Spiro compound

Abstract

Compounds and intermediates are provided. The present invention also provides compounds that bind to the universally expressed E3 ligase protein cereblon (CRBN), and uses thereof for the treatment of abnormal cell proliferation. The present invention also provides compounds useful as synthetic intermediates in the synthesis of bifunctional compounds that target protein degradation.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of June 3, 2019, application number 201980051945.7, and invention name “Spirocyclic Compounds”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of European Patent Application No. 18175701.4, filed on June 4, 2018, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0004] The present invention provides compounds that bind to the ubiquitously expressed E3 ligase protein cereblon (CRBN), which can change the substrate specificity of the CRBN E3 ubiquitin ligase complex, thereby leading to the degradation of intrinsic downstream proteins. The present invention also provides compounds that can be used as synthetic intermediates for preparing bifunctional compounds for target protein degradation. Therefore, the compounds of the present invention can be used to treat or prevent abnormal cell proliferation, including tumors and cancer. Background Art

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

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

[0007] There are more than 600 E3 ubiquitin ligases that promote the in vivo ubiquitination of different proteins, which can be divided into four families: HECT domain E3, U-box E3, monomeric RING E3 and multi-subunit E3. See generally Li et al. (PLOS One, 2008, 3, 1487), entitled “Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling.”; Berndsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307), entitled “New insights into ubiquitin E3 ligase mechanism”; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434), entitled “RING domain E3 ubiquitin ligases.”; Spratt et al. (Biochem. 2014, 458, 421-437), entitled “RBR E3 ubiquitin ligases: new structures, new insights, new questions."; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347), entitled "Roles of F-box proteins in cancer".

[0008] Cereblon is a protein that is encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, which highlights its physiological importance. Cereblon forms part of an E3 ubiquitin ligase protein complex that interacts with damaged DNA binding protein 1 (DDB1) to form an E3 ubiquitin ligase complex with Cullin 4 (CUL4A) and the E2 binding protein ROC1 (also known as RBX1), where it serves as a substrate receptor to select proteins for ubiquitination. Through mechanisms that have not yet been fully elucidated, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates many developmental processes, such as the formation of limbs and auditory vesicles. The end result is that this E3 ubiquitin ligase complex is important for limb growth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2 that functions as a DNA damage binding protein.

[0009] In an unrelated parallel study, Ito et al. (Science 2010, 327, 1345-1350), entitled "Identification of a Primary Target of Thalidomide Teratogenicity", described cereblon as a thalidomide binding protein. Studies have shown that thalidomide-cereblon binding in vivo may be related to the teratogenicity of thalidomide. After the discovery of thalidomide causing teratogenicity in the mid-1960s, it was found that the compound and related structures can be used as anti-inflammatory, anti-angiogenic and anti-cancer drugs (see Bartlett et al. (Nat. Rev. Cancer 2004, 4, 314-322), entitled "The Evolution of Thalidomide and Its Imid Derivatives as Anticancer Agents"). Thalidomide has been approved for the treatment of certain neoplastic diseases, including multiple myeloma, and is currently being studied together with the structural derivatives lenalidomide and pomalidomide for the treatment of a variety of other types of cancer (see Martiniani, R. et al. "Biological activity of lenalidomide and its underlying therapeutic effects in multiple myeloma" Adv Hematol, 2012, 2012: 842945; and Terpos, E. et al., "Pomalidomide: a novel drug to treat relapsed and Refractory multiple myeloma" Oncotargets and Therapy, 2013, 6: 531).

[0010] The disclosure of thalidomide binding to the cereblon E3 ubiquitin ligase led to studies to incorporate thalidomide and certain derivatives into compounds for targeted destruction of proteins. Celgene has disclosed imides for similar uses, including U.S. Patents 6,045,501; 6,315,720; 6,395,754; 6,561,976; 6,561,977; 6,755,784; 6,869,399; 6,908,432; 7,141,018; 7,230,012; 7,820, and those of 9,101,622.

[0011] Patent applications filed by C4 Therapeutics that describe compounds capable of binding to E3 ubiquitin ligases and target proteins for degradation include: WO 2017 / 197051, entitled “Amine-Linked C3-Glutarimide Degronimersfor Target Protein Degradation”; WO 2017 / 197055, entitled “Heterocyclic Degronimersfor Target Protein Degradation”; WO 2017 / 197036, entitled “Spirocyclic Degronimersfor Target Protein Degradation”; WO 2017 / 19704620, entitled “C3-Carbon Linked Glutarimide Degronimers for Target Protein Degradation”; WO 2017 / 197056, entitled “Bromodomain Targeting Degronimers for Target Protein Degradation.”; and WO 2018 / 237026, entitled “N / O-Linked Degrons and Degronimers for ProteinDegradation.”

[0012] Other patent applications describing protein degradation compounds include: WO 2015 / 160845; WO 2016 / 105518; WO 2016 / 118666; WO 2016 / 149668; WO 2016 / 197032; WO 2016 / 197114; WO 2017 / 007612; WO 2017 / 011371; WO 2017 / 011590; WO 2017 / 030814; WO 25 2017 / 046036; WO 2017 / 176708; WO 2017 / 176957; WO 2017 / 176598; WO 2017 / 180417; WO 2018 / 052945; WO 2018 / 052949; WO2018 / 053354; WO 2018 / 071606; WO 2018 / 102067; WO2018 / 102725; WO 2018 / 118598; WO2018 / 119357; WO 2018 / 119441; WO 2018 / 119448; WO2018 / 140809; WO 2018 / 144649; and WO2018 / 226542. Other related patent applications include: WO 2013 / 020557; WO 2013 / 063560; WO 2013 / 106643; WO 2016 / 011906; WO 2017 / 024318; and WO 2017 / 117473.

[0013] New compounds and therapeutic methods that bind to the E3 ligase protein cereblon are needed for treating various medical conditions, particularly abnormal cell proliferation. There is also a need for new compounds that can be used to prepare bifunctional molecules that can be used to degrade proteins involved in disease processes. Summary of the invention

[0014] In a first aspect, compounds are provided, which bind to cereblon and enhance the ubiquitination of proteins by cereblon-containing E3 ubiquitin ligase complexes, thereby leading to protein degradation and thus useful for treating abnormal cell proliferation and other diseases described herein, and their uses and manufacture. In a second aspect, compounds are provided that include a chemical moiety capable of binding cereblon, which can be used as a synthetic intermediate to prepare bifunctional compounds that degrade selected proteins via the ubiquitin proteasome pathway (UPP).

[0015] The compounds described herein can be administered to a host (e.g., a human) in need thereof in an effective amount, optionally in the form of a pharmaceutically acceptable salt and optionally in a pharmaceutically acceptable composition. The compounds can be administered for any therapeutic indication that can be treated by modulating the function or activity of a cereblon-containing E3 ubiquitin ligase protein complex, including but not limited to treating abnormal cell proliferation, such as cancer or tumors. In certain embodiments, the compounds described herein can modulate the natural activity of cereblon.

[0016] The present invention includes novel compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII-a, formula VIII-b, formula VIII-c, formula IX, formula X, formula XI, formula XII-a, formula XII-b, formula XII-c, formula XIII and formula XIV. In addition, the present invention includes the use of compounds generally in formula XV for treating conditions that can be treated by regulating the function or activity of E3 ubiquitin ligase protein complexes containing Cereblon. The present invention also includes the use of compounds generally in XVI in the preparation of bifunctional compounds that degrade target proteins through the ubiquitin proteasome pathway (UPP). The present invention also includes compounds of formula XVII-a, formula XVII-b, formula XVII-c, formula XVII-d, formula XVII-e, formula XVII-f and formula XVII-g.

[0017] In one aspect, a compound of Formula I is provided:

[0018]

[0019] or a pharmaceutically acceptable salt thereof; wherein:

[0020] A 1 Selected from aryl and R 1 substituted aryl; and

[0021] R 1 Selected from: -C(=O)-OC 1-6 -alkyl; -COOH; -NH-(C=O)-C 1-6 -alkyl; -NH2; and -NO2.

[0022] In another aspect, provided is a compound of Formula II:

[0023]

[0024] or a pharmaceutically acceptable salt thereof; wherein:

[0025] A 2 For R 1 substituted aryl;

[0026] and all other variables are as defined herein.

[0027] In another aspect, provided is a compound of formula III:

[0028]

[0029] or a pharmaceutically acceptable salt thereof; wherein:

[0030] Y is NH or CH2;

[0031] A 3 is selected from heteroaryl and R 2 substituted heteroaryl; and R 2 Selected from: -COOH; -C(=O)-OC 1-6 -alkyl; -NH2; and -NO2. In another aspect, a compound of formula IV is provided:

[0032]

[0033] or a pharmaceutically acceptable salt thereof; wherein:

[0034] A 4 For R 1a substituted aryl; and

[0035] R 1a Selected from: -C(=O)-OC 1-6 -alkyl; -COOH; and –NO2.

[0036] In another aspect, provided is a compound of Formula V:

[0037]

[0038] or a pharmaceutically acceptable salt thereof; wherein all variables are as defined herein. In another aspect, a compound of formula VI is provided:

[0039]

[0040] or a pharmaceutically acceptable salt thereof; wherein:

[0041] A 5 For R 2a substituted heteroaryl; and

[0042] R 2a Selected from –COOH and –C(=O)-OC 1-6 -alkyl.

[0043] In another aspect, provided is a compound of formula VII:

[0044]

[0045] or a pharmaceutically acceptable salt thereof; wherein:

[0046] A 6 For R 2 substituted heteroaryl; and

[0047] All other variables are as defined herein.

[0048] In another aspect, provided is a compound of Formula VIII-a, VIII-b or VIII-c:

[0049]

[0050] or a pharmaceutically acceptable salt thereof; wherein:

[0051] m is 0 or 1; and

[0052] All other variables are as defined herein.

[0053] In another aspect, provided is a compound of Formula IX:

[0054]

[0055] or a pharmaceutically acceptable salt thereof; wherein:

[0056] n is 0 or 1; and

[0057] All other variables are as defined herein.

[0058] In another aspect, a compound of formula X is provided:

[0059]

[0060] or a pharmaceutically acceptable salt thereof;

[0061] wherein all variables are as defined herein.

[0062] In another aspect, provided is a compound of formula XI:

[0063]

[0064] or a pharmaceutically acceptable salt thereof;

[0065] wherein all variables are as defined herein.

[0066] In another aspect, provided is a compound of Formula XII-a, XII-b or XII-c:

[0067]

[0068] or a pharmaceutically acceptable salt thereof; wherein:

[0069] R 2b Selected from: -COOH; -C(=O)-OC 1-6 -alkyl; and -NO2; and all other variables are as defined herein.

[0070] In another aspect, provided is a compound of Formula XIII:

[0071]

[0072] or a pharmaceutically acceptable salt thereof; wherein all variables are as defined herein. In another aspect, a compound of formula XIV is provided:

[0073]

[0074] or a pharmaceutically acceptable salt thereof; wherein all variables are as defined herein.

[0075] The present invention provides a compound of formula XV, or a pharmaceutically acceptable salt thereof,

[0076]

[0077] wherein substituents and variables are as described below and in the claims, or a pharmaceutically acceptable salt thereof.

[0078] The compounds of the invention are useful for the therapeutic and / or prophylactic treatment of cancer.

[0079] The compounds of the invention can further be used as part of a bifunctional compound comprising the compounds of the invention as an E3 ubiquitin ligase moiety linked to a moiety that binds to a target protein, wherein the target protein is accessible to the ubiquitin ligase to effect degradation of the protein.

[0080] In another aspect, there is provided a use of a compound of Formula XV or a pharmaceutically acceptable salt thereof for treating a condition that can be treated by modulating the function or activity of a cereblon containing E3 ubiquitin ligase protein complex:

[0081]

[0082] in:

[0083] A is selected from: aryl; 1 substituted aryl; heteroaryl; and 2 substituted heteroaryl, and

[0084] All other variables are as defined herein.

[0085] For clarity, as used herein, and are the same group selected from the following: aryl; 1 substituted aryl; heteroaryl; and 2 Substituted heteroaryl.

[0086] The compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to Formula XII-c, Formula XIII, Formula XIV and Formula XV are useful as therapeutic agents when administered in an effective amount to a host, typically a human, for the treatment of medical conditions including, but not limited to, abnormal cell proliferation, including tumors or cancer, or myeloproliferative or lymphoproliferative disorders such as B-cell or T-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorders; immune disorders, including autoimmune disorders, such as Addison's disease, celiac disease, disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type 1 diabetes; cardiogenic dysfunction, including hypercholesterolemia; infectious diseases, including viral or bacterial infections; inflammatory conditions, including asthma, chronic peptic ulcers, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, Crohn's disease, or hepatitis.

[0087] In certain embodiments, the invention provides for administering an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to Formula XII-c, Formula XIII, Formula XIV and Formula XV to treat a patient (e.g., a human) suffering from an infectious disease, wherein the treatment acts by binding to Cereblon or its E3 ligase or by an independent mechanism (optionally in combination with another biologically active agent). The disease state or disorder may be caused by a microbial or other exogenous agent such as a virus (as non-limiting examples, HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola, Flavivirus, Pestivirus, Rotavirus, Influenza, Coronavirus, EBV, Viral Pneumovirus, Drug-resistant virus, Avian influenza, RNA virus, DNA virus, Adenovirus, Poxvirus, Picornavirus, Togavirus, Orthomyxovirus, Retrovirus, or Hepadnavirus), bacteria (including but not limited to Gram-negative bacteria, Gram-positive bacteria, atypical bacteria, Staphylococcus, Streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, Meningitis, Gonorrhea, Chlamydiaceae, Mycoplasmaceae, etc.), fungi, protozoa, helminths, worms, prions, parasites, or other microorganisms.

[0088] In another aspect, disclosed compounds are provided that can be used as synthetic intermediates for preparing bifunctional compounds that cause degradation of selected proteins via the ubiquitin proteasome pathway (UPP). These compounds contain a functional group that can react with a second compound, wherein the second compound is capable of binding to a selected target protein, thereby generating a bifunctional compound as described above that can cause degradation of a selected protein via the UPP.

[0089] Thus, provided is a compound of Formula XVI, or a pharmaceutically acceptable salt thereof:

[0090]

[0091] in:

[0092] A X is selected from aryl and heteroaryl;

[0093] A "tail" is a chemical moiety comprising a reactive functional group that can be covalently attached to a protein-binding moiety to produce a targeted protein degradant, or

[0094] A "tail" is a chemical moiety that can be used to modify a property of a compound, such as hydrophobicity, hydrophilicity, solubility, drug delivery, pharmacokinetics, or other properties, such as charge, polarity, or fit within an active pocket;

[0095] In one embodiment, the "tail" is "T",

[0096] Where T is

[0097] X 1 Selected from key, NR 34 , CH2, CHR 34 , C(R 34 )2, O, and S;

[0098] X 22 is a functional group that can be used as a linker for a protein binding moiety; or X 22 is a group that covers (caps) valence bonds and is usually not a linking group; X 22 Representative examples include, but are not limited to, halogen, -NH2, -NHR 34 , -N(R 34 )2, hydroxyl, mercapto, -B(OH)2, -Sn(R 36 )3,-Si(R 36 )3, -OS(O)2 alkyl, -OS(O)2 haloalkyl, alkenyl, alkynyl, ethynyl, vinyl, -C(O)H, -NR 34 C(O) olefin, -NR34 C(O)alkyne, cyano, -SC(O)alkyl, OC(O)alkyl, heterocycle, -C(O)OH, hydrogen, alkyl, aryl, heteroaryl, aliphatic, heteroaliphatic, and carbocycle;

[0099] R 34 and R 34’ is independently selected at each occurrence from hydrogen, C1-C6 alkyl (e.g., methyl, ethyl, cyclopropyl, or C1-C3 alkyl), C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycle, aryl, heteroaryl, -(CO)R 36 , -(CS)R 36 , -(C=NH)R 36 , -(SO)R 36 , and -(SO2)R 36 ;

[0100] R 36 is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycle, aryl, heteroaryl, hydroxy, C1-C6 alkoxy, thio, C1-C6 thioalkyl, -NH2, -NH(C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocycle, aryl, or heteroaryl), and -N(independently C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocycle, aryl or heteroaryl)2;

[0101] R 20 , R 21 , R 22 , R 23 and R 24 are independently divalent or multivalent linking groups, including but not limited to covalent bonds, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -C(O)alkyl, -C(O)Oalkyl, -C(S)-, -SO2-, -S(O)-, -C(S)-, -C(O)NH-, -NHC(O)-, -N(alkyl)C(O)-, -C(O)N(alkyl)-, -O-, -S-, -NH-, -N(alkyl)-, -CH(-OR 26 )-,-CH(-NR 34 R 34’ )-,-C(-OR 26 )alkyl-,-C(-NR 34 R 34’ )alkyl-,-C(R 40 R 40 )-,-alkyl (R 27 )-alkyl(R 28)-,-C(R 27 R 28 )-,-P(O)(OR 26 )O-,-P(O)(OR 26 )-,-NR 34 C(O)NR 34’ -, olefin, haloalkyl, alkoxy, alkyne, heteroarylalkyl, aryl, arylalkyl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, carbocyclic, -(ethylene glycol) 1-6 -,-(lactic-co-glycolic acid) 1-6 -,-(propylene glycol) 1-6 -,-O-(CH2) 1-12 -O-, -NH-(CH2) 1-12 -NH-, -NH-(CH2) 1-12 -O-, -O-(CH2) 1-12 -NH-, -S-(CH2) 1-12 -O-, -O-(CH2) 1-12 -S-, -S-(CH2) 1-12 -S-, -S-(CH2) 1-12 -NH-, and -NH-(CH2) 1-12 -S-, wherein said 1-6 may be independently 1, 2, 3, 4, 5 or 6, wherein said 1-12 may be independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and wherein one or more of said CH2 or NH groups may be modified by replacing H with methyl, ethyl, cyclopropyl, F (if on carbon), etc., as described herein, and optionally, heteroatoms, heteroalkyl, aryl, heteroaryl or cycloaliphatic groups are interspersed in the chain. Certain non-limiting examples include -O-CH(CH3)-CH(CH3)CH-O-, -O-CH2-CH(CH3)CH-O-, -O-CH(CH3)-CH2CH-O-, etc.

