Tricyclic degrades of IKAROS and AIOLOS

Abstract

The present invention describes a tricyclic cerebron binding agent that degrades Ikaros or Ailoos by the ubiquitin proteasome pathway for use in therapeutic applications.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of April 10, 2020, an application number of 202080028010.X, and an invention title of "Tricyclic Degraders of IKAROS and AIOLOS".

[0002] Cross - Reference to Related Applications

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 833,107, filed on April 12, 2019, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0004] The present invention provides cereblon binders for degrading Ikaros (IKZF1) or Aiolos (IKZF3) via the ubiquitin proteasome pathway for the therapeutic applications further described herein. Background Art

[0005] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. Selective recognition and removal of damaged, misfolded, or excessive proteins are achieved through the ubiquitin-proteasome pathway (UPP). The UPP is central to regulating nearly all cellular processes, including antigen processing, apoptosis, organelle biogenesis, the cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, neural and muscle degeneration, morphogenesis of neural networks, regulation of cell surface receptors, ion channels, and the secretory pathway, responses to stress and extracellular regulators, ribosome biogenesis, and viral infection.

[0006] Covalent attachment of multiple ubiquitin molecules to terminal lysine residues by an E3 ubiquitin ligase marks the protein for degradation by the proteasome, where the protein is digested into small peptides and ultimately into its constituent amino acids, which serve as building blocks for new proteins. Defective proteasomal degradation is associated with a variety of clinical diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular diseases, and cancer.

[0007] 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 two decades that followed, four additional homologs have been identified: Helios (“IKZF2”), Aiolos (“IKZF3”), Eos (“IKZF4”), and Pegasus (“IKZF5”) (see John, L. B. and Ward, A. C. “The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity” Mol Immunol, 2011, 48: 1272 - 1278). Each homolog can generate several protein isoforms through alternative splicing, theoretically allowing for a large number of protein complexes to be generated through different combinations of the various homologs. Highly conserved among the family members is a set of two Cys2His2 zinc finger motifs at the C - terminus, which mediate protein - protein interactions between different members of the protein family. Up to four zinc finger motifs are present at the N - terminus for DNA sequence recognition; the number of these N - terminal zinc fingers varies due to alternative splicing. Isoforms lacking these N - terminal zinc fingers show a significant negative impact 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).

[0008] The various members of the Ikaros protein family are very differently distributed in vivo. Ikaros, Helios, and Aiolos are mainly present in lymphocytes and their corresponding progenitor cells. Additionally, Ikaros has been detected in the brain, and Ikaros and Helios have been detected in erythrocytes. Eos and Pegasus are more widely distributed, being present in skeletal muscle, liver, brain, and heart (see Perdomo, J. et al.). Eos and Pegasus, two members of the Ikaros protein family, have different 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. “The Ikaros finger of lymphocyte differentiation” Int J Hematol, 2014, 100: 220-229).

[0009] Ikaros is important for the normal development of lymphocytes. Deletion of the exon encoding the first three N-terminal zinc fingers results in mice lacking T cells, B cells, natural killer (NK) cells, and their progenitor cells. Genetic alterations of Ikaros are associated with poor outcomes in the treatment of acute lymphoblastic leukemia (ALL). Ikaros and Aiolos are involved in the proliferation of multiple myeloma cells, indicating a potential role in malignancies.

[0010] Thalidomide and its analogs lenalidomide and pomalidomide have attracted interest as immunomodulators and anti-tumor agents, especially in multiple myeloma (see Martiniani, R. et al. “Biological activities of lenalidomide and its potential therapeutic role in multiple myeloma” Adv Hematol, 2012, 2012: 842945; and Terpos, E. et al. “Pomalidomide: a new agent for the treatment of relapsed and refractory multiple myeloma” Oncotargets and Therapy, 2013, 6: 531). Although the exact mechanisms of action of thalidomide, lenalidomide, and pomalidomide are not clear, these compounds can be used to treat some cancers, including multiple myeloma. There are also uses in the treatment of renal cell carcinoma, glioblastoma, prostate cancer, melanoma, colorectal cancer, Crohn's disease, rheumatoid arthritis, Behçet's syndrome, breast cancer, head and neck cancer, ovarian cancer, chronic heart failure, graft-versus-host disease, and tuberculous meningitis.

[0011] 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 a major target for thalidomide teratogenicity", Science, 2010, 327: 1345). Cereblon is part of an E3 ubiquitin ligase complex that interacts with damaged DNA binding protein 1, forms an E3 ubiquitin ligase complex with Cullin 4 and the E2 binding protein ROC1 (also known as RBX1), where it acts as a substrate receptor to select proteins for ubiquitination.

[0012] The 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 Ikaros protein", Science, 2014, 343: 305 - 309; J. et al., "Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells", Science, 2014, 343: 301 - 305).

[0013] The disclosure of the binding of thalidomide to the cereblon E3 ubiquitin ligase led to studies to investigate the incorporation of thalidomide and certain derivatives into compounds to target the destruction of proteins. Celgene has disclosed imides for similar uses, including those in 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; 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.

[0014] WO 2020 / 006262 filed by Dana Farber Cancer Institute discloses cereblon modulators.

[0015] PCT / US19 / 24094 filed by C4 Therapeutics, Inc. discloses cereblon binders for degrading Ikaros.

[0016] An object of the present invention is to provide new compounds, uses and manufacturing methods for medical treatment that cause the degradation of Ikaros or Aiolos, including for the treatment of hematopoietic diseases involving abnormal cell proliferation, including tumors and cancers. SUMMARY OF THE INVENTION

[0017] New compounds that bind to cereblon and their uses and preparations are provided. It is believed that the binding of the disclosed compounds to cereblon results in an increased interaction of cereblon with Ikaros (IKZF1) or Aiolos (IKZF3), leading to their subsequent ubiquitination and degradation in the proteasome. A decrease in the level of Ikaros or Aiolos results in a change in the transcriptional regulation of their downstream proteins. Selected compounds have been found to be both effective binders of cereblon and show effective inhibition of multiple myeloma cell proliferation compared to pomalidomide.

[0018] The selected compounds disclosed herein, their pharmaceutically acceptable salts or their pharmaceutically acceptable compositions can be used to treat conditions mediated by Ikaros or Aiolos, such as hematological malignancies, such as multiple myeloma, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome or other target indications. Thus, in one embodiment, a method of treating a host (usually 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.

[0019] In one aspect, compounds of formula I are provided:

[0020]

[0021] or a pharmaceutically acceptable salt, N-oxide, isotopically derivative or prodrug thereof, optionally formulated in a pharmaceutically acceptable carrier;

[0022] wherein:

[0023] X 1 and X 2 are independently selected from CH and N;

[0024] R 1 is selected from hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, -NR 2 R 2' 、-OR 2 、-NR 2 R 4 、-OR 4 、-NR 2 R5 , -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 ;

[0025] R 2 and R 2' are each 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' ;

[0026] R 3 is selected from hydrogen, halogen, alkyl, haloalkyl, -OR 8 and -NR 8 R 8' ;

[0027] R 3' is selected from hydrogen, halogen, alkyl and haloalkyl;

[0028] Or R 3 and R 3' may combine with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring;

[0029] R 4Selected from cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each R 4 is optionally substituted with a group selected from R 6 , and wherein each R 4 is also optionally substituted with 1, 2, 3 or 4 groups independently selected from R 7 ;

[0030] R 5 is -C(O)R 6 ;

[0031] R 6 is selected from alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each R 6 is optionally substituted with 1, 2, 3 or 4 groups independently selected from R 9 ;

[0032] or R 6 is selected from alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocyclic, -CO-aryl, -CO-heteroaryl, -O-alkyl, -O-cycloalkyl, -O-heterocyclic, -O-aryl, -O-heteroaryl, -NR 2 -alkyl, -NR 2 -cycloalkyl, -NR 2 -heterocyclic, -NR 2 -aryl and -NR 2 -heteroaryl, wherein each R 6 is optionally substituted with 1, 2, 3 or 4 groups independently selected from R 9 ;

[0033] R 7 is independently selected from hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, 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' ;

[0034] or two R 7can be combined together to form an oxo group;

[0035] R 8 and R 8’ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl each time it appears;

[0036] R 9 is independently selected 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 ;

[0037] R 10 is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein each R 10 is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 11 ; and

[0038] R 11 is selected from: hydrogen; halogen; hydroxy; cyano; nitro; alkyl; haloalkyl; alkenyl optionally substituted by aryl or heteroaryl; alkynyl optionally substituted by aryl or heteroaryl; cycloalkyl; heterocycle; aryl optionally substituted by 1, 2, 3 or 4 halogen, alkyl or -OR 8 groups; aryl optionally substituted by 1, 2, 3 or 4 halogen, alkyl or -OR 8Group-substituted heteroaryl; optionally substituted by 1, 2, 3 or 4 halogens, alkyl or -OR 8 Group-substituted -CH2aryl; optionally substituted by 1, 2, 3 or 4 halogens, alkyl or -OR 8 Group-substituted -CH2heteroaryl; -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’ ;

[0039] or two Rs on the same carbon 11 The groups can combine together to form an oxo group.

[0040] or R 11 is independently selected from: halogen; hydroxy; cyano; nitro; alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl; heterocycle; aryl; heteroaryl; -CH2aryl; -CH2heteroaryl; -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 each R 11 group is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 12 ; and

[0041] R 12 is independently selected, each time it appears, from: halogen; hydroxy; cyano; nitro; alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl; heterocycle; aryl; heteroaryl; -CH2aryl; -CH2heteroaryl; -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' 。

[0042] In one embodiment, the compound of formula I is selected from formula I-a, formula I-b and formula I-c:

[0043]

[0044] wherein all variables are as defined herein.

[0045] In another embodiment, the compound of formula I is selected from formula I-d, formula I-e, formula I-f and formula I-g:

[0046]

[0047]

[0048] All variables are as defined herein.

[0049] In another aspect, the compound of formula I is selected from formula I-h:

[0050]

[0051] All variables are as defined herein.

[0052] In one aspect, there is provided a compound of formula (II):

[0053]

[0054] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally formulated in a pharmaceutically acceptable carrier;

[0055] wherein:

[0056] X 3 is selected from a bond, NR 2 , C(R 3 R 3’ ), O, C(O), C(S), S, S(O) and S(O)2;

[0057] R 20 , R 21 , R 22 , R 23 and R 24 are each independently selected 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, heterocycle, heteroaryl, bicyclic and carbocyclic; each of which is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 40 ; where R 20 , R 21 , R 22 , R 23 and R 24 cannot be selected such that:

[0058] 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

[0059] ii. -O-, -S- or -NR 2 - parts are adjacent to each other; or

[0060] iii. The parts are alternatively selected in an order that produces unstable molecules (defined as molecules having a shelf life of less than about 4 months (or less than about 6 months or 5 months) at ambient temperature, which is caused by decomposition resulting from the selection and order of parts R 20 , R 21 , R 22 , R 23 and R 24 );

[0061] R 25 is 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, heterocycle, bicyclic and cycloalkyl; wherein each R 25 group is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 12 ;

[0062] R 28 is independently selected from hydrogen, -NR 2 R 2’ , -OR 2 , -SR 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl;

[0063] R 40 is independently selected 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 group is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 12 ;

[0064] or two R 40 together form an oxo group;

[0065] And all other variables are as defined herein.

[0066] In one embodiment, the compounds described herein bind to cereblon, increase the interaction between cereblon and Ikaros (IKZF1) or Aiolos (IKZF3) and result in subsequent ubiquitination and degradation of proteins in the proteasome.

[0067] In one embodiment, the compounds of the invention selectively degrade IKZF1 and / or IKZF3 relative to one or more of IKZF2 and / or IKZF4 and / or IKZF5.

[0068] Accordingly, in some embodiments, based on this discovery, compounds and methods are provided for treating patients suffering from a disease mediated by Ikaros (IKZF1) or Aiolos (IKZF3). Ikaros (IKZF1) or Aiolos (IKZF3) are targeted for selective degradation by a method that comprises administering alone an effective amount of a selective compound described herein or in combination with another active agent to a patient in need (usually a human), optionally formulated in a pharmaceutically acceptable carrier. In one embodiment, the disease is a lymphatic disease. In one embodiment, the disease is leukemia. In one embodiment, the disease is lymphoid leukemia. In one embodiment, the disease is lymphocytic leukemia. In some embodiments, the disease is a hematological malignancy such as multiple myeloma, myelodysplastic syndromes such as 5q-syndrome, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma or chronic lymphocytic leukemia. In another embodiment, the selected compounds of the invention are administered to effect immunomodulation and reduce angiogenesis.

[0069] In other embodiments, compounds and methods are provided for treating diseases including but not limited to benign growths, tumors, cancers, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid-based proteinopathies, proteinopathies or fibrotic diseases. In addition, other diseases that can be treated with an effective amount of the compounds described herein are described below.

[0070] In certain embodiments, any of the compounds described herein has at least one desired atomic isotope substitution in an amount about that of the natural abundance of the isotope, i.e., enriched. In one embodiment, the compound comprises one deuterium or multiple deuterium atoms.

[0071] Other features and advantages of the invention will be apparent from the following detailed description and claims.

[0072] Accordingly, the present invention includes at least the following features:

[0073] (a) A compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivatives) or prodrug thereof;

[0074] (b) A compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for treating a disorder mediated by Ikaros or Aiolos;

[0075] (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, in treating a disease described herein in a patient (usually a human), including a disease mediated by Ikaros or Aiolos;

[0076] (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 disorder sensitive to said compound, as further described herein;

[0077] (e) A method for preparing a medicament for treating a disease described herein in a host, characterized by using a compound of formula I or formula II in the preparation;

[0078] (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;

[0079] (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;

[0080] (h) A method for preparing a medicament for treating cancer in a host, including any cancer described herein, characterized by using a compound of formula I or formula II in the preparation;

[0081] (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;

[0082] (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;

[0083] (k) A method for preparing a medicament for treating a tumor in a host, including any tumor described herein, characterized by using a compound of formula I or formula II in the preparation;

[0084] (l) The compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for treating immune, autoimmune or inflammatory diseases of a host;

[0085] (m) Use of the 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 immune, autoimmune or inflammatory diseases;

[0086] (n) A method for preparing a medicament for treating immune, autoimmune or inflammatory diseases of a host, characterized in that a compound of formula I or formula II is used in the preparation;

[0087] (o) The compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for treating hematological malignancies such as multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma;

[0088] (p) Use of the 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;

[0089] (q) A method for preparing a medicament for treating hematological malignancies of a host 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;

[0090] (r) A pharmaceutical composition comprising a therapeutically effective 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;

[0091] (s) The compounds as described herein as a mixture of enantiomers or diastereomers (if relevant), including racemates;

[0092] (t) The compounds as described herein in enantiomerically or diastereomerically (if relevant) enriched forms, including isolated enantiomers or diastereomers (i.e., with a purity greater than 85%, 90%, 95%, 97% or 99%); and

[0093] (u) A method for a therapeutic product, said therapeutic product containing an effective amount of a compound of formula I or formula II as described herein. Detailed Description

[0094] I. Definitions

[0095] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In the specification, the singular forms also include the plural forms unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice and testing of the present 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 admitted to be prior art of the claimed application. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not limiting.

[0096] Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains.

[0097] 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 if each were specifically described, unless expressly excluded by the context.

[0098] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" means "and / or". Unless otherwise stated herein, the recitation of a range of values is merely intended to be a shorthand method of referring individually to each value falling within the range, and each individual value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and are combinable independently. Unless otherwise stated herein or clearly contradicted by the context, all methods described herein can be performed in a suitable order. Unless otherwise stated, the use of example or exemplary language (e.g., "such as") is merely intended to better illustrate the invention and does not pose a limitation on the scope of the invention.

[0099] The present invention includes compounds described herein having at least one desired atomic isotope substitution in an amount higher than the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., atoms having the same number of protons but different numbers of neutrons. If isotope substitution is used, a common substitution is at least one deuterium for hydrogen substitution.

[0100] More generally, examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as 2 H, 3 H, 11 C,13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 35 S and 36 Cl. In one non-limiting embodiment, the isotopically 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 for radioactive treatment of patients. Additionally, any hydrogen atom present in the compounds of the invention can be replaced by 18 F atoms, and such substitution may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds of the invention and their prodrugs can generally be prepared by the procedures disclosed in the embodiments or examples and by the methods in the preparations described below, by replacing the non-isotopically labeled reagents with readily available isotopically labeled reagents.

[0101] As a general example and not a limitation, isotopes of hydrogen, e.g., deuterium ( 2 H) and tritium ( 3 H) can be used anywhere in the structures to achieve the desired results. Alternatively or additionally, isotopes of carbon, such as 13 C and 14 C, can be used.

[0102] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotope is enriched 90%, 95%, or 99% or more of the isotope at any position of interest. In one non-limiting embodiment, deuterium is enriched 90%, 95%, or 99% at the desired position.

[0103] In a non-limiting embodiment, replacement of hydrogen atoms by deuterium atoms can be provided in any of the compounds described herein. For example, when any group is or contains, for example, a methyl, ethyl, or methoxy group 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 combine 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 during metabolism of the compound in vivo, or is placed one, two, or three atoms away from the metabolic bond (e.g., may be referred to as α, β, or γ, or primary, secondary, or tertiary isotope effects).

[0104] The compounds of the present invention can form solvates with solvents (including water). Thus, 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 a compound of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex containing a compound 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 with isotopically substituted solvents, such as D2O, d6-acetone, d6-DMSO. Solvates can be in liquid or solid form.

[0105] A dash ("-") 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 ketone (C=O) group.

[0106] "Alkyl" is a branched or straight-chain saturated aliphatic hydrocarbon group. In a non-limiting embodiment, the alkyl contains from 1 to about 12 carbon atoms, more typically from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In a non-limiting embodiment, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5 or C1-C6. The specified ranges used herein represent alkyl groups having each member of the range described as a separate species. For example, the term C1-C6 alkyl as used herein represents straight-chain or branched-chain alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms, and is intended to represent each of these as a separate species. For example, the term C1-C4 alkyl as used herein represents straight-chain or branched-chain alkyl groups having 1, 2, 3 or 4 carbon atoms, and is intended to represent each of these as a separate 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.

[0107] "Alkenyl" is a straight-chain or branched-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, which double bonds may occur at stable points along the chain. The specified ranges used herein represent alkenyl groups having each member of the range described as a separate species, as described above for the alkyl portion. In a non-limiting embodiment, the alkenyl contains from 2 to about 12 carbon atoms, more typically from 2 to about 6 carbon atoms or from 2 to about 4 carbon atoms. In certain embodiments, the alkenyl is C2, C2-C3, C2-C4, C2-C5 or C2-C6. Examples of alkenyl 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 having at least one point of unsaturation.

[0108] "Alkynyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, which triple bonds can occur at any stable point along the chain. As used herein, a specified range indicates an alkynyl having each member of the range described as a separate species, as described above for alkyl moieties. In one non-limiting embodiment, the alkynyl contains from 2 to about 12 carbon atoms, more typically from 2 to about 6 carbon atoms or from 2 to about 4 carbon atoms. In certain embodiments, the alkynyl is C2, C2-C3, C2-C4, C2-C5 or C2-C6. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.

[0109] "Halo" and "halogen" are independently fluorine, chlorine, bromine or iodine.

[0110] "Haloalkyl" is a branched or straight-chain alkyl group substituted with one or more of the above halogen atoms up to the maximum allowable number of halogen atoms. Examples of haloalkyl 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 hydrogen atoms are replaced by halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0111] As used herein, "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, 14 π electrons in the ring array) providing 6-14 ring carbon atoms and zero heteroatoms in an aromatic ring system ("C 6-14 aryl"). In some embodiments, the aryl has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl has 14 ring carbon atoms ("C 14 aryl"; e.g., anthracenyl). "Aryl" also includes ring systems in which an aromatic ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, where the group or point of attachment is on the aromatic ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aromatic ring system. One or more fused cycloalkyl or heterocyclic groups can be 4- to 7-membered saturated or partially unsaturated cycloalkyl or heterocyclic groups.

[0112] The term "heterocyclic" refers to saturated and partially saturated ring groups containing heteroatoms, where there are 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, sulfur, boron, silicone and oxygen. The heterocycle can include monocyclic 3- to 10-membered rings, as well as 5- to 16-membered bicyclic systems (which can include bridged, fused and spiro-fused bicyclic systems). It does not include rings containing -O-O-, -O-S- or -S-S- 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, dihydrothienyl, 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]oxazinyl groups, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuranyl and dihydrothiazolyl.

[0113] "Heterocyclic" also includes groups in which the heterocyclic group is fused to an aryl or carbocyclic group, where the point of attachment is the heterocycle. "Heterocyclic" also includes groups in which the heterocyclic group is substituted with an oxo group (i.e., ). For example, partially unsaturated fused / condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as dihydroindole or isoindole; partially unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; partially unsaturated fused heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; and saturated fused heterocyclic groups containing 1 to 2 oxygen or sulfur atoms.

[0114] The term "heterocyclic" also includes "bicyclic heterocyclic". The term "bicyclic heterocyclic" means a heterocyclic as defined herein, wherein the heterocyclic has a bridging, fused or spiro moiety. The bridging, fused or spiro moiety of the heterocyclic can be a carbocyclic, heterocyclic or aryl group as long as a stable molecule is produced. Unless excluded by the context, the term "heterocyclic" includes bicyclic heterocyclic. Bicyclic heterocyclic includes groups in which the fused heterocyclic is substituted by an oxo group. Non-limiting examples of bicyclic heterocyclic include:

[0115]

[0116] The term "heteroaryl" means 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 atoms are optionally quaternized. Examples include but are not limited to unsaturated 5- to 6-membered hetero monocyclic 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 hetero monocyclic groups containing an oxygen atom, such as pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- to 6-membered hetero monocyclic groups containing a sulfur atom, such as 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered hetero monocyclic 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 hetero monocyclic 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 system. Examples of 8-, 9- or 10-membered bicyclic heteroaryl include benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazolyl and benzotriazolyl.

