Tricyclic degraders of ikaros and aiolos

Abstract

To provide: new compounds that cause the degradation of Ikaros or Aiolos for medical therapy, including the treatment of hematopoietic disorders that involve abnormal cellular proliferation, including tumors and cancers; and treatment methods.SOLUTION: As a tricyclic cereblon binder, a compound of formula I or II is provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 833,107, filed April 12, 2019, the entirety of which is incorporated herein by reference for all purposes.

[0002] The present invention provides cereblon-binding agents for the degradation of Ikaros (IKZF1) or Aiolos (IKZF3) by the ubiquitin-proteasome pathway for therapeutic uses as further described herein. [Background technology]

[0003] Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved by the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of nearly all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, neurodegeneration and muscular degeneration, neuronal network morphogenesis, regulation of cell surface receptors, ion channels and secretory pathways, responses to stress and extracellular regulators, ribosome biogenesis, and viral infection.

[0004] Covalent attachment of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases tags proteins for proteasomal degradation, where they are digested into small peptides and their constituent amino acids, which ultimately become the building blocks of new proteins. Defects in proteasomal degradation have been associated with a variety of clinical disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer, among others.

[0005] The Ikaros ("IKZF") family is a series of zinc finger protein transcription factors important for certain physiological processes, particularly lymphocyte development (see Non-Patent Document 1). Ikaros ("IKZF1") was first discovered in 1992 (see Non-Patent Document 2), and over the next 20 years, four additional homologs, Helios ("IKZF2"), Aiolos ("IKZF3"), Eos ("IKZF4"), and Pegasus ("IKZF5"), were identified (see Non-Patent Document 3). Each homolog gene can generate several protein isoforms through alternative splicing, theoretically allowing the generation of numerous protein complexes through different combinations of various homologs. A set of two C-terminal Cys2His2 zinc finger motifs, which mediate protein interactions between various members of this protein family, is highly conserved among members of this family. Up to four zinc finger motifs are present at the N-terminus for DNA sequence recognition, and the number of these N-terminal zinc fingers varies through alternative splicing. Isoforms lacking these N-terminal zinc fingers exhibit dominant-negative effects on transcriptional activation (see Non-Patent Document 4).

[0006] The distribution of the various members of the Ikaros protein family in the body varies greatly: Ikaros, Helios, and Aiolos are primarily present in lymphoid cells and their corresponding progenitor cells, Ikaros is additionally detected in the brain, and Ikaros and Helios are also detected in erythroid cells. Eos and Pegasus are more widespread and are found in skeletal muscle, liver, brain, and heart (see Non-Patent Documents 5, 6, and 7).

[0007] Ikaros is important for proper lymphocyte development. Deletion of the exons encoding the first three N-terminal zinc fingers results in mice lacking T cells, B cells, natural killer (NK) cells, and their progenitors. Genetic alterations in Ikaros are associated with poor outcomes in the treatment of acute lymphoblastic leukemia (ALL). Ikaros and Aiolos are involved in the proliferation of multiple myeloma cells, suggesting a potential role in malignancies.

[0008] The drug thalidomide and its analogs lenalidomide and pomalidomide have attracted interest as immunomodulatory and antineoplastic agents, particularly in multiple myeloma (see Non-Patent Document 8 and Non-Patent Document 9). Although the exact therapeutic mechanism of action of thalidomide, lenalidomide, and pomalidomide is unknown, these compounds are used to treat several cancers, including multiple myeloma. Clinical and preclinical studies are also being conducted for 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.

[0009] Thalidomide and its analogs have been found to bind to the ubiquitin ligase cereblon and redirect its ubiquitination activity (see Non-Patent Document 10). Cereblon is part of an E3 ubiquitin ligase complex, but it interacts with damaged DNA-binding protein 1 to form an E3 ubiquitin ligase complex with cullin 4 and the E2-binding protein ROC1 (also known as RBX1), which functions as a substrate receptor that selects proteins for ubiquitination.

[0010] Binding of lenalidomide to cereblon promotes subsequent binding of cereblon to Ikaros and Aiolos, leading to their ubiquitination and proteasomal degradation (see Non-Patent Document 11, Non-Patent Document 12).

[0011] The disclosure that thalidomide binds to cereblon E3 ubiquitin ligase has led to studies investigating the incorporation of thalidomide and certain derivatives into compounds for the targeted destruction of proteins. Celgene has published U.S. Patent Nos. 5,629,997, 5,729,985, 5,730,913, 5,749,092, 5,750,093, and 5,823,200. Other publications that disclose imids for similar uses include those in U.S. Pat. No. 4,513,529, ...

[0012] US Patent Application Publication No. 2009 / 0129999, filed by the Dana Farber Cancer Institute, discloses cereblon modulators.

[0013] Patent document 26 filed by C4 Therapeutics, Inc. discloses a method for the degradation of Ikaros. The paper discloses a cereblon binding agent for the treatment of rheumatoid arthritis. [Prior art documents] [Patent documents]

[0014] [Patent Document 1] U.S. Patent No. 6,045,501 [Patent Document 2] U.S. Patent No. 6,315,720 [Patent Document 3] U.S. Patent No. 6,395,754 [Patent Document 4] U.S. Patent No. 6,561,976 [Patent Document 5] U.S. Patent No. 6,561,977 [Patent Document 6] U.S. Patent No. 6,755,784 [Patent Document 7] U.S. Patent No. 6,869,399 [Patent Document 8] U.S. Patent No. 6,908,432 [Patent Document 9] U.S. Patent No. 7,141,018 [Patent Document 10] U.S. Patent No. 7,230,012 [Patent Document 11] U.S. Patent No. 7,820,697 [Patent Document 12] U.S. Patent No. 7,874,984 [Patent Document 13] U.S. Patent No. 7,959,566 [Patent Document 14] U.S. Patent No. 8,204,763 [Patent Document 15] U.S. Patent No. 8,315,886 [Patent Document 16] U.S. Patent No. 8,589,188 [Patent Document 17] U.S. Patent No. 8,626,531 [Patent Document 18] U.S. Patent No. 8,673,939 [Patent Document 19] U.S. Patent No. 8,735,428 [Patent Document 20] U.S. Patent No. 8,741,929 [Patent Document 21] U.S. Patent No. 8,828,427 [Patent Document 22] U.S. Patent No. 9,056,120 [Patent Document 23] U.S. Patent No. 9,101,621 [Patent Document 24] U.S. Patent No. 9,101,622 [Patent Document 25] International Publication No. 2020 / 006262 [Patent Document 26] International Application No. PCT / US19 / 24094 [Non-patent literature]

[0015] [Non-Patent Document 1] Fan, Y. and Lu, D. "The Ikaros family of zinc-finger proteins" Acta Pharmaceutica Sinica B, 2016, 6:513-521

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[0016] The object of the present invention is to provide new compounds, uses and manufacturing processes that cause the degradation of Ikaros or Aiolos for medical therapy, including the treatment of hematopoietic disorders associated with abnormal cell proliferation, including tumors and cancer. [Means for solving the problem]

[0017] New compounds that bind to cereblon are provided, along with their uses and preparations. It is believed that binding of the disclosed compounds to cereblon increases the interaction of cereblon with Ikaros (IKZF1) or Aiolos (IKZF3), resulting in their subsequent ubiquitination and proteasomal degradation. Decreased levels of Ikaros or Aiolos result in altered transcriptional regulation of their downstream proteins. Selected compounds are not only found to be potent binders of cereblon, but also exhibit potent inhibition of multiple myeloma cell growth compared to pomalidomide.

[0018] Select compounds disclosed herein, their pharmaceutically acceptable salts, or pharmaceutically acceptable compositions thereof, can be used to treat disorders mediated by Ikaros or Aiolos, such as hematopoietic malignancies such as multiple myeloma, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myelodysplastic syndrome, or other target indications. Accordingly, in one embodiment, there is provided a method of treating a host (typically a human) having a disorder mediated by Ikaros or Aiolos, comprising administering to the host an effective amount of a disclosed compound described herein, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition.

[0019] In one embodiment, a compound of Formula I: [ka] (In the ceremony X 1 and X 2 are independently selected from CH and N; R 1 is 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 R3’ )-OR 5 , -C(O)R 4 , -SR 4 , -SR 5 , -S(O)R 4 and -S(O)2R 4 is selected from R 2 and R 2’ is independently in each occurrence 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’ is selected from R 3 is hydrogen, halogen, alkyl, haloalkyl, -OR 8 and -NR 8 R 8’ is selected from R 3’ is selected from hydrogen, halogen, alkyl and haloalkyl; or R 3 and R 3’ can be combined with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring, R 4 is selected from cycloalkyl, heterocycle, aryl, and heteroaryl; and each R 4 is R 6 and each R 4 is R 7 Selected independently from optionally substituted with one, two, three or four groups R 5 -C(O)R 6 and R 6 is selected from alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl; and each R 6 is R 9optionally substituted with one, two, three, or four groups independently selected from or R 6 is 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 R 9 optionally substituted with 1, 2, 3, or 4 groups independently selected from R 7 is independently in each occurrence 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’ Selected from or or two R on the same carbon 7 may together form an oxo group, R 8 and R 8’ is independently selected in each occurrence from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl; R 9are independently 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)CHNR 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 is selected from R 10 is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl; and each R 10 is R 11 optionally substituted with 1, 2, 3, or 4 groups independently selected from R 11 is hydrogen; halogen; hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl optionally substituted with an aryl or heteroaryl group; alkynyl optionally substituted with an aryl or heteroaryl group; cycloalkyl; heterocycle; one, two, three or four halogens, alkyl or -OR 8 aryl optionally substituted with a group; one, two, three or four halogen, alkyl or -OR 8 heteroaryl optionally substituted with a group; one, two, three or four halogen, alkyl or -OR 8-CHaryl optionally substituted with one, two, three or four halogen, alkyl or -OR 8 -CH2 heteroaryl optionally substituted with a group; -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ;-C(O)OR 8 ;-C(O)-NR 8 R 8’ ;-C(O)CH2R 8 ;-C(O)CH2OR 8 ;-C(O)CH2-NR 8 R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8 ;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ;-SO2-OR 8 ; and -SO2-NR 8 R 8’ Selected from or or two R on the same carbon 11 the groups may together form an oxo group, or R 11 is, in each occurrence, independently halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -CHaryl, -CHheteroaryl, -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)R8 , -CH2-NR 2 -C(O)R 8 , -S(O)R 8 , -SO2R 8 , -SO2-OR 8 , oxo and -SO2-NR 8 R 8 ’ Selected from the R 11 Each of the groups is R 12 optionally substituted with 1, 2, 3, or 4 groups independently selected from R 12 is, in each occurrence, independently halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -CHaryl, -CHheteroaryl, -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 a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof.

[0020] In one embodiment, the compound of formula I is selected from the group consisting of formula Ia, formula Ib, and formula Ic: [ka] wherein all variables are as defined herein.

[0021] In another embodiment, the compound of formula I is selected from the group consisting of formula Id, formula Ie, formula If, and formula Ig: [ka] wherein all variables are as defined herein.

[0022] In another embodiment, the compound of formula I has formula Ih: [ka] wherein all variables are as defined herein.

[0023] In one embodiment, a compound of formula (II) optionally in a pharmaceutically acceptable carrier to form a composition: [ka] (In the ceremony X 3 is a bond, NR 2 , C(R 3 R 3’ ), O, C(O), C(S), S, S(O), and S(O)2; R 20 , R 21 , R 22 , R 23 and R 24 are, in each occurrence, independently a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, or -C(O)NR 2 -, -NR 2 C(O)-, -O-, -S-, -NR 2 -, -P(O)(R 28 )-, -P(O)-, alkene, alkyne, haloalkyl, aryl, heterocycle, heteroaryl, bicycle, and carbocycle, each of which is selected from the group consisting of R 40and R 20 , R 21 , R 22 , R 23 and R 24 teeth, i. -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -P(O)(R 28 )-, -P(O)- and -C(S)- moieties are adjacent to each other, or ii. -O-, -S- or -NR 2 - the parts are adjacent to each other, or iii. Otherwise, an unstable molecule will result (part R 20 , R 21 , R 22 , R 23 and R 24 (defined as resulting in a molecule having a shelf life of less than about 4 months (or alternatively, less than about 6 months or 5 months) at ambient temperature due to degradation resulting from the selection and order of R 25 is hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, -OR 2 , -NR 2 R 2’ , -NR 2 SO2R 28 , -OSO2R 28 , -SO2R 28 , haloalkyl, aryl, heteroaryl, heterocyclic, bicyclic, and cycloalkyl, wherein R 25 Each of the groups is R 12 optionally substituted with 1, 2, 3, or 4 groups independently selected from R 28 are independently hydrogen, -NR 2 R 2’ , -OR 2 , -SR 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl; R 40are independently hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azido, amino, cyano, -NR 2 R 2’ , -NR 2 SO2R 28 , -OSO2R 28 , -SO2R 28 , haloalkyl, aryl, heteroaryl, heterocycle, and cycloalkyl, wherein R 40 Each of the groups is R 12 optionally substituted with 1, 2, 3, or 4 groups independently selected from or two R's 40 together form an oxo group, wherein all other variables are as defined herein) or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug thereof is provided.

[0024] In one embodiment, the compounds described herein bind to cereblon and increase the interaction between cereblon and Ikaros (IKZF1) or Aiolos (IKZF3), resulting in the subsequent ubiquitination and degradation of the protein in the proteasome.

[0025] 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.

[0026] Thus, in some embodiments, based on this discovery, compounds and methods are provided for treating patients with disorders mediated by Ikaros (IKZF1) or Aiolos (IKZF3). Ikaros (IKZF1) or Aiolos (IKZF3) are targeted for selective degradation by a method comprising administering to a patient (typically a human) in need thereof an effective amount of a selected compound described herein, alone or in combination with another active agent, optionally in a pharmaceutically acceptable carrier to form a composition. In one embodiment, the disorder is a lymphatic disorder. In one embodiment, the disorder is leukemia. In one embodiment, the disorder is a leukemia. In embodiments, the disorder is lymphocytic leukemia. In one embodiment, the disorder is lymphoblastic leukemia. In some embodiments, the disorder is a hematological malignancy, e.g., multiple myeloma, myelodysplastic syndrome such as 5q-syndrome, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia. In another embodiment, selected compounds of the present invention are administered to achieve immunomodulation and reduce angiogenesis.

[0027] In other embodiments, the therapeutic agent is selected from the group consisting of, but not limited to, a benign tumor, a neoplasm, a tumor, a cancer, abnormal cell proliferation, an immune disorder, an inflammatory disorder, a graft-versus-host rejection, a viral infection, a bacterial infection, an amyloid-based proteinopathy, a proteinopathy, or a fibrosis. Compounds and methods for the treatment of disorders, including sexual disorders, are presented. Further, other disorders that can be treated using effective amounts of the compounds described herein are described below.

[0028] In certain embodiments, any compound described herein has an isotopic substitution of at least one desired atom at about the natural abundance of the isotope, i.e., enriched. In one embodiment, the compound contains one deuterium atom or multiple deuterium atoms.

[0029] Other features and advantages of the invention will be apparent from the following detailed description and claims.

[0030] To this end, the present invention includes at least the following features: (a) a compound of Formula I or Formula II described herein, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative), or prodrug thereof; (b) a compound of Formula I or Formula II described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, for the treatment of a disorder mediated by Ikaros or Aiolos; (c) the 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 the treatment of a patient, typically a human, having any one of the disorders described herein, including disorders mediated by Ikaros or Aiolos; (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 manufacture of a medicament for the treatment of a medical disorder susceptible to the compound as further described herein; (e) a method for the manufacture of a medicament for the treatment of a disorder described herein in a host, comprising using a compound of Formula I or Formula II in the manufacture; (f) a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, for the treatment of cancer in a host, including any cancer described herein; (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 manufacture of a medicament for the treatment of cancer, including any cancer described herein; (h) a method for the manufacture of a medicament for the treatment of cancer in a host, including any of the cancers described herein, comprising using a compound of Formula I or Formula II in the manufacture; (i) a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, for the treatment of a tumor in a host, including any tumor described herein; (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 manufacture of a medicament for the treatment of a tumor, including any tumor described herein; (k) a compound of formula I or formula II, as described herein, for use in the preparation thereof A method for the manufacture of a medicament for the treatment of a tumor in a host containing any tumor; (l) a compound of Formula I or Formula II described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, for the treatment of an immune disorder, an autoimmune disorder, or an inflammatory disorder in a host; (m) 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 manufacture of a medicament for the treatment of an immune disorder, an autoimmune disorder, or an inflammatory disorder; (n) a method for producing a medicament for treating an immune disorder, an autoimmune disorder, or an inflammatory disorder in a host, comprising using a compound of Formula I or Formula II in the production; (o) a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, for the treatment of a hematological malignancy such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma; (p) use of a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, in the manufacture of a medicament for the treatment of a hematological malignancy such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma; (q) a method for the preparation of a medicament for the treatment of hematological malignancies in a host, such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma, comprising using a compound of formula I or formula II in the preparation; (r) a pharmaceutical composition comprising an effective host therapeutic amount of a compound of Formula I or Formula II described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent; (s) the compounds described herein as mixtures of enantiomers or diastereomers (where appropriate), including racemates; (t) enantiomerically or diastereomerically (where appropriate) enriched forms of the compounds described herein, including isolated enantiomers or diastereomers (i.e., greater than 85%, 90%, 95%, 97%, or 99% pure), and (u) A process for preparing a therapeutic product containing an effective amount of a compound of Formula I or Formula II described herein. DETAILED DESCRIPTION OF THE INVENTION

[0031] I. Definition 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. As used herein, the singular forms "a," "an," and "the" 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 this application, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not admitted to be prior art to this application. In the case of conflict, the present specification, including definitions, will control. Additionally, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0032] Compounds are described using their proper names. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0033] In one embodiment of each compound described herein, the compound may be present in any form, including racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxymers, methyltrimethylsilyl ... The isomers may be in the form of isomers such as isomers, or rotamers.

[0034] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term "or" means "and / or." The recitation of ranges of values, unless otherwise stated herein, is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein by reference as if it were individually recited herein. The endpoints of all ranges are included within the range and are independently combinable. All methods described herein can be performed in any suitable order unless otherwise stated herein or clearly contradicted by context. The use of examples or exemplary language (e.g., "such as") is intended merely to better illustrate the invention. and does not represent a limitation on the scope of the invention unless otherwise stated.

[0035] The present invention includes compounds described herein that have at least one desired atom isotopic substitution at an amount greater than the natural abundance of the isotope, i.e., enriched. Isotopes are atoms with the same atomic number but different mass numbers, i.e., the same number of protons but different numbers of neutrons. When isotopic substitution is used, it is common to replace at least one hydrogen with deuterium.

[0036] More generally, examples of isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, e.g. 2 H, 3 H, 11 C. 13 C. 14 C.15 N, 17 O. 18 O. 18 F, 35 S, and 36 Examples include Cl. In one non-limiting embodiment, the isotopically labeled compounds are used in metabolic studies (e.g., 14 C), reaction kinetic studies (e.g. 2 H or 3 H), drug or substrate tissue distribution assays, or radiation treatment of patients, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT). Additionally, any hydrogen atoms present in the compounds of the present invention can be 18 It may be substituted with an F atom, which may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by following the procedures disclosed in the schemes or in the examples and preparations below, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0037] General examples, but not limitation, include isotopes of hydrogen, such as deuterium ( 2 H) and tritium ( 3 H) can be used at any position in the depicted structures where the desired result is achieved. Alternatively or additionally, isotopes of carbon, e.g. 13 C and 14 C can be used.

[0038] Isotopic substitution, e.g., deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced with deuterium. In certain embodiments, the isotope is enriched at any position of interest by 90%, 95%, or 99% or more. In one non-limiting embodiment, deuterium is enriched at the desired position by 90%, 95%, or 99%.

[0039] In one non-limiting embodiment, replacement of a hydrogen atom with a deuterium atom can occur in any compound described herein. For example, an alkyl residue may be deuterated if any of the groups is methyl, ethyl, or methoxy, or contains these, for example, by substitution (such as, in a non-limiting embodiment, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3). In certain other embodiments, if two substituents combine to form a ring, an unsubstituted carbon may be deuterated. In one embodiment wherein at least one deuterium is located on an atom bearing a bond that is broken during metabolism of the compound in vivo, or is 1, 2, or 3 atoms away from the bond that is metabolized (e.g., which may be referred to as an α, β, or γ or primary, secondary, or tertiary isotope effect).

[0040] The compounds of the present invention can form solvates with solvents (including water). Thus, in one non-limiting embodiment, the present invention includes the 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 include water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent may be isotopically substituted, for example, DO, d6-acetone, d6-DMSO. The solvate may be in liquid or solid form.

[0041] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH is attached through the carbon of the keto (C=O) group.

[0042] "Alkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, an alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms, or 1 to about 4 carbon atoms. In one non-limiting embodiment, an alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, an alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. As used herein, specified ranges refer to alkyl groups with each member of the range stated as a separate species. For example, as used herein, the term C1-C6 alkyl refers to a straight-chain or branched-chain alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, each of which is intended to be described as a separate species. For example, as used herein, the term C1-C4 alkyl refers to a straight-chain or branched-chain alkyl group having 1, 2, 3, or 4 carbon atoms, each of which is intended to be described as a separate species. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.

[0043] An "alkenyl" is a linear or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at any stable point along the chain. As used herein, specified ranges refer to alkenyl groups with each member of the range stated as a separate species, as described above for the alkyl moiety. In one non-limiting embodiment, an alkenyl contains 2 to about 12 carbon atoms, more typically 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In certain embodiments, an alkenyl is C2, C2-C3, C2-C4, C2-C5, or C2-C6. Examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also encompasses "cis" and "trans" alkenyl configurations, or alternatively, "E" and "Z" alkenyl configurations. The term "alkenyl" also encompasses cycloalkyl or carbocyclic groups with at least one point of unsaturation.

[0044] "Alkynyl" refers to a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain. As used herein, the specified ranges refer to alkynyl groups with each member of the range set forth as an independent species as described above for the alkyl moiety. In one non-limiting embodiment, alkynyl has 2 to about 12 carbon atoms. and more typically 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In certain embodiments, 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.

[0045] "Halo" and "halogen" are independently fluorine, chlorine, bromine, or iodine.

[0046] "Haloalkyl" refers to a branched or straight-chain alkyl group substituted with one or more of the above-mentioned halo atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Perhaloalkyl" refers to an alkyl group in which all hydrogen atoms have been replaced with halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0047] As used herein, "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms within the aromatic ring system ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl," e.g., anthracyl. "Aryl" also includes ring systems in which the aryl ring, as defined above, is fused to one or more cycloalkyl or heterocyclic groups, and the radical or point of attachment is on the aryl ring, in which case the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. The one or more fused cycloalkyl or heterocyclic groups may be 4- to 7-membered saturated or partially unsaturated cycloalkyl or heterocyclic groups.

[0048] The term "heterocycle" refers to saturated and partially saturated heteroatom-containing ring radicals in which one, two, three, or four heteroatoms are present, independently selected from nitrogen, sulfur, boron, silicon, and oxygen. Heterocycles can include monocyclic 3- to 10-membered rings and 5- to 16-membered bicyclic ring systems, which can include bridged, fused, and spiro-fused bicyclic ring systems. Heterocycles do not include rings containing -OO-, -OS-, or -SS- moieties. Examples of saturated heterocyclic groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl), saturated 3- to 6-membered heteromonocyclic groups containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl), and saturated 3- to 6-membered heteromonocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl). Examples of partially saturated heterocyclic radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, dihydro-1H-1λ'-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.

[0049] "Heterocycle" also includes groups in which a heterocycle radical is fused / fused to an aryl or carbocycle radical, where the point of attachment is the heterocyclic ring system. "Heterocycle" also includes groups in which the heterocycle radical is fused / fused to an oxo group (i.e., [ka] ), for example, a partially unsaturated fused heterocyclic group containing 1 to 5 nitrogen atoms, such as indoline or isoindoline; a partially unsaturated fused heterocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms; a partially unsaturated fused heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms; and a saturated fused heterocyclic group containing 1 or 2 oxygen or sulfur atoms.

[0050] The term "heterocycle" also includes "bicyclic heterocycle." The term "bicyclic heterocycle" refers to a heterocycle, as defined herein, with one bridged, fused, or spirocyclic portion of the heterocycle. The bridged, fused, or spirocyclic portion of the heterocycle can be a carbocyclic, heterocyclic, or aryl group, provided that a stable molecule results. Unless excluded by context, the term "heterocycle" includes bicyclic heterocycles. Bicyclic heterocycles include groups in which a fused heterocycle is substituted with an oxo group. Non-limiting examples of bicyclic heterocycles include: [ka] Examples include:

[0051] The term "heteroaryl" refers to a stable aromatic ring system containing one, two, three, or four heteroatoms independently selected from O, N, and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and the nitrogen atom(s) are optionally quarternized. Examples include unsaturated 5- or 6-membered heteromonocyclyl groups containing one to four nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl), etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing an oxygen atom, such as pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing a sulfur atom, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl); unsaturated 5- or 6-membered heteromonocyclic groups containing one or two oxygen atoms and one to three nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl); unsaturated 5- or 6-membered heteromonocyclic groups containing one or two sulfur atoms and one to three nitrogen atoms, such as thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3, In one embodiment, a "heteroaryl" group is an 8-, 9-, or 10-membered bicyclic ring system. Examples of 8-, 9-, or 10-membered bicyclic heteroaryl groups include benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazolyl, and benzotriazolyl.

[0052] As used herein, "carbocyclic," "carbocycle," or "cycloalkyl" refers to a ring system having all carbon ring atoms and 3 to 14 ring carbon atoms ("C 3~14In some embodiments, cycloalkyl groups have 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 9 ring carbon atoms ("C 3~9 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 7 ring carbon atoms ("C 3~7 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4~6 In some embodiments, a cycloalkyl group has 5 or 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 cycloalkyl). Exemplary C 3~6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3~8 The cycloalkyl group includes, but is not limited to, the above-mentioned C 3~6 Cycloalkyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), and the like. Exemplary C 3~10 The cycloalkyl group includes, but is not limited to, the above-mentioned C 3~8 Cycloalkyl groups, and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10 ), cyclodecenyl (C 10 As shown in the examples above, in certain embodiments, the cycloalkyl group may be saturated or 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, and the point of attachment is on the cycloalkyl ring, in which case the carbon number continues to represent the number of carbons in the carbocyclic ring system. The term "cycloalkyl" also includes ring systems in which a cycloalkyl ring, as defined above, contains a spirocyclic heterocyclic, aryl, or heteroaryl ring, and the point of attachment is on the cycloalkyl ring, in which case the carbon number continues to represent the number of carbons in the carbocyclic ring system. The term "cycloalkyl" also includes bicyclic or polycyclic fused, bridged, or spiro ring systems containing 5 to 14 carbon atoms and zero heteroatoms in the non-aromatic ring system. Representative examples of "cycloalkyl" include: [ka] These include, but are not limited to:

[0053] The term "bicyclic" refers to two fused rings, each of which may independently be carbocyclic, heterocyclic, or aryl. and heteroaryl. Non-limiting examples of bicyclic groups include: [ka] Examples include:

[0054] The term "bicyclic" is R 20 , R 21 , R 22 , R 23 or R 24 When used in connection with a divalent residue such as, the points of attachment can be on separate rings or on the same ring. In certain embodiments, both points of attachment are on the same ring. In certain embodiments, both points of attachment are on different rings. Non-limiting examples of divalent bicyclic groups include: [ka] Examples include:

[0055] "Dosage form" means a unitary administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal dosage forms, sublingual dosage forms, topical dosage forms, gels, mucosal dosage forms, etc. "Dosage form" can also include implants, such as optical implants.

