Tricyclic ligands for degrading IKZF2 or IKZF4

Abstract

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

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 091,875, filed October 14, 2020, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0003] This invention provides tricyclic hydroxycerebroside conjugates for the degradation of IKZF2 (Helios) and / or IKZF4 (Eos) via the ubiquitin-proteasome pathway for the treatment of medical conditions mediated by these transcription factors.

[0004] By incorporating references

[0005] The entire contents of the text file named "16010-057WO1_SequenceListing_ST25.txt", created on October 14, 2021 and measuring 3.94KB, are incorporated herein by reference. Background Technology

[0006] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP). UPP is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, neural and muscular degeneration, neural network morphogenesis, regulation of cell surface receptors, ion channels and secretory pathways, responses to stress and extracellular regulators, ribosome biogenesis, and viral infection.

[0007] The covalent attachment of multiple ubiquitin molecules to terminal lysine residues via E3 ubiquitin ligase marks the degradation of a protein by the proteasome, in which the protein is digested into small peptides and ultimately into the amino acids that form the building blocks of new proteins. Defective proteasome degradation is associated with a variety of clinical diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0008] The Ikaros (―IKZF”) family is a series of zinc finger protein transcription factors that are important for certain physiological processes, particularly lymphocyte development (see Fan, Y. and Lu, D. ―The Ikaros family of zinc-finger proteins” Acta Pharmaceutica Sinica B, 2016, 6:513-521). Ikaros (―IKZF1”) was first discovered in 1992 (see Georgopoulos, K. et al. ―Ikaros, an early lymphoid-specific transcription factor and aputative mediator for T cell commitment, Science, 1992, 258: 802-812), and four other homologs have been identified in the following two decades: Helios (―IKZF2”), Aiolos (―IKZF3”), Eos (―IKZF4”), and Pegasus (―IKZF5”) (see John, LB, and Ward, AC. The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity, Mol. Immunol, 2011, 48:1272-1278. Each homologous gene can generate several protein isoforms through alternative splicing, theoretically allowing for the generation of numerous protein complexes through different combinations of various homologs. Highly conserved among members of this family are a set of two Cys2His2 zinc finger motifs at the C-terminus, which mediate protein interactions between members of the protein family. Up to four zinc finger motifs exist at the N-terminus for recognizing DNA sequences, the number of which varies due to alternative splicing. Isoforms lacking these N-terminal zinc fingers exhibit a dominant-negative effect on transcriptional activation (see Winandy, S. et al. "A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma," Cell, 1995, 83:289-299).

[0009] The distribution of various members of the Ikaros protein family varies significantly in the body. Ikaros, Helios, and Aiolos are mainly found in lymphoid cells and their corresponding progenitor cells. Ikaros has also been detected in the brain, and Ikaros and Helios have also been detected in erythrocytes. EOS and Pegasus are more widely distributed and have been found in skeletal muscle, liver, brain, and heart (see 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; Schmitt, C. et al. ― Aiolos and Ikaros: regulators of lymphocyte development, homeostasis and lymphoproliferation” Apoptosis, 2002, 7: 277-284; Yoshida, T. and Georgopoulos, K. ― Ikaros fingers on lymphocyte differentiation” Int J Hematol, 2014, 100: 220-229).

[0010] Regulatory T cells (Tregs) are a specialized subset of T cells that suppress immune responses to maintain homeostasis, self-tolerance, and autoimmunity (PMID: 20672742). Tregs can inhibit T cell proliferation and cytokine production. Many Treg subsets exist.

[0011] Tregs suppress CD4+ and CD8+ T cells by consuming IL-2, limiting IL-2 expression, and upregulating CTLA4 to inhibit antigen-presenting cells (APCs). Tregs also produce cytokines (IL-10, IL-35, and TGF-β) to inhibit effector T cell activation, and secrete granzymes and / or perforin to disrupt effector cells. Furthermore, Tregs generate adenosine from ATP in the tumor microenvironment, which can prevent optimized T cell activation.

[0012] Tregs antagonize other T cells that attack tumors or cancer. In a cancerous environment, excessive Treg activity can prevent the immune system from destroying cancer cells. In autoimmune diseases, too few Tregs can allow other autoimmune cells to attack the body's own tissues. The percentage of circulating Tregs in patients with multiple myeloma is significantly higher than in healthy individuals, and patients with high Treg levels in multiple myeloma tend to have shorter lifespans.

[0013] Tregs are a subset of CD4+ T cells that express FoxP3 (forkhead box P3). FoxP3 is a transcription factor and a major regulator of pathways governing T cell development and function. 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 an important role in cancer development.

[0014] IKZF2 and IKZF4 are selectively expressed in Treg cells but not in effector or memory cells. FoxP3 / IKZF4 / CtBP1 form an inhibitory complex that suppresses gene expression (IL2, IFNγ) in Tregs and maintains their inhibitory signature. Knockdown of IKZF4 in Tregs eliminates the cells' ability to suppress immune responses and restores some effector functions. MiR-17 targets IKZF4 for degradation, and its overexpression reduces the inhibitory activity of Tregs. Tregs lacking miR-17 exhibit increased inhibition. Syngeneic tumor-bearing mice treated with mouse FoxP3 antisense oligonucleotides showed significantly reduced tumor growth. It is becoming clearer that IKZF4 plays a key role in controlling many inhibitory functions of Tregs through its interaction with FoxP3.

[0015] IKZF2 regulates Treg differentiation through a different mechanism than IKZF4. IKZF2 knockout in FoxP3-expressing Tregs promotes loss of repressive properties (accompanied by increased IL-2) and expression of T effector cytokines via STAT5 (which regulates 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 promotes leukemia development. IKZF2 regulates and maintains the chromatin accessibility and expression of the self-renewal transcription factors HOXA9 and MYC in leukemia stem cells. IKZF2 inhibits myelodifferentiation by suppressing the accessibility of myelodifferentiation genes containing the C / EBP motif.

[0016] Unlike IKZF1 and IKZF3, it is suggested that IKZF4 can be used as T. H A positive regulator of gene 1. It has been shown that IKZF4 expression is related to T... H The expression of gene 1 is correlated at both the transcriptional and protein levels. Therefore, IKZF4 in T... H In the regulation of differentiation and function, it may have the opposite effect to IKZF1 and IKZF3. Furthermore, unlike IKZF1 and IKZF3, IKZF4 can negatively regulate T... H 17. Differentiation. Similarly, IKZF4 appears to be related to T. FH IKZF1 and IKZF3 have opposite functions in cells.

[0017] IKZF2 and IKZF4 have not yet been, and may not be, selectively targeted by conventional small molecule inhibitors.

[0018] There is little research and progress on the identification and use of drugs that can selectively degrade IKZF2 and / or IKZF4.

[0019] Novartis has been shown to be an IKZF2 / 4 protein degrader in clinical trials. See Adcock, et al., Novartis AG, WO 2020 / 012334; Beckwith, et al., Novartis AG, WO 2020 / 012337; Visser, et al., Novartis AG, WO 2019 / 038717; and Binazzi, et al., Novartis AG, WO 2020 / 128972.

[0020] The Dana-Farber Cancer Institute has also filed patent applications in this general field: Gray, et al., Dana-Farber Cancer Institute, WO 2020 / 006264; and Verano, et al., Dana-Farber Cancer Institute, WO 2020 / 117759 and WO 2021 / 087093. Bristol-Myers Squibb has also filed applications for IKZF2 degrading agents, such as WO2021 / 101919 and WO2021 / 194914.

[0021] Ionis Pharmaceuticals and Astra Zeneca have reported a high-affinity oligonucleotide (AZD8701) that targets FoxP3, inhibits the immunosuppressive function of regulatory T cells, and produces antitumor effects in syngeneic mice (AACR Annual Meeting Abst 5561; April 2018).

[0022] PCT / US2019 / 24094 and PCT / US2020 / 02678, filed by C4 Therapeutics, Inc., disclose a hydroxycerebroside binder (IKZF1 / 3) for the degradation of Ikaros.

[0023] WO2021 / 127586, submitted by Calico Life Sciences LLC and AbbVie Inc, describes PTPN1 and PTPN2 ligands that are covalently bound to various hydroxycerebroside ligands.

[0024] Despite these efforts, there is still a need for compounds that catalyze the selective degradation of zinc finger proteins such as IKZF2 and IKZF4 for medical treatments, including for treating conditions involving abnormal cell proliferation, including tumors and cancer. Invention Overview

[0026] Certain tricyclic glutarimide compounds have been found to degrade IKZF2 and / or IKZF4. Furthermore, in some embodiments, these tricyclic compounds selectively degrade IKZF2 and / or IKZF4 compared to IKZF1 or IKZF3. Therefore, novel tricyclic compounds are provided that can be administered in effective amounts to a host, typically a human, to treat medical conditions that respond to drugs that selectively degrade IKZF2 and / or IKZF4, including, for example, abnormal cell proliferation, including cancer, inflammatory conditions, neurodegenerative diseases, and autoimmune diseases. This invention includes the aforementioned IKZF2 and / or IKZF4 degrading agents and their pharmaceutically acceptable salts, as well as their uses and preparation.

[0027] In some embodiments, in a standard HiBiT bioluminescence assay, the tricyclic compounds of the present invention exhibit in vitro degradation selectivity for IKZF2 and / or IKZF4 that exceeds that for IKZF1 and / or IKZF3 by at least about 1.5, 2, 3, 5, or even 10 times.

[0028] In some embodiments, the tricycloglutamyl imide or a pharmaceutically acceptable salt thereof described herein can be used to treat diseases in an immunosuppressive environment due to the presence of Treg cells and / or other relevant cytokines and mediators that reduce the host's normal immune response to the disease, by selectively degrading IKZF2 and / or IKZF4. In a non-limiting embodiment, upregulation of host biopsy biomarkers FoxP3 or IL-10, IL-35, or TGFβ can be tested to determine the optimal therapy.

[0029] The selected compounds disclosed herein, their pharmaceutically acceptable salts, or pharmaceutically acceptable combinations thereof may be used to treat conditions mediated by IKZF2 or IKZF4, such as solid tumors like lung cancer, including small cell lung cancer or non-small cell lung cancer (e.g., those refractory to PD-1 or PD-L1), melanoma (e.g., those refractory to PD-1 or PD-L1), breast cancer (including triple-negative breast cancer), or hematopoietic malignancies such as multiple myeloma, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelodysplastic syndromes, or other targeted indications. In some embodiments, the cancer is CLL with increased FoxP3 CD4+ cells. Jurkat cells (T-ALL) are known to express IKZF2 and IKZF4, and therefore these compounds may be used to treat T-ALL. Other 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-stabilized colorectal cancer, thymoma, and carcinoid.

[0030] In some embodiments, selective degraders of IKZF2 and / or IKZF4 are administered to a host in need in combination with another active agent (e.g., a checkpoint inhibitor, CAR-T therapy, a targeted antibody, an antibody-drug conjugate, or another standard of care therapy for the cancer being treated or for abnormal cell proliferation). In some embodiments, the patient has cancer that has progressed on immune checkpoint inhibitor therapy, has a high tumor burden, is older than approximately 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 can lead to activation of CD4+ T cells, CD8+ T cells, B cells, NK cells, macrophages, or dendritic cells and enhanced effector function.

[0031] This invention provides a compound of formula I:

[0032]

[0033] Or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition;

[0034] R 1 yes

[0035] Q 1 It is CH or N;

[0036] X is selected from bonds, alkyl groups, aliphatic groups, heterocyclic groups (which can be bonded through C and / or N in the ring), aryl groups, heteroaryl groups, bicyclic groups, and -NR groups. 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 may be optionally selected by 1, 2, 3 or 4 independently from non-hydrogen R, provided that the chemical valence allows for the formation of a stable compound. 40 Substituents of the substituents;

[0037] R 15 R 16 and R 17 Each time it appears, it is independently selected from the following: bond, alkyl group, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -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; each of which may be selected independently from 1, 2, 3, or 4 independently from R, where the chemical valence allows for the formation of a stable compound. 40 Substituents of R; and wherein R 15 R 16 and R 17 No more than two can be selected as keys;

[0038] R 18 Selected from hydrogen, halogen, cyano, -C(O)R 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 Alkenes, alkynes, haloalkyls, alkoxys, aryl groups, heterocyclics, aliphatic groups, heteroaliphatic groups, and heteroaryl groups; each of which may be selected independently from 1, 2, 3, or 4 R groups, provided that the chemical valence allows for the formation of a stable compound. 40 Substituents are substituted; and X, R 15 R 16 R 17 and R 18As is known to those skilled in the art, combinations of selections can be used to provide stable R under the environmental conditions of use and the required shelf life (e.g., at least about 2, 3, 4, 5, or 6 months or longer). 1 Partially; typically, X and R are chosen. 15 R 16 R 17 and R 18 This allows no more than one, two, or three heteroatoms to be sequentially connected;

[0039] R 27 Each time it appears, it is independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, cycloalkyl, aliphatic and heteroaliphatic groups;

[0040] R 40 Each time it appears, it is independently selected from hydrogen, aliphatic group, heteroaliphatic group, cyano, nitro, alkyl, halogen (specifically including F, Cl, Br), haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 ;

[0041] R 41 It is an aliphatic group, aryl group, heteroaryl group, or hydrogen;

[0042] A is selected from:

[0043]

[0044]

[0045] n is 0, 1, or 2;

[0046] X 3 It is NR 10 NR 6’ , O or S;

[0047] Q is CR 7 Or N;

[0048] R 3 It is hydrogen, alkyl, halogen, or haloalkyl;

[0049] or R 3 and R 6 Combined to form 1 or 2 carbon bonds;

[0050] or R 3 and R 4 They can be combined to form 1, 2, 3, or 4 carbon bonds;

[0051] or R3 and R 3 Adjacent R 4 Groups combine to form double bonds.

[0052] R 4 and R 5 Independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 ;

[0053] R 6 and R 7 Independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 ;

[0054] R 6 It is hydrogen, alkyl, or haloalkyl;

[0055] or R 3 and R 6 'Combined to form 1 or 2 carbon connections.'

[0056] Each R 10 and R 11 Independently selected from hydrogen, aliphatic group, alkyl group, haloalkyl group, heterocyclic group, aryl group, heteroaryl group, -C(O)R 12 -S(O)R 12 and -SO2R 12 ;

[0057] Each R 12 Independently selected from hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, -NR 13 R 14 and OR 13 ;and

[0058] R in each case 13 and R 14 It is independently selected from hydrogen, alkyl and haloalkyl.

[0059] Each combination of variables, substituents, embodiments, and compounds resulting from these combinations is considered specific and individually disclosed because, as is known to those skilled in the art, such description is for illustrative purposes only and is not intended to describe only the genus or even subgenus of the compound, but rather to provide each of the following substances as stable compounds under the environmental conditions of use and the required shelf life (e.g., at least about 2, 3, 4, 5, or 6 months or longer).

[0060] In some embodiments, the compounds described herein bind to hydroxycerebroside, increasing the interaction between hydroxycerebroside and IKZF2 or IKZF4 and leading to subsequent ubiquitination and degradation of the protein in the proteasome.

[0061] Therefore, based on this discovery, compounds and methods are provided for treating patients suffering from conditions mediated by IKZF2 or IKZF4, said conditions being lymphoid conditions in some embodiments. In some embodiments, said conditions are leukemia. In some embodiments, said conditions are lymphocytic leukemia. In some embodiments, said conditions are lymphoblastic leukemia. In some embodiments, said conditions are hematologic malignancies, such as multiple myeloma, myelodysplastic syndromes such as 5q- 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 invention are administered to achieve immunomodulation and reduce angiogenesis.

[0062] In other embodiments, compounds and methods for treating conditions are presented, including but not limited to benign growths, vegetations, tumors, cancers, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid-based proteases, proteases, or fibrotic conditions. Furthermore, other conditions that can be treated with effective amounts of the compounds described herein are described below.

[0063] In some embodiments, any compound described herein has at least one desired atomic substitution in an amount approximately equal to the natural abundance (i.e., enrichment) of the isotope.

[0064] Other features and advantages of the invention will be apparent from the following detailed description and claims.

[0065] Therefore, the present invention includes at least the following features:

[0066] (a) A compound of formula I as described herein, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivatives) or prodrug thereof;

[0067] (b) A compound of formula I as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for the treatment of conditions mediated by IKZF2 or IKZF4;

[0068] (c) A method of treating a patient in need (usually a person) comprising administering an effective amount of a compound of formula I as described herein or a pharmaceutically acceptable salt thereof, wherein the patient suffers from a condition described herein, such as a condition mediated by IKZF2 or IKZF4;

[0069] (d) A method of treating a patient in need (usually a person) comprising administering an effective amount of a compound of formula I as described herein or a pharmaceutically acceptable salt thereof, wherein the patient suffers from a hematologic malignancy, such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma;

[0070] (e) A method of treating a patient in need (usually a person) comprising administering an effective amount of a compound of formula I as 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 that typically presents an immunosuppressive environment;

[0071] (f) A method of treating a patient in need (usually a person) comprising administering an effective amount of a compound of formula I as 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 that typically presents an immunosuppressive environment, and wherein the patient is also administered an anti-PD-1 or anti-PD-L1 agent.

[0072] (g) Use in an effective amount of a compound of formula I as described herein or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof in the treatment of a patient (usually a human) suffering from any of the conditions described herein (including those mediated by IKZF2 or IKZF4).

[0073] (h) Use of a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, in the preparation of a medicament for treating a medical condition to which the compound is sensitive, as further described herein;

[0074] (i) A method for preparing a medicament for treating the diseases described herein in a host, characterized in that a compound of formula I is used in the preparation;

[0075] (j) A compound of Formula I as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, used to treat cancer in a host (including any cancer described herein);

[0076] (k) Use of a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, in the preparation of a medicament for the treatment of cancer (including any cancer described herein);

[0077] (l) A method for preparing a medicament for treating cancer in a host (including any cancer described herein), characterized in that a compound of formula I is used in the preparation;

[0078] (m) A compound of Formula I as described herein or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, used to treat tumors in a host (including any tumors described herein);

[0079] (n) Use of a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, in the preparation of a medicament for the treatment of tumors (including any tumors described herein);

[0080] (o) A method for preparing a medicament for treating tumors (including any tumors described herein) in a host, characterized in that a compound of formula I is used in the preparation;

[0081] (p) Compounds of Formula I as described herein, or pharmaceutically acceptable salts, isotopic derivatives or prodrugs thereof, for the treatment of immune, autoimmune, inflammatory, neurodegenerative or fibrotic conditions in the host.

[0082] (q) Use of a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, in the preparation of a medicament for the treatment of immune, autoimmune, inflammatory, neurodegenerative or fibrotic conditions.

[0083] (r) A method for preparing a medicament for treating immune, autoimmune, inflammatory, neurodegenerative or fibrotic conditions in a host, characterized in that a compound of formula I is used in the preparation;

[0084] (s) Compound of Formula I as described herein, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, for the treatment of hematologic malignancies such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma.

[0085] (t) Compounds of Formula I as described herein, or pharmaceutically acceptable salts, isotopic derivatives or prodrugs thereof, 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 typically exhibit an immunosuppressive environment;

[0086] (u) Use of a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, in the preparation of a medicament for the treatment of hematologic malignancies such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma;

[0087] (v) A method for preparing a medicament for treating hematologic malignancies such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma.

[0088] (w) A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I described herein or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, and a pharmaceutically acceptable carrier or diluent.

[0089] (x) Compounds as described herein, which are mixtures of enantiomers or diastereomers (as relevant), including racemic compounds;

[0090] (y) Compounds as described herein, in enantiomerically or diastereomeric (as relevant) enriched forms, including isolated enantiomers or diastereomeric compounds (i.e., greater than 85, 90, 95, 97, or 99% purity); and

[0091] (z) A method for preparing a therapeutic product containing an effective amount of a compound of formula I as described herein. Attached Figure Description

[0092] Figure 1 It is shown that it can be used with the intermediate 3-(5-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione to add a series of R 1 Synthetic schemes for non-limiting examples of the synthesis of functional groups.

[0093] Figure 2 It is shown that it can be used with intermediates 1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-5-carboxaldehyde derivatives to functionalize a series of R 1 Synthetic schemes for non-limiting examples of the synthesis of functional groups.

[0094] Figure 3This is a representative formula of the IKZF2 / 4 degradation compound of the present invention. Invention Details

[0096] definition

[0097] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In this specification, the singular form also includes the plural, unless the context clearly specifies otherwise. While methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this application, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference. References cited herein are not considered prior art to the claimed applications. In case of conflict, this specification (including definitions) shall prevail. Furthermore, materials, methods, and examples are illustrative only and not intended to be limiting.

[0098] Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0099] In certain embodiments of each compound described herein, the compound may be in the form of a racemic compound, an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of diastereomers, a tautomer, an N-oxide, or an isomer such as a rotational isomer, as if each were explicitly described unless the context explicitly excludes it.

[0100] The term "a / an" does not indicate a limitation of quantity, but rather the presence of at least one of the mentioned items. The term "or" refers to "and / or". Unless otherwise indicated herein, the description of ranges of values ​​is intended only as a shorthand method for referring one by one to each individual value falling within the range, and each individual value is incorporated into this specification as if it were described one by one herein. The endpoints of all ranges are included within the range and can be combined independently. Unless otherwise indicated herein or clearly contradicted by the context, all methods described herein may be performed in a suitable order. Unless otherwise stated, the use of examples or exemplary language (e.g., "as in") is intended only to better illustrate the invention and does not constitute a limitation on the scope of the invention.

[0101] This invention includes compounds described herein that have at least one desired isotopic substitution of an atom, in an amount exceeding the natural abundance of that isotope, i.e., enrichment. An isotope is an atom with the same atomic number but different mass numbers, i.e., atoms with the same number of protons but different numbers of neutrons. If isotopic substitution is used, the usual substitution is at least one deuterium-substituted hydrogen atom.

[0102] 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, respectively, as follows: 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 18 F, 35 S and 36 Cl. In one non-limiting embodiment, the isotope-labeled compound can be used for metabolic studies (e.g., using...) 14 C) Reaction kinetic studies (using, for example) 2 H or 3 H) Detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or for use in patient radiotherapy. Furthermore, any hydrogen atoms present in the compounds of this invention may be... 18 F-atom substitution, which may be particularly ideal for PET and SPECT studies. The isotopically labeled compounds and their prodrugs of the present invention can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents using the procedures disclosed in the embodiments or examples and the preparation methods described below.

[0103] As a general example and not a limitation, isotopes of hydrogen, such as deuterium (… 2 H) and tritium ( 3 H) can be used anywhere in the structure to achieve the desired result. Alternatively or additionally, isotopes of carbon, such as 13 C and 14 C.

[0104] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution refers to the substitution of at least one hydrogen atom with deuterium. In some embodiments, an isotope is enriched at any target location by 90, 95, or 99% or more. In a non-limiting embodiment, deuterium is enriched at the desired location by 90, 95, or 99%.

[0105] In a non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom may be provided in any of the compounds described herein. For example, when any group is or contains (e.g., by substitution) a methyl, ethyl, or methoxy group, the alkyl residue may be deuterated (in a non-limiting embodiment, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In some other embodiments, when two substituents combine to form a ring, the unsubstituted carbon may be deuterated. In some embodiments, at least one deuterium is located on an atom having a bond that breaks during metabolism in the compound, or on one, two, or three atoms away from the metabolic bond (e.g., which may be referred to as α, β, or γ, or a primary, secondary, or tertiary isotope effect).

[0106] The compounds of the present invention can form solvates with solvents, including water. Therefore, in a non-limiting embodiment, the present invention includes the solvated form of the compounds 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 are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent may be substituted with an isotope (e.g., D2O, d6-acetone, d6-DMSO). Solvates may be in liquid or solid form.

[0107] A dash (―-”) not between two letters or symbols is used to indicate the connection point of a substituent. For example, -(C=O)NH2 is connected to the carbon atom of a ketone (C=O) group.

[0108] "alkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl group contains 1 to about 8 carbon atoms. In some embodiments, the alkyl group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. Specific ranges as used herein indicate alkyl groups having each member of the range, each member of which is described as an independent substance. For example, the term C1-C6 alkyl as used herein indicates an alkyl group having 1... Alkyl groups are straight-chain or branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, and are intended to mean that each of these is described as a separate substance. For example, the term C1-C4 alkyl as used herein refers to a straight-chain or branched alkyl group having 1, 2, 3, or 4 carbon atoms, and is intended to mean that each of these is described as a separate substance. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.

[0109] "Alkenyl" is a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds, which may be present at a stable point along the chain. The specific ranges used herein refer to alkenyl groups having each member of the range, each member of which is described as an independent substance, as described above with respect to the alkyl portion. In one non-limiting embodiment, the alkenyl contains 2 to about 12 carbon atoms, more typically 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In some embodiments, the alkenyl is C2, C2-C3, C2-C4, C2-C5, or C2-C6. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also embodies "cis" and "trans" alkenyl geometries, or alternatively, "E" and "Z" alkenyl geometries. The term "alkenyl" also includes cycloalkyl or carbocyclic groups having at least one unsaturated point.

[0110] "Alynyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, which may be present at any stable point along the chain. The specific ranges used herein refer to alkynyl groups having each member of the range, each member of which is described as an independent substance, as described above with respect to the alkyl portion. In one non-limiting embodiment, the alkynyl group contains 2 to about 12 carbon atoms, more typically 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In some embodiments, the alkynyl group is C2, C2-C3, C2-C4, C2-C5, or C2-C6. Examples of alkynyl groups 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.

[0111] "Halogen" and "halogen" are independently fluorine, chlorine, bromine or iodine.

[0112] "Haloalkyl" refers to a branched or straight-chain alkyl group that is replaced by one or more of the aforementioned halogen atoms, up to a maximum permitted 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. "Hyperhaloalkyl" means an alkyl group in which all hydrogen atoms are replaced by halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0113] As used in this article, "-aryl" refers to a group of aromatic rings (-C). 6–14 The aryl group comprises a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a ring array) having 6-14 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has 6 ring carbon atoms (-C6 aryl; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (-C6 aryl). 10 Aryl group; for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (―C 14 "Aryl" (e.g., anthracene). "Aryl" also includes ring systems in which an aryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups, wherein the linking group or linking point is located on the aryl ring, and in this case, the number of carbon atoms still specifies the number of carbon atoms in the aryl ring system. The one or more fused cycloalkyl or heterocyclic groups can be 4 to 7-membered saturated or partially unsaturated cycloalkyl or heterocyclic groups.

[0114] "Arylalkyl" means an alkyl group substituted with an aryl group as defined herein or an aryl group substituted with an alkyl group as defined herein.