[0117] As used herein, "carbocyclic", "carbocycle" or "cycloalkyl" includes saturated or partially unsaturated (i.e., non-aromatic) groups containing all carbocyclic atoms, 3 to 14 ring carbon atoms and zero heteroatoms in a non-aromatic ring system ("C 3-14 cycloalkyl"). In some embodiments, the cycloalkyl has 3 to 10 ring carbon atoms ("C 3-10 cycloalkyl"). In some embodiments, the cycloalkyl has 3 to 9 ring carbon atoms ("C 3-9 cycloalkyl"). In some embodiments, the cycloalkyl has 3 to 8 ring carbon atoms ("C 3-8"cycloalkyl"). In some embodiments, the cycloalkyl has 3 to 7 ring carbon atoms ("C 3-7 "cycloalkyl"). In some embodiments, the cycloalkyl has 3 to 6 ring carbon atoms ("C 3-6 "cycloalkyl"). In some embodiments, the cycloalkyl has 4 to 6 ring carbon atoms ("C 4-6 "cycloalkyl"). In some embodiments, the cycloalkyl has 5 to 6 ring carbon atoms ("C 5-6 "cycloalkyl"). In some embodiments, the cycloalkyl has 5 to 10 ring carbon atoms ("C 5-10 "cycloalkyl"). Exemplary C 3-6 "cycloalkyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C 3-8 "cycloalkyls include, but are not limited to, the above C 3-6 "cycloalkyls and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), etc. Exemplary C 3-10 "cycloalkyls include, but are not limited to, the above C 3-8 "cycloalkyls and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), etc. As shown in the foregoing examples, in certain embodiments, the cycloalkyl can be saturated or can 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, where the point of attachment is on the cycloalkyl ring, and in such cases, the carbon number continues to represent the number of carbon atoms in the carbocyclic system. The term "cycloalkyl" also includes ring systems in which a cycloalkyl ring as defined above has a spiro heterocyclic, aryl, or heteroaryl ring, where the point of attachment is on the cycloalkyl ring, and in such cases, the carbon number continues to represent the number of carbon atoms in the carbocyclic system. The term "cycloalkyl" also includes bicyclic or polycyclic fused, bridged, or spiro systems containing 5 to 14 carbon atoms and zero heteroatoms in a non-aromatic ring. Representative examples of "cycloalkyl" include, but are not limited to

[0118] The term "bicyclic" refers to a ring system in which two rings are fused together and each ring is independently selected from carbocyclic, heterocyclic, aryl, and heteroaryl. Non-limiting examples of bicyclics include:

[0119] When the term "bicyclic" is used in a divalent residue such as R 20 , R21 , R 22 , R 23 or R 24 When used in the context of, the attachment points can be on different rings or on the same ring. In some embodiments, both attachment points are on the same ring. In some embodiments, both attachment points are on different rings. Non-limiting examples of bicyclics include:

[0120]

[0121] "Dosage form" refers to a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, spheres, creams, ointments, suppositories, inhalable dosage forms, transdermal dosage forms, oral, sublingual, topical, gels, mucosal, etc. "Dosage form" may also include implants, such as optical implants.

[0122] As used herein, "endogenous" refers to any material that is derived from or produced within an organism, cell, tissue, or system.

[0123] As used herein, the term "exogenous" refers to any material that is introduced into or produced outside of an organism, cell, tissue, or system.

[0124] As used herein, the term "modulate" refers to a detectable increase or decrease in the level of response of an individual as compared to the level of response of the individual in the absence of treatment or compound, and / or as compared to the level of response of an otherwise identical but untreated individual. The term includes disrupting and / or affecting a natural signal or response, thereby mediating a beneficial therapeutic response in an individual, preferably a human.

[0125] "Parenteral" administration of a compound includes, for example, subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intracardiac injection, or infusion techniques.

[0126] As used herein, a "pharmaceutical composition" is a composition comprising at least one active agent, such as a selected active compound as 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 are to be used together to treat any disease described herein.

[0127] 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. The salts of the compounds of the present invention can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (e.g., hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, when feasible, typical non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used. The salts of the compounds of the present invention also include solvates of the compounds and the compound salts.

[0128] Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal salts or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of the parent compounds formed from, for example, non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; and those formed from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethanesulfonic acid, HOOC-(CH2)n-COOH, where n is 0 - 4, etc., or using different acids that produce the same counterion. A list of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0129] The term "carrier" refers to a diluent, excipient or vehicle used in the use or delivery of an active agent.

[0130] "Pharmaceutically acceptable excipient" refers to an excipient that can be used to prepare a pharmaceutical composition / combination, which is generally safe and not biologically or otherwise objectionable for administration to a host, typically a human. In one embodiment, excipients that can be used for veterinary purposes are used.

[0131] "Patient" or "host" or "individual" refers to a human or non-human animal in need of treatment for any of the disorders specifically described herein. Generally, the host is a human. "Host" may alternatively refer to, for example, mammals, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0132] A "therapeutically effective amount" of the pharmaceutical composition / combination of the present invention refers to an amount that, when administered to a host, is effective to provide a therapeutic benefit such as improvement of symptoms or alleviation or mitigation of the disease itself.

[0133] Throughout this disclosure, various aspects of the present invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and should not be construed as a limitation on the scope of the present invention. The description of a range should be considered to have specifically disclosed all possible sub-ranges as well as the individual numerical values within that range. For example, a description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges 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 the individual numerical values 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.

[0134] II. Compounds of the Present Invention

[0135] Embodiments of "alkyl"

[0136] 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.

[0137] In one embodiment, "alkyl" has one carbon.

[0138] In one embodiment, "alkyl" has two carbons.

[0139] In one embodiment, "alkyl" has three carbons.

[0140] In one embodiment, "alkyl" has four carbons.

[0141] In one embodiment, "alkyl" has five carbons.

[0142] In one embodiment, "alkyl" has six carbons.

[0143] Non-limiting examples of "alkyl" include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0144] Other non-limiting examples of “alkyl” include: isopropyl, isobutyl, isopentyl, and isohexyl.

[0145] Other non-limiting examples of “alkyl” include: sec-butyl, sec-pentyl, and sec-hexyl.

[0146] Other non-limiting examples of “alkyl” include: tert-butyl, tert-pentyl, and tert-hexyl.

[0147] Other non-limiting examples of “alkyl” include: neopentyl, 3-pentyl, and active pentyl.

[0148] Embodiments of “haloalkyl”

[0149] 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.

[0150] In one embodiment, “haloalkyl” has one carbon.

[0151] In one embodiment, “haloalkyl” has one carbon and one halogen.

[0152] In one embodiment, “haloalkyl” has one carbon and two halogens.

[0153] In one embodiment, “haloalkyl” has one carbon and three halogens.

[0154] In one embodiment, “haloalkyl” has two carbons.

[0155] In one embodiment, “haloalkyl” has three carbons.

[0156] In one embodiment, “haloalkyl” has four carbons.

[0157] In one embodiment, “haloalkyl” has five carbons.

[0158] In one embodiment, “haloalkyl” has six carbons.

[0159] Non-limiting examples of “haloalkyl” include:

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

[0161] Other non-limiting examples of “haloalkyl” include:

[0162] Other non-limiting examples of "haloalkyl" include:

[0163] Embodiments of "aryl"

[0164] In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl).

[0165] In one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[0166] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a heterocycle, where the point of attachment is the aromatic ring. Non-limiting examples of "aryl" include dihydroindole, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the point of attachment of each group is on the aromatic ring.

[0167] For example, is an "aryl" group.

[0168] However, is a "heterocycle" group.

[0169] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a cycloalkyl, where the point of attachment is the aromatic ring. Non-limiting examples of "aryl" include indane and tetralin, where the point of attachment of each group is on the aromatic ring.

[0170] For example, is an "aryl" group.

[0171] However, is a "cycloalkyl" group.

[0172] Embodiments of "heteroaryl"

[0173] In one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0174] Non-limiting examples of 5-membered "heteroaryl" include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

[0175] Other non-limiting examples of 5-membered "heteroaryl" groups include:

[0176] In one embodiment, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e., pyridyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0177] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include:

[0178] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0179] Non-limiting examples of bicyclic "heteroaryl" include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azapyridazine, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

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

[0181] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0182] Other non-limiting examples of bicyclic "heteroaryl" include:

[0183] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0184] Non-limiting examples of bicyclic "heteroaryl" include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0185] Other non-limiting examples of bicyclic "heteroaryl" include:

[0186] Embodiments of "cycloalkyl"

[0187] 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.

[0188] In one embodiment, "cycloalkyl" has three carbons.

[0189] In one embodiment, "cycloalkyl" has four carbons.

[0190] In one embodiment, "cycloalkyl" has five carbons.

[0191] In one embodiment, "cycloalkyl" has six carbons.

[0192] In one embodiment, "cycloalkyl" has seven carbons.

[0193] In one embodiment, "cycloalkyl" has eight carbons.

[0194] In one embodiment, "cycloalkyl" has nine carbons.

[0195] In one embodiment, "cycloalkyl" has ten carbons.

[0196] Non-limiting examples of "cycloalkyl" include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0197] Other non-limiting examples of "cycloalkyl" include indane and tetralin, where the point of attachment of each group is on the cycloalkyl ring.

[0198] For example, is a "cycloalkyl" group.

[0199] However, is an "aryl" group.

[0200] Other examples of "cycloalkyl" include

[0201] Embodiments of "heterocycle"

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

[0203] 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.

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

[0205] In one embodiment, "heterocycle" refers to a cyclic ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0206] In one embodiment, "heterocycle" refers to a cyclic ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0207] Non-limiting examples of "heterocycle" include aziridine, ethylene oxide, thiirane, azetidine, 1,3-diazetidine, oxetane, and thiolane.

[0208] Other non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

[0209] Other non-limiting examples of "heterocycle" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0210] Other non-limiting examples of "heterocycle" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0211] Other non-limiting examples of "heterocycle" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the point of attachment of each group is on the heterocycle.

[0212] For example, is a "heterocycle" group.

[0213] However, is an "aryl" group.

[0214] Non-limiting examples of "heterocycle" also include:

[0215] Other non-limiting examples of "heterocycle" include:

[0216] Other non-limiting examples of "heterocycle" include:

[0217] Non-limiting examples of "heterocycle" also include:

[0218] Non-limiting examples of "heterocycle" also include:

[0219] Other non-limiting examples of "heterocycle" include:

[0220] Other non-limiting examples of "heterocycle" include:

[0221] Optional substituents

[0222] In one embodiment, a moiety described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with one substituent.

[0223] In one embodiment, a moiety described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with two substituents.

[0224] In one embodiment, the moiety that can be substituted with 1, 2, 3, or 4 substituents as described herein is substituted with three substituents.

[0225] In one embodiment, the moiety that can be substituted with 1, 2, 3, or 4 substituents as described herein is substituted with four substituents.

[0226] Non-limiting embodiments of the tricyclic nucleus

[0227] The tricyclic nucleus moiety has 1, 2, or 3 nitrogens.

[0228] In one embodiment, the compounds of Formula I are selected from:

[0229]

[0230] Non-limiting embodiments of Formula I:

[0231] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are selected from the following formulas:

[0232]

[0233] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are selected from the following formulas:

[0234]

[0235] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are selected from the following formulas:

[0236] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are selected from the following formulas:

[0237]

[0238]

[0239] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are selected from the following formulas:

[0240]

[0241] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are selected from the following formulas:

[0242]

[0243] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are selected from the following formulas:

[0244]

[0245] In certain embodiments, the compounds of the invention or pharmaceutically acceptable salts thereof are selected from the following formulae:

[0246]

[0247] In certain embodiments, the compounds of the invention or pharmaceutically acceptable salts thereof are selected from the following formulae:

[0248]

[0249] In certain embodiments, the compounds of the invention or pharmaceutically acceptable salts thereof are selected from the following formulae:

[0250]

[0251] In certain embodiments, the compounds of the invention are selected from:

[0252]

[0253]

[0254]

[0255]

[0256] In one embodiment, the compounds of formula I are selected from:

[0257]

[0258] In one embodiment, the compounds of formula I are selected from:

[0259]

[0260] In one embodiment, the compounds of formula I are selected from:

[0261]

[0262] In one embodiment, the compounds of formula I are selected from:

[0263]

[0264] In one embodiment, the compounds of formula I are selected from:

[0265]

[0266] In one embodiment, the compounds of formula I are selected from:

[0267]

[0268] In one embodiment, the compound of formula I is selected from:

[0269]

[0270] In one embodiment, the compound of formula I is selected from:

[0271]

[0272] In one embodiment, the compound of formula I is selected from:

[0273]

[0274] In one embodiment, the compound of formula I is selected from:

[0275]

[0276] In one embodiment, the compound of formula I is selected from:

[0277]

[0278] In one embodiment, the compound of formula I is selected from:

[0279]

[0280] In one embodiment, the compound of formula I is selected from:

[0281]

[0282] In one embodiment, the compound of formula I is selected from:

[0283]

[0284] In one embodiment, the compound of formula I is selected from:

[0285]

[0286] In one embodiment, the compound of formula I is selected from:

[0287]

[0288] In one embodiment, the compound of formula I is selected from:

[0289]

[0290] R 1 Non-limiting embodiments

[0291] In one embodiment of formula I, R 1Selected from -NH (substituted by R 6 -substituted cycloalkyl). In one embodiment of Formula I, R 1 is selected from -NH (substituted by R 6 -substituted heterocycle). In one embodiment of Formula I, R 1 is selected from -NH (substituted by R 6 -substituted aryl). In one embodiment of Formula I, R 1 is selected from -NH (substituted by R 6 -substituted heteroaryl). In one embodiment of Formula I, R 1 is selected from -N(CH3) (substituted by R 6 -substituted cycloalkyl). In one embodiment of Formula I, R 1 is selected from -N(CH3) (substituted by R 6 -substituted heterocycle). In one embodiment of Formula I, R 1 is selected from -N(CH3) (substituted by R 6 -substituted aryl). In one embodiment of Formula I, R 1 is selected from -N(CH3) (substituted by R 6 -substituted heteroaryl).

[0292] In one embodiment of Formula I, R 1 is selected from -O (substituted by R 6 -substituted cycloalkyl). In one embodiment of Formula I, R 1 is selected from -O (substituted by R 6 -substituted heterocycle). In one embodiment of Formula I, R 1 is selected from -O (substituted by R 6 -substituted aryl). In one embodiment of Formula I, R 1 is selected from -O (substituted by R 6 -substituted heteroaryl).

[0293] In one embodiment of Formula I, R 1 is selected from -S (substituted by R 6 -substituted cycloalkyl). In one embodiment of Formula I, R 1 is selected from -S (substituted by R 6 -substituted heterocycle). In one embodiment of Formula I, R 1 is selected from -S (substituted by R 6 -substituted aryl). In one embodiment of Formula I, R 1 is selected from -S (substituted by R 6 -substituted heteroaryl).

[0294] In one embodiment of Formula I, R 1 is selected from -NH-C(O)-(alkyl). In one embodiment of Formula I, R 1Selected from -NH-C(O)-(cycloalkyl). In one embodiment of formula I, R 1 Selected from -NH-C(O)-(heterocycle). In one embodiment of formula I, R 1 Selected from -NH-C(O)-(aryl). In one embodiment of formula I, R 1 Selected from -NH-C(O)-(heteroaryl). In one embodiment of formula I, R 1 Selected from -N(CH3)-C(O)-(alkyl). In one embodiment of formula I, R 1 Selected from -N(CH3)-C(O)-(cycloalkyl). In one embodiment of formula I, R 1 Selected from -N(CH3)-C(O)-(heterocycle). In one embodiment of formula I, R 1 Selected from -N(CH3)-C(O)-(aryl). In one embodiment of formula I, R 1 Selected from -N(CH3)-C(O)-(heteroaryl).

[0295] In one embodiment of formula I, R 1 Selected from -O-C(O)-(alkyl). In one embodiment of formula I, R 1 Selected from -O-C(O)-(cycloalkyl). In one embodiment of formula I, R 1 Selected from -O-C(O)-(heterocycle). In one embodiment of formula I, R 1 Selected from -O-C(O)-(aryl). In one embodiment of formula I, R 1 Selected from -O-C(O)-(heteroaryl).

[0296] In one embodiment of formula I, R 1 Selected from -S-C(O)-(alkyl). In one embodiment of formula I, R 1 Selected from -S-C(O)-(cycloalkyl). In one embodiment of formula I, R 1 Selected from -S-C(O)-(heterocycle). In one embodiment of formula I, R 1 Selected from -S-C(O)-(aryl). In one embodiment of formula I, R 1 Selected from -S-C(O)-(heteroaryl).

[0297] In one embodiment of formula I, R 1 Selected from -CH2(cycloalkyl substituted by R 6 ). In one embodiment of formula I, R 1 Selected from -CH2(heterocycle substituted by R 6 ). In one embodiment of formula I, R1 Selected from -CH2 (substituted by R 6 substituted aryl). In one embodiment of Formula I, R 1 Selected from -CH2 (substituted by R 6 substituted heteroaryl). In one embodiment of Formula I, R 1 Selected from -CF2 (substituted by R 6 substituted cycloalkyl). In one embodiment of Formula I, R 1 Selected from -CF2 (substituted by R 6 substituted heterocycle). In one embodiment of Formula I, R 1 Selected from -CF2 (substituted by R 6 substituted aryl). In one embodiment of Formula I, R 1 Selected from -CF2 (substituted by R 6 substituted heteroaryl). In one embodiment of Formula I, R 1 Selected from -CH(OH) (substituted by R 6 substituted cycloalkyl). In one embodiment of Formula I, R 1 Selected from -CH(OH) (substituted by R 6 substituted heterocycle). In one embodiment of Formula I, R 1 Selected from -CH(OH) (substituted by R 6 substituted aryl). In one embodiment of Formula I, R 1 Selected from -CH(OH) (substituted by R 6 substituted heteroaryl).

[0298] In one embodiment of Formula I, R 1 Selected from -CH2-C(O)-(alkyl). In one embodiment of Formula I, R 1 Selected from -CH2-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 Selected from -CH2-C(O)-(heterocycle). In one embodiment of Formula I, R 1 Selected from -CH2-C(O)-(aryl). In one embodiment of Formula I, R 1 Selected from -CH2-C(O)-(heteroaryl). In one embodiment of Formula I, R 1 Selected from -CF2-C(O)-(alkyl). In one embodiment of Formula I, R 1 Selected from -CF2-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 Selected from -CF2-C(O)-(heterocycle). In one embodiment of Formula I, R 1 Selected from -CF2-C(O)-(aryl). In one embodiment of Formula I, R 1Selected from -CF2-C(O)-(heteroaryl). In one embodiment of Formula I, R 1 Selected from -CH(OH)-C(O)-(alkyl). In one embodiment of Formula I, R 1 Selected from -CH(OH)-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 Selected from -CH(OH)-C(O)-(heterocycle). In one embodiment of Formula I, R 1 Selected from -CH(OH)-C(O)-(aryl). In one embodiment of Formula I, R 1 Selected from -CH(OH)-C(O)-(heteroaryl).

[0299] In one embodiment of Formula I, R 1 Selected from -CH2-NH(cycloalkyl substituted by R 6 ). In one embodiment of Formula I, R 1 Selected from -CH2-NH(heterocycle substituted by R 6 ). In one embodiment of Formula I, R 1 Selected from -CH2-NH(aryl substituted by R 6 ). In one embodiment of Formula I, R 1 Selected from -CH2-NH(heteroaryl substituted by R 6 ). In one embodiment of Formula I, R 1 Selected from -CH2-N(CH3)(cycloalkyl substituted by R 6 ). In one embodiment of Formula I, R 1 Selected from -CH2-N(CH3)(heterocycle substituted by R 6 ). In one embodiment of Formula I, R 1 Selected from -CH2-N(CH3)(aryl substituted by R 6 ). In one embodiment of Formula I, R 1 Selected from -CH2-N(CH3)(heteroaryl substituted by R 6 ).

[0300] In one embodiment of Formula I, R 1 Selected from -CH2-O(cycloalkyl substituted by R 6 ). In one embodiment of Formula I, R 1 Selected from -CH2-O(heterocycle substituted by R 6 ). In one embodiment of Formula I, R 1 Selected from -CH2-O(aryl substituted by R 6 ). In one embodiment of Formula I, R 1 Selected from -CH2-O(aryl substituted by R6 (substituted heteroaryl).

[0301] In one embodiment of Formula I, R 1 is selected from -CH2-NH-C(O)-(alkyl). In one embodiment of Formula I, R 1 is selected from -CH2-NH-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is selected from -CH2-NH-C(O)-(heterocycle). In one embodiment of Formula I, R 1 is selected from -CH2-NH-C(O)-(aryl). In one embodiment of Formula I, R 1 is selected from -CH2-NH-C(O)-(heteroaryl). In one embodiment of Formula I, R 1 is selected from -CH2-N(CH3)-C(O)-(alkyl). In one embodiment of Formula I, R 1 is selected from -CH2-N(CH3)-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is selected from -CH2-N(CH3)-C(O)-(heterocycle). 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 is selected from -CH2-N(CH3)-C(O)-(heteroaryl).

[0302] In one embodiment of Formula I, R 1 is selected from -CH2-O-C(O)-(alkyl). In one embodiment of Formula I, R 1 is selected from -CH2-O-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is selected from -CH2-O-C(O)-(heterocycle). In one embodiment of Formula I, R 1 is selected from -CH2-O-C(O)-(aryl). In one embodiment of Formula I, R 1 is selected from -CH2-O-C(O)-(heteroaryl).

[0303] In one embodiment of Formula I, R 1 is selected from -C(O)-(cycloalkyl substituted by R 6 ). In one embodiment of Formula I, R 1 is selected from -C(O)-(heterocycle substituted by R 6 ). In one embodiment of Formula I, R 1 is selected from -C(O)-(aryl substituted by R 6 ). In one embodiment of Formula I, R1 Selected from -C(O)-(heteroaryl substituted by R 6 )

[0304] In one embodiment of Formula I, R 1 is selected from -S(O)-(cycloalkyl substituted by R 6 ). In one embodiment of Formula I, R 1 is selected from -S(O)-(heterocycle substituted by R 6 ). In one embodiment of Formula I, R 1 is selected from -S(O)-(aryl substituted by R 6 ). In one embodiment of Formula I, R 1 is selected from -S(O)-(heteroaryl substituted by R 6 ).

[0305] In one embodiment of Formula I, R 1 is selected from -S(O)2-(cycloalkyl substituted by R 6 ). In one embodiment of Formula I, R 1 is selected from -S(O)2-(heterocycle substituted by R 6 ). In one embodiment of Formula I, R 1 is selected from -S(O)2-(aryl substituted by R 6 ). In one embodiment of Formula I, R 1 is selected from -S(O)2-(heteroaryl substituted by R 6 ).

[0306] In one embodiment of Formula I, R 1 is selected from:

[0307] In certain embodiments, R 1 is selected from halogen, hydrogen, amino or cyano.

[0308] In one embodiment, R 1 is bromine.