[0102] Where R 20 , R 21 , R 22 , R 23 and R 24 Each optionally selected from R 101 or as described in the definition section; wherein R 20 , R 21 , R 22 , R 23 and R 24 At least one of them is not a bond;

[0103] R 101is independently selected at each occurrence from hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO2, F, Cl, Br, I, CF3, NH2, NHalkyl, N(alkyl), aliphatic, and heteroaliphatic;

[0104] R 26 is selected from the group consisting of hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic;

[0105] R 27 and R 28 Independently selected from hydrogen, alkyl, amine, or together with the carbon atoms to which they are attached, form C(O), C(S), C=CH2, C3-C6 spirocarbocycle, or a 4-, 5- or 6-membered spiroheterocycle containing 1 or 2 heteroatoms selected from N and O, or form 1 or 2 carbon bridged rings;

[0106] R 40 at each occurrence selected from the group consisting of: hydrogen, alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocyclic), -N(alkyl)SO2(aryl, heteroaryl or heterocyclic)-NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, heterocyclic, and carbocyclic; and

[0107] All other variables are as defined herein.

[0108] In one embodiment, a compound of Formula XVI is provided that can be used to prepare a compound that causes degradation of a selected protein by UPP:

[0109] In one aspect, a compound of one of the following formulae is provided:

[0110]

[0111]

[0112] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0113] In a first aspect, the present invention provides compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII-a to formula VIII-c, formula IX, formula X, formula XI, formula XII-a to formula XII-c, formula XIII, formula XIV, formula XV, formula XVI and formula XVII-a to formula XVII-g as defined herein for use as therapeutically active substances.

[0114] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to Formula XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI and Formula XVII-a to XVII-g as defined herein and a therapeutically inert carrier.

[0115] In certain embodiments, the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI and Formula XVII-a to XVII-g have at least one desired atomic isotope substitution in an amount greater than the natural abundance of the isotope, i.e., enriched. In one embodiment, the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI and Formula XVII-a to XVII-g include one deuterium or multiple deuterium atoms.

[0116] The compounds of the present invention are useful for the therapeutic and / or prophylactic treatment of cancer.

[0117] The compounds of the invention can further be used as part of a bifunctional compound comprising the compounds of the invention as an E3 ubiquitin ligase moiety linked to a moiety that binds to a target protein, wherein the target protein is accessible to the ubiquitin ligase to effect degradation of the protein.

[0118] Other features and advantages of the application will be apparent from the following detailed description, and from the claims.

[0119] Therefore, the present invention includes at least the following features:

[0120] a) a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to Formula XII-c, Formula XIII, Formula XIV, XVI and Formula XVII-a to XVII-g, or a pharmaceutically acceptable salt thereof;

[0121] b) use of an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII-a to VIII-c, IX, X, XI, XII-a to XII-c, XIII, XIV, XV, XVI and XVII-a to XVII-g, or a pharmaceutically acceptable salt thereof, for treating a patient (including a human) having a disorder responsive to such treatment, including by modulating ubiquitination of cereblon-based proteins, said disorder including, for example, abnormal cell proliferation such as a tumor or cancer, an immune disorder, an autoimmune disorder or an inflammatory disorder, a cardiovascular disorder, an infectious disease or other disorder responsive to such treatment;

[0122] c) use of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to Formula XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI and Formula XVII-a to XVII-g, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a medical condition as further described herein;

[0123] d) a method for preparing a medicament intended for the therapeutic treatment of a condition in a host, characterized in that a compound of formula I, II, III, IV, V, VI, VII, VIII-a to VIII-c, IX, X, XI, XII-a to XII-c, XIII, XIV, XV, XVI and XVII-a to XVII-g is used in the preparation;

[0124] e) a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to Formula XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI and Formula XVII-a to XVII-g, or a pharmaceutically acceptable salt thereof, which can be used to treat abnormal cell proliferation in a host, such as cancer, including any cancer described herein;

[0125] f) Use of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to Formula XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI and Formula XVII-a to XVII-g, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating abnormal cell proliferation such as cancer (including any cancer described herein);

[0126] g) a method for preparing a medicament intended for therapeutic use in treating abnormal cell proliferation in a host, such as cancer (including any cancer described herein), characterized in that a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII-a to formula VIII-c, formula IX, formula X, formula XI, formula XII-a to formula XII-c, formula XIII, formula XIV, formula XV, formula XVI and formula XVII-a to XVII-g is used in the preparation;

[0127] h) a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to Formula XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI and Formula XVII-a to XVII-g, or a pharmaceutically acceptable salt thereof, which can be used to treat a tumor in a host, including any tumor described herein;

[0128] i) Use of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to Formula XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI and Formula XVII-a to XVII-g or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a tumor in a host (including any tumor described herein);

[0129] j) a method for preparing a medicament intended for therapeutic use in treating a tumor in a host (including any tumor described herein), characterized in that a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII-a to formula VIII-c, formula IX, formula X, formula XI, formula XII-a to formula XII-c, formula XIII, formula XIV, formula XV, formula XVI and formula XVII-a to XVII-g is used in the preparation;

[0130] k) a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to Formula XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI and Formula XVII-a to XVII-g, or a pharmaceutically acceptable salt thereof, which can be used to treat an immune, autoimmune or inflammatory disorder in a host;

[0131] l) Use of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to Formula XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI and Formula XVII-a to XVII-g or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an immune, autoimmune or inflammatory disorder in a host;

[0132] m) a method for preparing a medicament intended for therapeutic use for treating an immune, autoimmune or inflammatory disorder in a host, characterized in that a compound of formula I, II, III, IV, V, VI, VII, VIII-a to VIII-c, IX, X, XI, XII-a to XII-c, XIII, XIV, XV, XVI and XVII-a to XVII-g is used in the preparation;

[0133] n) a pharmaceutical preparation comprising an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to Formula XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI and Formula XVII-a to Formula XVII-g or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent;

[0134] o) compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to Formula XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI and Formula XVII-a to Formula XVII-g as described herein, in enantiomerically or diastereomerically (as relevant) enriched form, including as isolated enantiomers or diastereomers (i.e., greater than 85, 90, 95, 97 or 99% pure);

[0135] p) a method for preparing a therapeutic product containing an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to Formula XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI and Formula XVII-a to Formula XVII-g, or a pharmaceutically acceptable salt thereof; and

[0136] q) A method for preparing a bifunctional compound that degrades a selected protein via the ubiquitin proteasome pathway, characterized in that a compound of XVI or XVII-a to XVII-g is used in the preparation of the bifunctional compound.

[0137] This application also involves the following projects:

[0138] 1. A compound selected from the group consisting of:

[0139]

[0140] or a pharmaceutically acceptable salt thereof;

[0141] in:

[0142] Y is NH or CH2;

[0143] A 1 Selected from aryl and R 1 substituted aryl;

[0144] A 2 For R 1 substituted aryl;

[0145] A 3 is selected from heteroaryl and R 2 substituted heteroaryl;

[0146] A 4 For R 1a substituted aryl;

[0147] A 5 For R 2a substituted heteroaryl;

[0148] A 6 For R 2 substituted heteroaryl;

[0149] R 1 Selected from: -C(=O)-OC 1-6 -alkyl; -COOH; -NH-(C=O)-C 1-6 -alkyl; -NH2; and –NO2;

[0150] R 1aSelected from: -C(=O)-OC 1-6 -alkyl; -COOH; and –NO2;

[0151] R 2 Selected from: -COOH; -C(=O)-OC 1-6 -alkyl; -NH2; and -NO2; and

[0152] R 2a Selected from –COOH and –C(=O)-OC 1-6 -alkyl.

[0153] 2. Compounds of formula VIII-a, VIII-b or VIII-c:

[0154]

[0155] or a pharmaceutically acceptable salt thereof; wherein:

[0156] Y is NH or CH2;

[0157] R 1 Selected from: -C(=O)-OC 1-6 -alkyl; -COOH; -NH-(C=O)-C 1-6 -alkyl; -NH2; and –NO2;

[0158] R 1a Selected from: -C(=O)-OC 1-6 -alkyl; -COOH; and –NO2; and

[0159] m is 0 or 1.

[0160] 3. Compounds of formula IX:

[0161]

[0162] or a pharmaceutically acceptable salt thereof; wherein:

[0163] Y is NH or CH2;

[0164] R 1 Selected from: -C(=O)-OC 1-6 -alkyl; -COOH; -NH-(C=O)-C 1-6 -alkyl; -NH2; and –NO2;

[0165] m is 0 or 1; and

[0166] n is 0 or 1.

[0167] 4. Compounds of formula X:

[0168]

[0169] or a pharmaceutically acceptable salt thereof; wherein:

[0170] Y is NH or CH2;

[0171] R 2 Selected from: -COOH; -C(=O)-OC 1-6 -alkyl; -NH2; and -NO2; m is 0 or 1; and

[0172] n is 0 or 1.

[0173] 5. Compounds of formula XI:

[0174]

[0175] or a pharmaceutically acceptable salt thereof; wherein:

[0176] Y is NH or CH2;

[0177] R 2 Selected from: -COOH; -C(=O)-OC 1-6 -alkyl; -NH2; and -NO2; m is 0 or 1; and

[0178] n is 0 or 1.

[0179] 6. Compounds of formula XII-a, formula XII-b or formula XII-c:

[0180]

[0181] or a pharmaceutically acceptable salt thereof; wherein:

[0182] Y is NH or CH2;

[0183] R 2 Selected from: -COOH; -C(=O)-OC 1-6 -alkyl; -NH2; and –NO2; R 2b Selected from: -COOH; -C(=O)-OC 1-6 -alkyl; and -NO2; and m is 0 or 1.

[0184] 7. Compounds of formula XIII:

[0185]

[0186] or a pharmaceutically acceptable salt thereof; wherein:

[0187] Y is NH or CH2;

[0188] R 2Selected from: -COOH; -C(=O)-OC 1-6 -alkyl; -NH2; and -NO2; m is 0 or 1; and

[0189] n is 0 or 1.

[0190] 8. Compounds of formula XIV:

[0191]

[0192] or a pharmaceutically acceptable salt thereof; wherein:

[0193] Y is NH or CH2;

[0194] R 2 Selected from: -COOH; -C(=O)-OC 1-6 -alkyl; -NH2; and –NO2;

[0195] m is 0 or 1; and

[0196] n is 0 or 1.

[0197] 9. The compound of any one of items 1 to 3, wherein R 1 –C(=O)-OC 1-6 -alkyl.

[0198] 10. The compound of any one of items 1 to 3, wherein R 1 is –COOH.

[0199] 11. The compound of any one of items 1 to 3, wherein R 1 is –NH-(C=O)-C 1-6 -alkyl.

[0200] 12. The compound of any one of items 1 to 3, wherein R 1 is –NH2.

[0201] 13. The compound of any one of items 1 to 3, wherein R 1 is –NO2.

[0202] 14. The compound of any one of items 1 or 4-8, wherein R 2 is –COOH.

[0203] 15. The compound of any one of items 1 or 4-8, wherein R 2 –C(=O)-OC 1-6 -alkyl.

[0204] 16. The compound of any one of items 1 or 4-8, wherein R 2 is –NH2.

[0205] 17. The compound of any one of items 1 or 4-8, wherein R 2 is –NO2.

[0206] 18. The compound according to any one of items 3-5 or 7-8, wherein n is 0.

[0207] 19. The compound according to any one of items 3-5 or 7-8, wherein n is 1.

[0208] 20. The compound according to any one of items 2 to 19, wherein m is 0.

[0209] 21. The compound according to any one of items 2 to 19, wherein m is 1.

[0210] 22. The compound according to any one of items 1 to 21, wherein Y is NH.

[0211] 23. The compound of any one of items 1-21, wherein Y is CH2.

[0212] 24. Compounds of formula XVI:

[0213]

[0214] or a pharmaceutically acceptable salt thereof;

[0215] in:

[0216] Y is NH or CH2;

[0217] A X is selected from aryl and heteroaryl;

[0218] n is 0 or 1;

[0219] The "tail" is "T";

[0220] "T" is

[0221] X 1 Selected from key, NR 34 , CH2, CHR 34 , C(R 34 )2, O and S;

[0222] X 22 Selected from halogen, -NH2, -NHR 34 , -N(R 34 )2, hydroxyl, mercapto, -B(OH)2, -Sn(R 36 )3,-Si(R 36)3, -OS(O)2 alkyl, -OS(O)2 haloalkyl, alkenyl, alkynyl, ethynyl, vinyl, -C(O)H, -NR 34 C(O) olefin, -NR 34 C(O)alkyne, cyano, -SC(O)alkyl, OC(O)alkyl, heterocycle, -C(O)OH, hydrogen, alkyl, aryl, heteroaryl, aliphatic, heteroaliphatic, and carbocyclic;

[0223] R 34 and R 34’ is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycle, aryl, heteroaryl, -(CO)R 36 , -(CS)R 36 , -(C=NH)R 36 , -(SO)R 36 and -(SO2)R 36 ;

[0224] R 36 is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycle, aryl, heteroaryl, hydroxy, C1-C6 alkoxy, thio, C1-C6 thioalkyl, -NH2, -NH(C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocycle, aryl or heteroaryl), and -N(independently C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocycle, aryl or heteroaryl)2;

[0225] R 20 , R 21 , R 22 , R 23 and R 24 independently selected from a covalent bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -C(O)alkyl, -C(O)Oalkyl, -C(S)-, -SO2-, -S(O)-, -C(S)-, -C(O)NH-, -NHC(O)-, -N(alkyl)C(O)-, -C(O)N(alkyl)-, -O-, -S-, -NH-, -N(alkyl)-, -CH(-OR 26 )-,-CH(-NR 34 R 34’ )-,-C(-OR 26 )alkyl-,-C(-NR 34 R 34’ )alkyl-,-C(R 40 R 40 )-,-alkyl (R27 )-alkyl(R 28 )-,-C(R 27 R 28 )-,-P(O)(OR 26 )O-,-P(O)(OR 26 )-,-NR 34 C(O)NR 34’ -, olefin, haloalkyl, alkoxy, alkyne, heteroarylalkyl, aryl, arylalkyl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, carbocyclic, -(ethylene glycol) 1-6 -,-(lactic-co-glycolic acid) 1-6 -,-(propylene glycol) 1-6 -,-O-(CH2) 1-12 -O-, -NH-(CH2) 1-12 -NH-, -NH-(CH2) 1-12 -O-, -O-(CH2) 1-12 -NH-, -S-(CH2) 1-12 -O-, -O-(CH2) 1-12 -S-, -S-(CH2) 1-12 -S-, -S-(CH2) 1-12 -NH- and -NH-(CH2) 1-12 -S-;

[0226] The R 20 , R 21 , R 22 , R 23 and R 24 Each optionally selected from R 101 Substituents are substituted;

[0227] Where R 20 , R 21 , R 22 , R 23 and R 24 At least one of them is not a bond;

[0228] R 101 is independently selected at each occurrence from hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO2, F, Cl, Br, I, CF3, NH2, NHalkyl, N(alkyl), aliphatic, and heteroaliphatic;

[0229] R 26is selected from the group consisting of hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic;

[0230] R 27 and R 28 are independently selected from hydrogen, alkyl, amine, or together with the carbon atoms to which they are attached, form C(O), C(S), C=CH2, C3-C6 spirocarbocycle, or a 4-, 5- or 6-membered spiroheterocycle containing 1 or 2 heteroatoms selected from N and O, or form 1 or 2 carbon bridged rings; and

[0231] R 40 at each occurrence selected from the group consisting of: hydrogen, alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azide, amino, cyano, -NH(aliphatic), -N(aliphatic)2, -NHSO2(aliphatic), -N(aliphatic)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocyclic), -N(alkyl)SO2(aryl, heteroaryl or heterocyclic) -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, heterocyclic, and carbocyclic.

[0232] 25. The compound according to item 24, wherein Y is NH.

[0233] 26. The compound described in item 24, wherein Y is CH2.

[0234] 27. The compound of any one of items 24-26, wherein A X It is an aromatic group.

[0235] 28. The compound of any one of items 24-26, wherein A X It is a heteroaryl group.

[0236] 29. The compound according to any one of items 24-28, wherein n is 0.

[0237] 30. The compound according to any one of items 24 to 28, wherein n is 1.

[0238] 31. The compound of any one of items 24-30, wherein the "tail" is selected from:

[0239]

[0240] 32. The compound according to item 24, which is selected from:

[0241]

[0242]

[0243] Or a pharmaceutically acceptable salt thereof.

[0244] 33. A method of treating abnormal cell proliferation in a subject in need thereof, comprising administering an effective amount of a compound of any one of items 1 to 32, or a pharmaceutically acceptable salt thereof.

[0245] 34. The method of claim 33, wherein the abnormal cell proliferation is cancer.

[0246] 35. The method of claim 33, wherein the abnormal cell proliferation is a tumor.

[0247] 36. The method of claim 33, wherein the abnormal cell proliferation is multiple myeloma.

[0248] 37. Use of a compound according to any one of items 1 to 32 or a pharmaceutically acceptable salt thereof for treating abnormal cell proliferation in a subject in need thereof.

[0249] 38. Use of a compound according to any one of items 1 to 32 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating abnormal cell proliferation in a subject in need thereof.

[0250] 39. The use of any one of items 37 or 38, wherein the abnormal cell proliferation is cancer.

[0251] 40. The use of any one of items 37 or 38, wherein the abnormal cell proliferation is a tumor.

[0252] 41. The use of any one of items 37 or 38, wherein the abnormal cell proliferation is multiple myeloma.

[0253] 42. A compound according to any one of items 1 to 32 for use in treating abnormal cell proliferation in a subject in need thereof.

[0254] 43. The compound of claim 42, wherein the abnormal cell proliferation is cancer.

[0255] 44. The compound of claim 42, wherein the abnormal cell proliferation is a tumor.

[0256] 45. The compound of claim 42, wherein the abnormal cell proliferation is multiple myeloma.

[0257] 46. ​​A method of treating abnormal cell proliferation in a subject in need thereof, comprising administering an effective amount of a compound of Formula XV:

[0258]

[0259] or a pharmaceutically acceptable salt thereof; wherein:

[0260] Y is NH or CH2;

[0261] A is selected from: aryl; 1 substituted aryl; heteroaryl; and 2 substituted heteroaryl;

[0262] R 1 Selected from: -C(=O)-OC 1-6 -alkyl; -COOH; -NH-(C=O)-C 1-6 -alkyl; -NH2; and –NO2;

[0263] R 2 Selected from: -COOH; -C(=O)-OC 1-6 -alkyl; -NH2; and -NO2; and

[0264] n is 0 or 1.

[0265] 47. The method according to claim 46, wherein Y is NH.

[0266] 48. The method described in item 46, wherein Y is CH2.

[0267] 49. The method of any one of items 46-48, wherein A is an aromatic group or is replaced by R 1 Substituted aryl.

[0268] 50. The method of any one of items 46-49, wherein R 1 -C(=O)-OC 1-6 -alkyl.

[0269] 51. The method of any one of items 46-49, wherein R 1 is –COOH.

[0270] 52. The method of any one of items 46-49, wherein R 1 -NH-(C=O)-C 1-6 -alkyl.