[0056] As used herein, "endogenous" refers to any substance from or produced within an organism, cell, tissue, or system.

[0057] As used herein, the term "exogenous" refers to any substance introduced from or produced outside an organism, cell, tissue, or system.

[0058] The term "modulate," as used herein, means to mediate a detectable increase or decrease in the level of a response in a subject compared to the level of the response in the subject in the absence of a treatment or compound, and / or compared to the level of the response in an otherwise identical, but untreated, subject. This term encompasses disrupting and / or affecting an intrinsic signal or response to mediate a beneficial therapeutic response in a subject, preferably a human.

[0059] "Parenteral" administration of the compounds includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im) or intrasternal injection, or infusion techniques.

[0060] As used herein, a "pharmaceutical composition" is a composition that includes at least one active agent, such as a selected active compound described herein, and at least one other substance, such as a carrier. "Pharmaceutical combinations" are combinations of pharmaceutical agents that are combined into a single dosage form. or a combination of at least two active agents that can be given together in separate dosage forms. and is indicated for use in combination with other active agents to treat any of the disorders described herein.

[0061] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound has been modified by making inorganic and organic salts, acid addition salts, or base addition salts thereof, with the loss of biologically acceptable toxicity. Salts of the present compounds can be synthesized from parent compounds containing a basic or acidic moiety 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 (such as hydroxide, carbonate, bicarbonate, or the like 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 typically carried out in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical when practical. Salts of the present compounds also include solvates of the compounds and salts of the compounds.

[0062] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids, and quaternary ammonium salts. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as salts derived from acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) nIncluded are salts prepared from organic acids such as —COOH, where n is 0 to 4, or with a different acid that produces the same counterion. Additional suitable salts are listed, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418. (1985).

[0063] The term "carrier" refers to a diluent, excipient, or vehicle in which an active agent is used or delivered.

[0064] "Pharmaceutically acceptable excipient" means an excipient useful in preparing a pharmaceutical composition / combination that is generally safe and not biologically or otherwise unsuitable for administration to a host, usually a human. In one embodiment, an excipient acceptable for veterinary use is used.

[0065] A "patient" or "host" or "subject" is a human or non-human animal in need of treatment for any of the disorders specifically described herein. Typically, the host is a human. "Host" may alternatively refer to, for example, mammals, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0066] The "therapeutically effective amount" of the pharmaceutical composition / combination of the present invention means an amount that is effective in bringing about a therapeutic effect such as improvement of symptoms or alleviation or reduction of the disease itself when administered to a host.

[0067] Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is for convenience only and should not be construed as limiting the scope of the invention. The description of a range should be considered to specifically disclose all possible subranges and individual numerical values ​​within that range. For example, description of a range such as 1 to 6 specifically discloses subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6 should be considered to specifically disclose this. This is true regardless of the breadth of the scope.

[0068] II. Compounds of the Invention "Alkyl" Embodiments 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 or C2 alkyl.

[0069] In one embodiment, an "alkyl" contains 1 carbon.

[0070] In one embodiment, an "alkyl" contains 2 carbons.

[0071] In one embodiment, the "alkyl" contains 3 carbons.

[0072] In one embodiment, the "alkyl" contains 4 carbons.

[0073] In one embodiment, the "alkyl" contains 5 carbons.

[0074] In one embodiment, an "alkyl" contains 6 carbons.

[0075] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl and hexyl.

[0076] Additional non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0077] Additional non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0078] Additional non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0079] Additional non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and active pentyl.

[0080] "Haloalkyl" Embodiments 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 or C2 haloalkyl.

[0081] In one embodiment, the "haloalkyl" has 1 carbon.

[0082] In one embodiment, a "haloalkyl" has 1 carbon and 1 halogen.

[0083] In one embodiment, a "haloalkyl" has 1 carbon and 2 halogens.

[0084] In one embodiment, the "haloalkyl" has 1 carbon and 3 halogens.

[0085] In one embodiment, the "haloalkyl" has 2 carbons.

[0086] In one embodiment, the "haloalkyl" has 3 carbons.

[0087] In one embodiment, the "haloalkyl" has 4 carbons.

[0088] In one embodiment, the "haloalkyl" has 5 carbons.

[0089] In one embodiment, the "haloalkyl" has 6 carbons.

[0090] Non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0091] Additional non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0092] Additional non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0093] Additional non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0094] "Aryl" Embodiments In one embodiment, "aryl" is a six-carbon aromatic group (phenyl).

[0095] In one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[0096] In one embodiment, "aryl" is a six-carbon aromatic group fused to a heterocycle, with the point of attachment being the aryl ring. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where: The point of attachment of each group is on the aromatic ring.

[0097] for example, [ka] is an "aryl" group.

[0098] however, [ka] is a "heterocyclic" group.

[0099] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a cycloalkyl, where the point of attachment is on the aryl ring. Non-limiting examples of "aryl" include dihydroindene and tetrahydronaphthalene, where the point of attachment of each group is on the aromatic ring.

[0100] for example, [ka] is an "aryl" group.

[0101] however, [ka] is a "cycloalkyl" group.

[0102] "Heteroaryl" Embodiments In one embodiment, a "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0103] Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

[0104] Additional non-limiting examples of 5-membered "heteroaryl" groups include: [ka] Examples include:

[0105] In one embodiment, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (ie, pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0106] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include: [ka] Examples include:

[0107] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0108] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

[0109] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] Examples include:

[0110] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] Examples include:

[0111] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] Examples include:

[0112] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0113] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0114] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] Examples include:

[0115] "Cycloalkyl" Embodiments In one embodiment, "cycloalkyl" is C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3 or C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[0116] In one embodiment, the "cycloalkyl" has 3 carbons.

[0117] In one embodiment, the "cycloalkyl" has 4 carbons.

[0118] In one embodiment, the "cycloalkyl" has 5 carbons.

[0119] In one embodiment, the "cycloalkyl" has 6 carbons.

[0120] In one embodiment, the "cycloalkyl" has 7 carbons.

[0121] In one embodiment, the "cycloalkyl" has 8 carbons.

[0122] In one embodiment, the "cycloalkyl" has 9 carbons.

[0123] In one embodiment, the "cycloalkyl" has 10 carbons.

[0124] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0125] Additional non-limiting examples of "cycloalkyl" include dihydroindene and tetrahydronaphthalene, where the point of attachment of each group is on the cycloalkyl ring.

[0126] for example, [ka] is a "cycloalkyl" group.

[0127] however, [ka] is an "aryl" group.

[0128] Additional examples of "cycloalkyl" groups include: [ka] Examples include:

[0129] Heterocycle Embodiments In one embodiment, "heterocycle" refers to a cyclic ring having one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0130] In one embodiment, "heterocycle" refers to a cyclic ring having one nitrogen, one oxygen, and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0131] In one embodiment, "heterocycle" refers to a cyclic ring having two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0132] In one embodiment, "heterocycle" refers to a cyclic ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0133] In one embodiment, "heterocycle" refers to a cyclic ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0134] Non-limiting examples of "heterocycles" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.

[0135] Additional non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

[0136] Additional non-limiting examples of "heterocycle" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0137] Additional non-limiting examples of "heterocycle" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0138] Additional non-limiting examples of "heterocycle" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the point of attachment of each group is on the heterocycle.

[0139] for example, [ka] is a "heterocyclic" group.

[0140] however, [ka] is an "aryl" group.

[0141] Non-limiting examples of "heterocycle" include: [ka] Other examples include:

[0142] Additional non-limiting examples of "heterocycle" include: [ka] Examples include:

[0143] Additional non-limiting examples of "heterocycle" include: [ka] Examples include:

[0144] Non-limiting examples of "heterocycle" include: [ka] Other examples include:

[0145] Non-limiting examples of "heterocycle" include: [ka] Other examples include:

[0146] Additional non-limiting examples of "heterocycle" include: [ka] Examples include:

[0147] Additional non-limiting examples of "heterocycle" include: [ka] Examples include:

[0148] Optional Substituents In one embodiment, a moiety described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with 1 substituent.

[0149] In one embodiment, a moiety described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with 2 substituents.

[0150] In one embodiment, a moiety described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with 3 substituents.

[0151] In one embodiment, a moiety described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with 4 substituents.

[0152] Non-limiting embodiments of the tricyclic core The tricyclic core moiety has one, two or three nitrogens.

[0153] In one embodiment, the compound of formula I is [ka] is selected from.

[0154] Non-limiting embodiments of Formula I: In certain embodiments, the compounds of the present invention have the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0155] In certain embodiments, the compounds of the present invention have the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0156] In certain embodiments, the compounds of the present invention have the formula: [ka] and or a pharmaceutically acceptable salt thereof.

[0157] In certain embodiments, the compounds of the present invention have the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0158] In certain embodiments, the compounds of the present invention have the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0159] In certain embodiments, the compounds of the present invention have the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0160] In certain embodiments, the compounds of the present invention have the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0161] In certain embodiments, the compounds of the present invention have the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0162] In certain embodiments, the compounds of the present invention have the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0163] In certain embodiments, the compounds of the present invention have the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0164] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2025131679000049.tif215170TIFF2025131679000050.tif195170TIFF2025131679000051.tif196170TIFF2025131679000052.tif75170.

[0165] In one embodiment, the compound of formula I is [ka] is selected from.

[0166] In one embodiment, the compound of formula I is [ka] is selected from.

[0167] In one embodiment, the compound of formula I is [ka] is selected from.

[0168] In one embodiment, the compound of formula I is [ka] is selected from.

[0169] In one embodiment, the compound of formula I is [ka] and is selected from.

[0170] In one embodiment, the compound of formula I is [ka] is selected from.

[0171] In one embodiment, the compound of formula I is [ka] is selected from.

[0172] In one embodiment, the compound of formula I is [ka] is selected from.

[0173] In one embodiment, the compound of formula I is [ka] is selected from.

[0174] In one embodiment, the compound of formula I is [ka] is selected from.

[0175] In one embodiment, the compound of formula I is [ka] is selected from.

[0176] In one embodiment, the compound of formula I is [ka] is selected from.

[0177] In one embodiment, the compound of formula I is [ka] is selected from.

[0178] In one embodiment, the compound of formula I is [ka] is selected from.

[0179] In one embodiment, the compound of formula I is [ka] is selected from.

[0180] In one embodiment, the compound of formula I is [ka] is selected from.

[0181] In one embodiment, the compound of formula I is [ka] is selected from.

[0182] R 1 Non-limiting embodiments of In one embodiment of Formula I, R 1 is -NH(R 6 In one embodiment of Formula I, R 1 is -NH(R 6 In one embodiment of Formula I, R 1 is -NH(R 6 In one embodiment of Formula I, R 1 is -NH(R 6 In one embodiment of Formula I, R 1 is -N(CH3)(R 6 In one embodiment of Formula I, R 1 is -N(CH3)(R 6 In one embodiment of Formula I, R 1 is -N(CH3)(R 6 In one embodiment of Formula I, R 1 is -N(CH3)(R 6 and heteroaryl substituted with

[0183] In one embodiment of Formula I, R 1 is -O(R 6 In one embodiment of Formula I, R 1 is -O(R 6 In one embodiment of Formula I, R 1 is -O(R 6 In one embodiment of Formula I, R 1 is -O(R 6 and heteroaryl substituted with

[0184] In one embodiment of Formula I, R 1 -S(R 6 In one embodiment of Formula I, R 1 -S(R 6In one embodiment of Formula I, R 1 -S(R 6 In one embodiment of Formula I, R 1 -S(R 6 and heteroaryl substituted with

[0185] In one embodiment of Formula I, R 1 is selected from -NH-C(O)-(alkyl). In one embodiment of Formula I, R 1 is selected from -NH-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is selected from -NH-C(O)-(heterocycle). In one embodiment of Formula I, R 1 is selected from -NH-C(O)-(aryl). In one embodiment of Formula I, R 1 is selected from -NH-C(O)-(heteroaryl). In one embodiment of Formula I, R 1 is selected from -N(CH3)-C(O)-(alkyl) In one embodiment of Formula I, R 1 is selected from -N(CH3)-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is selected from -N(CH3)-C(O)- (heterocycle). In one embodiment of Formula I, R 1 is selected from -N(CH3)-C(O)-(aryl). In one embodiment of Formula I, R 1 is selected from -N(CH3)-C(O)-(heteroaryl).

[0186] In one embodiment of Formula I, R 1 is selected from -OC(O)-(alkyl). In one embodiment of Formula I, R 1 is selected from -OC(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is selected from -OC(O)- (heterocycle). In one embodiment of Formula I, R 1 is selected from -OC(O)-(aryl). In one embodiment of Formula I, R1 is selected from -OC(O)-(heteroaryl).

[0187] In one embodiment of Formula I, R 1 is selected from -SC(O)-(alkyl). In one embodiment of Formula I, R 1 is selected from -SC(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is selected from -SC(O)- (heterocycle). In one embodiment of Formula I, R 1 is selected from -SC(O)-(aryl). In one embodiment of Formula I, R 1 is selected from -SC(O)-(heteroaryl).

[0188] In one embodiment of Formula I, R 1 is -CH2(R 6 In one embodiment of Formula I, R 1 is -CH2(R 6 In one embodiment of Formula I, R 1 is -CH2(R 6 In one embodiment of Formula I, R 1 is -CH2(R 6 In one embodiment of Formula I, R 1 is -CF2(R 6 In one embodiment of Formula I, R 1 is -CF2(R 6 In one embodiment of Formula I, R 1 is -CF2(R 6 In one embodiment of Formula I, R 1 is -CF2(R 6 In one embodiment of Formula I, R 1 is -CH(OH)(R 6 In one embodiment of Formula I, R1 is -CH(OH)(R 6 In one embodiment of Formula I, R 1 is -CH(OH)(R 6 In one embodiment of Formula I, R 1 is -CH(OH)(R 6 and heteroaryl substituted with

[0189] In one embodiment of Formula I, R 1 is selected from -CH2-C(O)-(alkyl). In one embodiment of Formula I, R 1 is selected from -CH-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is selected from -CH-C(O)- (heterocycle). In one embodiment of Formula I, R 1 is selected from -CH2-C(O)-(aryl). In one embodiment of Formula I, R 1 is selected from -CH-C(O)-(heteroaryl). In one embodiment of Formula I, R 1 is selected from -CF2-C(O)-(alkyl). In one embodiment of Formula I, R 1 is selected from -CF2-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is selected from -CF2-C(O)- (heterocycle). In one embodiment of Formula I, R 1 is selected from -CF2-C(O)-(aryl). In one embodiment of Formula I, R 1 is selected from -CF2-C(O)-(heteroaryl). In one embodiment of Formula I, R 1 is selected from -CH(OH)-C(O)-(alkyl). In one embodiment of Formula I, R 1 is selected from -CH(OH)-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is selected from -CH(OH)-C(O)- (heterocycle). In one embodiment of Formula I, R 1 is selected from -CH(OH)-C(O)-(aryl). In one embodiment of Formula I, R1 is selected from -CH(OH)-C(O)-(heteroaryl).

[0190] In one embodiment of Formula I, R 1 is -CH2-NH(R 6 In one embodiment of Formula I, R 1 is -CH2-NH(R 6 In one embodiment of Formula I, R 1 is -CH2-NH(R 6 In one embodiment of Formula I, R 1 is -CH2-NH(R 6 In one embodiment of Formula I, R 1 is -CH2-N(CH3)(R 6 In one embodiment of Formula I, R 1 is -CH2-N(CH3)(R 6 In one embodiment of Formula I, R 1 is -CH2-N(CH3)(R 6 In one embodiment of Formula I, R 1 is -CH2-N(CH3)(R 6 and heteroaryl substituted with

[0191] In one embodiment of Formula I, R 1 is -CH2-O(R 6 In one embodiment of Formula I, R 1 is -CH2-O(R 6 In one embodiment of Formula I, R 1 is -CH2-O(R 6 In one embodiment of Formula I, R 1 is -CH2-O(R 6 and heteroaryl substituted with

[0192] 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 -CH-NH-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is selected from -CH-NH-C(O)- (heterocycle). In one embodiment of Formula I, R 1 is selected from -CH-NH-C(O)-(aryl). In one embodiment of Formula I, R 1 is selected from -CH-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 —CH—N(CH)—C(O)—(heteroaryl).

[0193] In one embodiment of Formula I, R 1 is selected from -CH2-OC(O)-(alkyl). In one embodiment of Formula I, R 1 is selected from -CH-OC(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is selected from -CH-OC(O)- (heterocycle). In one embodiment of Formula I, R 1 is selected from -CH2-OC(O)-(aryl). In one embodiment of Formula I, R 1 is selected from -CH2-OC(O)-(heteroaryl).

[0194] In one embodiment of Formula I, R 1 is -C(O)-(R 6In one embodiment of Formula I, R 1 is -C(O)-(R 6 In one embodiment of Formula I, R 1 is -C(O)-(R 6 In one embodiment of Formula I, R 1 is -C(O)-(R 6 and heteroaryl substituted with

[0195] In one embodiment of Formula I, R 1 is -S(O)-(R 6 In one embodiment of Formula I, R 1 is -S(O)-(R 6 In one embodiment of Formula I, R 1 is -S(O)-(R 6 In one embodiment of Formula I, R 1 is -S(O)-(R 6 and heteroaryl substituted with

[0196] In one embodiment of Formula I, R 1 is -S(O)2-(R 6 Cycloalkyl substituted with In one embodiment of Formula I, R 1 is -S(O)2-(R 6 In one embodiment of Formula I, R 1 is -S(O)2-(R 6 In one embodiment of Formula I, R 1 is -S(O)2-(R 6 and heteroaryl substituted with

[0197] In one embodiment of Formula I, R 1 teeth, [ka] is selected from.

[0198] In certain embodiments, R 1 is selected from halogen, hydrogen, amino, or cyano. 1 is bromine.

[0199] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R is a heterocycle optionally substituted with one or two groups selected from 9 is selected from hydrogen and alkyl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0200] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R is a heterocycle optionally substituted with one or two groups selected from 9 is alkyl and -C(O)R 10 where R 10 is a heterocycle. Non-limiting examples of this embodiment include: [ka] Examples include:

[0201] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R is a heterocycle optionally substituted with one or two groups selected from 9 is alkyl and -C(O)R 10 where R 10 is R 11 and R 11 is alkyl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0202] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R is a heterocycle optionally substituted with one or two groups selected from 9 is alkyl and -C(O)R 10 where R 10 is cycloalkyl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0203] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R is a heterocycle optionally substituted with one or two groups selected from 9 is alkyl and -C(O)R 10 where R 10 is R 11is cycloalkyl optionally substituted with R 11 is cyano. Non-limiting examples of this embodiment include: [ka] Examples include:

[0204] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R is a heterocycle optionally substituted with one or two groups selected from 9 is alkyl and -C(O)R 10 where R 10 is R 11 is cycloalkyl optionally substituted with R 11 is alkyl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0205] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R is a heterocycle optionally substituted with one or two groups selected from 9 is alkyl and -C(O)R 10 where R 10 is R 11 is cycloalkyl optionally substituted with R 11 is haloalkyl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0206] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R is a heterocycle optionally substituted with one or two groups selected from 9 is alkyl and -C(O)R 10 where R 10 is R 11 and R is alkyl optionally substituted with 11 is selected from hydrogen, hydroxyl, and cyano. Non-limiting examples of this embodiment include: [ka] Examples include:

[0207] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R is a heterocycle optionally substituted with one or two groups selected from 9 is alkyl and -C(O)R 10 where R 10 is haloalkyl. A non-limiting example of this embodiment Typical examples include: [ka] Examples include:

[0208] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R6 is R 9 In a further embodiment, R is a heterocycle optionally substituted with one or two groups selected from 9 is alkyl and -C(O)R 10 where R 10 is R 11 and R is alkyl optionally substituted with 11 is OR 8 A non-limiting example of this embodiment is: [ka] Examples include:

[0209] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R 9 -C(O)R 10 where R 10 is R 11 is heteroaryl or aryl optionally substituted with R 11 is selected from hydrogen and alkyl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0210] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R 9 is -C(O)NR 2 R 10 or -C(O)OR 10 where R10 is alkyl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0211] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R is a heterocycle optionally substituted with one or two groups selected from 9 is alkyl and -CHR 10 where R 10 is R 11 is cycloalkyl optionally substituted with R 11 is alkyl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0212] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R is a heterocycle optionally substituted with one or two groups selected from 9 is alkyl and -CHR 10 where R 10 is R 11 is cycloalkyl optionally substituted with R 11 is selected from haloalkyl or cyano. Non-limiting examples of this embodiment include: [ka] Examples include:

[0213] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R is a heterocycle optionally substituted with one or two groups selected from 9 is alkyl and -CHR 10 where R 10 is R 11 is cycloalkyl optionally substituted with R 11 is OR 8 A non-limiting example of this embodiment is: [ka] Examples include:

[0214] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R is a heterocycle optionally substituted with one or two groups selected from 9 is alkyl and -CHR 10 where R 10 is R 11 and R is alkyl optionally substituted with 11 is hydrogen, cyano and OR 8 Non-limiting examples of this embodiment include: [ka] Examples include:

[0215] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R 9 is R 10 and R 10 is cycloalkyl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0216] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 7 is replaced by R 6 heteroaryl substituted with, where R 6 is R 9 In a further embodiment, R is a heterocycle optionally substituted with one or two groups selected from 9 is alkyl and -C(O)R 10 Selected from R 10 is R 11 is cycloalkyl optionally substituted with R 11 is alkyl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0217] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is cycloalkyl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0218] In certain embodiments, R 1 -C(O)R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is a heterocycle. In a further embodiment, R 6 is R 9 optionally substituted with R 9 -C(O)OR 10 where R 10 Yes Non-limiting examples of this embodiment include: [ka] Examples include:

[0219] In certain embodiments, R 1 -CH(CH3)R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is a heterocycle. In a further embodiment, R 6 is R 9 optionally substituted with R 9 -C(O)OR 10 or -C(O)R 10 where R 10 is R 11 is alkyl or cycloalkyl optionally substituted with R 11 is selected from alkyl and hydrogen. Non-limiting examples of this embodiment include: [ka] Examples include:

[0220] In certain embodiments, R 1 is -CH(NH2)R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is a heterocycle. In a further embodiment, R6 is R 9 optionally substituted with R 9 -C(O)OR 10 or -C(O)R 10 where R 10 is R 11 is alkyl or cycloalkyl optionally substituted with R 11 is selected from alkyl and hydrogen. Non-limiting examples of this embodiment include: [ka] Examples include:

[0221] In certain embodiments, R 1 Ha-SR 4 , -S(O)R 4 or -S(O)2R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R 9 -C(O)R 10 where R 10 is R 11 is cycloalkyl optionally substituted with R 11 is alkyl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0222] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R 9 HA-OR 10 where R 10 is R 11and R is alkyl optionally substituted with 11 is aryl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0223] In certain embodiments, R 1 Ha-(CR 3 R 3’ )-R 4 where R 3 and R 3’ together with the carbons to which they are attached form a three-membered cycloalkyl ring, and R 4 is R 6 heteroaryl optionally substituted with 6 is R 9 In a further embodiment, R 9 -C(O)R 10 or -CH2R 10 where R 10 is R 11 is cycloalkyl optionally substituted with R 11 is alkyl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0224] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 aryl substituted with R 6 is R 9 In a further embodiment, R 9 is R 10 and R 10 is R 11 is a heterocycle optionally substituted with 11 -C(O)OR 8 , -C(O)R 8 or -SO2R8 and R 8 is alkyl, cycloalkyl, haloalkyl, or aryl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0225] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 aryl substituted with R 6 is R 9 In a further embodiment, R 9 is R 10 and R 10 is heterocycle or heteroaryl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0226] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 aryl substituted with R 6 is R 9 In a further embodiment, R 9 is R 10 and R 10 is R 11 heterocycle or heteroaryl optionally substituted with 11 is selected from hydrogen, alkyl, or haloalkyl. In one embodiment, two R 11 The groups taken together form an oxo group. Non-limiting examples of this embodiment include: [ka] Examples include:

[0227] In certain embodiments, R 1 Ha-CH2-R 4 where R 4 is R 6 aryl optionally substituted with R 6 is R 9 In a further embodiment, R 9 is R 10 where R 10 is R 11 and R 11 is -CHaryl optionally substituted with halogen. Non-limiting examples of this embodiment include: [ka] Examples include:

[0228] In certain embodiments, R 1 Ha-CH2-R 4 where R 4 is R 6 aryl optionally substituted with R 6 is R 9 In a further embodiment, R 9 is R 10 where R 10 is R 11 and R 11 is aryl optionally substituted with halogen. Non-limiting examples of this embodiment include: [ka] Examples include:

[0229] In certain embodiments, R 1 Ha-CH2-R 4 where R 4 is R 6 aryl optionally substituted with R 6 is R 9In a further embodiment, R 9 Ha-CH2R 10 or -C(O)R 10 where R 10 is R 11 is cycloalkyl optionally substituted with R 11 is hydrogen or alkyl. Non-limiting examples of this embodiment include: [ka] Examples include:

[0230] In certain embodiments, R 1 -(CH2)-R 4 where R 4 is R 6 heteroaryl optionally substituted with R 6 is R 9 In a further embodiment, R 9 is R 10 where R 10 R is selected from halogen and hydrogen 11 Non-limiting examples of this embodiment include: [ka] Examples include:

[0231] In certain embodiments, R 1 teeth, [ka] is selected from.

[0232] R 4 Non-limiting embodiments of In one embodiment of Formula I, R 4 teeth, [ka] is selected from.

[0233] In one embodiment of Formula I, R 4 teeth, [ka] is selected from.

[0234] In one embodiment of Formula I, R 4 teeth, [ka] is selected from.

[0235] In one embodiment of Formula I, R 4 teeth, [ka] is selected from.

[0236] In one embodiment of Formula I, R 4 teeth, [ka] is selected from.

[0237] In one embodiment of Formula I, R 4 teeth, [ka] is selected from.

[0238] In one embodiment of Formula I, R 4 teeth, [ka] and is selected from.

[0239] In one embodiment of Formula I, R 4 teeth, [ka] is selected from.

[0240] In one embodiment of Formula I, R 4 teeth, [ka] is selected from.

[0241] In one embodiment of Formula I, R 4 teeth, [ka] is selected from.

[0242] In one embodiment of Formula I, R 4 teeth, [ka] is selected from.

[0243] In one embodiment of Formula I, R 4 teeth, [ka] is selected from.

[0244] In certain embodiments, R 4 teeth, [ka] is selected from.

[0245] In one embodiment, the compound of formula I is [ka] Selected from TIFF2025131679000118.tif220170TIFF2025131679000119.tif207170TIFF2025131679000120.tif33170.

[0246] In one embodiment, the compound of formula I is [ka] Selected from TIFF2025131679000122.tif207170TIFF2025131679000123.tif161170.

[0247] In one embodiment, the compound of formula I is [ka] is selected from.

[0248] In one embodiment, the compound of formula I is [ka] is selected from.

[0249] In one embodiment, the compound of formula I is [ka] is selected from.

[0250] In one embodiment, the compound of formula I is [ka] Selected from TIFF2025131679000128.tif203170TIFF2025131679000129.tif159170.

[0251] In one embodiment, the compound of formula I is [ka] Selected from TIFF2025131679000131.tif218170TIFF2025131679000132.tif206170TIFF2025131679000133.tif65170.

[0252] In one embodiment, the compound of formula I is [ka] Selected from TIFF2025131679000135.tif210170TIFF2025131679000136.tif181170.

[0253] In one embodiment, the compound of formula I is [ka] Selected from TIFF2025131679000138.tif217170TIFF2025131679000139.tif206170TIFF2025131679000140.tif65170.