[0309] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is heteroaryl optionally substituted by R 6 and R 6 is a heterocycle optionally substituted by one or two groups selected from R 9 . In another embodiment, R 9 is selected from hydrogen and alkyl. Non-limiting examples of this embodiment include:

[0310] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is a heteroaryl optionally substituted with R 6 and R 6 is a heterocycle optionally substituted with one or two groups selected from R 9 . In another embodiment, R 9 is selected from alkyl and -C(O)R 10 , where R 10 is a heterocycle. Non-limiting examples of this embodiment include:

[0311]

[0312] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is a heteroaryl optionally substituted with R 6 and R 6 is a heterocycle optionally substituted with one or two groups selected from R 9 . In another embodiment, R 9 is selected from alkyl and -C(O)R 10 , where R 10 is a heterocycle optionally substituted with R 11 and R 11 is alkyl. Non-limiting examples of this embodiment include:

[0313]

[0314] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is a heteroaryl optionally substituted with R 6 and R 6 is a heterocycle optionally substituted with one or two groups selected from R 9 . In another embodiment, R 9 is selected from alkyl and -C(O)R 10 , where R 10 is cycloalkyl. Non-limiting examples of this embodiment include:

[0315]

[0316] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is a heteroaryl optionally substituted with R6 Substituted heteroaryl and R 6 is a heterocycle optionally substituted with 1 or 2 groups selected from R 9 . In another embodiment, R9 is selected from alkyl and -C(O)R 10 , where R 10 is a cycloalkyl optionally substituted with R 11 and R 11 is cyano. Non-limiting examples of this embodiment include:

[0317]

[0318] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is a heterocycle optionally substituted with R 6 and R 6 is a heterocycle optionally substituted with 1 or 2 groups selected from R 9 . In another embodiment, R 9 is selected from alkyl and -C(O)R 10 , where R 10 is a cycloalkyl optionally substituted with R 11 and R 11 is alkyl. Non-limiting examples of this embodiment include:

[0319]

[0320] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is a heterocycle optionally substituted with R 6 and R 6 is a heterocycle optionally substituted with 1 or 2 groups selected from R 9 . In another embodiment, R 9 is selected from alkyl and -C(O)R 10 , where R 10 is a cycloalkyl optionally substituted with R 11 and R 11 is haloalkyl. Non-limiting examples of this embodiment include:

[0321]

[0322] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is a heterocycle optionally substituted with R 6 and R 6is a heterocycle optionally substituted by one or two groups selected from R 9 . In another embodiment, R 9 is selected from alkyl and -C(O)R 10 , where R 10 is an alkyl optionally substituted by R 11 and R 11 is selected from hydrogen, hydroxy and cyano. Non-limiting examples of this embodiment include:

[0323]

[0324] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is a heteroaryl optionally substituted by R 6 and R 6 is a heterocycle optionally substituted by one or two groups selected from R 9 . In another embodiment, R 9 is selected from alkyl and -C(O)R 10 , where R 10 is haloalkyl. Non-limiting examples of this embodiment include:

[0325]

[0326] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is a heteroaryl optionally substituted by R 6 and R 6 is a heterocycle optionally substituted by one or two groups selected from R 9 . In another embodiment, R 9 is selected from alkyl and -C(O)R 10 , where R 10 is an alkyl optionally substituted by R 11 and R 11 is OR 8 . Non-limiting examples of this embodiment include:

[0327]

[0328] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is a heteroaryl optionally substituted by R 6 and R 6 is a heterocycle optionally substituted by R 9 . In another embodiment, R 9is -C(O)R 10 , wherein R 10 is heteroaryl or aryl optionally substituted with R 11 , and R 11 is selected from hydrogen and alkyl. Non-limiting examples of this embodiment include:

[0329]

[0330] In certain embodiments, R 1 is -(CH2)-R 4 , wherein R 4 is heteroaryl optionally substituted with R 6 and R 6 is heterocycle optionally substituted with R 9 . In another embodiment, R 9 is -C(O)NR 2 R 10 or -C(O)OR 10 , wherein R 10 is alkyl. Non-limiting examples of this embodiment include:

[0331]

[0332] In certain embodiments, R 1 is -(CH2)-R 4 , wherein R 4 is heteroaryl optionally substituted with R 6 and R 6 is heterocycle optionally substituted with one or two groups selected from R 9 . In another embodiment, R 9 is selected from alkyl and -CH2R 10 , wherein R 10 is cycloalkyl optionally substituted with R 11 and R 11 is alkyl. Non-limiting examples of this embodiment include:

[0333]

[0334] In certain embodiments, R 1 is -(CH2)-R 4 , wherein R 4 is heteroaryl optionally substituted with R 6 and R 6 is heterocycle optionally substituted with one or two groups selected from R 9 . In another embodiment, R 9 is selected from alkyl and -CH2R 10 , wherein R 10is an optionally R 11 -substituted cycloalkyl and R 11 is selected from haloalkyl or cyano. Non-limiting examples of this embodiment include:

[0335]

[0336] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is an optionally R 6 -substituted heteroaryl and R 6 is a heterocycle optionally substituted with 1 or 2 groups selected from R 9 . In another embodiment, R 9 is selected from alkyl and -CH2R 10 , where R 10 is an optionally R 11 -substituted cycloalkyl and R 11 is OR 8 . Non-limiting examples of this embodiment include:

[0337]

[0338] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is an optionally R 6 -substituted heteroaryl and R 6 is a heterocycle optionally substituted with 1 or 2 groups selected from R 9 . In another embodiment, R 9 is selected from alkyl and -CH2R 10 , where R 10 is an optionally R 11 -substituted alkyl and R 11 is selected from hydrogen, cyano, and OR 8 . Non-limiting examples of this embodiment include:

[0339]

[0340] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is an optionally R 6 -substituted heteroaryl and R 6 is an optionally R 9 -substituted heterocycle. In another embodiment, R 9 is R 10 and R 10is a cycloalkyl group. Non-limiting examples of this embodiment include:

[0341]

[0342] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is a heteroaryl group substituted by R 7 and substituted by R 6 , where R 6 is a heterocycle optionally substituted by one or two groups selected from R 9 . In another embodiment, R 9 is selected from alkyl and -C(O)R 10 and R 10 is a cycloalkyl group optionally substituted by R 11 and R 11 is alkyl. Non-limiting examples of this embodiment include:

[0343]

[0344] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is a heteroaryl group optionally substituted by R 6 and R 6 is a cycloalkyl group. Non-limiting examples of this embodiment include:

[0345]

[0346] In certain embodiments, R 1 is -C(O)R 4 , where R 4 is a heteroaryl group optionally substituted by R 6 and R 6 is a heterocycle. In another embodiment, R 6 is optionally substituted by R 9 and R 9 is -C(O)OR 10 , where R 10 is alkyl. Non-limiting examples of this embodiment include:

[0347]

[0348] In certain embodiments, R 1 is -CH(CH3)R 4 , where R 4 is a heteroaryl group optionally substituted by R 6 and R6 is a heterocycle. In another embodiment, R 6 is optionally substituted by R 9 and R 9 is -C(O)OR 10 or -C(O)R 10 , wherein R 10 is an alkyl or cycloalkyl optionally substituted by R 11 and R 11 is selected from alkyl and hydrogen. Non-limiting examples of this embodiment include:

[0349]

[0350] In certain embodiments, R 1 is -CH(NH2)R 4 , wherein R 4 is a heteroaryl optionally substituted by R 6 and R 6 is a heterocycle. In another embodiment, R 6 is optionally substituted by R 9 and R 9 is -C(O)OR 10 or -C(O)R 10 , wherein R 10 is an alkyl or cycloalkyl optionally substituted by R 11 and R 11 is selected from alkyl and hydrogen. Non-limiting examples of this embodiment include:

[0351]

[0352] In certain embodiments, R 1 is -SR 4 , -S(O)R 4 or -S(O)2R 4 , wherein R 4 is a heteroaryl optionally substituted by R 6 and R 6 is a heterocycle optionally substituted by R 9 . In another embodiment, R 9 is -C(O)R 10 , wherein R 10 is a cycloalkyl optionally substituted by R 11 and R 11 is alkyl. Non-limiting examples of this embodiment include:

[0353]

[0354] In certain embodiments, R 1is -(CH2)-R 4 , wherein R 4 is an optionally R 6 substituted heteroaryl and R 6 is an optionally R 9 substituted cycloalkyl. In another embodiment, R 9 is selected from -OR 10 , wherein R 10 is an optionally R 11 substituted alkyl and R 11 is aryl. Non-limiting examples of this embodiment include:

[0355]

[0356] In certain embodiments, R 1 is -(CR 3 R 3’ )-R 4 , wherein R 3 and R 3’ combine with the carbon to which they are attached to form a 3-membered cycloalkyl ring and R 4 is an optionally R 6 substituted heteroaryl, wherein R 6 is an optionally R 9 substituted heterocycle. In another embodiment, R 9 is -C(O)R 10 or -CH2R 10 , wherein R 10 is an optionally R 11 substituted cycloalkyl and R 11 is alkyl. Non-limiting examples of this embodiment include:

[0357]

[0358] In certain embodiments, R 1 is -(CH2)-R 4 , wherein R 4 is an aryl substituted by R 6 and R 6 is an optionally R 9 substituted alkyl. In another embodiment, R 9 is R 10 and R 10 is an optionally R 11 substituted heterocycle, wherein R 11 is -C(O)OR 8 , -C(O)R 8 or -SO2R 8 and R 8is alkyl, cycloalkyl, haloalkyl or aryl. Non-limiting examples of this embodiment include:

[0359]

[0360] In certain embodiments, R 1 is -(CH2)-R 4 where R 4 is an aryl group substituted with R 6 and R 6 is an alkyl group optionally substituted with R 9 In another embodiment, R 9 is R 10 and R 10 is a heterocycle or heteroaryl. Non-limiting examples of this embodiment include:

[0361]

[0362] In certain embodiments, R 1 is -(CH2)-R 4 where R 4 is an aryl group substituted with R 6 and R 6 is an alkyl group optionally substituted with R 9 In another embodiment, R 9 is R 10 and R 10 is a heterocycle or heteroaryl optionally substituted with R 11 where R 11 is selected from hydrogen, alkyl or haloalkyl. In one embodiment, two R 11 groups on the same carbon are joined together to form an oxo group. Non-limiting examples of this embodiment include:

[0363]

[0364] In certain embodiments, R 1 is -CH2-R 4 where R 4 is an aryl group optionally substituted with R 6 and R 6 is an alkyl group optionally substituted with R 9 In another embodiment, R 9 is R 10 where R 10 is a heterocycle optionally substituted with R 11 and R 11 is a -CH2 aryl group optionally substituted with halogen. Non-limiting examples of this embodiment include:

[0365]

[0366] In certain embodiments, R 1 is -CH2-R 4 , where R 4 is an aryl optionally substituted with R 6 and R 6 is an alkyl optionally substituted with R 9 . In another embodiment, R 9 is R 10 , where R 10 is a heterocycle optionally substituted with R 11 and R 11 is an aryl optionally substituted with a halogen. Non-limiting examples of this embodiment include:

[0367]

[0368] In certain embodiments, R 1 is -CH2-R 4 , where R 4 is an aryl optionally substituted with R 6 and R 6 is a heterocycle optionally substituted with R 9 . In another embodiment, R 9 is -CH2R 10 or -C(O)R 10 , where R 10 is a cycloalkyl optionally substituted with R 11 and R 11 is hydrogen or an alkyl. Non-limiting examples of this embodiment include:

[0369]

[0370] In certain embodiments, R 1 is -(CH2)-R 4 , where R 4 is a heteroaryl optionally substituted with R 6 and R 6 is a heterocycle optionally substituted with R 9 . In another embodiment, R 9 is selected from R 10 , where R 10 is a heteroaryl optionally substituted with an R 11 group selected from a halogen and hydrogen. Non-limiting examples of this embodiment include:

[0371]

[0372] In certain embodiments, R1 Selected from the following:

[0373]

[0374]

[0375] R 4 In one embodiment of Formula I, R 4 Selected from:

[0376]

[0377] In one embodiment of Formula I, R 4 Selected from:

[0378]

[0379] In one embodiment of Formula I, R 4 Selected from:

[0380]

[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]

[0389] In one embodiment of Formula I, R 4 Selected from:

[0390]

[0391] In one embodiment of Formula I, R 4 Selected from:

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

[0393]

[0394] In one embodiment of Formula I, R 4 is selected from:

[0395]

[0396] In one embodiment of Formula I, R 4 is selected from:

[0397]

[0398] In one embodiment of Formula I, R 4 is selected from:

[0399]

[0400] In certain embodiments, R 4 is selected from:

[0401]

[0402] In one embodiment, the compounds of Formula I are selected from:

[0403]

[0404]

[0405]

[0406] In one embodiment, the compounds of Formula I are selected from:

[0407]

[0408]

[0409]

[0410] In one embodiment, the compounds of Formula I are selected from:

[0411]

[0412] In one embodiment, the compounds of Formula I are selected from:

[0413]

[0414] In one embodiment, the compounds of Formula I are selected from:

[0415]

[0416] In one embodiment, the compound of Formula I is selected from:

[0417]

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

[0436]

[0437]

[0438]

[0439] In one embodiment, the compound of Formula I is selected from:

[0440]

[0441]

[0442]

[0443] In one embodiment, the compound of formula I is selected from:

[0444]

[0445]

[0446]

[0447] In one embodiment, the compound of formula I is selected from:

[0448]

[0449]

[0450]

[0451] In one embodiment, the compound of formula I is selected from:

[0452]

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

[0454]

[0455] In one embodiment, the compound of formula I is selected from:

[0456]

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

[0458]

[0459] R 6 For a non-limiting embodiment of formula I, in one embodiment of formula I, R 6 is selected from:

[0460] In one embodiment of formula I, R 6 is selected from:

[0461] In one embodiment of Formula I, R 6 is selected from:

[0462]

[0463] In one embodiment of Formula I, R 6 is selected from:

[0464]

[0465] In one embodiment of Formula I, R 6 is selected from:

[0466]

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

[0468]

[0469] In certain embodiments, R 6 is selected from:

[0470]

[0471] R 9 Non-limiting embodiments of

[0472] In one embodiment, R 9 is selected from:

[0473]

[0474] In one embodiment, R 9 is selected from:

[0475]

[0476] In one embodiment, R 9 is selected from:

[0477]

[0478] In one embodiment, R 9 is selected from:

[0479] In one embodiment, R 9 is

[0480] In one embodiment, R 9 is selected from:

[0481] In one embodiment, R9 Selected from:

[0482]

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

[0484] In one embodiment, R 9 Selected from:

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

[0486]

[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 is

[0502] In one embodiment, R 9 is

[0503] In one embodiment, R 9 is selected from:

[0504]

[0505] In one embodiment, R 9 is

[0506] In one embodiment, R 9 is selected from

[0507] In one embodiment, R 9 is selected from

[0508] In one embodiment, R 9 is

[0509] In one embodiment, R 9 is

[0510] In one embodiment, R 9 is

[0511] In one embodiment, R 9 is

[0512] In one embodiment, R 9 is

[0513] In one embodiment, R 9 is

[0514] In one embodiment, R 9 is selected from:

[0515]

[0516] In one embodiment, R 9 is selected from:

[0517]

[0518] In one embodiment, R 9 is

[0519] In one embodiment, R 9Selected from:

[0520]

[0521] In one embodiment, R 9 Selected from:

[0522]

[0523] In one embodiment, R 9 is

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

[0525]

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

[0527]

[0528] In one embodiment, R 9 is

[0529] In one embodiment, R 9 Selected from:

[0530]

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

[0532]

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

[0534]

[0535] In one embodiment, R 9 Selected from

[0536] In one embodiment, R 9 is

[0537] In one embodiment, R 9 is

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

[0539]

[0540] In one embodiment, R 9 is selected from:

[0541]

[0542] In one embodiment, R 9 is selected from:

[0543]

[0544] In one embodiment, R 9 is selected from:

[0545]

[0546] In one embodiment, R 9 is selected from:

[0547]

[0548] In one embodiment, R 9 is selected from:

[0549]

[0550] In one embodiment, R 9 is

[0551] In one embodiment, R 9 is

[0552] In one embodiment, R 9 is selected from:

[0553]

[0554] In one embodiment, R 9 is selected from:

[0555]

[0556] In one embodiment, R 9 is

[0557] In one embodiment, R 9 is selected from:

[0558] In one embodiment, R 9 is selected from:

[0559] In one embodiment, R 9Selected from:

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

[0561] In one embodiment, R 9 Selected from:

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

[0563] In one embodiment, R 9 is

[0564] In one embodiment, R 9 is

[0565] In one embodiment, R 9 Selected from:

[0566] In one embodiment, R 9 is

[0567] In one embodiment, R 9 Selected from:

[0568]

[0569] In one embodiment, R 9 Selected from:

[0570]

[0571] In one embodiment, R 9 Selected from:

[0572]

[0573] In one embodiment, R 9 is

[0574] In one embodiment, R 9 Selected from:

[0575]

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

[0577]

[0578] In one embodiment, R 9 is

[0579] In one embodiment, R 9 is selected from:

[0580]

[0581] In one embodiment, R 9 is selected from:

[0582]

[0583] In one embodiment, R 9 is selected from:

[0584]

[0585] In one embodiment, R 9 is selected from:

[0586] In one embodiment, R 9 is selected from:

[0587] In one embodiment, R 9 is selected from:

[0588] R 10 Non-limiting embodiments of

[0589] -C(O)R 10 Non-limiting examples of include:

[0590]

[0591]

[0592] -CH2R 10 Non-limiting examples of include:

[0593]

[0594]

[0595] R 10 Non-limiting examples of include:

[0596]

[0597] Non-limiting examples of the compound of Formula I or Formula II:

[0598] Representative examples of the compounds of Formula I or Formula II include:

[0599]

[0600]

[0601] Other representative examples of the compounds of Formula I or Formula II include:

[0602]

[0603]

[0604]

[0605]

[0606] Other representative examples of the compounds of Formula I or II include:

[0607]

[0608]

[0609]

[0610] In certain embodiments, the compounds of the present invention are selected from:

[0611]

[0612]

[0613]

[0614] In one embodiment, the compound of the present invention is or a pharmaceutically acceptable salt thereof.

[0615] Non-limiting isotope embodiments

[0616] In one embodiment, the compound is isotopically labeled.

[0617] 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 permitted by its valence. In one embodiment, the isotopic label is deuterium. In one embodiment, at least one deuterium is placed on an atom having a bond that breaks during in vivo metabolism of the compound, or one, two or three atoms away from the metabolic bond (e.g., which may be referred to as α, β or γ, or primary, secondary or tertiary isotope effects). In another embodiment, the isotopic label is 13 C. In another embodiment, the isotopic label is 18 F.

[0618] In certain embodiments, the compounds of the invention are selected from: or a pharmaceutically acceptable salt thereof.

[0619] In certain embodiments, the compounds of the invention are selected from: or a pharmaceutically acceptable salt thereof.

[0620] In certain embodiments, the compounds of the invention are selected from: or a pharmaceutically acceptable salt thereof.

[0621] In certain embodiments, the compounds of the invention are selected from the following formula:

[0622]

[0623] or a pharmaceutically acceptable salt thereof.

[0624] In certain embodiments, the compounds of the invention are selected from the following formula:

[0625]

[0626]

[0627]

[0628] or a pharmaceutically acceptable salt thereof.

[0629] In certain embodiments, the compounds of the invention are selected from the following formula: or a pharmaceutically acceptable salt thereof.

[0630] In certain embodiments, the compounds of the invention are selected from:

[0631] or a pharmaceutically acceptable salt thereof.

[0632] In certain embodiments, the compounds of the invention are selected from:

[0633] or a pharmaceutically acceptable salt thereof.

[0634] In certain embodiments, the compounds of the invention are selected from:

[0635] or a pharmaceutically acceptable salt thereof.

[0636] In certain embodiments, the compounds of the invention are selected from:

[0637] or a pharmaceutically acceptable salt thereof.

[0638] In certain embodiments, the compounds of the invention are selected from:

[0639] or a pharmaceutically acceptable salt thereof.

[0640] In certain embodiments, the compounds of the invention are selected from:

[0641] or a pharmaceutically acceptable salt thereof.

[0642] In certain embodiments, the compounds of the invention are selected from:

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649] or a pharmaceutically acceptable salt thereof.

[0650] In certain embodiments, the compounds of the invention are selected from:

[0651]

[0652] or a pharmaceutically acceptable salt thereof.

[0653] In any of the above structures having two deuteriums on a methylene group, the same molecule having one deuterium at that position is contemplated. In any of the above structures having three deuteriums on a methyl group, the same molecule having one or two deuteriums at that position is contemplated.

[0654] Other embodiments

[0655] 1. In certain embodiments, there is provided a compound of formula I or formula II

[0656]

[0657] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof;

[0658] Wherein:

[0659] X 1 and X 2 are independently selected from CH and N;

[0660] X 3 is selected from a bond, NR 2 , C(R 3 R 3’ ), O, C(O), C(S), S, S(O) and S(O)2;

[0661] R 1 is 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 , -(CR3 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 ;

[0662] R 2 and R 2' are each 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' ;

[0663] R 3 is selected from hydrogen, halogen, alkyl, haloalkyl, -OR 8 and -NR 8 R 8' ;

[0664] R 3' is selected from hydrogen, halogen, alkyl and haloalkyl;

[0665] or R 3 and R 3' may combine with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring;

[0666] R 4 is selected from cycloalkyl, heterocycle, aryl and heteroaryl, where each R 4 is optionally substituted with one selected from R6 is substituted by a group, and each R 4 is also optionally substituted by 1, 2, 3 or 4 groups independently selected from R 7 ;

[0667] R 5 is -C(O)R 6 ;

[0668] R 6 is selected from alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, and each R 6 is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 9 ;

[0669] or R 6 is selected from 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, and each R 6 is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 9 ;

[0670] R 7 is independently selected from hydrogen, halogen, hydroxyl, 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' ;

[0671] or two R 7 on the same carbon can combine together to form an oxo group;

[0672] R8 and R 8’ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl each time it appears;

[0673] R 9 is independently selected 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 ;

[0674] R 10 is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein each R 10 is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 11 ; and

[0675] R 11 is selected from: hydrogen; halogen; hydroxy; cyano; nitro; alkyl; haloalkyl; alkenyl optionally substituted by aryl or heteroaryl; alkynyl optionally substituted by aryl or heteroaryl; cycloalkyl; heterocycle; aryl optionally substituted by 1, 2, 3 or 4 halogen, alkyl or -OR 8 groups; heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, alkyl or -OR 8 groups; heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, alkyl or -OR 8Group-substituted -CH2 aryl; optionally substituted by 1, 2, 3 or 4 halogens, alkyl or -OR 8 Group-substituted -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’ ;

[0676] or two Rs on the same carbon 11 The groups can combine together to form an oxo group;

[0677] or R 11 is independently selected 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)R8 ;-SO2R 8 ; -SO2-OR 8 ; Oxo 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 substituted with a group; and

[0678] 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' ;

[0679] 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 R40 is substituted with substituents; wherein R 20 , R 21 , R 22 , R 23 and R 24 cannot be selected as follows:

[0680] 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

[0681] ii. -O-, -S- or -NR 2 - moieties are adjacent to each other; or

[0682] iii. the moieties are otherwise 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 caused by decomposition resulting from the selection and order of moieties R 20 , R 21 , R 22 , R 23 and R 24 );

[0683] R 25 is 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, heterocycle, bicyclic and cycloalkyl; wherein each R 25 group is optionally substituted with 1, 2, 3 or 4 groups independently selected from R 12 ;

[0684] R 28 is independently selected from hydrogen, -NR 2 R 2’ , -OR 2 , -SR 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl;

[0685] R 40 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, cyano, -NR 2 R 2' , -NR 2SO2R 28 、 -OSO2R 28 、 -SO2R 28 、 haloalkyl, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; wherein each R 40 group is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 12 .