[0271] 53. The method of any one of items 46-49, wherein R 1 is -NH2.

[0272] 54. The method of any one of items 46-49, wherein R 1 is –NO2.

[0273] 55. The method of any one of items 46-48, wherein A is heteroaryl or is replaced by R 2 Substituted heteroaryl.

[0274] 56. The method of item 55, wherein R 2 is –COOH.

[0275] 57. The method of item 55, wherein R 2 -C(=O)-OC 1-6 -alkyl.

[0276] 58. The method of item 55, wherein R 2 is –NH2.

[0277] 59. The method of item 55, wherein R 2 is –NO2.

[0278] 60. The method of any one of items 46-59, wherein n is 0.

[0279] 61. The method of any one of items 46-59, wherein n is 1.

[0280] 62. The method of any one of items 46-61, wherein the abnormal cell proliferation is cancer.

[0281] 63. The method of any one of items 46-61, wherein the abnormal cell proliferation is a tumor.

[0282] 64. The method of any one of items 46-61, wherein the abnormal cell proliferation is multiple myeloma.

[0283] 65. A pharmaceutical composition comprising an effective amount of a compound according to any one of items 1 to 32, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

[0284] 66. A compound of the formula,

[0285]

[0286] or a pharmaceutically acceptable salt thereof

[0287] in

[0288] Y is NH or CH2,

[0289] n is 0 or 1,

[0290] A is selected from

[0291] i.) aryl,

[0292] ii.) By R 1 Substituted aryl,

[0293] iii.) heteroaryl, and

[0294] iv.) By R2 substituted heteroaryl;

[0295] R 1 Selected from

[0296] i.) –C(=O)-OC 1-6 -alkyl,

[0297] ii.) –COOH,

[0298] iii.) -NH-C(=O)-C 1-6 -alkyl,

[0299] iv.) – NH2, and

[0300] v.)–NO2;

[0301] R 2 Selected from

[0302] i.) –COOH,

[0303] ii.) -C(=O)-OC 1-6 -alkyl,

[0304] iii.) –NH2, and

[0305] iv.)-NO2.

[0306] 67. The compound described in item 66, wherein

[0307] A is selected from

[0308] i.) aryl, in particular phenyl or 1,2,3,4-tetrahydronaphthyl,

[0309] ii.) an aryl group, in particular a phenyl group, which is replaced by R 1 , especially -NH-C(=O)-C 1-6 - alkyl substituted,

[0310] iii.) heteroaryl, in particular benzo[d]thiazolyl, pyrazolo[1,5-a]pyridinyl, thiazolo[4,5-b]pyridin-2-yl; and

[0311] iv.) heteroaryl, especially pyridyl, which is 2 ,in particular

[0312] -C(=O)-OC 1-6 -alkyl substitution.

[0313] 68. The compound described in item 66 or 67, wherein Y is NH.

[0314] 69. The compound described in item 66 or 67, wherein Y is CH2.

[0315] 70. The compound of any one of items 66-69, wherein n is 0.

[0316] 71. A compound according to any one of items 66-69, wherein n is 1.

[0317] 72. The compound of any one of items 66-71, or a pharmaceutically acceptable salt thereof, selected from

[0318] 7-((S)-1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0319] 7-Benzoyl-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0320] 7-(Benzo[d]thiazol-2-yl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0321] 7-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0322] 6-(2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl)nicotinate,

[0323] N-(3-(2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-carbonyl)phenyl)acetamide, N-(4-(2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-carbonyl)phenyl)acetamide,

[0324] 7-(Thiazolo[4,5-b]pyridin-2-yl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0325] 7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0326] (R)-7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0327] (S)-7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0328] 7-(Benzo[d]thiazol-2-yl)-2,7-diazaspiro[4.4]nonane-1,3-dione,

[0329] 7-Benzoyl-2,7-diazaspiro[4.4]nonane-1,3-dione,

[0330] 6-(6,8-dioxo-2,7-diazaspiro[4.4]nonan-2-yl)nicotinate, and

[0331] 7-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-2,7-diazaspiro[4.4]nonane-1,3-dione.

[0332] 73. A compound according to any one of items 66 to 72, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prophylactic treatment of cancer.

[0333] 74. Use of a compound according to any one of items 66 to 72 or a pharmaceutically acceptable salt thereof for the treatment and / or prophylactic treatment of cancer.

[0334] 75. Use of a compound according to any one of items 66 to 72 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and / or prophylactic treatment of cancer.

[0335] 76. A pharmaceutical composition comprising a compound according to any one of items 66 to 72, and a therapeutically inert carrier.

[0336] 77. A method for the therapeutic and / or prophylactic treatment of cancer, which method comprises administering an effective amount of a compound as defined in any one of items 66 to 72. DETAILED DESCRIPTION

[0337] I. Definitions

[0338] Unless otherwise indicated, the following terms used in this application (including the specification and claims) have the definitions given below. It must be noted that the singular forms "a", "an", and "the" used in the specification and the appended claims include plural references unless the context clearly dictates otherwise.

[0339] The term "C 1-6 "-alkyl", used alone or in combination with other groups, means a hydrocarbon group which may be straight or branched, with one or more branches, wherein the alkyl group generally contains 1 to 6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-isobutyl (isobutyl), 2-butyl (sec-butyl), t-butyl (tert-butyl), isopentyl, 2-ethylpropyl (2-methylpropyl), 1,2-dimethylpropyl, etc. A specific group is methyl.

[0340] The term "heteroaryl" refers to a monocyclic or bicyclic ring system of 5 to 12 ring atoms, containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon, and wherein all rings are aromatic. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, aza Base, diazepine 1,2-dopamine, ...

[0341] In one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0342] 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.

[0343] Additional non-limiting examples of 5-membered "heteroaryl" groups include:

[0344]

[0345] In one embodiment, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (ie, pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0346] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include:

[0347]

[0348] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0349] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole and benzothiazole.

[0350] Additional non-limiting examples of bicyclic "heteroaryl" groups include:

[0351]

[0352] Additional non-limiting examples of bicyclic "heteroaryl" groups include:

[0353]

[0354] Additional non-limiting examples of bicyclic "heteroaryl" groups include:

[0355]

[0356] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0357] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline and naphthyridine.

[0358] Additional non-limiting examples of bicyclic "heteroaryl" groups include:

[0359]

[0360] In an alternative embodiment, the "heteroaryl" group is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0361] The term "aryl" means a monovalent aromatic carbocyclic monocyclic or bicyclic ring system containing 6 to 10 carbon ring atoms and in which at least one ring is aromatic. Examples of aryl moieties include phenyl (Ph), indanyl, 1,2,3,4-tetrahydronaphthyl and naphthyl. Particular examples are phenyl and 1,2,3,4-tetrahydronaphthyl.

[0362] In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl).

[0363] In one embodiment, "aryl" is a 10 carbon aromatic group (naphthyl).

[0364] In an alternative embodiment, "aryl" is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0365] "Alkenyl" is a straight or branched aliphatic hydrocarbon group with one or more carbon-carbon double bonds, which may exist at a stable point along the chain. As used herein, a specified range represents an alkenyl group with each member of a range described as an independent species, as described above for the alkyl portion. In a non-limiting embodiment, the alkenyl group contains 2 to about 12 carbon atoms, more typically 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In certain embodiments, the alkenyl group is C2, C2-C3, C2-C4, C2-C5 or C2-C6. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term "alkenyl" also includes "cis" and "trans" alkenyl geometries, or "E" and "Z" alkenyl geometries. The term "alkenyl" also includes cycloalkyl or carbocyclic groups with at least one unsaturated point.

[0366] "Alkynyl" is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, which may exist at any stable point along the chain. As used herein, a specified range refers to an alkynyl group having each member of the range described as an independent species, as described above for the alkyl portion. In a non-limiting embodiment, the alkynyl group contains 2 to about 12 carbon atoms, more typically 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In certain embodiments, the alkynyl group is C2, C2-C3, C2-C4, C2-C5 or C2-C 6。 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0367] "Halo" or "halogen" are independently fluoro, chloro, bromo or iodo.

[0368] "Haloalkyl" is a branched or straight chain alkyl group substituted with one or more of the above halogen atoms, up to the maximum permissible 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.

[0369] In one embodiment, "haloalkyl" is C1-C 10 haloalkyl, C1-C9 haloalkyl, C1-C8 haloalkyl, C1-C7 haloalkyl, C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl and C1-C2 haloalkyl.

[0370] In one embodiment, a "haloalkyl" group has one carbon.

[0371] In one embodiment, a "haloalkyl" group has one carbon and one halogen.

[0372] In one embodiment, a "haloalkyl" group has one carbon and two halogens.

[0373] In one embodiment, a "haloalkyl" group has one carbon and three halogens.

[0374] In one embodiment, a "haloalkyl" group has two carbons.

[0375] In one embodiment, a "haloalkyl" group has three carbons.

[0376] In one embodiment, a "haloalkyl" group has four carbons.

[0377] In one embodiment, a "haloalkyl" group has five carbons.

[0378] In one embodiment, a "haloalkyl" group has six carbons.

[0379] Non-limiting examples of "haloalkyl" include:

[0380] Additional non-limiting examples of "haloalkyl" include:

[0381] Additional non-limiting examples of "haloalkyl" include:

[0382] Additional non-limiting examples of "haloalkyl" include:

[0383] The term "heterocycle" refers to saturated and partially saturated heteroatom-containing cyclic groups, wherein 1, 2, 3 or 4 heteroatoms are independently selected from nitrogen, sulfur, boron, silicon and oxygen. Heterocyclic rings may contain 3-1-membered monocyclic rings, as well as 5-16-membered bicyclic ring systems (which may include bridged, fused and spiro-fused bicyclic ring systems). It does not include rings containing -OO-, -OS- or -SS- moieties. Examples of saturated heterocyclic groups include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclic groups include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, isochromanyl, chromanyl, 1,2-dihydroquinolinyl, 1,2,3,4-tetrahydro-iso ... Quinolinyl, 1,2,3,4-tetrahydro-quinolinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuranyl and dihydrothiazolyl.

[0384] "Heterocycle" also includes groups in which a heterocyclic group is fused / condensed with an aryl or carbocyclic group, wherein the point of attachment is the heterocyclic ring. "Heterocyclic" also includes groups in which a heterocyclic group is substituted with an oxo group (i.e. ) substituted. For example, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms (such as indoline or isoindoline); partially unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; partially unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; and saturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms.

[0385] In one embodiment, "heterocycle" refers to a ring having one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0386] In one embodiment, "heterocycle" refers to a ring having one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0387] In one embodiment, "heterocycle" refers to a ring having two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0388] In one embodiment, "heterocycle" refers to a ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0389] In one embodiment, "heterocycle" refers to a ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0390] Non-limiting examples of "heterocycle" include aziridine, oxirane, thietane, azetidine, 1,3-diazetidine, oxetane and thietane.

[0391] Other non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine and imidazolidine.

[0392] Other non-limiting examples of "heterocycle" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane and 1,3-oxathiolane.

[0393] Additional non-limiting examples of "heterocycle" include: piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine and thiomorpholine.

[0394] Additional non-limiting examples of "heterocycle" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the point of attachment of each group is on the heterocycle.

[0395] For example, It is a "heterocyclic" group.

[0396] However, is an "aryl" group.

[0397] Non-limiting examples of "heterocycle" also include:

[0398]

[0399] Additional non-limiting examples of "heterocycle" include:

[0400]

[0401] Additional non-limiting examples of "heterocycle" include:

[0402]

[0403] Non-limiting examples of "heterocycle" include:

[0404]

[0405] Non-limiting examples of "heterocycle" include:

[0406]

[0407] Additional non-limiting examples of "heterocycle" include:

[0408]

[0409] Additional non-limiting examples of "heterocycle" include:

[0410]

[0411] The term "optionally substituted" means that the group herein is substituted with a moiety, which includes but is not limited to C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, C1–C 12 Heterocycloalkyl, C3-C 12 Heterocycloalkenyl, C1-C 10 Alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C 10 Alkylamino, C1-C 10 Dialkylamino, arylamino, diarylamino, C1-C 10 Alkylsulfonylamino, arylsulfonylamino, C1-C 10 Alkyl imino, aryl imino, C1-C 10 Alkylsulfonyl imide, arylsulfonyl imide, hydroxyl, halogen, thio, C1-C 10 Alkylthio, arylthio, C1-C 10 Alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidino, ureido, cyano, nitro, azido, acyl, thioacyl, acyloxy, carboxyl, and carboxylate.

[0412] As used herein, "carbocycle," "carbocycle," or "cycloalkyl" includes saturated or partially unsaturated (i.e., non-aromatic) groups containing all carbon ring atoms and 3 to 14 ring carbon atoms ("C 3–14 In some embodiments, the cycloalkyl group has 3 to 10 ring carbon atoms ("C 3–10 In some embodiments, a cycloalkyl group has 3 to 9 ring carbon atoms (“C 3–9In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3–8 In some embodiments, a cycloalkyl group has 3 to 7 ring carbon atoms (“C 3–7 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3–6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 "cycloalkyl"). Exemplary C 3–6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3–8 Cycloalkyl groups include but are not limited to the aforementioned C 3–6 Cycloalkyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), etc. Exemplary C 3–10 Cycloalkyl groups include but are not limited to the aforementioned C 3–8 Cycloalkyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9 10 ), cyclodecenyl (C 10 ) etc. As shown in the foregoing examples, in certain embodiments, the cycloalkyl group may be saturated or may contain one or more carbon-carbon double bonds.

[0413] In one embodiment, "cycloalkyl" is C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3-C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl or C6-C8 cycloalkyl.

[0414] In one embodiment, a "cycloalkyl" group has three carbons.

[0415] In one embodiment, a "cycloalkyl" group has four carbons.

[0416] In one embodiment, a "cycloalkyl" group has five carbons.

[0417] In one embodiment, a "cycloalkyl" group has six carbons.

[0418] In one embodiment, a "cycloalkyl" group has seven carbons.

[0419] In one embodiment, a "cycloalkyl" group has eight carbons.

[0420] In one embodiment, a "cycloalkyl" group has nine carbons.

[0421] In one embodiment, a "cycloalkyl" group has ten carbons.

[0422] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl.

[0423] In another embodiment, any suitable group may be present in a "substituted" or "optionally substituted" position if it is shown to form a stable molecule and meet the desired objectives of the present invention, and includes, but is not limited to, for example, halogen (which may independently be F, Cl, Br or I); cyano; hydroxy; nitro; azido; alkanoyl (such as C2-C6 alkanoyl); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl, including those with one or more thioether bonds; alkylsulfinyl; alkylsulfonyl, including those with one or more sulfonyl bonds; aminoalkyl, including groups with more than one N atom; aryl (e.g., phenyl, biphenyl, naphthyl, etc., each ring is substituted or unsubstituted); having, for example, 1 to 3 independent The invention also includes arylalkyl radicals having 1 to 3 separate or fused rings and 6 to about 14 or 18 ring carbon atoms, wherein benzyl is an exemplary arylalkyl radical; for example, arylalkoxy radicals having 1 to 3 separate or fused rings, wherein benzyloxy is an exemplary arylalkoxy radical; or saturated or partially unsaturated heterocyclic rings having 1 to 3 separate or fused rings having one or more N, O or S atoms, or heteroaryl radicals having 1 to 3 separate or fused rings having one or more N, O or S atoms, such as coumarinyl, quinolyl, isoquinolyl, quinazolinyl, pyridinyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl and pyrrolidinyl. Such groups may be further substituted, for example, with hydroxy, alkyl, alkoxy, halogen and amino groups. In certain embodiments, "optionally substituted" includes one or more substituents independently selected from the following: halogen, hydroxyl, amino, cyano, -CHO, -COOH, -CONH2, alkyl (including C1-C6 alkyl), alkenyl (including C2-C6 alkenyl), alkynyl (including C2-C6 alkynyl), -C1-C6 alkoxy, alkanoyl (including C2-C6 alkanoyl), C1-C6 alkyl ester, (mono- and di-C1-C6 alkylamino)C0-C2 alkyl, haloalkyl (including C1-C6 haloalkyl), hydroxyC1-C6 alkyl, ester, carbamate, urea, sulfonamide, -C1-C6 alkyl (heterocyclyl), C1-C6 alkyl (heteroaryl), -C1-C6 alkyl (C3-C7 cycloalkyl), O-C1-C6 alkyl (C3-C7 cycloalkyl), B (OH)2, phosphate, phosphonate and haloalkoxy (including C1-C6 haloalkoxy). In some embodiments, suitable groups present at "substituted" or "optionally substituted" positions are divalent, including, but not limited to, oxo (=O), =S, =CH2, etc. Suitable groups at "substituted" or "optionally substituted" positions may be monovalent, divalent, or trivalent, so that they form stable molecules and meet the desired purposes of the present invention.

[0424] In one embodiment, a group described herein as substituted with 1, 2, 3, or 4 substituents is substituted with one substituent.

[0425] In one embodiment, a group described herein as substituted with 1, 2, 3, or 4 substituents is substituted with two substituents.

[0426] In one embodiment, a group described herein as substituted with 1, 2, 3, or 4 substituents is substituted with three substituents.

[0427] In one embodiment, a group described herein as substituted with 1, 2, 3, or 4 substituents is substituted with four substituents.

[0428] The term "pharmaceutically acceptable" refers to the nature of materials useful in preparing pharmaceutical compositions that are generally safe, non-toxic, and neither biologically or otherwise undesirable and acceptable for veterinary as well as human pharmaceutical uses.

[0429] The term "pharmaceutically acceptable salt" refers to salts suitable for use in contact with human and animal tissues. Examples of suitable salts formed with inorganic and organic acids are, but are not limited to, salts of acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, succinic acid, sulfuric acid (sulfuric acid), tartaric acid, trifluoroacetic acid, and the like. Particular acids are formic acid, trifluoroacetic acid, and hydrochloric acid. Specific acids are hydrochloric acid, trifluoroacetic acid, and fumaric acid.

[0430] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, and the like; and those derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) n -COOH (wherein n is 0-4), etc., or salts prepared using different acids that produce the same counterion. Additional lists of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0431] The term "pharmaceutically acceptable auxiliary substances" refers to carriers and auxiliary substances, such as diluents or excipients, that are compatible with the other ingredients of the formulation.

[0432] The term "pharmaceutical composition" encompasses a product containing specified ingredients in predetermined amounts or proportions, as well as any product resulting directly or indirectly from combining specified ingredients in specified amounts. In particular, it includes a product containing one or more active ingredients and an optional carrier containing inert ingredients, as well as any product resulting directly or indirectly from the combination, complexation or aggregation of any or two or more ingredients or the dissociation of one or more ingredients, or other type of reaction or interaction of one or more ingredients.

