linked sideroblastic anemia, connective tissue disease, conotibial stump anomalous facies syndrome, Cooley's anemia (β-thalassemia), copper storage disease (Wilson's disease), copper transport disease Menkes disease, hereditary coproporphyria, Cowden syndrome, craniofacial joint abnormalities (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Kruschmann-Batten-Steinert syndrome (myotonic dystrophy), Behle-Stevenson gyroscal syndrome, primary hyperoxaluria, spondyloeiophygeous dysplasia (Stradwick type), Duchenne and Becker syndromes. Degenerative neurological disorders including DBMD, Usher syndrome, de Grouchy syndrome and Degerin-Sottas syndrome, developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse globoid body sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, myeloid protoporphyria, erythroblastic type 5-aminolevulinate synthase deficiency Porphyria, myeloid protoporphyria, erythropoiesis-producing uroporphyria, Friedreich's ataxia - familial paroxysmal polyserositis, latent cutaneous disease, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), pancreatic fibrous cyst, fragile X syndrome, galactosemia, hereditary brain disorder, giant cell hepatitis (neonatal hemochromatosis), Glenblatt-Strandbury syndrome (pseudoxanthoma elasticum), Günther's disease (congenital erythroblastic porphyria) Phosphorus, hemochromatosis, Hargren's syndrome, sickle cell anemia, hemophilia, hepatic myeloid porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenosis, achondroplasia, hypochromic anemia, immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome,Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney diseases including hyperoxaluria, Klinefelter syndrome, Kniist dysplasia, mottled dementia, Langer-Sardino achondroplasia, telangiectatic ataxia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniist dysplasia, Marfan syndrome, motor disorders, Mowat-Wilson syndrome, cystic fibrosis, Muwenke syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney achondroplasia, Niemann-Pick disease, Noak syndrome (Pfeiffer syndrome), Osler-Weber-Lange disease, Peutz-Jegers syndrome, polycystic kidney disease, polyosteid fibrous dysplasia (McKune-Albright syndrome), Peutz-Jegers syndrome, Prader-Raaphardt-Willi syndrome Group, hemochromatosis, primary hyperuricemia (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), chronic hereditary progressive chorea (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PX E (pseudoxanthoma elasticum), Rb (retinoblastoma), neurofibromatosis type 1, relapsing polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Licker syndrome, Riley-Day syndrome, Lucy-Lewy syndrome, severe chondrodysplasia with developmental delay and acanthosis nigricans (SADDAN), Lie-Fraumeni syndrome, sarcoma, mammary gland, leukemia and adrenal gland (sarcoma, Breast, leukemia, and adrenal gland (SBLA) syndrome, tuberous sclerosis (sclerosis tuberose (tuberous sclerosis)), SDAT, congenital SED (congenital spondyloepiphysis dysplasia), Stradwick type SED (Stradwick type spondyloepiphysis dysplasia), SEDc (congenital spondyloepiphysis dysplasia), Stradwick type SEMD (Stradwick type spondyloepiphysis dysplasia), Sprinzen syndrome, cutaneous pigmentation disorder, Smith-Lemle-Opitz syndrome, South African hereditary porphyria (atypical porphyria),These include infant-onset ascending hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, β-thalassemia, thyroid disorders, sausage-like neuropathy (hereditary pressure-fragility neuropathy), Treacher Collins syndrome, triplo-X syndrome (triple X syndrome), trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Floric disease, Waardenburg syndrome, Warburg-Schöf-Frederius syndrome, Wolf-Hirschhorn syndrome, Wolf's periodic disorder, Weissenbacher-Zweimüller syndrome, and xeroderma pigmentosum.

[0575] In one particular embodiment, a method for treating a solid tumor, such as non-small cell lung cancer or melanoma, is provided, comprising administering to a patient an effective amount of a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof. In another embodiment, a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, is used in a method for treating a solid tumor, such as non-small cell lung cancer or melanoma, comprising administering the compound to a patient.

[0576] In a particular embodiment, a method is provided for managing the progression of multiple myeloma, comprising administering an effective dose to a patient of a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof. In another embodiment, a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, is used in a method for managing the progression of multiple myeloma, comprising administering the compound to a patient.

[0577] In certain embodiments, solid tumors are resistant to treatment with anti-PD-1 agents.

[0578] In certain embodiments, solid tumors are resistant to treatment with anti-PD-1 agents.

[0579] In certain embodiments, solid tumors are resistant to treatment with anti-PD-L1 agents.

[0580] In certain embodiments, solid tumors are resistant to treatment with anti-PD-L1 agents.

[0581] In one particular embodiment, a method for treating multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof. In another embodiment, a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, is used in a method for treating multiple myeloma, comprising administering the compound to a patient.

[0582] In a particular embodiment, a method is provided for managing the progression of multiple myeloma, comprising administering an effective dose to a patient of a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof. In another embodiment, a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, is used in a method for managing the progression of multiple myeloma, comprising administering the compound to a patient.

[0583] In a particular embodiment, a method is provided for inducing a therapeutic response in a patient with multiple myeloma, as assessed by the International Uniform Response Criteria for Multiple Myeloma (IURC) (described in Durie BG M; et al. "International uniform response criteria for multiple myeloma. Leukemia 2006, 10(10):1-7"), comprising administering to the patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition.

[0584] In another embodiment, a method is provided for achieving a severe complete response, complete response, or very good partial response as assessed by the IURC for multiple myeloma in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition.

[0585] In another embodiment, a method is provided for achieving an extension of overall survival, progression-free survival, relapse-free survival, time to process, or disease-free survival in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof.

[0586] In another embodiment, a method is provided for achieving an extension of overall survival in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof.

[0587] In another embodiment, a method is provided for achieving an extension of progression-free survival in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof.

[0588] In another embodiment, a method is provided for achieving extension of relapse-free survival in patients with multiple myeloma, comprising administering to a patient an effective amount of a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof.

[0589] In another embodiment, a method is provided for achieving an extension of time to progression in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof.

[0590] In another embodiment, a method is provided for achieving an extension of disease-free survival in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof.

[0591] In addition to patients who have not previously received treatment, methods are also provided for treating patients who have previously received treatment for multiple myeloma but have not responded to standard therapy. In addition to patients who have not undergone surgery, additional methods are provided for treating patients who have undergone surgery to treat multiple myeloma. In addition to patients who have not undergone transplant therapy, methods are also provided for treating patients who have previously undergone transplant therapy.

[0592] The compounds described herein can be used for the treatment or management of relapsed, refractory, or resistant multiple myeloma. In some embodiments, the multiple myeloma is primary, secondary, tertiary, quaternary, or quintuple relapse. In certain embodiments, the compounds described herein can be used to reduce, maintain, or eliminate minimal residual disease (MRD).

[0593] The types of multiple myeloma that can be treated with the compounds described herein include, but are not limited to, monoclonal hypergammaglobulinemia of unspecified significance (MGUS), low-risk, intermediate-risk, or high-risk multiple myeloma, newly diagnosed multiple myeloma (including newly diagnosed low-risk, intermediate-risk, or high-risk multiple myeloma), transplant-eligible and non-transplant-eligible multiple myeloma, smoldering (painless) multiple myeloma (including low-risk, intermediate-risk, or high-risk smoldering multiple myeloma), active multiple myeloma, solitary plasmacytoma, plasma cell leukemia, central nervous system multiple myeloma, light chain myeloma, non-secretory myeloma, immunoglobulin D myeloma, and immunoglobulin E myeloma.

[0594] In some embodiments, the compounds described herein can be used to treat or manage multiple myeloma characterized by genetic abnormalities, such as, but not limited to, cyclin D translocations (e.g., t(11;14)(q13;q32), t(6;14)(p21;32), t(12;14)(p13;q32), or t(6;20)), MMSET translocations (e.g., t(4;14)(p16;q32)), MAF translocations (e.g., t(14;16)(q32;a32), t(20;22), t(16;22)(q11;q13), or t(14;20)(q32;q11)), or other chromosomal factors (e.g., 17p13 or deletion of chromosome 13, del(17 / 17p), non-hyperdiploidy, and (1q) amplification).

[0595] In a particular embodiment, a method for treating or managing multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug, as induction therapy.

[0596] In a particular embodiment, a method for treating or managing multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug, as a consolidation therapy.

[0597] In a particular embodiment, a method for treating or managing multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition, as maintenance therapy.

[0598] In certain embodiments, multiple myeloma is a plasma cell leukemia.

[0599] In certain embodiments, multiple myeloma is high-risk multiple myeloma. In some embodiments, high-risk multiple myeloma is relapsing or refractory. In certain embodiments, high-risk multiple myeloma relapses within 12 months of initial treatment. In other embodiments, high-risk multiple myeloma is characterized by one or more genetic abnormalities, such as del(17 / 17p) and t(14;16)(q32;q32). In some embodiments, high-risk multiple myeloma is relapsing or refractory to one, two, or three prior treatments.

[0600] In certain embodiments, multiple myeloma has a p53 mutation. In certain embodiments, the p53 mutation is a Q331 mutation. In certain embodiments, the p53 mutation is an R273H mutation. In certain embodiments, the p53 mutation is a K132 mutation. In certain embodiments, the p53 mutation is a K132N mutation. In certain embodiments, the p53 mutation is an R337 mutation. In certain embodiments, the p53 mutation is an R337L mutation. In certain embodiments, the p53 mutation is a W146 mutation. In certain embodiments, the p53 mutation is an S261 mutation. In certain embodiments, the p53 mutation is an S261T mutation. In certain embodiments, the p53 mutation is an E286 mutation. In certain embodiments, the p53 mutation is an E286K mutation. In certain embodiments, the p53 mutation is an R175 mutation. In certain embodiments, the p53 mutation is the R175H mutation. In certain embodiments, the p53 mutation is the E258 mutation. In certain embodiments, the p53 mutation is the E258K mutation. In certain embodiments, the p53 mutation is the A161 mutation. In certain embodiments, the p53 mutation is the A161T mutation.

[0601] In certain embodiments, multiple myeloma has a homozygous deletion of p53. In certain embodiments, multiple myeloma has a homozygous deletion of wild-type p53. In certain embodiments, multiple myeloma has wild-type p53.

[0602] In certain embodiments, multiple myeloma exhibits activation of one or more oncogenic drivers. In certain embodiments, one or more oncogenic drivers are selected from the group consisting of C-MAF, MAFB, FGFR3, MMset, cyclin D1, and cyclin D. In certain embodiments, multiple myeloma exhibits activation of C-MAF. In certain embodiments, multiple myeloma exhibits activation of MAFB. In certain embodiments, multiple myeloma exhibits activation of FGFR3 and MMset. In certain embodiments, multiple myeloma exhibits activation of C-MAF, FGFR3, and MMset. In certain embodiments, multiple myeloma exhibits activation of cyclin D1. In certain embodiments, multiple myeloma exhibits activation of MAFB and cyclin D1. In certain embodiments, multiple myeloma exhibits activation of cyclin D.

[0603] In certain embodiments, multiple myeloma has one or more chromosomal translocations. In certain embodiments, the chromosomal translocation is t(14;16). In certain embodiments, the chromosomal translocation is t(14;20). In certain embodiments, the chromosomal translocation is t(4;14). In certain embodiments, the chromosomal translocations are t(4;14) and t(14;16). In certain embodiments, the chromosomal translocation is t(11;14). In certain embodiments, the chromosomal translocation is t(6;20). In certain embodiments, the chromosomal translocation is t(20;22). In certain embodiments, the chromosomal translocations are t(6;20) and t(20;22). In certain embodiments, the chromosomal translocation is t(16;22). In certain embodiments, the chromosomal translocations are t(14;16) and t(16;22). In a particular embodiment, the chromosomal translocations are t(14;20) and t(11;14).

[0604] In certain embodiments, multiple myeloma has a Q331 p53 mutation, activation of C-MAF, and a chromosomal translocation at t(14;16). In certain embodiments, multiple myeloma has a homozygous deletion of p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In certain embodiments, multiple myeloma has a K132N p53 mutation, activation of MAFB, and a chromosomal translocation at t(14;20). In certain embodiments, multiple myeloma has wild-type p53, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In certain embodiments, multiple myeloma has wild-type p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In certain embodiments, multiple myeloma has a homozygous deletion of p53, activation of FGFR3, MMset, and C-MAF, and chromosomal translocations at t(4;14) and t(14;16). In certain embodiments, multiple myeloma has a homozygous deletion of p53, activation of cyclin D1, and chromosomal translocation at t(11;14). In certain embodiments, multiple myeloma has an R337L p53 mutation, activation of cyclin D1, and chromosomal translocation at t(11;14). In certain embodiments, multiple myeloma has a W146 p53 mutation, activation of FGFR3 and MMset, and chromosomal translocation at t(4;14). In certain embodiments, multiple myeloma has an S261T p53 mutation, activation of MAFB, and chromosomal translocations at t(6;20) and t(20;22). In certain embodiments, multiple myeloma has an E286K p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In certain embodiments, multiple myeloma has an R175H p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In certain embodiments, multiple myeloma has an E258K p53 mutation, activation of C-MAF, and chromosomal translocations at t(14;16) and t(16;22). In certain embodiments, multiple myeloma has wild-type p53, activation of MAFB and cyclin D1, and chromosomal translocations at t(14;20) and t(11;14).In a particular embodiment, multiple myeloma has an A161T p53 mutation, cyclin D activation, and a chromosomal translocation at t(11;14).

[0605] In some embodiments, multiple myeloma is a newly diagnosed multiple myeloma that is suitable for transplantation. In other embodiments, multiple myeloma is a newly diagnosed multiple myeloma that is not suitable for transplantation.

[0606] In some embodiments, multiple myeloma exhibits early progression (e.g., less than 12 months) after initial treatment. In other embodiments, multiple myeloma exhibits early progression (e.g., less than 12 months) after autologous stem cell transplantation. In yet another embodiment, multiple myeloma is refractory to lenalidomide. In yet another embodiment, multiple myeloma is refractory to pomalidomide. In some such embodiments, multiple myeloma is predicted to be refractory to pomalidomide (e.g., by molecular characterization). In yet another embodiment, multiple myeloma is relapsed or refractory to three or more treatments and is exposed to proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib) and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdomide, or avadomide), or is double refractory to proteasome inhibitors and immunomodulatory compounds. In yet another embodiment, multiple myeloma is relapsed or refractory to three or more prior therapies, including, for example, CD38 monoclonal antibodies (CD38 mAbs, e.g., daratumumab or isatuximab), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib or marizomib) and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdomide or avadomide), or is double refractory to proteasome inhibitors or immunomodulatory compounds and CD38 mAbs. In further embodiments, multiple myeloma is triple-refractory, for example, to proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib), immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdomide, or avadomide), and another activator described herein.

[0607] In a particular embodiment, a method is provided for treating or managing relapsed or refractory multiple myeloma in a patient with renal impairment or symptoms thereof, comprising administering to the patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition.

