Tricyclic degradants of IKAROS and AIOLOS

Abstract

The present invention describes tricyclic cereblon binders that degrade Ikaros or Aiolos via the ubiquitin proteasome pathway for therapeutic applications.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 833,107, filed April 12, 2019, which is hereby incorporated by reference in its entirety for all purposes. Technical Field

[0003] The present invention provides cereblon binders for use in the degradation of Ikaros (IKZF1) or Aiolos (IKZF3) via the ubiquitin proteasome pathway, for therapeutic applications as further described herein. Background Art

[0004] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. Selective recognition and removal of damaged, misfolded, or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). The UPP is central to regulating virtually all cellular processes, including antigen processing, apoptosis, organelle biogenesis, the cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, neural and muscle degeneration, neural network morphogenesis, regulation of cell surface receptors, ion channels, and secretory pathways, responses to stress and extracellular mediators, ribosome biogenesis, and viral infection.

[0005] The covalent attachment of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases marks proteins for degradation by the proteasome, where they are digested into small peptides and ultimately their component amino acids, which serve as building blocks for new proteins. Defective proteasomal degradation has been linked to a variety of clinical disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0006] The Ikaros ("IKZF") family is a series of zinc finger protein transcription factors that are important for certain physiological processes, especially lymphocyte development (see Fan, Y. and Lu, D. "The Ikaros zinc finger protein family" 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 putative mediator of T cell commitment" Science, 1992, 258:802-812), and in the following two decades, four additional homologs have been identified: Helios ("IKZF2"), Aiolos ("IKZF3"), Eos ("IKZF4"), and Pegasus ("IKZF5") (see John, LB and Ward, A.C. The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity" Mol. Immunol, 2011, 48: 1272-1278). Each homologous gene can produce several protein isoforms through alternative splicing, theoretically allowing the production of a large number of protein complexes through different combinations of various homologs. Highly conserved among members of this family is a set of two Cys2His2 zinc finger motifs at the C-terminus, which mediate protein interactions between different members of the protein family. There are up to four zinc finger motifs at the N-terminus for DNA sequence recognition; due to alternative splicing, the number of these N-terminal zinc fingers varies. Isoforms without these N-terminal zinc fingers show a significant negative effect on transcriptional activation (see Winandy, S. et al. "Dominant mutations in the Ikaros gene lead to rapid development of leukemia and lymphoma", Cell, 1995, 83: 289-299).

[0007] The distribution of the various members of the Ikaros protein family varies greatly in the body. Ikaros, Helios, and Aiolos are primarily found in lymphocytes and their corresponding progenitor cells, with Ikaros also detected in the brain, and both Ikaros and Helios in erythrocytes. Eos and Pegasus are more widely distributed, present in skeletal muscle, liver, brain, and heart (see Perdomo, J. et al.). Eos and Pegasus, two members of the Ikaros protein family, have 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 of lymphocyte differentiation,” Int J Hematol, 2014, 100: 220-229).

[0008] Ikaros is important for normal lymphocyte development. Deletion of the exons encoding the first three N-terminal zinc fingers results in mice lacking T cells, B cells, natural killer (NK) cells, and their progenitors. Genetic alterations in Ikaros are associated with poor outcomes in acute lymphoblastic leukemia (ALL) treatment. Ikaros and Aiolos are involved in the proliferation of multiple myeloma cells, suggesting a potential role in malignancy.

[0009] Thalidomide and its analogs, lenalidomide and pomalidomide, have attracted interest as immunomodulatory and antitumor agents, particularly in multiple myeloma (see Martiniani, R. et al., "Biological activity of lenalidomide and its potential therapeutic role in multiple myeloma," Adv Hematol, 2012, 2012:842-945; and Terpos, E. et al., "Pomalidomide: a novel agent for the treatment of relapsed and refractory multiple myeloma," Oncotargets and Therapy, 2013, 6:531). Although the precise mechanisms of action of thalidomide, lenalidomide, and pomalidomide remain unclear, these compounds are potentially useful in the treatment of several cancers, including multiple myeloma. They are also being investigated for the treatment of renal cell carcinoma, glioblastoma, prostate cancer, melanoma, colorectal cancer, Crohn's disease, rheumatoid arthritis, Bechet's syndrome, breast cancer, head and neck cancer, ovarian cancer, chronic heart failure, graft-versus-host disease, and tuberculous meningitis.

[0010] Thalidomide and its analogs have been found to bind to the ubiquitin ligase cereblon and alter its ubiquitination activity (see Ito, T. et al., "Identification of the primary target of thalidomide teratogenicity," Science, 2010, 327: 1345). Cereblon is part of an E3 ubiquitin ligase complex that interacts with damaged DNA binding protein 1 to form an E3 ubiquitin ligase complex with Cullin 4 and the E2 binding protein ROC1 (known as RBX1), where it acts as a substrate receptor to select proteins for ubiquitination.

[0011] Binding of lenalidomide to cereblon promotes subsequent binding of cereblon to Ikaros and Aiolos, leading to their ubiquitination and degradation by the proteasome (see Lu, G. et al. “The myeloma drug lenalidomide promotes cerebellum-dependent destruction of the Ikaros protein,” Science, 2014, 343:305-309; J. et al. "Lenalidomide leads to selective degradation of IKZF1 and IKZF3 in multiple myeloma cells", Science, 2014, 343: 301-305).

[0012] The disclosure of thalidomide binding to the cereblon E3 ubiquitin ligase has led to research investigating the incorporation of thalidomide and certain derivatives into compounds for targeted protein destruction. Celgene has disclosed imides for similar uses, including U.S. Patents 6,045,501; 6,315,720; 6,395,754; 6,561,976; 6,561,977; 6,755,784; 6,869,399; 6,908,432; 7,141,018; 7,230,012; 7,820,697 ; those in 7,874,984; 7,959,566; 8,204,763; 8,315,886; 8,589,188; 8,626,531; 8,673,939; 8,735,428; 8,741,929; 8,828,427; 9,056,120; 9,101,621; and 9,101,622.

[0013] WO 2020 / 006262, filed by the Dana Farber Cancer Institute, discloses cereblon modulators.

[0014] PCT / US19 / 24094 filed by C4 Therapeutics, Inc. discloses cereblon binders for degrading Ikaros.

[0015] An object of the present invention is to provide novel compounds, uses and methods of manufacture that lead to the degradation of Ikaros or Aiolos for use in medical treatments, including for the treatment of hematopoietic diseases involving abnormal cell proliferation, including tumors and cancers. Summary of the Invention

[0016] Provided are novel compounds that bind to cereblon, as well as their uses and preparation. It is believed that binding of the disclosed compounds to cereblon results in increased interaction of cereblon with Ikaros (IKZF1) or Aiolos (IKZF3), leading to their subsequent ubiquitination and degradation in the proteasome. Reduced levels of Ikaros or Aiolos can lead to changes in the transcriptional regulation of their downstream proteins. Selected compounds were found to be both effective binders of cereblon and to exhibit potent inhibition of multiple myeloma cell proliferation compared to pomalidomide.

[0017] Selected compounds disclosed herein, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof can be used to treat conditions mediated by Ikaros or Aiolos, such as hematological malignancies, such as multiple myeloma, leukemia, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, or other target indications. Thus, in one embodiment, a method of treating a host (typically a human) suffering from a disease mediated by Ikaros or Aiolos is provided, the method comprising administering to the host an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, optionally as a pharmaceutically acceptable composition.

[0018] In one aspect, compounds of formula I are provided:

[0019]

[0020] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition;

[0021] in:

[0022] X 1 and X 2 are independently selected from CH and N;

[0023] R 1 Selected from hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, -NR 2 R 2 '、-OR 2 、-NR 2 R 4 、-OR 4 、-NR 2R 5 、-OR 5 、-(CR 3 R 3 ')-R 4 、-(CR 3 R 3 ')-R 5 、-(CR 3 R 3 ')-NR 2 R 4 、-(CR 3 R 3 ')-NR 2 R 5 、-(CR 3 R 3 ')-OR 4 、-(CR 3 R 3 ')-OR 5 、-C(O)R 4 、-SR 4 、-SR 5 、-S(O)R 4 and -S(O)2R 4 ;

[0024] R 2 and R 2 ' is independently selected at each occurrence from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, -C(O)R 8 、-C(O)OR 8 、-C(O)-NR 8 R 8 '、-S(O)R 8 、-SO2R 8 、-SO2-OR 8 and -SO2-NR 8 R 8 ';

[0025] R 3 Selected from hydrogen, halogen, alkyl, haloalkyl, -OR 8 and -NR 8 R 8 ';

[0026] R 3 ' is selected from hydrogen, halogen, alkyl and haloalkyl;

[0027] or R 3 and R 3 'can combine with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring;

[0028] R 4is selected from cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each R 4 Optionally, one selected from R 6 substituted with a group, and each R 4 Also optionally 1, 2, 3 or 4 independently selected from R 7 The group substitution;

[0029] R 5 Yes-C(O)R 6 ;

[0030] R 6 is selected from alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each R 6 Optionally 1, 2, 3 or 4 independently selected from R 9 The group substitution;

[0031] or R 6 is selected from the group consisting of alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycle, -CO-aryl, -CO-heteroaryl, -O-alkyl, -O-cycloalkyl, -O-heterocycle, -O-aryl, -O-heteroaryl, -NR 2 -alkyl, -NR 2 -cycloalkyl, -NR 2 -Heterocycle, -NR 2 -aryl and -NR 2 -heteroaryl, wherein each R 6 Optionally 1, 2, 3 or 4 independently selected from R 9 The group substitution;

[0032] R 7 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -OR 8 、-NR 8 R 8 '、-C(O)R 8 、-C(O)OR 8 、-C(O)-NR 8 R 8 '、-OC(O)R 8 、-NR 2 -C(O)R 8 、-S(O)R 8 、-SO2R 8 、-SO2-OR 8 and -SO2-NR 8 R 8 ';

[0033] or two R on the same carbon 7can be combined together to form oxo groups;

[0034] R 8 and R 8’ is independently selected at each occurrence from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl;

[0035] R 9 is independently selected at each occurrence from hydrogen, halogen, cyano, nitro, R 10 、-CH2R 10 、-OR 10 、-NR 2 R 10 、-C(O)R 10 、-C(O)CH2R 10 、-C(O)CH2OR 10 、-C(O)CH2NR 2 R 10 、-OC(O)R 10 、-NR 2 -C(O)R 10 、-C(O)OR 10 、-C(O)NR 2 R 10 、-S(O)R 10 、-SO2R 10 、SO2CH2R 10 、-SO2CH2OR 10 、-SO2CH2NR 2 R 10 、-NR 2 SO2R 10 、-SO2-OR 10 and -SO2-NR 2 R 10 ;

[0036] R 10 is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein each R 10 Optionally 1, 2, 3 or 4 independently selected from R 11 substituted with a group; and

[0037] R 11 is selected from the group consisting of: hydrogen; halogen; hydroxy; cyano; nitro; alkyl; haloalkyl; alkenyl optionally substituted with aryl or heteroaryl; alkynyl optionally substituted with aryl or heteroaryl; cycloalkyl; heterocycle; optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR 8 aryl substituted with 1, 2, 3 or 4 halogen, alkyl or -OR 8Heteroaryl substituted with 1, 2, 3 or 4 halogen, alkyl or -OR 8 -CH2 aryl substituted with a group; optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR 8 -CH2 heteroaryl substituted with a group; -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ;-C(O)OR 8 ;-C(O)-NR 8 R 8’ ;-C(O)CH2R 8 ;-C(O)CH2OR 8 ;-C(O)CH2-NR 8 R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8 ;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ;-SO2-OR 8 ; and -SO2-NR 8 R 8’ ;

[0038] or two R on the same carbon 11 The groups may be combined together to form an oxo group.

[0039] or R 11 is independently selected at each occurrence from: halogen; hydroxy; cyano; nitro; alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl; heterocycle; aryl; heteroaryl; -CH2 aryl; -CH2 heteroaryl; -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ;-C(O)OR 8 ;-C(O)-NR 8 R 8’ ;-C(O)CH2R 8 ;-C(O)CH2OR 8 ;-C(O)CH2-NR 8 R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ;-SO2-OR 8 ; Oxo and -SO2-NR 8 R 8’ ; where each R 11 The group is optionally substituted by 1, 2, 3 or 4 independently selected R 12 substituted with a group; and

[0040] R 12 is independently selected at each occurrence from: halogen; hydroxy; cyano; nitro; alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl; heterocycle; aryl; heteroaryl; -CH2 aryl; -CH2 heteroaryl; -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ;-C(O)OR 8 ;-C(O)-NR 8 R 8’ ;-C(O)CH2R 8 ;-C(O)CH2OR 8 ;-C(O)CH2-NR 8 R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8 ;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ;-SO2-OR 8 ; oxo; and -SO2-NR 8 R 8 '.

[0041] In one embodiment, the compound of formula I is selected from formula Ia, formula Ib and formula Ic:

[0042]

[0043] wherein all variables are as defined herein.

[0044] In another embodiment, the compound of Formula I is selected from Formula Id, Formula Ie, Formula If, and Formula Ig:

[0045]

[0046]

[0047] wherein all variables are as defined herein.

[0048] In another aspect, the compound of formula I is selected from formula Ih:

[0049]

[0050] wherein all variables are as defined herein.

[0051] In one aspect, there is provided a compound of formula (II):

[0052]

[0053] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition;

[0054] in:

[0055] X 3 Selected from bond, NR 2 、C(R 3 R 3’ ), O, C(O), C(S), S, S(O) and S(O)2;

[0056] R 20 、R 21 、R 22 、R 23 and R 24 is independently selected at each occurrence from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -、-NR 2 C(O)-, -O-, -S-, -NR 2 -、-P(O)(R 28 )-, -P(O)-, alkenyl, alkynyl, haloalkyl, aryl, heterocyclic, heteroaryl, bicyclic and carbocyclic; each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 substituted by a substituent; wherein R 20 、R 21 、R 22 、R 23 and R 24 You cannot choose:

[0057] i.-C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -P(O)(R 28 )-, -P(O)-, -C(S)- moieties are adjacent to each other; or

[0058] ii. -O-, -S-, or -NR 2 -partially adjacent to each other; or

[0059] iii. The portions are additionally selected in an order that produces an unstable molecule (defined as a molecule having a shelf life of less than about 4 months (or less than about 6 months or 5 months) at ambient temperature, which is determined by the portion R 20 、R 21 、R 22 、R 23 and R 24 the decomposition caused by the choice and order of

[0060] R 25 Selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, cyano, -OR 2 、-NR 2 R 2 '、-NR 2 SO2R 28 、-OSO2R 28 、-SO2R 28 , haloalkyl, aryl, heteroaryl, heterocyclic, bicyclic and cycloalkyl; wherein each R 25 The group is optionally substituted by 1, 2, 3 or 4 independently selected R 12 The group substitution;

[0061] R 28 is independently selected at each occurrence from hydrogen, -NR 2 R 2’ 、-OR 2 、-SR 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl;

[0062] R 40 is independently selected at each occurrence from hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, cyano, -NR 2 R 2 '、-NR 2 SO2R 28 、-OSO2R 28 、-SO2R 28 , haloalkyl, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; wherein each R 40 The group is optionally substituted by 1, 2, 3 or 4 independently selected R 12 The group substitution;

[0063] or two R 40 Together they form an oxo group;

[0064] and wherein all other variables are as defined herein.

[0065] In one embodiment, the compounds described herein bind to cereblon, increase the interaction between cereblon and Ikaros (IKZF1) or Aiolos (IKZF3) and lead to subsequent ubiquitination and degradation of the protein in the proteasome.

[0066] In one embodiment, the compounds of the invention selectively degrade IKZF1 and / or IKZF3 over one or more of IKZF2 and / or IKZF4 and / or IKZF5.

[0067] Thus, in some embodiments, based on this discovery, compounds and methods for treating patients with diseases mediated by Ikaros (IKZF1) or Aiolos (IKZF3) are provided. Ikaros (IKZF1) or Aiolos (IKZF3) is targeted for selective degradation by a method comprising administering an effective amount of a selective compound described herein, alone or in combination with another active agent, to a patient (typically a human) in need thereof, optionally in a pharmaceutically acceptable carrier to form a composition. In one embodiment, the disease is a lymphoid disease. In one embodiment, the disease is a leukemia. In one embodiment, the disease is a lymphoid leukemia. In one embodiment, the disease is a lymphocytic leukemia. In some embodiments, the disease is a hematological malignancy, such as multiple myeloma, myelodysplastic syndrome such as 5q- syndrome, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia. In another embodiment, selected compounds of the present invention are administered to achieve immunomodulation and reduce angiogenesis.

[0068] In other embodiments, compounds and methods for treating diseases are provided, including but not limited to benign growths, tumors, tumors, cancers, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid-based protein diseases, protein diseases or fibrotic diseases. In addition, other diseases that can be treated with an effective amount of the compounds described herein are described below.

[0069] In certain embodiments, any compound described herein has at least one desired atomic isotope substituted in an amount about the natural abundance of the isotope, ie, enriched. In one embodiment, the compound includes one or more deuterium atoms.

[0070] Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.

[0071] Therefore, the present invention includes at least the following features:

[0072] (a) a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative), or prodrug thereof;

[0073] (b) a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, for use in treating a condition mediated by Ikaros or Aiolos;

[0074] (c) use of an effective amount of a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, for treating a disease described herein in a patient (typically a human), including a disease mediated by Ikaros or Aiolos;

[0075] (d) use of a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, in the preparation of a medicament for treating a medical condition susceptible to said compound, as further described herein;

[0076] (e) a method for preparing a medicament for treating a disease described herein in a host, characterized in that a compound of formula I or formula II is used in the preparation;

[0077] (f) a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, for treating cancer in a host, including any cancer described herein;

[0078] (g) Use of a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, in the preparation of a medicament for treating cancer, including any cancer described herein;

[0079] (h) 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 or Formula II is used in the preparation;

[0080] (i) a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, for treating a tumor in a host, including any tumor described herein;

[0081] (j) Use of a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, in the preparation of a medicament for treating a tumor, including any tumor described herein;

[0082] (k) a method for preparing a medicament for treating a tumor in a host, including any tumor described herein, characterized in that a compound of formula I or formula II is used in the preparation;

[0083] (1) A compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, for use in treating an immune, autoimmune, or inflammatory disease in a host;

[0084] (m) Use of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, as described herein, in the preparation of a medicament for treating immune, autoimmune, or inflammatory diseases;

[0085] (n) a method for preparing a medicament for treating an immune, autoimmune or inflammatory disease of a host, characterized in that a compound of formula I or formula II is used in the preparation;

[0086] (o) a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, for use in treating hematological malignancies such as multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma;

[0087] (p) Use of a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, in the preparation of a medicament for treating hematological malignancies such as multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma;

[0088] (q) a method for preparing a medicament for treating a host's hematological malignancies such as multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma, characterized in that a compound of Formula I or Formula II is used in the preparation;

[0089] (r) a pharmaceutical composition comprising an effective host therapeutic amount of a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, and a pharmaceutically acceptable carrier or diluent;

[0090] (s) compounds described herein as mixtures of enantiomers or diastereomers (where relevant), including racemates;

[0091] (t) enantiomerically or diastereomerically (where relevant) enriched forms of the compounds described herein, including isolated enantiomers or diastereomers (i.e., greater than 85%, 90%, 95%, 97% or 99% pure); and

[0092] (u) Methods for use in therapeutic products containing an effective amount of a compound of Formula I or Formula II as described herein. DETAILED DESCRIPTION

[0093] I. Definition

[0094] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this application belongs. In the specification, the singular also includes the plural, unless the context clearly provides otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice and testing of this application, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not considered to be prior art of the claimed application. In the event of conflict, this specification (including definitions) shall prevail. In addition, materials, methods and embodiments are illustrative only and not restrictive.

[0095] The compounds are described using standard nomenclature. Unless defined otherwise, 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 belongs.

[0096] In one embodiment of each compound described herein, the compound can be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, or isomer, such as a rotamer, as each is specifically described unless clearly excluded by the context.

[0097] The terms "one" and "an" do not represent a limit to quantity, but rather represent the presence of at least one referenced item. The term "or" refers to "and / or". Unless otherwise stated herein, the reference to a range of values ​​is intended only to be used as a shorthand method for individually referring to each individual value falling within the range, and each individual value is incorporated into the specification as if it were individually quoted herein. The endpoints of all ranges are included within the range and can be independently combined. Unless otherwise stated herein or clearly contradictory to the context, all methods described herein can be performed in a suitable order. Unless otherwise stated, the use of examples or exemplary language (e.g., "such as") is only intended to better illustrate the present invention without limiting the scope of the present invention.

[0098] The present invention includes compounds described herein having at least one desired atomic isotope substituted in an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms 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, a common substitution is the replacement of at least one hydrogen with deuterium.

[0099] More generally, examples of isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, for example, 2 H. 3 H. 11 C.13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 35 S and 36 In one non-limiting embodiment, isotope-labeled compounds can be used in metabolic studies (e.g. 14 C), reaction kinetics studies (e.g. 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 analysis, or radiotherapy for patients. In addition, any hydrogen atoms present in the compounds of the invention may be 18 F atom substitution, which may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by the procedures disclosed in the embodiments or examples and the methods described in the preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0100] By way of general example and not 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 can be used, such as 13 C and 14 C.

[0101] Isotope replacement, such as deuterium replacement, can be partial or complete. Partial deuterium replacement means that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotope is enriched in 90%, 95% or 99% or more of the isotope at any position of interest. In a non-limiting embodiment, deuterium is enriched in 90%, 95% or 99% at the desired position.

[0102] In one non-limiting embodiment, the replacement of hydrogen atoms by deuterium atoms can be provided in any compound described herein. For example, when any group is or comprises methyl, ethyl or methoxy, for example by substitution, the alkyl residue can be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H or OCD3, etc.). In certain other embodiments, when two substituents are combined to form a ring, the unsubstituted carbon can be deuterated. In one embodiment, at least one deuterium is placed on an atom whose bond breaks when the compound is metabolized in vivo, or is placed on one, two or three atoms (e.g., which can be referred to as α, β or γ, or primary, secondary or tertiary isotope effects) away from the metabolic bond.

[0103] The compounds of the present invention can form solvates with solvents (including water). Therefore, in a non-limiting embodiment, the present invention includes solvated forms of the compounds described herein. The term "solvate" refers to a molecular complex of the compounds of the present invention (including its salt) and 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 the compounds of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent can be isotopically substituted, such as solvates substituted with isotopes, such as D2O, d6-acetone, d6-DMSO. Solvate can be in liquid or solid form.

[0104] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH2 is attached through the carbon of the keto (C=O) group.

[0105] "Alkyl" is a branched or straight chain saturated aliphatic hydrocarbon group. In a non-limiting embodiment, the alkyl group contains 1 to about 12 carbon atoms, more generally 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In a non-limiting embodiment, the alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, the alkyl group is C1-C2, C1-C3, C1-C4, C1-C5 or C1-C6. As used herein, the designated range represents the alkyl group with each member of the scope described as an independent species. For example, the term C1-C6 alkyl used herein represents a straight or branched chain alkyl group with 1, 2, 3, 4, 5 or 6 carbon atoms, and is intended to represent that each of these is described as an independent species. For example, the term C1-C4 alkyl used herein represents a straight or branched chain alkyl group with 1, 2, 3 or 4 carbon atoms, and is intended to represent that each of these is described as an independent species. 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.

[0106] "Alkenyl" is a straight or branched aliphatic hydrocarbon group with one or more carbon-carbon double bonds that can occur at a stable point along the chain. As used herein, a specified range represents an alkenyl group with each member of a range described as an independent species, as described above for the alkyl portion. In a non-limiting embodiment, the alkenyl group contains 2 to about 12 carbon atoms, more typically 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In certain embodiments, the alkenyl group 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 includes "cis" and "trans" alkenyl geometries, or "E" and "Z" alkenyl geometries. The term "alkenyl" also includes cycloalkyl or carbocyclic groups with at least one unsaturated point.

[0107] " alkynyl " is a side chain or straight chain aliphatic hydrocarbon group with one or more carbon-carbon triple bonds, and this triple bond can occur at any stable point along the chain. As used herein, designated range represents the alkynyl of each member with the scope described as an independent species, as described above for the alkyl portion. In a non-limiting embodiment, alkynyl contains 2 to approximately 12 carbon atoms, more generally 2 to approximately 6 carbon atoms or 2 to approximately 4 carbon atoms. In certain embodiments, alkynyl is C2, C2-C3, C2-C4, C2-C5 or C2-C6. The example of alkynyl includes but is 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.

[0108] "Halo" and "halogen" are independently fluoro, chloro, bromo or iodo.

[0109] "Haloalkyl" refers to a branched or straight-chain alkyl group substituted with one or more of the above-mentioned halogen atoms, up to the 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. "Perhaloalkyl" refers to an alkyl group in which all of its hydrogen atoms are replaced with halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0110] As used herein, "aryl" refers to a radical in an aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aromatic ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, wherein the radical or point of attachment is on the aromatic ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. The one or more fused cycloalkyl or heterocyclic groups can be a 4- to 7-membered saturated or partially unsaturated cycloalkyl or heterocyclic group.

[0111] The term "heterocycle" refers to a saturated and partially saturated heteroatom-containing ring group having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, sulfur, boron, silicone and oxygen. The heterocycle may comprise a monocyclic 3-10 ring, and a 5-16-membered bicyclic ring system (which may include bridged, fused and spirofused bicyclic ring systems). It does not include rings containing -OO-, -OS- or -SS- moieties. Examples of saturated heterocyclic groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclic groups include, but are not limited to, dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, isochromanyl, chromanyl, 1,2-dihydroquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolinyl, 3,4-dihydro-2H-benzo[1,4]oxazepine 1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl.

[0112] "Heterocycle" also includes groups in which a heterocyclic group is fused to an aryl or carbocyclic group, where the point of attachment is the heterocyclic ring. "Heterocycle" also includes groups in which a heterocyclic group is substituted with an oxo group (i.e. ). For example, a partially unsaturated fused / condensed heterocyclic group containing 1 to 5 nitrogen atoms, such as dihydroindole or isoindole; a partially unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; a partially unsaturated fused heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; and a saturated fused heterocyclic group containing 1 to 2 oxygen or sulfur atoms.

[0113] The term "heterocycle" also includes "bicyclic heterocycles". The term "bicyclic heterocycle" means a heterocycle as defined herein wherein the heterocycle has a bridged, fused, or spirocyclic portion. The bridged, fused, or spirocyclic portion of the heterocycle may be carbocyclic, heterocyclic, or aryl, so long as a stable molecule results. Unless excluded by the context, the term "heterocycle" includes bicyclic heterocycles. Bicyclic heterocycles include groups wherein the fused heterocycle is substituted with an oxo group. Non-limiting examples of bicyclic heterocycles include:

[0114] 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 ring nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally tetrazed. Examples include, but are not limited to, unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, 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]; unsaturated 5- to 6-membered heteromonocyclic groups containing oxygen atoms, such as pyranyl, 2-furanyl, 3-furanyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing sulfur atoms , such as 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic 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 heteromonocyclic 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 one embodiment, 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, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazolyl and benzotriazolyl.

[0115] As used herein, "carbocyclic," "carbocycle," or "cycloalkyl" includes saturated or partially unsaturated (i.e., non-aromatic) groups containing all carbon ring atoms, 3 to 14 ring carbon atoms, and zero heteroatoms in a non-aromatic ring system ("C 3-14 In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 9 ring carbon atoms ("C 3-9 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8In some embodiments, a cycloalkyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring 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), cyclohexadienyl (C6), and the like. Exemplary C 3-8 Cycloalkyl includes but is not limited to the above C 3-6 Cycloalkyl and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), etc. Exemplary C 3-10 Cycloalkyl includes but is not limited to the above C 3-8 Cycloalkyl and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ) and the like. As shown in the foregoing examples, in certain embodiments, the cycloalkyl group may be saturated or may contain one or more carbon-carbon double bonds. The term "cycloalkyl" also includes ring systems in which a cycloalkyl ring as defined above is fused to a heterocyclic, aryl, or heteroaryl ring, wherein the point of attachment is on the cycloalkyl ring, and in this case, the carbon number continues to represent the number of carbons in the carbocyclic ring system. The term "cycloalkyl" also includes ring systems in which a cycloalkyl ring as defined above has a spirocyclic heterocyclic, aryl, or heteroaryl ring, wherein the point of attachment is on the cycloalkyl ring, and in this case, the carbon number continues to represent the number of carbon atoms in the carbocyclic ring system. The term "cycloalkyl" also includes bicyclic or polycyclic fused, bridged, or spirocyclic ring systems containing 5 to 14 carbon atoms and zero heteroatoms in the non-aromatic ring. Representative examples of "cycloalkyl" include, but are not limited to

[0116] The term "bicyclic" refers to a ring system in which two rings are fused together and each ring is independently selected from carbocycle, heterocycle, aryl and heteroaryl. Non-limiting examples of bicyclic rings include:

[0117]

[0118] When the term "bicyclic" is used in conjunction with a divalent residue such as R20 、R 21 、R 22 、R 23 or R 24 When used in the context of , the points of attachment can be on different rings or on the same ring. In certain embodiments, both points of attachment are on the same ring. In certain embodiments, both points of attachment are on different rings. Non-limiting examples of bicyclic rings include:

[0119] "Dosage form" refers to a unit for administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, pellets, creams, ointments, suppositories, inhalable dosage forms, transdermal dosage forms, oral, sublingual, topical, gel, mucosal, and the like. "Dosage form" may also include implants, such as optical implants.