[0686] 2. A compound of embodiment 1 of the following formula:

[0687]

[0688] or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof.

[0689] 3. The compound of embodiment 2, wherein:

[0690] R 6 is selected from alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein each R 6 is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 9 .

[0691] R 11 is selected from: hydrogen; halogen; hydroxy; cyano; nitro; alkyl; haloalkyl; alkenyl optionally substituted by aryl or heteroaryl; alkynyl optionally substituted by aryl or heteroaryl; cycloalkyl; heterocycle; aryl optionally substituted by 1, 2, 3 or 4 halogens, alkyl or -OR 8 groups; heteroaryl optionally substituted by 1, 2, 3 or 4 halogens, alkyl or -OR 8 groups; -CH2aryl optionally substituted by 1, 2, 3 or 4 halogens, alkyl or -OR 8 groups; -CH2heteroaryl optionally substituted by 1, 2, 3 or 4 halogens, alkyl or -OR 8 groups; -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’ ;

[0692] or two Rs on the same carbon may combine together to form an oxo group. 11 The groups may combine together to form an oxo group.

[0693] 4. A compound according to embodiment 1 or embodiment 2, wherein R 12 is selected from halogen, alkyl, and haloalkyl.

[0694] 5. A compound according to embodiment 1 or embodiment 2, wherein R 12 is selected from hydroxy, cyano, nitro, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl.

[0695] 6. A compound according to embodiment 1 or embodiment 2, wherein R12 is selected from: -CH2aryl; -CH2heteroaryl; -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' .

[0696] 7. A compound according to embodiment 1 or 2, wherein one R 12 substituent is halogen.

[0697] 8. A compound according to embodiment 1 or 2, wherein two R 12 substituents are halogen.

[0698] 9. The compound of embodiment 1 or 2, wherein one R 12 substituent is alkyl.

[0699] 10. The compound of embodiment 1 or 2, wherein two R 12 substituents are alkyl.

[0700] 11. The compound of embodiment 1 or 2, wherein one R 12 substituent is haloalkyl.

[0701] 12. The compound of embodiment 1 or 2, wherein one R 12 substituent is cycloalkyl.

[0702] 13. The compound of any one of embodiments 4 - 12, wherein R 11 is alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R 12 .

[0703] 14. The compound of any one of embodiments 4 - 12, wherein R 11 is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R 12 .

[0704] 15. The compound of any one of embodiments 4 - 12, wherein R 11 is heterocycle optionally substituted with 1, 2, 3, or 4 substituents selected from R 12 .

[0705] 16. The compound of any one of embodiments 4 - 12, wherein R 11 is aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R 12 .

[0706] 17. The compound of any one of embodiments 4 - 12, wherein R 11 is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R 12 .

[0707] 18. The compound of any one of embodiments 1 - 12, wherein R 11 is alkyl.

[0708] 19. The compound of any one of embodiments 1 - 12, wherein R 11 is cyano.

[0709] 20. The compound of any one of embodiments 1 - 12, wherein R 11 is haloalkyl.

[0710] 21. The compound of any one of embodiments 1-12, wherein R 11 is hydrogen.

[0711] 22. The compound of any one of embodiments 1-12, wherein R 11 is hydroxy.

[0712] 23. The compound of any one of embodiments 1-12, wherein R 11 is OR 8 .

[0713] 24. The compound of any one of embodiments 1-12, wherein R 11 is aryl.

[0714] 25. The compound of any one of embodiments 1-12, wherein R 11 is heteroaryl.

[0715] 26. The compound of any one of embodiments 1-12, wherein R 11 is -C(O)OR 8 , -C(O)R 8 or -SO2R 8 .

[0716] 27. The compound of any one of embodiments 1-12, wherein R 11 is -CH2aryl.

[0717] 28. The compound according to any one of embodiments 1-27, wherein R 1 is -NR 2 R 4 .

[0718] 29. The compound according to any one of embodiments 1-27, wherein R 1 is -OR 4 .

[0719] 30. The compound according to any one of embodiments 1-27, wherein R 1 is -C(O)R 4 .

[0720] 31. The compound according to any one of embodiments 1-27, wherein R 1 is -SR 4 .

[0721] 32. The compound according to any one of embodiments 1-27, wherein R 1 is -S(O)R 4 .

[0722] 33. The compound of any one of embodiments 1-27, wherein R 1is -S(O)2R 4 。

[0723] 34. A compound according to any one of embodiments 1 - 27, wherein the compound has the formula:

[0724] or a pharmaceutically acceptable salt thereof.

[0725] 35. A compound according to any one of embodiments 1 - 27, wherein the compound has the formula:

[0726] or a pharmaceutically acceptable salt thereof.

[0727] 36. A compound according to any one of embodiments 1 - 27, wherein the compound has the formula:

[0728] or a pharmaceutically acceptable salt thereof.

[0729] 37. A compound according to any one of embodiments 1 - 27, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

[0730] 38. A compound according to any one of embodiments 1 - 27, wherein R 1 is -(CR 3 R 3’ )-R 5 。

[0731] 39. A compound according to embodiment 37 or 38, wherein R 3 is hydrogen.

[0732] 40. A compound according to embodiment 37 or 38, wherein R 3 is -NR 8 R 8' 。

[0733] 41. A compound according to embodiment 37 or 38, wherein R 3 is alkyl.

[0734] 42. A compound according to any one of embodiments 37 - 41, wherein R 3' is hydrogen.

[0735] 43. A compound according to any one of embodiments 1 - 27, wherein R 1 is -NR 2 R 5 。

[0736] 44. A compound according to any one of embodiments 1 - 27, wherein R 1 is -OR 5 。

[0737] The compound of any one of embodiments 38 - 44, wherein R 5 is -C(O)alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 9 .

[0738] The compound of any one of embodiments 38 - 44, wherein R 5 is -C(O)heterocycle optionally substituted with 1, 2, 3, or 4 groups independently selected from R 9 .

[0739] The compound of any one of embodiments 38 - 44, wherein R 5 is -C(O)aryl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 9 .

[0740] The compound of any one of embodiments 38 - 44, wherein R 5 is -C(O)heteroaryl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 9 .

[0741] The compound of any one of embodiments 1 - 48, wherein the compound has the formula or a pharmaceutically acceptable salt thereof.

[0742] The compound of any one of embodiments 1 - 48, wherein the compound has the formula or a pharmaceutically acceptable salt thereof.

[0743] The compound of any one of embodiments 1 - 48, wherein the compound has the formula or a pharmaceutically acceptable salt thereof.

[0744] The compound of any one of embodiments 49 - 51, wherein R 4 is cycloalkyl substituted with one group selected from R 6 and optionally substituted with 1, 2, 3, or 4 groups independently selected from R 7 .

[0745] The compound of any one of embodiments 49 - 51, wherein R 4 is heterocycle substituted with one group selected from R 6 and optionally substituted with 1, 2, 3, or 4 groups independently selected from R 7 .

[0746] The compound according to any one of embodiments 49 - 51, wherein R 4is an aryl group substituted by a group selected from R 6 and optionally substituted by 1, 2, 3 or 4 groups independently selected from R 7 .

[0747] 55. A compound according to any one of embodiments 49 - 51, wherein R 4 is a heteroaryl group substituted by a group selected from R 6 and optionally substituted by 1, 2, 3 or 4 groups independently selected from R 7 .

[0748] 56. A compound according to any one of embodiments 49 - 51, wherein R 4 is 57. Embodiment

[0749] A compound according to any one of 49 - 51, wherein R 4 is

[0750] 58. A compound according to any one of embodiments 49 - 51, wherein R 4 is

[0751] 59. A compound according to any one of embodiments 49 - 51, wherein R 4 is

[0752] 60. A compound according to any one of embodiments 49 - 51, wherein R 4 is

[0753] 61. A compound according to any one of embodiments 1 - 60, wherein R 7 is selected from hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -OR 8 and -NR 8 R 8' .

[0754] 62. A compound according to any one of embodiments 1 - 60, wherein R 7 is 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-OR8 and -SO2-NR 8 R 8' 。

[0755] 63. A compound according to any one of embodiments 1 - 60, wherein one R 7 is hydrogen.

[0756] 64. A compound according to any one of embodiments 1 - 60, wherein two R 7 are hydrogen.

[0757] 65. A compound according to any one of embodiments 1 - 60, wherein three R 7 are hydrogen.

[0758] 66. A compound according to any one of embodiments 1 - 65, wherein one R 7 is halogen.

[0759] 67. A compound according to any one of embodiments 1 - 64, wherein two R 7 are halogen.

[0760] 68. A compound according to any one of embodiments 1 - 65, wherein one R 7 is alkyl.

[0761] 69. A compound according to any one of embodiments 1 - 64, wherein two R 7 are alkyl.

[0762] 70. A compound according to any one of embodiments 1 - 65, wherein one R 7 is haloalkyl.

[0763] 71. A compound according to any one of embodiments 1 - 64, wherein two R 7 are haloalkyl.

[0764] 72. A compound according to any one of embodiments 1 - 71, wherein R 6 is selected from:

[0765]

[0766] 73. A compound according to any one of embodiments 1 - 71, wherein R 6 is selected from:

[0767]

[0768] 74. A compound according to any one of embodiments 1 - 71, wherein R 6 is selected from:

[0769]

[0770] The compound of any one of embodiments 1-71, wherein R 6 is an alkyl group optionally substituted with 1, 2, 3 or 4 groups independently selected from R 9 .

[0771] 76. The compound of any one of embodiments 1-71, wherein R 6 is a cycloalkyl group optionally substituted with 1, 2, 3 or 4 groups independently selected from R 9 .

[0772] 77. The compound of any one of embodiments 1-71, wherein R 6 is a heterocycle optionally substituted with 1, 2, 3 or 4 groups independently selected from R 9 .

[0773] 78. The compound of any one of embodiments 1-71, wherein R 6 is an aryl group optionally substituted with 1, 2, 3 or 4 groups independently selected from R 9 .

[0774] 79. The compound of any one of embodiments 1-71, wherein R 6 is a heteroaryl group optionally substituted with 1, 2, 3 or 4 groups independently selected from R 9 .

[0775] 80. The compound of any one of embodiments 75-79, wherein R 6 is unsubstituted.

[0776] 81. The compound of any one of embodiments 75-79, wherein R 6 is substituted with 1 group selected from R 9 .

[0777] 82. The compound of any one of embodiments 75-79, wherein R 6 is substituted with 2 groups independently selected from R 9 .

[0778] 83. The compound of any one of embodiments 75-79, wherein R 6 is substituted with 3 groups independently selected from R 9 .

[0779] 84. The compound of any one of embodiments 75-79, wherein R 6 is substituted with 4 groups independently selected from R 9 .

[0780] 85. The compound of any one of embodiments 1-84, wherein R 9Selected from hydrogen, halogen, alkyl, haloalkyl, cyano and nitro.

[0781] 86. A compound according to any one of embodiments 1 - 84, wherein R 9 is selected from R 10 .

[0782] 87. A compound according to any one of embodiments 1 - 84, wherein R 9 is 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 .

[0783] 88. A compound according to embodiment 86 or 87, wherein R 10 is an alkyl group optionally substituted by 1, 2, 3 or 4 groups independently selected from R 11 .

[0784] 89. A compound according to embodiment 86 or 87, wherein R 10 is a haloalkyl group optionally substituted by 1, 2, 3 or 4 groups independently selected from R 11 .

[0785] 90. A compound according to embodiment 86 or 87, wherein R 10 is an alkenyl group optionally substituted by 1, 2, 3 or 4 groups independently selected from R 11 .

[0786] 91. The compound of embodiment 86 or 87, wherein R 10 is an alkynyl group optionally substituted with 1, 2, 3 or 4 groups independently selected from R 11 .

[0787] 92. The compound of embodiment 86 or 87, wherein R 10 is a cycloalkyl group optionally substituted with 1, 2, 3 or 4 groups independently selected from R 11 .

[0788] 93. The compound of embodiment 86 or 87, wherein the heterocycle of R 10 is optionally substituted with 1, 2, 3 or 4 groups independently selected from R 11 .

[0789] 94. The compound of embodiment 86 or 87, wherein R 10 is an aryl group optionally substituted with 1, 2, 3 or 4 groups independently selected from R 11 .

[0790] 95. The compound of embodiment 86 or 87, wherein R 10 is a heteroaryl group optionally substituted with 1, 2, 3 or 4 groups independently selected from R 11 .

[0791] 96. The compound of any one of embodiments 88 - 95, wherein R 10 is unsubstituted.

[0792] 97. The compound of any one of embodiments 88 - 95, wherein R 10 is substituted with 1 group selected from R 11 .

[0793] 98. The compound of any one of embodiments 88 - 95, wherein R 10 is substituted with 2 groups independently selected from R 11 .

[0794] 99. The compound of any one of embodiments 88 - 95, wherein R 10 is substituted with 3 groups independently selected from R 11 .

[0795] 100. The compound of any one of embodiments 88 - 95, wherein R 10 is substituted with 4 groups independently selected from R 11 .

[0796] 101. The compound of any one of embodiments 1 - 100, wherein R 2 , R 8 and R 8' are hydrogen.

[0797] The compound of any one of embodiments 1 - 100, wherein R 2 , R 8 and R 8' are alkyl.

[0798] The compound of any one of embodiments 1 - 71, wherein R 6 is selected from:

[0799]

[0800] The compound of any one of embodiments 1 - 71, wherein R 6 is selected from:

[0801]

[0802] The compound of any one of embodiments 1 - 71, wherein R 6 is selected from:

[0803]

[0804] The compound of embodiment 1, wherein the compound has the following formula:

[0805] or a pharmaceutically acceptable salt, N - oxide, isotope derivative or prodrug thereof.

[0806] The compound of embodiment 106, wherein the compound has the formula or a pharmaceutically acceptable salt, N - oxide, isotope derivative or prodrug thereof.

[0807] The compound of embodiment 106, wherein the compound has the formula or a pharmaceutically acceptable salt, N - oxide, isotope derivative or prodrug thereof.

[0808] The compound of embodiment 106, wherein the compound has the formula or a pharmaceutically acceptable salt, N - oxide, isotope derivative or prodrug thereof.

[0809] The compound of any one of embodiments 106 - 109, wherein X 3 is a bond.

[0810] The compound of any one of embodiments 106 - 109, wherein X 3 is C(R 3 R 3' ).

[0811] The compound of any one of embodiments 106 - 109, wherein X 3 is C(O).

[0812] 113. The compound of any one of embodiments 106 - 109, wherein X 3 is C(S).

[0813] 114. The compound of any one of embodiments 106 - 109, wherein X 3 is S(O).

[0814] 115. The compound of any one of embodiments 106 - 109, wherein X 3 is S(O)2.

[0815] 116. The compound of any one of embodiments 106 - 109, wherein X 3 is NR 2 .

[0816] 117. The compound of any one of embodiments 106 - 109, wherein X 3 is O.

[0817] 118. The compound of any one of embodiments 106 - 109, wherein X 3 is NR 2 .

[0818] 119. The compound of any one of embodiments 106 - 109, wherein X3 is O.

[0819] 120. The compound of any one of embodiments 106 - 109, wherein X 3 is S.

[0820] 121. The compound of any one of embodiments 106 - 120, wherein R 20 is a bond.

[0821] 122. The compound of any one of embodiments 106 - 120, wherein R 20 is an alkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 40 .

[0822] 123. The compound of any one of embodiments 106 - 120, wherein R 20 is an alkenyl or alkynyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 40 .

[0823] 124. The compound of any one of embodiments 106 - 120, wherein R 20 is an alkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R40 haloalkyl substituted with substituents

[0824] 125. The compound according to any one of embodiments 106 - 120, wherein R 20 is an aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40

[0825] 126. The compound according to any one of embodiments 106 - 120, wherein R 20 is a heteroaryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40

[0826] 127. The compound according to any one of embodiments 106 - 120, wherein R 20 is a heterocycle optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40

[0827] 128. The compound according to any one of embodiments 106 - 120, wherein R 20 is a bicyclic optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40

[0828] 129. The compound according to any one of embodiments 106 - 115, wherein R 20 is -O-.

[0829] 130. The compound according to any one of embodiments 106 - 115, wherein R 20 is -S-.

[0830] 131. The compound according to any one of embodiments 106 - 115, wherein R 20 is -NR 2 -.

[0831] 132. The compound according to 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)-.

[0832] 133. The compound according to any one of embodiments 106 - 132, wherein R 21 is a bond.

[0833] 134. The compound according to any one of embodiments 106 - 132, wherein R 21 is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R​​​​40 an alkyl substituted with a substituent

[0834] 135. A compound according to any one of embodiments 106 - 132, wherein R 21 is an alkenyl or alkynyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40

[0835] 136. A compound according to any one of embodiments 106 - 132, wherein R 21 is a haloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40

[0836] 137. A compound according to any one of embodiments 106 - 132, wherein R 21 is an aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40

[0837] 138. A compound according to any one of embodiments 106 - 132, wherein R 21 is a heteroaryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40

[0838] 139. A compound according to any one of embodiments 106 - 132, wherein R 21 is a heterocycle optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40

[0839] 140. A compound according to any one of embodiments 106 - 132, wherein R 21 is a bicyclic optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40

[0840] 141. A compound according to any one of embodiments 106 - 128, wherein R 21 is -O-.

[0841] 142. A compound according to any one of embodiments 106 - 128, wherein R 21 is -S-.

[0842] 143. A compound according to any one of embodiments 106 - 128, wherein R 21 is -NR 2 -.

[0843] 144. A compound according to 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)-.

[0844] 145. A compound according to any one of embodiments 106 - 144, wherein R 22 is a bond.

[0845] 146. A compound according to any one of embodiments 106 - 144, wherein R 22 is an alkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40 .

[0846] 147. A compound according to any one of embodiments 106 - 144, wherein R 22 is an alkenyl or alkynyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R40.

[0847] 148. A compound according to any one of embodiments 106 - 144, wherein R 22 is a haloalkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40 .

[0848] 149. A compound according to any one of embodiments 106 - 144, wherein R 22 is an aryl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40 .

[0849] 150. A compound according to any one of embodiments 106 - 144, wherein R 22 is a heteroaryl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40 .

[0850] 151. A compound according to any one of embodiments 106 - 144, wherein R 22 is a heterocycle optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40 .

[0851] 152. A compound according to any one of embodiments 106 - 144, wherein R 22 is a bicyclic group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40 .

[0852] 153. A compound according to any one of embodiments 106 - 143, wherein R 22is -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -, -P(O)(R 28 )- or -P(O)-.

[0853] 154. A compound according to any one of embodiments 106 - 140, wherein R 22 is -O-.

[0854] 155. A compound according to any one of embodiments 106 - 140, wherein R 22 is -S-.

[0855] 156. A compound according to any one of embodiments 106 - 140, wherein R 22 is -NR 2 -.

[0856] 157. A compound according to any one of embodiments 106 - 156, wherein R 23 or R 24 is a bond.

[0857] 158. A compound according to any one of embodiments 106 - 156, wherein R 23 or R 24 is an alkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40 .

[0858] 159. A compound according to any one of embodiments 106 - 156, wherein R 23 or R 24 is an alkenyl or alkynyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40 .

[0859] 160. A compound according to any one of embodiments 106 - 156, wherein R 23 or R 24 is a haloalkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40 .

[0860] 161. A compound according to any one of embodiments 106 - 156, wherein R 23 or R 24 is an aryl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40 .

[0861] 162. A compound according to any one of embodiments 106 - 156, wherein R 23 or R 24is a heteroaryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40 and the like.

[0862] 163. A compound according to any one of embodiments 106 - 156, wherein R 23 or R 24 is a heterocycle optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 40 and the like.

[0863] 164. A compound according to any one of embodiments 106 - 156, wherein R23 or R24 is a bicyclic optionally substituted with 1, 2, 3 or 4 substituents independently selected from R40.

[0864] 165. A compound according to 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)-.

[0865] 166. A compound according to any one of embodiments 106 - 156, wherein R 23 or R 24 is -O-.

[0866] 167. A compound according to any one of embodiments 106 - 156, wherein R 23 or R 24 is -S-.

[0867] 168. A compound according to any one of embodiments 106 - 156, wherein R 23 or R 24 is -NR2-.

[0868] 169. A compound according to any one of embodiments 106 - 168, wherein R 25 is hydrogen.

[0869] 170. A compound according to any one of embodiments 106 - 168, wherein R 25 is a halogen.

[0870] 171. A compound according to any one of embodiments 106 - 168, wherein R 25 is an alkyl optionally substituted with 1, 2, 3 or 4 groups independently selected from R 12 and the like.

[0871] 172. A compound according to any one of embodiments 106 - 168, wherein R25 Selected from alkenyl, alkynyl, hydroxy, alkoxy, azido, amino, cyano, -OR 2 , -NR 2 R 2' , -NR 2 SO2R 28 , -OSO2R 28 , -SO2R 28 , haloalkyl, aryl, heteroaryl, heterocycle, bicyclic and cycloalkyl; wherein each R 25 group is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 12 .

[0872] A compound according to any one of embodiments 106 - 172, wherein R 40 is selected from alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, cyano, haloalkyl, aryl, heteroaryl, heterocycle, oxo and cycloalkyl; wherein each R 40 group is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 12 .

[0873] A compound according to embodiment 173, wherein R 40 is unsubstituted.

[0874] A compound according to embodiment 1, wherein the compound is selected from:

[0875]

[0876]

[0877]

[0878] or a pharmaceutically acceptable salt thereof.

[0879] A compound according to embodiment 1, wherein the compound is selected from Table 2 or a pharmaceutically acceptable salt thereof. 177. A compound according to embodiment 1, wherein the compound has the structure

[0880] or a pharmaceutically acceptable salt thereof.

[0881] A compound according to embodiment 1, wherein the compound has the structure

[0882] or a pharmaceutically acceptable salt thereof.

[0883] A compound according to embodiment 1, wherein the compound has the structure

[0884] or a pharmaceutically acceptable salt thereof.