[0115] The term "heterocyclic" refers to a saturated or partially saturated heteroatom-containing cyclic group, wherein one, two, three, or four heteroatoms are independently selected from nitrogen, sulfur, boron, organosilicon, and oxygen. Heterocyclic groups can comprise monocyclic 3- to 10-membered rings and 5- to 16-membered bicyclic ring systems (which may include bridging, fused, and spiro-fused bicyclic ring systems). It does not include rings containing -OO-, -OS-, or -SS- motifs. Examples of saturated heterocyclic groups include saturated 3- to 4-membered rings containing nitrogen atoms. Six-membered heterocyclic groups [e.g., pyrrolyl, imidazoyl, piperidinyl, pyrrololinyl, piperazineyl]; saturated three- to six-membered heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; saturated three- to six-membered heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolyl]. Examples of partially saturated heterocyclic groups include, but are not limited to, dihydrothiophene, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolyl, imidazoyl, piperidinyl, pyrrololinyl, pyrazolyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazoyl, dihydrothiophene, 2,3-dihydro-benzo[1,4]dioxyl, dihydroindolyl, isodihydroindolyl, dihydrobenzothiophene, dihydrobenzofuranyl, isochromyl, chromanyl, 1,2-dihydroquinolinyl, and 1,2,3,4-tetrahydro-isoquinolinyl. 1,2,3,4-tetrahydro-quinolinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxalkyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazolyl-6-yl, dihydropyranyl, dihydrofuranyl and dihydrothiazolyl.

[0116] "Heterocyclic" also includes groups in which a heterocyclic group is fused / condensed with an aryl or carbocyclic group, wherein the connection point is a heterocyclic ring. "Heterocyclic" also includes groups in which a heterocyclic group is oxidized by an oxo group (i.e., Substituted groups. For example, partially unsaturated fused heterocyclic groups containing 1 to 5 nitrogen atoms, such as dihydroindole or isodihydroindole; partially unsaturated fused heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; partially unsaturated fused heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; and saturated fused heterocyclic groups containing 1 to 2 oxygen or sulfur atoms.

[0117] The term "heterocycle" also includes "bicyclic heterocycle". The term "bicyclic heterocycle" refers to a heterocycle as defined herein, wherein a bridging, fused, or spirocyclic portion of the heterocycle is present. The bridging, fused, or spirocyclic portion of the heterocycle can be a carbocyclic, heterocyclic, or aryl group, as long as a stable molecule is obtained. Unless the context excludes, the term "heterocycle" includes bicyclic heterocycles. Bicyclic heterocycles include groups in which the fused heterocycle is substituted with an oxo group. Non-limiting examples of bicyclic heterocycles include:

[0118]

[0119] The term "heteroaryl" refers to a stable aromatic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S, wherein the cyclic nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Examples include, but are not limited to, unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrroloyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; and unsaturated 5- to 6-membered heteromonocyclic groups containing oxygen atoms, such as pyranyl, 2-furanyl, 3-furanyl, etc. Unsaturated 5- to 6-membered heterocyclic groups containing sulfur atoms, such as 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5- to 6-membered heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. In some embodiments, the "heteroaryl" group is an 8, 9, or 10-membered bicyclic ring system. Examples of 8, 9, or 10-membered bicyclic heteroaryl groups include benzofuranyl, benzothiophenyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphridyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazoleyl, and benzotriazolyl.

[0120] "Heteroarylalkyl" means an alkyl group as defined herein that is substituted with a heteroaryl group as defined herein, or a heteroaryl group as defined herein that is substituted with an alkyl group as defined herein.

[0121] As used herein, "-carbocyclic", "-carbocyclic", or "-cycloalkyl" includes all carbon ring atoms and 3 to 14 ring carbon atoms (-C). 3–14 A cycloalkyl group is a saturated or partially unsaturated (i.e., non-aromatic) group with zero heteroatoms in a cycloalkyl or non-aromatic ring system. In some embodiments, the cycloalkyl group has 3 to 10 cyclic carbon atoms (-C). 3–10cycloalkyl group (“cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 9 cyclic carbon atoms (―C 3–9 cycloalkyl group (“cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (―C 3–8 cycloalkyl group (“cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 7 cyclic carbon atoms (―C 3–7 cycloalkyl group (“cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (―C 3–6 cycloalkyl group (“cycloalkyl”). In some embodiments, the cycloalkyl group has 4 to 6 cyclic carbon atoms (―C 4-6 cycloalkyl group (“cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (―C 5-6 cycloalkyl group (“cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (―C 5-10 Cycloalkyl). Exemplary C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). An example C... 3-8 Cycloalkyl groups include, but are not limited to, the above-mentioned C 3-6 Cycloalkyl groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), etc. An example C 3-10 Cycloalkyl groups include, but are not limited to, the above-mentioned C 3-8 Cycloalkyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 As illustrated in the foregoing examples, in some embodiments, the cycloalkyl group may be saturated or may contain one or more carbon-carbon double bonds. The term "cycloalkyl" also includes cyclic systems in which the cycloalkyl ring as defined above is fused with a heterocyclic, aryl, or heteroaryl ring, wherein the bonding point is on the cycloalkyl ring, and in this case, the number of carbon atoms continues to represent the number of carbon atoms in the carbocyclic system. The term "cycloalkyl" also includes cyclic systems in which the cycloalkyl ring as defined above has a spirocyclic heterocyclic, aryl, or heteroaryl ring, wherein the bonding point is on the cycloalkyl ring, and in this case, the number of carbon atoms continues to represent the number of carbon atoms in the carbocyclic system. The term "cycloalkyl" also includes bicyclic or polycyclic fused, bridged, or spirocyclic systems containing 5 to 14 carbon atoms and zero heteroatoms in a non-aromatic ring. Representative examples of "cycloalkyl" include, but are not limited to, those containing, but are not limited to, those containing, saturated carbon atoms or carbon atoms.

[0122] The term "bicyclic" refers to a ring system in which two rings are fused together, and each ring is independently selected from carbocyclic, heterocyclic, aryl, and heteroaryl rings. Non-limiting examples of bicyclic rings include:

[0123]

[0124] When the term "bicyclic" is used with divalent residues such as R 15 R 16 or R 17 When used in a context where both connection points are on different rings or on the same ring, the connection points can be on different rings. In some implementations, both connection points are on the same ring. In some implementations, both connection points are on different rings. Non-limiting examples of double rings include:

[0125]

[0126] "Dosage form" refers to the unit of administration of the active ingredient. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, balls, creams, ointments, suppositories, inhalable dosage forms, transdermal dosage forms, oral, sublingual, topical, gels, and mucosal dosage forms. "Dosage form" can also include implants, such as optical implants.

[0127] As used herein, "endogenous" means any material that originates from or is produced within an organism, cell, tissue, or system.

[0128] As used herein, the term "exogenous" means any material introduced from or produced outside of an organism, cell, tissue, or system.

[0129] As used herein, the term "modulation" refers to mediating a detectable increase or decrease in an individual's response level compared to their response level in the absence of treatment or compounds, and / or a comparison with the response levels of other individuals who are otherwise identical but untreated. This term includes disrupting and / or influencing natural signals or responses, thereby mediating a beneficial therapeutic response in an individual, preferably a human.

[0130] "Parenteral" administration of compounds includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im), or intrasternal injection, or infusion techniques.

[0131] As used herein, "pharmaceutical composition" is a composition comprising at least one active agent as described herein, selected active compounds, and at least one other substance such as a carrier. "Pharmaceutical combination" is a combination of at least two active agents that may be combined in a single dosage form or provided together in separate dosage forms, accompanied by instructions that the active agents are used together to treat any of the diseases described herein.

[0132] As used herein, "pharmaceutically acceptable salt" is a derivative of the disclosed compound wherein the parent compound is modified by preparing its inorganic and organic, acid or base addition salts, which are biologically acceptable and non-toxic. Salts of the compounds of the present invention can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, such salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (e.g., hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent or a mixture thereof. Typically, where feasible, non-aqueous media include diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Salts of the compounds of the present invention also include the compound and a solvate of the compound salt.

[0133] Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal salts or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of parent compounds formed from, for example, 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, aminosulfonic acid, phosphoric acid, nitric acid, etc.; and those derived from organic acids such 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, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-benzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethanesulfonic acid, HOOC-(CH2)n-COOH, where n is 0-4, etc., or using different acids that produce the same counterion. A list of other suitable salts can be found, for example, on page 1418 (1985) of Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa.

[0134] The term "carrier" refers to a diluent, excipient, or carrier that uses or delivers an active agent.

[0135] "Pharmaceutical-acceptable excipients" refers to excipients that can be used to prepare pharmaceutical compositions / combinations that are generally safe and are biologically or otherwise unsuitable for administration to a host, typically a human. In some embodiments, excipients suitable for veterinary use are used.

[0136] "Patient," "host," or "individual" refers to a human or non-human animal that requires treatment for any ailment specifically described herein. Typically, the host is a human. "Host" may alternatively refer to, for example, mammals, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0137] The "therapeutic effective amount" of the pharmaceutical composition / combination of the present invention refers to the amount that, when administered to the host, effectively provides therapeutic benefits such as improvement of symptoms or reduction or alleviation of the disease itself.

[0138] In some embodiments, a "prodrug" is in the form of the parent molecule that is metabolized or chemically converted into the parent molecule in vivo (e.g., in mammals or humans). Non-limiting examples of prodrugs include esters, amides (e.g., primary or secondary amines), carbonates, carbamates, phosphate esters, ketals, imines, oxazolidinyl and thiazolidinyl. Prodrugs may be designed to release the parent molecule upon pH change (e.g., in the stomach or intestine) or upon the action of an enzyme (e.g., an esterase or amidase).

[0139] In some embodiments, "stable" means that less than 10%, 5%, 3%, or 1% of the compound degrades under ambient conditions and has a shelf life of at least 3, 4, 5, or 6 months. In some embodiments, compounds stored under ambient conditions are stored at approximately room temperature and exposed to air and relative humidity less than approximately 40%, 50%, 60%, or 70%. In some embodiments, compounds stored under ambient conditions are stored at approximately room temperature under an inert gas (such as argon or nitrogen). Generally, the moiety described herein does not have more than one or two heteroatoms directly bonded to each other, unless the moiety is heteroaromatic.

[0140] Throughout this disclosure, various aspects of the invention can be presented in a scope format. It should be understood that the scope format description is merely for convenience and should not be construed as limiting the scope of the invention. It should be considered that the description of a scope specifically discloses all possible sub-scopes and the individual numerical values ​​within that scope. For example, a description of a scope such as 1 to 6 should be considered to have specifically disclosed sub-scopes, such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and individual numbers within that scope, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the scope.

[0141] II. Compounds of the present invention

[0142] Implementation scheme of "alkyl"

[0143] In some embodiments, "alkyl" is C1-C 10Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl.

[0144] In some implementations, "alkyl" has one carbon atom.

[0145] In some implementations, the "alkyl" has two carbon atoms.

[0146] In some implementations, the "alkyl" has three carbon atoms.

[0147] In some implementations, the "alkyl" has four carbon atoms.

[0148] In some implementations, the "alkyl" has five carbon atoms.

[0149] In some schemes, "-alkyl" has six carbons.

[0150] Non-limiting examples of "alkyl" include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0151] Other non-limiting examples of "-alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0152] Other non-limiting examples of "-alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0153] Other non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0154] Other non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and reactive pentyl.

[0155] Implementation scheme of "halogenated alkyl"

[0156] In some embodiments, "-haloalkyl" is C1-C 10 Halogenated alkyl, C1-C9 halogenated alkyl, C1-C8 halogenated alkyl, C1-C7 halogenated alkyl, C1-C6 halogenated alkyl, C1-C5 halogenated alkyl, C1-C4 halogenated alkyl, C1-C3 halogenated alkyl and C1-C2 halogenated alkyl.

[0157] In some implementations, the "-halogenated alkyl" has one carbon atom.

[0158] In some implementations, the "halogenated alkyl" has one carbon atom and one halogen.

[0159] In some implementations, the "halogenated alkyl" has one carbon atom and two halogens.

[0160] In some implementations, the "halogenated alkyl" has one carbon atom and three halogens.

[0161] In some implementations, the "haloalkyl" has two carbon atoms.

[0162] In some implementations, the "haloalkyl" has three carbons.

[0163] In some implementations, the "haloalkyl" has four carbons.

[0164] In some implementations, the "haloalkyl" has five carbons.

[0165] In some implementations, the "haloalkyl" has six carbons.

[0166] Non-limiting examples of "halogenated alkyl" include:

[0167] Other non-limiting examples of "haloalkyl" include:

[0168] Other non-limiting examples of "haloalkyl" include:

[0169] Other non-limiting examples of "haloalkyl" include:

[0170] Implementation plan for "aryl"

[0171] In some implementations, "-aryl" is a 6-carbon aromatic group (phenyl).

[0172] In some implementations, "-aryl" is a 10-carbon aromatic group (naphthyl).

[0173] In some embodiments, "-aryl" is a 6-carbon aromatic group fused to a heterocycle, wherein the linking point is an aromatic ring. Non-limiting examples of "-aryl" include dihydroindole, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the linking point of each group is on an aromatic ring.

[0174] For example, It is an aryl group.

[0175] However, It is a heterocyclic group.

[0176] In some embodiments, "-aryl" is a 6-carbon aromatic group fused to a cycloalkyl group, wherein the linking point is an aromatic ring. Non-limiting examples of "-aryl" include dihydroindene and tetrahydronaphthalene, wherein the linking point of each group is on an aromatic ring.

[0177] For example, It is an aryl group.

[0178] However, It is a cycloalkyl group.

[0179] Implementation plan of "hybrid aromatics"

[0180] In some embodiments, "heteroaryl" is a five-membered aromatic group containing one, two, three, or four nitrogen atoms.

[0181] Non-limiting examples of "5-membered heteroaryl" include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetraazole, isoxazole, oxazole, oxadiazole, oxtriazole, isothiazole, thiazole, thiazolium, and thiatriazole.

[0182] Other non-limiting examples of the 5-membered heteroaryl group include:

[0183]

[0184] In some embodiments, "heteroaryl" is a 6-membered aromatic group (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl) containing 1, 2, or 3 nitrogen atoms.

[0185] Non-limiting examples of 6-membered heteroaryl groups having one or two nitrogen atoms include:

[0186]

[0187] In some embodiments, "heteroaryl" is a 9-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0188] Non-limiting examples of "bicyclic heteroaryl" include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azapyridazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazol, benzoxazole and benzothiazol.

[0189] Other non-limiting examples of bicyclic heteroaryl groups include:

[0190]

[0191] Other non-limiting examples of bicyclic heteroaryl groups include:

[0192]

[0193] Other non-limiting examples of "bicyclic-heteroaryl" compounds include:

[0194]

[0195] In some embodiments, "heteroaryl" is a 10-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0196] Non-limiting examples of "bicyclic heteroaryl" include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, porphyrin, and naphthidine.

[0197] Other non-limiting examples of "bicyclic-heteroaryl" compounds include:

[0198]

[0199] "Cycloalkyl" implementation scheme

[0200] In some embodiments, "cycloalkyl" is a C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3-C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[0201] In some implementations, the "cycloalkyl" has three carbons.

[0202] In some implementations, "cycloalkyl" has four carbons.

[0203] In some implementations, the "cycloalkyl" has five carbons.

[0204] In some implementations, the "cycloalkyl" has six carbons.

[0205] In some implementations, the "cycloalkyl" has seven carbons.

[0206] In some implementations, the "cycloalkyl" has eight carbons.

[0207] In some implementations, the "cycloalkyl" has nine carbons.

[0208] In some implementations, the "cycloalkyl" has ten carbons.

[0209] Non-limiting examples of "cycloalkyl" include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0210] Other non-limiting examples of “cycloalkyl” include dihydroindene and tetrahydronaphthalene, wherein the linking point of each group is on the cycloalkyl ring.

[0211] For example, It is a cycloalkyl group.

[0212] However, It is an aryl group.

[0213] Other examples of "cycloalkyl" include

[0214] Implementation plan of "heterocyclic"

[0215] In some implementations, a "heterocycle" refers to a cyclic ring having one nitrogen atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0216] In some implementations, a "heterocycle" refers to a cyclic ring having one nitrogen atom, one oxygen atom, and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0217] In some implementations, a "heterocycle" refers to a cyclic ring having two nitrogen atoms and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0218] In some implementations, a "heterocycle" refers to a cyclic ring having one oxygen atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0219] In some implementations, a "heterocycle" refers to a cyclic ring having one sulfur atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0220] Non-limiting examples of "heterocyclic" include aziridine, ethylene oxide, thioheterocyclic butane, azirocyclic butane, 1,3-diazaheterocyclic butane, oxoheterocyclic butane, and thioheterocyclic butane.

[0221] Other non-limiting examples of "heterocyclic" compounds include pyrrolidine, 3-pyrrolidine, 2-pyrrolidine, pyrazolidine, and imidazoline.

[0222] Other non-limiting examples of "heterocyclic rings" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathionecyclopentane and 1,3-oxathionecyclopentane.

[0223] Other non-limiting examples of "heterocyclic" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiazide, 1,3-dithiazide, 1,4-dithiazide, morpholine, and thiomorpholine.

[0224] Other non-limiting examples of "heterocycles" include dihydroindole, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the bonding point of each group is on the heterocycle.

[0225] For example, It is a heterocyclic group. However, It is an "aryl" group. Non-limiting examples of "heterocyclic" groups also include:

[0226]

[0227] Other non-limiting examples of "heterocyclic rings" include:

[0228]

[0229] Other non-limiting examples of "heterocyclic rings" include:

[0230]

[0231] Non-limiting examples of "heterocyclic" also include:

[0232]

[0233] Non-limiting examples of "heterocyclic" also include:

[0234]

[0235] Other non-limiting examples of "heterocyclic rings" include:

[0236]

[0237] Other non-limiting examples of "heterocyclic rings" include:

[0238]

[0239] Optional substituents

[0240] In some embodiments, the portion described herein that can be replaced by 1, 2, 3 or 4 substituents is replaced by a single substituent.

[0241] In some embodiments, the portion described herein that can be replaced by 1, 2, 3 or 4 substituents is replaced by two substituents.

[0242] In some embodiments, the portion described herein that can be replaced by 1, 2, 3 or 4 substituents is replaced by three substituents.

[0243] In some embodiments, the portion described herein that can be replaced by 1, 2, 3 or 4 substituents is replaced by four substituents.

[0244] R 1 Implementation plan

[0245] In some implementations, R 1 Selected from:

[0246]

[0247] Each R' is independently selected from hydrogen, alkyl, haloalkyl, aryl, heterocyclic and heteroaryl.

[0248] In some implementations, R 1 It is a heterocyclic group that is optionally substituted by one or two substituents selected from R'.

[0249] In some implementations, R 1 It is a 6-membered heterocyclic group having one or two nitrogen atoms.

[0250] In some implementations, R1 It is a 6-membered heterocyclic group having one or two oxygen atoms.

[0251] In some implementations, R 1 Selected from:

[0252]

[0253]

[0254] In some implementations, R 1 Selected from:

[0255]

[0256] In some implementations, R 1 Selected from:

[0257]

[0258]

[0259] In some implementations, R 1 Selected from:

[0260]

[0261] In some implementations, R 1 Selected from:

[0262]

[0263]

[0264] In some implementations, R 1 Selected from:

[0265]

[0266] In some implementations, R 1 Selected from:

[0267]

[0268]

[0269] In some implementations, R 1 Selected from:

[0270]

[0271]

[0272]

[0273] In some implementations, R 1 Selected from:

[0274]

[0275]

[0276] In some implementations, R 1 Selected from:

[0277]

[0278] In some implementations, R 1 Selected from:

[0279]

[0280] In some implementations, R 1 Selected from: In some implementations, R 1 Selected from:

[0281]

[0282] In some implementations, R 1 Selected from:

[0283]

[0284] In some implementations, R 1 Selected from:

[0285]

[0286] In some implementations, R 1 Selected from:

[0287]

[0288] In some implementations, R 1 Selected from:

[0289]

[0290] In some implementations, R 1 Selected from:

[0291]

[0292]

[0293] In some implementations, R 1 Selected from:

[0294]

[0295]

[0296] In some implementations, R 1 Selected from:

[0297]

[0298]

[0299] In some implementations, R 1 Selected from:

[0300]

[0301] In some implementations, R 1 Selected from:

[0302]

[0303] In some implementations, R 1 Selected from:

[0304]

[0305] In some implementations, R 1 Selected from:

[0306]

[0307]

[0308] In some implementations, R 1 Selected from:

[0309]

[0310]

[0311] In some implementations, R 1 Selected from:

[0312]

[0313]

[0314] In some implementations, R 1 Selected from:

[0315]

[0316] In some implementations, R 1 Selected from:

[0317]

[0318]

[0319] In some implementations, R 1 Selected from:

[0320]

[0321] In some implementations, R 1 Selected from:

[0322]

[0323] In some implementations, R 1 Selected from:

[0324]

[0325] In some implementations, R 1 Selected from:

[0326]

[0327] In some implementations, R 1 Selected from:

[0328]

[0329]

[0330] In some implementations, R 1 Selected from:

[0331]

[0332] In some implementations, R 1 Selected from:

[0333]

[0334]

[0335] In some implementations, R 1 Selected from:

[0336]

[0337] In some implementations, R 1 Selected from:

[0338]

[0339] In some implementations, R1 Selected from:

[0340]

[0341]

[0342] In some implementations, R 1 Selected from:

[0343]

[0344] In some implementations, R 1 Selected from:

[0345]

[0346] In some implementations, R 1 Selected from:

[0347]

[0348] In some implementations, R 1 Selected from:

[0349]

[0350] In some implementations, R 1 Selected from:

[0351]

[0352] In some implementations, R 1 Selected from:

[0353]

[0354] In some implementations, R 1 Selected from:

[0355]

[0356] In some implementations, R 1 Selected from:

[0357]

[0358] In some implementations, R 1 Selected from:

[0359]

[0360] In some implementations, R 1 Selected from:

[0361]

[0362]

[0363] In some implementations, R 1 Selected from:

[0364]

[0365] In some implementations, R 1 Selected from:

[0366]

[0367] In some implementations, R 1 Selected from:

[0368]

[0369] In some implementations, R 1 Selected from:

[0370]

[0371] In some implementations, R 1 Selected from:

[0372]

[0373]

[0374] In some implementations, R 1 Selected from:

[0375]

[0376]

[0377] In some implementations, R 1 Selected from:

[0378]

[0379]

[0380] In some implementations, R 1 Selected from:

[0381]

[0382]

[0383] In some implementations, R 1 Selected from:

[0384]

[0385]

[0386] In some implementations, R 1 Selected from:

[0387]

[0388] In some implementations, R 1 Selected from:

[0389]

[0390]

[0391] In some implementations, R 1 Selected from:

[0392]

[0393] In some implementations, R 1 Selected from:

[0394]

[0395] In some implementations, R 1 Selected from:

[0396]

[0397]

[0398] In some implementations, R 1 Selected from:

[0399]

[0400] In some implementations, R 1 Selected from:

[0401]

[0402] In some implementations, R 1 Selected from:

[0403]

[0404] In some implementations, R 1 Selected from:

[0405]

[0406] In some implementations, R 1 Selected from:

[0407]

[0408]

[0409] In some implementations, R 1 Selected from:

[0410]

[0411]

[0412] In some implementations, R 1 Selected from:

[0413]

[0414] In some implementations, R 1 Selected from:

[0415]

[0416]

[0417] In some implementations, R 1 Selected from:

[0418]

[0419]

[0420] In some implementations, R 1 Selected from:

[0421]

[0422] In some implementations, R 1 Selected from:

[0423]

[0424] In some implementations, R 1 Selected from:

[0425]

[0426] In some implementations, R 1 Selected from:

[0427]

[0428] In some implementations, R 1 Selected from:

[0429]

[0430] In some implementations, R 1 Selected from:

[0431]

[0432] In some implementations, R 1 Selected from:

[0433]

[0434] Or its pharmaceutically acceptable salt, wherein:

[0435] R 42 It is hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclic, aliphatic or heteroaliphatic;

[0436] X 1 It is NR 19 , O or S;

[0437] X 2 It is CH2 or C(O);

[0438] R 19 Selected from alkyl, hydrogen, -C(O)NR 10 R 27 -C(O)OR 27 -C(O)R 27 Alkenes, alkynes, haloalkyls, alkoxys, aryl groups, heterocyclics, aliphatic groups, heteroaliphatic groups, heteroaryl groups; each of which may be selected independently by 1, 2, 3 or 4 radicals, where valence permits. 40 Substituents are used to form stable compounds;

[0439] R 20 It is an aliphatic group, including alkyl groups; and

[0440] R 23 It is hydrogen, alkyl, halogen, or haloalkyl.

[0441] In some implementations, R 1 Selected from:

[0442]

[0443] Or its pharmaceutically acceptable salt.

[0444] Non-limiting implementations of A: In some implementations, A is selected from:

[0445]

[0446] In some implementations, A is selected from:

[0447]

[0448] In some implementations, A is selected from:

[0449]

[0450] In some implementations, A is selected from:

[0451]

[0452] In some implementations, A is selected from:

[0453]

[0454] In some implementations, A is selected from:

[0455]

[0456] In some embodiments, the compound of formula I has the following formula:

[0457] Or its pharmaceutically acceptable salt, wherein:

[0458] R 2 yes and

[0459] X 4 Selected from alkyl, aliphatic, aryl, heteroaryl, bicyclic, and -NR groups. 27 -、-NR 10 -、-CR 40 R 41 -、-O-、-C(O-、-C(NR) 27 -, -C(S)-, -S(O)-, -S(O)2-, –S-, piperidine bonded to a tricyclic ring via N in the piperidine ring, 6-membered heterocycles having 2, 3, or 4 heteroatoms, and 4, 5, or 7-membered heterocycles having 1, 2, 3, or 4 heteroatoms; each of which may be optionally composed of 1, 2, 3, or 4 independently selected non-hydrogen R atoms, where valence permits. 40 Substituents are used to replace the compounds to form stable compounds.

[0460] In some embodiments, the compounds of the present invention are selected from:

[0461]

[0462]

[0463] Or its pharmaceutically acceptable salt.

[0464] In some embodiments, the compounds of the present invention are selected from:

[0465]

[0466]

[0467] Or its pharmaceutically acceptable salt.

[0468] In some embodiments, the compounds of the present invention are selected from:

[0469]

[0470]

[0471] Or its pharmaceutically acceptable salt.

[0472] X's implementation plan

[0473] In some implementations, X is a key.

[0474] In some implementations, X is oxygen.

[0475] In some implementations, X is sulfur.

[0476] In some implementations, X is -NR 27 -

[0477] In some implementations, X is -NR 10 -

[0478] In some implementations, X is -CR 40 R 41 -

[0479] In some implementations, X is -C(O)-.

[0480] In some implementations, X is -C(NR) 27 )-.

[0481] In some implementations, X is -C(S)-.

[0482] In some implementations, X is -S(O)2-.

[0483] In some implementations, X is -C(S)-.

[0484] In some implementations, X is -C(S)-.

[0485] In some implementations, X is -C(S)-.

[0486] In some implementations, X is a 5-membered aromatic heterocycle with the connection point in the 1,3 direction.

[0487] In some implementations, X is a 5-membered aromatic heterocycle with the connection point in the 1,2 direction.

[0488] In some implementations, X is a 6-membered aromatic heterocycle with the connection point in the 1,2 direction.

[0489] In some implementations, X is a 6-membered aromatic heterocycle with the connection point in the 1,3 direction.

[0490] In some implementations, X is a 6-membered aromatic heterocycle with the connection point in the 1,4 direction.

[0491] In some implementations, X is a 6-membered aromatic heterocycle with the connection point in the 1,3 direction.

[0492] In some implementations, X is a 5-membered heterocycle with the connection point in the 1,2 direction.