[0120] As used herein, "endogenous" refers to any material that originates from or is produced within an organism, cell, tissue, or system.

[0121] As used herein, the term "exogenous" refers to any material that is introduced from or originates outside an organism, cell, tissue, or system.

[0122] As used herein, the term "modulate" refers to mediating a detectable increase or decrease in the level of a response in a subject as compared to the level of the response in the absence of the treatment or compound, and / or as compared to the level of response in an otherwise identical, untreated subject. The term includes perturbing and / or influencing a natural signal or response, thereby mediating a beneficial therapeutic response in a subject, preferably a human.

[0123] "Parenteral" administration of a compound includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im) or intrasternal injection, or infusion techniques.

[0124] As used herein, a "pharmaceutical composition" is a composition comprising at least one active agent, such as a selected active compound described herein, and at least one other substance, such as a carrier. A "pharmaceutical combination" is a combination of at least two active agents, which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents be used together to treat any of the diseases described herein.

[0125] As used herein, "pharmaceutically acceptable salts" are derivatives of the disclosed compounds, 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 alkaline or acidic moieties by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid forms 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 base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent or in a mixture of the two. Typically, where feasible, typical non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Salts of the compounds of the present invention also include solvates of the compounds and compound salts.

[0126] Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal 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 the parent compound formed, for example, from non-toxic inorganic or organic acids. And by organic acid 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-toluenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH ) n-COOH, wherein n is 0-4 etc., or use the different acid that produces identical counterion.Can find the tabulation of other suitable salts in for example Remington's Pharmaceutical Sciences, the 17th edition, Mack Publishing Company, Easton, Pa., p.1418 (1985).

[0127] The term "carrier" refers to a diluent, excipient, or vehicle with which the active agent is employed or delivered.

[0128] "Pharmaceutically acceptable excipient" refers to an excipient that can be used to prepare a pharmaceutical composition / combination that is generally safe and biologically or otherwise unsuitable for administration to a host, typically a human. In one embodiment, an excipient that is acceptable for veterinary use is used.

[0129] A "patient" or "host" or "subject" is a human or non-human animal in need of treatment for any of the conditions specifically described herein. Typically, the host is a human. "Host" may alternatively refer to, for example, a mammal, a primate (e.g., a human), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, a fish, a bird, etc.

[0130] A "therapeutically effective amount" of the pharmaceutical composition / combination of the present invention refers to an amount effective to provide a therapeutic benefit, such as improvement of symptoms or alleviation or reduction of the disease itself, when administered to a host.

[0131] Throughout this disclosure, various aspects of the present invention may be presented in range format. It should be understood that the description in range format is merely for convenience and should not be construed as limiting the scope of the invention. It should be understood that the description of a range has specifically disclosed all possible subranges and each numerical value within that range. For example, a description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as single digits within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0132] II. Compounds of the Invention

[0133] Embodiments of "alkyl"

[0134] In one embodiment, "alkyl" is C1-C 10 alkyl, 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.

[0135] In one embodiment, an "alkyl" group has one carbon.

[0136] In one embodiment, an "alkyl" group has two carbons.

[0137] In one embodiment, an "alkyl" group has three carbons.

[0138] In one embodiment, an "alkyl" group has four carbons.

[0139] In one embodiment, an "alkyl" group has five carbons.

[0140] In one embodiment, an "alkyl" group has six carbons.

[0141] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0142] Other non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0143] Other non-limiting examples of "alkyl" include: sec-butyl, sec-pentyl, and sec-hexyl.

[0144] Other non-limiting examples of "alkyl" include tert-butyl, tert-amyl, and tert-hexyl.

[0145] Other non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and activated pentyl.

[0146] Embodiment of "haloalkyl"

[0147] In one embodiment, "haloalkyl" is C1-C 10 haloalkyl, C1-C9 haloalkyl, C1-C8 haloalkyl, C1-C7 haloalkyl, C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl and C1-C2 haloalkyl.

[0148] In one embodiment, a "haloalkyl" group has one carbon.

[0149] In one embodiment, a "haloalkyl" group has one carbon and one halogen.

[0150] In one embodiment, a "haloalkyl" group has one carbon and two halogens.

[0151] In one embodiment, a "haloalkyl" group has one carbon and three halogens.

[0152] In one embodiment, a "haloalkyl" group has two carbons.

[0153] In one embodiment, a "haloalkyl" group has three carbons.

[0154] In one embodiment, a "haloalkyl" group has four carbons.

[0155] In one embodiment, a "haloalkyl" group has five carbons.

[0156] In one embodiment, a "haloalkyl" group has six carbons.

[0157] Non-limiting examples of "haloalkyl" include:

[0158] Other non-limiting examples of "haloalkyl" include:

[0159] Other non-limiting examples of "haloalkyl" include:

[0160] Other non-limiting examples of "haloalkyl" include:

[0161] Embodiment of "aryl"

[0162] In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl).

[0163] In one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[0164] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a heterocycle, wherein the point of attachment is the aromatic ring. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the point of attachment of each group is on the aromatic ring.

[0165] For example, is an "aryl" group.

[0166] However, It is a "heterocyclic" group.

[0167] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a cycloalkyl group, wherein the point of attachment is the aromatic ring. Non-limiting examples of "aryl" include dihydroindane and tetrahydronaphthalene, wherein the point of attachment of each group is on the aromatic ring.

[0168] For example, is an "aryl" group.

[0169] However, is a "cycloalkyl" group.

[0170] Embodiments of "heteroaryl"

[0171] In one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0172] Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

[0173] Other non-limiting examples of 5-membered "heteroaryl" groups include:

[0174] In one embodiment, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (ie, pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0175] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include:

[0176] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0177] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaridazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

[0178] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0179] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0180] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0181] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0182] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0183] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0184] Embodiments of "cycloalkyl"

[0185] In one embodiment, "cycloalkyl" is 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.

[0186] In one embodiment, a "cycloalkyl" group has three carbons.

[0187] In one embodiment, a "cycloalkyl" group has four carbons.

[0188] In one embodiment, a "cycloalkyl" group has five carbons.

[0189] In one embodiment, a "cycloalkyl" group has six carbons.

[0190] In one embodiment, a "cycloalkyl" group has seven carbons.

[0191] In one embodiment, a "cycloalkyl" group has eight carbons.

[0192] In one embodiment, a "cycloalkyl" group has nine carbons.

[0193] In one embodiment, a "cycloalkyl" group has ten carbons.

[0194] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0195] Other non-limiting examples of "cycloalkyl" include indane and tetrahydronaphthalene, where the point of attachment of each group is on the cycloalkyl ring.

[0196] For example, is a "cycloalkyl" group.

[0197] However, is an "aryl" group.

[0198] Other examples of "cycloalkyl" include

[0199] Embodiment of "heterocycle"

[0200] In one embodiment, "heterocycle" refers to a cyclic ring having one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0201] In one embodiment, "heterocycle" refers to a cyclic ring having one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0202] In one embodiment, "heterocycle" refers to a cyclic ring having two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0203] In one embodiment, "heterocycle" refers to a cyclic ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0204] In one embodiment, "heterocycle" refers to a cyclic ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0205] Non-limiting examples of "heterocycle" include aziridine, oxirane, thietidine, azetidine, 1,3-diazetidine, oxetane, and thietane.

[0206] Other non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

[0207] Other non-limiting examples of "heterocycle" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0208] Other non-limiting examples of "heterocycle" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiazane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0209] Other non-limiting examples of "heterocycle" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the point of attachment of each group is on the heterocycle.

[0210] For example, It is a "heterocyclic" group.

[0211] However, is an "aryl" group.

[0212] Non-limiting examples of "heterocycle" also include:

[0213] Other non-limiting examples of "heterocycle" include:

[0214] Other non-limiting examples of "heterocycle" include:

[0215] Non-limiting examples of "heterocycle" also include:

[0216] Non-limiting examples of "heterocycle" also include:

[0217] Other non-limiting examples of "heterocycle" include:

[0218] Other non-limiting examples of "heterocycle" include:

[0219] Optional substituents

[0220] In one embodiment, a moiety described herein as substituted with 1, 2, 3, or 4 substituents is substituted with one substituent.

[0221] In one embodiment, a moiety described herein as substituted with 1, 2, 3, or 4 substituents is substituted with two substituents.

[0222] In one embodiment, a moiety described herein as substituted with 1, 2, 3, or 4 substituents is substituted with three substituents.

[0223] In one embodiment, a moiety described herein as substituted with 1, 2, 3, or 4 substituents is substituted with four substituents.

[0224] Non-limiting embodiments of tricyclic cores

[0225] The tricyclic core moiety has 1, 2 or 3 nitrogens.

[0226] In one embodiment, the compound of formula I is selected from:

[0227]

[0228]

[0229] Non-limiting embodiments of Formula I:

[0230] In certain embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is selected from the following formula:

[0231]

[0232] In certain embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is selected from the following formula:

[0233]

[0234]

[0235] In certain embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is selected from the following formula:

[0236]

[0237] In certain embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is selected from the following formula:

[0238]

[0239] In certain embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is selected from the following formula:

[0240]

[0241] In certain embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is selected from the following formula:

[0242]

[0243]

[0244] In certain embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is selected from the following formula:

[0245]

[0246] In certain embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is selected from the following formula:

[0247]

[0248] In certain embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is selected from the following formula:

[0249]

[0250] In certain embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is selected from the following formula:

[0251]

[0252] In certain embodiments, the compounds of the present invention are selected from:

[0253]

[0254]

[0255]

[0256]

[0257] In one embodiment, the compound of formula I is selected from:

[0258]

[0259] In one embodiment, the compound of formula I is selected from:

[0260]

[0261] In one embodiment, the compound of formula I is selected from:

[0262]

[0263] In one embodiment, the compound of formula I is selected from:

[0264]

[0265] In one embodiment, the compound of formula I is selected from:

[0266]

[0267] In one embodiment, the compound of formula I is selected from:

[0268]

[0269] In one embodiment, the compound of formula I is selected from:

[0270]

[0271] In one embodiment, the compound of formula I is selected from:

[0272]

[0273] In one embodiment, the compound of formula I is selected from:

[0274]

[0275] In one embodiment, the compound of formula I is selected from:

[0276]

[0277] In one embodiment, the compound of formula I is selected from:

[0278]

[0279] In one embodiment, the compound of formula I is selected from:

[0280]

[0281] In one embodiment, the compound of formula I is selected from:

[0282]

[0283] In one embodiment, the compound of formula I is selected from:

[0284]

[0285] In one embodiment, the compound of formula I is selected from:

[0286]

[0287] In one embodiment, the compound of formula I is selected from:

[0288]

[0289] In one embodiment, the compound of formula I is selected from:

[0290]

[0291] R 1 Non-limiting embodiments

[0292] In one embodiment of Formula I, R 1 Selected from -NH (with R 6 In one embodiment of Formula I, R 1 Selected from -NH (with R 6 In one embodiment of Formula I, R 1 Selected from -NH (with R 6 In one embodiment of Formula I, R 1 Selected from -NH (with R 6 In one embodiment of Formula I, R 1 Selected from -N(CH3)(with R 6 In one embodiment of Formula I, R 1 Selected from -N(CH3)(with R 6 In one embodiment of Formula I, R 1 Selected from -N(CH3)(with R 6 In one embodiment of Formula I, R 1 Selected from -N(CH3)(with R 6 substituted heteroaryl).

[0293] In one embodiment of Formula I, R 1 Selected from -O(by R 6 In one embodiment of Formula I, R 1 Selected from -O(by R 6 In one embodiment of Formula I, R 1 Selected from -O(by R 6 In one embodiment of Formula I, R 1 Selected from -O(by R 6 substituted heteroaryl).

[0294] In one embodiment of Formula I, R 1 Selected from -S (by R 6 In one embodiment of Formula I, R 1 Selected from -S (by R 6 In one embodiment of Formula I, R 1 Selected from -S (by R 6 In one embodiment of Formula I, R 1 Selected from -S (by R 6 substituted heteroaryl).

[0295] In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 Selected from -N(CH3)-C(O)-(heteroaryl).

[0296] In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 Selected from -OC(O)-(heteroaryl).

[0297] In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 Selected from -SC(O)-(heteroaryl).

[0298] In one embodiment of Formula I, R 1 Selected from -CH2 (by R6 In one embodiment of Formula I, R 1 Selected from -CH2 (by R 6 In one embodiment of Formula I, R 1 Selected from -CH2 (by R 6 In one embodiment of Formula I, R 1 Selected from -CH2 (by R 6 In one embodiment of Formula I, R 1 Selected from -CF2 (by R 6 In one embodiment of Formula I, R 1 Selected from -CF2 (by R 6 In one embodiment of Formula I, R 1 Selected from -CF2 (by R 6 In one embodiment of Formula I, R 1 Selected from -CF2 (by R 6 In one embodiment of Formula I, R 1 Selected from -CH(OH)(with R 6 In one embodiment of Formula I, R 1 Selected from -CH(OH)(with R 6 In one embodiment of Formula I, R 1 Selected from -CH(OH)(with R 6 In one embodiment of Formula I, R 1 Selected from -CH(OH)(with R 6 substituted heteroaryl).

[0299] In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 Selected from -CH(OH)-C(O)-(heteroaryl).

[0300] In one embodiment of Formula I, R 1 Selected from -CH2-NH (with R 6 In one embodiment of Formula I, R 1 Selected from -CH2-NH (with R 6 In one embodiment of Formula I, R 1 Selected from -CH2-NH (with R 6 In one embodiment of Formula I, R 1 Selected from -CH2-NH (with R 6 In one embodiment of Formula I, R 1 Selected from -CH2-N(CH3)(by R 6 In one embodiment of Formula I, R 1 Selected from -CH2-N(CH3)(by R 6 In one embodiment of Formula I, R 1 Selected from -CH2-N(CH3)(by R 6 In one embodiment of Formula I, R 1 Selected from -CH2-N(CH3)(by R 6 substituted heteroaryl).

[0301] In one embodiment of Formula I, R 1 Selected from -CH2-O (by R 6 In one embodiment of Formula I, R 1 Selected from -CH2-O (by R 6 In one embodiment of Formula I, R1 Selected from -CH2-O (by R 6 In one embodiment of Formula I, R 1 Selected from -CH2-O (by R 6 substituted heteroaryl).

[0302] In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 is selected from -CH2-NH-C(O)-(heteroaryl). In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 is selected from -CH2-N(CH3)-C(O)-(aryl). In one embodiment of Formula I, R 1 Selected from -CH2-N(CH3)-C(O)-(heteroaryl).

[0303] In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 In one embodiment of Formula I, R 1 Selected from -CH2-OC(O)-(heteroaryl).

[0304] In one embodiment of Formula I, R 1 Selected from -C(O)-(by R 6 In one embodiment of Formula I, R 1 Selected from -C(O)-(by R 6In one embodiment of Formula I, R 1 Selected from -C(O)-(by R 6 In one embodiment of Formula I, R 1 Selected from -C(O)-(by R 6 substituted heteroaryl).

[0305] In one embodiment of Formula I, R 1 Selected from -S(O)-(by R 6 In one embodiment of Formula I, R 1 Selected from -S(O)-(by R 6 In one embodiment of Formula I, R 1 Selected from -S(O)-(by R 6 In one embodiment of Formula I, R 1 Selected from -S(O)-(by R 6 substituted heteroaryl).

[0306] In one embodiment of Formula I, R 1 Selected from -S(O)2-(by R 6 In one embodiment of Formula I, R 1 Selected from -S(O)2-(by R 6 In one embodiment of Formula I, R 1 Selected from -S(O)2-(by R 6 In one embodiment of Formula I, R 1 Selected from -S(O)2-(by R 6 substituted heteroaryl).

[0307] In one embodiment of Formula I, R 1 Selected from:

[0308] In certain embodiments, R 1 is selected from halogen, hydrogen, amino or cyano.

[0309] In one embodiment, R 1 It's bromine.

[0310] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is optional R 6 substituted heteroaryl and R 6 is optionally 1 or 2 selected from R 9In another embodiment, R 9 is selected from hydrogen and alkyl. Non-limiting examples of this embodiment include:

[0311] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is optional R 6 substituted heteroaryl and R 6 is optionally 1 or 2 selected from R 9 In another embodiment, R 9 Selected from alkyl and -C(O)R 10 , where R 10 Is a heterocycle. Non-limiting examples of this embodiment include:

[0312]

[0313] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is optional R 6 substituted heteroaryl and R 6 is optionally 1 or 2 selected from R 9 In another embodiment, R 9 Selected from alkyl and -C(O)R 10 , where R 10 is optionally replaced by R 11 substituted heterocycle and R 11 Is an alkyl group. Non-limiting examples of this embodiment include:

[0314]

[0315] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is optional R 6 Substituted heteroaryl and R 6 is optionally 1 or 2 selected from R 9 In another embodiment, R 9 Selected from alkyl and -C(O)R 10 , where R 10 Is a cycloalkyl group. Non-limiting examples of this embodiment include:

[0316]

[0317] In certain embodiments, R1 Yes -(CH2)-R 4 , where R 4 Is optional R 6 substituted heteroaryl and R 6 is optionally 1 or 2 selected from R 9 In another embodiment, R9 is selected from alkyl and -C(O)R 10 , where R 10 is optionally replaced by R 11 Substituted cycloalkyl and R 11 Is a cyano group. Non-limiting examples of this embodiment include:

[0318]

[0319] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is optional R 6 substituted heteroaryl and R 6 is optionally 1 or 2 selected from R 9 In another embodiment, R 9 Selected from alkyl and -C(O)R 10 , where R 10 is optionally replaced by R 11 Substituted cycloalkyl and R 11 Is an alkyl group. Non-limiting examples of this embodiment include:

[0320]

[0321]

[0322] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is optional R 6 substituted heteroaryl and R 6 is optionally 1 or 2 selected from R 9 In another embodiment, R 9 Selected from alkyl and -C(O)R 10 , where R 10 is optionally replaced by R 11 Substituted cycloalkyl and R 11 Is a haloalkyl group. Non-limiting examples of this embodiment include:

[0323]

[0324] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is optional R 6 substituted heteroaryl and R 6 is optionally 1 or 2 selected from R 9 In another embodiment, R 9 Selected from alkyl and -C(O)R 10 , where R 10 is optionally replaced by R 11 Substituted alkyl and R 11 is selected from hydrogen, hydroxyl and cyano. Non-limiting examples of this embodiment include:

[0325]

[0326] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is optional R 6 substituted heteroaryl and R 6 is optionally 1 or 2 selected from R 9 In another embodiment, R 9 Selected from alkyl and -C(O)R 10 , where R 10 Is a haloalkyl group. Non-limiting examples of this embodiment include:

[0327]

[0328] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is optional R 6 substituted heteroaryl and R 6 is optionally 1 or 2 selected from R 9 In another embodiment, R 9 Selected from alkyl and -C(O)R 10 , where R 10 is optionally replaced by R 11 Substituted alkyl and R 11 is OR 8 Non-limiting examples of this embodiment include:

[0329]

[0330] In certain embodiments, R 1 Yes -(CH2)-R 4, where R 4 is optionally replaced by R 6 substituted heteroaryl and R 6 is optionally replaced by R 9 In another embodiment, R 9 Yes-C(O)R 10 , where R 10 is heteroaryl or optionally replaced by R 11 substituted aryl, and R 11 is selected from hydrogen and alkyl. Non-limiting examples of this embodiment include:

[0331]

[0332] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 is optionally replaced by R 6 substituted heteroaryl and R 6 is optionally replaced by R 9 In another embodiment, R 9 Yes -C(O)NR 2 R 10 or-C(O)OR 10 , where R 10 Is an alkyl group. Non-limiting examples of this embodiment include:

[0333]

[0334] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is optional R 6 substituted heteroaryl and R 6 is optionally 1 or 2 selected from R 9 In another embodiment, R 9 Selected from alkyl and -CH2R 10 , where R 10 is optionally replaced by R 11 Substituted cycloalkyl and R 11 Is an alkyl group. Non-limiting examples of this embodiment include:

[0335]

[0336] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is optional R 6 substituted heteroaryl and R6 is optionally 1 or 2 selected from R 9 In another embodiment, R 9 Selected from alkyl and -CH2R 10 , where R 10 is optionally replaced by R 11 Substituted cycloalkyl and R 11 is selected from haloalkyl or cyano. Non-limiting examples of this embodiment include:

[0337]

[0338] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is optional R 6 substituted heteroaryl and R 6 is optionally 1 or 2 selected from R 9 In another embodiment, R 9 Selected from alkyl and -CH2R 10 , where R 10 is optionally replaced by R 11 Substituted cycloalkyl and R 11 is OR 8 Non-limiting examples of this embodiment include:

[0339]

[0340] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is optional R 6 substituted heteroaryl and R 6 is optionally 1 or 2 selected from R 9 In another embodiment, R 9 Selected from alkyl and -CH2R 10 , where R 10 is optionally replaced by R 11 Substituted alkyl and R 11 Selected from hydrogen, cyano and OR 8 Non-limiting examples of this embodiment include:

[0341]

[0342] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 is optionally replaced by R 6substituted heteroaryl and R 6 is optionally replaced by R 9 In another embodiment, R 9 It is R 10 And R 10 Is a cycloalkyl group. Non-limiting examples of this embodiment include:

[0343]

[0344] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is R 7 Replaced by R 6 Substituted heteroaryl, wherein R 6 is optionally 1 or 2 selected from R 9 In another embodiment, R 9 Selected from alkyl and -C(O)R 10 And R 10 is optionally replaced by R 11 Substituted cycloalkyl and R 11 Is an alkyl group. Non-limiting examples of this embodiment include:

[0345]

[0346] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 is optionally replaced by R 6 substituted heteroaryl and R 6 Is a cycloalkyl group. Non-limiting examples of this embodiment include:

[0347]

[0348] In certain embodiments, R 1 Yes-C(O)R 4 , where R 4 is optionally replaced by R 6 substituted heteroaryl and R 6 In another embodiment, R 6 Optionally R 9 Replace and R 9 Yes-C(O)OR 10 , where R 10 Is an alkyl group. Non-limiting examples of this embodiment include:

[0349]

[0350] In certain embodiments, R 1 is -CH(CH3)R 4 , where R 4 is optionally replaced by R 6 substituted heteroaryl and R 6 In another embodiment, R 6 Optionally R 9 Replace and R 9 Yes-C(O)OR 10 or -C(O)R 10 , where R 10 is optionally replaced by R 11 Substituted alkyl or cycloalkyl and R 11 is selected from alkyl and hydrogen. Non-limiting examples of this embodiment include:

[0351]

[0352] In certain embodiments, R 1 is -CH(NH2)R 4 , where R 4 is optionally replaced by R 6 substituted heteroaryl and R 6 In another embodiment, R 6 Optionally R 9 Replace and R 9 Yes-C(O)OR 10 or -C(O)R 10 , where R 10 is optionally replaced by R 11 Substituted alkyl or cycloalkyl and R 11 is selected from alkyl and hydrogen. Non-limiting examples of this embodiment include:

[0353]

[0354] In certain embodiments, R 1 Yes-SR 4 、-S(O)R 4 or -S(O)2R 4 , where R 4 is optionally replaced by R 6 substituted heteroaryl and R 6 is optionally replaced by R 9 In another embodiment, R 9 Yes-C(O)R 10 , where R 10 is optionally replaced by R 11 Substituted cycloalkyl and R 11Is an alkyl group. Non-limiting examples of this embodiment include:

[0355]

[0356] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 is optionally replaced by R 6 substituted heteroaryl and R 6 is optionally replaced by R 9 In another embodiment, R 9 Select from -OR 10 , where R 10 is optionally replaced by R 11 Substituted alkyl and R 11 Is an aryl group. Non-limiting examples of this embodiment include:

[0357]

[0358] In certain embodiments, R 1 Yes-(CR 3 R 3’ )-R 4 , where R 3 and R 3’ Combined with the carbon to which they are attached to form a 3-membered cycloalkyl ring and R 4 Is optional R 6 Substituted heteroaryl, wherein R 6 is optionally replaced by R 9 In another embodiment, R 9 Yes-C(O)R 10 or -CH2R 10 , where R 10 is optionally replaced by R 11 Substituted cycloalkyl and R 11 Is an alkyl group. Non-limiting examples of this embodiment include:

[0359]

[0360] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is R 6 substituted aryl and R 6 Is optional R 9 In another embodiment, R 9 R 10 And R 10 R 11Substituted heterocyclic ring, wherein R 11 -C(O)OR 8 、-C(O)R 8 or-SO2R 8 And R 8 Is alkyl, cycloalkyl, haloalkyl or aryl. Non-limiting examples of this embodiment include:

[0361]

[0362]

[0363] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is R 6 substituted aryl and R 6 Is optional R 9 In another embodiment, R 9 It is R 10 And R 10 Is a heterocycle or a heteroaryl. Non-limiting examples of this embodiment include:

[0364]

[0365] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 Is R 6 substituted aryl and R 6 Is optional R 9 In another embodiment, R 9 It is R 10 And R 10 Is optional R 11 substituted heterocyclic or heteroaryl, wherein R 11 In one embodiment, two R on the same carbon 11 The groups are combined together to form an oxo group. Non-limiting examples of this embodiment include:

[0366]

[0367] In certain embodiments, R 1 Yes-CH2-R 4 , where R 4 is optionally replaced by R 6 substituted aryl and R 6 is optionally replaced by R 9 In another embodiment, R9 It is R 10 , where R 10 is optionally replaced by R 11 substituted heterocycle and R 11 Is a -CH aryl group optionally substituted by halogen. Non-limiting examples of this embodiment include:

[0368]

[0369] In certain embodiments, R 1 Yes-CH2-R 4 , where R 4 is optionally replaced by R 6 substituted aryl and R 6 is optionally replaced by R 9 In another embodiment, R 9 It is R 10 , where R 10 is optionally replaced by R 11 substituted heterocycle and R 11 Is an aryl group optionally substituted by halogen. Non-limiting examples of this embodiment include:

[0370]

[0371] In certain embodiments, R 1 Yes-CH2-R 4 , where R 4 is optionally replaced by R 6 substituted aryl and R 6 is optionally replaced by R 9 In another embodiment, R 9 Yes-CH2R 10 or -C(O)R 10 , where R 10 is optionally replaced by R 11 Substituted cycloalkyl and R 11 Is hydrogen or alkyl. Non-limiting examples of this embodiment include:

[0372]

[0373] In certain embodiments, R 1 Yes -(CH2)-R 4 , where R 4 is optionally replaced by R 6 substituted heteroaryl and R 6 is optionally replaced by R 9 In another embodiment, R 9 Selected from R 10 , where R10 is R optionally selected from halogen and hydrogen 11 Non-limiting examples of this embodiment include:

[0374]

[0375] In certain embodiments, R 1 Selected from the following:

[0376]

[0377]

[0378] R 4 In one embodiment of Formula I, R 4 Selected from:

[0379]

[0380] In one embodiment of Formula I, R 4 Selected from:

[0381]

[0382] In one embodiment of Formula I, R 4 Selected from:

[0383]

[0384] In one embodiment of Formula I, R 4 Selected from:

[0385]

[0386] In one embodiment of Formula I, R 4 Selected from:

[0387]

[0388] In one embodiment of Formula I, R 4 Selected from:

[0389]

[0390] In one embodiment of Formula I, R 4 Selected from:

[0391]

[0392] In one embodiment of Formula I, R 4 Selected from:

[0393] In one embodiment of Formula I, R 4 Selected from:

[0394]

[0395] In one embodiment of Formula I, R 4 Selected from:

[0396]

[0397] In one embodiment of Formula I, R 4 Selected from:

[0398]

[0399] In one embodiment of Formula I, R 4 Selected from:

[0400]

[0401]

[0402] In certain embodiments, R 4 Selected from:

[0403]

[0404] In one embodiment, the compound of formula I is selected from:

[0405]

[0406]

[0407]

[0408] In one embodiment, the compound of formula I is selected from:

[0409]

[0410]

[0411]

[0412] In one embodiment, the compound of formula I is selected from:

[0413]

[0414]

[0415] In one embodiment, the compound of formula I is selected from:

[0416]

[0417] In one embodiment, the compound of formula I is selected from:

[0418]

[0419]

[0420] In one embodiment, the compound of formula I is selected from:

[0421]

[0422]

[0423]

[0424] In one embodiment, the compound of formula I is selected from:

[0425]

[0426]

[0427]

[0428] In one embodiment, the compound of formula I is selected from:

[0429]

[0430]

[0431]

[0432] In one embodiment, the compound of formula I is selected from:

[0433]

[0434]

[0435]

[0436]

[0437] In one embodiment, the compound of formula I is selected from:

[0438]

[0439]

[0440]

[0441] In one embodiment, the compound of formula I is selected from:

[0442]

[0443]

[0444]

[0445] In one embodiment, the compound of formula I is selected from:

[0446]

[0447]

[0448]

[0449] In one embodiment, the compound of formula I is selected from:

[0450]

[0451]

[0452]

[0453] In one embodiment, the compound of formula I is selected from:

[0454]

[0455]

[0456]

[0457] In one embodiment, the compound of formula I is selected from:

[0458]

[0459]

[0460] In one embodiment, the compound of formula I is selected from:

[0461]

[0462] In one embodiment, the compound of formula I is selected from:

[0463]

[0464] In one embodiment, the compound of formula I is selected from:

[0465]

[0466] R 6 In one embodiment of Formula I, R 6 Selected from:

[0467] In one embodiment of Formula I, R 6 Selected from:

[0468] In one embodiment of Formula I, R 6 Selected from:

[0469]

[0470] In one embodiment of Formula I, R 6 Selected from:

[0471]

[0472] In one embodiment of Formula I, R 6 Selected from:

[0473]

[0474] In one embodiment of Formula I, R 6 Selected from:

[0475]

[0476]

[0477] In certain embodiments, R 6 Selected from:

[0478]

[0479] R 9 In one embodiment, R 9 Selected from:

[0480]

[0481] In one embodiment, R 9 Selected from:

[0482]

[0483] In one embodiment, R 9 Selected from:

[0484]

[0485] In one embodiment, R 9 Selected from:

[0486] In one embodiment, R 9 yes In one embodiment, R 9 Selected from:

[0487] In one embodiment, R 9 Selected from:

[0488]

[0489] In one embodiment, R 9 Selected from:

[0490]

[0491] In one embodiment, R 9 Selected from:

[0492]

[0493] In one embodiment, R 9 Selected from:

[0494]

[0495] In one embodiment, R 9 Selected from:

[0496]

[0497] In one embodiment, R 9 Selected from:.