[0885] 180. The compound of embodiment 1, wherein the compound has the structure or a pharmaceutically acceptable salt thereof.

[0886] 181. The compound of embodiment 1, wherein the compound has the structure or a pharmaceutically acceptable salt thereof.

[0887] 182. In certain embodiments, there is provided a pharmaceutical composition comprising the compound of any one of embodiments 1 - 181 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0888] 183. In certain embodiments, there is provided a method of treating a cereblon - mediated disease in a human, comprising administering to a human in need thereof an effective dose of the compound of any one of embodiments 1 - 181 or a pharmaceutically acceptable salt or composition thereof.

[0889] 184. The method of embodiment 183, wherein the disease is mediated by Ikaros or Aiolos.

[0890] 185. The method of embodiment 183 or 184, wherein the disease is cancer.

[0891] 186. The method of embodiment 183 or 184, wherein the disease is a tumor.

[0892] 187. The method of embodiment 183 or 184, wherein the disease is an immune, autoimmune or inflammatory disorder.

[0893] 188. The method of embodiment 183 or 184, wherein the disease is a hematological malignancy.

[0894] 189. The method of embodiment 183 or 184, wherein the disease is multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non - Hodgkin's lymphoma.

[0895] 190. In certain embodiments, there is provided a compound for use in 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.

[0896] 191. Use of the compound of embodiment 190, wherein the disease is mediated by Ikaros or Aiolos.

[0897] Use of the compound of embodiment 190 or 191, wherein the disease is cancer.

[0898] Use of the compound of embodiment 190 or 191, wherein the disease is a tumor.

[0899] Use of the compound of embodiment 190 or 191, wherein the disease is an immune, autoimmune or inflammatory disorder.

[0900] Use of the compound of embodiment 190 or 191, wherein the disease is a hematological malignancy.

[0901] Use of the compound of embodiment 190 or 191, wherein the disease is multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma.

[0902] In certain embodiments, provided is the use of a compound in the treatment of 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.

[0903] Use of embodiment 197, wherein the disease is mediated by Ikaros or Aiolos.

[0904] Use of embodiment 197 or 198, wherein the disease is cancer.

[0905] Use of embodiment 197 or 198, wherein the disease is a tumor.

[0906] Use of embodiment 197 or 198, wherein the disease is an immune, autoimmune or inflammatory disorder.

[0907] Use of embodiment 197 or 198, wherein the disease is a hematological malignancy.

[0908] Use of embodiment 197 or 198, wherein the disease is multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma.

[0909] III. Treatment methods

[0910] Any compound described herein can be used in an effective amount to treat a host in need thereof, including a human, optionally in a pharmaceutically acceptable carrier for treating any disorder described herein. In certain embodiments, the method comprises administering an effective amount of an active compound or a salt thereof as described herein, optionally comprising a pharmaceutically acceptable excipient, carrier or adjuvant (i.e., a pharmaceutically acceptable composition), optionally in combination or alternation with other therapeutic active agents or medicaments.

[0911] In one embodiment, the compounds of the invention selectively degrade IKZF1 and / or IKZF3 compared to one or more of IKZF2 and / or IKZF4 and / or IKZF5.

[0912] In one embodiment, the compound of formula I is used for treating the disorders described herein.

[0913] In one embodiment, the compound of formula II is used for treating the disorders described herein.

[0914] In one embodiment, the compound of formula I-a is used for treating the disorders described herein.

[0915] In one embodiment, the compound of formula I-b is used for treating the disorders described herein.

[0916] In one embodiment, the compound of formula I-c is used for treating the disorders described herein.

[0917] In one embodiment, the compound of formula I-d is used for treating the disorders described herein.

[0918] In one embodiment, the compound of formula I-e is used for treating the disorders described herein.

[0919] In one embodiment, the compound of formula I-f is used for treating the disorders described herein.

[0920] In one embodiment, the compound of formula I-g is used for treating the disorders described herein.

[0921] In one embodiment, the disorder treated by the compounds of the invention is an immunomodulatory disorder. In one embodiment, the disorder treated by the compounds of the invention is mediated by angiogenesis. In one embodiment, the disorder treated by the compounds of the invention is related to the lymphatic system.

[0922] In one embodiment, the pharmaceutically acceptable salts of the compounds of the invention, optionally in a pharmaceutical composition as described herein, are used to degrade Ikaros or Aiolos, which are mediators of conditions in a patient such as a human. The control of protein levels provided by any of the compounds of the invention provides treatment of a disease state or condition that is regulated via Ikaros or Aiolos by reducing the protein level in a cell (e.g., a cell of the patient) or by reducing the level of downstream proteins in the cell. In certain embodiments, the method comprises administering an effective amount of a compound as described herein, optionally comprising a pharmaceutically acceptable excipient, carrier, adjuvant (i.e., a pharmaceutically acceptable composition), optionally in combination or alternation with other therapeutic active agents or medicaments.

[0923] In one embodiment, the compounds of the invention are used to treat conditions including but not limited to benign growths, tumors, neoplasms, cancers, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid-based proteinopathies, proteinopathies or fibrotic diseases.

[0924] When used in conjunction with any compound, the terms "disease state" or "condition" refer to any disease state or condition mediated by Ikaros or Aiolos, such as cell proliferation, or any disease state or condition mediated by a protein downstream of Ikaros or Aiolos, and wherein degradation of such protein in a patient may provide beneficial treatment or alleviation of symptoms to a patient in need. In some cases, the disease state or condition may be cured.

[0925] In one embodiment, a compound as described herein or its corresponding pharmaceutically acceptable salt, isotopic derivative or prodrug may be used in an effective amount to treat a host, such as a human, suffering from lymphoma or a lymphocytic or myelocytic proliferative disorder or abnormality. For example, a compound as described herein may be administered to a host suffering from Hodgkin lymphoma or non-Hodgkin lymphoma. For example, the host may be suffering from non-Hodgkin lymphoma, such as but not limited to: AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK-cell lymphoma; Burkitt lymphoma; Burkitt-like lymphoma (small non-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 γ-δ T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; pediatric lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; therapy-related T-cell lymphoma; Langerhans cell histiocytosis; or Waldenström macroglobulinemia.

[0926] In another embodiment, a compound as described herein or its corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug 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: classical Hodgkin lymphoma (CHL) with nodular sclerosis; mixed cellularity CHL; lymphocyte depletion CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin lymphoma; or nodular lymphocyte-predominant HL.

[0927] In another embodiment, a compound as described herein or its corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug 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, Sjogren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes, alopecia areata, vasculitis, and temporal arteritis.

[0928] In certain embodiments, the disorder treated with the compounds of the invention is a disorder associated with abnormal cell proliferation. Abnormal cell proliferation, particularly hyperproliferation, can be caused by a variety of factors, including gene mutations, infections, exposure to toxins, autoimmune diseases, and benign or malignant tumor induction.

[0929] 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 disorders can be treated with an effective amount of a compound as described herein to achieve a reduction in symptoms (palliative agent) or a reduction in the underlying disease (disease modifier).

[0930] In one embodiment, a compound as described herein or its corresponding pharmaceutically acceptable salt, isotopically-derivatized compound, or prodrug may be used in an effective amount to treat a host, such as a human, suffering from a specific B-cell lymphoma or proliferative disorder, where the specific B-cell lymphoma or proliferative disorder is not limited to: multiple myeloma; diffuse large B-cell lymphoma; follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT); small 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; lymphoplasmacytic lymphoma; heavy chain disease, such as alpha heavy chain disease, gamma heavy chain disease, Mu heavy chain disease; plasmacytoma myeloma; solitary plasmacytoma of bone; extramedullary 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.

[0931] In one embodiment, a compound as described herein or its corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug can be used in an effective amount to treat a host, such as a human, suffering from a T-cell or NK-cell lymphoma. Examples of T-cell or NK-cell lymphomas include, but are not limited to: anaplastic lymphoma kinase (ALK)-positive, ALK-negative anaplastic large cell lymphoma, or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell 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, and lymphomatoid papulosis; adult T-cell leukemia / lymphoma (ATLL); blastic NK-cell lymphoma; enteropathy-type T-cell lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; nasal NK / T-cell lymphoma; therapy-related T-cell lymphoma; for example, lymphoma that occurs after solid organ or bone marrow transplantation; T-cell prolymphocytic leukemia; T-cell large granular lymphocyte leukemia; NK-cell chronic lymphoproliferative disorder; aggressive NK-cell leukemia; systemic EBV+ T-cell lymphoproliferative disease of childhood (associated with chronic active EBV infection); hydroa vacciniforme-like lymphoma; adult T-cell leukemia / lymphoma; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; or subcutaneous panniculitis-like T-cell lymphoma.

[0932] In one embodiment, a compound as described herein or its corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug can be used to treat a host, such as a human, suffering from leukemia. For example, the host may be suffering from acute or chronic leukemia of lymphocytic or myeloid origin, such as, but not limited to: acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); large granular lymphocyte 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; with cell maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); or megakaryocytic leukemia (M7).

[0933] There are many skin diseases associated with excessive cell proliferation. For example, psoriasis is a benign disease of human skin, typically characterized by plaques covered with thickened scales. The disease is caused by an increase in epidermal cell proliferation of unknown origin. Chronic eczema is also associated with significant hyperplasia of the epidermis. Other diseases caused by excessive proliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

[0934] Other hyperproliferative cell disorders include vascular proliferative disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancers.

[0935] Vascular proliferative disorders include angiogenic disorders and vasculogenic disorders. Proliferation of smooth muscle cells during plaque formation in vascular tissue results in, for example, restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[0936] Fibrotic disorders are generally due to the abnormal formation of the extracellular matrix. Examples of fibrotic disorders include cirrhosis and mesangial proliferative cell disorders. Cirrhosis is characterized by an increase in extracellular matrix components leading to the formation of liver scars. Cirrhosis can cause diseases such as liver cirrhosis. The increase in extracellular matrix leading to liver scars can also be caused by viral infections such as hepatitis. Adipocytes seem to play a major role in cirrhosis.

[0937] 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.

[0938] Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease, which is thought to be associated with the activity of autoreactive T cells and is caused by autoantibodies produced against collagen and IgE.

[0939] Other diseases 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 inflammation.

[0940] A compound as described herein or a pharmaceutically acceptable salt, isotopically labeled analogue, or prodrug thereof can be used in an effective amount to treat a host, such as a human, suffering from a proliferative disease, such as a myeloproliferative disease (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis with myeloid metaplasia (MMM), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mastocytosis disease (SMCD), and the like. 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.

[0941] In one embodiment, a compound as described herein or a pharmaceutically acceptable salt, isotopically labeled analogue, or prodrug thereof can be used in an effective amount to treat a host, such as a human, suffering from myelodysplastic syndrome (MDS), such as, but not limited to: refractory cytopenia with unilineage dysplasia, refractory anemia with ring sideroblasts (RARS), refractory anemia with ring sideroblasts - thrombocytosis (RARS-t), refractory cytopenia with multilineage dysplasia (RCMD), including RCMD with multilineage dysplasia and ring sideroblasts (RCMD-RS), refractory anemia with excess blasts I (RAEB-I) and II (RAEB-II), 5q- syndrome, refractory cytopenia in children, and the like.

[0942] In one embodiment, the compounds of the invention can provide a therapeutic effect by directly degrading Ikaros or Aiolos, which can alter the transcriptional regulation of proteins downstream of Ikaros or Aiolos.

[0943] The term "neoplasia" or "cancer" is used to refer to the pathological process that results in the formation and growth of a cancerous or malignant tumor, i.e., abnormal tissue that grows by cell proliferation, usually faster than normal tissue and continues to grow after the stimulus that initiated the new growth has ceased. Malignant tumors show 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 and cause the death of the patient unless adequately treated. As used herein, the term "neoplasia" is used to describe all cancerous disease states and includes or encompasses the pathological processes associated with malignant hematogenous, ascitic, and solid tumors. Exemplary cancers that can be treated by the compounds of the present invention alone or in combination with at least one additional anti-cancer agent include: squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, rhabdomyosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma multiforme, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineocytoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinoma. Other cancers that can be treated with the compounds according to the present invention include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL and Philadelphia chromosome-positive CML.

[0944] Other cancers that can be treated with the compounds disclosed in the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendiceal cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder cancer, bone cancer, myeloma, bowel cancer, brain cancer, brainstem glioma, breast cancer, triple (estrogen, progesterone, and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone, and HER-2 are negative), single negative (one of estrogen, progesterone, and HER-2 is negative), estrogen receptor positive, HER2 negative breast cancer, estrogen receptor negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2 negative breast cancer, HER2 positive or negative breast cancer, progesterone receptor negative breast cancer, progesterone receptor positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous 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 cholangiocarcinoma, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal cancer, intrahepatic cholangiocarcinoma, invasive / infiltrating breast cancer, islet cell carcinoma, jaw cancer, Kaposi 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, mesenchyme, mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic cervical squamous cell carcinoma, mixed glioma, monodermal teratoma, oral cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, uveal melanoma, oligodendroglioma, oral cancer, oral cancer, oropharyngeal cancer, osteosarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian primary 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 cancerPheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineocytoma, pituitary carcinoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvic carcinoma, rhabdomyosarcoma, salivary gland carcinoma, soft tissue sarcoma, osteosarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cord cancer, spinal cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsillar cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, 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 lymphocyte 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 disease, such as alpha heavy chain disease, gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extramedullary 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 disorder is adenoid cystic carcinoma. In one embodiment, the disorder is NUT midline carcinoma.,

[0945] In another embodiment, a compound or a pharmaceutically acceptable salt, isotopically labeled derivative, or prodrug thereof, as described herein, 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 enteropathy; autoimmune neutropenia; autoimmune hemolytic anemia; autoimmune hepatitis; autoimmune hypoparathyroidism; autoimmune inner ear disease; autoimmune lymphoproliferative syndrome; autoimmune myocarditis; autoimmune pancreatitis; autoimmune peripheral neuropathy; autoimmune ovarian failure; autoimmune polyendocrine syndrome; autoimmune progesterone dermatitis; autoimmune thrombocytopenic purpura; autoimmune thyroid disease; autoimmune urticaria; autoimmune uveitis; autoimmune vasculitis; Balo disease / Balo concentric sclerosis; Behçet's disease; Berger's disease; Bickerstaff encephalitis; Blau syndrome; bullous pemphigoid; cancer; Castleman disease; celiac disease; Chagas disease; chronic inflammatory demyelinating polyneuropathy; chronic obstructive pulmonary disease; chronic recurrent multifocal osteomyelitis; Churg-Strauss syndrome; cicatricial pemphigoid; Cogan syndrome; cold agglutinin disease; complement component 2 deficiency; contact dermatitis; cranial arteritis; CREST syndrome; Crohn's disease; Cushing's syndrome; cutaneous leukocytoclastic vasculitis; Degos disease; Dercum's disease; dermatitis herpetiformis; dermatomyositis; diabetes mellitus type 1; 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; fetal erythroblastosis; essential mixed cryoglobulinemia; Evan's syndrome; extrinsic and intrinsic reactive airway disease (asthma); progressive fibrodysplasia ossificans; 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-Schönlein purpura; herpes gestationis (pemphigoid gestationis); hidradenitis suppurativa; Hughes-Stovin syndrome; hypogammaglobulinemia; idiopathic inflammatory demyelinating diseases; idiopathic pulmonary fibrosis; idiopathic thrombocytopenic purpura; IgA nephropathy; immune glomerulonephritis; immune nephritis; immune pneumonia; inclusion body myositis; inflammatory bowel disease; interstitial cystitis;Juvenile idiopathic arthritis is also known as juvenile rheumatoid arthritis; Kawasaki disease; Lambert-Eaton myasthenic syndrome; leukocytoclastic vasculitis; lichen planus; lichen sclerosus; linear IgA disease (LAD); lupoid hepatitis also known as autoimmune hepatitis; lupus erythematosus; Maggiore syndrome; microscopic polyangiitis; Miller-Fisher syndrome; mixed connective tissue disease; morphea; Mucha-Habermann disease also known as pityriasis lichenoides et varioliformis acuta; multiple sclerosis; myasthenia gravis; myositis; Ménière's disease; narcolepsy; neuromyelitis optica (also Devic's disease); neuromyotonia; ocular cicatricial pemphigoid; opsoclonus syndrome; Ord's thyroiditis; palindromic rheumatism; PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus); paraneoplastic cerebellar degeneration; paroxysmal nocturnal hemoglobinuria (PNH); Parry-Romberg syndrome; pharyngitis; Priest-Turner syndrome; pemphigus vulgaris; periaxial encephalomyelitis; pernicious anemia; POEMS syndrome; polyarteritis nodosa; polymyalgia rheumatica; polymyositis; primary biliary cirrhosis; primary sclerosing cholangitis; progressive inflammatory neuropathy; psoriasis; psoriatic arthritis; pure red cell aplasia; pyoderma gangrenosum; Rasmussen encephalitis; Raynaud's phenomenon; Rett syndrome; relapsing polychondritis; restless legs syndrome; retroperitoneal fibrosis; rheumatic fever; rheumatoid arthritis; sarcoidosis; schizophrenia; Schmidt syndrome; Schnitzler syndrome; scleritis; scleroderma; sclerosing cholangitis; serum sickness; Sjögren's syndrome; spondyloarthropathy; stiff person syndrome; Still's disease; subacute bacterial endocarditis (SBE); Susac syndrome; Sweet syndrome; Sydenham's chorea; sympathetic ophthalmia; systemic lupus erythematosus; Takayasu 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, HTLV1, 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 allergy, atopic dermatitis, chronic pain and rhinitis.;

[0946] Skin contact allergies and asthma are just two examples of immune responses that may be associated with significant morbidity. Others include atopic dermatitis, eczema, Sjogren's syndrome, including keratoconjunctivitis sicca secondary to Sjogren's syndrome, alopecia areata, allergic reactions due to arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative conjunctivitis, cutaneous systemic lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may result in any one or more of the following symptoms or signs: itching, swelling, redness, blisters, crusting, ulceration, pain, desquamation, cracking, hair loss, scarring, or fluid exudation involving the skin, eyes, or mucous membranes.

[0947] In atopic dermatitis and eczema in general, immune-mediated leukocyte infiltration (particularly infiltration of 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 at sites outside the skin, such as the airways in asthma patients and the lacrimal glands of the eyes in keratoconjunctivitis sicca.

[0948] A compound or a pharmaceutically acceptable salt, isotopic variant, or prodrug thereof as described herein can be used in an effective amount to treat a host, such as a human, suffering from 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 applied topically. In some embodiments, a skin disease is treated by topically administering a compound known in the art in combination with a compound disclosed herein. In a non-limiting embodiment, the compounds of the present invention are used as topical agents for treating contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's syndrome, including keratoconjunctivitis sicca secondary to Sjogren'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 novel method can also be used to reduce infiltration of malignant leukocytes into the skin in diseases such as mycosis.

[0949] Disease states of disorders that can be treated using the compounds according to the present invention 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.

[0950] Other disease states or disorders 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.

[0951] Other disease states or conditions treatable by the compounds of the present invention include ceruloplasminemia, chondrogenesis type II, achondroplasia, craniofacial anomalies, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenosine deaminase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkalosis, alpha-1 antitrypsin deficiency, alpha-1 protease inhibitor, emphysema, amyotrophic lateral sclerosis, Alexander disease ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, angiokeratoma corporis diffusum, von Hippel-Lindau disease, Apert syndrome, arachnodactyly (Marfan syndrome), Stickler syndrome, arthrochalasia multiplex (Ehlers-Danlos syndrome, arthrochalasia type), ataxia telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beare-Stevenson cutis gyrata syndrome, familial Mediterranean fever, Benjamin syndrome, beta-thalassemia, bilateral acoustic 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 disease, Birt-Hogg-Dubé syndrome, brittle bone disease (osteogenesis imperfecta), thumb-toe syndrome (Rubinstein-Taybi syndrome), bronze diabetes / bronze cirrhosis (hemochromatosis), bulbospinal muscular atrophy (Kennedy disease), Berg-Gruetz syndrome (lipoprotein lipase deficiency), CGD chronic granulomatous disease, Campomelic dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cat cry, CAVD (congenital absence of vas deferens), Caylor cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, chondrodystrophy syndrome (achondroplasia), otospondylomegaepiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, lethal osteogenesis imperfecta, 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 deformity facial anemia, thalassemia (beta-thalassemia), copper storage disease (Wilson disease), copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial joint disorder (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Beare-Stevenson cutis verticis gyrata syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Strudwick type), muscular dystrophy, Duchenne and Becker types (DBMD), Arthus syndrome, degenerative neurological diseases, including deGrouchy syndrome and Dejerine-Sottas syndrome, developmental disorders, distal spinal muscular atrophy, type V, androgen insensitivity syndrome, diffuse globoid cell sclerosis (Krabbe disease), DiGeorge syndrome, deficiency of dihydrotestosterone receptor, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protoporphyria, deficiency of erythropoietic 5-aminolevulinate synthase, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia - familial Mediterranean fever, porphyria cutanea tarda, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), pancreatic fibrocystic disease, fragile X syndrome, galactosemia, hereditary brain diseases, giant cell hepatitis (neonatal hemochromatosis), Gronblad-Strandberg syndrome (pseudoxanthoma elasticum), Gunther disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren syndrome, sickle cell anemia, hemophilia, hepatic erythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, hypochondroplasia, immune system diseases, 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, multiple 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 fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion diseases, progeria (HutchinsonGilford progeria syndrome, progressive chorea, chronic hereditary (Huntington's) (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic academia, protoporphyria, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type I), recurrent polyserositis, retinal diseases, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast cancer, leukemia and adrenal (SBLA) syndrome, tuberous sclerosis, SDAT, SED congenital (spondyloepiphyseal dysplasia congenita), SED Strudwick (spondyloepiphyseal dysplasia, Strudwick type), SEDc (spondyloepiphyseal dysplasia congenita) SEMD, Strudwick type (metaphyseal chondrodysplasia, Strudwick type), Shprintzen syndrome, cutaneous pigmentation disorders, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (variegate porphyria), infantile ascending hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, β-thalassemia, thyroid diseases, giant axonal neuropathy (hereditary neuropathy with liability to pressure palsies), Treacher Collins syndrome, Triplo X syndrome (triple X syndrome), trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness ( syndromes), Vrolik's disease, Waardenburg syndrome, Warburg Sjo Fledelius syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disease, Weissenbacher-Zweymüller syndrome and xeroderma pigmentosum, etc.

[0952] In one embodiment, there is provided a method for treating multiple myeloma, comprising administering to a patient an effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt, isotopically labeled analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition for treating multiple myeloma. In another embodiment, a compound of Formula I or Formula II or a pharmaceutically acceptable salt, isotopically labeled analogue 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.