[0433] "Therapeutically effective amount" refers to the amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, and the judgment of the attending medical or veterinary doctor and other factors.

[0434] The terms "as defined herein" and "as described herein" when referring to a variable incorporate by reference the broad definition of that variable as well as the particular, more specific and most specific definitions, if any.

[0435] When referring to a chemical reaction, the terms "treating", "contacting" and "reacting" refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be understood that the reaction to produce the indicated and / or desired product may not necessarily result directly from the combination of the two reagents initially added, that is, one or more intermediates may be produced in the mixture, which ultimately lead to the formation of the indicated and / or desired product.

[0436] The term "aromatic" means the conventional concept of aromaticity as defined in the literature, in particular in IUPAC-Compendium of Chemical Terminology, 2nd edition, AD McNaught & A. Wilkinson (eds). Blackwell Scientific Publications, Oxford (1997).

[0437] The term "pharmaceutically acceptable excipient" refers to any therapeutically inactive and non-toxic ingredient such as a disintegrant, binder, filler, solvent, buffer, tonic agent, stabilizer, antioxidant, surfactant or lubricant used in formulating a pharmaceutical product.

[0438] Whenever a chiral carbon is present in a chemical structure, it is intended that all stereoisomers associated with that chiral carbon be encompassed by the structure, including pure stereoisomers and mixtures thereof.

[0439] Furthermore, the present invention includes all optical isomers, ie diastereomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers, and solvates of the compounds of formula XV.

[0440] The compounds described herein may contain one or more asymmetric centers and may therefore exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Depending on the nature of the various substituents on the molecule, additional asymmetric centers may be present. Each such asymmetric center will independently produce two optical isomers, and it is intended that all possible optical isomers and diastereomers in the mixture and pure or partially purified compounds are included in the present invention. The present invention is intended to cover all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separation can be achieved by appropriately modifying the methods disclosed herein, as known in the art. Their absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates, and if necessary, it can be derivatized with reagents containing asymmetric centers of known absolute configuration. If necessary, the racemic mixture of the compound can be separated to separate the individual enantiomers. Separation can be carried out by methods well known in the art, for example by coupling a racemic mixture of the compounds with an enantiomerically pure compound to form a diastereomeric mixture and then separating the individual diastereomers by standard methods such as fractional crystallization or chromatography.

[0441] In embodiments where an optically pure enantiomer is provided, an optically pure enantiomer means that the compound contains >90% by weight of the desired isomer, particularly >95% by weight of the desired isomer, more particularly >99% by weight of the desired isomer, the weight percentages being based on the total weight of the isomers of the compound. Chirally pure or chirally enriched compounds can be prepared by chiral selective synthesis or by separation of enantiomers. Separation of enantiomers can be performed on the final product or on a suitable intermediate.

[0442] Isotope substitution

[0443] The present invention includes compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to Formula XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI and Formula XVII-a to XVII-g having at least one desired atomic isotope substituted in an amount greater than the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., atoms having the same number of protons but different numbers of neutrons.

[0444] Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen and oxygen, such as 2 H. 3 H. 11 C. 13 C. 14 C. 15 N and 17 O. 18 In one non-limiting embodiment, isotopically labeled compounds can be used in metabolic studies (using, for example, 14 C) Reaction kinetics studies (using, for example, 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution determination, or for use in radiotherapy of patients. In particular, 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and the preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0445] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotope is 90, 95 or 99% or more isotopically enriched at any position of interest. In a non-limiting embodiment, deuterium is 90, 95 or 99% enriched at a desired position.

[0446] In a non-limiting embodiment, the substitution of hydrogen atoms can be provided as deuterium atoms in any compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII-a to formula VIII-c, formula IX, formula X, formula XI, formula XII-a to XII-c, formula XIII, formula XIV, formula XV, formula XVI and formula XVII-a to XVII-g. In a non-limiting embodiment, the substitution of hydrogen atoms as deuterium atoms occurs in one or more groups selected from the variables described herein. For example, when any group is or contains (e.g., by substitution) methyl, ethyl or methoxy, the alkyl residue can be deuterated (in a non-limiting embodiment, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CHDCHD2, OCDH2, OCD2H or OCD3, etc.). In certain other embodiments, when two substituents are combined to form a ring, the unsubstituted carbon can be deuterated.

[0447] II. Compounds of the Invention

[0448] The present invention provides compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII-a to VIII-c, formula IX, formula X, formula XI, formula XII-a to XII-c, formula XIII, formula XIV, formula XVI and formula XVII-a to XVII-g, and pharmaceutically acceptable salts thereof. The present invention also provides the use of compounds of formula XV, as further described herein.

[0449] Compounds of Formula I to Formula XIV

[0450] In one aspect, a compound of Formula I is provided:

[0451]

[0452] or a pharmaceutically acceptable salt thereof;

[0453] wherein all variables are as defined herein.

[0454] In some embodiments of Formula I, a compound selected from the following is provided:

[0455]

[0456] In another aspect, a compound of Formula II is provided:

[0457]

[0458] or a pharmaceutically acceptable salt thereof;

[0459] wherein all variables are as defined herein.

[0460] In some embodiments of Formula II, a compound selected from the following is provided:

[0461]

[0462] In another aspect, provided is a compound of formula III:

[0463]

[0464] or a pharmaceutically acceptable salt thereof;

[0465] wherein all variables are as defined herein.

[0466] In some embodiments of Formula III, a compound selected from the group consisting of:

[0467]

[0468] In some embodiments of Formula III, a compound selected from the group consisting of:

[0469]

[0470] In some embodiments of Formula III, a compound selected from the group consisting of:

[0471]

[0472]

[0473] In some embodiments of Formula III, a compound selected from the group consisting of:

[0474]

[0475] In some embodiments of Formula III, a compound selected from the group consisting of:

[0476]

[0477] In some embodiments of Formula III, a compound selected from the group consisting of:

[0478]

[0479]

[0480] In some embodiments of Formula III, a compound selected from the group consisting of:

[0481]

[0482] In some embodiments of Formula III, a compound selected from the group consisting of:

[0483]

[0484] In some embodiments of Formula III, a compound selected from the group consisting of:

[0485]

[0486]

[0487] In some embodiments of Formula III, a compound selected from the group consisting of:

[0488]

[0489] In another aspect, a compound of formula IV is provided:

[0490]

[0491] or a pharmaceutically acceptable salt thereof;

[0492] wherein all variables are as defined herein.

[0493] In some embodiments of Formula IV, a compound selected from the group consisting of:

[0494]

[0495] R 1a Selected from: -C(=O)-OC 1-6 -alkyl; -COOH; and –NO2.

[0496] In another aspect, a compound of Formula V is provided:

[0497]

[0498] or a pharmaceutically acceptable salt thereof;

[0499] wherein all variables are as defined herein.

[0500] In some embodiments of Formula V, a compound selected from the group consisting of:

[0501]

[0502] In another aspect, a compound of Formula VI is provided:

[0503]

[0504] or a pharmaceutically acceptable salt thereof;

[0505] wherein all variables are as defined herein.

[0506] In some embodiments of Formula VI, a compound selected from the group consisting of:

[0507]

[0508] In some embodiments of Formula VI, a compound selected from the group consisting of:

[0509]

[0510] In some embodiments of Formula VI, a compound selected from the group consisting of:

[0511]

[0512] In some embodiments of Formula VI, a compound selected from the group consisting of:

[0513]

[0514] In some embodiments of Formula VI, a compound selected from the group consisting of:

[0515]

[0516] In another aspect, a compound of Formula VII is provided:

[0517]

[0518] or a pharmaceutically acceptable salt thereof;

[0519] wherein all variables are as defined herein.

[0520] In some embodiments of Formula VII, a compound selected from the following is provided:

[0521]

[0522] In some embodiments of Formula VII, a compound selected from the following is provided:

[0523]

[0524] In some embodiments of Formula VII, a compound selected from the following is provided:

[0525]

[0526] In some embodiments of Formula VII, a compound selected from the following is provided:

[0527]

[0528] In some embodiments of Formula VII, a compound selected from the following is provided:

[0529]

[0530] In another aspect, provided are compounds of Formula VIII-a, VIII-b or VIII-c:

[0531]

[0532] or a pharmaceutically acceptable salt thereof;

[0533] wherein all variables are as defined herein.

[0534] In some embodiments of Formula VIII-a, a compound selected from the following is provided:

[0535]

[0536] In some embodiments of Formula VIII-b, a compound selected from the group consisting of:

[0537]

[0538] In some embodiments of Formula VIII-c, a compound selected from the following is provided:

[0539]

[0540] In another aspect, provided is a compound of Formula IX:

[0541]

[0542] or a pharmaceutically acceptable salt thereof;

[0543] wherein all variables are as defined herein.

[0544] In some embodiments of Formula IX, a compound selected from the group consisting of:

[0545]

[0546]

[0547] In some embodiments of Formula IX, a compound selected from the group consisting of:

[0548]

[0549]

[0550] In another aspect, a compound of formula X is provided:

[0551]

[0552] or a pharmaceutically acceptable salt thereof;

[0553] wherein all variables are as defined herein.

[0554] In some embodiments of Formula X, a compound selected from the following is provided:

[0555]

[0556]

[0557] In some embodiments of Formula X, a compound selected from the following is provided:

[0558]

[0559]

[0560] In another aspect, provided is a compound of Formula XI:

[0561]

[0562] or a pharmaceutically acceptable salt thereof;

[0563] wherein all variables are as defined herein.

[0564] In some embodiments of Formula XI, a compound selected from the following is provided:

[0565]

[0566]

[0567] In some embodiments of Formula XI, a compound selected from the following is provided:

[0568]

[0569]

[0570] In another aspect, provided is a compound of Formula XII-a, XII-b or XII-c:

[0571]

[0572] or a pharmaceutically acceptable salt thereof;

[0573] wherein all variables are as defined herein.

[0574] In some embodiments of Formula XII-a, a compound selected from the following is provided:

[0575]

[0576]

[0577] In some embodiments of Formula XII-b, a compound selected from the following is provided:

[0578]

[0579] In some embodiments of Formula XII-c, a compound selected from the following is provided:

[0580]

[0581] In another aspect, provided is a compound of Formula XIII:

[0582]

[0583] or a pharmaceutically acceptable salt thereof;

[0584] wherein all variables are as defined herein.

[0585] In some embodiments of Formula XIII, a compound selected from the group consisting of:

[0586]

[0587] In some embodiments of Formula XIII, a compound selected from the group consisting of:

[0588]

[0589] In another aspect, provided is a compound of Formula XIV:

[0590]

[0591] or a pharmaceutically acceptable salt thereof;

[0592] wherein all variables are as defined herein.

[0593] In some embodiments of Formula XIV, a compound selected from the group consisting of:

[0594]

[0595] In some embodiments of Formula XIV, a compound selected from the group consisting of:

[0596]

[0597]

[0598] Compound of formula XV

[0599] In another aspect, there is provided a use of a compound of formula XV or a pharmaceutically acceptable salt thereof for treating a therapeutic condition that can be treated by modulating the function or activity of a cereblon containing E3 ubiquitin ligase protein complex:

[0600]

[0601] wherein all variables are as defined herein.

[0602] In some embodiments, the compound of Formula XV used in the methods described herein is selected from:

[0603]

[0604] In some embodiments, the compound of Formula XV used in the methods described herein is selected from:

[0605]

[0606]

[0607] In some embodiments, the compound of Formula XV used in the methods described herein is selected from:

[0608]

[0609] In some embodiments, the compound of Formula XV used in the methods described herein is selected from:

[0610]

[0611]

[0612] In some embodiments, the compound of Formula XV used in the methods described herein is selected from:

[0613]

[0614]

[0615] In some embodiments, the compound of Formula XV used in the methods described herein is selected from:

[0616]

[0617]

[0618] In some embodiments, the compound of Formula XV used in the methods described herein is selected from:

[0619]

[0620]

[0621] In some embodiments, the compound of Formula XV used in the methods described herein is selected from:

[0622]

[0623] In some embodiments, the compound of Formula XV used in the methods described herein is selected from:

[0624]

[0625] In some embodiments, the compound of Formula XV used in the methods described herein is selected from:

[0626]

[0627]

[0628] In some embodiments, the compound of Formula XV used in the methods described herein is selected from:

[0629]

[0630]

[0631] In some embodiments, the compound of Formula XV used in the methods described herein is selected from:

[0632]

[0633]

[0634] In some embodiments, the compound of Formula XV used in the methods described herein is selected from:

[0635]

[0636] In some embodiments, the compound of Formula XV used in the methods described herein is selected from:

[0637]

[0638] Compounds of Formula XV for use in the methods described herein are also provided in the following enumerated embodiments, all of which can be combined individually.

[0639] E1: One embodiment of the present invention provides a compound of formula XV, or a pharmaceutically acceptable salt thereof,

[0640]

[0641] in

[0642] Y is NH or CH2,

[0643] n is 0 or 1,

[0644] A is selected from

[0645] i) aryl,

[0646] ii) By R 1 Substituted aryl,

[0647] iii) heteroaryl, and

[0648] iv) R 2 substituted heteroaryl;

[0649] R 1 Selected from

[0650] i) –C(=O)-OC 1-6 -alkyl,

[0651] ii) –COOH,

[0652] iii) -NH-C(=O)-C 1-6 -alkyl,

[0653] iv) – NH2, and

[0654] v) – NO2;

[0655] R 2 Selected from

[0656] i) –COOH,

[0657] ii) -C(=O)-OC 1-6 -alkyl,

[0658] iii) –NH2, and

[0659] iv)-NO2.

[0660] E2: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein

[0661] Y is NH or CH2,

[0662] n is 0 or 1,

[0663] A is selected from

[0664] i) aryl,

[0665] ii) By R 1 Substituted aryl,

[0666] iii) heteroaryl, and

[0667] iv) R 2 substituted heteroaryl;

[0668] R 1 -NH-C(=O)-C 1-6 -alkyl; and

[0669] R 2 -C(=O)-OC 1-6 -alkyl.

[0670] E3: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein

[0671] A is selected from

[0672] i) aryl, in particular phenyl or 1,2,3,4-tetrahydronaphthyl,

[0673] ii) an aryl group, in particular a phenyl group, which is replaced by R 1 , especially -NH-C(=O)-C 1-6 - alkyl substituted,

[0674] iii) heteroaryl, in particular benzo[d]thiazolyl, pyrazolo[1,5-a]pyridinyl, thiazolo[4,5-b]pyridin-2-yl; and

[0675] iv) heteroaryl, in particular pyridyl, which is replaced by R 2 , especially -C(=O)-OC 1-6 -alkyl substitution.

[0676] E4: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein A is aryl, in particular phenyl or 1,2,3,4-tetrahydronaphthyl.

[0677] E5: A compound of Formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein A is phenyl.

[0678] E6: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein A is 1,2,3,4-tetrahydronaphthyl.

[0679] E7: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein A is aryl, especially phenyl, which is replaced by R 1 , especially -NH-C(=O)-C 1-6 -alkyl substitution.

[0680] E8: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein A is phenyl, which is replaced by -NH-C(=O)-C 1-6 -alkyl substitution.

[0681] E9: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein A is phenyl substituted with -NH-C(=O)-CH3.

[0682] E10: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein A is heteroaryl, in particular benzo[d]thiazolyl, pyrazolo[1,5-a]pyridinyl, thiazolo[4,5-b]pyridin-2-yl.

[0683] E11: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein A is benzo[d]thiazolyl.

[0684] E12: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein A is pyrazolo[1,5-a]pyridinyl.

[0685] E13: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein A is thiazolo[4,5-b]pyridin-2-yl.

[0686] E14: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein A is heteroaryl, in particular pyridinyl, which is replaced by R 2 , especially -C(=O)-OC 1-6 -alkyl substitution.

[0687] E15: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein A is pyridyl, which is replaced by -C(=O)-OC 1-6 -alkyl substitution.

[0688] E16: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein A is pyridinyl substituted with -C(=O)-O-CH3.

[0689] E17: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein Y is NH.

[0690] E18: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein Y is CH2.

[0691] E19: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0692] E20: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0693] E21: A compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, selected from

[0694] 7-((S)-1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0695] 7-Benzoyl-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0696] 7-(Benzo[d]thiazol-2-yl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0697] 7-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0698] 6-(2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl)nicotinate,

[0699] N-(3-(2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-carbonyl)phenyl)acetamide, N-(4-(2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-carbonyl)phenyl)acetamide,

[0700] 7-(Thiazolo[4,5-b]pyridin-2-yl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0701] 7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0702] (R)-7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0703] (S)-7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

[0704] 7-(Benzo[d]thiazol-2-yl)-2,7-diazaspiro[4.4]nonane-1,3-dione,

[0705] 7-Benzoyl-2,7-diazaspiro[4.4]nonane-1,3-dione,

[0706] 6-(6,8-dioxo-2,7-diazaspiro[4.4]nonan-2-yl)nicotinate, and

[0707] 7-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-2,7-diazaspiro[4.4]nonane-1,3-dione.

[0708] E22: A compound, or a pharmaceutically acceptable salt thereof, having a chemical structure comprising:

[0709] PLC

[0710] in

[0711] L is a linker group;

[0712] C is a compound of formula I as described herein,

[0713] wherein L is chemically linked to C; and

[0714] P is a protein targeting portion that binds to a target protein or target polypeptide,

[0715] wherein L is chemically linked to P.

[0716] E23: A compound of formula PLC as described herein, wherein L is selected from:

[0717] i) –NHCH2-(CH2) 1-30- C(=O)NH-, especially

[0718] –NHCH2-(CH2) 6- C(=O)NH-, and

[0719] ii) –NH-(CH2CH2O) 1-25 -C(=O)NH-.

[0720] E24: A compound of formula PLC as described herein, selected from

[0721] i) P–NHCH2-(CH2) 1-30- C(=O)NH-C, especially

[0722] P–NHCH2-(CH2) 6- C(=O)NH-C, and

[0723] ii) P–NH-(CH2CH2O) 1-25 -C(=O)NH-C.

[0724] E25: A compound of formula PLC as described herein, wherein P is a BRD4 inhibitor, in particular wherein P is

[0725]

[0726] E26: A certain embodiment of the present invention relates to a compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.

[0727] E27: A certain embodiment of the present invention relates to a compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of cancer.

[0728] E28: A certain embodiment of the present invention relates to a compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for the therapeutic and / or prophylactic treatment of cancer.

[0729] E29: A certain embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula XV as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary substance.

[0730] E30: A certain embodiment of the present invention relates to a method for the therapeutic and / or prophylactic treatment of cancer by administering a compound of formula XV as described herein.

[0731] E31: A certain embodiment of the present invention relates to a compound of PLC as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0732] E32: A certain embodiment of the present invention relates to a compound of PLC as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of cancer.