[0498]

[0499] In one embodiment, R 9 Selected from:

[0500]

[0501] In one embodiment, R 9 Selected from:

[0502]

[0503] In one embodiment, R 9 Selected from:

[0504]

[0505] In one embodiment, R 9 Selected from:

[0506]

[0507] In one embodiment, R 9 Selected from:

[0508]

[0509] In one embodiment, R 9 yes

[0510] In one embodiment, R 9 yes

[0511] In one embodiment, R 9 Selected from:

[0512]

[0513] In one embodiment, R 9 yes

[0514] In one embodiment, R 9 Selected from

[0515] In one embodiment, R 9 Selected from

[0516] In one embodiment, R 9 yes

[0517] In one embodiment, R 9 yes

[0518] In one embodiment, R 9 yes

[0519] In one embodiment, R 9 yes

[0520] In one embodiment, R 9 yes

[0521] In one embodiment, R 9 yes

[0522] In one embodiment, R 9 Selected from:

[0523]

[0524] In one embodiment, R 9 Selected from:

[0525]

[0526] In one embodiment, R 9 yes In one embodiment, R 9 Selected from:

[0527]

[0528] In one embodiment, R 9 Selected from:

[0529]

[0530] In one embodiment, R 9 yes

[0531] In one embodiment, R 9 Selected from:

[0532]

[0533] In one embodiment, R 9 Selected from:

[0534]

[0535] In one embodiment, R 9 yes

[0536] In one embodiment, R 9 Selected from:

[0537]

[0538] In one embodiment, R 9 Selected from:

[0539]

[0540] In one embodiment, R 9 Selected from:

[0541]

[0542] In one embodiment, R 9 Selected from

[0543] In one embodiment, R 9yes

[0544] In one embodiment, R 9 yes

[0545] In one embodiment, R 9 Selected from:

[0546] In one embodiment, R 9 Selected from:

[0547]

[0548] In one embodiment, R 9 Selected from:

[0549]

[0550] In one embodiment, R 9 Selected from:

[0551]

[0552] In one embodiment, R 9 Selected from:

[0553]

[0554] In one embodiment, R 9 Selected from:

[0555]

[0556] In one embodiment, R 9 yes

[0557] In one embodiment, R 9 yes

[0558] In one embodiment, R 9 Selected from:

[0559]

[0560] In one embodiment, R 9 Selected from:

[0561]

[0562] In one embodiment, R 9 yes In one embodiment, R 9 Selected from:

[0563]

[0564] In one embodiment, R 9 Selected from:

[0565]

[0566] In one embodiment, R 9 Selected from:

[0567]

[0568] In one embodiment, R 9 Selected from:

[0569]

[0570] In one embodiment, R 9 Selected from:

[0571]

[0572] In one embodiment, R 9 Selected from:

[0573]

[0574] In one embodiment, R 9 yes

[0575] In one embodiment, R 9 yes

[0576] In one embodiment, R 9 Selected from:

[0577] In one embodiment, R 9 yes

[0578] In one embodiment, R 9 Selected from:

[0579]

[0580] In one embodiment, R 9 Selected from:

[0581]

[0582] In one embodiment, R 9 Selected from:

[0583]

[0584] In one embodiment, R 9 yes In one embodiment, R 9 Selected from:

[0585]

[0586] In one embodiment, R 9 Selected from:

[0587]

[0588] In one embodiment, R 9 yes

[0589] In one embodiment, R 9 Selected from:

[0590]

[0591] In one embodiment, R 9 Selected from:

[0592]

[0593] In one embodiment, R 9 Selected from:

[0594]

[0595] In one embodiment, R 9 Selected from:

[0596]

[0597] In one embodiment, R 9 Selected from:

[0598]

[0599] In one embodiment, R 9 Selected from:

[0600]

[0601] R 10 Non-limiting embodiments

[0602] -C(O)R 10 Non-limiting examples include:

[0603]

[0604]

[0605] -CH2R 10 Non-limiting examples include:

[0606]

[0607] R 10 Non-limiting examples include:

[0608]

[0609]

[0610] Non-limiting examples of compounds of Formula I or Formula II:

[0611] Representative examples of compounds of Formula I or Formula II include:

[0612]

[0613] Other representative examples of compounds of Formula I or Formula II include:

[0614]

[0615]

[0616]

[0617]

[0618] Other representative examples of compounds of Formula I or II include:

[0619]

[0620]

[0621]

[0622]

[0623] In certain embodiments, the compounds of the present invention are selected from:

[0624]

[0625]

[0626]

[0627] In one embodiment, the compound of the invention is or a pharmaceutically acceptable salt thereof.

[0628] Non-limiting isotope embodiments

[0629] In one embodiment, the compound is isotopically labeled.

[0630] In one embodiment, at least one R group independently selected from R1, R2, R3, R3', R4, R5, R6, R7, R8, R9, R10, R11, R12, R20, R21, R22, R23, R24, R25, R26, R28 or R40 is isotopically labeled with 1, 2 or more isotopes as allowed by valence. In one embodiment, the isotopic label is deuterium. In one embodiment, at least one deuterium is placed on an atom that has a bond that breaks during metabolism of the compound in vivo, or is one, two or three atoms away from a metabolic bond (e.g., which can be referred to as α, β or γ, or a primary, secondary or tertiary isotope effect). In another embodiment, the isotopic label is 13 C. In another embodiment, the isotopic label is 18 F.

[0631] In certain embodiments, the compounds of the present invention are selected from: or a pharmaceutically acceptable salt thereof.

[0632] In certain embodiments, the compounds of the present invention are selected from: or a pharmaceutically acceptable salt thereof.

[0633] In certain embodiments, the compounds of the present invention are selected from:

[0634] or a pharmaceutically acceptable salt thereof.

[0635] In certain embodiments, the compounds of the present invention are selected from the following formula:

[0636]

[0637]

[0638] or a pharmaceutically acceptable salt thereof.

[0639] In certain embodiments, the compounds of the present invention are selected from the following formula:

[0640]

[0641]

[0642]

[0643] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from the following formula:

[0644]

[0645]

[0646] or a pharmaceutically acceptable salt thereof.

[0647] In certain embodiments, the compounds of the present invention are selected from:

[0648]

[0649]

[0650] or a pharmaceutically acceptable salt thereof.

[0651] In certain embodiments, the compounds of the present invention are selected from:

[0652]

[0653]

[0654] or a pharmaceutically acceptable salt thereof.

[0655] In certain embodiments, the compounds of the present invention are selected from:

[0656]

[0657]

[0658] or a pharmaceutically acceptable salt thereof.

[0659] In certain embodiments, the compounds of the present invention are selected from:

[0660]

[0661]

[0662] or a pharmaceutically acceptable salt thereof.

[0663] In certain embodiments, the compounds of the present invention are selected from:

[0664]

[0665]

[0666] or a pharmaceutically acceptable salt thereof.

[0667] In certain embodiments, the compounds of the present invention are selected from:

[0668]

[0669]

[0670] or a pharmaceutically acceptable salt thereof.

[0671] In certain embodiments, the compounds of the present invention are selected from:

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680] or a pharmaceutically acceptable salt thereof.

[0681] In certain embodiments, the compounds of the present invention are selected from:

[0682]

[0683] or a pharmaceutically acceptable salt thereof.

[0684] In any of the above structures with two deuteriums on a methylene group, contemplate the same molecule with one deuterium at that position. In any of the above structures with three deuteriums on a methyl group, contemplate the same molecule with either one or two deuteriums at that position.

[0685] Other implementation plans

[0686] 1. In certain embodiments, a compound of Formula I or Formula II is provided

[0687]

[0688]

[0689] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof;

[0690] in:

[0691] X 1 and X 2 are independently selected from CH and N;

[0692] X 3 Selected from bond, NR 2 、C(R 3 R 3’ ), O, C(O), C(S), S, S(O) and S(O)2;

[0693] R 1 Selected from hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, -NR 2 R 2 '、-OR 2 、-NR 2 R 4 、-OR 4 、-NR 2 R 5 、-OR 5 、-(CR 3 R 3 ')-R 4 、-(CR 3 R 3 ')-R 5 、-(CR 3 R 3 ')-NR 2 R 4 、-(CR 3 R 3 ')-NR 2 R 5 、-(CR 3 R 3 ')-OR 4 、-(CR 3 R 3 ')-OR 5 、-C(O)R 4 、-SR 4 、-SR 5 、-S(O)R 4 and -S(O)2R 4 ;

[0694] R2 and R 2 ' is independently selected at each occurrence from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, -C(O)R 8 、-C(O)OR 8 、-C(O)-NR 8 R 8 '、-S(O)R 8 、-SO2R 8 、-SO2-OR 8 and -SO2-NR 8 R 8 ';

[0695] R 3 Selected from hydrogen, halogen, alkyl, haloalkyl, -OR 8 and -NR 8 R 8 ';

[0696] R 3 ' is selected from hydrogen, halogen, alkyl and haloalkyl;

[0697] or R 3 and R 3 'can combine with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring;

[0698] R 4 is selected from cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each R 4 Optionally, one selected from R 6 substituted with a group, and each R 4 Also optionally 1, 2, 3 or 4 independently selected from R 7 The group substitution;

[0699] R 5 Yes-C(O)R 6 ;

[0700] R 6 is selected from alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each R 6 Optionally 1, 2, 3 or 4 independently selected from R 9 The group substitution;

[0701] or R 6 is selected from the group consisting of alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycle, -CO-aryl, -CO-heteroaryl, -O-alkyl, -O-cycloalkyl, -O-heterocycle, -O-aryl, -O-heteroaryl, -NR 2 -alkyl, -NR 2 -cycloalkyl, -NR 2-Heterocycle, -NR 2 -aryl and -NR 2 -heteroaryl, wherein each R 6 Optionally 1, 2, 3 or 4 independently selected from R 9 The group substitution;

[0702] R 7 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -OR 8 、-NR 8 R 8 '、-C(O)R 8 、-C(O)OR 8 、-C(O)-NR 8 R 8 '、-OC(O)R 8 、-NR 2 -C(O)R 8 、-S(O)R 8 、-SO2R 8 、-SO2-OR 8 and -SO2-NR 8 R 8 ';

[0703] or two R on the same carbon 7 can be combined together to form oxo groups;

[0704] R 8 and R 8’ is independently selected at each occurrence from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl;

[0705] R 9 is independently selected at each occurrence from hydrogen, halogen, cyano, nitro, R 10 、-CH2R 10 、-OR 10 、-NR 2 R 10 、-C(O)R 10 、-C(O)CH2R 10 、-C(O)CH2OR 10 、-C(O)CH2NR 2 R 10 、-OC(O)R 10 、-NR 2 -C(O)R 10 、-C(O)OR 10 、-C(O)NR 2 R 10 、-S(O)R10 、-SO2R 10 、SO2CH2R 10 、-SO2CH2OR 10 、-SO2CH2NR 2 R 10 、-NR 2 SO2R 10 、-SO2-OR 10 and -SO2-NR 2 R 10 ;

[0706] R 10 is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein each R 10 Optionally 1, 2, 3 or 4 independently selected from R 11 substituted with a group; and

[0707] R 11 is selected from the group consisting of: hydrogen; halogen; hydroxy; cyano; nitro; alkyl; haloalkyl; alkenyl optionally substituted with aryl or heteroaryl; alkynyl optionally substituted with aryl or heteroaryl; cycloalkyl; heterocycle; optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR 8 aryl substituted with 1, 2, 3 or 4 halogen, alkyl or -OR 8 Heteroaryl substituted with 1, 2, 3 or 4 halogen, alkyl or -OR 8 -CH2 aryl substituted with a group; optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR 8 -CH2 heteroaryl substituted with a group; -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ;-C(O)OR 8 ;-C(O)-NR 8 R 8’ ;-C(O)CH2R 8 ;-C(O)CH2OR 8 ;-C(O)CH2-NR 8 R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8 ;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ;-SO2-OR 8; and -SO2-NR 8 R 8’ ;

[0708] or two R on the same carbon 11 The groups can be combined to form oxo groups;

[0709] or R 11 is independently selected at each occurrence from: halogen; hydroxy; cyano; nitro; alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl; heterocycle; aryl; heteroaryl; -CH2 aryl; -CH2 heteroaryl; -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ;-C(O)OR 8 ;-C(O)-NR 8 R 8’ ;-C(O)CH2R 8 ;-C(O)CH2OR 8 ;-C(O)CH2-NR 8 R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8 ;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ;-SO2-OR 8 ; Oxo and -SO2-NR 8 R 8’ ; where each R 11 The group is optionally substituted by 1, 2, 3 or 4 independently selected R 12 substituted with a group; and

[0710] R 12 is independently selected at each occurrence from: halogen; hydroxy; cyano; nitro; alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl; heterocycle; aryl; heteroaryl; -CH2 aryl; -CH2 heteroaryl; -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ;-C(O)OR 8 ;-C(O)-NR 8 R 8’ ;-C(O)CH2R 8 ;-C(O)CH2OR 8 ;-C(O)CH2-NR 8R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8 ;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ;-SO2-OR 8 ; oxo; and -SO2-NR 8 R 8 ';

[0711] R 20 、R 21 、R 22 、R 23 and R 24 is independently selected at each occurrence from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -、-NR 2 C(O)-, -O-, -S-, -NR 2 -、-P(O)(R 28 )-, -P(O)-, alkenyl, alkynyl, haloalkyl, aryl, heterocyclic, heteroaryl, bicyclic and carbocyclic; each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 substituted by a substituent; wherein R 20 、R 21 、R 22 、R 23 and R 24 You cannot choose:

[0712] i.-C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -P(O)(R 28 )-, -P(O)-, -C(S)- moieties are adjacent to each other; or

[0713] ii. -O-, -S-, or -NR 2 -partially adjacent to each other; or

[0714] iii. The portions are additionally selected in an order that produces an unstable molecule (defined as a molecule having a shelf life of less than about 4 months (or less than about 6 months or 5 months) at ambient temperature, which is determined by the portion R 20 、R 21 、R 22 、R 23 and R 24the decomposition caused by the choice and order of

[0715] R 25 Selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, cyano, -OR 2 、-NR 2 R 2 '、-NR 2 SO2R 28 、-OSO2R 28 、-SO2R 28 , haloalkyl, aryl, heteroaryl, heterocyclic, bicyclic and cycloalkyl; wherein each R 25 The group is optionally substituted by 1, 2, 3 or 4 independently selected R 12 The group substitution;

[0716] R 28 is independently selected at each occurrence from hydrogen, -NR 2 R 2’ 、-OR 2 、-SR 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl;

[0717] R 40 is independently selected at each occurrence from hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, cyano, -NR 2 R 2 '、-NR 2 SO2R 28 、-OSO2R 28 、-SO2R 28 , haloalkyl, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; wherein each R 40 The group is optionally substituted by 1, 2, 3 or 4 independently selected R 12 substituted by a group.

[0718] 2. Compounds according to embodiment 1 of the following formula:

[0719]

[0720] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof.

[0721] 3. The compound of embodiment 2, wherein:

[0722] R 6 is selected from alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each R 6 Optionally 1, 2, 3 or 4 independently selected from R 9 The group substitution;

[0723] R 11 is selected from the group consisting of: hydrogen; halogen; hydroxy; cyano; nitro; alkyl; haloalkyl; alkenyl optionally substituted with aryl or heteroaryl; alkynyl optionally substituted with aryl or heteroaryl; cycloalkyl; heterocycle; optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR 8 aryl substituted with 1, 2, 3 or 4 halogen, alkyl or -OR 8 Heteroaryl substituted with 1, 2, 3 or 4 halogen, alkyl or -OR 8 -CH2 aryl substituted with a group; optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR 8 -CH2 heteroaryl substituted with a group; -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ;-C(O)OR 8 ;-C(O)-NR 8 R 8’ ;-C(O)CH2R 8 ;-C(O)CH2OR 8 ;-C(O)CH2-NR 8 R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8 ;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ;-SO2-OR 8 ; and -SO2-NR 8 R 8’ ;

[0724] or two R on the same carbon 11 The groups may be combined together to form an oxo group.

[0725] 4. The compound of embodiment 1 or embodiment 2, wherein R 12 is selected from halogen, alkyl and haloalkyl.

[0726] 5. The compound of embodiment 1 or embodiment 2, wherein R 12 is selected from hydroxy, cyano, nitro, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl.

[0727] 6. The compound of embodiment 1 or embodiment 2, wherein R12 is selected from: -CH2 aryl; -CH2 heteroaryl; -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ;-C(O)OR 8 ;-C(O)-NR 8 R 8’ ;-C(O)CH2R 8 ;-C(O)CH2OR 8 ;-C(O)CH2-NR 8 R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8 ;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ;-SO2-OR 8 ; oxo; and -SO2-NR 8 R 8 '.

[0728] 7. The compound of embodiment 1 or 2, wherein one R 12 The substituent is halogen.

[0729] 8. The compound of embodiment 1 or 2, wherein both R 12 The substituent is halogen.

[0730] 9. The compound of embodiment 1 or 2, wherein one R 12 The substituent is an alkyl group.

[0731] 10. The compound of embodiment 1 or 2, wherein both R 12 The substituent is an alkyl group.

[0732] 11. The compound of embodiment 1 or 2, wherein one R 12 The substituent is a haloalkyl group.

[0733] 12. The compound of embodiment 1 or 2, wherein one R 12 The substituent is a cycloalkyl group.

[0734] 13. The compound of any one of embodiments 4-12, wherein R 11 is optionally 1, 2, 3 or 4 selected from R 12 The substituent is an alkyl group substituted with.

[0735] 14. The compound of any one of embodiments 4-12, wherein R 11 is optionally 1, 2, 3 or 4 selected from R 12 A cycloalkyl group substituted with a substituent.

[0736] 15. The compound of any one of embodiments 4-12, wherein R 11 is optionally 1, 2, 3 or 4 selected from R 12 The heterocyclic ring is substituted with a substituent.

[0737] 16. The compound of any one of embodiments 4-12, wherein R 11 is optionally 1, 2, 3 or 4 selected from R 12 The substituent is an aryl group substituted with.

[0738] 17. The compound of any one of embodiments 4-12, wherein R 11 is optionally 1, 2, 3 or 4 selected from R 12 A substituent is substituted with a heteroaryl group.

[0739] 18. The compound of any one of embodiments 1-12, wherein R 11 For alkyl.

[0740] 19. The compound of any one of embodiments 1-12, wherein R 11 It is a cyano group.

[0741] 20. The compound of any one of embodiments 1-12, wherein R 11 It is a halogenated alkyl group.

[0742] 21. The compound of any one of embodiments 1-12, wherein R 11 For hydrogen.

[0743] 22. The compound of any one of embodiments 1-12, wherein R 11 It is a hydroxyl group.

[0744] 23. The compound of any one of embodiments 1-12, wherein R 11 OR 8 .

[0745] 24. The compound of any one of embodiments 1-12, wherein R 11 It is an aryl group.

[0746] 25. The compound of any one of embodiments 1-12, wherein R 11 It is a heteroaryl group.

[0747] 26. The compound of any one of embodiments 1-12, wherein R 11 -C(O)OR8 、-C(O)R 8 or-SO2R 8 .

[0748] 27. The compound of any one of embodiments 1-12, wherein R 11 It is a -CH2 aryl group.

[0749] 28. A compound according to any one of embodiments 1-27, wherein R 1 -NR 2 R 4 .

[0750] 29. The compound of any one of embodiments 1-27, wherein R 1 For-OR 4 .

[0751] 30. A compound according to any one of embodiments 1-27, wherein R 1 -C(O)R 4 .

[0752] 31. A compound according to any one of embodiments 1-27, wherein R 1 For-SR 4 .

[0753] 32. A compound according to any one of embodiments 1-27, wherein R 1 -S(O)R 4 .

[0754] 33. The compound of any one of embodiments 1-27, wherein R 1 is -S(O)2R 4 .

[0755] 34. The compound of any one of embodiments 1-27, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

[0756] 35. The compound of any one of embodiments 1-27, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

[0757] 36. The compound of any one of embodiments 1-27, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

[0758] 37. The compound of any one of embodiments 1-27, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

[0759] 38. The compound of any one of embodiments 1-27, wherein R 1 For-(CR 3 R 3’ )-R 5 .

[0760] 39. The compound of embodiment 37 or 38, wherein R 3 For hydrogen.

[0761] 40. The compound of embodiment 37 or 38, wherein R 3 -NR 8 R 8 '.

[0762] 41. The compound of embodiment 37 or 38, wherein R 3 For alkyl.

[0763] 42. The compound of any one of embodiments 37-41, wherein R 3 ' is hydrogen.

[0764] 43. A compound according to any one of embodiments 1-27, wherein R 1 -NR 2 R 5 .

[0765] 44. A compound according to any one of embodiments 1-27, wherein R 1 For-OR 5 .

[0766] 45. The compound of any one of embodiments 38-44, wherein R 5 is optionally substituted by 1, 2, 3 or 4 independently selected from R 9 -C(O)alkyl substituted with a group.

[0767] 46. ​​The compound of any one of embodiments 38-44, wherein R 5 is optionally substituted by 1, 2, 3 or 4 independently selected from R 9 -C(O)heterocycle substituted with a group.

[0768] 47. The compound of any one of embodiments 38-44, wherein R 5 is optionally substituted by 1, 2, 3 or 4 independently selected from R 9 -C(O)aryl substituted with a group.

[0769] 48. The compound of any one of embodiments 38-44, wherein R 5 is optionally substituted by 1, 2, 3 or 4 independently selected from R 9 -C(O)heteroaryl substituted with a group.

[0770] 49. The compound of any one of embodiments 1-48, wherein the compound has the formula or a pharmaceutically acceptable salt thereof.

[0771] 50. The compound of any one of embodiments 1-48, wherein the compound has the formula or a pharmaceutically acceptable salt thereof.

[0772] 51. The compound of any one of embodiments 1-48, wherein the compound has the formula or a pharmaceutically acceptable salt thereof.

[0773] 52. The compound of any one of embodiments 49-51, wherein R 4 is selected by a 6 and optionally substituted by 1, 2, 3 or 4 groups independently selected from R 7 substituted by a group.

[0774] 53. The compound of any one of embodiments 49-51, wherein R 4 is selected by a 6 and optionally substituted by 1, 2, 3 or 4 groups independently selected from R 7 substituted by a group.

[0775] 54. A compound according to any one of embodiments 49-51, wherein R 4 is selected by a 6 and optionally substituted by 1, 2, 3 or 4 groups independently selected from R 7 substituted by a group.

[0776] 55. The compound of any one of embodiments 49-51, wherein R 4 is selected by a 6 and optionally substituted by 1, 2, 3 or 4 groups independently selected from R 7 substituted by a group.

[0777] 56. The compound of any one of embodiments 49-51, wherein R 4 yes

[0778] 57. The compound of any one of embodiments 49-51, wherein R 4 yes

[0779] 58. The compound of any one of embodiments 49-51, wherein R 4 yes

[0780] 59. The compound of any one of embodiments 49-51, wherein R 4 yes

[0781] 60. The compound of any one of embodiments 49-51, wherein R 4 yes

[0782] 61. The compound of any one of embodiments 1-60, wherein R 7 Selected from hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -OR 8 and -NR 8 R 8 '.

[0783] 62. The compound of any one of embodiments 1-60, wherein R 7 Selected from hydrogen, halogen, alkyl, haloalkyl, -C(O)R 8 、-C(O)OR 8 、-C(O)-NR 8 R 8 '、-OC(O)R 8 、-NR 2 -C(O)R 8 、-S(O)R 8 、-SO2R 8 、-SO2-OR 8 and -SO2-NR 8 R 8 '.

[0784] 63. The compound of any one of embodiments 1-60, wherein one R 7 For hydrogen.

[0785] 64. The compound of any one of embodiments 1-60, wherein both R 7 For hydrogen.

[0786] 65. The compound of any one of embodiments 1-60, wherein three R 7 For hydrogen.

[0787] 66. The compound of any one of embodiments 1-65, wherein one R 7 It is a halogen.

[0788] 67. The compound of any one of embodiments 1-64, wherein both R 7 It is a halogen.

[0789] 68. The compound of any one of embodiments 1-65, wherein one R 7For alkyl.

[0790] 69. The compound of any one of embodiments 1-64, wherein both R 7 For alkyl.

[0791] 70. The compound of any one of embodiments 1-65, wherein one R 7 It is a halogenated alkyl group.

[0792] 71. The compound of any one of embodiments 1-64, wherein both R 7 It is a halogenated alkyl group.

[0793] 72. The compound of any one of embodiments 1-71, wherein R 6 Selected from:

[0794]

[0795] 73. The compound of any one of embodiments 1-71, wherein R 6 Selected from:

[0796]

[0797] 74. The compound of any one of embodiments 1-71, wherein R 6 Selected from:

[0798]

[0799] 75. The compound of any one of embodiments 1-71, wherein R 6 is optionally substituted by 1, 2, 3 or 4 independently selected from R 9 An alkyl group substituted with a group.

[0800] 76. The compound of any one of embodiments 1-71, wherein R 6 is optionally substituted by 1, 2, 3 or 4 independently selected from R 9 A cycloalkyl group substituted with a group.

[0801] 77. The compound of any one of embodiments 1-71, wherein R 6 is optionally substituted by 1, 2, 3 or 4 independently selected from R 9 A heterocyclic ring substituted with a group.

[0802] 78. The compound of any one of embodiments 1-71, wherein R 6 is optionally substituted by 1, 2, 3 or 4 independently selected from R 9 An aryl group substituted with a group.

[0803] 79. The compound of any one of embodiments 1-71, wherein R 6is optionally substituted by 1, 2, 3 or 4 independently selected from R 9 A heteroaryl group substituted with a group.

[0804] 80. The compound of any one of embodiments 75-79, wherein R 6 Not replaced.

[0805] 81. The compound of any one of embodiments 75-79, wherein R 6 Selected by 1 R 9 substituted by a group.

[0806] 82. The compound of any one of embodiments 75-79, wherein R 6 2 independently selected from R 9 substituted by a group.

[0807] 83. The compound of any one of embodiments 75-79, wherein R 6 3 independently selected from R 9 substituted by a group.

[0808] 84. The compound of any one of embodiments 75-79, wherein R 6 4 independently selected from R 9 substituted by a group.

[0809] 85. The compound of any one of embodiments 1-84, wherein R 9 is selected from hydrogen, halogen, alkyl, haloalkyl, cyano and nitro.

[0810] 86. The compound of any one of embodiments 1-84, wherein R 9 Selected from R 10 .

[0811] 87. The compound of any one of embodiments 1-84, wherein R 9 Selected from -CH2R 10 、-OR 10 、-NR 2 R 10 、-C(O)R 10 、-C(O)CH2R 10 、-C(O)CH2OR 10 、-C(O)CH2NR 2 R 10 、-OC(O)R 10 、-NR 2 -C(O)R 10 、-C(O)OR 10 、-C(O)NR 2 R 10 、-S(O)R 10、-SO2R 10 、SO2CH2R 10 、-SO2CH2OR 10 、-SO2CH2NR 2 R 10 、-NR 2 SO2R 10 、-SO2-OR 10 and -SO2-NR 2 R 10 .

[0812] 88. The compound of embodiment 86 or 87, wherein R 10 is optionally substituted by 1, 2, 3 or 4 independently selected from R 11 An alkyl group substituted with a group.

[0813] 89. The compound of embodiment 86 or 87, wherein R 10 is optionally substituted by 1, 2, 3 or 4 independently selected from R 11 A haloalkyl group substituted with a group.

[0814] 90. The compound of embodiment 86 or 87, wherein R 10 is optionally substituted by 1, 2, 3 or 4 independently selected from R 11 An alkenyl group substituted with a group.

[0815] 91. The compound of embodiment 86 or 87, wherein R 10 is optionally substituted by 1, 2, 3 or 4 independently selected from R 11 An alkynyl group substituted with a group.

[0816] 92. The compound of embodiment 86 or 87, wherein R 10 is optionally substituted by 1, 2, 3 or 4 independently selected from R 11 A cycloalkyl group substituted with a group.

[0817] 93. The compound of embodiment 86 or 87, wherein R 10 The heterocyclic ring is optionally substituted by 1, 2, 3 or 4 independently selected R 11 substituted by a group.

