Tricyclic degrader of Ikaros and Aiolos

Abstract

We describe tricyclic cereblon binding agents for the degradation of Ikaros or Aiolos by the ubiquitin proteasome pathway for therapeutic use.

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 Apr. 12, 2019. The entire disclosure of this application is hereby incorporated by reference in its entirety for all purposes.

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

Background Art

[0003] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. The selective identification and removal of damaged, misfolded or excessive proteins are achieved by the ubiquitin - proteasome pathway (UPP). The UPP is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, neurodegeneration and myopathy, morphogenesis of neural circuitry, regulation of cell surface receptors, ion channels and secretory pathways, response to stress and extracellular regulators, ribosome biosynthesis, and viral infection.

[0004] The covalent attachment of multiple ubiquitin molecules to the terminal lysine residue by an E3 ubiquitin ligase labels the protein for proteasomal degradation, and the protein is digested into small peptides and ultimately its constituent amino acids, which become the building blocks of new proteins. Defects in proteasomal degradation have been associated with various clinical disorders, including in particular Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease and cancer.

[0005] The Ikaros (「IKZF」) family is a series of zinc finger protein transcription factors that are 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 in the following 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 by alternative splicing, and theoretically, a large number of protein complexes can be generated by different combinations of various homologs. The C-terminal two Cys 2 His 2 A set of zinc finger motifs is highly conserved among the members of this family. Up to four zinc finger motifs are present at the N-terminus for DNA sequence recognition, and the number of these N-terminal zinc fingers varies by alternative splicing. Isoforms without these N-terminal zinc fingers exhibit a dominant negative effect on transcriptional activation (see Non-Patent Document 4).

[0006] The distributions of the various members of the Ikaros protein family in the body are very different. Ikaros, Helios, and Aiolos are mainly present in lymphoid cells and their corresponding progenitor cells. Additionally, Ikaros is detected in the brain, and Ikaros and Helios are detected in erythroid cells. Eos and Pegasus are more widespread and are found in skeletal muscle, liver, brain, and heart (see Non-Patent Document 5, Non-Patent Document 6, Non-Patent Document 7).

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

[0008] The drugs thalidomide, and its analogs lenalidomide and pomalidomide, have attracted particular interest as immunomodulatory agents and anti-neoplastic drugs in multiple myeloma (see Non-Patent Documents 8 and 9). The exact therapeutic mechanism of action of thalidomide, lenalidomide, and pomalidomide is unknown, but these compounds are used in the treatment of several cancers, including multiple myeloma. Clinical and preclinical studies regarding 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 have also been conducted.

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

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

[0011] The disclosure that thalidomide binds to cereblon E3 ubiquitin ligase led to research investigating the incorporation of thalidomide and certain derivatives into compounds for targeted protein destruction. Celgene has disclosed imids for similar uses, including those of Patent Documents 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24.

[0012] Patent Document 25, applied for by the Dana Farber Cancer Institute, discloses cereblon regulators.

[0013] Patent Document 26, applied for by C4 Therapeutics, Inc., discloses cereblon binders for the degradation of Ikaros.

Prior Art Documents

Patent Documents

[0014]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Patent Document 9

[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

Non-patent Document 2

Non-patent Document 3

Non-patent Document 4

Non-patent Document 5

Non-patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Summary of the Invention

Problems to be Solved by the Invention

[0016] An object of the present invention is to provide a new compound, use, and manufacturing process that cause the degradation of Ikaros or Aiolos for medical therapies including the treatment of hematopoietic disorders associated with abnormal cell proliferation including tumors and cancers.

Means for Solving the Problems

[0017] Provide new compounds that bind to cereblon, along with their use and manufacture. It is believed that the binding of the disclosed compounds to cereblon increases the interaction between cereblon and Ikaros (IKZF1) or Aiolos (IKZF3), resulting in their subsequent ubiquitination and degradation by the proteasome. A decrease in the levels of Ikaros or Aiolos results in changes in the transcriptional regulation of their downstream proteins. The selected compounds are not only strong binders of cereblon but also shown to strongly inhibit the growth of multiple myeloma cells compared to pomalidomide.

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

[0019] In one aspect, Formula I in a pharmaceutically acceptable carrier, optionally forming a composition:

Chemical Formula

[0020] In one embodiment, the compound of formula I is selected from formula I-a, formula I-b, and formula I-c:

Chemical formula

[0021] In another embodiment, the compound of formula I is selected from formula I-d, formula I-e, formula I-f, and formula I-g:

Chemical formula

[0022] In another aspect, the compound of formula I is formula I-h:

Chemical formula

[0023] In one aspect, a compound of formula (II) in a pharmaceutically acceptable carrier optionally for forming a composition:

Chemical formula

[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 subsequent ubiquitination and proteasomal degradation of the protein.

[0025] In one embodiment, the compounds of the invention selectively degrade IKZF1 and / or IKZF3 with respect to one or more of IKZF2 and / or IKZF4 and / or IKZF5.

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

[0027] In other embodiments, without limitation, compounds and methods for the treatment of disorders including benign tumors, neoplasms, tumors, cancers, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid-based proteinopathy, proteinopathy or fibrotic disorders are presented. Further, other disorders that can be treated using an effective amount of the compounds described herein are listed below.

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

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

[0030] For this reason, 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, isotope derivative (including deuterated derivatives) or prodrug thereof, (b) A compound of formula I or formula II described herein, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, for the treatment of a disorder mediated by Ikaros or Aiolos, (c) Use of an effective amount of a compound of formula I or formula II described herein, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, in the treatment of a patient, typically a human, having any one of the disorders described herein, including a disorder mediated by Ikaros or Aiolos, (d) Use of a compound of formula I or formula II described herein, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, in the manufacture of a medicament for the treatment of a medical disorder sensitive to the compound as further described herein, (e) A method for manufacturing a medicament for the treatment of a disorder described herein in a host, characterized by using a compound of formula I or formula II, (f) A compound of formula I or formula II described herein, or a pharmaceutically acceptable salt, isotope 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 described herein, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, in the manufacture of a medicament for the treatment of cancer including any cancer described herein, (h) A method for manufacturing a medicament for the treatment of cancer in a host including any cancer described herein, characterized by using a compound of formula I or formula II, (i) A compound of formula I or formula II described herein, or a pharmaceutically acceptable salt, isotope 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, isotope derivative or prodrug thereof, in the manufacture of a medicament for the treatment of tumors including any tumor described herein, (k) A method for manufacturing a medicament for the treatment of tumors in a host including any tumor described herein, characterized by using a compound of formula I or formula II in the manufacture, (l) A compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, for the treatment of immune disorders, autoimmune disorders or inflammatory disorders in a host, (m) Use of a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, in the manufacture of a medicament for the treatment of immune disorders, autoimmune disorders or inflammatory disorders, (n) A method for manufacturing a medicament for the treatment of immune disorders, autoimmune disorders or inflammatory disorders in a host, characterized by using a compound of formula I or formula II in the manufacture, (o) A compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, for the treatment of hematological malignancies 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, isotope derivative or prodrug thereof, in the manufacture of a medicament for the treatment of hematological malignancies such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma, (q) A method for manufacturing 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, characterized by using a compound of formula I or formula II in the manufacture, (r) A pharmaceutical composition comprising an effective therapeutically amount of a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotope 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) containing a racemate, (t) The compounds described herein in enriched form as enantiomers or as diastereomers (where appropriate) containing 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. Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In this specification, the singular forms also include the plural forms unless the context clearly dictates otherwise. Methods and materials similar or equivalent to those described herein can be used in the practice and testing of the present application, but the preferred methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference. The references cited herein are not admitted to be prior art to the present application. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and not intended to be limiting.

[0032] Compounds are described using their official 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 the present invention belongs.

[0033] In one embodiment of each compound described herein, the compound can be in the form of an isomer such as a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, or rotamer, as if each were specifically recited, unless clearly excluded by the context.

[0034] The terms "a" and "an" are not intended to limit the quantity, but rather to indicate the presence of at least one of the items being referred to. The term "or" means "and / or". The listing of a range of values is intended to serve simply as a convenient way of referring individually to each separate value falling within the range, unless otherwise specified herein, and each separate value is hereby incorporated by reference as if it were individually recited herein. All endpoints of a range are included within the range and may be combined independently. All methods described herein can be performed in a suitable order, unless otherwise specified herein or clearly precluded by context. The use of the words "such as" is intended merely to better illustrate the invention and does not indicate a limitation of the scope of the invention unless otherwise claimed.

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

[0036] More generally, examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 35 S, and 36 Cl, respectively. In one non-limiting embodiment, the isotope-labeled compounds are used for metabolic studies (e.g., using 14 C), kinetic studies (e.g., 2 H or3 It can be used in detection or imaging techniques including drug or substrate tissue distribution assays or radiotherapy of patients using H, for example, positron emission tomography (PET) or single photon emission computed tomography (SPECT). Additionally, any hydrogen atom present in the compounds of the present invention can be 18 substituted with an F atom, and this substitution may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds of the present invention and their prodrugs can generally be prepared by replacing readily available non-isotope-labeled reagents with isotope-labeled reagents and performing the schemes or the procedures disclosed in the following examples and preparations.

[0037] As a general example, but not limited to, isotopes of hydrogen, such as deuterium ( 2 H) and tritium ( 3 H), can be used at any site of the structures described where the desired results are achieved. Alternatively or additionally, isotopes of carbon, such as 13 C and 14 C can be used.

[0038] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is enriched at 90%, 95% or 99% or more at any position of the subject. In one non-limiting embodiment, deuterium is enriched at 90%, 95% or 99% at the desired position.

[0039] In one non-limiting embodiment, the substitution of hydrogen atoms with deuterium atoms can be effected in any of the compounds described herein. For example, any of the groups may be methyl, ethyl or methoxy, or contain them by substitution, and the alkyl residue may be deuterated (in a non-limiting embodiment, CDH 2 、CD 2 H、CD 3 、CH 2 CD 3 、CD 2 CD3 , CHDCH 2 D, CH 2 CD 3 , CHDCHD 2 , OCDH 2 , OCD 2 H or OCD 3 etc.). In certain other embodiments, when two substituents combine to form a ring, the unsubstituted carbon may be deuterated. In one embodiment, at least one deuterium is located on an atom having a bond that is cleaved during metabolism of the compound in vivo or is 1, 2, or 3 atoms away from the bond being metabolized (e.g., it 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 compounds in solvated forms as described herein. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex containing a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent can be isotope-substituted, such as D 2 O, d 6 -acetone, d 6 -DMSO are included. The solvate can be in liquid form or solid form.

[0041] A dash symbol ("-") not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH 2 attaches via the carbon of the keto (C=O) group.

[0042] "Alkyl" is a branched or straight-chain saturated aliphatic hydrocarbon group. In a non-limiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms. In a non-limiting embodiment, alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, alkyl is C 1 ~C 2 、C 1 ~C 3 、C 1 ~C 4 、C 1 ~C 5 、or C 1 ~C 6 . The specified ranges used herein indicate alkyl groups having each member of the ranges described as independent species. For example, the term C 1 ~C 6 alkyl as used herein is intended to mean a straight-chain or branched-chain alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, each described as an independent species. For example, the term C 1 ~C 4 alkyl as used herein is intended to mean a straight-chain or branched-chain alkyl group having 1, 2, 3, or 4 carbon atoms, each described as an independent 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] "Alkenyl" is a linear or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur at stable points along the chain. The specified ranges used herein indicate alkenyl groups having each member of the ranges described as independent species as described above for the alkyl moiety. In a non-limiting embodiment, alkenyl contains from 2 to about 12 carbon atoms, more generally from 2 to about 6 carbon atoms or from 2 to about 4 carbon atoms. In certain embodiments, alkenyl is C 2 C 2 ~C 3 C 2 ~C 4 C 2 ~C 5 or C 2 ~C 6 . Examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" includes "cis" and "trans" alkenyl configurations, or alternatively "E" and "Z" alkenyl configurations. The term "alkenyl" also encompasses cycloalkyl or carbocyclic groups having at least one point of unsaturation.

[0044] "Alkynyl" is a branched or linear aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can occur at any stable point along the chain. The specified ranges used herein indicate alkynyl groups having each member of the ranges described as independent species as described above for the alkyl moiety. In a non-limiting embodiment, alkynyl contains from 2 to about 12 carbon atoms, more generally from 2 to about 6 carbon atoms or from 2 to about 4 carbon atoms. In certain embodiments, alkynyl is C 2 C 2 ~C 3 C 2 ~C 4 C 2 ~C 5 or C 2 ~C 6It is. 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 each independently fluorine, chlorine, bromine, or iodine.

[0046] "Haloalkyl" is a branched or straight-chain alkyl group substituted with one or more of the above halo atoms up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Perhaloalkyl" means an alkyl group in which all hydrogen atoms are replaced by 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., where 6, 10, or 14 π electrons are shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms within the aromatic ring system (the "C 6~14 aryl"). In some embodiments, the aryl group has 6 ring carbon atoms (the "C 6 aryl", e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (the "C 10 aryl", e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (the "C 14"Aryl", for example anthracyl. "Aryl" also includes a ring system in which one or more of the above-defined aryl rings are fused with one or more cycloalkyl or heterocyclic groups and the radical or point of attachment is on the aryl ring, and in such cases 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 "heterocyclic ring" refers to a saturated and partially saturated heteroatom-containing ring radical having one, two, three or four heteroatoms independently selected from nitrogen, sulfur, boron, silicon and oxygen. The heterocyclic ring can include monocyclic rings having 3 to 10 members, and bicyclic ring systems having 5 to 16 members (which may include bridged fused and spiro-fused bicyclic ring systems). The heterocyclic ring does not include rings containing -O-O-, -O-S- or -S-S- moieties. Examples of saturated heterocyclic groups include saturated 3- to 6-membered heteromonocyclic groups containing one to four nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl), saturated 3- to 6-membered heteromonocyclic groups containing one or two oxygen atoms and one to three nitrogen atoms (e.g., morpholinyl), and saturated 3- to 6-membered heteromonocyclic groups containing one or two sulfur atoms and one to three 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, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl.

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

[0050] The term "heterocyclic ring" also includes "bicyclic heterocyclic rings". The term "bicyclic heterocyclic ring" represents a heterocyclic ring as defined herein having one cross-linked, fused or spiro cyclic moiety. The cross-linked, fused or spiro cyclic moiety of the heterocyclic ring can be a carbocyclic, heterocyclic or aryl group as long as a stable molecule results. Unless excluded by context, the term "heterocyclic ring" includes bicyclic heterocyclic rings. Bicyclic heterocyclic rings include groups in which the fused heterocyclic ring is substituted with an oxo group. Non-limiting examples of bicyclic heterocyclic rings include [Chem.] and the like.

[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 ring nitrogen and sulfur atoms (if any) are optionally oxidized and nitrogen atoms (if any) 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); unsaturated 5- or 6-membered heteromonocyclic groups containing an oxygen atom such as pyranyl, 2-furyl, 3-furyl; unsaturated 5- or 6-membered heteromonocyclic groups containing a sulfur atom such as 2-thienyl, 3-thienyl; unsaturated 5- or 6-membered heteromonocyclic groups containing one or two oxygen atoms and one to three nitrogen atoms such as oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl); unsaturated 5- or 6-membered heteromonocyclic groups containing one or two sulfur atoms and one to three nitrogen atoms such as thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl), but are not limited thereto. In one embodiment, the "heteroaryl" group is an 8-, 9-, or 10-membered bicyclic ring system. Examples of 8-, 9-, or 10-membered bicyclic heteroaryl groups include benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazolyl, and benzotriazolyl.

[0052] As used herein, "carbocyclic", "carbocycle", or "cycloalkyl" refers to all carbon ring atoms in a non-aromatic ring system and three to fourteen ring carbon atoms ("C" 3~14"(cycloalkyl") and a saturated or partially unsaturated (i.e., non-aromatic) group containing 0 heteroatoms. In some embodiments, the cycloalkyl group has 3 to 10 ring carbon atoms ("C 3~10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 9 ring carbon atoms ("C 3~9 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 7 ring carbon atoms ("C 3~7 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 cycloalkyl"). In some embodiments, the cycloalkyl group has 4 to 6 ring carbon atoms ("C 4~6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 or 6 ring carbon atoms ("C 5~6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 cycloalkyl"). Exemplary C 3~6 cycloalkyl groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), etc. Exemplary C 3~8 cycloalkyl groups include, but are not limited to, the above-mentioned C 3~6 cycloalkyl groups, and cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7) cycloheptatrienyl (C 7 ) cyclooctyl (C 8 ) cyclooctenyl (C 8 ) etc. are mentioned. Exemplary C 3~10 cycloalkyl groups include, but are not limited to, the above-mentioned C 3~8 cycloalkyl groups, and cyclononyl (C 9 ) cyclononenyl (C 9 ) cyclodecyl (C 10 ) cyclodecenyl (C 10 ) etc. are mentioned. As shown in the above examples, in certain embodiments, the cycloalkyl group may be saturated or may contain one or more carbon-carbon double bonds. The term "cycloalkyl" also includes a ring system in which the cycloalkyl ring defined above is fused to one heterocyclic ring, aryl or heteroaryl ring and the attachment point is on the cycloalkyl ring, and in such a case, the number of carbon atoms continues to represent the number of carbon atoms in the carbocyclic ring system. The term "cycloalkyl" also includes a ring system in which the cycloalkyl ring defined above has a spirocyclic heterocyclic ring, aryl or heteroaryl ring and the attachment point is on the cycloalkyl ring, and in such a case, the number of carbon atoms continues to represent the number of carbon atoms 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 0 heteroatoms in the non-aromatic ring system. Representative examples of "cycloalkyl" include

Chemical formula

[0053] The term "bicyclic" refers to a ring system in which two rings are fused and each ring is independently selected from a carbocyclic ring, heterocyclic ring, aryl and heteroaryl. Non-limiting examples of bicyclic groups include

Chemical formula

[0054] When the term "bicyclic" is R 20 R 21 R22 , R 23 or R 24 When used in connection with a divalent residue such as, etc., the attachment points may be on separate rings or on the same ring. In certain embodiments, both attachment points are on the same ring. In certain embodiments, both attachment points are on different rings. Non-limiting examples of divalent bicyclic groups include

Chemical formula

[0055] "Dosage form" means a unit of 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, oral dosage forms, sublingual dosage forms, topical dosage forms, gels, mucosal dosage forms, etc. "Dosage form" may also include implants, such as optical implants.

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

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

[0058] The term "modulate", as used herein, means to mediate a detectable increase or decrease in the level of response in a subject compared to the level of response in the subject in the absence of treatment or compound and / or compared to the level of response in an untreated subject that is otherwise identical. This term encompasses disturbing 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 (s.c.), intravenous (i.v.), intramuscular (i.m.) or intrasternal injection, or infusion methods.

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

[0061] As used herein, a "pharmaceutically acceptable salt" is a derivative of a disclosed compound in which the parent compound is modified by making its inorganic and organic salts, acid addition salts or base addition salts, with loss of biologically unacceptable toxicity. The salts of the present compounds can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in the free acid form with a stoichiometric amount of the appropriate base (hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or reacting these compounds in the free base form with a stoichiometric amount of the 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 practicable. The salts of the present compounds further include solvates of the compounds and the 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, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts of parent compounds formed 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, nitric acid, and organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH 2 ) n -COOH (wherein n is from 0 to 4) and salts prepared from such organic acids or using different acids that generate the same counterion. A more complete list of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

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

[0064] "Pharmaceutically acceptable excipient" generally means an excipient that is safe, not biologically or otherwise inappropriate for administration to a host (usually a human), and useful in the preparation of pharmaceutical compositions / formulations. In one embodiment, excipients acceptable for veterinary use are employed.

[0065] "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 / agent of the present invention means an amount effective to bring about a therapeutic effect such as improvement of symptoms or reduction or alleviation of the disease itself when administered to a host.

[0067] Throughout the present disclosure, various aspects of the present invention may be presented in a range format. It should be understood that the description in range format is for convenience only and should not be construed as a limitation on the scope of the present invention. The description of a range should be considered to specifically disclose all possible sub-ranges and individual numerical values within that range. For example, a description of a range such as 1 to 6 should be considered to specifically disclose sub-ranges 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, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0068] II. Compounds of the Present Invention Embodiments of "alkyl" In one embodiment, "alkyl" is C 1 ~C 10 alkyl, C 1 ~C 9 alkyl, C 1 ~C 8 alkyl, C 1 ~C 7 alkyl, C 1 ~C 6 alkyl, C 1 ~C 5 alkyl, C 1 ~C 4 alkyl, C 1 ~C 3 alkyl, or C 1 or C 2 alkyl.

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

[0070] In one embodiment, "alkyl" contains two carbon atoms.