[0733] E33: A certain embodiment of the present invention relates to a compound of PLC as described herein, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of cancer.

[0734] E34: A certain embodiment of the present invention relates to a pharmaceutical composition comprising a PLC compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary substance, in particular an inert carrier.

[0735] E35: A certain embodiment of the present invention relates to a method for the therapeutic and / or prophylactic treatment of cancer by administering to a patient a compound of PLC as described herein or a pharmaceutically acceptable salt thereof.

[0736] Furthermore, the present invention includes all optical isomers, ie diastereomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers, and solvates of the compounds of formula I.

[0737] Salts of compounds of formula XV

[0738] In the case where the compound of formula XV is basic, it can be converted into the corresponding acid addition salt. The conversion is accomplished by treatment with at least a stoichiometric amount of a suitable acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and an organic acid, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Typically, the free base is dissolved in an inert organic solvent such as ether, ethyl acetate, chloroform, ethanol or methanol, and the acid is added to a similar solvent. The temperature is maintained between 0°C and 50°C. The resulting salt may precipitate spontaneously or may be brought out of solution with a less polar solvent.

[0739] Insofar as their preparation is not described in the examples, compounds of formula XV or PLC and all intermediates can be prepared according to analogous methods or according to the methods described herein. Starting materials are commercially available known in the art or can be prepared by methods known in the art or analogous thereto.

[0740] It will be appreciated that the compounds of general formula XV or formula PLC in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.

[0741] Compound of formula XVI

[0742] In another aspect, provided is a compound of Formula XVI, or a pharmaceutically acceptable salt thereof:

[0743]

[0744] wherein all variables are as defined herein.

[0745] In some embodiments, provided is a compound of Formula XVI selected from:

[0746]

[0747]

[0748]

[0749] In some embodiments of Formula XVI, a compound selected from the group consisting of:

[0750]

[0751] Where T is In some embodiments of Formula XVI, a compound selected from the group consisting of:

[0752]

[0753]

[0754] Where T is In some embodiments of Formula XVI, a compound selected from the group consisting of:

[0755]

[0756] Where T is

[0757] In some embodiments of Formula XVI, a compound selected from the group consisting of:

[0758]

[0759]

[0760] Where T is In some embodiments of Formula XVI, a compound selected from the group consisting of:

[0761]

[0762]

[0763] Where T is In some embodiments of Formula XVI, a compound selected from the group consisting of:

[0764]

[0765] Where T is In some embodiments of Formula XVI, a compound selected from the group consisting of:

[0766]

[0767] Where T is In some embodiments of Formula XVI, a compound selected from the group consisting of:

[0768]

[0769]

[0770] Where T is In some embodiments of Formula XVI, a compound selected from the group consisting of:

[0771]

[0772] Where T is In some embodiments of Formula XVI, a compound selected from the group consisting of:

[0773]

[0774] In some embodiments of Formula XVI, a compound selected from the group consisting of:

[0775]

[0776] In some embodiments of Formula XVI, a compound selected from the group consisting of:

[0777]

[0778]

[0779] Where T is In some embodiments of Formula XVI, a compound selected from the group consisting of:

[0780]

[0781] Where T is In some embodiments of Formula XVI, a compound selected from the group consisting of:

[0782]

[0783] Where T is Compounds of formula XVII-a to XVII-g

[0784] In one embodiment, a compound of Formula XVII-a is provided:

[0785]

[0786] wherein all variables are as defined herein.

[0787] In some embodiments of Formula XVI or XVII-a, Selected from:

[0788]

[0789] In one embodiment, a compound of Formula XVII-b is provided:

[0790]

[0791] wherein all variables are as defined herein.

[0792] In some embodiments of Formula XVI or XVII-b, Selected from:

[0793]

[0794] In one embodiment, a compound of Formula XVII-c is provided:

[0795]

[0796] wherein all variables are as defined herein.

[0797] In some embodiments of Formula XVI or XVII-d, Selected from:

[0798]

[0799] In one embodiment, a compound of Formula XVII-d is provided:

[0800]

[0801] wherein all variables are as defined herein.

[0802] In some embodiments of Formula XVI or XVII-d, Selected from:

[0803]

[0804] In one embodiment, a compound of Formula XVII-e is provided:

[0805] wherein all variables are as defined herein.

[0806] In some embodiments of XVI or XVII-e, Selected from:

[0807]

[0808] In one embodiment, a compound of Formula XVII-f is provided:

[0809]

[0810] wherein all variables are as defined herein.

[0811] In some embodiments of Formula XVI or XVII-f, Selected from:

[0812] In one embodiment, a compound of Formula XVII-g is provided:

[0813]

[0814] wherein all variables are as defined herein.

[0815] In some embodiments of Formula XVI or XVII-g, Selected from:

[0816] III. Tail Implementation Method

[0817] In one embodiment, the "tail" is a moiety selected from Formula TI, Formula T-II, Formula T-III, Formula T-IV, Formula TV, Formula T-VI, and Formula T-VII:

[0818]

[0819]

[0820] where all variables are defined as above.

[0821] In another embodiment, the "tail" is a moiety selected from the group consisting of formulas T-VIII, T-IX and TX:

[0822]

[0823] wherein all variables are as defined above. In other embodiments of T-VIII, T-IX and TX, a carbocycle is used in place of a heterocycle.

[0824] The following are non-limiting examples of "tail" parts that can be used in the present invention. Based on this description, those skilled in the art will understand how to use all "tail" parts that will achieve the goals of the present invention.

[0825] As some non-limiting examples, Formula TI, Formula T-II, Formula T-III, Formula T-IV, Formula TV, Formula T-VI or Formula T-VII include:

[0826]

[0827]

[0828]

[0829] In other embodiments, the "tail" is selected from:

[0830]

[0831] In other embodiments, the "tail" is selected from:

[0832]

[0833]

[0834] R 20 , R 21 , R 22 , R 23 and R 24 Non-limiting examples of parts include:

[0835]

[0836] R 20 , R 21 , R 22 , R 23 and R 24 Additional non-limiting examples of portions include:

[0837]

[0838] R 20 , R 21 , R 22 , R 23 and R 24 Additional non-limiting examples of portions include:

[0839] In other embodiments, the "tail" is an optionally substituted ethylene glycol having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 ethylene glycol units, or an optionally substituted alkyl group interspersed with optionally substituted O, N, S, P or Si atoms. In certain embodiments, the "tail" is flanked, substituted or interspersed with aryl, phenyl, benzyl, alkyl, alkylene or heterocyclic groups. In certain embodiments, the "tail" can be asymmetric or symmetrical. In some embodiments, the "tail" is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, between about 2 to about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units. In any embodiment of the compounds described herein, the "tail" group can be any suitable part as described herein.

[0840] In other embodiments, the "tail" is selected from:

[0841] -NR 61 (CH2) n1 -(lower alkyl)-X 22 , -NR 61 (CH2) n1 -(lower alkoxy)-X 22 ,

[0842] -NR 61 (CH2) n1 -(lower alkoxy)-OCH2-X 22 , -NR 61 (CH2) n1 -(lower alkoxy)-(lower alkyl)-OCH2-X 22 ,

[0843] -NR 61 (CH2) n1 -(Cycloalkyl)-(lower alkyl)-OCH2-X 22 , -NR 61 (CH2) n1 -(Heterocycloalkyl)-X 22 ,

[0844] -NR 61 (CH2CH2O) n1 -(lower alkyl)-O-CH2-X 22 ,

[0845] -NR 61 (CH2CH2O) n1 -(Heterocycloalkyl)-O-CH2-X 22 ,

[0846] -NR 61 (CH2CH2O) n1 -Aryl-O-CH2-X 22 , -NR 61 (CH2CH2O) n1 -(Heteroaryl)-O-CH2-X 22 ,

[0847] -NR 61 (CH2CH2O) n1 -(cycloalkyl)-O-(heteroaryl)-O-CH2-X 22 ,

[0848] -NR 61 (CH2CH2O) n1 -(Cycloalkyl)-O-aryl-O-CH2-X 22 ,

[0849] -NR 61 (CH2CH2O) n1 -(lower alkyl)-NH-aryl-O-CH2-X 22 ,

[0850] -NR 61 (CH2CH2O) n1-(lower alkyl)-O-aryl-CH2-X 22 ,

[0851] -NR 61 (CH2CH2O) n1 -cycloalkyl-O-aryl-X 22 , -NR 61 (CH2CH2O) n1 -cycloalkyl-O-heteroaryl-X 22 ,

[0852] -NR 61 (CH2CH2) n1 -(Cycloalkyl)-O-(Heterocyclic)-CH2-X 22 ,

[0853] -NR 61 (CH2CH2) n1 -(Heterocyclic)-(Heterocyclic)-CH2-X 22 , and -NR 61 -(Heterocyclic)-CH2-X 22 ;

[0854] wherein n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and R 61 is H, methyl or ethyl.

[0855] In other embodiments, the "tail" is selected from:

[0856] -N(R 61 )-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OCH2-X 22 ,

[0857] -O-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OCH2-X 22 ,

[0858] -O-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1-O(CH2) q1 -O(CH2) r1 -OH;

[0859] -N(R 61 )-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OH;

[0860] -(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OH;

[0861] -(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OCH2-X 22 ;

[0862] -O(CH2) m1 O(CH2) n2 O(CH2) p1 O(CH2) q1 OCH2-X 22 ;

[0863] -O(CH2) m1 O(CH2) n2 O(CH2) p1 O(CH2) q1 OCH2-X 22 ;in

[0864] m1, n2, o1, p1, q1 and r1 are independently 1, 2, 3, 4 or 5; and R 61 is H, methyl or ethyl.

[0865] In other embodiments, the "tail" is selected from:

[0866]

[0867] m1, n2, o1, p1, q2, and r1 are independently 1, 2, 3, 4 or 5. In another embodiment, the "tail" is selected from:

[0868]

[0869] In other embodiments, the "tail" is selected from:

[0870]

[0871] In other embodiments, the "tail" is selected from:

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878] Where R 71 is -O-, -NH, N-alkyl, heteroaliphatic, aliphatic or -NMe. In another embodiment, the "tail" is selected from:

[0879]

[0880]

[0881]

[0882]

[0883]

[0884] In other embodiments, the "tail" is selected from:

[0885]

[0886] In other embodiments, the "tail" is selected from:

[0887]

[0888] In other embodiments, the "tail" is selected from:

[0889]

[0890]

[0891] In other embodiments, the "tail" is selected from:

[0892]

[0893] In the above implementation, select X 22 Make the compound sufficiently stable or achieve its intended use.

[0894] In other embodiments, the "tail" is selected from:

[0895]

[0896] In certain embodiments, the "tail" is selected from:

[0897]

[0898] In certain embodiments, the "tail" is selected from:

[0899]

[0900]

[0901] In the above structure, represent

[0902] In certain embodiments, the "tail" may be a linear chain of 4-24 carbon atoms, wherein one or more carbon atoms in the linear chain may be replaced or substituted by oxygen, nitrogen, amide, fluorinated carbon, etc., such as the following:

[0903]

[0904]

[0905] In certain embodiments, the "tail" may be a non-linear chain, and may be or include an aliphatic or aromatic or heteroaromatic cyclic moiety.

[0906] In certain embodiments, the "tail" may include continuous, partially continuous or non-continuous ethylene glycol unit groups ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, between about 2 to about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units, for example, 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units.

[0907] In certain embodiments, the "tail" may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 fluorine substituents. In another embodiment, the "tail" is perfluorinated. In yet another embodiment, the "tail" is a partially or fully fluorinated polyether. Non-limiting examples of fluorinated "tails" include:

[0908]

[0909] X 22 Representative examples include:

[0910]

[0911] In certain embodiments, the length may be adjusted as desired and may also be adjusted as required for the desired application.

[0912] IV. Treatment Methods

[0913] Compounds of Formula Ia, Ib, II, IIIa, IIIb, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XIV-a to XIV-x, or XV-a to XV-t can be used to treat a host (including humans) in need thereof in an effective amount to treat any of the disorders described herein, optionally in a pharmaceutically acceptable carrier.

[0914] As used herein, the term "treatment" and the like refers to any effect that provides a benefit to a patient to whom the compounds of the invention are administered, including the treatment of any disease state or condition that is modulated by a protein to which the compounds of the invention bind. Exemplary non-limiting disease states or conditions that can be treated using compounds according to the invention are described above, including cancer.

[0915] The term "disease state or condition" when used in connection with a compound of Formula Ia, Ib, II, IIIa, IIIb, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XIV-a to XIV-x, or XV-a to XV-t refers to any therapeutic indication that can be treated, for example, by reducing the activity of cereblon or a cereblon-containing E3 ligase. Non-limiting examples of the use of cereblon binders are multiple myeloma, hematological disorders such as myelodysplastic syndrome, cancer, tumors, abnormal cell proliferation, HIV / AIDS, HBV, HCV, hepatitis, Crohn's disease, sarcoidosis, graft-versus-host disease, rheumatoid arthritis, Behcet's disease, tuberculosis, and myelofibrosis. Other indications include myeloproliferative or lymphoproliferative disorders such as B-cell or T-cell lymphoma, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorders; immune disorders, including autoimmune disorders such as Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, arthritis (particularly rheumatoid arthritis), lupus, or type I diabetes; cardiogenic dysfunction diseases, including hypercholesterolemia; infectious diseases, including viral and / or bacterial infections, as generally described herein; inflammatory conditions, including asthma, chronic peptic ulcers, tuberculosis, rheumatoid arthritis, periodontitis, and ulcerative colitis.

[0916] In certain embodiments, the present invention provides for administering a compound of Formula Ia, Ib, II, IIIa, IIIb, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XIV-a to XIV-x, or XV-a to XV-t to a patient (e.g., a human) suffering from an infectious agent, wherein the treatment is targeted to a target protein of the infectious agent, optionally in combination with another biologically active agent. The disease state or condition may be a disease caused by a microbial or other exogenous agent such as a virus (as non-limiting examples, HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola, Flavivirus, Pestivirus, Rotavirus, Influenza, Coronavirus, EBV, Viral Pneumovirus, Drug-Resistant Virus, Avian Flu, RNA Virus, DNA Virus, Adenovirus, Poxvirus, Picornavirus, Togavirus, Orthomyxovirus, Retrovirus, or Hepadnavirus), bacteria (Gram-negative, Gram-positive), fungi, protozoa, helminths, worms, prions, parasites, or other microorganisms, or a disease state that may be caused by overexpression of a protein, which results in the disease state and / or condition.

[0917] In certain embodiments, the condition treated with the compounds of the invention is a disorder associated with abnormal cell proliferation. Abnormal cell proliferation, particularly hyperproliferation, can be caused by a variety of factors, including genetic mutations, infection, exposure to toxins, autoimmune disorders, and benign or malignant tumor induction.

[0918] There are many skin conditions associated with excessive cell proliferation. For example, psoriasis is a benign disease of human skin that is usually characterized by plaques covered with thickened scales. The disease is caused by increased proliferation of epidermal cells for unknown reasons. Chronic eczema is also associated with significant excessive proliferation of the epidermis. Other diseases caused by excessive proliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

[0919] Other hyperproliferative cell disorders include vascular proliferative disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors and cancer.

[0920] Vascular proliferative disorders include angiogenesis and vasculogenic disorders. Proliferation of smooth muscle cells during plaque development in vascular tissue leads to, for example, restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[0921] Fibrotic disorders are generally due to abnormal formation of the extracellular matrix. Examples of fibrotic disorders include liver cirrhosis and mesangial proliferative cell disorders. Liver cirrhosis is characterized by an increase in extracellular matrix components, leading to the formation of liver scarring. Liver cirrhosis can cause diseases such as cirrhosis of the liver. Increased extracellular matrix leading to liver scarring can also be caused by viral infections such as hepatitis. Fat cells appear to play a major role in liver cirrhosis.

[0922] 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, transplant rejection and glomerulopathy.

[0923] Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease that is thought to be associated with the activity of autoreactive T cells and is caused by autoantibodies raised against collagen and IgE.

[0924] Other diseases that may include an abnormal cell proliferation component include Behcet'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.

[0925] Skin contact hypersensitivity and asthma are just two examples of immune responses that can be associated with significant morbidity. Other examples include atopic dermatitis, eczema, Sjögren's syndrome (including keratoconjunctivitis sicca secondary to Sjögren's syndrome), alopecia areata, allergic reactions due to arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may result in any one or more of the following symptoms or signs: itching, swelling, redness, blisters, crusting, ulcers, pain, scaling, cracking, hair loss, scarring, or fluid exudation involving the skin, eyes, or mucous membranes.

[0926] In atopic dermatitis and eczema in general, immune-mediated infiltration of leukocytes (particularly monocytes, lymphocytes, neutrophils, and eosinophils) into the skin plays an important role in the pathogenesis of these diseases. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Immune-mediated leukocyte infiltration also occurs at sites other than the skin, such as the airways in asthma and the tear-producing eye glands in keratoconjunctivitis sicca.

[0927] In one non-limiting embodiment, the compounds of the 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 reactions due to arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. The novel method can also be used to reduce the infiltration of malignant leukocytes to the skin in diseases such as mycosis fungoides. These compounds can also be used to treat aqueous deficient dry eye conditions (e.g., immune-mediated keratoconjunctivitis) in patients suffering therefrom by topical administration of the compounds to the eye.

[0928] Disease states treatable according to the invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, ciliary diseases, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease 1 (PKD1) or 2 (PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome.

[0929] Other disease states or conditions that may be treated by the compounds according to the invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorders, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes, type 2 diabetes, epilepsy, Guillain-Barre 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.