[0953] In one embodiment, there is provided a method for controlling the progression of multiple myeloma, comprising administering to a patient an effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt, isotopically labeled analogue 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, isotopically labeled analogue 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.

[0954] In one embodiment, there is provided a method for inducing a treatment response in a patient with multiple myeloma, the treatment response being evaluated by the International Uniform Response Criteria (IURC) for multiple myeloma (described in "International Uniform Response Criteria for Multiple Myeloma" by Durie B.G.M. et al., Leukemia 2006, 10(10):1-7), comprising administering to the patient an effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt, isotopically labeled analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0955] In another embodiment, there is provided a method for achieving a stringent complete response, complete response or very good partial response, as evaluated 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, isotopically labeled analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0956] In another embodiment, there is provided a method for increasing overall survival, progression-free survival, event-free survival, time to 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, isotopically labeled analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0957] In another embodiment, a method of achieving an increase in 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, isotopically labeled analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0958] In another embodiment, a method of achieving an increase in progression-free survival in a patient with multiple myeloma is provided, the method comprising administering to the patient an effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt, isotopically labeled analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0959] In another embodiment, a method of achieving an increase in event-free survival in a patient with multiple myeloma is provided, the method comprising administering to the patient an effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt, isotopically labeled analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0960] In another embodiment, a method of achieving an increase in 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, isotopically labeled analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0961] In another embodiment, a method of achieving an increase in 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, isotopically labeled analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0962] In addition to patients who have not been previously treated, methods of treating patients who have previously received treatment for multiple myeloma but are unresponsive to standard therapies are provided. In addition to patients who have not undergone surgery, other methods are provided for treating patients who have undergone surgery in an attempt to treat multiple myeloma. In addition to those patients who have not received transplant therapy, methods of treating patients who have previously received transplant therapy are provided.

[0963] The compounds described herein can be used to treat or control recurrent, refractory or drug-resistant multiple myeloma. In some embodiments, the multiple myeloma is primary, secondary, tertiary, quaternary or quinary recurrence. In one embodiment, the compounds described herein can be used to reduce, maintain or eliminate minimal residual disease (MRD).

[0964] The types of multiple myeloma that can be treated with the compounds described herein include, but are not limited to: monoclonal gammopathy of undetermined significance (MGUS); low-risk, intermediate-risk or high-risk multiple myeloma; newly diagnosed multiple myeloma, including 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.

[0965] In some embodiments, the compounds described herein can be used to treat or control multiple myeloma characterized by genetic abnormalities, such as, but not limited to: cyclin D translocations (e.g., t(11;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32); or t(6;20)); MMSET translocations (e.g., t(4;14)(p16;q32); MAF translocations (e.g., t(14;16)(q32;a32); t(20;22); t(16;22)(q11;q13); or t(14;20)(q32;q11); or other chromosomal factors (e.g., deletion of 17p13 or chromosome 13; del(17 / 17p), non-hyperdiploidy and gain (1q)).

[0966] In one embodiment, there is provided a method for treating or controlling multiple myeloma, comprising administering to a patient an effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally formulated in a pharmaceutically acceptable carrier, as induction therapy.

[0967] In one embodiment, there is provided a method for treating or controlling multiple myeloma, comprising administering to a patient an effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally formulated in a pharmaceutically acceptable form of a carrier, as consolidation therapy.

[0968] In one embodiment, there is provided a method for treating or controlling multiple myeloma, comprising administering to a patient an effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally formulated in a pharmaceutically acceptable form of a carrier, as maintenance therapy.

[0969] In one embodiment, the multiple myeloma is plasma cell leukemia.

[0970] 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 is relapsed or refractory to one, two, or three prior treatments.

[0971] In one embodiment, the multiple myeloma has a p53 mutation. In one embodiment, the p53 mutation is the Q331 mutation. In one embodiment, the p53 mutation is the R273H mutation. In one embodiment, the p53 mutation is the K132 mutation. In one embodiment, the p53 mutation is the K132N mutation. In one embodiment, the p53 mutation is the R337 mutation. In one embodiment, the p53 mutation is the R337L mutation. In one embodiment, the p53 mutation is the W146 mutation. In one embodiment, the p53 mutation is the S261 mutation. In one embodiment, the p53 mutation is the S261T mutation. In one embodiment, the p53 mutation is the E286 mutation. In one embodiment, the p53 mutation is the E286K mutation. In one embodiment, the p53 mutation is the R175 mutation. In one embodiment, the p53 mutation is the R175H mutation. In one embodiment, the p53 mutation is the E258 mutation. In one embodiment, the p53 mutation is the E258K mutation. In one embodiment, the p53 mutation is the A161 mutation. In one embodiment, the p53 mutation is the A161T mutation.

[0972] 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.

[0973] 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.

[0974] In one embodiment, 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 translocation is 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).

[0975] In one embodiment, multiple myeloma has a Q331 p53 mutation, activation of C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, multiple myeloma has a homozygous deletion of p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, multiple myeloma has a K132N p53 mutation, activation of MAFB, and a chromosomal translocation at t(14;20). In one embodiment, multiple myeloma has wild-type p53, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma has wild-type p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, multiple myeloma has a homozygous deletion of p53, activation of FGFR3, MMset and C-MAF, and chromosomal translocations at t(4;14) and t(14;16). In one embodiment, multiple myeloma has a homozygous deletion of p53, activation of cyclin D1, and a chromosomal translocation at t(11;14). In one embodiment, multiple myeloma has an R337L p53 mutation, activation of cyclin D1, and a chromosomal translocation at t(11;14). In one embodiment, multiple myeloma has a W146 p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma has an S261T p53 mutation, activation of MAFB, and chromosomal translocations at t(6;20) and t(20;22). In one embodiment, multiple myeloma has an E286K p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma has an R175H p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, 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, 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, multiple myeloma has an A161T p53 mutation, activation of cyclin D, and a chromosomal translocation at t(11;14).

[0976] In some embodiments, multiple myeloma is newly diagnosed multiple myeloma suitable for transplantation. In other embodiments, multiple myeloma is newly diagnosed multiple myeloma not suitable for transplantation.

[0977] In some embodiments, multiple myeloma exhibits early progression (e.g., less than 12 months) after initial treatment. In other embodiments, multiple myeloma exhibits early progression (e.g., less than 12 months) after autologous stem cell transplantation. In another embodiment, multiple myeloma is refractory to lenalidomide. In 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, ibedademstat, or avadomide), or has dual resistance to a proteasome inhibitor and an immunomodulatory compound.

[0978] In other embodiments, multiple myeloma is refractory or relapsed to 3 or more prior therapies, including, for example, a CD38 monoclonal antibody (CD38mAb, e.g., daratumumab or isatuximab), a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, ibedademstat, or avadomide), or has dual resistance to a proteasome inhibitor or an immunomodulatory compound and a CD38mAb. In other embodiments, multiple myeloma is triple refractory, e.g., multiple myeloma is refractory to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib), an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, ibedademstat, or avadomide), and one other active agent as described herein.

[0979] In one embodiment, a method for treating or controlling relapsed or refractory multiple myeloma in a patient having impaired renal function or symptoms thereof is provided, the method comprising administering to the patient an effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt, isotopically labeled analogue, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0980] In another embodiment, a method for treating or controlling 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, isotopically labeled analogue, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, wherein the frail patient is characterized as being unsuitable for induction therapy or intolerant to dexamethasone therapy. In other embodiments, the frail patient is an elderly person, e.g., greater than 65 years old.

[0981] In another embodiment, there is provided a method for treating or controlling quadruple refractory or relapsed multiple myeloma, comprising administering to a patient an effective amount of a compound of formula I or formula II or a pharmaceutically acceptable salt, isotopically labeled analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0982] In another embodiment, there is provided a method for treating or controlling newly diagnosed multiple myeloma that is not transplant eligible, comprising administering to a patient an effective amount of a compound of formula I or formula II or a pharmaceutically acceptable salt, isotopically labeled analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0983] In another embodiment, there is provided a method for treating or controlling newly diagnosed multiple myeloma that is not transplant eligible, comprising administering to a patient an effective amount of a compound of formula I or formula II or a pharmaceutically acceptable salt, isotopically labeled analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, as an additional therapy or as maintenance therapy after transplantation.

[0984] In another embodiment, there is provided a method for treating or controlling high-risk multiple myeloma that has relapsed or is refractory to one, two or three prior therapies, comprising administering to a patient an effective amount of a compound of formula I or formula II or a pharmaceutically acceptable salt, isotopically labeled analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0985] In some embodiments, a patient to be treated with one of the compounds described herein has not been treated with multiple myeloma therapy prior to dosing. In some embodiments, a patient to be treated with one of the compounds described herein has been treated with multiple myeloma therapy prior to dosing. In some embodiments, a patient to be treated with one of the compounds described herein has developed resistance to multiple myeloma therapy. In some embodiments, a patient to be treated with one of the compounds described herein has developed resistance to one, two or three multiple myeloma therapies selected from CD38 antibodies (CD38 mAB, such as daratumumab or isatuximab), proteasome inhibitors (such as bortezomib, carfilzomib, ixazomib or marizomib) and immunomodulatory compounds (such as thalidomide, lenalidomide, pomalidomide, ibedademstat or avadomide).

[0986] Regardless of the age of the patient, the compounds described herein can be used to treat a 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.

[0987] IV. Combination Therapies

[0988] Any of the compounds described herein can be used, alone or in combination, in an effective amount to treat a host, such as a human, having a disorder described herein.

[0989] The term "bioactive agent" or "other therapeutic agent" is used to describe an agent other than a compound according to the invention that can be used in combination with or in alternation with a compound of the invention to achieve a desired therapeutic outcome. In one embodiment, the compounds of the invention and other therapeutic agents are administered in such a way that they are active in the body during an overlapping time period, such as having overlapping Cmax, Tmax, AUC or other pharmacokinetic parameters. In another embodiment, the compounds of the invention and other therapeutic agents 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.

[0990] In one aspect of this embodiment, the other therapeutic agent is an immunomodulator, 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, T cell activation V-domain Ig suppressor (VISTA) inhibitors, small molecules, peptides, nucleotides or other inhibitors. In certain aspects, the immunomodulator is an antibody, such as a monoclonal antibody.

[0991] 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 inhibit 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 the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro). In one embodiment, the PD-1 inhibitor is BGB-A317. In one embodiment, the PD-L1 inhibitor is MED14736. In one embodiment, the PD-L2 inhibitor is rHIgM12B7A.

[0992] 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.

[0993] 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.

[0994] In one embodiment, the checkpoint inhibitor is a GITR agonist. In one embodiment, the GITR agonist is an anti-GITR antibody, such as TRX518.

[0995] 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.

[0996] 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.

[0997] In one embodiment, the checkpoint inhibitor is an IDO inhibitor, such as INCB24360 or indoximod.

[0998] In another embodiment, the active compounds described herein can be administered in combination or alternately with an effective amount of an androgen (such as testosterone) inhibitor to treat abnormal tissues of the male reproductive system such as prostate cancer or testicular cancer. The inhibitors include, but are not limited to, selective androgen receptor modulators, selective androgen receptor degraders, complete androgen receptor degraders, or another form of partial or complete androgen antagonist. In one embodiment, the 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, topilutamide, abiraterone acetate, and cimetidine.

[0999] In one embodiment, the other therapeutic 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.

[1000] In one embodiment, the other therapeutic active agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso), olita, nagitinib (ASP8273), nazartinib (EGF8756), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272); 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).

[1001] In one embodiment, the other therapeutic active agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.

[1002] In one embodiment, the other therapeutic active agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, ofatumumab, ibritumomab tiuxetan, tositumomab, and ocrelizumab.

[1003] In one embodiment, the other therapeutic active agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib.

[1004] In one embodiment, the other therapeutic 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]piperazin-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-[l,l'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (obatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl)-1H-pyrrol-2-yl)methylene]-4-methoxypyrrol-2-ylidene]indole; mesylate)), 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-carboxylate, nilotinib-d3, TW-37 (N-[4-[[2-(1,1-dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid or G3139 (Oblimersen).

[1005] In one embodiment, the other therapeutic active agent is a kinase inhibitor. In one embodiment, the kinase inhibitor is selected from phosphoinositide 3-kinase (PI3K) inhibitors, Bruton's tyrosine kinase (BTK) inhibitors or spleen tyrosine kinase (Syk) inhibitors or combinations thereof.

[1006] Examples of PI3 kinase inhibitors include, but are not limited to: wortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib, Palomid529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib) (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin -9-yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-phenoxy-2-butanoyl 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-(methoxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-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-morpholinyl-1H-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2-morpholinyl-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]quinazoline), AS252424 (5-[1-[5-(4-fluoro-2-hydroxyphenyl)-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-bis(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-morpholinylthieno[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-chromen-2-yl)morpholin-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-carboxylate), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea) (gedatolisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-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]isochromen-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.,

[1007] Examples of BTK inhibitors include: ibrutinib (also known as PCI-32765) (Imbruvica TM)(1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), a diphenylaminopyrimidine-based inhibitor, 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 by reference 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-dibromophenyl)acrylamide), GDC-0834 ([R-N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide], CGI-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-((3-Acrylamidophenyl)amino))-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpyridinecarboxamide), CTA056 (7-Benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(1,4)-Dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono 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-methylpiperazin-1-yl)pyridin-2-ylamino]-6-oxo-1,6-dihydropyridin-3-yl}-phenyl)-2H-isoquinolin-1-one), and other molecules capable of inhibiting BTK activity, such as those BTK inhibitors disclosed by Akinleye et al. in Journal of Hematology&Oncology, 2013, 6:59, the entire content of which is incorporated herein by reference.,

[1008] 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]oxazin -4-yl]methyl 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]oxazin -4(3H)-yl)methyl sodium phosphate), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxamide), imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d)]pyrimidin-4-amine), 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)pyrimidine-5-carboxamide hydrochloride), 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]oxazine -3(4H)-one), piceatannol (3-hydroxy resveratrol), 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 by reference in its entirety), Compound D (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein by reference 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 by reference 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 by reference in its entirety), apigenin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein by reference in its entirety), quercetin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614 - 3643 (incorporated herein by reference 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 by reference 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 by reference in its entirety), quercetin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614 - 3643, incorporated herein by reference in its entirety).

[1009] In one embodiment, the other therapeutic 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-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol), refametinib / BAY869766 / RDEA119 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridinyl]methyl]-4-methyl-7-pyrimidin-2-yloxycoumarin-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-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. Alk-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.

[1010] In one embodiment, the other therapeutic 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)-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]azepin-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-pyridinecarboxamide 1-oxide), PLX-4720, Dabrafenib (GSK2118436), GDC-0879, RAF265, AZ628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (Encorfenib).

[1011] In one embodiment, the other therapeutic agent is an AKT inhibitor, including but not limited to MK-2206, GSK690693, Perifosine (KRX-0401), GDC-0068, Trabectedin, AZD5363, Honokiol, PF-04691502, and Miltefosine; an 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.

[1012] In one embodiment, the other therapeutic active agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to: rapamycin and its analogs, everolimus (Afinitor), temsirolimus, deforolimus, sirolimus, and rapalogs. Examples of MEK inhibitors include, but are not limited to: 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-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (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-0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoyl)amino]-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-oxazin-2-yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).

[1013] In one embodiment, the other therapeutic active agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12DLODER.

[1014] In one embodiment, the other therapeutic active agent is a HSP inhibitor. HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and radicicol.

[1015] Other bioactive compounds include, for example, everolimus, trabectedin, albumin-bound 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 inhibitor, VEGFR inhibitor, aurora kinase inhibitor, PIK-1 regulator, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, IGFR-TK inhibitor, anti-HGF antibody, focal adhesion kinase inhibitor, Map kinase kinase (mek) inhibitor, VEGF trap antibody, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitenecan, tilmifene, oblimersen, ticilimumab, ipilimumab, gossypol, BIO111, 131-I-TM-601, ALT-110, BIO140, CC8490, cilengitide, gemcitabine, IL13-PE38QQR, INO1001, IPdR1KRX-0402, anthrone, 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-(methylsulfonylpiperidinomethyl)-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, Ionafarnib, BMS-214662, Tipifarnib; Amifostine, NVP-LAQ824, Octanoylbenzohydroxamic Acid, Valproic Acid, Trichostatin A, FK-228, SU11248, Sorafenib, KRN951, Aminoglutethimide, Anacrine, Anagrelide, L-Asparaginase, Bacillus Calmette-Guerin (BCG), Doxorubicin, Bleomycin, Buserelin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Clodronate, Cyproterone, Cytarabine, Dacarbazine, Actinomycin D, Daunorubicin, Diethylstilbestrol, Epirubicin, Fludarabine, Fludrocortisone, Fluoxymesterone, Flutamide, Gleevec, Gemcitabine, Hydroxyurea, Demethoxydaunorubicin, Ifosfamide, Imatinib, Leuprolide, Levamisole, Lomustine, Ketamine, Melphalan, 6-Mercaptopurine, Mesna, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Nilutamide, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, Plicamycin, Porfimer Sodium, Procarbazine, Raltitrexed, Rituximab, Streptozocin, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Tretinoin, Vinzolidine, 13-cis-Retinoic Acid, Phenylalanine Mustard, Uracil Mustard, Estramustine, Altretamine, Floxuridine, 5-Deoxyuridine, Cytarabine, 6-Mercaptopurine, Deoxycoformycin, Calcitriol, Valrubicin, Mithramycin, Vinblastine, Vinorelbine, Topotecan, Razoxin, Marimastat, COL-3, Nevastatin, BMS-275291, Squalamine, Endostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Droloxifene, Idoxifene, Spironolactone, Finasteride, Cimetidine, Trastuzumab, Denileukin, Gefitinib, Bortezomib, Paclitaxel, Paclitaxel without Cremophor EL, Docetaxel, Epothilone B, BMS-247550, BMS-310705, Droloxifene, 4-Hydroxytamoxifen, Pipoxifene, ERA-923, Azoxifene, Fulvestrant, Acoxifene, 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, darbepoetin alfa, epoetin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol acetate, immunoglobulin, mechlorethamine, methylprednisolone, ibritumomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, 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, tropisetron, pegfilgrastim, epoetin alfa, epoetin beta, darbepoetin alfa and mixtures thereof.

[1016] In one embodiment, other therapeutic active agents are selected from, but not limited to: imatinib mesylate dasatinib nilotinib bosutinib trastuzumab trastuzumab-DM1, pertuzumab (PerjetaTM), lapatinib gefitinib erlotinib cetuximab panitumumab vandetanib vemurafenib vorinostat romidepsin bexarotene alitretinoin tretinoin carfilzomib (KyprolisTM), pralatrexate bevacizumab, aflibercept sorafenib sunitinib pazopanib regorafenib and cabozantinib (CometriqTM).

[1017] In some aspects, the other therapeutic active agents are anti-inflammatory agents, chemotherapeutic agents, radiotherapy agents, other therapeutic agents or immunosuppressive agents.

[1018] Suitable chemotherapeutic additional therapeutic active agents include, but are not limited to: radioactive molecules, toxins (also known as cytotoxins or cytotoxic agents), which include any reagent harmful to cell viability, and liposomes or other carriers containing chemotherapeutic compounds. Conventional anticancer drugs include: vincristine or liposomal vincristine daunorubicin (daunomycin or ) or doxorubicin cytarabine (cytosine arabinoside, ara-C or ), L-asparaginase or PEG-L-asparaginase (pegaspargase or ), etoposide (VP-16), teniposide 6-mercaptopurine (6-MP or ), methotrexate, cyclophosphamide prednisone, dexamethasone (Decadron), imatinib dasatinib nilotinib bosutinib and ponatinib (Iclusig TMExamples of other suitable chemotherapeutic agents include, but are not limited to, 1-dehydrotestosterone, 5-fluorouracil decarboxazid, 6-mercaptopurine, 6-thioguanine, actinomycin D, doxorubicin, aldesleukin, alkylating agents, allopurinol sodium, atrotamide, 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, calcitriol calcium, calicheamicin, capecitabine, carboplatin, lomustine (C CNU), carmustine (BSNU), chloramphenicol, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, Cyclothosphamide, cyclohexamine, cytarabine, cytarabine, cytochalasin B, dacarbazine, actinomycin, actinomycin (formerly actinomycin), daunorubicin hydrochloride, daunorubicin citrate, denileukin toxin, dexrazoxane, dibromoamine mannitol, dihydroxyanthraquinone, docetaxel, dolasetron mesylate, doxorubicin hydrochloride, dronabinol, Escherichia coli L-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogen, estradiol, estradiol Sodium phosphite, ethidium bromide, ethinyl estradiol, etidronate sodium, etoposide citrate factor, 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 α-2b, irinotecan hydrochloride, letrozole, folinic acid calcium, leuprolide 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, polyphenprosan 20 with carmustine implant, propfil 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.

[1019] Other therapeutic agents that can be co-administered with the degraders disclosed herein can include: bevacizumab, sunitinib, sorafenib, 2-methoxyestradiol or 2ME2, fenretinide, vatalanib, vandetanib, aflibercept, volociximab, elotuzumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, ficlatuzumab, atacicept, rituximab, alemtuzumab, aldesleukin, atezolizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, datopotamab, HLL1, huN901-DM1, atimolol, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat, mapatumumab, lesatumumab, dulaglutide, ABT-737, oblimersen, pralatrexate, taltrimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidone, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rituximab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), palbociclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

[1020] 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 "cover" 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 new blood vessel growth. 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 receptor from sending its normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells.

[1021] In one aspect of the invention, the other therapeutic active agent is an immunosuppressant. The immunosuppressant can be a calcineurin inhibitor, such as cyclosporine or ascomycin, such as cyclosporine A FK506 (tacrolimus), pimecrolimus, mTOR inhibitors, such as rapamycin or its derivatives, such as sirolimus everolimus temsirolimus, zotarolimus, biolimus-7, biolimus-9, rapamycin analogs, such as deforolimus, azathioprine, campath 1H, S1P receptor modulators, such as fingolimod or its analogs, anti-IL-8 antibodies, mycophenolic acid or its salts, such as sodium salt or its prodrugs, such as mycophenolate mofetil OKT3 prednisone, brequinar sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tracrolimus, leflunomide CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab daclizumab imidazoquin, methotrexate, dexamethasone, ISAtx-247, SDZ ASM981 (pimecrolimus, )、CTLA4lg (abatacept), belatacept, LFA3lg, etanercept (sold by Immunex )、adalimumab infliximab anti-LFA-1 antibody, natalizumab enlimomab, gavacizumab, anti-thymocyte immunoglobulin, sipuleucel-T, alefacept, efalizumab, pantethine, mesalazine, ansacol, codeine phosphate, benzoate, fenbufen, naproxen, diclofenac, etodolac and indomethacin, aspirin and ibuprofen.