[0493] In some implementations, X is a 5-membered heterocycle with the connection point in the 1,3 direction.

[0494] In some implementations, X is a 6-membered heterocycle with the connection point in the 1,2 direction.

[0495] In some implementations, X is a 6-membered heterocycle with the connection point in the 1,3 direction.

[0496] In some implementations, X is a 6-membered heterocycle with the connection point in the 1,4 direction.

[0497] In some implementations, X is a bicyclic heterocycle having one heteroatom.

[0498] In some implementations, X is a bicyclic heterocycle having two heteroatoms.

[0499] In some embodiments, X is a bicyclic heterocycle having one heteroatom and one linker bonded to nitrogen and another linker bonded to carbon.

[0500] In some embodiments, X is a bicyclic heterocycle with one heteroatom and both connection sites are bonded to carbon.

[0501] In some embodiments, X is a bicyclic heterocycle with two heteroatoms, and both connection sites are bonded to nitrogen.

[0502] In some implementations, X is a bicyclic heterocycle having two heteroatoms.

[0503] In some implementations, X is a fused bicycloalkanes.

[0504] In some implementations, X is a spiro-bicycloalkane.

[0505] In some implementations, X is selected from:

[0506]

[0507] R 4 and R 5 Implementation plan

[0508] In some implementations, R 4 It is hydrogen.

[0509] In some implementations, R 4 It is an alkyl group.

[0510] In some implementations, R 4 It's fluorine.

[0511] In some implementations, R 4 It is chlorine.

[0512] In some implementations, R 4 It is bromine.

[0513] In some implementations, R 4 It is a haloalkyl group.

[0514] In some implementations, R 4 Yes - OR 10 .

[0515] In some implementations, R 4 It is -SR 10 .

[0516] In some implementations, R 4 It is -S(O)R 12 .

[0517] In some implementations, R 4 Yes - SO2R 12 .

[0518] In some implementations, R 4 Yes -NR 10 R 11 .

[0519] In some implementations, R 5 It is hydrogen.

[0520] In some implementations, R 5 It is an alkyl group.

[0521] In some implementations, R 5 It is a haloalkyl group.

[0522] In some implementations, R 5 Yes - OR10 .

[0523] In some implementations, R 5 It is -SR 10 .

[0524] In some implementations, R 5 It is -S(O)R 12 .

[0525] In some implementations, R 5 Yes - SO2R 12 .

[0526] In some implementations, R 5 Yes -NR 10 R 11 .

[0527] In some implementations, R 4 and R 5 Selected from:

[0528] R 6 and R 7 Implementation plan

[0529] In some implementations, R 6 It is hydrogen.

[0530] In some implementations, R 6 It is an alkyl group.

[0531] In some implementations, R 6 It's fluorine.

[0532] In some implementations, R 6 It is chlorine.

[0533] In some implementations, R 6 It is bromine.

[0534] In some implementations, R 6 It is a haloalkyl group.

[0535] In some implementations, R 6 Yes - OR 10 .

[0536] In some implementations, R 6 It is -SR 10 .

[0537] In some implementations, R 6 It is -S(O)R 12 .

[0538] In some implementations, R6 Yes - SO2R 12 .

[0539] In some implementations, R 6 Yes -NR 10 R 11 .

[0540] In some implementations, R 7 It is hydrogen.

[0541] In some implementations, R 7 It is an alkyl group.

[0542] In some implementations, R 7 It's fluorine.

[0543] In some implementations, R 7 It is chlorine.

[0544] In some implementations, R 7 It is bromine.

[0545] In some implementations, R 7 It is a haloalkyl group.

[0546] In some implementations, R 7 Yes - OR 10 .

[0547] In some implementations, R 7 It is -SR 10 .

[0548] In some implementations, R 7 It is -S(O)R 12 .

[0549] In some implementations, R 7 Yes - SO2R 12 .

[0550] In some implementations, R 7 Yes -NR 10 R 11 .

[0551] In some implementations, R 6 and R 7 Selected from:

[0552] R 10 and R 11 Implementation plan

[0553] In some implementations, R 10 and R 11 It is hydrogen.

[0554] In some implementations, R 10 It is hydrogen.

[0555] In some implementations, R 11 It is hydrogen.

[0556] In some implementations, R 10 It is an alkyl group.

[0557] In some implementations, R 10 It is a methyl group.

[0558] In some implementations, R 10 It is an aliphatic group.

[0559] In some implementations, R 10 It is a haloalkyl group.

[0560] In some implementations, R 10 It is a heterocyclic ring.

[0561] In some implementations, R 10 It is an aryl group.

[0562] In some implementations, R 10 It is a heteroaryl group.

[0563] In some implementations, R 10 It is -C(O)R 12 .

[0564] In some implementations, R 10 It is -S(O)R 12 .

[0565] In some implementations, R 10 Yes - SO2R 12 .

[0566] In some implementations, R 11 It is an alkyl group.

[0567] In some implementations, R 11 It is a methyl group.

[0568] In some implementations, R 11 It is an aliphatic group.

[0569] In some implementations, R 11 It is a haloalkyl group.

[0570] In some implementations, R 11 It is a heterocyclic ring.

[0571] In some implementations, R 11 It is an aryl group.

[0572] In some implementations, R 11 It is a heteroaryl group.

[0573] In some implementations, R 11 It is -C(O)R 12 .

[0574] In some implementations, R 11 It is -S(O)R 12 .

[0575] In some implementations, R 11 Yes - SO2R 12 .

[0576] R 12 Implementation plan

[0577] In some implementations, R 12 It is hydrogen.

[0578] In some implementations, R 12 It is an alkyl group.

[0579] In some implementations, R 12 It is a haloalkyl group.

[0580] In some implementations, R 12 It is a heterocyclic ring.

[0581] In some implementations, R 12 It is an aryl group.

[0582] In some implementations, R 12 It is a heteroaryl group.

[0583] In some implementations, R 12 Yes -NR 13 R 14 .

[0584] In some implementations, R 12 OR 13 R 15 R 16 and R 17 Implementation plan

[0585] In some implementations, R 15 It is a key.

[0586] In some implementations, R 15 It is an alkyl group.

[0587] In some implementations, R 15 It is an aliphatic group.

[0588] In some implementations, R 15 It is an aryl group.

[0589] In some implementations, R 15 It's the Second Ring Road.

[0590] In some implementations, R 15 It is an olefin.

[0591] In some implementations, R 15 It is an alkyne.

[0592] In some implementations, R 15 It is a haloalkyl group.

[0593] In some implementations, R 15 It is an alkoxy group.

[0594] In some implementations, R 15 It is a heteroaryl group.

[0595] In some implementations, R 15 It is a heterocyclic ring.

[0596] In some implementations, R 15 It is a cycloalkyl group.

[0597] In some implementations, R 15 It is a heteroaliphatic base.

[0598] In some implementations, R 15 Yes -NR 27 -

[0599] In some implementations, R 15 Yes -NR 10 .

[0600] In some implementations, R 15 Yes -CR 40 R 41 -

[0601] In some implementations, R 15 It is oxygen.

[0602] In some implementations, R 15 It is -C(O)-.

[0603] In some implementations, R 15 It is -C(S)-.

[0604] In some implementations, R 15 It's sulfur.

[0605] In some implementations, R15 It is -C(S)-.

[0606] In some implementations, R 15 It is -OC(O)-.

[0607] In some implementations, R 15 It is -C(O)O-.

[0608] In some implementations, R 15 It is -C(O)NR 27 -

[0609] In some implementations, R 15 Yes -NR 27 C(O)-.

[0610] In some implementations, R 15 Yes -NR 10 -

[0611] In some implementations, R 15 It is a 6-membered aryl group with the connection point in the 1,2 direction.

[0612] In some implementations, R 15 It is a 6-membered aryl group with the connection point in the 1,3 direction.

[0613] In some implementations, R 15 It is a 6-membered aryl group with the connection point in the 1,4 direction.

[0614] In some implementations, R 15 It is a 6-membered aryl group with the connection point in the 1,2 direction.

[0615] In some implementations, R 15 It is a heteroaryl group with the connection point in the 1,2 direction.

[0616] In some implementations, R 15 It is a heteroaryl group with the connection point in the 1,2 direction.

[0617] In some implementations, R 15 It is an aryl group with the connection point in the 1,2 direction.

[0618] In some implementations, R 16 It is a key.

[0619] In some implementations, R 16 It is an alkyl group.

[0620] In some implementations, R 16 It is an aliphatic group.

[0621] In some implementations, R16 It is an aryl group.

[0622] In some implementations, R 16 It's the Second Ring Road.

[0623] In some implementations, R 16 It is an olefin.

[0624] In some implementations, R 16 It is an alkyne.

[0625] In some implementations, R 16 It is a haloalkyl group.

[0626] In some implementations, R 16 It is an alkoxy group.

[0627] In some implementations, R 16 It is a heteroaryl group.

[0628] In some implementations, R 16 It is a heterocyclic ring.

[0629] In some implementations, R 16 It is a cycloalkyl group.

[0630] In some implementations, R 16 It is a heteroaliphatic base.

[0631] In some implementations, R 16 Yes -NR 27 -

[0632] In some implementations, R 16 Yes -NR 10 .

[0633] In some implementations, R 16 Yes -CR 40 R 41 -

[0634] In some implementations, R 16 It is oxygen.

[0635] In some implementations, R 16 It is -C(O)-.

[0636] In some implementations, R 16 It is -C(S)-.

[0637] In some implementations, R 16 It's sulfur.

[0638] In some implementations, R 16 It is -C(S)-.

[0639] In some implementations, R 16 It is -OC(O)-.

[0640] In some implementations, R 16 It is -C(O)O-.

[0641] In some implementations, R 16 It is -C(O)NR 27 -

[0642] In some implementations, R 16 Yes -NR 27 C(O)-.

[0643] In some implementations, R 16 Yes -NR 10 -

[0644] In some implementations, R 16 It is a 6-membered aryl group with the connection point in the 1,2 direction.

[0645] In some implementations, R 16 It is a 6-membered aryl group with the connection point in the 1,3 direction.

[0646] In some implementations, R 16 It is a 6-membered aryl group with the connection point in the 1,4 direction.

[0647] In some implementations, R 16 It is a 6-membered aryl group with the connection point in the 1,2 direction.

[0648] In some implementations, R 16 It is a heteroaryl group with the connection point in the 1,2 direction.

[0649] In some implementations, R 16 It is a heteroaryl group with the connection point in the 1,2 direction.

[0650] In some implementations, R 16 It is an aryl group with the connection point in the 1,2 direction.

[0651] In some implementations, R 17 It is a key.

[0652] In some implementations, R 17 It is an alkyl group.

[0653] In some implementations, R 17 It is an aliphatic group.

[0654] In some implementations, R 17 It is an aryl group.

[0655] In some implementations, R 17 It's the Second Ring Road.

[0656] In some implementations, R 17 It is an olefin.

[0657] In some implementations, R 17 It is an alkyne.

[0658] In some implementations, R 17 It is a haloalkyl group.

[0659] In some implementations, R 17 It is an alkoxy group.

[0660] In some implementations, R 17 It is a heteroaryl group.

[0661] In some implementations, R 17 It is a heterocyclic ring.

[0662] In some implementations, R 17 It is a cycloalkyl group.

[0663] In some implementations, R 17 It is a heteroaliphatic base.

[0664] In some implementations, R 17 Yes -NR 27 -

[0665] In some implementations, R 17 Yes -NR 10 .

[0666] In some implementations, R 17 Yes -CR 40 R 41 -

[0667] In some implementations, R 17 It is oxygen.

[0668] In some implementations, R 17 It is -C(O)-.

[0669] In some implementations, R 17 It is -C(S)-.

[0670] In some implementations, R 17 It's sulfur.

[0671] In some implementations, R 17 It is -C(S)-.

[0672] In some implementations, R17 It is -OC(O)-.

[0673] In some implementations, R 17 It is -C(O)O-.

[0674] In some implementations, R 17 It is -C(O)NR 27 -

[0675] In some implementations, R 17 Yes -NR 27 C(O)-.

[0676] In some implementations, R 17 Yes -NR 10 -

[0677] In some implementations, R 17 It is a 6-membered aryl group with the connection point in the 1,2 direction.

[0678] In some implementations, R 17 It is a 6-membered aryl group with the connection point in the 1,3 direction.

[0679] In some implementations, R 17 It is a 6-membered aryl group with the connection point in the 1,4 direction.

[0680] In some implementations, R 17 It is a 6-membered aryl group with the connection point in the 1,2 direction.

[0681] In some implementations, R 17 It is a heteroaryl group with the connection point in the 1,2 direction.

[0682] In some implementations, R 17 It is a heteroaryl group with the connection point in the 1,2 direction.

[0683] In some implementations, R 17 It is an aryl group with the connection point in the 1,2 direction.

[0684] In some implementations, R 18 It is hydrogen.

[0685] In some implementations, R 18 It is halogen.

[0686] In some implementations, R 18 It is a cyano group.

[0687] In some implementations, R 18 It is -C(O)OR 27 .

[0688] In some implementations, R 18 It is an alkyl group.

[0689] In some implementations, R 18 It is -C(O)NR 10 R 27 .

[0690] In some implementations, R 18 Yes -NR 27 C(O)R 27 .

[0691] In some implementations, R 18 Yes – NR 10 R 27 .

[0692] In some implementations, R 18 It is SR 27 .

[0693] In some implementations, R 18 It is a haloalkyl group.

[0694] In some implementations, R 18 It is an alkoxy group.

[0695] In some implementations, R 18 It is an aryl group.

[0696] In some implementations, R 18 It is a heterocyclic ring.

[0697] In some implementations, R 18 It is an aliphatic group.

[0698] In some implementations, R 18 It is a heteroaliphatic base.

[0699] In some implementations, R 18 It is a heteroaryl group.

[0700] In some implementations, R 18 Yes - OR 27 .

[0701] R 19 Implementation plan

[0702] In some implementations, R 19 It is an alkyl group.

[0703] In some implementations, R 19 It is hydrogen.

[0704] In some implementations, R 19 It is -C(O)NR10 R 27 .

[0705] In some implementations, R 19 It is -C(O)OR 27 .

[0706] In some implementations, R 19 It is -C(O)R 27 .

[0707] In some implementations, R 19 It is an olefin.

[0708] In some implementations, R 19 It is an alkyne.

[0709] In some implementations, R 19 It is a haloalkyl group.

[0710] In some implementations, R 19 It is an alkoxy group.

[0711] In some implementations, R 19 It is an aryl group.

[0712] In some implementations, R 19 It is a heterocyclic ring.

[0713] In some implementations, R 19 It is an aliphatic group.

[0714] In some implementations, R 19 It is a heteroaliphatic base.

[0715] In some implementations, R 19 It is a heteroaryl group.

[0716] R 20 Implementation plan

[0717] In some implementations, R 20 It is an aliphatic group.

[0718] In some implementations, R 20 It is an alkyl group.

[0719] In some implementations, R 20 Selected from:

[0720]

[0721] R 23 Implementation plan

[0722] In some implementations, R 23 It is hydrogen.

[0723] In some implementations, R 23 It's fluorine.

[0724] In some implementations, R 23 It is bromine.

[0725] In some implementations, R 23 It is chlorine.

[0726] In some implementations, R 23 It is a haloalkyl group.

[0727] In some implementations, R 23 Selected from:

[0728]

[0729] R 27 Implementation plan

[0730] In some implementations, R 27 It is hydrogen.

[0731] In some implementations, R 27 It is an alkyl group.

[0732] In some implementations, R 27 It is an arylalkyl group.

[0733] In some implementations, R 27 It is a heteroarylalkyl group.

[0734] In some implementations, R 27 It is an olefin.

[0735] In some implementations, R 27 It is an alkyne.

[0736] In some implementations, R 27 It is an aryl group.

[0737] In some implementations, R 27 It is a heteroaryl group.

[0738] In some implementations, R 27 It is a heterocyclic ring.

[0739] In some implementations, R 27 It is a cycloalkyl group.

[0740] In some implementations, R 27 It is an aliphatic group.

[0741] In some implementations, R 27 It is a heteroaliphatic base.

[0742] In some implementations, R 27 Selected from:

[0743]

[0744] R 40 Implementation plan

[0745] In some implementations, R 40 It is hydrogen.

[0746] In some implementations, R 40 It is an aliphatic group.

[0747] In some implementations, R 40 It is a heteroaliphatic base.

[0748] In some implementations, R 40 It is a cyano group.

[0749] In some implementations, R 40 It is a nitro group.

[0750] In some implementations, R 40 It is an alkyl group.

[0751] In some implementations, R 40 It's fluorine.

[0752] In some implementations, R 40 It is chlorine.

[0753] In some implementations, R 40 It is bromine.

[0754] In some implementations, R 40 It is a haloalkyl group.

[0755] In some implementations, R 40 Yes - OR 10 .

[0756] In some implementations, R 40 It is -SR 10 .

[0757] In some implementations, R 40 It is -S(O)R 12 .

[0758] In some implementations, R 40 Yes - SO2R 12 .

[0759] In some implementations, R 40 Yes -NR 10 R11 .

[0760] In some implementations, R 40 Selected from:

[0761] R 41 Implementation plan

[0762] In some implementations, R 41 It is an aliphatic group.

[0763] In some implementations, R 41 It is a heteroaryl group.

[0764] In some implementations, R 41 It is hydrogen.

[0765] In some implementations, R 41 It is an aliphatic group.

[0766] In some implementations, R 41 It is an aliphatic group.

[0767] In some implementations, R 41 It is an aliphatic group.

[0768] In some implementations, R 41 Selected from:

[0769] R 42 Implementation plan

[0770] In some implementations, R 42 Selected from:

[0771]

[0772] Non-limiting examples of compounds of formula I

[0773] Representative examples of compounds of formula I include:

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781] Or its pharmaceutically acceptable salt.

[0782] Non-restrictive isotope implementation scheme

[0783] In some embodiments, the compound is isotopically labeled. In some embodiments, it is independently selected from 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 is isotopically labeled using isotopes with 1, 2, or more valence states. In some embodiments, the isotopic label is deuterium. In some embodiments, at least one deuterium is placed on an atom having a bond that is broken during metabolism within the compound, or one, two, or three atoms distant from metabolic bonds (e.g., which may be referred to as α, β, or γ, or primary, secondary, or tertiary isotope effects). In another embodiment, the isotopic label is... 13 C. In another embodiment, isotope labeling is 18 F.

[0784] III. Treatment Methods

[0785] Any tricyclic compound described herein can be used in an effective amount to treat a host in need, including humans, optionally in a pharmaceutically acceptable carrier to treat any of the conditions described herein. In some embodiments, the method includes administering an effective amount of an active compound as described herein or a salt thereof, optionally including a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), optionally in combination with or alternating with other therapeutic agents or pharmaceutical agents.

[0786] In some embodiments, the compounds of the present invention selectively degrade IKZF2 and / or IKZF4 compared to one or more of IKZF1 and / or IKZF3 and / or IKZF5.

[0787] In some embodiments, the condition treated by the compounds of the present invention is an immunomodulatory condition. In some embodiments, the condition treated by the compounds of the present invention is angiogenesis-mediated. In some embodiments, the condition treated by the compounds of the present invention is related to the lymphatic system.

[0788] In some embodiments, pharmaceutically acceptable salts of the compounds of the present invention, optionally in pharmaceutical compositions as described herein, are used to degrade IKZF2 or IKZF4, which are mediators of conditions affecting patients, such as humans. Control of protein levels provided by any of the compounds of the present invention provides treatment for disease states or conditions that are modulated by reducing protein levels in cells (e.g., the patient's cells) or by reducing levels of downstream proteins within the cells via IKZF2 or IKZF4. In some embodiments, the method comprises administering an effective amount of a compound as described herein, optionally including pharmaceutically acceptable excipients, carriers, adjuvants (i.e., pharmaceutically acceptable compositions), optionally in combination with or alternating with other therapeutically active agents or pharmaceutical agents.

[0789] In some embodiments, the compounds of the present invention are used to treat conditions, including but not limited to benign growths, tumors, lumps, cancers, abnormal cell proliferation, immune disorders, inflammatory conditions, graft-versus-host rejection, viral infections, bacterial infections, amyloid-based proteopathies, proteopathies, or fibrotic diseases.

[0790] When used in combination with any compound, the term "disease state" or "symptom" refers to any disease state or symptom mediated by IKZF2 or IKZF4, such as cell proliferation, or any disease state or symptom mediated by proteins downstream of IKZF2 or IKZF4, wherein the degradation of such proteins in the patient's body can provide beneficial treatment or symptom relief for the patient in need. In some cases, the disease state or symptom can be cured.

[0791] In some embodiments, a host, such as a human, suffering from lymphoma or a lymphocyte or bone marrow cell proliferation disorder or abnormality may be treated with an effective amount of the compound described herein or its corresponding pharmaceutically acceptable salt, isotope derivative, or prodrug. For example, the compound described herein may be administered to a host suffering from Hodgkin lymphoma or non-Hodgkin lymphoma. For example, the host may have non-Hodgkin's lymphoma, such as, but not limited to: AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK-cell lymphoma; Burkitt lymphoma; Burkitt-like lymphoma (small non-lytic cell lymphoma); diffuse small cleaved cell 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; transformed lymphoma; treatment-related T-cell lymphoma; Langerhans cell histiocytosis; or Waldenström macroglobulinemia.

[0792] In another embodiment, a host, such as a human, suffering from Hodgkin lymphoma may be treated with an effective amount of the compound as described herein or its corresponding pharmaceutically acceptable salt, isotope derivative, or prodrug, such as, tuberous sclerosis classical Hodgkin lymphoma (CHL); mixed-cell CHL; lymphocyte-depleted CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin lymphoma; or nodular lymphocyte-predominant HL.

[0793] In another embodiment, a host suffering from an immunomodulatory disorder, such as a human, may be treated with an effective amount of the compound as described herein or its corresponding pharmaceutically acceptable salt, isotope derivative, or prodrug. Non-limiting examples of immunomodulatory disorders include: arthritis, lupus, celiac disease, Sjögren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes, alopecia areata, vasculitis, and temporal arteritis.

[0794] In some embodiments, the condition treated with the compounds of the present invention is a condition related to abnormal cell proliferation. Abnormal cell proliferation, particularly excessive proliferation, can be caused by a variety of factors, including gene mutations, infections, exposure to toxins, autoimmune diseases, and benign or malignant tumors.

[0795] Abnormal proliferation of B cells, T cells, and / or NK cells can lead to a variety of diseases, such as cancer, proliferative disorders, and inflammatory / immune diseases. Hosts, such as humans, suffering from any of these conditions can be treated with effective amounts of compounds as described herein to achieve symptom reduction (palliative agents) or reduction of underlying disease (disease modulators).

[0796] In some embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives, or prodrugs, can be used in effective amounts to treat a host, such as a human, with a specific B-cell lymphoma or proliferative disorder, including but 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; marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary exudative lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; hairy cell leukemia; splenic lymphoma / leukemia, unclassifiable; diffuse splenic erythromycin small B-cell lymphoma; hairy cell ... Cellular leukemia variants; lymphoplasmacytic lymphoma; heavy chain diseases, such as alpha heavy chain disease, gamma heavy chain disease, and Mu heavy chain disease; plasmacytic myeloma; solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicular center lymphoma; large B-cell lymphoma rich in T cells / histocytes; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL, leg type; ALK + large B-cell lymphoma; plasmablastic lymphoma; HHV8-associated multicentric large B-cell lymphoma; Kassman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma; or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0797] In some embodiments, the compounds described herein, or their corresponding pharmaceutical salts, isotope derivatives, or prodrugs, can be used in effective amounts to treat a host with T-cell or NK-cell lymphoma, such as a human, for example, T-cell or NK-cell lymphomas, including, but 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, such as mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorders; primary cutaneous invasive epidermal CD8+ cytotoxic T-cell lymphoma; primary cutaneous γ-δ T-cell lymphoma; primary cutaneous small / medium CD4+ T-cell lymphoma. Tumors and lymphomatoid papulosis; adult T-cell leukemia / lymphoma (ATLL); blastoblastic NK-cell lymphoma; enteropathy-associated T-cell lymphoma; blood-splenic γ-δ T-cell lymphoma; lymphoblastic lymphoma; nasal NK / T-cell lymphoma; treatment-associated T-cell lymphoma; lymphoma following solid organ or bone marrow transplantation; T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; NK-cell chronic lymphoproliferative disorder; aggressive NK-cell leukemia; childhood systemic EBV+ T-cell lymphoproliferative disorder (associated with chronic active EBV infection); Hydroa vaccinia-like lymphoma; adult T-cell leukemia / lymphoma; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; or subcutaneous panniculitis-like T-cell lymphoma.

[0798] In some embodiments, the compound as described herein, or its corresponding pharmaceutically acceptable salt, isotope derivative, or prodrug, may be used to treat a host, such as a human, suffering from leukemia. For example, the host may have acute or chronic leukemia of lymphocytic or bone marrow origin, such as, but 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); large granular lymphoblastic leukemia; or adult T-cell chronic leukemia. In one implementation, the patient has acute myeloid leukemia, such as undifferentiated AML (M0); myeloblastic leukemia (M1; with / without minimum cell maturation); myeloblastic leukemia (M2; cell maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroblastic leukemia (M6); or megakaryoblastic leukemia (M7).

[0799] Many skin diseases are associated with excessive cell proliferation. For example, psoriasis is a benign skin disease in humans, typically characterized by plaques covered with thickened scales. This disease is caused by an unexplained increase in the proliferation of epidermal cells. Chronic eczema is also associated with significant excessive proliferation of the epidermis. 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.

[0800] Other proliferative cell disorders include angiogenesis disorders, fibrosis disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancer.

[0801] Angiogenic disorders include vascular origin disorders and angiogenesis 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.

[0802] Fibrotic disorders are typically caused by abnormal formation of the extracellular matrix. Examples of fibrotic disorders include cirrhosis and mesangial proliferative cell disease. Cirrhosis is characterized by an increase in extracellular matrix components, leading to liver scarring. Cirrhosis can cause diseases such as liver cirrhosis. The increase in extracellular matrix leading to liver scarring can also be caused by viral infections such as hepatitis. Adipocytes appear to play a major role in cirrhosis.

[0803] Mesangial diseases are caused by the abnormal proliferation of mesangial cells. Diseases of excessive mesangial cell proliferation include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrocisic nephropathy, thrombotic microangiopathy syndrome, transplant rejection, and glomerulonephropathy.

[0804] Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease, thought to be related to the activity of autoreactive T cells and caused by autoantibodies against collagen and IgE.

[0805] Other diseases that may include abnormal cell proliferation components include Bechet syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, postdialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and general inflammation.

[0806] The compounds described herein, or their pharmaceutically acceptable salts, isotope analogs, or prodrugs, can be used in effective amounts to treat hosts with proliferative disorders, such as humans, including myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myelomecosis with myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), eosinophilia (HES), systemic mast cell disease (SMCD), etc. In another embodiment, the compounds provided herein can be used to treat essential myelofibrosis, post-polycythemia vera myelofibrosis, post-esophagectomy myelofibrosis, and secondary acute myeloid leukemia.