[0254] In one embodiment, the compound of formula I is [ka] Selected from TIFF2025131679000142.tif211170TIFF2025131679000143.tif184170.

[0255] In one embodiment, the compound of formula I is [ka] Selected from TIFF2025131679000145.tif219170TIFF2025131679000146.tif204170TIFF2025131679000147.tif63170.

[0256] In one embodiment, the compound of formula I is [ka] Selected from TIFF2025131679000149.tif210170TIFF2025131679000150.tif183170.

[0257] In one embodiment, the compound of formula I is [ka] Selected from TIFF2025131679000152.tif179170TIFF2025131679000153.tif136170.

[0258] In one embodiment, the compound of formula I is [ka] Selected from TIFF2025131679000155.tif180170TIFF2025131679000156.tif180170TIFF2025131679000157.tif90170.

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

[0260] In one embodiment, the compound of formula I is [ka] is selected from.

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

[0262] In one embodiment, the compound of formula I is [ka] is selected from.

[0263] R 6 Non-limiting embodiments of In one embodiment of Formula I, R 6 teeth, [ka] is selected from.

[0264] In one embodiment of Formula I, R 6 teeth, [ka] is selected from.

[0265] In one embodiment of Formula I, R 6 teeth, [ka] is selected from.

[0266] In one embodiment of Formula I, R 6 teeth, [ka] is selected from.

[0267] In one embodiment of Formula I, R 6 teeth, [ka] is selected from.

[0268] In one embodiment of Formula I, R 6 teeth, [ka] is selected from.

[0269] In certain embodiments, R 6teeth, [ka] is selected from.

[0270] R 9 Non-limiting embodiments of In one embodiment, R 9 teeth, [ka] is selected from.

[0271] In one embodiment, R 9 teeth, [ka] is selected from.

[0272] In one embodiment, R 9 teeth, [ka] is selected from.

[0273] In one embodiment, R 9 teeth, [ka] is selected from.

[0274] In one embodiment, R 9 teeth, [ka] is.

[0275] In one embodiment, R 9 teeth, [ka] is selected from.

[0276] In one embodiment, R 9 teeth, [ka] is selected from.

[0277] In one embodiment, R 9 teeth, [ka] is selected from.

[0278] In one embodiment, R 9 teeth, [ka] is selected from.

[0279] In one embodiment, R 9 teeth, [ka] is selected from.

[0280] In one embodiment, R 9 teeth, [ka] is selected from.

[0281] In one embodiment, R 9 teeth, [ka] is selected from.

[0282] In one embodiment, R 9 teeth, [ka] is selected from.

[0283] In one embodiment, R9 teeth, [ka] is selected from.

[0284] In one embodiment, R 9 teeth, [ka] is selected from.

[0285] In one embodiment, R 9 teeth, [ka] and is selected from.

[0286] In one embodiment, R 9 teeth, [ka] is selected from.

[0287] In one embodiment, R 9 teeth, [ka] is.

[0288] In one embodiment, R 9 teeth, [ka] is.

[0289] In one embodiment, R 9 teeth, [ka] is selected from.

[0290] In one embodiment, R9 teeth, [ka] is.

[0291] In one embodiment, R 9 teeth, [ka] is selected from.

[0292] In one embodiment, R 9 teeth, [ka] is selected from.

[0293] In one embodiment, R 9 teeth, [ka] is.

[0294] In one embodiment, R 9 teeth, [ka] is.

[0295] In one embodiment, R 9 teeth, [ka] is.

[0296] In one embodiment, R 9 teeth, [ka] is.

[0297] In one embodiment, R 9 teeth, [ka] is.

[0298] In one embodiment, R 9 teeth, [ka] is.

[0299] In one embodiment, R 9 teeth, [ka] is selected from.

[0300] In one embodiment, R 9 teeth, [ka] is selected from.

[0301] In one embodiment, R 9 teeth, [ka] is.

[0302] In one embodiment, R 9 teeth, [ka] is selected from.

[0303] In one embodiment, R 9 teeth, [ka] is selected from.

[0304] In one embodiment, R 9 teeth, [ka] is.

[0305] In one embodiment, R 9 teeth, [ka] is selected from.

[0306] In one embodiment, R 9 teeth, [ka] is selected from.

[0307] In one embodiment, R 9 teeth, [ka] is.

[0308] In one embodiment, R 9 teeth, [ka] is selected from.

[0309] In one embodiment, R 9 teeth, [ka] is selected from.

[0310] In one embodiment, R 9 teeth, [ka] is selected from.

[0311] In one embodiment, R 9 teeth, [ka] is selected from.

[0312] In one embodiment, R 9 teeth, [ka] is.

[0313] In one embodiment, R 9 teeth, [ka] is.

[0314] In one embodiment, R 9 teeth, [ka] is selected from.

[0315] In one embodiment, R 9 teeth, [ka] is selected from.

[0316] In one embodiment, R 9 teeth, [ka] is selected from.

[0317] In one embodiment, R 9 teeth, [ka] is selected from.

[0318] In one embodiment, R 9 teeth, [ka] is selected from.

[0319] In one embodiment, R 9 teeth, [ka] is selected from.

[0320] In one embodiment, R 9 teeth, [ka] is.

[0321] In one embodiment, R 9 teeth, [ka] is.

[0322] In one embodiment, R 9 teeth, [ka] is selected from.

[0323] In one embodiment, R 9 teeth, [ka] is selected from.

[0324] In one embodiment, R 9 teeth, [ka] is.

[0325] In one embodiment, R 9 teeth, [ka] is selected from.

[0326] In one embodiment, R 9 teeth, [ka] is selected from.

[0327] In one embodiment, R 9 teeth, [ka] is selected from.

[0328] In one embodiment, R 9 teeth, [ka] is selected from.

[0329] In one embodiment, R 9 teeth, [ka] is selected from.

[0330] In one embodiment, R 9 teeth, [ka] is selected from.

[0331] In one embodiment, R 9 teeth, [ka] is.

[0332] In one embodiment, R 9 teeth, [ka] is.

[0333] In one embodiment, R9 teeth, [ka] is selected from.

[0334] In one embodiment, R 9 teeth, [ka] is.

[0335] In one embodiment, R 9 teeth, [ka] is selected from.

[0336] In one embodiment, R 9 teeth, [ka] is selected from.

[0337] In one embodiment, R 9 teeth, [ka] is selected from.

[0338] In one embodiment, R 9 teeth, [ka] is.

[0339] In one embodiment, R 9 teeth, [ka] is selected from.

[0340] In one embodiment, R 9 teeth, [ka] is selected from.

[0341] In one embodiment, R 9 teeth, [ka] is.

[0342] In one embodiment, R 9 teeth, [ka] is selected from.

[0343] In one embodiment, R 9 teeth, [ka] is selected from.

[0344] In one embodiment, R 9 teeth, [ka] is selected from.

[0345] In one embodiment, R 9 teeth, [ka] is selected from.

[0346] In one embodiment, R 9 teeth, [ka] is selected from.

[0347] In one embodiment, R 9 teeth, [ka] is selected from.

[0348] R 10 Non-limiting embodiments of -C(O)R 10 Non-limiting examples of [ka] Examples include:

[0349] -CH2R 10 Non-limiting examples of [ka] Examples include:

[0350] R 10 Non-limiting examples of [ka] Examples include:

[0351] Non-limiting examples of compounds of Formula I or Formula II: Representative examples of compounds of formula I or formula II include: [ka] Examples include:

[0352] Additional representative examples of compounds of Formula I or Formula II include: [ka] Examples include TIFF2025131679000252.tif183170TIFF2025131679000253.tif206170TIFF2025131679000254.tif201170TIFF2025131679000255.tif35170.

[0353] Additional representative examples of compounds of Formula I or Formula II include: [ka] Examples include TIFF2025131679000257.tif204170, TIFF2025131679000258.tif193170, and TIFF2025131679000259.tif131170.

[0354] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2025131679000261.tif191170TIFF2025131679000262.tif194170TIFF2025131679000263.tif123170.

[0355] In one embodiment, the compound of the present invention is [ka] or a pharmaceutically acceptable salt thereof.

[0356] Non-Limiting Isotopic Embodiments In one embodiment, the compound is isotopically labeled. 1 , R 2 , R 3 , R 3’ , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 28 or R40 At least one R group independently selected from is isotopically labeled with one, two, or more isotopes, as valence permits. In one embodiment, the isotopic label is deuterium. In one embodiment, at least one deuterium is located on an atom bearing a bond that is broken during metabolism of the compound in vivo, or is one, two, or three atoms away from a bond that is metabolized (e.g., which may be referred to as an α, β, or γ, or primary, secondary, or tertiary isotope effect). In another embodiment, the isotopic label is 13 C. In another embodiment, the isotope label is 18 It's F.

[0357] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0358] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0359] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0360] In certain embodiments, the compounds of the present invention have the formula: [ka] TIFF2025131679000269.tif113170 or a pharmaceutically acceptable salt thereof.

[0361] In certain embodiments, the compounds of the present invention have the formula: [ka] TIFF2025131679000271.tif189170TIFF2025131679000272.tif138170TIFF2025131679000273.tif170170 or a pharmaceutically acceptable salt thereof.

[0362] In certain embodiments, the compounds of the present invention have the formula: [ka] TIFF2025131679000275.tif114170 or a pharmaceutically acceptable salt thereof.

[0363] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0364] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0365] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0366] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0367] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0368] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0369] In certain embodiments, the compounds of the present invention are [ka] TIFF2025131679000283.tif178170TIFF2025131679000284.tif187170TIFF2025131679000285.tif183170TIFF2025131679000286.tif183170TIFF2025131679000287.tif178170TIFF2025131679000288.tif183170TIFF2025131679000289.tif90170, or a pharmaceutically acceptable salt thereof.

[0370] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0371] In any of the above structures where there are two deuteriums on the methylene, the same molecule is envisioned with one deuterium at that position. In any of the above structures where there are three deuteriums on the methyl, the same molecule is envisioned with one or two deuteriums at that position.

[0372] Additional Embodiments 1. In certain embodiments, a compound of Formula I or Formula II: [ka] (In the formula, X 1 and X 2 are independently selected from CH and N; X 3 is a bond, NR 2 , C(R 3 R 3’ ), O, C(O), C(S), S, S(O) and S(O)2; R 1 is 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 is selected from R 2 and R 2’is independently in each occurrence 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’ is selected from R 3 is hydrogen, halogen, alkyl, haloalkyl, -OR 8 and -NR 8 R 8’ is selected from R 3’ is selected from hydrogen, halogen, alkyl and haloalkyl; or R 3 and R 3’ can be combined with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring, R 4 is selected from cycloalkyl, heterocycle, aryl, and heteroaryl; and each R 4 is R 6 and each R 4 is R 7 optionally substituted with 1, 2, 3, or 4 groups independently selected from R 5 -C(O)R 6 and R 6 is selected from alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl; and each R 6 is R 9 optionally substituted with one, two, three, or four groups independently selected from or R 6is 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 R 9 optionally substituted with 1, 2, 3, or 4 groups independently selected from R 7 is independently in each occurrence 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’ Selected from or or two R on the same carbon 7 may together form an oxo group, R 8 and R 8’ is independently selected in each occurrence from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl; R 9 are independently hydrogen, halogen, cyano, nitro, R 10 , -CH2R 10 , -OR 10 , -NR2 R 10 , -C(O)R 10 , -C(O)CH2R 10 , -C(O)CH2OR 10 , -C(O)CHNR 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 is selected from R 10 is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl; and each R 10 is R 11 optionally substituted with 1, 2, 3, or 4 groups independently selected from R 11 is hydrogen; halogen; hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl optionally substituted with an aryl or heteroaryl group; alkynyl optionally substituted with an aryl or heteroaryl group; cycloalkyl; heterocycle; one, two, three or four halogens, alkyl or -OR 8 aryl optionally substituted with a group; one, two, three or four halogen, alkyl or -OR 8 heteroaryl optionally substituted with a group; one, two, three or four halogen, alkyl or -OR 8 -CHaryl optionally substituted with one, two, three or four halogen, alkyl or -OR 8 -CH2 heteroaryl optionally substituted with a group; -OR8 ;-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’ Selected from or or two R on the same carbon 11 the groups may together form an oxo group, or R 11 is, in each occurrence, independently halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -CHaryl, -CHheteroaryl, -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’ Selected from the R 11 Each of the groups is R 12 optionally substituted with 1, 2, 3, or 4 groups independently selected from R 12 is, in each occurrence, independently halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -CHaryl, -CHheteroaryl, -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’ is selected from R 20 , R 21 , R 22 , R 23 and R 24 are, in each occurrence, independently a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, or -C(O)NR 2 -, -NR 2 C(O)-, -O-, -S-, -NR 2 -, -P(O)(R 28 )-, -P(O)-, alkene, alkyne, haloalkyl, aryl, selected from the group consisting of heterocycle, heteroaryl, bicycle, and carbocycle, each of which is R 40 and R 20 , R 21 , R 22 , R 23 and R 24 teeth, i. -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -P(O)(R 28 )-, -P(O)- and -C(S)- moieties are adjacent to each other, or ii. -O-, -S- or -NR 2 - the parts are adjacent to each other, or iii. Otherwise, an unstable molecule will result (part R 20 , R 21 , R 22 , R 23 and R 24 (defined as resulting in a molecule having a shelf life of less than about 4 months (or alternatively, less than about 6 months or 5 months) at ambient temperature due to degradation resulting from the selection and order of R 25 is hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, -OR 2 , -NR 2 R 2’ , -NR 2 SO2R 28 , -OSO2R 28 , -SO2R 28 , haloalkyl, aryl, heteroaryl, heterocyclic, bicyclic, and cycloalkyl, wherein R 25 Each of the groups is R 12 optionally substituted with 1, 2, 3, or 4 groups independently selected from R 28 are independently hydrogen, -NR 2 R 2’ , -OR 2 , -SR 2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl; R 40 are independently hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azido, amino, cyano, -NR 2 R 2’ , -NR 2 SO2R 28 , -OSO2R 28 , -SO2R 28 , haloalkyl, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl, wherein R 40 Each of the groups is R 12 or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug thereof.

[0373] 2.Formula: [ka] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug thereof, wherein

[0374] 3.R 6 is selected from alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl; and each R 6 is R 9 optionally substituted with 1, 2, 3, or 4 groups independently selected from R 11 is hydrogen; halogen; hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl optionally substituted with an aryl or heteroaryl group; alkynyl optionally substituted with an aryl or heteroaryl group; cycloalkyl; heterocycle; one, two, three or four halogens, alkyl or -OR 8 aryl optionally substituted with a group; one, two, three or four halogen, alkyl or -OR 8heteroaryl optionally substituted with a group; one, two, three or four halogen, alkyl or -OR 8 -CHaryl optionally substituted with one, two, three or four halogen, alkyl or -OR 8 -CH2 heteroaryl optionally substituted with a group; -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ;-C(O)OR 8 ;-C(O)-NR 8 R 8’ ;-C (O)CH2R 8 ;-C(O)CH2OR 8 ;-C(O)CH2-NR 8 R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8 ;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ;-SO2-OR 8 ; and -SO2-NR 8 R 8’ Selected from or or two R on the same carbon 11 The compound of embodiment 2, wherein the groups may together form an oxo group.

[0375] 4.R 12 The compound of embodiment 1 or embodiment 2, wherein is selected from halogen, alkyl, and haloalkyl.

[0376] 5.R 12 The compound of embodiment 1 or 2, wherein is selected from hydroxyl, cyano, nitro, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl.

[0377] 6.R 12 -CH2 aryl, -CH2 heteroaryl, -OR 8 , -NR8 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’ The compound of embodiment 1 or 2, selected from:

[0378] 7. One R 12 The compound of embodiment 1 or 2, wherein the substituent is halogen.

[0379] 8. The Two R's 12 The compound of embodiment 1 or 2, wherein the substituent is halogen.

[0380] 9. One R 12 The compound of embodiment 1 or 2, wherein the substituent is alkyl.

[0381] 10. The Two R's 12 The compound of embodiment 1 or 2, wherein the substituent is alkyl.

[0382] 11. One R 12 The compound of embodiment 1 or 2, wherein the substituent is haloalkyl.

[0383] 12. One R 12 The compound of embodiment 1 or 2, wherein the substituent is cycloalkyl.

[0384] 13.R 11 But R12 The compound of any one of embodiments 4-12, wherein the alkyl is optionally substituted with 1, 2, 3, or 4 substituents selected from:

[0385] 14.R 11 But R 12 The compound of any one of embodiments 4-12, wherein the cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents selected from:

[0386] 15.R 11 But R 12 The compound of any one of embodiments 4 to 12, wherein the heterocycle is optionally substituted with 1, 2, 3, or 4 substituents selected from:

[0387] 16.R 11 But R 12 The compound of any one of embodiments 4-12, wherein the aryl is optionally substituted with 1, 2, 3, or 4 substituents selected from:

[0388] 17.R 11 But R 12 The compound of any one of embodiments 4-12, wherein the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from:

[0389] 18.R 11 The compound of any one of embodiments 1-12, wherein is alkyl.

[0390] 19.R 11 The compound of any one of embodiments 1-12, wherein is cyano.

[0391] 20.R 11 The compound of any one of embodiments 1-12, wherein is haloalkyl.

[0392] 21.R 11 The compound of any one of embodiments 1-12, wherein is hydrogen.

[0393] 22.R 11The compound of any one of embodiments 1-12, wherein is hydroxyl.

[0394] 23.R 11 OR 8 13. The compound of any one of embodiments 1-12, wherein

[0395] 24.R 11 The compound of any one of embodiments 1-12, wherein is aryl.

[0396] 25.R 11 The compound of any one of embodiments 1-12, wherein is heteroaryl.

[0397] 26.R 11 -C(O)OR 8 , -C(O)R 8 or -SO2R 8 13. The compound of any one of embodiments 1-12, wherein

[0398] 27.R 11 The compound of any one of embodiments 1-12, wherein is -CH2aryl.

[0399] 28.R 1 Ga-NR 2 R 4 The compound of any one of embodiments 1-27, wherein

[0400] 29.R 1 -OR 4 The compound of any one of embodiments 1-27, wherein

[0401] 30.R 1 -C(O)R 4 The compound of any one of embodiments 1-27, wherein

[0402] 31.R 1 Ga-SR 4 The compound of any one of embodiments 1-27, wherein

[0403] 32.R 1 -S(O)R4 The compound of any one of embodiments 1-27, wherein

[0404] 33.R 1 -S(O)2R 4 The compound of any one of embodiments 1-27, wherein

[0405] 34.Formula: [ka] or a pharmaceutically acceptable salt thereof.

[0406] 35.Formula: [ka] or a pharmaceutically acceptable salt thereof.

[0407] 36.Formula: [ka] or or a pharmaceutically acceptable salt thereof.

[0408] 37.Formula: [ka] or a pharmaceutically acceptable salt thereof.

[0409] 38.R 1 -(CR 3 R 3’ )-R 5 The compound of any one of embodiments 1-27, wherein

[0410] 39.R 3 39. The compound of embodiment 37 or 38, wherein is hydrogen.

[0411] 40.R 3 Ga-NR 8 R 8’ 39. The compound of embodiment 37 or 38, wherein

[0412] 41.R 3 39. The compound of embodiment 37 or 38, wherein is alkyl.

[0413] 42.R 3’ The compound of any one of embodiments 37-41, wherein is hydrogen.

[0414] 43.R 1 Ga-NR 2 R 5 The compound of any one of embodiments 1-27, wherein

[0415] 44.R 1 -OR 5 The compound of any one of embodiments 1-27, wherein

[0416] 45.R 5 But R 9 The compound of any one of embodiments 38-44, wherein the alkyl is —C(O)alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0417] 46.R 5 But R 9 The compound of any one of embodiments 38-44, wherein the heterocycle is —C(O)heterocycle optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0418] 47.R 5 But R 9 The compound of any one of embodiments 38-44, wherein the aryl is -C(O)aryl optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0419] 48.R 5 But R 9The compound of any one of embodiments 38-44, which is -C(O)heteroaryl optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0420] 49.Formula: [ka] or a pharmaceutically acceptable salt thereof.

[0421] 50.Formula: [ka] or a pharmaceutically acceptable salt thereof.

[0422] 51.Formula: [ka] or a pharmaceutically acceptable salt thereof.

[0423] 52.R 4 But R 6 and R 7 The compound of any one of embodiments 49-51, wherein the cycloalkyl is optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0424] 53.R 4 But R 6 and R 7 The compound of any one of embodiments 49-51, wherein the heterocycle is optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0425] 54.R 4 But R 6 and R 7The compound of any one of embodiments 49-51, wherein the aryl is optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0426] 55.R 4 But R 6 and R 7 The compound of any one of embodiments 49-51, wherein the heteroaryl is optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0427] 56.R 4 but, [ka] 52. The compound of any one of embodiments 49-51, wherein

[0428] 57.R 4 but, [ka] 52. The compound of any one of embodiments 49-51, wherein

[0429] 58.R 4 but, [ka] 52. The compound of any one of embodiments 49-51, wherein

[0430] 59.R 4 but, [ka] 52. The compound of any one of embodiments 49-51, wherein

[0431] 60.R 4 but, [ka] 52. The compound of any one of embodiments 49-51, wherein

[0432] 61.R 7 is hydrogen, halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, - OR 8 and -NR 8 R 8’ The compound of any one of embodiments 1-60, selected from:

[0433] 62.R 7 is hydrogen, halogen, alkyl, haloalkyl, -C(O)R 8 , -C(O)OR 8 , -C(O)-NR 8 R 8’ , -OC(O)R 8 , -NR 2 -C(O)R 8 , -S(O)R 8 , -SO2R 8 , -SO2-OR 8 , and -SO2-NR 8 R 8’ The compound of any one of embodiments 1-60, selected from:

[0434] 63. One R 7 The compound of any one of embodiments 1-60, wherein is hydrogen.

[0435] 64. Two R's 7 The compound of any one of embodiments 1-60, wherein is hydrogen.

[0436] 65. The Three R's 7 The compound of any one of embodiments 1-60, wherein is hydrogen.

[0437] 66. One R 7 The compound of any one of embodiments 1-65, wherein is halogen.

[0438] 67. Two R's 7 The compound of any one of embodiments 1-64, wherein is a halogen atom.

[0439] 68. One R 7 The compound of any one of embodiments 1-65, wherein is alkyl.

[0440] 69. Two R's 7 The compound of any one of embodiments 1-64, wherein is alkyl.

[0441] 70. One R 7 The compound of any one of embodiments 1-65, wherein is haloalkyl.

[0442] 71. Two R's 7 The compound of any one of embodiments 1-64, wherein is haloalkyl.

[0443] 72.R 6 but, [ka] The compound of any one of embodiments 1-71, selected from:

[0444] 73.R 6 but, [ka] The compound of any one of embodiments 1-71, selected from:

[0445] 74.R 6 but, [ka] The compound of any one of embodiments 1-71, selected from:

[0446] 75.R 6 But R 9 The compound of any one of embodiments 1-71, wherein R is alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0447] 76.R 6 But R 9The compound of any one of embodiments 1-71, wherein the cycloalkyl is optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0448] 77.R 6 But R 9 The compound of any one of embodiments 1-71, wherein the heterocycle is optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0449] 78.R 6 But R 9 The compound of any one of embodiments 1-71, wherein the aryl is optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0450] 79.R 6 But R 9 The compound of any one of embodiments 1-71, wherein the heteroaryl is optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0451] 80.R 6 The compound of any one of embodiments 75-79, wherein is unsubstituted.

[0452] 81.R 6 R 9 The compound of any one of embodiments 75-79, substituted with one group selected from:

[0453] 82.R 6 R 9 The compound of any one of embodiments 75-79, substituted with two groups independently selected from:

[0454] 83.R 6 R 9 The compound of any one of embodiments 75-79, substituted with three groups independently selected from:

[0455] 84.R 6 R 9The compound of any one of embodiments 75-79, substituted with four groups independently selected from:

[0456] 85.R 9 The compound of any one of embodiments 1-84, wherein is selected from hydrogen, halogen, alkyl, haloalkyl, cyano, and nitro.

[0457] 86.R 9 R 10 The compound of any one of embodiments 1-84, selected from:

[0458] 87.R 9 Ga-CH2R 10 , -OR 10 , -NR 2 R 10 , -C(O)R 10 , -C(O)CH2R 10 , -C(O)CH2OR 10 , -C(O)CHNR 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 The compound of any one of embodiments 1-84, selected from:

[0459] 88.R 10 But R 11 88. The compound of embodiment 86 or 87, wherein R is alkyl optionally substituted with 1, 2, 3 or 4 groups independently selected from:

[0460] 89.R 10 But R 11 88. The compound of embodiment 86 or 87, wherein the aryl group is haloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0461] 90.R 10 But R 11 88. The compound of embodiment 86 or 87, wherein R is alkenyl optionally substituted with 1, 2, 3 or 4 groups independently selected from:

[0462] 91.R 10 But R 11 88. The compound of embodiment 86 or 87, wherein the alkynyl is optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0463] 92.R 10 But R 11 88. The compound of embodiment 86 or 87, wherein R is cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0464] 93.R 10 But R 11 88. The compound of embodiment 86 or 87, wherein the heterocycle is optionally substituted with 1, 2, 3 or 4 groups independently selected from:

[0465] 94.R 10 But R 11 88. The compound of embodiment 86 or 87, wherein R is aryl optionally substituted with 1, 2, 3 or 4 groups independently selected from:

[0466] 95.R 10 But R 11 88. The compound of embodiment 86 or 87, wherein the heteroaryl is optionally substituted with 1, 2, 3 or 4 groups independently selected from:

[0467] 96.R 10 The compound of any one of embodiments 88-95, wherein is unsubstituted.

[0468] 97.R 10 R 11 The compound of any one of embodiments 88-95, substituted with one group selected from:

[0469] 98.R 10 R 11 The compound of any one of embodiments 88-95, substituted with two groups independently selected from:

[0470] 99.R 10 R 11 The compound of any one of embodiments 88-95, substituted with three groups independently selected from:

[0471] 100.R 10 R 11 The compound of any one of embodiments 88-95, substituted with four groups independently selected from:

[0472] 101.R 2 , R 8 and R 8’ The compound of any one of embodiments 1-100, wherein is hydrogen.

[0473] 102.R 2 , R 8 and R 8’ The compound of any one of embodiments 1-100, wherein is alkyl.

[0474] 103.R 6 but, [ka] The compound of any one of embodiments 1-71, selected from:

[0475] 104.R 6 but, [ka] The compound of any one of embodiments 1-71, selected from:

[0476] 105.R 6 but, [ka] The compound of any one of embodiments 1-71, selected from:

[0477] 106.Formula: [ka] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug thereof, wherein

[0478] 107.Formula: [ka] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, wherein

[0479] 108.Formula: [ka] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, wherein

[0480] 109.Formula: [ka] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, wherein

[0481] 110.X 3 The compound of any one of embodiments 106-109, wherein is a bond.

[0482] 111.X 3 is C(R 3 R 3’109. The compound of any one of embodiments 106-109, wherein

[0483] 112.X 3 The compound of any one of embodiments 106-109, wherein is C(O).

[0484] 113.X 3 The compound of any one of embodiments 106-109, wherein is C(S).

[0485] 114.X 3 The compound of any one of embodiments 106-109, wherein is S(O).

[0486] 115.X 3 The compound of any one of embodiments 106-109, wherein is S(O)2.

[0487] 116.X 3 NR 2 The compound of any one of embodiments 106-109, wherein

[0488] 117.X 3 The compound of any one of embodiments 106-109, wherein is O.