[0071] In one embodiment, "alkyl" contains three carbon atoms.

[0072] In one embodiment, "alkyl" contains four carbon atoms.

[0073] In one embodiment, "alkyl" contains five carbon atoms.

[0074] In one embodiment, "alkyl" contains six carbon atoms.

[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] Embodiments of "haloalkyl" In one embodiment, "haloalkyl" is C 1 ~C 10 haloalkyl, C 1 ~C9 Haloalkyl, C 1 ~C 8 Haloalkyl, C 1 ~C 7 Haloalkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 5 Haloalkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 3 Haloalkyl and C 1 or C 2 is a haloalkyl.

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

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

[0083] In one embodiment, "haloalkyl" has 1 carbon atom and 2 halogen atoms.

[0084] In one embodiment, "haloalkyl" has 1 carbon atom and 3 halogen atoms.

[0085] In one embodiment, "haloalkyl" has 2 carbon atoms.

[0086] In one embodiment, "haloalkyl" has 3 carbon atoms.

[0087] In one embodiment, "haloalkyl" has 4 carbon atoms.

[0088] In one embodiment, "haloalkyl" has 5 carbon atoms.

[0089] In one embodiment, "haloalkyl" has 6 carbon atoms.

[0090] Non-limiting examples of "haloalkyl" include [Chemical formula] include the following.

[0091] Additional non-limiting examples of "haloalkyl" include [Chemical formula] include the following.

[0092] Additional non-limiting examples of "haloalkyl" include [Chemical formula] include the following.

[0093] Additional non-limiting examples of "haloalkyl" include [Chemical formula] include the following.

[0094] Embodiments of "aryl" In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl).

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

[0096] In one embodiment, "aryl" is a 6-carbon aromatic group condensed to a heterocyclic ring where the point of attachment is 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, [Chemical formula] is an "aryl" group.

[0098] However, [Chemistry] is a "heterocyclic ring" group.

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

[0100] For example, [Chemistry] is an "aryl" group.

[0101] However, [Chemistry] is a "cycloalkyl" group.

[0102] Embodiments of "heteroaryl" In one embodiment, "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 [Chemistry] are included.

[0105] In one embodiment, "heteroaryl" is a 6-membered aromatic group containing one, two or three nitrogen atoms (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl and pyrazinyl).

[0106] Non-limiting examples of 6-membered "heteroaryl" groups having one or two nitrogen atoms include

Chemical formula

[0107] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing one or two 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

Chemical formula

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

Chemical formula

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

Chemical formula

[0112] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing one or two 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

Chemical Structure

[0115] Embodiments of "cycloalkyl" In one embodiment, "cycloalkyl" is C 3 ~C 8 cycloalkyl, C 3 ~C 7 cycloalkyl, C 3 ~C 6 cycloalkyl, C 3 ~C 5 cycloalkyl, C 3 or C 4 cycloalkyl, C 4 ~C 8 cycloalkyl, C 5 ~C 8 cycloalkyl or C 6 ~C 8 cycloalkyl.

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

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

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

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

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

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

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

[0123] In one embodiment, "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,

Chemical formula

[0127] However,

Chemical formula

[0128] Additional examples of "cycloalkyl" groups include

Chemical formula

[0129] Embodiments of "heterocycle" In one embodiment, "heterocyclic ring" refers to a cyclic ring having one nitrogen and three, four, five, six, seven, or eight carbon atoms.

[0130] In one embodiment, "heterocyclic ring" refers to a cyclic ring having one nitrogen, one oxygen, and three, four, five, six, seven, or eight carbon atoms.

[0131] In one embodiment, "heterocyclic ring" refers to a cyclic ring having two nitrogens and three, four, five, six, seven, or eight carbon atoms.

[0132] In one embodiment, "heterocyclic ring" refers to a cyclic ring having one oxygen and three, four, five, six, seven, or eight carbon atoms.

[0133] In one embodiment, "heterocyclic ring" refers to a cyclic ring having one sulfur and three, four, five, six, seven, or eight carbon atoms.

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

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

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

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

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

[0139] For example,

Chem.

[0140] However,

Chem.

[0141] Non-limiting examples of "heterocyclic ring" include

Chem.

[0142] Additional non-limiting examples of "heterocyclic ring" include

Chem.

[0143] Additional non-limiting examples of "heterocyclic ring" include

Chem.

[0144] Non-limiting examples of "heterocyclic ring" include

Chem.

[0145] Non-limiting examples of "heterocyclic ring" include

Chem.

[0146] Additional non-limiting examples of "heterocyclic ring" include

Chem.

[0147] Additional non-limiting examples of "heterocyclic ring" include

Chem.

[0148] Any substituent In one embodiment, the moieties described herein that can be substituted with one, two, three, or four substituents are substituted with one substituent.

[0149] In one embodiment, the moieties described herein that can be substituted with one, two, three, or four substituents are substituted with two substituents.

[0150] In one embodiment, the moieties described herein that can be substituted with one, two, three, or four substituents are substituted with three substituents.

[0151] In one embodiment, the moieties described herein that can be substituted with one, two, three, or four substituents are substituted with four 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

Chem.

[0154] Non-limiting embodiments of formula I: In certain embodiments, the compounds of the present invention have the formula:

Chem.

[0155] In certain embodiments, the compound of the present invention has the formula:

Chem.

[0156] In certain embodiments, the compound of the present invention has the formula:

Chem.

[0157] In certain embodiments, the compound of the present invention has the formula:

Chem.

[0158] In certain embodiments, the compound of the present invention has the formula:

Chem.

[0159] In certain embodiments, the compound of the present invention has the formula:

Chem.

[0160] In certain embodiments, the compound of the present invention has the formula:

Chem.

[0161] In certain embodiments, the compounds of the invention have the formula:

Chemical formula

[0162] In certain embodiments, the compounds of the invention have the formula:

Chemical formula

[0163] In certain embodiments, the compounds of the invention have the formula:

Chemical formula

[0164] In certain embodiments, the compounds of the invention are

Chemical formula

[0165] In one embodiment, the compound of formula I is

Chemical formula

[0166] In one embodiment, the compound of formula I is

Chemical formula

[0167] In one embodiment, the compound of formula I is

Chemical formula

[0168] In one embodiment, the compound of formula I is

Chemical formula

[0169] In one embodiment, the compound of formula I is

Chemical formula

[0170] In one embodiment, the compound of formula I is

Chemical formula

[0171] In one embodiment, the compound of formula I is

Chemical formula

[0172] In one embodiment, the compound of formula I is

Chemical formula

[0173] In one embodiment, the compound of formula I is

Chemical formula

[0174] In one embodiment, the compound of Formula I is

Chemical formula

[0175] In one embodiment, the compound of Formula I is

Chemical formula

[0176] In one embodiment, the compound of Formula I is

Chemical formula

[0177] In one embodiment, the compound of Formula I is

Chemical formula

[0178] In one embodiment, the compound of Formula I is

Chemical formula

[0179] In one embodiment, the compound of Formula I is

Chemical formula

[0180] In one embodiment, the compound of Formula I is

Chemical formula

[0181] In one embodiment, the compound of Formula I is

Chemical formula

[0182] R 1 non-limiting embodiments of In one embodiment of Formula I, R 1 is -NH(R 6 cycloalkyl substituted with). In one embodiment of Formula I, R 1 is -NH(R 6 heterocyclic ring substituted with). In one embodiment of Formula I, R 1 is -NH(R 6 aryl substituted with). In one embodiment of Formula I, R 1 is -NH(R 6 heteroaryl substituted with). In one embodiment of Formula I, R 1 is -N(CH 3 )(R 6 cycloalkyl substituted with). In one embodiment of Formula I, R 1 is -N(CH 3 )(R 6 heterocyclic ring substituted with). In one embodiment of Formula I, R 1 is -N(CH 3 )(R 6 aryl substituted with). In one embodiment of Formula I, R 1 is -N(CH 3 )(R 6 heteroaryl substituted with).

[0183] In one embodiment of Formula I, R 1 is -O(R 6 cycloalkyl substituted with). In one embodiment of Formula I, R 1 is -O(R 6 heterocyclic ring substituted with). In one embodiment of Formula I, R 1 is -O(R 6 aryl substituted with). In one embodiment of Formula I, R 1 is -O(R 6selected from (heteroaryl) substituted with

[0184] In one embodiment of Formula I, R 1 is selected from -S(R 6 substituted cycloalkyl). In one embodiment of Formula I, R 1 is selected from -S(R 6 substituted heterocycle). In one embodiment of Formula I, R 1 is selected from -S(R 6 substituted aryl). In one embodiment of Formula I, R 1 is selected from -S(R 6 substituted heteroaryl).

[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(CH 3 )-C(O)-(alkyl). In one embodiment of Formula I, R 1 is selected from -N(CH 3 )-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is selected from -N(CH 3 )-C(O)-(heterocycle). In one embodiment of Formula I, R 1 is selected from -N(CH 3 )-C(O)-(aryl). In one embodiment of Formula I, R 1 is selected from -N(CH 3 )-C(O)-(heteroaryl).

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

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

[0188] In one embodiment of formula I, R 1 is -CH 2 (cycloalkyl substituted with R 6 ). In one embodiment of formula I, R 1 is -CH 2 (heterocycle substituted with R 6 ). In one embodiment of formula I, R 1 is -CH 2 (aryl substituted with R 6 ). In one embodiment of formula I, R 1 is -CH 2 (heteroaryl substituted with R 6 ). In one embodiment of formula I, R 1 is -CF 2 (cycloalkyl substituted with R 6 ). In one embodiment of formula I, R1 is -CF 2 (R 6 substituted complex ring), selected from. In one embodiment of Formula I, R 1 is -CF 2 (R 6 substituted aryl), selected from. In one embodiment of Formula I, R 1 is -CF 2 (R 6 substituted heteroaryl), selected from. In one embodiment of Formula I, R 1 is -CH(OH)(R 6 substituted cycloalkyl), selected from. In one embodiment of Formula I, R 1 is -CH(OH)(R 6 substituted complex ring), selected from. In one embodiment of Formula I, R 1 is -CH(OH)(R 6 substituted aryl), selected from. In one embodiment of Formula I, R 1 is -CH(OH)(R 6 substituted heteroaryl), selected from.

[0189] In one embodiment of Formula I, R 1 is -CH 2 -C(O)-(alkyl), selected from. In one embodiment of Formula I, R 1 is -CH 2 -C(O)-(cycloalkyl), selected from. In one embodiment of Formula I, R 1 is -CH 2 -C(O)-(complex ring), selected from. In one embodiment of Formula I, R 1 is -CH 2 -C(O)-(aryl), selected from. In one embodiment of Formula I, R 1 is -CH 2 -C(O)-(heteroaryl), selected from. In one embodiment of Formula I, R 1 is -CF 2 -C(O)-(alkyl), selected from. In one embodiment of Formula I, R 1 is -CF 2-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is -CF 2 -C(O)-(heterocycle). In one embodiment of Formula I, R 1 is -CF 2 -C(O)-(aryl). In one embodiment of Formula I, R 1 is -CF 2 -C(O)-(heteroaryl). In one embodiment of Formula I, R 1 is -CH(OH)-C(O)-(alkyl). In one embodiment of Formula I, R 1 is -CH(OH)-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is -CH(OH)-C(O)-(heterocycle). In one embodiment of Formula I, R 1 is -CH(OH)-C(O)-(aryl). In one embodiment of Formula I, R 1 is -CH(OH)-C(O)-(heteroaryl).

[0190] In one embodiment of Formula I, R 1 is -CH 2 -NH(cycloalkyl substituted with R 6 ). In one embodiment of Formula I, R 1 is -CH 2 -NH(heterocycle substituted with R 6 ). In one embodiment of Formula I, R 1 is -CH 2 -NH(aryl substituted with R 6 ). In one embodiment of Formula I, R 1 is -CH 2 -NH(heteroaryl substituted with R 6 ). In one embodiment of Formula I, R 1 is -CH 2 -N(CH 3 )(cycloalkyl substituted with R 6 ). In one embodiment of Formula I, R 1 is -CH2 -N(CH 3 )(R 6 substituted heterocyclic ring) selected from. In one embodiment of formula I, R 1 is -CH 2 -N(CH 3 )(R 6 substituted aryl) selected from. In one embodiment of formula I, R 1 is -CH 2 -N(CH 3 )(R 6 substituted heteroaryl) selected from.

[0191] In one embodiment of formula I, R 1 is -CH 2 -O(R 6 substituted cycloalkyl) selected from. In one embodiment of formula I, R 1 is -CH 2 -O(R 6 substituted heterocyclic ring) selected from. In one embodiment of formula I, R 1 is -CH 2 -O(R 6 substituted aryl) selected from. In one embodiment of formula I, R 1 is -CH 2 -O(R 6 substituted heteroaryl) selected from.

[0192] In one embodiment of formula I, R 1 is -CH 2 -NH-C(O)-(alkyl) selected from. In one embodiment of formula I, R 1 is -CH 2 -NH-C(O)-(cycloalkyl) selected from. In one embodiment of formula I, R 1 is -CH 2 -NH-C(O)-(heterocyclic ring) selected from. In one embodiment of formula I, R 1 is -CH 2 -NH-C(O)-(aryl) selected from. In one embodiment of formula I, R 1 is -CH 2-NH-C(O)-(heteroaryl). In one embodiment of Formula I, R 1 is -CH 2 -N(CH 3 )-C(O)-(alkyl). In one embodiment of Formula I, R 1 is -CH 2 -N(CH 3 )-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is -CH 2 -N(CH 3 )-C(O)-(heterocycle). In one embodiment of Formula I, R 1 is -CH 2 -N(CH 3 )-C(O)-(aryl). In one embodiment of Formula I, R 1 is -CH 2 -N(CH 3 )-C(O)-(heteroaryl).

[0193] In one embodiment of Formula I, R 1 is -CH 2 -O-C(O)-(alkyl). In one embodiment of Formula I, R 1 is -CH 2 -O-C(O)-(cycloalkyl). In one embodiment of Formula I, R 1 is -CH 2 -O-C(O)-(heterocycle). In one embodiment of Formula I, R 1 is -CH 2 -O-C(O)-(aryl). In one embodiment of Formula I, R 1 is -CH 2 -O-C(O)-(heteroaryl).

[0194] In one embodiment of Formula I, R 1 is -C(O)-(cycloalkyl substituted with R 6 ). In one embodiment of Formula I, R 1 is -C(O)-(R 6selected from a complex ring substituted with). In one embodiment of Formula I, R 1 is selected from -C(O)-(R 6 aryl substituted with). In one embodiment of Formula I, R 1 is selected from -C(O)-(R 6 heteroaryl substituted with).

[0195] In one embodiment of Formula I, R 1 is selected from -S(O)-(R 6 cycloalkyl substituted with). In one embodiment of Formula I, R 1 is selected from -S(O)-(R 6 complex ring substituted with). In one embodiment of Formula I, R 1 is selected from -S(O)-(R 6 aryl substituted with). In one embodiment of Formula I, R 1 is selected from -S(O)-(R 6 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 complex ring substituted with). In one embodiment of Formula I, R 1 is -S(O) 2 -(R 6 aryl substituted with). In one embodiment of Formula I, R 1 is -S(O) 2 -(R 6 heteroaryl substituted with).

[0197] In one embodiment of Formula I, R 1 is

Chemical formula

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

[0199] In certain embodiments, R 1 is -(CH 2 )-R 4 wherein R 4 is heteroaryl optionally substituted with R 6 and R 6 is a heterocyclic ring optionally substituted with one or two groups selected from R 9 . In a further embodiment, R 9 is selected from hydrogen and alkyl. Non-limiting examples of this embodiment include

Chemical formula

[0200] In certain embodiments, R 1 is -(CH 2 )-R 4 wherein R 4 is heteroaryl optionally substituted with R 6 and R 6 is a heterocyclic ring optionally substituted with one or two groups selected from R 9 . In a further embodiment, R 9 is selected from alkyl and -C(O)R 10 wherein R 10 is a heterocyclic ring. Non-limiting examples of this embodiment include

Chemical formula

[0201] In certain embodiments, R 1 is -(CH 2 )-R 4 wherein R 4 is R 6is a heteroaryl optionally substituted with, R 6 is R 9 is a heterocycle optionally substituted with one or two groups selected from R 9 is alkyl and -C(O)R 10 selected from, where R 10 is R 11 is a heterocycle optionally substituted with, R 11 is alkyl. Non-limiting examples of this embodiment include

Chemical formula

[0202] In a particular embodiment, R 1 is -(CH 2 )-R 4 where R 4 is R 6 is a heteroaryl optionally substituted with, R 6 is R 9 is a heterocycle optionally substituted with one or two groups selected from R 9 is alkyl and -C(O)R 10 selected from, where R 10 is cycloalkyl. Non-limiting examples of this embodiment include

Chemical formula

[0203] In a particular embodiment, R 1 is -(CH 2 )-R 4 where R 4 is R 6 is a heteroaryl optionally substituted with, R 6 is R 9 is a heterocycle optionally substituted with one or two groups selected from R 9 is alkyl and -C(O)R 10 selected from, where R 10 is R11 is a cycloalkyl optionally substituted with 11 , and R 11 is cyano. Non-limiting examples of this embodiment include

Chemical formula

[0204] In a particular embodiment, R 1 is -(CH 2 )-R 4 wherein R 4 is a heteroaryl optionally substituted with R 6 , and R 6 is a heterocyclic ring optionally substituted with one or two groups selected from R 9 . In a further embodiment, R 9 is selected from alkyl and -C(O)R 10 wherein R 10 is a cycloalkyl optionally substituted with R 11 , and R 11 is alkyl. Non-limiting examples of this embodiment include

Chemical formula

[0205] In a particular embodiment, R 1 is -(CH 2 )-R 4 wherein R 4 is a heteroaryl optionally substituted with R 6 , and R 6 is a heterocyclic ring optionally substituted with one or two groups selected from R 9 . In a further embodiment, R 9 is selected from alkyl and -C(O)R 10 wherein R 10 is a cycloalkyl optionally substituted with R 11 , and R 11 is haloalkyl. Non-limiting examples of this embodiment include

Chemical formula

[0206] In a particular embodiment, R 1 is -(CH 2 )-R 4 , where R 4 is heteroaryl optionally substituted with R 6 , and R 6 is a heterocyclic ring optionally substituted with one or two groups selected from R 9 . In a further embodiment, R 9 is selected from alkyl and -C(O)R 10 , where R 10 is alkyl optionally substituted with R 11 , and R 11 is selected from hydrogen, hydroxyl and cyano. Non-limiting examples of this embodiment include

Chemical formula

[0207] In a particular embodiment, R 1 is -(CH 2 )-R 4 , where R 4 is heteroaryl optionally substituted with R 6 , and R 6 is a heterocyclic ring optionally substituted with one or two groups selected from R 9 . In a further embodiment, R 9 is selected from alkyl and -C(O)R 10 , where R 10 is haloalkyl. Non-limiting examples of this embodiment include

Chemical formula

[0208] In a particular embodiment, R 1 is -(CH 2 )-R 4and wherein R 4 is heteroaryl optionally substituted with R 6 and R 6 is a heterocycle optionally substituted with one or two groups selected from R 9 . In a further embodiment, R 9 is selected from alkyl and -C(O)R 10 wherein R 10 is alkyl optionally substituted with R 11 and R 11 is OR 8 . Non-limiting examples of this embodiment include

Chemical formula

[0209] In certain embodiments, R 1 is -(CH 2 )-R 4 wherein R 4 is heteroaryl optionally substituted with R 6 and R 6 is a heterocycle optionally substituted with R 9 . In a further embodiment, R 9 is -C(O)R 10 wherein R 10 is heteroaryl or aryl optionally substituted with R 11 and R 11 is selected from hydrogen and alkyl. Non-limiting examples of this embodiment include

Chemical formula

[0210] In certain embodiments, R 1 is -(CH 2 )-R 4 wherein R 4 is heteroaryl optionally substituted with R 6 and R 6 is R 9is a complex ring optionally substituted with. In a further embodiment, R 9 is -C(O)NR 2 R 10 or -C(O)OR 10 wherein R 10 is alkyl. Non-limiting examples of this embodiment include

Chemical Formula

[0211] In a particular embodiment, R 1 is -(CH 2 )-R 4 wherein R 4 is heteroaryl optionally substituted with R 6 and R 6 is a complex ring optionally substituted with one or two groups selected from R 9 . In a further embodiment, R 9 is selected from alkyl and -CH 2 R 10 wherein R 10 is cycloalkyl optionally substituted with R 11 and R 11 is alkyl. Non-limiting examples of this embodiment include

Chemical Formula

[0212] In a particular embodiment, R 1 is -(CH 2 )-R 4 wherein R 4 is heteroaryl optionally substituted with R 6 and R 6 is a complex ring optionally substituted with one or two groups selected from R 9 . In a further embodiment, R 9 is selected from alkyl and -CH 2 R 10 wherein R 10 is R 11is a cycloalkyl optionally substituted with, R 11 is selected from haloalkyl or cyano. Non-limiting examples of this embodiment include

Chemical formula

[0213] In a particular embodiment, R 1 is -(CH 2 )-R 4 , where R 4 is a heteroaryl optionally substituted with R 6 , and R 6 is a heterocycle optionally substituted with one or two groups selected from R 9 . In a further embodiment, R 9 is selected from alkyl and -CH 2 R 10 , where R 10 is a cycloalkyl optionally substituted with R 11 , and R 11 is OR 8 . Non-limiting examples of this embodiment include

Chemical formula

[0214] In a particular embodiment, R 1 is -(CH 2 )-R 4 , where R 4 is a heteroaryl optionally substituted with R 6 , and R 6 is a heterocycle optionally substituted with one or two groups selected from R 9 . In a further embodiment, R 9 is selected from alkyl and -CH 2 R 10 , where R 10 is an alkyl optionally substituted with R 11 , and R 11 is hydrogen, cyano and OR 8is selected from. As non-limiting examples of this embodiment, [Chemical formula] are included.