[0608] In another embodiment, a method is provided for treating or managing relapsed or refractory multiple myeloma in a frail patient, comprising administering to the patient an effective amount of a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof, wherein the frail patient is unsuitable for induction therapy or intolerant to dexamethasone treatment. In another embodiment, the frail patient is elderly, for example, over 65 years of age.

[0609] In another embodiment, a method is provided for treating or managing fourth-line relapsed or refractory multiple myeloma, comprising administering to a patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition.

[0610] In another embodiment, a method is provided for treating or managing newly diagnosed transplant-unsuitable multiple myeloma, comprising administering to a patient an effective amount of a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof.

[0611] In another embodiment, a method is provided for treating or managing newly diagnosed transplant-unsuitable multiple myeloma, comprising administering to a patient an effective amount of a compound of formula I in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof, as an alternative therapy or post-transplant maintenance therapy.

[0612] In another embodiment, a method is provided for treating or managing high-risk multiple myeloma that is relapsed or refractory to one, two, or three prior therapies, comprising administering to a patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition.

[0613] In some embodiments, patients targeted for treatment with one of the compounds described herein have not been treated with multiple myeloma therapy prior to administration. In some embodiments, patients targeted for treatment with one of the compounds described herein have been treated with multiple myeloma therapy prior to administration. In some embodiments, patients targeted for treatment with one of the compounds described herein have developed drug resistance to multiple myeloma therapy. In some embodiments, patients targeted for treatment with one of the compounds described herein have developed resistance to one, two, or three multiple myeloma therapies, therapies selected from CD38 antibodies (CD38 mAbs, e.g., daratumumab or isatuximab), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib or marizomib), and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdamide or avadomide).

[0614] The compounds described herein can be used to treat patients regardless of their age. In some embodiments, the subjects are 18 years of age or older. In other embodiments, the subjects are 18, 25, 35, 40, 45, 50, 55, 60, 65, or over 70 years of age. In other embodiments, the patient is under 65 years of age. In other embodiments, the patient is over 65 years of age. In certain embodiments, the patient is an elderly multiple myeloma patient, for example, over 65 years of age. In certain embodiments, the patient is an elderly multiple myeloma patient, for example, over 75 years of age.

[0615] Certain proteins that have a β-hairpin turn containing glycine at a major position ("g-loop proteins" or "g-loop degrons") have been reported to act as "structural degrons" for cereblon when cereblon also binds to thalidomide-like molecule (IMiD) neosubstrate proteins. Such "g-loop degron"-containing proteins generally include small antiparallel β-sheets that form a β-hairpin with an α-turn, have a geometric arrangement of three skeletal hydrogen bond acceptors (positions i, i+1, and i+2) at the apex of the turn, and have a glycine residue at the major position (i+3) (e.g., "A novel cereblon modulator recruits GSPT1 to the CRL4-CRBN ubiquitin ligase." by Matyskiela, et al., Nature 535, 252-257 (2016), and "Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN." by Sievers et al., Science 362). See eaat0572 (2018). These g-loop deglons have been identified in many proteins, including, but not limited to, Sal-like 4 (SALL4), GSPT1, IKFZ1, IKFZ3, and CK1α, ZFP91, ZNF93, etc.

[0616] In some embodiments, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade a protein containing g-loop degron, where the protein is a protein kinase, a C2H2-containing zinc finger protein, an RNA recognition motif-containing protein, a zinc β-ribbon-containing protein, a β-propeller-containing protein, a P-loop NTPase-containing protein, and a really interesting new gene. The proteins are selected from the following: gene)(RING) finger domain-containing proteins, SRC homology 3 (SH3) domain-containing proteins, immunoglobulin E-set domain-containing proteins, Tudor domain-containing proteins, zinc finger FYVE / PHD type-containing proteins, Ig-like domain-containing proteins, ubiquitin-like domain-containing proteins, concanavalin-like domain-containing proteins, C1 domain-containing proteins, plextrin homology (PH) domain-containing proteins, OB-fold domain-containing proteins, NADP-Rossmann-fold domain-containing proteins, actin-like ATPase domain-containing proteins, and helix-turn-helix (HTH) domain-containing proteins.In some embodiments, protein kinases, C2H2-containing zinc finger proteins, RNA recognition motif-containing proteins, zinc β-ribbon-containing proteins, β-propeller-containing proteins, P-loop NTPase-containing proteins, Really Interesting New Gene (RING) finger domain-containing proteins, SRC homology 3 (SH3) domain-containing proteins, immunoglobulin E-set domain-containing proteins, Tudor domain-containing proteins, zinc finger FYVE / PHD type-containing proteins, Ig-like domain-containing proteins, ubiquitin-like domain-containing proteins, concanavalin-like domain-containing proteins, C1 domain-containing proteins, plextrin homology (PH) domain-containing proteins, OB-fold domain-containing proteins, NADP-Rossmann-fold domain-containing proteins, actin-like ATPase domain-containing proteins, or helix-turn-helix (HTH) domain-containing proteins are overexpressed or contain gain-of-function mutations. In some embodiments, deglon is stabilized by internal hydrogen bonding from ASX and ST motifs.

[0617] In some embodiments, a tricyclic heterobifunctional compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition as described herein, to degrade a protein having "g-loop degron," where "g-loop degron" comprises a [D / N]XX[S / T]G motif (SEQ ID NO: 1), where D = aspartic acid, N = asparagine, X can be any amino acid residue, S = serine, T = threonine, and G = glycine. In a particular embodiment, the "g-loop degron"-containing protein comprises the amino acid sequence DXXSG (SEQ ID NO: 2), where D = aspartic acid, X can be any amino acid residue, S = serine, and G = glycine. In another embodiment, the "g-loop degron"-containing protein comprises the amino acid sequence NXXSG (SEQ ID NO: 3), where N = asparagine, X can be any amino acid residue, S = serine, and G = glycine. In yet another embodiment, the "g-loop degron"-containing protein comprises the amino acid sequence DXXTG (SEQ ID NO: 4), where D = aspartic acid, X can be any amino acid residue, T = threonine, and G = glycine. In yet another embodiment, the "g-loop degron"-containing protein comprises the amino acid sequence NXXTG (SEQ ID NO: 5), where N = asparagine, X can be any amino acid residue, T = threonine, and G = glycine. In some embodiments, the "g-loop degron"-containing protein comprises the amino acid sequence CXXCG (SEQ ID NO: 6), where C = cysteine, X can be any amino acid residue, and G = glycine. In a particular embodiment, the "g-loop degron"-containing protein comprises the amino acid sequence NXXNG (SEQ ID NO: 7), where N = asparagine, X can be any amino acid residue, and G = glycine.

[0618] In some embodiments, the tricyclic heterobifunctional compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade a protein having a C2H2 zinc finger domain containing "g-loop degron". In some embodiments, the zinc finger domain has a consensus sequence CXXCG (SEQ ID NO: 8), where C = cysteine, X = any amino acid, and G = glycine. In alternative embodiments, the protein having the zinc finger domain has a consensus sequence QCXXCG (SEQ ID NO: 9), where C = cysteine, X = any amino acid, G = glycine, and Q = glutamine. In further embodiments, the zinc finger domain has the consensus sequence QC-X2-CG-X3-F-X5-L-X2-H-X3-H (SEQ ID NO: 10), where C=cysteine, X=any amino acid, G=glycine, Q=glutamine, F=phenylalanine, L=leucine, and H=histidine. In some embodiments, the C2H2 zinc finger domain comprises X2-C-X2-CG-X2-C-X5 (SEQ ID NO: 11), where C=cysteine, X=any amino acid, and G=glycine. In some embodiments, the C2H2 zinc finger domain-containing protein is overexpressed. In some embodiments, the expression of the C2H2 zinc finger-containing protein is associated with diseases or disorders, including but not limited to cancer.

[0619] For example, the compounds of the present invention or their pharmaceutically acceptable salts are administered to a host in a pharmaceutical composition as described herein to degrade atypical E3 ubiquitin ligase (ZFP91), a zinc finger protein. Atypical E3 ubiquitin ligase, a zinc finger protein, contains Cys2-His2 zinc fingers and protects tumor cell survival and confers chemoresistance through the destabilization of forkhead box A1 (FOXA1) (see, for example, Tang, et al., "The ubiquitinase ZFP91 promotes tumor cell survival and confers chemoresistance through FOXA1 destabilization," Carcinogenesis, Col. 41(1), Jan. 2020). The atypical E3 ubiquitin ligase, a zinc finger protein, is thought to act through the regulation of the non-classical NF-κB pathway. Its overexpression leads to increased activation of the NF-κB signaling pathway and is associated with many cancers, including gastric, breast, colon, kidney, ovarian, pancreatic, prostate, sarcoma, and melanoma (see, for example, Paschke, "ZFP91 zinc finger protein expression pattern in normal tissues and cancers," Oncol Lett. 2019; Mar; 17(3):3599-3606). In certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used in any pharmaceutical composition described herein to degrade atypical E3 ubiquitin ligase, which is a zinc finger protein, and to treat cancers including, but not limited to, gastric cancer, breast cancer, colon cancer, lung cancer, kidney cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and melanoma.In certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used in any pharmaceutical composition described herein to degrade atypical E3 ubiquitin ligase, which is a zinc finger protein, in order to treat sarcoma, melanoma, or gastric cancer.

[0620] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host in a pharmaceutical composition as described herein to degrade zinc finger protein 276 (ZFP276).

[0621] In yet another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host, optionally in a pharmaceutical composition as described herein, to degrade zinc finger protein 653 (ZFP653). Zinc finger protein 653 may act as a more general transcriptional repressor by competing with GRIP1 and other p160 coactivators for binding to SF1 (see, for example, Borud et al., "Cloning and characterization of a novel zinc finger protein that modulates the transcriptional activity of nuclear receptors," Molec. Endocr. 17: 2303-2319, 2003).

[0622] Another example involves administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a host, optionally in a pharmaceutical composition as described herein, to degrade zinc finger protein 692 (ZFP692). Zinc finger protein 692, also known as AICAR response element-binding protein (AREBP), contains Cys2-His2 zinc fingers and is considered a major modulator of hepatic glucose production regulated by AMPK in vivo (see Shirai et al., "AICAR response element binding protein (AREBP), a key modulator of hepatic glucose production regulated by AMPK in vivo." Biochem Biophys Res Commun. 2011 Oct 22;414(2):287-91). Overexpression of this protein and its overexpression are associated with the promotion of colon adenocarcinoma and metastasis by activating the PI3K / AKT pathway (see, for example, "Zinc finger protein 692 promotes colon adenocarcinoma cell growth and metastasis by activating the PI3K / AKT pathway." Int J Oncol. 2019 May; 54(5): 1691-1703), as well as the development of metastasis in lung adenocarcinoma and lung cancer.Knockdown of zinc finger protein 692 expression via short interfering RNA reduced cell invasion, increased apoptosis in lung cancer cells, and suppressed lung cancer tumor growth in xenograft models (see, for example, Zhang et al., "ZNF692 promotes proliferation and cell mobility in lung adenocarcinoma," Biochem Biophys Res Commun. 2017 Sep 2;490(4):1189-1196). Therefore, in certain embodiments, the compounds of the present invention or their pharmaceutically active salts may be used optionally in the pharmaceutical compositions described herein to degrade zinc finger protein 692 and treat lung cancer or colon cancer, including lung adenocarcinoma or carcinoma or colon adenocarcinoma.

[0623] The tricyclic compound of the present invention or its pharmaceutically acceptable salt can also be administered to a host in an effective amount in a pharmaceutical composition as described herein to degrade zinc finger protein 827 (ZFP827). Zinc finger protein 827 is a zinc finger protein that binds to a nuclear receptor and regulates the alternative telomere elongation (ALT) pathway by recruiting the nucleosome remodeling and histone deacetylation (NURD) complex to telomeres to induce homologous recombination (see, for example, Conomos, D., Reddel, RR, and Pickett, HA, "NuRD-ZNF827 recruitment to telomeres creates a molecular scaffold for homologous recombination," Nature Struct. Molec. Biol. 21: 760-770, 2014). Zinc finger protein 827 is associated with ALT-related promyelocytic leukemia (PML), nucleolus (APB), and other telomere abnormalities. Therefore, in certain embodiments, the compounds of the present invention or their pharmaceutically active salts may be optionally used in the pharmaceutical compositions described herein to degrade ZNF827 in ALT-related disorders, including, but not limited to, ALT-positive promyelocytic leukemia, osteosarcoma, adrenal / PNS neuroblastoma, breast cancer, glioblastoma, colorectal cancer, pancreatic neuroendocrine tumors (NETs), neuroendocrine tumors, colorectal cancer, liver cancer, soft tissue cancers including leiomyosarcoma, malignant fibrous histiocytoma, liposarcoma, gastric cancer / gastric cancer, testicular cancer, and thyroid cancer.

[0624] In other embodiments, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade the E4F transcription factor 1 protein (E4F1). E4F transcription factor 1 is thought to function as a ubiquitin ligase for p53 and is a major posttranslational regulator of p53, playing a crucial role in determining the survival or death of p53-regulated cells (see, for example, Le Cam et al., "The E4F protein is required for mitotic progression during embryonic cell cycles," Molec. Cell. Biol. 24: 6467-6475, 2004). Overexpression of E4F1 has been associated with the development of myeloid leukemia cells (see, for example, Hatachi et al., "E4F1 deficiency results in oxidative stress-mediated cell death of leukemic cells," J Exp Med. 2011 Jul 4; 208(7): 1403-1417). Therefore, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used in any pharmaceutical composition described herein to degrade E4F transcription factor 1, and not limited to, acute myeloid leukemia (AML), undifferentiated AML, myeloblastic leukemia with minimal cell maturation, myeloblastic leukemia with cell maturation, promyelocytic leukemia, myelomonocytic leukemia, myelomonocytic leukemia with eosinophilia, monocytic leukemia To treat diseases, myeloid leukemias including erythroleukemia, megakaryoblastic leukemia, chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML), chronic myelomonocytic leukemia (CMML), myeloproliferative neoplasms, such as polycythemia (PV), essential thrombocythemia (ET), myelodysplasia with myelofibrosis (MMM), eosinophilic syndrome (HES), systemic mast cell disease (SMCD), myelofibrosis, and primary myelofibrosis.E4F1 expression is also essential for survival in p53-deficient cancer cells (see, for example, Rodier et al., "The Transcription Factor E4F1 Coordinates CHK1-Dependent Checkpoint and Mitochondrial Functions," Cell Reports Volume 11, ISSUE 2, pp. 220-233, April 14, 2015). Therefore, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in pharmaceutical compositions described herein to degrade E4F transcription factor 1 and treat p53 deficiency-related disorders, including, but not limited to, ovarian cancer, small cell lung cancer, pancreatic cancer, head and neck squamous cell carcinoma, and triple-negative breast cancer.