[0930] Other disease states or conditions that may be treated by the compounds according to the invention include aceruloplasminosis, achondroplasia type II, achondroplasia, pointed head, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenyloylsuccinate lyase deficiency, adrenal reproductive syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuria ocher, alpha 1-antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen Insensitivity syndrome, anemia, diffuse body angiokeratoma, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, spider feet (Marfan syndrome), Stickler syndrome, congenital multiple arthrogryposis (Ehlers-Danlos syndrome # arthrogryposis type), ataxia telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Bill-Stevensson skin gyration syndrome, familial Mediterranean fever, Benjamin syndrome, beta-thalassemia, bilateral acoustic neurofibromatosis (neurofibromatosis type II), factor V Leiden thrombophilia, Bloch-Sulzberg syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bo Navier-Ulrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion disease, Bert-Hoeg-Dub syndrome, brittle bone disease (osteogenesis imperfecta), broad finger syndrome (BroadThumb-Hallux syndrome) (Rubinstein-Taybi syndrome), bronze diabetes / bronze cirrhosis (hemochromatosis), bulbar muscular atrophy (Kennedy disease), Berg-Grutz syndrome (lipoprotein lipase deficiency), CGD chronic granulomatous disease, camptolimb dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cat cry syndrome, CAVD (congenital absence of the vas deferens), Caylor cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), Cystic fibrosis, congenital hypothyroidism, chondrodystrophy syndrome (achondroplasia), otospondyloepiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, thanatophoric 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, cone abnormal face syndrome, Wenkuli anemia (beta-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial joint deformity (Crouzon syndrome),Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Kirschman-Batten-Steinert syndrome (myotonic dystrophy), Bill-Stevensson skin gyration syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Stradwick type), Duchenne and Becker muscular dystrophy (DBMD), Usher syndrome, degenerative neurological diseases (including deGrown syndrome and DeGeliner-Sotas syndrome), developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse globuloid sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protoporphyria, erythrocyte 5-aminolevulinic acid syndrome enzyme deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia-familial paroxysmal polyserositis, porphyria cutanea tarda, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), pancreatic fibrocystic disease, fragile X syndrome, galactosemia, inherited brain disorders, giant cell hepatitis (neonatal hemochromatosis), Grunblad-Standberg syndrome (pseudoxanthoma elasticum), Genda disease (congenital erythropoietic porphyria), hemochromatosis, Holgren syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington disease, Hutchinson-Gilford Progeria syndrome (progeria), hyperandrogenism, chondrodysplasia, hypochromic anemia, immune system disorders (including X-linked severe combined immunodeficiency), Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney disease (including hyperoxaluria), Klinefelter syndrome, Knister dysplasia, intermittent dementia, Langer-Sardino achondroplasia, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders (including Knister dysplasia), Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Mink syndrome, neurofibromatosis , Nance-Inslee syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Lundy disease, Piots-Jeghers syndrome, polycystic kidney disease, polyostotic fibrous dysplasia (McCune-Albright syndrome), Piots-Jeghers syndrome, Prader-Labatt-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary (Huntington) (Huntington disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy,Pulmonary hypertension, PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen disease (neurofibromatosis type I), relapsing polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Reck syndrome, Riley-Day syndrome, Lucey-Levy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma of the breast, leukemia, and adrenal (SBLA) syndrome, tuberous sclerosis (tubercular sclerosis), SDAT, congenital SED (congenital spondyloepiphyseal dysplasia), Stradwick SED (Stradwick type spondyloepiphyseal dysplasia), SEDc (congenital spondyloepiphyseal dysplasia), SEMD, Stradwick type (Stradwick type spondyloepiphyseal dysplasia), epiphyseal dysplasia), Shprintzen syndrome, skin pigmentation disorders, Smith-Lemley-Opitz syndrome, South African hereditary porphyria (variant porphyria), hereditary spastic paralysis of infantile onset, speech and communication disorders, sphingolipid storage disorders, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, dachshund neuropathy (hereditary neuropathy with a tendency to pressure palsy), Treacher Collins syndrome, Triplo X syndrome, trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (, syndrome), Vrolik disease, Waardenburg syndrome, Warburg Sjo Fledelius syndrome, Weissenbacher-Zweymüller syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disease, Weissenbacher-Zweymüller syndrome and xeroderma pigmentosum, etc.

[0931] The term "tumor" or "cancer" is used throughout this specification to refer to the following pathological process: it leads to cancerous or malignant tumors, that is, abnormal tissues that grow more rapidly than normal through cell proliferation and continue to grow after the stimulus that initiates new growth has ceased. Malignant tumors exhibit partial or complete lack of structural organization and functional coordination in the case of normal tissues, and most invade surrounding tissues, metastasize to several sites, are likely to reappear after attempted removal, and will cause death of the patient unless adequately treated. As used herein, the term tumor is used to describe all cancer disease states, and includes or encompasses pathological processes associated with malignant hematogenous, ascites, and solid tumors. Exemplary cancers that can be treated by the compounds of the invention, alone or in combination with at least one other anticancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and stomach cancer; leukemias; benign and malignant lymphomas, especially Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloid proliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, Myosoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma and schwannoma; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratoma. Other cancers that can be treated using the compounds according to the invention include, for example, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-BALL, pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL and Philadelphia chromosome-positive CML.

[0932] Other cancers that can be treated using the disclosed compounds according to the present invention include, for example, acute myeloid leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, intestinal cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of the estrogen, progesterone and HER-2 are negative), single negative (one of the estrogen, progesterone and HER-2 is negative), estrogen receptor positive, HER2 negative breast cancer. Adenocarcinoma, estrogen receptor negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, tubular A breast cancer, tubular B breast cancer, Her2 negative breast cancer, HER2 positive or negative breast cancer, progesterone receptor negative breast cancer, progesterone receptor positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, bile duct cancer, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, Ewing sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, stomach Intestinal carcinoid, Gastrointestinal stromal tumor (GIST), Germ cell tumor, Glioblastoma multiforme (GBM), Glioma, Hairy cell leukemia, Head and neck cancer, Hemangioendothelioma, Hodgkin lymphoma, Hypopharyngeal cancer, Infiltrating ductal carcinoma (IDC), Infiltrating lobular carcinoma (ILC), Inflammatory breast cancer (IBC), Intestinal cancer, Intrahepatic bile duct carcinoma, Invasive / invasive breast cancer, Islet cell carcinoma, Jaw cancer, Kaposi's sarcoma, Kidney cancer, Laryngeal cancer, Leiomyosarcoma, Leptomeningeal metastasis, Leukemia, Lip cancer, Liposarcoma, Liver cancer, Lobular carcinoma in situ, Low-grade astrocytoma, Lung cancer, Lymph node cancer, Lymphoma, Male breast cancer, Medullary carcinoma, Medulloblastoma, Melanoma, Meningioma, Merkel cell carcinoma, Mesenchymal chondrosarcoma, Mesenchymal tumor, Mesothelioma Tumors metastatic breast cancer, metastatic melanoma, metastatic squamous cell carcinoma, cervical cancer, mixed glioma, solitary teratoma, oral cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cancer, nasopharyngeal cancer, cervical cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, eye melanoma, oligodendroglioma, mouth cancer, oral cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian primary peritoneal cancer, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer,Peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumors, pineoblastoma, pituitary adenocarcinoma, primary central nervous system (CNS) lymphoma, prostate cancer, colorectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, osteosarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial muscle Tumors, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma / thymic cancer, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular cancer, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (AML subtype), large granular lymphocytic leukemia, adult T-cell chronic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; splenic lymphoma / leukemia, unclassifiable cancer, splenic diffuse red pulp small B-cell lymphoma; plasma cell lymphoma; heavy chain disease, e.g., alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous 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, plasma cell lymphoma; large B-cell lymphoma caused by HHV8-related multicentric Castleman disease; unclassifiable B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma, or unclassifiable B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0933] In one embodiment, the cancer is NUT midline carcinoma.

[0934] In one embodiment, the cancer is adenoid cystic carcinoma.

[0935] The term "biologically active agent" is used to describe an agent other than a compound according to the invention, which is used in combination with the compounds of the invention as an agent having biological activity to help achieve the intended treatment, inhibition and / or prevention / prevention of the condition for which the compounds of the invention are used. Preferred biologically active agents for use herein include those having pharmacological activities similar to those of the compounds of the invention used or administered, including, for example, anticancer agents, antiviral agents, particularly including anti-HIV agents and anti-HCV agents, antibacterial agents, antifungal agents, and the like.

[0936] In one embodiment, a method for treating multiple myeloma is provided, comprising administering to a patient an effective amount of a compound as described herein or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition. In another embodiment, a compound as described herein or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, is used in a method for treating multiple myeloma, wherein the method comprises administering the compound to a patient.

[0937] In one embodiment, a method for controlling the progression of multiple myeloma is provided, comprising administering to a patient an effective amount of a compound as described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition. In another embodiment, a compound as described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, is used in a method for controlling the progression of multiple myeloma, wherein the method comprises administering the compound to a patient.

[0938] In one embodiment, a method is provided for inducing a therapeutic response in a patient with multiple myeloma as assessed by the International Uniform Response Criteria (IURC) for multiple myeloma (described in Durie BGM; et al., "International uniform response criteria for multiple myeloma. Leukemia 2006, 10(10): 1-7), comprising administering to the patient an effective amount of a compound as described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0939] In another embodiment, a method is provided to achieve stringent complete remission, complete remission or very good partial remission in a patient with multiple myeloma as assessed by the IURC for multiple myeloma, the method comprising administering to the patient an effective amount of a compound described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0940] In another embodiment, a method for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient with multiple myeloma is provided, comprising administering to the patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0941] In another embodiment, a method of achieving increased overall survival in a patient with multiple myeloma is provided, the method comprising administering to the patient an effective amount of a compound described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0942] In another embodiment, a method of achieving increased progression-free survival in a patient with multiple myeloma is provided, the method comprising administering to the patient an effective amount of a compound described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0943] In another embodiment, a method of achieving increased event-free survival in a patient with multiple myeloma is provided, the method comprising administering to the patient an effective amount of a compound described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0944] In another embodiment, a method of achieving increased time to progression in a patient with multiple myeloma is provided, the method comprising administering to the patient an effective amount of a compound described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0945] In another embodiment, a method of achieving increased disease-free survival in a patient with multiple myeloma is provided, the method comprising administering to the patient an effective amount of a compound described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0946] Methods of treating patients who have been previously treated for multiple myeloma but who have not responded to standard therapy, in addition to those patients who have not been previously treated, are also provided. Additional methods of treating patients who have undergone surgery in an attempt to treat multiple myeloma, in addition to those patients who have not undergone surgery, are also provided. Methods of treating patients who have previously received a transplant, in addition to those patients who have not received a transplant, are also provided.

[0947] The compounds described herein can be used to treat or manage relapsed, refractory or resistant multiple myeloma. In some embodiments, the multiple myeloma is a primary, secondary, tertiary, quadruple or quintuple relapsed multiple myeloma. In one embodiment, the compounds described herein can be used to reduce, maintain or eliminate minimal residual disease (MRD).

[0948] Types of multiple myeloma that can be treated with the compounds described herein include, but are not limited to: monoclonal gammopathy of undetermined significance; low-risk, intermediate-risk, or high-risk multiple myeloma; newly diagnosed multiple myeloma, including low-risk, intermediate-risk, or high-risk newly diagnosed multiple myeloma; transplant-eligible and transplant-ineligible multiple myeloma; smoldering (indolent) multiple myeloma (including low-risk, intermediate-risk, or high-risk smoldering multiple myeloma); active multiple myeloma; solitary plasmacytoma; plasma cell leukemia; central nervous system multiple myeloma; light chain myeloma; non-secretory myeloma; immunoglobulin D myeloma; and immunoglobulin E myeloma.

[0949] In some embodiments, the compounds described herein can be used to treat or manage multiple myeloma characterized by genetic abnormalities such as, but not limited to: cyclin D translocation (e.g., t(11;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32); or t(6;20);); MMSET translocation (e.g., t(4;14)(p16;q32); MAF translocation (e.g., t(14;16)(q32;a32); t(20;22); t(16;22)(q11;q13); or t(14;20)(q32;q11); or other chromosomal factors (e.g., deletion 17p13 or chromosome 13; del(17 / 17p), non-hyperdiploidy, and gain(1q)).

[0950] In one embodiment, a method for treating or managing multiple myeloma as an induction therapy is provided, comprising administering to a patient an effective amount of a compound as described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0951] In one embodiment, a method for treating or managing multiple myeloma as consolidation therapy is provided, comprising administering to the patient an effective amount of a compound as described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0952] In one embodiment, a method for treating or managing multiple myeloma as a maintenance therapy is provided, comprising administering to a patient an effective amount of a compound as described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0953] In one embodiment, the multiple myeloma is a plasma cell leukemia.

[0954] 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 genetic abnormalities, such as one or more of del(17 / 17p) and t(14;16)(q32;q32). In some embodiments, the high-risk multiple myeloma is relapsed or refractory to one, two or three prior treatments.

[0955] In one embodiment, the multiple myeloma has a p53 mutation. In one embodiment, the p53 mutation is a Q331 mutation. In one embodiment, the p53 mutation is a R273H mutation. In one embodiment, the p53 mutation is a K132 mutation. In one embodiment, the p53 mutation is a K132N mutation. In one embodiment, the p53 mutation is 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.

[0956] In one embodiment, the multiple myeloma has a homozygous deletion of p53. In one embodiment, the multiple myeloma has a homozygous deletion of wild-type p53. In one embodiment, the multiple myeloma has wild-type p53.

[0957] In one embodiment, multiple myeloma shows activation of one or more oncogenic drivers. In one embodiment, the one or more oncogenic drivers are selected from C-MAF, MAFB, FGFR3, MMset, cyclin D1, and cyclin D. In one embodiment, multiple myeloma shows activation of C-MAF. In one embodiment, multiple myeloma shows activation of MAFB. In one embodiment, multiple myeloma shows activation of FGFR3 and MMset. In one embodiment, multiple myeloma shows activation of C-MAF, FGFR3 and MMset. In one embodiment, multiple myeloma shows activation of cyclin D1. In one embodiment, multiple myeloma shows activation of MAFB and cyclin D1. In one embodiment, multiple myeloma shows activation of cyclin D.

[0958] In one embodiment, multiple myeloma has one or more chromosomal translocations. In one embodiment, the chromosomal translocation is t(14;16). In one embodiment, the chromosomal translocation is t(14;20). In one embodiment, the chromosomal translocation is t(4;14). In one embodiment, the chromosomal translocation is t(4;14) and t(14;16). In one embodiment, the chromosomal translocation is t(11;14). In one embodiment, the chromosomal translocation is t(6;20). In one embodiment, the chromosomal translocation is t(20;22). In one embodiment, the chromosomal translocation is t(6;20) and t(20;22). In one embodiment, the chromosomal translocation is t(16;22). In one embodiment, the chromosomal translocation is t(14;16) and t(16;22). In one embodiment, the chromosomal translocation is t(14;20) and t(11;14).

[0959] In one embodiment, the multiple myeloma has a Q331 p53 mutation, C-MAF activation, and a chromosomal translocation at t(14;16). In one embodiment, the multiple myeloma has a homozygous deletion of p53, C-MAF activation, and a chromosomal translocation at t(14;16). In one embodiment, the multiple myeloma has a K132N p53 mutation, MAFB activation, and a chromosomal translocation at t(14;20). In one embodiment, the multiple myeloma has wild-type p53, FGFR3 and MMset activation, and a chromosomal translocation at t(4;14). In one embodiment, the multiple myeloma has wild-type p53, C-MAF activation, and a chromosomal translocation at t(14;16). In one embodiment, the multiple myeloma has a homozygous deletion of p53, FGFR3, MMset, and C-MAF activation, and chromosomal translocations at t(4;14) and t(14;16). In one embodiment, the multiple myeloma has a homozygous deletion of p53, cyclin D1 activation, and a chromosomal translocation at t(11;14). In one embodiment, the multiple myeloma has a R337L p53 mutation, cyclin D1 activation, and a chromosomal translocation at t(11;14). In one embodiment, the multiple myeloma has a W146 p53 mutation, FGFR3 and MMset activation, and a chromosomal translocation at t(4;14). In one embodiment, the multiple myeloma has a S261T p53 mutation, MAFB activation, and chromosomal translocations at t(6;20) and t(20;22). In one embodiment, the multiple myeloma has an E286K p53 mutation, FGFR3 and MMset activation, and a chromosomal translocation at t(4;14). In one embodiment, the multiple myeloma has a R175H p53 mutation, FGFR3 and MMset activation, and a chromosomal translocation at t(4;14). In one embodiment, the multiple myeloma has an E258K p53 mutation, C-MAF activation, and chromosomal translocations at t(14;16) and t(16;22). In one embodiment, the multiple myeloma has wild-type p53, MAFB and cyclin D1 activation, and chromosomal translocations at t(14;20) and t(11;14). In one embodiment, the multiple myeloma has an A161T p53 mutation, cyclin D activation, and chromosomal translocations at t(11;14).

[0960] In some embodiments, the multiple myeloma is newly diagnosed multiple myeloma that is eligible for transplantation. In other embodiments, the multiple myeloma is newly diagnosed multiple myeloma that is not eligible for transplantation.

[0961] In some embodiments, multiple myeloma shows early progression (e.g., less than 12 months) after initial treatment. In other embodiments, multiple myeloma shows early progression (e.g., less than 12 months) after autologous stem cell transplantation. In another embodiment, multiple myeloma is refractory to lenalidomide. In another embodiment, multiple myeloma is refractory to pomalidomide. In some such embodiments, multiple myeloma is predicted to be refractory to pomalidomide (e.g., by molecular characterization). In another embodiment, multiple myeloma is relapsed or refractory to 3 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 avadomide), or is double refractory to a proteasome inhibitor and an immunomodulatory compound. In other embodiments, the multiple myeloma is relapsed or refractory to three or more prior therapies, including, for example, a CD38 monoclonal antibody (CD38 mAb, e.g., daratumumab or isatuximab), a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide), or is double resistant to a proteasome inhibitor or an immunomodulatory compound and a CD38 mAb. In other embodiments, the multiple myeloma is triple refractory, e.g., the multiple myeloma is refractory to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib), an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide), and another active agent, as described herein.

[0962] In one embodiment, a method for treating or managing relapsed or refractory multiple myeloma in a patient with impaired renal function or symptoms thereof is provided, comprising administering to the patient an effective amount of a compound described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0963] In another embodiment, a method for treating or managing relapsed or refractory multiple myeloma in a frail patient is provided, comprising administering to the patient an effective amount of a compound described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, wherein the frail patient is characterized by being unsuitable for induction therapy or intolerant to dexamethasone treatment. In other embodiments, the frail patient is an elderly person, for example, older than 65 years old.

[0964] In another embodiment, a method for treating or managing fourth-line relapsed or refractory multiple myeloma is provided, comprising administering to a patient an effective amount of a compound described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0965] In another embodiment, a method for treating or managing newly diagnosed, transplant-unsuitable multiple myeloma is provided, comprising administering to the patient an effective amount of a compound described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0966] In another embodiment, a method for treating or managing newly diagnosed multiple myeloma that is not suitable for transplantation is provided, comprising administering to the patient an effective amount of a compound described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, as an additional therapy or maintenance therapy after transplantation.

[0967] In another embodiment, a method for treating or managing high risk multiple myeloma that has relapsed or is refractory to one, two or three prior therapies is provided, comprising administering to the patient an effective amount of a compound described herein or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0968] In some embodiments, prior to administration, the patient to be treated by one of the compounds described herein has not been treated with multiple myeloma therapy. In some embodiments, the patient to be treated by one of the compounds described herein has been treated by multiple myeloma therapy before administration. In some embodiments, the patient to be treated by one of the compounds described herein has developed resistance to multiple myeloma therapy. In some embodiments, the patient to be treated by one of the compounds described herein has developed resistance to one, two or three multiple tumor tumor therapies, wherein the therapy is selected from CD38 antibodies (CD38 mAbs, e.g., daratumumab or isatuximab), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib or marizomib) and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iberdomide or avadomide).