[0489] 118.X 3 NR 2 The compound of any one of embodiments 106-109, wherein

[0490] 119.X 3 The compound of any one of embodiments 106-109, wherein is O.

[0491] 120.X 3 The compound of any one of embodiments 106-109, wherein is S.

[0492] 121.R 20 The compound of any one of embodiments 106-120, wherein is a bond.

[0493] 122.R 20 But R 40The compound of any one of embodiments 106-120, wherein R is alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0494] 123.R 20 But R 40 The compound of any one of embodiments 106-120, which is an alkene or alkyne optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0495] 124.R 20 But R 40 The compound of any one of embodiments 106-120, wherein the aryl group is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0496] 125.R 20 But R 40 The compound of any one of embodiments 106-120, wherein the aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0497] 126.R 20 But R 40 The compound of any one of embodiments 106-120, wherein the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0498] 127.R 20 But R 40 The compound of any one of embodiments 106-120, wherein the heterocycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0499] 128.R 20 But R 40 The compound of any one of embodiments 106-120, wherein the ring is a bicyclic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0500] 129.R 20The compound of any one of embodiments 106-115, wherein is —O—.

[0501] 130.R 20 The compound of any one of embodiments 106-115, wherein is -S-.

[0502] 131.R 20 Ga-NR 2 The compound of any one of embodiments 106-115, wherein

[0503] 132.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)-.

[0504] 133.R 21 The compound of any one of embodiments 106-132, wherein is a bond.

[0505] 134.R 21 But R 40 The compound of any one of embodiments 106-132, wherein R is alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0506] 135.R 21 But R 40 The compound of any one of embodiments 106-132, which is an alkene or alkyne optionally substituted with 1, 2, 3 or 4 substituents independently selected from:

[0507] 136.R 21 But R 40 The compound of any one of embodiments 106 to 132, wherein the alkyl is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from thing.

[0508] 137.R 21 But R 40The compound of any one of embodiments 106-132, wherein the aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0509] 138.R 21 But R 40 The compound of any one of embodiments 106-132, wherein the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0510] 139.R 21 But R 40 The compound of any one of embodiments 106-132, wherein the heterocycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0511] 140.R 21 But R 40 The compound of any one of embodiments 106-132, wherein the bicyclic ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0512] 141.R 21 The compound of any one of embodiments 106-128, wherein is —O—.

[0513] 142.R 21 The compound of any one of embodiments 106-128, wherein is -S-.

[0514] 143.R 21 Ga-NR 2 The compound of any one of embodiments 106-128, wherein

[0515] 144.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)-.

[0516] 145.R 22The compound of any one of embodiments 106-144, wherein is a bond.

[0517] 146.R 22 But R 40 The compound of any one of embodiments 106-144, wherein R is alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0518] 147.R 22 But R 40 The compound of any one of embodiments 106-144, which is an alkene or alkyne optionally substituted with 1, 2, 3 or 4 substituents independently selected from:

[0519] 148.R 22 But R 40 The compound of any one of embodiments 106-144, wherein the alkyl is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0520] 149.R 22 But R 40 The compound of any one of embodiments 106-144, wherein the aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0521] 150.R 22 But R 40 The compound of any one of embodiments 106-144, wherein the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0522] 151.R 22 But R 40 The compound of any one of embodiments 106-144, wherein the heterocycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0523] 152.R 22 But R 40 one, two, three or four substituents independently selected from The compound of any one of embodiments 106-144, wherein R is a bicyclic ring optionally substituted with R.

[0524] 153.R 22 is -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -, -P(O)(R 28 )- or -P(O)-.

[0525] 154.R 22 The compound of any one of embodiments 106-140, wherein is —O—.

[0526] 155.R 22 The compound of any one of embodiments 106-140, wherein is -S-.

[0527] 156.R 22 Ga-NR 2 The compound of any one of embodiments 106-140, wherein

[0528] 157.R 23 or R 24 The compound of any one of embodiments 106-156, wherein is a bond.

[0529] 158.R 23 or R 24 But R 40 The compound of any one of embodiments 106-156, wherein R is alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0530] 159.R 23 or R 24 But R 40 The compound of any one of embodiments 106-156, which is an alkene or alkyne optionally substituted with 1, 2, 3 or 4 substituents independently selected from:

[0531] 160.R 23 or R 24 But R40 The compound of any one of embodiments 106-156, wherein the aryl group is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0532] 161.R 23 or R 24 But R 40 The compound of any one of embodiments 106-156, wherein the aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0533] 162.R 23 or R 24 But R 40 The compound of any one of embodiments 106-156, wherein the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0534] 163.R 23 or R 24 But R 40 The compound of any one of embodiments 106-156, wherein the heterocycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0535] 164.R 23 or R 24 But R 40 The compound of any one of embodiments 106-156, wherein the bicyclic ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0536] 165.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)-.

[0537] 166.R 23 or R 24The compound of any one of embodiments 106-156, wherein is —O—.

[0538] 167.R 23 or R 24 The compound of any one of embodiments 106-156, wherein is -S-.

[0539] 168.R 23 or R 24 Ga-NR 2 The compound of any one of embodiments 106-156, wherein

[0540] 169.R 25 The compound of any one of embodiments 106-168, wherein is hydrogen.

[0541] 170.R 25 The compound of any one of embodiments 106-168, wherein is halogen.

[0542] 171.R 25 But R 12 The compound of any one of embodiments 106-168, wherein R is alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:

[0543] 172.R 25 Alkene, alkyne, hydroxyl, alkoxy, azide, amino, cyano, -OR 2 , -NR 2 R 2’ , -NR 2 SO2R 28 , -OSO2R 28 , -SO2R 28 , haloalkyl, aryl, heteroaryl, heterocyclic, bicyclic, and cycloalkyl, wherein R 25 Each of the groups is R 12 The compound of any one of embodiments 106-168, optionally substituted with 1, 2, 3 or 4 groups independently selected from:

[0544] 173.R 40is selected from alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azido, amino, cyano, haloalkyl, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; 40 Each of the groups is R 12 The compound of any one of embodiments 106-172, optionally substituted with 1, 2, 3 or 4 groups independently selected from:

[0545] 174.R 40 The compound of embodiment 173, wherein is unsubstituted.

[0546] 175. [ka] TIFF2025131679000316.tif205170TIFF2025131679000317.tif175170, or a pharmaceutically acceptable salt thereof.

[0547] 176. The compound of embodiment 1, selected from Table 2 or a pharmaceutically acceptable salt thereof.

[0548] 177. Structure: [ka] or a pharmaceutically acceptable salt thereof.

[0549] 178. Structure: [ka] or a pharmaceutically acceptable salt thereof.

[0550] 179. Structure: [ka] or a pharmaceutically acceptable salt thereof.

[0551] 180. Structure: [ka] or a pharmaceutically acceptable salt thereof.

[0552] 181. Structure: [ka] or a pharmaceutically acceptable salt thereof.

[0553] 182. In certain embodiments, provided is a pharmaceutical composition comprising a compound of any one of embodiments 1-181 or a pharmaceutical salt thereof and a pharmaceutically acceptable excipient.

[0554] 183. In certain embodiments, provided is a method of treating a disorder mediated by cereblon in a human, comprising administering an effective dose of a compound of any one of embodiments 1-181, or a pharmaceutically acceptable salt or composition thereof, to a human in need thereof.

[0555] 184. The method of embodiment 183, wherein the disorder is mediated by Ikaros or Aiolos.

[0556] 185. The method of embodiment 183 or 184, wherein the disorder is cancer.

[0557] 186. The method of embodiment 183 or 184, wherein the disorder is a tumor.

[0558] 187. The method of embodiment 183 or 184, wherein said disorder is an immune disorder, an autoimmune disorder, or an inflammatory disorder.

[0559] 188. The method of embodiment 183 or 184, wherein the disorder is a hematological malignancy.

[0560] 189. The method of embodiment 183 or 184, wherein said disorder is multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma.

[0561] 190. In certain embodiments, provided is a compound selected from the compound of any one of embodiments 1-181 or a pharmaceutically acceptable salt or composition thereof for use in the manufacture of a medicament for the treatment of a disorder mediated by cereblon in a human.

[0562] 191. The compound for use in embodiment 190, wherein said disorder is mediated by Ikaros or Aiolos.

[0563] 192. The compound for use in embodiment 190 or 191, wherein said disorder is cancer.

[0564] 193. The compound for use in embodiment 190 or 191, wherein the disorder is a tumor.

[0565] 194. The compound for use in embodiment 190 or 191, wherein said disorder is an immune disorder, an autoimmune disorder or an inflammatory disorder.

[0566] 195. The compound for use in embodiment 190 or 191, wherein said disorder is a hematological malignancy.

[0567] 196. The compound for use in embodiment 190 or 191, wherein said disorder is multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0568] 197. In certain embodiments, there is provided the use of a compound for the treatment of a disorder mediated by cereblon in a human, wherein the compound is selected from the compound of any one of embodiments 1 to 181 or a pharmaceutically acceptable salt or composition thereof.

[0569] 198. The use of embodiment 197, wherein the disorder is mediated by Ikaros or Aiolos.

[0570] 199. The use of embodiment 197 or 198, wherein the disorder is cancer.

[0571] 200. The use of embodiment 197 or 198, wherein the disorder is a tumor.

[0572] 201. The use of embodiment 197 or 198, wherein said disorder is an immune disorder, an autoimmune disorder or an inflammatory disorder.

[0573] 202. The use of embodiment 197 or 198, wherein the disorder is a hematological malignancy.

[0574] 203. The use of embodiment 197 or 198, wherein said disorder is multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0575] III. Treatment method Any of the compounds described herein can be used in a therapeutically effective amount to treat a host, including a human, in need thereof, optionally in a pharmaceutically acceptable carrier, to treat any of the disorders described herein. In certain embodiments, the method comprises administering an effective amount of an active compound described herein or a salt thereof, optionally including a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), optionally in combination or alternation with an additional therapeutically active agent or combination of therapeutically active agents.

[0576] 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.

[0577] In one embodiment, the compounds of formula I are used to treat the disorders described herein.

[0578] In one embodiment, a compound of formula II is used to treat a disorder described herein.

[0579] In one embodiment, a compound of formula Ia is used to treat a disorder described herein.

[0580] In one embodiment, a compound of formula Ib is used to treat a disorder described herein.

[0581] In one embodiment, a compound of Formula Ic is used to treat a disorder described herein.

[0582] In one embodiment, a compound of formula Id is used to treat a disorder described herein.

[0583] In one embodiment, a compound of formula Ie is used to treat a disorder described herein.

[0584] In one embodiment, a compound of formula If is used in the treatment of a disorder described herein.

[0585] In one embodiment, a compound of formula Ig is used to treat a disorder described herein.

[0586] In one embodiment, the disorder treated by the compounds of the invention is an immunomodulatory disorder. The disorders treated by the compounds of the invention are mediated by angiogenesis. In one embodiment, the disorders treated by the compounds of the invention are associated with the lymphatic system.

[0587] In one embodiment, a compound of the invention or a pharmaceutical salt thereof, optionally in a pharmaceutical composition described herein, is used to degrade Ikaros or Aiolos, a mediator of a disorder affecting a patient, such as a human. The control of protein levels achieved by any of the compounds of the invention results in the treatment of a disease state or condition modulated by Ikaros or Aiolos by reducing the level of that protein in a cell, e.g., a patient's cell, or by reducing the level of a downstream protein in the cell. In certain embodiments, the method comprises administering an effective amount of a compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), in combination or alternation with an additional therapeutically active agent or combination of therapeutically active agents.

[0588] In one embodiment, the compounds of the invention are used to treat disorders including, but not limited to, benign tumors, neoplasms, tumors, cancer, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloidotic proteinoses, proteinoses, or fibrotic disorders.

[0589] The term "disease state" or "pathological condition," when used in connection with any compound, is intended to 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 downstream protein of Ikaros or Aiolos, the degradation of which in a patient may provide beneficial therapy or symptomatic relief to a patient in need thereof. In some cases, the disease state or condition may be cured.

[0590] In one embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in an effective amount to treat a host, e.g., a human, having a lymphoma, or a lymphocytic or myeloid proliferative disorder or abnormality. For example, the compounds described herein can be administered to a host suffering from Hodgkin's lymphoma or non-Hodgkin's lymphoma. For example, the host may be suffering from, but not limited to, AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK-cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small non-cleaved cell lymphoma); small cleaved cell diffuse lymphoma (DSCCL); chronic lymphocytic leukemia / small lymphocytic lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathic type. The patient may have T-cell lymphoma; follicular lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; childhood lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; therapy-related T-cell lymphoma; non-Hodgkin's lymphoma such as Langerhans cell histiocytosis or Waldenstrom's macroglobulinemia.

[0591] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in an effective amount to treat a host, e.g., a human, having Hodgkin lymphoma, such as, but not limited to, nodular sclerosing classical Hodgkin lymphoma (CHL), mixed cellularity CHL, lymphopenic CHL, lymphocyte-rich CHL, lymphocyte-predominant Hodgkin lymphoma, or nodular lymphocyte-predominant HL.

[0592] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in an effective amount to treat a host, e.g., a human, having an immunomodulatory condition. Non-limiting examples of immunomodulatory conditions include arthritis, lupus, celiac disease, Sjogren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes, alopecia areata, vasculitis, and temporal arteritis.

[0593] In certain embodiments, the conditions treated using the compounds of the invention are disorders associated with abnormal cell proliferation. Abnormal cell proliferation, particularly hyperproliferation, can result from a wide range of factors, including genetic mutations, infections, exposure to toxins, autoimmune disorders, and the induction of benign or malignant tumors.

[0594] Abnormal proliferation of B cells, T cells, and / or NK cells can result in a wide range of diseases, including cancer, proliferative disorders, and inflammatory / immune diseases. A host, e.g., a human, afflicted with any of these disorders can be treated with an effective amount of a compound described herein to reduce (palliate) symptoms. achieve a reduction in the underlying disease (disease-modifying agent) It is possible.

[0595] In one embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs thereof, are used to treat a variety of diseases, including, but not limited to, multiple myeloma; diffuse large B-cell lymphoma; follicular lymphoma; mucosa-associated lymphoid tissue lymphoma ( MALT); small cell lymphocytic lymphoma; diffuse poorly differentiated lymphocytic lymphoma; mediastinal large B-cell lymphoma; 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; diffuse red pulp small B-cell lymphoma; hairy cell leukemia-subtype; lymphoplasmacytic lymphoma; heavy chain diseases, e.g., alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease; plasma cell myeloma; isolated plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicle center lymphoma; T-cell / histiocytocyte-rich large B-cell lymphoma The compounds may be used in effective amounts to treat a host, e.g., a human, having certain B-cell lymphomas or proliferative disorders, such as: lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of 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 arising in HHV8-associated multicentric Castleman disease; unclassifiable B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma; or unclassifiable B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma.

[0596] In one embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs thereof, are useful in treating a variety of conditions, including, but not limited to, anaplastic lymphoma kinase (ALK)-positive, ALK-negative anaplastic large cell lymphoma or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphomas, such as mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous gamma-delta T-cell lymphoma; primary cutaneous small / medium cell CD4+ T-cell lymphoma and lymphomatoid papulosis; adult T-cell leukemia / lymphoma (ATLL); blastic It can be used in an effective amount to treat a host, e.g., a human, having a T-cell or NK-cell lymphoma, such as 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, lymphomas arising after solid organ or bone marrow transplantation; T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; chronic lymphoproliferative disorder of NK cells; rapidly progressive NK-cell leukemia; systemic EBV+ T-cell lymphoproliferative disorder of children (associated with chronic active EBV infection); vaccinia bullosa-like lymphoma; adult T-cell leukemia / lymphoma; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; or subcutaneous panniculitis-like T-cell lymphoma.

[0597] In one embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used to treat a host, such as a human, with leukemia. For example, the host may suffer 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 lymphocytic leukemia; or adult T-cell chronic leukemia. In one embodiment, the patient has acute myeloid leukemia, such as undifferentiated AML (M0); myeloblastic leukemia (M1; with / without minimal cellular maturation); myeloblastic leukemia (M2; with cellular maturation); promyelocytic leukemia (M3 or M3 subtype (M3V)); myelomonocytic leukemia (M4 or M4 subtype with eosinophilia (M4E)); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7).

[0598] There are many skin disorders associated with cell hyperproliferation. For example, psoriasis is a benign disease of human skin that is generally characterized by plaques covered with thickened scales. This disease is caused by increased proliferation of epidermal cells for unknown reasons. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, warts, and verruca vulgaris. Pemphigus vulgaris, actinic keratosis, basal cell carcinoma and squamous cell carcinoma.

[0599] Other hyperproliferative cell disorders include blood vessel proliferation disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors and cancers.

[0600] Blood vessel proliferative disorders include neovascular and angiogenic disorders. The proliferation of smooth muscle cells during the development of plaques in vascular tissue causes, for example, restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[0601] Fibrotic disorders are often caused by abnormal formation of extracellular matrix. Examples of fibrotic disorders include liver cirrhosis and mesangial proliferative cell disorders. Liver cirrhosis is characterized by an increase in extracellular matrix components, which leads to the formation of liver scars. Liver cirrhosis can lead to diseases such as cirrhosis of the liver. The increase in extracellular matrix that leads to liver scars can also be caused by viral infections such as hepatitis. Lipid cells appear to play an important role in liver cirrhosis.

[0602] Mesangial disorders are caused by abnormal proliferation of mesangial cells, and include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, graft rejection, and glomerulopathy.

[0603] Another disease with a proliferative component is rheumatoid arthritis, which is generally considered an autoimmune disease associated with the activity of autoreactive T cells and thought to result from autoantibodies produced against collagen and IgE.

[0604] Other disorders that may involve an abnormal cell proliferative component include Behcet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immune deficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and general inflammation.

[0605] The compounds described herein, or pharmaceutically acceptable salts, isotopic analogs, or prodrugs thereof, can be used in effective amounts to treat a host, e.g., a human, having a proliferative condition, such as myeloproliferative disorder (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mastocytosis (SMCD), etc. In another embodiment, the compounds provided herein are useful for the treatment of primary myelofibrosis, post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis, and secondary acute myeloid leukemia.

[0606] In one embodiment, the compounds described herein, or pharmaceutically acceptable salts, isotopic analogs, or prodrugs thereof, can be used in an effective amount to treat a host, e.g., a human, having a myelodysplastic syndrome (MDS), such as, but not limited to, refractory cytopenia with single lineage dysplasia, refractory anemia with ringed sideroblasts (RARS), refractory anemia-thrombocytosis with ringed sideroblasts (RARS-t), refractory cytopenia with multilineage dysplasia (RCMD), including RCMD with multilineage dysplasia and ringed sideroblasts (RCMD-RS), refractory anemia with excess blasts I (RAEB-I) and II (RAEB-II), 5q-syndrome, and refractory cytopenia of childhood.

[0607] In one embodiment, compounds of the invention may exert their therapeutic effect through direct degradation of Ikaros or Aiolos, which may alter the transcriptional regulation of proteins downstream of Ikaros or Aiolos.

[0608] The term "neoplasia" or "cancer" refers to a cancerous or malignant new growth, i.e., They often grow faster than normal through cell proliferation, and the stimulus that initiated the new growth is It is used to refer to a pathological process that results in the formation and growth of abnormal tissue that continues to grow even after it has stopped. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissue, most invade surrounding tissues, metastasize to several sites, may recur after attempted removal, and cause patient death if not properly 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 tumors, ascites tumors, and solid tumors. Exemplary cancers that can be treated by the present compounds 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, cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's lymphoma, and leukemia. Sarcomas, including sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma; intestinal 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. Additional cancers that can be treated using the compounds according to the invention include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

[0609] Additional cancers that can be treated using the compounds disclosed herein include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal carcinoma, anaplastic astrocytoma, angiosarcoma, appendix carcinoma, astrocytoma, basal cell carcinoma, B-cell lymphoma, bile duct carcinoma, bladder cancer, bone cancer, bone marrow cancer, intestinal cancer, brain cancer, brainstem glioma, breast cancer, triple (estrogen, progesterone, and HER-2) negative breast cancer, double negative breast cancer (estrogen, progesterone, and HER-2) negative breast cancer, and HER-2 negative breast cancer. Negative for two of estrogen, progesterone and HER-2), Single Negative (Negative for one of estrogen, progesterone and HER-2), Estrogen Receptor Positive, HER2 Negative Breast Cancer, Estrogen Receptor Negative Breast Cancer, Estrogen Receptor Positive Breast Cancer, Metastatic Breast Cancer, Luminal A Breast Cancer, Luminal B Breast Cancer, Her2 Negative Breast Cancer, HER2 Positive or Negative Breast Cancer, Progesterone Receptor Negative Breast Cancer, Progesterone Receptor Positive Breast Cancer, Recurrent Breast Cancer, Carcinoid Tumor, Cervical Cancer, Cholangiocarcinoma, Chronic Lymphocytic Leukemia (CL) L), chronic myeloid leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic cholangiocarcinoma, ocular cancer, fallopian tubes Cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumor (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasion Inflammatory lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal cancer, intrahepatic cholangiocarcinoma, invasive / infiltrating breast cancer, islet cell carcinoma, jaw cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastasis, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous cell neck cancer, mixed glioma, monodermal teratoma, mouth cancer, mucinous carcinoma , mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, cervical cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, intraocular melanoma, oligodendroglioma, oral cancer, oral cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, primary ovarian peritoneal cancer, ovarian sex cord-stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, scrotal cancer Stalk cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal tumor, pineoblastoma, pituitary cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, vertebral cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, and undiagnosed certain cancers, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, Large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, Juvenile myelomonocytic leukemia (JMML), Acute promyelocytic leukemia (AML subtype), Large granular lymphocytic leukemia, Adult T-cell chronic leukemia, Diffuse large B-cell lymphoma, Follicular lymphoma; Mucosa-associated lymphoid tissue lymphoma (MALT), Small cell lymphocytic lymphoma, Mediastinal large B-cell lymphoma, Nodal marginal zone B-cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary effusion lymphoma; or Lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; Splenic lymphoma / leukemia unclassifiable; Diffuse red pulp small B-cell lymphoma; Lymphoid Plasma cell lymphoma; heavy chain diseases such as alpha heavy chain disease, gamma heavy chain disease, and mu heavy chain disease; plasma cell myeloma; isolated plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicle center lymphoma; T-cell / histiocytocyte-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 arising in HHV8-associated multicentric Castleman disease; unclassifiable B-cell lymphoma with features intermediate to those of diffuse large B-cell lymphoma, or unclassifiable B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma. In one embodiment, the disorder is adenoid cystic carcinoma. In one embodiment, the disorder is NUT midline carcinoma.

[0610] In another embodiment, the compounds described herein, or pharmaceutically acceptable salts, isotopic derivatives, or prodrugs thereof, can be used in an effective amount to treat a host, e.g., a human, having an autoimmune disorder. Examples include acute disseminated encephalomyelitis (ADEM); Addison's disease; agammaglobulinemia; alopecia areata; amyotrophic lateral sclerosis (also known as Lou Gehrig's disease or motor neuron disease); ankylosing spondylitis; antiphospholipid syndrome; antisynthetase syndrome; atopic allergy; atopic dermatitis; autoimmune aplastic anemia; autoimmune arthritis; autoimmune cardiomyopathy; autoimmune enteropathy; autoimmune granulocytopenia; autoimmune hemolytic anemia; autoimmune hepatitis; autoimmune hypoparathyroidism; autoimmune inner ear disease; autoimmune lymphoproliferative syndrome; autoimmune myocarditis; autoimmune pancreatitis; autoimmune peripheral neuropathy; autoimmune ovarian failure; autoimmune polyglandular syndrome; autoimmune progesterone dermatitis; autoimmune thrombocytopenic purpura; autoimmune thyroid disorders; autoimmune urticaria; autoimmune uveitis; autoimmune vasculitis; and Baro's disease. disease) / Barrow concentric sclerosis;Behçet's disease;Berger's disease;Bickerstaff encephalitis;Blau syndrome;Bullous pemphigoid;Cancer;Castleman's disease;Celiac disease;Chagas disease;Chronic inflammatory demyelinating polyneuropathy;Chronic inflammatory demyelinating polyneuropathy;Chronic obstructive pulmonary disease;Chronic relapsing multiple osteomyelitis;Churg-Strauss syndrome;Cicatricial pemphigoid;Cogan's syndrome;Cold agglutinin disease;Complement component 2 deficiency;Contact dermatitis;Cranial arteritis;CREST syndrome;Crohn's disease;Cushion disease Ng's syndrome; cutaneous leukocytoclastic vasculitis; Degos disease; Dercum's disease; dermatitis herpetiformis; dermatomyositis; type 1 diabetes; diffuse cutaneous systemic sclerosis; discoid lupus erythematosus; Dressler's syndrome; drug-induced lupus; eczema; endometriosis; enthesitis-associated arthritis; eosinophilic fasciitis; eosinophilic gastroenteritis; eosinophilic pneumonia; epidermolysis bullosa acquisita; erythema nodosum; erythroblastosis fetalis; essential mixed cryoglobulinemia; Evans syndrome; extrinsic and intrinsic reactive airway disease (asthma); fibrodysplasia ossificans progressiva fibrosing alveolitis (or idiopathic pulmonary fibrosis);gastritis;gastrointestinal pemphigoid;glomerulonephritis;Goodpasture's syndrome;Graves' disease;Guillain-Barré syndrome (GBS);Hashimoto's encephalopathy;Hashimoto's disease;hemolytic anemia;Henoch-Schönlein purpura;herpes gestationis (gestational pemphigoid);hidradenitis suppurativa;Hughes-Stovin syndrome;hypogammaglobulinemia;idiopathic inflammatory demyelinating disease;idiopathic pulmonary fibrosis;idiopathic thrombocytopenic purpura;IgA nephropathy;immune glomerulonephritis;immune nephritis;immune pneumonitis;inclusion body myositis;inflammatory bowel disease;interstitial cystitis;juvenile idiopathic arthritis, also known as juvenile rheumatoid arthritis; Kawasaki disease; Lambert-Eaton myasthenic syndrome; leukocytoclastic vasculitis; lichen planus; lichen sclerosus; linear immunoglobulin A disease (LAD); lupoid hepatitis, also known as autoimmune hepatitis; lupus erythematosus; Majeed syndrome; microscopic polyangiitis; Miller-Fisher syndrome; mixed connective tissue disease; localized scleroderma; Mucha-Habermann disease, also known as acute pityriasis lichenoidis; multiple sclerosis; myasthenia gravis; myositis; Meniere's disease; narcolepsy; neuromyelitis optica (also known as Devic's disease); neuromyotonia; ophthalmic cicatricial pemphigoid; opsoclonus-myoclonus syndrome; Ord's thyroiditis; relapsing rheumatoid arthritis Urine; PANDAS (pediatric autoimmune streptococcal neuropsychiatric disorders); paraneoplastic cerebellar degeneration; paroxysmal nocturnal hemoglobinuria (PNH); Parry-Romberg syndrome; pars planitis; Parsonage-Turner syndrome; pemphigus vulgaris; perivenous encephalomyelitis; pernicious anemia; POEMS syndrome; polyarteritis nodosa; polymyalgia rheumatica; polymyositis; primary biliary cirrhosis; primary sclerosing cholangitis; progressive inflammatory neuropathy; psoriasis; psoriatic arthritis; pure red cell aplasia; pyoderma gangrenosum; Rasmussen encephalitis; Raynaud's phenomenon; Reiter's syndrome; relapsing polychondritis; restless legs syndrome; retroperitoneal fibrosis; rheumatic fever; rheumatoid arthritis; sarcoid The conditions include, but are not limited to, schizophrenia, Schmidt's syndrome, Schnitzler's syndrome, scleritis, scleroderma, sclerosing cholangitis, serum sickness, Sjogren's syndrome, spondyloarthropathy, stiff-person syndrome, Still's disease, subacute bacterial endocarditis (SBE), Susac's syndrome, Sweet's syndrome, Sydenham's chorea, sympathetic ophthalmia, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis (also known as "giant cell arteritis"); thrombocytopenia, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, undifferentiated spondyloarthropathy, urticarial vasculitis, vasculitis, vitiligo, viral diseases such as Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV-1, varicella-zoster virus (VZV), and human papillomavirus (HPV); or Wegener's granulomatosis. In some embodiments, the autoimmune disease is an allergic condition, including those caused by asthma, food allergies, atopic dermatitis, chronic pain, and rhinitis.