[0625] In another embodiment, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade zinc finger protein 517 (ZFP517). Zinc finger protein 517 has been identified as an oncogenic driver in adrenocortical carcinoma (ACC) (see, for example, Rahane et al., “Establishing a human adrenocortical carcinoma (ACC)-specific gene mutation signature,” Cancer Genet. 2019; 230:1-12). Therefore, in certain embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in conjunction with zinc finger protein 517, optionally in a pharmaceutical composition described herein, to treat adrenocortical carcinoma.

[0626] In yet another embodiment, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade zinc finger protein 582 (ZFP582). Zinc finger protein 582 is thought to be involved in nDNA damage response, proliferation, cell cycle regulation, and neoplastic transformation, most notably in cervical cancer, esophageal cancer, and colorectal cancer (e.g., "Methylomic analysis identifies frequent DNA methylation of zinc finger protein 582 (ZNF582) in cervical neoplasms." by Huang et al., PLoS One 7: e41060, 2012; and "Aberrant DNA methylation of PAX1, SOX1 and ZNF582 genes as potential biomarkers for esophageal squamous cell carcinoma." by Tang et al., Biomedicine & Pharmacotherapy Volume). See "Analysis of DNA Methylation in Bowel Lavage Fluid for Detection of Colorectal Cancer" by Harada et al., 120, December 2019, 109488, Cancer Prev Res; 7(10); 1002-10; 2014. Accordingly, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in pharmaceutical compositions described herein to degrade zinc finger protein 582 and treat cancers, including but not limited to cervical cancer including cervical adenocarcinoma, esophageal cancer including squamous cell carcinoma and squamous cell adenocarcinoma, and colorectal cancer.

[0627] In another embodiment, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade zinc finger protein 654 (ZFP654).

[0628] Alternatively, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof may be administered to a host in an effective amount in a pharmaceutical composition as described herein to degrade zinc finger protein 787 (ZFP787).

[0629] The tricyclic compound of the present invention or its pharmaceutically acceptable salt can be administered to a host in an effective amount, optionally in a pharmaceutical composition as described herein, to degrade the hypermethylated in cancer 1 (HIC1) protein in cancer. The hypermethylated in cancer 1 protein contains an N-terminal BTB / POZ protein-protein interaction domain and five Kruppel-like C2H2 zinc finger motifs in its C-terminal half (see, for example, Deltour et al., "The carboxy-terminal end of the candidate tumor suppressor gene HIC-1 is phylogenetically conserved." Biochim. Biophys. Acta 1443: 230-232, 1998). Miller-Dieker syndrome is characterized by impaired expression of hypermethylated protein 1 genes in cancer (see, for example, Grimm et al., "Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a candidate gene for the Miller-Dieker syndrome." Hum. Molec. Genet. 8: 697-710, 1999).

[0630] The tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host in an effective amount, optionally in a pharmaceutical composition as described herein, to degrade hypermethylated in cancer 2 (HIC2) protein in cancer.

[0631] The tricyclic compound of the present invention or its pharmaceutically acceptable salt can be administered to a host in an effective amount, optionally in a pharmaceutical composition as described herein, to degrade GDNF-inducible zinc finger protein 1 (GZF1). GDNF-inducible zinc finger protein 1 is a transcriptional regulator that binds to the 12 bp GZF1 response element (GRE) and represses gene transcription (see, for example, Morinaga et al., "GDNF-inducible zinc finger protein 1 is a sequence-specific transcriptional repressor that binds to the HOXA10 gene regulatory region," Nucleic Acids Res. 33: 4191-4201, 2005).

[0632] Alternatively, the Odd-Skipped Related 1 (OSR1) protein can be degraded by administering, for example, an effective amount of the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof to a host, optionally in a pharmaceutical composition as described herein. The Odd-Skipped Related 1 protein contains three C2H2 type zinc fingers, a tyrosine phosphorylation site, and several putative PXXP SH3 binding motifs (see, for example, Katoh, M., "Molecular cloning and characterization of OSR1 on human chromosome 2p24," Int. J. Molec. Med. 10: 221-225, 2002).

[0633] In another embodiment, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade the odd-skipped related 2 (OSR2) protein.

[0634] In yet another embodiment, the SAL-like 4 (SALL4) protein can be degraded by administering an effective amount of a selected tricyclic compound or a pharmaceutically acceptable salt thereof to a host, optionally in a pharmaceutical composition as described herein. The SAL-like 4 protein has three SAL-type C2H2 double zinc finger domains, the second of which has a single C2H2 zinc finger attached to its C-terminus and an N-terminal C2HC zinc finger motif typical of vertebrate SAL-like proteins. Mutations in the SAL-like 4 protein are associated with the development of Duane-radial row syndrome (see, for example, Borozdin et al., "SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism," J. Med. Genet. 41: e113, 2004). Overexpression of the SAL-like 4 protein is associated with the promotion, growth, and metastasis of many cancers, including lung cancer, gastric cancer, liver cancer, kidney cancer, myelodysplastic syndromes, germ cell and sex cord-stromal tumors including anaplastic germ cell tumors, yolk sac tumors, and choriocarcinoma, as well as leukemia. Accordingly, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used in any pharmaceutical composition described herein to degrade SAL-like 4 protein and to treat cancers including, but not limited to, gastric cancer, liver cancer, kidney cancer, myelodysplastic syndrome, undifferentiated germ cell tumors, yolk sac tumors, and germ cell-sex cord-stromal tumors including choriocarcinoma, as well as leukemia.

[0635] The B-cell lymphoma 6 (BCL6) protein can also be degraded by administering an effective amount of a selected tricyclic compound or a pharmaceutically acceptable salt thereof to a host, optionally in a pharmaceutical composition as described herein. B-cell lymphoma 6 contains an autonomous transrepressor domain, and two discontinuous regions containing a POZ motif mediate the maximum trans-repressive activity. Translocation of the B-cell lymphoma 6 gene is associated with the development of myeloproliferative disorders such as non-Hodgkin lymphoma. Overexpression of B-cell lymphoma 6 prevents the increase of reactive oxygen species and inhibits chemotherapy-induced apoptosis in cancer cells (see, for example, Tahara et al., "Overexpression of B-cell lymphoma 6 alters gene expression profile in a myeloma cell line and is associated with decreased DNA damage response," Cancer Sci. 2017 Aug;108(8):1556-1564, and Cardenas et al., "The expanding role of the BCL6 oncoprotein as a cancer therapeutic target," Clin Cancer Res. 2017 Feb 15; 23(4): 885-893). Accordingly, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in pharmaceutical compositions described herein to degrade B-cell lymphoma 6 and to treat, but not limited to, hematological malignancies or solid tumors, such as, but not limited to, B-cell leukemia or lymphoma, such as, but not limited to, diffuse large B-cell lymphoma (DLBCL) and ABC-DLBCL subtypes, B-cell acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, and non-small cell lung cancer.

[0636] Furthermore, a selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof is optionally administered to a host in an effective amount in a pharmaceutical composition as described herein to degrade the B-cell lymphoma 6B (BCL6B) protein. The B-cell lymphoma 6B protein contains an N-terminal POZ domain and five C-terminal zinc finger motifs and is thought to act as a transcriptional repressor (see, for example, Okabe et al., "BAZF, a novel Bcl6 homolog, functions as a transcriptional repressor," Molec. Cell. Biol. 18: 4235-4244, 1998). Overexpression of B-cell lymphoma 6B protein has been associated with the development of germ cell tumors (Ishii et al., "FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5 and Bcl6b through MAP2K1 activation," Development 139, 1734-1743 (2012)). Therefore, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in pharmaceutical compositions described herein to degrade B-cell lymphoma 6B and treat cancers including, but not limited to, undifferentiated germ cell tumors and seminomas, and, but not limited to, germ cell tumors, teratomas, yolk sac tumors, and germ cell carcinomas, including choriocarcinoma.

[0637] Alternatively, the early growth response 1 (EGR1) protein can be degraded by administering an effective amount of a selected tricyclic compound or a pharmaceutically acceptable salt thereof to a host, optionally in a pharmaceutical composition as described herein. Early growth response 1 protein has been shown to be involved in the proliferation and survival of not only prostate cancer cells but also glioma cells by directly regulating the expression of the transforming growth factor-beta-1 gene and modulating several target genes, including cyclin D2 (CCND2), p19 (Ink4d), and Fas (e.g., "Erg1 promotes growth and survival of prostate cancer cells: identification of novel Egr1 target genes." by Virolle et al., J. Biol. Chem. 278: 11802-11810, 2003; "Inhibition of EGR1 inhibits glioma proliferation by targeting CCND1 promoter." by Chen et al., Journal of Experimental & Clinical Cancer Research Volume 36, Article number: 186). (See 2017). One mechanism used by Egr1 to confer resistance to apoptotic signaling is Egr1's ability to inhibit Fas expression, which leads to insensitivity to FasL. Therefore, in certain embodiments, compounds of the present invention or pharmaceutically active salts thereof may be used optionally in pharmaceutical compositions described herein to degrade early growth response 1 protein and treat cancers including, but not limited to, prostate cancer or, but not limited to, gliomas including pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme.

[0638] In yet another embodiment, the early growth response 4 (EGR4) protein can be degraded by administering an effective amount of a selected tricyclic compound or a pharmaceutically acceptable salt thereof to a host, optionally in a pharmaceutical composition as described herein. The early growth response 4 protein contains three zinc fingers of the C2 / H2 subtype near its carboxyl terminus (see, for example, Crosby et al., “Neural-specific expression, genomic structure, and chromosomal localization of the gene encoding the zinc-finger transcription factor NGFI-C.” Proc. Nat. Acad. Sci. 89: 4739-4743, 1992). Overexpression of early growth response 4 protein is associated with the development of cholangiocarcinoma (see, for example, Gong et al., "Gramicidin inhibits cholangiocarcinoma cell growth by suppressing EGR4," Artificial Cells, Nanomedicine, and Biotechnology, 48:1, 53-59 (2019)). Therefore, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used, optionally in pharmaceutical compositions described herein, to degrade early growth response 4 protein and treat cancer, including but not limited to cholangiocarcinoma.

[0639] In certain embodiments, a selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade Sal-like 1 (SALL1) protein.

[0640] In alternative embodiments, the Sal-like 3 (SALL3) protein can be degraded by administering an effective amount of a selected tricyclic compound or a pharmaceutically acceptable salt thereof to a host, optionally in a pharmaceutical composition as described herein. The SALL3 protein comprises four double zinc finger (DZF) domains, each containing a sequence identical to or closely related to the SAL box, which is a characteristic 8-amino acid stretch within a second zinc finger motif.

[0641] In yet another embodiment, a selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount in a pharmaceutical composition as described herein to degrade the tumor protein p63 (TP63). Overexpression of the tumor protein p63 is associated with poor development and prognosis of lung cancer, radiation resistance in oral and head and neck cancers, and squamous cell carcinoma of the skin (see, for example, Massion et al., "Significance of p63 amplification and overexpression in lung cancer development and prognosis," Cancer Res. 2003 Nov 1;63(21):7113-21, and Moergel et al., "Overexpression of p63 is associated with radiation resistance and prognosis in oral squamous cell carcinoma," Oral Oncol. 2010 Sep;46(9):667-71). Accordingly, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used in any pharmaceutical composition described herein to degrade tumor protein p63 and treat cancers, including, but not limited to, non-small cell lung cancer, small cell lung cancer, head and neck cancer, and squamous cell carcinoma of the skin.

[0642] In yet another embodiment, a selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade widely-interspaced zinc finger (WIZ) proteins.

[0643] The selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof may also be administered to a host in an effective amount in a pharmaceutical composition as described herein to degrade Zinc Finger and BTB Domain Containing Protein 7A (ZBTB7A). The expression of zinc finger and BTB domain-containing protein 7A is associated with many cancers, including prostate cancer, non-small cell lung cancer, bladder cancer, breast cancer, ovarian cancer, oral squamous cell carcinoma, and hepatocellular carcinoma (see, for example, Han et al., "ZBTB7A Mediates the Transcriptional Repression Activity of the Androgen Receptor in Prostate Cancer," Cancer Res 2019;79:5260-71, and Molloy et al., "ZBTB7A governs estrogen receptor alpha expression in breast cancer," Journal of Molecular Cell Biology, Volume 10, Issue 4, August 2018, Pages 273-284). Accordingly, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in pharmaceutical compositions described herein to degrade zinc finger and BTB domain-containing protein 7A and to treat cancers, including, but not limited to, prostate cancer, non-small cell lung cancer, breast cancer, oral squamous cell carcinoma, prostate cancer, ovarian cancer, glioma, bladder cancer, and hepatocellular carcinoma.

[0644] In other embodiments, selected tricyclic compounds of the present invention or pharmaceutically active salts thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition as described herein, to degrade zinc finger and BTB domain-containing protein 7B (ZBTB7B). Expression of zinc finger and BTB domain-containing protein 7B is associated with breast cancer, prostate cancer, urothelial carcinoma, cervical cancer, and colorectal cancer. Therefore, in certain embodiments, compounds of the present invention or pharmaceutically active salts thereof can be used, optionally in a pharmaceutical composition as described herein, to degrade zinc finger and BTB domain-containing protein 7B and treat cancers, including, but not limited to, breast cancer, prostate cancer, urothelial carcinoma, cervical cancer, and colorectal cancer.

[0645] A selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition as described herein, to degrade casein kinase I alpha I (CK1α or CK1 alpha). CK1 alpha is a bifunctional regulator of NF-κB (see, for example, Bidere et al., "Casein kinase 1-alpha governs antigen-receptor-induced NF-kappa-B activation and human lymphoma cell survival," Nature 458: 92-96, 2009). CK1 alpha dynamically associates with the CBM complex upon T cell receptor binding and is involved in cytokine production and lymphocyte proliferation. However, CK1 alpha kinase activity plays a contrasting role in subsequently promoting CARMA1 phosphorylation and inactivation. Therefore, CK1 alpha has a dual "gating" function that first promotes receptor-induced NF-κB and then terminates it. ABC DLBCL cells require CK1 alpha for constitutive NF-κB activity, indicating that CK1 alpha functions as a conditionally essential malignant gene.CK1 alpha expression is associated with myelodysplastic diseases accompanied by 5q (del(5q) MDS) depletion (see, for example, Kronke, et al., "Lenalidomide induces ubiquitination and degradation of CK1-alpha in del(5q) MDS." Nature 523: 183-188, 2015), colorectal cancer, breast cancer, leukemia, multiple myeloma, lung cancer, diffuse large B-cell lymphoma, non-small cell lung cancer, and pancreatic cancer (see, for example, Richter et al., "CK1α overexpression correlates with poor survival in colorectal cancer." BMC Cancer. 2018; 18: 140, Jiang et al.). This is related to the article "Casein kinase 1α: biological mechanisms and theranostic potential" by al. (see Cell Commun Signal. 2018; 16: 23). Accordingly, in some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in the pharmaceutical compositions described herein to degrade casein kinase I alpha-I and treat cancers including, but not limited to, colorectal cancer, breast cancer, leukemia, multiple myeloma, lung cancer, diffuse large B-cell lymphoma, non-small cell lung cancer, and pancreatic cancer; myelodysplastic syndromes including, but not limited to, 5q syndrome, refractory cytopenia with monocytic lineage dysplasia, refractory anemia, refractory neutropenia, and refractory thrombocytopenia; refractory anemia with ring sideroblasts, refractory cytopenia with polycytic lineage dysplasia (RCMD), refractory anemia with supervast blasts (REAB) I and II, refractory anemia with blast plasia in the transitional phase (RAEB-T), chronic myelomonocytic leukemia (CMML), unclassifiable myelodysplasia, and refractory cytopenia in childhood (childhood dysplasia).