[0818] 94. The compound of embodiment 86 or 87, wherein R 10 is optionally substituted by 1, 2, 3 or 4 independently selected from R 11 An aryl group substituted with a group.

[0819] 95. The compound of embodiment 86 or 87, wherein R 10 is optionally substituted by 1, 2, 3 or 4 independently selected from R 11 A heteroaryl group substituted with a group.

[0820] 96. The compound of any one of embodiments 88-95, wherein R 10 Not replaced.

[0821] 97. The compound of any one of embodiments 88-95, wherein R 10 Selected by 1 R 11 substituted by a group.

[0822] 98. The compound of any one of embodiments 88-95, wherein R 10 2 independently selected from R 11 substituted by a group.

[0823] 99. The compound of any one of embodiments 88-95, wherein R 10 3 independently selected from R 11 substituted by a group.

[0824] 100. The compound of any one of embodiments 88-95, wherein R 10 4 independently selected from R 11 substituted by a group.

[0825] 101. The compound of any one of embodiments 1-100, wherein R 2 、R 8 and R 8 'It's hydrogen.

[0826] 102. The compound of any one of embodiments 1-100, wherein R 2 、R 8 and R 8 ' is an alkyl group.

[0827] 103. The compound of any one of embodiments 1-71, wherein R 6 Selected from:

[0828]

[0829] 104. The compound of any one of embodiments 1-71, wherein R 6 Selected from:

[0830]

[0831] 105. The compound of any one of embodiments 1-71, wherein R 6 Selected from:

[0832]

[0833] 106. The compound of embodiment 1, wherein the compound has the formula: or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof.

[0834] 107. The compound of embodiment 106, wherein the compound has the formula or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof.

[0835] 108. The compound of embodiment 106, wherein the compound has the formula or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof.

[0836] 109. The compound of embodiment 106, wherein the compound has the formula or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof.

[0837] 110. The compound of any one of embodiments 106-109, wherein X 3 It is a key.

[0838] 111. The compound of any one of embodiments 106-109, wherein X 3 It is C(R 3 R 3 ').

[0839] 112. The compound of any one of embodiments 106-109, wherein X 3 It is C(O).

[0840] 113. The compound of any one of embodiments 106-109, wherein X 3 It is C(S).

[0841] 114. The compound of any one of embodiments 106-109, wherein X 3 It is S(O).

[0842] 115. The compound of any one of embodiments 106-109, wherein X 3 It is S(O)2.

[0843] 116. The compound of any one of embodiments 106-109, wherein X 3 It is NR 2 .

[0844] 117. The compound of any one of embodiments 106-109, wherein X 3 It's O.

[0845] 118. The compound of any one of embodiments 106-109, wherein X 3 It is NR 2 .

[0846] 119. The compound of any one of embodiments 106-109, wherein X3 is O.

[0847] 120. The compound of any one of embodiments 106-109, wherein X 3 It’s S.

[0848] 121. The compound of any one of embodiments 106-120, wherein R 20 It is a key.

[0849] 122. The compound of any one of embodiments 106-120, wherein R 20 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The substituent is an alkyl group substituted with.

[0850] 123. The compound of any one of embodiments 106-120, wherein R 20 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The substituents are alkenyl or alkynyl substituted.

[0851] 124. The compound of any one of embodiments 106-120, wherein R 20 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 A haloalkyl group substituted with a substituent.

[0852] 125. The compound of any one of embodiments 106-120, wherein R 20 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The substituent is an aryl group substituted with.

[0853] 126. The compound of any one of embodiments 106-120, wherein R 20 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The substituent is a heteroaryl group substituted with.

[0854] 127. The compound of any one of embodiments 106-120, wherein R 20 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The heterocyclic ring is substituted with a substituent.

[0855] 128. The compound of any one of embodiments 106-120, wherein R 20 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 A bicyclic ring substituted with a substituent.

[0856] 129. The compound of any one of embodiments 106-115, wherein R 20 It is -O-.

[0857] 130. The compound of any one of embodiments 106-115, wherein R 20 Yes -S-.

[0858] 131. The compound of any one of embodiments 106-115, wherein R 20 Yes-NR 2 -.

[0859] 132. The compound of any one of embodiments 106-111, wherein R 20 is -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -、-P(O)(R 28 )-or-P(O)-.

[0860] 133. The compound of any one of embodiments 106-132, wherein R 21 It is a key.

[0861] 134. The compound of any one of embodiments 106-132, wherein R 21 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The substituent is an alkyl group substituted with.

[0862] 135. The compound of any one of embodiments 106-132, wherein R 21 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The substituents are alkenyl or alkynyl substituted.

[0863] 136. The compound of any one of embodiments 106-132, wherein R 21 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 A haloalkyl group substituted with a substituent.

[0864] 137. The compound of any one of embodiments 106-132, wherein R 21 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The substituent is an aryl group substituted with.

[0865] 138. The compound of any one of embodiments 106-132, wherein R 21 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The substituent is a heteroaryl group substituted with.

[0866] 139. The compound of any one of embodiments 106-132, wherein R 21 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The heterocyclic ring is substituted with a substituent.

[0867] 140. The compound of any one of embodiments 106-132, wherein R 21 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 A bicyclic ring substituted with a substituent.

[0868] 141. The compound of any one of embodiments 106-128, wherein R 21 Yes -O-.

[0869] 142. The compound of any one of embodiments 106-128, wherein R 21 Yes -S-.

[0870] 143. The compound of any one of embodiments 106-128, wherein R 21 -NR 2 -.

[0871] 144. The compound of any one of embodiments 106-131, wherein R 21 is -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -、-P(O)(R 28 )-or-P(O)-.

[0872] 145. The compound of any one of embodiments 106-144, wherein R 22 It is a key.

[0873] 146. The compound of any one of embodiments 106-144, wherein R 22 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The substituent is an alkyl group substituted with.

[0874] 147. The compound of any one of embodiments 106-144, wherein R 22 is alkenyl or alkynyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R40.

[0875] 148. The compound of any one of embodiments 106-144, wherein R 22 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 A haloalkyl group substituted with a substituent.

[0876] 149. The compound of any one of embodiments 106-144, wherein R 22 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The substituent is an aryl group substituted with.

[0877] 150. The compound of any one of embodiments 106-144, wherein R 22 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 A substituent is substituted with a heteroaryl group.

[0878] 151. The compound of any one of embodiments 106-144, wherein R 22 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The heterocyclic ring is substituted with a substituent.

[0879] 152. The compound of any one of embodiments 106-144, wherein R 22 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 A bicyclic ring substituted with a substituent.

[0880] 153. The compound of any one of embodiments 106-143, wherein R 22 is -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -、-P(O)(R 28 )-or-P(O)-.

[0881] 154. The compound of any one of embodiments 106-140, wherein R 22 Yes -O-.

[0882] 155. The compound of any one of embodiments 106-140, wherein R 22 Yes -S-.

[0883] 156. The compound of any one of embodiments 106-140, wherein R 22 Yes-NR 2 -.

[0884] 157. The compound of any one of embodiments 106-156, wherein R 23 or R 24 is the key.

[0885] 158. The compound of any one of embodiments 106-156, wherein R 23 or R 24 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The substituent is an alkyl group substituted with.

[0886] 159. The compound of any one of embodiments 106-156, wherein R 23 or R 24 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The substituents are alkenyl or alkynyl substituted.

[0887] 160. The compound of any one of embodiments 106-156, wherein R 23 or R 24 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 A haloalkyl group substituted with a substituent.

[0888] 161. The compound of any one of embodiments 106-156, wherein R 23 or R 24 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The substituent is an aryl group substituted with.

[0889] 162. The compound of any one of embodiments 106-156, wherein R 23 or R 24 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The substituent is a heteroaryl group substituted with.

[0890] 163. The compound of any one of embodiments 106-156, wherein R 23 or R 24 is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 The heterocyclic ring is substituted with a substituent.

[0891] 164. The compound of any one of embodiments 106-156, wherein R23 or R24 ​​is a bicyclic ring optionally substituted with 1, 2, 3 or 4 substituents independently selected from R40.

[0892] 165. The compound of any one of embodiments 106-156, wherein R 23 or R 24 is -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -、-P(O)(R 28 )-or-P(O)-.

[0893] 166. The compound of any one of embodiments 106-156, wherein R 23 or R 24 It is -O-.

[0894] 167. The compound of any one of embodiments 106-156, wherein R 23 or R 24 For -S-.

[0895] 168. The compound of any one of embodiments 106-156, wherein R 23 or R 24 It is -NR2-.

[0896] 169. The compound of any one of embodiments 106-168, wherein R 25 For hydrogen.

[0897] 170. The compound of any one of embodiments 106-168, wherein R 25 It's a halogen.

[0898] 171. The compound of any one of embodiments 106-168, wherein R 25 is optionally substituted by 1, 2, 3 or 4 independently selected from R 12 An alkyl group substituted with a group.

[0899] 172. The compound of any one of embodiments 106-168, wherein R 25 Selected from alkenyl, alkynyl, hydroxyl, alkoxy, azido, amino, cyano, -OR 2 、-NR 2 R 2 '、-NR 2 SO2R 28 、-OSO2R 28 、-SO2R 28 , haloalkyl, aryl, heteroaryl, heterocyclic, bicyclic and cycloalkyl; wherein each R 25 The group is optionally substituted by 1, 2, 3 or 4 independently selected R 12 The group substitution;

[0900] 173. The compound of any one of embodiments 106-172, wherein R 40 is selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, cyano, haloalkyl, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; wherein each R 40 The group is optionally substituted by 1, 2, 3 or 4 independently selected R 12 substituted by a group.

[0901] 174. The compound of embodiment 173, wherein R 40 Not replaced.

[0902] 175. The compound of embodiment 1, wherein the compound is selected from:

[0903]

[0904]

[0905]

[0906] or a pharmaceutically acceptable salt thereof.

[0907] 176. The compound of embodiment 1, wherein the compound is selected from Table 2 or a pharmaceutically acceptable salt thereof.

[0908] 177. The compound of embodiment 1, wherein the compound has the structure or a pharmaceutically acceptable salt thereof.

[0909] 178. The compound of embodiment 1, wherein the compound has the structure or a pharmaceutically acceptable salt thereof.

[0910] 179. The compound of embodiment 1, wherein the compound has the structure or a pharmaceutically acceptable salt thereof.

[0911] 180. The compound of embodiment 1, wherein the compound has the structure or a pharmaceutically acceptable salt thereof.

[0912] 181. The compound of embodiment 1, wherein the compound has the structure or a pharmaceutically acceptable salt thereof.

[0913] 182. In certain embodiments, a pharmaceutical composition is provided comprising a compound according to any one of embodiments 1-181 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0914] 183. In certain embodiments, a method of treating a disease mediated by cereblon in a human is provided, comprising administering to a human in need thereof an effective dose of a compound of any one of embodiments 1-181 or a pharmaceutically acceptable salt or composition thereof.

[0915] 184. The method of embodiment 183, wherein the disease is mediated by Ikaros or Aiolos.

[0916] 185. The method of embodiment 183 or 184, wherein the disease is cancer.

[0917] 186. The method of embodiment 183 or 184, wherein the disease is a tumor.

[0918] 187. The method of embodiment 183 or 184, wherein the disease is an immune, autoimmune or inflammatory disorder.

[0919] 188. The method of embodiment 183 or 184, wherein the disease is a hematological malignancy.

[0920] 189. The method of embodiment 183 or 184, wherein the disease is multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma.

[0921] 190. In certain embodiments, a compound is provided for the preparation of a medicament for treating a cereblon-mediated disease in a human, wherein the compound is selected from any one of Embodiments 1-181 or a pharmaceutically acceptable salt or composition thereof.

[0922] 191. Use of a compound according to embodiment 190, wherein the disease is mediated by Ikaros or Aiolos.

[0923] 192. Use of a compound according to embodiment 190 or 191, wherein the disease is cancer.

[0924] 193. Use of a compound according to embodiment 190 or 191, wherein the disease is a tumor.

[0925] 194. Use of a compound according to embodiment 190 or 191, wherein the disease is an immune, autoimmune or inflammatory disorder.

[0926] 195. Use of a compound according to embodiment 190 or 191, wherein the disease is a hematological malignancy.

[0927] 196. Use of a compound according to embodiment 190 or 191, wherein the disease is multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0928] 197. In certain embodiments, there is provided a use of a compound for treating a cereblon-mediated disease in a human, wherein the compound is selected from any one of embodiments 1-181 or a pharmaceutically acceptable salt or composition thereof.

[0929] 198. The use of embodiment 197, wherein the disease is mediated by Ikaros or Aiolos.

[0930] 199. The use of embodiment 197 or 198, wherein the disease is cancer.

[0931] 200. The use according to embodiment 197 or 198, wherein the disease is a tumor.

[0932] 201. The use of embodiment 197 or 198, wherein the disease is an immune, autoimmune or inflammatory disorder.

[0933] 202. The use of embodiment 197 or 198, wherein the disease is a hematological malignancy.

[0934] 203. The use of embodiment 197 or 198, wherein the disease is multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0935] III. Treatment Methods

[0936] Any of the compounds described herein can be used to treat a host in need thereof, including a human, in an effective amount, optionally in a pharmaceutically acceptable carrier to treat any of the conditions described herein. In certain embodiments, the method comprises administering an effective amount of an active compound as described herein or a salt thereof, optionally comprising a pharmaceutically acceptable excipient, carrier or adjuvant (i.e., a pharmaceutically acceptable composition), optionally in combination or alternating with other therapeutically active agents or combinations of agents.

[0937] In one embodiment, the compounds of the invention selectively degrade IKZF1 and / or IKZF3 over one or more of IKZF2 and / or IKZF4 and / or IKZF5.

[0938] In one embodiment, the compounds of Formula I are used to treat the conditions described herein.

[0939] In one embodiment, the compound of Formula II is used to treat the conditions described herein.

[0940] In one embodiment, the compounds of Formula Ia are used to treat the conditions described herein.

[0941] In one embodiment, the compound of Formula Ib is used to treat the conditions described herein.

[0942] In one embodiment, the compound of Formula Ic is used to treat the conditions described herein.

[0943] In one embodiment, the compound of Formula Id is used to treat a condition described herein.

[0944] In one embodiment, the compounds of Formula Ie are used to treat the conditions described herein.

[0945] In one embodiment, the compound of Formula If is used to treat the conditions described herein.

[0946] In one embodiment, the compound of Formula Ig is used to treat the conditions described herein.

[0947] In one embodiment, the condition treated by the compounds of this invention is an immunomodulatory condition. In one embodiment, the condition treated by the compounds of this invention is mediated by angiogenesis. In one embodiment, the condition treated by the compounds of this invention is related to the lymphatic system.

[0948] In one embodiment, a pharmaceutically acceptable salt of a compound of the invention, optionally in a pharmaceutical composition as described herein, is used to degrade Ikaros or Aiolos, which is a mediator of a condition affecting a patient, such as a human. The control of protein levels provided by any of the compounds of the invention provides treatment for a disease state or condition that is regulated via Ikaros or Aiolos by reducing protein levels in a cell (e.g., a patient's cell) or by reducing the level of a downstream protein in the cell. In certain embodiments, the method comprises administering an effective amount of a compound as described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant (i.e., a pharmaceutically acceptable composition), optionally in combination or alternating with other therapeutically active agents or combinations of agents.

[0949] In one embodiment, the compounds of the present invention are used to treat disorders including, but not limited to, benign growths, neoplasms, tumors, cancers, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid-based proteinopathies, proteinopathies, or fibrotic diseases.

[0950] The term "disease state" or "condition," when used in connection with any compound, refers to any disease state or condition mediated by Ikaros or Aiolos, such as cell proliferation, or any disease state or condition mediated by proteins downstream of Ikaros or Aiolos, and in which degradation of such proteins in a patient provides beneficial treatment or relief of symptoms to the patient in need thereof. In some cases, the disease state or condition can be cured.

[0951] In one embodiment, the compounds as described herein or their corresponding pharmaceutically acceptable salts, isotopic derivatives or prodrugs can be used in an effective amount to treat a host, such as a human, suffering from a lymphoma or a lymphocyte or myeloid cell proliferative disorder or abnormality. For example, the compounds described herein can be administered to a host suffering from Hodgkin's lymphoma or non-Hodgkin's lymphoma. For example, the subject may have a non-Hodgkin lymphoma, such as, but not limited to, AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK-cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small non-cleaved 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 gamma-delta 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; therapy-related T-cell lymphoma; Langerhans cell histiocytosis; or Waldenstrom's macroglobulinemia.

[0952] In another embodiment, a compound as described herein, or a corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, can be used in an effective amount to treat a host, such as a human, suffering from Hodgkin lymphoma, such as, but not limited to, tuberous sclerosis classical Hodgkin lymphoma (CHL); mixed cell CHL; lymphocyte-depleted CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin lymphoma; or nodular lymphocyte-predominant HL.

[0953] In another embodiment, the compounds as described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in an effective amount to treat a host, such as a human, suffering from an immunomodulatory disorder. 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.

[0954] In certain embodiments, the conditions treated with the compounds of the present invention are conditions associated with abnormal cell proliferation. Abnormal cell proliferation, particularly hyperproliferation, can be caused by a variety of factors, including genetic mutations, infection, exposure to toxins, autoimmune diseases, and induction of benign or malignant tumors.

[0955] Abnormal proliferation of B cells, T cells and / or NK cells can lead to a variety of diseases, such as cancer, proliferative diseases and inflammatory / immune diseases. A host, such as a human, suffering from any of these conditions can be treated with an effective amount of a compound as described herein to achieve a reduction in symptoms (palliatives) or a reduction in the underlying disease (disease modifiers).

[0956] In one embodiment, the compounds as described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in an effective amount to treat a host, such as a human, having a specific B-cell lymphoma or proliferative disease, which specific B-cell lymphoma or proliferative disease is 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; nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; hairy cell leukemia; splenic lymphoma / leukemia, unclassifiable; splenic diffuse red pulp small B-cell lymphoma; hairy cell leukemia; variant of leukemia; lymphoplasmacytic lymphoma; heavy chain diseases, such as alpha heavy chain disease, gamma heavy chain disease, and mu heavy chain disease; plasma cell myeloma; solitary plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicle center lymphoma; T cell / histiocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL, leg type; ALK+ large B-cell lymphoma; plasmablastic lymphoma; HHV8-associated multicentric large B-cell lymphoma; Castleman 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.

[0957] In one embodiment, the compounds as described herein or their corresponding pharmaceutical salts, isotopic derivatives or prodrugs can be used in an effective amount to treat a host, such as a human, with a T cell or NK cell lymphoma, such as 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 lymphoma, such as mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T cell lymphoproliferative disease; primary cutaneous aggressive epidermotropic CD8+ cytotoxic T cell lymphoma; primary cutaneous gamma-delta T cell lymphoma; primary cutaneous small / medium CD4+ T cell lymphoma; tumours and lymphomatoid papulosis; adult T-cell leukemia / lymphoma (ATLL); blastic NK-cell lymphoma; enteropathy-type T-cell lymphoma; hematosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; nasal NK / T-cell lymphoma; therapy-related T-cell lymphomas, such as those arising after 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; systemic EBV+ T-cell lymphoproliferative disorder of childhood (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.

[0958] In one embodiment, the compounds as described herein or their corresponding pharmaceutically acceptable salts, isotopic derivatives or prodrugs can be used to treat a host, such as a human, suffering from leukemia. For example, the host may have an acute or chronic leukemia of lymphocyte or bone marrow origin, such as, but not limited to: acute lymphocytic 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 lymphocytic leukemia; or adult T-cell chronic leukemia. In one embodiment, the patient has acute myeloid leukemia, such as undifferentiated AML (M0); myeloblastic leukemia (M1; with / without minimal 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); erythrocytic leukemia (M6); or megakaryocytic leukemia (M7).

[0959] There are many skin diseases associated with excessive cell proliferation. For example, psoriasis is a benign disease of the human skin characterized by patches of skin covered with thickened scales. The disease is caused by an unexplained increase in the proliferation of epidermal cells. Chronic eczema is also associated with significant overproduction of epidermal cells. Other diseases caused by excessive skin cell proliferation include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratoses, basal cell carcinoma, and squamous cell carcinoma.

[0960] Other hyperproliferative cellular disorders include vascular proliferative disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancer.

[0961] Vascular proliferative disorders include angiogenic disorders and angiogenic disorders. The proliferation of smooth muscle cells during plaque formation in vascular tissue leads to, for example, restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[0962] Fibrotic conditions are generally caused by abnormal formation of the extracellular matrix. Examples of fibrotic conditions include cirrhosis and mesangial proliferative cell disorders. Cirrhosis is characterized by an increase in extracellular matrix components, leading to scarring of the liver. Cirrhosis can lead to conditions such as cirrhosis. Increased extracellular matrix leading to liver scarring can also be caused by viral infections such as hepatitis. Fat cells appear to play a major role in cirrhosis.

[0963] Mesangial diseases are caused by abnormal proliferation of mesangial cells. Mesangial hyperproliferative cell diseases include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection, and glomerulopathy.

[0964] Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease that is thought to be associated with the activity of autoreactive T cells and is caused by autoantibodies produced against collagen and IgE.

[0965] Other disorders that may include an abnormal cell proliferation component include Bechet syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and general inflammatory conditions.

[0966] The compounds as described herein, or pharmaceutically acceptable salts, isotopic analogs or prodrugs thereof, can be used in an effective amount to treat a host, such as a human, with a proliferative disease, such as myeloproliferative disease (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), hypereosinophilia (HES), systemic mast cell disease (SMCD), etc. In another embodiment, the compounds provided herein can be used to treat primary myelofibrosis, post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis and secondary acute myeloid leukemia.

[0967] In one embodiment, the compounds as described herein, or pharmaceutically acceptable salts, isotopic analogs or prodrugs thereof, can be used in an effective amount to treat a host, such as a human, with myelodysplastic syndrome (MDS), such as but not limited to: refractory cytopenias with unilineage dysplasia, refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts-thrombocythemia (RARS-t), refractory cytopenias with multilineage dysplasia (RCMD), including RCMD and ringed sideroblasts with multilineage dysplasia (RCMD-RS), refractory amenorrhea with excess blasts I (RAEB-I) and II (RAEB-II), 5q- syndrome, refractory cytopenia in children, etc.

[0968] In one embodiment, the compounds of the invention may provide a therapeutic effect by directly degrading Ikaros or Aiolos, which may alter the transcriptional regulation of proteins downstream of Ikaros or Aiolos.

[0969] The terms "neoplasia" or "cancer" are used to refer to the pathological process that leads to the formation and growth of cancerous or malignant tumors, i.e., abnormal tissue that grows by cell proliferation, usually more rapidly than normal tissue and continues to grow after the stimulus that initiated new growth has ceased. Malignant tumors display 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 and lead to patient death unless adequately treated. As used herein, the term "neoplasia" is used to describe all cancerous disease states and includes or encompasses pathological processes associated with malignant hematogenous, ascites, and solid tumors. Exemplary cancers that may be treated by the compounds of the present invention, alone or in combination with at least one additional anticancer agent, include: squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular and renal cell carcinoma, bladder cancer, intestinal 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 stomach cancer; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, and leukemia. Liposarcoma, myoscoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, 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, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratoma. Other cancers that can be treated using 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, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[0970] Other cancers that can be treated using the compounds disclosed herein include, for example, acute myeloid leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical cancer, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, intestinal cancer, brain cancer, brainstem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of the following are negative), single negative (one of the following are negative), estrogen receptor positive, HER2 negative breast cancer , estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, HER2-negative breast cancer, HER2-positive or -negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, bile duct cancer, 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, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, stomach Intestinal carcinoid, gastrointestinal stromal tumor (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC), colorectal cancer, intrahepatic bile duct cancer, invasive / infiltrating breast cancer, islet cell carcinoma, jaw cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastasis, 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, interstitial Mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic cervical squamous cell carcinoma, mixed glioma, monodermal teratoma, oral cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, fungal disease, myelodysplastic syndrome, nasal cancer, nasopharyngeal cancer, cervical cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cancer, oropharyngeal cancer, osteosarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, primary ovarian peritoneal cancer, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer,Pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineocytoma, pituitary cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, osteosarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cord cancer, spinal cord cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma / thymic cancer, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, 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 lymphocytic leukemia, adult T-cell chronic leukemia, diffuse large B-cell lymphoma, follicular Lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; splenic lymphoma / leukemia, unclassifiable, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, such as alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicle center lymphoma, T cell / histiocyte-rich large B cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymic) large B cell lymphoma; primary cutaneous DLBCL, leg type, ALK + large B cell lymphoma, plasmablastic lymphoma; large B cell lymphoma caused by HHV8-related multicentric, Castleman 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. In one embodiment, the condition is adenoid cystic carcinoma. In one embodiment, the condition is NUT midline carcinoma.

[0971] In another embodiment, the compounds as described herein, or pharmaceutically acceptable salts, isotopic derivatives, or prodrugs thereof, can be used in an effective amount to treat a host, such as a human, suffering from an autoimmune disease. Examples include, but are not limited to, acute disseminated encephalomyelitis (ADEM); Addison's disease; agammaglobulinemia; alopecia areata; amyotrophic lateral sclerosis (also known as Lou Gehrig's disease; motor neuron disease); ankylosing spondylitis; antiphospholipid syndrome; antisynthetase syndrome; atopic allergy; atopic dermatitis; autoimmune aplastic anemia; autoimmune arthritis; autoimmune cardiomyopathy; autoimmune bowel disease; autoimmune granulocytopenia; autoimmune hemolytic anemia; autoimmune hepatitis; autoimmune hypoparathyroidism; autoimmune inner ear disease; autoimmune lymphoproliferative syndrome; autoimmune myocarditis; autoimmune pancreatitis; autoimmune Immune peripheral neuropathy; autoimmune ovarian failure; autoimmune polyendocrine syndrome; autoimmune progestogen-induced dermatitis; autoimmune thrombocytopenic purpura; autoimmune thyroid disease; autoimmune urticaria; autoimmune uveitis; autoimmune vasculitis; Balo disease / Balo concentric sclerosis; Behçet's disease; Berger's disease; Bickerstaff encephalitis; Blau syndrome; bullous pemphigoid; cancer; Castleman's disease; celiac disease; Chagas disease; chronic inflammatory demyelinating polyneuropathy; chronic inflammatory demyelinating polyneuropathy; chronic obstructive pulmonary disease; chronic relapsing multifocal osteomyelitis; Churg-Strauss syndrome; cicatricial pemphigoid; Cogan's syndrome; cold agglutinin disease; complement 2 deficiency; contact dermatitis; cranial arteritis; CREST syndrome; Crohn's disease; Cushing's syndrome; cutaneous leukocytoclastic vasculitis; DeGou disease; Dercum disease; dermatitis herpetiformis; dermatomyositis; type 1 diabetes mellitus; diffuse cutaneous systemic sclerosis; discoid lupus erythematosus; Dressler syndrome; drug-induced lupus; eczema; endometriosis; arthritis associated with enthesitis; eosinophilic fasciitis; eosinophilic gastroenteritis; eosinophilic pneumonia; epidermolysis bullosa; erythema nodosum; erythroblastosis fetalis; essential mixed cryoglobulinemia; Evan's syndrome; extrinsic and intrinsic reactivity Airway disease (asthma); fibrodysplasia ossificans progressiva; fibrosing 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; Henoch-Schonlein purpura; herpes gestationis (pemphigoid gestationis); hidradenitis suppurativa; Hughes-Stowan syndrome; hypogammaglobulinemia; idiopathic inflammatory demyelinating disease; idiopathic pulmonary fibrosis; idiopathic thrombocytopenic purpura; IgA nephropathy; immune glomerulonephritis; immune nephritis; immune pneumonitis; 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 sclerosus; linear IgA disease (LAD); lupus hepatitis (also known as autoimmune hepatitis); lupus erythematosus; Magid syndrome; microscopic polyangiitis; Miller-Fisher syndrome; mixed connective tissue disease; morphea; Mucha-Habermann disease (also known as pityriasis lichenoides, acute pox-like); multiple sclerosis; myasthenia gravis; myositis; Meniere's disease; narcolepsy; neuromyelitis optica (also Devic's disease); neuromyotonia; ocular cicatricial pemphigoid; oculomyoclonic syndrome; Ord's thyroiditis; palindromic rheumatic disease; PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococci); paraneoplastic cerebellar degeneration; paroxysmal nocturnal hemoglobinuria (PNH); Parry-Romberg syndrome; tonsillitis; Parson-Turner syndrome; pemphigus vulgaris; peripheral encephalomyelitis; pernicious anemia; POEMS syndrome; polyarteritis nodosa; polymyositis rheumatica pain; polymyositis; primary biliary cirrhosis; primary sclerosing cholangitis; progressive inflammatory neuropathy; psoriasis; psoriatic arthritis; pure red cell aplasia; pyoderma gangrenosum; Rasmussen encephalitis; Raynaud's phenomenon; Rett's syndrome; relapsing polychondritis; restless legs syndrome; retroperitoneal fibrosis; rheumatic fever; rheumatoid arthritis; sarcoidosis; schizophrenia; Schmidt's syndrome; Schnitzler's syndrome; scleritis; scleroderma; sclerosing cholangitis; serum sickness; Sjögren's syndrome; spondyloarthropathies; stiff person syndrome; Still's disease; subacute myelopathy Acute bacterial endocarditis (SBE); Susac's syndrome; Sweet's syndrome; Sydenham's chorea; sympathetic ophthalmia; systemic lupus erythematosus; Takayasu's arteritis; temporal arteritis (also known as "giant cell arteritis"); thrombocytopenia; Tolosa-Hunt syndrome; transverse myelitis; ulcerative colitis; undifferentiated connective tissue disease; undifferentiated spondyloarthropathy; 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 embodiments, the autoimmune disease is an allergic disease, including those from asthma, food allergies, atopic dermatitis, chronic pain, and rhinitis.