[1022] 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-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluorobenzonitrile 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.

[1023] In some embodiments, the degraders described herein are administered in combination with or alternating with one or more cellular immunotherapeutic agents. In some embodiments, the cellular immunotherapeutic agent is an engineered immune cell. 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 an engineered T cell receptor targeting a specific cancer antigen into immune effector cells derived from a patient or donor, such as T cells or natural killer cells. Alternatively, chimeric antigen receptor (CAR) therapy generally involves introducing a chimeric antigen receptor targeting a specific cancer antigen into immune effector cells derived from a patient or donor, such as T cells, natural killer cells or macrophages. A key advantage of CARs compared to TCRs is their ability to bind to cancer cells even when their antigen is not presented on the surface via MHC, which makes more cancer cells vulnerable to attack. However, CAR cells can only recognize antigens that are naturally expressed on their own cell surface, and thus the range of potential antigen targets is smaller than that of TCRs.

[1024] 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 that naturally exists on mature B cells and is typically expressed by lymphoma and myeloma cells; CD19, a receptor present on the surface of almost all B cells that affects their growth, development, and activity and is typically expressed by leukemia, lymphoma, and myeloma cells; CD22, a receptor mainly present on the surface of mature B cells and typically expressed by leukemia and lymphoma cells; CD30, a receptor expressed on certain types of activated immune cells and typically expressed by leukemia and lymphoma cells; CD33, a surface receptor found on several types of immune cells and 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 that is involved in proliferation and differentiation and is typically expressed by leukemia and lymphoma cells; CEA, a protein involved in cell adhesion that is typically produced only before birth and is often abnormally expressed in cancer and may contribute to metastasis; EBV-related antigen, an exogenous viral protein expressed by cancer cells infected with 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 and is typically 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 and is typically overexpressed in certain cancers (especially breast cancer) and is associated with metastasis; HPV-related antigen, an exogenous viral protein expressed by cancer cells developed due to infection with human papillomavirus (HPV); MAGE antigen, the genes that produce these proteins are typically turned off in adult cells but can be reactivated in cancer cells, marking them as abnormal to the immune system; mesothelin, a protein typically overexpressed in cancer and may contribute to metastasis; MUC-1, a glycoprotein typically overexpressed in cancer; NY-ESO-1, a protein typically produced only before birth but often abnormally expressed in cancer; PSCA, a surface protein found in multiple cell types and typically overexpressed by cancer cells; PSMA, a surface protein found on prostate cells and typically overexpressed by prostate cancer cells; ROR1, a tyrosine kinase-like orphan receptor mainly expressed before birth rather than in adult tissues but often abnormally expressed in cancer, which may promote cancer cell metastasis and prevent cancer cell death; WT1, a protein that promotes cancer progression and is abnormally expressed in cancer patients, especially leukemia patients; and claudin 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 tisagenlecleucel CD19-targeted CAR T cell immunotherapy; approved for subsets of patients with leukemia and lymphoma. In some embodiments, the engineered CAR therapy is Lisocabtagene maraleucel (Bristol-Myers Squibb Co.): a CD19-targeted CART cell immunotherapy 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 a 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 a CD20 / CD22 dual-targeted CAR-T cell therapy. Compositions and methods for deriving CAR immune cells are described, for example, in U.S. Patent No. 5,359,046 (Cell Genesys); U.S. Patent No. 5,712,149 (Cell Genesys); U.S. Patent No. 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, USA); U.S. Patent No. 8,911,993 (University of Pennsylvania, USA); U.S. Patent No. 8,399,645 (St. Jude Children's Research Hospital); U.S. Patent No. 8,906,682 (University of Pennsylvania, USA); U.S. Patent No. 8,916,381 (University of Pennsylvania, USA); U.S. Patent No. 8,975,071 (University of Pennsylvania, USA); U.S. Patent No. 9,102,760 (University of Pennsylvania, USA); U.S. 9,4644 (University of Pennsylvania, USA); U.S. Patent No. 9,855,298 (Gilead); U.S. Patent No. 10,144,770 (St. Jude Children's Research Hospital); U.S. Patent No. 10,266,580 (University of Pennsylvania, USA); U.S. Patent No. 10,189,903 (Seattle Children's Hospital); WO2014 / 011988 (University of Pennsylvania, USA); WO2014 / 145252; WO2014 / 153270 (Novartis AG); 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.

[1025] In some embodiments, the immunotherapy is non-engineered adoptive cell therapy. Adoptive cell therapy is a method for enhancing the immune system's ability 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 a patient or a donor, stimulated in the presence of antigen-presenting cells carrying tumor- or virus-associated antigens, and then expanded ex vivo. In some embodiments, the adoptive cell therapy is tumor-infiltrating lymphocyte (TIL) therapy, which harvests naturally occurring T cells that have infiltrated a patient's tumor, then activates and expands them, and then injects them back into the patient. In some embodiments, the non-engineered adoptive cell therapy includes autologous or allogeneic immune cells, such as αβ T cells that are activated to target multiple potential antigens. One strategy for developing antigen-specific non-engineered T cells involves ex vivo expansion of T cells by in vitro stimulation of patient-derived (autologous) or donor-derived (allogeneic) T cells with antigen specificity. These strategies typically involve the isolation of peripheral blood mononuclear cells (PBMCs) and exposure of the 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 a library of overlapping peptides of multiple targeting antigens, such as a library of multiple 15-mer peptides 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: US2011 / 0182870 (Baylor College of Medicine); US2015 / 0010519 (Baylor College of Medicine); US2015 / 0017723 (Baylor College of Medicine); WO2006026746 (U.S. Government, Department of Health and Human Services); US2015 / 0044258 (Cell Medicine / Kurr Therapeutics); WO2016 / 154112 (National Children's 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 leukemic and preleukemic cells", March 24, 2011, Blood 117(12):3353-3362; Bollard et al., "Manufacture of GMP-grade cytotoxic T lymphocytes specific for LMP1 and LMP2 for patients with EBV-associated lymphoma", May 2011, Cytotherapy 13(5):518-522; Ramos et al., "Human papillomavirus type 16 E6 / E7-specific cytotoxic T lymphocytes for adoptive immunotherapy of HPV-related 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 Research, September 15, 2013; 19(18):5079-5091; Ngo et al., "Supplementing 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, non-engineered, activated immune cells combined or alternately administered with the degrader compositions described herein are selected from: activated CD4+ T-cells (T-helper cells), CD8+ T-cells (cytotoxic T-lymphocytes), CD3+ / CD56+ natural killer T cells (CD3+ NKT), and γδ T cells (γδ T cells) or combinations 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 γδ T cells (γδ T cells).

[1026] In some embodiments, the immunotherapy is a bispecific T cell engager (BiTE). A bispecific T cell engager directs T cells to target and bind to a specific antigen 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 in 4-week cycles.

[1027] In certain embodiments, other therapeutic agents are inhibitors of Ikaros (“IKZF1”) and / or Aiolos (“IKZF3”). In another embodiment, the other therapeutic agent is an inhibitor of Helios (“IKZF2”). In another embodiment, the other therapeutic agent is an inhibitor of Eos (“IKZF4”). In another embodiment, the other therapeutic agent is an inhibitor of Pegasus (“IKZF5”). In another embodiment, the other therapeutic agent is a cereblon ligand.

[1028] Non-limiting examples of cereblon ligands that can be used in combination with the compounds of the present invention include: thalidomide, lenalidomide, pomalidomide, and epomadostat.

[1029] In another embodiment, additional compounds that can 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.

[1030] In another embodiment, additional compounds that can be used in combination with the compounds of the present invention are selected from those described in the following: WO2019 / 060693, WO2019 / 060742, WO2019 / 133531, WO2019 / 140380, WO2019 / 140387, WO2010 / 010177, WO2020 / 010210 or WO2020 / 010227.

[1031] In another embodiment, additional compounds that can be used in combination with the compounds of the present invention are selected from those described in the following: 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.

[1032] In another embodiment, additional compounds that can be used in combination with the compounds of the present invention are selected from those described in the following: WO2016 / 105518, WO2017 / 007612, WO2017 / 024317, WO2017 / 024318, WO2017 / 024319, WO2017 / 117473, WO2017 / 117474, WO2017 / 185036, WO2018 / 064589, WO2018 / 148440, WO2018 / 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.

[1033] In another embodiment, additional compounds that can 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, WO 2017 / 115218, WO2018 / 220149, WO2018 / 237026, WO2019 / 099868, WO2019 / 121562, WO2019 / 149922, WO2019 / 191112, WO2019 / 204354, WO2019 / 236483 or WO2020 / 051235.

[1034] V. Pharmaceutical Compositions

[1035] Any compound disclosed herein can be administered as a pure chemical, but more typically as a pharmaceutical composition, which includes an effective amount for a host (usually a human) in need of such treatment for any of the diseases described herein. Accordingly, the present disclosure provides pharmaceutical compositions that contain 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 can contain the compound or salt as the sole active agent, or in an alternative embodiment, the pharmaceutical composition can contain the compound and at least one additional active agent.

[1036] In certain embodiments, the dosage form of the pharmaceutical composition comprises from about 0.0005 mg to about 2000 mg of the active compound, from about 0.001 mg to about 1000 mg of the active compound, from about 0.001 mg to about 600 mg of the 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 the 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 the 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 the 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 the 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 the 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 the active compound. In another embodiment, the dosage form of the pharmaceutical composition comprises from about 0.01 mg to about 10 mg, from about 0.05 mg to about 8 mg, or from about 0.05 mg to about 6 mg, or from about 0.05 mg to about 5 mg of the active compound. In another embodiment, the dosage form of the pharmaceutical composition comprises from about 0.1 mg to about 10 mg, from about 0.5 mg to about 8 mg, or from about 0.5 mg to about 6 mg, or from about 0.5 mg to about 5 mg of the 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 the 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 the active compound or a salt thereof.

[1037] The pharmaceutical composition may also include a molar ratio of the active compound and other therapeutic active agents. In non-limiting illustrative embodiments, the pharmaceutical composition may contain an anti-inflammatory or immunosuppressive agent and a compound of the present invention in a molar ratio of about at most 0.5:1, about at most 1:1, about at most 2:1, about at most 3:1, or about at most 1.5:1 to about up to 4:1. The compounds disclosed herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, by implants (including ocular implants), transdermally, by buccal administration, rectally, as eye drops, by injection (including ocular injection), intravenously, intra-aortically, intracranially, subcutaneously, intraperitoneally, subcutaneously, intranasally, sublingually or rectally or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. For ocular delivery, as needed, for example, by intravitreal, intrastromal, intracameral, subtenon, subretinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periorbital, transscleral, retrobulbar, posterior juxtascleral, perikeratomal or lacrimal duct injection, or through mucus, mucin or mucosal barriers, in an immediate release or controlled release manner or by an ocular device.

[1038] 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 preparation, medical device, suppository, oral or sublingual preparation, parenteral preparation or eye drops. Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized unit doses, which contain an appropriate amount of the active ingredient, such as an effective amount to achieve the desired purpose.

[1039] The carrier includes excipients and diluents, and must have a high enough purity and a low enough toxicity to be suitable for administration to the patient being treated. The carrier can be inert or can have its own pharmaceutical benefits. The amount of the carrier used in combination with the compound is sufficient to provide an actual amount of material for administration per unit dose of the compound.

[1040] Carrier classes include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavorants, glidants, lubricants, preservatives, stabilizers, surfactants, tabletting agents and wetting agents. Some carriers may be listed in more than one class, for example, vegetable oils can be used as lubricants in some formulations and as diluents in other formulations. A pharmaceutically acceptable carrier is a carrier that does not cause any serious adverse reactions in the human body when administered in the amounts to be used in the corresponding pharmaceutical composition. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, tragacanth powder, malt, gelatin; talc and vegetable oils. Optional active agents can be included in the pharmaceutical composition, which can substantially not interfere with the activity of the compounds of the present invention.

[1041] The pharmaceutical composition / combination can be formulated for oral administration. These compositions can contain any amount of the active compound that achieves the desired result, such as a compound between 0.1% by weight and 99% by weight (wt.%), including for example at least about 5 wt.% of the compound. Some embodiments contain from about 25 wt.% to about 50 wt.% or from about 5 wt.% to about 75 wt.% of the compound.

[1042] Preparations suitable for rectal administration are usually in the form of unit-dose suppositories. These can be prepared by mixing the active compound with one or more conventional solid carriers such as cocoa butter and then shaping the resulting mixture.

[1043] 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 can be used include petrolatum, lanolin, polyethylene glycol, alcohols, transdermal penetration enhancers, and combinations of two or more of these.

[1044] Preparations suitable for transdermal administration can be in the form of discrete patches, adapted to remain in intimate contact with the epidermis of the recipient for an extended period of 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 optionally buffered aqueous solution of the active compound. In one embodiment, a microneedle patch or device is provided for delivering a drug across or into biological tissue, particularly the skin. The microneedle patch or device allows for the delivery of a drug across or into the skin or other tissue barrier at a clinically relevant rate with minimal or no tissue damage, pain or irritation.

[1045] 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 devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers and dry powder inhalers. There are a variety of types of nebulizers available, including jet nebulizers, ultrasonic nebulizers and vibrating mesh nebulizers. The choice of a suitable pulmonary delivery device depends on parameters such as the nature of the drug and its formulation, the site of action and the pathophysiology of the lung.

[1046] 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 entirety). Examples are US8,192,408 (Psivida Us, Inc.) entitled "Ocular trocar assembly"; US7,585,517 (Macusight, Inc.) entitled "Transcleral delivery"; US5,710,182 and US5,795,913 (Santen OY) entitled "Ophthalmic composition"; US8,663,639 entitled "Preparations for treating ocular diseases and disorders"; US8,486,960 entitled "Preparations and methods for vascular permeability-related diseases or disorders"; US8,367,097 and US8,927,005 entitled "Liquid preparations for treating diseases or disorders"; US7,455,855 (Santen Pharmaceutical Co., Ltd.) entitled "Delivery of substances and drug delivery systems using the same);WO / 2011 / 050365 entitled "Suitable Therapeutic Protections for Vision and Pain"; and WO / 2009 / 145842 (Forsight Labs, LLC) entitled "Therapeutic Devices for Pain Management and Vision"; US9,066,779 and US8,623,395 entitled "Implantable Therapeutic Devices"; WO / 2014 / 160884 entitled "Ocular Implants for Delivering 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 / 152959 and US20140276482 entitled "Systems for Sustained Intraocular Delivery of Poorly Soluble Compounds from Implantable Delivery System Implants"; US8,905,963 and US9,033,911 entitled "Injector Devices and Drug Delivery Methods"; 2015 / 057554 entitled "Formulations and Methods for Increasing or Decreasing Mucus"; US8,715,712 and US8,939,948 entitled "Ocular Insertion Devices and Methods"; WO / 2013 / 116061 entitled "Methods and Devices for Insertion and Removal of Therapeutic Devices"; WO1022 / 066775 entitled "Ophthalmic Systems for Sustained Release of Drugs to the Eye"; WO / 2015 / 085234 and WO / 2012 / 019176 entitled "Implantable Therapeutic Devices"; WO / 2012 / 065006 entitled "Methods and Devices for Determining Porous Structures for Drug Delivery"; WO / 2010 / 141729 entitled "Anterior Segment Drug Delivery"; WO / 2011 / 050327 entitled "Corneal Denervation Methods for the Treatment of Ocular Pain"; WO / 2013 / 022801 entitled "Delivery of Small Molecules with Implants"; WO / 2012 / 019047 entitled "Subconjunctival Implants for Posterior Segment Drug Delivery"; WO / 2012 / 068549 entitled "Therapeutic Agent Formulations for Implantable Devices"; WO / 2012 / 019139 entitled "Combined Delivery Methods and Devices"; WO / 2013 / 040426 entitled "Ocular Insertion Devices and Methods"; WO / 2012 / 019136 entitled "Injector 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 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"; US / 2007 / 0043030 entitled "Pharmaceutical composition for treating premature ejaculation by pulmonary inhalation"; US7,845,349 entitled "Inhaler"; US / 2012 / 0114709 and US8,101,160 entitled "Formulations for inhalation devices"; US / 2013 / 0287854 entitled "Compositions and uses"; US / 2014 / 0037737 and US / 8,580,306 entitled "Particles for pharmaceutical compositions"; US / 2015 / 0174343 entitled "Mixing channels for inhalation devices"; US7,744,855 and US / 2010 / 0285142 entitled "Methods for manufacturing particles for pharmaceutical compositions"; US7,541,022, US / 2009 / 0269412 and US / 2015 / 0050350 (Vectura Limited) entitled "Pharmaceutical formulations for dry powder inhalers".

[1047] Other non-limiting examples of how to deliver active compounds are provided in the following documents: WO / 2015 / 085251 (Envisia Therapeutics, Inc.) titled "Intraocular Implants for the Treatment of Ocular Diseases"; WO / 2011 / 008737 titled "Engineered Aerosol Particles and Related Methods"; WO / 2013 / 082111 titled "Geometrically Engineered Particles and Methods for Modulating Macrophage or Immune Responses"; WO / 2009 / 132265 titled "Degradable Compounds and Their Methods, Particularly Particle Replication in Non-Wetting Templates"; WO / 2010 / 099321 titled "Interventional Drug Delivery Systems and Related Methods"; WO / 2008 / 100304 titled "Polymeric Particle Composites with High-Fidelity Ordered, Sized, and Shaped Particles"; WO / 2007 / 024323 (Liquidia Technologies, Inc. and the University of North Carolina at Chapel Hill) titled "Methods, Systems, and Materials for Nanoparticle Fabrication"; WO / 2010 / 009087 (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.) titled "Iontophoresis of Controlled Release Formulations in the Eye"; WO / 2009 / 132206 titled "Compositions and Methods for Intracellular Delivery and Release of Substances"; WO / 2007 / 133808 titled "Nanoparticles for Cosmetic Applications"; WO / 2007 / 056561 titled "Medical Devices, Materials, and Methods"; WO / 2010 / 065748 titled "Methods for Fabricating Patterned Materials"; WO / 2007 / 081876 (Liquidia Technologies, Inc.) titled "Nanostructured Surfaces for Biomedical / Biomaterials Applications and Their Processes."

[1048] Other non-limiting examples of drug delivery devices and methods include, for example: US20090203709 (Abbott Laboratories) entitled "Drug Dosage Forms for Oral Administration of Tyrosine Kinase Inhibitors"; US20050009910 entitled "Delivery of Active Drugs to the Posterior Segment of the Eye by Subconjunctival or Periocular Delivery of Prodrugs"; US20130071349 entitled "Degradable Polymers for Lowering Intraocular Pressure"; US8,481,069 entitled "Tyrosine Kinase Microspheres"; US8,465,778 entitled "Method for Manufacturing Tyrosine Kinase Microspheres"; US8,409,607 entitled "Sustained Release Intraocular Implants Containing Tyrosine Kinase Inhibitors and Related Methods"; US8,512,738 and US2014 / 0031408 entitled "Degradable Intravitreal Tyrosine Kinase Implants"; US2014 / 0294986 entitled "Microsphere Drug Delivery System for Sustained Intraocular Release"; US8,911,768 (Allergan, Inc.) entitled "Methods for Treating Retinopathy with Extended Therapeutic Effect"; US6,495,164 (Alkermes Controlled Therapeutics, Inc.) entitled "Preparation of Injectable Suspensions with Improved Injectability"; WO2014 / 047439 (Akina, Inc.) entitled "Degradable Microspheres Containing Filler Materials"; WO2010 / 132664 (Baxter International Inc., Baxter Healthcare SA) entitled "Compositions and Methods for Drug Delivery"; US20120052041 (Brigham and Women's Hospital, Inc.) entitled "Polymer Nanoparticles with Enhanced Drug Loading Capacity and Methods of Use Thereof"; US20140178475, US20140248358, and US20140249158 (BIND Therapeutics, Inc.) entitled "Therapeutic Nanoparticles Containing Therapeutic Agents and Methods of Making and Using the Same"; US5,869,103 (Danbiosyst UK Ltd.) entitled "Polymeric Microparticles for Drug Delivery"; US8628801 (University of Navarra) entitled "PEGylated Nanoparticles"; US2014 / 0107025 (Jade Therapeutics, LLC) entitled "Ocular Drug Delivery System"; US6,287,588 entitled "Drug Delivery System with Improved Release Characteristics Composed of Microparticles and Biodegradable Gels and Methods of Use Thereof"; US6,589,549 (Macromed, Inc.);US6,007,845 and US5,578,325 (Massachusetts Institute of Technology) titled "Nanoparticles and Microparticles of Nonlinear Hydrophobic Multiblock Polymers"; US20040234611, US20080305172, US20120269894, and US20130122064 (Novartis Ag) titled "Ophthalmic Long-Acting Formulations for Periocular or Subconjunctival Administration"; US6,413,539 (Poly-Med, Inc.) titled "Block Polymers"; US20070071756 (Peyman) titled "Delivery of Agents to Improve Inflammation"; US20080166411 (Pfizer, Inc.) titled "Injectable Sustained Formulations and Methods for Providing Sustained Release of Substantially Soluble Drugs Containing Nanoparticles"; US6,706,289 (PR Pharmaceuticals, Inc.) titled "Methods and Compositions for Enhancing Delivery of Bioactive Molecules"; and US8,663,674 (Surmodics) titled "Microparticles Containing Matrices for Drug Delivery".

[1049] VI. General Synthesis

[1050] The compounds described herein can be prepared by methods known to those skilled in the art. In one non-limiting embodiment, the disclosed compounds can be prepared using the following scheme.