[0807] In some embodiments, the compound described herein or its pharmaceutically acceptable salt, isotope analog, or prodrug may be used in an effective amount to treat a host with myelodysplastic syndromes (MDS), such as a human, including, but not limited to: refractory cytopenia with monolineage dysplasia, refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts-thrombocytosis (RARS-t), refractory cytopenia with multilineage dysplasia (RCMD), including RCMD with multilineage dysplasia and ringed sideroblasts (RCMD-RS), refractory amenorrhea with excessive blast cells I (RAEB-I) and II (RAEB-II), 5q- syndrome, refractory cytopenia in children, etc.

[0808] In one embodiment, the compounds of the present invention can provide therapeutic effects by directly degrading Helios or Eos, which can alter the transcriptional regulation of downstream proteins of Helios or Eos.

[0809] The terms "tumor formation" or "cancer" are used to refer to the pathological process that leads to the formation and growth of cancerous or malignant tumors. This involves abnormal tissue that grows through cell proliferation, typically faster than normal tissue, and continues to grow even after the stimulus that triggered new growth has ceased. Malignant tumors exhibit a partial or complete lack of structural organization and functional coordination with normal tissue. Most invade surrounding tissues, metastasize to multiple sites, and are likely to recur after attempted resection, leading to patient death unless adequate treatment is received. As used herein, the term "tumor formation" is used to describe all cancerous disease states and includes or encompasses the pathological processes associated with malignant hematogenous, ascites, and solid tumors. Exemplary cancers that can be treated alone or in combination with at least one other anticancer agent include: squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, colorectal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, sarcoma, peripheral neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, etc. Glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell carcinoma, meningioma, meningeal sarcoma, neurofibroma, and schwannoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratoma. Other cancers that can be treated with the compounds according to the invention include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphocytic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-BALL, pre-B lymphoma, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[0810] Other cancers that can be treated with the compounds disclosed in this invention include, for example, acute myeloid leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendiceal cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, colorectal cancer, brain cancer, brainstem glioma, breast cancer, triple (estrogen, progesterone, and HER-2) negative breast cancer, double-negative breast cancer (two of estrogen, progesterone, and HER-2 are negative), single-negative (one of estrogen, progesterone, and HER-2 is negative), estrogen receptor-positive, HER2-negative breast cancer. Estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, metastatic breast cancer, luminal type A breast cancer, luminal type 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, chondroma, chondrosarcoma, chronic lymphocytic leukemia (CLL), 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 sarcoma, extrahepatic bile duct cancer, ocular cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, stomach Intestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), inflammatory breast cancer (IBC), colorectal cancer, intrahepatic cholangiocarcinoma, invasive / invasive breast cancer, islet cell carcinoma, jawbone cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal... Metastatic breast cancer, metastatic melanoma, metastatic squamous cell carcinoma of the neck, mixed glioma, monodermal teratoma, oral cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, fungal infections, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal carcinoma, cervical cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteosarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumors, primary ovarian peritoneal cancer, ovarian sex cord-stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, sinus cancer, parathyroid carcinoma, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancerPheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineal cell carcinoma, pituitary cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis carcinoma, rhabdomyosarcoma, salivary gland carcinoma, soft tissue sarcoma, osteosarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cord cancer, spinal cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterus cancer, uterine cancer ... Uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-BALL, Pre-B lymphoma, large B-cell lymphoma, Burkitts 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 lymphoblastic leukemia, adult T-cell chronic leukemia, diffuse large B-cell lymphoma, follicular lymphoma. Lymphoma; Mucosa-associated lymphoid tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B-cell lymphoma, marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary exudative lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; splenic lymphoma / leukemia, unclassifiable, diffuse splenic erythromycin small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain disease, such as alpha heavy chain disease, gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicular center lymphoma, Large B-cell lymphoma rich in T cells / histocytes; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL, leg type, ALK + large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma caused by HHV8-associated multicentric disease, Castleman's disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma. In some embodiments, the condition is adenoid cystic carcinoma. In some embodiments, the condition is NUT midline carcinoma.

[0811] In another embodiment, the compound described herein, or its pharmaceutically acceptable salt, isotope derivative, or prodrug, may be used in an effective amount to treat a host suffering from an autoimmune disease, such as a human. Examples include, but are not limited to: acute disseminated encephalomyelitis (ADEM); Addison's disease; agammaglobulinemia; alopecia areata; amyotrophic lateral sclerosis (also called Luger's disease; motor neuron disease); ankylosing spondylitis; antiphospholipid syndrome; antisynergistic 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; and so on. Immune peripheral neuropathy; autoimmune ovarian failure; autoimmune polyendocrine syndrome; autoimmune progesterone dermatitis; autoimmune thrombocytopenic purpura; autoimmune thyroid disease; autoimmune urticaria; autoimmune uveitis; autoimmune vasculitis; Balo disease / Balo concentric sclerosis; Behçet's disease; Bergey's disease; Bickerstaff encephalitis; Blau syndrome; bullous pemphigoid; cancer; Kassman's disease; celiac disease; Chagas disease; chronic inflammatory demyelinating polyneuropathy; chronic obstructive pulmonary disease; chronic relapsing multifocal osteomyelitis; Churg-Strauss disease. Syndrome; Cicatricial pemphigoid; Cogan syndrome; Cold agglutinin disease; Supplement 2 deficiency; Contact dermatitis; Cranial arteritis; CREST syndrome; Crohn's disease; Cushing's syndrome; Cutaneous leukocytoclastic vasculitis; Dego's disease; Dercum's disease; Herpetic dermatitis; Dermatomyositis; Type 1 diabetes; Diffuse systemic sclerosis of the cutaneous region; Discoid lupus erythematosus; Dereskir syndrome; Drug-induced lupus; Eczema; Endometriosis; Enthes-associated arthritis; Eosinophilic fasciitis; Eosinophilic gastroenteritis; Eosinophilic pneumonia; Epidermolysis bullosa; Erythema nodosum; Erythroblastosis; Basic mixed cryoglobulinemia; Evan's syndrome; External and internal reactivity Airway diseases (asthma); progressive fibrosis; fibrotic alveolitis (or idiopathic pulmonary fibrosis); gastritis; gastrointestinal pemphigoid; glomerulonephritis; Goodpasture syndrome; Graves' disease; Guillain-Barré syndrome (GBS); Hashimoto's encephalopathy; Hashimoto's thyroiditis; hemolytic anemia; allergic purpura; herpes gestationis (pemphigoid of pregnancy); hidradenitis suppurativa; Hughes-Stoven 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 sclerosis; linear IgA disease (LAD); lupus hepatitis, also known as autoimmune hepatitis; systemic lupus erythematosus; Majid syndrome; microscopic polyangiitis; Miller-Fisher syndrome; mixed connective tissue disease; morphea; Mucha-Habermann disease, also known as acute pustular lichenoid pityriasis; multiple sclerosis; myasthenia gravis; myositis; Meniere's disease; narcolepsy; neuromyelitis optica (also known as Dweck's disease); neuromuscular rigidity; ocular cicatricial pemphigoid; ocular myoclonus syndrome; Auder's thyroiditis; palindromic rheumatism; PANDAS (a streptococcal-associated pediatric autoimmune neuropsychiatric disorder); paraneoplastic cerebellar degeneration; paroxysmal nocturnal hemoglobinuria (PNH); Parry-Romberg syndrome; tonsillitis; Clerk-Turner syndrome; pemphigus vulgaris; peripheral encephalomyelitis; pernicious anemia; POEMS syndrome; polyarteritis nodosa; polymyalgia rheumatica Pain; Polymyositis; Primary biliary cirrhosis; Primary sclerosing cholangitis; Progressive inflammatory neuropathy; Psoriasis; Psoriatic arthritis; Pure red cell aplasia; Pyoderma gangrenosa; Rasmussen encephalitis; Raynaud's phenomenon; Ritter syndrome; Relapsing polychondritis; Restless legs syndrome; Retroperitoneal fibrosis; Rheumatic fever; Rheumatoid arthritis; Sarcoidosis; Schmidt syndrome; Schnitzler syndrome; Scleritis; Scleroderma; Sclerosing cholangitis; Serum sickness; Sjögren's syndrome; Spondyloarthropathy; Stiff-person syndrome; Still's disease; Sub Acute bacterial endocarditis (SBE); Sussac syndrome; Sweet syndrome; Sidnam's chorea; sympathetic ophthalmia; systemic lupus erythematosus; Goran's arteritis; temporal arteritis (also known as "giant cell arteritis"); thrombocytopenia; Tolosa-Hunt syndrome; transverse myelitis; ulcerative colitis; undifferentiated connective tissue disease; indiscriminate spondyloarthritis; urticarial vasculitis; vasculitis; vitiligo; viral diseases such as Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTL V1, varicella-zoster virus (VZV), and human papillomavirus (HPV); or Wegener's granulomatosis. In some implementations, autoimmune diseases are allergic diseases, including those arising from asthma, food allergies, atopic dermatitis, chronic pain, and rhinitis.

[0812] Skin contact allergies and asthma are just two examples of immune responses that may be associated with a significant incidence rate. Others 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 conjunctivitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may cause any one or more of the following symptoms or signs: itching, swelling, redness, blisters, crusting, ulceration, pain, scaling, cracking, hair loss, scarring, or fluid exudation involving the skin, eyes, or mucous membranes.

[0813] In atopic dermatitis and eczema in general, immune-mediated leukocyte infiltration (particularly monocytes, lymphocytes, neutrophils, and eosinophils) into the skin plays a crucial role in the pathogenesis of these diseases. Chronic eczema is also associated with significant epidermal hyperplasia. Immune-mediated leukocyte infiltration also occurs in sites outside the skin, such as the airways of asthmatic patients and the lacrimal glands of eyes with keratoconjunctivitis sicca.

[0814] The compounds described herein, or their pharmaceutically acceptable salts, isotopic variants, or prodrugs, can be used in effective amounts to treat hosts with skin diseases such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rashes, skin irritation, and skin allergies (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances (including certain drugs) can cause skin allergies when used topically. In some embodiments, skin diseases are treated by combining compounds known in the art with those disclosed herein through topical application. In one non-limiting embodiment, the compounds of the present invention are used as topical agents for treating contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjögren's syndrome, including keratoconjunctivitis sicca secondary to Sjögren's syndrome, alopecia areata, allergic reactions due to arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. This new method can also be used to reduce the infiltration of skin by malignant leukocytes in diseases such as fungal infections.

[0815] Disease conditions that can be treated with the compounds according to the invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, cilia, 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 (PKD1) or PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, and Turner syndrome.

[0816] Other disease states or conditions that can be treated with the compounds of this invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorder, 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.

[0817] Other disease states or conditions that can be treated with the compounds of this invention include ceruloplasminemia, type II chondrodysplasia, chondrodysplasia, cranial malformations, type 2 Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous polyposis, ALA dehydratase deficiency, adenosine lyase deficiency, adrenogenous syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaline aciduria, Alexander disease, alkaline acidosis, α1-antitrypsin deficiency, α-1 protease inhibitors, emphysema, amyotrophic lateral sclerosis (ALS), Alexander disease with ALA dehydratase deficiency, Anderson-Fabry disease, and androgen insensitivity. Syndrome, anemic body angiokeratoma, von Hippel-Lindau disease, Apert syndrome, arachnoidosis (Marfan syndrome), Stickler syndrome, Ehlers-Danlos syndrome (joint laxity type), ataxia-telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff's disease, neurofibromatosis type II, Beare-Stevenson gyrate scalp syndrome, familial Mediterranean fever, Benjamin syndrome, β-thalassemia, bilateral auditory neurofibromatosis (neurofibromatosis type II), factor VLeiden's tendency to thrombosis, Bloch-Sulzberger syndrome (incontinence of pigmentation), Bloom syndrome, X-linked siderocytic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prions, Birt-Hogg-Dubé syndrome, osteogenesis imperfecta, Rubinstein-Taybi syndrome, bronze diabetes / bronze cirrhosis (hemochromatosis), bulbospinal muscular atrophy. Kennedy's disease, Berg-Grutz syndrome (lipoprotein lipase deficiency), chronic granulomatous granulomatosis (CGD), Campomelic dysplasia, biotinylate deficiency, cardiomyopathy (Noonan syndrome), cat-like crying, CAVD (congenital absence of vas deferens), Caylor's cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, achondroplasia syndrome (chondrodysplasia), auricular hypertrophy and epiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia Ehlers-Danlos syndrome, lethal osteodystrophy, Coffin-Lowry syndrome, Cockayne syndrome, familial adenomatous polyposis, congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disease, nasal condyle, facial anemia, thalassemia (β-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes disease), hereditary coprophytic porphyria, Cowden syndrome Comorbidities, craniofacial joint disorders (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotrophic lateral dystrophy), Beare-Stevenson gyrate scalp syndrome, primary hyperoxaluria, Strudwick type vertebral metaphysema, muscular dystrophy, Duchenne and Becker type (DBMD), Arthur syndrome, degenerative neurological diseases, including deGrouchy syndrome and Dejerine-Sottas syndrome, developmental disorders, distal spinal muscular atrophy, type V, androgen insensitivity syndrome, diffuse spheroid sclerosis (Krabbe disease), DeGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protoporphyria, erythropoietic 5-aminolevulinic acid synthase deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Feridhe's ataxia - familial sudden onset multiple lesions Sexual serositis, porphyria cutanea tarda, familial barosensitive neuropathy, primary pulmonary hypertension (PPH), pancreatic cystic fibrosis, fragile X syndrome, galactosemia, hereditary brain disorders, giant cell hepatitis (neonatal hemochromatosis), Gronblad-Strandberg syndrome (pseudoxanthomas elastica), Gunther's disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren's syndrome, sickle cell anemia, hemophilia, hepatoretrophoblastic porphyria (HEP), Hippel-Lindau disease (von Willebrand disease) Hippel-Lindau disease, Huntington's disease, Hutchinson-Gilford progeria, hyperandrogenemia, hypochondroitinemia, immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, kidney diseases including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia, lacunar dementia, Langer-Saldino chondrodysplasia, ataxia-telangiectasia, Lynch syndrome, lysylhydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome, and so on. Motion disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, McCune-Albright syndrome, Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome, hemochromatosis, Lesch-Nyhan syndrome, primary pulmonary hypertension, primary Alzheimer's disease, prions, premature aging (Hutchinson's disease)Gilford's progeria syndrome, progressive chorea, chronic hereditary (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthomas elastica), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type I), relapsing polyserositis, retinal diseases, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast cancer, leukemia and adrenal gland (SBLA) syndrome, tuberous sclerosis, SDAT, SED congenital (congenital vertebral epiphyseal dysplasia), SED Strudwick (vertebral epiphyseal dysplasia, Strudwick type), SEDc (congenital vertebral epiphyseal dysplasia), SEMD, Strudwick type (vertebral diaphysis dysplasia, Strudwick type), Shprintzen syndrome, hyperpigmentation, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (porphyria variegata), infantile ascending spastic paralysis, speech and communication disorders, sphingolipidosis, Ty-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, β-thalassemia, thyroid disease, giant spot disease (hereditary neuropathy with pressure paralysis), Treacher Collins syndrome, Triplo X syndrome, Down syndrome, Trisomy 21, Trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness. (Syndromes), Vrolik disease, Waardenburg syndrome, Warburg-Sjo-Fledelius syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disease, Weissenbacher-Zweymüller syndrome, and xeroderma pigmentosum, etc.

[0818] In some embodiments, a method of treating solid tumors, 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 or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition for treating multiple myeloma. In another embodiment, a method of treating solid tumors, such as non-small cell lung cancer or melanoma, wherein the method comprises administering the compound to a patient.

[0819] In some embodiments, a method for controlling the progression of 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, optionally in a pharmaceutically acceptable carrier to form a composition. In another embodiment, a method for controlling the progression of multiple myeloma using a compound of formula I or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, wherein the method comprises administering the compound to a patient.

[0820] In some implementations, solid tumors are resistant to treatment with anti-PD-1 agents.

[0821] In some implementation schemes, solid tumors are difficult to treat with anti-PD-1 agents.

[0822] In some implementations, solid tumors are resistant to treatment with anti-PD-L1 agents.

[0823] In some implementation schemes, solid tumors are difficult to treat with anti-PD-L1 agents.

[0824] In one embodiment, a method for controlling the progression of 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, optionally in a pharmaceutically acceptable carrier to form a composition. In another embodiment, a method for treating multiple myeloma using a compound of formula I or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, wherein the method comprises administering the compound to a patient.

[0825] In some embodiments, a method for controlling the progression of 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, optionally in a pharmaceutically acceptable carrier to form a composition. In another embodiment, a method for controlling the progression of multiple myeloma using a compound of formula I or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, wherein the method comprises administering the compound to a patient.

[0826] In some embodiments, a method is provided for inducing a therapeutic response in a patient with multiple myeloma, the therapeutic response being assessed by the International Unified Standard for Response to Multiple Myeloma (IURC) (described in Durie BGM et al., “International Unified Standard for Response to 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, optionally in a pharmaceutically acceptable carrier to form a composition.

[0827] In another embodiment, a method is provided to achieve a strictly complete response, a complete response, or a very good partial response, such as the assessment of multiple myeloma in patients with multiple myeloma by an IURC, comprising administering to the patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0828] In another embodiment, a method is provided to increase overall survival, progression-free survival, event-free survival, treatment time, or disease-free survival in patients 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, optionally in a pharmaceutically acceptable carrier to form a composition.

[0829] In another embodiment, a method for achieving increased overall survival in patients with multiple myeloma is provided, comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt, isotope analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0830] In another embodiment, a method for achieving increased progression-free survival in a patient with multiple myeloma is provided, the method comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt, isotope analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0831] In another embodiment, a method for achieving increased event-free survival in a patient with multiple myeloma is provided, the method comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt, isotope analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0832] In another embodiment, a method for achieving an increase in progression time in a patient with multiple myeloma is provided, comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt, isotope analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0833] In another embodiment, a method for achieving increased disease-free survival in patients with multiple myeloma is provided, comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt, isotope analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0834] In addition to previously untreated patients, treatment options are provided for patients who have previously received multiple myeloma treatment but have not responded to standard therapy. In addition to patients who have not undergone surgery, alternative treatment options are provided for patients who have undergone surgery to attempt treatment for multiple myeloma. In addition to those who have not received transplant therapy, treatment options are provided for patients who have previously received transplant therapy.

[0835] The compounds described herein can be used to treat or control relapsed, refractory, or drug-resistant multiple myeloma. In some embodiments, the multiple myeloma is primary, secondary, and has relapsed three, four, or five times. In some embodiments, the compounds described herein can be used to reduce, maintain, or eliminate minimal residual disease (MRD).

[0836] The types of multiple myeloma that can be treated with the compounds described herein include, but are not limited to: monoclonal gammopathy of undetermined significance (MGUS); low-risk, intermediate-risk, or high-risk multiple myeloma; newly diagnosed multiple myeloma (including low-risk, intermediate-risk, or high-risk newly diagnosed multiple myeloma); multiple myeloma that is eligible for transplantation and that is not eligible for transplantation; smoldering (indolent) 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-secreting myeloma; immunoglobulin D myeloma; and immunoglobulin E myeloma.

[0837] In some embodiments, the compounds described herein can be used to treat or control 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., deletion of 17p13 or chromosome 13; del(17 / 17p), nonhyperdiploidy, and gain(1q)).

[0838] In some embodiments, a method for treating or controlling 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, optionally forming a composition in a pharmaceutically acceptable carrier as an induction therapy.

[0839] In some embodiments, a method for treating or controlling 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, optionally in a pharmaceutically acceptable form as a carrier to form a composition as a consolidation therapy.

[0840] In some embodiments, a method for treating or controlling 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, optionally in a pharmaceutically acceptable form to form a composition as maintenance therapy.

[0841] In some implementations, multiple myeloma is plasma cell leukemia.

[0842] In some embodiments, the multiple myeloma is high-risk multiple myeloma. In some embodiments, the high-risk multiple myeloma is relapsed or refractory. In some embodiments, the high-risk multiple myeloma relapses within 12 months of the first treatment. In another embodiment, the high-risk multiple myeloma is characterized by a genetic abnormality, such as one or more of del(17 / 17p) and t(14;16)(q32;q32). In some embodiments, the high-risk multiple myeloma relapses or is refractory to one, two, or three prior treatments.

[0843] In some embodiments, multiple myeloma has a p53 mutation. In some embodiments, the p53 mutation is a Q331 mutation. In some embodiments, the p53 mutation is an R273H mutation. In some embodiments, the p53 mutation is a K132 mutation. In some embodiments, the p53 mutation is a K132N mutation. In some embodiments, the p53 mutation is an R337 mutation. In some embodiments, the p53 mutation is an R337L mutation. In some embodiments, the p53 mutation is a W146 mutation. In some embodiments, the p53 mutation is an S261 mutation. In some embodiments, the p53 mutation is an S261T mutation. In some embodiments, the p53 mutation is an E286 mutation. In some embodiments, the p53 mutation is an E286K mutation. In some embodiments, the p53 mutation is an R175 mutation. In some embodiments, the p53 mutation is an R175H mutation. In some embodiments, the p53 mutation is an E258 mutation. In some implementations, the p53 mutation is the E258K mutation. In some implementations, the p53 mutation is the A161 mutation. In some implementations, the p53 mutation is the A161T mutation.

[0844] In some embodiments, the multiple myeloma has a homozygous deletion of p53. In some embodiments, the multiple myeloma has a homozygous deletion of wild-type p53. In some embodiments, the multiple myeloma has wild-type p53.

[0845] In some embodiments, multiple myeloma exhibits activation of one or more oncogenic drivers. In some embodiments, the one or more oncogenic drivers are selected from the group consisting of C-MAF, MAFB, FGFR3, MMset, cyclin D1, and cyclin D. In some embodiments, multiple myeloma exhibits activation of C-MAF. In some embodiments, multiple myeloma exhibits activation of MAFB. In some embodiments, multiple myeloma exhibits activation of FGFR3 and MMset. In some embodiments, multiple myeloma exhibits activation of C-MAF, FGFR3, and MMset. In some embodiments, multiple myeloma exhibits activation of cyclin D1. In some embodiments, multiple myeloma exhibits activation of MAFB and cyclin D1. In some embodiments, multiple myeloma exhibits activation of cyclin D.

[0846] In some embodiments, multiple myeloma has one or more chromosomal translocations. In some embodiments, the chromosomal translocation is t(14;16). In some embodiments, the chromosomal translocation is t(14;20). In some embodiments, the chromosomal translocation is t(4;14). In some embodiments, the chromosomal translocation is t(4;14) and t(14;16). In some embodiments, the chromosomal translocation is t(11;14). In some embodiments, the chromosomal translocation is t(6;20). In some embodiments, the chromosomal translocation is t(20;22). In some embodiments, the chromosomal translocation is t(6;20) and t(20;22). In one embodiment, the chromosomal translocation is t(16;22). In some embodiments, the chromosomal translocation is t(14;16) and t(16;22). In some embodiments, the chromosomal translocation is t(14;20) and t(11;14).

[0847] In some embodiments, the multiple myeloma has a Q331 p53 mutation, C-MAF activation, and a chromosomal translocation at t(14;16). In some embodiments, the multiple myeloma has a homozygous deletion of p53, C-MAF activation, and a chromosomal translocation at t(14;16). In some embodiments, the multiple myeloma has a K132N p53 mutation, MAFB activation, and a chromosomal translocation at t(14;20). In some embodiments, the multiple myeloma has wild-type p53, FGFR3, and MMset activation, and a chromosomal translocation at t(4;14). In some embodiments, the multiple myeloma has wild-type p53, C-MAF activation, and a chromosomal translocation at t(14;16). In some embodiments, the multiple myeloma has a homozygous deletion of p53, FGFR3, MMset, and C-MAF activation, and chromosomal translocations at t(4;14) and t(14;16). In some embodiments, the multiple myeloma has a homozygous deletion of p53, activation of cyclin D1, and a chromosomal translocation at t(11;14). In some embodiments, the multiple myeloma has an R337L p53 mutation, activation of cyclin D1, and a chromosomal translocation at t(11;14). In some embodiments, the multiple myeloma has a W146 p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In some embodiments, the multiple myeloma has an S261T p53 mutation, activation of MAFB, and chromosomal translocations at t(6;20) and t(20;22). In some embodiments, the multiple myeloma has an E286K p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In some embodiments, the multiple myeloma has an R175H p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In some embodiments, the multiple myeloma has an E258K p53 mutation, activation of C-MAF, and chromosomal translocations at t(14;16) and t(16;22). In some embodiments, the multiple myeloma has wild-type p53, activation of MAFB and cyclin D1, and chromosomal translocations at t(14;20) and t(11;14). In some embodiments, the multiple myeloma has an A161T p53 mutation, activation of cyclin D, and a chromosomal translocation at t(11;14).

[0848] In some implementations, multiple myeloma is a newly diagnosed multiple myeloma suitable for transplantation. In other implementations, multiple myeloma is a newly diagnosed multiple myeloma unsuitable for transplantation.

[0849] 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 another embodiment, multiple myeloma is refractory to lenalidomide. In yet another embodiment, multiple myeloma is refractory to pomalidomide. In some such embodiments, pomalidomide refractory is predicted (e.g., by molecular characterization). In another embodiment, multiple myeloma has relapsed three or more times or is unresponsive to treatment and is exposed to proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, opzomib, or marizomib) and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iberdole, or avalodoride), or is dually resistant to proteasome inhibitors and immunomodulatory compounds. In other embodiments, multiple myeloma is relapsed or refractory to three or more prior therapies, including, for example, CD38 monoclonal antibodies (CD38 mAbs, such as daratumumab or isetuximab), proteasome inhibitors (such as bortezomib, carfilzomib, ixazomib, or marizomib), and immunomodulatory compounds (such as thalidomide, lenalidomide, pomalidomide, iberdoamine, or avallidomide), or dual resistance to proteasome inhibitors or immunomodulatory compounds and CD38 mAbs. In other embodiments, multiple myeloma is triple-refractory, for example, multiple myeloma is refractory to proteasome inhibitors (such as bortezomib, carfilzomib, ixazomib, opzomib, or marizomib), immunomodulatory compounds (such as thalidomide, lenalidomide, pomalidomide, iberdoamine, or avallidomide), and one other active agent, as described herein.

[0850] In some embodiments, a method is provided for treating or controlling relapsed or refractory multiple myeloma in a patient with impaired renal function or symptoms thereof, the method comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt, isotope analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0851] In another embodiment, a method is provided for treating or controlling relapsed or refractory multiple myeloma in a frail patient, comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, wherein the frail patient is characterized as being unsuitable for induction therapy or intolerant to dexamethasone treatment. In other embodiments, the frail patient is an elderly person, for example, older than 65 years.

[0852] In another embodiment, a method for treating or controlling fourth-line relapsed or refractory 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, optionally in a pharmaceutically acceptable carrier to form a composition.

[0853] In another embodiment, a method for treating or controlling newly diagnosed, unsuitable 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, optionally in a pharmaceutically acceptable carrier to form a composition.

[0854] In another embodiment, a method for treating or controlling newly diagnosed, unsuitable 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, optionally in a pharmaceutically acceptable carrier to form a composition as another therapy or post-transplant maintenance therapy.