[0611] Skin contact hypersensitivity and asthma are just two examples of immune responses that can be associated with significant morbidity. Others include atopic dermatitis, eczema, Sjögren's syndrome, including keratoconjunctivitis sicca secondary to Sjögren's syndrome, alopecia areata, allergic reactions due to arthropod stings, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may produce any one or more of the following symptoms or signs: itching, swelling, redness, blisters, crusting, ulceration, pain, scaling, cracking, hair loss, scarring, or exudation of fluid from the skin, eyes, or mucous membranes.

[0612] In atopic dermatitis and eczema, immune-mediated leukocyte infiltration into the skin (particularly infiltration of monocytes, lymphocytes, neutrophils, and eosinophils) generally plays an important role in the pathogenesis of these diseases. Chronic eczema is also associated with marked hyperproliferation of the epidermis. Immune-mediated leukocyte infiltration can also occur in sites other than the skin, such as the airways in asthma and the tear-producing glands of the eye in keratoconjunctivitis sicca.

[0613] The compounds described herein, or pharmaceutically acceptable salts, isotopic variants, or prodrugs thereof, can be used in an effective amount to treat a host, e.g., a human, having a skin disorder, such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, skin rash, skin irritation, or skin sensitization (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances, including some pharmaceuticals, can cause skin sensitization when applied topically. In some embodiments, skin disorders are treated by topical administration of art-known compounds in combination with compounds disclosed herein. In one non-limiting embodiment, the compounds of the present invention are used topically to treat contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's syndrome, including keratoconjunctivitis sicca secondary to Sjogren's syndrome, alopecia areata, allergic responses due to arthropod stings, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. This novel method may also be useful in reducing skin infiltration by malignant leukocytes in diseases such as mycosis fungoides.

[0614] Disease states or conditions that can be treated using the compounds of the present invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, cilia-related disorders, cleft palate, diabetes, heart disease, high blood pressure, 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 1 (PKD1) or 2 (PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, and Turner syndrome.

[0615] Further disease states or conditions that may be treated by the compounds according to the 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's syndrome, vasculitis.

[0616] Further additional disease states or conditions that can be treated by the compounds of the present invention include aceruloplasminemia, achondroplasia type II, achondroplasia, acrocephaly, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuric ochrodialysis, alpha 1-antitrypsin deficiency, alpha 1 proteinase inhibitor deficiency, emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, diffuse corporis Angioma, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, arachnodactyly (Marfan syndrome), Stickler syndrome, congenital multiple arthrochalasia (Ehlers-Danlos syndrome, multiple arthrochalasia type), ataxia-telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Behre-Stevenson gyriform scalp syndrome, familial Mediterranean fever, Benjamin syndrome, β-thalassemia, bilateral acoustic neurofibromatosis (neurofibromatosis type II), factor V Leiden 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, osteoporosis (osteogenesis imperfecta), broad hallux syndrome (Broad Thumb-Hallux syndrome) (Rubin Stein-Taybi syndrome), bronze diabetes mellitus / bronzed cirrhosis (He Mochromatosis), Spinal-bulbar muscular atrophy (Kennedy's disease), Buerger-Grütz syndrome (lipoprotein lipase deficiency), Chronic Granulomatous Disease (CGD), Flexor Limb Dysplasia, Biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Criss-Cat syndrome, Congenital Absence of the Vas Deferens (CAVD), Cailler Cardio-Facial Syndrome (CBAVD), Congenital Erythroblastic Porphyria (CEP), Saccular Cystic fibrosis, congenital hypothyroidism, achondroplasia syndrome (achondroplasia), otospondylomegaly epiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, lethal dysplasia, Coffin-Lowry syndrome, Cockayne syndrome (familial adenomatous polyposis), congenital erythroblastic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disease, conotruncal dysfacies syndrome, Cooley anemia (β-thalassemia), copper storage disease (Wilson's disease), copper transport disease Degenerative neurological disorders including Menkes disease, hereditary coproporphyria, Cowden syndrome, craniofacial joint abnormalities (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Behre-Stevenson gyriform scalp syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Strudwick type), Duchenne and Becker muscular dystrophy (DBMD), Usher syndrome, deGrouchy syndrome, and Dejerine-Sottas syndrome, developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse globoid body sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protoporphyria erythropoietic 5-aminolevulinic acid synthase deficiency, erythroblastic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia-familial paroxysmal polyserositis, late-onset dermatosis, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), pancreatic fibrous cyst, fragile X syndrome, galactosemia, hereditary encephalopathy, giant cell hepatitis (neonatal hemochromatosis), Glenblack syndrome Doe-Strandberry syndrome (pseudoxanthoma elasticum), Gunther's disease (congenital erythroblastic porphyria), hemochromatosis, Hallgren's syndrome, sickle cell anemia, hemophilia, hepatic erythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford-Progeria syndrome (progeria), hyperandrogenism, hypochondroplasia, hypochromic anemia,Immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney diseases including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia, patchy dementia, Langer-Sardino achondroplasia, 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-Lange disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyostotic fibrous dysplasia (McCune-Albright syndrome), Poi Tujeghers syndrome, Prader-Larbhardt-Willi syndrome, hemochromatosis, primary hyperuricemia (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), chronic hereditary progressive chorea (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type I), recurrent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Lucy-Lewy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia and adrenal gland leukemia, and adrenal gland) (SBLA) syndrome, tuberous sclerosis (tuberous sclerosis), SDAT, congenital SED (congenital spondyloephyseal dysplasia), Strudwickian SED (Strudwickian Spondyloepiphyseal Dysplasia), SEDc (Spondyloepiphyseal Dysplasia Congenita), Strudwickian SEMD (Strudwickian Spondyloepiphyseal Dysplasia), Shprintzen syndrome, skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (variegate porphyria), infantile-onset ascending porphyria Hereditary spastic paraparesis, speech and communication disorders, sphingolipidoses, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, sausage 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 (Alström syndrome), Frolik disease, Waardenburg syndrome, Warburg-Shaw-Fredelius syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disorder, Weissenbacher-Zweimüller syndrome, and xeroderma pigmentosum.

[0617] In one embodiment, a method of treating multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition. In another embodiment, a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, is used in a method of treating multiple myeloma, comprising administering the compound to a patient.

[0618] In one embodiment, a method of managing the progression of multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition. In another embodiment, a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, is used in a method of managing the progression of multiple myeloma, comprising administering the compound to a patient.

[0619] In one embodiment, there is provided a method for inducing a therapeutic response, as assessed by the International Uniform Response Criteria for Multiple Myeloma (IURC) (described in Durie BG M; et al. "International uniform response criteria for multiple myeloma. Leukemia 2006, 10(10):1-7), in a patient having multiple myeloma, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0620] In another embodiment, there is provided a method of achieving a stringent complete response, complete response, or very good partial response in a patient with multiple myeloma as assessed by the IURC for multiple myeloma, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0621] In another embodiment, a method for improving overall survival, progression-free survival, relapse-free survival, time to process or progression-free survival in a patient with multiple myeloma comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition. Methods for achieving prolonged disease survival are provided.

[0622] In another embodiment, there is provided a method of achieving increased overall survival in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0623] In another embodiment, there is provided a method of achieving prolonged progression-free survival in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0624] In another embodiment, there is provided a method of achieving prolonged relapse-free survival in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0625] In another embodiment, there is provided a method of achieving prolongation of time to progression in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0626] In another embodiment, there is provided a method of achieving prolonged disease-free survival in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0627] Methods for treating patients who have previously been treated for multiple myeloma but have not responded to standard therapy are also provided, in addition to previously untreated patients. Additional methods are provided for treating patients who have undergone surgery to treat multiple myeloma, in addition to patients who have not undergone surgery. Methods are also provided for treating patients who have previously undergone transplant therapy, in addition to patients who have not undergone transplant therapy.

[0628] The compounds described herein can be used to treat or manage relapsed, refractory, or resistant multiple myeloma. In some embodiments, the multiple myeloma is in first, second, third, fourth, or fifth relapse. In one embodiment, the compounds described herein can be used to reduce, maintain, or eliminate minimal residual disease (MRD).

[0629] Types of multiple myeloma that can be treated using the compounds described herein include, but are not limited to, monoclonal gammopathy of undetermined significance (MGUS), low-risk, intermediate-risk, or high-risk multiple myeloma, newly diagnosed multiple myeloma (including low-risk, intermediate-risk, or high-risk newly diagnosed multiple myeloma), 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.

[0630] In some embodiments, the compounds described herein can be used to treat or manage multiple myeloma characterized by genetic abnormalities, such as, but not limited to, cyclin D translocations (e.g., t(11;14)(q13;q32), t(6;14)(p21;32), t(12;14)(p13;q32), or t(6;20)), MMSET translocations (e.g., t(4;14)(p16;q32)), MAF translocations (e.g., t(14;16)(q32;a32), t(20;22), t(16;22)(q11;q13), or t(14;20)(q32;q11)), or other chromosomal elements (e.g., 17p13 or chromosome 13 deletions, del(17 / 17p), non-hyperdiploidy, and (1q) amplification).

[0631] In one embodiment, as induction therapy, optionally a pharmaceutically acceptable carrier to form a composition. Methods for treating or managing multiple myeloma are provided, comprising administering to a patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, in an acceptable carrier.

[0632] In one embodiment, there is provided a method of treating or managing 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 analog, or prodrug thereof, as consolidation therapy, optionally in a pharmaceutically acceptable carrier to form a composition.

[0633] In one embodiment, there is provided a method of treating or managing 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 analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, as a maintenance therapy.

[0634] In one embodiment, the multiple myeloma is plasma cell leukemia.

[0635] 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 has relapsed within 12 months of initial treatment. In another embodiment, the high-risk multiple myeloma is characterized by one or more genetic abnormalities, such as del(17 / 17p) and t(14;16)(q32;q32). In some embodiments, the high-risk multiple myeloma is relapsed or refractory to one, two, or three prior treatments.

[0636] In one embodiment, the multiple myeloma has a p53 mutation. In one embodiment, the p53 mutation is a Q331 mutation. In one embodiment, the p53 mutation is a R273H mutation. In one embodiment, the p53 mutation is a K132 mutation. In one embodiment, the p53 mutation is a K132N mutation. In one embodiment, the p53 mutation is a R337 mutation. In one embodiment, the p53 mutation is a R337L mutation. In one embodiment, the p53 mutation is a W146 mutation. In one embodiment, the p53 mutation is a S261 mutation. In one embodiment, the p53 mutation is a S261T mutation. In one embodiment, the p53 mutation is an E286 mutation. In one embodiment, the p53 mutation is an E286K mutation. In one embodiment, the p53 mutation is a R175 mutation. In one embodiment, the p53 mutation is a R175H mutation. In one embodiment, the p53 mutation is an E258 mutation. In one embodiment, the p53 mutation is an E258K mutation. In one embodiment, the p53 mutation is an A161 mutation. In one embodiment, the p53 mutation is an A161T mutation.

[0637] 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.

[0638] In one embodiment, the multiple myeloma exhibits activation of one or more oncogenic drivers. In one embodiment, the 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, the multiple myeloma exhibits activation of C-MAF. In one embodiment, the multiple myeloma exhibits activation of MAFB. In one embodiment, the multiple myeloma exhibits activation of FGFR3 and MMset. In one embodiment, the multiple myeloma exhibits activation of C-MAF, FGFR3, and MMset. In one embodiment, the multiple myeloma exhibits activation of cyclin D1. In one embodiment, the multiple myeloma exhibits activation of MAFB and cyclin D1. In one embodiment, the multiple myeloma exhibits cyclin D activation.

[0639] In one embodiment, the multiple myeloma has one or more chromosomal translocations. In one embodiment, the chromosomal translocation is t(14;16). In one embodiment, the chromosomal translocation is t(14;20). In one embodiment, the chromosomal translocation is t(4;14). In one embodiment, the chromosomal 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).

[0640] In one embodiment, the multiple myeloma has a Q331 p53 mutation, activated C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, the multiple myeloma has a homozygous deletion of p53, activated C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, the multiple myeloma has a K132N p53 mutation, activated MAFB, and a chromosomal translocation at t(14;20). In one embodiment, the multiple myeloma has wild-type p53, activated FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, the multiple myeloma has wild-type p53, activated C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, the multiple myeloma has a homozygous deletion of p53, activation of FGFR3, MMset, and C-MAF, and a chromosomal translocation at t(4;14) and t(14;16). In one embodiment, the multiple myeloma has a homozygous deletion of p53, activation of cyclin D1, and a chromosomal translocation at t(11;14). In one embodiment, the multiple myeloma has a R337L p53 mutation, activation of cyclin D1, and a chromosomal translocation at t(11;14). In one embodiment, the multiple myeloma has a W146 p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, the multiple myeloma has a S261T p53 mutation, activation of MAFB, and a chromosomal translocation at t(6;20) and t(20;22). In one embodiment, the multiple myeloma has an E286K p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, the multiple myeloma has a R175H p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, the multiple myeloma has an E258K p53 mutation, activation of C-MAF, and a chromosomal translocation at t(14;16) and t(16;22). In one embodiment, the multiple myeloma has wild-type p53, activation of MAFB and cyclin D1, and a chromosomal translocation at t(14;20) and t(11;14).In one embodiment, the multiple myeloma has an A161T p53 mutation, activated cyclin D, and a chromosomal translocation at t(11;14).

[0641] In some embodiments, the multiple myeloma is transplant-eligible newly diagnosed multiple myeloma. In other embodiments, the multiple myeloma is transplant-ineligible newly diagnosed multiple myeloma.

[0642] In some embodiments, the multiple myeloma shows early progression (e.g., less than 12 months) after initial treatment. In other embodiments, the multiple myeloma shows early progression (e.g., less than 12 months) after autologous stem cell transplant. In another embodiment, the multiple myeloma is refractory to lenalidomide. In another embodiment, the multiple myeloma is refractory to pomalidomide. In some such embodiments, the multiple myeloma is predicted to be refractory to pomalidomide (e.g., by molecular characterization). In another embodiment, The multiple myeloma is relapsed or refractory to three or more lines of therapy and has been exposed to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib) and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iveldomide, or avadomide), or is dual refractory to a proteasome inhibitor and an immunomodulatory compound. In yet other embodiments, the multiple myeloma is relapsed or refractory to three or more prior therapies, including, for example, a CD38 monoclonal antibody (CD38 mAb, e.g., daratumumab or isatuximab), a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iveldomide, or avadomide), or is dual refractory to a proteasome inhibitor or immunomodulatory compound and a CD38 mAb. In yet other embodiments, the multiple myeloma is triple refractory, for example, the multiple myeloma is refractory to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib), an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iveldomide, or avadomide), and another active agent described herein.

[0643] In one embodiment, there is provided a method for treating or managing relapsed or refractory multiple myeloma in a patient with impaired renal function or symptoms thereof, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0644] In another embodiment, a method of treating or managing relapsed or refractory multiple myeloma in a frail patient is provided, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, wherein the frail patient is characterized by non-compliance with induction therapy or intolerance to dexamethasone treatment. In other embodiments, the frail patient is elderly, e.g., over 65 years of age.

[0645] In another embodiment, a method for treating fourth line recurrent or refractory rheumatoid arthritis comprises administering to a patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition. Methods for treating or managing curable multiple myeloma are provided.

[0646] In another embodiment, there is provided a method of treating or managing newly diagnosed transplant-ineligible 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 analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0647] In another embodiment, there is provided a method of treating or managing newly diagnosed, transplant-ineligible multiple myeloma, comprising administering to a patient, as an alternative therapy or post-transplant maintenance therapy, an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0648] In another embodiment, there is provided a method of treating or managing high-risk multiple myeloma that is relapsed or refractory to one, two, or three prior treatments, comprising administering to a patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0649] In some embodiments, the patient to be treated with one of the compounds described herein has not been treated with a multiple myeloma therapy prior to administration. A patient being treated with one of the compounds described herein has been treated with a multiple myeloma therapy prior to administration. In some embodiments, a patient being treated with one of the compounds described herein has developed drug resistance to the multiple myeloma therapy. In some embodiments, a patient being treated with one of the compounds described herein has developed resistance to one, two, or three multiple myeloma therapies, the therapies being selected from a CD38 antibody (CD38 mAb, e.g., daratumumab or isatuximab), a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iveldomide, or avadomide).

[0650] The compounds described herein can be used to treat patients regardless of their age. In some embodiments, the subject is 18 years of age or older. In other embodiments, the subject is over 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years of age. In other embodiments, the patient is under 65 years of age. In other embodiments, the patient is over 65 years of age. In one embodiment, the patient is an elderly multiple myeloma patient, e.g., a patient over 65 years of age. In one embodiment, the patient is an elderly multiple myeloma patient, e.g., a patient over 75 years of age.

[0651] IV. Combination Therapy 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.

[0652] The terms "bioactive agent" or "additional therapeutically active agent" are used to describe agents other than a compound according to the present invention that can be used in combination or alternation with a compound of the present invention to achieve a desired outcome of therapy. In one embodiment, a compound of the present invention and an additional therapeutically active agent are administered such that they are active in vivo during an overlapping period, e.g., their Cmax, Tmax, AUC, or other pharmacokinetic parameters overlap. In another embodiment, a compound of the present invention and an additional therapeutically active agent that do not have overlapping pharmacokinetic parameters, but one of which has a therapeutic impact on the therapeutic efficacy of the other, are administered to a host in need thereof.

[0653] In one aspect of this embodiment, the additional therapeutically active agent is a checkpoint inhibitor, including, by way of non-limiting example, a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a CTLA-4 inhibitor, a LAG-3 inhibitor, a TIM-3 inhibitor, a V-domain Ig suppressor of T-cell activation (VISTA) inhibitor, a small molecule In certain embodiments, the immunomodulator is an antibody, such as a monoclonal antibody.

[0654] PD-1 inhibitors that bind to the PD-1 receptor, blocking the interaction between PD-1 and PD-L1, and inhibiting immunosuppression include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, and AMP-224 (AstraZeneca and PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro) and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors that bind to the PD-L1 receptor, blocking the interaction between PD-1 and PD-L1 and inhibiting immunosuppression, include, for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and Medimmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibit immunosuppression include ipilimumab and 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.

[0655] 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.

[0656] In one embodiment, the checkpoint inhibitor is an OX40 agonist. In one embodiment, the checkpoint inhibitor is an anti-OX40 antibody, e.g., anti-OX40 or MEDI6469.

[0657] In one embodiment, the checkpoint inhibitor is a GITR agonist. In one embodiment, the GITR agonist is an anti-GITR antibody, such as TRX518.

[0658] 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.

[0659] In one embodiment, the checkpoint inhibitor is a CD40 agonist. In one embodiment, the CD40 agonist is an anti-CD40 antibody, such as CF-870893.

[0660] In one embodiment, the checkpoint inhibitor is an IDO inhibitor, such as INCB24360 or indoximod.

[0661] In another embodiment, the active compounds described herein can be administered in effective amounts in combination or alternation with an effective amount of an androgen (e.g., testosterone) inhibitor, including, but not limited to, a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist, for the treatment of abnormal tissues of the male reproductive system, such as prostate cancer or testicular cancer. In one embodiment, the prostate or testicular cancer is androgen-resistant. Non-limiting examples of antiandrogenic compounds are provided in WO 2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of antiandrogenic compounds include enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topirutamide, abiraterone acetate, and cimetidine.

[0662] In one embodiment, the additional therapeutically active agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib, alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113.

[0663] In one embodiment, the additional therapeutically active agent is an EGFR inhibitor. Examples include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso), olmutinib (Olita), nacotinib (ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL 647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer).

[0664] In one embodiment, the additional therapeutically active agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.

[0665] In one embodiment, the additional therapeutically active agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, ofatumumab, ibritumomab, tositumomab, and ocrelizumab.

[0666] In one embodiment, the additional therapeutically active agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib.

[0667] In one embodiment, the additional therapeutically active agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), and venetoclax (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl). [4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl]-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trimethylamino)-4-pyridin-1-yl)-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263 ((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trimethylamino)-4-pyridin-1-yl)-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), Fluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (Ovatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole; methanesulfonic acid)), 2-Methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), Pogosin, Ethyl 2- amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-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).

[0668] In one embodiment, the additional therapeutically active agent is a kinase inhibitor. In one embodiment, the kinase inhibitor is a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or A combination thereof is selected.

[0669] Examples of PI3 kinase inhibitors include wortmannin, demethoxyviridin, perifosine, idelalisib, pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS- 9820, BKM120, GDC-0032 (taselisib), (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-phenoxy-2-butanyl hydrogen (S)-methylphosphonate; or methyl(oxo) {[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridyl diphenyl}benzenesulfonamide) (omipalisib), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ( (R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-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]quinaz), AS 252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), buparlisib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(1H-indazol-4-yl)-6-[ [4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (RG7422 and also known as 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- oate), 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) (gedatricib), 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(, dactolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide) and GSK1059615 (5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione), PX886 ([(3aR, 6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-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 sonolicib) ), LY294002, AZD8186, PF-4989216, piraralisib, GNE-317, PI-3065, PI-103, NU7441 (KU- 57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib (GDC-0980; RG7422), and structures described in WO 2014 / 071109.

[0670] Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica™) (1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), dianilinopyrimidine inhibitors such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics (see U.S. Patent Application 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)propenamide), GDC-0834 (RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746 (4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(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-methylpicolinamide), 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), dolobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-( 2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one) and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one), as well as other molecules capable of inhibiting BTK activity, such as Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59, which is incorporated herein by reference in its entirety.

[0671] 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 (sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide), 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) 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]oxazin-3(4H)-one), piceatannol (3-hydroxyresveratrol), YM193306 (See Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643). Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety), Compound D (Singh et al. See, Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety). See references herein for details), PRT060318 (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein by reference), luteolin (Singh et al. 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 (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 (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 (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 (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety), and morin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety).

[0672] In one embodiment, the additional therapeutically active agent is a MEK inhibitor. MEK inhibitors are known, such as 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 / MSC 1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-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) 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]-benzamide), ]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655(3,Examples of such compounds include 4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2hydroxyethoxy)-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-733, and PD318088.

[0673] In one embodiment, the additional therapeutically active agent is a Raf inhibitor. Raf inhibitors are known, such as vemurafenib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide; 4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl)phenyl]benzamide]), methyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-bromoardisine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), sorafenib N-oxide ( 4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (encorafenib).

[0674] In one embodiment, the additional therapeutically active agent is an AKT inhibitor, including but not limited to MK-2206, GSK690693, perifosine (KRX-0401), GDC-0068, triciribine, AZD5363, honokiol, PF-04691502, and miltefosine, an FLT-3 inhibitor, including but not limited to P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tanzutinib (MLN518), ENMD-2076, and KW-2449, or a combination thereof.

[0675] In one embodiment, the additional therapeutically active agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus. Examples of MEK inhibitors include trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]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), and XL-518 / GD C-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) (4-bromo-2-fluorophenyl)amino)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-ylamino)

[0033] Examples of compounds that may be used include, but are not limited to, 2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2-yl)methyl)benzamide), 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).

[0676] In one embodiment, the additional therapeutically active agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER.

[0677] In one embodiment, the additional therapeutically active agent is an HSP inhibitor, including but not limited to geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG), and radicicol.

[0678] Additional biologically active compounds include, for example, everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, Aurora kinase inhibitors, PIK-1 modulators, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, focal adhesion kinase inhibitors, Map kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edoteca Phosphorus, tetrandrine, rubitecan, tesmilifene, oblimersen , ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanton, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, 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, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxycaproate Roxiprogesterone, 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, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid acid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyprotease ron, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate Cetirizine, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine, en Dostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, ido Idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, Pak Ritaxel, Paclitaxel without Cremophor, Docetaxel, Epothilone B, BMS-247550, BMS-310705, Droloxifene, 4-Hydroxytamoxifen, Pipendoxifene, ERA-923, Arzoxifene, Fulvestrant, Acolbifene, Lasofoxifene, Idoxifene, TSE-424, HMR-3339, ZK186619, Topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin , erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone steroids, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulins, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol These include dol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0679] In one embodiment, the additional therapeutically active agent is imatinib mesylate (Gleevac™), dasatinib (Sprycel™), nilotinib (Tasigna™), bosutinib (Bosulif™), trastuzumab (Herceptin™), trastuzumab-DM1, pertuzumab (Perjeta™), lapatinib (Tykerb™), gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), panitumumab (Vectibix™), vandetanib (Caprelsa™), vemurafenib (Zelboraf™), vorinostat (Zoli). nza™), romidepsin (Istodax™), bexarotene (Tagretin™), alitretinoin (Panretin™), tretinoin (Vesanoid™), carfilzomib (Kyprolis™), pralatrexate (Folotyn™), bevacizumab (Avastin™), Ziv-aflibercept (Zaltrap™), sorafenib (Nexavar™), sunitinib (Sutent™), pazopanib (Votrient™), regorafenib (Stivarga™), and cabozantinib (Cometriq™).

[0680] In certain embodiments, the additional therapeutically active agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an additional therapeutic agent, or an immunosuppressant agent.

[0681] Suitable chemotherapy additional therapeutically active agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic drugs, any agent detrimental to cell viability, and liposomes or other vesicles containing chemotherapeutic compounds. Common anti-cancer drugs include vincristine (Oncovin™) or liposomal vincristine (Marqibo™), daunorubicin (daunomycin or Cerubidine™) or doxorubicin (Adriamycin™), cytarabine (cytosine arabinoside, ara-C or Cytosar™), L-asparaginase (Elspar™) or PEG-L-asparaginase (peguaspargase or Oncaspar™), etho These include fluticasone (VP-16), teniposide (Vumon™), 6-mercaptopurine (6-MP or Purinethol™), methotrexate, cyclophosphamide (Cytoxan™), prednisone, dexamethasone (Decadron), imatinib (Gleevec™), dasatinib (Sprycel™), nilotinib (Tasigna™), bosutinib (Bosulif™), and ponatinib (Iclusig™).Examples of additional suitable chemotherapeutic agents include 1-dehydrotestosterone, 5-fluorouracil, dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC), antimitotic agents, cis-dichlorodiamineplatinum(II) (DDP) (cisplatin), diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, live BCG bacteria (BCG), live) (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, leucovorin calcium, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, cyclothosphamide, and cytarabi. cytarabine, cytochalasin B, cytoxan, dacarbazine, dactinomycin, dactinomycin (formerly actinomycin), daunorubicin HCl, daunorubicin citrate, denileukin diftitox, dexrazoxane, dibromomannitol, dihydroxy anthracin dione, docetaxel, docetaxel mesylate Racetron, doxorubicin HCl, dronabinol, Escherichia coli (E. coli) L-asparagus ginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine sodium phosphate, ethidium bromide, ethinyl estradiol, etidronate, etoposide, citrovorum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCl, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCl, hydroxyurea, idarubicin HCl, ifosfamide, interferon α-2b, irinotecan HCl, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCl, lidocaine, lomustine, maytansinoids, mechlorethamine HCl, medroxyprogesterone acetate, megestrol acetate, melphalan HCl, mercaptopurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCl, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCl, primycin, porfimer sodium, procaine, procarbazine HCl, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa chlorambucil chlorambucil), thioguanine, thiotepa, topotecan HCl, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0682] Additional therapeutic agents that can be administered in combination with the degrading agents disclosed herein include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol, The drugs include 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DM1, and atiplosin. Remod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinstat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, These include talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), abemaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

[0683] In one embodiment, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Like antibodies naturally produced by B cells, these MAbs can "coat" the surface of cancer cells and induce their destruction by the immune system. For example, bevacizumab 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 VEGF binds to bevacizumab, it is unable to interact with its cell receptor, preventing signaling that leads to new blood vessel growth. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the target receptor from sending normal growth-promoting signals. They may also induce apoptosis and activate the immune system to destroy tumor cells.