[0215] In a particular embodiment, R 1 is -(CH 2 )-R 4 , where R 4 is a heteroaryl optionally substituted with R 6 , and R 6 is a heterocyclic ring optionally substituted with R 9 . In a further embodiment, R 9 is R 10 , and R 10 is cycloalkyl. As non-limiting examples of this embodiment, [Chemical formula] are included.

[0216] In a particular embodiment, R 1 is -(CH 2 )-R 4 , where R 4 is a heteroaryl substituted with R 7 and substituted with R 6 , where R 6 is a heterocyclic ring optionally substituted with one or two groups selected from R 9 . In a further embodiment, R 9 is selected from alkyl and -C(O)R 10 , R 10 is a cycloalkyl optionally substituted with R 11 , and R 11 is alkyl. As non-limiting examples of this embodiment, [Chemical formula] are included.

[0217] In a particular embodiment, R 1Ha-(CH 2 )-R 4 where R 4 is R 6 is heteroaryl optionally substituted with 6 is cycloalkyl. Non-limiting examples of this embodiment include: [ka] Examples include:

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

[0219] In certain embodiments, R 1 -CH(CH 3 )R 4 where R 4 is R 6 is heteroaryl optionally substituted with 6 is a heterocycle. In a further embodiment, R 6 is R 9 Optionally replaced by 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: [Chemistry] include the following.

[0220] In a particular embodiment, R 1 is -CH(NH 2 )R 4 wherein R 4 is heteroaryl optionally substituted with R 6 and R 6 is a heterocyclic ring. In a further embodiment, R 6 is optionally substituted with R 9 and R 9 is -C(O)OR 10 or -C(O)R 10 wherein R 10 is alkyl or cycloalkyl optionally substituted with R 11 and R 11 is selected from alkyl and hydrogen. Non-limiting examples of this embodiment include [Chemistry] include the following.

[0221] In a particular embodiment, R 1 is -SR 4 , -S(O)R 4 or -S(O) 2 R 4 wherein R 4 is heteroaryl optionally substituted with R 6 and R 6 is a heterocyclic ring optionally substituted with R 9 In a further embodiment, R 9 is -C(O)R 10 wherein R 10 is cycloalkyl optionally substituted with R 11 and R 11 is alkyl. Non-limiting examples of this embodiment include [Chemistry] include the following.

[0222] In certain embodiments, R 1 is -(CH 2 )-R 4 wherein R 4 is heteroaryl optionally substituted with R 6 and R 6 is cycloalkyl optionally substituted with R 9 . In a further embodiment, R 9 is selected from -OR 10 wherein R 10 is alkyl optionally substituted with R 11 and R 11 is aryl. Non-limiting examples of this embodiment include

Chemical Formula

[0223] In certain embodiments, R 1 is -(CR 3 R 3’ )-R 4 wherein R 3 and R 3’ together with the carbon to which they are attached form a 3-membered cycloalkyl ring, and R 4 is heteroaryl optionally substituted with R 6 wherein R 6 is a heterocyclic ring optionally substituted with R 9 . In a further embodiment, R 9 is -C(O)R 10 or -CH 2 R 10 wherein R 10 is cycloalkyl optionally substituted with R 11 and R 11 is alkyl. Non-limiting examples of this embodiment include

Chemical Formula

[0224] In certain embodiments, R 1 is -(CH 2 )-R 4 wherein R 4 is aryl substituted with R 6 and R 6 is alkyl optionally substituted with R 9 . In a further embodiment, R 9 is R 10 and R 10 is a heterocyclic ring optionally substituted with R 11 wherein R 11 is -C(O)OR 8 , -C(O)R 8 or -SO 2 R 8 and R 8 is alkyl, cycloalkyl, haloalkyl or aryl. Non-limiting examples of this embodiment include

Chemical formula

[0225] In certain embodiments, R 1 is -(CH 2 )-R 4 wherein R 4 is aryl substituted with R 6 and R 6 is alkyl optionally substituted with R 9 . In a further embodiment, R 9 is R 10 and R 10 is a heterocyclic ring or heteroaryl. Non-limiting examples of this embodiment include

Chemical formula

[0226] In certain embodiments, R 1 is -(CH 2 )-R 4 wherein R 4 is aryl substituted with R 6 ​6 is alkyl optionally substituted by R 9 In a further embodiment, R 9 is R 10 and R 10 is R 11 is a heterocyclic ring or heteroaryl optionally substituted by R 11 is selected from hydrogen, alkyl or haloalkyl. In one embodiment, two R 11 groups on the same carbon combine to form an oxo group. Non-limiting examples of this embodiment include

Chemical formula

[0227] is -CH 1 -R 2 wherein R 4 is aryl optionally substituted by R 4 and R 6 is alkyl optionally substituted by R 6 In a further embodiment, R 9 is R 9 wherein R 10 is a heterocyclic ring optionally substituted by R 10 and R 11 is -CH 11 aryl optionally substituted by halogen. Non-limiting examples of this embodiment include 2 In a certain specific embodiment, R

Chemical formula

[0228] is -CH 1 -R 2 wherein R 4 is aryl optionally substituted by R 4 and R 6 is alkyl optionally substituted by R 6 In a further embodiment, R 9 is R 9 is R10 and where R 10 is a heterocyclic ring optionally substituted with R 11 and R 11 is an aryl optionally substituted with halogen. Non-limiting examples of this embodiment include

Chemical Formula

[0229] In a particular embodiment, R 1 is -CH 2 -R 4 and where R 4 is an aryl optionally substituted with R 6 and R 6 is a heterocyclic ring optionally substituted with R 9 . In a further embodiment, R 9 is -CH 2 R 10 or -C(O)R 10 and where R 10 is a cycloalkyl optionally substituted with R 11 and R 11 is hydrogen or alkyl. Non-limiting examples of this embodiment include

Chemical Formula

[0230] In a particular embodiment, R 1 is -(CH 2 )-R 4 and where R 4 is a heteroaryl optionally substituted with R 6 and R 6 is a heterocyclic ring optionally substituted with R 9 . In a further embodiment, R 9 is selected from R 10 where R 10 is a heteroaryl optionally substituted with an R 11 group selected from halogen and hydrogen. Non-limiting examples of this embodiment include [Chemical formula] include the following.

[0231] In a certain specific embodiment, R 1 is [Chemical formula] selected from the following.

[0232] R 4 non-limiting embodiments of In one embodiment of Formula I, R 4 is [Chemical formula] selected from the following.

[0233] In one embodiment of Formula I, R 4 is [Chemical formula] selected from the following.

[0234] In one embodiment of Formula I, R 4 is [Chemical formula] selected from the following.

[0235] In one embodiment of Formula I, R 4 is [Chemical formula] selected from the following.

[0236] In one embodiment of Formula I, R 4 is [Chemical formula] selected from the following.

[0237] In one embodiment of formula I, R 4 is

Chemical formula

[0238] In one embodiment of formula I, R 4 is

Chemical formula

[0239] In one embodiment of formula I, R 4 is

Chemical formula

[0240] In one embodiment of formula I, R 4 is

Chemical formula

[0241] In one embodiment of formula I, R 4 is

Chemical formula

[0242] In one embodiment of formula I, R 4 is

Chemical formula

[0243] In one embodiment of formula I, R 4 is

Chemical formula

[0244] In certain embodiments, R 4 is

Chemical formula

[0245] In one embodiment, the compound of formula I is

Chemical formula

[0246] In one embodiment, the compound of formula I is

Chemical formula

[0247] In one embodiment, the compound of formula I is

Chemical formula

[0248] In one embodiment, the compound of formula I is

Chemical formula

[0249] In one embodiment, the compound of formula I is

Chemical formula

[0250] In one embodiment, the compound of formula I is

Chem.

[0251] In one embodiment, the compound of formula I is

Chem.

[0252] In one embodiment, the compound of formula I is

Chem.

[0253] In one embodiment, the compound of formula I is

Chem.

[0254] In one embodiment, the compound of formula I is

Chem.

[0255] In one embodiment, the compound of formula I is

Chemical formula

[0256] In one embodiment, the compound of formula I is

Chemical formula

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

Chemical formula

[0258] In one embodiment, the compound of formula I is

Chemical formula

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

Chemical formula

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

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

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

[0263] R 6 Non-limiting embodiments In one embodiment of formula I, R 6 is [Chemical formula] selected from

[0264] In one embodiment of formula I, R 6 is [Chemical formula] selected from

[0265] In one embodiment of formula I, R 6 is [Chemical formula] selected from

[0266] In one embodiment of formula I, R 6 is [Chemical formula] selected from

[0267] In one embodiment of formula I, R6 is selected from [Chemical formula] In one embodiment of Formula I, R

[0268] is selected from 6 is selected from [Chemical formula] In a certain specific embodiment, R

[0269] is selected from 6 is selected from [Chemical formula] In a non - limiting embodiment of R

[0270] R 9 In one embodiment, R is selected from 9 is selected from [Chemical formula] In one embodiment, R

[0271] is selected from 9 is selected from [Chemical formula] In one embodiment, R

[0272] is selected from 9 is selected from [Chemical formula] In one embodiment, R

[0273] is selected from 9 is selected from [Chemical formula] In one embodiment, R

[0274] In one embodiment, R 9 is

Chemical formula

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

Chemical formula

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

Chemical formula

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

Chemical formula

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

Chemical formula

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

Chemical formula

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

Chemical formula

[0281] In one embodiment, R 9 is [Chemical formula] selected from

[0282] In one embodiment, R 9 is [Chemical formula] selected from

[0283] In one embodiment, R 9 is [Chemical formula] selected from

[0284] In one embodiment, R 9 is [Chemical formula] selected from

[0285] In one embodiment, R 9 is [Chemical formula] and selected from

[0286] In one embodiment, R 9 is [Chemical formula] selected from

[0287] In one embodiment, R 9 is [Chemical formula] is

[0288] In one embodiment, R 9 is

Chemical formula

[0289] In one embodiment, R 9 is

Chemical formula

[0290] In one embodiment, R 9 is

Chemical formula

[0291] In one embodiment, R 9 is

Chemical formula

[0292] In one embodiment, R 9 is

Chemical formula

[0293] In one embodiment, R 9 is

Chemical formula

[0294] In one embodiment, R 9 is

Chemical formula

[0295] In one embodiment, R9 is [Chem.] .

[0296] In one embodiment, R 9 is [Chem.] .

[0297] In one embodiment, R 9 is [Chem.] .

[0298] In one embodiment, R 9 is [Chem.] .

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

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

[0301] In one embodiment, R 9 is [Chem.] .

[0302] In one embodiment, R 9 is [Chemical formula] selected from

[0303] In one embodiment, R 9 is [Chemical formula] selected from

[0304] In one embodiment, R 9 is [Chemical formula] is

[0305] In one embodiment, R 9 is [Chemical formula] selected from

[0306] In one embodiment, R 9 is [Chemical formula] selected from

[0307] In one embodiment, R 9 is [Chemical formula] is

[0308] In one embodiment, R 9 is [Chemical formula] selected from

[0309] In one embodiment, R 9 is [Chemical formula] selected from

[0310] In one embodiment, R 9 is

Chemical formula

[0311] In one embodiment, R 9 is

Chemical formula

[0312] In one embodiment, R 9 is

Chemical formula

[0313] In one embodiment, R 9 is

Chemical formula

[0314] In one embodiment, R 9 is

Chemical formula

[0315] In one embodiment, R 9 is

Chemical formula

[0316] In one embodiment, R 9 is

Chemical formula

[0317] In one embodiment, R 9 is

Chemical formula

[0318] In one embodiment, R 9 is

Chemical formula

[0319] In one embodiment, R 9 is

Chemical formula

[0320] In one embodiment, R 9 is

Chemical formula

[0321] In one embodiment, R 9 is

Chemical formula

[0322] In one embodiment, R 9 is

Chemical formula

[0323] In one embodiment, R 9 is

Chemical formula

[0324] In one embodiment, R 9 is

Chemical formula

[0325] In one embodiment, R 9 is

Chemical formula

[0326] In one embodiment, R 9 is

Chemical formula

[0327] In one embodiment, R 9 is

Chemical formula

[0328] In one embodiment, R 9 is

Chemical formula

[0329] In one embodiment, R 9 is

Chemical formula

[0330] In one embodiment, R 9 is

Chemical formula

[0331] In one embodiment, R 9 is [Chemical formula] .

[0332] In one embodiment, R 9 is [Chemical formula] .

[0333] In one embodiment, R 9 is selected from [Chemical formula] .

[0334] In one embodiment, R 9 is [Chemical formula] .

[0335] In one embodiment, R 9 is selected from [Chemical formula] .

[0336] In one embodiment, R 9 is selected from [Chemical formula] .

[0337] In one embodiment, R 9 is selected from [Chemical formula] .

[0338] In one embodiment, R 9 is

Chemical formula

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

Chemical formula

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

Chemical formula

[0341] In one embodiment, R 9 is

Chemical formula

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

Chemical formula

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

Chemical formula

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

Chemical formula

[0345] In one embodiment, R 9is selected from [Chemical formula] In one embodiment, R

[0346] is selected from 9 is [Chemical formula] In one embodiment, R

[0347] is selected from 9 is [Chemical formula] In one embodiment, R

[0348] Non-limiting embodiments of R 10 -C(O)R Non-limiting examples of include 10 [Chemical formula] are as follows

[0349] -CH 2 R 10 Non-limiting examples of include [Chemical formula] are as follows

[0350] Non-limiting examples of R 10 include [Chemical formula] are as follows

[0351] Non-limiting examples of the compound of formula I or formula II: Representative examples of the compound of formula I or formula II include [Chemical formula] ​include the following.

[0352] Additional representative examples of the compounds of Formula I or Formula II include [Chemical formula] TIFF0007692362000252.tif183170TIFF0007692362000253.tif206170TIFF0007692362000254.tif201170TIFF0007692362000255.tif35170include the following.

[0353] Additional representative examples of the compounds of Formula I or Formula II include [Chemical formula] TIFF0007692362000257.tif204170TIFF0007692362000258.tif193170TIFF0007692362000259.tif131170include the following.

[0354] In certain embodiments, the compounds of the present invention are [Chemical formula] selected from TIFF0007692362000261.tif191170TIFF0007692362000262.tif194170TIFF0007692362000263.tif123170.

[0355] In one embodiment, the compounds of the present invention are [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0356] Non-limiting isotope embodiments In one embodiment, the compound is isotopically labeled. In one embodiment, R 1 , R 2 , R3 , 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 R 40 At least one R group independently selected from is isotopically labeled with one, two or more isotopes to the extent permitted by the valence. In one embodiment, the isotopic label is deuterium. In one embodiment, at least one deuterium is located on an atom having a bond that is cleaved during metabolism of the compound in vivo or is 1, 2 or 3 atoms away from the bond being metabolized (e.g., can 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 isotopic label is 18 F.

[0357] In certain embodiments, the compounds of the invention are

Chemical formula

[0358] In certain embodiments, the compounds of the invention are

Chemical formula

[0359] In certain embodiments, the compounds of the invention are

Chemical formula

[0360] In certain embodiments, the compounds of the present invention have the formula:

Chemical formula

[0361] In certain embodiments, the compounds of the present invention have the formula:

Chemical formula

[0362] In certain embodiments, the compounds of the present invention have the formula:

Chemical formula

[0363] In certain embodiments, the compounds of the present invention

Chemical formula

[0364] In certain embodiments, the compounds of the present invention

Chemical formula

[0365] In certain embodiments, the compounds of the present invention are

Chemical formula

[0366] In certain embodiments, the compounds of the present invention are

Chemical formula

[0367] In certain embodiments, the compounds of the present invention are

Chemical formula

[0368] In certain embodiments, the compounds of the present invention are

Chemical formula

[0369] In certain embodiments, the compounds of the present invention are

Chemical formula

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

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

[0372] Additional Embodiments 1. In a particular embodiment, Formula I or Formula II: [Chemistry] (wherein, 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 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 R5 , -(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 selected from, R 2 and R 2’ are in each case independently 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’ selected from, R 3 is hydrogen, halogen, alkyl, haloalkyl, -OR 8 and -NR 8 R 8’ selected from, R 3’ is selected from hydrogen, halogen, alkyl and haloalkyl, or or R 3 and R 3’ can together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl ring, R 4 is selected from cycloalkyl, heterocycle, aryl and heteroaryl, each R 4 is optionally substituted with one group selected from R 6 , and each R 4 is optionally substituted with one, two, three or four groups independently selected from R 7 , R 5 is -C(O)R6 and R 6 is selected from alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, and each R 6 is optionally substituted with one, two, three or four groups independently selected from R 9 or R 6 is selected from alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycle, -CO-aryl, -CO-heteroaryl, -O-alkyl, -O-cycloalkyl, -O-heterocycle, -O-aryl, -O-heteroaryl, -NR 2 -alkyl, -NR 2 -cycloalkyl, -NR 2 -heterocycle, -NR 2 -aryl and -NR 2 -heteroaryl, and each R 6 is optionally substituted with one, two, three or four groups independently selected from R 9 and R 7 is, in each case independently, 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’ or two Rs on the same carbon may combine together to form an oxo group 7 and R8 and R 8’ is, in each case independently, selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, R 9 is, in each case 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 , SO 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 selected from R 10 is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, and each R 10 is optionally substituted with one, two, three or four groups independently selected from R 11 ​ 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 halogens, alkyl or -OR 8 heteroaryl optionally substituted with a group; one, two, three or four halogens, alkyl or -OR 8 -CH optionally substituted with a group 2 aryl; one, two, three or four halogens, alkyl or -OR 8 -CH optionally substituted with a 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’ is selected from, or two Rs on the same carbon 11The base may form an oxo group integrally. or R 11 is, in each case independently, 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’ selected from, and each of the R 11 groups is optionally substituted with one, two, three or four groups independently selected from R 12 . R 12 is, in each case independently, 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)R8 、 -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’ selected from the group consisting of R 20 、 R 21 、 R 22 、 R 23 and R 24 are each independently selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -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, bicyclic and carbocyclic, each optionally substituted with one, two, three or four substituents independently selected from R 40 and R 20 、 R 21 、 R 22 、 R 23 and R 24 are i. -C(O)-, -C(O)O-, -OC(O)-, -SO 2 -, -S(O)-, -P(O)(R28 )-, -P(O)-, and -C(S)- moieties are adjacent to each other, or, ii. -O-, -S-, or -NR 2 - moieties are adjacent to each other, or, iii. Otherwise, an unstable molecule is formed (defined as a molecule having a shelf life of less than about 4 months (or alternatively less than about 6 months or 5 months) at room temperature due to decomposition resulting from the selection and order of moieties R 20 , R 21 , R 22 , R 23 and R 24 such that the moieties cannot be selected in an order where they are selected in a defined sequence), R 25 is selected from 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, heterocycle, bicyclic, and cycloalkyl, each of its R 25 groups being optionally substituted with one, two, three, or four groups independently selected from R 12 ), R 28 is in each case independently selected from hydrogen, -NR 2 R 2’ , -OR 2 , -SR 2 , alkyl, haloalkyl, alkenyl, alkyne, cycloalkyl, heterocycle, aryl, and heteroaryl, R 40 is in each case independently selected from hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, -NR 2 R 2’ , -NR 2 SO 2 R 28 , -OSO2 R 28 、 -SO 2 R 28 、 haloalkyl, aryl, heteroaryl, heterocycle, oxo and cycloalkyl, and each of its R 40 groups is independently selected from one, two, three or four groups optionally substituted with R 12 ), or a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof is provided.