[0646] The selected tricyclic compounds of the present invention or their pharmaceutically acceptable salts can optionally be administered to a host in an effective amount in a pharmaceutical composition as described herein to degrade Family with Sequence Similarity 83 member H (FAM83H). FAM83H is thought to be involved in the progression of human cancers along with tumor-associated molecules such as MYC and β-catenin, and its overexpression has been associated with lung cancer, breast cancer, colon cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, esophageal cancer, glioma, hepatocellular carcinoma, thyroid cancer, renal cell carcinoma, osteosarcoma, and gastric cancer (see, for example, Kim et al., "FAM83H is involved in stabilization of β-catenin and progression of osteosarcomas," Journal of Experimental & Clinical Cancer Research volume 38, Article number: 267 (2019)). Accordingly, in some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in pharmaceutical compositions described herein to decompose FAM83H and treat cancers including, but not limited to, lung cancer, breast cancer, colon cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, esophageal cancer, glioma, thyroid cancer, and, but not limited to, liver cancer including hepatocellular carcinoma, renal cell carcinoma, osteosarcoma, and gastric cancer.

[0647] Alternatively, the zinc finger and BTB domain-containing protein 16 (ZBTB16) can be degraded by administering an effective amount of a selected tricyclic compound or pharmaceutically active salt thereof to a host, optionally in a pharmaceutical composition as described herein. Overexpression and translocation of ZBTB16 have been associated with the development of various hematological cancers, including acute promyelocytic leukemia (see, for example, Zhang et al., "Genomic sequence, structure organization, molecular evolution, and aberrant rearrangement of promyelocytic leukemia zinc finger gene." Proc. Nat. Acad. Sci. 96: 11422-11427, 1999). Accordingly, in some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in the pharmaceutical compositions described herein to degrade ZBTB16 and treat cancers, including but not limited to acute promyelocytic leukemia, acute lymphoblastic leukemia, adult T-cell lymphoma / ATL, and Burkitt lymphoma, including but not limited to leukemia or lymphoma, and including but not limited to hematological cancers.

[0648] In alternative embodiments, AT-rich interaction domain-containing protein 2 (ARID2) can be degraded by administering an effective amount of a selected tricyclic compound or pharmaceutically salt thereof to a host, optionally in a pharmaceutical composition as described herein. ARID2 is a subunit of the PBAF chromatin-remodeling complex, which promotes ligand-dependent transcriptional activation by nuclear receptors (see, for example, Yan et al., "PBAF chromatin-remodeling complex requires a novel specificity subunit, BAF200, to regulate expression of selective interferon-responsive genes," Genes Dev. 19: 1662-1667, 2005).

[0649] In another embodiment, a selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade polybromo-associated BAF (PBAF). Mutations in PBAF have been associated with the development of synovial sarcoma and multiple myeloma (see, for example, Alfert et al., “The BAF complex in development and disease,” Epigenetics & Chromatin volume 12, Article number: 19 (2019)). Therefore, in some embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof can be used, optionally in a pharmaceutical composition described herein, to degrade PBAF and treat cancers, including, but not limited to, synovial sarcoma and multiple myeloma.

[0650] In other embodiments, selected tricyclic compounds of the present invention, upon administration after binding to cereblon to form a new phenotype surface, can bind to numerous neosubstrates, thus resulting in a “multiple pharmacological” form. For example, the tricyclic compounds can bind to and degrade IRAK4, IKZF1 and / or IKZF3 and / or Aiolos. In other examples, upon administration, the tricyclic compounds can degrade two or more of the proteins named above or herein, for example, SALL4 and IKZF1 / 3 or IKZF2 / 4.

[0651] In certain embodiments, the tricyclic compounds of the present invention exhibit at least about 1.5-fold, 2-fold, 3-fold, 5-fold, or even 10-fold degradation selectivity in vitro compared to IKZF2 and / or IKZF4 than to IKZF1 and / or IKZF3 in a standard HiBiT bioluminescence assay. The HiBiT assay is a known assay fully described in the literature.

[0652] IV. Combination Therapy A selected compound of Formula I or a pharmaceutically acceptable salt thereof may be used in an effective amount, either alone or in combination, to treat a patient, as further described herein.

[0653] The compounds disclosed herein, including but not limited to those described herein, can be used alone or in combination in effective amounts with other compounds of the present invention, other bioactive agents, or second therapeutic agents to treat patients, such as humans, who have disorders described herein.

[0654] The term "bioactive agent" is used to describe active substances other than the selected compounds of the present invention that can be used in combination with or alternately with the compounds of the present invention to achieve a desired therapeutic outcome. In certain embodiments, the compounds and bioactive agents of the present invention are administered such that they have overlapping periods during which they are active in vivo, for example, Cmax, Tmax, AUC, or other pharmacokinetic parameters. In other embodiments, the compounds and bioactive agents of the present invention are administered to a patient in need, where they do not have overlapping pharmacokinetic parameters, but one has a therapeutic effect on the therapeutic efficacy of the other.

[0655] In one embodiment of this invention, the bioactive agent is an immunomodulatory agent that includes, but is not limited to, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, checkpoint inhibitors including V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecules, peptides, nucleotides, or other inhibitors. In a particular embodiment, the immunomodulatory agent is an antibody such as a monoclonal antibody.

[0656] Examples of PD-1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor and thereby inhibit immunosuppression include nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). Examples of PD-L1 inhibitors that inhibit immunosuppression by blocking the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor include atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). Examples of CTLA-4 checkpoint inhibitors that inhibit immunosuppression by binding to CTLA-4 include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884, and AGEN2041 (Agenus). Examples of LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the PD-1 and LAG-3 dual inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

[0657] In certain embodiments, the checkpoint inhibitor is selected from nivolumab / OPDIVO®, pembrolizumab / KEYTRUDA®, and inhibitors of PDL2 / lg fusion proteins such as pidilizumab / CT-011, MPDL3280A / RG7446, MEDI4736, MSB0010718C, BMS 936559, AMP 224, or inhibitors of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof.

[0658] In another embodiment, one of the active compounds described herein may be administered in combination or alternately in an effective dose with an effective dose of an estrogen inhibitor, including but not limited to a SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor degrader), full estrogen receptor degrader, or another form of partial or full estrogen antagonist or agonist, for the treatment of abnormal tissues of the female reproductive system, such as breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. Partial anti-estrogens such as raloxifene and tamoxifen retain some estrogen-like effects, including estrogen-like stimulation of uterine growth and, in some cases, estrogen-like effects in progressing breast cancer that actually stimulate tumor growth. In contrast, fulvestrant, a full anti-estrogen, has no estrogen-like effects on the uterus and is effective in tamoxifen-resistant tumors.

[0659] Non-limiting examples of anti-estrogen compounds are presented in International Publication 2014 / 19176, assigned to Astra Zeneca; International Publication 2013 / 090921, International Publication 2014 / 203129, International Publication 2014 / 203132, and U.S. Patent Application Publication 2013 / 0178445, assigned to Olema Pharmaceuticals; and U.S. Patents 9,078,871, 8,853,423, and 8,703,810, as well as U.S. Patent Application Publication 2015 / 0005286, International Publication 2014 / 205136, and International Publication 2014 / 205138.

[0660] Additional, non-limiting examples of anti-estrogenic compounds include SERMs such as anoldrin, bazedoxifene, propalestrol, chlorotrianicene, clomiphene citrate, cyclophenyl, rasofoxifene, olmeroxifene, raloxifene, tamoxifene, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozol, formestan, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allylestrenol, chlormadinone acetate, cyproterone acetate, dermadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone.

[0661] Other estrogen ligands that can be used in accordance with the present invention include U.S. Patent Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, International Publication No. 2011 / 156518, U.S. Patent Nos. 8,455,534 and 8,299,112, U.S. Patent Nos. 9,078,871; 8,853,423; 8,703,810; U.S. Patent Application Publication No. 2015 / 0005286; and International Publication No. 2014 / 2 Patent No. 05138, U.S. Patent Application Publication No. 2016 / 0175289, U.S. Patent Application Publication No. 2015 / 0258080, International Publication No. 2014 / 191726, International Publication No. 2012 / 084711; International Publication No. 2002 / 013802; International Publication No. 2002 / 004418; International Publication No. 2002 / 003992; International Publication No. 2002 / 003991; International Publication No. 2002 / 003990; International Publication No. 2002 / 003989; International Publication No. 2002 / 003988 International Publication No. 2002 / 003986; International Publication No. 2002 / 003977; International Publication No. 2002 / 003976; International Publication No. 2002 / 003975; International Publication No. 2006 / 078834; US Patent No. 6821989; US Patent Application Publication No. 2002 / 0128276; US Patent No. 6777424; US Patent Application Publication No. 2002 / 0016340; US Patent No. 6326392; US Patent No. 6756401; US ​​Patent Application Publication No. 2002 / 0013327 It is described in U.S. Patent No. 6512002, U.S. Patent No. 6632834, U.S. Patent Application Publication No. 2001 / 0056099, U.S. Patent No. 6583170, U.S. Patent No. 6479535, International Publication No. 1999 / 024027, U.S. Patent No. 6005102, European Patent No. 0802184, U.S. Patent No. 5998402, U.S. Patent No. 5780497, U.S. Patent No. 5880137, International Publication No. 2012 / 048058 and International Publication No. 2007 / 087684.

[0662] In another embodiment, the active compounds described herein may be administered in combination with or alternately in effective doses of a selective androgen receptor modulator, selective androgen receptor degrader, complete androgen receptor degrader, or another form of partial or complete androgen antagonist for the treatment of abnormal tissue of the male reproductive system, such as prostate cancer or testicular cancer. In a particular embodiment, prostate or testicular cancer is androgen-resistant.

[0663] Non-limiting examples of antiandrogenic compounds are presented in International Publication No. 2011 / 156518 and U.S. Patents Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of antiandrogenic compounds include enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topirutamide, abiraterone acetate, and cimetidine.

[0664] In certain embodiments, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib, alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113.

[0665] In certain embodiments, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Dirotrif), rosiletinib (CO-1686), osimertinib (Tagrisso), olmutinib (Orita), nacotinib (ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), and neratinib (HKI- Examples include abitinib (AC0010), EAI045, tarloxotinib (TH-4000;PR-610), PF-06459988 (Pfizer), tesevatinib (XL647;EXEL-7647;KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804;Pfizer).

[0666] In certain embodiments, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.

[0667] In certain embodiments, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, ofatumumab, ibritumomab, tocitumomab, and ocrelizumab.

[0668] In certain embodiments, the bioactive agent is a JAK3 inhibitor. An example of a JAK3 inhibitor is tasocitinib.

[0669] In certain embodiments, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]aminophenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridine-5-yl)oxy]benzamide), and ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]pi [Perazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide)(navitoclax), ABT-263((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((tri Fluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (Obatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrole-2-yl)methylidene]-4-methoxypyrrole-2-ylidene]indole; methanesulfonic acid), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazole-2-ylamino)-phenyl ester), pogosin, ethyl 2- Examples include amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate, nilotinib-d3, TW-37 (N-[4-[[2-(1,1-dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide), apogossiporone (ApoG2), HA14-1, AT101, sabutoclax, gumbognate, or G3139 (oblimersene).

[0670] In certain embodiments, the bioactive agent is a kinase inhibitor. In certain embodiments, the kinase inhibitor is selected from phosphoinositide 3-kinase (PI3K) inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, or splenic tyrosine kinase (Syk) inhibitors, or a combination thereof.

[0671] Examples of PI3 kinase inhibitors include wartmannin, demethoxypyridine, perifosine, idelalisib, pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (tasericib), (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazole-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-9-yl]pyrazole-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-phenoxy-2-butanyl hydrogen ( S)-methylphosphonate; or methyl(oxo){[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458(2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide) (Omiparisib), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidine-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-9 -yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820((S)-1-(4-((2-(2-aminopyrimidine-5-yl)-7-methyl-4-mohydroxypropane(mohydroxypropan)-1-one), GS-1101(5-fluoro-3-phenyl-2-([S])-1-[9H-purine-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409(N-(4-(N-(3-((3,5-Dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4 methylbenzamide), BAY80-6946(2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz), AS 252424(5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidin-2,4-dione), CZ 24832(5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridin-3-sulfonamide), Buparlicib(5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941(2-(1H-indazole-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl ]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980((S)-1-(4-((2-(2-aminopyrimidine-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126((8S,14S,17S)-14-(carboxymethyl) -8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-oate), PF-05212384(N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-( 4,6-di-4-morpholinyl-1,3,5-triazine-2-yl)phenyl]urea) (dactolisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinoline-1-yl]phenyl}propannitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5-Dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide) and GSK1059615 (5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(propa-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethylene) (Chill)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib), LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpericib, IC-87114, TGI100713, CH5132799, PKI-402, copanlicib (BAY 80-6946), XL Examples include, but are not limited to, 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, and apitricib (GDC-0980; RG7422).

[0672] Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica®) (1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-yl]propa-2-en-1-one), dianilinopyrimidine inhibitors, such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidine-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see U.S. Patent Application Publication No. 2011 / 0117073, which in whole forms part of this specification), dasatinib (N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidine-4-ylamino)thiazole-5-carboxamide), LFM-A13 (α-cyano-β -Hydroxy-β-methyl-N-(2,5-dibromophenyl)propenamide), GDC-0834(RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazine-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazine-6-yl)phenyl)benzamide, CGI-1746(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazine-2-yl)phenyl)benzamide), CNX-774(4-(4- ((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidine-2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056(7-benzyl-1-(3-(piperidine-1-yl)propyl)-2-(4-(pyridine-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxaline-6(5H)-one), GDC-0834((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazine-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazine-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059(Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazole-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindorin-6-yl)-9-(1-methyl-1H-pyrazole-4-yl)benzo[h][1,6]naphthili Examples include dzin-2(1H)-one) and RN486(6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridine-3-yl}phenyl)-2H-isoquinoline-1-one), as well as other molecules capable of inhibiting BTK activity, such as the BTK inhibitors disclosed in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59 (which in whole constitutes part of this specification by reference).