[0972] Skin contact allergies and asthma are just two examples of immune responses that may be associated with significant morbidity. Others include atopic dermatitis, eczema, 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 conjunctivitis, ulcerative conjunctivitis, cutaneous systemic 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, ulcers, pain, scaling, cracking, hair loss, scarring, or drainage involving the skin, eyes, or mucous membranes.

[0973] In atopic dermatitis and eczema in general, immune-mediated infiltration of leukocytes (particularly monocytes, lymphocytes, neutrophils, and eosinophils) into the skin plays an important role in the pathogenesis of these diseases. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Immune-mediated leukocyte infiltration also occurs in sites other than the skin, such as the airways of asthmatics and the tear glands of eyes with keratoconjunctivitis sicca.

[0974] Compounds as described herein or pharmaceutically acceptable salts, isotopic variants or prodrugs thereof can be used in effective amounts to treat a host, such as a human, with a skin disease such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rash, skin irritation, skin allergy (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 topical administration of compounds known in the art in combination with the compounds disclosed herein. In one non-limiting embodiment, the compounds of the present invention are used as topical agents for the treatment of contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjögren's syndrome, including keratoconjunctivitis sicca secondary to Sjögren's syndrome, alopecia areata, allergic 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. The new approach could also be used to reduce skin infiltration by malignant white blood cells in diseases such as fungal infections.

[0975] Disease states in which the compounds according to the present invention can be used to treat disorders include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, 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 2 (PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome.

[0976] Other disease states or conditions that can be treated by the compounds of the present invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorders, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes, type 2 diabetes, epilepsy, Guillain-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette syndrome, vasculitis.

[0977] Other disease states or conditions treatable by the compounds of the present invention include ceruloplasminemia, chondrodysplasia type II, achondroplasia, craniocephaly, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenylate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkali aciduria, Alexander disease, alkali acidosis, alpha 1-antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alexander disease ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity. syndrome, anemic angiokeratoma of the body, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, arachnoid disease (Marfan syndrome), Stickler syndrome, arthrogryposis multiplex (Ehlers-Danlos syndrome # arthrogryposis type), ataxia-telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beare-Stevenson gyricular scalp syndrome, familial Mediterranean fever, Benjamin syndrome, beta-thalassemia, bilateral auditory neurofibromatosis (neurofibromatosis type II), factor VLeiden thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion diseases, Birt-Hogg-Dubé syndrome, brittle bone disease (osteogenesis imperfecta), Rubinstein-Taybi syndrome, bronze diabetes / bronze cirrhosis (hemochromatosis), bulbospinal myopathy Atrophy (Kennedy disease), Berg-Grutz syndrome (lipoprotein lipase deficiency), chronic granulomatous granulomatous disease (CGD), Campomelic dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), meow-like cry, CAVD (congenital absence of the vas deferens), Caylor cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, chondrodystrophy syndrome (achondroplasia), auris hypertrophic epiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia Ehlers-Danlos syndrome, thanatosinosis, 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 cone anemia, thalassemia (beta-thalassemia), copper storage disease (Wilson disease), copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome Syndrome, craniofacial joint disorders (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Beare-Stevenson gyrus syndrome, primary hyperoxaluria, spondylometaphyseal dysplasia (Strudwick type), muscular dystrophy, Duchenne and Becker type (DBMD), Usher syndrome, degenerative neurological diseases, including deGrouchy syndrome and Dejerine-Sottas syndrome, developmental disabilities, distal spinal muscular atrophy, type V, androgen insensitivity syndrome, diffuse glomerulosclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protoporphyria, erythropoietic 5-aminolevulinic acid synthase deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Feldmann's ataxia-familial multiple dysplasia serositis, porphyria cutanea tarda, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), pancreatic fibrocystic disease, fragile X syndrome, galactosemia, hereditary brain disorders, giant cell hepatitis (neonatal hemochromatosis), Gronblad-Strandberg syndrome (pseudoxanthoma elasticum), Gunther disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, hypochondroitinemia, immune system disorders, including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney diseases, including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia, lacunar dementia, Langer-Saldino chondrodysplasia, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders, including Kniest dysplasia, Marfan syndrome, Movement 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, polyostotic fibrodysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary Alzheimer's disease, prion disease, progeria (Hutchinson disease),Gilford progeria syndrome), progressive chorea, chronic hereditary (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen disease (neurofibromatosis type I), relapsing polyserositis, retinal disease, 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 (SBLA) syndrome, tuberous sclerosis (tuberous sclerosis), SDAT, SED congenital (spondyloepiphyseal dysplasia congenita), SED Strudwick (spondyloepiphyseal dysplasia, Strudwick type), SEDc (spondyloepiphyseal dysplasia congenita), SEMD, Strudwick type (cone-metaphysis dysplasia, Strudwick type), Shprintzen syndrome, skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (variegate porphyria), ascending hereditary spastic paralysis of the infantile type, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, giant plaque neuropathy (hereditary neuropathy with pressure palsy), Treacher Collins syndrome, Triplo X syndrome, trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness ( syndrome), Vrolik disease, Waardenburg syndrome, WarburgSjo Fledelius syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disease, Weissenbacher-Zweymüller syndrome and xeroderma pigmentosum, etc.

[0978] In one embodiment, a method for treating multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition to treat multiple myeloma. In another embodiment, a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, is used in a method for treating multiple myeloma, wherein the method comprises administering the compound to a patient.

[0979] 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 Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition. In another embodiment, a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, is used in a method for controlling the progression of multiple myeloma, wherein the method comprises administering the compound to a patient.

[0980] In one embodiment, a method of inducing a therapeutic response in a patient with multiple myeloma as assessed by the International Uniform Response Criteria for Multiple Myeloma (IURC) (described in Durie BGM et al., "International Uniform Response Criteria for Multiple Myeloma," Leukemia 2006, 10(10): 1-7) is provided, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0981] In another embodiment, a method is provided for achieving a stringent complete response, a complete response, or a very good partial response as assessed by the IURC for multiple myeloma in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0982] In another embodiment, a method is provided for increasing overall survival, progression-free survival, event-free survival, time on treatment, or disease-free survival in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0983] In another embodiment, a method of achieving increased overall survival in a patient with multiple myeloma is provided, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0984] In another embodiment, a method for achieving increased progression-free survival in a patient with multiple myeloma is provided, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0985] In another embodiment, a method for achieving increased event-free survival in a patient with multiple myeloma is provided, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0986] In another embodiment, a method of achieving increased time to progression in a patient with multiple myeloma is provided, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0987] In another embodiment, a method for achieving increased disease-free survival in a patient with multiple myeloma is provided, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0988] Methods of treating patients who have been previously treated for multiple myeloma but have not responded to standard therapy are provided, in addition to patients who have not received prior treatment. Methods of treating patients who have undergone surgery in an attempt to treat multiple myeloma are provided, in addition to patients who have not received surgery. Methods of treating patients who have previously received a transplant are provided, in addition to patients who have not received a transplant.

[0989] 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, three times, four times or five times relapsed. In one embodiment, the compounds described herein can be used to reduce, maintain or eliminate minimal residual disease (MRD).

[0990] 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 newly diagnosed low-risk, intermediate-risk, or high-risk multiple myeloma); transplant-eligible and transplant-ineligible multiple myeloma; 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-secretory myeloma; immunoglobulin D myeloma; and immunoglobulin E myeloma.

[0991] In some embodiments, the compounds described herein can be used to treat or manage multiple myeloma characterized by a genetic abnormality, such as, but not limited to, a cyclin D translocation (e.g., t(11;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32); or t(6;20);); an MMSET translocation (e.g., t(4;14)(p16;q32); a MAF translocation (e.g., t(14;16)(q32;a32); t(20;22); t(16;22)(q11;q13); or t(14;20)(q32;q11); or other chromosomal factors (e.g., 17p13 or deletion of chromosome 13; del(17 / 17p), non-hyperdiploidy, and gain(1q)).

[0992] In one embodiment, a method for treating or managing multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, as an induction therapy.

[0993] In one embodiment, a method for treating or managing multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable form as a carrier composition, as a consolidation therapy.

[0994] In one embodiment, a method for treating or managing multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable form as a carrier composition, as a maintenance therapy.

[0995] In one embodiment, the multiple myeloma is a plasma cell leukemia.

[0996] In one embodiment, the multiple myeloma is high-risk multiple myeloma. In some embodiments, the high-risk multiple myeloma is relapsed or refractory. In one embodiment, the high-risk multiple myeloma relapses within 12 months of the first treatment. In another embodiment, the high-risk multiple myeloma is characterized by genetic abnormalities, 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 therapies.

[0997] In one embodiment, the multiple myeloma has a p53 mutation. In one embodiment, the p53 mutation is a Q331 mutation. In one embodiment, the p53 mutation is an R273H mutation. In one embodiment, the p53 mutation is a K132 mutation. In one embodiment, the p53 mutation is a K132N mutation. In one embodiment, the p53 mutation is an R337 mutation. In one embodiment, the p53 mutation is an R337L mutation. In one embodiment, the p53 mutation is a W146 mutation. In one embodiment, the p53 mutation is an S261 mutation. In one embodiment, the p53 mutation is an S261T mutation. In one embodiment, the p53 mutation is an E286 mutation. In one embodiment, the p53 mutation is an E286K mutation. In one embodiment, the p53 mutation is an R175 mutation. In one embodiment, the p53 mutation is an R175H mutation. In one embodiment, the p53 mutation is an E258 mutation. In one embodiment, the p53 mutation is an E258K mutation. In one embodiment, the p53 mutation is an A161 mutation. In one embodiment, the p53 mutation is an A161T mutation.

[0998] In one embodiment, the multiple myeloma has a homozygous deletion of p53. In one embodiment, the multiple myeloma has a homozygous deletion of wild-type p53. In one embodiment, the multiple myeloma has wild-type p53.

[0999] In one embodiment, multiple myeloma shows activation of one or more oncogenic drivers. In one embodiment, one or more oncogenic drivers are selected from the group consisting of C-MAF, MAFB, FGFR3, MMset, cyclin D1, and cyclin D. In one embodiment, multiple myeloma shows activation of C-MAF. In one embodiment, multiple myeloma shows activation of MAFB. In one embodiment, multiple myeloma shows activation of FGFR3 and MMset. In one embodiment, multiple myeloma shows activation of C-MAF, FGFR3, and MMset. In one embodiment, multiple myeloma shows activation of cyclin D1. In one embodiment, multiple myeloma shows activation of MAFB and cyclin D1. In one embodiment, multiple myeloma shows activation of cyclin D.

[1000] In one embodiment, the multiple myeloma has one or more chromosomal translocations. In one embodiment, the chromosomal translocation is t(14;16). In one embodiment, the chromosomal translocation is t(14;20). In one embodiment, the chromosomal translocation is t(4;14). In one embodiment, the chromosomal translocations are t(4;14) and t(14;16). In one embodiment, the chromosomal translocation is t(11;14). In one embodiment, the chromosomal translocation is t(6;20). In one embodiment, the chromosomal translocation is t(20;22). In one embodiment, the chromosomal translocation is t(6;20) and t(20;22). In one embodiment, the chromosomal translocation is t(16;22). In one embodiment, the chromosomal translocation is t(14;16) and t(16;22). In one embodiment, the chromosomal translocation is t(14;20) and t(11;14).

[1001] In one embodiment, the multiple myeloma has a Q331 p53 mutation, activation of C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, the multiple myeloma has a homozygous deletion of p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, the multiple myeloma has a K132N p53 mutation, activation of MAFB, and a chromosomal translocation at t(14;20). In one embodiment, the multiple myeloma has wild-type p53, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, the multiple myeloma has wild-type p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, the multiple myeloma has a homozygous deletion of p53, activation of FGFR3, MMset, and C-MAF, and a chromosomal translocation at t(4;14) and t(14;16). In one embodiment, the multiple myeloma has a homozygous deletion of p53, activation of cyclin D1, and a chromosomal translocation at t(11;14). In one embodiment, the multiple myeloma has a R337L p53 mutation, activation of cyclin D1, and a chromosomal translocation at t(11;14). In one embodiment, the multiple myeloma has a W146 p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, the multiple myeloma has a S261T p53 mutation, activation of MAFB, and chromosomal translocations at t(6;20) and t(20;22). In one embodiment, the multiple myeloma has an E286K p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, the multiple myeloma has a R175H p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, the multiple myeloma has an E258K p53 mutation, activation of C-MAF, and chromosomal translocations at t(14;16) and t(16;22). In one embodiment, 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 one embodiment, the multiple myeloma has an A161T p53 mutation, activation of cyclin D, and a chromosomal translocation at t(11;14).

[1002] In some embodiments, the multiple myeloma is a newly diagnosed multiple myeloma that is suitable for transplantation. In other embodiments, the multiple myeloma is a newly diagnosed multiple myeloma that is not suitable for transplantation.

[1003] In some embodiments, multiple myeloma shows early progression (e.g., less than 12 months) after initial treatment. In other embodiments, multiple myeloma shows early progression (e.g., less than 12 months) after autologous stem cell transplantation. In another embodiment, multiple myeloma is refractory to lenalidomide. In another embodiment, multiple myeloma is refractory to pomalidomide. In some such embodiments, multiple myeloma is predicted to be refractory to pomalidomide (e.g., by molecular characterization). In another embodiment, multiple myeloma is refractory to 3 or more relapses or treatments and is exposed to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib) and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, ibrolimumab, or avadomide), or has dual resistance to a proteasome inhibitor and an immunomodulatory compound.

[1004] In other embodiments, the multiple myeloma is relapsed or refractory to three or more prior therapies, including, for example, a CD38 monoclonal antibody (CD38mAb, such as daratumumab or isetuximab), a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iberdolimide, or avadomide), or is double resistant to a proteasome inhibitor or immunomodulatory compound and a CD38mAb. In other embodiments, the multiple myeloma is triple refractory, e.g., the multiple myeloma is refractory to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib), an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iberdolimide, or avadomide), and one other active agent, as described herein.

[1005] In one embodiment, a method for treating or managing relapsed or refractory multiple myeloma in a patient with impaired renal function or symptoms thereof is provided, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[1006] In another embodiment, a method for treating or managing relapsed or refractory multiple myeloma in a frail patient is provided, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, wherein the frail patient is characterized by being unsuitable for induction therapy or intolerant to dexamethasone treatment. In other embodiments, the frail patient is an elderly person, e.g., older than 65 years old.

[1007] In another embodiment, a method for treating or managing fourth-line relapsed or refractory multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[1008] In another embodiment, a method for treating or managing newly diagnosed, transplant-unsuitable multiple myeloma is provided, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[1009] In another embodiment, a method for treating or managing newly diagnosed multiple myeloma that is not suitable for transplantation is provided, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, as an additional therapy or maintenance therapy after transplantation.

[1010] In another embodiment, a method for treating or managing high-risk multiple myeloma that has relapsed or is refractory to one, two or three prior therapies is provided, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[1011] 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, wherein the therapy is selected from a CD38 antibody (CD38mAB, such as daratumumab or isatuximab), a proteasome inhibitor (such as bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (such as thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide).

[1012] Regardless of the patient's age, the compounds described herein can be used to treat the patient. 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 less than 65 years of age. In other embodiments, the patient is over 65 years of age. In one embodiment, the patient is an elderly multiple myeloma patient, such as a patient over 65 years of age. In one embodiment, the patient is an elderly multiple myeloma patient, such as a patient over 75 years of age.

[1013] IV. Combination Therapy

[1014] Any of the compounds described herein may be used alone or in combination in an effective amount to treat a host, such as a human, suffering from a condition described herein.

[1015] The term "biologically active agent" or "other therapeutically active agent" is used to describe an agent, other than a compound according to the present invention, that can be used in combination or alternation with a compound according to the present invention to achieve a desired therapeutic outcome. In one embodiment, the compound according to the present invention and the other therapeutically active agent are administered in such a manner that they are active in vivo over overlapping time periods, e.g., have overlapping time periods for Cmax, Tmax, AUC, or other pharmacokinetic parameters. In another embodiment, the compound according to the present invention and the other therapeutically active agent are administered to a host in need thereof that do not have overlapping pharmacokinetic parameters, however, one has a therapeutic impact on the therapeutic efficacy of the other.

[1016] In one aspect of this embodiment, other therapeutic active agents are immunomodulators, including but not limited to checkpoint inhibitors, including as non-limiting examples PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V domain Ig inhibitors (VISTA) inhibitors of T cell activation, small molecules, peptides, nucleotides or other inhibitors. In some aspects, immunomodulators are antibodies, such as monoclonal antibodies.

[1017] PD-1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor and thereby inhibit immunosuppression include, 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 Incyrote Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor and thereby inhibiting immunosuppression include, for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibit immunosuppression include, but are not limited to, ipilimumab, tremelimumab (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 dual PD-1 and LAG-3 inhibitors MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro). In one embodiment, PD-1 inhibitors are BGB-A317. In one embodiment, PD-L1 inhibitors are MED14736. In one embodiment, PD-L2 inhibitors are rHIgM12B7A.

[1018] In one embodiment, the checkpoint inhibitor is a B7 inhibitor, such as a B7-H3 inhibitor or a B7-H4 inhibitor. In one embodiment, the B7-H3 inhibitor is MGA271.

[1019] In one embodiment, the checkpoint inhibitor is an OX40 agonist. In one embodiment, the checkpoint inhibitor is an anti-OX40 antibody, such as anti-OX-40 or MEDI6469.

[1020] In one embodiment, the checkpoint inhibitor is a GITR agonist. In one embodiment, the GITR agonist is an anti-GITR antibody, such as TRX518.

[1021] In one embodiment, the checkpoint inhibitor is a CD137 agonist. In one embodiment, the CD137 agonist is an anti-CD137 antibody, such as PF-05082566.

[1022] In one embodiment, the checkpoint inhibitor is a CD40 agonist. In one embodiment, the CD40 agonist is an anti-CD40 antibody, such as CF-870,893.

[1023] In one embodiment, the checkpoint inhibitor is an IDO inhibitor, such as INCB24360 or indoximod.

[1024] In another embodiment, the active compounds described herein can be combined or alternately administered with an effective amount of an androgen (e.g., testosterone) inhibitor to treat abnormal tissues of the male reproductive system such as prostate cancer or testicular cancer, and the inhibitor includes but is not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist. In one embodiment, prostate cancer or testicular cancer is androgen-resistant. Non-limiting examples of anti-androgen compounds are provided in WO2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Other non-limiting examples of anti-androgen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topiramide, abiraterone acetate, and cimetidine.

[1025] In one embodiment, the other therapeutically active 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 AP2611.

[1026] In one embodiment, the other therapeutically active agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso), omatinib (Olita), nagutinib (ASP8273), nazartinib (EGF8756), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; P B272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ-8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer).

[1027] In one embodiment, the other therapeutically active agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab-emtansine, and pertuzumab.

[1028] In one embodiment, the other therapeutically active agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, ofatumumab, ibritumomab tiuxetan, tositumomab, and omeprazole.

[1029] In one embodiment, the other therapeutically active agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasotinib.

[1030] In one embodiment, the other therapeutically active agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include: venetoclax, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-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), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazine -1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylthiobutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263 ((R)-4-(4-((4'-chloro-4,4-dimethyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl]sulfonylbenzamide) acyl)phenyl)sulfonyl)benzamide), GX15-070 (obaklavamethanesulfonate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl)-1H-pyrrol-2-yl)methylene]-4-methoxypyrrol-2-ylidene]indole; methanesulfonic acid), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), pogosin, ethyl 2-amino-6-bromo-4-(1 -cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylic acid ethyl ester, 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, gambogic acid, or G3139 (Oblimersen).

[1031] In one embodiment, the other therapeutically active agent is a kinase inhibitor. In one embodiment, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.

[1032] Examples of PI3 kinase inhibitors include, but are not limited to, wortmannin, demethoxyvirin, perifosine, idelalisib, Pictilisib, Palomid 529, ZSTK 474, PWT 33597, CUDC-907 and AEZS-136, duvelisib, GS-9820, BKM 120, GDC-0032 (Taselisib) (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine -9-yl]pyrazol-1-yl]-2-methylpropionamide), MLN-1117 ((2R)-1-phenoxy-2-butyryl hydrogen (S)-methylphosphonate; or methyl (oxo){[(2R)-1-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-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolyl]-3-pyridinyl}benzenesulfonamide) (omipalisib), TGX-221 ((±) -7-methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[l,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-hydroxypropan-1-one), GS- 1101 (5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin), AS252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z) -ylidene]-thiazolidine-2,4-dione), CZ24832 (5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), Buparlisib (5-[2,6-di(4-morpholinyl))-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chroman-2)-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecanoate), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[ 4-(4,6-di-4-morpholino-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)quinoxaline)2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 ( 5-[[4-(4-pyridyl)-6-quinolyl]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-hexahydroindeno[4,5h]isochroman-10-yl]acetate (also known as sonolisib)), LY294002, AZD8186, PF-4989216, pilaralisib , GNE-317, PI-3065, PI-103(KU8-75), HS173, 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) and the structures described in WO2014 / 071109.

[1033] 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, which is incorporated herein in its entirety), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide], LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-isobromophenyl)acrylamide), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl CGI-5604-(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-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774 (4-(4-((4-( (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 Pharmaceutical), 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-acryloylindol-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-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-isoquinolin-1-one), as well as other molecules capable of inhibiting BTK activity, such as those disclosed by Akinleye et al. in Journal of Hematology & Oncology, 2013, 6:59, the entire contents of which are incorporated herein by reference.

[1034] Syk inhibitors include, for example, cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fostamatinib ([6-({5-fluoro-2-[(3,4,5)-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazepine -4-yl] dihydrogen phosphate), fostamatinib 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]oxazepine -4(3H)-yl)methyl phosphate), BAY61-3606 (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-carboxylic acid amide), imatinib (Gleev ac; 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1-(tert-butyl)-3-(4- PRT-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)-4-(m-tolylamino)pyrimidine-5-carboxamide R112 (3,3'-((5-fluoropyrimidine-2,4-diyl)bis(azanediyl))biphenol), 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]oxazepine -3(4H)-one), piceatannol (3-hydroxyresveratrol), YM193306 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), Compound D (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors (Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors), J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), PRT060318 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), luteolin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), apigenin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors (Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors), J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors (Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors), J. Med. Chem.2012, 55, 3614-3643, incorporated herein in its entirety), fisetin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), myricetin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), morin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), Kinase (SYK) Inhibitors (Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors), J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety).

[1035] In one embodiment, the other therapeutically active agent is a MEK inhibitor. MEK inhibitors are well known and include, for example, trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroaniline)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pim asertib / AS703026 / MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol), refametinib / 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-dihydroxypropyloxy]-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 / A RRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-(3-oxo-1,2-oxazepine alkyl-2-yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX02189, BIX02188, binimetinib, SL-327, TAK-3183, PD318088.

[1036] In one embodiment, the other therapeutically active 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), Sorafenib Tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide; 4-methylbenzenesulfonate), AZ628 (3- (2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-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)phenyl]benzamide) )-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-bromoaldimine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), sorafenib oxide (4-[4-[[[[4-chloro [-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-picolinamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120 and GX818 (Encorfenib).

[1037] In one embodiment, the other therapeutically active agent is an AKT inhibitor, including but not limited to MK-2206, GSK690693, perifosine (KRX-0401), GDC-0068, triciribine, AZD5363, honokiol, PF-04691502 and miltefosine; a FLT-3 inhibitor, including but not limited to P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tandutinib (MLN518), ENMD-2076 and KW-2449, or a combination thereof.

[1038] In one embodiment, the other therapeutically active agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, defostiolimus, sirolimus, and rapamycin. Examples of MEK inhibitors include, but are not limited to, tametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinob (6-(4-bromo-2-chloroaniline)-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 (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol) (cobimetinib), refametinib / BAY869766 / RDEA119 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-032590 1(N-[(2R)-2,3-dihydroxypropyloxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162(5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766(3- [[3-fluoro-2-(methylsulfamoylamino)-4-pyridinyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazin-2yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).

[1039] In one embodiment, the other therapeutically active agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12DLODER.

[1040] In one embodiment, the other therapeutically active agent is a HSP inhibitor.HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and radix sclerotin.

[1041] Other biologically active compounds include, for example, everolimus, trabectedin, nab-paclitaxel, TLK286, AV-299, DN-101, pazopanib, GSK690693, RTA744, ON0910 sodium, AZD6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD1152, 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, Ma P-kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, panitumumab, amrubicin, ogofollumab, Lep-ETU, nolatrexed, AZD2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitenecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio-111, 131-I-TM-601, ALT-110, BIO140, CC8490, cilengitide, gimatecan, IL13-PE38QQR, INO1001, IPdR1, KRX-0402, Lucanthone, LY317615, neuradiab, vitespan, RTA744, Sdx102, talampanel, atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposomal Doxorubicin, 5'-Deoxy-5-fluorouridine, Vincristine, Temozolomide, ZK-304709, Seliciclib; PD0325901, AZD-6244, Capecitabine, 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, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperidinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprorelin acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide,Nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafartnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, anacrilin, anagrelide, L-asparaginase, Bacillus Calmette-Guérin (BCG) , doxorubicin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, daunorubicin, ifosfamide, imatinib, leuprorelin, levamisole, lomustine, ketamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, prucaloprine lindane, profil sodium, procarbazine, raltitrexed, rituximab, streptozotocin, teniposide, testosterone, thalazine, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, hexamethylmelamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, endostatin, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD1 21974, interleukin-12, IM862, angiostatin, vitaxol, droloxifene, idoxifene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin, gefitinib, bortezine, paclitaxel, paclitaxel without hydrogenated castor oil, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pinzazolidine, ERA-923, azooxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin,ZM336372, L-779,450, PEG-filgrastim, adabepoetin, erythropoietin, granulocyte colony-stimulating factor, zolamdronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol acetate, immune globulin, nitrogen mustard, methylprednisolone, irinotecan Motuzumab, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, edidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, toposetron, pegfilgrastim, erythropoietin, epoetin alfa, darbetin alfa, and mixtures thereof.

[1042] In one embodiment, the other therapeutically active agent is selected from but not limited to: imatinib mesylate Dasatinib Nilotinib Bosutinib Trastuzumab Trastuzumab-DM1, pertuzumab (Perjeta™), lapatinib Gefitinib Erlotinib Cetuximab Panitumumab Vandetanib Vemurafenib Vorinostat Romidepsin Bexarotene Alitretinoin retinoic acid Carfilzomib (Kyprolis™), pralatrexate Bevacizumab, aflibercept Sorafenib Sunitinib Pazopanib Regorafenib and cabozantinib (Cometriq™).

[1043] In certain aspects, the other therapeutically active agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, another therapeutic agent, or an immunosuppressant.

[1044] Suitable chemotherapeutic additional therapeutic agents include, but are not limited to, radioactive molecules, toxins (also known as cytotoxins or cytotoxic agents), which include any agent that is detrimental to cell viability, and liposomes or other carriers containing chemotherapeutic compounds. Conventional anticancer drugs include: vincristine Liposomal vincristine Daunorubicin (daunorubicin or ) or doxorubicin Cytarabine (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 (Decadron), imatinib Dasatinib Nilotinib Bosutinib and ponatinib (Iclusig TMExamples of other suitable chemotherapeutic agents include, but are not limited to, 1-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, doxorubicin, aldesleukin, alkylating agents, allopurinol sodium, atropine, amifostine, anastrozole, anthraquinone (AMC), antimitotic agents, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, BCG active (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, bleomycin calcium, calicheamicin, capecitabine, carboplatin, lomustine (C CNU), carmustine (BSNU), chloramphenicol, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, cyclothosphamide, cyclophosphamide, cytarabine, cytarabine, cytochalasin B, dacarbazine, dactinomycin, daunorubicin hydrochloride, daunorubicin citrate, denileukin toxin, dexrazoxane, dibromide mannitol, dihydroxyanthraquinone, docetaxel, dolasetron mesylate, doxorubicin hydrochloride, dronabinol, Escherichia coli L-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol, estralimus Sodium phosphate, ethidium bromide, ethinyl estradiol, etidronate sodium, etoposide citrate, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine hydrochloride, glucocorticoids, goserelin acetate, gramicidin D, granisetron hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, interferon alpha-2b, irinotecan hydrochloride, letrozole, folinic acid calcium, leuprorelin acetate, levamisole hydrochloride, lidocaine, lomustine, maytansine, mechlorethamine hydrochloride, medroxyprogesterone acetate, megestrol acetate, melphalan hydrochloride, mercaptopurine, mesna, methotrexate, methyltestosterone Ketone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron hydrochloride, paclitaxel, pamidronate disodium, pentostatin, pilocarpine hydrochloride, pirlimycin, polyphenprosin 20 with carmustine implant, profil sodium, procaine, procarbazine HCL, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, tacozolin, teniposide, tenoposide, testolactone, tetracaine, thiopental chlorambucil, thioguanine, thiotepa, topotecan hydrochloride, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[1045] Other therapeutic agents that can be administered in combination with the degraders disclosed herein may include: bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasteride, vatalanib, vandetanib, aflibercept, volociximab, elasizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, fentolimumab, atatuzumab, Xipu, rituximab, alemtuzumab, aldesleukin, atelizumab, tocilizumab, temsirolimus, everolimus, rucamumab, datuzumab, HLL1, huN901-DM1, atilimod, natalizumab, bortezomib, carfilzomib, marizomib, tadalafil, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat, mapatumumab, lexalimumab, dulalemin, ABT-737, oblimersen, plitiktide, tapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), pomacicillin (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necituzumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

[1046] In one embodiment, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to antibodies naturally produced by B cells, these MAbs 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 the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cell receptor, thereby preventing the signaling that leads to the growth of new blood vessels. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets the human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal pro-growth signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells.