[0373] 2. Formula:

Chemical Structure

[0374] 3. R 6 is selected from alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, and each R 6 is optionally substituted with one, two, three or four groups independently selected from R 9 and 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; aryl optionally substituted with one, two, three or four halogen, alkyl or -OR 8 groups; heteroaryl optionally substituted with one, two, three or four halogen, alkyl or -OR 8 groups; -CH 8 aryl optionally substituted with one, two, three or four halogen, alkyl or -OR 2 groups; -CH 8 heteroaryl optionally substituted with one, two, three or four halogen, alkyl or -OR 2 groups; -OR 8 ; -NR 8 R8’ ;-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’ is selected from, or two R groups on the same carbon 11 may combine to form an oxo group, the compound of Embodiment 2.

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

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

[0377] 6. R 12 is -CH 2 aryl, -CH 2 heteroaryl, -OR 8 , -NR 8 R 8’ , -C(O)R 8 , -C(O)OR 8 , -C(O)-NR8 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’ A compound of Embodiment 1 or 2 selected from

[0378] 7. One R 12 The substituent is halogen, a compound of Embodiment 1 or 2.

[0379] 8. Two Rs 12 The substituent is halogen, a compound of Embodiment 1 or 2.

[0380] 9. One R 12 The substituent is alkyl, a compound of Embodiment 1 or 2.

[0381] 10. Two Rs 12 The substituent is alkyl, a compound of Embodiment 1 or 2.

[0382] 11. One R 12 The substituent is haloalkyl, a compound of Embodiment 1 or 2.

[0383] 12. One R 12 The substituent is cycloalkyl, a compound of Embodiment 1 or 2.

[0384] 13. R11 is alkyl optionally substituted with one, two, three or four substituents selected from R 12 A compound according to any one of Embodiments 4 to 12.

[0385] 14. R 11 is cycloalkyl optionally substituted with one, two, three or four substituents selected from R 12 A compound according to any one of Embodiments 4 to 12.

[0386] 15. R 11 is heterocyclic optionally substituted with one, two, three or four substituents selected from R 12 A compound according to any one of Embodiments 4 to 12.

[0387] 16. R 11 is aryl optionally substituted with one, two, three or four substituents selected from R 12 A compound according to any one of Embodiments 4 to 12.

[0388] 17. R 11 is heteroaryl optionally substituted with one, two, three or four substituents selected from R 12 A compound according to any one of Embodiments 4 to 12.

[0389] 18. R 11 is alkyl. A compound according to any one of Embodiments 1 to 12.

[0390] 19. R 11 is cyano. A compound according to any one of Embodiments 1 to 12.

[0391] 20. R 11 is haloalkyl. A compound according to any one of Embodiments 1 to 12.

[0392] 21. R 11 is hydrogen. A compound according to any one of Embodiments 1 to 12.

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

[0394] 23.R 11 is OR 8 The compound of any one of Embodiments 1 to 12, wherein R is OR.

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

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

[0397] 26.R 11 is -C(O)OR 8 , -C(O)R 8 or -SO 2 R 8 The compound of any one of Embodiments 1 to 12, wherein R is -C(O)OR, -C(O)R or -SO₂R.

[0398] 27.R 11 is -CH 2 aryl, The compound of any one of Embodiments 1 to 12, wherein R is -CH aryl.

[0399] 28.R 1 is -NR 2 R 4 The compound of any one of Embodiments 1 to 27, wherein R is -NR₂.

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

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

[0402] 31.R 1 is -SR 4 The compound of any one of Embodiments 1 to 27, wherein R is -SR.

[0403] 32.R 1 is -S(O)R 4 A compound according to any one of Embodiments 1 to 27.

[0404] 33.R 1 is -S(O) 2 R 4 A compound according to any one of Embodiments 1 to 27.

[0405] 34. Formula:

Chemical formula

[0406] 35. Formula:

Chemical formula

[0407] 36. Formula:

Chemical formula

[0408] 37. Formula:

Chemical formula

[0409] 38.R 1 is -(CR 3 R 3’ )-R 5 A compound according to any one of Embodiments 1 to 27.

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

[0411] 40.R 3 is -NR 8 R 8’ The compound of Embodiment 37 or 38, wherein is.

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

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

[0414] 43.R 1 is -NR 2 R 5 The compound of any one of Embodiments 1 to 27, wherein is.

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

[0416] 45.R 5 is, R 9 The compound of any one of Embodiments 38 to 44, wherein is -C(O)alkyl optionally substituted with one, two, three or four groups independently selected from R.

[0417] 46.R 5 is, R 9 The compound of any one of Embodiments 38 to 44, wherein is -C(O)heterocycle optionally substituted with one, two, three or four groups independently selected from R.

[0418] 47.R 5 is, R 9 The compound of any one of Embodiments 38 to 44, wherein is -C(O)aryl optionally substituted with one, two, three or four groups independently selected from R.

[0419] 48.R 5 is, R 9A compound according to any one of embodiments 38 to 44, which is -C(O) heteroaryl optionally substituted with one, two, three or four groups independently selected therefrom.

[0420] 49. Formula:

Chemical formula

[0421] 50. Formula:

Chemical formula

[0422] 51. Formula:

Chemical formula

[0423] 52. R 4 is substituted with one group selected from R 6 and is cycloalkyl optionally substituted with one, two, three or four groups independently selected from R 7 A compound according to any one of embodiments 49 to 51.

[0424] 53. R 4 is substituted with one group selected from R 6 and is heterocycle optionally substituted with one, two, three or four groups independently selected from R 7 A compound according to any one of embodiments 49 to 51.

[0425] 54. R 4 is substituted with one group selected from R 6 and R 7A compound of any one of Embodiments 49 to 51, which is aryl optionally substituted with one, two, three or four groups independently selected from

[0426] 55.R 4 is substituted with one group selected from R 6 and is heteroaryl optionally substituted with one, two, three or four groups independently selected from R 7 A compound of any one of Embodiments 49 to 51.

[0427] 56.R 4 is

Chemical formula

[0428] 57.R 4 is

Chemical formula

[0429] 58.R 4 is

Chemical formula

[0430] 59.R 4 is

Chemical formula

[0431] 60.R 4 is

Chemical formula

[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’ and is selected from any one compound of Embodiments 1 to 60.

[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 , -SO 2 R 8 , -SO 2 -OR 8 , and -SO 2 -NR 8 R 8’ and is selected from any one compound of Embodiments 1 to 60.

[0434] 63.One R 7 is hydrogen, and is any one compound of Embodiments 1 to 60.

[0435] 64.Two Rs 7 are hydrogen, and is any one compound of Embodiments 1 to 60.

[0436] 65.Three Rs 7 are hydrogen, and is any one compound of Embodiments 1 to 60.

[0437] 66.One R 7 is halogen, and is any one compound of Embodiments 1 to 65.

[0438] 67.Two Rs 7 are halogen, and is any one compound of Embodiments 1 to 64.

[0439] 68. One R 7 is alkyl, a compound according to any one of Embodiments 1 to 65.

[0440] 69. Two Rs 7 is alkyl, a compound according to any one of Embodiments 1 to 64.

[0441] 70. One R 7 is haloalkyl, a compound according to any one of Embodiments 1 to 65.

[0442] 71. Two Rs 7 is haloalkyl, a compound according to any one of Embodiments 1 to 64.

[0443] 72. R 6 is

Chemical formula

[0444] 73. R 6 is

Chemical formula

[0445] 74. R 6 is

Chemical formula

[0446] 75. R 6 is alkyl optionally substituted with one, two, three or four groups independently selected from 9 a compound according to any one of Embodiments 1 to 71.

[0447] 76. R6 is cycloalkyl optionally substituted with one, two, three or four groups independently selected from R 9 A compound according to any one of Embodiments 1 to 71.

[0448] 77.R 6 is heterocycle optionally substituted with one, two, three or four groups independently selected from R 9 A compound according to any one of Embodiments 1 to 71.

[0449] 78.R 6 is aryl optionally substituted with one, two, three or four groups independently selected from R 9 A compound according to any one of Embodiments 1 to 71.

[0450] 79.R 6 is heteroaryl optionally substituted with one, two, three or four groups independently selected from R 9 A compound according to any one of Embodiments 1 to 71.

[0451] 80.R 6 is unsubstituted. A compound according to any one of Embodiments 75 to 79.

[0452] 81.R 6 is substituted with one group selected from R 9 A compound according to any one of Embodiments 75 to 79.

[0453] 82.R 6 is substituted with two groups independently selected from R 9 A compound according to any one of Embodiments 75 to 79.

[0454] 83.R 6 is substituted with three groups independently selected from R 9 A compound according to any one of Embodiments 75 to 79.

[0455] 84.R 6 is 9A compound of any one of Embodiments 75 to 79, substituted with four groups independently selected therefrom.

[0456] 85.R 9 is hydrogen, halogen, alkyl, haloalkyl, cyano or nitro, a compound of any one of Embodiments 1 to 84.

[0457] 86.R 9 is R 10 selected from, a compound of any one of Embodiments 1 to 84.

[0458] 87.R 9 is -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 SO 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 10A compound selected from any one of Embodiments 1 to 84.

[0459] 88. R 10 wherein R 11 is alkyl optionally substituted with one, two, three or four groups independently selected from R

[0460] 89. R 10 wherein R 11 is haloalkyl optionally substituted with one, two, three or four groups independently selected from R

[0461] 90. R 10 wherein R 11 is alkenyl optionally substituted with one, two, three or four groups independently selected from R

[0462] 91. R 10 wherein R 11 is alkynyl optionally substituted with one, two, three or four groups independently selected from R

[0463] 92. R 10 wherein R 11 is cycloalkyl optionally substituted with one, two, three or four groups independently selected from R

[0464] 93. R 10 wherein R 11 is heterocycle optionally substituted with one, two, three or four groups independently selected from R

[0465] 94. R 10 wherein R 11 is aryl optionally substituted with one, two, three or four groups independently selected from R

[0466] 95. R 10 wherein R11 The compound of embodiment 86 or 87, which is heteroaryl optionally substituted with one, two, three or four groups independently selected from

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

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

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

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

[0471] 100.R 10 R is 11 The compound of any one of embodiments 88 - 95, wherein R is 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 R, R and R are hydrogen.

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

[0474] 103.R 6 R is

Chemical formula

[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 pharma- ceutically acceptable salt, N-oxide, isotopic derivative, or prodrug thereof, which is a compound of embodiment 1:

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

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

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

[0481] 110.X 3 is a bond, a compound of any one of Embodiments 106 to 109.

[0482] 111.X 3 is C(R 3 R 3’ ) and is a compound of any one of Embodiments 106 to 109.

[0483] 112.X 3 is C(O) and is a compound of any one of Embodiments 106 to 109.

[0484] 113.X 3 is C(S) and is a compound of any one of Embodiments 106 to 109.

[0485] 114.X 3 is S(O) and is a compound of any one of Embodiments 106 to 109.

[0486] 115.X 3 is S(O) 2 and is a compound of any one of Embodiments 106 to 109.

[0487] 116.X 3 is NR 2 and is a compound of any one of Embodiments 106 to 109.

[0488] 117.X 3 is O and is a compound of any one of Embodiments 106 to 109.

[0489] 118.X 3 is NR 2 and is a compound of any one of Embodiments 106 to 109.

[0490] 119.X 3 is O and is a compound of any one of Embodiments 106 to 109.

[0491] 120.X 3A compound of any one of Embodiments 106 to 109, which is S.

[0492] 121.R 20 A compound of any one of Embodiments 106 to 120, in which is a bond.

[0493] 122.R 20 is 40 alkyl optionally substituted with one, two, three or four substituents independently selected from R

[0494] 123.R 20 is 40 alkene or alkyne optionally substituted with one, two, three or four substituents independently selected from R

[0495] 124.R 20 is 40 haloalkyl optionally substituted with one, two, three or four substituents independently selected from R

[0496] 125.R 20 is 40 aryl optionally substituted with one, two, three or four substituents independently selected from R

[0497] 126.R 20 is 40 heteroaryl optionally substituted with one, two, three or four substituents independently selected from R

[0498] 127.R 20 is 40 heterocyclic optionally substituted with one, two, three or four substituents independently selected from R

[0499] 128.R 20 is one, two, three or four substituents independently selected from R 40 and is a bicyclic optionally substituted with one, two, three or four substituents independently selected from R, a compound of any one of Embodiments 106 to 120.

[0500] 129.R 20 is -O-, a compound of any one of Embodiments 106 to 115.

[0501] 130.R 20 is -S-, a compound of any one of Embodiments 106 to 115.

[0502] 131.R 20 is -NR 2 -, a compound of any one of Embodiments 106 to 115.

[0503] 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 )- or -P(O)-, a compound of any one of Embodiments 106 to 111.

[0504] 133.R 21 is a bond, a compound of any one of Embodiments 106 to 132.

[0505] 134.R 21 is alkyl optionally substituted with one, two, three or four substituents independently selected from R 40 , a compound of any one of Embodiments 106 to 132.

[0506] 135.R 21 is alkene or alkyne optionally substituted with one, two, three or four substituents independently selected from R 40 , a compound of any one of Embodiments 106 to 132.

[0507] 136.R21 is optionally substituted with one, two, three or four substituents independently selected from R 40 and is haloalkyl, a compound of any one of embodiments 106 to 132.

[0508] 137.R 21 is optionally substituted with one, two, three or four substituents independently selected from R 40 and is aryl, a compound of any one of embodiments 106 to 132.

[0509] 138.R 21 is optionally substituted with one, two, three or four substituents independently selected from R 40 and is heteroaryl, a compound of any one of embodiments 106 to 132.

[0510] 139.R 21 is optionally substituted with one, two, three or four substituents independently selected from R 40 and is a heterocyclic ring, a compound of any one of embodiments 106 to 132.

[0511] 140.R 21 is optionally substituted with one, two, three or four substituents independently selected from R 40 and is bicyclic, a compound of any one of embodiments 106 to 132.

[0512] 141.R 21 is -O-, a compound of any one of embodiments 106 to 128.

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

[0514] 143.R 21 is -NR 2 -, a compound of any one of embodiments 106 to 128.

[0515] 144.R 21is -C(O)-, -C(O)O-, -OC(O)-, -SO 2 -, -S(O)-, -C(S)-, -C(O)NR 2 -, -P(O)(R 28 )- or -P(O)-, a compound of any one of embodiments 106 to 131.

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

[0517] 146.R 22 is alkyl optionally substituted with one, two, three or four substituents independently selected from R 40 , a compound of any one of embodiments 106 to 144.

[0518] 147.R 22 is alkene or alkyne optionally substituted with one, two, three or four substituents independently selected from R 40 , a compound of any one of embodiments 106 to 144.

[0519] 148.R 22 is haloalkyl optionally substituted with one, two, three or four substituents independently selected from R 40 , a compound of any one of embodiments 106 to 144.

[0520] 149.R 22 is aryl optionally substituted with one, two, three or four substituents independently selected from R 40 , a compound of any one of embodiments 106 to 144.

[0521] 150.R 22 is heteroaryl optionally substituted with one, two, three or four substituents independently selected from R 40 , a compound of any one of embodiments 106 to 144.

[0522] 151.R 22 is R40 A compound of any one of Embodiments 106 to 144, which is a heterocyclic ring optionally substituted with one, two, three or four substituents independently selected from

[0523] 152.R 22 is a bicyclic ring optionally substituted with one, two, three or four substituents independently selected from 40 A compound of any one of Embodiments 106 to 144, which is a bicyclic ring optionally substituted with one, two, three or four substituents independently selected from

[0524] 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)-, a compound of any one of Embodiments 106 to 143.

[0525] 154.R 22 is -O-, a compound of any one of Embodiments 106 to 140.

[0526] 155.R 22 is -S-, a compound of any one of Embodiments 106 to 140.

[0527] 156.R 22 is -NR 2 -, a compound of any one of Embodiments 106 to 140.

[0528] 157.R 23 or R 24 is a bond, a compound of any one of Embodiments 106 to 156.

[0529] 158.R 23 or R 24 is alkyl optionally substituted with one, two, three or four substituents independently selected from 40 A compound of any one of Embodiments 106 to 156, which is alkyl optionally substituted with one, two, three or four substituents independently selected from

[0530] 159.R 23or R 24 is an alkene or alkyne optionally substituted with one, two, three or four substituents independently selected from R 40 A compound of any one of Embodiments 106 to 156.

[0531] 160.R 23 or R 24 is a haloalkyl optionally substituted with one, two, three or four substituents independently selected from R 40 A compound of any one of Embodiments 106 to 156.

[0532] 161.R 23 or R 24 is an aryl optionally substituted with one, two, three or four substituents independently selected from R 40 A compound of any one of Embodiments 106 to 156.

[0533] 162.R 23 or R 24 is a heteroaryl optionally substituted with one, two, three or four substituents independently selected from R 40 A compound of any one of Embodiments 106 to 156.

[0534] 163.R 23 or R 24 is a heterocyclic ring optionally substituted with one, two, three or four substituents independently selected from R 40 A compound of any one of Embodiments 106 to 156.

[0535] 164.R 23 or R 24 is a bicyclic ring optionally substituted with one, two, three or four substituents independently selected from R 40 A compound of any one of Embodiments 106 to 156.

[0536] 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)-, a compound of any one of embodiments 106 to 156.

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

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

[0539] 168.R 23 or R 24 is -NR 2 -, a compound of any one of embodiments 106 to 156.

[0540] 169.R 25 is hydrogen, a compound of any one of embodiments 106 to 168.

[0541] 170.R 25 is halogen, a compound of any one of embodiments 106 to 168.

[0542] 171.R 25 is alkyl optionally substituted with one, two, three or four groups independently selected from R 12 , a compound of any one of embodiments 106 to 168.

[0543] 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, selected from haloalkyl, aryl, heteroaryl, heterocyclic, bicyclic and cycloalkyl, wherein each of the R 25 groups is optionally substituted with one, two, three or four groups independently selected from R 12 , a compound of any one of embodiments 106 to 168.

[0544] 173. R 40 is selected from alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclic, oxo and cycloalkyl, wherein each of the R 40 groups is optionally substituted with one, two, three or four groups independently selected from R 12 , a compound of any one of embodiments 106 to 172.

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

[0546] 175.

Chemical formula

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

[0548] 177. Structure:

Chemical formula

[0549] 178. Structure:

Chemical formula

[0550] 179. Structure:

Chem.

[0551] 180. Structure:

Chem.

[0552] 181. Structure:

Chem.

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

[0554] 183. In certain embodiments, there is provided a method of treating a disorder mediated by cereblon in a human, comprising administering to a human in need thereof an effective dose of a compound of any one of Embodiments 1 to 181 or a pharmaceutically acceptable salt or composition 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 according to embodiment 183 or 184, wherein the disorder is an immune disorder, an autoimmune disorder or an inflammatory disorder.

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

[0560] 189. The method according to embodiment 183 or 184, wherein the disorder is multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma.

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

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

[0563] 192. The compound for use according to embodiment 190 or 191, wherein the disorder is cancer.

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

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

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

[0567] 196. The compound for use according to embodiment 190 or 191, wherein the disorder is multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma or non-Hodgkin 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 any one of the compounds 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 the 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 the disorder is multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma.

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

[0576] In one embodiment, the compounds of the present 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 for the treatment of the disorders described herein.

[0578] In one embodiment, the compounds of formula II are used for the treatment of the disorders described herein.

[0579] In one embodiment, the compounds of formula I-a are used for the treatment of the disorders described herein.

[0580] In one embodiment, the compounds of formula I-b are used for the treatment of the disorders described herein.

[0581] In one embodiment, the compounds of formula I-c are used for the treatment of the disorders described herein.

[0582] In one embodiment, the compounds of formula I-d are used for the treatment of the disorders described herein.

[0583] In one embodiment, the compounds of formula I-e are used for the treatment of the disorders described herein.

[0584] In one embodiment, the compounds of formula I-f are used for the treatment of the disorders described herein.

[0585] In one embodiment, the compounds of formula I-g are used for the treatment of the disorders described herein.

[0586] In one embodiment, the disorder treated by the compounds of the present invention is an immunomodulatory disorder. In one embodiment, the disorder treated by the compounds of the present invention is mediated by angiogenesis. In one embodiment, the disorder treated by the compounds of the present invention is related to the lymphatic system.

[0587] In one embodiment, the compound of the invention or a pharmaceutically acceptable salt thereof in the pharmaceutical composition described herein, is optionally used to degrade Ikaros or Aiolos, mediators of disorders that affect patients such as humans. The control of protein levels obtained by any of the compounds of the invention results in the treatment of disease states or pathologies modulated by Ikaros or Aiolos by reducing the level of that protein in cells, such as the cells of a patient, or by reducing the level of downstream proteins in the cell. In certain embodiments, the method optionally comprises administering an effective amount of a compound described herein, optionally in combination with or alternating with an additional therapeutic active agent or combination of therapeutic active agents, which includes pharmaceutically acceptable excipients, carriers, adjuvants (i.e., a pharmaceutically acceptable composition).