[0855] In another embodiment, a method for treating or controlling high-risk multiple myeloma that has relapsed or is refractory to one, two, or three prior treatments 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, optionally in a pharmaceutically acceptable carrier to form a composition.

[0856] In some embodiments, the patient to be treated with one of the compounds described herein has not been treated with multiple myeloma therapy prior to administration. In some embodiments, the patient to be treated with one of the compounds described herein has been treated with multiple myeloma therapy prior to administration. In some embodiments, the patient to be treated with one of the compounds described herein has developed resistance to multiple myeloma therapy. In some embodiments, the patient to be treated with one of the compounds described herein has developed resistance to one, two, or three multiple myeloma therapies selected from CD38 antibodies (CD38 mAB, such as daratumumab or itatuximab), proteasome inhibitors (such as bortezomib, carfilzomib, ixazomib, or marizomib), and immunomodulatory compounds (such as thalidomide, lenalidomide, pomalidomide, iberdole, or avalodoride).

[0857] Regardless of the patient's age, the compounds described herein can be used to treat patients. In some embodiments, the individual is 18 years of age or older. In other embodiments, the individual is over 18, 25, 35, 40, 45, 50, 55, 60, 65, or 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 some embodiments, the patient is an elderly patient with multiple myeloma, such as a patient over 65 years of age. In some embodiments, the patient is an elderly patient with multiple myeloma, such as a patient over 75 years of age.

[0858] It has been reported that when cerebroside also binds to novel thalidomide-like (IMiD) substrate proteins, certain proteins with β-hairpin turns containing glycine at key positions (“g-ring proteins” or “g-ring degradation determinants”) act as “structural degradation determinants” for cerebroside. These proteins containing “g-ring degradation determinants” typically consist of small antiparallel β-sheets forming β-hairpins with α-turns, where a geometric arrangement of three main-chain hydrogen bond acceptors is present at the apex of the turn (positions i, i+1, and i+2), with a glycine residue at the key position (i+3) (see, for example, Matyskiela et al., A novelcereblon modulator recruits GSPT1 to the CRL4-CRBN ubiquitin ligase. Nature 535, 252-257 (2016); Sievers et al., Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science). 362, eaat0572 (2018)). These g-ring degradation determinants have been identified in many proteins, including but not limited to Sal-like 4 (SALL4), GSPT1, IKFZ1, IKFZ3, and CKla, ZFP91, ZNF93, etc.

[0859] In some embodiments, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition as described herein, can be administered to the host in an effective amount to degrade a protein containing a g-ring degradation determinant, wherein the protein is selected from protein kinases, zinc finger proteins containing C2H2, proteins containing RNA recognition motifs, proteins containing zinc β-bands, proteins containing β-propellers, proteins containing P-ring NTPases, proteins containing a novel gene of interest (RING) finger domain, proteins containing an SRC homology 3 (SH3) domain, proteins containing an immunoglobulin E-group domain, proteins containing a Tudor domain, proteins containing a zinc finger FYVE / PHD type, proteins containing an Ig-like domain, proteins containing a ubiquitin-like domain, proteins containing a concanavalin A-like domain, proteins containing a C1 domain, proteins containing a Pleckstrin homology (PH) domain, proteins containing an OB-sheet domain, proteins containing NAD+, and proteins containing... Proteins containing the Prossman-fold domain, proteins containing the actin-like ATPase domain, and proteins containing the helical-turn-helical (HTH) domain. In some embodiments, protein kinases, zinc finger proteins containing C2H2, proteins containing RNA recognition motifs, proteins containing zinc β-bands, proteins containing β-propellers, proteins containing P-cyclic NTPases, proteins containing the RING-finger domain of genuine interest, proteins containing the Tudor-domain, proteins containing the zinc finger FYVE / PHD-type, proteins containing Ig-like domains, proteins containing ubiquitin-like domains, proteins containing concanavalin A-like domains, proteins containing the C1 domain, proteins containing the Pleckstrin homology (PH) domain, proteins containing the OB-fold domain, proteins containing the NAD Prossman-fold domain, proteins containing the actin-like ATPase domain, or proteins containing the helical-turn-helical (HTH) domain are overexpressed or contain gain-of-function mutations.

[0860] In some implementations, the degradation determinant is stabilized by internal hydrogen bonds from the ASX motif and the ST motif.

[0861] In some embodiments, the tricyclic isobifunctional compound of the present invention, or a pharmaceutically acceptable salt thereof, optionally in the pharmaceutical compositions described herein, can be administered to the host in an effective amount to degrade a protein having a "g-cycle degradation determinant," wherein the "g-cycle degradation determinant" comprises the motif [D / N]XX[S / T]G (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 some embodiments, the protein containing the "g-cycle degradation determinant" 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 protein containing the "g-cycle degradation determinant" 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 another embodiment, the protein containing the "g-cycle degradation determinant" 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 another embodiment, the protein containing the "g-cycle degradation determinant" 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 protein containing the "g-cycle degradation determinant" comprises the amino acid sequence CXXCG (SEQ ID NO: 6), where C = cysteine, X can be any amino acid residue, and G = glycine. In some embodiments, the protein containing the "g-cycle degradation determinant" comprises the amino acid sequence NXXNG (SEQ ID NO: 7), where N = asparagine, X can be any amino acid residue, and G = glycine.

[0862] In some embodiments, the tricyclic isobifunctional compound of the present invention, or a pharmaceutically acceptable salt thereof, optionally in the pharmaceutical compositions described herein, can be administered to the host in an effective amount to degrade a protein having a C2H2 zinc finger domain containing a "g-cyclic degradation determinant". In some embodiments, the zinc finger domain has a consortium sequence CXXCG (SEQ ID NO:8), wherein C = cysteine, X = any amino acid, and G = glycine. In another embodiment, the protein having the zinc finger domain has a consortium sequence QCXXCG (SEQ ID NO:9), wherein C = cysteine, X = any amino acid, G = glycine, and Q = glutamine. In yet another embodiment, the zinc finger domain has a consortium sequence QC-X2-CG-X3-F-X5-L-X2-H-X3-H (SEQ ID NO:9). NO:10), wherein 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 contains X2-C-X2-CG-X2-C-X5 (SEQ ID NO:11), wherein C = cysteine, X = any amino acid, and G = glycine. In some embodiments, proteins containing the C2H2 zinc finger domain are overexpressed. In some embodiments, the expression of C2H2 zinc finger proteins is associated with diseases or conditions, including but not limited to cancer.

[0863] For example, the compound of the present invention, or a pharmaceutical salt thereof, optionally included in a pharmaceutical composition as described herein, is administered to the host to degrade the zinc finger protein, atypical E3 ubiquitin ligase (ZFP91). The zinc finger protein, atypical E3 ubiquitin ligase, contains a Cys2-His2 zinc finger and protects tumor cell survival by chemoresistance through forkhead box A1 (FOXA1) destabilization (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). Zinc finger proteins, atypical E3 ubiquitin ligases, are believed to function via the non-canonical NF-κB pathway, and their overexpression leads to increased activation of the NF-κB signaling pathway, which has been associated with numerous cancers, including gastric cancer, breast cancer, colon cancer, kidney cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and melanoma (see, for example, Paschke, ZFP91 zincfinger protein expression pattern in normal tissues and cancers. Oncol Lett. 2019; Mar; 17(3):3599-3606). In some embodiments, compounds of the present invention, or pharmaceutically acceptable salts thereof, optionally included in pharmaceutical compositions as described herein, are used to degrade zinc finger proteins, atypical E3 ubiquitin ligases, for the treatment of cancers, including but not limited to gastric cancer, breast cancer, colon cancer, lung cancer, kidney cancer, ovarian cancer, pancreatic cancer, gastric cancer, prostate cancer, sarcoma, and melanoma. In some embodiments, compounds of the present invention, or pharmaceutically acceptable salts thereof, optionally included in pharmaceutical compositions as described herein, are used to degrade zinc finger proteins, atypical E3 ubiquitin ligases, for the treatment of sarcoma, melanoma, or gastric cancer.

[0864] In another embodiment, the compound of the present invention or a pharmaceutical salt thereof, optionally in the pharmaceutical composition described herein, is administered to the host to degrade zinc finger protein 276 (ZFP276).

[0865] In yet another embodiment, the compound of the present invention, or a pharmaceutical salt thereof, optionally in the pharmaceutical composition described herein, is administered to the host to degrade zinc finger protein 653 (ZFP653). Zinc finger protein 653 can act as a more general repressor of transcription by competitively binding to SF1 with GRIP1 and other p160 coactivators (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).

[0866] As another example, compounds of the present invention, or pharmaceutical salts thereof, optionally included in pharmaceutical compositions as described herein, are administered to the host in an effective amount to degrade zinc finger protein 692 (ZFP692). Zinc finger protein 692, also known as AICAR response element binding protein (AREBP), contains a Cys2-His2 zinc finger and is believed to be a key regulator 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 zinc finger protein 692 is associated with promoting colon adenocarcinoma and metastasis by activating the PI3K / AKT pathway (see, for example, Xing et al., 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 by short interfering RNA reduced cell invasion and increased apoptosis in lung cancer cells and inhibited lung cancer tumor growth in xenograft models (see, for example, Zhang et al., ZNF692 promotes proliferation and cell mobility in lung adenocarcinoma. Biochem Biophys ResCommun. 2017 Sep 2; 490(4):1189-1196). Therefore, in some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts, optionally in the pharmaceutical compositions described herein, are used to degrade zinc finger protein 692 to treat lung or colon cancer, including lung adenocarcinoma or lung or colon adenocarcinoma.

[0867] The tricyclic compound of the present invention, or its pharmaceutically acceptable salt, optionally included in the pharmaceutical compositions described herein, may also be administered to the host in an effective amount to degrade zinc finger protein 827 (ZFP827). Zinc finger protein 827 is a zinc finger protein that regulates the alternative elongation (ALT) pathway of telomeres by binding to nuclear receptors and recruiting the nucleosome remodeling and histone deacetylation (NURD) complex to telomeres to induce homologous recombination (see, for example, Conomos, D., Reddel, RR, Pickett, HANuRD-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-associated promyelocytic leukemia (PML) nucleosome (APB) and other telomere aberrations. Therefore, in some embodiments, the compound of the present invention or its pharmaceutical salt, optionally in the pharmaceutical composition described herein, is used to degrade ZNF827 in ALT-related conditions, including but not limited to ALT-positive promyelocytic leukemia, osteosarcoma, adrenal / PNS neuroblastoma, breast cancer, glioblastoma, colorectal cancer, pancreatic neuroendocrine tumor (NET), neuroendocrine tumor, colorectal cancer, liver cancer, soft tissue cancer including leiomyosarcoma, malignant fibrous histiocytoma, liposarcoma, gastric cancer, testicular cancer, and thyroid cancer.

[0868] In other embodiments, the tricyclic compound of the present invention, or a pharmaceutically acceptable salt thereof, optionally in the pharmaceutical composition described herein, is applied to the host in an effective amount to degrade the E4F transcription factor 1 protein (E4F1). E4F transcription factor 1 is believed to function as a ubiquitin ligase of p53 and is a key post-translational regulator of p53, playing an important role in cell life or death decisions controlled by p53 (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). E4F1 overexpression is 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 some embodiments, the compounds of the present invention or their pharmaceutical salts, optionally in the pharmaceutical compositions described herein, are used to degrade E4F transcription factor 1 to treat myeloid leukemia, including but not limited to acute myeloid leukemia (AML), undifferentiated AML, minimally cellular myeloblastic leukemia, cellularly mature myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, myelomonocytic leukemia with eosinophilia, monocytic leukemia, erythroleukemia, megakaryocytic leukemia, chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML), chronic myelomonocytic leukemia (CMML), myeloproliferative neoplasms, including, for example, polycythemia vera (PV), idiopathic thrombocythemia (ET), myelometra 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, P220-233, April 14, 2015).Therefore, in some embodiments, the compounds of the present invention or their pharmaceutical salts, optionally in the pharmaceutical compositions described herein, are used to degrade E4F transcription factor 1 to treat p53-deficiency-related conditions, including but not limited to ovarian cancer, small cell lung cancer, pancreatic cancer, head and neck squamous cell carcinoma, and triple-negative breast cancer.

[0869] In another embodiment, the tricyclic compound of the present invention, or a pharmaceutically acceptable salt thereof, optionally included in the pharmaceutical composition described herein, is applied to the host in an effective amount to degrade zinc finger protein 517 (ZFP517). Zinc finger protein 517 has been identified as a carcinogenic 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 some embodiments, the compound of the present invention, or a pharmaceutically acceptable salt thereof, optionally included in the pharmaceutical composition described herein, is used to degrade zinc finger protein 517 to treat adrenocortical carcinoma.

[0870] On the other hand, the tricyclic compound of the present invention or its pharmaceutical salt, optionally in the pharmaceutical composition described herein, is applied to the host in an effective amount to degrade zinc finger protein 582 (ZFP582). Zinc finger protein 582 is believed to be involved in n DNA damage response, proliferation, cell cycle control, and tumor transformation, most notably in cervical cancer, esophageal cancer, and colorectal cancer (see, for example, Huang et al., Methylomic analysis identifies frequent DNA methylation of zinc finger protein 582 (ZNF582) in cervical neoplasms. PLoS One 7:e41060, 2012; Tang et al., Aberrant DNA methylation of PAX1, SOX1 and ZNF582 genes as potential biomarkers for esophageal squamous cell carcinoma. Biomedicine & Pharmacotherapy Volume 120, December 2019, 109488; Harada et al., Analysis of DNA Methylation in Bowel Lavage Fluid for Detection of Colorectal Cancer. Cancer Prev Res; 7(10); 1002-10; 2014). Therefore, in some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts, optionally in the pharmaceutical compositions described herein, are used to degrade zinc finger protein 582 to treat cancers, including but not limited to cervical cancer, including cervical adenocarcinoma; esophageal cancer, including squamous cell carcinoma and adenocarcinoma; and colorectal cancer.

[0871] In another embodiment, the tricyclic compound of the present invention or a pharmaceutical salt thereof, optionally in the pharmaceutical composition described herein, is applied to the host in an effective amount to degrade zinc finger protein 654 (ZFP654).

[0872] Alternatively, the tricyclic compound of the present invention or its pharmaceutical salt, optionally present in the pharmaceutical compositions described herein, may be administered to the host in an effective amount to degrade zinc finger protein 787 (ZFP787).

[0873] The tricyclic compound of the present invention, or a pharmaceutically acceptable salt thereof, optionally in the pharmaceutical compositions described herein, can be applied to the host in an effective amount to degrade hypermethylated proteins in cancer 1 (HIC1). Hypermethylated proteins in cancer 1 contain an N-terminal BTB / POZ protein-protein interaction domain and a 5 kruppel-like C2H2 zinc finger motif in their 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). Hypermethylation is also expressed in the cancer 1 protein gene disorder Miller-Dieker syndrome (see, for example, Grimm et al., Isolation and embryonic expression of the novel mouse gene Hicl, the homologue of HIC1, acandidate gene for the Miller-Dieker syndrome. Hum. Molec. Genet. 8:697-710, 1999).

[0874] The tricyclic compound of the present invention, or a pharmaceutical salt thereof, optionally in the pharmaceutical composition described herein, is applied to the host in an effective amount to degrade the hypermethylated (HIC2) protein in cancer 2.

[0875] The tricyclic compound of the present invention, or a pharmaceutically acceptable salt thereof, optionally in the pharmaceutical compositions described herein, can be administered to the host in an effective amount to degrade GDNF-inducible zinc finger protein 1 (GZF1). GDNF-inducible zinc finger protein 1 is a transcriptional regulator that binds to a 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).

[0876] Alternatively, for example, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof, optionally included in the pharmaceutical composition described herein, can be administered to the host in an effective amount to degrade the Odd Skipped-associated 1 (OSR1) protein. The Odd Skipped-associated 1 protein contains three C2H2-type zinc fingers, one 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).

[0877] On the other hand, the tricyclic compound of the present invention or its pharmaceutical salt, optionally in the pharmaceutical composition described herein, is applied to the host in an effective amount to degrade the Odd Skipped-associated 2 (OSR2) protein.

[0878] In yet another embodiment, the selected tricyclic compound of the invention or its pharmaceutically acceptable salt, optionally included in the pharmaceutical composition described herein, can be administered to the host in an effective amount to degrade the SAL-like 4 (SALL4) protein. The SAL-like 4 protein has three SAL-type C2H2 double zinc finger domains, the second of which has a single C2H2 zinc finger linked at 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 syndromes (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: el 13, 2004). Overexpression of SAL-like 4 protein is associated with the promotion, growth, and metastasis of various cancers, including lung cancer, gastric cancer, liver cancer, kidney cancer, myelodysplastic syndromes, germ cell-sex cord-stromal tumors (including dysgerminoma, yolk sac tumors, and choriocarcinoma), and leukemia. Therefore, in some embodiments, compounds of the present invention or pharmaceutically acceptable salts thereof, optionally included in pharmaceutical compositions as described herein, are used to degrade SAL-like 4 protein to treat cancers, including but not limited to gastric cancer, liver cancer, kidney cancer, myelodysplastic syndromes, germ cell-sex cord-stromal tumors (including dysgerminoma, yolk sac tumors, and choriocarcinoma), and leukemia.

[0879] Selected tricyclic compounds of the present invention, or pharmaceutically acceptable salts thereof, optionally included in pharmaceutical compositions as described herein, can also be applied to the host in an effective amount to degrade the B-cell lymphoma 6 (BCL6) protein. BCL6 contains an autonomous trans-repressor domain and two non-adjacent regions, including the POZ motif, mediating maximal trans-repressor activity. Translocations of the BCL6 gene are associated with the development of myeloproliferative disorders such as non-Hodgkin's lymphoma. Overexpression of B-cell lymphoma6 prevents the increase of reactive oxygen species and inhibits chemotherapeutic-induced apoptosis in cancer cells (see, for example, Tahara et al., Overexpression of B-cell lymphoma6alters gene expression profile in a myelomacell line and is associated with decreased DNA damage response. Cancer Sci. 2017 Aug; 108(8):1556-1564; Cardenas et al., The expanding role of the BCL6oncoprotein as a cancer therapeutic target. Clin Cancer Res. 2017 Feb 15; 23(4):885-893). Therefore, in some embodiments, the compounds of the present invention or their pharmaceutical salts, optionally in the pharmaceutical compositions described herein, are used to degrade B-cell lymphoma 6 to treat cancer, including but not limited to hematologic 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-acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, and non-small cell lung cancer.

[0880] In addition, the selected tricyclic compound of the present invention or its pharmaceutically acceptable salt, optionally included in the pharmaceutical composition described herein, is administered to the host in an effective amount 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 believed 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 the B-cell lymphoma 6B protein is 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 some embodiments, the compounds of the present invention or their pharmaceutical salts, optionally in the pharmaceutical compositions described herein, are used to degrade B-cell lymphoma 6B to treat cancer, including but not limited to germ cell carcinomas, including but not limited to germ cell tumors, including dysgerminomas and seminomas, teratomas, yolk sac tumors and choriocarcinomas.

[0881] Alternatively, the selected tricyclic compound of the present invention or its pharmaceutically acceptable salt, optionally included in the pharmaceutical composition described herein, can be applied to the host in an effective amount to degrade the Early Growth Response 1 (EGR1) protein. The EGR1 protein directly controls the expression of the transforming growth factor-β1 gene and has been shown to participate in the proliferation and survival of prostate cancer cells and glioma cells by regulating several target genes, including cyclin D2 (CCND2), p19 (Ink4d), and Fas (see, for example, Virolle et al., Ergl promotes growth and survival of prostate cancer cells: identification of novel Egr1 target genes. J. Biol. Chem. 278:11802-11810, 2003; Chen et al., Inhibition of EGR1 inhibits glioma proliferation by targeting CCND1 promoter. Journal of Experimental & Clinical Cancer Research Volume 36, Article number: 186 (2017)). One mechanism by which Egr1 confers resistance to apoptosis signals is its ability to inhibit Fas expression, resulting in insensitivity to FasL. Therefore, in some embodiments, compounds of the present invention or pharmaceutically acceptable salts thereof, optionally in pharmaceutical compositions as described herein, are used to degrade the Early Growth Response 1 protein for the treatment of cancers, including but not limited to prostate cancer or gliomas, including but not limited to pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme.

[0882] On the other hand, the selected tricyclic compound of the present invention or its pharmaceutical salt, optionally included in the pharmaceutical composition described herein, can be administered to the host in an effective amount to degrade the early growth response 4 (EGR4) protein. The EGR4 protein contains three C2 / H2 isoforms of zinc fingers 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 the EGR4 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 some embodiments, the compounds of the present invention or their pharmaceutical salts, optionally in the pharmaceutical compositions described herein, are used to degrade the early growth response 4 protein to treat cancer, including but not limited to cholangiocarcinoma.

[0883] In some respects, the selected tricyclic compounds of the present invention or their pharmaceutical salts, optionally included in pharmaceutical compositions as described herein, can be applied in effective amounts to the host to degrade Sal-like 1 (SALL1) protein.

[0884] In one embodiment, the selected tricyclic compound of the present invention or its pharmaceutically acceptable salt, optionally in the pharmaceutical composition described herein, can be applied to the host in an effective amount to degrade the Sal-like 3 (SALL3) protein. The SALL3 protein contains four double zinc finger (DZF) domains, each containing a sequence identical or closely related to the SAL cassette, and a characteristic eight-amino acid stretch in the second zinc finger motif.

[0885] In yet another embodiment, the selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof, optionally included in the pharmaceutical composition described herein, may be applied to the host in an effective amount to degrade the tumor protein p63 (TP63). Overexpression of the tumor protein p63 is associated with lung cancer development and poor prognosis, radiation resistance in oral and head and neck cancers, and squamous cell carcinoma of the skin (see, for example, Masson et al., Significance of p63 amplification and overexpression in lung cancer development and prognosis. Cancer Res. 2003 Nov1; 63(21):7113-21; 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). Therefore, in some embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof, optionally included in the pharmaceutical composition described herein, is used to degrade the tumor protein p63 to 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.

[0886] In yet another embodiment, the selected tricyclic compound of the present invention or its pharmaceutical salt, optionally in the pharmaceutical composition described herein, can be applied to the host in an effective amount to degrade wide-spaced zinc finger (WIZ) proteins.

[0887] The selected tricyclic compound of the present invention or its pharmaceutical salt, optionally included in the pharmaceutical composition described herein, can also be applied to the host in an effective amount to degrade protein 7A (ZBTB7A), which contains a zinc finger and a BTB domain. Expression of protein 7A, containing a zinc finger and a BTB domain, is associated with many cancers, including prostate cancer, non-small cell lung cancer, bladder cancer, breast cancer, prostate 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; Molloy et al., ZBTB7A governs estrogen receptoralpha expression in breast cancer. Journal of Molecular Cell Biology, Vol. 10, No. 4, August 2018, pp. 273-284). Therefore, in some embodiments, the compounds of the present invention or their pharmaceutical salts, optionally in the pharmaceutical compositions described herein, are used to degrade protein 7A containing the zinc finger and BTB domain for the treatment of cancer, 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.

[0888] In other respects, the selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof, optionally included in the pharmaceutical compositions described herein, can be applied in an effective amount to the host to degrade protein 7B (ZBTB7B), which contains a zinc finger and a BTB domain. Expression of protein 7B, containing a zinc finger and a BTB domain, is associated with breast cancer, prostate cancer, urothelial carcinoma, cervical cancer, and colorectal cancer. Therefore, in some embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof, optionally included in the pharmaceutical compositions described herein, is used to degrade protein 7B, which contains a zinc finger and a BTB domain, for the treatment of cancers, including but not limited to breast cancer, prostate cancer, urothelial carcinoma, cervical cancer, and colorectal cancer.

[0889] The selected tricyclic compound of the invention or its pharmaceutically acceptable salt, optionally included in the pharmaceutical compositions described herein, can be administered to the host in an effective amount to degrade casein kinase I,αI (CK1α or CK1-α). CK1-α is a bifunctional regulator of NF-κ-B (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-α dynamically associates with the CBM complex on T cell receptors to participate in cytokine production and lymphocyte proliferation. However, CK1-α kinase activity has the opposite effect by subsequently promoting the phosphorylation and inactivation of CARMA1. Therefore, CK1-α has a dual "gating" function, first promoting and then terminating receptor-induced NF-κ-B. ABC DLBCL cells require CK1-α for constitutive NF-κ-B activity, indicating that CK1-α plays a conditionally essential role as a malignant tumor gene. CK1-α expression is associated with myelodysplastic disorders accompanied by depletion of 5q(del(5q)MDS (see, e.g., Kronke et al., Lenalidomide induces subiquitination 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, e.g., Richter et al., CK1-α overexpression correlates with poor survival in colorectal cancer. BMC Cancer. 2018; 18:140; Jiang et al., Casein kinasela: biological mechanisms and (Related to theranostic potential. Cell Commun Signal. 2018; 16:23).Therefore, in some embodiments, the compounds of the present invention or their pharmaceutical salts, optionally in the pharmaceutical compositions described herein, are used to degrade casein kinase I, αI to 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, pancreatic cancer, myelodyplastic syndromes, including but not limited to 5q- syndrome, refractory cytopenia with monolineage dysplasia, refractory anemia, refractory neutropenia and refractory thrombocytopenia, refractory anemia with ring sideroblasts, refractory cytopenia with multilineage dysplasia (RCMD), refractory anemia with excess germ cells (REAB) I and II, refractory anemia with excess germ cells in transformation (RAEB-T), chronic myelomonocytic leukemia (CMML), unclassified myelodyplasia, and refractory cytopenia in childhood (childhood dysplasia).

[0890] The selected tricyclic compound of the present invention or its pharmaceutical salt, optionally included in the pharmaceutical compositions described herein, can also be applied to the host in an effective amount to degrade family 83 member H (FAM83H) with sequence similarity. FAM83H is believed to be involved in the progression of human cancers along with tumor-associated molecules such as MYC and β-catenin, and overexpression is 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 P-catenin and progression of osteosarcomas. Journal of Experimental & Clinical Cancer Research, volume 38, article number: 267 (2019)). Therefore, in some embodiments, the compounds of the present invention or their pharmaceutical salts, optionally in the pharmaceutical compositions described herein, are used to degrade FAM83H to 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, liver cancer (including but not limited to hepatocellular carcinoma), renal cell carcinoma, osteosarcoma, and gastric cancer.

[0891] Alternatively, the selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof, optionally included in the pharmaceutical composition described herein, can be applied to the host in an effective amount to degrade protein 16 (ZBTB16), which contains the zinc finger and BTB domain. Overexpression and translocation of ZBTB16 have been associated with the development of various hematologic malignancies, including acute promyelocytic leukemia (see, for example, Zhang et al., Genomic sequence, structural organization, molecular evolution, and aberrant rearrangement of promyelocytic leukemia zinc fingergene. Proc. Nat. Acad. Sci. 96:11422-11427, 1999). Therefore, in some embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof, optionally included in the pharmaceutical composition described herein, is used to degrade ZBTB16 to treat cancers, including but not limited to hematologic malignancies, including but not limited to leukemia or lymphoma, including but not limited to acute promyelocytic leukemia, acute lymphoblastic leukemia, adult T-cell lymphoma / ATL, and Burkitt lymphoma.