[1047] In one aspect of the invention, the other therapeutically active agent is an immunosuppressant. The immunosuppressant may be a calcineurin inhibitor, such as cyclosporine or an ascomycin, such as cyclosporine FK506 (tacrolimus), pimecrolimus, mTOR inhibitors such as rapamycin or its derivatives such as sirolimus Everolimus Temsirolimus, zotarolimus, umamiolimus-7, umamiolimus-9, rapamycin analogs such as defostiolimus, azathioprine, Campas 1H, S1P receptor modulators such as fingolimod or its analogs, anti-IL-8 antibodies, mycophenolic acid or a salt thereof, such as the sodium salt, or a prodrug thereof, such as mycophenolate mofetil Prednisone, Buquina sodium, OKT4, T10B9.A-3A, 33B3.1,15-deoxyspergualin, triperimoxazole, leflunomide CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab Daclizumab Imidazolidinone, methotrexate, dexamethasone, ISAtx-247, SDZ ASM981 (pimecrolimus, ), CTLA4lg (abatacept), belatacept, LFA3lg, etanercept (by Immunex Sales), Adalimumab Infliximab Anti-LFA-1 antibody, natalizumab Enmoluzumab, gavimodanconazole, antithymocyte immunoglobulin, ceprizumab, alefacept, efalizumab, pantequinoxaline, mesalamine, ansacrine, codeine phosphate, benzoate, fenbufen, naproxen, diclofenac, etodolac, and indomethacin, aspirin, and ibuprofen.

[1048] In one embodiment, the additional therapy is bendamustine. In one embodiment, the additional therapy is obinutuzumab. In one embodiment, the additional therapy is a proteasome inhibitor, such as ixazomib or oprozomib. In one embodiment, the additional therapy is a histone deacetylase inhibitor, such as ACY241. In one embodiment, the additional therapy is a BET inhibitor, such as GSK525762A, OTX015, BMS-986158, TEN-010, CPI-0610, INCB54329, BAY1238097, FT-1101, ABBV-075, BI894999, GS-5829, GSK1210151A (I-BET-151), CPI-203, RVX-208, XD46, MS436, PFI-1, RVX2135, ZEN3365, XD14, ARV-771, MZ-1, PLX5117, 4-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one, EP11313, and EP11336. In one embodiment, the additional therapy is an MCL-1 inhibitor, such as AZD5991, AMG176, MIK665, S64315, or S63845. In one embodiment, the additional therapy is an LSD-1 inhibitor, such as ORY-1001, ORY-2001, INCB-59872, IMG-7289, TAK-418, GSK-2879552, 4-[2-(4-amino-piperidin-1-yl)-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluoro-benzonitrile, or a salt thereof. In one embodiment, the additional therapy is a CS1 antibody, such as elotuzumab. In one embodiment, the additional therapy is a CD38 antibody, such as daratumumab or isatuximab. In one embodiment, the additional therapy is a BCMA antibody or antibody conjugate, such as GSK2857916 or BI836909.

[1049] In some embodiments, the degraders described herein are combined with one or more cellular immunotherapeutics or administered alternately. In some embodiments, the cellular immunotherapeutics are engineered immune cells. Engineered immune cells include, for example, but not limited to, engineered T cell receptor (TCR) cells and engineered chimeric antigen receptor (CAR) cells. Engineered T cell receptor (TCR) therapy generally involves introducing engineered T cell receptors targeting specific cancer antigens into immune effector cells derived from patients or donors, such as T cells or natural killer cells. Alternatively, chimeric antigen receptor (CAR) therapy generally involves introducing chimeric antigen receptors targeting specific cancer antigens into immune effector cells derived from patients or donors, such as T cells, natural killer cells or macrophages. Compared to TCR, a key advantage of CAR is that they can bind to cancer cells, even if their antigens are not presented on the surface by MHC, which makes more cancer cells vulnerable to attack. However, CAR cells can only recognize antigens that are naturally expressed on the cell surface, so the range of potential antigen targets is smaller than TCR.

[1050] In some embodiments, the immunotherapeutic agent is an engineered TCR or CAR immune cell, wherein the TCR or CAR targets one or more tumor-associated antigens selected from the following: BCMA, an important signaling receptor naturally present on mature B cells, commonly expressed by lymphoma and myeloma cells; CD19, a receptor present on the surface of almost all B cells that can affect their growth, development and activity, commonly expressed by leukemia, lymphoma and myeloma cells; CD22, a receptor predominantly present on the surface of mature B cells, commonly expressed by leukemia and lymphoma cells; CD30, a receptor expressed on certain types of activated immune cells, commonly expressed by leukemia and lymphoma cells; CD33: a receptor expressed on several types of surface receptors found on immune cells, often expressed by leukemia cells; CD56, a protein found on both neurons and natural killer immune cells; CD123 (also known as IL-3R), a receptor found on immune cells involved in proliferation and differentiation, often expressed by leukemia and lymphoma cells; CEA, a protein involved in cell adhesion that is normally produced only before birth and is often abnormally expressed in cancer and may cause metastasis; EBV-related antigens, foreign viral proteins expressed by cancer cells infected with the Epstein-Barr virus (EBV); EGFR, a pathway that controls cell growth and is frequently mutated in cancer; GD2, a pathway that controls cell growth, adhesion, and migration , which is often abnormally overexpressed in cancer cells; GPC3, a cell surface protein thought to be involved in regulating growth and cell division; HER2, a pathway that controls cell growth, is often overexpressed in certain cancers (especially breast cancer) and has been linked to metastasis; HPV-related antigens, foreign viral proteins expressed by cancer cells that develop as a result of infection with the human papillomavirus (HPV); MAGE antigens, the genes that produce these proteins are normally turned off in adult cells but can be reactivated in cancer cells, marking them as abnormal by the immune system; mesothelin, a protein that is often overexpressed in cancer and may contribute to metastasis; MUC-1, a glycoprotein that is often overexpressed in cancer; NY-E SO-1, a protein normally produced only before birth but often aberrantly expressed in cancer; PSCA, a surface protein found on multiple cell types and often overexpressed by cancer cells; PSMA, a surface protein found on prostate cells and often overexpressed by prostate cancer cells; ROR1, a tyrosine kinase-like orphan receptor that is primarily expressed before birth and not in adult tissues but is often aberrantly expressed in cancer and may promote cancer cell metastasis and prevent cancer cell death; WT1, a protein that promotes cancer progression and is aberrantly expressed in cancer patients, particularly those with leukemia; and occludin 18.2, a surface protein overexpressed in certain esophageal cancers and involved in invasion and survival.In some embodiments, the engineered CAR therapy is Axicabtagene ciloleucel. CAR T cell immunotherapy targeting CD19; approved for a subset of lymphoma patients. In some embodiments, the engineered CAR therapy is siliformin. CAR T cell immunotherapy targeting CD19; approved for subsets of leukemia and lymphoma patients. In some embodiments, the engineered CAR therapy is Lisocabtagene maraleucel (Bristol-Myers Squibb Co.): CAR T cell immunotherapy targeting CD19 for the treatment of relapsed / refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL). In some embodiments, the engineered CAR therapy is BCMA CAR-T therapy, such as, but not limited to, JNJ-4528 (Johnson & Johnson) and KITE-585 (Gilead). In some embodiments, the engineered CAR-T therapy is a dual-specific CAR-T targeting BCMA and CD38. In some embodiments, the engineered CAR therapy is CD20 / CD22 dual-targeted CAR-T cell therapy. Compositions and methods for deriving CAR immune cells are described, for example, in U.S. Pat. Nos. 5,359,046 (Cell Genesys); 5,712,149 (Cell Genesys); 6,103,521 (Cell Genesys); U.S. Patent No. 7,446,190 (Memorial Sloan Kettering Cancer Center); U.S. Patent No. 7,446,179 (City of Hope); U.S. Patent No. 7,638,325 (University of Pennsylvania); U.S. Patent No. 8,911,993 (University of Pennsylvania); U.S. Patent No. 8,399,645 (St. Jude Children's Hospital); U.S. Patent No. 8,906,682 (University of Pennsylvania); U.S. Patent No. 8,916,381 (University of Pennsylvania); U.S. Patent No. 8,975,071 (University of Pennsylvania); U.S. Patent No. 9,102,760 (University of Pennsylvania); U.S. Patent No. 9,4644 (University of Pennsylvania) Jude Children's Hospital); U.S. Patent No. 10,266,580 (University of Pennsylvania); U.S. Patent No. 10,189,903 (Seattle Children's Hospital); WO2014 / 011988 (University of Pennsylvania); WO2014 / 145252; WO2014 / 153270 (Novartis); US2018 / 0360880 (Memorial Sloan Kettering Cancer Center); WO2017 / 0243 (Dana-Farber Cancer Institute); WO2016 / 115177 (Juno Therapeutics, Inc.); each of which is incorporated herein by reference.

[1051] In some embodiments, immunotherapy is non-engineered adoptive cell therapy. Adoptive cell therapy is a method for enhancing the ability of the immune system to fight diseases (such as tumors and viral infections). According to this method, immune cells, such as T cells or NK cells, are collected from patients or donors, stimulated in the presence of antigen-presenting cells carrying tumor- or virus-associated antigens, and then amplified in vitro. In some embodiments, adoptive cell therapy is tumor-infiltrating lymphocyte (TIL) therapy, which harvests naturally occurring T cells that have infiltrated patient tumors, which are then activated and amplified and then injected into the patient. In some embodiments, non-engineered adoptive cell therapy includes autologous or allogeneic immune cells, such as αβT cells activated to target multiple potential antigens. A strategy for developing targeted non-engineered T cells involves stimulating patient-derived (autologous) or donor-derived (allogeneic) T cells in vitro by antigen-specificity to carry out ex vivo amplification of T cells. These strategies typically involve the separation of peripheral blood mononuclear cells (PBMC) and exposing cells to one or more tumor-associated antigens. In particular, methods for generating multi-antigen-specific T cells focus on priming and activating T cells with multiple overlapping peptide libraries targeting multiple antigens, such as multiple 15mer peptide libraries overlapping by 11 amino acids, spanning the entire amino acid sequence of several target antigens (see, for example, commercially available overlapping peptide library products from JPT Technologies or Miltenyi).Strategies for activating ex vivo autologous or allogeneic immune effector cells to target tumor-associated antigens are described, for example, in US 2011 / 0182870 (Baylor College of Medicine); US 2015 / 0010519 (Baylor College of Medicine); US 2015 / 0017723 (Baylor College of Medicine); WO 2006026746 (U.S. Government, Department of Health and Human Services); US 2015 / 0044258 (Cell Medicine / Kurr =Therapeutics); WO2016 / 154112 (Children's National Medical Center); WO2017 / 203356 (Queensland Institute of Medical Research); WO2018 / 005712 (Geneius Biotechnology, Inc.); Vara et al., "Accelerated production of antigen-specific T cells for preclinical and clinical applications using gas-permeable rapid expansion culture vessels (G-Rex)," April 2010, Journal of Immunotherapy, 33(3):305-315; Shafer et al., "Antigen-specific cytotoxic T lymphocytes can target drug-resistant side population tumor cells in Hodgkin lymphoma," May 2010, Leukemia Lymphoma 51(5):870-880; Quintarelli et al., "Highly active cytotoxic T lymphocytes specific for a novel PRAME-derived peptide can target leukemia and leukemia precursor cells," March 24, 2011, Blood 117(12):3353-3362; Bollard et al., “Generation of GMP-grade cytotoxic T lymphocytes specific for LMP1 and LMP2 for patients with EBV-associated lymphomas,” May 2011, Cell Therapy 13(5):518-522; Ramos et al., “Human papillomavirus type 16 E6 / E7-specific cytotoxic T lymphocytes for adoptive immunotherapy of HPV-associated malignancies,” January 2013, Immunotherapy 36(1): 66-76; Weber et al., "Generation of tumor antigen-specific T cell lines from pediatric patients with acute lymphoblastic leukemia - implications for immunotherapy," Clinical Cancer Res, Sep 15, 2013; 19(18): 5079-5091; Ngo et al., "Recruiting antigen-presenting cells to generate T lymphocytes with broad target specificity," Journal of Immunotherapy, May 2014, 37(4): 193-203; each of which is incorporated herein by reference. In some embodiments, the non-engineered, activated immune cells administered in combination or alternation with the degrader composition described herein are selected from the group consisting of: activated CD4+ T-cells (T-helper cells), CD8+ T-cells (cytotoxic T-lymphocytes), CD3+ / CD56+ natural killer T cells (CD3+NKT), and gamma delta T cells (gamma delta T cells), or a combination thereof.In some embodiments, adoptive cell therapy is a composition comprising CD4+T cells (T- helper cells). In some embodiments, adoptive cell therapy is a composition comprising CD8+T cells (cytotoxic T- lymphocytes). In some embodiments, adoptive cell therapy is a composition comprising CD3+ / CD56+ natural killer T cells (CD3+NKT). In some embodiments, adoptive cell therapy is a composition comprising CD4+T cells (T- helper cells), CD8+T cells (cytotoxic T- lymphocytes), CD3+ / CD56+ natural killer T cells (CD3+NKT) and γδT cells (γδT cells).

[1052] In some embodiments, the immunotherapy is a bispecific T cell engager (BiTE). Bispecific T cell engagers guide T cells to target and bind to specific antigens on the surface of cancer cells. For example, blinatumomab (Amgen), a BiTE, was recently approved as a second-line therapy for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. Blinatumomab is administered by continuous intravenous infusion on a 4-week cycle.

[1053] In certain embodiments, the additional therapeutic agent is an inhibitor of Ikaros ("IKZF1") and / or other inhibitors of Aiolos ("IKZF3"). In another embodiment, the additional therapeutic agent is an inhibitor of Helios ("IKZF2"). In another embodiment, the additional therapeutic agent is an inhibitor of Eos ("IKZF4"). In another embodiment, the additional therapeutic agent is an inhibitor of Pegasus ("IKZF5"). In another embodiment, the additional therapeutic agent is a cereblon ligand.

[1054] Non-limiting examples of cereblon ligands that can be used in combination with the compounds of the present invention include: thalidomide, lenalidomide, pomalidomide, and ipodomide.

[1055] In another embodiment, the additional compounds that may be used in combination with the compounds of the present invention are selected from those described in WO2012 / 175481, WO2015 / 085172, WO2015 / 085172, WO2017 / 067530, WO2017 / 121388, WO2018 / 108147, WO2018 / 118947, WO2019 / 038717, WO2019 / 191112, WO2020 / 006233, WO2020 / 006262, WO2020 / 006265 or WO2020 / 012334.

[1056] In another embodiment, the additional compounds that may be used in combination with the compounds of the present invention are selected from those described in WO2019 / 060693, WO2019 / 060742, WO2019 / 133531, WO2019 / 140380, WO2019 / 140387, WO2010 / 010177, WO2020 / 010210 or WO2020 / 010227.

[1057] In another embodiment, the additional compounds that can be used in combination with the compounds of the present invention are selected from those described in WO2015 / 160845, WO2016 / 118666, WO2016 / 149668, WO2016 / 197032, WO2016 / 197114, WO2017 / 011371, WO2017 / 0115901, WO2017 / 030814, WO2017 / 176708, WO2018 / 053354, WO2018 / 0716060, WO2018 / 102067, WO2018 / 118598, WO2018 / 119357, WO2018 / 119441, WO2018 / 119448, WO2018 / 140809, WO2018 / 226542, WO2019 / 023553, WO2019 / 099926, WO2019 / 195201, WO2019 / 195609, WO2019 / 199816, WO2020 / 023851, WO2020 / 041331 or WO2020 / 051564.

[1058] In another embodiment, the additional compounds that can be used in combination with the compounds of the present invention are selected from those described in WO2016 / 105518, WO2017 / 007612, WO2017 / 024317, WO2017 / 024318, WO2017 / 024319, WO2017 / 117473, WO2017 / 117474, WO2017 / 185036, WO2018 / 064589, WO2018 / 148440, WO2018 / 148641 02018 / 148443, WO2018 / 226978, WO2019 / 014429, WO2019 / 079701, WO2019 / 094718, WO2019 / 094955, WO2019 / 118893, WO2019 / 165229, WO2020 / 006262, WO2020 / 018788, WO2020 / 069105, WO2020 / 069117, or WO2020 / 069125.

[1059] In another embodiment, the additional compounds that may be used in combination with the compounds of the present invention are selected from those described in WO2017 / 197036, WO2017 / 197046, WO2017 / 197051, WO2017 / 197055, WO2017 / 197056, WO2017 / 115218, WO2018 / 220149, WO2018 / 237026, WO2019 / 099868, WO2019 / 121562, WO2019 / 149922, WO2019 / 191112, WO2019 / 204354, WO2019 / 236483 or WO2020 / 051235.

[1060] V. Pharmaceutical Compositions

[1061] Any of the compounds disclosed herein can be administered as a pure chemical, but more typically as a pharmaceutical composition comprising an effective amount for a host (typically a human) in need of such treatment for any of the diseases described herein. Thus, the present disclosure provides pharmaceutical compositions comprising an effective amount of a compound or a pharmaceutically acceptable salt 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, the pharmaceutical composition may contain the compound and at least one additional active agent.

[1062] In certain embodiments, the dosage form of the pharmaceutical composition comprises from about 0.0005 mg to about 2000 mg of active compound, from about 0.001 mg to about 1000 mg of active compound, from about 0.001 mg to about 600 mg of active compound, or from about 0.001 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 100 mg, 200 mg, or 300 mg of active compound. In another embodiment, the dosage form of the pharmaceutical composition comprises from about 0.01 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, or 100 mg of active compound, from about 0.05 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, or 100 mg of active compound, from about 0.1 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 50 mg of active compound, from about 0.02 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 50 mg of active compound, or from about 0.5 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 50 mg of active compound. In another embodiment, the dosage form of the pharmaceutical composition comprises about 0.01 mg to about 10 mg, about 0.05 mg to about 8 mg, or about 0.05 mg to about 6 mg, or about 0.05 mg to about 5 mg of active compound. In another embodiment, the dosage form of the pharmaceutical composition comprises about 0.1 mg to about 10 mg, about 0.5 mg to about 8 mg, or about 0.5 mg to about 6 mg, or about 0.5 mg to about 5 mg of active compound. Non-limiting examples are dosage forms having at least about 0.0005 mg, 0.001 mg, 0.01 mg, 0.1 mg, 1 mg, 2.5 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 750 mg of active compound or a salt thereof. Alternative non-limiting examples are dosage forms having no greater than about 0.01 mg, 0.1 mg, 1 mg, 2.5 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg or 750 mg of active compound or a salt thereof.

[1063] The pharmaceutical composition may also include active compounds and other therapeutic agents in a molar ratio. In non-limiting illustrative embodiments, the pharmaceutical composition may contain an anti-inflammatory or immunosuppressant agent and a compound of the present invention in a molar ratio of approximately 0.5: 1, approximately 1: 1, approximately 2: 1, approximately 3: 1, or approximately 1.5: 1 to approximately 4: 1. The compounds disclosed herein may be administered orally, topically, parenterally, by inhalation or spraying, sublingually, by implants (including eye implants), transdermal, by oral administration, rectum, as eye drops, injections (including eye injections), intravenously, intraaortically, intracranially, subcutaneously, intraperitoneally, subcutaneously, nasally, sublingually or rectumally, or by other means, in a dosage unit formulation containing a conventional pharmaceutically acceptable carrier. For ocular delivery, administration can be by immediate or controlled release, as desired, for example, by intravitreal, intrastromal, intracameral, subtenonous, subretinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxta-scleral, pericorneal, or lacrimal injection, or through mucus, mucin, or mucosal barriers, or by ocular device.

[1064] The pharmaceutical composition can be formulated into any pharmaceutically useful form, such as an aerosol, cream, gel, pill, injection or infusion solution, capsule, tablet, syrup, transdermal patch, subcutaneous patch, dry powder, inhalation formulation, medical device, suppository, oral or sublingual formulation, parenteral formulation or eye drops. Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized unit doses containing an appropriate amount of the active ingredient, such as an effective amount to achieve the desired purpose.

[1065] The carrier includes an excipient and a diluent and must be of sufficiently high purity and sufficiently low toxicity to make it suitable for administration to the patient being treated. 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 material for administration per unit dose of the compound.

[1066] Carrier categories include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavorings, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one category, for example, a vegetable oil may be used as a lubricant in some formulations and as a diluent in others. A pharmaceutically acceptable carrier is one that does not cause any serious adverse reactions in humans when administered in the amounts that would be used in the corresponding pharmaceutical composition. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, tragacanth powder, malt, gelatin; talc, and vegetable oils. Optional active agents may be included in the pharmaceutical composition that do not substantially interfere with the activity of the compounds of the invention.

[1067] Pharmaceutical compositions / combinations can be formulated for oral administration. These compositions can contain any amount of active compound to achieve the desired result, for example, between 0.1% and 99% by weight (wt.%) of the compound, including, for example, at least about 5% by weight of the compound. Some embodiments contain from about 25% to about 50% by weight or from about 5% to about 75% by weight of the compound.

[1068] Formulations suitable for rectal administration are conveniently presented as unit-dose suppositories. These can be prepared by mixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and shaping the resulting mixture.

[1069] Preparations suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Carriers that may be used include petrolatum, lanolin, polyethylene glycol, alcohol, transdermal enhancers and combinations of two or more thereof.

[1070] Preparations suitable for transdermal administration can be in the form of discrete patches suitable for maintaining close contact with the epidermis of the recipient for a long time. Preparations suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6): 318 (1986)) and are generally in the form of an optional buffered aqueous solution of the active compound. In one embodiment, a microneedle patch or device is provided for delivering the drug through or into biological tissue, particularly the skin. The microneedle patch or device allows the drug to be delivered through or into the skin or other tissue barriers at a clinically relevant rate with minimal or no stimulation to the damage, pain or irritation of the tissue.

[1071] Preparations suitable for pulmonary administration can be delivered by a variety of passive breath-driven and active power-driven single / multi-dose dry powder inhalers (DPIs). The equipment most commonly used for respiratory delivery includes nebulizers, metered dose inhalers, and dry powder inhalers. Various types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of suitable pulmonary delivery devices depends on parameters such as the properties of the drug and its formulation, site of action, and the pathophysiology of the lungs.

[1072] Many methods and devices for drug delivery are known in the art. Non-limiting examples are described in the following patents and patent applications (incorporated herein by reference in their entireties). Examples are U.S. Pat. No. 8,192,408 (Psivida U.S., Inc.), entitled “Ocular trocar assembly”; U.S. Pat. No. 7,585,517 (Macusight, Inc.), entitled “Transcleral delivery”; U.S. Pat. Nos. 5,710,182 and 5,795,913 (Santen OY), entitled “Ophthalmic composition”; U.S. Pat. No. 8,663,639, entitled “Formulations for treating ocular diseases and conditions”; U.S. Pat. No. 8,486,960, entitled “Formulations and methods for treating diseases or conditions associated with vascular permeability”; U.S. Pat. Nos. 8,367,097 and 8,927,005, entitled “Liquid formulations for treating diseases or conditions”; and U.S. Pat. No. 7,455,855 (Santen Pharmaceutical Co., Ltd.), entitled “Delivery of substances and drug delivery systems using the same.”); WO / 2011 / 050365, entitled “Suitable Therapeutic Shield for Vision and Pain”; and WO / 2009 / 145842, entitled “Therapeutic Device for Pain Management and Vision” (Forsight Labs, LLC); US9,066,779 and US8,623,395, entitled “Implantable Therapeutic Device”; WO / 2014 / 160884, entitled “Ocular Implant for Delivery of Therapeutic Substances”; US8,399,006, US8,277,830, US8,808,727, US8,298,578, and WO / 2010 / 088548, entitled “Posterior Segment Drug Delivery”; WO / 2014 / 160884, entitled “System for Sustained Intraocular Delivery of Low Solubility Compounds from a Dispensing Delivery System Implant”. 14 / 152959 and US20140276482; US8,905,963 and US9,033,911, entitled “Injection Device and Drug Delivery Method”; 2015 / 057554, entitled “Preparations and Methods for Increasing or Reducing Mucus”; US8,715,712 and US8,939,948, entitled “Ocular Insertion Device and Method”; WO / 2013 / 116061, entitled “Methods and Apparatus for Insertion and Removal of Therapeutic Devices”; WO11, entitled “Ophthalmic System for Sustained Release of Drugs to the Eye” 022 / 066775; WO / 2015 / 085234 and WO / 2012 / 019176 entitled “Implantable Therapeutic Devices”; WO / 2012 / 065006 entitled “Methods and Apparatus for Determining Porous Structures for Drug Delivery”; WO / 2010 / 141729 entitled “Anterior Segment Drug Delivery”; WO / 2011 / 050327 entitled “Corneal Denervation Methods for Treatment of Ocular Pain”; WO / 2013 / 022801 entitled “Small Molecule Delivery with Implants”; and WO / 2013 / 022801 entitled “Delivery of Small Molecules with Implants for WO / 2012 / 019047 entitled “Subconjunctival Implant for Posterior Segment Drug Delivery”; WO / 2012 / 068549 entitled “Therapeutic Agent Formulation for Implant Device”; WO / 2012 / 019139 entitled “Combined Delivery Methods and Devices”; WO / 2013 / 040426 entitled “Ocular Insertion Devices and Methods”; WO / 2012 / 019136 entitled “Injection Devices and Methods for Drug Delivery”; WO / 2013 / 040247 (ForSight Vision4, Inc.); US / 2014 / 0352690 entitled “Inhalation device with feedback system”; US8,910,625 and US / 2015 / 0165137 (Vectura GmbH) entitled “Inhalation device for aerosol therapy”; US6,948,496 entitled “Inhaler”; US / 2005 / 0152849 entitled “Powder containing anti-adhesive material for use in dry powder inhaler”; US6,582,678, US8,137,657, US / 2003 / 0202944 and US / 2010 / 0330188 entitled “Carrier particles for dry powder inhaler”; US6,221,338 entitled “Method for producing particles for dry powder inhaler”; US6,989,155 entitled “Powder”; U.S. Pat. No. 5,832,678 entitled “Pharmaceutical composition for treating premature ejaculation by pulmonary inhalation”; S / 2007 / 0043030; US7,845,349, entitled “Inhaler”; US / 2012 / 0114709 and US8,101,160, entitled “Formulations for use in inhalation devices”; US / 2013 / 0287854, entitled “Compositions and uses”; US / 2014 / 0037737 and US8,580,306, entitled “Particles for use in pharmaceutical compositions”; US / 2015 / 0174343, entitled “Mixing channel for inhalation device”; US7,744,855 and US / 2010 / 0285142, entitled “Method of manufacturing particles for pharmaceutical compositions”; US7,541,022, US / 2009 / 0269412, and US / 2015 / 0050350, entitled “Pharmaceutical formulation for dry powder inhaler” (Vectura Limited).

[1073] Other non-limiting examples of how to deliver active compounds are provided in the following: WO / 2015 / 085251 entitled “Intracameral Implants for Treating Ocular Diseases” (Envisia Therapeutics, Inc.); WO / 2011 / 008737 entitled “Engineered Aerosol Particles and Related Methods”; WO / 2013 / 082111 entitled “Geometrically Engineered Particles and Methods for Modulating Macrophage or Immune Responses”; WO / 2009 / 132265 entitled “Degradable Compounds and Methods Thereof, Particularly Particle Replication in Non-Wetting Templates”; WO / 2010 / 099321 entitled “Interventional Drug Delivery Systems and Related Methods”; WO / 2008 / 100304 entitled “Polymer Particle Composites Having High-Fidelity Order, Size, and Shape Particles”; WO / 2007 / 024323 entitled “Nanoparticle Manufacturing Methods, Systems, and Materials” (Liquidia Technologies, Inc. and the University of North Carolina at Chapel Hill); WO / 2010 / 009087 entitled “Iontophoresis for Controlled Release Formulations in the Eye” (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.); WO / 2009 / 132206 entitled “Compositions and Methods for Intracellular Delivery and Release of Substances”; WO / 2007 / 133808 entitled “Nanoparticles for Cosmetic Applications”; WO / 2007 / 056561 entitled “Medical Devices, Materials and Methods”; WO / 2010 / 065748 entitled “Methods of Making Patterned Materials”; and WO / 2007 / 081876 entitled “Nanostructured Surfaces for Biomedical / Biomaterial Applications and Processes Thereof” (Liquidia Technologies, Inc.).