[0684] In one embodiment of the invention, the additional therapeutically active agent is an immunosuppressant. Immunosuppressants include calcineurin inhibitors such as cyclosporine or ascomycin, e.g., cyclosporine A (NEORAL™), FK506 (tacrolimus), pimecrolimus, mTOR inhibitors such as rapamycin or its derivatives, e.g., sirolimus (RAPAMUNE™), everolimus (Certican™), temsirolimus, zotarolimus, biolimus-7, biolimus-9, rapalogs such as ridaforolimus, azathioprine, campath 1H, S1P receptor modulators such as fingolimod or analogs thereof, anti-IL-8 antibodies, mycophenolic acid or a salt thereof, e.g., the sodium salt or a prodrug thereof, e.g., mycophenolate mofetil (CELLCEPT™), OKT3 (ORTHOCLONE OKT3™), prednisone, ATGAM™, THYMOGLOBULIN™, brequinar sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, leflunomide (ARAVA™), CTLAI-Ig, anti-CD25, anti IL2R, basiliximab (SIMULECT™), daclizumab (ZENAPAX™), mizoribine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel™), CTLA4Ig (abatacept), belatacept, LFA3Ig, etanercept (Enb by Immunex) rel™), adalimumab (Humira™), infliximab (Remicade™), anti-LFA-1 antibody, natalizumab (Antegren™), enlimomab, gavilimomab, anti-thymocyte immunoglobulin G (anti-thymocyte globulin G), It can be burin, siplizumab, alefacept, efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen.

[0685] 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, e.g., ixazomib or oprozomib. In one embodiment, the additional therapy is a histone deacetylase inhibitor, e.g., 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, BI 894999, 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-(methanesulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one, EP11313, and EP11336. In one embodiment, the additional therapy is an MCL-1 inhibitor, e.g., AZD5991, AMG176, MIK665, S64315, or S63845. In one embodiment, the additional therapy is an LSD-1 inhibitor, e.g., ORY-1001, ORY-2001, INCB-59872, IMG-7289, TAK-418, GSK-2879552, 4-[2-(4-amino-piperidin-1-yl)-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydro pyrimidin-4-yl]-2-fluoro-benzonitrile or a salt thereof. In one embodiment, the additional therapy is a CS1 antibody, e.g., elotuzumab. In one embodiment, the additional therapy is a CD38 antibody, e.g., daratumumab or isatuximab. In one embodiment, the additional therapy is a BCMA antibody or antibody conjugate, e.g., GSK2857916 or BI 836909.

[0686] In some embodiments, the degrading agents described herein are administered in combination or alternation with one or more cellular immunotherapies. In some embodiments, the cellular immunotherapies are engineered immune cells. Engineered immune cells include, but are not limited to, engineered T cell receptor (TCR) cells and engineered chimeric antigen receptor (CAR) cells. Engineered T cell receptor (TCR) therapy generally involves the introduction of an engineered T cell receptor targeting a specific cancer antigen into immune effector cells, such as T cells or natural killer cells, derived from a patient or donor. Alternatively, chimeric antigen receptor (CAR) therapy generally involves the introduction of a chimeric antigen receptor targeting a specific cancer antigen into immune effector cells, such as T cells, natural killer cells, or macrophages, derived from a patient or donor. One important advantage of CARs compared to TCRs is their ability to bind to cancer cells even when those antigens are not presented on the surface by MHC, potentially making the cancer cells more susceptible to attack. However, CAR cells can only recognize antigens that are naturally expressed on the cell surface, and the range of potential antigen targets is smaller than that of TCRs.

[0687] In some embodiments, the immunotherapy is an engineered TCR or CAR immune cell, wherein the TCR or CAR is an engineered TCR or CAR that is capable of expressing any of the following: BCMA, an important signaling receptor naturally found on mature B cells and often expressed by lymphoma and myeloma cells; CD19, a receptor found on the surface of nearly all B cells that influences their growth, development, and activity and is often expressed by leukemia, lymphoma, and myeloma cells; CD22, a receptor found primarily on the surface of mature B cells and often expressed by leukemia and lymphoma cells; CD30, a receptor expressed on certain types of activated immune cells and often 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 often expressed by leukemia and lymphoma cells; CEA, a protein that is often overexpressed and may contribute to metastasis; EBV-associated antigen, a foreign viral protein expressed by Epstein-Barr virus (EBV)-infected cancer cells; EGFR, a pathway that controls cell growth and is often mutated in cancer; GD2, a pathway that controls cell growth, adhesion, and migration and is often aberrantly 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 commonly overexpressed in some cancers, particularly breast cancers, and associated with metastasis; HPV-associated antigen, a foreign viral protein expressed by cancer cells that develop as a result of infection with the human papillomavirus (HPV); MAGE antigens (the genes that produce these proteins are normally turned off in adult cells but can be reactivated in cancer cells, flagging them as abnormal to the immune system); mesothelin, a protein that is commonly overexpressed in cancer and may aid in metastasis; MUC-1, a glycocoat protein that is commonly overexpressed in cancer;NY-ESO-1, a protein that is often aberrantly expressed in cancer; PSCA, a surface protein found on several cell types and often overexpressed by cancer cells; PSMA, a surface protein found on prostate cells and often overexpressed by prostate cancer cells; ROR1, a tyrosine kinase-like orphan receptor that is primarily expressed in prenatal rather than adult tissues but is often aberrantly expressed in cancer and may promote cancer cell metastasis and prevent cancer cell death; The modified CAR therapy targets one or more tumor-associated antigens selected from WT1, a protein that promotes progression of cancer and is aberrantly expressed in patients with cancer, particularly leukemia, and Claudin 18.2, a surface protein that is overexpressed in some esophageal cancers and is involved in invasion and survival. In some embodiments, the modified CAR therapy is axicabtagene ciloreucel (Yescarta™), a CD19-targeted CAR T-cell immunotherapy approved for a subset of patients with lymphoma. In some embodiments, the modified CAR therapy is tisagenlecleucel (Kymriah™), a CD19-targeted CAR T-cell immunotherapy approved for a subset of patients with leukemia and lymphoma. In some embodiments, the modified CAR therapy is lisocabtagene malareucel (Bristol-Myers Squibb Co.), a CD19-targeted CAR T-cell immunotherapy used to treat relapsed / refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL). In some embodiments, the modified CAR therapy is a BCMA CAR-T therapy, such as, but not limited to, JNJ-4528 (Johnson & Johnson) and KITE-585 (Gilead). The CAR-T therapy is a bispecific CAR-T that targets BCMA and CD38. In some embodiments, the engineered CAR therapy is a CD20 / CD22 dual-targeted CAR-T cell therapy. Compositions and methods for inducing CAR immune cells are described, for example, in U.S. Pat. No. 5,359,046 (Cell Genesys), U.S. Pat. No. 5,712,149 (Cell Genesys), U.S. Pat. No. 6,103,521 (Cell Genesys), U.S. Pat. No. 7,446,190 (Memorial Sloan Kettering Cancer Center), U.S. Pat. No. 7,446,179 (City of Hope), U.S. Pat. No. 7,638,325 (University of Pennsylvania), U.S. Pat. No. 8,911,993 (University of Pennsylvania), U.S. Pat. No. 8,399,645 (St. Jude's Children's Hospital), U.S. Patent No. 8,906,682 (University of Pennsylvania), U.S. Patent No. 8,916,381 (University of Pennsylvania), U.S. Patent No. 8,975,071 (University of Pennsylvania), U.S. Patent No. 9,102,760 (University of Pennsylvania), U.S. Patent No. 9,4644 (University of Pennsylvania), U.S. Patent No. 9,855,298 (Gilead), U.S. Patent No. 10,144,770 (St. Jude Children's Hospital), U.S. Patent No. 10,266,580 (University of Pennsylvania), U.S. Patent No. 10,189,903 (Seattle Children's Hospital), International Publication No. 2014 / 011988 ( University of Pennsylvania), WO 2014 / 145252, WO 2014 / 153270 (Novartis AG), U.S. Patent Application Publication No. 2018 / 0360880 (Memorial Sloan Kettering Cancer Center), WO 2017 / 0243 (Dana-Farber and WO 2016 / 115177 (Juno Therapeutics, Inc.), each of which is incorporated herein by reference.

[0688] In some embodiments, the immunotherapy is unmodified adoptive cell therapy. Adoptive cell therapy is an approach used to enhance the immune system's ability to fight diseases such as tumors and viral infections. According to this approach, immune cells, such as T cells or NK cells, are collected from a patient or donor, stimulated in the presence of antigen-presenting cells bearing tumor- or virus-associated antigens, and then expanded ex vivo. In some embodiments, the adoptive cell therapy is tumor-infiltrating lymphocyte (TIL) therapy, in which natural T cells that have already infiltrated a patient's tumor are harvested, activated, expanded, and then reinfused back into the patient. In some embodiments, unmodified adoptive cell therapy involves autologous or allogeneic immune cells, such as αβ T cells, activated to target multiple potential antigens. One strategy used to generate targeted unmodified T cells involves ex vivo expansion of T cells by antigen-specific stimulation of patient-derived (autologous) or donor-derived (allogeneic) T cells ex vivo. These strategies generally involve isolation of peripheral blood mononuclear cells (PBMCs) and exposure of the cells to one or more tumor-associated antigens. In particular, an approach to generate multi-antigen-specific T cells involves priming and activating T cells using multiple target antigen overlapping peptide libraries, e.g., multiple libraries of 15-mer peptides that overlap by 11 amino acids across 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 for targeting tumor-associated antigens have been described, for example, in U.S. Patent Application Publication No. 2011 / 0182870 (Baylor College of Medicine), U.S. Patent Application Publication No. 2015 / 0010519 (Baylor College of Medicine), U.S. Patent Application Publication No. 2015 / 0017723 (Baylor College of Medicine), WO 2006026746 (U.S. Department of Health and Human Services), U.S. Patent Application Publication No. 2015 / 0044258 (Cell Medica / Kurr Therapeutics), WO 2016 / 154112 (Children's National Medical Center), WO 2017 / 203356 (Queensland Institute of Medical Research), WO 2018 / 005712 (Geneius Biotechnology, Inc.), Vera et al. al. Accelerated Production of Antigen-Specific T Cells for Pre-clinical and Clinical Applications using Gas-permeable Rapid Expansion Cultureware (G-Rex), April 2010 Journal of Immunotherapy 33(3):305-315, Shafer et al. Antigen-specific Cytotoxic T Lymphocytes can Target Chemoresistant Side-Population Tumor Cells in Hodgkin's Lymphoma; May 2010 Leukemia Lymphoma 51(5): 870-880, Quintarelli et al. High Avidity Cytotoxic T Lymphocytes Specific for a New PRAME-derived Peptide can Target Leukemic and Leukemic-precursor 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-associated Malignancies, January 2013 Immunotherapy 36(1): 66-76、Weber et al. Generation of tumor antigen-specific T cell lines from pediatric patients with acute lymphoblastic leukemia - implications for immunotherapy, Clinical Cancer Research 2013 September 15; 19(18): 5079-5091, and Ngo et al. Complementation of antigen-presenting cells to generate T lymphocytes with broad target specificity, Journal of Immunotherapy. 2014 May; 37(4): 193-203, each of which is incorporated herein by reference. In some embodiments, the unmodified activated immune cells administered in combination or alternation with the degradation-inducing drug 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 a combination thereof. In some embodiments, the adoptive cell therapy is a composition comprising CD4+ T cells (T helper cells). In some embodiments, the adoptive cell therapy is a composition comprising CD8+ T cells (cytotoxic T lymphocytes). In some embodiments, the adoptive cell therapy is a composition comprising CD3+ / CD56+ natural killer T cells (CD3+NKT). In some embodiments, the 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).

[0689] In some embodiments, the immunotherapy is a bispecific T cell engager (BiTE). Bispecific T cell engagers induce T cells to target and bind to specific antigens on the surface of cancer cells. For example, the BiTE blinatumomab (Amgen) is ) was recently approved as second-line therapy in Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. Blinatumomab is given by continuous intravenous infusion in 4-week cycles.

[0690] In certain embodiments, the additional therapeutically active agent is an additional inhibitor of Ikaros ("IKZF1") and / or Aiolos ("IKZF3"). In another embodiment, the additional therapeutically active agent is an inhibitor of Helios ("IKZF2"). In one embodiment, the additional therapeutically active agent is an inhibitor of Eos ("IKZF4"). In another embodiment, the additional therapeutically active agent is an inhibitor of Pegasus ("IKZF5"). In another embodiment, the additional therapeutically active agent is a cereblon ligand.

[0691] Non-limiting examples of cereblon ligands that can be used in combination with the compounds of the present invention include thalidomide, lenalidomide, pomalidomide, and iverdomide.

[0692] In another embodiment, the additional compound that can be used in combination with the compound of the invention is selected from the compounds described in WO 2012 / 175481, WO 2015 / 085172, WO 2015 / 085172, WO 2017 / 067530, WO 2017 / 121388, WO 2017 / 201069, WO 2018 / 108147, WO 2018 / 118947, WO 2019 / 038717, WO 2019 / 191112, WO 2020 / 006233, WO 2020 / 006265 or WO 2020 / 012334.

[0693] In another embodiment, the additional compound that can be used in combination with the compound of the invention is selected from the compounds described in WO 2019 / 060693, WO 2019 / 060742, WO 2019 / 133531, WO 2019 / 140380, WO 2019 / 140387, WO 2010 / 010177, WO 2020 / 010210 or WO 2020 / 010227.

[0694] In another embodiment, additional compounds that can be used in combination with the compounds of the present invention are those described in WO 2015 / 160845, WO 2016 / 118666, WO 2016 / 149668, WO 2016 / 197032, WO 2016 / 197114, WO 2017 / 011371, WO 2017 / 0115901, WO 2017 / 030814, WO 2017 / 176708, WO 2018 / 053354, WO 2018 / 0716060, WO 2018 / 102067, WO 2018 / 102068, WO 2018 / 102069, WO 2018 / 102070, WO 2018 / 102081, WO 2018 / 102082, WO 2018 / 102083, WO 2018 / 102084, WO 2018 / 102085, WO 2018 / 102086, WO 2018 / 102087, WO 2018 / 102088, WO 2018 / 102089 ...1, WO 2018 / 102082, WO 2018 / 102084, WO 2018 / 102085, WO 2018 / 102086, WO 201 The compound is selected from the compounds described in International Publication No. 2018 / 118598, International Publication No. 2018 / 119357, International Publication No. 2018 / 119441, International Publication No. 2018 / 119448, International Publication No. 2018 / 140809, International Publication No. 2018 / 226542, International Publication No. 2019 / 023553, International Publication No. 2019 / 099926, International Publication No. 2019 / 195201, International Publication No. 2019 / 195609, International Publication No. 2019 / 199816, International Publication No. 2020 / 023851, International Publication No. 2020 / 041331 or International Publication No. 2020 / 051564.

[0695] In another embodiment, additional compounds that can be used in combination with the compounds of the present invention are those described in WO 2016 / 105518, WO 2017 / 007612, WO 2017 / 024317, WO 2017 / 024318, WO 2017 / 024319, WO 2017 / 117473, WO 2017 / 117474, WO 2017 / 185036, WO 2018 / 064589, WO 2018 / 148 440, WO 2018 / 148443, WO 2018 / 226978, WO 2019 / 014429, WO 2019 / 079701, WO 2019 / 094718, WO 2019 / 094955, WO 2019 / 118893, WO 2019 / 165229, Patent Document 25, WO 2020 / 018788, WO 2020 / 069105, WO 2020 / 069117 or WO 2020 The compound is selected from the compounds described in US Pat. No. 6,912,555.

[0696] In another embodiment, additional compounds that can be used in combination with the compounds of the present invention are those described in WO 2017 / 197036, WO 2017 / 197046, WO 2017 / 197051, WO 2017 / 197055, WO 2017 / 197056, WO 2017 / 115218, WO 2018 / 2201 49, WO 2018 / 237026, WO 2019 / 099868, WO 2019 / 121562, WO 2019 / 149922, WO 2019 / 191112, WO 2019 / 204354, WO 2019 / 236483 or WO 2020 / 051235.

[0697] V. Pharmaceutical Compositions Any of the compounds disclosed herein can be administered as the neat chemical, but are more typically administered as a pharmaceutical composition containing an effective amount to a host, typically a human, in need of such treatment for any of the disorders described herein. Accordingly, the present disclosure provides pharmaceutical compositions comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, for any of the uses described herein. The pharmaceutical composition may contain only the compound or salt as the active agent, or in alternative embodiments, the compound and at least one additional active agent.

[0698] In certain embodiments, the pharmaceutical composition is in a dosage form containing about 0.0005 mg to about 2000 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 600 mg, or about 0.001 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 100 mg, 200 mg, or 300 mg of active compound. In another embodiment, the pharmaceutical composition is in a dosage form containing about 0.01 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, or 100 mg, about 0.05 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, or 100 mg, about 0.1 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 50 mg, about 0.02 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 50 mg, or about 0.5 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 50 mg of active compound. In another embodiment, the pharmaceutical composition is a dosage form containing about 0.01 mg to about 10 mg, about 0.05 mg to about 8 mg, or about 0.05 mg to about 6 mg, or about 0.05 mg to about 5 mg of active compound. In another embodiment, the pharmaceutical composition is a dosage form containing about 0.1 mg to about 10 mg, about 0.5 mg to about 8 mg, or about 0.5 mg to about 6 mg, or about 0.5 mg to about 5 mg of active compound. Non-limiting examples include dosage forms containing 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, 700 mg, or 750 mg of active compound or a salt thereof. Alternative non-limiting examples are dosage forms containing up to 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, 700 mg, or 750 mg of active compound or a salt thereof.

[0699] Pharmaceutical compositions may also include a molar ratio of the active compound and the additional therapeutically active agent. In non-limiting exemplary embodiments, the pharmaceutical composition may contain a molar ratio of the anti-inflammatory or immunosuppressant to the compound of the present invention of at most about 0.5:1, at most about 1:1, at most about 2:1, at most about 3:1, or at most about 1.5:1 to at most about 4:1. The compounds disclosed herein can be administered orally, topically, parenterally, by inhalation or spray, sublingually, by implant, including ocular implant, transdermally, buccally, rectally, by eye drops, or as a steroid or anti-inflammatory agent. Injectables, including intraocular injections, can be administered intravenously, intraaortally, intracranially, subdermally, intraperitoneally, subcutaneously, nasally, sublingually, rectally, or by other means in dosage unit formulations containing conventional pharmaceutically acceptable carriers. For intraocular delivery, the compounds can be administered, for example, by intravitreal, intrastromal, intracameral, sub-Tenon, subretinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, periclinal, or lacrimal injection, as desired, or in an immediate or controlled release manner via a mucus, mucin, or mucosal barrier, or by an intraocular device.

[0700] The pharmaceutical compositions can be formulated as any pharmaceutically useful form, such as an aerosol, cream, gel, pill, injection or infusion solution, capsule, tablet, syrup, transdermal patch, subcutaneous patch, dry powder, inhalation formulation in a medical device, suppository, buccal or sublingual formulation, parenteral formulation, or eye drops. Some dosage forms, such as tablets and capsules, are divided into suitably sized unit doses containing an appropriate amount of the active ingredient, e.g., an effective amount to achieve a desired purpose.

[0701] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to the patient being treated. Carriers may be inert or may have their own medicinal properties. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound.

[0702] Types of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be classified into more than one category; for example, vegetable oils may be used as lubricants in some formulations and as diluents in other formulations. A pharmaceutically acceptable carrier is one that does not cause any significant adverse reactions in the human body when administered in the amounts used in the corresponding pharmaceutical composition. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Any active agent that does not substantially interfere with the activity of the compound of the present invention may be included in the pharmaceutical composition.

[0703] Pharmaceutical compositions / combinations can be formulated for oral administration. These compositions can contain any amount of the active compound that achieves the desired results, for example, 0.1% to 99% by weight (wt.%) of the compound (e.g., containing at least about 5% by weight of the compound). Some embodiments contain about 25% to about 50% by weight or about 5% to about 75% by weight of the compound.

[0704] Formulations suitable for rectal administration are typically presented as unit-dose suppositories, which may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[0705] Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers that can be used include petrolatum, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.

[0706] Formulations suitable for transdermal administration can be provided as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)), and typically take the form of an optionally buffered aqueous solution of the active compound. In one embodiment, a microneedle patch or device is applied across biological tissue, particularly the skin. Microneedle patches or devices are provided for the delivery of drugs across or into the skin or other tissue barriers at clinically relevant rates with little or no damage, pain, or irritation to the tissue.

[0707] Formulations suitable for pulmonary administration can be delivered by a wide range of passively and actively powered single / multiple dose dry powder inhalers (DPIs). The most commonly used devices for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of a suitable pulmonary delivery device depends on parameters such as the properties of the drug and its formulation, the site of action, and the pathophysiology of the lungs.

[0708] Many methods and devices for drug delivery are known in the art. Non-limiting examples are described in the following patents and patent applications, which are incorporated herein by reference in their entirety: U.S. Pat. No. 8,192,408 (Psivida U.S., Inc.), entitled "Ocular trocar assembly"; U.S. Pat. No. 7,585,517 (Macusight, Inc.), entitled "Transcleral delivery"; U.S. Pat. No. 5,710,182 (Ophthalmic composition); and U.S. Pat. No. 5,710,182 (Ophthalmic composition). No. 8,663,695 (Santen OY) entitled "Formulations for treating ocular diseases and conditions" No. 39, entitled "Formulations and methods for vascular permeability-related diseases or conditions," No. 8,486,960, U.S. Patent No. 8,367, entitled "Liquid formulations for treatment of diseases or conditions"; No. 097 and U.S. Patent No. 8,927,005, U.S. Patent No. 7,455,855 (Santen Pharmaceutical Co., Ltd.) entitled "Delivery substance and drug delivery system using the same"; U.S. Patent No. 7,455,855 (Santen Pharmaceutical Co., Ltd.) entitled "Relief of vision and pain" WO 2011 / 050365 entitled "Conformable Therapeutic Shield For Vision and Pain" and WO 2011 / 050366 entitled "Therapeutic Device for Pain Management and Vision" No. 2009 / 145842 (Forsight Labs, LLC); U.S. Pat. No. 9,066,779 and U.S. Pat. No. 8,623,395, entitled "Implantable therapeutic device"; International Publication No. WO 2014 / 160884, entitled "Ophthalmic Implant for Delivering Therapeutic Substances"; U.S. Pat. No. 6,623,395, entitled "Posterior segment drug delivery"; No. 8,399,006, U.S. Pat. No. 8,277,830, U.S. Pat. No. 8,795,712, U.S. Pat. No. 8,808,727, U.S. Pat. No. 8,298,578, and International Publication No. WO 2010 / 088548, WO 2014 / 152959 entitled "Systems for Sustained Intraocular Delivery of Low Solubility Compounds from a Port Delivery System Implant," and U.S. Patent Application Publication No. 20140276482, entitled "Injector apparatus and method for drug delivery." No. 8,905,963 and U.S. Pat. No. 9,033,911, "Formulations and Methods for Increasing or Reducing Mucus" WO 2015 / 057554 entitled "Ocular insert apparatus and methods," U.S. Pat. No. 8,715,712 entitled "Ocular insert apparatus and methods," and U.S. Pat. No. 8,939,948, entitled "Insertion and Removal Methods and Apparatus for Therapeutic Devices," International Publication No. WO 2008 / 0239948. International Publication No. 13 / 116061, entitled "Ophthalmic System for Sustained Release of Drug to the Eye" and International Publication No. 2014 / 066775, entitled "Implantable Therapeutic Device" International Publication Nos. WO 2015 / 085234 and WO 2012 / 019176 entitled "Methods and Apparatus to Determine Porous Structures for Drug Delivery", WO 2012 / 065006 entitled "Anterior Segment Drug Delivery", WO 2010 / 141729 entitled "Corneal Denervation for Treatment of Ocular Pain", WO 2011 / 050327 entitled "Corneal Denervation for Treatment of Ocular Pain", WO 2013 / 022801 entitled "Small Molecule Delivery with Implantable Therapeutic Device" and WO 2014 / 022802 entitled "Posterior Segment Drug Delivery" International Publication No. WO 2012 / 019047, entitled "Subconjunctival Implant for Posterior Segment Drug Delivery," and "Clinical Procedures for Implanted Devices," WO 2012 / 068549 entitled "Therapeutic Agent Formulations for Implanted Devices" and WO 2012 / 019139 entitled "Combined Delivery Methods and Apparatus" and "Intraocular Implants" International Publication No. 2013 entitled "Ocular Insert Apparatus and Methods" / 040426, entitled "Injector Apparatus and Method for Drug Delivery," and WO 2012 / 019136, entitled "Fluid Exchange No. WO 2013 / 040247 (ForSight Vision4, Inc.), entitled "Fluid Exchange Apparatus and Methods," U.S. Patent Application Publication No. 2014 / 0352690, entitled "Inhalation Device with Feedback System," U.S. Patent No. 8,910,625 and U.S. Patent Application Publication No. 2015 / 0165137 (Vectura GmbH), entitled "Inhalation Device for Use in Aerosol Therapy," U.S. Patent No. 6,948,496, entitled "Inhalers," U.S. Patent Application Publication No. 2005 / 0152849, entitled "Powders comprising anti-adherent materials for use in dry powder inhalers," and U.S. Patent Application Publication No. 2006 / 0152849, entitled "Dry Powder Inhaler No. 6,582,678 entitled "Carrier particles for use in dry powder inhalers," U.S. Patent No. 8,137,657, U.S. Patent Application Publication Nos. 2003 / 0202944 and 2010 / 0330188, U.S. Patent No. 6,221,338 entitled "Method of producing particles for use in dry powder inhalers," U.S. Patent No. 6,989,155 entitled "Powders," and U.S. Patent No. 6,989,155 entitled "Method of producing particles for use in dry powder inhal ... U.S. Patent Application Publication No. 2007 / 0043030, entitled "Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation," U.S. Patent No. 7,845,349, entitled "Inhaler," and U.S. Patent No. 7,845,349, entitled "Pharmaceutical compositions for use in inhaler devices." U.S. patent application entitled "Formulations for Use in Inhaler Devices" Publication No. 2012 / 0114709 and U.S. Patent No. 8,101,160, U.S. Patent Application Publication No. 2013 / 028785 entitled "Compositions and Uses" No. 4, U.S. Patent Application Publication No. 2014 / 0037737 entitled "Particles for Use in a Pharmaceutical Composition" and U.S. Patent No. 8, No. 580,306, entitled "Mixing Channel for an Inhalation Device," and U.S. Patent Application Publication No. 2015 / 0174343, entitled "Mixing Channel for Use in Pharmaceutical Compositions." No. 7,744,855 and U.S. Patent Application Publication No. 2010 / 0285142, entitled "Method of making particles for use in a pharmaceutical composition," U.S. Patent No. 7,541,022, entitled "Pharmaceutical formulations for dry powder inhalers," U.S. Patent No. Patent Application Publication No. 2009 / 0269412 and U.S. Patent Application Publication No. 2015 / 0050350 (Vectura Limited).