[0673] Syk inhibitors include cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazine-1-yl)phenyl)aminopyrimidine-5-carboxamide), entospletinib (6-(1H-indazole-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazine-8-amine), and fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl (Lu)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidine-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridine-2-ylamino)-pyridazine-3-carboxylic acid amide), imatinib (Gleevec; 4-[(4-methylpiperazine-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridine-3-yl)pyrimidine-2-yl]amino}phenyl) benzamide), staurosporine, GSK143 ( 2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2(1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine), PRT-060318(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607(4-((3-(2H-1,2,3-triazole-2-yl)phenyl)amino)-2-(((1R,R112(3,3'-((5-fluoropyrimidine-2,4-diyl)bis(azandiyl))diphenol), R348(3-ethyl-4-methylpyridine), R406(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidine-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazine-3(4H)-one), piceatannol(3-hydroxyresveratrol), YM193306(Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, See 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the entire text is incorporated herein by reference)), Compound D (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the entire text is incorporated herein by reference)), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, See 3614-3643 (the entirety of which constitutes part of this specification by reference), luteolin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,See 3614-3643 (which in whole form constitutes part of this specification by reference), apigenin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (which in whole form constitutes part of this specification by reference)), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (which in whole form constitutes part of this specification by reference)), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, Examples include, but are not limited to, 3614-3643 (see 3614-3643, which in whole form constitutes part of this specification by reference), myricetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (which in whole form constitutes part of this specification by reference)), and morin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (which in whole form constitutes part of this specification by reference)).

[0674] In certain embodiments, the bioactive agent is a MEK inhibitor. MEK inhibitors are known, for example, trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidine-1(2H)-yl}phenyl)acetamide), selmetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), and pimacertib / AS703026 / MSC 1935369((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidine-2-yl]azetidine-3-ol), refametinib / BAY869766 / RDEA119(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901(N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-flu Oro-4-iodophenyl)amino]-benzamide), TAK733((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162(5-[(4-bromo-2-fluorophenyl)amino ]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766(3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidine-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655(3,Examples include 4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxadinan-2-yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX02189, BIX02188, vinimetinib, SL-327, TAK-733, and PD318088.

[0675] In certain embodiments, the bioactive agent is a Raf inhibitor. Known Raf inhibitors include, for example, vemurafenib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide; 4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazoline-6-ylamino)phenyl)benzamide), NVP-BHG712(4-methyl-3-(1-methyl-6-(pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265(1-methyl-5-[2-[5-(trifluoro Methyl)-1H-imidazole-2-yl]pyridine-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazole-2-amine), 2-bromoardicine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridine-4-yl)-1H-imidazole-4-yl)phenol), sorafenib N-oxide ( Examples include 4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (encorafenib).

[0676] In certain embodiments, the bioactive agent is, but is not limited to, an AKT inhibitor comprising MK-2206, GSK690693, perifosine (KRX-0401), GDC-0068, trisirivine, AZD5363, honokiol, PF-04691502, and miltefosine; or, but is not limited to, an FLT-3 inhibitor comprising P406, dovitinib, quizartinib (AC220), amvatinib (MP-470), tanzutinib (MLN518), ENMD-2076, and KW-2449; or a combination thereof.

[0677] In certain embodiments, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridafololimus, sirolimus, and defololimus. Examples of MEK inhibitors include trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidine-1(2H-yl}phenyl)acetamide) and selumetinib (6-(4-bromo-2-chloroanilino)-7 -Fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimacertib / AS703026 / MSC1935369((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973(1-({3,4-difluoro-2-[(2-fluoro (-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidine-2-yl]azetidine-3-ol) (cobimetinib), refametinib / BAY869766 / RDEA119 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfone) N-amide), PD-0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162(5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766(3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidine-2-yloxychromen-2-one), WX-554, R04987655 / C Examples include, but are not limited to, H4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxadinan-2-yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).

[0678] In certain embodiments, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER.

[0679] In certain embodiments, the bioactive agent is an HSP inhibitor. Examples of HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and radicicol.

[0680] Additional bioactive compounds include, for example, everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, and AZD 1152, Enzastaurin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitor, VEGFR inhibitor, Aurora kinase inhibitor, PIK-1 modulator, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, IGFR-TK inhibitor, Anti-HGF antibody, Focal adhesion plaque kinase inhibitor, Map kinase (mek) inhibitor, VEGF trap antibody, pemetrexed, panitumumab, amrubicin, olegobomab, Lep-etu, noratexide, azd2171, batabulin, ofatumumab, zanorimumab, edtecalin, tetrandrin, lubitecan, tesmilifene, oblimersen, tisilimmab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, sirengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, rucanton, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, Taranpanel, Atracentane, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Sericiclib; PD0325901, AZD-6244, Capecitabine, L-Glutamic Acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-, Disodium Salt Heptahydrate, Camptothecin, PEG-labeled Irinotecan, Tamoxifen, Toremifene Citrate, Anastrazole, Exemestane, Letrozole,DES (Diethylstilbestrol), Estradiol, Estrogen, Conjugated Estrogen, Bevacizumab, IMC-1C11, CHIR-258); 3-[5-(Methylsulfonylpiperazine methyl)-Indolyl-Quinolone, Batalanib, AG-013736, AVE-0005, Goserelin Acetate, Leuprolide Acetate, Triptorelin Pamoate, Medroxyprogesterone Acetate, Hydroxyprogesterone Caproate, Megestrol Acetate Raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, ronafarnib, BMS-214662, tipifarnib; amifostin, NVP-LAQ824, suberoyl analide hydroxamic acid (acid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrin, anagrelide, L-asparaginase, Calmette-Guéran bacillus (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine, hidol Roxyurea, Idarubicin, Ifosfamide, Imatinib, Leuprolide, Levamisole, Lomustine, Mechloretamine, Melphalan, 6-Mercaptopurine, Mesna, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Niltamide, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, Plicamycin, Porfimer, Procarbazine, Larcitrexed, Rituximab, Streptozocin, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Tretinoin, Vindesine, 13-Cis-Retinoic Acid, Phenylalanine Mustard, Uracil Mustard, Estramustine,Altretamine, phloxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, barrubicin, mitramycin, vinblastine, vinorelbine, topotecan, razoxin, marimast, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifen, idoxyfen e) Spironolactone, finasteride, cimitidine, trastuzumab, denileukin difutitox, gefitinib, bortezomib, paclitaxel, paclitaxel without cremofol, docetaxel, epotilon B, BMS-247550, BMS-310705, droloxifen, 4-hydroxytamoxifen, pipendoxifen, ERA-923, alzoxifen, fulvestrant, acorbifen, rasofoxifen, idoxifen, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wartmannin, ZM336372, L-779,450, PEG-filgrastim, Darbepoetin, Erythropoetin, Granulocyte colony-stimulating factor, Zoledronate, Prednisone, Cetuximab, Granulocyte macrophages Dicolony-stimulating factor, histrelin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone,Examples include ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tocitumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, drasetron, tropisetron, pegfilgrastim, erytropoetin, epoetin α, darbepoetin α, and mixtures thereof.

[0681] In certain embodiments, the compound is administered in combination with ifosfamide.

[0682] In certain embodiments, the bioactive agents include imatinib mesylate (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), trastuzumab (Herceptin®), trastuzumab-DM1, pertuzumab (Perjeta®), lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), cetuximab (Erbitux®), panitumumab (Vectibix®), vandetanib (Caprelsa®), vemurafenib (Zelboraf®), and vorinostat (Zolin). Selected from, but not limited to, za(trademark), romidepsin (Istodax(trademark)), bexarotene (Tagretin(trademark)), alitretinoin (Panretin(trademark)), tretinoin (Vesanoid(trademark)), carfilzomib (Kyprolis(trademark)), pralatrexate (Folotyn(trademark)), bevacizumab (Avastin(trademark)), Ziv-aflibercept (Zaltrap(trademark)), sorafenib (Nexavar(trademark)), sunitinib (Sutent(trademark)), pazopanib (Votrient(trademark)), regorafenib (Stivarga(trademark)), and cabozantinib (Cometriq(trademark)).

[0683] In certain embodiments, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an additional therapeutic agent, or an immunosuppressant.

[0684] Suitable chemotherapeutic bioactive agents include, but are not limited to, radiomolecules, cytotoxins, or toxins also known as cytotoxic agents, as well as any active substance harmful to cell viability, and liposomes or other vesicles containing chemotherapeutic compounds. Common anticancer drugs include vincristine (Oncovin®) or liposomal vincristine (Marqibo®), daunorubicin (Daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), cytarabine (cytosine arabinoside, ara-C or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (Pegasparagase or Oncaspar®), and Examples include toposide (VP-16), teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), methotrexate, cyclophosphamide (Cytoxan®), prednisone, dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig®).

[0685] Examples of suitable additional chemotherapeutic agents include 1-dehydrotestosterone, 5-fluorouracil, dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altoretamine, amiphostine, anastrozole, anthramycin (AMC), antimitotic agents, cis-dichlorodiamine platinum(II) (DDP) (cisplatin), diaminodichloroplatin, anthracyclines, antibiotics, antimetabolites, asparaginase, and BCG bacteria (BCG). (live) (in bladder), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, leucovorin calcium, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogen, cyclophosphamide, cyclotosphamide, cytarabine, cytarabine, cytochalasin B, cytoxane, dacarbazine, dactinomycin, dactinomycin (formerly actinomycin), daunorubicin HCl, daunorubicin citrate, denileukin difutitox, dexrazoxane, dibromomannitol, dihydroxyanthracine dione dione), docetaxel, drasetron mesylate, doxorubicin HCl, dronabinol, Escherichia coli (E. coli)coli) L-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogen, estradiol, estramustine sodium phosphate, ethidium bromide, ethinylestradiol, etidronate, etoposide, citroborum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCl, glucocorticoid, goserelin acetate, gramicidin D, granisetron HCl, hydroxyurea, idarubicin HCl, ifosfamide, interferon α-2b, irinotecan HCl, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCl, lidocaine, lomustine, maytansinoid, Mechloretamine HCl, medroxyprogesterone acetate, megestrol acetate, melphalan HCl, mercaptopurine, mesna, methotrexate, methyltestosterone, mitramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCl, paclitaxel, disodium pamidronate, pentostatin, pilocarpine HCl, primycin, polyfeprozan 20 carmustine implant, porfimer sodium, procaine, procarbazine HCl, propranolol, rituximab, salglamostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testactone, tetracaine, thioepachlorambucil Examples include, but are not limited to, chlorambucil, thioguanine, thiotepa, topotecan HCl, toremifene citrate, trastuzumab, tretinoin, barrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0686] In some embodiments, the compounds of the present invention are administered in combination with chemotherapeutic agents (e.g., cytotoxic agents or other chemical compounds useful for the treatment of cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folate analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracendione-substituted ureas, methylhydrazine derivatives, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. 5-fluorouracil (5-FU), leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel are also included. Non-exclusive examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carbocon, meturedopa and uredopa; ethyleneimines and methylamelamines including altoretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; acetogenins (especially bratacin and bratacinone); camptothecin (including its synthetic analog topotecan); and briosta Chloristatin; calistatin; CC-1065 (including its synthetic analogues adzelesin, karzelesin, and bizelesin); cryptophycin (especially cryptophycin 1 and cryptophycin 8); drastatin; duocalmycin (including synthetic analogues KW-2189 and CB1-TM1); eryuterobin; pancratistatin; sarcodictiin; spongistatin; chlorambucil, chlornafadin, cyclophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobuenvicin, fenesterine, prednimastine, trophosphamide, uracil mustard, and other nitrogen mustards;Nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimustine; antibiotics such as engineeric antibiotics (e.g., calicheamicin, especially calicheamicin γII and calicheamicin ωII (see, e.g., Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994))); dinemicins including dinemicin A; bisphosphonates such as clodronate; esperamicin; and neocarcinostatin chromophores and related pigment proteins engineeric antibiotic chromophores), acrasinomycin, actinomycin, anthramycin, azaserin, bleomycin, kakutinomycin, carabicin, caminomycin, cardinophilin, ku Romomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN (trademark) (doxorubicin including morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinodoxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogaramycin, olibomycin, pepro Mycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, zolubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimethrexate; fludarabine, 6-me Purine analogs such as lucaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and phloxuridine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; and anti-adrenal agents such as aminoglutethimide, mitotane, and trilostane;Folic acid supplements such as frolinic acid; acegraton; aldofamide glycoside; aminolevulinic acid; enyluracil; amsacrin; bestrabusil; bisanthren; edatrexate; defofamine; demecolsin; diaziquan; elfomithine; eriptinium acetate; epotilon; etogluside; gallium nitrate; hydroxyurea; lentinan; ronidamin; maytansinoids such as maytansine and anthamitosine; mitogluzone; mitoxantrone; mopidamol; nitracrin; pentostatin; fenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK (trademark) polysaccharide complex (JHS Natural Products, Eugene, OR); Lazoxane; Rhizoxin; Sizofuran; Spirogermanium; Tenuazonic acid; Triadiquan; 2,2',2''-Trichlorotriethylamine; Trichothecene (especially T-2 toxin, verracurin A, loridine A and anguidin); Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Taxoids, e.g., TAXOL (trademark) (Paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE (trademark) (American Pharmaceutical), an albumin-modified nanoparticle formulation of paclitaxel that does not contain cremofol. Partners, Schaumberg, IL) and TAXOTERE (trademark) docetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR (trademark) gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum-coordinated complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE (trademark) vinorelbine; novantrone; teniposide; edatrexate; daunomycin;Examples include aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and any pharmaceutically acceptable salts, acids, or derivatives of the above. Two or more chemotherapeutic agents can be used in a cocktail administered in combination with the compounds of the present invention. Suitable combination chemotherapy regimens are known in the art. For example, combination regimens are described in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355(9209): 1041-1047 (2000).

[0687] Additional therapeutic agents that can be administered in combination with the compounds disclosed herein include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol i.e., 2ME2, finasunate, batalanib, vandetanib, aflibercept, boroximab, etalacizumab (MEDI-522), sirengitide, erlotinib, cetuximab, panitumumab, gefitinib, and trastuz. Mab, dovitinib, figtumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dasetuzumab, HLL1, huN901-DM1, atiprimode, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nel mesylate Finavir, indinavir sulfate, belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxife Examples include AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), abemaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

[0688] In certain embodiments, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to antibodies naturally produced by B cells, these MAbs can "coat" the surface of cancer cells and induce their destruction by the immune system. For example, bevacizumab is a protein secreted by tumor cells and other cells in the tumor microenvironment that targets vascular endothelial growth factor (VEGF), which promotes the development of tumor angiogenesis. When VEGF binds to bevacizumab, it is unable to interact with its cell receptor, thus interfering with the signaling that leads to the growth of new blood vessels. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets the human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the target receptor from sending normal growth-promoting signals. They may also induce apoptosis and activate the immune system to destroy tumor cells.