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

[0589] The terms "disease state" or "pathology" when used in connection with any compound, are intended to refer to any disease state or pathology mediated by Ikaros or Aiolos such as cell proliferation, or any disease state or pathology mediated by proteins downstream of Ikaros or Aiolos, and the degradation of such proteins in a patient can result in a beneficial therapy or alleviation of symptoms for a patient in need thereof. In some cases, the disease state or pathology may be curable.

[0590] In one embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives or prodrugs, can be used in an effective amount to treat a host, such as a human, having lymphoma, or a lymphocytic or myelogenous proliferative disorder or abnormality. For example, the compounds described herein can be administered to a host suffering from Hodgkin lymphoma or non-Hodgkin lymphoma. For example, the host may be, but is not limited to, AIDS-related lymphoma; undifferentiated large cell lymphoma; angioimmunoblastic lymphoma; blastic NK cell lymphoma; Burkitt 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; enteropathy-type T cell lymphoma; follicular lymphoma; hepatosplenic γ-δ T cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T cell lymphoma; pediatric lymphoma; peripheral T cell lymphoma; primary central nervous system lymphoma; T cell leukemia; transformed lymphoma; therapy-related T cell lymphoma; Langerhans cell histiocytosis or Waldenström macroglobulinemia, etc.

[0591] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives or prodrugs, can be used in an effective amount to treat a host, such as a human, having Hodgkin lymphoma, such as, but not limited to, nodular sclerosis classical Hodgkin lymphoma (CHL), mixed cellularity CHL, lymphocyte-depleted 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, isotope derivatives or prodrugs can be used in an effective amount to treat a host, such as 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 with 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 give rise to a wide range of diseases such as cancer, proliferative disorders, and inflammatory / immune diseases. A host, such as a human, suffering from any of these disorders can be treated with an effective amount of the compounds described herein to achieve a reduction in symptoms (palliative agent) or a reduction in the underlying disease (disease modifying agent).

[0595] In one embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives or prodrugs, include, but are not limited to, multiple myeloma; diffuse large B-cell lymphoma; follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT); small lymphocytic lymphoma; diffuse poorly differentiated lymphocytic lymphoma; mediastinal large B-cell lymphoma; nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; hairy cell leukemia; unclassifiable splenic lymphoma / leukemia; diffuse splenic red pulp small B-cell lymphoma; hairy cell leukemia - subtype; lymphoplasmacytic lymphoma; heavy chain disease, such as alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease; plasmacytic myeloma; solitary plasmacytoma of bone; extramedullary plasmacytoma; primary cutaneous follicle center lymphoma; T-cell / histiocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL leg type; ALK+ large B-cell lymphoma; plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease; unclassifiable B-cell lymphoma with intermediate features of diffuse large B-cell lymphoma; or unclassifiable B-cell lymphoma with intermediate features of diffuse large B-cell lymphoma and classical Hodgkin lymphoma, etc. A host having a specific B-cell lymphoma or proliferative disorder, such as a human, can be used in an effective amount for treatment.

[0596] In one embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives or prodrugs, include, but are not limited to, undifferentiated lymphoma kinase (ALK)-positive, ALK-negative anaplastic large cell lymphoma or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T cell lymphoma, such as mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T cell proliferative disorder; primary cutaneous progressive epidermotropic CD8+ cytotoxic T cell lymphoma; primary cutaneous γ-δ T cell lymphoma; primary cutaneous small / medium cell type CD4+ T cell lymphoma and lymphomatoid papulosis; adult T cell leukemia / lymphoma (ATLL); blastic NK cell lymphoma; enteropathy-type T cell lymphoma; hepatosplenic γ-δ T cell lymphoma; lymphoblastic lymphoma; nasal NK / T cell lymphoma; therapy-related T cell lymphoma; for example, lymphoma occurring 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 in children (associated with chronic active EBV infection); vaccinia-like lymphoproliferative disorder; adult T cell leukemia / lymphoma; enteritis-associated T cell lymphoma; hepatosplenic T cell lymphoma; or subcutaneous panniculitis-like T cell lymphoma, etc., and can be used in an effective amount to treat a host, such as a human, having a T cell or NK cell lymphoma.

[0597] In one embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives or prodrugs can be used to treat a host, such as a human, having leukemia. For example, the host may have acute or chronic leukemia of lymphoid or myeloid origin, including 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 or without minimal cell maturation); myeloblastic leukemia (M2; with cell 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 numerous skin disorders associated with cell overproliferation. For example, psoriasis is a benign disease of human skin characterized generally by plaques covered with thick scale. This disease results from an increased proliferation of epidermal cells of unknown cause. Chronic eczema is also associated with marked hyperplasia of the epidermis. Other diseases resulting from the overproliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

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

[0600] Angiogenic disorders include neovascularization disorders and vasculogenic disorders. The proliferation of smooth muscle cells in the process of plaque development 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] Fibrosis is often caused by abnormal formation of the extracellular matrix. Examples of fibrosis include cirrhosis and mesangial proliferative cell disorders. Cirrhosis is characterized by an increase in extracellular matrix components that result in the formation of liver scars. Cirrhosis can cause diseases such as liver cirrhosis. The increase in extracellular matrix that results in liver scars may also be due to viral infections such as hepatitis. Adipocytes seem to play an important role in cirrhosis.

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

[0603] Another disease due to proliferative components is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease associated with the activity of autoreactive T cells and caused by autoantibodies produced against collagen and IgE.

[0604] Other disorders that may contain abnormal cell proliferative components include Behçet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and general inflammation.

[0605] The compounds described herein, or pharmaceutically acceptable salts, isotope analogs or prodrugs thereof, can be used in an effective amount to treat hosts, such as humans, having proliferative pathologies such as myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis with myeloid metaplasia (MMM), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mastocytosis with cutaneous involvement (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, isotope analogs or prodrugs thereof, can be used in an effective amount to treat a host, such as a human, having myelodysplastic syndrome (MDS), including but not limited to refractory cytopenia with single lineage dysplasia, refractory anemia with ring sideroblasts (RARS), refractory anemia with ring sideroblasts and thrombocytosis (RARS-t), refractory cytopenia with multilineage dysplasia (RCMD) including RCMD with ring sideroblasts (RCMD-RS), refractory anemia with excess blasts I (RAEB-I) and II (RAEB-II), 5q- syndrome, pediatric refractory cytopenia, etc.

[0607] In one embodiment, the compounds of the present invention can provide a therapeutic effect by directly degrading Ikaros or Aiolos, which can change the transcriptional regulation of proteins downstream of Ikaros or Aiolos.

[0608] The terms "neoplasia" or "cancer" are used to refer to a carcinogenic or malignant neoplasm, i.e., a pathological process that results in the formation and growth of abnormal tissue that in many cases grows by cell proliferation more rapidly than normal and continues to grow after the stimulus that initiated the new growth has ceased. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissue, most invade surrounding tissues, some metastasize to distant sites, are likely to recur after attempts at removal, and, if not appropriately treated, cause death of the patient. As used herein, the term neoplasia is used to describe all carcinogenic disease states and includes or encompasses the pathological processes associated with malignant hematogenous tumors, ascitic tumors, and solid tumors. Exemplary cancers that can be treated with the present compounds, either alone or in combination with at least one additional anti-cancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, as well as carcinomas of the kidney, bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas including Ewing sarcoma, angiosarcoma, Kaposi sarcoma, liposarcoma, rhabdomyosarcoma, peripheral neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and schwannoma; carcinomas of the intestine, breast, prostate, cervix, uterus, lung, ovary, testis, thyroid, astrocytoma, esophagus, pancreas, stomach, liver, colon, melanoma; carcinosarcoma, Hodgkin disease, Wilms tumor, and teratocarcinoma. Additional cancers that can be treated with the compounds of the present invention include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, large cell type B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

[0609] Additional cancers that can be treated with the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendiceal cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brainstem glioma, breast cancer, triple (estrogen, progesterone, and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone, and HER-2 are negative), single negative (one of estrogen, progesterone, and HER-2 is negative), estrogen receptor positive, HER2 negative breast cancer, estrogen receptor negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2 negative breast cancer, HER2 positive or negative breast cancer, progesterone receptor negative breast cancer, progesterone receptor positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, epithelioma, epitheloid sarcoma, esophageal cancer, Ewing sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube 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 lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal cancer, intrahepatic bile duct cancer, invasive / infiltrating breast cancer, islet cell cancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastasis, leukemia, lip cancer, liposarcoma, liver cancer, non-invasive lobular carcinoma, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal (mesenchymous) mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous cell carcinoma of the neck, mixed glioma, monodermal teratoma, mouthcancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, fungating polyposis, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, cervical cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, intraocular melanoma, anaplastic glioma, oral cavity cancer, oral cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, primary peritoneal cancer of the ovary, ovarian sex cord-stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal gland tumor, pineoblastoma, pituitary cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvic cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, paranasal sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsillar cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, cancer of undetermined diagnosis, 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-BALL, Pre-B lymphoma, large cell type B cell lymphoma, Burkitt lymphoma, B cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (subtype of AML), large granular lymphocyte leukemia, adult T cell chronic leukemia, diffuse large cell type B cell lymphoma, follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT), small cell type lymphocytic lymphoma, mediastinal large cell type B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large cell type B cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B cell prolymphocytic leukemia; unclassifiable splenic lymphoma / leukemia, diffuse red pulp small B cell lymphoma; lymphoplasmacytic lymphoma; heavy chain disease, such as alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasmacytic myeloma, solitary plasmacytoma of bone; extramedullary plasmacytoma; primary cutaneous follicle center lymphoma, T cell / histiocyte-rich large cell type B cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL in the elderly; primary mediastinal (thymic) large cell type B cell lymphoma, primary cutaneous DLBCL leg type, ALK+ large cell type B cell lymphoma, plasmablastic lymphoma; large cell type B cell lymphoma occurring in HHV8-associated multicentric Castleman disease; unclassifiable B cell lymphoma having intermediate features of diffuse large cell type B cell lymphoma, or unclassifiable B cell lymphoma having intermediate features of diffuse large cell type B cell lymphoma and classical Hodgkin lymphoma. In one embodiment, the disorder is adenoid cystic carcinoma. In one embodiment, the disorder is NUT midline carcinoma.

[0610] In another embodiment, the compounds described herein, or pharmaceutically acceptable salts, isotope derivatives or prodrugs thereof, can be used in an effective amount to treat a host having an autoimmune disorder, such as a human. Examples include acute disseminated encephalomyelitis (ADEM); Addison's disease; agammaglobulinemia; alopecia areata; amyotrophic lateral sclerosis (also known as Lou Gehrig's disease; motor neuron disease); ankylosing spondylitis; antiphospholipid antibody syndrome; anti-synthetase 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 insufficiency; polyendocrine autoimmune syndrome; autoimmune progesterone dermatitis; autoimmune thrombocytopenic purpura; autoimmune thyroid disorder; autoimmune urticaria; autoimmune uveitis; autoimmune vasculitis; Balo disease / Balo concentric sclerosis; Behçet's disease; Berger's disease; Bickerstaff encephalitis; Braun syndrome; bullous pemphigoid; cancer; Castleman disease; celiac disease; Chagas disease; chronic inflammatory demyelinating polyneuropathy; chronic obstructive pulmonary disease; chronic recurrent multifocal osteomyelitis; Churg-Strauss syndrome; cicatricial pemphigoid; Cogan syndrome; cold agglutinin disease; complement component 2 deficiency; contact dermatitis; cranial arteritis; CREST syndrome; Crohn's disease; Cushing's syndrome; cutaneous leukocytoclastic vasculitis; Degos disease; Darier's disease; dermatitis herpetiformis; dermatomyositis; type 1 diabetes; diffuse cutaneous systemic sclerosis; discoid lupus erythematosus; Dressler syndrome; drug-induced lupus; eczema; endometriosis; enthesitis-related arthritis; eosinophilic fasciitis; eosinophilic gastroenteritis; eosinophilic pneumonia; epidermolysis bullosa acquisita; erythema nodosum; fetal erythroblastosis; essential mixed cryoglobulinemia; Evans syndrome; exogenous and endogenous reactive airway diseases (asthma); progressive osseous heteroplasia; fibrosing alveolitis (or idiopathic pulmonary fibrosis); gastritis; gastrointestinal pemphigoid; glomerulonephritis; Goodpasture syndrome; Graves' disease; Guillain-Barré syndrome (GBS); Hashimoto's encephalopathy; Hashimoto's disease; hemolytic anemia; Henoch-Schönlein purpura;Herpes gestationis (pemphigoid gestationis); Hidradenitis suppurativa; Hughes-Stovin syndrome; Hypogammaglobulinemia; Idiopathic inflammatory demyelinating diseases; Idiopathic pulmonary fibrosis; Idiopathic thrombocytopenic purpura; IgA nephropathy; Immune glomerulonephritis; Immune nephritis; Immune pneumonia; Inclusion body myositis; Inflammatory bowel disease; Interstitial cystitis; Juvenile idiopathic arthritis, also known as juvenile rheumatoid arthritis; Kawasaki disease; Lambert-Eaton myasthenic syndrome; Leukocytoclastic vasculitis; Lichen planus; Lichen sclerosus; Linear IgA disease (LAD); Lupoid hepatitis, also known as autoimmune hepatitis; Lupus erythematosus; Magid syndrome; Microscopic polyangiitis; Miller-Fisher syndrome; Mixed connective tissue disease; Localized scleroderma; Mucha-Habermann disease, also known as acute pityriasis lichenoides et varioliformis acuta; Multiple sclerosis; Myasthenia gravis; Myositis; Ménière's disease; Narcolepsy; Neuromyelitis optica (also known as Devic's disease); Neuromyotonia; Ocular cicatricial pemphigoid; Opsoclonus-myoclonus syndrome; Ord's thyroiditis; Relapsing rheumatism; PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections); Paraneoplastic cerebellar degeneration; Paroxysmal nocturnal hemoglobinuria (PNH); Parry-Romberg syndrome; Pars planitis; Persistent Müllerian duct 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; Pyridoxine-responsive anemia; Pyoderma gangrenosum; Rasmussen encephalitis; Raynaud's phenomenon; Reiter's syndrome; Relapsing polychondritis; Restless legs syndrome; Retroperitoneal fibrosis; Rheumatic fever; Rheumatoid arthritis; Sarcoidosis; Schizophrenia; Schmidt syndrome; Schnitzler syndrome; Scleritis; Scleroderma; Sclerosing cholangitis; Serum sickness; Sjögren's syndrome; Spondyloarthritis; Stiff-person syndrome; Still's disease; Subacute bacterial endocarditis (SBE); Susac syndrome; Sweet syndrome; Sydenham chorea; Sympathetic ophthalmia; Systemic lupus erythematosus; Takayasu arteritis; Temporal arteritis (also known as giant cell arteritis); Thrombocytopenia; Troisi-Hunt syndrome; Transverse myelitis; Ulcerative colitis; Undifferentiated connective tissue disease; Undifferentiated spondyloarthritis; 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, among others, but not limited to these. In some embodiments, the autoimmune disease is an allergic condition including those due to asthma, food allergy, atopic dermatitis, chronic pain, and rhinitis.;

[0611] Cutaneous contact hypersensitivity and asthma are just two examples of immune responses that can be associated with a significant prevalence. Others include atopic dermatitis, eczema, Sjögren's syndrome including dry keratoconjunctivitis secondary to Sjögren's syndrome, alopecia areata, allergic responses due to arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous erythema-todes, scleroderma, vaginitis, proctitis, and drug rashes. These pathologies can give rise to 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 body fluids occurring on the skin, eyes, or mucosa.

[0612] In atopic dermatitis and eczema, immune-mediated leukocyte infiltration into the skin (particularly infiltration of monocytes, lymphocytes, neutrophils, and eosinophils) contributes significantly to the development of these diseases. Chronic eczema is also associated with marked hyperplasia of the epidermis. Immune-mediated leukocyte infiltration also occurs in sites other than the skin, such as the airways in asthma and the tear-producing gland of the eye in dry keratoconjunctivitis.

[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, such as a human, having a skin disorder such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), etc. For example, certain substances containing some pharmaceuticals may cause skin sensitization when applied topically. In some embodiments, the skin disorder is treated by topical administration of a compound known in the art in combination with the compounds disclosed herein. In one non-limiting embodiment, the compounds of the present invention are used as topical agents for the treatment of contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's syndrome including keratoconjunctivitis sicca secondary to Sjogren's syndrome, alopecia areata, allergic responses due to arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous erythema-todes, scleroderma, vaginitis, proctitis and drug eruptions. This novel method may also be useful for reducing infiltration of the skin by malignant white blood cells in diseases such as mycosis fungoides.

[0614] Disease states or conditions that can be treated using the compounds according to the present invention include, for example, autoimmune diseases such as asthma, multiple sclerosis, various cancers, cilia-related diseases, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive disorders, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney 1 (PKD1) or 2 (PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome.

[0615] Additional disease states or conditions that can be treated by the compounds according to the present invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorders, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes, type 2 diabetes, epilepsy, Guillain - Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive - compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette syndrome, vasculitis.

[0616] Additional disease states or conditions that can be treated by the compounds according to the invention include, in particular, aceruloplasminemia, achondrogenesis type II, achondroplasia, acrocephaly, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, familial adenomatous polyposis, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuric tissue browning, alpha1-antitrypsin deficiency, alpha-1 proteinase inhibitor deficiency, emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, enamel hypoplasia, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity, anemia, diffuse cutaneous angiosarcoma, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, arachnodactyly (Marfan syndrome), Stickler syndrome, congenital multiple joint laxity (Ehlers-Danlos syndrome # multiple joint laxity type), ataxia telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Baraitser-Stevenson craniofacial syndrome, familial Mediterranean fever, Benjamin syndrome, beta-thalassemia, bilateral acoustic neuroma (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, Bard-Hogdduve syndrome, osteoporosis (osteogenesis imperfecta), broad thumb-hallux syndrome (Rubinstein-Taybi syndrome), bronze diabetes / bronze cirrhosis (hemochromatosis), bulbospinal muscular atrophy (Kennedy disease), Burger-Gruetz syndrome (lipoprotein lipase deficiency), CGD chronic granulomatous disease, camptomelic dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cri du chat syndrome, CAVD (congenital vas deferens defect), Keller heart face syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, chondrodysplasia syndrome (achondroplasia), oto-spinal macroepiphysial dysplasia, Lesch-Nyhan syndrome,Galactosemia, Ehlers-Danlos syndrome, lethal dysplasia, Coffin-Lowry syndrome, Cockayne syndrome (familial adenomatous polyposis), congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disease, conotruncal anomaly face syndrome, Cooley anemia (β-thalassemia), copper accumulation disease (Wilson disease), copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial joint anomalies (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Kufs disease (myotonic dystrophy), Byler-Stevenson cutis verticis gyrata syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Strudwick type), Duchenne and Becker muscular dystrophy (DBMD), Asherman syndrome, Dogruzy syndrome and degenerative neurological diseases including Dejerine-Sottas syndrome, developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity, diffuse globoid cell sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity, Down syndrome, dwarfism, erythropoietic protoporphyria, erythrocyte type 5-aminolevulinate synthase deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich ataxia-familial episodic polyserositis, late-onset cutaneous, familial dysautonomic neuropathy, primary pulmonary hypertension (PPH), pancreatic fibrosis cyst, fragile X syndrome, galactosemia, hereditary brain disorder, giant cell hepatitis (neonatal hemochromatosis), Grönblad-Strandberg syndrome (elastic fiber pseudoxanthoma), Gunther disease (congenital erythropoietic porphyria), hemochromatosis, Hallervorden-Spatz syndrome, sickle cell anemia, hemophilia, hepatic erythropoietic porphyria (HEP), von Hippel-Lindau disease, Huntington disease, Hutchinson-Gilford-Progeria syndrome (progeria), hyperandrogenism, chondrodysplasia, hypochromic anemia, immune system disorders including X-linked severe combined immunodeficiency, Insl-Astry syndrome, Jackson-Weiss syndrome, Joubert syndrome,Renal diseases including Lesch-Nyhan syndrome, Jackson-Weiss syndrome, hyperoxaluria, Klinefelter syndrome, Kneist dysplasia, mottled dementia, Langer-Saldino achondrogenesis, ataxia telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kneist dysplasia, Marfan syndrome, movement disorders, Moebius-Wilson syndrome, cystic fibrosis, Muenke syndrome, neurofibromatosis, Nance-Horan syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Fife syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney, polyostotic fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Labhart-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) (Huntington disease), progressive muscular atrophy, spinal muscular atrophy, propionic academia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), von Recklinghausen disease (neurofibromatosis type I), recurrent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, type 3 RFALS, Ricker syndrome, Riley-Day syndrome, Lucy-Levy syndrome, severe achondroplasia with developmental delay and melanosis (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia, and adrenal gland (SBLA) syndrome, tuberous sclerosis (sclerosis tuberose (tuberous sclerosis)), SDAT, congenital SED (congenital spondyloepiphyseal dysplasia), Strudwick type SED (Strudwick type spondyloepiphyseal dysplasia), SEDc (congenital spondyloepiphyseal dysplasia), Strudwick type SEMD (Strudwick type spondyloepimetaphyseal dysplasia), Schprintzen syndrome, skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (variant porphyria),Infantile-onset ascending hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, β-thalassemia, thyroid diseases, sausage-like neuropathy (hereditary pressure sensitivity neuropathy), Treacher Collins syndrome, Triple X syndrome (Trisomy X), Trisomy 21 (Down syndrome), Trisomy X, VHL syndrome (von Hippel-Lindau disease), vision impairment and blindness (Alström syndrome), phloridzin disease, Waardenburg syndrome, Warburg-Sho-Fredelius syndrome, Wolf-Hirschhorn syndrome, Wolf periodic disease, Vaisenbacher-Tschermak syndrome, and xeroderma pigmentosum are included.