[0969] Regardless of the age of the patient, the compounds described herein can be used to treat the patient. In some embodiments, the subject is not 18 years of age or older. In other embodiments, the subject is older than 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years of age. In other embodiments, the patient is less than 65 years of age. In other embodiments, the patient is older than 65 years of age. In one embodiment, the patient is an elderly multiple myeloma patient, such as a patient older than 65 years of age. In one embodiment, the patient is an elderly multiple myeloma patient, such as a patient older than 75 years of age.

[0970] V. Combination Therapy

[0971] Compounds of Formula Ia, Ib, II, IIIa, IIIb, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XIV-a to XIV-x, or XV-a to XV-t can be used alone or in combination in an effective amount to treat a host (e.g., a human) suffering from a disorder as described herein.

[0972] The disclosed compounds described herein can be used alone or in combination with another compound of the invention or another biologically active agent in an effective amount to treat a host (eg, a human) suffering from a disorder described herein.

[0973] The term "biologically active agent" is used to describe an agent other than a selected compound according to the invention that can be used in combination or in alternation with a compound of the invention to achieve a desired therapeutic outcome. In one embodiment, the compound of the invention and the biologically active agent are administered in overlapping time periods in a manner that they are active in vivo, e.g., time periods with overlapping Cmax, Tmax, AUC or other pharmacokinetic parameters. In another embodiment, the compound of the invention and the biologically active agent are administered to a host in need thereof that does not have overlapping pharmacokinetic parameters, however, one has a therapeutic impact on the therapeutic effect of the other.

[0974] In one aspect of this embodiment, the bioactive agent is an immunomodulator, including but not limited to checkpoint inhibitors, including PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V domain Ig inhibitors of T cell activation (VISTA) inhibitors, small molecules, peptides, nucleotides or other inhibitors as non-limiting examples. In some aspects, the immunomodulator is an antibody, such as a monoclonal antibody.

[0975] VI. Pharmaceutical Compositions

[0976] As disclosed herein, the compounds of formula Ia, formula Ib, formula II, formula IIIa, formula IIIb, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV, formula XV, formula XIV-a to XIV-x, or formula XV-a to XV-t can be administered as pure chemicals, but more usually as pharmaceutical compositions, which include an effective amount for a host (usually a human) in need of treatment of any of the conditions described herein. Therefore, the present disclosure provides a pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier for any use described herein. The pharmaceutical composition may contain a compound or salt as the sole active agent, or in an alternative embodiment, contain the compound and at least one additional active agent.

[0977] In some embodiments, the pharmaceutical composition is in a dosage form containing about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an active compound and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an additional activating agent in a unit dosage form. Examples are dosage forms with at least 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of an active compound or its salt. The pharmaceutical composition may also include a molar ratio of an active compound and an additional activating agent. For example, the pharmaceutical composition may contain a molar ratio of the anti-inflammatory agent or the immunosuppressant of about 0.5: 1, about 1: 1, about 2: 1, about 3: 1, or about 1.5: 1 to about 4: 1. The compounds disclosed herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, by implantation (including ophthalmic implants), transdermally, by buccal administration, rectally, as an ophthalmic solution, injection (including ocular injection), intravenously, intraaortically, intracranial, subcutaneously, intraperitoneally, subcutaneously, nasally, sublingually or rectally or by other means, in the form of dosage unit formulations containing conventional pharmaceutically acceptable carriers. For ocular delivery, the compounds can be administered, as desired, for example, by intravitreal, intrastromal, intracameral, subtenon, subretinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, scleral, periocular, transscleral, retrobulbar, posterior scleral, limbal or lacrimal injection, or through mucus, mucin or mucosal barriers, in an immediate or controlled release manner or by an ocular device.

[0978] The pharmaceutical composition can be formulated into any pharmaceutically useful form, for example, into an aerosol, cream, gel, pill, injection or infusion solution, capsule, tablet, syrup, transdermal patch, subcutaneous patch, dry powder, inhalation preparation, medical device, suppository, oral or sublingual preparation, parenteral preparation or ophthalmic solution. Some dosage forms (such as tablets and capsules) are subdivided into appropriately sized unit doses containing an appropriate amount of the active ingredient, for example, an effective amount to achieve the desired purpose.

[0979] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the patient being treated. The carrier may be inert, or it may have its own pharmaceutical benefits. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material for administering the compound per unit dose.

[0980] Classes of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one category, e.g., vegetable oils may be used as lubricants in some formulations and as diluents in other formulations. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Optional active agents may be included in the pharmaceutical composition that do not substantially interfere with the activity of the compounds of the invention.

[0981] Pharmaceutical compositions / combinations can be formulated for oral administration. These compositions can contain any amount of active compound to achieve the desired result, for example, between 0.1 and 99 weight percent (wt.%) of the compound, and typically at least about 5 wt.% of the compound. Some embodiments contain about 25 wt.% to about 50 wt.% or about 5 wt.% to about 75 wt.% of the compound.

[0982] Formulations suitable for rectal administration are conveniently presented as unit dose suppositories. These can be prepared by mixing the active compound with one or more conventional solid carriers (eg, cocoa butter) and then shaping the resulting mixture.

[0983] Preparations suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Carriers that may be used include petrolatum, lanolin, polyethylene glycols, alcohols, skin penetration enhancers and combinations of two or more thereof.

[0984] Preparations suitable for transdermal administration can be presented as discrete patches, which are suitable for keeping close contact for a long period of time with the epidermis of the recipient. Preparations suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6): 318 (1986)), and generally take the form of an optional buffered active compound aqueous solution. In one embodiment, a microneedle patch or device is provided for passing or entering biological tissue, particularly skin, by drug delivery. Microneedle patch or device allow drug to be delivered with a clinically relevant rate through or into skin or other tissue barriers, and minimal or no damage, pain or stimulation to tissue.

[0985] Preparations suitable for administration to the lungs can be delivered by a variety of passive breath-driven and active power-driven single / multi-dose dry powder inhalers (DPIs). The devices most commonly used for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of suitable pulmonary delivery devices depends on parameters such as the properties of the drug and its preparation, the site of action, and the pathophysiology of the lungs.

[0986] The compounds and pharmaceutically acceptable salts described herein can be used as therapeutically active substances, for example, in the form of pharmaceutical preparations. Pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, they can also be administered rectally (for example, in the form of suppositories) or parenterally (for example, in the form of injection solutions).

[0987] The compounds described herein and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic carriers to produce pharmaceutical preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. However, depending on the nature of the active substance, in the case of soft gelatin capsules, carriers are generally not required. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils, etc. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.

[0988] In addition, the pharmaceutical preparations may contain pharmaceutically acceptable auxiliary substances, such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other substances of therapeutic value.

[0989] The present invention also provides a medicament containing a compound of the invention or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, as well as a process for its production, which comprises bringing one or more compounds of formula I and / or a pharmaceutically acceptable salt thereof and (if desired) one or more other therapeutically valuable substances into a galenic administration form together with one or more therapeutically inert carriers.

[0990] The dosage can vary within a wide range and, of course, must be adjusted to individual needs in each specific case. In the case of oral administration, the dosage for adults can vary between about 0.01 mg to about 1000 mg per day of a compound of the general formula VII, general formula XIII or a corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage can be administered in a single dose or in divided doses and, in addition, the upper limit can be exceeded when an upper limit is found.

[0991] The following examples illustrate the invention but are not intended to limit it, but are merely representative thereof. The pharmaceutical preparations conveniently contain about 1-500 mg, especially 1-100 mg, of a compound of formula XIV. Examples of compositions according to the invention are:

[0992] Example A

[0993] Tablets of the following composition are manufactured in the usual manner:

[0994]

[0995] Table 1: Possible tablet compositions

[0996] Manufacturing Process

[0997] 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

[0998] 2. Dry the granules at 50°C.

[0999] 3. Pass the granules through suitable grinding equipment.

[1000] 4. Add ingredient 5 and mix for three minutes; compress on a suitable press.

[1001] Example B-1

[1002] Capsules of the following composition are manufactured:

[1003]

[1004]

[1005] Table 2: Possible capsule composition

[1006] Manufacturing Process

[1007] 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

[1008] 2. Add ingredients 4 and 5 and mix for 3 minutes.

[1009] 3. Pack into suitable capsules.

[1010] The compound of formula VII or XIII, lactose and corn starch are first mixed in a mixer and then mixed in a pulverizer. The mixture is returned to the mixer; talc is added thereto and mixed thoroughly. The mixture is filled into suitable capsules, such as hard gelatin capsules, by machine.

[1011] Example B-2

[1012] Soft gelatin capsules of the following composition are manufactured:

[1013] Element mg / capsule Compounds of formula VII or XIII 5 Yellow wax 8 Hydrogenated soybean oil 8 Partially hydrogenated vegetable oil 34 Soybean Oil 110 total 165

[1014] Table 3: Possible soft gelatin capsule composition

[1015]

[1016]

[1017] Table 4: Possible soft gelatin capsule compositions

[1018] Manufacturing Process

[1019] The compound of formula VII or XIII is dissolved in the hot melt of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are processed according to conventional procedures.

[1020] Example C

[1021] Prepare suppositories of the following composition:

[1022] Element mg / suppository Compounds of formula VII or XIII 15 Suppository base 1285 total 1300

[1023] Table 5: Possible suppository compositions

[1024] Manufacturing Process

[1025] The suppository base is melted in a glass or steel container, mixed thoroughly and cooled to 45°C. Then, the powdered compound of formula VII or XIII is added thereto and stirred until it is completely dispersed. The mixture is poured into a suppository mold of appropriate size and allowed to stand until cooled; the suppositories are then removed from the mold and individually wrapped in wax paper or metal foil.

[1026] Example D

[1027] Prepare an injection solution of the following composition:

[1028]

[1029]

[1030] Table 6: Possible compositions of injection solutions

[1031] Manufacturing Process

[1032] The compound of formula VII or XIII is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by adding a residual amount of water. The solution is filtered, and the vial is filled with an appropriate excess and sterilized.

[1033] Example E

[1034] Make a sachet of the following composition:

[1035] Element mg / sachet Compounds of formula VII or XIII 50 Lactose, fine powder 1015 Microcrystalline cellulose (AVICEL PH 102) 1400 Sodium Carboxymethyl Cellulose 14 Polyvinylpyrrolidone K 30 10 Magnesium Stearate 10 Flavoring Additives 1 total 2500

[1036] Table 7: Possible sachet compositions

[1037] Manufacturing Process

[1038] The compound of formula VII or XIII is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavoring additives and filled into sachets.

[1039] VII. Uses of the Compounds

[1040] The compounds of formula Ia, Ib, II, IIIa, IIIb, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XIV-a to XIV-x, or XV-a to XV-t of the present invention bind to the ubiquitously expressed E3 ligase protein cereblon (CRBN) and change the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in endogenous downstream protein degradation. Therefore, the compounds of the present invention can be used to treat or prevent various cancers.

[1041] In one aspect, the present invention provides a compound of Formula Ia, Ib, II, IIIa, IIIb, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XIV-a to XIV-x, or XV-a to XV-t as described herein for use as a therapeutically active substance.

[1042] In a further aspect, the present invention provides a compound of Formula Ia, Ib, II, IIIa, IIIb, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XIV-a to XIV-x, or XV-a to XV-t as described herein for use in treating or preventing cancer.

[1043] In a further aspect, the present invention provides use of a compound of Formula Ia, Ib, II, IIIa, IIIb, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XIV-a to XIV-x, or XV-a to XV-t as described herein for treating or preventing cancer.

[1044] In a further aspect, the present invention provides a method for treating or preventing cancer, comprising administering to a subject a therapeutically effective amount of a compound of Formula Ia, Ib, II, IIIa, IIIb, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XIV-a to XIV-x, or XV-a to XV-t as described herein.

[1045] In a further aspect, the present invention provides the use of a compound of Formula Ia, Ib, II, IIIa, IIIb, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XIV-a to XIV-x, or XV-a to XV-t as described herein for the manufacture of a medicament for the treatment or prevention of cancer.

[1046] Compounds of Formula Ia, Ib, II, IIIa, IIIb, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XIV-a to XIV-x, or XV-a to XV-t can also be used to prepare bifunctional degrader compounds by linking them to a protein targeting moiety that binds to a target protein or target polypeptide, similar to the bifunctional compounds that have been described in, for example, WO2013020557, WO2013063560, WO 2013106643, WO2015160845, WO2016011906, WO2016105518, WO2017007612, WO2017024318 and WO2017117473.

[1047] General synthesis example

[1048] The preparation of the compounds of the present invention can be carried out in a sequential or convergent synthetic route. In the following schemes 1-2 and in the description of specific examples, the synthesis of the compounds of the present invention is shown. The skills required for reacting and purifying the resulting products are known to those skilled in the art. Unless otherwise indicated, the substituents and indices used in the following method descriptions have the meanings given herein above.

[1049] In more detail, the compounds of the present invention can be prepared by the method given below, by the method given in the examples or by a similar method. Suitable reaction conditions for each reaction step are known to those skilled in the art. The reaction sequence is not limited to the sequence shown in the following scheme, however, the sequence of reaction steps can be freely changed according to the starting material and its respective reactivity. The starting material is commercially available, or can be prepared by methods similar to the method given below, by the method described in the reference cited in the specification or the examples or by methods known in the art.

[1050] In more detail, the compounds of the present invention can be prepared by the method given below, by the method given in the examples or by a similar method. Suitable reaction conditions for each reaction step are known to those skilled in the art. The reaction sequence is not limited to the sequence shown in the following scheme, however, the sequence of reaction steps can be freely changed according to the starting material and its respective reactivity. The starting material is commercially available, or can be prepared by methods similar to the method given below, by the method described in the reference cited in the specification or the examples or by methods known in the art.

[1051] Solution 1

[1052]

[1053] The substituents are as described in the claims, and Y is NH or CH2

[1054] Step A: The formation of the amide bond can be accomplished by coupling reaction between spiro-piperidine 1 and carboxylic acid 2 in the presence of a coupling agent such as DCC, EDC, TBTU or HATU and an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine in a halogenated solvent such as dichloromethane or 1,2-dichloroethane or an ether solvent such as diethyl ether, dioxane, THF, DME or TBME or a polar aprotic organic solvent such as N,N-dimethylformamide for 2-18 hours at room temperature or at elevated temperature.

[1055] Preferred conditions are HATU and N,N-diisopropylethylamine in N,N-dimethylformamide at room temperature for 15 hours.

[1056] Alternatively, the formation of the amide bond can be accomplished by a coupling reaction between the spiro-piperidine 1 and the acid chloride 2a, which is formed in situ from the carboxylic acid 2. The acid chloride 2a can be prepared in situ from the corresponding carboxylic acid 2 by treatment with 1-chloro-N,N,2-trimethylpropenamine (CAS 26189-59-3) in a halogenated solvent such as dichloromethane or 1,2-dichloroethane, or in an ethereal solvent such as diethyl ether, dioxane, THF, DME or TBME at temperatures between 0°C and room temperature according to the method of Ghosez et al. (J. Chem. Soc., Chem. Commun. 1979, 1180; Org. Synth. 1980, 59, 26-34). The amide bond formation can then be accomplished by reacting the acid chloride 2a with the spiro-piperidine 1 in a halogenated solvent such as dichloromethane or 1,2-dichloroethane, or in an ethereal solvent such as diethyl ether, dioxane, THF, DME, or TBME in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, or N-methylmorpholine. Preferred conditions are N,N-diisopropylethylamine in THF for 1 hour at room temperature.

[1057] Solution 2

[1058]

[1059] The substituents are as described in the claims, and Y is NH or CH2. EWG is an electron withdrawing group such as -CN, -CO2R, -SO2R or -NO2, and hal is F or Cl.

[1060] Step A: Nucleophilic Aromatic Substitution (S N Ar) reaction can be accomplished by reaction of spiro-piperidine 1 with an electron-deficient mono- or fused bicyclic heteroaromatic compound 4 bearing a suitable leaving group such as fluorine or chlorine in a polar aprotic organic solvent such as N,N-dimethylformamide or N-methylpyrrolidone in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine at elevated temperature.

[1061] Examples of suitable spiro-piperidine compounds 1 include, but are not limited to, 1,3,7-triazaspiro[4.4]nonane-2,4-dione (CAS 908099-69-4) or 2,7-diazaspiro[4.4]nonane-1,3-dione (CAS 1308384-60-2), or their corresponding salts 1,3,7-triazaspiro[4.4]nonane-2,4-dione hydrochloride (CAS 1334146-82-5) or 2,7-diazaspiro[4.4]nonane-1,3-dione hydrochloride (CAS 1609399-87-2).

[1062] Examples of suitable electron-deficient heteroaromatic compounds 4 bearing a suitable leaving group include, but are not limited to, 2-chlorobenzo[d]thiazole (CAS 615-20-3), methyl 6-chloronicotinate (CAS 73781-91-6) or 2-chlorothiazolo[4,5-b]pyridine (CAS 152170-30-4).

[1063] Preferred conditions are N,N-diisopropylethylamine in N,N-dimethylformamide at 100°C for 1 hour.

[1064] Representative Embodiments of the Invention

[1065] The following examples are provided to illustrate the present invention. They should not be considered as limiting the scope of the present invention, but merely as representative thereof.

[1066] If desired, the separation and purification of the compounds and intermediates described herein can be carried out by any suitable separation or purification method, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low pressure or high pressure liquid chromatography or a combination of these procedures. Specific descriptions of suitable separation and separation steps can be referred to the preparation methods and embodiments below. However, other equivalent separation or separation procedures can certainly be used. The racemic mixture of the chiral compounds of the present invention can be separated using chiral HPLC. The racemic mixture of chiral synthetic intermediates can also be separated using chiral HPLC.

[1067] Example 1: Synthesis of 7-benzoyl-1,3,7-triazaspiro[4.4]nonane-2,4-dione: To a solution of 1,3,7-triazaspiro[4.4]nonane-2,4-dione (100 mg, 645 μmol, eq: 1; CAS 908099-69-4) and benzoic acid (82.6 mg, 677 μmol, eq: 1.05; CAS 65-85-0) in N,N-dimethylformamide (1 ml) was added DIPEA (110 mg, 149 μl, 851 μmol, eq: 4; CAS 7087-68-5) and HATU (121 mg, 319 μmol, eq: 1.5; CAS 148893-10-1). The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (30 ml), and the layers were separated. The aqueous layer was washed with two 20 ml portions of ethyl acetate. The combined organic layers were washed with a 30 ml portion of water / brine (1: 1), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by preparative HPLC (YMC-Triart C18, 12 nm, 5 μm, 100 x 30 mm, CH3CN / H2O+0.1%HCOOH) to give 7-benzoyl-1,3,7-triazaspiro[4.4]nonane-2,4-dione (14.1 mg, 54.4 μmol, 8.4% yield) as a white solid, MS (ISP): 260.0 ([M+H] + ).