[0892] In an alternative embodiment, the selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof, optionally in the pharmaceutical composition as described herein, can be applied to the host in an effective amount to degrade protein 2 (ARID2), which is rich in AT-interacting domains. ARID2 is a subunit of the PBAF chromatin remodeling complex, which promotes ligand-dependent transcriptional activation of 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. GenesDev. 19:1662-1667, 2005).

[0893] On the other hand, selected tricyclic compounds of the present invention, or pharmaceutically acceptable salts thereof, optionally included in pharmaceutical compositions as described herein, can be applied in an effective amount to the host to degrade polybrominated associated bacillus fibrous fibrous fumarole (PBAF). Mutations in PBAF are 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, compounds of the present invention, or pharmaceutically acceptable salts thereof, optionally included in pharmaceutical compositions as described herein, are used to degrade PBAF to treat cancers, including but not limited to synovial sarcoma and multiple myeloma.

[0894] In other embodiments, when applied after binding with hydroxycerebrosides and forming a neodeformed surface, the selected tricyclic compounds of the present invention are capable of binding a variety of novel substrates, producing a "multi-pharmacological" form. For example, the tricyclic compounds can bind to and degrade IRAK4, IKZF1, and / or IKZF3, and / or Aiolos. In other instances, the tricyclic compounds, upon application, are capable of degrading two or more proteins named above or herein, such as SALL4 and IKZF1 / 3 or IKZF2 / 4.

[0895] In some embodiments, in a standard HiBiT bioluminescence assay, the tricyclic compounds of the present invention exhibit in vitro degradation selectivity for IKZF2 and / or IKZF4 that exceeds that for IKZF1 and / or IKZF3 by at least about 1.5, 2, 3, 5, or even 10 times. The HiBiT assay is a well-known assay that has been extensively described in the literature.

[0896] VI. Combination therapy

[0897] The selected Formula I compound or its pharmaceutically acceptable salt may be used alone or in combination in effective amounts to treat patients as further described herein.

[0898] The disclosed compounds described herein can be used in effective amounts, alone or in combination with another compound of the present invention or another bioactive agent or a second therapeutic agent, to treat patients, such as humans, suffering from conditions including, but not limited to, those described herein.

[0899] The term "bioactive agent" is used to describe agents, not selected according to the invention, that can be used in combination with or alternately with compounds of the invention to achieve a desired therapeutic outcome. In some embodiments, the compounds and bioactive agents of the invention are administered in such a manner that they have in vivo activity over overlapping time periods, for example, having overlapping Cmax, Tmax, AUC, or other pharmacokinetic parameters. In another embodiment, the compounds and bioactive agents of the invention are administered to a patient in need of this treatment, and they do not have overlapping pharmacokinetic parameters; however, one has a therapeutic effect on the efficacy of the other.

[0900] In one aspect of this embodiment, the bioactive agent is an immunomodulator, including but not limited to checkpoint inhibitors, such as, as non-limiting examples, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, T-cell activation V-domain Ig inhibitor (VISTA) inhibitors, small molecules, peptides, nucleotides, or other inhibitors. In some aspects, the immunomodulator is an antibody, such as a monoclonal antibody.

[0901] PD-1 inhibitors that inhibit immunosuppression by binding to the PD-1 receptor and blocking the interaction between PD-1 and PD-L1 include, for example, 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.). PD-L1 inhibitors, which inhibit immunosuppression by binding to the PD-L1 receptor and blocking the interaction between PD-1 and PD-L1, include, for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors, which bind to CTLA-4 and inhibit immunosuppression, include, but are not limited to, ipilimumab, trimemumab (AstraZeneca and MedImmune), AGEN1884, and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

[0902] In some implementations, the checkpoint inhibitor is selected from nivolumab / Pembrolizumab / Inhibitors of pipidilizumab / CT-011, MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS936559, a PDL2 / lg fusion protein such as AMP 224, or inhibitors of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or combinations thereof.

[0903] In yet another embodiment, one of the active compounds described herein may be combined with or alternately administered in an effective amount of an estrogen inhibitor to treat abnormal tissues of the female reproductive system, such as breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. The estrogen inhibitor includes, but is not limited to, SERMs (selective estrogen receptor modulators), SERDs (selective estrogen receptor degraders), complete estrogen receptor degraders, or other forms of partial or complete estrogen antagonists or agonists. 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 during breast cancer progression, which actually stimulate tumor growth. In contrast, fulvestrant, a completely anti-estrogenic agent, has no estrogen-like effects on the uterus and is effective in tamoxifen-resistant tumors.

[0904] Non-limiting examples of anti-estrogenic compounds are provided in: WO 2014 / 19176 assigned to Astra Zeneca; WO 2013 / 090921, WO 2014 / 203129, WO 2014 / 203132 and US2013 / 0178445 assigned to Olema Pharmaceuticals; U.S. Patents 9,078,871, 8,853,423 and 8,703,810; and US 2015 / 0005286, WO 2014 / 205136 and WO 2014 / 205138.

[0905] Other non-limiting examples of anti-estrogenic compounds include: SERMS such as diacetylcholine, bardoxifen, broparestriol, chlorotrianisene, clomiphene citrate, cyclofennig, lasoxifene, olmexifen, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testosterone, anastrozole, exemestane, fazodazole, formexane, and letrozole; and anti-gonadotropic hormones such as leuprorelin, cetrorexone, allylestradiol, chlormedrone acetate, cyproterone acetate, dimagestrol acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, norethindrone acetate, progesterone, and spironolactone.

[0906] Other estrogen ligands that can be used according to the present invention are described in U.S. Patent Nos. 4,418,068, 5,478,847, 5,393,763 and 5,457,117; WO 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; US 2015 / 0005286; WO 2014 / 205138; US 2016 / 0175289; US 2015 / 0258080; WO 2014 / 191726; WO 2012 / 084711; WO 2002 / 013802; WO 2002 / 004418; WO2002 / 003992; WO 2002 / 003991; WO 2002 / 003990; WO 2002 / 003989; WO 2002 / 003988; WO2002 / 003986; WO 2002 / 003977; WO 2002 / 003976; WO 2002 / 003975; WO 2006 / 078834; US6821989; US 2002 / 0128276; US 6777424; US 2002 / 0016340; US 6326392; US 6756401; US2002 / 0013327; US 6512002; US 6632834; US 2001 / 0056099; US 6583170; US 6479535; WO1999 / 024027; US 6005102; EP 0802184; US 5998402; US 5780497; US 5880137; WO 2012 / 048058 and WO 2007 / 087684.

[0907] In another embodiment, the active compound described herein may be administered in combination with or alternately with an effective amount of an androgen (such as testosterone) inhibitor to treat abnormal tissues of the male reproductive system, such as prostate cancer or testicular cancer. The androgen inhibitor includes, but is not limited to, selective androgen receptor modulators, selective androgen receptor degraders, complete androgen receptor degraders, or other forms of partial or complete androgen antagonists. In some embodiments, the prostate cancer or testicular cancer is androgen-resistant.

[0908] Non-limiting examples of antiandrogen compounds are provided in WO 2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Further non-limiting examples of antiandrogen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, alliinolactone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

[0909] In some implementations, 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.

[0910] In some implementations, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), roxitinib (CO-1686), osimertinib (Tagrisso), omalatinib (Olita), naquotinib (ASP8273), nazatinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), and neratinib (HK). I-272; PB272); Avitinib (AC0010), EAI045, Tasotinib (TH-4000; PR-610), PF-06459988 (Pfizer), Tesevatinib (XL647; EXEL-7647; KD-019), Transtinib, WZ-3146, WZ8040, CNX-2006, and Dacomitinib (PF-00299804; Pfizer).

[0911] In some implementations, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, trastuzumab emtansine, and pertuzumab.

[0912] In some implementations, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include octotuzumab, rituximab, ofamumab, tiimomab, tosimomumab, and ocrelizumab.

[0913] In some implementations, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tofacitinib.

[0914] In some 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-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl]-N-[[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), and ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R )-4-(dimethylamino)-1-phenylsulfonylbutane-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide (navitoclax), ABT-263((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l,l'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butane-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070(obatoclax methanesulfonate) mesylate), (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrolo-2-yl)methylene]-4-methoxypyrrolo-2-yl]indolemethanesulfonic acid), 2-methoxy-antimycin A3, YC137(4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazolylamino)-phenyl ester), pogosin, 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxo) Ethyl 4H-chromene-3-carboxylate (N-ethyl), nilotinib-d3, TW-37 (N-[4-[[2-(1,1-dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogeic acid, or G3139 (Oblimersen).

[0915] In some embodiments, the bioactive agent is a kinase inhibitor. In one embodiment, the kinase inhibitor is selected from phosphoinositol 3-kinase (PI3K) inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, or spleen tyrosine kinase (Syk) inhibitors, or combinations thereof.

[0916] Examples of PI3 kinase inhibitors include, but are not limited to, Wortmannin, demethylammonium oleoresin, pireflactin, idelalisib, Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib)(2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazaza-9-yl]pyrazol-1-yl]-2 -Methylpropionamide), MLN-1117((2R)-1-phenoxy-2-butylhydro(S)-methylphosphonate; or methyl(oxo){[(2R)-l-phenoxy-2-butyl]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-(methoxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide)(omipalisib), TGX-221((±)-7-methyl-2-(morpholine- 4-yl)-9-(l-phenylaminoethyl)-pyrido[l,2-a]pyrimidin-4-one), GSK2636771(2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazolium-4-carboxylic acid dihydrochloride), KIN-193((R)-2-((l-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820((S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-hydroxypropane-1-one), GS-1101(5-fluoro-3-phenyl) (N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalo-2-yl)aminosulfonyl)phenyl)-3-methoxy-4-methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[l,2-c]quinaz), AS252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidin-2,4-Diketone), CZ 24832 (5-(2-amino-8-fluoro-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), Buparlisib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinylamine), GDC-0941 (2-(lH-indazol-4-yl)-6-[[4-(methylsulfonyl)-l-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-) Aminopyrimidin-5-yl)-7-methyl-4-morpholinothiopheno[3,2-d]pyrimidin-6-yl)methyl)piperazin-l-yl)-2-hydroxypropane-l-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholin-4-onthium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-ester), PF- 05212384(N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea)(gedatolisib), LY3023414, BEZ235(2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propionitrile)(dactolisib), XL-765(N-(3-(N-(3- (3,5-Dimethoxyphenylamino)quinoxalin-2-yl)aminosulfonyl)phenyl)-3-methoxy-4-methylbenzamide) and GSK1059615 (5-[[4-(4-pyridyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindene[4,5h] isocyanen-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, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib (GDC-0980; RG7422).

[0917] Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica). TM(1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), diphenylaminopyrimidine-based inhibitors such as AVL-101 and AVL-291 / 292(N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide)(Avila Therapeutics (see U.S. Patent Publication No. 2011 / 0117073, the entire contents of which are incorporated herein by reference), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazolyl-5-carboxamide], LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)acrylamide), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-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]pyrazin-6-yl)phenyl)benzamide, CGI-1746(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholin-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774(4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpyridinamide), CTA056(7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxaline- 6(5H)-ketone), GDC-0834((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-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-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindoline-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthidin-2(1H)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinoline-1-one), and other molecules capable of inhibiting BTK activity, such as those BTK inhibitors disclosed in Akinleye etah, Journal of Hematology & Oncology, 2013, 6:59, the entire contents of which are incorporated herein by reference.

[0918] Syk inhibitors include, but are not limited to, cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidin-5-carboxamide), entospletinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), and fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxy) [(3,2-b][1,4]oxazine-4-yl]methyl dihydrophosphate), fotentinib disodium salt ((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]pyrimidin-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxamide), imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl]-N- (4-Methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), cruciferine, GSK143(2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidin-5-carboxamide), PP2(1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PR T-060318(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112(3,3'-((5-fluoropyrimidine-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112(3,3'-((5-fluoropyrimidine-2-yl)phenyl)amino)-4-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazine-3(4H)-one), leucopicrin (3-hydroxyresveratrol), YM193306 (see Singh et al.).Compounds containing 7-azaindole, leucine, ER-27319 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the full text of which 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 full text of which is incorporated herein by reference), and PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the full text of which is incorporated herein by reference), and PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the full text of which is incorporated herein by reference), are also mentioned. Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the full text of which is incorporated herein by reference), luteolin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the full text of which is incorporated herein by reference), apigenin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the full text of which is incorporated herein by reference), quercetin ... Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the full text of which is incorporated herein by reference), spleen tyrosine (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the full text of which is incorporated herein by reference), myricetin (see Singh et al.).Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the full text of which is incorporated herein by reference), and linalool (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the full text of which is incorporated herein by reference).

[0919] In some embodiments, the bioactive agent is a MEK inhibitor. MEK inhibitors are known and include, for example, trametinib / GSKl120212 (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]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), Pimasertib / AS703026 / MSC1935369((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973(l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azacyclobutane-3-ol), Refamitinib / BAY869766 / RDEAl 19(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-fluoro-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), R051267 66(3-[[3-fluoro-2-(methylaminosulfonylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromene-2-one), WX-554, R04987655 / CH4987655(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinyl-2-yl) Methylbenzamide 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, Cobitinib, PD98059, BIX 02189, BIX 02188, Bimetinib, SL-327, TAK-733, PD318088.

[0920] In some embodiments, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, vemurafinib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide) and sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridin-2-carbamoyl) 4-Methylbenzenesulfonate (amine), AZ628(3-(2-cyanopropane-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712(4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl) phenyl)benzamide), RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazole-2-amine), 2-Bromoaldisine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]aza-4,8-dione), Raf kinase inhibitor IV ( 2-Chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), sorafenib N-oxide (4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (cannafenib).

[0921] In some embodiments, the bioactive agent is an AKT inhibitor, including but not limited to MK-2206, GSK690693, perifol, (KRX-0401), GDC-0068, tricerebroside, AZD5363, honokiol, PF-04691502, and mitefol (an FLT-3 inhibitor), including but not limited to P406, dovirtinib, quezatinib (AC220), amuvatinib (MP-470), tandutinib (MLN518), ENMD-2076, and KW-2449, or combinations thereof.

[0922] In some embodiments, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogues, everolimus (Afinitor), tesimolimus, ridaforolimus, sirolimus, and deforolimus. Examples of MEK inhibitors include, but are not limited to, trametinib / GSKl120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyridino[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroaniline)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), and pimasertib / AS703026 / MSC1935369 ((S)). -N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973(l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azacyclobutane-3-ol) (cobimetinib), refamitinib / BAY869766 / RDEAl19(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), P D-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-methylpyridino[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), R051267 66(3-[[3-fluoro-2-(methylaminosulfonylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromene-2-one), WX-554, R04987655 / CH4987655(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazin-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).

[0923] In some implementations, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER.

[0924] In some embodiments, the bioactive agent is an HSP inhibitor. HSP inhibitors include, but are not limited to, geldmycin or 17-N-allylamino-17-demethoxygeldmycin (17AAG) and Radicicol.

[0925] Other 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 inhibitors, VEGFR inhibitors, aurora kinase inhibitors, PIK-1 modulators, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, focal adhesion kinase inhibitors, Map kinase kinase (mek) inhibitors, VEGF Traps, Pemetrexed, Panitumumab, Amrubicin, Oregovanimab, Lep-etu, Noratrexed, AZD2171, Batabulin, Atumumab, Zanolimumab, Edotecarin, Tetrandrine, Rubitecan, Pertozulil, Oblimersen, Texilimumab, Ipilimumab, Gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Ciligenitide, Gematometaconazole, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, Lucanthone, LY317615, Neuradiab, Vitespan, RTA 744, Sdx 102. Talenpanel, Atrasentan, Xr 311, Romidipsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Doxorubicin Liposome, 5′-Deoxy-5-Fluorouracil, Vincristine, Temozolomide, ZK-304709, Celicillin; PD0325901, AZD-6244, Capecitabine Tadalafil, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl] disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumabIMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprorelin acetate, triptorelin dihydroxynaphthyl acetate, 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, EK B-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, Tipifanib; Amifostine, NVP-LAQ824, S-diphenylamine hydroxamic acid, Valproic acid, Trichostatin A, FK-228, SU11248, Sorafenib, KRN951, Aminoglutamine, Acridine, Anagrelide, L-Asparaginase, BCG, Doxorubicin, Bleomycin, Buserellin, Carboplatin, Carmustine, Chlorandibularia mustard, Cisplatin, Cladribine, Clodronate, Cyproterone acetate, Cytarabine, Dacarbazine, Daunorubicin Diethylstilbestrol, Epirubicin, Fludarabine, Fludrocortisone, Flumethasone, Flutamide, Gleevec, Gemcitabine, Hydroxyurea, Idarubicin, Ifosfamide, Imatinib, Leuprorelin, Levotetramazole, Lomustine, Nitrogen Mustard, Melphalan, 6-Mercaptopurine, Mesna, Methotrexate, Mitomycin, Mitotan, Mitoxantrone, Nilutamide, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, Pucarimycin, Phofem sodium, Procarbazine, Raltitrexed, Rituximab, Strepzocin, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Retinoic Acid, Vinpocetine, 13-cis- Retinoic acid, phenylalanine mustard, uracil mustard, estradiol mustard, hexamethylmelamine, fluorouridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxymyopicrin, calcitriol, pentorubicin, photomycin, vinblastine, vinorelbine, topotecan, razoxin, marimasitol, COL-3, neovastatin, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, interleukin diftitox, gefitinib, bortezomib, paclitaxel, paclitaxel without polyoxyethylene castor oil.Docetaxel, Epomycin B, BMS-247550, BMS-310705, Droxifen, 4-Hydroxytamoxifen, Pipendoxifene, ERA-923, Azoxifen, Fulvestrant, Acobifen, Lasoxifene, Indoxifene, TSE-424, HMR-3339, ZK186619, Topotecan, PTK787 / ZK 222584, VX-745, PD184352, Rapamycin, 40-O-(2-hydroxyethyl)-Rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wolman penicillin, ZM3363 72, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronic acid, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histamine, PEGylated interferon α-2a, interferon α-2a, PEGylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemcitabine Monoclonal antibodies, hydrocortisone, interleukin-11, dexrazoxen, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, medroxyprogesterone acetate, immunoglobulin, nitrogen mustard, methylprednisolone, ibritgumomabtiuxetan, androgens, decitabine, hexamethylmelamine, besalodin, tosimomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, daunorubicin liposomes, Edwina-asparaginase, Strontium 89, cassopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, fluperidone, dronabinol, dexamethasone, methylprednisolone, prochlorazine, granisetron, ondansetron, dolasetron, tropisetron, PEG-filgrastim, erythropoietin, epoetopin α, dabepone α, and mixtures thereof.

[0926] In some implementations, the compound is applied in combination with ifosfamide.

[0927] In some embodiments, the bioactive agent is selected from, but is not limited to, imatinib mesylate. Dasatinib Nilotinib Bosutinib Trastuzumab Trastuzumab-DM1, Pertuzumab (Perjeta™), Lapatinib Gefitinib Erlotinib cetuximab Panitumumab Van der Thani Vimofini Vorinostat Romidesin Besarodine Alivenic acid Retinoic acid Carfilzomib (Kyprolis™), Prattrixa bevacizumab Abersipu Sorafenib Sunitinib Pazopanib Regorafenib And cabozantinib (Cometriq™).

[0928] In some respects, bioactive agents are anti-inflammatory agents, chemotherapeutic agents, radiotherapy agents, other therapeutic agents, or immunosuppressants.

[0929] Suitable chemotherapeutic bioactive agents include, but are not limited to, radioactive molecules, toxins (also known as cytotoxic agents or cytotoxic agents), including any agent harmful to cell viability, and liposomes or other vesicles containing chemotherapeutic compounds. Common anticancer drugs include vincristine. Or vincristine liposomes daunorubicin (daunorubicin or (or Dorothy star) Cytarabine (cytosine arabinoside, ara-C or...) L-asparaginase Or PEG-L-asparaginase (pegaspargase or Etoposide (VP-16), Teniposide 6-Mercaptopurine (6-MP or Methotrexate, cyclophosphamide Prednisone, Dexamethasone (Decatelon), Imatinib Dasatinib Nilotinib Bosutinib and punatinib (Iclusig) TM ).

[0930] Other suitable examples of chemotherapeutic agents include, but are not limited to, 1-dehydrotestosterone, 5-fluorouracil dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, doxorubicin, aldehyde interleukin, alkylating agents, allopurinol sodium, hexamethylmelamine, amifostine, anastrozole, atracin (AMC), antimitotic agents, cis-dichlorodiamineplatin(II)(DDP), diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, live BCG (intravesical), betamethasone sodium phosphate, and betamethasone acetate. Bicalutamide, Bleomycin Sulfate, Busulfan, Leucovorin, Carbazin, Capecitabine, Carboplatin, Lomustine (CCNU), Carmustine (BSNU), Chlorobasilar Indica, Cisplatin, Cladribine, Colchicine, Conjugated Estrogen, Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytochalasin B, Cytoxan, Dacarbazine, Dermatomycin, Dermatomycin (formerly Actinomycin), Daunorubicin Hydrochloride, Daunorubicin Citrate, DenileukinDiftitox, Dexazosin, Dibromomannitol, Dihydroxyanthraxetine dione, Docetaxel, Dolastron Mesylate, Doxorubicin Hydrochloride, Droscannabinol, Escherichia coli L-Asparaginase, Ipecain, Epoetin-α, Erwinia L-Asparaginase, Esterified Estrogen, Estradiol, Estryl Mustard Sodium Phosphate, Ethidium Bromide, Ethynyl Estradiol, Etidronate, Etoposide, Citric Acid Factor, Etoposide Phosphate, Filgrastin, Fluorouracil, Fluconazole Fludarabine phosphate, fluorouracil, flutamide, leucovorin, gemcitabine hydrochloride, glucocorticoids, goserelin acetate, bacitracin D, granisetron hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, interferon alpha-2b, irinotecan hydrochloride, letrozole, calcium leucovorin, leuprorelin acetate, levamisole hydrochloride, lidocaine, lomustine, maytansinoid, nitrogen mustard hydrochloride, medroxyprogesterone acetate, megestrol acetate Melphalan hydrochloride, mercaptopurine, mesna, methotrexate, methyltestosterone, sclerosomycin, mitomycin C, mitotane, mitoxantrone, nilumethicone, octreotide acetate, ondansetron hydrochloride, paclitaxel, disodium pamidronate, pentostatin, pilocarpine hydrochloride, priloin, polyphenylprotein 20 with carmustine implant, porphyrin sodium, procaine, procarbazine hydrochloride, propranolol, rituximab, samoxicillin, streptozotocin, tamoxifen, purpuric acid Taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa, chlorambucil, thioguanine, thiotepa, topotecan hydrochloride, toremifene citrate, trastuzumab, retinoic acid, pentorubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0931] In some embodiments, the compounds of the present invention are administered in combination with chemotherapeutic agents (e.g., cytotoxic agents or other chemical compounds that can be used to treat cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferon, platinum coordination complexes, anthrone-substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical hormones, progesterone, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel.Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, indomethacin, and piperazine; chlorpromazine derivatives such as benzothiopepa, carboquinone, metopepa, and uredopa; ethyleneimine and methylmelamine derivatives, including hexamethylmelamine, tratamiamine, triethylenephosphamide, triethylenethiophosphamide, and tris(hydroxymethylmelamine); anechoic acid lactones (especially bratacin and bratacinone); camptothecin (including the synthetic analogue topotecan); lichenin; callystatin; CC-1065 (including its synthetic analogues adolexin, carzolin, and bizolin); cryptophytes (especially cryptophyte 1 and cryptophyte 8); dolalastatin; duocarmycin (including synthetic analogues, KW-2189, and CB1-TM1); eleuth... erobin); pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, naphthyl mustard, chophosphatamide, estradiol, ifosfamide, dichloroethyl methylamine, oxynitrogen hydrochloride, melphalan, neonitrogen mustard, benzyl mustard cholesterol, pine oxynitrogen mustard, trofenamide, uracil mustard; nitrourea such as carmustine, chloramphenicol, formustine, lomustine, nimustine, and ranimnustine; antibiotics such as ethynylene antibiotics (e.g., calcipomycin, especially calcipomycin γll and calcipomycin ωll) (see, for example, Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994)); anthracyclines (dynemicins), including dynemicin A; Bisphosphonates, such as clophosphonate; esporomycin; and neo-cancer inhibitor chromophores and related chromoprotein ethynylene antibiotic chromophores), aclamycin, actinomycin, autramycin, azaserine, bleomycin, actinomycin C, carabicin, erythromycin, carcinomamycin, chromomycinis, actinomycin D, daunorubicin, detoxin, 6-diazo-5-oxo-L-leucine. (Doxorubicin, including morpholine doxorubicin, cyanomorpholine doxorubicin, 2-pyrrole doxorubicin, and deoxydoxorubicin), epirubicin, isorubicin, idarubicin, metharubicin, mitomycin C, nogalamycin, oligomycin, pepromycin, potfiromycin, puromycin, triamcinolone acetonide, rodorubicin, streptomycin, streptourea Mycoplasma, tuberculin, ubenimex, fenestrated statin, zorobacterium; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as folate, methotrexate, pteroyltriglutamate, trimethoprim; purine analogs such as fludarabine, 6-mercaptopurine, thioimidazoline, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azouridine, carmoflurane, cytarabine, dideoxyuridine, docefluorourine. Benzyl, Enoxabin, Fluorouracil; Androgens such as Calotestosterone, Oxymethylandrosten Propionate, Epithrostanol, Meandrogene, Testrolide; Antiadrenergics such as Aminolamide, Mantopanol, Tralostan; Folic acid supplements such as Leucovorin; Acetylpyridinol; Aldoxycycline glycoside; Aminolevulinic acid; Enuracil; Aminolamine; Bestrabucil; Bismutharin; Idatraxa; Defofamine; Demeclopramide; Dexaquinone; Eloni Elfomithine; Hydroxypyrazole acetate; epothilone; Etogluconol; Gallium nitrate; Hydroxyurea; Lentinan; Clonidamine; Maytansine alkaloids such as maytansine and anthraquinone; Mitoguanidine hydrazone; Mitoanthraquinone; Mopidanmol; Diamine nitroacetate; Pentostatin; Nitrosamine mustard; Pirarubicin; Loxoanthraquinone; Podophyllinic acid; 2-Ethylhydrazide; Procarbazine; Polysaccharide complexes (JHS Natural Products, Eugene, OR); razorylene; xisophiran; germanium spiroamine; tenuazonicacid; triaminoquinone; 2,2',2"-trichlorotriethylamine; trichosporins (especially T-2mycin, verracurin A, baculosporin A, and serpentin); urethane; vincristine; dacarbazine; mannitol mustard; dibromomannitol; dibromoeutherol; piperbbromobromo; gacytosine; cytarabine ("Ara-C"); cyclophosphamide; thiotepa; taxanes, for example, (Paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ) Paclitaxel in albumin-engineered nanoparticle formulations without polyoxyethylene castor oil (American Pharmaceutical Partners, Schaumberg, IL) and Docetaxel (Rhone-Poulenc Rorer, Antony, France); Chlorobutyrate; Gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vincristine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Vinorelbine; Noantor; Teniposide; Idatrox; Daunorubicin; Aminopterin; Xeloda; Ibayronate; Irinotecan (e.g., CPT-1); topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DMFO); Retinoids such as retinoic acid; Capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing substances. Two or more chemotherapeutic agents may be used in combination with the compounds of the present invention. Suitable dosing regimens for combination chemotherapy are known in the art. For example, combination dosing 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).