[0709] Additional non-limiting examples of methods for delivering active compounds are described in the publication entitled "Intracameral Implant for Treatment of an Ocular Condition." WO 2015 / 085251 (Envisia Therapeutics, Inc.) entitled "Engineered Aerosol Particles and Associated Methods"; WO 2011 / 008737 (Geometrically Engineered Particles and Methods for Modulating Macrophages or Immune Responses) International Publication No. WO 2013 / 082111, entitled "For Modulating Macrophage or Immune Responses," International Publication No. WO 2009 / 132265, entitled "Degradable compounds and methods of use thereof, particularly with particle replication in non-wetting templates," International Publication No. WO 2010 / 099321, entitled "Interventional drug delivery system and associated methods," and International Publication No. WO 2010 / 099321, entitled "Polymer particle composite having high fidelity, size and shape particles." International Publication No. WO 2008 / 100304 entitled "Liquidia nanoparticles with high fidelity order, size, and shape" and International Publication No. WO 2007 / 024323 entitled "Nanoparticle fabrication methods, systems, and materials" (Liquidia Nanoparticles). Technologies, Inc. and the University of North Carolina at Chapel Hill); "Controlled Release in the Eye" International Publication No. WO 2010 / 009087 (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.) entitled "Iontophoretic Delivery of a Controlled-Release Formulation in the Eye" and "Intracellular Delivery and Release of Cargo"

[0005] Nanoparticles for cosmetic applications are presented in International Publication No. WO 2009 / 132206, entitled "Compositions and Methods for Intracellular Delivery and Release of Cargo," International Publication No. WO 2007 / 133808, entitled "Nano-particles for cosmetic applications," International Publication No. WO 2007 / 056561, entitled "Medical device, materials, and methods," International Publication No. WO 2010 / 065748, entitled "Method for producing patterned materials," and International Publication No. WO 2007 / 081876, entitled "Nanostructured surfaces for biomedical / biomaterial applications and processes thereof" (Liquidia Technologies, Inc.).

[0710] Additional non-limiting examples of drug delivery devices and methods include, for example, U.S. Patent Application Publication No. 200900000, entitled "Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor." No. 203709 (Abbott Laboratories); "Subconjunctival or periocular delivery of prodrugs" A US study entitled "Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug" Publication No. 20050009910, entitled "Biodegradable polymers for lowering intraocular pressure"; Publication No. 20130071349, entitled "Tyrosine kinase microspheres"; and U.S. Patent No. 8,481,069, entitled "Method of making tyrosine kinase microspheres." U.S. Patent No. 8,465,778, U.S. Patent No. 8,409,607 entitled "Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods," U.S. Patent No. 8,512,738 entitled "Biodegradable intravitreal tyrosine kinase implants," and U.S. Patent No. Publication No. 2014 / 0031408, entitled "Microsphere Drug Delivery System for Sustained Intraocular Release," and U.S. Patent Application Publication No. 2014 / 0294986, entitled "Methods For Treating Retinopathy With Extended Therapeutic Effect." " (Allergan, Inc.); U.S. Patent No. 8,911,768 entitled "Improved Injectability"; No. 6,495,164 (Alkermes Controlled Therapeutics, Inc.) entitled "Preparation of injectable suspensions having improved injectability"; WO 2014 / 047439 (Akina, Inc.) entitled "Biodegradable Microcapsules Containing Filling Material"; WO 2010 / 132664 (Baxter International Inc. Baxter Healthcare SA) entitled "Compositions And Methods For Drug Delivery"; WO 2010 / 132664 (Baxter International Inc. Baxter Healthcare SA) entitled "Polymer nanoparticles with improved drug loading and their use"; U.S. Patent Application Publication No. 20120052041 (The Brigham and Women's Hospital, Inc.) entitled "Polymeric nanoparticles with enhanced drug loading and methods of use thereof"; U.S. Patent Application Publication No. 20140178475 (The Brigham and Women's Hospital, Inc.) entitled "Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same"; No. 20140248358 and U.S. Patent Application Publication No. 20140249158 (BIND Therapeutics, Inc.); U.S. Patent No. 5,869,103 (Danbiosyst UK Ltd.) entitled "Polymer microparticles for drug delivery"; U.S. Patent No. 8,628,801 (University of Navarre) entitled "Pegylated Nanoparticles"; U.S. Patent Application Publication No. 2014 / 0107025 (Jade Therapeutics, LLC) entitled "Ocular drug delivery system composed of microparticles and biodegradable gel with improved release profile"; U.S. Patent No. 6,287,588 entitled "Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof," U.S. Patent No. 6,589,549 (Macromed, Inc.) entitled "Bioactive agent delivering system comprised of microparticles within a biodegradable material to improve release profiles," U.S. Patent No. 6,007,845 entitled "Nanoparticles and microparticles of non-linear hydrophilichydrophobic multiblock copolymers," and U.S. Patent No. 5,578,333 entitled "Nanoparticles and microparticles of non-linear hydrophilichydrophobic multiblock copolymers," No. 25 (Massachusetts Institute of Technology); "For periocular or subconjunctival administration" U.S. Patent Application Publication No. 20040234611, U.S. Patent Application Publication No. 20080305172, U.S. Patent Application Publication No. 20120269894, and U.S. Patent Application Publication No. 20130122064 (Novartis Ag); U.S. Patent No. 6,413,539 (Poly-Med, Inc.) entitled "Block polymer"; U.S. Patent Application Publication No. 20070071756 (Peyman) entitled "Delivery of an agent to ameliorate inflammation"; "Injectable Depot - Formulations and methods for providing sustained release of poorly soluble drugs containing nanoparticles (Injectable Depot U.S. Patent Application Publication No. 20080166411 (Pfizer, Inc.) entitled "Formulations And Methods For Providing Sustained Release Of Poorly Soluble Drugs Comprising Nanoparticles"; U.S. Patent No. 20080166411 (Pfizer, Inc.) entitled "Methods and compositions for enhanced delivery of bioactive molecules"; No. 6,706,289 (PR Pharmaceuticals, Inc.); and Microparticle containing matrices for drug delivery No. 8,663,674 (Surmodics) entitled "Ultra-High-Performance Liquid Crystal Display Device."

[0711] VI. General synthesis The compounds described herein can be prepared by methods known to those skilled in the art. In one non-limiting example, the disclosed compounds can be made using the following scheme:

[0712] Compounds of the invention that have a stereocenter may, for convenience, be drawn without stereochemistry. Those skilled in the art will recognize that enriched enantiomers and diastereomers can be prepared by methods known in the art. Exemplary methods for obtaining optically active materials include at least the following:

[0713] i) Physical Separation of Crystals - a technique in which visible crystals of the individual enantiomers are manually separated. This technique can be used when crystals of the separate enantiomers are present, i.e. the material is a conglomerate, and the crystals are visually distinguishable.

[0714] ii) Simultaneous crystallization - a technique in which the individual enantiomers are separately crystallized from a solution of the racemate, which is only possible if the enantiomers are conglomerates in the solid state.

[0715] iii) Enzymatic resolution - a technique for partially or completely separating a racemate by virtue of the difference in the reaction rates of the enantiomers with an enzyme.

[0716] iv) Enzymatic Asymmetric Synthesis - a synthetic technique that uses an enzymatic reaction in at least one step of the synthesis to obtain an enantiomerically pure or enantiomerically enriched synthetic precursor of a desired enantiomer.

[0717] v) Chemical asymmetric synthesis - a synthetic technique in which a desired enantiomer is synthesized from an achiral precursor under conditions that result in asymmetry (ie, chirality) in the product, which may be achieved by means of a chiral catalyst or chiral auxiliary.

[0718] vi) Diastereomeric separation - a technique in which a racemate is reacted with an enantiomerically pure reagent (chiral auxiliary) that converts the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization due to their more distinct structural differences, followed by removal of the chiral auxiliary to give the desired enantiomer.

[0719] vii) First and second order asymmetric transformations - rapid equilibration of diastereomers derived from the racemate and preponderance of dissolution of the diastereomer derived from the desired enantiomer. This technique results in the preferential crystallization of the diastereomer derived from the desired enantiomer, which disrupts the equilibrium and ultimately converts essentially all of the material from the desired enantiomer to the crystalline diastereomer. The desired enantiomer is then liberated from the diastereomer.

[0720] viii) Kinetic Resolution - This technique refers to achieving partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by the unequal reaction rates of enantiomers with chiral, non-racemic reagents or catalysts under kinetic conditions.

[0721] ix) Enantiospecific synthesis from non-racemic precursors - during synthesis A synthetic technique that yields a desired enantiomer from non-chiral starting materials with little or no loss of stereochemical integrity.

[0722] x) Chiral Liquid Chromatography - a technique in which enantiomers of a racemate are separated in a liquid mobile phase by virtue of their different interactions with a stationary phase (including by chiral HPLC). The stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral material to effect the different interactions.

[0723] xi) Chiral gas chromatography - a technique in which the racemate is volatilized and the enantiomers are separated by their different interactions in a gaseous mobile phase by a column containing a fixed non-racemic chiral adsorbent phase.

[0724] xii) Extraction with chiral solvents- a technique in which enantiomers are separated by selective dissolution of one enantiomer in a particular chiral solvent.

[0725] xiii) Transport across chiral membranes—a technique in which a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one of which contains the racemate, and a driving force such as a concentration or pressure difference results in preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral properties of the membrane, which allows only one enantiomer of the racemate to pass through.

[0726] xiv) Simulated moving bed chromatography is used in one embodiment. A wide variety of chiral stationary phases are commercially available.

[0727] General synthetic scheme 1 [ka] In some embodiments, compounds of Formula I or II can be synthesized according to the route presented in General Synthetic Scheme 1. In Step 1, compound G1-1 is reacted with butyllithium (or alternatively, another organolithium reagent, such as, for example, tert-butyllithium, sec-butyllithium, phenyllithium, or methyllithium, or a Grignard reagent, such as, for example, isopropylmagnesium bromide or ethylmagnesium bromide) in an organic solvent (e.g., tetrahydrofuran or diethyl ether) at low temperature (typically, −78° C. to −40° C.), followed by the addition of G1-2 to provide G1-3. In Step 2, compound G1-3 is reacted with trifluoroacetic acid (or alternatively, another strong oxyacid, such as, for example, triflic acid) and triethylsilane (or alternatively, another organosilane, such as, for example, phenylsilane, or an organotin hydride, such as, for example, tributyltin hydride) in an organic solvent (e.g., 1,2-dichloroethane) with heating (e.g., at about 60° C. or alternatively, by microwave irradiation) to provide G1-4. In step 3, compound G1-4 is reacted with a base (such as sodium hydride) in an organic solvent (such as dimethylformamide or dichloromethane), followed by the addition of G1-5 to give G1-6.

[0728] General synthetic scheme 2 [ka] In some embodiments, compounds of Formula I or Formula II can be synthesized according to the route presented 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 (e.g., manganese dioxide or other reagent suitable for oxidizing alcohols) in an organic solvent (e.g., acetonitrile) to provide G2-2. In Step 2, G2-2 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), followed by the addition of G2-3 to provide G2-4. In Step 3, G2-4 is reacted with a suitable carbonyl reducing agent (e.g., sodium cyanoborohydride) in an organic solvent (e.g., ethanol or methanol) to provide G2-5.

[0729] General synthetic scheme 3 [ka] In some embodiments, compounds of Formula I or Formula II can be synthesized according to the route presented 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) and DAST (or e.g., In step 2, compound G3-2 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane) followed by the addition of G3-3 to give G3-4.

[0730] General synthetic scheme 4 [ka] In some embodiments, compounds of Formula I or Formula II can be synthesized according to the route presented 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 (e.g., dichloromethane) to provide G4-2. In Step 2, compound G4-2 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), followed by the addition of G4-3 to provide G4-4.

[0731] General synthetic scheme 5 [ka] In some embodiments, compounds of Formula I or Formula II can be synthesized according to the route shown in General Synthetic Scheme 5. In Step 1, compounds G5-1 and G5-2 are reacted in the presence of a palladium catalyst (e.g., palladium(II) acetate, Pd(dba) or other suitable palladium catalysts used in Buchwald-Hartwig coupling conditions), a phosphine ligand (e.g., BINAP, Xantphos or other suitable phosphine ligands used in Buchwald-Hartwig coupling conditions), and a base (e.g., potassium tert-butoxide, cesium carbonate or other suitable bases used in Buchwald-Hartwig coupling conditions) in an organic solvent (e.g., toluene, THF, dioxane or DMF) at elevated temperature to yield G5-3. In Step 2, compound G5-3 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), followed by the addition of G5-4 to yield G5-5.

[0732] General synthetic scheme 6 [ka] In some embodiments, compounds of Formula I or Formula II can be synthesized according to the route presented in General Synthetic Scheme 6. In Step 1, compound G6-1 is reacted with a metal hydroxide (e.g., sodium hydroxide or potassium hydroxide) in the presence of a palladium catalyst (e.g., Pd2(dba)3) and a phosphine ligand (e.g., xantphos) in an organic solvent (e.g., dioxane) and water to yield compound G6-2. In Step 2, G6-2 is protected with an appropriate protecting group (e.g., Boc or Cbz) using standard conditions to yield compound G6-3. In Step 3, G6-3 and G6-5 are reacted with a copper catalyst (e.g., copper acetate) and a base (e.g., pyridine or DMAP) in an organic solvent (e.g., 1,2-dichloroethane) at elevated temperatures (e.g., about 80°C) to yield compound G6-6. In Step 4, the protecting group PG in G6-6 is removed using standard conditions appropriate for the particular group to yield compound G6-7. In step 5, compound G6-7 is reacted with a base (such as sodium hydride) in an organic solvent (such as dimethylformamide or dichloromethane), followed by the addition of G6-8 to give G6-9.

[0733] Non-limiting examples of the present invention Where chirality is indicated in the synthetic schemes below, the designation indicates the relative chirality of that stereocenter and is not an absolute designation. For example: [ka] is shown with a wedge bond to indicate that the designated chiral center has been resolved by chiral chromatography. However, the absolute chirality of that stereocenter is instead indicated by [ka] In this case, when intermediate 3a is reacted with racemic bromoglutarimide, the resulting compound 280 can be a mixture of diastereomers. [ka]

[0734] Similarly, when an achiral lactam is reacted with racemic glutarimide in the experiment below, the resulting compound may be a mixture of enantiomers. For example, when intermediate 7 is reacted with racemic bromoglutarimide, the resulting intermediate 9 may be a mixture of enantiomers. [ka]

[0735] A resulting compound may be a mixture of enantiomers unless otherwise indicated as having the designated stereochemistry, for example: [ka]

[0736] Those skilled in the art can separate mixtures of these enantiomers using techniques known in the art, including chiral chromatography, crystallization, transport across chiral membranes, or extraction with chiral solvents. Indeed, these techniques have been used to separate some of the compounds listed below. For example, the intermediate [ka] were separated by chiral chromatography using a preparative HPLC method. Similarly, enantiomeric mixtures of glutarimides can be resolved by these techniques, including chiral chromatography. For example, a mixture of compound 67 and compound 68 was resolved by chiral chromatography using a preparative HPLC method. The resulting separated compounds had an enantiomeric excess of 99%. [ka]

[0737] After separation, the absolute chirality can be determined by known techniques, including the structure determination of various crystalline forms. 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).

[0738] A mixture of enantiomers can also be resolved in a synthetic sequence using techniques known in the art. For example, enzymatic resolution and enzymatic asymmetric synthesis can be used to resolve chiral centers. Additionally, a mixture of enantiomers can be resolved by incorporating a protecting group or using a chiral salt. When a chiral protecting group or salt is used, the mixture of enantiomers temporarily becomes a mixture of diastereomers, which can be physically separated using known techniques.

[0739] When the compound of the present invention is a mixture of diastereomers, they can also be separated by methods known in the art. For example, the mixture of diastereomers can be separated by chromatographic methods including reverse-phase or normal-phase HPLC, silica gel chromatography, moving bed chromatography and preparative TLC. The mixture of diastereomers can also be separated by crystallization. [Example]

[0740] Example 1: Synthesis of 3-(2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 1): [ka] To a stirred solution of 1H-benzo[cd]indol-2-one 1 (100.0 mg, 591.09 μmol) in DMF (2 mL) was added sodium hydride (60% dispersion in mineral oil, 24.91 mg, 650.20 μmol, 60% purity) at 0° C., and the reaction mixture was heated at 60° C. for 30 min. 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 h. A new spot formed along with unreacted starting material. Additional 3-bromopiperidine-2,6-dione 2 (113.50 mg, 591.09 μmol) was added, and the reaction mixture was again heated for 24 h. The reaction mixture was diluted with ethyl acetate, washed with water, and the organic fraction was separated. The reaction mixture was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 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, yield 5.81%, purity 96.28%) 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.

[0741] 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) [ka] Step 1: Preparation of 6-bromobenzo[cd]indol-2(1H)-one (2): To a stirred suspension of 1H-benzo[cd]indol-2-one 1 (3.0 g, 17.73 mmol) in CHCl3 (50.0 mL), bromine (2.15 g, 26.60 mmol, 1.44 mL) was added dropwise with cooling, and the reaction mixture was stirred at room temperature for 48 h. Sodium thiosulfate solution was poured into the reaction mixture with cooling, and the yellow solid that 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 (4 g, 16.12 mmol, 90.93% yield) as a yellow solid. LC MS: ES+ 248.1, 250.0 (bromopa turn).

[0742] Step 2: Preparation of tert-butyl 4-(4-(hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (4): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 2-2 (1.6 g, 6.45 mmol) in THF (7 mL) was added butyllithium (2.2 M, 9.38 mL) at -78 °C. After the addition was complete, the temperature was raised to -40 °C and the reaction mixture was stirred at the same temperature for 30 min. tert-Butyl 4-(4-hydroxybenzo[cd]indol-2-one) in THF (7 mL) was added. 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 3 (1.80 g, 6.45 mmol) 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 solution and diluted with ethyl acetate. The layers were separated, and the organic layer was washed with water. The organic layer was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0% to 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).

[0743] Step 3: Preparation of 2,2,2-trifluoroacetic acid salt of 6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one (5): To a stirred solution of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 4 (500.0 mg, 1.11 mmol) in DCE (3 mL) was added triethylsilane (518.51 mg, 4.46 mmol, 712.24 μL) and trifluoroacetic acid (1.02 g, 8.92 mmol, 687.08 μL) and the reaction was stirred at 70 °C under microwave irradiation for 30 min. The solvent in the reaction mixture was evaporated under reduced pressure to give a crude product, which was washed with 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, which was used without further purification. LC MS: ES+ 333.0

[0744] Step 4: Preparation of tert-butyl 4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (6): To a stirred solution of 6-[(1-piperidin-1-ium-4-ylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one 2,2,2-trifluoroacetate 5 (500.0 mg, 1.12 mmol) in DCM (5 mL) was added triethylamine (340.00 mg, 3.36 mmol, 468.32 μL) with cooling, followed by di-tert-butyl dicarbonate (366.67 mg, 1.68 mmol, 385.56 μL), and the reaction was continued at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and the organic fraction was separated. The organic layer was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude material which was purified by flash chromatography (using 0% to 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 sticky solid. LC MS: ES+ 433.0.

[0745] 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): tert-Butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxamide in DMF (1 mL) To a stirred solution of sylate 6 (300.0 mg, 693.62 μmol), sodium hydride (60% dispersion in mineral oil, 53.15 mg, 1.39 mmol, 60% purity) was added with cooling, and the reaction mixture was heated at 60° C. for 30 min. 3-Bromopiperidine-2,6-dione 7 (133.18 mg, 693.62 μmol) was then added, and the reaction was heated at 60° C. for 4 h. Subsequently, additional 3-bromopiperidine-2,6-dione (133.18 mg, 693.62 μmol) was added, and the reaction was stirred at 60° C. for an additional 16 h. The reaction mixture was diluted with ethyl acetate, washed with water, and the organic fraction was separated. The reaction mixture was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude material which was first purified by column chromatography followed by preparative TLC plate (eluted with 60% ethyl acetate-hexane) to give tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate (compound 2) (20.0 mg, 33.11 μmol, 4.77% yield, 90% purity) as a 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.

[0746] 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) [ka] Step 1: Preparation of 3-(2-oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride (2): To a stirred solution of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 1 (100.0 mg, 183.95 μmol) in dioxane (1 mL) was added hydrochloric acid in dioxane (183.95 μmol, 8 mL), and the reaction was stirred at room temperature for 2 h. TLC analysis indicated complete consumption of the starting material. 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-chloro-4-piperidyl)pyrazol-4-yl]methyl]-2-pyrazol-4-yl]methyl. -Oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione 2 (88.0 mg, 183.35 μmol, 99.67% yield) was obtained as a yellow solid. LC MS: ES+ 444.1.

[0747] 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-chloro-4-piperidyl)pyrazol-4-yl]methyl]-2-oxo-benzo[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), followed by HATU (104.57 mg, 275.02 μmol) and N,N-diisopropylethylamine (71.09 mg, 550.05 μmol, 95.81 μL) at 0° C. The reaction mixture was then stirred at room temperature for 16 hours. It was diluted with ethyl acetate and water, and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3, water, and brine, dried over sodium sulfate, and concentrated. The crude material was purified by preparative TLC (eluted with 3% MeOH / DCM) to give 3-[6-[[1-[1-(cubane-1-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione (compound 3) (55.0 mg, 94.77 μmol, 51.69% yield, 98.84% purity) as a yellow solid. 1 H 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, LC MS: ES+ 574.5.

[0748] Example 4 Synthesis of 3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 4) [ka] Step 1: Preparation of 6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one hydrochloride (2): To a stirred solution of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 1 (100.0 mg, 183.95 μmol) in dioxane (1 mL), hydrochloric acid in dioxane (183.95 μmol, 8 mL) was added, 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-chloro-4-piperidyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione 2 (88.0 mg, 183.35 μmol, 99.67% yield) as a yellow solid. LC MS: ES+ 444.1.

[0749] 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-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 2 (98.0 mg, 265.68 μmol) and 1-methylcyclobutanecarboxylic acid 3 (30.33 mg, 265.68 μmol) in DMF (2.0 mL) at 0 °C, HATU (151.53 mg, 398.53 μmol) and N,N-diisopropylethylamine (171.69 mg, 1.33 mmol, 231.38 μL) were added, 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 layers were 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-piperidyl]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

[0750] 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-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4 (66.0 mg, 154.02 μmol) in DMF (1 mL), sodium hydride (60% dispersion in mineral oil, 11.80 mg, 308.03 μmol) was added under cooling, and the reaction mixture was heated at 60° C. for 30 min. 3-Bromopiperidine-2,6-dione 5 (29.57 mg, 154.02 μmol) was then added, and the reaction was heated at 60° C. for 4 h. Subsequently, additional 3-bromopiperidine-2,6-dione (29.57 mg, 154.02 μmol) was added, and the reaction was continued at 60° C. for an additional 16 h. The reaction mixture was diluted with ethyl acetate, washed with water, and the organic fraction was separated. The organic layer was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude product, which was first purified by column chromatography followed by preparative TLC (plates developed in 60% ethyl acetate-DCM) to give 3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]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.

[0751] Example 5. Synthesis of N-(tert-butyl)-4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-N-methylpiperidine-1-carboxamide (Compound 5) [ka] To an equimolar mixture of HCl salt 1 and tert-butyl(methyl)carbamic acid chloride in DMF (6 mL / mmol) is added DIPEA (4.0 equivalents) at 0° C. The resulting solution is stirred at ambient temperature for 16 hours. The reaction mixture is then diluted with ethyl acetate and washed with aqueous NaHCO, water (three times), and brine. The organic layer is then dried over anhydrous NaSO and concentrated under reduced pressure. The crude mass is then purified by CombiFlash® ISCO column eluted with 2% methanol in DCM to give N-(tert-butyl)-4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-N-methylpiperidine-1-carboxamide (compound 5).

[0752] Example 6 Synthesis of tert-butyl 4-(4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 6) and tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)(hydroxy)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 7) [ka] 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, manganese(IV) oxide (10 equivalents) is added, and the reaction mixture is stirred at room temperature for 16 hours. TLC and LCMS indicate the formation of the product. The reaction mixture is filtered through a Celite pad, and the filtrate is concentrated under reduced pressure to give a crude mass, which is purified by Combiflash chromatography using 1.5% MeOH-DCM as the eluent to give the desired product, tert-butyl 4-(4-(2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 2.

[0753] Step 2: Synthesis of tert-butyl 4-(4-(1-...