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

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

[0619] In one embodiment, there is provided a method of inducing a treatment response evaluated by the International Uniform Response Criteria (IURC) for multiple myeloma (Durie B. G. 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, isotope analog or prodrug thereof, in a pharmaceutically acceptable carrier optionally forming a composition.

[0620] In another embodiment, there is provided a method of achieving a stringent complete response, complete response or very good partial response evaluated by the IURC for multiple myeloma 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, isotope analog or prodrug thereof, in a pharmaceutically acceptable carrier optionally forming a composition.

[0621] In another embodiment, there is provided a method of achieving an extension of overall survival, progression-free survival, relapse-free survival, time to progression or disease-free survival 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, isotope analog or prodrug thereof, in a pharmaceutically acceptable carrier optionally forming a composition.

[0622] In another embodiment, there is provided a method of achieving an extension of overall survival 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, isotope analog or prodrug thereof, in a pharmaceutically acceptable carrier optionally forming a composition.

[0623] In another embodiment, there is provided a method of achieving an extended progression-free survival 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, isotope analog or prodrug thereof, in a pharmaceutically acceptable carrier optionally forming a composition.

[0624] In another embodiment, there is provided a method of achieving an extended relapse-free survival 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, isotope analog or prodrug thereof, in a pharmaceutically acceptable carrier optionally forming a composition.

[0625] In another embodiment, there is provided a method of achieving an extended time to progression 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, isotope analog or prodrug thereof, in a pharmaceutically acceptable carrier optionally forming a composition.

[0626] In another embodiment, there is provided a method of achieving an extended disease-free survival 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, isotope analog or prodrug thereof, in a pharmaceutically acceptable carrier optionally forming a composition.

[0627] In addition to patients who have not been previously treated, methods of treating patients who have previously been treated for multiple myeloma but who do not respond to standard therapy are also provided. In addition to patients who have not undergone surgery, additional methods of treating patients who have undergone surgery for the treatment of multiple myeloma are provided. In addition to patients who have not received transplantation therapy, methods of treating patients who have previously received transplantation therapy are also provided.

[0628] The compounds described herein can be used for the treatment or management of relapsed, refractory or resistant multiple myeloma. In some embodiments, the multiple myeloma is primary, secondary, tertiary, quaternary or quinary 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 with the compounds described herein include monoclonal gammopathy of undetermined significance (MGUS), low-risk, intermediate-risk or high-risk multiple myeloma, newly diagnosed multiple myeloma (including newly diagnosed low-risk, intermediate-risk or high-risk multiple myeloma), transplant-eligible and transplant-ineligible multiple myeloma, smoldering (asymptomatic) 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, but are not limited thereto.

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

[0631] In one embodiment, a method of treating or managing multiple myeloma is provided, which includes administering to a patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier optionally forming a composition, as an induction therapy.

[0632] In one embodiment, a method of treating or managing multiple myeloma is provided, which includes administering to a patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier optionally forming a composition, as a consolidation therapy.

[0633] In one embodiment, a method of treating or managing multiple myeloma is provided, which includes administering to a patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier optionally forming a composition, as a maintenance therapy.

[0634] In one embodiment, the multiple myeloma is plasmacytic 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 the first 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 previous treatments.

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

[0637] In one embodiment, multiple myeloma has a homozygous deletion of p53. In one embodiment, multiple myeloma has a homozygous deletion of wild-type p53. In one embodiment, multiple myeloma has wild-type p53.

[0638] In one embodiment, multiple myeloma exhibits activation of one or more cancer drivers. In one embodiment, the one or more cancer drivers are selected from the group consisting of C-MAF, MAFB, FGFR3, MMset, Cyclin D1, and Cyclin D. In one embodiment, multiple myeloma exhibits activation of C-MAF. In one embodiment, multiple myeloma exhibits activation of MAFB. In one embodiment, multiple myeloma exhibits activation of FGFR3 and MMset. In one embodiment, multiple myeloma exhibits activation of C-MAF, FGFR3, and MMset. In one embodiment, multiple myeloma exhibits activation of Cyclin D1. In one embodiment, multiple myeloma exhibits activation of MAFB and Cyclin D1. In one embodiment, multiple myeloma exhibits activation of Cyclin D.

[0639] In one embodiment, multiple myeloma has one or more chromosomal translocations. In one embodiment, the chromosomal translocation is t(14;16). In one embodiment, the chromosomal translocation is t(14;20). In one embodiment, the chromosomal translocation is t(4;14). In one embodiment, the chromosomal translocations are t(4;14) and t(14;16). In one embodiment, the chromosomal translocation is t(11;14). In one embodiment, the chromosomal translocation is t(6;20). In one embodiment, the chromosomal translocation is t(20;22). In one embodiment, the chromosomal translocations are t(6;20) and t(20;22). In one embodiment, the chromosomal translocation is t(16;22). In one embodiment, the chromosomal translocations are t(14;16) and t(16;22). In one embodiment, the chromosomal translocations are t(14;20) and t(11;14).

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

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

[0642] In some embodiments, multiple myeloma exhibits early progression (e.g., less than 12 months) after initial treatment. In other embodiments, multiple myeloma exhibits early progression (e.g., less than 12 months) after autologous stem cell transplantation. In another embodiment, multiple myeloma is refractory to lenalidomide. In another embodiment, multiple myeloma is refractory to pomalidomide. In some such embodiments, multiple myeloma is predicted to be refractory to pomalidomide (e.g., by molecular profiling). In another embodiment, multiple myeloma is relapsed or refractory to three or more treatments 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, iberdomide, or abadomide), or is doubly refractory to a proteasome inhibitor and an immunomodulatory compound. In yet another embodiment, multiple myeloma is relapsed or refractory to three or more previous therapies including, e.g., 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, iberdomide, or abadomide), or is doubly refractory to a proteasome inhibitor or an immunomodulatory compound and a CD38 mAb. In yet another embodiment, multiple myeloma is triply refractory, e.g., multiple myeloma is refractory to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib), an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iberdomide, or abadomide), and another active agent described herein.

[0643] In one embodiment, provided is a method of treating or managing relapsed or refractory multiple myeloma in a patient having renal dysfunction 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, isotope analog or prodrug thereof, in a pharmaceutically acceptable carrier optionally forming a composition.

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

[0645] In another embodiment, provided is a method of treating or managing relapsed or refractory multiple myeloma in the fourth line, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotope analog or prodrug thereof, in a pharmaceutically acceptable carrier optionally forming a composition.

[0646] In another embodiment, provided is a method of treating or managing newly diagnosed transplant - ineligible multiple myeloma, comprising administering to the patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotope analog or prodrug thereof, in a pharmaceutically acceptable carrier optionally forming a composition.

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

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

[0649] In some embodiments, a patient being treated with one of the compounds described herein has not been treated with multiple myeloma therapy prior to administration. In some embodiments, a patient being treated with one of the compounds described herein has been treated with multiple myeloma therapy prior to administration. In some embodiments, a patient being treated with one of the compounds described herein exhibits drug resistance to multiple myeloma therapy. In some embodiments, a patient being treated with one of the compounds described herein exhibits resistance to one, two or three multiple myeloma therapies, the therapies being selected from CD38 antibodies (CD38 mAbs, such as daratumumab or isatuximab), proteasome inhibitors (such as bortezomib, carfilzomib, ixazomib or marizomib) and immunomodulatory compounds (such as thalidomide, lenalidomide, pomalidomide, iberdomid or abadomid).

[0650] The compounds described herein can be used for treating patients regardless of the patient's 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, such as a patient over 65 years of age. In one embodiment, the patient is an elderly multiple myeloma patient, such as a patient over 75 years of age.

[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 term "bioactive agent" or "additional therapeutic active agent" is used to describe an agent other than a compound according to the invention that can be used in combination with or alternately to a compound of the invention to achieve the desired result of therapy. In one embodiment, the compound of the invention and the additional therapeutic active agent are administered such that they have a period of overlap during which they are active in vivo, e.g., a period during which Cmax, Tmax, AUC or other pharmacokinetic parameters overlap. In another embodiment, the compound of the invention and the additional therapeutic active agent, which do not have overlapping pharmacokinetic parameters but one has a therapeutic effect on the therapeutic efficacy of the other, are administered to a host in need thereof.

[0653] In one aspect of this embodiment, the additional therapeutic active agent is an immune modulator including, but not limited to, checkpoint inhibitors such as PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecules, peptides, nucleotides or other inhibitors. In certain aspects, the immune modulator is an antibody such as a monoclonal antibody.

[0654] Examples of PD-1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor and inhibit immunosuppression include nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). Examples of PD-L1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor and inhibit immunosuppression include atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). Examples of CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibit immunosuppression include ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884, and AGEN2041 (Agenus), but are not limited thereto. Examples of LAG-3 checkpoint inhibitors include BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual inhibitor of PD-1 and LAG-3, MGD013 (MacroGenics), but are not limited thereto. 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, such as anti-OX-40 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 an effective amount in combination with or alternately with an inhibitor of androgens (such as testosterone), 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 genital system such as prostate cancer or testicular cancer. In one embodiment, the prostate or testicular cancer is androgen resistant. Non-limiting examples of anti-androgen compounds are presented in International Publication No. WO 2011 / 156518, as well as U.S. Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of anti-androgen compounds include enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topralutamide, abiraterone acetate, and cimetidine.

[0662] In one embodiment, the additional therapeutic 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 therapeutic agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso), olmutinib (Olita), naquotinib (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 (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006 and dacomitinib (PF-00299804; Pfizer).

[0664] In one embodiment, the additional therapeutic 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 therapeutic agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, ofatumumab, ibritumomab, tositumomab and ocrelizumab.

[0666] In one embodiment, the additional therapeutic agent is a JAK3 inhibitor. An example of a JAK3 inhibitor is tasocitinib.

[0667] In one embodiment, the additional therapeutic agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-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((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (obatoclax 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), pogostin, 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 therapeutic agent is a kinase inhibitor. In one embodiment, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.

[0669] Examples of PI3 kinase inhibitors include wortmannin, demethoxybirubin, 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-pyridinyl}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), BAY 80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz(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 (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-oate), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N’-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea) (gedatolisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,(5-((Dimethoxyphenyl)amino)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-hexahydroinden[4,5h]isochromen-10-yl]acetate (also known as sonolisib)), LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, 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 International Publication No. 2014 / 071109, including, but not limited to, these.,

[0670] Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica (trademark)) (1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see U.S. Patent 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 (R-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), CGI-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,(R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide, GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-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), and other molecules capable of inhibiting BTK activity, such as the BTK inhibitors disclosed in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59 (which is hereby incorporated 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-aminocyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxamide), imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,((2S)-2-Aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5-Fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), 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), Piceatanol (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, Piceatanol, ER-27319 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (which is hereby incorporated by reference in its entirety)), Compound D (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (which is hereby incorporated by reference in its entirety)), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (which is hereby incorporated by reference in its entirety)), Luteolin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,See 3614-3643 (which is hereby incorporated by reference in its entirety and forms part of this specification), apigenin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (which is hereby incorporated by reference in its entirety and forms part of this specification)), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (which is hereby incorporated by reference in its entirety and forms part of this specification)), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (which is hereby incorporated by reference in its entirety and forms part of this specification)), myricetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (which is hereby incorporated by reference in its entirety and forms part of this specification)), morin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (which is hereby incorporated by reference in its entirety and forms part of this specification)).

[0672] In one embodiment, the additional therapeutic active agent is a MEK inhibitor. MEK inhibitors are known and include, for example, trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / 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-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoyl amino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxycoumen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinane-2-yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX02189, BIX02188, binimetinib, SL-327, TAK-733, PD318088, etc.

[0673] In one embodiment, the additional therapeutic agent is a Raf inhibitor. Raf inhibitors are known and include, for example, 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)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazole-2-amine), 2-bromoaldisine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]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-2pyridinecarboxamide 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 therapeutic agent is, but is not limited to, an AKT inhibitor including MK-2206, GSK690693, perifosine (KRX-0401), GDC-0068, trichostatin, AZD5363, honokiol, PF-04691502, and miltefosine; an FLT-3 inhibitor including, but not limited to, P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tandutinib (MLN518), ENMD-2076, and KW-2449; or a combination thereof.

[0675] In one embodiment, the additional therapeutic 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), XL-518 / GDC-0973 (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol) (cobimetinib), refametinib / BAY869766 / RDEA119 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-Gione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoyl amino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxycoumen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinane-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), among others, but not limited thereto.,

[0676] In one embodiment, the additional therapeutic 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 therapeutic agent is a HSP inhibitor. Examples of HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG), and radicicol.

[0678] Additional bioactive compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitor, VEGFR inhibitor, aurora kinase inhibitor, PIK-1 modulator, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, IGFR-TK inhibitor, anti-HGF antibody, focal adhesion plaque kinase inhibitor, Map kinase (mek) inhibitor, VEGF trap antibody, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, tisilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, sirengeptide, gimitecan, IL13-PE38QQR, INO 1001, IPdR 1KRX-0402, Lucanton, LY317615, Neuradiab, Vitespan, Rta 744, Sdx 102, Tarpanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Bortezomib, Etoposide, Gemcitabine, Doxorubicin, Liposomal Doxorubicin, 5'-Deoxy-5-fluorouridine, Vincristine, Temozolomide, ZK-304709, Celiclib; PD0325901, AZD-6244, Capecitabine, L-Glutamic Acid, N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, Disodium Salt Heptahydrate, Camptothecin, PEG-Labeled Irinotecan, Tamoxifen, Toremifene Citrate, Anastrozole, Exemestane, Letrozole, DES (Diethylstilbestrol), Estradiol, Estrogen, Conjugated Estrogen, Bevacizumab, IMC-1C11, CHIR-258); 3-[5-(Methylsulfonylpiperazinemethyl)-indolyl-quinoline, Batalanib, AG-013736, AVE-0005, Goserelin Acetate, Leuprolide Acetate, Triptorelin Pamoate, Medroxyprogesterone Acetate, Hydroxyprogesterone Caproate, Megestrol Acetate, Raloxifene, Bicalutamide, Flutamide, Nilutamide, Megestrol Acetate, CP-724714; TAK-165, HKI-272, Erlotinib, Lapatinib, Canertinib, ABX-EGF Antibody, Arbitux, EKB-569, PKI-166, GW-572016, Lonafarnib, BMS-214662, Tipifarnib; Amifostine, NVP-LAQ824, Suberoyl Analide Hydroxamic 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,Cyproterone, 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, Mitomycin, Mitotane, Mitoxantrone, Nilutamide, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, Plicamycin, Porfimer, Procarbazine, Raltitrexed, Rituximab, Streptozocin, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Tretinoin, Vincdesine, 13-cis-Retinoic acid, Phenylalanine Mustard, Uracil Mustard, Estramustine, Altretamine, Floxuridine, 5-Deoxyuridine, Cytosine Arabinoside, 6-Mercaptopurine, Deoxycoformycin, Calcitriol, Valrubicin, Mitramycin, Vinblastine, Vinorelbine, Topotecan, Lazoxamide, Marimastat, COL-3, Neovastat, BMS-275291, Squalamine, Endostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Droloxifene, Idoxyfene, Spironolactone, Finasteride, Cimitidine, Trastuzumab, Denileukin Diftitox, Gefitinib, Bortezomib, Paclitaxel, Paclitaxel without Cremophor, Docetaxel, Epothilone B, BMS-247550, BMS-310705, Droloxifene, 4-Hydroxytamoxifen, Pipendoxifene, ERA-923, Arzoxifene, Fulvestrant, Acolbifene, Lasofoxifene, Idoxyfene, 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, zoledronic acid, 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, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin α, darbepoetin α and mixtures thereof are mentioned.

[0679] In one embodiment, the additional therapeutic agent is selected from, but not limited to, 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 (Zolinza™), 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 therapeutic agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiation therapy agent, an additional therapeutic agent, or an immunosuppressive agent.

[0681] Suitable additional therapeutic agents for chemotherapy include, but are not limited to, radioactive molecules, toxins also known as cytotoxins or cytotoxic drugs, any agent harmful to the viability of cells, and liposomes or other vesicles containing chemotherapy compounds. Common anticancer drugs include vincristine (Oncovin™) or liposomal vincristine (Marqibo™), daunorubicin (daunomycin or Cerubidine™) or doxorubicin (Adriamycin™), cytarabine (cytosine arabinoside, ara-C or Cytosar™), L-asparaginase (Elspar™) or PEG-L-asparaginase (pegaspargase or Oncaspar™), etoposide (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-dichlorodiammineplatinum(II) (DDP) (cisplatin), diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, live BCG (BCGlive) (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 estrogen, cyclophosphamide, cyclothosphamide, cytarabine, cytarabine, cytochalasin B, cytoxan, dacarbazine, dactinomycin, dactinomycin (formerly actinomycin), daunorubicin HCL, daunorubicin citrate, denileukin diftitox, dexrazoxane, dibromomannitol, dihydroxy anthracin dione, docetaxel, droxidopa mesylate, doxorubicin HCL, dronabinol, Escherichia coli (E.coli) L-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogen, estradiol, estramustine phosphate sodium, ethidium bromide, ethinyl estradiol, etidronate, etoposide, citrovorum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folic acid, gemcitabine HCL, glucocorticoid, goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea, idarubicin HCL, ifosfamide, interferon α-2b, irinotecan HCL, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine, lomustine, maytansinoid, mechlorethamine HCL, medroxyprogesterone acetate, megestrol acetate, melphalan HCL, mercaptopurine, mesna, methotrexate, methyltestosterone, mitomycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL, primycin (plimycin), polifeprosan 20 carmustine implant, porfimer sodium, procaine, procarbazine HCL, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate and vinorelbine tartrate are mentioned, but not limited thereto.

[0682] Additional therapeutic agents that can be administered in combination with the degrading agent disclosed herein include bevacizumab, sunitinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, batiraneib, vandetanib, aflibercept, brolucizumab, etaracizumab (MEDI-522), sirukumab, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukin, atorizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, 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, luxolitinib (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. Similar to the antibodies naturally produced by B cells, these MAbs can "coat" the cancer cell surface and induce its destruction by the immune system. For example, bevacizumab is a protein secreted by tumor cells and other cells in the tumor microenvironment and targets vascular endothelial growth factor (VEGF), which promotes the development of tumor blood vessels. When VEGF binds to bevacizumab, it cannot interact with its cell receptor, preventing the signaling that leads to the growth of new blood vessels. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets the human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the target receptor from sending normal growth-promoting signals. These may also induce apoptosis and activate the immune system to destroy tumor cells.