[0932] Other therapeutic agents that can be administered in combination with the compounds disclosed herein may include bevacizumab, sunitinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalani, vandetanib, aflibercept, voloximab, edazolizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, and dovirte. Nitrofurazone, Fentuximab, Atacicept, Rituximab, Alemumab, Interleukin, Atezolizumab, Tocilizumab, Tessirolimus, Everolizumab, Lucarumumab, Darcyzazumab, HLL1, huN901-DM1, Atipremod, Natazumab, Bortezomib, Carfilzomib, Marizomib, Tanspiramycin, Saquinavir Mesylate, Ritonavir, Neferunavir Mesylate, Indinavir Sulfate Belistat, Perbisstat, Mapamoumab, Lesamumab, Dulanamine, ABT-737, Olimerson, Plitidepsin, Talmazimod, P276-00, Enzastaurin, Tipifarnib, Perifolfen, Imatinib, Dasatinib, Lenalidomide, Thalidomide, Simvastatin, Celecoxib, Badoxifene, AZD4547, Rituximab, Oxalidomide Platinum (Eloxatin), PD0332991, Ribociclib (LEE011), Pomazenil (LY2835219), HDM201, Fulvestrant (Faslodex), Exemestane (Aromasin), PIM447, Ruxotinib (INC424), BGJ398, Nexituzumab, Pemetrexed (Alimta), and Ramucirumab (IMC-1121B).

[0933] In some implementations, an additional treatment 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 may "coat" the surface of cancer cells, triggering the immune system to destroy them. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor microenvironment that promotes tumor angiogenesis. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, thus blocking the signaling that leads to new blood vessel growth. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), while trastuzumab targets human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the target receptor from sending its normal growth-promoting signals. They may also induce apoptosis and activate the immune system to destroy tumor cells.

[0934] In one aspect of the invention, the bioactive agent is an immunosuppressant. The immunosuppressant may be a calcineurin inhibitor, such as cyclosporine or ascomycin, for example cyclosporine A. FK506 (tacrolimus), pimecrolimus, mTOR inhibitors, such as rapamycin or its derivatives, such as sirolimus Everolimus Tesirolimus, zotalimus, eumetolimus-7, eumetolimus-9, rapamycin analogues such as lidafolimus, azathioprine, campath 1H, S1P receptor modulators such as fingolimod or its analogues, anti-IL-8 antibodies, mycophenolic acid or its salts such as sodium salt, or its prodrugs such as mycophenolate mofetil. OKT3 (ORTHOCLONE) Prednisone Buquina sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyguanidin, tropelimus, leflunomide CTLAI-Ig, anti-CD25, anti-IL2R, balithiba Dalizumab Imidazolidin, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus) ), CTLA4lg (abasipra), Berazip, LFA3lg, Enarcept (made by Immunex) (For Sale) Adalimumab Infliximab Anti-LFA-1 antibody, nastatin Enmumab, golimumab, anti-thymocyte immunoglobulin, cilizumab, afaxicept, efalizumab, phendex, mesalazine, aconitine, codeine phosphate, benorylate, fenbufen, naproxen, diclofenac, etodoxacin and indomethacin, aspirin and ibuprofen.

[0935] In some embodiments, the bioactive agent is a therapeutic agent, which is a biological agent used in cancer treatment such as a cytokine (e.g., interferon or interleukin (e.g., IL-2)). In some embodiments, the biological agent is an anti-angiogenic agent, such as an anti-VEGF agent, for example, bevacizumab. In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that activates a target to stimulate an anticancer response or antagonizes antigens important to cancer. Such agents include... (rituximab); (Dalizumab); (Bariximab); (palizumab); (infliximab); (Trastuzumab); (Gitocilizumab ozomicin); (alemumab); (Imozolomide); (adalimumab); (Omalizumab); (Tosimomab-l-131); (Elilizumab); (Cetuximab); (Bevacizumab); (Natazumab); (Tocilizumab); (Panitumumab); (Lanibizumab); (Ikuzumab); (Cetuximab); (Golizumab); (Canazumab); (Ustekinumab); (Ophamumab); (Desulamab); (Movitez monoclonal antibody); (Rashicuzumab); (Belimumab); (Ipilimumab); (Bentuximab); (Pertuzumab); (Trastuzumab emtansine); and (Oxtuzumab). Also includes antibody-drug conjugates.

[0936] Combination therapy may include therapeutic agents that are non-pharmacological treatments. For example, the compound may be administered in addition to radiation therapy, cryotherapy, hyperthermia, and / or surgical resection of tumor tissue.

[0937] In some 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 after the second therapeutic agent, at most 1 hour, at most 2 hours, at most 3 hours, at most 4 hours, at most 5 hours, at most 6 hours, at most 7 hours, at most 8 hours, at most 9 hours, at most 10 hours, at most 11 hours, at most 12 hours, at most 13 hours, at most 14 hours, at most 16 hours, at most 17 hours, at most 18 hours, at most 19 hours, at most 20 hours, at most 21 hours, at most 22 hours, at most 23 hours, at most 24 hours, or at most 1-7 days, 1-14 days, 1-21 days, or 1-30 days.

[0938] In some embodiments, the second therapeutic agent is administered at a different dosage schedule than the compound of the present invention. For example, the second therapeutic agent may have a treatment holiday of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days per treatment cycle. In another embodiment, the first therapeutic agent has a treatment holiday. For example, the first therapeutic agent may have a treatment holiday of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days per treatment cycle. In some embodiments, both the first and second therapeutic agents have treatment holidays.

[0939] V. Pharmaceutical Composition

[0940] Compounds of Formula I as described herein may be administered as pure chemicals, but more commonly as pharmaceutical compositions comprising an amount effective for a patient, or a normal person, requiring such treatment to treat any of the conditions described herein. Therefore, this disclosure provides pharmaceutical compositions comprising an effective amount of the compound or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, for any of the uses described herein. The pharmaceutical composition may contain the compound or salt as the sole active agent, or, in alternative embodiments, contain the compound and at least one additional active agent.

[0941] Typically, the compositions of this disclosure will be administered in a therapeutically effective amount via any acceptable mode of administration. A suitable dosage range depends on numerous factors such as the severity of the disease to be 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 administration is intended, and the preferences and experience of the relevant physician. Those skilled in the art who treat such diseases will be able to determine the therapeutically effective amount of the compositions of this disclosure for a given disease without excessive experimentation and relying on personal knowledge and the disclosure of this application.

[0942] In some embodiments, the pharmaceutical composition is a dosage form containing, in a unit dosage form, about 0.005 mg to about 2000 mg, about 1 mg to about 1000 mg, about 10 mg to about 800 mg, or about 20 mg to about 600 mg of an active compound 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 another active agent. Examples include dosage forms having at least about 0.005, 0.01, 0.025, 0.05, 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of an active compound or a salt thereof and up to about 1 gram of an active compound or a salt thereof.

[0943] In some embodiments, the pharmaceutical composition is in the form of a unit 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 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 another active agent. Examples include dosage forms having at least 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of the active compound or a salt thereof.

[0944] In some embodiments, the compounds disclosed herein or used as described are administered once daily (QD), twice daily (BID), or three times daily (TID). In some embodiments, the compounds disclosed herein or used as described are administered at least once daily 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 longer.

[0945] In some embodiments, the compounds of the present invention are administered once, twice, three times, or four times daily.

[0946] In some embodiments, the compound of the present invention is administered orally once daily. In some embodiments, the compound of the present invention is administered orally twice daily. In some embodiments, the compound of the present invention is administered orally three times daily. In some embodiments, the compound of the present invention is administered orally four times daily.

[0947] In some embodiments, the compound of the present invention is administered intravenously once daily. In some embodiments, the compound of the present invention is administered intravenously twice daily. In some embodiments, the compound of the present invention is administered intravenously three times daily. In some embodiments, the compound of the present invention is administered intravenously four times daily.

[0948] In some embodiments, the application of the compounds of the present invention has treatment breaks between treatment cycles. For example, the compounds may have treatment breaks of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle.

[0949] In some implementations, a loading dose is administered to initiate treatment. For example, the compound may be administered at a dose at least about 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, 4.5x, 5x, 5.5x, 6x, 6.5x, 7x, 7.5x, 8x, 8.5x, 9x, 9.5x, or 10x higher than the maintenance dose for a treatment cycle to initiate treatment. Other exemplary loading doses include doses at least about 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, 4.5x, 5x, 5.5x, 6x, 6.5x, 7x, 7.5x, 8x, 8.5x, 9x, 9.5x, or 10x higher than the first 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days of treatment, followed by a maintenance dose for the remaining days of treatment in the treatment cycle.

[0950] The pharmaceutical composition may also contain an active compound and other active agents in a molar ratio. For example, the 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.

[0951] These compositions may contain any amount of the active compound that achieves the desired results, such as 0.1 to 99 wt.% of the compound, and typically 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.

[0952] The drug or therapeutically effective amount of a composition is delivered to the patient. The exact effective amount will vary from patient to patient and will depend on species, age, subject's body size and health status, the nature and extent of the disease being treated, the advice of the treating physician, and the choice of therapeutic agent or combination of therapeutic agents to be administered. The effective amount for a given situation can be determined through routine laboratory testing.

[0953] In some embodiments, the therapeutic dose may be, for example, in the range of about 0.0001 mg / kg to about 25 mg / kg body weight. The dose may be administered to the subject as many times as needed to reduce and / or alleviate the signs, symptoms, or cause of the considered condition, or to induce any other desired changes in the biological system. When necessary, formulations with an enteric coating suitable for sustained or controlled release administration of the active ingredient may be prepared.

[0954] In some implementations, the dosage is in the range of about 0.001-10 mg / kg of 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. kg, approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 1.5 mg / kg, approximately 2.0 mg / kg, approximately 2.5 mg / kg, approximately 3.0 mg / kg, approximately 3.5 mg / kg, approximately 4.0 mg / kg, approximately 4.5 mg / kg, approximately 5.0 mg / kg, approximately 5.5 mg / kg, approximately 6.0 mg / kg, approximately 6.5 mg / kg, approximately 7.0 mg / kg, approximately 7.5 mg / kg, approximately 8.0 mg / kg, approximately 9.0 mg / kg, approximately 9.5 mg / kg, or approximately 10 mg / kg.

[0955] In some embodiments, the therapeutic dose may be, for example, in the range of about 0.01 mg / kg to about 250 mg / kg body weight, and more typically about 0.1 mg / kg to about 10 mg / kg. The dose may be administered to the subject as many times as needed to reduce and / or alleviate the signs, symptoms, or cause of the suspected condition, or to induce any other desired changes in the biological system. When necessary, formulations with an enteric coating suitable for sustained or controlled release administration of the active ingredient may be prepared.

[0956] In some implementations, the dosage is in the range of about 0.01-100 mg / kg of 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, and about 10 mg / kg. g, approximately 15 mg / kg, approximately 20 mg / kg, approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 55 mg / kg, approximately 60 mg / kg, approximately 65 mg / kg, approximately 70 mg / kg, approximately 75 mg / kg, approximately 80 mg / kg, approximately 85 mg / kg, approximately 90 mg / kg, approximately 95 mg / kg, or approximately 100 mg / kg.

[0957] Pharmaceutical formulations are preferably unit dosage forms. In such dosage forms, the formulation is subdivided into unit doses containing suitable amounts of the active ingredient. A unit dosage form can be a packaged formulation containing discrete amounts of the formulation, such as tablets, capsules, and powders packaged in vials or ampoules. Alternatively, the unit dosage form itself can be a capsule, tablet, sachets, or lozenge, or it can be a packaged form of any of these in suitable amounts.

[0958] In some implementations, the compound is administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include: acetates, adipates, alginates, ascorbic acid salts, aspartates, benzenesulfonates, benzoates, hydrogen sulfates, borates, butyrates, camphorates, camphor sulfonates, citrates, cyclopentanepropionates, digluconate, dodecyl sulfates, ethanesulfonates, fumarates, gluconate, glyceryl phosphates, hemisulfates, heptarates, hexanoates, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrates, oleates, oxalates, palmitates, dihydroxynaphthalate, pectates, persulfates, 3-phenylpropionate, phosphates, picrates, neopentanoate, propionate, stearates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates, undecanoates, and valerates. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0959] Therefore, the compositions of this disclosure can be administered as pharmaceutical formulations, including those suitable for oral (including sublingual and sublingual), rectal, nasal, topical, transdermal, pulmonary, vaginal, or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous, and intravenous) administration, injection, inhalation or spray, intra-aortic, intracranial, subdermal, intraperitoneal, subcutaneous, or other means of administration containing conventionally pharmaceutically acceptable carriers. Typical administration methods are oral, topical, or intravenous, using convenient daily dosing regimens that can be adjusted according to the degree of discomfort.

[0960] Depending on the intended mode of administration, the pharmaceutical composition may be in the form of a solid, semi-solid, or liquid dosage form, such as tablets, suppositories, pills, capsules, powders, liquids, syrups, suspensions, creams, ointments, lotions, pastes, gels, sprays, aerosols, foams, or oils, injections or infusion solutions, transdermal patches, subcutaneous patches, inhaled preparations, medical devices, suppositories, sublingual or oral preparations, parenteral preparations, or eye drops, preferably in a unit dosage form suitable for a precise single dose.

[0961] Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized unit doses containing suitable amounts of the active ingredient, such as an effective amount to achieve the desired purpose. The composition will contain an effective amount of the selected drug combined with a pharmaceutically acceptable carrier, and may also include other pharmaceutical agents, adjuvants, diluents, buffers, etc.

[0962] The carrier comprises excipients and diluents and must possess sufficiently high purity and low toxicity to be suitable for administration to the treated patient. The carrier may be inert or may have its own pharmaceutical benefits. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of application material per unit dose of the compound.

[0963] The categories of carriers include, but are not limited to, adjuvants, binders, buffers, colorants, diluents, disintegrants, excipients, emulsifiers, flavoring agents, gels, glidants, lubricants, preservatives, stabilizers, surfactants, solubilizers, tablets, wetting agents, or curing materials.

[0964] Some carriers may be listed in more than one category; for example, vegetable oils may be used as lubricants in some formulations and as diluents in others.

[0965] Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, powdered tragacanth gum, malt, gelatin; talc, petrolatum, lanolin, polyethylene glycol, alcohols, transdermal penetration enhancers, and vegetable oils. The pharmaceutical composition may contain optional active agents that substantially do not interfere with the activity of the compounds of the present invention.

[0966] Some excipients include, but are not limited to, liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, and ethanol. Depending on the therapeutic target, compounds may be provided, for example, in solid, liquid, spray-dried material, micron-sized particles, nanoparticles, controlled-release systems, etc. Excipients suitable for non-liquid formulations are also known to those skilled in the art. A detailed discussion of pharmaceutically acceptable excipients and salts is available in Remington's Pharmaceutical Sciences (18th edition) (Easton, Pennsylvania: Mack Publishing Company, 1990).

[0967] In addition, auxiliary substances, such as wetting agents or emulsifiers, biological buffers, and surfactants, can be present in such media. Biological buffers can be any pharmacologically acceptable solution, and they provide the required pH for the formulation, i.e., a pH within a physiologically acceptable range. Examples of buffer solutions include saline, phosphate-buffered saline, Tris-buffered saline, Hank's buffered saline, etc.

[0968] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. Compositions suitable for liquid pharmaceutical administration can be prepared, for example, by dissolving, dispersing, etc., the active compound as described herein and optional adjuvants in an excipient such as water, saline, dextran aqueous solution, glycerol, ethanol, etc., to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc., for example, sodium acetate, sorbitol monolaurate, triethanolamine acetate sodium, triethanolamine oleate, etc. Practical methods for preparing such dosage forms are known or will be obvious to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences cited above.

[0969] In another embodiment, the use of a penetration enhancer excipient is provided, the penetration enhancer excipient comprising polymers such as: polycationic (chitosan and its quaternary ammonium derivatives, poly-L-arginine, amination gelatin); polyanionic (N-carboxymethyl chitosan, polyacrylic acid); and thiolized polymers (carboxymethyl cellulose-cysteine, polycarbofil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugate).

[0970] In some embodiments, the excipients are selected from butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, croscarmellose, croscarmellose, citric acid, crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium glycolate starch, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0971] Pharmaceutical compositions / combinations are formulated for oral administration. For oral administration, the compositions are typically in the form of tablets, capsules, soft gel capsules, or may be aqueous or non-aqueous solutions, suspensions, or syrups. Tablets and capsules are typical forms of oral administration. Tablets and capsules for oral use may contain one or more commonly used carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are often also added. Typically, the compositions disclosed herein can be combined with oral, non-toxic, pharmaceutically acceptable inert carriers such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. In addition, suitable binders, lubricants, disintegrants, and colorants may be introduced into the mixture when desired or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth, or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. The lubricants used in these formulations include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum.

[0972] When using liquid suspensions, the active agent may be combined with any orally administered, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc., as well as with emulsifiers and suspending agents. Flavoring agents, coloring agents, and / or sweeteners may also be added if desired. Other optional components introduced into the oral formulations herein include, but are not limited to, preservatives, suspending agents, thickeners, etc.

[0973] For ocular delivery, compounds may be administered as needed, such as via intravitreal, intrastromal, anterior chamber, subfascial, subretinal, retrobulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, suprascleral, periocular, transscleral, retrobulbar, posterior juxtascleral, pericorneal, or lacrimal duct injection, or via mucus, mucin, or mucosal barriers, either immediately or in a controlled manner, or via ocular devices.

[0974] Parenteral formulations can be prepared in conventional forms, or as liquid solutions or suspensions, solid forms suitable for dissolution or suspension in a liquid prior to injection, or as emulsions. Typically, sterile injectable suspensions are formulated using suitable carriers, dispersants or wetting agents, and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in acceptable, non-toxic, parenteral diluents or solvents. Acceptable media and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils, fatty esters, or polyols are commonly used as solvents or suspension media. Furthermore, parenteral administration may involve the use of slow-release or sustained-release systems to maintain a constant dose level.

[0975] Parenteral administration includes intra-articular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient, 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 involve introducing the formulations of this disclosure into the patient through a needle or catheter propelled by a sterile syringe or some other mechanical device such as a continuous infusion system. The formulations provided in this disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.

[0976] The parenteral formulations according to this disclosure include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or media include propylene glycol, polyethylene glycol, vegetable oils (such as olive oil and corn oil), gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. They can be sterilized, for example, by filtration through a bacteria retaining filter, by introducing a sterilizing agent into the composition, by irradiating the composition, or by heating the composition. They can also be manufactured using sterile water or some other sterile injectable media just before use.

[0977] Sterile injectable solutions are prepared by introducing a desired amount of one or more of the disclosed compounds, along with various other ingredients listed above, into a suitable solvent and then filtering and sterilizing. Typically, dispersions are prepared by introducing various sterilized active ingredients into a sterile medium containing a base dispersion medium and desired other ingredients from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, typical preparation methods are vacuum drying and freeze-drying techniques, which produce powders of the active ingredient plus any other desired ingredients from their previously sterile filtered solutions. Thus, for example, a parenteral composition suitable for injection is prepared by stirring 10% by volume of propylene glycol and water with 1.5% by weight of the active ingredient. The solution is isotonicized with sodium chloride and sterilized.

[0978] Alternatively, the pharmaceutical compositions of this disclosure can be administered in suppository form for rectal administration. Suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0979] The pharmaceutical compositions disclosed herein can also be administered via nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the pharmaceutical formulation field and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, propellants such as fluorocarbons or nitrogen, and / or other conventional solubilizers or dispersants.

[0980] Formulations for sublingual administration include tablets, lozenges, gels, etc. Alternatively, sublingual 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 mucous membrane tissue using conventional transdermal drug delivery systems, i.e., transdermal patches, where the agent is typically contained in a laminated structure serving as a drug delivery device for fixation to the body surface. In such a structure, the drug composition is typically contained in a layer or reservoir beneath an upper backing layer. The laminated device may contain a single reservoir or may contain multiple reservoirs. In some embodiments, the reservoir comprises a polymer matrix of a pharmaceutically acceptable contact adhesive material for securing 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, polyurethane, etc.

[0981] Alternatively, the drug-containing reservoir and the skin-contact adhesive may exist as separate and distinct layers. The adhesive beneath the reservoir could be a polymer matrix as described above, or it could be a liquid or gel reservoir, or take other forms. In these laminates, the backing layer, which acts as the upper surface of the device, serves as a key structural element of the laminate structure and provides considerable flexibility to the device. The material chosen for the backing layer should be substantially impermeable to the active agent and any other materials present.

[0982] The compositions disclosed herein can be formulated for aerosol administration, particularly for use in the respiratory tract, including intranasal administration. The compounds may, for example, typically have a particle size of, for example, about 5 micrometers or smaller. Such particle size can be obtained by means known in the art, such as by micronization. The active ingredient is provided in a pressurized package along with a suitable propellant such as a chlorofluorocarbon (CFC) such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may also conveniently contain a surfactant such as lecithin. The dosage of the drug can be controlled by a metering valve.

[0983] Alternatively, the active ingredient can be provided in the form of a dry powder, such as a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose, and polyvinylpyrrolidone (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition can be present in unit dose form, for example in capsules or cartridges packaged in gelatin or blister packs, from which the powder can be administered by means of an inhaler.

[0984] Formulations suitable for rectal administration are typically available as unit-dose suppositories. These suppositories are prepared by mixing the active compound with one or more conventional solid carriers, such as cocoa butter, and then molding the resulting mixture.

[0985] In some embodiments, the pharmaceutical composition is suitable for local application to the skin using the administration methods defined above.

[0986] In some embodiments, the pharmaceutical composition is suitable for transdermal administration and may be in the form of a discrete patch, which is adapted to maintain close contact with the recipient's epidermis for an extended period. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3(6):318(1986)) and are typically in the form of an optional buffered aqueous solution of the active compound.

[0987] In some implementations, microneedle patches or devices are provided to deliver drugs through or into biological tissues, particularly the skin. Microneedle patches or devices allow for the delivery of drugs across or into skin or other tissue barriers at clinically relevant rates with minimal or no damage, pain, or irritation to the tissue.

[0988] Suitable formulations for lung delivery can be delivered via a wide range of passively driven and actively powered single / multi-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 screen nebulizers. The selection of a suitable lung delivery device depends on parameters such as the nature and formulation of the drug, the site of action, and the pathophysiology of the lungs.

[0989] VI. General Synthesis

[0990] The compounds described herein can be prepared by methods known to those skilled in the art. In one non-limiting example, the disclosed compounds can be prepared using the following scheme.

[0991] For convenience, the compounds of this invention having a stereocenter can be drawn without stereochemistry. Those skilled in the art will recognize that pure or enriched 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:

[0992] i) Physical separation of crystals – a technique for manually separating macroscopic crystals of individual enantiomers. This technique can be used if individual enantiomers exist, i.e., the material is conglomerate and the crystals are visually distinct;

[0993] ii) Simultaneous crystallization—a technique for crystallizing individual enantiomers separately from a solution of a racemic compound, which is only possible when the enantiomers are solid aggregates;

[0994] iii) Enzymatic resolution – a technique for partially or completely separating racemic compounds by using the different reaction rates of enantiomers with enzymes;

[0995] iv) Enzymatic asymmetric synthesis – a synthetic technique in which at least one step of the synthesis uses an enzymatic reaction to obtain a synthetic precursor of the desired enantiomer that is pure or enriched.

[0996] v) Chemical asymmetric synthesis – a synthetic technique in which the desired enantiomers are synthesized from achiral precursors under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved by chiral catalysts or chiral auxiliaries.

[0997] vi) Diastereomer Separation – A technique that converts a single enantiomer into a diastereomer by reacting a racemic compound with an enantiomer-pure reagent (chiral auxiliary agent). The resulting diastereomers are then separated by chromatography or crystallization using their now more pronounced structural differences, followed by removal of the chiral auxiliary agent to obtain the desired enantiomer;

[0998] vii) Primary and secondary asymmetric transformations—rapid equilibrium is achieved from the diastereomers of the racemic compound, resulting in a quantitative advantage in the solution of the diastereomers of the desired enantiomer. The preferential crystallization of the desired enantiomer perturbs this equilibrium, ultimately leading to the conversion of virtually all material from the desired enantiomer to the crystalline diastereomer. The desired enantiomer is then released from the diastereomer.

[0999] viii) Kinetic resolution – This technique refers to the partial or complete resolution of racemic compounds (or further resolution of partially resolved compounds) by means of different reaction rates of enantiomers with chiral non-racemic reagents or catalysts under kinetic conditions.

[1000] ix) Enantiospecific synthesis from non-racemic precursors—synthetic techniques in which the desired enantiomers are obtained from achiral starting materials and in which the stereochemical integrity is not compromised or is only minimally compromised during synthesis;

[1001] x) Chiral liquid chromatography—a technique for separating enantiomers of racemic compounds in a liquid mobile phase by means of their different interactions with the stationary phase (including vial-type chiral HPLC). The stationary phase may be made of a chiral material, or the mobile phase may contain other chiral materials to stimulate different interactions;

[1002] xi) Chiral gas chromatography – a technique for volatilizing racemic compounds and separating enantiomers by means of their different interactions with a column containing a fixed non-racemic chiral adsorbent phase in a gaseous mobile phase.

[1003] xii) Chiral solvent extraction – a technique for separating enantiomers by means of the preferential dissolution of an enantiomer in a specific chiral solvent;

[1004] xiii) Transchiral membrane transport—a technique for bringing a racemic compound into contact with a thin-film barrier. This barrier typically separates two miscible fluids, one of which contains the racemic compound, and driving forces such as concentration or pressure differential cause preferential transport across the membrane barrier. Separation occurs due to the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemic compound to pass through.

[1005] xiv) In some implementations, simulated moving bed chromatography is used. A wide variety of commercially available chiral stationary phases are available.

[1006] General Synthesis Scheme 1

[1007]

[1008] In some respects, compound I can be synthesized according to the route provided in General Synthetic Scheme 1. In step 1, intermediate 1 is reacted with 2 in an organic solvent (e.g., dimethyl sulfoxide, acetonitrile, or dioxane) at elevated temperatures in the presence of a copper catalyst (e.g., copper iodide (I), copper chloride (I), or another copper catalyst suitable for Ullmann coupling conditions), a ligand (e.g., bipyridine, 1,10-phenanthroline, dimethyl ethylenediamine, or another ligand suitable for Ullmann coupling conditions), and a base (e.g., cesium carbonate, potassium carbonate, tripotassium phosphate, or another base suitable for Ullmann coupling conditions) to give 3. In step 2, 3 is reacted with triphosgene in dichloromethane in the presence of aluminum trichloride to give 4. In step 3, intermediate 4 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., tetrahydrofuran or dichloromethane), and then 5 is added to give 6.