[1051] For convenience, the compounds of the present invention having stereocenters can be drawn without stereochemistry. Those skilled in the art will recognize that pure or enriched enantiomers and diastereomers can be prepared by methods known in the art. Examples of methods for obtaining optically active materials include at least the following methods:

[1052] i) Physical separation of crystals - A technique for manually separating macroscopic crystals of individual enantiomers. This technique can be used if there are crystals of the individual enantiomers, i.e., the material is an aggregate and the crystals are visually distinct;

[1053] ii) Simultaneous crystallization - A technique in which individual enantiomers crystallize separately from a racemic solution, which is only possible when the enantiomers are solid coalescences;

[1054] iii) Enzymatic resolution - A technique for partially or completely separating a racemate by the different reaction rates of the enantiomers with an enzyme;

[1055] 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;

[1056] 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 with the help of chiral catalysts or chiral auxiliaries;

[1057] vi) Diastereo separation - a technique whereby 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 with the aid of their now more distinct structural differences, followed by removal of the chiral auxiliary to obtain the desired enantiomer;

[1058] vii) Primary and secondary asymmetric transformations - a technique by which the diastereomers of a racemate equilibrate rapidly to give rise to a predominance in solution of the diastereomer from the desired enantiomer, wherein preferential crystallization of the diastereomer from the desired enantiomer disturbs the equilibrium, ultimately in principle all the material is converted from the desired enantiomer to the crystalline diastereomer. The desired enantiomer is then liberated from the diastereomer;

[1059] viii) Kinetic resolution - This technique refers to the partial or complete resolution of racemates (or further resolution of partially resolved compounds) through the unequal reaction rates of enantiomers with chiral non-racemic reagents or catalysts under kinetic conditions;

[1060] 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;

[1061] x) Chiral liquid chromatography – a technique that separates the enantiomers of a racemate in a liquid mobile phase by their differential interactions with the stationary phase (including vial chiral HPLC). The stationary phase can be made of chiral materials, or the mobile phase can contain other chiral materials to induce differential interactions;

[1062] 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;

[1063] xii) Chiral solvent extraction – a technique for separating enantiomers by preferentially dissolving one enantiomer in a specific chiral solvent;

[1064] xiii) Transchiral membrane transport - a technique in which a racemate is brought into contact with a thin film barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force, such as a concentration or pressure difference, causes preferential transport through the membrane barrier. Separation occurs because the non-racemic chiral nature of the membrane only allows one enantiomer of the racemate to pass through;

[1065] xiv) Simulated moving bed chromatography is used in one embodiment. A variety of chiral stationary phases are commercially available.

[1066] General synthetic scheme 1

[1067]

[1068]

[1069] In some aspects, compounds of Formula I or Formula II can be synthesized according to the routes provided in General Synthetic 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 (usually from -78 °C to -40 °C), and then G1-2 is added to provide G1-3. In Step 2, compound G1-3 is heated (such as at about 60 °C or by microwave irradiation) 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) 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), and then G1-5 is added to provide G1-6.

[1070] General synthetic scheme 2

[1071]

[1072] In some aspects, compounds of Formula I or Formula II can be synthesized according to the routes provided in General Synthetic Scheme 2. In Step 1, compound G2-1 (prepared according to the procedure outlined in General Synthetic Scheme 1 for compound G1-3) is reacted with an oxidizing agent (such as manganese dioxide or other reagents suitable for the oxidation of alcohols) in an organic solvent (such as acetonitrile) to provide G2-2. In Step 2, G2-2 is reacted with a base (such as sodium hydride) in an organic solvent (such as dimethylformamide or dichloromethane), and then G2-3 is added to provide G2-4. In Step 3, G2-4 is reacted with a suitable carbonyl reducing agent (such as sodium cyanoborohydride) in an organic solvent (such as ethanol or methanol) to provide G2-5.

[1073] General Synthetic Scheme 3

[1074]

[1075] In some aspects, the compounds of Formula I or Formula II can be synthesized according to the route provided in General Synthetic Scheme 3. In Step 1, Compound G3-1 (prepared according to the procedure outlined in General Synthetic Scheme 2 for Compound G2-2) is reacted with DAST (or other suitable nucleophilic fluorinating reagent, such as Deoxo-Fluor) in an organic solvent (such as dichloromethane) to provide G3-2. In Step 2, Compound G3-2 is reacted with a base (such as sodium hydride) in an organic solvent (such as dimethylformamide or dichloromethane), and then G3-3 is added to provide G3-4.

[1076] General Synthetic Scheme 4

[1077]

[1078]

[1079] In some aspects, the compounds of Formula I or Formula II can be synthesized according to the route provided in General Synthetic Scheme 4. In Step 1, Compound G4-1 (prepared according to the procedure outlined in General Synthetic Scheme 1 for Compound G1-3) is reacted with DAST (or other suitable nucleophilic fluorinating reagent, such as Deoxo-Fluor) in an organic solvent (such as dichloromethane) to provide G4-2. In Step 2, Compound G4-2 is reacted with a base (such as sodium hydride) in an organic solvent (such as dimethylformamide or dichloromethane), and then G4-3 is added to provide G4-4.

[1080] General Synthetic Scheme 5

[1081]

[1082] In some aspects, the compounds of Formula I or Formula II can be synthesized according to the routes provided in General Synthetic Scheme 5. In Step 1, in the presence of a palladium catalyst (such as palladium(II) acetate, Pd2(dba)3 or other suitable palladium catalysts for Buchwald-Hartwig coupling conditions), a phosphine ligand (such as BINAP, XantPhos or other suitable phosphine ligands used in Buchwald-Hartwig coupling conditions) and a base (such as potassium tert-butoxide, cesium carbonate or other suitable bases used in Buchwald-Hartwig coupling conditions), Compound G5-1 reacts with G5-2 in an organic solvent (such as toluene, THF, dioxane or DMF) at an elevated temperature to provide G5-3. In Step 2, Compound G5-3 reacts with a base (such as sodium hydride) in an organic solvent (such as dimethylformamide or dichloromethane), and then G5-4 is added to provide G5-5.

[1083] General Synthetic Scheme 6

[1084]

[1085] In some aspects, the compounds of Formula I or Formula II can be synthesized according to the routes provided in General Synthetic Scheme 6. In Step 1, in the presence of a palladium catalyst (such as Pd2(dba)3) and a phosphine ligand (such as XantPhos), Compound G6-1 reacts with a metal hydroxide (such as sodium hydroxide or potassium hydroxide) in an organic solvent (such as dioxane) and water to provide G6-2. In Step 2, G6-2 is protected with a suitable protecting group (such as Boc or Cbz group) using standard conditions to provide Compound G6-3. In Step 3, in the presence of a copper catalyst (such as copper acetate) and a base (such as pyridine or DMAP), G6-3 reacts with G6-5 in an organic solvent (such as 1,2-dichloroethane) at an elevated temperature (such as about 80 °C) to provide Compound G6-6. In Step 4, the protecting group PG in G6-6 is removed using standard conditions applicable to the specific group to provide G6-7. In Step 5, Compound G6-7 reacts with a base (such as sodium hydride) in an organic solvent (such as dimethylformamide or dichloromethane), and then G6-8 is added to provide G6-9.

[1086] Non-limiting examples of the present invention

[1087] In the case where chirality is depicted in the following synthetic schemes, the designation shows the relative chirality of the stereocenter rather than the absolute designation. For example,

[1088] represented by a wedge bond, indicating that the specified chiral center has been separated by chiral chromatography. However, the absolute chirality of this stereocenter may be Then when intermediate 3a reacts with racemic bromosuccinimide, the resulting compound 280 can be a mixture of diastereoisomers.

[1089]

[1090] Similarly, when a non-chiral lactam reacts with racemic succinimide in the following experiments, the resulting compound can be a mixture of enantiomers. For example, when intermediate 7 reacts with racemic bromosuccinimide, the resulting intermediate 9 can be a mixture of enantiomers.

[1091]

[1092] Unless otherwise specified as having a particular stereochemistry, the resulting compound can be a mixture of enantiomers. For example,

[1093] These mixtures of enantiomers can be separated by those skilled in the art using techniques known in the art, including chiral chromatography, crystallization, transport across chiral membranes, or extraction with chiral solvents. In fact, these techniques are used to separate several of the following compounds. For example, intermediate

[1094] is separated by chiral chromatography using preparative HPLC techniques. Similarly, enantiomeric mixtures of succinimides can be resolved by these techniques, including chiral chromatography. For example, a mixture of compound 67 and compound 68 is separated by chiral chromatography using preparative HPLC techniques. The enantiomeric excess of the resulting separated compounds is 99%.

[1095]

[1096] Once separated, the absolute chirality can be assigned by known techniques, including the determination of the structures 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).

[1097] Mixtures of enantiomers can also be resolved during the synthesis by 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 using chiral protecting groups or salts, the mixture of enantiomers temporarily becomes a mixture of diastereoisomers, allowing physical separation using known techniques.

[1098] When the compounds of the present invention are mixtures of diastereoisomers, they can also be resolved by techniques known in the art. For example, mixtures of diastereoisomers can be separated by chromatographic techniques, including reverse or normal phase HPLC, silica gel chromatography, moving bed chromatography and preparative TLC. Diastereomeric mixtures can also be separated by crystallization.

[1099] Example 1: Synthesis of 3-(2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 1)

[1100]

[1101] 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% mineral oil dispersion (24.91 mg, 650.20 μmol, 60% purity), and then 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. A new spot was formed together with the unreacted starting material. Another portion of 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 layer was separated. Then the reaction mixture was 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 give 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 pale yellow solid. 1 H NMR (d6-DMSO, 400 MHz) δ 11.13 (s, 1H), 8.24 (d, J = 8.08 Hz, 1H), 8.11 (d, J = 6.92 Hz, 1H), 7.84 (t, J = 7.56 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 7.76 Hz, 1H), 7.17 (d, J = 7.12 Hz, 1H), 5.46 (dd, J = 12.76, 5.08 Hz, 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.

[1102] 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)

[1103]

[1104] Step 1: Preparation of 6-bromobenzo[cd]indol-2(1H)-one (2): Bromine (2.15 g, 26.60 mmol, 1.44 mL) was added dropwise to a stirred suspension of 1H-benzo[cd]indol-2-one 1 (3.0 g, 17.73 mmol) in CHCl3 (50.0 mL) under cooling, and the reaction mixture was stirred at room temperature for 48 h. A sodium thiosulfate solution was poured into the reaction mixture under cooling, and the yellow solid formed was filtered through a sintered funnel. The resulting solid was washed with cold water and pentane and azeotroped with toluene to give 6-bromo-1H-benzo[cd]indol-2-one 2-2 as a yellow solid (4 g, 16.12 mmol, 90.93% yield). LCMS: ES+ 248.1, 250.0 (bromine mode).

[1105] 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): At -78 °C, butyllithium (2.2 M, 9.38 mL) was added 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). 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 warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride 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 give 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, 400 MHz) δ 10.70 (s, 1H), 8.34 (d, J = 8.28 Hz, 1H), 7.95 (d, J = 6.96 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.28 (s, 1H), 6.93 (d, J = 7.2 Hz, 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).

[1106] Step 3: Preparation of 6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one 2,2,2-trifluoroacetate (5): Triethylsilane (518.51 mg, 4.46 mmol, 712.24 μL) and trifluoroacetic acid (1.02 g, 8.92 mmol, 687.08 μL) were added 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), and the reaction was stirred for 30 minutes under microwave irradiation at 70 °C. The solvent in the reaction mixture was evaporated under reduced pressure to give a crude product, which was washed with diethyl ether and pentane to give 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, 100.47% yield), as a brown gum and used without further purification. LC MS: ES+ 333.0.

[1107] 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): Triethylamine (340.00 mg, 3.36 mmol, 468.32 μL) was added 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), and the mixture was cooled. 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 part was separated. Then the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product, which was purified by flash chromatography (using 0 - 5% MeOH - DCM) to give 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 viscous solid. LCMS: ES+ 433.0.

[1108] 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): Sodium hydride (60% mineral oil dispersion, 53.15 mg, 1.39 mmol, 60% purity) was added 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) under cooling, and the reaction mixture was heated at 60 °C for 30 minutes. Then 3-bromopiperidine-2,6-dione 7 (133.18 mg, 693.62 μmol) was added, and the reaction was heated at 60 °C for 4 hours. Then 3-bromopiperidine-2,6-dione (133.18 mg, 693.62 μmol) was added again, and the reaction was stirred at 60 °C for another 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water, and the organic layer was separated. Then the reaction mixture was 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-oxobenzo[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 pale yellow solid. 1 H NMR (d6-DMSO, 400 MHZ) δ 11.11 (s, 1H), 8.37 (d, J = 8.24 Hz, 1H), 8.08 (d, J = 6.92 Hz, 1H), 7.83 (t, J = 7.58 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J = 7.36 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J = 7.28 Hz, 1H), 5.43 (dd, J = 12.76, 5.0 Hz, 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.

[1109] 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)

[1110]

[1111] 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-dioxopiperidin-3-yl)-2-oxobenzo[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 dioxane solution of hydrochloric acid (183.95 μmol, 8 mL), and the reaction was stirred at room temperature for 2 h. 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 give 3-[6-[[1-(1-chloropiperidin-4-yl)pyrazol-4-yl]methyl]-2-oxobenzo[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.

[1112] 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 a stirred solution of 3-[6-[[1-(1-chloropiperidin-4-yl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 2 (88.0 mg, 183.35 μmol) in DMF (3.0 mL) was added cubane-1-carboxylic acid (27.16 mg, 183.35 μmol), then HATU (104.57 mg, 275.02 μmol) and N,N-diisopropylethylamine (71.09 mg, 550.05 μmol, 95.81 μL) were added at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. It was diluted with ethyl acetate and water and separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution, 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-oxobenzo[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. 11H NMR (d6-DMSO, 400 MHz) δ 11.09 (s, 1H), 8.36 (d, J = 8.16 Hz, 1H), 8.08 (d, J = 7.0 Hz, 1H), 7.83 (t, J = 7.62 Hz, 1H), 7.60 (s, 1H), 7.35 (d, J = 7.32 Hz, 1H), 7.31 (s, 1H), 7.06 (d, J = 7.24 Hz, 1H), 5.42 (dd, J = 12.48, 5.24 Hz, 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.

[1113] Example 4: Synthesis of 3-(6-((1-(1-(1-Methylcyclobutanecarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 4)

[1114]

[1115]

[1116] 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-dioxopiperidin-3-yl)-2-oxobenzo[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 dioxane solution of hydrochloric acid (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 give 3-[6-[[1-(1-chloropiperidin-4-yl)pyrazol-4-yl]methyl]-2-oxobenzo[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.

[1117] 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-methylcyclobutane carboxylic 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 give the crude product. The crude residue was purified by CombiFlash chromatography (eluting with 1%-1.5% MeOH in DCM) to give 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 pale yellow solid. LC MS: ES+ 429.3.

[1118] Step 3: Preparation 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): To a stirred solution of 6-[[1-[1-(1-Methylcyclobutanecarbonyl)-4-piperidinyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4 (66.0 mg, 154.02 μmol) in DMF (1 mL), sodium hydride (60% mineral oil dispersion, 11.80 mg, 308.03 μmol) was added under cooling, and the reaction mixture was heated at 60 °C for 30 minutes. Then 3-Bromopiperidine-2,6-dione 5 (29.57 mg, 154.02 μmol) was added, and the reaction was heated at 60 °C for 4 hours, and then 3-Bromopiperidine-2,6-dione (29.57 mg, 154.02 μmol) was added again, 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. Then the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product, which was purified first by column chromatography and then by preparative TLC (developing plate in 60% ethyl acetate-DCM) to give 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 pale yellow solid. 1 H NMR (d6-DMSO, 400MHZ) δ 11.11 (s, 1H), 8.37 (d, J = 8.44 Hz, 1H), 8.08 (d, J = 6.44 Hz, 1H), 7.85 - 7.83 (m, 1H), 7.60 (s, 1H), 7.35 (d, J = 7.12 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J = 6.84 Hz, 1H), 5.46 - 5.42 (m, 1H), 4.39 - 4.37 (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.

[1119] Synthesis of Example 5. 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)

[1120]

[1121] At 0 °C, DIPEA (4.0 equiv) was added to an equimolar mixture of HCl salt 1 and tert-butyl(methyl)carbamoyl chloride in DMF (6 mL / mmol). The resulting solution was stirred at ambient temperature for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with aqueous NaHCO3, 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, eluting 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).

[1122] Example 6. Synthesis of tert-Butyl 4-(4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-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]indol-6-yl)(hydroxy)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 7)

[1123]

[1124]

[1125] 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]indol-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 h. TLC and LCMS showed the formation of the product. 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 the 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.

[1126] 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% mineral oil dispersion, 1 equiv), and the reaction mixture was refluxed at 60 °C for 30 min. A solution of (3-bromopiperidine-2,6-dione) (0.5 equiv) in THF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution, and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with aqueous and brine solutions. The organic portion 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 afford Compound 6.

[1127] 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 triacetoxyborohydride (1.2 equiv) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 h. 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%-2% methanol in DCM) to give Compound 7.

[1128] 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)

[1129]

[1130] 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 at -30 °C was added DAST (3 eq.), 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 reaction was quenched with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated, and purified by column chromatography (silica, gradient, 0%-2% methanol in DCM) to give 2.

[1131] 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% mineral oil dispersion, 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 with heating, and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine solution. Then the organic phase was 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 Compound 8.

[1132] Example 8: Synthesis of 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 9)

[1133]

[1134] Steps 1-3: 4-(Morpholinomethyl)benzaldehyde was prepared according to Steps 1-3 of the literature procedure provided in WO2015 / 086636.

[1135] Step 4: Synthesis of 6-(hydroxy(4-(morpholinomethyl)phenyl)methyl)benzo[cd]indol-2(1H)-one (7): At -78 °C, n-butyllithium (2.2 equivalents) was added to a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 6 (1 equivalent) in THF. 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 5 (1 equivalent) in THF (7 mL) was added at -78 °C, and then the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and diluted with ethyl acetate. The layers were separated, and the organic phase was washed with water. Then the organic phase was 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 give the desired product 7.

[1136] Step 5: Synthesis of 6-(4-(morpholinomethyl)benzyl)benzo[cd]indol-2(1H)-one (8): Triethylsilane (3 equivalents) and trifluoroacetic acid (10 equivalents) were added to a stirred solution of 7 in DCE, and the reaction was stirred under microwave irradiation at 70 °C for 30 minutes. 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 give 8 as a brown gum, which was used without further purification.

[1137] Step 6: Synthesis of 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 9): Sodium hydride (60% mineral oil dispersion, 1 equivalent) was added to a stirred solution of 8 in THF, and the reaction mixture was refluxed at 60 °C for 30 minutes. A solution of 3-bromopiperidine-2,6-dione 9 (0.5 equivalent) in THF was also heated at 60 °C. After 30 minutes, the first suspension was added to the second solution under heating, and heating was continued for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine solution. Then the organic portion was 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.

[1138] Example 9. Synthesis of 3-(6-amino-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 10)

[1139]

[1140] Step 1: Synthesis of 6-nitrobenzo[cd]indol-2(1H)-one (2): Nitric acid was added to a stirred solution of 1 in acetic acid at 0 °C, and the resulting reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After 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.

[1141] Step 2: Synthesis of 3-(6-nitro-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (4): Sodium hydride (60% mineral oil dispersion, 1 equiv) was added to a stirred solution of compound 2 in THF, and the reaction mixture was refluxed at 60 °C for 30 min. A solution of 3-bromopiperidine-2,6-dione 3 (0.5 equiv) 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. Then the organic portion was 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 give 4.

[1142] 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 min. 10% Pd / C (30 wt%) was added to the reaction mixture, and hydrogenation was carried out under a hydrogen balloon for 16 h. Filtered through diatomaceous earth and concentrated under reduced pressure to give the solid compound 10.

[1143] 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)

[1144]

[1145]

[1146] 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 for 5 minutes under an argon atmosphere. 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 again for 2 minutes under an argon atmosphere. The reaction mixture was heated to 90 °C and maintained for 16 hours. After the SM reaction was exhausted, the mixture was filtered through a Celite bed and concentrated in vacuo. Purification by CombiFlash column chromatography (eluting with a hexane solution of 15% ethyl acetate) afforded 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]+.

[1147] ...

Claims

1. A compound of formula I or formula II or a pharmaceutically acceptable salt or isotopic derivative thereof; Wherein: X 1 and X 2 are independently selected from CH and N; X 3 selected from a bond, NR 2 , C(R 3 R 3’ ), O, C(O), C(S), S, S(O) and S(O)2; 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 ; R 2 and R 2' is independently selected 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' ; R 3 selected from hydrogen, halogen, alkyl, haloalkyl, -OR 8 and -NR 8 R 8' ; R 3' selected from hydrogen, halogen, alkyl and haloalkyl; or R 3 and R 3' may combine with the carbon atoms to which they are attached to form 3- to 6-membered cycloalkyl rings; R 4 selected from cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each R 4 is optionally substituted by one group selected from R 6 and wherein each R 4 is further optionally substituted by 1, 2, 3 or 4 groups independently selected from R 7 ; R 5 is -C(O)R 6 ; R 6 selected from alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each R 6 is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 9 ; or R 6 selected from 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 is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 9 ; R 7 independently selected 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' ; or two Rs on the same carbon 7 may combine to form an oxo group; R 8 and R 8’ are each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl each time they appear; R 9 is independently selected 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 ; R 10 selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein each R 10 is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 11 ; R 11 Selected from: hydrogen; halogen; hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl optionally substituted by aryl or heteroaryl; alkynyl optionally substituted by aryl or heteroaryl; cycloalkyl; heterocycle; aryl optionally substituted by 1, 2, 3 or 4 halogens, alkyl or -OR 8 groups; heteroaryl optionally substituted by 1, 2, 3 or 4 halogens, alkyl or -OR 8 groups; -CH2aryl optionally substituted by 1, 2, 3 or 4 halogens, alkyl or -OR 8 groups; -CH2heteroaryl optionally substituted by 1, 2, 3 or 4 halogens, alkyl or -OR 8 groups; -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’ ; or two Rs on the same carbon 11 groups may combine together to form an oxo group; or R 11 is independently selected, at each occurrence, from: halogen; hydroxy; cyano; nitro; alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl; heterocycle; aryl; heteroaryl; -CH2aryl; -CH2heteroaryl; -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 each R 11 group is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 12 ; R 12 independently selected from, at each occurrence: halogen; hydroxy; cyano; nitro; alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl; heterocycle; aryl; heteroaryl; -CH2aryl; -CH2heteroaryl; -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' ; R 20 、R 21 、R 22 、R 23 and R 24 are each independently selected, at each occurrence, from the group consisting of: a bond, an alkyl group, -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)-, an alkenyl group, an alkynyl group, a haloalkyl group, an aryl group, a heterocycle, a heteroaryl group, a bicyclic group, and a carbocyclic group; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 40 ; and wherein R 20 、R 21 、R 22 、R 23 and R 24 are not selected such that: 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 ii. -O-, -S- or -NR 2 - moieties are adjacent to each other; or iii. The parts are alternatively selected in an order that produces unstable molecules (unstable molecules are defined as molecules that have a shelf life of less than about 4 months (or less than about 6 months or 5 months) when stored at ambient temperature, which is caused by decomposition resulting from the selection and order of parts R 20 , R 21 , R 22 , R 23 , and R 24 ); 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, heterocycle, bicyclic and cycloalkyl; wherein each R 25 group is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 12 ; R 28 independently selected from hydrogen, -NR 2 R 2’ , -OR 2 , -SR 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl; and R 40 independently selected 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 group is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 12 ;

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