[0689] In one aspect of the present invention, the bioactive agent is an immunosuppressant. The immunosuppressant is a calcineurin inhibitor, such as cyclosporine or ascomycin, such as cyclosporine A (NEORAL®), FK506 (tacrolimus), or pimecrolimus; an mTOR inhibitor, such as rapamycin or its derivatives, such as sirolimus (RAPAMUNE®), everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9; apalog, such as ridafololimus; azathioprine; camphopurine 1H; an S1P receptor modulator, such as fingolimod or its analogues; an anti-IL-8 antibody; a mycophenolic acid or its salt, such as sodium salt or its prodrug, such as mycophenolate mofetil (CELLCEPT®), or OKT3 (ORTHOCLONE OKT3(trademark), prednisone, ATGAM(trademark), THYMOGLOBULIN(trademark), Brequinal sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxysperguarine, tresperimus, leflunomide (ARAVA(trademark)), CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab (SIMULECT(trademark)), daclizumab (ZENAPAX(trademark)), mizoribine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM This may include 981 (pimecrolimus, Elidel®), CTLA4Ig (abatacept), belatacept, LFA3Ig, etanercept (marketed as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), anti-LFA-1 antibody, natalizumab (Antegren®), enrimomab, gavilimomab, anti-thymocyte immunoglobulin, cyprizumab, alefacept, efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benolilate, fenbufen, naprosin, diclofenac, etodolac, and indomethacin, aspirin, and ibuprofen.

[0690] In some embodiments, the bioactive agent is a therapeutic agent, such as a biological preparation (e.g., cytokines used in cancer treatment, such as interferons or interleukins (e.g., IL-2)). In some embodiments, the biological preparation is an angiogenesis inhibitor, such as an anti-VEGF agent, such as bevacizumab (AVASTIN®). In some embodiments, the biological preparation is an immunoglobulin-based biological preparation, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof), that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important to cancer.Such active ingredients include RITUXAN (trademark) (rituximab), ZENAPAX (trademark) (daclizumab), SIMULECT (trademark) (basiliximab), SYNAGIS (trademark) (palivizumab), REMICADE (trademark) (infliximab), HERCEPTIN (trademark) (trastuzumab), MYLOTARG (trademark) (gemtuzumab ozogamicin), and CAMPATH (trademark) (alemtuzumab). Mab), ZEVALIN (trademark) (ibritumomab tiuxetan), HUMIRA (trademark) (adalimumab), XOLAIR (trademark) (omalizumab), BEXXAR (trademark) (tositumomab-l-131), RAPTIVA (trademark) (efalizumab), ERBITUX (trademark) (cetuximab), AVASTIN (trademark) (bevacizumab), TYSABRI (trademark) (natalizumab), ACTEMR (trademark) (Tocilizumab), VECTIBIX (trademark) (panitumumab), LUCENTIS (trademark) (ranivizumab), SOURIS (trademark) (eculizumab), CIMZIA (trademark) (certolizumab pegol), SIMPONI (trademark) (golimumab), ILARIS (trademark) (canakinumab), STELARA (trademark) (ustekinumab), ARZERRA (trademark) (ofatumumab), PROLIA (trademark) (deno Examples include sumab, NUMAX (trademark) (motavizumab), ABTHRAX (trademark) (laxibakumab), BENLYSTA (trademark) (belimumab), YERVOY (trademark) (ipilimumab), ADCETRIS (trademark) (brentuximab vedotin), PERJETA (trademark) (pertuzumab), KADCYLA (trademark) (adtrastuzumab emtansine), and GAZYVA (trademark) (obinutuzumab). Antibody-drug conjugates are also included.

[0691] Combination therapy may include non-pharmacological therapeutic agents. For example, the compound may be administered in addition to radiotherapy, cryotherapy, hyperthermia, and / or surgical excision of tumor tissue.

[0692] In certain embodiments, the first and second therapeutic agents are administered simultaneously or sequentially in either order. The first therapeutic agent may be administered immediately before or immediately after the second therapeutic agent, at a maximum interval of 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 16 hours, 17 hours, up to 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or up to 1 to 7 days, 1 to 14 days, 1 to 21 days, or 1 to 30 days before or after.

[0693] In certain embodiments, the second therapeutic agent is administered on a different dosing schedule than the compound of the present invention. For example, the second therapeutic agent may have a treatment break of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days per treatment cycle. In other embodiments, the first therapeutic agent has a treatment break. For example, the first therapeutic agent may have a treatment break of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days per treatment cycle. In certain embodiments, both the first and second therapeutic agents have treatment breaks.

[0694] V. Pharmaceutical Compositions The compounds of formula I described herein may be administered as pure (neat) chemicals, but more typically they are administered as pharmaceutical compositions containing an effective amount to patients, typically humans, who require such treatment for any of the disorders described herein. Accordingly, this disclosure provides pharmaceutical compositions comprising an effective amount of the compound or a pharmaceutically acceptable salt thereof for any of the uses described herein, together with at least one pharmaceutically acceptable carrier. The pharmaceutical compositions may contain only the compound or salt as an activator, or, in alternative embodiments, the compound and at least one additional activator.

[0695] In general, the compositions of this disclosure are administered in therapeutically effective doses by any of the acceptable methods of administration. The preferred dose range depends on a number of factors, including the severity of the disease being treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication for which the administration is intended, and the preferences and experience of the physicians involved. A person skilled in the art treating such diseases can determine the therapeutically effective dose of the compositions of the disclosure for a given disease by relying on their personal knowledge and the disclosures of this application, without conducting excessive experiments.

[0696] In a particular embodiment, the pharmaceutical composition is a dosage form containing approximately 0.005 mg to approximately 2000 mg, approximately 1 mg to approximately 1000 mg, approximately 10 mg to approximately 800 mg, or approximately 20 mg to approximately 600 mg of an active compound, and optionally approximately 0.1 mg to approximately 2000 mg, approximately 10 mg to approximately 1000 mg, approximately 100 mg to approximately 800 mg, or approximately 200 mg to approximately 600 mg of an additional activator. Examples include dosage forms containing at least approximately 0.005 mg, 0.01 mg, 0.025 mg, 0.05 mg, 0.1 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 750 mg of the active compound or its salt, and up to approximately 1 g of the active compound or its salt.

[0697] In a particular embodiment, the pharmaceutical composition is a dosage form containing about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an active compound in a unit dosage form, and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an additional activator. An example is a dosage form containing at least 0.1 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 750 mg of an active compound or a salt thereof.

[0698] In some embodiments, the compounds disclosed herein or used as described herein are administered once daily (QD), twice daily (BID), or three times daily (TID). In some embodiments, the compounds disclosed herein or used as described herein are administered at least once a day for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days or more.

[0699] In certain embodiments, the compound of the present invention is administered once, twice, three times, or four times a day.

[0700] In certain embodiments, the compound of the present invention is administered orally once a day. In certain embodiments, the compound of the present invention is administered orally twice a day. In certain embodiments, the compound of the present invention is administered orally three times a day. In certain embodiments, the compound of the present invention is administered orally four times a day.

[0701] In certain embodiments, the compound of the present invention is administered intravenously once daily. In certain embodiments, the compound of the present invention is administered intravenously twice daily. In certain embodiments, the compound of the present invention is administered intravenously three times daily. In certain embodiments, the compound of the present invention is administered intravenously four times daily.

[0702] In some embodiments, the compounds of the present invention are administered with treatment rest days in between treatment cycles. For example, the compounds may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 treatment rest days in each treatment cycle.

[0703] In some embodiments, treatment is initiated by administering a loading dose. For example, treatment can be initiated by administering the compound at a dosage that is at least about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 9 times, 9.5 times, or 10 times higher than the maintenance dose in a treatment cycle. Additional exemplary loading doses include a maintenance dose for the remaining treatment days in a treatment cycle, following a dose at least about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 5 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 9 times, 9.5 times, or 10 times higher in the first 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days of treatment.

[0704] A pharmaceutical composition may contain an active compound and an additional activator in a certain molar ratio. For example, a pharmaceutical composition may contain an anti-inflammatory agent or immunosuppressant in a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4:1.

[0705] These compositions may contain any amount of the active compound to achieve the desired result, for example, 0.1% to 99% (wt%) of the compound, usually at least about 5 wt%. Some embodiments contain about 25 wt% to about 50 wt% or about 5 wt% to about 75 wt% of the compound.

[0706] A pharmaceutically or therapeutically effective amount of the composition is delivered to the patient. The exact effective dose varies from patient to patient and depends on species, age, physique and health of the subject, the nature and severity of the condition being treated, the recommendations of the treating physician, and the therapeutic agent or combination of therapeutic agents selected for administration. The effective dose for a given situation can be determined by routine experiments.

[0707] In certain embodiments, the therapeutic dose may be, for example, in the range of about 0.0001 mg / kg (body weight) to about 25 mg / kg (body weight). The subject may be administered a dose required to reduce and / or alleviate the signs, symptoms, or causes of the disorder in question, or to bring about any other desired changes in the biological system. If desired, the formulation may be prepared using an enteric coating adapted for sustained-release or controlled-release administration of the active ingredient.

[0708] In a particular embodiment, the dose is in the range of about 0.001 mg / kg to 10 mg / kg (patient body weight), for example, about 0.0001 mg / kg, about 0.0005 mg / kg, about 0.001 mg / kg, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.15 mg / kg, about 0.2 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.35 mg / kg, about 0.4 mg / kg, about 0.45 mg / kg The amounts are approximately 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, 4.5 mg / kg, 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.0 mg / kg, 7.5 mg / kg, 8.0 mg / kg, 8.5 mg / kg, 9.0 mg / kg, 9.5 mg / kg, or 10 mg / kg.

[0709] In certain embodiments, the therapeutic dose may be, for example, in the range of about 0.01 mg / kg to about 250 mg / kg (body weight) in at least one dose, more typically in the range of about 0.1 mg / kg to about 10 mg / kg. The subject may be given as many doses as necessary to reduce and / or alleviate the signs, symptoms or causes of the disorder in question, or to bring about any other desired changes in the biological system. If necessary, formulations with enteric coatings suitable for sustained-release or controlled-release administration of the active ingredient may be prepared.

[0710] In certain embodiments, the dose is in the range of about 0.01 mg / kg to 100 mg / kg (patient body weight), for example, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about The dosages are approximately 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, or 100 mg / kg.

[0711] Pharmaceutical preparations are preferably in unit dosage forms. In such dosage forms, the preparation is subdivided into unit doses containing an appropriate amount of the active ingredient. A unit dosage form may be a packaged preparation in which individual amounts of the preparation, such as packaged tablets, capsules, and powder in vials or ampoules, are included in the packaging. Alternatively, a unit dosage form may be the capsule, tablet, cachet, or lozenge itself, or an appropriate number of any of these in packaged form.

[0712] In certain embodiments, the compound is administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include acetate, adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, and 2-hydroxyethanesulfonate. Examples include sodium sulfate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate. Representative alkali metal salts or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, and magnesium, as well as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Other examples include non-toxic ammonium, quaternary ammonium, and amine cations.

[0713] Therefore, the compositions of this disclosure may be administered as pharmaceutical formulations suitable for oral (including oral and sublingual), rectal, nasal, topical, percutaneous, pulmonary, vaginal, or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous, and intravenous) administration, injection, inhalation, or spray, or by other means of administration including conventional pharmaceutically acceptable carriers. Typical administration methods include oral, topical, or intravenous administration using a simple daily dosing schedule that can be adjusted according to the degree of discomfort.

[0714] Depending on the intended method of administration, the pharmaceutical composition may be in solid, semi-solid, or liquid dosage forms, such as tablets, suppositories, pills, capsules, powders, liquids, syrups, suspensions, creams, ointments, lotions, pastes, gels, sprays, aerosols, foams, or oils, injections or infusions, transdermal patches, subcutaneous patches, inhalation formulations, medical devices, suppositories, oral or sublingual formulations, parenteral formulations, or eye drops, preferably in unit dosage forms suitable for a single dose of a precise amount.

[0715] Several dosage forms, such as tablets and capsules, are subdivided into unit doses of appropriate size containing an appropriate amount of the active ingredient, for example, an amount effective in achieving the desired purpose. The composition contains an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and may further contain other pharmaceuticals, adjuvants, diluents, buffers, etc.

[0716] The carrier, containing additives and diluents, must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to the patient being treated. The carrier may be inert or may have pharmaceutically active properties of its own. The amount of carrier used in combination with the compound is sufficient to provide a useful amount of the substance for administration per unit dose of the compound.

[0717] Examples of carrier classes include, but are not limited to, adjuvants, binders, buffers, colorants, diluents, disintegrants, additives, emulsifiers, flavorings, gels, flow enhancers, lubricants, preservatives, stabilizers, surfactants, solubilizers, tableting agents, wetting agents, or solidifying agents.

[0718] Several carriers may belong to two or more classes; for example, vegetable oil can be used as a lubricant in some formulations and as a diluent in others.

[0719] Examples of pharmaceutically acceptable carriers include sugars, starches, cellulose, tragacanth powder, malt, gelatin, talc, petrolatum, lanolin, polyethylene glycol, alcohols, transdermal enhancers, and vegetable oils. Any activator that does not substantially interfere with the activity of the compounds of the present invention may be included in the pharmaceutical composition.

[0720] Some additives include, but are not limited to, liquids such as water, saline solution, glycerol, polyethylene glycol, hyaluronic acid, and ethanol. Compounds can be provided in the form of solids, liquids, spray-dried materials, microparticles, nanoparticles, controlled-release systems, etc., depending on the therapeutic purpose. Additives suitable for non-liquid formulations are also known to those skilled in the art. A thorough discussion of pharmaceutically acceptable additives and salts can be found in Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).

[0721] Furthermore, auxiliary substances such as wetting agents or emulsifiers, physiological buffers, and surfactants may be present in the vehicle. The physiological buffer can be any solution that is pharmacologically acceptable and gives the formulation a desired pH, i.e., a physiologically acceptable pH range. Examples of buffer solutions include physiological saline, phosphate-buffered physiological saline, Tris-buffered saline, and Hanks-buffered saline.

[0722] Examples of conventional non-toxic solid carriers for solid compositions include pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate. Liquid pharmaceutically administerable compositions can be prepared, for example, by dissolving and dispersing the active compounds described herein and any pharmaceutical adjuvants in additives such as water, physiological saline, aqueous dextrose, glycerol, ethanol, etc., thereby forming a solution or suspension. If necessary, the administered pharmaceutical composition may contain small amounts of non-toxic auxiliary substances such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitan monolaurate, sodium triethanolamine acetate, and triethanolamine oleate. Practical methods for preparing such dosage forms are known or obvious to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences mentioned above.

[0723] In yet another embodiment, the use of penetration-enhancing additives is provided, which include polymers such as polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, amination gelatin), polyanions (N-carboxymethyl chitosan, polyacrylic acid), and thiolated polymers (carboxymethylcellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugate).