[1068] Example 2: Synthesis of 7-((S)-1,2,3,4-tetrahydronaphthalene-1-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione (1:1 epimers): The title compound was obtained (as a 1:1 epimer mixture) in analogy to Example 1, using (S)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (CAS 85977-52-2) instead of benzoic acid to give a white solid. MS (ISP): 314.1 ([M+H] + ).

[1069] Example 3: Synthesis of 7-(Benzo[d]thiazol-2-yl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione: To a suspension of 2-chlorobenzo[d]thiazole (21.9 mg, 129 μmol, eq: 1; CAS 615-20-3) and DIPEA (50 mg, 67.5 μl, 387 μmol, eq: 3) in N,N-dimethylformamide (435 μl) was added 1,3,7-triazaspiro[4.4]nonane-2,4-dione (20 mg, 129 μmol, eq: 1; CAS 908099-69-4). The reaction mixture was stirred at 100°C for 1 hour. The reaction mixture was poured into ethyl acetate / tetrahydrofuran (1: 1) and washed sequentially with water and saturated brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 5% methanol / dichloromethane) to give 7-(benzo[d]thiazol-2-yl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione (18 mg, 62.4 μmol, 48.4% yield) as a white solid. MS (ISP): 289.2 ([M+H] + ).

[1070] Example 4: Synthesis of 7-(pyrazolo[1,5-a]pyridine-3-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione: The title compound was obtained similarly to Example 1, using pyrazolo[1,5-a]pyridine-3-carboxylic acid (CAS 16205-46-2) instead of benzoic acid to obtain a white solid. MS (ISP): 300.1 ([M+H] + ).

[1071] Example 5: Synthesis of 6-(2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl)nicotinate: The title compound was obtained similarly to Example 3, using 6-chloronicotinate (CAS 73781-91-6) instead of 2-chlorobenzo[d]thiazole to obtain a white solid. MS (ISP): 291.1 ([M+H] + ).

[1072] Example 6: Synthesis of N-(3-(2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-carbonyl)phenyl)acetamide: The title compound was obtained similarly to Example 1, using 3-acetamidobenzoic acid (CAS 587-48-4) instead of benzoic acid to obtain a white solid. MS (ISP): 633.3 ([2M+H] + ).

[1073] Example 7: Synthesis of N-(4-(2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-carbonyl)phenyl)acetamide: The title compound was obtained similarly to Example 1, using 4-acetamidobenzoic acid (CAS 556-08-1) instead of benzoic acid to obtain a white solid. MS (ISP): 317.1 ([M+H] + ).

[1074] Example 8: Synthesis of 7-(thiazo[4,5-b]pyridin-2-yl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione: The title compound was obtained similarly to Example 3, using 2-chlorothiazo[4,5-b]pyridine (CAS 152170-30-4) instead of 2-chlorobenzo[d]thiazole to obtain a white solid. MS (ISP): 290.0 ([M+H] + ).

[1075] Example 9: Synthesis of 7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione: The title compound was obtained similarly to Example 1, using benzo[d]thiazole-5-carboxylic acid (CAS 68867-17-4) instead of benzoic acid to give a white solid. MS (ISP): 317.0 ([M+H] + ).

[1076] Example 10: Synthesis of 6-(6,8-dioxo-2,7-diazaspiro[4.4]non-2-yl)nicotinate

[1077] Step a) Synthesis of 7-benzyl-2,7-diazaspiro [4.4] nonane-1,3-dione: 1-benzyl-3-(carboxymethyl) pyrrolidine-3-carboxylic acid (310 mg, 1.18 mmol, eq: 1; CAS 885958-89-4) and urea (141 mg, 2.35 mmol, eq: 2; CAS 57-13-6) were combined. The neat reaction mixture was heated at 200 ° C for 1 hour. The reaction mixture was poured into tetrahydrofuran and washed with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 10% methanol / dichloromethane) to give 7-benzyl-2,7-diazaspiro [4.4] nonane-1,3-dione (133 mg, 544 μmol, 46.2% yield) as a colorless amorphous oil. MS(ISP):245.2([M+H] + ).

[1078] Step b) Synthesis of 2,7-diazaspiro [4.4] nonane-1,3-dione hydrochloride: 10% palladium on carbon (28.3 mg, 26.6 μmol, eq: 0.05) was added to a solution of 7-benzyl-2,7-diazaspiro [4.4] nonane-1,3-dione (130 mg, 532 μmol, eq: 1) in methanol (40 ml). The reaction mixture was stirred for 3 hours at room temperature under a hydrogen atmosphere. The catalyst was collected by filtration and washed with methanol. 2M HCl / Et2O solution (5.32 ml, 10.6 mmol, eq: 20) was added to the filtrate. The filtrate was then concentrated in vacuo. The product was dissolved in water and freeze-dried to obtain 2,7-diazaspiro [4.4] nonane-1,3-dione hydrochloride (91 mg, 477 μmol, 89.7% yield) as a white solid. MS (ISP): 155.1 ([M+H] + ).

[1079] Step c) Synthesis of 6-(6,8-dioxo-2,7-diazaspiro[4.4]nonane-2-yl)nicotinate: DIPEA (50.9 mg, 68.7 μl, 393 μmol, eq: 3) was added to a suspension of 2,7-diazaspiro[4.4]nonane-1,3-dione hydrochloride (25 mg, 131 μmol, eq: 1) and 6-chloronicotinate (22.5 mg, 131 μmol, eq: 1; CAS 73781-91-6) in N,N-dimethylformamide (0.5 ml). The reaction mixture was stirred at 100 ° C for 2 hours. The reaction mixture was poured into ethyl acetate / tetrahydrofuran (1: 2) and washed with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 10% methanol / dichloromethane) to give methyl 6-(6,8-dioxo-2,7-diazaspiro[4.4]nonan-2-yl)nicotinate (13 mg, 44.9 μmol, 34.3% yield) as a white solid. MS (ISP): 290.0 ([M+H] + ).

[1080] Example 11: Synthesis of 7-(Benzo[d]thiazol-2-yl)-2,7-diazaspiro[4.4]nonane-1,3-dione: The title compound was obtained similarly to Example 10, except that 2-chlorobenzo[d]thiazole (CAS 615-20-3) was used in step c instead of 6-chloronicotinate to give a white solid. MS (ISP): 288.0 ([M+H] + ).

[1081] Example 12: Synthesis of 7-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2,7-diazaspiro[4.4]nonane-1,3-dione: 1-Chloro-N,N,2-trimethylpropyleneamine (17.8 mg, 17.6 μl, 133 μmol, eq: 1.2; CAS 26189-59-3) was added to a suspension of pyrazolo[1,5-a]pyridine-3-carboxylic acid (18 mg, 111 μmol, eq: 1; CAS 16205-46-2) in tetrahydrofuran (0.5 ml) at 0-5° C. The reaction mixture was stirred at room temperature for 1 hour to obtain a yellow solution. The acyl chloride solution was then added to a suspension of 2,7-diazaspiro [4.4] nonane-1,3-dione hydrochloride (21.2 mg, 111 μmol, eq: 1) and DIPEA (43 mg, 58.2 μl, 333 μmol, eq: 3) in tetrahydrofuran (0.5 ml). The reaction mixture was stirred at room temperature for 30 minutes. The organic mixture was poured into ethyl acetate / tetrahydrofuran (1: 3) and washed with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 10% methanol / dichloromethane) to give 7- (pyrazolo [1,5-a] pyridine-3-carbonyl) -2,7-diazaspiro [4.4] nonane-1,3-dione (9 mg, 30.2 μmol, 27.2% yield) as a white solid. MS (ISP): 299.1 ([M+H] + ).

[1082] Example 13: Synthesis of 7-benzoyl-2,7-diazaspiro[4.4]nonane-1,3-dione: To a suspension of 2,7-diazaspiro[4.4]nonane-1,3-dione hydrochloride (21 mg, 110 μmol, eq: 1) and DIPEA (42.7 mg, 57.7 μl, 330 μmol, eq: 3) in tetrahydrofuran (0.5 ml) was added benzoyl chloride (15.5 mg, 12.8 μl, 110 μmol, eq: 1; CAS 98-88-4). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ethyl acetate / tetrahydrofuran (1:3) and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 10% methanol / dichloromethane) to give 7-benzoyl-2,7-diazaspiro[4.4]nonane-1,3-dione (7 mg, 27.1 μmol, 24.6% yield) as a white solid. MS (ISP): 259.0 ([M+H] + ).

[1083] Example 14: Synthesis of 7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione (Enantiomer 1): Separation of the enantiomers of 7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione (Example 9) was performed using chiral HPLC: Reprosil Chiral NR column with n-heptane / ethanol + NH4OAc: (60:40) to give 7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione (Enantiomer 1) (4.7 mg, white solid), retention time = 11.7 min. MS (ISP): 317.0 ([M+H] + ).

[1084] Example 15: Synthesis of 7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione (Enantiomer 2): Separation of the enantiomers of 7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione (Example 9) was performed using chiral HPLC: Reprosil Chiral NR column with n-heptane / ethanol + NH4OAc: (60:40) to give 7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione (Enantiomer 2) (5.1 mg, white solid), retention time = 12.3 min. MS (ISP): 317.0 ([M+H] + ).

[1085] Pharmacological tests

[1086] The compounds according to the invention and their pharmaceutically acceptable salts have valuable pharmacological properties. The compounds were investigated according to the tests given below.

[1087] Dual fluorescence reporter gene assay

[1088] In order to measure BRD4 protein abundance in mammalian cell systems with medium throughput, a dual fluorescence reporter system was developed based on the principles described in Collins et al., Biochem J, 2017, 474 (7), 1127-1147. A transient expression vector containing a BRD4 coding sequence (NM_058243.2) fused to a fluorescent tag was designed. The vector was synthesized at ATUM (Newark, CA, USA) using the pD2610 CMV backbone and constructed as follows: C-terminal version BRD4_eGFP–IRES–FresnoRFP_NLS, N-terminal version eGFP_BRD4–IRES–FresnoRFP_NLS, empty vector control eGFP–IRES–FresnoRFP_NLS. The C-terminal version was used for reporter gene assays because it has the best assay window. HEK293A cells (Invitrogen, catalog number R705-07) were cultured in Dulbecco's modified Eagle's medium (DMEM), 10% fetal bovine serum, 2 mM L-glutamine, 1% penicillin / streptomycin. Plasmid transfection was performed using Lipofectamine 2000 according to the manufacturer's protocol (Invitrogen, Carlsbad, CA, USA). 40 hours after transfection, cells were seeded at a density of 40'000 / 100 μl / 96-well flat bottom and 8 hours later were treated with compounds (10 mM stock in DMSO) in a 10-point dilution range of 0–25 μM. After 16 hours of treatment, cells were washed with PBS, resuspended in Accumax solution (Sigma-Aldrich Cat. No. A7089), and analyzed by flow cytometry (CytoFlex S, Beckman Coulter). Single compartments were gated based on their forward and side scatter profiles and doublets were excluded using pulse width. At least 20'000 cells were collected for each sample. BRD4-eGFP low / medium cells (<10 6 FL1-A mean fluorescence intensity (MFI). A factor was derived to normalize BRD4-eGFP values ​​to the RFP protein abundance control (20x FL1A-GFP / FL11A-RFP), and median and mode values ​​were then calculated and used for comparisons between treatment conditions.

[1089] Capillary-based immunoassay to measure endogenous BRD4 levels

[1090] The biological activity of the selected compound was confirmed in another assay (the critical value of BRD4-eGFP level was reduced by> 20%), which allows quantitative endogenous BRD4 levels. For this reason, HEK293A cells (source and culture conditions are shown above) were seeded in 400'000 / 300ul / 48 wells and processed by the compound concentration shown after 6 hours. After 16 hours of treatment, the cells were washed with PBS and lysed in 50 μl UREA lysis buffer (10mM Tris-HCl pH 8, 2% CHAPS, 7M UREA, 0.4% DTT), and the buffer was supplemented with 1x protease inhibitor mixture (Complete Mini, Roche) and 1x phosphatase inhibitor mixture (PhosSTOP, Sigma-Aldrich). Then according to the manufacturer's protocol (Protein Simple / Bio-Techne, San Jose, California, 95134USA), samples were analyzed by Peggy Sue or WES capillary-based immunoassay system. The antibodies used were anti-BRD4 (Cell signaling, CST 13440 1:50) and anti-vinculin (Sigma, V9131, 1:4000). To quantify BRD4 protein levels, the peak signal area was normalized to the vinculin loading control and DMSO conditions (Yen, H.-CS et al., Global Protein Stability Profiling in Mammalian Cells. Science 322, 918-923, doi: 10.1126 / science.1160489 (2008)).

[1091] Fluorescence direct binding protocol

[1092] The affinity of the compound for proteins containing one or more tryptophans can be determined by monitoring the fluorescence emission in direct mode. Depending on the amount of protein available, the measurement can be performed manually in a cuvette on an ISS-PC1 photon counting fluorimeter or automatically in a well plate of a fluorescence plate reader device. Fluorescence titrations are performed at 20 ° C in a selected binding assay buffer using a defined constant protein concentration for changes in ligand concentration. A small aliquot of a known ligand concentration dissolved in DMSO is added and fluorescence excited at 280 nm is recorded at 340 nm. The fluorescence intensity was corrected for protein dilution and filter effects (Birdsall, B. et al., (1983). Anal. Biochem. 132, 353–361). The corrected fluorescence intensity is plotted against the ligand concentration and fitted using a four-parameter Sigmoidal function, from which the equilibrium dissociation constant K is calculated using the law of mass action (assuming a 1:1 protein-ligand complex). d (Eftink, Methods Enzymol. 1997; 278:221-57).

[1093] Fluorescence direct binding protocol methods include:

[1094] 1) Optimize measurement parameters to minimize protein consumption and minimize dilution effects and DMSO content

[1095] 2) Titration measurements of the protein against the ligand were performed in at least 12 titration steps to obtain a good S-curve fit

[1096] 3) Repeat the same titration measurement with the ligand alone for calibration

[1097] 4) Check the stability of the protein by titration against DMSO alone

[1098] 5) Determine the molar extinction coefficient of the ligand at 280 and 340 nm using a UV spectrophotometer

[1099] 6) Use Excel template to correct the raw data of the measurement

[1100] 7) Quadratic binding fitting and K were performed using GraphPad Prism software D Evaluate.

[1101] Table 8. Description of proteins and buffers (reference compound: thalidomide)

[1102]

[1103] Table 9: ISS-PCI settings

[1104] Device ISS-PC1 Excitation wavelength [nm] 280 Emission wavelength [nm] 340 Colorimetric cup Hellma 115F-QS Volume [μL] 500

[1105] Table 10: Protein preparation

[1106] Protein volume [μL] Buffer volume [μL] Protein concentration [M] 1.8@2.54mg / ml 498.2 5.0E-8

[1107] Table 11: Titration steps

[1108]

[1109]

[1110] Table 12: Affinity of selected compounds for proteins

[1111]

[1112]

[1113]

[1114]

[1115] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[1116] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will readily appreciate, based on the teachings of this invention, that certain changes and modifications may be made thereto without departing from the spirit or scope of this invention as defined in the appended claims.

Claims

1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof; in: Y is NH or CH2; n is 0 or 1; T is X 1 Selected from key, NR 34 , CH2, CHR 34 , C(R 34 )2 and O; X 22 Selected from halogen, -NH2, -NHR 34 , a 3-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, -C(O)OH, hydrogen, C1-C6 alkyl, phenyl and a 5-10 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S; R 34 is independently selected at each occurrence from hydrogen and C1-C6 alkyl; R 20 , R 21 , R 22 , R 23 and R 24 independently selected from a covalent bond, C1-C6 alkyl, -C(O)-, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH-, -NHC(O)-, -N(C1-C6 alkyl)C(O)-, -C(O)N(C1-C6 alkyl)-, -NH-, C1-C6 alkoxy and phenyl; The R 20 , R 21 , R 22 , R 23 and R 24 Each optionally selected from R 101 Substituents are substituted; Where R 20 , R 21 , R 22 , R 23 and R 24 At least one of is not a bond; and R 101 is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, phenyl, CN, -COOC1-C6 alkyl, COOH, NO2, F, Cl, Br, CF3, NH2 and NH C1-C6 alkyl.

2. The compound of claim 1, wherein Y is NH.

3. The compound of claim 1, wherein Y is CH2.

4. The compound of any one of claims 1-3, wherein n is 0.

5. The compound of any one of claims 1-3, wherein n is 1.

6. The compound of any one of claims 1-3, wherein T is selected from:

7. The compound of claim 6, selected from: and or a pharmaceutically acceptable salt thereof.

8. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cancer in a subject in need thereof.

9. The use of claim 8, wherein the cancer is multiple myeloma.

10. Use of a compound of formula XV or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein the compound of formula XV is: in: Y is NH or CH2; A is selected from: phenyl; 1 substituted phenyl; a 5-10 membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O and S; and R 2 substituted 5-10 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S; R 1 Selected from: -C(=O)-OC 1-6 -alkyl; -COOH; -NH-(C=O)-C 1-6 -alkyl; and -NH2; R 2 Selected from: -COOH; -C(=O)-OC 1-6 -alkyl; and -NH2; and n is 0 or 1.

11. The use according to claim 10, wherein Y is NH.

12. The use according to claim 10, wherein Y is CH2.

13. The use according to claim 10, wherein A is phenyl or is replaced by R 1 Substituted phenyl.

14. The use of claim 10, wherein R 1 -C(=O)-OC 1-6 -alkyl.

15. The use of claim 10, wherein R 1 is –COOH.

16. The use of claim 10, wherein R 1 -NH-(C=O)-C 1-6 -alkyl.

17. The use of claim 10, wherein R 1 is -NH2.

18. The use according to claim 10, wherein A is a 5-10 membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O and S or is replaced by R 2 Substituted 5-10 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S.

19. The use of claim 18, wherein R 2 is –COOH.

20. The use of claim 18, wherein R 2 -C(=O)-OC 1-6 -alkyl.

21. The use of claim 18, wherein R 2 is –NH2.

22. The use according to claim 10, wherein n is 0.

23. The use of claim 10, wherein n is 1.

24. The use of claim 10, wherein the cancer is multiple myeloma.

25. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

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