Claims

1. Formula I or Formula II: 【Chemical 1】 (In the formula, X １ and X ２ is independently selected from CH and N; X ３ is bond, NR ２ , C(R ３ R ３’ ), O, C(O), C(S), S, S(O) and S(O) ２ is selected from R １ is 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) ２ R ４ is selected from R ２ and R ２’ is independently in each occurrence 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 , -SO ２ R ８ , -SO ２ -OR ８ and -SO ２ -NR ８ R ８’ is selected from R ３ is hydrogen, halogen, alkyl, haloalkyl, -OR ８ and -NR ８ R ８’ is selected from R ３’ is selected from hydrogen, halogen, alkyl and haloalkyl; or R ３ and R ３’ can be combined with the carbons to which they are attached to form a 3- to 6-membered cycloalkyl ring; R ４ is selected from cycloalkyl, heterocycle, aryl, and heteroaryl; and each R ４ is R ６ and each R ４ is R ７ optionally substituted with 1, 2, 3, or 4 groups independently selected from R ５ Ha-C(O)R ６ and R ６ is selected from alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl; and each R ６ is R ９ optionally substituted with one, two, three, or four groups independently selected from or R ６ is 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 R ９ optionally substituted with 1, 2, 3, or 4 groups independently selected from R ７ is independently in each occurrence 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 , -SO ２ R ８ , -SO ２ -OR ８ and -SO ２ -NR ８ R ８’ Selected from or or two R on the same carbon ７ may together form an oxo group, R ８ and R ８’ is independently selected in each occurrence from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl; R ９ are independently hydrogen, halogen, cyano, nitro, R １０ , -CH ２ R １０ , -OR １０ , -NR ２ R １０ , -C(O)R １０ , —C(O)CH ２ R １０ , —C(O)CH ２ OR １０ , —C(O)CH ２ NR 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 , -SO ２ R １０ , S.O. ２ CH ２ R １０ , -SO ２ CH ２ OR １０ , -SO ２ CH ２ NR ２ R １０ , -NR ２ SO ２ R １０ , -SO ２ -OR １０ and -SO ２ -NR ２ R １０ is selected from R １０ is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl; and each R １０ is R １１ optionally substituted with 1, 2, 3, or 4 groups independently selected from R １１ is hydrogen; halogen; hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl optionally substituted with an aryl or heteroaryl group; alkynyl optionally substituted with an aryl or heteroaryl group; cycloalkyl; heterocycle; one, two, three or four halogens, alkyl or -OR ８ aryl optionally substituted with a group; one, two, three or four halogen, alkyl or -OR ８ heteroaryl optionally substituted with a group; one, two, three or four halogen, alkyl or -OR ８ optionally substituted with a —CH group ２ aryl; one, two, three or four halogens, alkyl or -OR ８ optionally substituted with a —CH group ２ Heteroaryl; -OR ８ ;-NR ８ R ８’ -C(O)R ８ -C(O)OR ８ -C(O)-NR ８ R ８’ -C(O)CH ２ R ８ -C(O)CH ２ OR ８ -C(O)CH ２ -NR ８ R ８’ -OC(O)R ８ ;-NR ２ -C(O)R ８ ;-CH ２ -OC(O)R ８ ;-CH ２ -NR ２ -C(O)R ８ -S(O)R ８ ;-SO ２ R ８ ;-SO ２ -OR ８ and -SO ２ -NR ８ R ８’ Selected from or or two R on the same carbon １１ the groups may together form an oxo group, or R １１ is independently in each occurrence halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -CH ２ Aryl, —CH ２ Heteroaryl, —OR ８ , -NR ８ R ８’ , -C(O)R ８ , -C(O)OR ８ , —C(O)—NR ８ R ８’ , —C(O)CH ２ R ８ , —C(O)CH ２ OR ８ , —C(O)CH ２ -NR ８ R ８’ , -OC(O)R ８ , -NR ２ -C(O)R ８ , -CH ２ -OC(O)R ８ , -CH ２ -NR ２ -C(O)R ８ , -S(O)R ８ , -SO ２ R ８ , -SO ２ -OR ８ , oxo and —SO ２ -NR ８ R ８’ and R １１ Each of the groups is R １２ optionally substituted with 1, 2, 3, or 4 groups independently selected from R １２ is independently in each occurrence halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -CH ２ Aryl, —CH ２ Heteroaryl, —OR ８ , -NR ８ R ８’ , -C(O)R ８ , -C(O)OR ８ , —C(O)—NR ８ R ８’ , —C(O)CH ２ R ８ , —C(O)CH ２ OR ８ , —C(O)CH ２ -NR ８ R ８’ , -OC(O)R ８ , -NR ２ -C(O)R ８ , -CH ２ -OC(O)R ８ , -CH ２ -NR ２ -C(O)R ８ , -S(O)R ８ , -SO ２ R ８ , -SO ２ -OR ８ , oxo and —SO ２ -NR ８ R ８’ is selected from R ２０ , R ２１ , R ２２ , R ２３ and R ２４ are in each case independently a bond, an alkyl group, -C(O)-, -C(O)O-, -OC(O)-, -SO ２ -, -S(O)-, -C(S)-, -C(O)NR ２ -, -NR ２ C(O)-, -O-, -S-, -NR ２ -, -P(O)(R ２８ )-, -P(O)-, alkene, alkyne, haloalkyl, aryl, heterocycle, heteroaryl, bicycle, and carbocycle, each of which is selected from the group consisting of R ４０ and R ２０ , R ２１ , R ２２ , R ２３ and R ２４ teeth, i. -C(O)-, -C(O)O-, -OC(O)-, -SO ２ -, -S(O)-, -P(O)(R ２８ )-, —P(O)- and —C(S)- moieties are adjacent to one another, or ii. —O—, —S—, or —NR ２ - the moieties are adjacent to each other, or iii. Otherwise, an unstable molecule will result (part R ２０ , R ２１ , R ２２ , R ２３ and R ２４ (defined as resulting in a molecule having a shelf life of less than about 4 months (or alternatively, less than about 6 months or 5 months) at ambient temperature due to degradation resulting from the selection and order of R ２５ is hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, -OR ２ , -NR ２ R ２’ , -NR ２ SO ２ R ２８ , -OSO ２ R ２８ , -SO ２ R ２８ , haloalkyl, aryl, heteroaryl, heterocyclic, bicyclic, and cycloalkyl, wherein R ２５ Each of the groups is R １２ optionally substituted with 1, 2, 3, or 4 groups independently selected from R ２８ are independently in each occurrence hydrogen, —NR ２ R ２’ , -OR ２ , -SR ２ , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl; R ４０ is independently in each occurrence hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azido, amino, cyano, -NR ２ R ２’ , -NR ２ SO ２ R ２８ , -OSO ２ R ２８ , -SO ２ R ２８ , haloalkyl, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl, wherein R ４０ Each of the groups is R １２ or a pharmaceutically acceptable salt or isotopic derivative thereof.

2. formula: 【Chemistry 2】 2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof.

3. R ６ is selected from alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl; and each R ６ is R ９ optionally substituted with 1, 2, 3, or 4 groups independently selected from R １１ is hydrogen; halogen; hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl optionally substituted with an aryl or heteroaryl group; alkynyl optionally substituted with an aryl or heteroaryl group; cycloalkyl; heterocycle; one, two, three or four halogens, alkyl or -OR ８ aryl optionally substituted with a group; one, two, three or four halogen, alkyl or -OR ８ heteroaryl optionally substituted with a group; one, two, three or four halogen, alkyl or -O R ８ optionally substituted with a —CH group ２ aryl; one, two, three or four halogens, alkyl or -OR ８ optionally substituted with a —CH group ２ Heteroaryl; -OR ８ ;-NR ８ R ８’ -C(O)R ８ -C(O)OR ８ -C(O)-NR ８ R ８’ -C(O)CH ２ R ８ -C(O)CH ２ OR ８ -C(O)CH ２ -NR ８ R ８’ -OC(O)R ８ ;-NR ２ -C(O)R ８ ;-CH ２ -OC(O)R ８ ;-CH ２ -NR ２ -C(O)R ８ -S(O)R ８ ;-SO ２ R ８ ;-SO ２ -OR ８ and -SO ２ -NR ８ R ８’ Selected from or or two R on the same carbon １１ The compound of claim 2 , wherein the groups may together form an oxo group.

4. R １２ 3. The compound of claim 1 or 2, wherein is selected from halogen, alkyl and haloalkyl.

5. R １２ 3. The compound of claim 1 or 2, wherein is selected from hydroxyl, cyano, nitro, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl.

6. R １２ Ga-CH ２ Aryl, —CH ２ Heteroaryl, —OR ８ , -NR ８ R ８’ , -C(O)R ８ , -C(O)OR ８ , —C(O)—NR ８ R ８’ , —C(O)CH ２ R ８ , —C(O)CH ２ OR ８ , —C(O)CH ２ -NR ８ R ８’ , -OC(O)R ８ , -NR ２ -C(O)R ８ , -CH ２ -OC(O)R ８ , -CH ２ -NR ２ -C(O)R ８ , -S(O)R ８ , -SO ２ R ８ , -SO ２ -OR ８ , oxo and —SO ２ -NR ８ R ８’ 3. The compound according to claim 1 or 2, selected from:

7. One R １２ 3. The compound of claim 1 or 2, wherein the substituent is a halogen.

8. Two R's １２ 3. The compound of claim 1 or 2, wherein the substituent is a halogen.

9. One R １２ 3. The compound of claim 1 or 2, wherein the substituent is alkyl.

10. Two R's １２ 3. The compound of claim 1 or 2, wherein the substituent is alkyl.

11. One R １２ 3. The compound of claim 1 or 2, wherein the substituent is haloalkyl.

12. One R １２ 3. The compound of claim 1 or 2, wherein the substituent is cycloalkyl.

13. R １１ But, R １２ 13. The compound of any one of claims 4 to 12, wherein the alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from:

14. R １１ But, R １２ 13. The compound of any one of claims 4 to 12, which is cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents selected from:

15. R １１ But, R １２ 13. The compound of any one of claims 4 to 12, which is a heterocycle optionally substituted with 1, 2, 3 or 4 substituents selected from:

16. R １１ But, R １２ 13. The compound of any one of claims 4 to 12, wherein the aryl is optionally substituted with one, two, three or four substituents selected from:

17. R １１ But, R １２ 13. The compound of any one of claims 4 to 12, which is heteroaryl optionally substituted with 1, 2, 3 or 4 substituents selected from:

18. R １１ The compound of any one of claims 1 to 12, wherein is alkyl.

19. R １１ The compound of any one of claims 1 to 12, wherein is cyano.

20. R １１ The compound of any one of claims 1 to 12, wherein is haloalkyl.

21. R １１ The compound of any one of claims 1 to 12, wherein is hydrogen.

22. R １１ The compound of any one of claims 1 to 12, wherein is hydroxyl.

23. R １１ is OR ８ The compound according to any one of claims 1 to 12,

24. R １１ The compound of any one of claims 1 to 12, wherein is aryl.

25. R １１ The compound of any one of claims 1 to 12, wherein is heteroaryl.

26. R １１ -C(O)OR ８ , -C(O)R ８ or -SO ２ R ８ The compound according to any one of claims 1 to 12,

27. R １１ Ga-CH ２ The compound of any one of claims 1 to 12, which is aryl.

28. R １ Ga-NR ２ R ４ The compound according to any one of claims 1 to 27,

29. R １ Ga-OR ４ The compound according to any one of claims 1 to 27,

30. R １ -C(O)R ４ The compound according to any one of claims 1 to 27,

31. R １ Ga-SR ４ The compound according to any one of claims 1 to 27,

32. R １ Ga-S(O)R ４ The compound according to any one of claims 1 to 27,

33. R １ Ga-S(O) ２ R ４ The compound according to any one of claims 1 to 27,

34. formula: 【Chemistry 3】 28. The compound according to any one of claims 1 to 27, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

35. formula: 【Chemistry 4】 28. The compound according to any one of claims 1 to 27, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

36. formula: 【Chemistry 5】 28. The compound according to any one of claims 1 to 27, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

37. formula: 【Chemistry 6】 28. The compound according to any one of claims 1 to 27, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

38. R １ But-(CR ３ R ３’ )-R ５ The compound according to any one of claims 1 to 27,

39. R ３ 39. The compound of claim 37 or 38, wherein is hydrogen.

40. R ３ Ga-NR ８ R ８’ 39. The compound of claim 37 or 38, wherein:

41. R ３ 39. The compound of claim 37 or 38, wherein is alkyl.

42. R ３’ The compound of any one of claims 37 to 41, wherein is hydrogen.

43. R １ Ga-NR ２ R ５ The compound according to any one of claims 1 to 27,

44. R １ Ga-OR ５ The compound according to any one of claims 1 to 27,

45. R ５ But, R ９ 45. The compound of any one of claims 38 to 44, which is -C(O)alkyl optionally substituted with 1, 2, 3 or 4 groups independently selected from:

46. R ５ But, R ９ 45. The compound of any one of claims 38 to 44, which is a -C(O)heterocycle optionally substituted with 1, 2, 3 or 4 groups independently selected from:

47. R ５ But, R ９ 45. The compound of any one of claims 38 to 44, which is -C(O)aryl optionally substituted with 1, 2, 3 or 4 groups independently selected from:

48. R ５ But, R ９ 45. The compound of any one of claims 38 to 44, which is -C(O)heteroaryl optionally substituted with 1, 2, 3, or 4 groups independently selected from:

49. formula: 【Chemistry 7】 49. The compound of any one of claims 1 to 48, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

50. formula: 【Chemistry 8】 49. The compound of any one of claims 1 to 48, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

51. formula: 【Chemistry 9】 49. The compound of any one of claims 1 to 48, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

52. R ４ But, R ６ and R ７ 52. The compound of any one of claims 49-51, which is cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:

53. R ４ But, R ６ and R ７ one independently selected from 52. The compound of any one of claims 49 to 51, which is a heterocycle optionally substituted with two, three or four groups.

54. R ４ But, R ６ and R ７ 52. The compound of any one of claims 49 to 51, which is aryl optionally substituted with one, two, three or four groups independently selected from:

55. R ４ But, R ６ and R ７ 52. The compound of any one of claims 49 to 51, which is heteroaryl optionally substituted with one, two, three or four groups independently selected from:

56. R ４ but, 【Chemistry 10】 The compound according to any one of claims 49 to 51,

57. R ４ but, 【Chemistry 11】 The compound according to any one of claims 49 to 51,

58. R ４ but, 【Chemistry 12】 The compound according to any one of claims 49 to 51,

59. R ４ but, 【Chemistry 13】 The compound according to any one of claims 49 to 51,

60. R ４ but, 【Chemistry 14】 The compound according to any one of claims 49 to 51,

61. R ７ is hydrogen, halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -OR ８ and -NR ８ R ８’ 61. The compound of any one of claims 1 to 60, selected from:

62. R ７ is 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 , -SO ２ R ８ , -SO ２ -OR ８ , and -SO ２ -NR ８ R ８’ 61. The compound of any one of claims 1 to 60, selected from:

63. One R ７ The compound of any one of claims 1 to 60, wherein is hydrogen.

64. Two R's ７ The compound of any one of claims 1 to 60, wherein is hydrogen.

65. The Three Rs ７ The compound of any one of claims 1 to 60, wherein is hydrogen.

66. One R ７ 66. The compound of any one of claims 1 to 65, wherein is halogen.

67. Two R's ７ The compound of any one of claims 1 to 64, wherein is halogen.

68. One R ７ The compound of any one of claims 1 to 65, wherein is alkyl.

69. Two R's ７ The compound of any one of claims 1 to 64, wherein is alkyl.

70. One R ７ The compound of any one of claims 1 to 65, wherein is haloalkyl.

71. Two R's ７ The compound of any one of claims 1 to 64, wherein is haloalkyl.

72. R ６ but, 【Chemistry 15】 72. The compound of any one of claims 1 to 71, selected from:

73. R ６ but, 【Chemistry 16】 72. The compound of any one of claims 1 to 71, selected from:

74. R ６ but, 【Chemistry 17】 72. The compound of any one of claims 1 to 71, selected from:

75. R ６ But, R ９ 72. The compound of any one of claims 1 to 71, wherein the alkyl is optionally substituted with one, two, three or four groups independently selected from:

76. R ６ But, R ９ 72. The compound of any one of claims 1 to 71, which is cycloalkyl optionally substituted with one, two, three or four groups independently selected from:

77. R ６ But, R ９ 72. The compound of any one of claims 1 to 71, which is a heterocycle optionally substituted with one, two, three or four groups independently selected from:

78. R ６ But, R ９ 72. The compound of any one of claims 1 to 71, which is aryl optionally substituted with one, two, three or four groups independently selected from:

79. R ６ But, R ９ 72. The compound of any one of claims 1 to 71, which is heteroaryl optionally substituted with one, two, three or four groups independently selected from:

80. R ６ 80. The compound of any one of claims 75 to 79, wherein is unsubstituted.

81. R ６ is R ９ 80. The compound of any one of claims 75 to 79, substituted with one group selected from:

82. R ６ is R ９ 80. The compound of any one of claims 75 to 79, substituted with two groups independently selected from:

83. R ６ is R ９ 80. The compound of any one of claims 75 to 79, substituted with three groups independently selected from:

84. R ６ is R ９ 80. The compound of any one of claims 75 to 79, substituted with four groups independently selected from:

85. R ９ 85. The compound of any one of claims 1 to 84, wherein is selected from hydrogen, halogen, alkyl, haloalkyl, cyano and nitro.

86. R ９ is R １０ 85. The compound of any one of claims 1 to 84, selected from:

87. R ９ が-CH ２ R １０ 、-OR １０ 、-NR ２ R １０ 、-C(O)R １０ 、-C(O) CH ２ R １０ , —C(O)CH ２ OR １０ , —C(O)CH ２ NR 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 , -SO ２ R １０ , S.O. ２ CH ２ R １０ , -SO ２ CH ２ OR １０ , -SO ２ CH ２ NR ２ R １０ , -NR ２ SO ２ R １０ , -SO ２ -OR １０ and -SO ２ -NR ２ R １０ 85. The compound of any one of claims 1 to 84, selected from:

88. R １０ But, R １１ 88. The compound of claim 86 or 87, wherein R is alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:

89. R １０ But, R １１ 88. The compound of claim 86 or 87, wherein the haloalkyl is optionally substituted with one, two, three, or four groups independently selected from:

90. R １０ But, R １１ 88. The compound of claim 86 or 87, wherein the alkenyl is optionally substituted with one, two, three, or four groups independently selected from:

91. R １０ But, R １１ 88. The compound of claim 86 or 87, which is alkynyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:

92. R １０ But, R １１ 88. The compound of claim 86 or 87, wherein R is cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:

93. R １０ But, R １１ 88. The compound of claim 86 or 87, which is a heterocycle optionally substituted with one, two, three or four groups independently selected from:

94. R １０ But, R １１ 88. The compound of claim 86 or 87, wherein R is aryl optionally substituted with one, two, three or four groups independently selected from:

95. R １０ But, R １１ 88. The compound of claim 86 or 87, which is heteroaryl optionally substituted with one, two, three or four groups independently selected from:

96. R １０ The compound of any one of claims 88 to 95, wherein is unsubstituted.

97. R １０ is R １１ 96. The compound of any one of claims 88 to 95, substituted with one group selected from:

98. R １０ is R １１ 96. The compound of any one of claims 88 to 95, substituted with two groups independently selected from:

99. R １０ is R １１ 96. The compound of any one of claims 88 to 95, substituted with three groups independently selected from:

100. R １０ is R １１ 96. The compound of any one of claims 88 to 95, substituted with four groups independently selected from:

101. R ２ , R ８ and R ８’ The compound of any one of claims 1 to 100, wherein is hydrogen.

102. R ２ , R ８ and R ８’ The compound of any one of claims 1 to 100, wherein is alkyl.

103. R ６ but, 【Chemistry 18】 72. The compound of any one of claims 1 to 71, selected from:

104. R ６ but, 【Chemistry 19】 72. The compound of any one of claims 1 to 71, selected from:

105. R ６ but, 【Chemistry 20】 72. The compound of any one of claims 1 to 71, selected from:

106. formula: 【Chemical 21】 or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof.

107. formula: 【Chemical 22】 or a pharmaceutically acceptable salt, or isotopic derivative thereof.

108. formula: 【Chemical 23】 or a pharmaceutically acceptable salt, or isotopic derivative thereof.

109. formula: 【Chemistry 24】 or a pharmaceutically acceptable salt, or isotopic derivative thereof.

110. X ３ The compound of any one of claims 106 to 109, wherein is a bond.

111. X ３ is C(R ３ R ３’ 110. The compound according to any one of claims 106 to 109, wherein

112. X ３ The compound of any one of claims 106 to 109, wherein is C(O).

113. X ３ The compound of any one of claims 106 to 109, wherein is C(S).

114. X ３ The compound of any one of claims 106 to 109, wherein is S(O).

115. X ３ is S (O) ２ The compound according to any one of claims 106 to 109,

116. X ３ NR ２ The compound according to any one of claims 106 to 109,

117. X ３ The compound of any one of claims 106 to 109, wherein is O.

118. X ３ The compound of any one of claims 106 to 109, wherein is NH.

119. X ３ is N (CH ３ 110. The compound according to any one of claims 106 to 109, wherein

120. X ３ The compound of any one of claims 106 to 109, wherein is S.

121. R ２０ The compound of any one of claims 106 to 120, wherein is a bond.

122. R ２０ But, R ４０ 121. The compound of any one of claims 106-120, wherein the alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

123. R ２０ But, R ４０ 121. The compound of any one of claims 106 to 120, which is an alkene or alkyne optionally substituted with 1, 2, 3 or 4 substituents independently selected from:

124. R ２０ But, R ４０ 121. The compound of any one of claims 106-120, which is haloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from:

125. R ２０ But, R ４０ 121. The compound of any one of claims 106-120, which is aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from:

126. R ２０ But, R ４０ 121. The compound of any one of claims 106-120, which is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

127. R ２０ But, R ４０ 121. The compound of any one of claims 106 to 120, which is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

128. R ２０ But, R ４０ 121. The compound of any one of claims 106-120, which is a bicyclic ring optionally substituted with 1, 2, 3 or 4 substituents independently selected from:

129. R ２０ The compound of any one of claims 106 to 115, wherein is -O-.

130. R ２０ The compound of any one of claims 106 to 115, wherein is -S-.

131. R ２０ Ga-NR ２ The compound according to any one of claims 106 to 115, wherein

132. R ２０ is -C(O)-, -C(O)O-, -OC(O)-, -SO ２ -, -S(O)-, -C(S)-, -C(O)NR ２ -, -P(O)(R ２８ 112. The compound according to any one of claims 106 to 111, wherein the compound is -P(O)- or -P(O)-.

133. R ２１ The compound of any one of claims 106 to 132, wherein is a bond.

134. R ２１ But, R ４０ 133. The compound of any one of claims 106-132, wherein the alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

135. R ２１ But, R ４０ 133. The compound of any one of claims 106 to 132, which is an alkene or alkyne optionally substituted with 1, 2, 3 or 4 substituents independently selected from:

136. R ２１ But, R ４０ 133. The compound of any one of claims 106-132, which is haloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from:

137. R ２１ But, R ４０ 133. The compound of any one of claims 106-132, which is aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from:

138. R ２１ But, R ４０ 133. The compound of any one of claims 106-132, which is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

139. R ２１ But, R ４０ 133. The compound of any one of claims 106 to 132, which is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

140. R ２１ But, R ４０ 133. The compound of any one of claims 106-132, which is a bicyclic ring optionally substituted with 1, 2, 3 or 4 substituents independently selected from:

141. R ２１ The compound of any one of claims 106 to 128, wherein is -O-.

142. R ２１ The compound of any one of claims 106 to 128, wherein is -S-.

143. R ２１ Ga-NR ２ The compound according to any one of claims 106 to 128, wherein

144. R ２１ is -C(O)-, -C(O)O-, -OC(O)-, -SO ２ -, -S(O)-, -C(S)-, -C(O)NR ２ -, -P(O)(R ２８ )- or -P(O)-.

145. R ２２ The compound of any one of claims 106 to 144, wherein is a bond.

146. R ２２ But, R ４０ 145. The compound of any one of claims 106-144, wherein the alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

147. R ２２ But, R ４０ 145. The compound of any one of claims 106 to 144, which is an alkene or alkyne optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

148. R ２２ But, R ４０ 145. The compound of any one of claims 106 to 144, which is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

149. R ２２ But, R ４０ 145. The compound of any one of claims 106-144, which is aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from:

150. R ２２ But, R ４０ 145. The compound of any one of claims 106-144, which is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

151. R ２２ But, R ４０ 145. The compound of any one of claims 106 to 144, which is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

152. R ２２ But, R ４０ 145. The compound of any one of claims 106-144, which is a bicyclic ring optionally substituted with 1, 2, 3 or 4 substituents independently selected from:

153. R ２２ is -C(O)-, -C(O)O-, -OC(O)-, -SO ２ -, -S(O)-, -C(S)-, -C(O)NR ２ -, -P(O)(R ２８ )- or -P(O)-.

154. R ２２ The compound of any one of claims 106 to 140, wherein is -O-.

155. R ２２ The compound of any one of claims 106 to 140, wherein is -S-.

156. R ２２ Ga-NR ２ The compound according to any one of claims 106 to 140, wherein

157. R ２３ or R ２４ The compound of any one of claims 106 to 156, wherein is a bond.

158. R ２３ or R ２４ But, R ４０ 157. The compound of any one of claims 106 to 156, wherein the alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

159. R ２３ or R ２４ But, R ４０ 157. The compound of any one of claims 106 to 156, which is an alkene or alkyne optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

160. R ２３ or R ２４ But, R ４０ 157. The compound of any one of claims 106 to 156, which is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

161. R ２３ or R ２４ But, R ４０ 157. The compound of any one of claims 106 to 156, which is aryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

162. R ２３ or R ２４ But, R ４０ 157. The compound of any one of claims 106 to 156, which is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

163. R ２３ or R ２４ But, R ４０ 157. The compound of any one of claims 106 to 156, which is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

164. R ２３ or R ２４ But, R ４０ 157. The compound of any one of claims 106-156, which is a bicyclic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

165. R ２３ or R ２４ is -C(O)-, -C(O)O-, -OC(O)-, -SO ２ -, -S(O)-, -C(S)-, -C(O)NR ２ -, -P(O)(R ２８ )- or -P(O)-.

166. R ２３ or R ２４ The compound of any one of claims 106 to 156, wherein is -O-.

167. R ２３ or R ２４ The compound of any one of claims 106 to 156, wherein is -S-.

168. R ２３ or R ２４ Ga-NR ２ The compound according to any one of claims 106 to 156, wherein

169. R ２５ The compound of any one of claims 106 to 168, wherein is hydrogen.

170. R ２５ The compound of any one of claims 106 to 168, wherein is halogen.

171. R ２５ But, R １２ 169. The compound of any one of claims 106-168, wherein the alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

172. R ２５ is alkene, alkyne, hydroxyl, alkoxy, azide, amino, cyano, -OR ２ , -NR ２ R ２’ , -NR ２ SO ２ R ２８ , -OSO ２ R ２８ , -SO ２ R ２８ , haloalkyl, aryl, heteroaryl, heterocyclic, bicyclic, and cycloalkyl, wherein R ２５ Each of the groups is R １２ 169. The compound of any one of claims 106 to 168, optionally substituted with 1, 2, 3, or 4 groups independently selected from:

173. R ４０ is selected from alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azido, amino, cyano, haloalkyl, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; ４０ Each of the groups is R １２ 173. The compound of any one of claims 106 to 172, optionally substituted with 1, 2, 3, or 4 groups independently selected from:

174. R ４０ is unsubstituted.

175. 【Chemistry 25】 【change】 【change】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

176.

26. 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

177. structure: 【Chemical 27】 2. The compound of claim 1, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

178. structure: 【Chemical Formula 28】 2. The compound of claim 1, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

179. structure: 【Chemical Formula 29】 2. The compound of claim 1, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

180. structure: 【Chemistry 30】 2. The compound of claim 1, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

181. structure: 【Chemical 31】 2. The compound of claim 1, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

182. 182. A pharmaceutical composition comprising a compound according to any one of claims 1 to 181 or a pharmaceutical salt thereof and a pharmaceutically acceptable excipient.

183. 182. A method of treating a cereblon-mediated disorder in a human, comprising administering to a human in need thereof an effective dose of a compound of any one of claims 1-181 or a pharmaceutically acceptable salt or composition thereof.

184. 184. The method of claim 183, wherein the disorder is mediated by Ikaros or Aiolos.

185. 185. The method of claim 183 or 184, wherein the disorder is cancer.

186. 185. The method of claim 183 or 184, wherein the disorder is a tumor.

187. 185. The method of claim 183 or 184, wherein the disorder is an immune disorder, an autoimmune disorder, or an inflammatory disorder.

188. 185. The method of claim 183 or 184, wherein the disorder is a hematological malignancy.

189. 185. The method of claim 183 or 184, wherein the disorder is multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma.

190. 182. A compound selected from the compounds of any one of claims 1 to 181 or pharmaceutically acceptable salts or compositions thereof for use in the manufacture of a medicament for the treatment of a cereblon-mediated disorder in a human.

191. 191. The compound for use according to claim 190, wherein the disorder is mediated by Ikaros or Aiolos.

192. 192. The compound for use according to claim 190 or 191, wherein the disorder is cancer.

193. 192. The compound for use according to claim 190 or 191, wherein the disorder is a tumor.

194. 192. The compound for use according to claim 190 or 191, wherein the disorder is an immune disorder, an autoimmune disorder or an inflammatory disorder.

195. 192. The compound for use according to claim 190 or 191, wherein the disorder is a hematological malignancy.

196. 192. The compound for use according to claim 190 or 191, wherein the disorder is multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma.

197. 182. Use of a compound for the treatment of a disorder mediated by cereblon in a human, wherein the compound is selected from the compound of any one of claims 1 to 181 or a pharmaceutically acceptable salt or composition thereof.

198. 198. The use of claim 197, wherein the disorder is mediated by Ikaros or Aiolos.

199. 199. The use of claim 197 or 198, wherein the disorder is cancer.

200. 199. The use of claim 197 or 198, wherein the disorder is a tumor.

201. 199. The use of claim 197 or 198, wherein the disorder is an immune disorder, an autoimmune disorder, or an inflammatory disorder.

202. 199. The use of claim 197 or 198, wherein the disorder is a hematological malignancy.

203. 199. The use of claim 197 or 198, wherein the disorder is multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma.

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