[1074] Other non-limiting examples of drug delivery devices and methods include, for example: US20090203709 (Abbott Laboratories), entitled “Oral Administration of a Tyrosine Kinase Inhibitor Pharmaceutical Dosage Form”; US20050009910, entitled “Delivery of an Active Drug to the Posterior of the Eye by Subconjunctival or Periocular Delivery of a Prodrug”; US20130071349, entitled “Degradable Polymers for Reducing Intraocular Pressure”; US8,481,069, entitled “Tyrosine Kinase Microspheres”; US8,465,778, entitled “Methods for Making Tyrosine Kinase Microspheres”; US8,409, entitled “Sustained Release Intraocular Implants Containing Tyrosine Kinase Inhibitors and Related Methods”. 607; US8,512,738 and US2014 / 0031408 entitled “Degradable intravitreal tyrosine kinase implant”; US2014 / 0294986 entitled “Microsphere drug delivery system for sustained intraocular release”; US8,911,768 (Allergan, Inc.) entitled “Retinopathy treatment method with prolonged therapeutic effect”; US6,495,164 (Alkermes) entitled “Preparation of injectable suspension with improved injectability” and US Pat. No. 5,869,103, entitled “Polymer nanoparticles for drug delivery” (Danbiosyst UK Ltd.). Ltd.); US8628801 entitled “PEGylated Nanoparticles” (University of Navarra); US2014 / 0107025 entitled “Ocular Drug Delivery System” (Jade Therapeutics, LLC); US6,287,588 entitled “Drug Delivery System with Improved Release Properties Composed of Microparticles and Biodegradable Gel and Method of Use Thereof”; US6,589,549 entitled “Biologically Active Agent Delivery System Composed of Biodegradable Microparticles to Improve Release Properties” (Macromed, Inc.); US6,007,845 and US5,578,325 entitled “Nanoparticles and microparticles of nonlinear hydrophobic multisegmented polymers” (Massachusetts Institute of Technology); US20040234611, US20080305172, US20120269894 and US20130122064 entitled “Ophthalmic depot formulations for periocular or subconjunctival drug delivery” (Novartis Ag); US6,413,539 entitled “Block Polymers” (Poly-Med, Inc.); US20070071756 entitled “Delivery of Agents to Ameliorate Inflammation” (Peyman); US20080166411 entitled “Injectable Sustained Formulations and Methods for Providing Sustained Release of Nearly Soluble Drugs Containing Nanoparticles” (Pfizer, Inc.); US6,706,289 entitled “Methods and Compositions for Enhancing Delivery of Bioactive Molecules” (PR Pharmaceuticals, Inc.); and US8,663,674 entitled “Microparticles Containing Matrix for Drug Delivery” (Surmodics).

[1075] VI. General Synthesis

[1076] The compounds described herein can be prepared by methods known to those skilled in the art. In a non-limiting example, the disclosed compounds can be prepared using the following schemes.

[1077] For convenience, compounds of the present invention having stereocenters may 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 methods:

[1078] i) Physical separation of crystals – a technique whereby macroscopic crystals of individual enantiomers are manually separated. This technique can be used if crystals of the individual enantiomers are present, i.e. the material is an aggregate and the crystals are visually distinct;

[1079] ii) Simultaneous crystallization - a technique whereby individual enantiomers are crystallized separately from a solution of the racemate, which is possible only when the enantiomers are aggregates in the solid state;

[1080] iii) Enzymatic resolution - a technique that allows for the partial or complete separation of racemates by exploiting the different reaction rates of the enantiomers with enzymes;

[1081] iv) Enzymatic asymmetric synthesis - a synthetic technique in which at least one step in the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;

[1082] v) Chemical asymmetric synthesis - a synthetic technique by which the desired enantiomer is 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;

[1083] vi) Diastereomeric separation - a technique in which a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) to convert the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization, due to their now more distinct structural differences, followed by removal of the chiral auxiliary to yield the desired enantiomer;

[1084] vii) Primary and secondary asymmetric transformations - a technique by which the diastereomers of a racemate equilibrate rapidly, resulting in a preponderance of diastereomers from the desired enantiomer in solution, wherein preferential crystallization of the diastereomer from the desired enantiomer disturbs the equilibrium, ultimately resulting in, in principle, all of the material being converted from the desired enantiomer to the crystalline diastereomer. The desired enantiomer is then liberated from the diastereomers;

[1085] viii) Kinetic resolution - This technique involves the partial or complete resolution of a racemate (or further resolution of a partially resolved compound) through the unequal reaction rates of enantiomers with a chiral non-racemic reagent or catalyst under kinetic conditions;

[1086] ix) Enantiospecific synthesis of non-racemic precursors - a synthetic technique in which the desired enantiomer is obtained from achiral starting materials and the stereochemical integrity is not compromised or only minimally compromised during the synthetic process;

[1087] x) Chiral liquid chromatography – a technique that separates the enantiomers of a racemate in a liquid mobile phase by virtue of their differential interactions with the stationary phase (including vial chiral HPLC). The stationary phase can be made of a chiral material, or the mobile phase can contain other chiral materials to induce differential interactions;

[1088] xi) Chiral gas chromatography - a technique whereby the racemate is volatilized and the enantiomers are separated by their different interactions in the gaseous mobile phase with a chromatographic column containing a stationary non-racemic chiral adsorbent phase;

[1089] xii) Chiral solvent extraction – a technique for separating enantiomers by preferentially dissolving one enantiomer in a specific chiral solvent;

[1090] xiii) Transport across chiral membranes – a technique where a racemate is brought into contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force, such as concentration or pressure differential, results in preferential transport across the membrane barrier. Separation occurs because the non-racemic chiral nature of the membrane allows only one enantiomer of the racemate to pass through;

[1091] xiv) In one embodiment simulated moving bed chromatography is used. A variety of chiral stationary phases are commercially available.

[1092] General Synthesis Scheme 1

[1093]

[1094] In some aspects, compounds of Formula I or Formula II can be synthesized according to the routes provided in General Synthesis Scheme 1. In step 1, compound G1-1 is reacted with butyllithium (or another organolithium reagent, such as tert-butyllithium, sec-butyllithium, phenyllithium or methyllithium, or a Grignard reagent, such as isopropylmagnesium bromide or ethylmagnesium bromide) in an organic solvent (such as tetrahydrofuran or diethyl ether) at low temperature (typically -78°C to -40°C), followed by the addition of G1-2 to provide G1-3. In step 2, compound G1-3 is reacted with trifluoroacetic acid (or another strong oxygen-containing acid, such as trifluoromethanesulfonic acid) and triethylsilane (or another organosilane, such as phenylsilane, or an organotin hydride, such as tributyltin hydride) in an organic solvent (such as 1,2-dichloroethane) by heating (e.g., about 60°C or microwave irradiation) to provide G1-4. In step 3, compound G1-4 is reacted with a base (such as sodium hydride) in an organic solvent (such as dimethylformamide or dichloromethane) followed by the addition of G1-5 to provide G1-6.

[1095] General synthetic scheme 2

[1096]

[1097] In some aspects, compounds of Formula I or Formula II can be synthesized according to the routes provided in General Synthesis Scheme 2. In step 1, compound G2-1 (prepared according to the procedure outlined in General Synthesis Scheme 1 for compound G1-3) is reacted with an oxidizing agent (e.g., manganese dioxide or other suitable reagents for alcohol oxidation) in an organic solvent (e.g., acetonitrile) to provide G2-2. In step 2, G2-2 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane) followed by the addition of G2-3 to provide G2-4. In step 3, G2-4 is reacted with a suitable carbonyl reducing agent (e.g., sodium cyanoborohydride) in an organic solvent (e.g., ethanol or methanol) to provide G2-5.

[1098] General synthetic scheme 3

[1099]

[1100] In some aspects, compounds of Formula I or Formula II can be synthesized according to the route provided in General Synthesis Scheme 3. In step 1, compound G3-1 (prepared according to the procedure outlined in General Synthesis Scheme 2 for compound G2-2) is reacted with DAST (or other suitable nucleophilic fluorination reagents, such as Deoxo-Fluor) in an organic solvent (e.g., dichloromethane) to provide G3-2. In step 2, compound G3-2 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), followed by the addition of G3-3 to provide G3-4.

[1101] General Synthesis Scheme 4

[1102]

[1103] In some aspects, compounds of Formula I or Formula II can be synthesized according to the routes provided in General Synthesis Scheme 4. In step 1, compound G4-1 (prepared according to the procedure outlined in General Synthesis Scheme 1 for compound G1-3) is reacted with DAST (or other suitable nucleophilic fluorinating reagents, such as Deoxo-Fluor) in an organic solvent (e.g., dichloromethane) to provide G4-2. In step 2, compound G4-2 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), followed by the addition of G4-3 to provide G4-4.

[1104] General Synthesis Scheme 5

[1105]

[1106] In some aspects, compounds of Formula I or Formula II can be synthesized according to the routes provided in General Synthesis Scheme 5. In step 1, compound G5-1 is reacted with G5-2 in an organic solvent (e.g., toluene, THF, dioxane, or DMF) at elevated temperature in the presence of a palladium catalyst (e.g., palladium(II) acetate, Pd2(dba)3, or other suitable palladium catalysts for Buchwald-Hartwig coupling conditions), a phosphine ligand (e.g., BINAP, XantPhos, or other suitable phosphine ligands used in Buchwald-Hartwig coupling conditions), and a base (e.g., potassium tert-butoxide, cesium carbonate, or other suitable bases used in Buchwald-Hartwig coupling conditions) to provide G5-3. In step 2, compound G5-3 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), followed by the addition of G5-4 to provide G5-5.

[1107] General Synthesis Scheme 6

[1108]

[1109] In some aspects, compounds of Formula I or Formula II can be synthesized according to the route provided in General Synthesis Scheme 6. In step 1, compound G6-1 is reacted with a metal hydroxide (e.g., sodium hydroxide or potassium hydroxide) in an organic solvent (e.g., dioxane) and water in the presence of a palladium catalyst (e.g., Pd2(dba)3) and a phosphine ligand (e.g., XantPhos) to provide G6-2. In step 2, G6-2 is protected with an appropriate protecting group (e.g., a Boc or Cbz group) using standard conditions to provide compound G6-3. In step 3, G6-3 is reacted with G6-5 at elevated temperature (e.g., about 80°C) in an organic solvent (e.g., 1,2-dichloroethane) in the presence of a copper catalyst (e.g., copper acetate) and a base (e.g., pyridine or DMAP) to provide compound G6-6. In step 4, the protecting group PG in G6-6 is removed using standard conditions applicable to the particular group to provide G6-7. In step 5, compound G6-7 is reacted with a base (such as sodium hydride) in an organic solvent (such as dimethylformamide or dichloromethane) followed by the addition of G6-8 to provide G6-9.

[1110] Non-limiting embodiments of the present invention

[1111] Where chirality is depicted in the following synthetic schemes, the designation indicates the relative chirality of the stereocenter rather than the absolute designation. For example,

[1112] The use of a wedge-shaped bond indicates that the designated chiral center has been resolved by chiral chromatography. However, the absolute chirality of this stereocenter may be When intermediate 3a is then reacted with racemic bromoglutarimide, the resulting compound 280 may be a mixture of diastereomers.

[1113]

[1114] Similarly, when an achiral lactam is reacted with racemic glutarimide in the following experiment, the resulting compound may be a mixture of enantiomers. For example, when intermediate 7 is reacted with racemic bromoglutarimide, the resulting intermediate 9 may be a mixture of enantiomers.

[1115]

[1116] Unless otherwise indicated with a specific stereochemistry, the resulting compounds may be mixtures of enantiomers. For example,

[1117]

[1118] These enantiomeric mixtures can be separated by a skilled artisan using techniques known in the art, including chiral chromatography, crystallization, transport across chiral membranes, or extraction with chiral solvents. In fact, these techniques were used to separate several of the following compounds. For example, the intermediate Separation by chiral chromatography using preparative HPLC techniques. Similarly, mixtures of glutarimide enantiomers can be resolved using these techniques, including chiral chromatography. For example, a mixture of compound 67 and compound 68 was separated by chiral chromatography using preparative HPLC techniques. The enantiomeric excess of the resulting isolated compound was 99%.

[1119]

[1120] Once isolated, absolute chirality can be assigned by known techniques, including structural determination of various forms of crystals. For example, X-ray diffraction can be used on crystals of compounds such as Compound 67 and Compound 68 to determine whether they are (R) or (S).

[1121] Mixtures of enantiomers can also be resolved during synthesis using techniques known in the art. For example, enzymatic resolution and enzymatic asymmetric synthesis can be used to resolve chiral centers. In addition, mixtures of enantiomers can be resolved by installing protecting groups or using chiral salts. When chiral protecting groups or salts are used, the mixture of enantiomers temporarily becomes a mixture of diastereomers, allowing for physical separation using known techniques.

[1122] When the compounds of the present invention are mixtures of diastereomers, they can also be separated by techniques known in the art. For example, mixtures of diastereomers can be separated by chromatographic techniques, including reversed-phase or normal-phase HPLC, silica gel chromatography, moving bed chromatography, and preparative TLC. Mixtures of diastereomers can also be separated by crystallization.

[1123] Example 1: Synthesis of 3-(2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 1)

[1124]

[1125] To a stirred solution of 1H-benzo[cd]indol-2-one 1 (100.0 mg, 591.09 μmol) in DMF (2 mL) at 0°C was added sodium hydride 60% dispersion in mineral oil (24.91 mg, 650.20 μmol, 60% purity), and the reaction mixture was heated at 60°C for 30 minutes. 3-Bromopiperidine-2,6-dione 2 (113.50 mg, 591.09 μmol) was added, and the reaction mixture was heated at 60°C for 24 hours. New spots formed along with unreacted starting material. Additional 3-Bromopiperidine-2,6-dione 2 (113.50 mg, 591.09 μmol) was added, and the reaction mixture was heated again for 24 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and the organic portion was separated. The reaction mixture was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude compound, which was purified by preparative TLC plate (eluted with 2% MeOH-DCM) to afford 3-(2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 1) (10 mg, 34.35 μmol, 5.81% yield, 96.28% purity) as a light yellow solid. 1 H NMR (d6-DMSO, 400MHZ) δ11.13(s,1H),8.24(d,J=8.08Hz,1H),8.11(d,J=6.92Hz,1H),7.84(t,J=7.56Hz,1H),7.68(d,J=8.4Hz,1H),7.54(t,J=7. 76Hz,1H),7.17(d,J=7.12Hz,1H),5.46(dd,J=12.76,5.08Hz,1H),3.00- 2.91(m,1H),2.82-2.71(m,1H),2.67-2.63(m,1H),2.12-2.09(m,1H); LC MS:ES+281.2.

[1126] Example 2: Synthesis of tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 2)

[1127]

[1128]

[1129] Step 1: Preparation of 6-bromobenz[cd]indol-2(1H)-one (2): To a stirred suspension of 1H-benzo[cd]indol-2-one 1 (3.0 g, 17.73 mmol) in CHCl₃ (50.0 mL) was added bromine (2.15 g, 26.60 mmol, 1.44 mL) dropwise under cooling, and the reaction mixture was stirred at room temperature for 48 hours. Sodium thiosulfate solution was poured into the reaction mixture under cooling, and the resulting yellow solid was filtered through a sintered funnel. The resulting solid was washed with cold water and pentane, and azeotroped with toluene to afford 6-bromo-1H-benzo[cd]indol-2-one 2-2 (4 g, 16.12 mmol, 90.93% yield) as a yellow solid. LCMS: ES+ 248.1, 250.0 (bromine mode).

[1130] Step 2: Preparation of tert-butyl 4-(4-(hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (4): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 2-2 (1.6 g, 6.45 mmol) in THF (7 mL) was added butyl lithium (2.2 M, 9.38 mL) at -78 °C. After the addition was complete, the temperature was raised to -40 °C and the reaction mixture was stirred at the same temperature for 30 minutes. A solution of tert-butyl 4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate 3 (1.80 g, 6.45 mmol) in THF (7 mL) was added at -78 °C and the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and diluted with ethyl acetate. The layers were separated and the organic layer was washed with water. The organic layer was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to afford tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 4 (527 mg, 1.17 mmol, 18.22% yield) as a brown solid. 1H NMR(d6-DMSO,400MHZ)δ10.70(s,1H),8.34(d,J=8.28Hz,1H),7.95(d,J=6.96Hz,1H), 7.72(t,J=7.6Hz,1H),7.59-7.52(m,2H),7.28(s,1H),6.93(d,J=7.2Hz,1H),6.22(br s,1H),5.80(br s,1H),4.27-4.21(m,1H),4.00-3.96(m,2H),2.84-2.82(m,2H),1.91-1.87(m,2H),1.72-1.64(m,2H),1.39(s,9H).

[1131] Step 3: Preparation of 2,2,2-trifluoroacetic acid salt of 6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one (5): To a stirred solution of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 4 (500.0 mg, 1.11 mmol) in DCE (3 mL) were added triethylsilane (518.51 mg, 4.46 mmol, 712.24 μL) and trifluoroacetic acid (1.02 g, 8.92 mmol, 687.08 μL), and the reaction was stirred at 70°C under microwave irradiation for 30 min. The solvent in the reaction mixture was evaporated under reduced pressure to give the crude product, which was washed with ether and pentane to afford 6-[(1-piperidin-1-ium-4-ylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one; 2,2,2-trifluoroacetate salt 5 (500.0 mg, 1.12 mmol, 100.47% yield) as a brown gum that was used without further purification. LC MS: ES+ 333.0.

[1132] Step 4: Preparation of tert-butyl 4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (6): To a stirred solution of 6-[(1-piperidin-1-ium-4-ylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one; 2,2,2-trifluoroacetate 5 (500.0 mg, 1.12 mmol) in DCM (5 mL) was added triethylamine (340.00 mg, 3.36 mmol, 468.32 μL), cooled, and then di-tert-butyl dicarbonate (366.67 mg, 1.68 mmol, 385.56 μL) was added and the reaction was continued at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine solution, and the organic portion was separated. The organic layer was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product, which was purified by flash chromatography using 0-5% MeOH-DCM to afford tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 6 (300.0 mg, 693.62 μmol, 61.93% yield) as a yellow sticky solid. LCMS: ES+ 433.0.

[1133] Step 5: Preparation of tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 2): To a stirred solution of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 6 (300.0 mg, 693.62 μmol) in DMF (1 mL) was added sodium hydride (60% dispersion in mineral oil, 53.15 mg, 1.39 mmol, 60% purity) with cooling, and the reaction mixture was heated at 60°C for 30 min. 3-Bromopiperidine-2,6-dione 7 (133.18 mg, 693.62 μmol) was then added and the reaction was heated at 60° C. for 4 hours, followed by the addition of 3-bromopiperidine-2,6-dione (133.18 mg, 693.62 μmol) and the reaction was stirred for an additional 16 hours at 60° C. The reaction mixture was diluted with ethyl acetate and washed with water, and the organic portion was separated. The reaction mixture was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product, which was first purified by column chromatography and then by preparative TLC plate (eluted with 60% ethyl acetate-hexane) to give tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidinyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate (Compound 2) (20.0 mg, 33.11 μmol, 4.77% yield, 90% purity) as a light yellow solid. 1 H NMR(d6-DMSO,400MHZ)δ11.11(s,1H),8.37(d,J=8.24Hz,1H),8.08(d,J=6.92Hz,1H),7.8 3(t,J=7.58Hz,1H),7.59(s,1H),7.35(d,J=7.36Hz,1H),7.31(s,1H),7.07(d,J=7.28Hz, 1H),5.43(dd,J=12.76,5.0Hz,1H),4.24-4.23(m,1H),4.17(s,2H),4.00-3.96(m,2H),2. 96-2.66(m,5H),2.09-2.06(m,1H),1.91-1.88(m,2H),1.72-1.66(m,2H),1.39(m,9H); LC MS:ES+544.3.

[1134] Example 3: Synthesis of 3-(6-((1-(1-(cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 3)

[1135]

[1136] Step 1: Preparation of 3-(2-oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride (2): To a stirred solution of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidinyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 1 (100.0 mg, 183.95 μmol) in dioxane (1 mL) was added a solution of hydrochloric acid in dioxane (183.95 μmol, 8 mL) and the reaction was stirred at room temperature for 2 hours. TLC analysis showed complete consumption of the starting material. The solvent in the reaction mixture was evaporated under reduced pressure, and the residue was washed with diethyl ether and pentane to afford 3-[6-[[1-(1-chloro-4-piperidinyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione 2 (88.0 mg, 183.35 μmol, 99.67% yield) as a yellow solid. LC MS: ES+ 444.1.

[1137] Step 2: Preparation of 3-(6-((1-(1-(cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 3): To 3-[6-[[1-(1-chloro-4-piperidinyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione, To a stirred solution of 6-diketone 2 (88.0 mg, 183.35 μmol) in DMF (3.0 mL) was added cubane-1-carboxylic acid (27.16 mg, 183.35 μmol), followed by the addition of HATU (104.57 mg, 275.02 μmol) and N,N-diisopropylethylamine (71.09 mg, 550.05 μmol, 95.81 μL) at 0°C. The reaction mixture was then stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate and water, and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and brine, dried over sodium sulfate, and concentrated. The crude material was purified by preparative TLC (eluting with 3% MeOH / DCM) to give 3-[6-[[1-[1-(cubane-1-carbonyl)-4-piperidinyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 3) (55.0 mg, 94.77 μmol, 51.69% yield, 98.84% purity) as a yellow solid. 1H NMR(d6-DMSO,400MHZ)δ11.09(s,1H),8.36(d,J=8.16Hz,1H),8.08(d,J=7.0Hz,1H),7.83(t,J=7.62Hz,1H),7.60(s,1H) ,7.35(d,J=7.32Hz,1H),7.31(s,1H),7.06(d,J=7.24Hz,1H),5.42(dd,J=12.48,5.24Hz,1H),4.33-4.31(m,2H),4.18(br s,5H),3.97(br s,4H),3.38-3.34(m,1H),3.20-3.13(m,1H),2.97-2.90(m,1H),2.79-2.62(m,3H ),2.10-2.07(m,1H),2.01-1.92(m,2H),1.83-1.79(m,1H),1.67-1.64(m,1H); LC MS:ES+574.5.

[1138] Example 4: Synthesis of 3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 4)

[1139]

[1140] Step 1: Preparation of 6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one hydrochloride (2): To a stirred solution of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidinyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 1 (100.0 mg, 183.95 μmol) in dioxane (1 mL) was added hydrochloric acid solution in dioxane (183.95 μmol, 8 mL) and the reaction was stirred at room temperature for 2 hours. The solvent in the reaction mixture was evaporated under reduced pressure, and the residue was washed with ether and pentane to afford 3-[6-[[1-(1-chloro-4-piperidinyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione 2 (88.0 mg, 183.35 μmol, 99.67% yield) as a yellow solid. LC MS: ES+ 444.1.

[1141] Step 2: Preparation of 6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one: To a stirred solution of 6-[[1-(1-chloro-4-piperidinyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 2 (98.0 mg, 265.68 μmol) and 1-methylcyclobutanecarboxylic acid 3 (30.33 mg, 265.68 μmol) in DMF (2.0 mL) was added HATU (151.53 mg, 398.53 μmol) and N,N-diisopropylethylamine (171.69 mg, 1.33 mmol, 231.38 μL) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then extracted with ethyl acetate, and the combined organic layers were washed with water and saturated sodium bicarbonate solution and dried over sodium sulfate. The organic layer was then concentrated under reduced pressure to afford the crude product. The crude residue was purified by CombiFlash chromatography (eluting with 1%-1.5% MeOH in DCM) to afford 6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidinyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4 (66 mg, 154.02 μmol, 57.97% yield) as a light yellow solid. LC MS: ES+ 429.3.

[1142] Step 3: Preparation of 3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (Compound 4): To a stirred solution of 6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidinyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indole-2-one 4 (66.0 mg, 154.02 μmol) in DMF (1 mL) was added sodium hydride (60% dispersion in mineral oil, 11.80 mg, 308.03 μmol) with cooling and the reaction mixture was heated at 60°C for 30 min. 3-Bromopiperidine-2,6-dione 5 (29.57 mg, 154.02 μmol) was then added and the reaction was heated at 60° C. for 4 hours, followed by the addition of 3-bromopiperidine-2,6-dione (29.57 mg, 154.02 μmol) and the reaction continued at 60° C. for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water, and the organic portion was separated. The organic layer was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product, which was first purified by column chromatography and then by preparative TLC (plates were developed in 60% ethyl acetate-DCM) to afford 3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidinyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 4) (15.0 mg, 27.21 μmol, 17.66% yield, 97.87% purity) as a light yellow solid. 1 HNMR(d6-DMSO,400MHZ)δ11.11(s,1H),8.37(d,J=8.44Hz,1H),8.08(d,J=6.44Hz,1H),7.85-7.83(m,1H ),7.60(s,1H),7.35(d,J=7.12Hz,1H),7.31(s,1H),7.07(d,J=6.84Hz,1H),5.46-5.42(m,1H),4.39-4.3 7(m,1H),4.31-4.29(m,1H),4.18(s,2H),3.60-3.58(m,1H),3.04-2.91(m,3H),2.77-2.62(m,2H),2.41- 2.32(m,3H),2.09-2.07(m,1H),1.92-1.90(m,3H),1.78-1.76(m,3H),1.64-1.61(m,2H),1.33(s,3H); LC MS:ES+540.4.

[1143] Example 5. Synthesis of N-(tert-butyl)-4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-N-methylpiperidine-1-carboxamide (Compound 5)

[1144]

[1145] To an equimolar mixture of HCl salt 1 and tert-butyl (methyl) carbamoyl chloride in DMF (6 mL / mmol) was added DIPEA (4.0 equivalents) at 0 ° C. The resulting solution was stirred at ambient temperature for 16 hours. The reaction mixture was then diluted with ethyl acetate and washed with a NaHCO3 aqueous solution, water (x3) and brine. The organic layer was then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was then purified by CombiFlash ISCO column and eluted with 2% methanol in DCM to give N-(tert-butyl)-4-(4-((1-(2,6-dioxopiperidin-3-yl)-2)-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-N-methylpiperidine-1-carboxamide (Compound 5).

[1146] Example 6. Synthesis of tert-butyl 4-(4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 6) and tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)(hydroxy)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 7)

[1147]

[1148]

[1149] Step 1: Synthesis of tert-butyl 4-(4-(2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2): To a stirred solution of tert-butyl 4-(4-(hydroxy(2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 1 in acetonitrile was added manganese(IV) oxide (10 equiv) and the reaction mixture was stirred at room temperature for 16 hours. TLC and LCMS showed product formation. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the crude material, which was purified by combiflash chromatography using 1.5% MeOH-DCM as eluent to afford the desired product tert-butyl 4-(4-(2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 2.

[1150] Step 2: Synthesis of tert-butyl 4-(4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 6): To a stirred solution of compound 2 in THF was added sodium hydride (60% dispersion in mineral oil, 1 eq) and the reaction mixture was refluxed at 60°C for 30 minutes. A THF solution of (3-bromopiperidine-2,6-dione) (0.5 eq) was also heated at 60°C. After 30 minutes, the first suspension was added to the second solution and heating was continued for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine solution. The organic portion was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude compound. The crude compound was then purified by flash chromatography to obtain compound 6.

[1151] Step 3: Synthesis of tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)(hydroxy)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 7): A stirred solution of Compound 6 in ethanol was cooled to 0°C and sodium borotriacetoxyhydride (1.2 equiv) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 hours. It was quenched with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated and purified by column chromatography using (silica, gradient, 0% to 2% methanol in DCM) to give Compound 7.

[1152] Example 7. Synthesis of tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)difluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 8)

[1153]

[1154] Step 1: Synthesis of tert-butyl 4-(4-(difluoro(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2): To a stirred solution of 1 in DCM was added DAST (3 equiv.) at -30°C and the reaction mixture was stirred at the same temperature for 30 min and then slowly warmed to room temperature. LC-MS showed the desired product. The product was quenched with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated and purified by column chromatography using (silica, gradient, 0% to 2% methanol in DCM) to afford 2.

[1155] Step 2: Synthesis of tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)difluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 8): To a stirred solution of compound 2 in THF was added sodium hydride (60% dispersion in mineral oil, 1 eq), and the reaction mixture was refluxed at 60°C for 30 minutes. A solution of 3-bromopiperidine-2,6-dione 3 (0.5 eq) in THF was also heated at 60°C. After 30 minutes, the first suspension was added to the second solution with heating, and heating was continued for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine solution. The organic phase was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give compound 8.

[1156] Example 8: Synthesis of 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 9)

[1157]

[1158] Steps 1-3: 4-(Morpholinomethyl)benzaldehyde was prepared according to steps 1-3 of the literature procedure provided in WO2015 / 086636.

[1159] Step 4: Synthesis of 6-(hydroxy(4-(morpholinomethyl)phenyl)methyl)benz[cd]indole-2(1H)-one (7): To a stirred solution of 6-bromo-1H-benzo[cd]indole-2-one 6 (1 eq) in THF was added butyllithium (2.2 eq) at -78°C. After completion of addition, the temperature was raised to -40°C and the reaction mixture was stirred at the same temperature for 30 minutes. A solution of 5 (1 eq) in THF (7 mL) was added at -78°C and the reaction mixture was then warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and diluted with ethyl acetate. The layers were separated and the organic phase was washed with water. The organic phase was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to afford the desired product 7.