[0684] In one aspect of the present invention, the additional therapeutic agent is an immunosuppressant. The immunosuppressant can be a calcineurin inhibitor, such as cyclosporine or ascomycin, such as cyclosporine A (NEORAL™), FK506 (tacrolimus), pimecrolimus, an mTOR inhibitor, such as rapamycin or its derivatives, such as sirolimus (RAPAMUNE™), everolimus (Certican™), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, such as ridafolimus, azathioprine, campath 1H, an S1P receptor modulator, such as fingolimod or an analog thereof, an anti-IL-8 antibody, mycophenolic acid or a salt thereof, such as the sodium salt or a prodrug thereof, such as 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 (sold as Enbrel™ by Immunex), adalimumab (Humira™), infliximab (Remicade™), an anti-LFA-1 antibody, natalizumab (Antegren™), enlimomab, gavilimomab, anti-thymocyte immunoglobulin, cypressmab, alefacept, efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naproxen, 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 such as ixazomib or oprozomib. In one embodiment, the additional therapy is a histone deacetylase inhibitor such as ACY241. In one embodiment, the additional therapy is a BET inhibitor such as GSK525762A, OTX015, BMS-986158, TEN-010, CPI-0610, INCB54329, BAY1238097, FT-1101, ABBV-075, 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 such as AZD5991, AMG176, MIK665, S64315 or S63845. In one embodiment, the additional therapy is an LSD-1 inhibitor such as ORY-1001, ORY-2001, INCB-59872, IMG-7289, TAK-418, GSK-2879552, 4-[2-(4-amino-piperidin-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluoro-benzonitrile or a salt thereof. In one embodiment, the additional therapy is a CS1 antibody such as elotuzumab. In one embodiment, the additional therapy is a CD38 antibody such as daratumumab or isatuximab. In one embodiment, the additional therapy is a BCMA antibody or antibody conjugate such as GSK2857916 or BI 836909.

[0686] In some embodiments, the degradation-inducing agents described herein are administered in combination with or alternately with one or more cell immunotherapies. In some embodiments, the cell immunotherapy is a modified immune cell. Examples of modified immune cells include, but are not limited to, modified T cell receptor (TCR) cells and modified chimeric antigen receptor (CAR) cells. Modified T cell receptor (TCR) therapy generally involves the introduction of a modified T cell receptor that targets 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 that targets 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, making cancer cells more susceptible to their attack. However, CAR cells can only recognize antigens that are naturally expressed on the cell surface by themselves, and the range of potential antigen targets is smaller than that of TCRs.

[0687] In some embodiments, the immunotherapy is modified TCR or CAR immune cells, and the TCR or CAR is an important signaling receptor that is naturally found on mature B cells and is often expressed by lymphoma and myeloma cells, BCMA, which is found on the surface of almost all B cells, affects their growth, development, and activity, CD19, a receptor that is often expressed by leukemia, lymphoma, and myeloma cells, CD22, a receptor that is mainly found on the surface of mature B cells and is often expressed by leukemia and lymphoma cells, CD30, a receptor that is expressed on certain types of activated immune cells and is often expressed by leukemia and lymphoma cells, CD33, a surface receptor that is found on several types of immune cells and is often expressed by leukemia cells, CD56, a protein that is found on both neurons and natural killer immune cells, CD123 (also known as IL-3R), a receptor that is found on immune cells, is involved in proliferation and differentiation, and is often expressed by leukemia and lymphoma cells, CEA, a protein that is involved in cell adhesion, is usually produced only before birth, is often abnormally expressed in cancer, and can contribute to metastasis, EBV-related 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 abnormally overexpressed in cancer cells, GPC3, a cell surface protein that is thought to be involved in the regulation of growth and cell division, HER2, a pathway that controls cell growth and is generally overexpressed in some cancers, especially breast cancer, and is associated with metastasis, HPV-related antigen, a foreign viral protein expressed by cancer cells resulting from infection with human papillomavirus (HPV), MAGE antigens (the genes that produce these proteins are usually off in adult cells but are reactivated in cancer cells and can flag them as abnormal to the immune system), mesothelin, a protein that is generally overexpressed in cancer and can assist in metastasis, MUC-1, a glycoprotein that is generally overexpressed in cancer, is usually produced only before birth, butNY-ESO-1, a protein often abnormally expressed in cancer; PSCA, a surface protein found in some 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 mainly expressed prenatally rather than in adult tissues, is often abnormally expressed in cancer, may promote cancer cell metastasis and prevent cancer cell death; WT1, a protein that promotes cancer progression and is abnormally expressed in patients with cancer, especially leukemia; and Claudin 18.2, a surface protein overexpressed in some esophageal cancers and involved in invasion and survival. One or more tumor-associated antigens selected from these are targeted. In some embodiments, the modified CAR therapy is axicabtagene ciloleucel (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 maraleucel (Bristol-Myers Squibb Co.), a CD19-targeted CAR T cell immunotherapy used in the treatment of 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). In some embodiments, the modified CAR-T therapy is a bispecific CAR-T targeting BCMA and CD38. In some embodiments, the modified 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. Patent No. 5,359,046 (Cell Genesys), U.S. Patent No. 5,712,149 (Cell Genesys),U.S. Patent No. 6,103,521 (Cell Genesys), U.S. Patent No. 7,446,190 (Memorial Sloan Kettering Cancer Center), U.S. Patent No. 7,446,179 (City of Hope), U.S. Patent No. 7,638,325 (University of Pennsylvania), U.S. Patent No. 8,911,993 (University of Pennsylvania), U.S. Patent 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), International Publication No. 2014 / 145252, International Publication No. 2014 / 153270 (Novartis AG), U.S. Patent Application Publication No. 2018 / 0360880 (Memorial Sloan Kettering Cancer Center), International Publication No. 2017 / 0243 (Dana Farber Cancer Institute), International Publication No. 2016 / 115177 (Juno Therapeutics, Inc.), each of which is incorporated herein by reference in its entirety.

[0688] In some embodiments, the immunotherapy is non-modified adoptive cell therapy. Adoptive cell therapy is an approach used to enhance the ability of the immune system 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 having tumor or virus-related antigens, and then expanded ex vivo. In some embodiments, the adoptive cell therapy is tumor-infiltrating lymphocyte (TIL) therapy, in which naturally occurring T cells that have already infiltrated the patient's tumor are collected, activated, expanded, and then reinfused into the patient. In some embodiments, the non-modified adoptive cell therapy includes autologous or allogeneic immune cells, such as αβ T cells, that are activated to target multiple potential antigens. One strategy used to generate targeted non-modified T cells involves the 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 the isolation of peripheral blood mononuclear cells (PBMCs) and the exposure of the cells to one or more tumor-associated antigens. In particular, the approach to generating multi-antigen-specific T cells has focused on the priming and activation of T cells using multiple libraries of targeted antigen overlapping peptide libraries, such as multiple libraries of 15-mer peptides that overlap by 11 amino acids across the entire amino acid sequences of several target antigens (see, for example, overlapping peptide library products commercially available from JPT Technologies or Miltenyi). Strategies for activating ex vivo autologous or allogeneic immune effector cells for the targeting of tumor-associated antigens are 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), International Publication No. 2006026746 (U.S. Department of Health and Human Services), U.S. Patent Application Publication No. 2015 / 0044258 (Cell Medica / Kurr Therapeutics), International Publication No. 2016 / 154112 (Children's National Medical Center), International Publication No. 2017 / 203356 (QueenslandInstitute of Medical Research), International Publication No. 2018 / 005712 (Geneius Biotechnology, Inc.), Vera et 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, 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 are described, each of which is incorporated herein by reference. In some embodiments, the non - modified activated immune cells administered in combination with or alternately with the degradation - inducing pharmaceutical compositions described herein are selected from activated CD4+ T cells (T - helper cells), CD8+ T cells (cytotoxic T lymphocytes), CD3+ / CD56+ natural killer T cells (CD3+ NKT), and γδ T cells (γδ T cells), or combinations thereof. In some embodiments, adoptive cell therapy is a composition comprising CD4+ T cells (T - helper cells). In some embodiments, adoptive cell therapy is a composition comprising CD8+ T cells (cytotoxic T lymphocytes). In some embodiments, adoptive cell therapy is a composition comprising CD3+ / CD56+ natural killer T cells (CD3+ NKT). In some embodiments, adoptive cell therapy is a composition comprising CD4+ T cells (T - helper cells), CD8+ T cells (cytotoxic T lymphocytes), CD3+ / CD56+ natural killer T cells (CD3+ NKT), and γδ T cells (γδ T cells).

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

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

[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 iberdomid.

[0692] In another embodiment, the additional compound that can be used in combination with the compounds of the present invention is selected from the compounds described in International Publication No. WO 2012 / 175481, International Publication No. WO 2015 / 085172, International Publication No. WO 2015 / 085172, International Publication No. WO 2017 / 067530, International Publication No. WO 2017 / 121388, International Publication No. WO 2017 / 201069, International Publication No. WO 2018 / 108147, International Publication No. WO 2018 / 118947, International Publication No. WO 2019 / 038717, International Publication No. WO 2019 / 191112, International Publication No. WO 2020 / 006233, Patent Document 25, International Publication No. WO 2020 / 006265, or International Publication No. WO 2020 / 012334.

[0693] In another embodiment, the additional compounds that can be used in combination with the compounds of the present invention are selected from the compounds described in International Publication No. WO 2019 / 060693, International Publication No. WO 2019 / 060742, International Publication No. WO 2019 / 133531, International Publication No. WO 2019 / 140380, International Publication No. WO 2019 / 140387, International Publication No. WO 2010 / 010177, International Publication No. WO 2020 / 010210, or International Publication No. WO 2020 / 010227.

[0694] In another embodiment, the additional compounds that can be used in combination with the compounds of the present invention are selected from the compounds described in International Publication No. WO 2015 / 160845, International Publication No. WO 2016 / 118666, International Publication No. WO 2016 / 149668, International Publication No. WO 2016 / 197032, International Publication No. WO 2016 / 197114, International Publication No. WO 2017 / 011371, International Publication No. WO 2017 / 0115901, International Publication No. WO 2017 / 030814, International Publication No. WO 2017 / 176708, International Publication No. WO 2018 / 053354, International Publication No. WO 2018 / 0716060, International Publication No. WO 2018 / 102067, International Publication No. WO 2018 / 118598, International Publication No. WO 2018 / 119357, International Publication No. WO 2018 / 119441, International Publication No. WO 2018 / 119448, International Publication No. WO 2018 / 140809, International Publication No. WO 2018 / 226542, International Publication No. WO 2019 / 023553, International Publication No. WO 2019 / 099926, International Publication No. WO 2019 / 195201, International Publication No. WO 2019 / 195609, International Publication No. WO 2019 / 199816, International Publication No. WO 2020 / 023851, International Publication No. WO 2020 / 041331, or International Publication No. WO 2020 / 051564.

[0695] In another embodiment, the additional compound that can be used in combination with the compounds of the present invention is selected from the compounds 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 / 148440, 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 / 069125.

[0696] In another embodiment, the additional compound that can be used in combination with the compounds of the present invention is selected from the compounds described in WO 2017 / 197036, WO 2017 / 197046, WO 2017 / 197051, WO 2017 / 197055, WO 2017 / 197056, WO 2017 / 115218, WO 2018 / 220149, 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 a neat chemical substance, but more typically are administered as a pharmaceutical composition containing an effective amount for a host, typically a human, in need of such treatment for any of the disorders described herein. Accordingly, the present disclosure provides a pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof for any of the uses described herein together with at least one pharmaceutically acceptable carrier. The pharmaceutical composition may contain only the compound or salt as the active agent, or alternatively, in an alternative embodiment, the compound and at least one additional active agent.

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

[0699] The pharmaceutical composition may also contain an active compound and an additional therapeutically active agent in a certain molar ratio. In non-limiting exemplary embodiments, the pharmaceutical composition may contain an anti-inflammatory agent or an immunosuppressive agent in a molar ratio of up to about 0.5:1, up to about 1:1, up to about 2:1, up to about 3:1, or up to about 1.5:1 to up to about 4:1 relative to the compound of the present invention. The compounds disclosed herein can be administered orally, topically, parenterally, by inhalation or spray, sublingually, by implant including an ocular implant, transdermally, by buccal administration, rectally, as an injection including an eye drop, an intraocular injection, intravenously, intra-aortally, intracranially, subdermally, intraperitoneally, subcutaneously, intranasally, sublingually or rectally, or by other means in a dosage unit formulation containing a conventional pharmaceutically acceptable carrier. For intraocular delivery, the compound can be administered as desired, for example, by intravitreal, intrastromal, intracameral, sub-Tenon's, subretinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periorbital, transscleral, retrobulbar, near posterior sclera, perikeratonal or lacrimal duct injection, or by immediate or controlled release via mucus, mucin or mucosal gateways, or by an intraocular device.

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

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

[0702] Examples of carrier types include, but are not limited to, binders, buffers, coloring agents, diluents, disintegrants, emulsifiers, flavoring agents, glidents, lubricants, preservatives, stabilizers, surfactants, tabletting agents, and wetting agents. Some carriers may fall into two or more categories; for example, vegetable oils can 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, celluloses, tragacanth powder, malt, gelatin; talc, and vegetable oils. Any active agent that does not substantially interfere with the activity of the compounds of the present invention may be included in the pharmaceutical composition.

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

[0704] Formulations suitable for rectal administration are usually given as unit dose suppositories. These can be prepared by mixing the active compound with one or more conventional solid carriers, such as cocoa butter, and then shaping the resulting mixture.

[0705] Formulations suitable for topical application to the skin preferably take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils. Carriers that can be used include petrolatum, lanolin, polyethylene glycol, alcohols, transdermal enhancers, and combinations of two or more of these.

[0706] Formulations suitable for transdermal administration can be provided as individual patches adapted to remain in intimate contact with the recipient's epidermis over an extended period of time. Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, e.g., 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 provided for the delivery of drugs across or into living tissue, particularly skin. The microneedle patch or device enables drug delivery across or into 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 passive breath-driven and active power-driven single / multiple-dose dry powder inhalers (DPIs). Devices most commonly used 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 choice of a suitable pulmonary delivery device is determined by parameters such as the nature of the drug and its formulation, the site of action, and the pathophysiology of the lung.

[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 hereby incorporated by reference in their entirety). Examples include U.S. Patent No. 8,192,408 to Psivida Us, Inc. entitled "Ocular trocar assembly"; U.S. Patent No. 7,585,517 to Macusight, Inc. entitled "Transcleral delivery"; U.S. Patent Nos. 5,710,182 and 5,795,913 to Santen OY entitled "Ophthalmic composition"; U.S. Patent No. 8,663,639 entitled "Formulations for treating ocular diseases and conditions", U.S. Patent No. 8,486,960 entitled "Formulations and methods for vascular permeability-related diseases or conditions", U.S. Patent Nos. 8,367,097 and 8,927,005 entitled "Liquid formulations for treatment of diseases or conditions", U.S. Patent No. 7,455,855 to Santen Pharmaceutical Co., Ltd. entitled "Delivering substance and drug delivery system using the same"; International Publication No. WO 2011 / 050365 to Forsight Labs, entitled "Conformable Therapeutic Shield For Vision and Pain", and International Publication No. WO 2009 / 145842 to Forsight Labs, entitled "Therapeutic Device for Pain Management and Vision",LLC); U.S. Patent No. 9,066,779 entitled "Implantable therapeutic device", U.S. Patent No. 8,623,395, International Publication No. WO 2014 / 160884 entitled "Ophthalmic Implant for Delivering Therapeutic Substances", U.S. Patent No. 8,399,006 entitled "Posterior segment drug delivery", U.S. Patent No. 8,277,830, U.S. Patent No. 8,795,712, U.S. Patent No. 8,808,727, U.S. Patent No. 8,298,578 and International Publication No. WO 2010 / 088548, International Publication No. WO 2014 / 152959 and U.S. Patent Application Publication No. US 2014 / 0276482 entitled "Systems for Sustained Intraocular Delivery of Low Solubility Compounds from a Port Delivery System Implant", U.S. Patent No. 8,905,963 and U.S. Patent No. 9,033,911 entitled "Injector apparatus and method for drug delivery", International Publication No. WO 2015 / 057554 entitled "Formulations and Methods for Increasing or Reducing Mucus", U.S. Patent No. 8,715,712 and U.S. Patent No. 8,939,948 entitled "Ocular insert apparatus and methods", International Publication No. WO 2013 / 116061 entitled "Insertion and Removal Methods and Apparatus for Therapeutic Devices", "Ophthalmic System for Sustained Release of Drug to theWO 2014 / 066775 entitled "Eye)", WO 2015 / 085234 and WO 2012 / 019176 entitled "Implantable Therapeutic Device", WO 2012 / 065006 entitled "Methods and Apparatus to determine Porous Structures for Drug Delivery", WO 2010 / 141729 entitled "Anterior Segment Drug Delivery", WO 2011 / 050327 entitled "Corneal Denervation for Treatment of Ocular Pain", WO 2013 / 022801 entitled "Small Molecule Delivery with Implantable Therapeutic Device", WO 2012 / 019047 entitled "Subconjunctival Implant for Posterior Segment Drug Delivery", WO 2012 / 068549 entitled "Therapeutic Agent Formulations for Implanted Devices", WO 2012 / 019139 entitled "Combined Delivery Methods and Apparatus", WO 2013 / 040426 entitled "Ocular Insert Apparatus and Methods", WO 2012 / 019136 entitled "Injector Apparatus and Method for Drug Delivery", WO 2012 / 019136 entitled "Fluid Exchange Apparatus andInternational Publication No. 2013 / 040247 entitled "Methods" (ForSight Vision4, Inc.), 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 entitled "Inhalation Device for Use in Aerosol Therapy" (Vectura GmbH); 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", U.S. Patent No. 6,582,678, U.S. Patent No. 8,137,657, U.S. Patent Application Publication No. 2003 / 0202944 and U.S. Patent Application Publication No. 2010 / 0330188 entitled "Carrier particles for use in dry powder inhalers", 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", 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", "Formulations for Use in Inhaler DeviceU.S. Patent Application Publication No. 2012 / 0114709 entitled "Devices", U.S. Patent No. 8,101,160, U.S. Patent Application Publication No. 2013 / 0287854 entitled "Compositions and Uses", U.S. Patent Application Publication No. 2014 / 0037737 entitled "Particles for Use in a Pharmaceutical Composition" and U.S. Patent No. 8,580,306, U.S. Patent Application Publication No. 2015 / 0174343 entitled "Mixing Channel for an Inhalation Device", U.S. Patent 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, U.S. 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 include International Publication No. WO 2015 / 085251, entitled "Intracameral Implant for Treatment of an Ocular Condition" (Envisia Therapeutics, Inc.); International Publication No. WO 2011 / 008737, entitled "Engineered Aerosol Particles, and Associated Methods"; International Publication No. WO 2013 / 082111, entitled "Geometrically Engineered Particles and Methods 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"; International Publication No. WO 2008 / 100304, entitled "Polymer particle composite having high fidelity order, size, and shape particles"; and International Publication No. WO 2007 / 024323, entitled "Nanoparticle fabrication methods, systems, and materials" (Liquidia Technologies, Inc.and the University of North Carolina at Chapel Hill); International Publication No. WO 2010 / 009087 entitled "Iontophoretic Delivery of a Controlled-Release Formulation in the Eye" (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.) and 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", 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. 20090203709 (Abbott Laboratories) entitled "Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor";U.S. Patent Application Publication No. 20050009910 entitled "Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug", U.S. Patent Application Publication No. 20130071349 entitled "Biodegradable polymers for lowering intraocular pressure", U.S. Patent No. 8,481,069 entitled "Tyrosine kinase microspheres", U.S. Patent No. 8,465,778 entitled "Method of making tyrosine kinase microspheres", 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 and U.S. Patent Application Publication No. 2014 / 0031408 entitled "Biodegradable intravitreal tyrosine kinase implants", U.S. Patent Application Publication No. 2014 / 0294986 entitled "Microsphere Drug Delivery System for Sustained Intraocular Release", U.S. Patent No. 8,911,768 entitled "Methods For Treating Retinopathy With Extended Therapeutic Effect" (Allergan, Inc.);U.S. Patent No. 6,495,164 (Alkermes Controlled Therapeutics, Inc.) titled "Preparation of injectable suspensions having improved injectability"; International Publication No. WO 2014 / 047439 (Akina, Inc.) titled "Biodegradable Microcapsules Containing Filling Material"; International Publication No. WO 2010 / 132664 (Baxter International Inc., Baxter Healthcare SA) titled "Compositions And Methods For Drug Delivery"; U.S. Patent Application Publication No. 20120052041 (The Brigham and Women’s Hospital, Inc.) titled "Polymeric nanoparticles with enhanced drug loading and methods of use thereof"; U.S. Patent Application Publication Nos. 20140178475, 20140248358 and 20140249158 (BIND Therapeutics, Inc.) titled "Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same"; U.S. Patent No. 5,869,103 (Danbiosyst UK Ltd.) titled "Polymer microparticles for drug delivery"; U.S. Patent No. 8628801 (University of Navarra) titled "Pegylated Nanoparticles"U.S. Patent Application Publication No. 2014 / 0107025 entitled "Ocular drug delivery system" (Jade Therapeutics, LLC); 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 entitled "Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles" (Macromed, Inc.); U.S. Patent No. 6,007,845 and U.S. Patent No. 5,578,325 entitled "Nanoparticles and microparticles of non-linear hydrophilichydrophobic multiblock copolymers" (Massachusetts Institute of Technology); U.S. Patent Application Publication Nos. 20040234611, 20080305172, 20120269894 and 20130122064 entitled "Ophthalmic depot formulations for periocular or subconjunctival administration" (Novartis Ag); U.S. Patent No. 6,413,539 entitled "Block polymer" (Poly-Med, Inc.);U.S. Patent Application Publication No. 20070071756 (Peyman) entitled "Delivery of an agent to ameliorate inflammation"; U.S. Patent Application Publication No. 20080166411 (Pfizer, Inc.) entitled "Injectable Depot Formulations And Methods For Providing Sustained Release Of Poorly Soluble Drugs Comprising Nanoparticles"; U.S. Patent No. 6,706,289 (PR Pharmaceuticals, Inc.) entitled "Methods and compositions for enhanced delivery of bioactive molecules"; and U.S. Patent No. 8,663,674 (Surmodics) entitled "Microparticle containing matrices for drug delivery".;

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

[0712] The compounds of the invention having a stereocenter can, for convenience, be depicted without stereochemistry. It will be recognized by those skilled in the art that pure or enriched enantiomers and diastereomers can be prepared by methods known in the art. Examples of methods for obtaining optically active materials include, but are not limited to, the following.