[0724] In certain embodiments, the additive is selected from butylated hydroxytoluene (BHT), calcium carbonate, dibasic calcium phosphate, calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0725] Pharmaceutical compositions / combinations can be formulated for oral administration. For oral administration, compositions generally take the form of tablets, capsules, softgel capsules, or aqueous or non-aqueous solutions, suspensions, or syrups. Tablets and capsules are typical forms of oral administration. Tablets and capsules for oral administration may contain one or more commonly used carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. Typically, the compositions of this disclosure can be combined with non-toxic, pharmaceutically acceptable, inert carriers for oral administration, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, and sorbitol. Furthermore, suitable binders, lubricants, disintegrants, and colorants may be incorporated into the mixture as desired or as needed. Suitable binders include natural sugars such as starch, gelatin, glucose, or β-lactose, natural and synthetic rubbers such as corn syrup, gum arabic, and tragacanth gum, or sodium alginate, carboxymethylcellulose, polyethylene glycol, and wax. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Disintegrants, though not limited to these, include starch, methylcellulose, agar, bentonite, and xanthan gum.

[0726] When using a liquid suspension, the activator can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, or water, as well as emulsifiers and suspending agents. Flavorings, colorants, and / or sweeteners may be added as needed. Other optional components to be incorporated into the oral formulations herein include, but are not limited to, preservatives, suspending agents, and thickeners.

[0727] For intraocular delivery, the compound can be administered as desired, for example, intravitreous, intramammary, anterior chamber, sub-Tenon's capsule, subretinal, retrobulbar, peribulbar, superchoroidal, conjunctiva, subconjunctival, superscleral, periocular, transscleral, retrobulbar, near the posterior sclera, pericorneal, or lacrimal duct injection, or via mucus, mucin, or the mucosal barrier in an immediate or controlled release manner, or by an intraocular device.

[0728] Parenteral formulations can be prepared as liquid solutions or suspensions, in solid forms suitable for solubilization or suspension in liquids before injection, or in conventional forms as emulsions. Typically, sterile injection suspensions are formulated according to methods known in the art using suitable carriers, dispersants or wetting agents and suspending agents. Sterile injection formulations can also be sterile injection solutions or suspensions in parenterally acceptable diluents or solvents that are non-toxic to an acceptable degree. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils, fatty acid esters, or polyols have conventionally been used as solvents or suspension media. Furthermore, parenteral administration may involve the use of sustained-release or continuous-release systems to maintain a certain level of dose.

[0729] Parenteral administration includes intra-articular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injection solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the recipient to whom the formulation is intended, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. Administration via certain parenteral routes may include introducing the formulation of the Disclosure into the patient's body through a needle or catheter propelled by a sterile syringe or any other mechanical device such as a continuous infusion system. The formulations provided by the Disclosure may be administered using syringes, injectors, pumps, or any other device permitted for parenteral administration in the art.

[0730] The formulations of this disclosure for parenteral administration include aqueous or non-aqueous sterile solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such formulations may contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. These can be sterilized, for example, by filtration through a bacteria-retaining filter, incorporation of a sterilizing agent into the composition, irradiation of the composition, or heating of the composition. They can also be prepared immediately before use using sterile water or any other sterile injectable medium.

[0731] Sterile injectable solutions are prepared by incorporating one or more of the compounds of this disclosure in the required amounts into a suitable solvent containing, as necessary, various other components listed above, followed by filtration sterilization. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other required components from those listed above. For sterile powders for the preparation of sterile injectable solutions, typical preparation methods are vacuum drying and freeze-drying, which yield powders of the active ingredient and any additional desired components from a pre-sterilized filtered solution. For example, a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of the active ingredient with 10% by volume of propylene glycol and water. The solution is isotonicized with sodium chloride and sterilized.

[0732] Alternatively, the pharmaceutical compositions of this disclosure may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the active ingredient with a suitable non-irritating additive that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Examples of such materials include cocoa butter, beeswax, and polyethylene glycol.

[0733] The pharmaceutical compositions of this disclosure may also be administered by nasal aerosol or inhalation. Such compositions may be prepared according to methods known in the art of pharmaceutical formulations and may be prepared as a solution in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, propellants such as fluorocarbons or nitrogen, and / or other conventional solubilizers or dispersants.

[0734] Formulations for oral administration include tablets, lozenges, gels, etc. Alternatively, oral administration can be achieved using transmucosal delivery systems known to those skilled in the art. The compounds of this disclosure can also be delivered through the skin or mucosal tissue using conventional transdermal drug delivery systems, i.e., transdermal "patches" containing the active ingredient within a laminated structure that typically acts as a drug delivery device attached to the body surface. In such structures, the drug composition is typically contained in a layer beneath the upper backing layer, i.e., a "reservoir." The laminated device may contain a single reservoir or multiple reservoirs. In certain embodiments, the reservoir includes a polymer matrix of a pharmaceutically acceptable contact adhesive material that serves to adhere the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylene, polysiloxane, polyisobutylene, polyacrylate, and polyurethane.

[0735] Alternatively, the drug-containing reservoir and the skin-contact adhesive may exist as separate layers, in which case the adhesive lies beneath the reservoir, which may be a polymer matrix as described above, or a liquid or gel reservoir, or in some other form. The backing layer in these laminates, which forms the top surface of the device, functions as the main structural element of the laminate structure and gives much of the device its flexibility. The material selected for the backing layer needs to be substantially impermeable to the activator and any other materials present.

[0736] The compositions of this disclosure can be formulated for aerosol administration, including intranasal administration, particularly to the airways. The compounds may generally have small particle sizes, for example, about 5 microns or less. Such particle sizes can be obtained by means known in the art, such as micronization. The active ingredient is provided in a pressurized pack with a suitable propellant, such as a chlorofluorocarbon (CFC), for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may also conveniently contain a surfactant such as lecithin. The drug dose can be controlled by a metering valve.

[0737] Alternatively, the active ingredient can be provided in the form of a dry powder, a mixed powder of compounds in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose and polyvinylpyrrolidine (PVP), etc. The powder carrier forms a gel in the nasal cavity. For example, the powder composition can be provided in a unit dose form, such as in gelatin capsules or cartridges, or in a blister pack, from which the powder can be administered by inhaler.

[0738] Formulations suitable for rectal administration are typically provided as unit-dose suppositories. These can be prepared by mixing the active compound with one or more conventional solid carriers, such as cocoa butter, and then molding the resulting mixture.

[0739] In certain embodiments, the pharmaceutical composition is suitable for topical application to the skin using the administration method defined above.

[0740] In certain embodiments, the pharmaceutical composition may be suitable for transdermal administration and may be delivered as individual patches adapted to remain in close contact with the recipient's epidermis for extended periods. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)), typically in the form of optionally buffered aqueous solutions of the active compound.

[0741] In certain embodiments, a microneedle patch or device is provided for the delivery of drugs to or into biological tissue, particularly the skin. The microneedle patch or device enables drug delivery at clinically relevant rates to or into the barriers of the skin or other tissues with little or no damage, pain, or irritation to the tissue.

[0742] Formulations suitable for pulmonary administration can be delivered by a wide range of passive and active single / multiple dose dry powder inhalers (DPIs). The most commonly used devices for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of a suitable lung delivery device depends on parameters such as the properties of the drug and its formulation, the site of action, and the pathophysiology of the lung.

[0743] VI. General synthesis The compounds described herein can be prepared by methods known to those skilled in the art. In a non-limiting example, the compounds disclosed may be prepared using the following scheme.

[0744] For convenience, the compounds of the present invention having stereocenters may be depicted without stereochemistry. It will be recognized by those skilled in the art that pure or concentrated enantiomers and diastereomers can be prepared by methods known in the art. Examples of methods for obtaining optically active materials include, at least, the following:

[0745] i) Physical separation of crystals - a technique for manually separating the visible crystals of individual enantiomers. This technique can be used when separate enantiomer crystals exist, i.e., the material is a conglomerate and the crystals are visually identifiable.

[0746] ii) Simultaneous crystallization - This is a technique for separately crystallizing individual enantiomers from a racemic solution, and is only possible if the enantiomers are conglomerates in the solid state.

[0747] iii) Enzymatic resolution - A technique for partially or completely separating a racemic mixture by the difference in reaction rates between enantiomers and enzymes.

[0748] iv) Enzyme-asymmetric synthesis - A synthetic technique that uses an enzymatic reaction in at least one step of synthesis to obtain a synthetic precursor of a desired enantiomer, either pure as an enantiomer or concentrated as an enantiomer.

[0749] v) Chemical asymmetric synthesis - synthetic techniques for synthesizing a desired enantiomer from an achiral precursor under conditions that result in asymmetricity (i.e., chirality) in the product, which can be achieved by a chiral catalyst or chiral auxiliary agent.

[0750] vi) Diastereomer Separation - A technique for reacting a racemic compound with a pure reagent (chiral auxiliary) as an enantiomer, converting the individual enantiomers into diastereomers. Subsequently, the resulting diastereomers are separated by chromatography or crystallization based on clearer structural differences, and the chiral auxiliary is removed to obtain the desired enantiomer.

[0751] vii) Primary and secondary asymmetric transformations - Techniques to rapidly equilibrate diastereomers derived from racemates, thereby creating preponderance for the dissolution of diastereomers derived from the desired enantiomer, or to disrupt equilibrium through preferential crystallization of diastereomers derived from the desired enantiomer, ultimately converting all materials from the desired enantiomer to crystalline diastereomers in principle. Subsequently, the desired enantiomer is released from the diastereomer.

[0752] viii) Kinetic resolution - This technique refers to the achievement of partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by the uneven reaction rates of enantiomers with chiral, non-racemic reagents or catalysts under kinetic conditions.

[0753] ix) Enantiospecific synthesis from non-racemic precursors - synthetic techniques for obtaining desired enantiomers from non-chiral starting materials in which stereochemical integrity is not or is only slightly impaired during synthesis.

[0754] x) Chiral liquid chromatography—a technique for separating racemic enantiomers in a liquid mobile phase by different interactions with the stationary phase (including by chiral HPLC). The stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral materials to induce different interactions.

[0755] xi) Chiral gas chromatography - A technique for separating enantiomers in a gas mobile phase by different interactions between a racemic mixture and a column equipped with a fixed non-racemic chiral adsorbent phase.

[0756] xii) Extraction with chiral solvents - A technique in which enantiomers are separated by selective dissolution of one enantiomer in a specific chiral solvent.

[0757] xiii) Transport across chiral membranes - a technique for placing racemates in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing a racemate, and a driving force such as a difference in concentration or pressure results in preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral properties of the membrane, which allow only one enantiomer of the racemate to pass through.

[0758] xiv) Pseudo-mobile bed chromatography is used in a particular embodiment. A variety of chiral stationary phases are commercially available.

[0759] General Synthesis Scheme 1 [ka]

[0760] In some embodiments, compounds of formula I can be synthesized according to the route shown in general synthesis scheme 1. In step 1, intermediates 1 and 2 are reacted at high temperature in an organic solvent (e.g., dimethyl sulfoxide, acetonitrile, or dioxane) in the presence of a copper catalyst (e.g., copper(I) iodide, copper(I) chloride, or alternatively another suitable copper catalyst used under Ullmann coupling conditions), a ligand (e.g., bipyridine, 1,10-phenanthroline, dimethylethylenediamine, or alternatively another suitable ligand used under Ullmann coupling conditions), and a base (e.g., cesium carbonate, potassium carbonate, tribasic potassium phosphate, or alternatively another suitable base used under Ullmann coupling conditions) to obtain 3. In step 2, 3 and triphosgene are reacted in dichloromethane in the presence of aluminum trichloride to obtain 4. In step 3, intermediate 4 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., tetrahydrofuran or dichloromethane), followed by the addition of 5 to obtain 6.

[0761] General Synthesis Scheme 2 [ka]

[0762] In some embodiments, compounds of formula I can be synthesized according to the route shown in general synthesis scheme 2. In step 1, intermediates 1 and 2 are reacted at high temperature in an organic solvent (e.g., toluene, THF, dioxane, or DMF) in the presence of a palladium catalyst (e.g., palladium(II) acetate, Pd2(dba)3, or alternatively another suitable palladium catalyst used under Buchwald-Hartwig coupling conditions), a phosphine ligand (e.g., BINAP, xanthophos, or alternatively another suitable phosphine ligand used under Buchwald-Hartwig coupling conditions), and a base (e.g., potassium tert-butoxide, cesium carbonate, or alternatively another suitable base used under Buchwald-Hartwig coupling conditions) to obtain 3.

[0763] General Synthesis Scheme 3 [ka]

[0764] In some embodiments, compounds of formula I can be synthesized according to the route shown in general synthesis scheme 3. In step 1, intermediates 1 and 2 are reacted at high temperature in an organic solvent (e.g., toluene, DMA, or dioxane) in the presence of a palladium catalyst (e.g., PdCl2(dppf), PdCl2(PPh3), or another suitable palladium catalyst used alternatively under Miyaura coupling conditions), a ligand (e.g., XPhos, PPh3, or another suitable ligand used alternatively under Miyaura coupling conditions), and a base (e.g., potassium acetate, potassium ethoxide, potassium carbonate, or another suitable base used alternatively under Miyaura coupling conditions) to obtain 3. In step 2, intermediate 3 is reacted with EtOH at high temperature to obtain 4. In step 3, compounds 4 and 5 are reacted in an organic solvent (e.g., methanol, acetonitrile, or dichloromethane) under ambient air in the presence of a copper catalyst (e.g., copper(II) bromide, copper(II) acetate, or another suitable copper catalyst used under Chan-Lam coupling conditions) and a base (e.g., pyridine, 4-dimethylaminopyridine, potassium tert-butoxide, or another suitable base used under Chan-Lam coupling conditions) to obtain compound 6.

[0765] General Synthesis Scheme 4 [ka]

[0766] In some embodiments, compounds of formula I can be synthesized according to the route shown in general synthesis scheme 4. In step 1, intermediates 1 and 2 are reacted at high temperature in an organic solvent (e.g., dimethoxyethane, THF, or toluene) in the presence of a palladium catalyst (e.g., Pd(OAc)2, Pd(PPh3)4, or alternatively another suitable palladium catalyst), a ligand (e.g., P(p-MeOPh)3, PPh3, PCy3, or alternatively another suitable ligand), water, and pivalic anhydride to obtain 3.

[0767] General Synthesis Scheme 5 [ka]

[0768] In some embodiments, compounds of formula I can be synthesized according to the route shown in general synthesis scheme 5. In step 1, intermediate 1 is reacted with a suitable carbonyl reducing agent (e.g., sodium borohydride) in an organic solvent (e.g., ethanol or methanol) to obtain 2.

[0769] General Synthesis Scheme 6 [ka]

[0770] In some embodiments, compounds of formula I can be synthesized according to the route shown in general synthesis scheme 6. In step 1, intermediates 1 and 2 are reacted in an organic solvent (e.g., dichloromethane or toluene) in the presence of a suitable drying agent (e.g., molecular sieve or MgSO4) to obtain 3. In step 2, the imine of 3 is reduced to an amino group with a suitable reducing agent.