[1160] Step 5: Synthesis of 6-(4-(morpholinomethyl)benzyl)benzo[cd]indol-2(1H)-one (8): To a stirred solution of 7 in DCE were added triethylsilane (3 eq.) and trifluoroacetic acid (10 eq.), and the reaction was stirred under microwave irradiation at 70° C. for 30 min. The solvent in the reaction mixture was evaporated under reduced pressure to obtain the crude product, which was washed with diethyl ether and pentane to afford 8 as a brown gum, which was used without further purification.

[1161] Step 6: Synthesis of 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 9): To a stirred solution of 8 in THF was added sodium hydride (60% dispersion in mineral oil, 1 eq.), and the reaction mixture was refluxed at 60 °C for 30 min. A solution of 3-bromopiperidine-2,6-dione 9 (0.5 eq.) in THF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating, and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine solution. The organic portion was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude compound. The crude compound was then purified by flash chromatography to obtain compound 9.

[1162] Example 9. Synthesis of 3-(6-amino-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 10)

[1163]

[1164] Step 1: Synthesis of 6-nitrobenzo[cd]indol-2(1H)-one (2): To a stirred solution of 1 in acetic acid was added nitric acid at 0°C and the resulting reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was added to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine solution and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired product 2, which was further purified by column chromatography or recrystallization.

[1165] Step 2: Synthesis of 3-(6-nitro-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (4): To a stirred solution of compound 2 in THF was added sodium hydride (60% dispersion in mineral oil, 1 eq.) and the reaction mixture was refluxed at 60°C for 30 min. A solution of 3-bromopiperidine-2,6-dione 3 (0.5 eq.) in THF was also heated at 60°C. After 30 min, the first suspension was added to the second solution under heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine solution. The organic portion was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude compound. The crude compound was then purified by flash chromatography to obtain 4.

[1166] Step 3: Synthesis of 3-(6-amino-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 10): A stirred solution of 4 in ethanol was degassed with argon for 10 minutes. 10% Pd / C (30 wt%) was added to the reaction mixture, and hydrogenation was performed under a hydrogen balloon for 16 hours. The mixture was filtered through celite and concentrated under reduced pressure to provide Compound 10 as a solid.

[1167] Example 10. Synthesis of tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 11) and 3-(6-((1-(1-((2r,3r,5r,6r,7r,8r)-cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 12)

[1168]

[1169]

[1170] Step 1: Synthesis of tert-butyl 4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (3): To a stirred solution of tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (20 mg, 75.09 μmol) and 6-bromo-1H-benzo[cd]indol-2-one (18.63 mg, 75.09 μmol) in toluene (5 mL) in a sealed tube was added potassium tert-butoxide (25.28 mg, 225.28 μmol) and the reaction mixture was degassed under argon for 5 minutes. Pd2(dba)3 (6.88 mg, 7.51 μmol) and BINAP (4.68 mg, 7.51 μmol) were added and the reaction mixture was purged under argon again for 2 minutes. The reaction mixture was heated to 90° C. for 16 hours. After the SM reaction was exhausted, the mixture was filtered through a bed of celite and concentrated in vacuo. Purification by CombiFlash column chromatography (eluting with 15% ethyl acetate in hexane) provided tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate 3 as a yellow liquid. LCMS(ES+)=249.9[M+H]+.

[1171] Step 2: Synthesis of tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 11): To a stirred solution of compound 3 in THF was added sodium hydride (60% dispersion in mineral oil, 1 eq.), and the reaction mixture was refluxed at 60 °C for 30 min. A THF solution of 3-bromopiperidine-2,6-dione 4 (0.5 eq.) was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating, and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine solution. The organic portion was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude compound. The crude compound was then purified by flash chromatography to obtain compound 11.

[1172] Step 3: Synthesis of 3-(2-oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (5): To a stirred solution of compound 11 in 1,4-dioxane was added HCl in dioxane (4M). The reaction mixture was stirred at 25°C for 16 hours. After complete consumption of the starting material, the reaction was concentrated under reduced pressure. The resulting solid was washed with 10-20% ethyl acetate in hexane and dried to afford the title compound 5.

[1173] Step 4: Synthesis of 3-(6-((1-(1-((2r,3r,5r,6r,7r,8r)-cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (Compound 12): To a stirred solution of 5 and cubane-1-carboxylic acid (1 eq) in DMF (2 mL) were added HATU (1.5 eq) and DIPEA (3 eq) and the reaction mixture was stirred at 25 °C for 16 h. Completion of the reaction was determined by LC-MS. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC using 100% ethyl acetate to give Compound 12 as a solid.

[1174] Example 11. Synthesis of 3-(6-(4-(morpholinomethyl)phenoxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 13)

[1175]

[1176]

[1177] Step 1: Synthesis of 6-hydroxybenzo[cd]indole-2(1H)-one (2): To a stirred solution of 1 in dioxane (8 mL) and water (2 mL) was added potassium hydroxide (2 equiv). The resulting solution was degassed with N2 for 15 min, followed by the addition of (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (5%) and tert-butyl Xphos (15%). The reaction mixture was heated at 100°C in a sealed tube for 12 h. After the desired PDT was formed according to LC-MS, the reaction mixture was filtered through a bed of celite and washed with ethyl acetate. The combined organic layers were separated and evaporated. The crude residue was purified by column chromatography to afford 2 as a solid.

[1178] Step 2: Synthesis of tert-butyl 6-hydroxy-2-oxobenzo[cd]indole-1(2H)-carboxylate (3): To a stirred solution of 2 in methanol (5 mL) and triethylamine (2 equiv) was slowly added di-tert-butyl dicarbonate (1.5 equiv). After completion of the reaction as confirmed by TLC and LC-MS, the solvent was removed. The crude product was extracted with ethyl acetate and water. The organic layer was dried over Na2SO4. The solvent was removed in vacuo to give the desired product 3.

[1179] Step 3: Synthesis of tert-butyl 6-(4-(morpholinomethyl)phenoxy)-2-oxobenzo[cd]indole-1(2H)-carboxylate (5): To a stirred solution of 3 and 4 in DCE was added pyridine (2 eq). The reaction mixture was degassed with oxygen followed by the addition of copper acetate (0.1 eq) and DMAP (0.1 eq). The reaction mixture was heated at 80°C for 24 h. After completion of the reaction, the solvent was removed and the crude product was extracted with ethyl acetate and water. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo to afford the desired product 5.

[1180] Step 4: Synthesis of 6-(4-(morph...

Claims

1. Compounds of Formula I or a pharmaceutically acceptable salt thereof; in: X 1 and X 2 are independently selected from CH and N; R 1 is selected from hydrogen, halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, -NH2, -OR 2 、-OH、-NR 2 R 4 、-OR 4 、-(CR 3 R 3 ')-R 4 、-C(O)R 4 、-SR 4 、-S(O)R 4 and -S(O)2R 4 ; R 2 is independently selected at each occurrence from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, a 3-8 membered heterocycle having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, phenyl, naphthyl, heteroaryl, -C(O)R 8 、-C(O)OR 8 、-C(O)-NR 8 R 8 '、-S(O)R 8 、-SO2R 8 、-SO2-OR 8 and -SO2-NR 8 R 8 '; R 3 is selected from hydrogen, halogen, C1-C4 alkyl and C1-C4 haloalkyl; R 3 ' is selected from hydrogen, halogen, C1-C4 alkyl and C1-C4 haloalkyl; or R 3 and R 3 'can combine with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring; R 4 is selected from C3-C8 cycloalkyl, 3-8 membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, phenyl, naphthyl and heteroaryl, wherein each R 4 Optionally, one selected from R 6 substituted with a group, and each R 4 Also optionally 1, 2, 3 or 4 independently selected from R 7 The group substitution; R 6 is selected from C1-C4 alkyl, C3-C8 cycloalkyl, a 3-8 membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, phenyl, naphthyl, heteroaryl, -CO-C1-C4 alkyl, -CO-C3-C8 cycloalkyl, -CO-(a 3-8 membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen), -CO-(phenyl or naphthyl), -CO-(heteroaryl), -O-C1-C4 alkyl, -O-C3-C8 cycloalkyl, -O-(a 3-8 membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen), -O-(phenyl or naphthyl), -O-(heteroaryl), -NR 2 -C1-C4 alkyl, -NR 2 -C3-C8 cycloalkyl, -NR 2 -(3-8 membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen), -NR 2 -(phenyl or naphthyl) and -NR 2 -(heteroaryl), wherein each R 6 Optionally 1, 2, 3 or 4 independently selected from R 9 The group substitution; R 7 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, a 3-8 membered heterocycle having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, phenyl, naphthyl, heteroaryl, -OR 8 、-NR 8 R 8 ',-C(O)R 8 、-C(O)OR 8 、-C(O)-NR 8 R 8 '、-OC(O)R 8 、-NR 2 -C(O)R 8 、-S(O)R 8 、-SO2R 8 、-SO2-OR 8 and -SO2-NR 8 R 8 '; or two R on the same carbon 7 can be combined together to form oxo groups; R 8 and R 8’ is independently selected at each occurrence from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, a 3-8 membered heterocycle having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, phenyl, naphthyl and heteroaryl; R 9 is independently selected at each occurrence from hydrogen, halogen, cyano, nitro, R 10 、-CH2R 10 、-OR 10 、-NR 2 R 10 、-C(O)R 10 、-C(O)CH2R 10 、-C(O)CH2OR 10 、-C(O)CH2NR 2 R 10 、-OC(O)R 10 、-NR 2 -C(O)R 10 、-C(O)OR 10 、-C(O)NR 2 R 10 、-S(O)R 10 、-SO2R 10 、SO2CH2R 10 、-SO2CH2OR 10 、-SO2CH2NR 2 R 10 、-NR 2 S02R 10 、-SO2-OR 10 and -SO2-NR 2 R 10 ; R 10 Selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C 11 Cycloalkyl, 3-11 membered heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, phenyl, naphthyl and heteroaryl, wherein each R 10 Optionally 1, 2, 3 or 4 independently selected from R 11 The group substitution; R 11 is independently selected at each occurrence from: halogen; hydroxy; cyano; nitro; C1-C4 alkyl; C1-C4 haloalkyl; C2-C4 alkenyl; C2-C4 alkynyl; C3-C8 cycloalkyl; a 3-8 membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen; phenyl; naphthyl; heteroaryl; -CH2 (phenyl or naphthyl); -CH2 (heteroaryl); -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ; -C(O)OR 8 ;-C(O)-NR 8 R 8’ ; -C(O)CH2R 8 ; -C(O)CH2OR 8 ; -C(O)CH2-NR 8 R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8 ;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ; -SO2-OR 8 ; and -SO2-NR 8 R 8’ ; where each R 11 The group is optionally composed of 1, 2, 3 or 4 independently selected R 12 The group substitution; or two R on the same carbon 11 The groups may be combined together to form an oxo group; and R 12 is independently selected at each occurrence from: halogen; hydroxy; cyano; nitro; C1-C4 alkyl; C1-C4 haloalkyl; C2-C4 alkenyl; C2-C4 alkynyl; C3-C8 cycloalkyl; a 3-8 membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen; phenyl; naphthyl; heteroaryl; -CH2 (phenyl or naphthyl); -CH2 (heteroaryl); -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ; -C(O)OR 8 ;-C(O)-NR 8 R 8’ ; -C(O)CH2R 8 ; -C(O)CH2OR 8 ; -C(O)CH2-NR 8 R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8 ;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ; -SO2-OR 8 ; oxo; and -SO2-NR 8 R 8 '; wherein the heteroaryl group is selected from a 5- to 6-membered heteromonocyclic heteroaryl group containing 1 to 3 nitrogen atoms; a 2-furyl group; a 3-furyl group; a 2-thienyl group; a 3-thienyl group; a 5- to 6-membered heteromonocyclic heteroaryl group containing 1 oxygen atom and 1 to 2 nitrogen atoms; a 5- to 6-membered heteromonocyclic heteroaryl group containing 1 sulfur atom and 1 to 2 nitrogen atoms; and an 8-, 9- or 10-membered bicyclic heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from O, N and S.

2. The compound according to claim 1, wherein R 12 Selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl.

3. The compound according to claim 1, wherein R 12 is selected from hydroxy, cyano, nitro, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, a 3-8 membered heterocycle having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, phenyl and heteroaryl, wherein the heteroaryl is as defined in claim 1.

4. The compound according to claim 1, wherein R 12 Selected from: -CH2phenyl; -CH2(heteroaryl); -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ; -C(O)OR 8 ;-C(O)-NR 8 R 8’ ; -C(O)CH2R 8 ; -C(O)CH2OR 8 ; -C(O)CH2-NR 8 R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8 ;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ; -SO2-OR 8 ; oxo; and -SO2-NR 8 R 8 ', wherein the heteroaryl group is as defined in claim 1.

5. The compound according to claim 1, wherein one R 12 The substituent is halogen.

6. The compound according to claim 1, wherein two R 12 The substituent is halogen.

7. The compound according to claim 1, wherein one R 12 The substituent is a C1-C4 alkyl group.

8. The compound according to claim 1, wherein two R 12 The substituent is a C1-C4 alkyl group.

9. The compound according to claim 1, wherein one R 12 The substituent is a C1-C4 haloalkyl group.

10. The compound according to claim 1, wherein one R 12 The substituent is a C3-C8 cycloalkyl group.

11. The compound according to claim 1, wherein R 11 is optionally 1, 2, 3 or 4 selected from R 12 A C1-C4 alkyl group substituted with a substituent.

12. The compound according to claim 1, wherein R 11 is optionally 1, 2, 3 or 4 selected from R 12 A C3-C8 cycloalkyl group substituted with a substituent.

13. The compound according to claim 1, wherein R 11 is optionally 1, 2, 3 or 4 selected from R 12 The substituents are substituted with a 3- to 8-membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen.

14. The compound according to claim 1, wherein R 11 is optionally 1, 2, 3 or 4 selected from R 12 The substituent is substituted with phenyl or naphthyl.

15. The compound according to claim 1, wherein R 11 is optionally 1, 2, 3 or 4 selected from R 12 A heteroaryl group substituted with a substituent, wherein the heteroaryl group is as defined in claim 1.

16. The compound according to claim 1, wherein R 11 It is a C1-C4 alkyl group.

17. The compound according to claim 1, wherein R 11 It is cyano.

18. The compound according to claim 1, wherein R 11 It is a C1-C4 haloalkyl group.

19. The compound according to claim 1, wherein R 11 It is methyl.

20. The compound according to claim 1, wherein R 11 It is hydroxyl.

21. The compound according to claim 1, wherein R 11 OR 8 .

22. The compound according to claim 1, wherein R 11 It is phenyl.

23. The compound according to claim 1, wherein R 11 is a heteroaryl group, wherein the heteroaryl group is as defined in claim 1.

24. The compound according to claim 1, wherein R 11 -C(O)OR 8 、-C(O)R 8 or-SO2R 8 .

25. The compound according to claim 1, wherein R 11 It is -CH2phenyl.

26. The compound according to claim 1, wherein R 1 -C(O)R 4 .

27. The compound according to claim 1, wherein R 1 -S(O)R 4 .

28. The compound according to claim 1, wherein R1 is -S(O)2R 4 .

29. The compound of claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

30. The compound of claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

32. The compound of claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

33. The compound according to claim 1, wherein R 3 For hydrogen.

34. The compound according to claim 1, wherein R 3 It is a C1-C4 alkyl group.

35. The compound according to claim 1, wherein R 3’ For hydrogen.

36. The compound of claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

37. The compound of claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

38. The compound of claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

39. A compound according to any one of claims 1 to 38, wherein R 4 is selected by a 6 and optionally substituted by 1, 2, 3 or 4 groups independently selected from R 7 A C3-C8 cycloalkyl group substituted with a group.

40. A compound according to any one of claims 1-38, wherein R 4 is selected by a 6 and optionally substituted by 1, 2, 3 or 4 groups independently selected from R 7 A 3- to 8-membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen which is substituted by a group.

41. A compound according to any one of claims 1-38, wherein R 4 is selected by a 6 and optionally substituted by 1, 2, 3 or 4 groups independently selected from R 7 A phenyl group substituted with a group.

42. A compound according to any one of claims 1-38, wherein R 4 is selected by a 6 and optionally substituted by 1, 2, 3 or 4 groups independently selected from R 7 A heteroaryl group substituted with a group, wherein the heteroaryl group is as defined in claim 1.

43. A compound according to any one of claims 1-38, wherein R 4 yes 44. A compound according to any one of claims 1-38, wherein R 4 yes 45. A compound according to any one of claims 1-38, wherein R 4 yes 46. ​​A compound according to any one of claims 1-38, wherein R 4 yes 47. A compound according to any one of claims 1-28 and 33-38, wherein R 1 yes 48. A compound according to any one of claims 1-38, wherein R 7 is selected from hydrogen, halogen, hydroxy, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, a 3-8 membered heterocycle having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, phenyl, heteroaryl, -OR 8 and-NR 8 R 8 ', wherein the heteroaryl group is as defined in claim 1.

49. A compound according to any one of claims 1-38, wherein R 7 is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, -C(O)R 8 、-C(O)OR 8 、-C(O)-NR 8 R 8 '、-OC(O)R 8 、-NR 2 -C(O)R 8 、-S(O)R 8 、-SO2R 8 、-SO2-OR 8 and -SO2-NR 8 R 8 '.

50. A compound according to any one of claims 1-38, wherein one R 7 For hydrogen.

51. according to the compound described in any one of claims 1-38, wherein two R 7 For hydrogen.

52. according to the compound described in any one of claims 1-38, wherein three R 7 For hydrogen.

53. A compound according to any one of claims 1-38, wherein one R 7 It is a halogen.

54. according to the compound described in any one of claims 1-38, wherein two R 7 It is a halogen.

55. A compound according to any one of claims 1-38, wherein one R 7 It is a C1-C4 alkyl group.

56. according to the compound described in any one of claims 1-38, wherein two R 7 It is a C1-C4 alkyl group.

57. A compound according to any one of claims 1-38, wherein one R 7 It is a C1-C4 haloalkyl group.

58. according to the compound described in any one of claims 1-38, wherein two R 7 It is a C1-C4 haloalkyl group.

59. according to the compound described in any one of claims 1-38, wherein R 6 Selected from:

60. A compound according to any one of claims 1-38, wherein R 6 Selected from:

61. according to the compound described in any one of claims 1-38, wherein R 6 Selected from:

62. according to the compound described in any one of claims 1-38, wherein R 6 is optionally 1, 2, 3 or 4 independently selected from R 9 C1-C4 alkyl substituted with a group.

63. according to the compound described in any one of claims 1-38, wherein R 6 is optionally 1, 2, 3 or 4 independently selected from R 9 A C3-C8 cycloalkyl group substituted with a group.

64. according to the compound described in any one of claims 1-38, wherein R 6 is optionally 1, 2, 3 or 4 independently selected from R 9 A 3- to 8-membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen which is substituted by a group.

65. according to the compound described in any one of claims 1-38, wherein R 6 is optionally 1, 2, 3 or 4 independently selected from R 9 A phenyl group substituted with a group.

66. A compound according to any one of claims 1-38, wherein R 6 is optionally 1, 2, 3 or 4 independently selected from R 9 A heteroaryl group substituted with a group, wherein the heteroaryl group is as defined in claim 1.

67. A compound according to any one of claims 1-38, wherein R 6 Not replaced.

68. A compound according to any one of claims 1-38, wherein R 6 Selected by 1 9 The group is substituted.

69. A compound according to any one of claims 1-38, wherein R 6 2 independently selected from R 9 The group is substituted.

70. A compound according to any one of claims 1-38, wherein R 6 3 independently selected from R 9 The group is substituted.

71. according to the compound described in any one of claims 1-38, wherein R 6 4 independently selected from R 9 The group is substituted.

72. A compound according to any one of claims 1-38, wherein R 9 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano and nitro.

73. A compound according to any one of claims 1-38, wherein R 9 Selected from R 10 .

74. according to the compound described in any one of claims 1-38, wherein R 9 Selected from -CH2R 10 、-OR 10 、-NR 2 R 10 、-C(O)R 10 、-C(O)CH2R 10 、-C(O)CH2OR 10 、-C(O)CH2NR 2 R 10 、-OC(O)R 10 、-NR 2 -C(O)R 10 、-C(O)OR 10 、-C(O)NR 2 R 10 、-S(O)R 10 、-SO2R 10 、SO2CH2R 10 、-SO2CH2OR 10 、-SO2CH2NR 2 R 10 、-NR 2 S02R 10 、-SO2-OR 10 and -SO2-NR 2 R 10 .

75. according to the compound described in any one of claims 1-38, wherein R 10 is optionally 1, 2, 3 or 4 independently selected from R 11 A C1-C6 alkyl group substituted with a group.

76. A compound according to any one of claims 1-38, wherein R 10 is optionally 1, 2, 3 or 4 independently selected from R 11 C1-C6 haloalkyl substituted with a group.

77. A compound according to any one of claims 1-38, wherein R 10 is optionally 1, 2, 3 or 4 independently selected from R 11 A C2-C4 alkenyl group substituted with a group.

78. A compound according to any one of claims 1-38, wherein R 10 is optionally 1, 2, 3 or 4 independently selected from R 11 A C2-C4 alkynyl substituted with a group.

79. according to the compound described in any one of claims 1-38, wherein R 10 is optionally 1, 2, 3 or 4 independently selected from R 11 C3-C 11 Cycloalkyl.

80. A compound according to any one of claims 1-38, wherein R 10 is optionally 1, 2, 3 or 4 independently selected from R 11 A 3- to 11-membered heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen which is substituted by a group.

81. according to the compound described in any one of claims 1-38, wherein R 10 is optionally 1, 2, 3 or 4 independently selected from R 11 A phenyl group substituted with a group.

82. according to the compound described in any one of claims 1-38, wherein R 10 is optionally 1, 2, 3 or 4 independently selected from R 11 A heteroaryl group substituted with a group, wherein the heteroaryl group is as defined in claim 1.

83. according to the compound described in any one of claims 1-38, wherein R 10 Not replaced.

84. according to the compound described in any one of claims 1-38, wherein R 10 Selected by 1 11 The group is substituted.

85. according to the compound described in any one of claims 1-38, wherein R 10 2 independently selected from R 11 The group is substituted.

86. according to the compound described in any one of claims 1-38, wherein R 10 3 independently selected from R 11 The group is substituted.

87. according to the compound described in any one of claims 1-38, wherein R 10 4 independently selected from R 11 The group is substituted.

88. according to the compound described in any one of claims 1-38, wherein R 2 , R 8 and R 8’ For hydrogen.

89. according to the compound described in any one of claims 1-38, wherein R 2 , R 8 and R 8’ It is a C1-C4 alkyl group.

90. according to the compound described in any one of claims 1-38, wherein R 6 Selected from 91. according to the compound described in any one of claims 1-38, wherein R 6 Selected from:

92. according to the compound described in any one of claims 1-38, wherein R 6 Selected from:

93. The compound of the formula or a pharmaceutically acceptable salt thereof; in: R 2 is independently selected at each occurrence from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, a 3-8 membered heterocycle having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, phenyl, naphthyl, heteroaryl, -C(O)R 8 、-C(O)OR 8 、-C(O)-NR 8 R 8 '、-S(O)R 8 、-SO2R 8 、-SO2-OR 8 and -SO2-NR 8 R 8 '; R 3 is selected from hydrogen, halogen, C1-C4 alkyl and C1-C4 haloalkyl; R 3 ' is selected from hydrogen, halogen, C1-C4 alkyl and C1-C4 haloalkyl; or R 3 and R 3 'can combine with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring; R 7 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, a 3-8 membered heterocycle having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, phenyl, naphthyl, heteroaryl, -OR 8 、-NR 8 R 8 ',-C(O)R 8 、-C(O)OR 8 、-C(O)-NR 8 R 8 '、-OC(O)R 8 、-NR 2 -C(O)R 8 、-S(O)R 8 、-SO2R 8 、-SO2-OR 8 and -SO2-NR 8 R 8 '; or two R on the same carbon 7 can be combined together to form oxo groups; R 8 and R 8’ is independently selected at each occurrence from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, a 3-8 membered heterocycle having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, phenyl, naphthyl and heteroaryl; R 9 is independently selected at each occurrence from hydrogen, halogen, cyano, nitro, R 10 、-CH2R 10 、-OR 10 、-NR 2 R 10 、-C(O)R 10 、-C(O)CH2R 10 、-C(O)CH2OR 10 、-C(O)CH2NR 2 R 10 、-OC(O)R 10 、-NR 2 -C(O)R 10 、-C(O)OR 10 、-C(O)NR 2 R 10 、-S(O)R 10 、-SO2R 10 、SO2CH2R 10 、-SO2CH2OR 10 、-SO2CH2NR 2 R 10 、-NR 2 S02R 10 、-SO2-OR 10 and -SO2-NR 2 R 10 ; R 10 Selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C 11 Cycloalkyl, 3-11 membered heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, phenyl and heteroaryl, wherein each R 10 Optionally 1, 2, 3 or 4 independently selected from R 11 The group substitution; R 11 is independently selected at each occurrence from: halogen; hydroxy; cyano; nitro; C1-C4 alkyl; C1-C4 haloalkyl; C2-C4 alkenyl; C2-C4 alkynyl; C3-C8 cycloalkyl; a 3-8 membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen; phenyl; naphthyl; heteroaryl; -CH2 (phenyl or naphthyl); -CH2 (heteroaryl); -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ;-C(O)OR 8 ;-C(O)-NR 8 R 8’ ; -C(O)CH2R 8 ; -C(O)CH2OR 8 ; -C(O)CH2-NR 8 R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8 ;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ; -SO2-OR 8 ; and -SO2-NR 8 R 8’ ; where each R 11 The group is optionally composed of 1, 2, 3 or 4 independently selected R 12 The group substitution; or two R on the same carbon 11 The groups may be combined together to form an oxo group; and R 12 is independently selected at each occurrence from: halogen; hydroxy; cyano; nitro; C1-C4 alkyl; C1-C4 haloalkyl; C2-C4 alkenyl; C2-C4 alkynyl; C3-C8 cycloalkyl; a 3-8 membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen; phenyl; naphthyl; heteroaryl; -CH2 (phenyl or naphthyl); -CH2 (heteroaryl); -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ;-C(O)OR 8 ;-C(O)-NR 8 R 8’ ; -C(O)CH2R 8 ; -C(O)CH2OR 8 ; -C(O)CH2-NR 8 R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8 ;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ; -SO2-OR 8 ; oxo; and -SO2-NR 8 R 8 '; wherein the heteroaryl group is selected from a 5- to 6-membered heteromonocyclic heteroaryl group containing 1 to 3 nitrogen atoms; a 2-furyl group; a 3-furyl group; a 2-thienyl group; a 3-thienyl group; a 5- to 6-membered heteromonocyclic heteroaryl group containing 1 oxygen atom and 1 to 2 nitrogen atoms; a 5- to 6-membered heteromonocyclic heteroaryl group containing 1 sulfur atom and 1 to 2 nitrogen atoms; and an 8-, 9- or 10-membered bicyclic heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from O, N and S.

94. The compound according to claim 93, wherein R 3 For hydrogen.

95. The compound according to claim 93, wherein R 3 It is a C1-C4 alkyl group.

96. The compound according to claim 94, wherein R 3 ' is hydrogen.

97. The compound according to claim 93, wherein one R 7 For hydrogen.

98. The compound according to claim 93, wherein two R 7 For hydrogen.

99. The compound according to claim 93, wherein three R 7 For hydrogen.

100. The compound according to claim 93, wherein one R 7 It is a halogen.

101. The compound according to claim 93, wherein two R 7 It is a halogen.

102. The compound according to claim 93, wherein one R 7 It is a C1-C4 alkyl group.

103. The compound according to claim 93, wherein two R 7 It is a C1-C4 alkyl group.

104. The compound according to claim 93, wherein one R 7 It is a C1-C4 haloalkyl group.

105. The compound according to claim 93, wherein two R 7 It is a C1-C4 haloalkyl group.

106. The compound of claim 1, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

107. A compound, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

108. The compound of claim 1, wherein the compound has the structure: or a pharmaceutically acceptable salt thereof.

109. The compound of claim 1, wherein the compound has the structure: or a pharmaceutically acceptable salt thereof.

110. The compound of claim 1, wherein the compound has the structure: or a pharmaceutically acceptable salt thereof.

111. The compound of claim 1, wherein the compound has the structure: or a pharmaceutically acceptable salt thereof.

112. Compounds having the following structure: or a pharmaceutically acceptable salt thereof.

113. The compound of claim 1, wherein the compound has the structure: or a pharmaceutically acceptable salt thereof.

114. The compound of claim 1, wherein the compound has the structure: or a pharmaceutically acceptable salt thereof.

115. A pharmaceutical composition comprising a compound according to any one of claims 1 to 114 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

116. Use of a compound according to any one of claims 1 to 114 or a pharmaceutical composition according to claim 115 for the preparation of a medicament for treating a condition mediated by Ikaros or Aiolos in a human, wherein the condition is a hematological malignancy.

117. The use according to claim 116, wherein the hematological malignancy is multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma.

118. The use according to any one of claims 116-117, wherein the compound has the following structure: or a pharmaceutically acceptable salt thereof.

119. The use according to any one of claims 116-117, wherein the compound has the following structure: or a pharmaceutically acceptable salt thereof.

120. The use according to any one of claims 116-117, wherein the compound has the following structure: or a pharmaceutically acceptable salt thereof.

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