[1009] General Synthesis Scheme 2

[1010]

[1011] In some respects, compound I can be synthesized according to the route provided in General Synthetic Scheme 2. In step 1, intermediates 1 and 2 are reacted in an organic solvent (e.g., toluene, THF, dioxane, or DMF) at elevated temperatures in the presence of a palladium catalyst (e.g., palladium(II) acetate, Pd2(dba)3, or another palladium catalyst suitable for Buchwald-Hartwig coupling conditions), a phosphine ligand (e.g., BINAP, XantPhos, or another phosphine ligand suitable for Buchwald-Hartwig coupling conditions), and a base (e.g., potassium tert-butoxide, cesium carbonate, or another base suitable for Buchwald-Hartwig coupling conditions) to give 3.

[1012] General Synthesis Scheme 3

[1013]

[1014] In some respects, compound I can be synthesized according to the route provided in General Synthetic Scheme 3. In step 1, intermediate 1 is reacted with 2 in an organic solvent (e.g., toluene, DMA, or dioxane) at elevated temperatures in the presence of a palladium catalyst (e.g., PdCl2(dppf), PdCl2(PPh3), or another palladium catalyst suitable for Miyaura coupling conditions), a ligand (e.g., Xphos, PPh3, or another ligand suitable for Miyaura coupling conditions), and a base (e.g., potassium acetate, potassium ethoxide, potassium carbonate, or another base suitable for Miyaura coupling conditions) to give 3. In step 2, intermediate 3 is reacted with EtOH at elevated temperatures to give 4. In step 3, compounds 4 and 5 are reacted in an organic solvent (e.g., methanol, acetonitrile, or dichloromethane) in ambient air in the presence of a copper catalyst (e.g., copper(II), copper(II) acetate, or another copper catalyst suitable for 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 give 6.

[1015] General Synthesis Scheme 4

[1016]

[1017] In some respects, compound I can be synthesized according to the route provided in General Synthetic Scheme 4. In step 1, intermediates 1 and 2 are reacted in an organic solvent (e.g., dimethoxyethane, THF, or toluene) at elevated temperatures in the presence of a palladium catalyst (e.g., Pd(OAc)2, Pd(PPh3)4, or another suitable palladium catalyst), a ligand (e.g., P(p-MeOPh)3, PPh3, PCy3, or another suitable ligand), water, and neopentanoic anhydride to give 3.

[1018] General Synthesis Scheme 5

[1019]

[1020] In some respects, compound I can be synthesized according to the route provided in General Synthetic 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 give 2.

[1021] General Synthesis Scheme 6

[1022]

[1023] In some respects, compound I can be synthesized according to the route provided in General Synthetic 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 give 3. In step 2, the imine of 3 is reduced to an amino group using a suitable reducing agent.

[1024] General Synthesis Scheme 7

[1025]

[1026] In some respects, compound I can be synthesized according to the route provided in General Synthesis Scheme 7. In step 1, intermediates 1 and 2 are reacted in an aqueous organic solvent (e.g., 10:1 toluene:water, 5:1 THF:water, or 1:1 ethanol:water) at elevated temperatures in the presence of a palladium catalyst (e.g., Pd(OAc)2, Pd2dba3, or another palladium catalyst suitable for Suzuki coupling conditions), a ligand (e.g., Xphos, PCy3, or another ligand suitable for Suzuki coupling conditions), and a base (e.g., sodium carbonate, tripotassium phosphate, potassium carbonate, or another base suitable for Suzuki coupling conditions) to give 3.

[1027] General Synthesis Scheme 8

[1028]

[1029] In some respects, compound 1 can be synthesized according to the route provided in General Synthesis Scheme 8. In step 1, intermediate 1 is reacted with intermediate 2 in an organic solvent (e.g., DMF) at elevated temperatures in the presence of a palladium precatalyst (e.g., Pd(OAc)2, Pd2dba3, or another palladium catalyst suitable for palladium-catalyzed carbonylation), a base (e.g., triethylamine, diisopropylethylamine, or another base suitable for palladium-catalyzed carbonylation), CO gas, and a ligand (e.g., XantPhos, PCy3, or another ligand suitable for palladium-catalyzed carbonylation) to give 3.

[1030] Example 1. Compound 1 and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzo[cd]indole-2(1H)-one

[1031]

[1032]

[1033] Step 1: Synthesis of 2-chloro-1-(4,8-dibromonaphth-1-yl)ethyl-1-one: A DCE (2000 mL) solution of 1,5-dibromonaphthyl (162 g, 566.51 mmol) under stirring was cooled to 0 °C and 2-chloroacetyl chloride (83.18 g, 736.46 mmol, 58.57 mL) was added dropwise. The resulting solution was stirred at 0 °C for 15 min, followed by the addition of anhydrous aluminum chloride (98.20 g, 736.46 mmol, 40.25 mL) in portions. The resulting reaction mixture was then slowly warmed to room temperature and stirred for 16 h. After completion (monitored by TLC), the reaction mixture was poured into ice-cold water and extracted twice with DCM. The combined organic extracts were further washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (100-200 μL silica; gradient: 0-5% EtOAc in hexane) yielded a grayish-white solid, 150 g (390 mmol), 2-chloro-1-(4,8-dibromo-1-naphthyl)ethenone. Yield: 69%. 1 H NMR (d 6 -DMSO,400MHZ)δ8.36(dd,J=8.48,0.72Hz,1H),8.11-8.07(m,2H),7.69(t,J=8.04Hz,1H),7.59(d,J=7.8Hz,1H),5.05(s,2H);

[1034] Step 2: Synthesis of 4,8-dibromo-1-naphthylcarboxylic acid: Sodium nitrite (30.27 g, 438.75 mmol) was added to a solution of 151 g (416.62 mmol) of 2-chloro-1-(4,8-dibromo-1-naphthyl)ethenneone in 1.8 L of sulfuric acid at room temperature, and the resulting reaction mixture was stirred at 65 °C for 45 min. After completion (monitored by TLC), the reaction mixture was poured into 2 L of cold water and the resulting solid was filtered off. The solid obtained therefrom was added to a 10% sodium carbonate solution (4 L) and stirred at room temperature for 30 min. The mixture was filtered; the filtrate was carefully acidified with concentrated HCl under vigorous stirring and filtered again to remove insoluble impurities. The filtrate (aqueous) was then extracted (twice) with ethyl acetate. The combined organic extracts were further washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 4,8-dibromonaphthyl-1-carboxylic acid (110 g, 299 mmol) as a light brown solid. Yield: 72%. 1 H NMR (d 6-DMSO,400MHZ)δ13.48(br s,1H),8.33(d,J=8.36Hz,1H),8.09(d,J=7.4Hz,1H),8.01(d,J=7.72Hz,1H),7.65(t,J=8.0Hz,1H),7.59(d,J=7.72Hz,1H); LC MS[MH] - 328.90.

[1035] Step 3: Synthesis of 5-bromobenzo[cd]indole-2(1H)-one: Copper powder (3.25 g, 51.22 mmol) was added to a suspension of 4,8-dibromonaphth-1-carboxylic acid (65 g, 196.99 mmol) in ammonia water (700 mL) under stirring, and the resulting reaction mixture was stirred at 80 °C for 2 hours. After completion (monitored by TLC), the reaction mixture was poured into ice-cooled water and slowly acidified with concentrated HCl (pH ~2) under vigorous stirring. The resulting yellow precipitate was filtered off and further dried under reduced pressure to give a brown solid 5-bromo-1H-benzo[cd]indole-2-one (39 g, 151.68 mmol). Yield: 77%. 1 H NMR (d 6 -DMSO,400MHZ)δ10.88(s,1H),8.05(d,J=7.44Hz,1H),7.88(d,J=7.4Hz,1H),7.61(t,J=7.8Hz,1H),7.53(d,J=8.56Hz,1H),7.04(d,J=7.0Hz,1H); LC MS[M+H] + 248.2, 250.1.

[1036] Step 4: Synthesis of 3-(5-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (Compound 1): Sodium hydride (60% dispersion in mineral oil) (38.61 g, 1.01 mol) was added in portions to a suspension of 5-bromo-1H-benzo[cd]indol-2-one (25 g, 100.78 mmol) in dry THF (250 mL) while maintaining the temperature below 5 °C. Once the addition was complete, the resulting mixture was slowly warmed to room temperature and stirred for 15 min. The reaction mixture was cooled again to 0 °C and 3-bromopiperidin-2,6-dione (96.75 g, 503.88 mmol) was added in portions. The resulting reaction mixture was heated at 70 °C for 1 h. After completion (monitored by TLC), the reaction mixture was slowly poured into crushed ice and extracted with ethyl acetate (x3). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was ground with diethyl ether and pentane to give the desired compound 3-(5-bromo-2-oxo-benzo[cd]indol-1-yl)piperidine-2,6-dione (16 g, 34.27 mmol) as a light yellow solid. Yield: 34%. 1 H NMR (d 6 -DMSO,400MHZ)δ11.14(s,1H),8.12(d,J=7.48Hz,1H),7.99(d,J=7.44Hz,1H),7.72-7.62(m,2H),7.26(d, LC MS[M+H] + 359.07, 361.02.

[1037] Step 5: Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzo[cd]indole-2(1H)-one: Bis(pinacolyl)diboron (307 mg, 1.21 mmol, 1.5 eq) was added to a stirred solution of 5-bromo-1H-benzo[cd]indole-2-one (200 mg, 806 μmol, 1 eq) in 1,4-dioxane (10 mL), followed by the addition of thoroughly dried potassium acetate (237 mg, 2.42 mmol, 3 eq). The resulting reaction mixture was thoroughly degassed with argon for 15 min. Then, Pd(dppf)Cl2·DCM (66 mg, 81 μmol, 0.1 eq) was added, and the reaction mixture was heated at 100 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through a diatomaceous earth mat, then washed with EtOAc. The combined filtrates were then washed with cold water, dried over sodium sulfate, and concentrated under reduced pressure to give crude 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-1H-benzo[cd]indol-2-one (200 mg, 406 μmol, 60% purity), a crude brown gelatinous substance, which was used directly without further purification. Yield: 35%. LC-MS [M+H] + 296.2. Example 2.5-Chloromethyl-1-(4-methoxy-benzyl)-1H-benzo[cd]indol-2-one

[1038]

[1039] Step 1: Synthesis of 5-bromo-1-(4-methoxy-benzyl)-1H-benzo[cd]indol-2-one: Sodium hydride (60% dispersion in mineral oil) (7.255 g, 302.297 mmol) was added to a stirred solution of 5-bromo-1H-benzo[cd]indol-2-one (50.0 g, 201.532 mmol) in 150 mL of DMF at 0 °C, and the reaction mixture was stirred at the same temperature for 30 min. Then, 4-methoxybenzyl chloride (32.806 mL, 241.8 mmol) was added, and the reaction mixture was slowly warmed to room temperature and stirred for another 30 min. After the reaction was complete (monitored by TLC), the reactants were quenched with crushed ice and extracted with EtOAc. The organic extract was further washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (100-200 μL silica; gradient: 0-1% EtOAc in DCM) yielded a yellow solid, 5-bromo-1-(4-methoxy-benzyl)-1H-benzo[cd]indol-2-one (66 g, 179.36 mmol). Yield: 89%. 1 H NMR (d 6-DMSO,400MHZ)δ8.09(d,J=7.44Hz,1H),7.98(d,J=7.44Hz,1H),7.65-7.56(m,2H),7.32(d, LC MS[M+H] + 367.80, 369.84.

[1040] Step 2: Synthesis of 1-(4-methoxy-benzyl)-5-vinyl-1H-benzo[cd]indol-2-one: Argon gas was bubbled through a toluene (800 mL) solution of 5-bromo-1-(4-methoxy-benzyl)-1H-benzo[cd]indol-2-one (66 g, 179.348 mmol) under stirring for 20 minutes. Tributylvinyltin (55.037 mL, 188.315 mmol), triphenylphosphine (2.352 g, 8.967 mmol), and tetrakis(triphenylphosphine)palladium (10.363 g, 8.967 mmol) were added, and the reaction mixture was heated at 110 °C for 16 hours. After the reaction was complete (monitored by TLC), the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (100-200 μL silica; gradient: 0-20% EtOAc in hexane) to give a yellow solid 1-(4-methoxy-benzyl)-5-vinyl-1H-benzo[cd]indol-2-one (45 g, 141.68 mmol). Yield: 79%. 1 H NMR (d 6 -DMSO,400MHZ)δ8.07-8.03(m,2H),7.85(d,J=8.64Hz,1H),7.59-7.49(m,2H),7.31(d,J=8.6Hz,2H),7.12( d,J=7.12Hz,1H),6.87(d,J=8.56Hz,2H),6.15(d,J=17.44Hz,1H),5.66(d,J=11.16Hz,1H),3.69(s,3H); LC MS[M+H] + 316.02

[1041] Step 3: Synthesis of 1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-benzo[cd]indole-5-carboxaldehyde: A 4% aqueous solution of OsO4 (572 mg, 507.35 μmol, 14.3 mL) was added to a solution of 1-(4-methoxy-benzyl)-5-vinyl-1H-benzo[cd]indole-2-one (45 g, 112.5 mmol) in water (100 mL) and THF (300 mL) under stirring. The reaction mixture was stirred at room temperature for 20 minutes, and then sodium periodate (60.157 g, 281.25 mmol) was added. The resulting reaction mixture was then stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and washed with THF and EtOAc. The collected filtrate was then dried over sodium sulfate and concentrated under reduced pressure to give a brown solid, 1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-benzo[cd]indole-5-carboxaldehyde (28 g, 87.75 mmol). Yield: 78%. 1 H NMR (d 6 -DMSO,400MHZ)δ10.48(s,1H),8.41(d,J=7.12Hz,1H),8.37(d,J=8.64Hz,1H),8.27(d,J=7.08Hz,1H),7.65- 7.61(m,1H),7.33(d,J=8.6Hz,2H),7.18(d,J=7.2Hz,1H),6.88(d,J=8.6Hz,2H),5.03(s,2H),3.69(s,3H); LC MS[M+H] + 317.98

[1042] Step 4: Synthesis of 5-hydroxymethyl-1-(4-methoxy-benzyl)-1H-benzo[cd]indole-2-one: Sodium borohydride (10.024 g, 264.984 mmol) was slowly added to a methanol (250 mL) solution of 1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-benzo[cd]indole-5-carboxaldehyde (28 g, 88.324 mmol) under stirring at 0 °C, and the resulting reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and slowly poured into crushed ice. The resulting solid precipitate was filtered off and dried appropriately under reduced pressure. Purification by column chromatography (100-200 μL silica; gradient: 0-5% MeOH in DCM) yielded a yellow solid, 5-hydroxymethyl-1-(4-methoxy-benzyl)-1H-benzo[cd]indol-2-one (22 g, 68.89 mmol). Yield: 78%. 1H NMR(d6-DMSO,400MHZ)δ8.05(d,J=7.2Hz,1H),7.82(d,J=7.12Hz,1H),7.70(d,J=8.48Hz,1H),7.47(t,J=7.84Hz,1H),7.30( d,J=8.48Hz,2H),7.09(d,J=7.12Hz,1H),6.87(d,J=8.56Hz,2H),5.53(t,J=5.52Hz,1H),5.05-5.02(m,4H),3.69(s,3H); LC MS[M+H] + 319.8

[1043] Step 5: Synthesis of 5-chloromethyl-1-(4-methoxy-benzyl)-1H-benzo[cd]indole-2-one: At 0 °C, Et3N (28.837 mL, 206.897 mmol) and methanesulfonyl chloride (206.897 mmol, 16.015 mL) were added to a suspension of 5-hydroxymethyl-1-(4-methoxy-benzyl)-1H-benzo[cd]indole-2-one (22 g, 68.966 mmol) in DCM (350 mL) under stirring. The resulting reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by TLC), the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, and brine, dried over sodium sulfate, and concentrated under reduced pressure to give a yellow solid of 5-chloromethyl-1-(4-methoxy-benzyl)-1H-benzo[cd]indole-2-one (19 g, 56.55 mmol). Yield: 82%. 1 H NMR (d 6 -DMSO,400MHZ)δ8.07(d,J=7.12Hz,1H),7.90(d,J=7.16Hz,1H),7.80(d,J=8.6Hz,1H),7.55(t,J=7.88Hz,1H) ,7.31(d,J=8.6Hz,2H),7.13(d,J=7.16Hz,1H),6.87(d,J=8.6Hz,2H),5.30(s,2H),5.03(s,2H),3.69(s,3H);

[1044] Example 3. Synthesis of 3-(2-oxo-5-vinyl-benzo[cd]indol-1-yl)piperidin-2,6-dione (compound 2) and 1-(2,6-dioxo-3-piperidinyl)-2-oxo-benzo[cd]indol-5-carboxaldehyde (compound 3)

[1045]

[1046] Step 1: Synthesis of 3-(2-oxo-5-vinyl-benzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 2): Argon gas was purged into a toluene (500 mL) solution of 20 g, 55.68 mmol, under stirring for 20 min. Tributylvinyltin (22.95 g, 72.39 mmol, 21.06 mL), triphenylphosphine (730.26 mg, 2.78 mmol), and tetrakis(triphenylphosphine)palladium (3.22 g, 2.78 mmol) were added, and the reaction mixture was heated at 110 °C for 16 h. After the reaction was complete (monitored by TLC), the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (100-200 μL silica; gradient: 0-10% MeOH in DCM) to give a yellow solid 3-(2-oxo-5-vinyl-benzo[cd]indol-1-yl)piperidin-2,6-dione (14.3 g, 32.85 mmol). Yield: 59%. LC MS [M+H] + 307.2

[1047] Step 2: Synthesis of 1-(2,6-dioxo-3-piperidinyl)-2-oxo-benzo[cd]indole-5-carboxaldehyde: A 4% OsO4 aqueous solution (572 mg, 507.35 μmol, 2 mL) was added to a solution of 3-(2-oxo-5-vinyl-benzo[cd]indole-1-yl)piperidin-2,6-dione (14 g, 45.70 mmol) in water (12 mL) and THF (36 mL) under stirring. The reaction mixture was stirred at room temperature for 20 minutes, and then sodium periodate (24.44 g, 114.26 mmol) was added. The resulting reaction mixture was then stirred at room temperature for 4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and washed with 20% IPA in THF and DCM. The collected filtrate was then dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (100-200 μL silica; gradient: 0-5% MeOH in DCM) to give a yellow solid 1-(2,6-dioxo-3-piperidinyl)-2-oxo-benzo[cd]indole-5-carboxaldehyde (8 g, 16.91 mmol). Yield: 37%. 1HNMR(d6-DMSO,400MHZ)δ11.16(s,1H),10.52(s,1H),8.46-8.43(m,2H),8.31-8.30(m,1H),7.71-7.67(m,1H),7.27-7.2 5(m,1H),5.48(dd,J=12.48,4.84Hz,1H),2.95-2.90(m,1H),2.79-2.74(m,1H),2.68-2.63(m,1H),2.13-2.08(m,1H); LC MS[M+H] + 309.0.

[1048] Example 4. 3-[5-(diphenylmethyleneamino)-2-oxo-benzo[cd]indol-1-yl]piperidin-2,6-dione (compound 4), 3-(5-amino-2-oxo-benzo[cd]indol-1-yl)piperidin-2,6-dione (compound 4), and 3-(5-fluoro-2-oxo-benzo[cd]indol-1-yl)piperidin-2,6-dione (compound 5)

[1049]

[1050] Step 1: Synthesis of 5-(diphenylmethyleneamino)-1H-benzo[cd]indol-2-one: Sodium tert-butoxide (29.05 g, 302.33 mmol) was added to a toluene (1500 mL) solution of 5-bromo-1H-benzo[cd]indol-2-one (25 g, 100.78 mmol) and benzophenone imine (36.53 g, 201.55 mmol, 33.82 mL) under stirring, and the resulting reaction mixture was degassed with argon for 10 min. Then, (5-diphenylphosphino-9,9-dimethyl-xanthon-4-yl)-diphenyl-phosphine (11.66 g, 20.16 mmol) and (1E,4E)-1,5-diphenylpentan-1,4-dien-3-one palladium (9.23 g, 10.08 mmol) were added, and the reaction mixture was heated at 80 °C for 16 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with cold water and extracted with EtOAc (x2). The crude extract was then dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 μL silica; gradient: 0-20% EtOAc in hexane) to give a yellow solid 5-(diphenylmethyleneamino)-1H-benzo[cd]indol-2-one (20 g, 41.31 mmol). Yield: 41%. LC MS [M+H] + 349.40.

[1051] Step 2: Synthesis of 3-[5-(diphenylmethyleneamino)-2-oxo-benzo[cd]indol-1-yl]piperidin-2,6-dione (Compound 4): At 0 °C, sodium hydride (60% dispersion in mineral oil) (16.50 g, 430.54 mmol) was added in portions to a suspension of 5-(diphenylmethyleneamino)-1H-benzo[cd]indol-2-one (10 g, 28.70 mmol) in THF (100 mL) under stirring. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled back to 0 °C and 3-bromoglutarimide (33.07 g, 172.22 mmol) was added in portions. The reaction mixture was warmed back to room temperature and heated at 70 °C for 4 hours. After completion (monitored by TLC), the reaction mixture was slowly poured into crushed ice. The aqueous fraction was extracted with ethyl acetate (x3), and the combined organic layers were separated, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was then ground with diethyl ether and pentane to give the desired compound, 3-[5-(diphenylmethyleneamino)-2-oxo-benzo[cd]indol-1-yl]piperidin-2,6-dione (10 g, 21.81 mmol), as a yellow solid. Yield: 76%. LC MS [M+H] + 460.0.

[1052] Step 3: Synthesis of 3-(5-amino-2-oxo-benzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 4): 15 mL of aqueous HCl (2N) was added to a THF (100 mL) solution of 10 g, 21.76 mmol, and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion (monitored by TLC), the reaction mixture was concentrated to dryness, and HCl in 20 mL of 1,4-dioxane (4N) was added, and the reaction was stirred for 30 minutes. The reaction mixture was concentrated to dryness again and ground with diethyl ether to remove impurities. The crude product was then alkalized with saturated sodium bicarbonate solution and washed with 30% EtOAc / hexane. The insoluble substance found at the junction of the aqueous and organic layers was filtered off and appropriately dried to give the desired compound 3-(5-amino-2-oxo-benzo[cd]indol-1-yl)piperidine-2,6-dione (5.5 g, 18.71 mmol) as a yellow solid. Yield: 86%. 1 H NMR (d 6-DMSO,400MHZ)δ11.03(s,1H),7.78(d,J=8.52Hz,1H),7.72(d,J=7.88Hz,1H),7.29(t,J=7.86Hz,1H),7.13(br s,2H),6.98(d,J=7.2Hz,1H),6.73(d,J=7.88Hz,1H),5.34(dd,J=12.64,5.2Hz,1H),2 .98-2.88(m,1H),2.76-2.69(m,1H),2.66-2.60(m,1H),2.03-1.98(m,1H); LCMS[M+H] + 296.2.

[1053] Step 4: Synthesis of 3-(5-fluoro-2-oxo-benzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 5): 48% trifluoroborane hydrofluoric acid (1.19 g, 13.55 mmol, 40 mL) was added to a THF (8 mL) solution of 3-(5-amino-2-oxo-benzo[cd]indol-1-yl)piperidine-2,6-dione (4 g, 13.55 mmol) under stirring at 0 °C, followed by the addition of a 4 mL solution of sodium nitrite (2.80 g, 40.64 mmol, 1.29 mL) in water. After the addition was complete, the reaction mixture was stirred at this temperature for 1 hour, followed by the addition of sodium tetrafluoroborate (7.44 g, 67.73 mmol, 3.01 mL). The resulting reaction mixture was then warmed to room temperature and filtered. The collected solid was further washed with diethyl ether and dried under high vacuum to give the corresponding diazonium salt as a brown solid. The resulting solid was then suspended in p-xylene (50 mL) and heated at 140 °C for 2 ...

Claims

1. The following compound: (I) Or its pharmaceutically acceptable salt; in: R 1 yes ; Q 1 It is CH or N; A is ; X is selected from bonds, heterocycles, and -O-; R 15 and R 16 Each time it appears, it is independently selected from key, -C(O)-, -O-, -NR. 27 -、-C(R 40 R 41 )-, phenyl, heterocyclic, C 3-6 Cycloalkyl and heteroaryl; each of which may be selected independently from one or two R groups, where valence permits. 40 Substituents of the substituents; R 17 Selected from bond, -C(O)-, -SO2-, -O-, -NR 27 -、-C(R 40 R 41 )-, phenyl, heterocyclic and heteroaryl; each of which may be optionally selected by one or two independently from R, where valence allows. 40 Substituents; Where R 15 R 16 and R 17 No more than two can be selected as keys; R 18 Selected from hydrogen, halogens, -C(O)R 27 -C(O)OR 27 C 1-4 Alkyl, -C(O)NR 10 R 27 -NR 27 C(O)R 27 –NR 10 R 27 -OR 27 C 1-4 Haloalkyl, C 1-4 Alkoxy, phenyl, heterocyclic, and heteroaryl; each of which may be selected independently from one or two R groups, where valence permits. 40 Substituents of the substituents; R 27 Each time it appears, it is independently selected from hydrogen and C. 1-4 Alkyl, phenyl, heteroaryl, and heterocyclic compounds; R 40 Each time it appears, it is independently selected from hydrogen, C 1-4 Alkyl, halogen, C 1-4 Halogenated alkyl groups, -OR 10 and -NR 10 R 11 ; R 41 It is hydrogen; and Each R 10 and R 11 Independently selected from hydrogen and C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; in, The heterocycle is selected from nitrogen-containing heterocyclic butyl, pyrrolyl, imidazoalkyl, piperidinyl, pyrazolyl, piperazinyl, morpholinyl, indololinyl, and isoindololinyl; and The heteroaryl group is selected from pyrrole, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

2. The compound according to claim 1, having the following formula: ； Or its pharmaceutically acceptable salt.

3. The compound according to claim 1, having the following formula: ； Or its pharmaceutically acceptable salt.

4. The compound according to claim 1, wherein the compound is ; Or its pharmaceutically acceptable salt.

5. The compound according to any one of claims 1-4, wherein R 15 Selected from bonds, heterocycles, phenyl groups, and heteroaryl groups.

6. The compound according to any one of claims 1-4, wherein R 16 Selected from bonds, heterocycles, heteroaryl groups, -O- and -NR 27 - 7. The compound according to any one of claims 1-4, wherein R 17 Selected from bonds, heterocycles, phenyl groups, and heteroaryl groups.

8. The compound according to any one of claims 1-4, wherein R 18 Selected from hydrogen, halogens, -C(O)R 27 -C(O)OR 27 -C(O)NR 10 R 27 -NR 27 C(O)R 27 -NR 10 R 27 and -OR 27 .

9. The compound according to any one of claims 1-4, wherein R 18 It is a phenyl, heterocyclic, or heteroaryl group, each optionally selected by one or two independent groups chosen from R. 40 Substituents are substituted.

10. A compound, wherein the compound is selected from: , , and ; Or its pharmaceutically acceptable salt.

11. The compound according to claim 1, wherein the compound is selected from: and ; Or its pharmaceutically acceptable salt.

12. A pharmaceutical composition comprising a compound according to any one of claims 1-11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

13. Use of an effective amount of the compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof or the composition of claim 12 in the preparation of a medicament for treating human multiple myeloma, Hodgkin lymphoma or non-Hodgkin lymphoma mediated by hydroxycerebroside, IKZF2 and / or IKZF4.

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