[0771] General Synthesis Scheme 7 [ka]

[0772] In some embodiments, compounds of formula I can be synthesized according to the route shown in general synthesis scheme 7. In step 1, intermediates 1 and 2 are reacted at high temperature in an aqueous organic solvent (e.g., 10:1 toluene:water, 5:1 THF:water, or 1:1 ethanol:water) in the presence of a palladium catalyst (e.g., Pd(OAc)2, Pd2dba3, or another suitable palladium catalyst used alternatively under Suzuki coupling conditions), a ligand (e.g., XPhos, PCy3, or another suitable ligand used alternatively under Suzuki coupling conditions), and a base (e.g., sodium carbonate, tribasic potassium phosphate, potassium carbonate, or another suitable base used alternatively under Suzuki coupling conditions) to obtain 3.

[0773] General synthesis scheme 8 [ka]

[0774] In some embodiments, the compounds of formula 1 can be synthesized according to the route shown in general synthesis scheme 8. In step 1, intermediate 1 and intermediate 2 are reacted at high temperature in an organic solvent (e.g., DMF) in the presence of a palladium pre-catalyst (e.g., Pd(OAc) 2, Pd 2 dba 3, or alternatively another suitable palladium catalyst used in palladium-catalyzed carbonylation), a base (e.g., triethylamine, diisopropylethylamine, or alternatively another base used in palladium-catalyzed carbonylation), CO gas, and a ligand (e.g., xanthophos, PCy 3, or alternatively another suitable ligand used in palladium-catalyzed carbonylation reactions) to obtain 3. [Section 1] formula: JPEG0007863100000157.jpg32170 (In the formula, R 1 teeth, JPEG0007863100000158.jpg17170 And, Q 1 is CH or N, X can be a bond, alkyl, aliphatic, heterocyclic (which can be bonded via C and / or N within the ring), aryl, heteroaryl, bicyclic, or -NR. 27 -, -NR 10 -, -CR 40 R 41 -, -O-, -C(O)-, -C(NR 27 )-, -C(S)-, -S(O)-, -S(O) 2 - and -S- are selected, and each is non-hydrogen R to the extent that the valency allows to form a stable compound. 40 Optionally substituted with one, two, three, or four substituents independently selected from, R 15 、R 16 , and R 17 These are, independently, bonded, alkyl, -C(O)-, -C(O)O-, -OC(O)-, and -SO 2 -, -S(O)-, -C(S)-, -C(O)NR 27 -, -NR 27 C(O)-, -O-, -S-, -NR 27 -, -NR 10 -, -C(R 40 R 41 )-, bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, cycloalkyl, heteroaliphatic, and heteroaryl compounds are selected from the group, and each is present in a range of valencies that allows it to form a stable compound, R 40 Optionally substituted with one, two, three, or four substituents independently selected from R 15 、R 16 , and R 17 Two or fewer of these are selected as the combination, R 18 These are hydrogen, halogen, cyano, -C(O)OR 27 , -C(O)OR 27 , alkyl, -C(O)NR 10 R 27 , -NR 27 C(O)R 27 , -NR 10 R 27 , -OR 27 , -SR 27 R is selected from alkenes, alkynes, haloalkyls, alkoxys, aryls, heterocyclics, aliphatic, heteroaliphatic, and heteroaryls, each within the range of valency allowed to form a stable compound. 40 Optionally substituted with one, two, three, or four substituents independently selected from X, R 15 、R16 、R 17 and R 18 However, stable R under ambient operating conditions and desired storage life 1 Selected in combination as known to those skilled in the art, to provide parts R 27 Each of these is independently selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, cycloalkyl, aliphatic, and heteroaliphatic. R 40 These are, independently, hydrogen, aliphatic, heteroaliphatic, cyano, nitro, alkyl, halogen, haloalkyl, and -OR. 10 , -SR 10 ,-S(O)R 12 , -SO 2 R 12 , and -NR 10 R 11 Selected from, R 41 These are aliphatic, aryl, heteroaryl, or hydrogen. A is JPEG0007863100000159.jpg94170 Selected from, n is 0, 1, or 2. X 3 , NR 10 , NR 6’ , O, or S, Q is CR 7 or N, R 3 is hydrogen, alkyl, halogen, or haloalkyl, or R 3 and R 6 They bond to form a one-carbon linkage or a two-carbon linkage, or R 3 and R 4 They bond to form a 1-carbon linkage, a 2-carbon linkage, a 3-carbon linkage, or a 4-carbon linkage, or R 3 and R 3 R adjacent to 4 The groups bond together to form a double bond. R 4 and R 5 These are hydrogen, alkyl, halogen, haloalkyl, -OR 10 , -SR 10 ,-S(O)R 12 , -SO 2 R 12 , and -NR 10 R 11 Selected independently from, R 6 and R 7 These are hydrogen, alkyl, halogen, haloalkyl, -OR 10 , -SR 10 ,-S(O)R 12 , -SO 2 R 12 , and -NR 10 R 11 Selected independently from, R 6 ' is hydrogen, alkyl, or haloalkyl, or R 3 and R 6 ' combines to form a 1-carbon linkage or a 2-carbon linkage, Each R 10 and R 11 These are independently hydrogen, aliphatic, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, and -C(O)R 12 ,-S(O)R 12 , and -SO 2 R 12 Selected from, Each R 12 These are independently hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, and -NR. 13 R 14 , and OR 13 Selected from, R 13 and R 14 A compound of (each independently selected from hydrogen, alkyl, and haloalkyl) or a pharmaceutically acceptable salt thereof. [Section 2] formula: JPEG0007863100000160.jpg28170 The compounds listed in item 1, or pharmaceutically acceptable salts thereof. [Section 3] formula: JPEG0007863100000161.jpg29170 The compounds listed in item 1, or pharmaceutically acceptable salts thereof. [Section 4] A is JPEG0007863100000162.jpg29170 The compound described in any one of items 1 to 3. [Section 5] A is JPEG0007863100000163.jpg28170 The compound described in any one of items 1 to 3. [Section 6] A is JPEG0007863100000164.jpg24170 The compound described in any one of items 1 to 3. [Section 7] A is JPEG0007863100000165.jpg28170 The compound described in any one of items 1 to 3. [Section 8] A is JPEG0007863100000166.jpg29170 The compound described in any one of items 1 to 3. [Section 9] A is JPEG0007863100000167.jpg29170 The compound described in any one of items 1 to 3. [Section 10] n is 1, and the compound is one of the compounds listed in any one of items 1 to 9. [Section 11] R 4 The compound described in item 10, wherein hydrogen is present. [Section 12] R 4 The compound described in item 10, wherein the compound is alkyl. [Section 13] R 4 The compound is a halogen, as described in item 10. [Section 14] R 3 and R 4 The compounds according to any one of claims 1 to 4 or 6 to 10, wherein the atoms bond to form a 1-carbon linkage, a 2-carbon linkage, a 3-carbon linkage, or a 4-carbon linkage. [Section 15] The compound described in any one of items 1 to 9, where n is 0. [Section 16] The compound described in any one of items 1 to 9, where n is 2. [Section 17] A is JPEG0007863100000168.jpg28170 The compound described in any one of items 1 to 3. [Section 18] A is JPEG0007863100000169.jpg28170 The compound described in any one of items 1 to 3. [Section 19] A is JPEG0007863100000170.jpg28170 The compound described in any one of items 1 to 3. [Section 20] R 3 A compound described in any one of items 17 to 19, wherein the compound is hydrogen. [Section 21] R 3 A compound described in any one of items 17 to 19, wherein the compound is alkyl. [Section 22] R 3 A compound described in any one of items 17 to 19, wherein is a haloalkyl compound. [Section 23] R 3 The compound is methyl, as described in any one of items 17 to 19. [Section 24] A is JPEG0007863100000171.jpg28170 The compound described in any one of items 1 to 3. [Section 25] Q is N, the compound as described in item 18 or 24. [Section 26] Q is CH, a compound as described in item 18 or 24. [Section 27] A is JPEG0007863100000172.jpg30170 The compound described in any one of items 1 to 3. [Section 28] A is JPEG0007863100000173.jpg28170 The compound described in any one of items 1 to 3. [Section 29] A is JPEG0007863100000174.jpg28170 The compound described in any one of items 1 to 3. [Section 30] R 6 The compound described in item 28 or 29, wherein the compound is hydrogen. [Section 31] R 6 The compound described in item 28 or 29, wherein the compound is alkyl. [Section 32] R 6 The compound described in item 28 or 29, wherein is a haloalkyl. [Section 33] R 6 A compound described in item 28 or 29...

Claims

1. formula: 【Chemistry 1】 (In the formula, R １ teeth, 【Chemistry 2】 And, Q １ is CH or N, X is selected from bonding, alkyl, aliphatic, heterocyclic, aryl, heteroaryl, bicyclic, -NR ２７ -, -NR １０ -, -CR ４０ R ４１ -, -O-, -C(O)-, -C(NR ２７ ), -C(S)-, -S(O)-, -S(O) ２ - and -S-, each of which is optionally substituted with one or two substituents independently selected from non-hydrogen R ４０ within the range permitted by the valence number R １５ , R １６ , and R １７ These are, independently, bonded, alkyl, -C(O)-, -C(O)O-, -OC(O)-, and -SO ２ -, -S(O)-, -C(S)-, -C(O)NR ２７ -, -NR ２７ C(O)-, -O-, -S-, -NR ２７ -, -NR １０ -, -C(R ４０ R ４１ )- Selected from the group consisting of bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, cycloalkyl, heteroaliphatic, and heteroaryl, each within the range permitted by the valency, R ４０ Optionally substituted with one or two substituents independently selected from R １５ , R １６ , and R １７ Two or fewer of these are selected as the combination, R １８ is hydrogen, halogen, cyano, -C(O)OR ２７ , -C(O)OR ２７ , alkyl, -C(O)NR １０ R ２７ , -NR ２７ C(O)R ２７ , -NR １０ R ２７ , -OR ２７ , -SR ２７ Selected from alkenes, alkynes, haloalkyls, alkoxys, aryls, heterocyclics, aliphatic, heteroaliphatic, and heteroaryls, each is R within the range permitted by its valency. ４０ Optionally substituted with one or two substituents independently selected from, R ２７ Each of these is independently selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, cycloalkyl, aliphatic, and heteroaliphatic. R ４０ These are, independently, hydrogen, aliphatic, heteroaliphatic, cyano, nitro, alkyl, halogen, haloalkyl, and -OR １０ , -SR １０ , -S(O)R １２ , -SO ２ R １２ , and -NR １０ R １１ Selected from, R ４１ These are aliphatic, aryl, heteroaryl, or hydrogen. A is, 【Transformation 3】 Selected from, n is 1, X ３ NR １０ , NR ６’ , O, or S, R ３ is hydrogen, alkyl, halogen, or haloalkyl, or R ３ and R ６ They bond together to form a one-carbon linkage or a two-carbon linkage, or R ３ and R ４ They bond together to form a 1-carbon linkage, a 2-carbon linkage, a 3-carbon linkage, or a 4-carbon linkage, or R ３ and R ３ R adjacent to ４ The groups bond together to form a double bond. R ４ and R ５ is hydrogen, alkyl, halogen, haloalkyl, -OR １０ , -SR １０ , -S(O)R １２ , -SO ２ R １２ , and -NR １０ R １１ Selected independently from, R ６ and R ７ is hydrogen, alkyl, halogen, haloalkyl, -OR １０ , -SR １０ , -S(O)R １２ , -SO ２ R １２ , and -NR １０ R １１ Selected independently from, R ６ ' is hydrogen, alkyl, or haloalkyl, or R ３ and R ６ ' combines to form a one-carbon linkage or a two-carbon linkage, Each R １０ and R １１ These are independently hydrogen, aliphatic, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, and -C(O)R. １２ , -S(O)R １２ , and -SO ２ R １２ Selected from, Each R １２ These are independently hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, and -NR １３ R １４ , and OR １３ Selected from, and, R １３ and R １４ A compound of (each independently selected from hydrogen, alkyl, and haloalkyl) or a pharmaceutically acceptable salt thereof.

2. formula: 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. formula: 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. A is, 【Transformation 6】 The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. A is, 【Transformation 7】 The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

6. A is, 【Transformation 8】 The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

7. R ４ The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

8. A is, 【Chemistry 9】 The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

9. R ３ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

10. R ６ The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein X is a heterocyclic, aryl, heteroaryl, bicyclic, -NR 27-, -C(O)-, -O-, -S-, -C(NR 27)-, -CR 40 R 41-, or a bond.

12. R １５ The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein is a bond, alkyl, heterocyclic, aryl, heteroaryl, bicyclic, or haloalkyl.

13. R １６ The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein is a bond, alkyl, heterocyclic, aryl, heteroaryl, bicyclic, haloalkyl, -S(O)2-, -C(O)-, -C(O)O-, -O-, or -NR10-.

14. R １７ The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein is a bond, alkyl, heterocyclic, aryl, heteroaryl, bicyclic, or haloalkyl.

15. R １８ The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein is hydrogen, halogen, -C(O)R 27, -C(O)OR 27, -C(O)NR 10 R 27, -NR 27 C(O)R 27, -NR 10 R 27, or -OR 27.

16. R １８ is aryl, heterocycle, or heteroaryl, each optionally substituted with one or two substituents independently selected from ４０ R, according to any one of claims 1 to 14, for a compound or a pharmaceutically acceptable salt thereof. 【Request Item 17】 【Chemistry 10】 【change】 【change】 【change】 【change】 【change】 A compound selected from or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, for treating cereblon, IKZF2, and / or IKZF4-mediated disorders in human patients.

19. The pharmaceutical composition according to claim 18, wherein the disorder is mediated by IKZF2 or IKZF4.

20. The pharmaceutical composition according to claim 18 or 19, wherein the disorder is cancer or a tumor.

21. The pharmaceutical composition according to claim 18 or 19, wherein the disorder is an immune disorder, an autoimmune disorder, or an inflammatory disorder.

22. The pharmaceutical composition according to claim 18 or 19, wherein the disorder is a hematological malignancy.

23. The pharmaceutical composition according to claim 18 or 19, wherein the disorder is small cell lung cancer, non-small cell lung cancer, melanoma, breast cancer, triple-negative breast cancer, multiple myeloma, leukemia, chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, or myelodysplastic syndrome.

24. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for treating cereblon, IKZF2, and / or IKZF4-mediated disorders in human patients.

25. The use according to claim 24, wherein the aforementioned interference is mediated by Ikaros or Aiolos.

26. The use according to claim 24 or 25, wherein the aforementioned disorder is cancer or a tumor.

27. The use according to claim 24 or 25, wherein the disorder is an immune disorder, an autoimmune disorder, or an inflammatory disorder.

28. The use according to claim 24 or 25, wherein the aforementioned disorder is a hematological malignancy.

29. The use according to claim 24 or 25, wherein the disorder is small cell lung cancer, non-small cell lung cancer, melanoma, breast cancer, triple-negative breast cancer, multiple myeloma, leukemia, chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, or myelodysplastic syndrome.

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