[0713] i) Physical separation of crystals - A technique for manually separating the visually distinguishable crystals of individual enantiomers. This technique can be used when crystals of separate enantiomers exist, i.e., the material is a conglomerate and the crystals are visually distinguishable.

[0714] ii) Simultaneous crystallization - A technique for separately crystallizing individual enantiomers from a racemic solution, which is only possible when the enantiomers are conglomerates in the solid state.

[0715] iii) Enzymatic resolution - A technique for partially or completely separating a racemate based on the difference in the reaction rates of 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 a synthetic precursor of the desired enantiomer that is pure as an enantiomer or enriched as an enantiomer.

[0717] v) Chemical asymmetric synthesis - A synthetic technique for synthesizing the desired enantiomer from an achiral precursor under conditions that result in asymmetry (i.e., chirality) in the product, which can be achieved by a chiral catalyst or a chiral auxiliary.

[0718] vi) Diastereomer separation - A technique for reacting a racemic compound with a reagent (chiral auxiliary) that is pure as an enantiomer to convert the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization based on more distinct structural differences, and the chiral auxiliary is removed to obtain the desired enantiomer.

[0719] vii) Primary and secondary asymmetric transformation - A technique for rapidly equilibrating diastereomers derived from a racemate to create a preponderance in the dissolution of diastereomers derived from the desired enantiomer, or for the preferential crystallization of diastereomers derived from the desired enantiomer to disrupt the equilibrium and ultimately convert, in principle, all of the material from the desired enantiomer to crystalline diastereomers. The desired enantiomer is then liberated from the diastereomer.

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

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

[0722] x) Chiral liquid chromatography - A technique for separating the enantiomers of a racemate in a liquid mobile phase by their different interactions with a stationary phase (including those by chiral HPLC). The stationary phase may be made of a chiral material, or the mobile phase may contain an additional chiral material to cause different interactions.

[0723] xi) Chiral gas chromatography - A technique for separating enantiomers in a gas mobile phase by their different interactions with a column equipped with a fixed non-racemic chiral adsorption phase after volatilizing the racemate.

[0724] xii) Extraction with chiral solvents - A technique for separating enantiomers by the selective dissolution of one enantiomer into a specific chiral solvent.

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

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

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

[0728] General synthetic scheme 2 [Chemical formula] In some embodiments, the 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 reagents suitable for the oxidation of alcohols) in an organic solvent (e.g., acetonitrile) to obtain 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 obtain 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 obtain G2-5.

[0729] General Synthetic Scheme 3

Chemical Structure

[0730] General Synthetic Scheme 4

Chemical Structure

[0731] General Synthetic Scheme 5

Chemical Structure

[0732] General Synthetic Scheme 6

Chemical Structure

[0733] Non-limiting examples of the present invention When chirality is shown in the following synthetic scheme, the designation indicates the relative chirality of the stereocenter and is not an absolute designation. For example,

Chemical formula

Chemical formula

Chemical formula

[0734] Similarly, when an achiral lactam is reacted with a racemic glutamic imide in the following experiments, the resulting compound can be a mixture of enantiomers. For example, when intermediate 7 is reacted with racemic bromo glutamic imide, the resulting intermediate 9 can be a mixture of enantiomers.

Chemical formula

[0735] Unless otherwise indicated, the resulting compound can be a mixture of enantiomers having the specified stereochemistry. For example, it is as follows.

Chemical formula

[0736] One of ordinary skill in the art can separate these mixtures of enantiomers using techniques known in the art, including chiral chromatography, crystallization, transport across a chiral membrane, or extraction with a chiral solvent. In fact, some of the following compounds were separated using these techniques. For example, intermediate

Chemical formula

Chemical formula

[0737] After separation, the absolute chirality can be specified by known methods including the determination of the crystal structures of various forms. For example, X-ray diffraction can be used for the 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 the synthetic sequence using methods known in the art. For example, chiral centers can be resolved using enzymatic resolution and enzymatic asymmetric synthesis. Additionally, a mixture of enantiomers can be resolved by incorporating protecting groups or using chiral salts. When using a chiral protecting group or salt, the mixture of enantiomers temporarily becomes a mixture of diastereomers, enabling physical separation using known methods.

[0739] If the compounds of the present invention are a mixture of diastereomers, they can also be resolved by methods known in the art. For example, a 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. A 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):

Chemical formula

[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) [Chemical] Step 1: Preparation of 6-bromobenzo[cd]indol-2(1H)-one (2): CHCl 3 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 formed yellow solid was filtered through a sintered funnel. The obtained solid was washed with cold water and pentane and azeotroped with toluene to give 6-bromo-1H-benzo[cd]indol-2-one 2 (4 g, 16.12 mmol, yield 90.93%) as a yellow solid. LC MS: ES+ 248.1, 250.0 (bromine pattern).

[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 (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 minutes. Tert-butyl 4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate 3 (1.80 g, 6.45 mmol) in THF (7 mL) was added at -78 °C, and the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and diluted with ethyl acetate. The layers were separated and the organic layer was washed with water. The organic layer was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude compound, which was purified by flash chromatography using 0%→5% MeOH-DCM to give tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 4 (527 mg, 1.17 mmol, 18.22% yield) as a brown solid. 1H NMR (d6-DMSO, 400 MHZ) δ 10.70 (s, 1H), 8.34 (d, J = 8.28 Hz, 1H), 7.95 (d, J = 6.96 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.59-7.52 (m, 2H), 7.28 (s, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.22 (br s, 1H), 5.80 (br s, 1H), 4.27-4.21 (m, 1H), 4.00-3.96 (m, 2H), 2.84-2.82 (m, 2H), 1.91-1.87 (m, 2H), 1.72-1.64 (m, 2H), 1.39 (s, 9H).

[0743] Step 3: Preparation of 2,2,2-trifluoroacetate (5) of 6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one 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 for 30 min under microwave irradiation. The solvent in the reaction mixture was evaporated under reduced pressure to give the crude product, which was washed with ether and pentane to afford 6-[(1-piperidin-1-ium-4-ylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one 2,2,2-trifluoroacetate 5 (500.0 mg, 1.12 mmol, yield 100.47%) as a brown gummy substance, 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), triethylamine (340.00 mg, 3.36 mmol, 468.32 μL) was added while cooling, followed by di-tert-butyl dicarbonate (366.67 mg, 1.68 mmol, 385.56 μL). The reaction was continued at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine solution, 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 material, which was purified by flash chromatography (using 0%→5% MeOH-DCM) to afford tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 6 (300.0 mg, 693.62 μmol, 61.93% yield) as a yellow sticky solid. 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): To a stirred solution of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 6 (300.0 mg, 693.62 μmol) in DMF (1 mL) was added sodium hydride (60% dispersion in mineral oil, 53.15 mg, 1.39 mmol, purity 60%) while cooling, and the reaction mixture was heated at 60 °C for 30 minutes. Then 3-bromopiperidine-2,6-dione 7 (133.18 mg, 693.62 μmol) was added, and the reaction was heated at 60 °C for 4 hours. Subsequently, 3-bromopiperidine-2,6-dione (133.18 mg, 693.62 μmol) was further added, and the reaction was stirred at 60 °C for an additional 16 hours. 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 obtain the crude material, which was first purified by column chromatography and then by preparative TLC plates (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, yield 4.77%, purity 90%) 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-(Quabain-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 3) [Chemical formula] 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 (183.95 μmol, 8 mL) in dioxane, and the reaction mixture was stirred at room temperature for 2 hours. Complete consumption of the starting material was indicated by TLC analysis. The solvent in the reaction mixture was evaporated under reduced pressure, and the residue was washed with ether and pentane to obtain 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.

[0747] Step 2: Preparation of 3-(6-((1-(1-(Quabain-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 3): 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 with 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. Then, the reaction mixture was stirred at room temperature for 16 h. This was diluted with ethyl acetate and water, and the layers were separated. The organic layer was washed with saturated NaHCO 3 aqueous solution, water and brine, dried over sodium sulfate and concentrated. The crude material was purified by preparative TLC (eluting with 3% MeOH / DCM) to give 3-[6-[[1-[1-(cubane-1-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 3) (55.0 mg, 94.77 μmol, yield 51.69%, purity 98.84%) 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, 3H), 2.10-2.07 (m, 1H), 2.01-1.92 (m, 2H), 1.83-1.79 (m, 1H), 1.67-1.64 (m, 1H); LC MS: ES+ 574.5.

[0748] Example 4: Synthesis of 3-(6-((1-(1-(1-methylcyclobutanecarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 4) [Chemical formula] 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...

Claims

1. Formula I: 【Chemical 1】 (wherein X １ and X ２ are independently selected from CH and N, R １ is selected from hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, -NR ２ R ２’ , -OR ２ , -NR ２ R ４ , -OR ４ , -NR ２ R ５ , -OR ５ , -(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 and is selected from R ２ and R ２’ in each case independently is 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 selected from hydrogen, halogen, alkyl, haloalkyl, -OR ８ and -NR ８ R ８’ and is selected from R ３’ is selected from hydrogen, halogen, alkyl and haloalkyl, or or R ３ and R ３’ can form a 3- to 6-membered cycloalkyl ring integrally with the carbon to which they are attached R ４ is selected from cycloalkyl, heterocycle, aryl and heteroaryl, and each R ４ is optionally substituted with one group selected from R ６ and each R ４ is optionally substituted with one, two, three or four groups independently selected from R ７ ​ R ５ is -C(O)R ６ and R ６ is alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocyclic, -CO-aryl, -CO-heteroaryl, -O-alkyl, -O-cycloalkyl, -O-heterocyclic, -O-aryl, -O-heteroaryl, -NR ２ -alkyl, -NR ２ -cycloalkyl, -NR ２ -heterocyclic, -NR ２ -aryl and -NR ２ -heteroaryl, and each R ６ is independently selected from one, two, three or four groups optionally substituted with R ９ and is optionally substituted with one, two, three or four groups independently selected from R ７ is, in each case independently, 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’ is selected from, or or two Rs on the same carbon may combine to form an oxo group, ７ and R ８ and R ８’ in each case is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, and R ９ in each case is 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 , SO 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 selected from, R １０ is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, and each R １０ is optionally substituted with one, two, three or four groups independently selected from R １１ ; Two Rs on the same carbon １１ may combine to form an oxo group, or R １１ is, in each case independently, 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, and each of its R １１ groups is optionally substituted with one, two, three or four groups independently selected from R １２ , R １２ is, in each case independently, 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’ (selected from) the compound of, or a pharmaceutically acceptable salt thereof.

2. R ６ is selected from alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, and each R ６ is optionally substituted with one, two, three or four groups independently selected from R ９ and R １１ where R is 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; aryl optionally substituted with one, two, three or four halogen, alkyl or -OR ８ groups; heteroaryl optionally substituted with one, two, three or four halogen, alkyl or -OR ８ groups; -CH optionally substituted with one, two, three or four halogen, alkyl or -OR ８ aryl; -CH optionally substituted with one, two, three or four halogen, alkyl or -OR ２ groups; -CH optionally substituted with one, two, three or four halogen, alkyl or -OR ８ heteroaryl; -OR ２ ; -NR ８ R ８ ; -C(O)R ８’ ; -C(O)OR ８ ; -C(O)-NR ８ R ８ ; -C(O)CH ８’ R ２ ; -C(O)CH ８ OR ２ ; -C(O)CH ８ -NR ２ R ８ ; -OC(O)R ８’ ; -NR ８ -C(O)R ２ ; -CH ８ -OC(O)R ２ ; -CH ８ -NR ２ -C(O)R ２ ; -S(O)R ８ ; -SO ８ R ２ ; -SO ８ -OR ２ ; and -SO ８ -NR ２ R ８ R ８’ is selected from, or or two Rs on the same carbon may combine to form an oxo group, the compound according to claim 1. １１ The compound according to claim 1, wherein the two Rs on the same carbon may combine to form an oxo group.

3. R １２ The compound according to claim 1, wherein R is selected from halogen, alkyl and haloalkyl.

4. R １２ The compound according to claim 1, wherein R is selected from hydroxyl, cyano, nitro, alkenyl, alkynyl, cycloalkyl, heterocyclic ring, aryl and heteroaryl.

5. R １２ is -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’ The compound according to claim 1, selected from

6. R １１ is alkyl optionally substituted with one, two, three or four substituents selected from R １２ The compound according to claim 1, wherein R is alkyl optionally substituted with one, two, three or four substituents selected from R

7. R １１ is cycloalkyl optionally substituted with one, two, three or four substituents selected from R １２ The compound according to claim 1, wherein R

8. R １１ wherein R １２ is a heterocyclic ring optionally substituted with one, two, three or four substituents selected from R, the compound according to claim 1.

9. R １１ wherein R １２ is aryl optionally substituted with one, two, three or four substituents selected from R, according to claim 1

10. R １１ wherein R １２ is heteroaryl optionally substituted with one, two, three or four substituents selected from R, the compound according to claim 1.

11. R １１ is -C(O)OR ８ 、-C(O)R ８ or -SO ２ R ８ The compound according to claim 1, wherein it is

12. R １１ is -CH ２ The compound according to claim 1, wherein it is aryl.

13. Formula: 【Chemical 2】 the compound according to any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. Formula: 【Chemical Formula 3】 the compound according to any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof.

15. Formula: [Chemical Formula 4] the compound according to any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof.

16. Formula: 【Chemical Formula 5】 the compound according to any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof.

17. Formula: [Chemical Formula 6] the compound according to Claim 16, or a pharmaceutically acceptable salt thereof.

18. R ７ wherein R is hydrogen, halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic ring, aryl, heteroaryl, -OR ８ and -NR ８ R ８’ and the compound according to any one of claims 1 to 17, which is selected from the group consisting of

19. 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’ selected from, the compound according to any one of claims 1 to 17.

20. One R ７ The compound according to any one of claims 1 to 17, wherein R is hydrogen.

21. Two Rs ７ The compound according to any one of claims 1 to 17, wherein the two Rs are hydrogen.

22. Three Rs ７ The compound according to any one of claims 1 to 17, wherein the three Rs are hydrogen.

23. One R ７ The compound according to any one of claims 1 to 22, wherein one R is a halogen.

24. R ６ wherein R ９ is alkyl optionally substituted with one, two, three or four groups independently selected from R, according to any one of claims 1 to 16.

25. R ６ wherein R ９ is cycloalkyl optionally substituted with one, two, three or four groups independently selected from R, according to any one of claims 1 to 16.

26. R ６ is a heterocyclic ring optionally substituted with one, two, three or four groups independently selected from ９ R, the compound according to any one of claims 1 to 16.

27. R ６ wherein R ９ is aryl optionally substituted with one, two, three or four groups independently selected from R, according to any one of claims 1 to 16.

28. R ６ is a heteroaryl optionally substituted with one, two, three or four groups independently selected from ９ R, a compound according to any one of claims 1 to 16.

29. R ６ The compound according to any one of claims 24 to 28, wherein R is not substituted.

30. R ６ wherein R ９ is replaced by one group selected from R, and the compound according to any one of claims 24 to 28.

31. R ６ is replaced by two groups independently selected from R ９ The compound according to any one of claims 24 to 28, which is substituted with.

32. R ６ is replaced by three groups independently selected from R ９ The compound according to any one of claims 24 to 28, which is substituted with.

33. R ６ is replaced by four groups independently selected from R ９ The compound according to any one of claims 24 to 28, which is substituted with.

34. R ９ The compound according to any one of claims 1 to 28 and 30 to 33, wherein R is selected from hydrogen, halogen, alkyl, haloalkyl, cyano and nitro.

35. R ９ wherein R １０ is selected from those of any one of claims 1 to 28 and 30 to 33, the compound according to claim.

36. R ９ is -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 ,SO 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 selected from, a compound according to any one of claims 1 to 28 and 30 to 33.

37. R １０ is alkyl optionally substituted with one, two, three or four groups independently selected from １１ R, according to claim 35 or 36.

38. R １０ is a haloalkyl optionally substituted with one, two, three or four groups independently selected from １１ R, according to claim 35 or 36.

39. R １０ is alkenyl optionally substituted with one, two, three or four groups independently selected from １１ R, according to claim 35 or 36 of the compound.

40. R １０ is alkynyl optionally substituted with one, two, three or four groups independently selected from １１ R, according to claim 35 or 36 of the compound.

41. R １０ is cycloalkyl optionally substituted with one, two, three or four groups independently selected from １１ R, the compound according to claim 35 or 36.

42. R １０ is a heterocyclic ring optionally substituted with one, two, three or four groups independently selected from １１ R, the compound according to claim 35 or 36.

43. R １０ wherein R １１ is aryl optionally substituted with one, two, three or four groups independently selected from R, according to claim 35 or 36.

44. R １０ is a heteroaryl optionally substituted with one, two, three or four groups independently selected from １１ R, the compound according to claim 35 or 36.

45. R １０ A compound according to any one of claims 37 to 44, wherein R is not substituted.

46. R １０ is replaced by one group selected from R １１ The compound according to any one of claims 37 to 44, which is substituted with.

47. R １０ where R １１ is substituted with two groups independently selected from R, a compound according to any one of claims 37 to 44.

48. R １０ is replaced by three groups independently selected from R １１ The compound according to any one of claims 37 to 44, which is substituted with.

49. R １０ where R １１ is substituted with four groups independently selected from R, a compound according to any one of claims 37 to 44.

50. R ２ 、 R ８ and R ８’ is hydrogen, a compound according to any one of claims 1 to 49.

51. R ２ , R ８ and R ８’ is alkyl, the compound according to any one of claims 1 to 49.

52. 【Fig. 7】 【Chem.】 【Chem.】 selected from, the compound according to Claim 1, or a pharmaceutically acceptable salt thereof.

53. 【Fig. 8】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 selected from, the compound according to Claim 1, or a pharmaceutically acceptable salt thereof.

54. Structure: 【Chemical Formula 9】 the compound according to Claim 1, or a pharmaceutically acceptable salt thereof.

55. Structure: 【Chemical Formula 10】 the compound according to Claim 1, or a pharmaceutically acceptable salt thereof.

56. Structure: 【Chemical 11】 the compound according to Claim 1, or a pharmaceutically acceptable salt thereof.

57. A pharmaceutical composition comprising the compound according to any one of Claims 1 to 56, or a pharmaceutical salt thereof, and a pharmaceutically acceptable excipient.

58. A pharmaceutical composition comprising the compound according to any one of Claims 1 to 56, or a pharmaceutically acceptable salt thereof, for treating a disorder mediated by cereblon in humans.

59. The pharmaceutical composition according to Claim 58, wherein the disorder is mediated by Ikaros or Aiolos.

60. The pharmaceutical composition according to claim 58 or 59, wherein the disorder is cancer.

61. The pharmaceutical composition according to claim 58 or 59, wherein the disorder is a tumor.

62. The pharmaceutical composition according to claim 58 or 59, wherein the disorder is an immune disorder, an autoimmune disorder or an inflammatory disorder.

63. The pharmaceutical composition according to claim 58 or 59, wherein the disorder is a hematological malignancy.

64. The pharmaceutical composition according to claim 58 or 59, wherein the disorder is multiple myeloma.

65. The pharmaceutical composition according to claim 58 or 59, wherein the disorder is leukemia.

66. The pharmaceutical composition according to claim 58 or 59, wherein the disorder is lymphoblastic leukemia.

67. The pharmaceutical composition according to claim 58 or 59, wherein the disorder is chronic lymphocytic leukemia.

68. The pharmaceutical composition according to claim 58 or 59, wherein the disorder is Hodgkin lymphoma.

69. The pharmaceutical composition according to claim 58 or 59, wherein the disorder is non-Hodgkin lymphoma.

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